The U.S. Environmental Protection Agency (EPA) announced on May 20, 2024, the availability of and solicited public comment on the draft manufacturer-requested risk evaluation (MRRE) for di-isodecyl phthalate (DIDP) and the draft physical chemical, fate, and hazard assessments for di-isononyl phthalate (DINP) prepared under the Toxic Substances Control Act (TSCA). 89 Fed. Reg. 43847. In its May 17, 2024, press release, EPA states that it preliminarily determined that all but one of the uses of DIDP that EPA evaluated under TSCA do not contribute to unreasonable risk to human health.  Additionally, EPA preliminarily determined that DINP causes liver damage at lower concentrations than DIDP, and unlike DIDP, could cause cancer at higher levels of exposure. Comments on the draft documents are due July 19, 2024.

DIDP

According to EPA’s press release, DIDP is used to make building and construction materials; automotive care and fuel products; and other commercial and consumer products, including adhesives and sealants, paints and coatings, and electrical and electronic products. EPA states:

When manufactured or used to make products, DIDP can be released into the water where most of it will end up in the sediment at the bottom of lakes and rivers. If it is released into the air, it will attach to dust particles and then be deposited onto land or into water. Indoors, DIDP has the potential over time to come out of products and adhere to dust particles. If it does, people could inhale or ingest dust that contains DIDP.

EPA states that it found that DIDP has the potential to cause developmental toxicity and harm the liver. EPA notes that, like the U.S. Consumer Product Safety Commission (CPSC), Health Canada, the European Chemicals Agency, and Australia’s National Industrial Chemicals Notification and Assessment Scheme, “EPA did not find enough evidence to preliminarily determine that DIDP causes cancer.”

In the draft risk evaluation for DIDP, EPA preliminarily determined that DIDP poses unreasonable risk of injury to human health to workers exposed to it. EPA also preliminarily determined that DIDP does not pose unreasonable risk of injury to human health for consumers or the general population or pose unreasonable risk to the environment. EPA states that it preliminarily determined that only one of the 47 conditions of use (COU) of DIDP that are subject to TSCA contribute to the unreasonable risk to workers: “if unprotected workers were to spray adhesives and sealants that contain DIDP with high-pressure sprayers, because doing so could create high concentrations of DIDP in mist that an unprotected worker could inhale.” EPA notes that it is not certain whether this use is ongoing and expects that public comments “will help address this uncertainty.”

EPA did not evaluate uses and potential exposure pathways that are not by statute covered by TSCA, such as food packaging. According to EPA, past assessments, including CPSC’s risk assessment, found that DIDP exposure comes primarily from diet for women, infants, toddlers, and children. EPA states that it is possible that DIDP could pose risks to human health through uses or exposure pathways that are not regulated under TSCA. While EPA is preliminarily concluding that only one TSCA COU contributes to its draft unreasonable risk finding for DIDP, EPA notes that “this conclusion cannot be extrapolated to form conclusions about uses of DIDP that are not subject to TSCA, and that EPA did not evaluate.”

DINP

According to EPA, although DIDP and DINP have similar uses, EPA identified several important differences in the potential effects on human health posed by DIDP and DINP. EPA states that both can cause developmental toxicity and liver damage, “but DINP is considered the more toxic of the two because effects are observed at lower levels of exposure in rodent models.” For DIDP, EPA determined that the evidence is not strong enough to conclude that it can cause cancer in people. By contrast, EPA notes that it determined that “DINP could cause cancer at higher levels of exposure than those that cause liver damage and developmental toxicity.”

Because of these hazard differences, EPA is requesting peer review of the DINP human hazard assessments before releasing the full draft risk evaluation for public comment later this year. While EPA will not request a peer review of the full risk evaluation for DINP, EPA states that the peer review on the DINP hazard assessments will cover all the scientific questions that need to be addressed for the DINP risk evaluation. According to EPA, for DINP, “EPA will use the same exposure models used for the DIDP risk evaluation that are being released for peer review today and may use the same models for the other phthalate chemicals as well.”

EPA states that although the evidence suggests that DIDP does not cause effects on the developing male reproductive system commonly known as phthalate syndrome, “DINP does have the potential to cause phthalate syndrome. Therefore, EPA is including DINP in its cumulative risk assessment along with five other phthalate chemicals that have the potential to cause phthalate syndrome, while DIDP is excluded from the cumulative risk assessment.”

Peer Review

EPA will submit the draft documents to its Science Advisory Committee on Chemicals (SACC) for peer review. On July 23, 2024, SACC will consider the scope and clarity of the draft charge questions for the peer review. Written comments on the scope and clarity of the charge questions are due by 12:00 p.m. (EDT) on July 19, 2024. To request time to present oral comments, stakeholders must register by 12:00 p.m. (EDT) on July 19, 2024. For those not making oral comments, registration will remain open through the end of the meeting. On July 30-August 2, 2024, SACC will consider the draft documents and public comments for peer review. To request time to present oral comments, stakeholders must register by 12:00 p.m. (EDT) on July 26, 2024. For those not making oral comments, registration will remain open through the end of the meeting. To allow sufficient time for EPA to process requests for special accommodations, EPA asks that requests be submitted at least ten business days in advance of the meeting.

Commentary

EPA’s MRREs on DIDP and DINP are included in a proposed consent decree that would require EPA to transmit notices of the final risk evaluations on these substances to the Office of the Federal Register by no later than December 31, 2024. Our initial impression of this proposed deadline was that EPA would not likely meet this requirement. For discussion, see our memorandum dated May 10, 2024. We are now, however, cautiously optimistic that EPA may meet this proposed deadline for DIDP. It is less clear that EPA will be able to complete its assessment for DINP, although EPA’s use of the exposure models for DIDP will make EPA’s completion of the DINP risk assessment more efficient. We provide further discussion on these statements below.

