Opportunities in Assessing and Regulating Organohalogen Flame Retardants (OFRs) as a Class in Consumer Products

Abstract

Background: In 2015, the U.S. Consumer Product Safety Commission (CPSC) received and then, in 2017, granted a petition under the Federal Hazardous Substances Act to declare certain groups of consumer products as banned hazardous substances if they contain nonpolymeric, additive organohalogen flame retardants (OFRs). The petitioners asked the CPSC to regulate OFRs as a single chemical class with similar health effects. The CPSC later sponsored a National Academy of Sciences, Engineering, and Medicine (NASEM) report in 2019, which ultimately identified 161 OFRs and grouped them into 14 subclasses based on chemical structural similarity. In 2021, a follow-up discussion was held among a group of scientists from both inside and outside of the CPSC for current research on OFRs and to promote collaboration that could increase public awareness of CPSC work and support the class-based approach for the CPSC's required risk assessment of OFRs. Objectives: Given the extensive data collected to date, there is a need to synthesize what is known about OFR and how class-based regulations have previously managed this information. This commentary discusses both OFR exposure and OFR toxicity and fills some gaps for OFR exposure that were not within the scope of the NASEM report. The objective of this commentary is therefore to provide an overview of the OFR research presented at SOT 2021, explore opportunities and challenges associated with OFR risk assessment, and inform CPSC's work on an OFR class-based approach. Discussion: A class-based approach for regulating OFRs can be successful. Expanding the use of read-across and the use of New Approach Methodologies (NAMs) in assessing and regulating existing chemicals was considered as a necessary part of the class-based process. Recommendations for OFR class-based risk assessment include the need to balance fire and chemical safety and to protect vulnerable populations, including children and pregnant women. The authors also suggest the CPSC should consider global, federal, and state OFR regulations. The lack of data or lack of concordance in toxicity data could present significant hurdles for some OFR subclasses. The potential for cumulative risks within or between subclasses, OFR mixtures, and metabolites common to more than one OFR all add extra complexity for class-based risk assessment. This commentary discusses scientific and regulatory challenges for a class-based approach suggested by NASEM. This commentary is offered as a resource for anyone performing class-based assessments and to provide potential collaboration opportunities for OFR stakeholders

Headnote

Background: In 2015, the U.S. Consumer Product Safety Commission (CPSC) received and then, in 2017, granted a petition under the Federal Hazardous Substances Act to declare certain groups of consumer products as banned hazardous substances if they contain nonpolymeric, additive organohalogen flame retardants (OFRs). The petitioners asked the CPSC to regulate OFRs as a single chemical class with similar health effects. The CPSC later sponsored a National Academy of Sciences, Engineering, and Medicine (NASEM) report in 2019, which ultimately identified 161 OFRs and grouped them into 14 subclasses based on chemical structural similarity. In 2021, a follow-up discussion was held among a group of scientists from both inside and outside of the CPSC for current research on OFRs and to promote collaboration that could increase public awareness of CPSC work and support the class-based approach for the CPSC's required risk assessment of OFRs.

Objectives: Given the extensive data collected to date, there is a need to synthesize what is known about OFR and how class-based regulations have previously managed this information. This commentary discusses both OFR exposure and OFR toxicity and fills some gaps for OFR exposure that were not within the scope of the NASEM report. The objective of this commentary is therefore to provide an overview of the OFR research presented at SOT 2021, explore opportunities and challenges associated with OFR risk assessment, and inform CPSC's work on an OFR class-based approach.

Discussion: A class-based approach for regulating OFRs can be successful. Expanding the use of read-across and the use of New Approach Methodologies (NAMs) in assessing and regulating existing chemicals was considered as a necessary part of the class-based process. Recommendations for OFR class-based risk assessment include the need to balance fire and chemical safety and to protect vulnerable populations, including children and pregnant women. The authors also suggest the CPSC should consider global, federal, and state OFR regulations. The lack of data or lack of concordance in toxicity data could present significant hurdles for some OFR subclasses. The potential for cumulative risks within or between subclasses, OFR mixtures, and metabolites common to more than one OFR all add extra complexity for class-based risk assessment. This commentary discusses scientific and regulatory challenges for a class-based approach suggested by NASEM. This commentary is offered as a resource for anyone performing class-based assessments and to provide potential collaboration opportunities for OFR stakeholders, https://doi.org/10.1289/EHP12725

These authors contributed to this work while Consumer Product Safety Commission (CPSC) employees and left CPSC after drafting this manuscript.

Address correspondence to Xinrong Chen. Email: xinrong_chen@hotmail. com

All authors have contributed equally to this work.

The authors declare they have nothing to disclose.

Received 10 January 2023; Revised 24 October 2023; Accepted 5 December 2023; Published 4 January 2024.

Note to readers with disabilities: EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Introduction

Organohalogen Flame Retardants and the Petition

Flame retardants (FRs) are chemicals added to materials to improve their resistance to ignition or reduce flame spread after ignition occurs, as defined by World Health Organization.1 "Additive" FRs are applied to the surface of a material or blended with a polymer during the manufacturing process. Because additive FRs are not co-valently bound to the substrate, they have the potential to be released from the product over time owing to volatilization, given that many of these chemicals are semivolatile organic chemicals (S VOCs), or shed from foam or textile particles eroding over time, thereby leading to human and environmental exposure.2'3 In addition, SVOCs may bind to suspended particles, leading to exposure from dust ingestion and particulate inhalation. Other environmental exposures are possible from contaminated foods or drinking water. In the United States, household products are subject to a combination of mandatory and voluntary flammability standards. Most flammabil-ity standards are performance-based standards; that is, they do not specify how to meet the standard.4 Depending on the end-use application, these standards can sometimes be met without using additive FRs. However, additive FRs may be an effective and cost-efficient approach to meet certain flammability standards.

In 2015, a coalition of petitioners asked the U.S. Consumer Product Safety Commission (CPSC) to ban the use of additive, non-polymeric organohalogen flame retardants (OFRs) "as a class" in four categories of consumer goods: children's products, upholstered furniture, mattresses, and plastic components of household electronics.5 The petitioners reasoned that all OFRs are hazardous, data gaps can be filled by read-across, and a class-based approach was needed to prevent regrettable substitution. Read-across is defined as using toxicity data from well-studied (data-rich) chemicals to predict the toxicity of structurally related chemicals. The concept of read-across is often used in predictive toxicology when experimental data are limited. The CPSC granted the petition in 2017,6 and sponsored a National Academy of Science, Engineering, and Medicine (NASEM) report in 2019,7 on how to conduct the hazard assessment for OFRs as a chemical class.

NASEM Report

The NASEM report titled "A Class Approach to Hazard Assessment of Organohalogen Flame Retardants" is a document sponsored by the CPSC that provides some suggestions on how to apply a class approach.7 The NASEM concluded that OFRs cannot be assessed as a single class. They identified 14 subclasses, including 161 OFRs (Table 1). Additional work by CPSC staff and others has expanded the inventory of OFRs.8 The NASEM report outlined a plan for hazard identification-the first step in risk assessment-using read-across and New Approach Methodologies (NAMs). NAM studies encompass computational modeling, in vitro assays in human and animal cells and tissues, and toxicity testing that uses alternative animal species, such as zebrafish and nematodes. The NASEM report included two cases studies for hazard assessment: Case Study 1: Polyhalogenated Organophosphates (PHOPs), and Case Study 2: Polyhalogenated Bisphenol Aliphatics. The NASEM report also included an example of a hazardous subclass: polybrominated di-phenyl ethers (PBDEs). Some of the 14 classes-such as PBDEs and PHOPs-have been in use since the 1970s, and although PBDEs have been phased out of production owing to environmental and human health concerns, they are still widely detected in the environment and in people.9

The NASEM's class-based approach relies on using data on "tested" or "data-rich" chemicals to serve as anchors for making inferences about data-poor (OFRs with little or no toxicity data) chemicals within a class,10 in other words, using read-across methods. The NASEM points out that NAMs, such as in vitro assays, quantitative structure-activity relationship (QSAR, a computational model used to predict toxicity of chemicals that have limited data), and toxicogenomics can help demonstrate whether the members share similar hazard characteristics with the anchor chemicals. Dose-response assessments may be based on relative potency factors or surrogate chemicals.

