[Federal Register Volume 87, Number 151 (Monday, August 8, 2022)]
[Proposed Rules]
[Pages 48128-48140]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-16908]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 372

[EPA-HQ-TRI-2022-0262; FRL-2425.1-04-OCSPP]
RIN 2025-AA17


Addition of Diisononyl Phthalate Category; Community Right-to-
Know Toxic Chemical Release Reporting

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rulemaking; supplemental notice.

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SUMMARY: On September 5, 2000, in response to a petition filed under 
the Emergency Planning and Community Right-to-Know Act (EPCRA), EPA 
issued a proposed rule to add a diisononyl phthalate (DINP) category to 
the list of toxic chemicals subject to the reporting requirements under 
EPCRA and the Pollution Prevention Act (PPA). EPA proposed to add this 
chemical category to the EPCRA toxic chemical list based on its 
preliminary conclusion that this category met the EPCRA toxicity 
criterion. EPA has updated its hazard assessment for DINP and is 
proposing to add DINP as a category defined to include branched alkyl 
di-esters of 1,2 benzenedicarboxylic acid in which alkyl ester moieties 
contain a total of nine carbons. The updated hazard assessment 
demonstrates that the proposed DINP category meets the EPCRA toxicity 
criterion because the members of the category can reasonably be 
anticipated to cause cancer and serious or irreversible chronic health 
effects in humans; specifically, developmental, kidney, and liver 
toxicity. EPA is proposing to add the DINP category to the toxic 
chemical list on this basis and is requesting comment on the updated 
DINP hazard assessment and associated updated economic analysis.

DATES: Comments must be received on or before October 7, 2022.

ADDRESSES: Submit your comments, identified by docket identification 
(ID) number EPA-HQ-TRI-2022-0262, using the Federal eRulemaking Portal 
at https://www.regulations.gov. Follow the online instructions for 
submitting comments. Do not submit electronically any information you 
consider to be Confidential Business Information (CBI) or other 
information whose disclosure is restricted by statute. Additional 
instructions on commenting and visiting the docket, along with more 
information about dockets generally, is available at https://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: 
    For technical information contact: Daniel R. Bushman, Data 
Gathering and Analysis Division (7406M), Office of Pollution Prevention 
and Toxics, Environmental Protection Agency, 1200 Pennsylvania Ave. NW, 
Washington, DC 20460-0001; telephone number: (202) 566-0743; email: 
[email protected].
    For general information contact: The Emergency Planning and 
Community Right-to-Know Hotline; telephone numbers: toll free at (800) 
424-9346 (select menu option 3) or (703) 348-5070 in the Washington, DC 
Area and International; or go to https://www.epa.gov/home/epa-hotlines.

SUPPLEMENTARY INFORMATION: 

I. General Information

A. Does this action apply to me?

    You may be potentially affected by this action if you own or 
operate a facility that manufactures, processes, or otherwise uses any 
chemicals in the proposed DINP category. The following list of North 
American Industrial Classification System (NAICS) codes is not intended 
to be exhaustive, but rather

[[Page 48129]]

provides a guide to help readers determine whether this document 
applies to them. Facilities subject to reporting under EPCRA section 
313 include:
     Facilities included in the following NAICS manufacturing 
codes (corresponding to Standard Industrial Classification (SIC) codes 
20 through 39): 311*, 312*, 313*, 314*, 315*, 316, 321, 322, 323*, 324, 
325*, 326*, 327, 331, 332, 333, 334*, 335*, 336, 337*, 339*, 111998*, 
211130*, 212324*, 212325*, 212393*, 212399*, 488390*, 511110, 511120, 
511130, 511140*, 511191, 511199, 512230*, 512250*, 519130*, 541713*, 
541715* or 811490*. *Exceptions and/or limitations exist for these 
NAICS codes.
     Facilities included in the following NAICS codes 
(corresponding to SIC codes other than SIC codes 20 through 39): 211130 
(corresponds to SIC code SIC 1321, Natural Gas Liquids and SIC 2819, 
Industrial Inorganic Chemicals, Not Elsewhere Classified); or 212111, 
212112, 212113 (corresponds to SIC code 12, Coal Mining (except 1241)); 
or 212221, 212222, 212230, 212299 (corresponds to SIC code 10, Metal 
Mining (except 1011, 1081, and 1094)); or 221111, 221112, 221113, 
221118, 221121, 221122, 221330 (limited to facilities that combust coal 
and/or oil for the purpose of generating power for distribution in 
commerce) (corresponds to SIC codes 4911, 4931, and 4939, Electric 
Utilities); or 424690, 425110, 425120 (limited to facilities previously 
classified in SIC code 5169, Chemicals and Allied Products, Not 
Elsewhere Classified); or 424710 (corresponds to SIC code 5171, 
Petroleum Bulk Terminals and Plants); or 562112 (limited to facilities 
primarily engaged in solvent recovery services on a contract or fee 
basis (previously classified under SIC code 7389, Business Services, 
NEC)); or 562211, 562212, 562213, 562219, 562920 (limited to facilities 
regulated under the Resource Conservation and Recovery Act, subtitle C, 
42 U.S.C. 6921 et seq.) (corresponds to SIC code 4953, Refuse Systems).
     Federal facilities.
    A more detailed description of the types of facilities covered by 
the NAICS codes subject to reporting under EPCRA section 313 can be 
found at: https://www.epa.gov/toxics-release-inventory-tri-program/tri-covered-industry-sectors. To determine whether your facility would be 
affected by this action, you should carefully examine the applicability 
criteria in 40 CFR part 372, subpart B. Federal facilities are required 
to report under Executive Order 13834 (https://www.govinfo.gov/content/pkg/FR-2018-05-22/pdf/2018-11101.pdf) as explained in the Implementing 
Instructions from the Council on Environmental Quality (https://www.sustainability.gov/pdfs/eo13834_instructions.pdf). If you have 
questions regarding the applicability of this action to a particular 
entity, consult the person listed under FOR FURTHER INFORMATION 
CONTACT.

B. What action is the Agency taking?

    In response to a petition, EPA is proposing to add DINP as a 
category to the list of toxic chemicals subject to the reporting 
requirements under section 313 of EPCRA. As discussed in more detail 
later in this document, EPA is proposing to conclude that the members 
of the DINP category meet the EPCRA section 313(d)(2)(B) criteria for 
listing.

