Assessing Human Exposure to Chemicals in Materials, Products and Articles: The International Risk Management Landscape for Phthalates

Abstract

Risk-based chemical safety assessments are increasingly being conducted to support chemical management decisions and informed substitution to protect public health. Rapid evaluation and prioritization of large numbers of chemicals used in materials, products, and other indoor articles has become a major focus of chemical risk management strategies. Internationally, although a shared understanding of the value of rapid risk-based evaluations appears to be emerging, implementation strategies and associated management decisions vary from one agency and jurisdiction to another. This paper highlights the international chemical risk management landscape focusing on phthalates as an example, and reviews how phthalate exposure assessments have been performed, resulting at times in different decisions based on the application of scientific information within different policy contexts. In general, the need for efficient and effective risk-based assessment approaches is driving increased needs for high-quality exposure data and validated, mechanistic exposure models. Further development of mechanistic models and related parameters will reduce uncertainties in exposure estimates and support scientific risk-based evaluations of chemical/product combinations for a variety of decisions.

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1. Introduction

New materials, products, and other indoor articles (collectively referred to as products) are introduced to the market on an almost daily basis, but many of the chemicals present in those products have not been assessed for potential human health risks because little or no information on hazard and exposure exists to support such assessments.^1–3 Testing protocols for existing chemicals are time-consuming and costly, given the large number of chemicals that are manufactured.^{2, 3} The risk associated with the use of chemicals is a function of exposure and toxicity, with chemical risk assessments requiring reliable estimates of both.³ Globally, many policies now aim to rapidly identify high-risk chemicals and products to protect public health and the environment. For this purpose, risk-based assessment strategies are needed that enable the management of increasing numbers of chemicals with minimal information and with a range of stakeholders in mind. Based on these assessments, decisions on chemicals of concern in products may include limiting their use or recommending that they be replaced with safer substitutes (Informed Substitution, IS).^{4, 5} To address the need to evaluate the safety of an increasing number of chemicals in commerce within the context of real-world product use, computational tools for assessing exposures to chemicals have improved since the early 2000s, especially in their ability to quickly process large quantities of data.⁶ As a result, a transition is in progress from traditional, hazard-driven, single-chemical assessments towards risk-based, high-throughput (HT) modeling approaches.^{2, 6, 7} Lately, these approaches have been summarized and discussed as New Approach Methodologies (NAMs), which refers to any non-animal technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment.^8–10

Phthalates are a group of semi-volatile organic compounds (SVOCs) that are present in a variety of products and ubiquitous in indoor environments. Because of concerns about potential negative health effects, this class of chemicals has been relatively well studied. Phthalate risk assessments have been conducted by a range of authorities, with a variety of actions taken by chemical managers around the world. Thus, phthalates illustrate how different jurisdictions are considering risks associated with exposure to chemicals in products. Section S1 and Tables S1 and S2 in the Supplementary Information (SI) provide information on phthalates commonly subjected to regulation and/or risk assessments.

As decision makers and responsible agencies work to incorporate both established and emerging science for assessing risks, new challenges have appeared. The objectives of this paper are to: (1) review management policies that apply to phthalates in products across a range of jurisdictions; (2) consider how phthalate exposure assessments have been conducted; and (3) identify key scientific challenges and propose an approach for addressing gaps to improve predictive exposure tools for risk-based chemical management.

2. An Overview of International Drivers for Risk Assessment of Phthalates in Products

In the following sections, chemical risk management regulations and activities in Europe, Canada, the US and in Australia are described. These regions currently have the most detailed policies in place. A summary and comparison of the regulations and activities is provided in Table 1, which also describes where phthalates are regulated and how.

Table 1:

Summary and comparison of chemical risk management regulations and activities in Europe, Canada, the US and Australia with focus on phthalates.