CPSC Plan for Class-Based Risk Assessment

Following the public release of the 2019 NASEM report, CPSC staff developed a plan for an OFR project,11 by following general principles of risk assessment and the class-based approach recommended by the NASEM. The CPSC's approach for chemical hazards like OFRs are usually risk based.12 The CPSC recent regulation on phthalate by cumulative risk assessment approach is a good example.10 The CPSC has a statutory requirement to convene a Chronic Hazard Advisory Panel (CHAP) before proposing a regulation based on carcinogenicity, mutagenicity, or teratogenicity. Part of the CPSC OFR plan is to cooperate as closely as possible with other federal agency programs, including those of the National Institute of Environmental Health Sciences (NIEHS), the National Toxicology Program (NTP), and the U.S. Environmental Protection Agency (EPA). Currently, the CPSC and the NIEHS are in the process of searching and screening literature to collect data and information. The OFR risk assessment will likely focus on health effects common across subclass members, such as neurode-velopmental toxicity, reproductive and developmental toxicity, endocrine disruption, and cancer.

Objective of the Commentary

Given the extensive data collected to date, there is a need to synthesize what is known about OFR, and how class-based regulations have previously managed this information. This commentary discusses both OFR exposure and OFR toxicity and fills some gaps for OFR exposure that were not within the scope of the NASEM report. The objective of this commentary is therefore to provide an overview of the OFR research presented at Society of Toxicology (SOT) 2021, explore opportunities and challenges associated with OFR risk assessment, and inform the CPSC's work on an OFR class-based approach.

Discussion

Opportunities in Regulating OFRs as a Class

Based on the currently available data, the authors think there is an opportunity to assess the health risks and, where appropriate, regulate OFRs as 14 subclasses. Evidence includes representative exposure data, specifically National Health and Nutrition Examination Survey (NHANES) data available for some OFRs, indicating that U.S. general population OFR exposure levels are chronic and often higher in younger individuals. In particular, there is evidence that vulnerable populations, and specifically infants and young children, are receiving elevated exposures to OFRs.13'14 There are ample toxicity data, including 2-y bioassay data available for some OFRs. Some OFRs share a common toxicity end point, making cumulative risk assessment possible. These points are expanded upon below.

OFR Exposure in the U.S. General Population

OFRs are widely detected in both the blood and urine of pregnant women, infants, children, and adults in the United States (e.g., NHANES data; Table 2 for PBDEs, Table 3 for PHOPs).18 In the U.S. general population, average plasma PBDE [2,2',4,4'-tetra-bromodiphenyl ether (BDE 47), 2,2',4,4',5-pentabromodiphenyl ether (BDE 99), 2,2',4,4',6-pentabromodiphenyl ether (BDE 100), 2,2',4,4',5,5'-hexabromodiphenyl ether (BDE 153)] concentrations (in nanograms per gram lipid) decreased about 13% per year

in children (birth to 9 years of age) between 1998 and 2013 according to data from the NHANES.20 Further analyses demonstrated that PBDE (BDE 47, 99, 100) exposure decreased 4.5-19.6% per each 2-y survey period in adults (2005-2006 to 2013-2014).17 PHOPs have shorter half-lives in the body and exposure is often assessed by measuring their metabolites in urine.21 In contrast to trends observed for PBDEs, exposure to PHOPs has been more constant. For example, in July 2022, the NHANES released four data cycles (2011-2012,2013-2014,2015-2016,2017-2018) for PHOP urinary levels and reported no significant differences over time.

The pathway between specific products and individual exposures may be direct (e.g., via dermal direct contact) or indirect (e.g., via dust). Many OFRs are SVOCs22; they are frequently found in settled dust, airborne particulate matter, and on household surfaces. Exposure to OFRs in dust may occur from inhalation, dermal absorption, and incidental ingestion.23 Exposure pathways for OFRs with low volatility [e.g., BDE 209, decabromodiphenyl ethane (DBDPE)] are often through incidental ingestion of dust, whereas pathways for OFRs with higher volatility (e.g., many of the PHOPs) seem to be primarily via inhalation and dermal absorption.24'25 A number of studies have investigated OFRs in consumer products. For example, PBDEs, PHOPs, and Firemaster 550 [FM550, a mixture of bis(2-ethyhexyl) 2,3,4,5-tetrabromophthalate, 2-ethylhexyl-2,3,4,5-tetrabromobenzoate, triphenyl phosphate, and isopropylated triphenyl phosphate (related commercial products have the same ingredients in different relative proportions)] were detected in mattresses, sofas, baby products, and infant car seats.26 The use or presence of sofas, baby products, and infant car seats have been associated with higher levels of OFRs. For example, pentabromodiphenyl ether (pentaBDE) dust levels were 6 times higher and blood levels were 2.5 times higher in homes containing a sofa treated with PentaBDE compared with homes with sofas that were not treated with PentaBDE.27 DBDPE and decabromodiphenyl ether (decaBDE) have been detected and measured in television (TV) enclosures in the United States,28 and some data suggest that TVs are a source of

FRs found in settled dust in residential settings. In particular, one study noted that FR concentrations in dust increased with proximity to a TV.29 In addition, the presence of bromine in electronics (notably TVs) was associated with higher levels of BDE 209 in paired house dust samples.30 In addition, studies suggest that removal of these products can have a significant impact on human exposure. For example, OFRs dust levels decreased when OFR-containing products were removed from the home.31

OFR Exposure in U.S. Vulnerable Populations

Vulnerable populations who are expected to have elevated exposures, or to be more sensitive to exposures, include fetuses, infants, children, pregnant women, the elderly, and social and economically disadvantaged groups.32 Of note, a study centered in North Carolina (Hammel et al.) found that bis-(l-chloro-2-propyl) phosphate [BCPP, a tris(chloropropyl) phosphate (TCPP, or TCIPP) metabolite] urinary levels were much higher in 6-wk-old infants and 12-month-old children than in older children (Table 3).19 In a study conducted in Japan, the urinary concentrations of 7-y-old children for bis (1, 3-dichloro-2-propyl) phosphate [BDCPP, a tris(l,3-dichloro-2-propyl) phosphate (TDCPP, or TDCIPP) metabolite] and bis(l-chloro-2-propyl)l-hydroxy-2-propyl phosphate (BCIPHIPP, a TCPP metabolite) increased by 13% per year from 2012 to 2017.33 Cumulatively, these studies indicate that exposure to PHOPs is chronic, higher in infants and younger children, and with no evidence that exposure levels are decreasing with time. The socioeconomic status associated vulnerability might be caused by increased exposure to secondhand or older furniture containing OFR owing to a lack of financial resources to purchase new furniture without added FRs, or stress and poverty interaction with exposure. Both the CPSC and the U.S. EPA have policies that prioritize risk assessment of vulnerable populations that include age, socioeconomic status, and other demographics. Biomonitoring studies of parent-infant pairs and NHANES data show that children's exposure to many OFRs is typically 2-3 times higher than for adults. Of note, BCPP (a TCPP metabolite) levels in urine for 6-wk-old infants were 13.9 ng/mL,19 ~ 70 times higher (Table 3) than the 0.2 ng/mL for levels measured in children 3-19 years of age (2017-2018 NHANES data). The reason for this elevated level of infant BCPP/TCPP exposure might be due to differences in metabolic pathways in infants vs. children, or to other factors that need further investigation. Urinary concentrations of BDCPP (the primary metabolite of TDCPP) for children 6-11 years of age (2.2 ng/mL) were ~ 70% higher than those measured in children 12-19 years of age (1.3 ng/mL; 2013-2014 NHANES) (Table 3). Children have higher exposures for several reasons, including breastfeeding, increased hand-to-mouth activity, different breathing zones than the general population, crawling behaviors, increased ingestion of dust via hand-to-mouth behavior, increased inhalation (relative to body weight), and the potential presence of OFRs in toys, infant car seats, other children's products, or children's furniture that may contain OFRs to meet flam-mability standards.26