C. What is the Agency's authority for taking this action?

    This action is issued under EPCRA sections 313(d), 313(e)(1) and 
328, 42 U.S.C. 11023(d), 11023(e)(1) and 11048. EPCRA is also referred 
to as Title III of the Superfund Amendments and Reauthorization Act of 
1986.
    EPCRA section 313, 42 U.S.C. 11023, requires owners/operators of 
certain facilities that manufacture, process, or otherwise use listed 
toxic chemicals in amounts above reporting threshold levels to report 
their facilities' environmental releases and other waste management 
information on such chemicals annually. These facility owners/operators 
must also report pollution prevention and recycling data for such 
chemicals, pursuant to PPA section 6607, 42 U.S.C. 13106.
    Under EPCRA section 313(c), Congress established an initial list of 
toxic chemicals subject to EPCRA toxic chemical reporting requirements 
that was comprised of 308 individually listed chemicals and 20 chemical 
categories.
    EPCRA section 313(d) authorizes EPA to add or delete chemicals from 
the list and sets criteria for these actions. EPCRA section 313(d)(2) 
states that EPA may add a chemical to the list if any of the listing 
criteria in EPCRA section 313(d)(2) are met. Therefore, to add a 
chemical, EPA must determine that at least one criterion is met, but 
need not determine whether any other criterion is met. Conversely, to 
remove a chemical from the list, EPCRA section 313(d)(3) dictates that 
EPA must determine that none of the criteria in EPCRA section 313(d)(2) 
are met. The listing criteria in EPCRA section 313(d)(2)(A)-(C) are as 
follows:
     The chemical is known to cause or can reasonably be 
anticipated to cause significant adverse acute human health effects at 
concentration levels that are reasonably likely to exist beyond 
facility site boundaries as a result of continuous, or frequently 
recurring, releases.
     The chemical is known to cause or can reasonably be 
anticipated to cause in humans: cancer or teratogenic effects, or 
serious or irreversible reproductive dysfunctions, neurological 
disorders, heritable genetic mutations, or other chronic health 
effects.
     The chemical is known to cause or can be reasonably 
anticipated to cause, because of its toxicity, its toxicity and 
persistence in the environment, or its toxicity and tendency to 
bioaccumulate in the environment, a significant adverse effect on the 
environment of sufficient seriousness, in the judgment of the 
Administrator, to warrant reporting under this section.
    EPA often refers to the EPCRA section 313(d)(2)(A) criterion as the 
``acute human health effects criterion;'' the EPCRA section 
313(d)(2)(B) criterion as the ``chronic human health effects 
criterion;'' and the EPCRA section 313(d)(2)(C) criterion as the 
``environmental effects criterion.''
    Under EPCRA section 313(e)(1), any person may petition EPA to add 
chemicals to or delete chemicals from the list. EPA issued a statement 
of policy in the Federal Register of February 4, 1987 (52 FR 3479) 
providing guidance regarding the recommended content of and format for 
petitions. On May 23, 1991 (56 FR 23703), EPA issued guidance regarding 
the recommended content of petitions to delete individual members of 
the metal compounds categories reportable under EPCRA section 313. EPA 
published in the Federal Register of November 30, 1994 (59 FR 61432) 
(FRL-4922-2) a statement clarifying its interpretation of the EPCRA 
section 313(d)(2) and (d)(3) criteria for modifying the EPCRA section 
313 list of toxic chemicals.

D. Why is the Agency taking this action?

    EPA is taking this action in response to a petition submitted under 
EPCRA section 313(e)(1). EPA is required to respond to petitions by 
ether initiating a rulemaking to grant the petition or publishing an 
explanation of why the petition is denied. In this case, EPA is 
proposing to grant the petition to list DINP.

E. What are the estimated incremental impacts of this action?

    EPA prepared an economic analysis for this action entitled, 
``Economic Analysis for the Addition of Diisononyl Phthalate Category; 
Community Right-

[[Page 48130]]

to-Know Toxic Chemical Release Reporting'' which presents an analysis 
of the costs of the proposed addition of the DINP category (Reference 
(Ref.) 1). EPA estimates that this action would result in an additional 
198 to 396 reports being filed annually. EPA estimates that the costs 
of this action will be approximately $920,938 to $1,839,925 in the 
first year of reporting and approximately $438,542 to $876,155 in the 
subsequent years. In addition, EPA has determined that of the 181 to 
362 small businesses affected by this action, none are estimated to 
incur annualized cost impacts of more than 1%. Thus, this action is not 
expected to have a significant adverse economic impact on a substantial 
number of small entities.

F. What should I consider as I prepare my comments for EPA?

    1. Submitting CBI. Do not submit CBI information to EPA through 
https://www.regulations.gov or email. Clearly mark the part or all of 
the information that you claim to be CBI. For CBI information in a disk 
or CD-ROM that you mail to EPA, mark the outside of the disk or CD-ROM 
as CBI and then identify electronically within the disk or CD-ROM the 
specific information that is claimed as CBI. In addition to one 
complete version of the comment that includes information claimed as 
CBI, a copy of the comment that does not contain the information 
claimed as CBI must be submitted for inclusion in the public docket. 
Information so marked will not be disclosed except in accordance with 
procedures set forth in 40 CFR part 2.
    2. Tips for preparing your comments. When preparing and submitting 
your comments, see the commenting tips at https://www.epa.gov/dockets/commenting-epa-dockets#tips.

II. What is the petition and EPA's response?

A. Who submitted the petition and what was requested?

    On February 29, 2000, EPA received a petition from the Washington 
Toxics Coalition (which is now called Toxic-Free Future) requesting 
that EPA add DINP to the list of toxic chemicals subject to reporting 
under EPCRA Section 313 and PPA section 6607 (Ref. 2). The petitioner 
indicated that the composition of DINP varies, and that DINP is known 
by at least three CAS numbers: 28553-10-0, 68515-48-0, and 71549-78-5. 
The petitioner asserted that DINP causes cancer, systemic toxicity, 
developmental toxicity, and endocrine disruption, and therefore should 
be added to the list of chemicals subject to reporting under EPCRA 
Section 313 and PPA section 6607. The petitioner also stated that DINP 
is a dangerous phthalate ester used as the principal plasticizer in 
toys and other products used by children and adults. The petitioner 
asserted that in all studies conducted to measure DINP exposure from 
children's use of plastic, DINP migrates from the plastic into saliva 
when the plastic item is chewed or put into the child's mouth. (Ref. 2)

B. How did EPA initially respond to the petition?

    In response to the petition to add DINP to the EPCRA section 313 
list of toxic chemicals, EPA published a proposed rule to add DINP as a 
category to the EPCRA section 313 list (65 FR 53681, September 5, 2000) 
(FRL-6722-3). The proposed rule was based on information contained in 
the hazard assessment for DINP that was developed in response to the 
petition. EPA proposed to list the DINP category based on cancer and 
serious or irreversible chronic health effects including liver, kidney, 
and developmental toxicity. In response to comments on the proposal, 
EPA revised its hazard assessment for DINP and issued a notice of data 
availability (NODA) requesting comments on the revised hazard 
assessment (70 FR 34437, June 14, 2005) (FRL-7532-4). In the NODA, EPA 
proposed to list DINP based on serious or irreversible chronic health 
effects including liver, kidney, and developmental toxicity but 
reserved judgment on whether cancer was an endpoint of concern for 
DINP.