Jurisdiction	Regulatory Authority	Agency	Actions	Status
EU	Regulation (EC) No 1907/2007 Registration, Evaluation, Authorization and Restriction of Chemicals (REACH)	ECHA	Risk Assessment Reports conducted for DBP, DINP, and DIDP in 2003, for BBP in 2007, and for DEHP in 2008. New information to DINP and DIDP was summarized in a 2013 report. ECHA and Denmark submitted an Annex XV Restriction Report on DEP, DBP, BBP, and DIBP in 2016, proposing a ban of these phthalates in all products. RAC and SEAC published opinions on the Restriction Report in 2017. These recommendations were in favor of the proposed actions. These opinions were followed by an update of Annex XVII Entry 51 in Dec. 2018. Sunset date refers to the date after which a company needs authorization in order to put the product on the market.	On Candidate List (year of inclusion): – DEHP, DBP, BBP (2008) – DIBP (2010) – DMEP, DIHpP, DHNUP (2011) – DIPP (2012) – DPP, DHEXP (2013) – DHP (2014) – 610P (2015) – DCHP (2018) On Authorization List/Annex XIV (Sunset date): – DEHP, DBP, BBP, DIBP (Feb. 21, 2015), authorization applications were only received for certain uses of DEHP and DBP. – DIPP, DMEP, DPP, DIHpP, DHNUP (July 4, 2020) Restricted (Annex XVII): – Entry 51: DEHP, DBP, BBP in toys and child care articles; starting July 2020 in all articles and also including DIBP – Entry 52: DINP, DIDP, DNOP in toys and child care articles that can be placed in the mouth
EU	Regulation (EC) No 1272/2008 Classification, packaging and labelling of chemicals and their mixtures (CLP)	ECHA	According to Part 3 of Annex VI to CLP, a substance may be classified as carcinogenic, mutagenic or toxic for reproduction based on the following categorization: – Category 1A: Classification is based on human evidence – Category 1B: Classification is based on animal evidence (presumed human toxicant) – Category 2: Suspected human toxicant but evidence is not convincing to place in Category 1A or 1B	Fulfilling CLP criteria for Cat. 1B (reproductive toxicity): – DEHP, DBP, BBP, DIBP, DPP, DHEXP, DCHP, DIPP, DMEP Fulfilling CLP criteria for Cat. 2 (reproductive toxicity): – DNOP
EU	(EC) No 1223/2009 Cosmetic Products Regulation; Decision 2006/257/EC Inventory and nomenclature for ingredients in cosmetic products	ECHA	The Cosmetic Ingredient Database (CosIng) contains information on cosmetic substances and ingredients. A 2007 opinion by the EU Scientific Committee on Consumer products found DEP in cosmetics to be safe at current levels of use.	Prohibited in cosmetic products (Annex II of (EC) No 1223/2009): – DEHP (Ref 677) – DBP (675) – BBP ( 1152) – DMEP (678) – DPP, DIPP (1151)
EU	(EC) No 1935/2004 Food Contact Materials (FCM); (EU) No 10/2011 on plastic materials and articles intended to come into contact with food	EFSA	Opinion published in 2005 regarding use of DEHP, DBP, BBP, DINP and DIDP in food contact materials. Draft scientific opinion updating the 2005 document published and endorsed for public consultation Feb 6, 2019	Authorized for use as FCM (Annex I of (EU) No 10/2011): – As additives or polymer production aids: DEHP, DBP, BBP, DINP, and DIDP – As plasticizer in repeated-use FCMs for non-fatty foods: DEHP and DBP – As plasticizers in repeated-use FCMs: BBP, DIDP, and DINP – As plasticizers in single-use FCMs for non-fatty foods (with exceptions): BBP, DIDP, and DINP – DAP permitted as starting substance
EU	Other Authorities	ECHA, EC, and national agencies	– Directive 2009/48/EC, Toy Safety Directive: Phthalates (and other chemicals) classified as carcinogenic, mutagenic, or toxic for reproduction under CLP are prohibited in toys (with exemptions) – Directive 2011/65/EU, the Restriction of Hazardous Substances (RoHS) Directive, last amended by Directive (EU) 2017/2102, and Directive (EU) 2015/863 amending Annex II to Directive 2011/65/EU: restricting DEHP, DBP, BBP, and DIBP in electrical and electronic equipment (0.1 wt% maximum concentration). – Directive (EU) 2018/851, amending Directive 2008/98/EC on waste: Establishment of a new database by ECHA for waste treatment operators and consumers. The database will also contain information on products containing SVHCs on the Candidate List (thus, include phthalates on the Candidate List). – Additional national regulations regarding phthalates in place in Denmark and the Czech Republic
Canada	Bill C-307 (Phthalate Control Act) in relation to the Medical Devices Regulations (SOR/98–282) enabled by the Food and Drugs Act (R.S.C., 1985, c. F-27)	-	In 2007, Bill C-307 passed in the House of Commons after its third reading. The bill requires – regulations being made regarding DEHP in cosmetics under the Food and Drugs Act (see below), – the addition of certain products to Part I, Schedule I of the Hazardous Products Acta (Phthalates Regulations, see below), – the regulation of use and labeling of medical devices containing DEHP, and – the reassessment of BBP and DBP under CEPA 1999 (see below).	As published in 2008, manufacturers have to report if medical device contains more than 0.1 wt% DEHP.
Canada	Canadian Environmental Protection Act (CEPA), 1999 (S.C. 1999, c. 33)	ECCC, HC	DEHP, DBP, and DNOP were assessed in 1993–1994 by ECCC and HC under the Priority Substances Assessment Program. It was found that DEHP was harmful to human health. Several phthalates were subject to the categorization of the DSL based on persistence, bioaccumulation potential, and inherent toxicity to the environment. Based on Sections 68 and 74 of CEPA 1999, ECCC and HC published four State of the Science (SoS) reports regarding the Phthalate Substance Grouping in 2015: – Short-Chain Phthalate Esters – Medium-Chain Phthalate Esters – Long-Chain Phthalate Esters – DINP ECCC and HC also published a Proposed Approach for Cumulative Risk Assessment of Phthalates in 2015. In June 2017, DEHP was one of 50 substances announced as toxic as defined under Section 71 of CEPA 1999. In October 2017, ECCC and HC published a Draft Screening Assessment of the Phthalate Substance Grouping based on the SoS reports and also including 14 additional phthalates from the Domestic Substances List: – Short-chain: DEP – Medium-chain: DPrP, DEHP, DBP, BBP, DnHP, 79P, DIOP – Long-chain: 610P, DnOP, D911P, D911P-2, DIUP, DTDP	The 2017 Draft Screening Assessment concluded that only B79P and DEHP might be released to the environment at levels potentially harmful to the environment or its biological diversity (i.e., they meet the criteria under Section 64(a) of CEPA 1999). None of the substances in the Phthalate Substance Grouping is considered harmful to human health at current level of exposure. The 1994 conclusion regarding DEHP is still in place. The Draft Screening Assessment was open to public comments for 60 days after publication on Oct. 7, 2017. A final screening assessment decision has not yet been published. Phthalates were subject to the CMP Environmental Monitoring and Surveillance Program (2017–2018).11
Canada	Phthalates Regulations (SOR/2016–188) under Canada Consumer Product Safety Act (CCPSA) (S.C. 2010, c. 21)	HC	The first version of the Phthalates Regulations was registered in 2010 as SOR/2010–298 with principally the same content as the current version.	Annexed (Jun. 2016): – DEHP, DBP, BBP: Not allowed at concentrations above 1,000 mg/kg in toys or child care articles – DINP, DIDP, DNOP: Not allowed at concentrations above 1,000 mg/kg in toys or child care articles that can be placed in the mouth of a child under the age of 4 years
Canada	Cosmetics Regulations (C.R.C., c. 869), enabled by the Food and Drugs Act (R.S.C., 1985, c. F-27)	HC	DBP and DEP are primarily used in cosmetics, according to HC. A 2011 study by the Government of Canada identified DBP and DEP as the only phthalates present in significant quantity in cosmetics. The study concluded that the overall exposure to phthalates from use of cosmetic and personal care products is low and is unlikely to pose a health risk.12	Cosmetic Ingredient Hotlist (2009 update) includes DEHP as a prohibited ingredient in reflection of its addition to Schedule 1 of CEPA 1999 (Toxic substances list).
USA	Toxic Substances Control Act (TSCA), amended 2016 by the Frank R. Lautenberg Chemical Safety for the 21st Century Act, and others13	US EPA	In 2012, the US EPA published the Phthalates Action Plan, listing – DEHP – DBP – BBP – DIBP – DINP – DIDP – DnPP – DNOP as phthalates of interest due to toxicity, prevalence in the environment and widespread use and human exposure. US EPA, US FDA, and CPSC are intended to work together on a coordinated approach to address manufacturing, processing, distribution, and/or use of these phthalates. In 2014, the US EPA issued a Significant New Use Rule (SNUR) for DnPP which requires notification of the US EPA by manufacturers and processors regarding new uses of DnPP. DEHP, DBP, BBP, DNOP, DINP, DIDP, and DIBP were added in 2014 to the TSCA Work Plan for Chemical Assessments. DnPP was not added because it is no longer in commerce.	All eight phthalates are subject to Inventory Update Reporting to the TSCA Chemical Substance Inventory
USA	Additional Authorities	US EPA	– Safe Drinking Water Act: DEHP is allowed at a maximum contaminant level (MCL) of 0.006 mg/L – Clean Air Act: DEHP and DBP listed as hazardous air pollutants – Resource Conservation and Recovery Act: phthalates regulated as hazardous waste if discarded as a commercial chemical product – Emergency Planning and Community Right-to-know Act: DEHP and DBP are reportable to the Toxic Release Inventory (TRI) – Endocrine Disruptor Screening Program: Includes DEHP, DBP, and BBP