It is important to note that many sources and products can contribute to OFR exposure (Figure 1), not all of which are under the CPSC's jurisdiction. For example, although polyur-ethane foam (PUF) containing OFRs is often found in upholstered furniture, which is within the CPSC's jurisdiction, foams containing OFRs are also used in cars and in airplanes, which are not regulated by the CPSC. The National Highway Traffic Safety Administration (NHTSA) regulates cars and the Federal Aviation Administration regulates airplanes. Children's car seats also fall under the same standards as car interiors.26 In contrast, the U.S. EPA has broad authority over various "conditions of use" under the Toxics Substance Control Act (TSCA).

OFR Toxicity

The OFR family includes a large number of chemicals with different physical chemical properties and a wide range of toxic effects.34'35 Overall, the most common health effects associated with data-rich (herein signifying well-tested chemicals) OFRs include cancer [Table 4 for PBDE, PHOP, tetrabromobisphenol A (TBBPA)44] and developmental neurotoxicity (DNT; Table 5).7>45>55>56 Vulnerable populations who are likely more sensitive to effects from exposure to OFRs include fetuses (pregnant women), infants, and children. The population characteristics related to vulnerability (e.g., lifestyle, culture, diet, daily activities) and susceptibility (e.g., genetics, life stage, gender) are important because these factors, in conjunction with the toxicity of OFRs, could translate into differential health risks.57 Compared with other OFRs, toxicity data for PBDEs are relatively rich, and several systematic reviews have been published for this subclass.55'58 All four data-rich OFRs in the PHOP family induced cancers in the animal 2-y cancer bioassay. Specifically, oral exposure of TCPP (data is available, NTP report is pending on publish),41 tris(2-chloroethyl) phosphate (TCEP),21 TDCPP,42 and oral40 and dermal59 exposure of tris (2,3-dibrompropyl) phosphate (TDBPP)-induced cancers in animals. Kidney, liver, uterus, and thyroid tumors or chronic toxicity were the most reported toxic effects for the PHOP subclass. In addition to the parent compounds, the metabolite of TDBPP, bis (2,3-dibromopropyl) phosphate (Bis-BP, or BDBPP) was also reported to induce cancers in the organs of rats, including the liver.60'61 The cancer and chronic effects of OFRs are summarized in Table 4.

BDE 47, BDE 99, BDE 100, BDE 153, and 3,3',4,4',5,'5',6,6'-decabromodiphenyl ether (BDE 209) were reported to cause DNT in the brain, as indicated by reduced intelligence quotient (IQ), attention deficit hyperactivity disorder (ADHD), and other attention-related behavioral conditions in children.56'58 PBDEs were also associated with other effects, such as growth delay in children.62 In some cases, PBDE showed sex-specific effects. For example, PBDE maternal exposure was associated with behavioral issues in 12-y-old boys, but not in girls63; prenatal exposure to PBDEs were inversely associated with shorter anogenital distance in boys.64 Similar sex-specific endocrine effects were also reported for phthalates.10 In recent years, new data indicates PHOPs also cause DNT.7 For example, TDCPP was associated with withdrawal, attention problems, depression, hyperactivity, and aggression in children.54 The OFR epidemiological evidence is summarized in Table 5.

In addition to humans, OFRs were also reported to cause developmental and thyroid effects in other species. For example, TCEP exposure increased levels of triiodothyronine (T3) thyroid hormones and induced neurotoxicity in mice.48 Hexabromocyclododecane (HBCD) was associated with thyroid and developmental brain effects in rats.46'47 TCPP and TDCPP can act as thyroid antagonists in the frog.65 TDCPP decreased T3 and thyroxine (T4) in male and increased T3 and T4 levels in female zebrafish.52 Parental exposure to TDCPP in zebrafish decreased T4 and increased T3 levels in the offspring.49 TBBPA exposure caused consistent, progressive, and dose-related decreases in T4 levels in both male and female rats in an NTP 90-d study.44 The TBBPA inhibition effect on T4 was also reported by other groups.50'51 It was demonstrated that elevated thyroid stimulating hormone in pregnant women is associated with decreased IQ in the offspring53 and thyroid hormones are essential for normal brain development in vertebrates.66 BDE-47, BDE-99, TBBPA, and HBCD are widely used as reference chemicals in thyroid assays recommended by the Organization for Economic Cooperation and Development (OECD).67 HBCD (one of the OFRs) reduced T4 levels in rats68 was determined by the U.S. EPA as a hazard end point for developmental toxicity and was carried forward for dose-response analysis for the TSC A risk evaluation.69

Regulatory Case Studies for Class-Based Approach

Although there is considerable complexity and some science-based considerations in applying a class-based approach, the ability to conduct extensive and timely testing for hundreds of OFRs in animals or humans is limited. There are several case studies where agencies have used a class-based framework to assess and inform regulatory decision-making for substances in the United States and in Europe.70 Examples include polychlorinated biphenyls (PCBs), which do not have a single common mode of action, but nonetheless are regulated as a class.71 Dioxins are regulated as a class and the regulation used a toxic equivalency factor approach.72 Particulate matter in ambient air is regulated as a class, despite being very complex in composition.73 The CPSC used a class-based approach to assess the risks from phthalates10 and in rulemaking.74 A class-based approach is currently being used in Europe for per- and poly-fluoroalkyl substances (PFAS) by the European Chemicals Agency (ECHA).75 PFAS are regulated as a chemical class under the California Safer Consumer Products Program.76 The U.S. EPA developed a cluster-based approach for assessing FR risk based on chemical structural similarity, which is similar to the NASEM approach to defining 14 subclasses of OFRs based on chemical structural similarity.77 Most case studies described here are regulatory case studies in which a group of chemicals are evaluated based on certain types of health concerns. The regulatory agencies, jurisdiction, and products involved in these studies are quite different. The CPSC phthalate example used a cumulative risk assessment approach, and it is highly relevant to OFRs, except many OFRs are data poor. The U.S. EPA cluster-based FR approach is also relevant, but it is still in its investigational stage.

OFR Collaboration and Resource Sharing Opportunities

The CPSC OFR project is defined as an OFR risk assessment project that was initiated by a petition, and funded by the CPSC with data analyses conducted by staff and contractors. The scope and progress of the project are updated on an annual basis. The final goal is to determine whether to regulate, and if yes, how to regulate OFR as a chemical class. The CPSC is collaborating with the NTP, the NIEHS, and the U.S. EPA Office of Research and Development and Office of Chemical Safety and Pollution Prevention data collection of existing health and safety data from OFR manufacturers on 30 FRs substances through a TSCA 8d rule78 to inform the OFR project. Currently, the CPSC is working with the NTP to support OFR literature searching and screening.79 Several U.S. EPA TSCA programs overlap with the CPSC OFR project: the TSCA Work Plan80; the persistent, bioaccumulative and toxic (PBT) rule81; the bromi-nated flame retardants (BFR) program82; the TSCA First 10 chemicals subject to risk evaluation83; and the TSCA 20 high-priority 2019 designation chemicals.84 The individual OFRs that are covered under the TSCA and are of interest to the CPSC include HBCD,85 decaBDE,86 TCEP, and TBBPA. The TSCA directed the U.S. EPA to take immediate action on PBT chemicals like decaBDE86 without risk evaluation. However, some PBT chemicals, such as HBCD, have undergone risk evaluations69 and are in TSCA risk management review because unreasonable risks were identified. The U.S. EPA coordinates with the OECD for hazard and exposure assessment through Working Parties by sharing data, assessments, models, tools, and test guideline development. The U.S. EPA also coordinates with other federal agencies for information sharing. The U.S.