C. How is EPA updating its response to the petition?

    Note that a considerable amount of time has elapsed since the DINP 
petition was received and EPA published the 2000 proposal and 2005 
NODA. Therefore, EPA has prepared an updated hazard assessment based on 
currently available information, including studies developed since 2005 
(Ref. 3). EPA has also updated the economic analysis for the addition 
of the DINP category (Ref. 1). For the reasons more fully explained in 
the updated hazard assessment (Ref. 3), EPA is now proposing to list 
the DINP category based on our preliminary conclusion that it is 
reasonably anticipated to cause cancer and serious or irreversible 
chronic health effects including developmental, kidney, and liver 
toxicity.
    This supplemental proposal provides the public an opportunity to 
comment on all aspects of the proposed addition of the DINP category to 
the EPCRA section 313 toxic chemical list. EPA specifically requests 
comments on all parts of the updated hazard assessment and updated 
economic analysis as well as any other issues related to the addition 
of the DINP category. Note that EPA does not intend to respond to 
comments received in response to its 2000 proposal to add the DINP 
category to the EPCRA toxic chemicals list or those received in 
response to the associated 2005 NODA. This supplemental proposal 
presents an updated hazard assessment for DINP and an updated economic 
analysis for the proposed action. As such, comments on the prior hazard 
assessment and prior economic analysis are not relevant to the current 
proposed action. If a commenter believes a previously submitted comment 
is relevant to this proposed action, the commenter should resubmit the 
comment to the docket for this supplemental proposal. Also note that 
DINP is also undergoing a risk evaluation required under section 6(b) 
of the Toxic Substances Control Act (TSCA) and that the scientific 
analyses used for this listing will undergo further analyses and review 
as part of the TSCA risk evaluation process. Having chemicals on the 
TRI list can be helpful to the TSCA risk evaluation process, as well as 
any related risk management activities, as TRI can provide information 
concerning releases and waste management activities. Such information 
can help inform what potential exposures are present, as well as help 
identify facilities that deal with a given chemical (e.g., chemicals in 
the proposed TRI DINP category). Nevertheless, EPA is not requesting 
comment in response to this present Notice on any issues related to the 
TSCA 6(b) risk evaluation as part of this rulemaking; rather, only 
comments directly related to the TRI listing proposal are relevant to 
this action.

III. What is EPA's technical evaluation of the toxicity of DINP?

A. What is the chemistry and use of DINP?

    The DINP category for purposes of this action is a category of 
chemicals that includes the branched alkyl di-esters of 1,2 
benzenedicarboxylic acid in which the alkyl ester moieties contain a 
total of nine carbons. The DINP category is a family of di-ester 
phthalates widely used as plasticizers. These chemicals are colorless, 
oily liquids with high boiling points, low volatilities, and are poorly 
soluble in water (less than 10-4 milligrams per liter (mg/
L)). Multiple Chemical Abstracts Service (CAS) numbers are associated 
with DINPs

[[Page 48131]]

including 28553-12-0, 71549-78-5, 14103-61-8 and 68515-48-0. There is 
no single generic CAS number that represents all DINPs. The chemicals 
represented by CAS numbers 28553-12-0 and 71549-78-5 consist of a 
mixture of isomers (compounds which have the same molecular formula but 
differ in the arrangement of their atoms). CAS number 14103-61-8 
represents a single isomeric structure of DINP (bis(3,5,5-
trimethylhexyl) phthalate). The alkyl ester moieties of the diisononyl 
phthalate esters represented by the three CAS numbers stated above are 
branched and contain a total of nine carbons. These alkyl ester 
moieties are represented by the molecular formula 
C9H19. The molecular formulas of these nine-
carbon alkyl ester moieties are the same for these DINP isomers. They 
differ in structure mainly due to the variable location of the methyl 
group on the alkyl ester moieties. CAS number 68515-48-0 is also a 
DINP, but unlike the chemicals represented by the other three CAS 
numbers discussed above, 68515-48-0 consists of di-ester phthalates 
with nine-carbon alkyl ester moieties (approximately 70% by weight), 
mixed with lesser amounts of di-ester phthalates with eight- and ten-
carbon alkyl ester moieties.
    Of the chemicals represented by the four CAS numbers stated above, 
two (68515-48-0 and 28553-12-0) were reported by industry to EPA under 
the Chemical Data Reporting regulations at 40 CFR part 711 as having 
production volumes of greater than 25,000 pounds per year per 
manufacturing or importing site. While reviewing data for the hazard 
assessments, EPA noted that only a limited number of studies reported 
the CAS numbers for the DINP test chemical base stocks. When studies 
did report CAS numbers, the CAS numbers were either 68515-48-0 or 
28553-12-0. These two CAS numbers represent the primary DINP products 
manufactured commercially in the United States. Again, these two CAS 
numbers represent a mixture of DINP isomers and not any one single 
specific DINP isomer. There was no literature available for review 
which identified a single specific DINP isomer as the test chemical. 
Please refer to EPA's updated hazard assessment (Ref. 3) for more 
details on the chemistry and environmental fate of DINP.
    The principle use of DINP is as a plasticizer, particularly in the 
production of polyvinyl chloride (PVC) (Ref. 3). The treatment of 
plastics with DINP provides greater flexibility and softness to the 
final product. Some of the uses of DINP treated plastics are the 
production of coated fabrics, plastic toys, electrical insulation, and 
vinyl flooring. On October 27, 2017, the U.S. Consumer Product Safety 
Commission (CPSC) issued a final phthalates rule (82 FR 49938, 16 CFR 
part 1307) that made permanent the interim prohibition on children's 
toys that can be placed in a child's mouth and child care articles that 
contain concentrations of more than 0.1 percent of DINP.