USA	Federal Food, Drug, and Cosmetic Act	US FDA	In 2001, the FDA published a safety assessment of DEHP released from PVC medical devices. In 2002, a draft guidance document for medical devices made with PVC containing DEHP was published. The document was not finalized. According to the FDA’s latest survey of cosmetics in 2010, DEP is the only phthalate still commonly used in cosmetics. DBP and DMP are rarely used.14 In 2012, the US Cosmetic Ingredient Review Expert Panel confirmed DBP and DEP as “safe as used” in cosmetics. The FDA published a Guidance Document in 2012 on the allowable level of DEHP in bottled water. The respective final rule (76 FR 64810) became effective in April 2012. In 2012, the Center for Drug Evaluation and Research published a “Guidance for Industry” document regarding limiting the use of certain phthalates (i.e., DEHP and DBP) in CDER-regulated products (e.g., prescription drugs).	FDA actions in place: – Fair Packaging and Labeling Act: any ingredient including phthalates has to be declared on cosmetic products (except in fragrances) – Rule 76 FR 64810 amending the FDA bottled water quality standards regulations (21 CFR 165): DEHP is allowed at a maximum contaminant level (MCL) of 0.006 mg/L – Title 21: Food and Drugs: Lists multiple phthalates allowed in various food-contact applications
USA	CPSC Rule “Prohibition of Children’s Toys and Child Care Articles Containing Specified Phthalates” (82 FR 49938) under the Consumer Product Safety Improvement Act (CPSIA)	CPSC	In 2008, CPSIA amended the Consumer Product Safety Act of 1972. Section 108 of the CPSIA established permanent and interim prohibitions on the sale of certain consumer products containing specific phthalates. It had also directed the CPSC to convene a Chronic Hazard Advisory Panel (CHAP) to study the effects on children’s health of all phthalates and phthalate alternatives used in children’s toys and child care articles and to provide recommendations regarding prohibitions of any phthalates or phthalate alternatives. In 2014, CHAP issued its final report. In its conclusion, CHAP recommended to restrict eight phthalates permanently. The CPSC rule of 2017 (82 FR 49938, effective in April 2018) is a direct outcome of the results published in the CHAP report.	The 2014 CHAP report is to date the most comprehensive risk assessment of the phthalates listed in the US EPA Phthalates Action Plan. It evaluated 14 phthalates (DBP, BBP, DEHP, DNOP, DINP, DIDP, DMP, DEP, DIBP, DPENP, DHEXP, DCHP, DIOP, and DPHP) and six additional phthalate alternatives. CPSIA had restricted DEHP, DBP, and BBP in children’s toys and child care articles to less than 0.1%. The 2017 CPSC rule further prohibits levels greater than 0.1% of DINP, DIBP, DPENP, DHEXP, and DCHP in toys and child care articles.
USA	Other Activities	Other	In 2008, the National Research Council (US) Committee on the Health Risks of Phthalates published “Phthalates and Cumulative Risk Assessment: The Tasks Ahead”.15 The Centers for Disease Control and Prevention (CDC) has published a Phthalates Factsheet on the National Biomonitoring Program website. It includes links to Public Health Statements and ToxFAQs for DEHP, DnBP, DNOP, and DEP, all published between 1995 and 2002.16
California	Proposition 65 (officially: Safe Drinking Water and Toxic Enforcement Act of 1986) Safer Consumer Products (SCP) Program based on the Green Chemistry Law of 2008	OEHHA DTSC	OEHHA maintains a list of chemicals known to cause cancer, birth defects, or reproductive harm. Businesses are required to provide warnings on products if Californians might be exposed to chemicals on the list at or above certain levels by that product.17–19 SCP came into effect in 2013. DTSC publishes a list of candidate chemicals and priority products that might become subject to regulations under the SCP program.20, 21	The following phthalates are on the Proposition 65 list: DEBP, DBP, BBP, DIDP, DINP, and DnHP.22 The list is available at https://calsafer.dtsc.ca.gov/cms/search/
Washington	Children’s Safe Products Act of 2008 and Children’s Safe Products Reporting Rule of 2011 The Pollution Prevention for Our Future Act (SB 5135-B)	Department of Ecology Multiple	The law limits the use certain chemicals and flame retardants in children’s products sold in Washington. It also requires manufacturers to report if children’s products contain any chemical on the list of Chemicals of High Concern to Children (part of the Reporting Rule).23, 24 The legislation requires state agencies to identify and regulate classes of chemicals that pose a health risk to sensitive populations and endangered species.25, 26	Phthalates in children’s products above 0.1% by weight are prohibited. The list of Chemicals of High Concern to Children was last amended in 2017 and includes DCHP, DEP, DIBP, DBP, DnHP, BBP, DEHP, DMEP, DNOP, DPP, DIDP, or DINP.27 Phthalates as a class are listed as priority chemicals in the Act.26
Maine	Safer Chemicals in Children’s Products Rules (Toxic Chemicals in Children’s Products Law of 2008)	Department of Environmental Protection	The Department maintains a list of chemicals of concern, of which some chemicals can be designated as chemicals of high concern and further as priority chemicals. Manufacturers selling certain children’s products in Maine containing any of the priority chemicals at levels higher than the minimum amount have to file a report with the Department.	Reporting required for DEHP, DBP, BBP, and DEP in certain children’s products, which are categorized as priority chemicals.28
Minnesota	Toxic Free Kids Act of 2009 (Minn. Statutes 2010 116.9401 – 116.9407)	Minnesota Department of Health	The Act was signed into law in 2009. It requires MDH to maintain a Chemicals of High Concern List and a Priority Chemicals List.29, 30	The latest update of the Chemicals of High Concern List was published in September 2016. It includes DCHP, DEP, DBP, DnHP, BBP, DEHP, DMEP, DMP, DAP, DPP, DIPP, DIDP, DINP, and some mono-ester phthalates.31 The Priority Chemicals List includes DEHP, DBP, and BBP.32
Vermont	Chemical of High Concern in Children’s Products Rule under Act 188 (2014), now 18 V.S.A. Ch. 38A	Department of Health	Manufacturers using chemicals designated by the State of Vermont as Chemicals of High Concern to Children are required to report information about these chemicals to the Health Department.33–35	On the list of Chemicals of High Concern to Children: DEHP, DNOP, DIDP, DINP, DEP, DBP, BBP, and DHEXP. Proposed additions to the list: DMEP, DPP, DCHP, and DIBP.36
Oregon	Toxic-Free Kids Act of 2015 (SB 478-B)	Oregon Health Authority	Manufacturers of children’s products sold in Oregon are required to report products that contain one or more high priority chemicals of concern for children’s health, and ultimately remove these chemicals or seek a waiver.37	The list of chemicals of concern for children’s health includes BBP, DEHP, DBP, DEP, DIDP, DINP, DHEXP, and DNOP.38
Australia	Industrial Chemicals (Notification and Assessment) Act 1989; Industrial Chemicals (Registration Charge—General) Act 1997; Industrial Chemicals (Registration Charge—Customs) Act 1997; Industrial Chemicals (Registration Charge—Excise) Act 1997; Industrial Chemicals (Notification and Assessment) Regulations 1990	NICNAS under the Australian Government’s Department of Health	NICNAS maintains the Australian Inventory of Chemical Substances (AICS) database where any new industrial chemical has to be included before its industrial use is permitted. Before a chemical is listed in AICS, NICNAS assesses it for health and environmental risks. However, several chemicals and products are not regulated by NICNAS, for example pesticides, agricultural products, and food. Priority Existing Chemicals include DEHP, DBP, BBP, DMEP, DEP, DIDP, DNOP, DINP, and DMP. List of endocrine active chemicals includes DEHP, DBP, BBP.	Industrial chemicals regulation in Australia is subject to reforms, which are currently underway. The new Australian Industrial Chemical Introduction Scheme (AICIS) will replace the National Industrial Chemicals Notification and Assessment Scheme (NICNAS). With AICIS, updated Industrial Chemical Rules and Categorization Guidelines will come into effect. Tier II of IMAP assessment of 24 phthalates (see Table S1 in the SI) was completed in March 2019. The recommendations are focused on DEHP. It was identified as needing further evaluation and it is recommended to add DEHP to the list of chemicals routinely monitored in wastewater treatment effluents and surface waters.39
Australia	Australian Consumer Law of 2011, enabled by the Competition and Consumer Act of 2010	Australian Competition and Consumer Commission	The Australian Consumer Law enables the ACCC to ban products on a permanent or interim basis. A permanent ban of DEHP in children’s plastic items is in place.40	The law bans product that are intended for use by children three years of age or younger, contain more than 1% by weight of DEHP, and are products that can readily be mouthed by children three years of age or younger.41
OECD	-	-	DEHP, DBP, BBP, DMEP, 79P, DIHpP, DHNUP, and DNHpP have been sponsored under the Cooperative Chemicals Assessment Programme. Publications are available on DEHP, DBP, DMEP, 79P, DIHhP, and DHNUP. BBP and DNHpP have been sponsored for assessment, but no publication is currently available.42