EPA and the CPSC have been working together for many years on test method development, data gap filling, and data evaluation, in an effort to reduce duplication and share resources.

The CPSC's goal is to address fire hazards without introducing a new hazard (i.e., toxicity). To achieve this goal, collaboration between fire experts and toxicologists may promote a better understanding of the benefits and risks for both fire and chemical safety.87 The authors consider that a side-by-side comparison for risk, such as injury, disease, or death between these two types of hazards would be beneficial to consumers and the scientific community. Collaborations among academia, government, nongovernment organizations (NGOs), and industry may lead to the use of less toxic alternative OFRs and more environmentally friendly alternatives.

In summary, both toxicity data, such as the NTP 2-y cancer bioassay, and exposure data, such as NHANES human biomoni-toring data in the U.S. general population, are available for some OFRs. Vulnerable populations, such as infants and children, show higher exposure and there is a need to protect these subpo-pulations. There are regulatory case studies available, and a demonstrated history of collaboration between different regulatory authorities. These are all opportunities that could facilitate OFRs being regulated as a class.

Challenges in Assessing and Regulating OFRs as a Class

Although there is reason to be optimistic about the class-based approach, there are several scientific and regulatory challenges. The broad scope that includes a wide range of consumer products, large number of chemicals, and large number of subclasses, is a significant challenge. The CPSC may consider the potential for cumulative and aggregate risks within each subclass if available data support such action under the CPSC's statutory authority. The marketplace for OFRs has changed in the past several years owing to increased regulatory activities and increased public awareness of the OFR risk. Changes include which chemicals are used, type of incorporation into products either covalently incorporated or additive uses, types of products that contain OFRs, and availability of alternatives to FR chemicals to meet flammability requirements. The authors consider that the marketplace is likely to continue changing, and all these add additional real-time challenges to CPSC OFR work.

Regulatory Acceptance ofNAMs

NAMs provide a valuable approach to generate timely and useful information to inform decision-making while also avoiding or significantly reducing the use of animal testing. The CPSC authors indicate certain NAMs are accepted by the CPSC to support development of cautionary labeling for certain products that contain a hazardous substance; currently accepted NAMs address skin irritation, eye irritation, and skin sensitization, for example. For the OFR project, the CPSC will evaluate the expansion of the application of NAMs to a class-based approach, as recommended by the NASEM report. The staff plan for OFRs11 proposes the use of NAMs in combination with data from traditional animal methods to support risk assessment and CPSC rulemaking. The U.S. EPA authors indicate that the U.S. EPA uses certain NAMs in the New Chemicals Program, which generally evaluates exposures and hazard from data-poor chemicals. Furthermore, they indicate that TSCA Section 5 requires manufacturers or importers to provide certain data and existing test data in the notifier's possession or control (or otherwise reasonably ascertainable) concerning human and environmental effects; however, they are not required to generate new data when submitting the premanufacture notification (PMN) for new chemical regulation. In this case, NAMs are often used when laboratory studies or monitoring data are not available or need to be supplemented. The U.S. EPA has also used NAMs to identify adverse outcome pathway development and for hazard characterization and has a list of accepted alternative testing NAMs.88 In its December 2021 NAMs Work Plan, the U.S. EPA expressed commitment to NAM applicability to regulatory decisions and prioritizing efforts and resources toward activities that aim to reduce the use of vertebrate animal testing.89

QSAR models have been used for screening and priority-setting for years. Furthermore, read-across is now used for pre-market registration in Europe. NAMs are more widely accepted by regulatory agencies, such as the U.S. EPA89 and the CPSC.90 However, the authors indicate that as we proceed from screening and prioritizing to setting regulatory exposure limits and regulating existing chemicals, the strength of evidence needed and the level of scrutiny increase, whereas the tolerance for uncertainty decreases (Figure 2).

Cross-Jurisdictional Challenges for Exposure Assessment

Real-life exposure to OFRs is complicated and highly variable. Source characterization for OFR exposure assessment requires matching hundreds of OFRs into dozens of product categories. Most consumer products are within the CPSC's jurisdiction. However, as mentioned earlier, some consumer products are not within the CPSC's jurisdiction or are only sometimes within the CPSC's jurisdiction. For example, the CPSC authors indicate that infant car seats when brought into the home are within the CPSC's jurisdiction. However, when infant car seats are used in an automobile, they under the jurisdiction of the NHTSA. Like the infant car seat situation, the time an adult spends in a car has an impact on OFR exposure,91 but cars are not regulated by the CPSC. The authors think it is important to consider the micro-environment in which a consumer product is used, as well as exposure from sources outside of the CPSC's jurisdiction because the exposures measured in humans (such as NHANES data) come from all sources of exposure, not just products regulated by the CPSC. This approach provides a measure of the relative exposure from CPSC and non-CPSC products. The CPSC plans to regulate products in the CPSC's jurisdiction where appropriate.

Exposure Sources Challenge

In addition to conducting exposure assessment for CPSC-regulated products, the authors think it is important to consider background sources of exposure, such as diet and ingestion of drinking water, for the exposure assessment. OFR exposure in humans is also influenced by factors, such as age, obesity, and OFR half-life.17 Some commercial OFRs are mixtures, such as FM550 and DE-71 (a pentabromodiphenyl ether mixture). Others may share common metabolites, which may confound exposure estimates. In addition, some OFRs are used for other purposes, such as a plasticizer (e.g., some of the chlorinated organophosphate esters), and may have nothing to do with reducing flammability.77 This may lead to inaccurate exposure estimates when using human biomonitoring data, such as the NHANES, if one assumes all exposures were from OFRs used solely to address flammability. In general, there are more data gaps for currently used OFRs (e.g., PHOPs) than older legacy OFRs (e.g., PBDEs). OFRs evaluated by the U.S. EPA TSCA programs are a valuable resource for the CPSC given they conduct comprehensive risk evaluation on identified conditions of use.

Conclusions

In conclusion, the CPSC can consider regulating OFRs based on the 14 subclasses defined by the NASEM. Based on data and trends from a few subclasses for about 10 data-rich chemicals, some OFRs share a number of common toxicity end points, although it is not clear whether they share common modes of action. However, there is no or little data available on the majority of individual OFRs within the 14 subclasses.

Some in the scientific community are advocating for the expanded use of NAMs in regulatory settings. Federal agencies, including the Food and Drug Administration (FDA),92 the U.S. EPA,89 and the CPSC,90 support the development and appropriate use of NAMs. Conversely, the traditional risk assessment framework relies heavily on human and animal data as defined by the National Research Council (NRC).93 A class-based approach will require increased use of reliable NAMs and read-across, in combination with human and animal data.