B. What technical data supports EPA's proposed addition of the DINP 
category to the EPCRA section 313 list?

    EPA reviewed the available data on human health and ecological 
effects associated with DINP and has presented this information in an 
updated hazard assessment document (Ref. 3). Based on EPA's evaluation 
of the available data, EPA is proposing to conclude that DINP satisfies 
the criteria for listing under EPCRA section 313(d)(2)(B) because the 
members of the category can reasonably be anticipated to cause cancer 
and serious or irreversible chronic health effects in humans; 
specifically, developmental, kidney, and liver toxicity. Brief 
summaries of the available human health information that support 
listing the DINP category under EPCRA section 313(d)(2)(B) are provided 
in this Unit. Readers should consult the updated hazard assessment 
document (Ref. 3) for more detailed information about the effects 
discussed here as well as other human health and ecological effects 
associated with DINP.
    1. What carcinogenicity data were found for DINP? In the following 
subsections a-c, EPA discusses some of the available cancer data for 
DINP. Subsection d summarizes the cancer data that supports EPA's 
proposed conclusion that DINP can reasonably be anticipated to cause 
cancer in humans. Additional information is provided in the updated 
DINP hazard assessment (Ref. 3).
    EPA's evaluation used a weight of the evidence (or weight-of-
evidence (WoE)) approach, which means a comprehensive evaluation of 
evidence and information, taking into consideration the strengths, 
limitations, and uncertainties across streams of evidence within a 
discipline. This yields a qualitative, overall summary of the strength 
of each evidence stream and an overall judgment across all relevant 
evidence (Ref. 4).
    a. Liver Tumors. Chronic dietary exposure to DINP induced liver 
tumors in male and female rats fed 12,000 parts per million (ppm) (Ref. 
5), in male mice fed 4,000 ppm and above, and in female mice fed 1,500 
ppm and above (Ref. 6) when tested in 2-year oral bioassays. An 
increased incidence of liver carcinoma was also observed in male rats 
fed 6,000 ppm in the 2-year bioassay conducted by Lington et al. (Ref. 
7), although the response did not reach statistical significance. These 
data indicate that DINP is a liver carcinogen in rats and mice.
    The mode of action (MOA) for induction of hepatic tumors in rodents 
by DINP is by inducing peroxisome proliferation. Peroxisome 
proliferators are a structurally diverse group of non-mutagenic 
chemicals that induce a broad range of responses via interaction with 
peroxisome proliferator activated receptors (PPAR). There is evidence 
to suggest that the liver tumors which develop in rats and mice 
chronically exposed to DINP are mechanistically related to activation 
of PPAR receptor subtype alpha (PPAR[alpha]) (Refs. 8, 9 and 10). 
Transgenic mice that lack PPAR[alpha] are generally resistant to the 
pleiotropic effects of peroxisome proliferators, such as peroxisome 
proliferation, liver enlargement, and liver cancer (Refs. 11 and 12). 
There have been no 2-year studies of DINP in transgenic mice that lack 
PPAR[alpha] to determine whether tumors would develop in this scenario. 
However, there are long term studies (about 70 weeks) available that 
show, development of hepatocellular carcinomas in PPAR[alpha] 
transgenic mice with human PPAR[alpha] agonists (GW7647), suggesting 
that PPARA is indeed responsible for carcinogenesis albeit at a 
dimished level (~35-72%) to a rodent PPAR[alpha] driven carcinogenesis 
(Refs. 13 and 14).
    There are no adequate epidemiological studies on cancer in humans 
exposed to PPAR[alpha] agonists. Humans and non-human primates express 
functional PPAR[alpha], and hypolipidemic drugs are known to act 
through PPAR[alpha] in humans. However, in vivo studies of DINP in 
primates (e.g., Refs. 15 and 16) and in vitro studies of cultured 
primate or human cells (Refs. 17 and 18) exposed to DINP or its 
metabolite mono-isononyl phthalate (MINP) suggest that primates 
(including humans) are resistant to the induction of peroxisome 
proliferation. The basis for the species differences in these studies 
is unknown but may be related to differences in the quantity of 
PPAR[alpha] or to differences in the regulatory sequences of the rodent 
and primate genes (Ref. 18). Human and mouse adenoviral recombinant 
PPAR[alpha] expressed in PPAR[alpha] deficient mice fully restored the 
development of peroxisome proliferator-induced immediate pleiotropic 
responses, including peroxisome proliferation and enhanced expression 
of genes involved in lipid metabolism, suggesting that the human

[[Page 48132]]

PPAR[alpha] is functionally competent and is equally as dose-sensitive 
as mouse PPAR[alpha] in inducing peroxisome proliferation within the 
context of mouse liver environment (Ref. 19). Absolute levels of 
PPAR[alpha] are generally thought to be lower in human compared with 
rodent liver. However, PPAR[alpha] amount varies by an order of 
magnitude among individuals (Refs. 20 and 21); for example, one of the 
six human samples examined expressed levels comparable to the mouse in 
one study (Ref. 22).
    New information has emerged from recent literature (post 2005), on 
the mechanism(s) by which multiple nuclear receptors are activated by 
chemicals producing certain carcinogenic responses in rodents, 
including advances in the understanding of the underlying genetic 
factors that mediate the biochemical and cellular responses to such 
chemicals (summarized in Refs. 23, 24, and 25). To study the question 
of whether peroxisome proliferating chemicals such as DINP are a hazard 
to humans considering this new information, several panels and 
workshops have been convened and charged with reviewing the state of 
the science on the relationship between peroxisome proliferation and 
hepatocarcinogenesis in rodents and the human relevance of PPAR[alpha]-
induced liver tumors. One of the first panels, composed of government, 
academic and industry scientists and organized by Toxicology Excellence 
for Risk Assessment (TERA), concluded that significant quantitative 