Note:

^aThe Canada Consumer Product Safety Act (CCPSA) replaced Part I of the Hazardous Products Act in 2010.

2.1. Europe

The European Commission (EC) acknowledges the importance of exposure science and of harmonized, integrated, and robust methodologies and tools for all types of chemical exposure assessment. Prominent stakeholders are the different EC services, European Union (EU) member states, the World Health Organization (WHO), the European Chemicals Agency (ECHA), the European Environment Agency (EEA), non-governmental organization (NGOs), and various international partners. The General Product Safety Directive (2001/95/EC), the Classification, packaging and labelling of chemicals and their mixtures (CLP) regulation (EC No 1272/2008) and the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation (EC No 1907/2007) are the key elements of European exposure and risk assessment strategies.

REACH aims to improve the protection of public health and the environment from risks associated with exposures to chemicals, either for industrial or for consumer use.⁴³ REACH requires companies to manage possible risks linked to chemicals they use and introduce to the market, although the specifics depend on the production and import volume of the chemical.⁴³ Registration of a chemical with ECHA is obligatory for all chemicals (existing and new) that are produced in or imported into the EU in volumes of more than one metric ton per year.⁴⁴ As part of the registration dossier, manufacturers are required to perform a chemical safety assessment for substances that are produced or imported in quantities of 10 metric tons per year per registrant, in accordance with Article 14 of REACH.⁴⁵ Depending on the outcome of multiple hazard assessment steps, an additional exposure assessment might be necessary for relevant exposure scenarios.⁴⁵ ECHA provides a set of guidelines on how to conduct an exposure assessment as part of the Chemical Safety Report.^46–48 Table S3 in the SI provides a list of tools recommended by ECHA for occupational and consumer exposure assessments in the context of the REACH chemical registration process. At ECHA, the registration dossiers are evaluated for compliance with the requirements.⁴³

The Substances of Very High Concern (SVHC) Roadmap is part of REACH and serves as a guideline for the management of chemicals that have been identified as being of concern for human health and/or the environment.^49–51 The following chemical groups are intended to be covered by the roadmap: 1) Carcinogenic, mutagenic, and reprotoxic (CMR) substances, 2) sensitizers, 3) persistent, bio-accumulative, and toxic (PBT) or very persistent, very bio-accumulative (vPvB) substances, 4) endocrine disruptors (EDs), and 5) petroleum/coal stream chemicals that are CMR or PBT substances.⁴⁹ ECHA aims to have a complete Candidate List of SVHCs by the end of 2020, and the full database of REACH and CLP is thus regularly screened to identify chemicals of concern. To date, the Candidate List contains 191 chemicals, including 13 phthalates (see Table 1).⁵²

Annex XIV to REACH, usually referred to as the “Authorization List”, lists chemicals subject to authorization under the REACH regulation, meaning that they are not permitted to be put on the market or to be used after a given date (the “Sunset date”) without specific use authorization.⁴⁵ Addition to the Authorization List thus means an automatic phase-out of a substance, unless specific uses are authorized. As of Spring 2019, 43 chemicals are on the Authorization List, including nine phthalates, of which four (i.e., DEHP, DBP, BBP and DIBP) had a Sunset date in 2015 (see Table 1).⁵³ The Candidate List is regularly evaluated by ECHA to decide which chemicals should be placed on the Authorization List.^{54, 55} This prioritization process is primarily based on the information in the registration dossiers on uses and volumes of the chemical. If a chemical is not moved to the Authorization List during a prioritization process, it will be reviewed during the next prioritization process together with other candidates.⁵⁵ Please refer to Table 1 for a current list of phthalates on the Candidate List and on the Authorization List.

Annex XVII to REACH, which includes all the restrictions adopted in the framework of REACH, came into action in 2009.^{45, 56, 57} Entries 51 and 52 name DEHP, DBP, BBP, DINP, DIDP, and DNOP as restricted chemicals (see Table 1 for details). Entry 51 has recently been updated, initiated by an Annex XV Restriction Report submitted by ECHA and Denmark, which included risk assessments of DEHP, BBP, DBP and DIBP.⁵⁸

In addition, several other regulations apply to the use of phthalates in more specific cases, for example the Cosmetic Products Regulation (EC No 1223/2009)⁵⁹, Regulation (EC) No 1935/2004 on Food Contact Materials (FCMs) and Regulation (EU) No 10/2011 on plastic materials and products intended to come into contact with food, as well as the Toy Safety Directive (2009/48/EC). Furthermore, the Restriction of Hazardous Substances (RoHS) Directive (2011/65/EU), last amended by Directive (EU) 2017/2102, is part of the EU waste policy and legislation and restricts the use of toxic chemicals in electric and electronic equipment.⁶⁰ Annex II to the RoHS directive was amended by Directive (EU) 2015/863 to restrict DEHP, DBP, BBP and DIBP in electrical and electronic equipment to a maximum level of 0.1% by weight.⁶¹

2.2. Canada

Two departments, Health Canada (HC) and Environment and Climate Change Canada (ECCC), are primarily responsible for the risk assessment of chemicals.⁶² Additionally, Canada’s provinces are responsible for the control and management of chemicals, which requires close coordination of efforts at the federal and provincial levels.⁶³ The Canadian Environmental Protection Act of 1999 (CEPA 1999) as one principal federal statute regulates the evaluation of new and existing chemicals based on their properties and possible exposure to the public and the environment.⁶⁴ Under CEPA 1999, HC and ECCC are required to maintain a Priority Substance List (PSL) of chemicals that have to be assessed to decide if a chemical meets the criteria of a toxic chemical as described in Part 5, Section 64, of CEPA 1999.^64–66 These assessments have to be completed within five years of the addition of a chemical to the PSL. If a chemical is identified as “CEPA toxic”, it is recommended for addition to the Toxic Substances List (Schedule 1) of CEPA 1999. To date, DEHP is the only phthalate on Schedule 1.⁶⁷ Canada’s Cosmetic Ingredient Hotlist, which aggregates information on substances regulated under the Cosmetics Regulations and the Food and Drugs Act, includes DEHP as a prohibited ingredient, reflecting its addition to Schedule 1.^{68, 69}