EPA identified unreasonable risks to average adult workers and female workers of reproductive age based on inhalation exposures from aerosol generation during the application of DIDP-containing adhesives and sealants. This was the only COU where EPA determined there were unreasonable risks (i.e., calculated margins of exposure that ranged from 2.9 to 4.8). These unreasonable risks would, however, translate to risk management requirements of a respirator with an assigned protection factor (APF) of 10. Based on EPA’s preliminary findings, there are multiple possible outcomes for EPA’s MRRE on DIDP. We discuss three below, assuming that the TSCA SACC will concur with EPA’s approaches and findings.

EPA may receive public comments that the application of adhesives and sealants COU is not ongoing; if that is the case, it is not clear how EPA will proceed. If the high-pressure spray exposures are not intended or known, will EPA still conclude such COUs are “foreseen”? In that case, we expect EPA to conclude that DIDP, as a whole chemical, presents an unreasonable risk, and will proceed with risk management. If EPA concludes that the spray exposures are not foreseen, EPA would presumably conclude that DIDP does not present unreasonable risk and DIDP would therefore be the first TSCA Section 6 action to lead to a final determination of no unreasonable risk. EPA could identify high-pressure spray use as a “significant new use” under its TSCA Section 5(a)(2) authority and issue a TSCA significant new use rule (SNUR). A SNUR will prevent companies from starting or resuming this COU without first being evaluated by EPA as a significant new use notice (SNUN).

If this COU is ongoing, EPA may receive information during the public comment period on the draft MRRE or subsequently on the draft risk management rule that supports to EPA’s satisfaction that entities that engage in this COU can comply with an existing chemical exposure limit (ECEL). Under this outcome, EPA will likely proceed with a final risk management rule that requires compliance with a workplace chemical protection program (WCPP) including an ECEL, rather than banning this COU. In the absence of submitted information (e.g., occupational monitoring data), EPA will likely move to ban this COU during risk management. These outcomes would be comparable to EPA’s decision making on its final risk management rule on methylene chloride. For discussion, see our memorandum dated May 17, 2024.

We are pleasantly surprised that EPA concluded that protecting against the non-cancer effects of DINP would address DINP’s carcinogenicity. In its other assessments, EPA routinely included application of a linear low-dose extrapolation (i.e., no threshold) for evaluating carcinogenic risks from substances, like DINP, with positive carcinogenicity data. For discussion, see our memorandum dated October 30, 2023. This typically serves as a point of scientific disagreement between EPA, regulated entities, and academics. See for example, Dourson et al. (2017), Lafranconi et al. (2023), and Cohen et al. (2023). In contrast, for DINP and its proposed assessment approaches, EPA stated:

Under the Guidelines for Carcinogen Risk Assessment [citation omitted], EPA reviewed the weight of evidence and determined that DINP is Not Likely to be Carcinogenic to Humans at doses below levels that do not result in PPARα activation (KE1 [key event 1]).

[T]he non-cancer chronic POD…based on non-cancer liver effects…will adequately account for all chronic toxicity, including carcinogenicity, which could potentially result from exposure to DINP.

EPA typically justifies using a linear low-dose extrapolation, even for well-studied chemical substances, by concluding that there is “insufficient information to determine the [carcinogenic] MOA” (e.g., 1,4-dioxane) or that “specific information…are lacking” (e.g., methylene chloride). The 2005 Guidelines for Carcinogenic Risk Assessment (the 2005 Guidelines) distinguish between MOA and “mechanism of action,” which indicates an allowance for some degree of uncertainty given that the latter “implies a more detailed understanding” than MOA. Given this history, EPA’s conclusion that the carcinogenic MOA for DINP supports a nonlinear (i.e., threshold) approach is remarkable, especially since EPA accepted some degree of uncertainty with its MOA analysis by stating that “not all of the non-cancer liver effects observed in rodents are consistent with PPARα activation (e.g., spongiosis hepatis).” This represents the first time that EPA has apparently accepted this distinction (i.e., MOA versus mechanism of action) in a draft hazard assessment under TSCA Section 6 for a chemical substance with positive carcinogenicity data.

We expect EPA’s conclusions to be met with opposition based on previous evaluations performed by other agencies. For example, California’s Office of Environmental Health Hazard Assessment (OEHHA) evaluated DINP and in 2015 issued a no significant risk level of 146 µg/day, based on a linear low-dose extrapolation. We believe that the nonlinear (i.e., threshold) approach versus the linear low-dose (i.e., no threshold) approach will be a point of disagreement during the public comment period and peer review on DINP with proponents and opponents on both sides. Differences of scientific opinion on the appropriateness of using the nonlinear approach in the DINP hazard assessment may lead to internal delays while EPA resolves disagreements.

Interested persons may wish to review EPA’s draft risk evaluation on DIDP and its draft hazard assessments on DINP. We believe that each of these will be precedent setting for different reasons (i.e., EPA’s use of the exposure model for DIDP for other phthalates, the possible no unreasonable risk conclusions on DIDP, and application of a nonlinear approach to cancer for DINP). EPA’s preliminary conclusions may be welcomed by regulated entities, but that reception  does not negate the need for public comments and/or providing additional information. The increase in unreasonable risks that EPA identified in its final risk evaluation on Colour Index Pigment Violet 29 (PV29) versus its draft versions on this substance illustrates this point. For discussion, see our memorandum dated September 9, 2022.