differences in PPAR[alpha]-induced liver effects associated with 
hepatic tumor formation exist between humans and rodents (Ref. 24). 
Based on quantitative differences between species, most panel members 
felt that the PPAR[alpha] MOA for liver tumorigenesis is ``not relevant 
to humans;'' however, several panel members concluded that it was more 
appropriate to conclude that the PPAR[alpha] mode of action is 
``unlikely to be relevant to humans.'' In a subsequent workshop 
sponsored by the Toxicology Forum, the human relevance of rodent 
PPAR[alpha] and constitutive androstane receptor (CAR) mediated modes 
of action for liver tumors were considered by industry, academic, and 
government experts (Refs. 23 and 26). Similar to the first panel, most 
workshop participants concluded that the PPAR[alpha] and CAR modes of 
action are not relevant to humans based on qualitative and quantitative 
differences. However, there is evidence to show that the mouse and 
human PPAR[alpha] expression levels are almost similar (Rakhshandehroo 
et al Ref. 27) and the set of genes/pathways regulated are similar to 
one another.
    In considering the role of PPAR[alpha] in inducing liver tumors, 
the California Office of Environmental Health Hazard Assessment (OEHHA) 
classified DINP as a carcinogen under California's Proposition 65 based 
in part on evidence that DINP can induce liver tumors in mice and rats 
(Refs. 28 and 9) and concluded that there was sufficient evidence to 
suggest that ``PPAR alpha activation may not be causally related to 
DINP-induced liver tumors in rats and mice'' and that other mechanisms 
may be involved (Ref. 29). Similarly, Environment Canada and Health 
Canada concluded that the mechanisms of DINP-induced liver 
tumorigenesis have not been fully elucidated, but that there is 
sufficient evidence to suggest that multiple mechanisms, including 
PPAR[alpha]-independent mechanisms, may be involved (Ref. 30). Based on 
this, Health Canada (Ref. 10) concluded that the phthalates in their 
evaluation (including DINP) pose a carcinogenic hazard to humans. While 
the relevance of PPAR[alpha]-mediated carcinogenic MOA to humans is not 
entirely clear, evidence suggests that peroxisome proliferating 
chemicals such as DINP are a hazard to humans because of its ability to 
cause liver cancer.
    b. Kidney Tumors. In the study conducted in rats by Moore (Ref. 5), 
renal tubule cell carcinoma was observed in 2/65 high-dose (12,000 ppm) 
males and 4/50 recovery males compared to 0/65 in the control group. 
The response in recovery males was statistically significant relative 
to the control group. In the Lington et al. study (Ref. 7), renal 
tubule cell carcinoma was observed in 1/80 low-dose (300 ppm) males and 
2/80 high-dose males (6,000 ppm). No preneoplastic or neoplastic 
lesions were observed in females. Treatment-related histopathologic 
changes in the kidneys of rats were consistent with male rat-specific 
[alpha]2u-globulin nephropathy. Additional evidence for [alpha]2u-
globulin nephropathy was obtained in the retrospective evaluation of 
archived kidney tissue from the Lington et al. study (Ref. 7) conducted 
by Caldwell et al. (Ref. 31).
    As discussed in the updated hazard assessment (Ref. 3), the data 
obtained in these studies were evaluated against published criteria for 
male-specific [alpha]2u-globulin nephropathy and its relevance to 
kidney tumors in humans (USEPA (Ref. 32); International Agency for 
Research on Cancer (IARC) 1999 (Ref. 33)). The EPA criteria (Ref. 32) 
are: (1) Increase in number and size of hyaline (protein) droplets in 
kidney proximal tubule cells of treated male rats; (2) 
Immunohistochemical evidence of [alpha]2u-globulin accumulating protein 
in the hyaline droplets; and (3) Histopathological evidence of kidney 
lesions associated with [alpha]2u-globulin nephropathology. The IARC 
criteria (Ref. 33) are: (1) Tumors occur only in male rats; (2) Acute 
exposure exacerbates hyaline droplet formation; (3) [alpha]2u-Globulin 
accumulates in hyaline droplets; (4) Subchronic lesions include 
granular casts and linear papillary mineralization; (5) Absence of 
hyaline droplets and other histopathological changes in female rats and 
mice; and (6) Negative for genotoxicity. Additional IARC Supporting 
Evidence includes: (1) Reversible binding of chemical to [alpha]2u-
globulin; (2) Increased sustained cell proliferation in proximal tubule 
(P2 segment) and (3) Dose-response relationship between hyaline droplet 
severity and renal tumor incidence. For DINP, the EPA criteria for the 
[alpha]2u-globulin MOA have been met. However, for DINP, only three of 
the IARC criteria were met (1, 3, and 6) the other three criteria (2, 
4, and 5) were not met. The data for DINP do not meet any of the IARC 
supporting criteria. In addition, the evaluation noted that (1) kidney 
weight increases along with histopathological changes (increase tubule 
cell pigmentation) were identified in female rats and (2) exposure 
resulted in nephropathy in female mice. Thus, [alpha]2u-globulin 
accumulation in the renal tubules of male rats alone do not explain the 
MOA for renal tubule carcinomas observed in DINP-exposed rodents.
    Based on this evaluation, EPA along with the California 
Environmental Protection Agency (CalEPA) (Ref. 9) and the Consumer 
Product Safety Commission (Refs. 34 and 35) have determined that DINP-
induced kidney tumors are relevant to estimating cancer hazard to 
humans as part of WoE approach described in Unit III.B.1.
    c. Mononuclear Cell Leukemia (MNCL). The incidence of MNCL was 
significantly elevated in male and female rats exposed to DINP in the 
diet when compared to study control animals and the corresponding 
spontaneous/background incidence in two independent chronic/
carcinogenicity rat studies (Refs. 5 and 7). The key issue in use of 
these data to assess the hazard of DINP exposure is the relevance of 
MNCL to human health as part of the WoE to suggest the carcinogenic 
hazard of DINP to humans. As fully explained in the revised hazard 
assessment (Ref. 3), the WoE supports a finding that DINP can 
reasonably be anticipated to cause MNCL in humans.