Between 1999 and 2006, HC and ECCC categorized approximately 23,000 chemicals on Canada’s Domestic Substances List (DSL), identifying about 4,000 chemicals that warranted additional research and possible risk management measures, and hundreds of New Substance Notifications that were submitted annually before and during that period.^{70, 71} In 2006, the Canadian government launched the Chemicals Management Plan (CMP) to further review those 4,000 chemicals and also to allow consistent assessment of chemicals used in Canada, to protect public health and the environment.⁷² Part of the CMP was the Substance Groupings Initiative, aiming to identify structurally or functionally related substances to increase assessment and management efficiencies, support IS decisions, and maximize stakeholder engagement.⁷³ Nine substance groupings were announced in 2011. The Phthalate Substance Grouping includes 14 phthalates (see Table S2-A in the SI) with 14 additional phthalates on the DSL (Table S2-B in the SI). The substances in the Phthalate Substance Grouping had been identified based on Section 74 criteria of CEPA 1999⁶⁴ (i.e., a substance is on the DSL because it is expected to have great exposure potential to Canadians, because it is persistent or bioaccumulative and inherently toxic to humans or non-humans, or because it is manufactured in or imported into Canada) or because of existing human health concerns⁷³.

Based on Sections 68 and 74 of CEPA 1999, ECCC and HC published four “State of the Science” (SoS) reports in 2015, addressing the Phthalate Substance Grouping.^74–77 The agencies also proposed an approach for cumulative risk assessment of these phthalates under the CMP.^{78, 79} In October 2017, ECCC and HC published a Draft Screening Assessment of the Phthalate Substance Grouping according to the approach proposed in 2015.⁸⁰ In the Draft, it was concluded that only B79P and DEHP are potentially harmful to the environment or biological diversity. DEHP, which had first been assessed in 1994, was confirmed as harmful to human health at current levels of exposure, but none of the other phthalates was found to pose a potential risk.⁸⁰ The Draft was published in the Canada Gazette in October 2017, marking the beginning of a 60-day public comment period. ⁸¹ To date, the Draft has not been finalized.

Another important part of Canada’s Approach to properly treating potentially harmful chemicals is the Canada Consumer Product Safety Act (CCPSA) passed in 2010.⁸² One of the regulations made under CCPSA is the Phthalates Regulations (SOR/2016–188).⁸³ The key provisions of CCPSA focus on evaluating the safety of products on the Canadian market that might contain toxic chemicals or might pose risks to consumers in other ways. CCPSA clarifies responsibilities of manufacturers, importers, and retailers for documentation, reporting, product safety testing, and packaging and labelling.⁸⁴

2.3. United States

For historical context, the Phthalates Action Plan of 2012 described the United States Environmental Protection Agency’s (US EPA) course of action at that time to address concerns regarding eight specific phthalates that were selected based on toxicity and evidence of pervasive human and environmental exposure (see Table 1).⁸⁵ The Plan not only covered actions by the US EPA, but also reviewed management activities undertaken by the Consumer Products Safety Commission (CPSC) and the US Food and Drug Administration (US FDA), as well as by US state and various international governments.⁸⁵ Several more recent US EPA actions have been taken to manage phthalates, as listed in Table 1.

2.3.1. US Environmental Protection Agency

The 2016 Frank R. Lautenberg Chemical Safety for the 21st Century Act, which amends the Toxic Substances Control Act (TSCA), requires the US EPA to evaluate the safety of new chemicals prior to entering commerce as well as the safety of existing chemicals.⁸⁶ For new chemicals, manufacturers have to file Pre-manufacture Notices (PMNs) including data on chemical identity, structure, use categories, manufactured amounts, and also on existing toxicological data, but they are not required to perform toxicity tests or exposure assessments. The US EPA has to conduct a review and make an affirmative finding within a certain review period after notification by the manufacturer.⁸⁷ Information submitted with the notification and a set of predictive tools are used to evaluate the risks, which then inform risk management (see Section S2 and Table S4 in the SI). Based on the outcome, the US EPA has several response options, for example ordering further toxicity testing, or imposing restrictions regarding manufacture (including import), processing, distribution, use, and/or release of the chemical.⁸⁸

For existing chemicals, the US EPA established the TSCA Work Plan to focus and direct the activities of its Existing Chemicals Program. The TSCA Work Plan contains 90 chemicals, which were selected based on high scores in a two-step screening process that combined toxicity, exposure, and persistence and bioaccumulation information.^{89, 90} Several groups of chemicals for which the US EPA had previously developed Action Plans were included in the TSCA Work Plan, among them seven phthalates (see Table 1).⁹¹ Chemicals designated as high-priority undergo further risk evaluation to determine if a chemical presents an unreasonable risk to human health or the environment.⁹² Depending on the outcome of the evaluation, possible risk management options include labeling, manufacturing restrictions, or exposure prevention.⁹³ To date, the risk evaluation step has been initiated for 10 chemicals, although none of those are phthalates.⁹²

Under TSCA, the US EPA has also proposed a longer-term, risk-based approach for parsing chemicals on the TSCA Active Inventory, which are not currently on the TSCA Work Plan, into bins that can be used to inform multiple activities and priorities throughout the US EPA.⁹⁴ In this context, NAMs may be used to develop information to fill gaps where traditional data are not available.^{95, 96}

2.3.2. US Food and Drug Administration

The US FDA regulates food additives, food contact substances and packaging, drugs used by humans and animals, cosmetic products, medical devices, and tobacco products. ⁹⁷ Under the 1997 Food and Drug Administration Modernization Act, which amends the Federal Food, Drug, and Cosmetic Act.⁹⁸ Title 21: Food and Drugs of the Code of Federal Regulations lists multiple phthalates that are permitted for use in FCMs, including limitations of the allowable amount.^{99, 100} The reevaluation of phthalates in FCMs has been encouraged several times over the last years by NGOs¹⁰¹ and politicians¹⁰², and several studies address risk assessment approaches for those materials.^103–105 That includes the restriction of DEHP in bottled water¹⁰⁶ and limitations of the use of certain phthalates as excipients in products regulated by the Center for Drug Evaluation and Research (CDER)¹⁰⁷.