There are still questions to be answered. These include the lack of mixtures studies to support cumulative risk assessment. Is it reasonable to assume dose additivity among OFRs in the same subclass? How do we evaluate OFRs in different subclasses if they share common toxicity end points? Another question is whether read-across can be used to support class-based approaches. In some cases, such as exposure from dust or exposures estimated from biomonitoring studies, it may be difficult or impossible to attribute the exposure source to a specific type of consumer product. Here, we recommend five notable areas that need extra research for the CPSC OFR project. The first area is to address the lack of information for data-poor OFRs; the second area is more evidence is needed for PHOP DNT effects; the third area is how to interpret NAMs, such as zebrafish data for OFRs; the fourth area recommends more mixtures studies for OFR cumulative effects within and between subclasses; and the fifth area is exposure data directly associated with consumer products. In summary, there are both opportunities and challenges in regulating OFRs as a class in consumer products. The CPSC has made some progress on the OFR project through staff analysis and contract work, as well as through collaboration with other agencies. Some data gaps can be addressed through additional research on exposure and selective nominations to the NTP for toxicity testing focusing on NAMs. Overall, the feedback and support from the scientific community provide a sense of optimism that the class-based approach is feasible for OFRs.

Acknowledgments

This manuscript reflects a 2021 SOT OFR workshop. Alice Thaler [retired from the Consumer Product Safety Commission (CPSC)] contributed to the design of the workshop. Mary Kelleher contributed to the CPSC internal process of the workshop and the manuscript. Kristina Hatlelid, Joanna Matheson, Charles Bevington, Gordon John, and Eric Hooker contributed to the CPSC organohalogen flame retardant (OFR) project and critical review of this manuscript. Stefanie Marques and Adrienne Layton contributed to the development of the OFR schematic in Figure 1.

The opinions expressed in this commentary are those of the authors. They do not necessarily reflect the views of their respective institutions. This manuscript has not been approved by, and does not necessarily represent the views of, the U.S. Consumer Product Safety Commission, the U.S. Environmental Protection Agency, or the National Institute of Environmental Health Sciences.

References

References

1. WHO (World Health Organization). 1997. Flame retardants: a general introduction. https://apps.who.int/iris/handle/10665/41961?show=full [accessed 21 December 2023].

2. Blum A, Ames BN. 1977. Flame-retardant additives as possible cancer hazards. Science 195(4273): 17-23, PMID: 831254, https://doi.org/10.1126/science.831254.

3. Stapleton HM, Klosterhaus S, Keller A, Ferguson PL, van Bergen S, Cooper E, et al. 2011. Identification of flame retardants in polyurethane foam collected from baby products. Environ Sci Technol 45(12):5323-5331, PMID: 21591615, https://doi.org/10.1021/es2007462.

4. CPSC (Consumer Product Safety Commission). 2017. Staff Briefing Package: in response to Petition HP15-1, requesting rulemaking on certain products containing organohalogen flame retardants. https://www.cpsc.gov/s3fs-public/Petition-HP-15-1-Requesting-Rulemaking-on-Certain-Products-Containing-0rganohalogen-Flame-Retardants-May242017.pdf [accessed 21 December 2023].

5. CPSC. 2015. Petition HP 15-1: products containing organohalogen flame retardants. https://www.regulations.gov/docket/CPSC-2015-0022 [accessed 21 December 2023].

6. CPSC. 2017. Guidance document on hazardous additive, non-polymeric organohalogen flame retardants in certain consumer products. Docket No. CPSC-2015-0022. Fed Reg 82(187):45268-45269. https://www.govinfo.gov/conten1/pkg/ FR-2017-09-28/pdf/2017-20733.pdf [accessed 21 December 2023].

7. NASEM (National Academy of Sciences, Engineering, and Medicine). 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: National Academies Press.

8. Bevington C, Williams AJ, Guider C, Baker NC, Meyer B, Babich MA, et al. 2022. Development of a flame retardant and an organohalogen flame retardant chemical inventory. Sci Data 9(1 ):295, https://doi.org/10.1038/s41597-022-01351-0.

9. U.S. EPA (U.S. Environmental Protection Agency). 2012. Polybrominated diphenylethers (PBDEs) significant new use rules (SNUR). https://www.epa.gov/ assessing-and-managing-chemicals-under-tsca/polybrominated-diphenylethers-pbdes-significant-new-use [accessed 21 December 2023].

10. CPSC. 2014. Report to the U.S. Consumer Product Safety Commission by the Chronic Hazard Advisory Panel on Phthalates and Phthalate Alternatives. https://www.cpsc.gov/s3fs-public/CHAP-REP0RT-With-Appendices.pdf [accessed 21 December 2023].

11. CPSC. 2020. Staff Briefing Package: Project Plan: Organohalogen Flame Retardant Chemicals Assessment. https://www.cpsc.gov/s3fs-public/0FR-plan-report-package-final.pdf [accessed 21 December 2023].

12. CPSC. 2011. Federal Hazardous Substances Act. https://www.cpsc.gov/s3fs-public/pdfs/blk_pdf_fhsa.pdf.

13. Hoffman K, Gearhart-Serna L, Lorber M, Webster TF, Stapleton HM. 2017. Estimated tris(1,3-dichloro-2-propyl) phosphate exposure levels for U.S. infants suggest potential health risks. Environ Sci Technol Lett 4(8):334-338, PMID: 34853794, https://doi.org/10.1021/acs.estlett.7b00196.

14. Babich MA, Chen X. 2019. Risk Assessment of the Flame Retardant Chemical Tris (1, 3-Dichloro-2-Propyl) Phosphate (TDCPP). https://www.toxicology.org/ pubs/docs/Tox/2019Tox.pdf [accessed 21 December 2023].

15. Sjodin A, Jones RS, FocantJF, Lapeza C,Wang RY, McGahee EE III, et al. 2004. Retrospective time-trend study of polybrominated diphenyl ether and polybrominated and polychlorinated biphenyl levels in human serum from the United States. Environ Health Perspect 112(6):654-658, PMID: 15121506, https://doi.org/10.1289/ ehp.112-1241957.

16. Woodruff TJ, Zota AR, Schwartz JM. 2011. Environmental chemicals in pregnant women in the United States: NHANES 2003-2004. Environ Health Perspect 119(6):878-885, PMID: 21233055, https://doi.org/10.1289/ehp. 1002727.

17. Sjodin A, Jones RS, Wong LY, Caudill SP, Calafat AM. 2019. Polybrominated diphenyl ethers and biphenyl in serum: time trend study from the National Health and Nutrition Examination Survey for years 2005/06 through 2013/14. Environ Sci Technol 53(10):6018-6024, PMID: 31002243, https://doi.org/10.1021/acs.est 9b00471.

18. CDC (Centers for Disease Control and Prevention). 2022. NHANES Questionnaires, Datasets, and Related Documentation, https://wwwn.cdc.gov/nchs/nhanes/ default.aspx [accessed 21 December 2023].

19. Hammel SC, Zhang S, Lorenzo AM, Eichner B, Stapleton HM, Hoffman K. 2020. Young infants' exposure to organophosphate esters: breast milk as a potential source of exposure. Environ Int 143:106009, PMID: 32771876, https://doi.org/10. 1016/j.envint.2020.106009.

20. Cowell WJ, Sjodin A, Jones R, Wang Y, Wang S, Herbstman JB. 2019. Temporal trends and developmental patterns of plasma polybrominated diphenyl ether concentrations over a 15-year period between 1998 and 2013. J Expo Sci Environ Epidemiol 29(1):49-60, PMID: 29618764, https://doi.org/10.1038/ S41370-018-0031-3.

21. NTP (National Toxicology Program). 1991. Toxicology and carcinogenesis studies of tris(2-chloroethyl)phosphate (CAS No. 115-96-8) in F344/N rats and B6C3Fa mice (gavage studies), https://ntp.niehs.nih.gov/sites/defaul1/files/ntp/htdocs/lt_ rpts/tr391.pdf [accessed 21 December 2023].