[[Page 48133]]

    MNCL, also referred to as large granular lymphocyte (LGL) leukemia 
or T (lymphocyte) leukemia, is a spontaneously occurring neoplasm of 
the hematopoietic system that is one of the most common tumor types in 
the Fischer-344 rat strain. MNCL is life threatening in Fischer rats 
and results in a decreased life span. In contrast, MNCL is rare in 
other strains of rats and does not occur in mice. Although MNCL is 
recognized as a common neoplasm in Fischer rats, the MOA for induction 
of MNCL is not completely understood. In addition, there are differing 
views on the existence of a close human correlate to MNCL (Refs. 31 and 
36).
    The increased mortality due to MNCL in DINP-treated rats suggests 
that DINP is associated with the elevated incidence, progression, and 
severity of MNCL. Findings indicate that the time to onset of tumor was 
decreased and the disease was more severe in treated than in control 
animals. On the basis of these data, the increase in severity of MNCL 
with increasing dose in male rats is indicative of a carcinogenic 
response to DINP. However, EPA notes that there are several sources of 
uncertainty in the interpretation of the experimental data. These 
include high and variable background rate and possible strain-
specificity as well as incomplete information on the MOA for induction 
of MNCL. However, full details on MOA are not required to establish a 
cancer hazard unless there is evidence to suggest that the MOA is not 
applicable to an assessment of human cancer, which is not the case in 
the context of MNCL derived cancer hazard discussed here.
    Overall, there is some scientific uncertainty as to the human 
significance of the MNCL observed in rats, and whether DINP can 
reasonably be anticipated to cause MNCL in humans. However, the WoE 
within the MNCL dataset supports a finding that DINP can reasonably be 
anticipated to cause MNCL in humans.
    d. Additional considerations and conclusions. As discussed above in 
sections a through c and in full detail in the updated hazard 
assessment (Ref. 2), evidence for carcinogenicity of DINP is provided 
by multiple studies in rats and mice exposed chronically via oral 
route. Statistically significant increases in many tumor types were 
observed in rats and mice such as increase in hepatocellular tumors 
(Refs. 5 and 7), hepatocellular adenoma and carcinoma (Refs. 5, 6, and 
37) mononuclear cell leukemia of the spleen (Refs. 5, 6, and 7), and 
renal tubular cell carcinomas (Refs. 5, 6, and 7). In addition, other 
non-significant increases in tumor types considered rare and/or 
uncommon were noted in DINP-treated animals, including renal tubular 
and transitional cell carcinoma (Refs. 5, 6, and 7), pancreatic islet 
cell carcinoma (Refs. 6 and 37), testicular interstitial (Leydig) cell 
carcinoma (Ref. 37), and uterine adenocarcinoma (Ref. 37). All the 
above enumerated significant and non-significant increases in tumor, 
carcinoma and adenomas were also evaluated by CPSC in 2001 and 2010 
(Refs. 34 and 35).
    To date, DINP has been classified as a human carcinogen by OEHHA of 
CalEPA, but not by any international agencies. OEHHA has published a 
document on the evidence on the carcinogenicity of DINP in which 
members of the Carcinogen Identification Committee (CIC) conclude that 
DINP has been clearly shown, through scientifically valid testing 
according to generally accepted principles, to cause cancer and should 
be listed under California's Proposition 65 as a carcinogen (Ref. 9). 
Accordingly, DINP was listed under California's Proposition 65 at the 
end of 2013 (Ref. 28). California OEHHA (Ref. 24) cites evidence from 
multiple studies in mice and rats to support the Proposition 65 listing 
of DINP, including identification of:
     Liver tumors in female SD rats;
     Liver tumors in male and female F344 rats;
     Liver tumors in male and female B6C3F1 mice;
     Mononuclear cell leukemia (MNCL) in male and female F344 
rats;
     Renal tubular cell carcinomas, which are rare or uncommon, 
in male F344 rats;
     Renal transitional cell carcinomas, which are rare, in 
male F344 rats;
     Pancreatic islet cell carcinomas, which are rare, in male 
SD rats and female B6C3F1 mice;
     Testicular interstitial (Leydig) cell carcinomas, which 
are uncommon, in male SD rats; and
     Uterine adenocarcinomas, which are rare, in female SD 
rats.
    DINP, similar to other phthalates, was negative in the limited 
number of genotoxic assays and ruled-out as a genotoxic carcinogen. 
However, that determination leaves non-genotoxic mechanisms for 
consideration as plausible carcinogenic mechanisms for DINP. DINP has 
been found to induce in vitro cell transformation in only one out of 
eight studies conducted with Balb/c-3T3 A31 mouse cells (Refs. 38 and 
39). DINP binds to PPAR and activates both rodent and human PPAR[alpha] 
and PPAR gamma but not PPAR beta receptors (Ref. 40). MINP, the 
metabolite of DINP, activated both the mouse and human PPAR[alpha] and 
PPAR gamma receptors, but the degree of PPAR[alpha] and PPAR gamma 
activation was greater for the mouse receptor than for the human 
receptor for both receptor types in the tested conditions (Ref. 40).
    DINP has been shown to activate human CAR (hCAR2) and pregnane X 
receptor (PXR), and the metabolites of DINP, specifically MINP, 
activates hCAR2 isoform, suggesting that DINP and its metabolites have 
more than one MOA (Ref. 41). DINP has also been shown to promote and 
induce tumorigenesis in a variety of cell types through aryl 
hydrocarbon receptors (AhR)-mediated genomic and nongenomic pathways 
(Ref. 42). DINP induces several changes in rodent liver consistent with 
PPAR[alpha] activation (Ref. 41). DINP induces some of these liver 
changes independently of PPAR[alpha] activation as shown in 
PPAR[alpha]-null mice (Ref. 12).
    Tumor necrosis factor-alpha (TNF-[alpha]) plays a pivotal role in a 
number of cell signaling pathways involved in inflammation, cell 
proliferation, and apoptosis (Ref. 43). Although inconsistently 
reported with DINP treatment, TNF-[alpha] functional perturbation 
contributes to carcinogenesis (Ref. 43). In studies conducted in a 
human promonocyte cell line, DINP reduced phagocytosis in a dose-
dependent manner and increased TNF-[alpha] levels (Ref. 44). DINP is 
shown to inhibit hepatic gap junctional intercellular communication 
(GJIC), and the inhibition of GJIC has been proposed as a non-genotoxic 
carcinogenic mechanism in rodents exposed to DINP for 2 or 4 weeks 
(Refs. 45 and 46).
    In considering the structure activity relationships (i.e., the 
read-across approach) between similar phthalates, DINP is structurally 
similar to di(2-ethylhexyl)phthalate (DEHP). Both the phthalates have 
phthalic acid as the common structure with different branched alkyl 
chains for the ester portion. DEHP has an eight carbon alkyl chain with 
an ethyl branch at the 2 position and DINP has a nine carbon alkyl 
chain with a methyl group at various positions. One of the commercially 
available DINP mixtures (CAS number 68515-48-0) contains ~70% nine-
carbon alkyl ester chains with the rest being eight- and ten-carbon 
alky ester chains. Analog searches with AIM (https://www.epa.gov/tsca-screening-tools/analog-identification-methodology-aim-tool) and GenRA 
(https://comptox.epa.gov/genra), identified DEHP as the analog to DINP. 
DEHP and DINP are carcinogenic in rodents, are metabolized via similar

[[Page 48134]]