The US FDA also monitors the safety of cosmetic products that are being marketed. Phthalates represent one group of selected cosmetic ingredients that is addressed by the US FDA.^{14, 108} The agency states that the effect of phthalates on human health is still unclear, if there is an effect at all, and emphasizes that the US FDA does not have evidence that phthalates as used in cosmetics pose a safety risk. DEP is highlighted as the only phthalate of relevance in cosmetics to date.¹⁰⁸ As with any other ingredient, phthalates in cosmetics (except fragrances) have to be declared on a label, in accordance with the Fair Packaging and Labeling Act.¹⁰⁹ It has to be noted that the exclusion of fragrances has a relatively large impact on the number of cosmetics for which phthalates have to be listed, because they are frequently used in fragrances.¹¹⁰

2.3.3. US Consumer Product Safety Commission

The 1972 Consumer Product Safety Act (CPSA) and its 2008 amendment, the Consumer Product Safety Improvement Act (CPSIA), enable the CPSC to develop standards, publish bans and recalls, and control the use of certain chemicals (including phthalates) in products.^{111, 112} A special focus is put on products intended for infants and children. As required by the CPSIA, the CPSC convened a Chronic Hazard Advisory Panel (CHAP) to perform a study of the effects of phthalates and phthalate alternatives that are used in children’s toys and child care articles on children’s health.¹¹³

The CPSC rule Prohibition of Children’s Toys and Child Care Articles Containing Specified Phthalates effective April 2018 prohibits levels greater than 0.1% of DINP, DIBP, DPENP, DHEXP and DCHP in toys and child care articles¹¹⁴ and is a direct result of the CHAP report. Previously, the CPSIA had already banned DEHP, DBP and BBP at levels higher than 0.1% in toys and child care articles.¹¹² Additionally, the CPSC is pursuing efforts in human factors engineering (HFE) on phthalates and other substances to inform product design and use.^{115, 116}

2.3.4. US States

In addition to federal actions, several US states have passed laws requiring manufacturers to report the use of certain chemicals in consumer or children’s products, or even restricting use of specific chemicals completely.¹¹⁷ Some of these laws, for example the Safer Consumer Products (SCP) program of the California Department of Toxic Substances Control (DTSC), require manufacturers and other responsible entities to conduct an alternatives analysis for the informed substitution of hazardous chemicals in products with safer alternatives.^{20, 21, 118} The DTSC recently released their Priority Product Work Plan for 2018–2020, which describes the product categories selected for evaluation to identify those categories from which future Priority Products will be proposed.¹¹⁹ These include personal care products, cleaning products, furnishings, building products, consumable office and school supplies, food packaging, and lead-acid batteries.¹¹⁹ The regulation requires manufacturers or other responsible entities to perform an alternatives analysis to determine how to reduce impacts to human health and to the environment.¹²⁰ The alternatives analysis process compares an existing Priority Product (a product that contains a chemical of concern) with potential alternatives such as chemical substitution or product redesign. It also evaluates important impacts on human and environmental health of a product throughout its life cycle from manufacture through use and disposal.¹²¹ In addition, the DTSC provides a list of Candidate Chemicals that might become subject to regulations under the SCP program.²¹ The list contains over 50 phthalates, including those named in the TSCA Phthalate Action Plan and multiple metabolites. The entire DTSC database can be searched on the CalSAFER website.¹²² Candidate Chemicals for Priority Products are identified based on a range of lists, for example the EU Candidate List of SVHCs in accordance with Article 59 of Regulation (EC) 1907/2006 and US EPA’s Toxics Release Inventory (TRI) database. ¹²³ Chemicals might also be identified as Candidate Chemicals if they have been acknowledged as hazardous to human and/or environmental health based on certain criteria established by the DTSC.¹²³

The State of Washington Department of Ecology passed the Children’s Safe Products Act in 2008²³ and the Children’s Safe Products Reporting Rule in 2011²⁴. The Act limits the content of phthalates in general (individually or in combination) in children’s products to 0.1% by weight.²³ The list of Chemicals of High Concern to Children (CHCC) is part of the Reporting Rule and includes 12 phthalates, among other chemicals, that have to be reported to the Department of Ecology if they are present in a children’s product.^{24, 27} In April of 2019, Washington State passed The Pollution Prevention for Our Future Act (SB 5135), which gives the Department of Ecology the authority to “determine regulatory actions to increase transparency and to reduce the use of priority chemicals in priority products”²⁶. This new law specifically identifies five chemical classes including per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), flame retardants, phthalates, and bisphenols.²⁵ Products that may be identified as priorities include personal care products, food packaging, and building materials. The legislation authorizes the Department of Ecology to restrict or prohibit priority substances when it determines that a safer alternative is feasible and available, or if doing so is necessary to protect the health of sensitive populations.²⁵ The bill calls for the first set of priority products to be identified by the Department of Ecology by June 1, 2020.²⁶ Efforts to implement this law are currently underway.

Additional State regulations addressing phthalates can be found in Table 1, for example Maine’s Toxic Chemicals in Children’s Products Law and Safer Chemicals in Children’s Products Rules and Oregon’s Toxic-Free Kids Act.^{124, 125} Lists of chemicals of (high) concern and of prioritized chemicals are usually part of those regulations.

2.4. Australia

The regulation of industrial chemicals in Australia is subject to reforms, which were announced in 2015 and are currently underway.¹²⁶ The reforms are the result of stakeholder consultation and international best practice considerations.¹²⁶ Most significantly, the new Australian Industrial Chemical Introduction Scheme (AICIS) will replace the National Industrial Chemicals Notification and Assessment Scheme (NICNAS, which had been established in 1990) and is proposed to commence on July 1, 2020.^{126, 127} With AICIS, updated Industrial Chemical Rules and Categorization Guidelines will come into effect.¹²⁸

Many phthalates, including DEHP and DBP, are listed as Priority Existing Chemicals (PECs), meaning that they are suspected to be of potential negative impact for workplace health and safety, public health, or environmental health (see Table 1).^{129, 130} NICNAS lists several phthalates as endocrine active chemicals¹³¹ and performed an Inventory Multi-tiered Assessment and Prioritization (IMAP) assessment of phthalates resulting in a report³⁹ that was last updated in March 2019, concluding the Tier II assessment (see Table S1 in the SI). NICNAS also provides hazard information on multiple phthalates.¹³²

From the consumer perspective, the Australian Competition and Consumer Commission (ACCC) is responsible for compliance with the Australian Consumer Law (ACL), which is part of the Competition and Consumer Act of 2010 (CCA).^{133, 134} The ACL came into effect in 2011 and provides a national product safety system with the same regulations for all states and territories.¹³⁵ The focus of the ACCC is product safety regulations and provisions, including interim and permanent bans, for example of DEHP in children’s products.^{40, 41}

2.5. Comparing International Phthalate Exposure Assessment Approaches

The overview of the international chemical risk management policies presented above reveals that there is an appreciation of the need for a comprehensive chemical risk management strategy. However, it also shows how various regulatory authorities approach the task in different ways. Focusing on phthalates shows a range of conclusions that have been reached over the years. DEHP is subject to most regulations and restrictions and its potential for negative health impacts has been widely acknowledged. DBP, BBP, DINP and DIBP are relatively widely regulated, but with exceptions. Several other phthalates are mentioned in different legislative contexts but not in all of them. DEP for example is part of assessments in the US and of Canada’s Phthalate Substance Grouping list, but is not considered in the EU or in Australia (Table S1 in the SI). B79P has been the only substance (beside DEHP) that was found potentially harmful to environmental health in Canada. Australia has included B79P in their IMAP assessment where it was identified as persistent. In the EU, B79P has been registered under REACH and is listed as a priority chemical for evaluation by a member state, while in the US, it is not considered in any list. Overall, the number of phthalates considered in Canada and Australia in their risk assessment approaches exceeds those of the US and the EU, although the EU has several evaluations pending, for which different member states are responsible. Clearly, the bureaucratic apparatus of the EU works very differently than in the other countries, also resulting in different types of risk assessments.