22. CPSC. 2015. Environmental Concentrations and Consumer Exposure Data for Selected Flame Retardants (TBB, TBPH, TBBPA, ATO). https://www.cpsc.gov/ s3fs-public/Environmental%20Concentrations%20and%20Consumer%20Exposure% 20Data%20for%20Selected%20Flame%20Retardants.pdf [accessed 21 December 2023].

23. Beko G, Weschler CJ, Langer S, Callesen M, Toftum J, Clausen G. 2013. Children's phthalate intakes and resultant cumulative exposures estimated from urine compared with estimates from dust ingestion, inhalation and dermal absorption in their homes and daycare centers. PLoS One 8(4):e62442, PMID: 23626820, https://doi.org/10.1371/journal.pone.0062442.

24. Lagalante AF, Shedden CS, Greenbacker PW. 2011. Levels of polybrominated diphenyl ethers (PBDEs) in dust from personal automobiles in conjunction with studies on the photochemical degradation of decabromodiphenyl ether (BDE-209). Environ Int 37(5):899-906, PMID: 21458859, https://doi.Org/10.1016/j.envint 2011.03.007.

25. Brommer S, Harrad S, Van den Eede N, Covaci A. 2012. Concentrations of organophosphate esters and brominated flame retardants in German indoor dust samples. J Environ Monit 14(9):2482-2487, PMID: 22854617, https://doi.org/10. 1039/c2em30303e.

26. Cooper EM, Kroeger G, Davis K, Clark CR, Ferguson PL, Stapleton HM. 2016. Results from screening polyurethane foam based consumer products for flame retardant chemicals: assessing impacts on the change in the furniture flamma-bility standards. Environ Sci Technol 50(19): 10653-10660, PMID: 27552529, https://doi.Org/10.1021/acs.est.6b01602.

27. Hammel SC, Hoffman K, Lorenzo AM, Chen A, Phillips AL, Butt CM, et al. 2017. Associations between flame retardant applications in furniture foam, house dust levels, and residents' serum levels. Environ Int 107:181-189, PMID: 28750223, https://doi.Org/10.1016/j.envint.2017.07.015.

28. Schreder E, Peele C, Uding N. 2017. TV Reality: Toxic flame retardants in TVs. https://toxicfreefuture.org/wp-conten1/uploads/2017/09/T\/-Reality-Report-FINAL1. pdf [accessed 21 December 2023].

29. Brandsma SH, Sellstrom U, de Wit CA, de Boer J, Leonards PEG. 2013. Dust measurement of two organophosphorus flame retardants, resorcinol bis(diphe-nylphosphate) (RBDPP) and bisphenol A bis(diphenylphosphate) (BPA-BDPP), used as alternatives for BDE-209. Environ Sci Technol 47(24):14434-14441, PMID: 24261654, https://doi.org/10.1021/es404123q.

30. Allen JG, McClean MD, Stapleton HM, Webster TF. 2008. Linking PBDEs in house dust to consumer products using X-ray fluorescence. Environ Sci Technol 42(11):4222-4228, PMID: 18589991, https://doi.org/10.1021/es702964a.

31. Rodgers KM, Bennett D, Moran R, Knox K, Stoiber T, Gill R, et al. 2021. Do flame retardant concentrations change in dust after older upholstered furniture is replaced? Environ Int 153:106513, PMID: 33770624, https://doi.Org/10.1016/j. envint.2021.106513.

32. Varshavsky JR, Sen S, Robinson JF, Smith SC, Frankenfield J, Wang Y, et al. 2020. Racial/ethnic and geographic differences in polybrominated diphenyl ether (PBDE) levels across maternal, placental, and fetal tissues during mid-gestation. Sci Rep 10(1):12247, PMID: 32699379, https://doi.org/10.1038/s41598-020-69067-y.

33. Bastiaensen M, Ait Bamai Y, Araki A, Goudarzi H, Konno S, Ito S, et al. 2020. Temporal trends and determinants of PFR exposure in the Hokkaido Study. Int J Hyg Environ Health 228:113523, PMID: 32305863, https://doi.Org/10.1016/j.ijheh. 2020.113523.

34. de Boer J, Stapleton HM. 2019. Toward fire safety without chemical risk. Science 364(6437):231-232, PMID: 31000649, https://doi.Org/10.1126/science.aax2054.

35. Birnbaum LS, Cohen Hubal EA. 2006. Polybrominated diphenyl ethers: a case study for using biomonitoring data to address risk assessment questions. Environ Health Perspect 114(11 ):1770-1775, PMID: 17107866, https://doi.org/10. 1289/ehp.9061.

36. NTP. 2022. Toxicology/Carcinogenicity. Cancer Evaluation Criteria. https://ntp. niehs.nih.gov/whatwestudy/testpgm/cartox/index.html [accessed 21 December 2023].

37. NTP. 1986. Toxicology and carcinogenesis studies of decabromodiphenyl oxide (CAS No. 1163-19-5/ in F344/N rats and B6C3F1 mice (feed studies/. https://ntp.niehs.nih.gov/sites/default/files/ntp/htdocs/lt_rpts/tr309.pdf [accessed 21 December 2023].

38. NTP. 2016. NTP Technical Report on the Toxicology Studies of a Pentabromodiphenyl Ether Mixture [DE-71 (Technical Grade)] (CASRN 32534-81-9) in F344/N Rats and B6C3F1/N Mice and Toxicology and Carcinogenesis Studies of a Pentabromodiphenyl Ether Mixture [DE-71 (Technical Grade)] in Wistar Han [Crl: WI(Han)]Rats and B6C3F1/N Mice (Gavage Studies), https://ntp.niehs.nih.gov/ ntp/htdocs/lt_rpts/tr589_508.pdf [accessed 21 December 2023].

39. Dunnick JK, Pandiri AR, Merrick BA, Kissling GE, Cunny H, Mutlu E, et al. 2018. Carcinogenic activity of pentabrominated diphenyl ether mixture (DE-71) in rats and mice. Toxicol Rep 5:615-624, PMID: 29868454, https://doi.0rg/IO.IOI6/j.toxrep. 2018.05.010.

40. NCI (National Cancer Institute). 1978. Bioassay of Tris (2,3-dibromopropyl) Phosphate for Possible Carcinogenicity (CAS No. 126-72-7). Bethesda, MD: NCI. https://ntp.niehs.nih.gov/sites/default/files/ntp/htdocs/lt_rpts/tr076.pdf [accessed 21 December 2023].

41. NTP. 2023. NTP Technical Report on the Toxicology and Carcinogenesis Studies of an Isomeric Mixture of Tris(chloropropyl) Phosphate Administered in Feed to Sprague Dawley (Hsd: Sprague DawlefSD") Rats and B6C3F1/N Mice. NTP TR 602. https://ntp.niehs.nih.gov/sites/default/files/2023-06/tr602_ 508.pdf [accessed 21 December 2023].

42. Stauffer Chemical Co. 1981. A two-year oral toxicity/carcinogenicity study of FYROL FR-2 in rats (Volumes l-IV) (Final Reports) with attachments, cover sheets and letter dated 09-30-81. Submitted to the U.S. Environmental Protection Agency under TSCA Section 8(e), 580-2180 EPA document no. 88-8100282. Microfiche no. OTS204911. September 30,1981.

43. Freudenthal R, Henrich RT. 2000. Chronic toxicity and carcinogenic potential of tris-(1,3-dichloro-2-propyl) phosphate in Sprague-Dawley rat. Int J Toxicol 19(2):119-125, https://doi.org/10.1080/109158100224926.

44. NTP. 2014. NTP Technical Report on the Toxicology Studies ofTetrabromobisphenol A. (CASRN 79-94-7) in F344/NTac Rats and B6C3F1/N Mice and Toxicology and Carcinogenesis Studies of Tetrabromobisphenol A in Wistar Han [Crl:WI(Han)] Rats and B6C3F1/N Mice (Gavage Studies), https://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/ tr587_508.pdf [accessed 21 December 2023].