detoxification pathways, and have similar modes of action (e.g., 
PPAR[alpha] is believed to play a role in liver tumorigenesis for most 
phthalates (Refs. 23 and 24). Due to these similarities, DEHP 
carcinogenicity data is useful for a read-across approach to DINP. DEHP 
has been classified by IARC as a Group 2B (possibly carcinogenic to 
humans) carcinogen (Refs. 47 and 48); by EPA as a Class B2 (Probable 
human carcinogen) carcinogen (Ref. 49); by the National Toxicology 
Program (NTP) to be reasonably anticipated to be a human carcinogen 
(Ref. 50); and is listed by CalEPA under California's Proposition 65 as 
causing cancer (Ref. 51). These previous assessments indicate DEHP is a 
carcinogenic hazard to humans. Based on available toxicity data for 
DINP in multiple species (mouse and rats) and adverse effects on 
multiple tissues (liver, kidney, uterus and testicular), with similar 
mechanism of action (MOA), through activation of multiple toxicity 
pathways by multiple nuclear receptors (such as PPAR[alpha]/[gamma], 
CAR, AhR), leading to cancer in multiple organs and structural 
similarities between DEHP and DINP, it is reasonable to assume that 
DINP would be a carcinogenic hazard to humans.
    In summary, the available literature as discussed above and in the 
updated hazard assessment (Ref. 3), provides evidence that DINP can be 
reasonably anticipated to cause cancer in humans. EPA proposes to 
conclude that the available cancer data provides a sufficient basis for 
listing DINP on the EPCRA section 313 toxic chemicals list pursuant to 
EPCRA section 313(d)(2)(B)(i) because it demonstrates that DINP can 
reasonably be anticipated to cause cancer in humans.
    2. What chronic developmental toxicity data were found for DINP? In 
this section, EPA discusses the available developmental toxicity data 
that supports EPA's proposed conclusion that DINP can reasonably be 
anticipated to cause serious or irreversible developmental effects in 
humans. Additional information is provided in the updated hazard 
assessment (Ref. 3).
    The available data for developmental toxicity (see Table 22 of Ref. 
3) generally shows a consistent pattern of effects within the window of 
exposure (in utero, prenatal, and post natal exposure). The results of 
the one- and two-generation reproductive studies indicate that DINP 
affects post natal growth, as evident from significantly reduced pup 
growth at doses of 143-285 milligrams per kilogram per day (mg/kg/day) 
(during gestation and lactation (Refs. 52 and 53)). The results of two 
developmental toxicity studies on DINP (Refs. 52 and 53) are also 
consistent. In both studies, DINP exposure in utero resulted in 
increased incidences of rudimentary lumbar and/or supernumerary 
cervical ribs and adverse renal effects in fetuses. Hellwig et al. 
(Ref. 52) identified a no-observed-adverse-effect level (NOAEL) and a 
lowest-observed-adverse-effect level (LOAEL) of 200 and 1,000 mg/kg/
day, respectively, for these developmental effects. EPA has identified 
lower NOAEL and LOAEL values of 100 and 500 mg/kg/day, respectively, 
based on effects observed in the developmental study conducted by 
Waterman et al. (Ref. 53). DINP causes malformations of the 
reproductive tract and alterations in fetal testicular testosterone 
production and content in male offspring of rats exposed to 750 mg/kg/
day during gestation (Refs. 54 and 55).
    In a study of male sexual development, timed pregnant Crl:CD 
Sprague-Dawley rats were administered the test substance in corn oil 
via oral gavage at target doses of 0 (vehicle), 50, 250, or 750 mg/kg/
day (corresponding to mean analytical doses of 0, 47, 242, or 760 mg/
kg/day) from gestation days (GDs) 12-19 (Ref. 56). The maternal NOAEL 
and LOAEL were determined to be 47 and 242 mg/kg/day based on increased 
liver weights in dams. The developmental NOAEL and LOAEL were 
determined to be 47 and 242 mg/kg/day based on induction of 
multinucleated gonocytes (MNGs) and reduced testosterone in fetal 
testes.
    In a prenatal developmental toxicity study, timed pregnant female 
Sprague-Dawley rats (20/group, 24 controls) were administered the test 
substance in the diet at target concentrations of 0 (base diet), 760, 
3,800, or 11,400 ppm (target doses of 0, 50, 250, or 750 mg/kg/day, 
respectively) from GD 12 through post natal day (PND) 14 (Ref. 57). The 
study identified a LOAEL for maternal effects of 11,400 ppm (~750 mg/
kg/day) based on reduced body weight, body weight gain, and food 
consumption during gestation and lactation; the NOAEL was 3,800 ppm 
(~250 mg/kg/day). The developmental LOAEL was 3,800 ppm (~250 mg/kg/
day) for effects seen in male pups, including reduced pup weight and 
increased MNGs at greater than 3,800 ppm and decreased anogenital 
distance (AGD) and increased Leydig cell (LC) aggregation at 11,400 
ppm. The developmental NOAEL was found to be 760 ppm (~50 mg/kg/day).
    The WoE from the available reproductive and developmental toxicity 
studies that were considered and presented in Table 22 of the hazard 
assessment (Ref. 3) demonstrates that DINP causes serious or 
irreversible developmental effects in animals. The adverse effects 
include decreased body weight of pups during lactation in a rat two-
generation reproductive toxicity study and in a multi-dose perinatal 
exposure study (Refs. 53 and 54); adverse renal and skeletal effects 
observed in two rat developmental toxicity studies (Refs. 52 and 58); 
altered sexual differentiation observed in a single dose gavage study 
(750 mg/kg/day) of perinatally-exposed male rats (Ref. 55); and 
occurrence of histological lesions in the ovaries and testes of male 
and female rats exposed perinatally via the diet (1,164-2,656 mg/kg/
day) (Ref. 59).
    Reduction in the mean body weight of pups exposed to DINP either 
for one generation, two generations, or perinatally is a sensitive 
indicator of developmental toxicity, in part because it is a continuous 
variable. The Agency believes that the weight of evidence indicates 
reduced pup body weight is a serious effect because (1) the observed 
responses were statistically significant; (2) the responses were dose-
related, (3) the reductions ranged from 9-43% below control values (a 
range that is consistent with biological significance); (4) the 
magnitude of the response tended to increase with DINP exposure over 
time via lactation exposure during the post-natal period; (5) the 
reductions were observed in both sexes and in both F1 and F2 
generations of the two-generation study; (6) the weight reductions were 
noted in both one- and two-generation and perinatal exposure studies; 
and (7) the response may have long-term consequences. Although there is 
always a question as to whether weight reduction is a permanent or 
transitory effect, little is known about the long-term consequences of 
short-term fetal or neonatal weight changes; however, a previous study 
has shown that exposure to chemicals during organogenesis that reduced 
pup birth weight also permanently reduced adult mouse weight with about 
50% of the chemicals (about 40 tested) (Ref. 60), and there is growing 
epidemiological evidence of the long-term consequences of low birth 
weight in humans (Ref. 61). Therefore, EPA has concerns for potentially 
serious developmental effects of DINP in humans.
    The kidney and skeletal variations observed in rats treated with 
DINP are serious because they are structural effects that indicate that 
development has been disrupted. The observed renal effects and skeletal 
variations occurred in the absence of or at minimal maternal toxicity. 
In particular, the occurrence of extra cervical ribs may be of serious

[[Page 48135]]