Comprehensive risk assessments should account for exposures to all populations by all pathways from manufacture and use of chemicals. Even a narrower focus only on exposure to chemicals released from products present in the indoor environment is challenging, not only because of the enormous variety of products and chemicals, but also because chemicals are emitted to, and can migrate among, different media in the built environment. The dominant exposure pathways depend on the specific product, the way it is used, the specific chemical ingredient and its interactions with other chemicals, and characteristics of the exposed individual(s), as for example children might be more exposed to some chemicals than adults.

Several risk assessments addressing phthalates have been conducted by governmental authorities over the past two decades. In many cases, these assessments have provided the scientific basis for the chemical risk management actions described above. All of them include an assessment of consumer exposure to phthalates in products as part of the risk assessment to some extent, but a closer look at these consumer exposure assessments is warranted.

The assessment reports published on DNOP¹³⁶ in 1993 and on DEHP¹³⁷ and DBP¹³⁸ in 1994 by the Canadian Government were among the first to address exposure to and hazard posed by phthalates as part of regulatory action. These assessments primarily focus on exposure via drinking water, ambient air, soil and food. For DEHP, the possibility of exposure via indoor air and children’s product is mentioned, but because of data limitations, only overall exposure estimates were derived.¹³⁷ The report on DNOP further highlights the problem of contamination of samples because of the ubiquity of phthalates as plasticizers in products, but the transport and fate of phthalates originating from these products is not further explored.¹³⁶ Instead, possible ways of entry and fate in the outdoor environment are discussed as main contributors to potential exposures.^136–138

These reports were followed a decade later by EU risk assessment reports on DBP¹³⁹, DIDP¹⁴⁰ and DINP¹⁴¹ (all in 2003), BBP in 2007¹⁴² and DEHP in 2008¹⁴³. The EU reports address both potential human and environmental health risks and differentiate between occupational and consumer exposure, as well as exposure of certain subpopulations. The choice of subpopulation also influenced the exposure pathways considered, for example the dust-ingestion pathway was more important for young children but less important for adults.

Each assessment was drafted by one EU member state in cooperation with experts from other member states and then peer-reviewed by the Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE). The risk assessment modeling tool European Union System for the Evaluation of Substances (EUSES) was used in some capacity to derive phthalate concentrations in environmental media (water, soil, ambient air) and the Estimation and Assessment of Substance Exposure (EASE) tool for workplace exposure predictions was used to assess exposure in several occupational settings. None of these tools or the underlying principles and assumptions was addressed in any detail in the reports, even though the literature exists (see for example Berding et al.¹⁴⁴ or Schwartz et al.¹⁴⁵ for information on EUSES and Cherrie and Hughson¹⁴⁶ or Creely et al.¹⁴⁷ for information on EASE). Depending on the intended use of a phthalate and available data, consumer exposure received more or less attention, with a clear temporal trend becoming visible: While the three reports of 2003 (DBP, DIDP and DINP)^139–141 give consumer exposure via the indoor environment (i.e., not by direct contact with a product) only a cursory review, these sections in the 2007 and 2008 reports^{142, 143} are more detailed and give at least some mention of possible emission mechanisms, particularly into indoor air. It is also clear that DEHP had been investigated most thoroughly.¹⁴³ Thus, DEHP emission and partitioning onto particles is addressed to some extent, but still limited by a lack of data. The general approach to deriving scenario-based consumer exposure estimates is based on literature data (i.e. studies conducted in Europe, the US, or Canada) and simple equations, for example taken from Deisinger et al. 1998¹⁴⁸ and Wormuth et al. 2006¹⁴⁹, respectively. The consumer exposure modeling tool ConsExpo was briefly mentioned in the exposure assessment of DBP (see Delmaar et al.¹⁵⁰ and Delmaar and Schuur¹⁵¹ for more information on ConsExpo).¹³⁹ In addition, daily intake (DI) estimates were derived based on biomonitoring data, where available.^139–143

In 2013, ECHA followed up on DINP and DIDP, reviewing the literature that had been published in the meantime and addressing a disagreement regarding the no-observed-adverse-effect-level (NOAEL) values for DINP used in the 2003 EU Risk Assessment.¹⁵² The 2013 report confirms the (lower) NOAEL value used by CSTEE, other EU agencies and the CPSC, and furthermore confirms previously identified risks (i.e., from mouthing of toys) and thus the restriction of DINP and DIDP in toys and child care articles that can be mouthed (Entry 52 of Annex XVII to REACH). The exposure assessment section of the risk assessment focuses on specific scenarios based on product groups, such as children’s toys, but also considers exposure via indoor air and house dust. Concentrations are estimated based on literature reviews and DI values are calculated on that basis, but without detail. Emission and partitioning mechanisms are not discussed.¹⁵²

In 2014, CHAP published a risk assessment of 14 phthalates and six phthalate alternatives used in children’s toys and child care articles.¹¹³ The CHAP report features the most comprehensive risk assessment on phthalates conducted in the US to date and had a direct impact on subsequent legislative measures.^{114, 153} However, it is narrower than the EU assessments, focusing on exposure of children and women of reproductive age to phthalates in consumer products and toys. Environmental or ecological exposure is not considered, except where these human subpopulations might be concerned. Similar to the EU reports, the scenario-based exposure assessment equations applied in the CHAP report are based on empirically established correlations^{148, 149} in combination with data from the literature. These empirical equations are not mechanistically consistent in describing phthalate emission and transport and do not reflect current state-of-the science mechanistic understanding of phthalates emission, transport, and resulting exposure.¹⁵³

Canada’s SoS reports of 2015 cover the Phthalates Substance Grouping, in particular short-chain phthalates⁷⁴, medium-chain phthalates^{75, 76}, long-chain phthalates⁷⁶ and DINP⁷⁷, which is considered medium-chain for human health and long-chain for environmental risk assessment. These reports, together with the proposed approach for cumulative phthalate risk assessment⁷⁸, make up the basis for the 2017 Draft Screening Assessment⁸⁰ report, which summarizes the findings from the SoS reports with respect to potential harm to ecology and human health posed by phthalates. An additional 14 phthalates were included to address the possibility of cumulative risk (see Tables S2-A and S2-B in the SI). Sources and uses of phthalates in products were identified based on industry surveys and served as a starting point to develop exposure scenarios. Exposure estimates, e.g. in indoor air or dust, were taken from studies in Canada, China, Sweden, Germany, and the US – for example the CHAP report and the EU risk assessment reports. ConsExpo was again the only modeling tool mentioned when deriving exposure estimates for DMP in cosmetic products. The emphasis of the SoS reports and Draft Assessment was clearly on deriving concentration and DI values and not on evaluating phthalate emissions and transport.⁸⁰