45. Moser VC, Phillips P, Mcdaniel K, Jarema K, Paul K, Hedge J, et al. 2014. Predictions of developmental neurotoxicity potential of TDCPP. https://cfpub. epa.gov/si/si_public_record_report.cfm?Lab=NHEERL&dirEntryld=270930 [accessed 21 December 2023].

46. WIL Research Laboratories. 2001. A 90-day oral (gavage) toxicity study of HBCD in rats, https://hero.epa.gov/hero/index.cfm/reference/details/reference_id/787787 [accessed 21 December2023].

47. SaegusaY, Fujimoto H,Woo GH, Inoue K,Takahashi M, Mitsumori K, etal. 2009. Developmental toxicity of brominated flame retardants, tetrabromobisphenol A and 1,2,5,6,9,10-hexabromocyclododecane, in rat offspring after maternal exposure from mid-gestation through lactation. Reprod Toxicol 28(4):456-467, PMID: 19577631, https://doi.Org/10.1016/j.reprotox.2009.06.011.

48. Wang C, Chen Z, Lu Y, Wang L, Zhang Y, Zhu X, et al. 2020. Neurotoxicity and related mechanisms of flame retardant TCEP exposure in mice. Toxicol Mech Methods 30(7):490^96, PMID: 32397869, https://doi.org/10.1080/15376516.2020. 1765060.

49. Ren X, Wang W, Zhao X, Ren B, Chang L 2019. Parental exposure to tris(1,3-dichloro-2-propyl) phosphate results in thyroid endocrine disruption and inhibition of growth in zebrafish offspring. Aquat Toxicol 209:132-141, PMID: 30771614, https://doi.Org/10.1016/j.aquatox.2019.02.004.

50. Cope RB, Kacew S, Dourson M. 2015. A reproductive, developmental and neu-robehavioral study following oral exposure of tetrabromobisphenol A on Sprague-Dawley rats. Toxicology 329:49-59, PMID: 25523853, https://doi.org/10. 1016/j.tox.2014.12.013.

51. Chen X, Bevington C, Harrad S, Babich M. 2020. Risk assessment of the flame-retardant chemical tetrabromobisphenol A (TBBPA). In: SOT59th Annual Meeting and Tox Expo. 15-19 March 2020. Anaheim, California: Society of Toxicology. Poster Session Abstract 2220. https://www.toxicology.org/pubs/docs/Tox/2020Tox. pdf [accessed 21 December 2023].

52. Liu X, Cai Y, Wang Y, Xu S, Ji K, Choi K. 2019. Effects of tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and triphenyl phosphate (TPP) on sex-dependent alterations of thyroid hormones in adult zebrafish. Ecotoxicol Environ Saf 170:25-32, PMID: 30508752, https://doi.Org/10.1016/j.ecoenv.2018.11.058.

53. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. 1999. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 341(8):549-555, PMID: 10451459, https://doi.org/10.1056/NEJM199908193410801.

54. Doherty BT, Hoffman K, Keil AP, Engel SM, Stapleton HM, Goldman BD, et al. 2019. Prenatal exposure to organophosphate esters and behavioral development in young children in the Pregnancy, Infection, and Nutrition Study. Neurotoxicology 73:150-160, PMID: 30951742, https://doi.Org/10.1016/j.neuro.2019.03.007.

55. NASEM. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: National Academies Press.

56. Eskenazi B, Chevrier J, Rauch SA, Kogut K, Harley KG, Johnson C, et al. 2013. In utero and childhood polybrominated diphenyl ether (PBDE) exposures and neu-rodevelopment in the CHAMAC0S study. Environ Health Perspect 121(2):257-262, PMID: 23154064, https://doi.org/10.1289/ehp.1205597.

57. U.S. EPA. 2019. Guidelines for Human Exposure Assessment, page 42, section 4.2, Vulnerability and Susceptibility in Exposure Assessment E PA/100/B-19/001. https://www.epa.gov/sites/defaul1/files/2020-01/documents/guidelines_for_human_ exposure_assessment_final2019.pdf [accessed 21 December 2023].

58. Lam J, Lanphear BP, Bellinger D, Axelrad DA, McPartland J, Sutton P, et al. 2017. Developmental PBDE exposure and IQ/ADHD in childhood: a systematic review and meta-analysis. Environ Health Perspect 125(8):086001, PMID: 28799918, https://doi.org/10.1289/EHP1632.

59. Van Duuren BL, Loewengart G, Seidman I, Smith AC, Melchionne S. 1978. Mouse skin carcinogenicity tests of the flame retardants tris(2,3-dibromopropyl) phosphate, tetrakis(hydroxymethyl)phosphonium chloride, and polyvinyl bro-midel. Cancer Res 38(10):3236-3240., PMID: 688215.

60. Takada K, Naito K, Kobayashi K, Tobe M, Kurokawa Y, Fukuoka M. 1991. Carcinogenic effects of bis(2,3-dibromopropyl)-phosphate in Wistar rats. J Appl Toxicol 11 (5):323-331, PMID: 1783736, https://doi.Org/10.1002/jat.2550110505.

61. IARC (International Agency for Research on Cancer). 1999. Tris(2,3-dibromopropyl) phosphate (Group 2A). In: Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide. 71:905-921. https://monographs.iarc.who.int/wp-conten1/ uploads/2018/06/mono71.pdf [accessed 23 March 2022].

62. Liu YJ, Xie Y, Tian YK, Liu H, He CD, An SL, et al. 2022. Associations between polybrominated diphenyl ethers concentrations in human placenta and small for gestational age in southwest China. Front Public Health 10:812268, PMID: 35211445, https://doi.org/10.3389/fpubh.2022.812268.

63. Hartley K, MacDougall MC, Terrizzi B, Xu Y, Cecil KM, Chen A, et al. 2022. Gestational exposure to polybrominated diphenyl ethers and social skills and problem behaviors in adolescents: the HOME study. Environ Int 159:107036, PMID: 34896668, https://doi.Org/10.1016/j.envint.2021.107036.

64. Luan M, Liang H, Yang F, Yuan W, Chen A, Liu X, et al. 2019. Prenatal polybrominated diphenyl ethers exposure and anogenital distance in boys from a Shanghai birth cohort. Int J Hyg Environ Health 222(3):513-523, PMID: 30713057, https://doi.Org/10.1016/j.ijheh.2019.01.008.

65. Zhang Q, Ji C, Yin X, Yan L, Lu M, Zhao M. 2016. Thyroid hormone-disrupting activity and ecological risk assessment of phosphorus-containing flame retardants by in vitro, in vivo and in silico approaches. Environ Pollut 210:27-33, PMID: 26701863, https://doi.Org/10.1016/j.envpol.2015.11.051.

66. Fini JB, Mughal BB, Le Mevel S, Leemans M, Lettmann M, Spirhanzlova P, et al. 2017. Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos. Sci Rep 7:7:43786, PMID: 28266608, https://doi.org/10.1038/srep43786.

67. 0ECD (Organization for Economic Co-operation and Development). 2014. New scoping document on in vitro and ex vivo assays for the identification of modulators of thyroid hormone signalling. Series on Testing and Assessment. No. 207. ENV/JM/MONO(2014)23. https://www.oecd-ilibrary.org/environment/new-scoping-document-on-in-vitro-and-ex-vivo-assays-for-the-identification-of-modulators-of-thyroid-hormone-signalling_9789264274716-en [accessed 21 December 2023].

68. Ema M, Fujii S, Hirata-Koizumi M, Matsumoto M. 2008. Two-generation reproductive toxicity study of the flame retardant hexabromocyclododecane in rats. Reprod Toxicol 25(3):335-351, PMID: 18262388, https://doi.0rg/IO.IOI6/j.reprotox. 2007.12.004.