In 2016, ECHA and the Danish EPA submitted a REACH Annex XV Restriction Report on four phthalates, DEHP, DBP, BBP and DIBP, stating that the use of these phthalates in products is not sufficiently controlled.⁵⁸ The assessment focuses on human health risks posed by phthalates in products and on exposures originating from the presence of these products in the indoor environment. For the exposure assessment section, biomonitoring data from the European DEMOCOPHES project is used. Additionally, modeling of exposure via the indoor environment, food, and consumer products is also addressed. The report itself does not give much detail, but the information provided in the annexes is vast. However, what it comes down to is a literature review to establish parameters for populating DI calculation equations. The equations were taken from the 2008 EU Risk Assessment on DEHP¹⁴³, the REACH Guidance document Chapter R.15⁴⁸, and the US EPA Exposure Factors Handbook¹⁵⁴. Overall, the report does not add much to the existing canon of exposure assessments for these phthalates.

Australia’s IMAP assessment of phthalates is the latest example of a risk assessment for phthalates on a governmental level, as Tier II of the multi-tier assessment was completed in March 2019.³⁹ The IMAP assessment framework is set up to address both risks to the environment and to human health, however, the assessment only considers environmental risks and is relatively short compared to other risk assessments. It references many of the previously described assessment reports.³⁹

With the exception of the IMAP assessment, the various exposure assessments all include exposure estimates derived from both biomonitoring data and scenario-based exposure estimates. These approaches complement each other and can give a relatively complete picture of the exposure situation if the results are combined effectively and with an understanding of the strengths and weaknesses of each approach.^{155, 156} With studies such as the National Health and Nutrition Examination Survey (NHANES), the Canadian Health Measures Survey (CHMS), and the European Demonstration of a study to Coordinate and Perform Human biomonitoring on a European Scale (DEMOCOPHES) project providing more information, the trend is to put more emphasis on biomonitoring results. In comparison, scenario-based exposure assessments rely mostly on a similar (though expanding) body of literature and equations, often citing each other in the process. Exposure models are applied only during the last step of an assessment, i.e., to calculate DI values that can be compared to the biomonitoring-based data. Although biomonitoring data provide direct evidence of exposure, these are only available for a small number of chemicals. As such, estimating exposures for data poor chemicals or predicting potential exposures for new chemicals requires additional insights on the behavior of chemicals in indoor environments. Fortunately, the awareness that a combination of approaches is needed is increasing among scientists focused on these topics.^157–159 Comprehensive assessments aimed at estimating the potential for exposures of concern should include both a mechanistic description of the exposure pathway from the source to the exposed individual and, where available, biomonitoring data so that they complement each other. Mechanistically derived exposure estimates can serve as input for validated pharmacokinetic models to estimate internal exposure levels. Also, biomonitoring data can be used to back-calculate exposure for validating mechanistic exposure estimates.

This review of phthalate exposure highlights important limitations in assessment strategies and gaps in the information supporting exposure estimates for a class of data-rich chemicals. The associated uncertainties vary with data availability for different phthalates.^{58, 80, 113} A strategy to address uncertainties in exposure estimates and scarcity of data is to use mechanistic models that describe emission of chemicals from products and their transport in the indoor environment. Mechanistic models, also referred to as process-based models, describe well-established physicochemical processes such as diffusion or sorption and can be fairly easily generalized and varied in complexity based on the needs of the assessment. The US EPA ExpoCast model challenge, in which approximately 50 exposure-data-rich chemicals were ranked based on actual exposure estimates or exposure potential using several different approaches, showed that only mechanistic exposure modeling tools were able to rapidly evaluate and rank potential exposure for most of the chemicals.^{155, 160} Many assessments reviewed above were unable to incorporate mechanistic exposure information because the models and parameters are lacking or insufficient. Instead, these assessments rely on measured concentrations in exposure media obtained from the literature that may not be directly associated with an exposed population, thus potentially limiting applicability for effective risk management.

Occupational exposure is to some extent an exception, because the scenarios under consideration are relatively well defined, thus modeling tools reflecting those scenarios are better established. Even though Chapter R.15 of ECHA’s “Guidance on Information Requirements and Chemical Safety Assessment”⁴⁸ for REACH provides a long list of possible modeling tools for consumer exposure, none of them is used in ECHA’s own risk assessments.

The result of neglecting to incorporate an understanding of physicochemical processes that influence exposure, including emission and transport, is the introduction of uncertainty in the relative importance of exposure scenarios. Given the impetus to evaluate large numbers of chemicals rapidly and efficiently, multidisciplinary approaches that build strength from multiple data streams and incorporate understanding of important mechanisms to estimate potential for exposures is crucial for enabling decisions that support chemical management decisions to protect public health.

It has been demonstrated that exposure assessors rely to a large extent on a set of published data and simple equations for their phthalate risk assessments that have not changed much over the past decades, even though the ability to model exposure mechanisms has greatly improved. This makes it difficult to include new information and advanced exposure methodologies to improve exposure assessments conducted under different authorities. Of the evaluated phthalates, DEHP is the most thoroughly investigated and thus most heavily regulated. Unfortunately, the approach for conducting these exposure and risk assessments is not generalizable and therefore limits opportunities to examine other phthalates with less available information.

3. Outlook

Chemical risk management strategies focus increasingly on the rapid prioritization of large numbers of chemicals in products present indoors to protect humans from potentially harmful exposures, but the implementation approaches vary among countries, national agencies and research institutions. Biomonitoring data and measures of chemical occurrence in environmental media provide the most direct evidence of exposure. However, to predict potential for exposure and/or to mitigate exposure, information on products and pathways is required. Mechanistic modeling enables this understanding and can therefore inform health protective decisions and actions. An understanding of the emission mechanisms of a product based on readily available product characteristics, such as its shape, size, and primary use, would greatly improve chemical screening and prioritization efforts, as emphasized in the 2017 National Academies of Sciences, Engineering, and Medicine report.⁶ For these reasons, we are currently developing a generic mechanistic framework for predicting chemical emission, partitioning and exposure in indoor environments for rapid exposure assessment and chemical prioritization. The framework will incorporate new knowledge on the fundamental mechanisms governing indoor exposure to chemicals (in particular phthalates and other SVOCs) released from products. The framework will include mechanistically-consistent source emission categories and exposure pathways that are congruent with these source categories and the subsequent chemical distribution among indoor compartments. It will also have a modular structure to vary its level of complexity and to accommodate different types of chemical groups. Its purpose will be to serve as an additional tool for rapid risk ranking and screening based on potential exposure as well as comparative exposure analysis for informed substitution. Importantly, this mechanistic exposure modeling framework will enable access to predictive algorithms that can be used to enhance high-throughput exposure methodologies and risk assessment workflows tailored to specific chemical risk research and management decisions. In addition, the framework will advance efforts to harmonize exposure assessments that are being made, for example, by the Organization for Economic Co-operation and Development (OECD).^{161, 162}