69. U.S. EPA. 2020. Risk Evaluation for Cyclic Aliphatic Bromide Cluster (HBCD). https://www.epa.gov/assessing-and-managing-chemicals-under-tsca/risk-evaluation-cyclic-aliphatic-bromide-cluster-hbcd [accessed 21 December 2023].

70. Maffini MV, Rayasam SDG, Axelrad DA, Birnbaum LS, Cooper C, Franjevic S, et al. 2023. Advancing the science on chemical classes. Environ Health 21 (suppl 1):120, PMID: 36635752, https://doi.org/10.1186/s12940-022-00919-y.

71. U.S. EPA. 1979. PCBs; manufacturing, processing, distribution in commerce and use prohibitions. Docket No. FRL 1075-2. Fed Reg 44(106):31514-31558. https://www.govinfo.gov/content/pkg/FR-1979-05-31/pdf/FR-1979-05-31.pdf [accessed 21 December 2023].

72. Van den Berg M, Birnbaum LS, Denison M, De Vito M, Farland W, Feeley M, et al. 2006. The 2005 World Health Organization revaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds. Toxicol Sci 93(2):223-241, PMID: 16829543, https://doi.org/10.1093/ toxsci/kfl055.

73. U.S. EPA. 2016. Fine Particulate Matter National Ambient Air Quality Standards: state implementation plan requirements. Docket Nos. EPA-HQ-OAR-2013-0691: FRL-9946-36-0AR. RIN: 2060-AQ48. Fed Reg 81(164):58010 58162. https://www. govinfo.gov/content/pkg/FR-2016-08-24/pdf/2016-18768.pdf [accessed 21 December 2023].

74. CPSC. 2017. Prohibition of children's toys and child care articles containing specified phthalates. Docket No. CPSC-2014-0033. Fed Reg 82(207):49938-49982. https://www.govinfo.gov/conten1/pkg/FR-2017-10-27/pdf/2017-23267.pdfIaccessed 21 December 2023].

75. ECHA (European Chemicals Agency). 2022. Perfluoroalkyl chemicals (PFASs). https://echa.europa.eu/hot-topics/perfluoroalkyl-chemicals-pfas [accessed 21 December 2023].

76. Balan SA, Mathrani VC, Guo DF, Algazi AM. 2021. Regulating PFAS as a chemical class under the California Safer Consumer Products Program. Environ Health Perspect 129(2):025001, PMID: 33595352, https://doi.Org/10.1289/EH P7431.

77. U.S. EPA. 2015. TSCA Work Plan Chemical Problem Formulation and Data Needs Assessment: Brominated Phthalates Cluster Flame Retardants. https:// www.epa.gov/sites/default/files/2015-09/documents/brominated_phthalates_ cluster_data_needs_assessment.pdf [accessed 21 December 2023].

78. U.S. EPA. 2021. Health and safety data reporting; addition of 20 high-priority substances and 30 organohalogen flame retardants. Docket Nos. EPA-HQ-OPPT-2020-0474; FRL-10020-38. RIN: 2070-AB11. Fed Reg 86(122):34147 34154. https://www.govinfo.gov/content/pkg/FR-2021-06-29/pdf/2021-13212.pdf [accessed 21 December 2023].

79. NIEHS (National Institute of Environmental Health Sciences). 2021. National Toxicology Program Board of Scientific Counselors June 8, 2021, Summary Minutes, https://ntp.niehs.nih.gov/sites/defaul1/files/ntp/about_ntp/bsc/2021/june/ minutesbsc20210608_508.pdf [accessed 21 December 2023].

80. U.S. EPA. 2014. TSCA Work Plan Chemicals, https://www.epa.gov/assessing-and-managing-chemicals-under-tsca/tsca-work-plan-chemicals [accessed 21 December 2023].

81. U.S. EPA. 2021. Current and Future PBT rules, https://www.epa.gov/assessing-and-managing-chemicals-under-tsca/current-and-future-actions-pbt-rules [accessed 21 December 2023].

82. Chen X. 2021. The scientific challenges in regulating organohalogen flame retardants (OFRs) as a class in consumer products. In: SOT 61st Annual Meeting and Tox Expo. March 2021. Virtual event: Society of Toxicology. Workshop Session Abstract 1288. https://www.toxicology.org/pubs/docs/Tox/ 2021Tox.pdf [accessed 21 December 2023].

83. U.S. EPA. 2016. Designation often chemical substances for initial risk evaluations under the Toxic Substances Control Act. Docket Nos. EPA-HQ-OPPT-2016-0718; FRL-9956-47. Fed Reg 81(243):91927-91929. https://www.govinfo.gov/content/pkg/ FR-2016-12-19/pdf/2016-30468.pdf [accessed 21 December 2023].

84. U.S. EPA. 2019. High-priority substance designations under the Toxic Substances Control Act (TSCA) and initiation of risk evaluation on high-priority substances; notice of availability. Docket Nos. EPA-HQ-OPPT-2019-0131; FRL-10003-15. Fed Reg 84(249):71924 71935. https://www.govinfo.gov/content/pkg/ FR-2019-12-30/pdf/2019-28225.pdf [accessed 21 December 2023].

85. U.S. EPA. 2022. Cyclic aliphatic bromide cluster (HBCD); revision to the Toxic Substances Control Act (TSCA) risk determination; notice of availability. Docket Nos. EPA-HQ-OPPT-2019-0237; FRL-9283-03-OCSPP. Fed Reg 87(124):38747-38757. https://www.govinfo.gov/conten1/pkg/FR-2022-06-29/pdf/2022-13805.pdf [accessed 21 December 2023].

86. U.S. EPA. 2021. Decabromodiphenyl ether (decaBDE); regulation of persistent, bioaccumulative, and toxic chemicals under TSCA Section 6(h). Docket Nos. EPA-HQ-OPPT-2019-0080; FRL-10018-87. EPA. Fed Reg 86(3):880-894. https:// www.govinfo.gov/conten1/pkg/FR-2021-01-06/pdf/2020-28686.pdf [accessed 21 December 2023].

87. Rodgers KM, Swetschinski LR, Dodson RE, Alpert HR, Fleming JM, Rudel RA. 2019. Health toll from open flame and cigarette-started fires on flame-retardant furniture in Massachusetts, 2003-2016. Am J Public Health 109(9): 1205-1211, PMID: 31318595, https://doi.org/10.2105/AJPH.2019.305157.

88. U.S. EPA. 2019. Updates to the EPA List of Alternative Test Methods to Animal Testing, https://www.epa.gov/chemicals-under-tsca/updates-epa-list-alternative-test-methods-animal-testing [accessed 21 December 2023].

89. U.S. EPA. 2021. New Approach Methods Work Plan, https://www.epa.gov/system/ files/documents/2021-1 Vnams-work-plan_11J5_21_508-tagged.pdf [accessed 21 December 2023].

90. CPSC. 2022. Final Guidance for Industry and Test Method Developers. https://www. regulations.gov/documen1/CPSC-2021-0006-0010 [accessed 21 December 2023].

91. Reddam A, Tait G, Herkert N, Hammel SC, Stapleton HM, Volz DC. 2020. Longer commutes are associated with increased human exposure to tris(1,3-dichloro-2-propyl) phosphate. Environ Int 136:105499, PMID: 31999975, https://doi.org/10. 1016/j.envint.2020.105499.

92. FDA (U.S. Food and Drug Administration). 2017. FDA'S Predictive Toxicology Roadmap. https://www.fda.gov/media/109634/download [accessed 21 December 2023].

93. NRC (National Research Council). 1983. Risk Assessment in the Federal Government:Managing the Process. Washington, DC: National Academies Press.