health consequence. As noted by National Toxicology Program Center for 
the Evaluation of Risks to Human Reproduction (Ref. 62), supernumerary 
cervical ribs are an uncommon finding, and their presence may indicate 
a disruption of gene expression leading to this structural anomaly. In 
addition, there is concern that cervical ribs may interfere with normal 
nerve function and blood flow.
    The effects on sexual differentiation observed in male rats by Gray 
et al. (Ref. 54) are serious because they represent gross morphological 
malformations not normally seen in development of this species. The 
discrepancy between the antiandrogenic effects observed in the 
perinatal exposure study (Ref. 54) and the absence of similar effects 
in the two-generation reproductive study conducted by Waterman et al. 
(Ref. 53) may be explained, in part, by the dose (750 mg/kg) used by 
Gray et al. (Ref. 54) and by differences in the protocol used for each 
study. Exposures during gestation in the two-generation study did not 
reach the dose that was used in the Gray et al. (Ref. 54) perinatal 
exposure study during gestation (approximately 560 mg/kg/day vs. 750 
mg/kg/day, respectively) and the reproductive parameters affected in 
the study by Gray et al. (Ref. 54), including nipple retention, 
anogenital distance, age at testes descent, and age at preputial 
separation, were not measured in the two-generation reproductive study.
    Furthermore, the number of F1 animals examined by Waterman et al. 
(Ref. 53) was not sufficient to detect the low (7.7%) but statistically 
significant incidence of malformations observed by Gray et al. (Ref. 
54). The perinatal exposure study reported by Masutomi et al. (Ref. 59) 
did not detect the same type of alterations reported by Gray et al. 
(Ref. 54), although the administered dietary concentrations resulted in 
doses (306.7-656.7 mg/kg/day and 1,164-2,657 mg/kg/day) that bracketed 
the single gavage dose of 750 mg/kg/day administered by Gray et al. 
(Ref. 54). However, Masutomi et al. (Ref. 59) examined fewer litters (5 
vs. 14), examined fewer pups (number of pups and developmental 
endpoints examined prior to culling were not reported) and did not 
report use of the same type of detailed internal and external 
examinations used by Gray et al. (Ref. 54) to detect areolas, retained 
nipples, and other developmental effects. In addition, the differing 
routes of administration (gavage vs. diet) used in these studies may 
have resulted in different peak blood concentrations of DINP.
    Although the study by Gray et al. (Ref. 54) used a single dose and 
a NOAEL/LOAEL could not be established, the observed effects indicate 
that DINP has the potential for antiandrogenic effects in neonatal male 
rats when tested at 750 mg/kg/day. The effects of DINP on sexual 
differentiation were characterized by the study authors as 
malformations for the tested species and are therefore believed to be 
permanent (i.e., not transient or reversible) and adverse. The observed 
effects may have resulted from inhibition of fetal testis hormone 
production during sexual differentiation, a process that is critical in 
all mammals including humans. It has been demonstrated that several 
other structurally related phthalate esters (dibutyl phthalate (DBP), 
DEHP, and benzyl butyl phthalate (BBP)) also alter sexual 
differentiation and do so by altering fetal testis testosterone 
production and/or content (Refs. 63 and 64) and insulin-like hormone 3 
(Insl3) production (Ref. 65), resulting in malformations of male 
reproductive tissues that require these hormones for development. The 
results of a recent study by Borch et al. (Ref. 55), which showed 
decreased fetal testis production and content of testosterone in 
offspring of female rats treated with DINP during gestation, are 
consistent with this pattern and increase the WoE for disruption of 
testosterone synthesis as a potential MOA for the observed effects on 
the male reproductive system. Although information is currently lacking 
on (1) the precise mechanism(s) responsible for DINP-induced 
malformations and its relevance to humans, and (2) the critical window 
of susceptibility for these effects during reproductive development, 
based upon the WoE, EPA concludes that humans can reasonably be 
anticipated to be affected if exposed to sufficient concentrations of 
DINP or its metabolites at critical stages of reproductive development.
    In summary, the available literature as discussed above and in the 
updated hazard assessment (Ref. 3), provides evidence that DINP can be 
reasonably anticipated to cause developmental toxicity in humans. EPA 
proposes to conclude that the available developmental toxicity data 
provides a sufficient basis for listing DINP on the EPCRA section 313 
toxic chemicals list pursuant to EPCRA section 313(d)(2)(B)(ii) because 
it demonstrates that DINP can reasonably be anticipated to cause 
serious or irreversible chronic developmental toxicity.
    3. What chronic kidney toxicity data were found for DINP? In this 
section, EPA discusses the available kidney toxicity data that supports 
EPA's proposed conclusion that DINP can reasonably be anticipated to 
cause chronic kidney toxicity in humans. Additional information is 
provided in the updated hazard assessment (Ref. 3).
    The kidney is both a cancer and a non-cancer target organ of DINP 
in chronic toxicity studies in rats and mice. In rats, increased 
relative kidney weights were seen in a 21-day (Ref. 66) and three 2-
year rodent studies of DINP (Refs. 5, 6, and 7). In the 2-year study 
conducted by Lington et al. (Ref. 7), exposure to dietary levels of 152 
and 307 mg/kg/day increased relative kidney weights of both male and 
female rats. An increase in tubular cell pigment was also noted in the 
tubular epithelium of high-dose males at 18 months. In the 2-year study 
reported by Moore (Ref. 5), increased relative kidney weights occurred 
in rats receiving dietary doses greater than 359 mg/kg/day for males 
and 442 mg/kg/day for females. Urinalysis findings from the chronic 
studies included significant increases in urine output and 
corresponding decreases in electrolyte levels in high-dose males, 
suggesting compromised ability to concentrate urine in the renal tubule 
epithelium. These effects occurred at the same dosages that produced 
changes in kidney weights. In the Moore (Ref. 5) study, serum urea 
levels (a marker of kidney toxicity) were significantly increased in 
rats exposed to 359 mg/kg/day and higher during the second half of the 
study. Increases in urine volume and kidney lesions were observed in 
the recovery group exposed to 733 mg/kg/day.
    In the Moore (Ref. 5) study, male rats with increased kidney 
weights also had increased mineralization of renal papillae. However, 
it is unlikely that the histological effects reported (mineralization 
of renal papillae in male rats and pigmentation of kidney tubule cells) 
account for the increased weights of the kidneys because routine 
histological observations do not account for observations of 
mineralizations and pigmentations in the kidney.
    The kidney was also a target organ for DINP toxicity in the chronic 
study in mice (Ref. 6). Kidney weights were significantly decreased at 
doses of 1,500 ppm (276 mg/kg/day) and above in male mice. This 
decrease in kidney weight correlated with clinical chemistry findings 
of higher urine volumes accompanied by lower osmolarity (with lower 
concentrations of sodium, potassium and chlorides) in the highest dose 
group and recovery groups of both sexes. The urinalysis findings 
suggest compromised ability to concentrate urine in the renal tubule 
epithelium.

[[Page 48136]]

Histopathology findings included a DINP-induced increase in the 
incidence of chronic progressive nephropathy in females of the highest 
dose group (but not in males). Granular pitted/rough kidneys were 
observed in female mice receiving the 8,000 ppm diet (1,888 mg/kg/day) 
and corresponded to increased incidence/severity of treatment-related 
nephropathy. The recovery group had a decreased incidence of chronic 
progressive nephropathy, suggesting that the effects of DINP were 
partially reversible upon cessation of DINP treatment or that cessation 
of treatment prevented exacerbation of existing lesions. Kidney changes 
in female mice (increased incidence and severity of nephrotoxicity) 
occurred at 8,000 ppm (1,888 mg/kg/day) and in male and female rats 
(increased kidney weights, compromised ability to concentrate urine) at 
6,000 ppm (359 and 442 mg/kg/day, respectively). Such changes are 
indicative of kidney toxicity. Although effects in male rats appear to 
be due to [alpha]2u-globulin nephropathy, the toxic kidney effects in 
female mice and increased kidney weights in female rats cannot be 
explained by an [alpha]2u-globulin MOA.
    In summary, the available literature as discussed above and in the 
updated hazard assessment (Ref. 3), provides evidence that DINP can be 
reasonably anticipated to cause chronic kidney toxicity in humans. EPA 
proposes to conclude that the available kidney toxicity data provides a 
sufficient basis for listing DINP on the EPCRA section 313 toxic 
chemicals list pursuant to EPCRA section 313(d)(2)(B)(ii) because it 
demonstrates that DINP can reasonably be anticipated to cause serious 
or irreversible chronic effects on the kidney.
    4. What chronic liver toxicity data were found for DINP? In this 
section, EPA discusses the available liver toxicity data that supports 
EPA's proposed conclusion that DINP can reasonably be anticipated to 
cause chronic liver toxicity in humans. Additional information is 
provided in the updated hazard assessment (Ref. 3).
    Adverse liver effects were noted in rats following chronic DINP 
exposure in three independent studies (Refs. 5, 6, and 7). Spongiosis 
hepatis, also called cystic or microcystic degeneration, has been 
identified as the most sensitive non-neoplastic response resulting from 
DINP exposure and is thus considered the critical non-cancer effect. 
The incidence of spongiosis hepatis was dose-related, and significantly 
elevated in male rats chronically treated with DINP in three studies 
conducted by different laboratories (Refs. 5, 6, and 7). In the Lington 
et al. (1997) study (Ref. 7), the LOAEL for spongiosis hepatis was 152 
mg/kg/day, while the LOAEL in the Moore study (Ref. 5) was 359 mg/kg/
day; the NOAELs were 15 and 88 mg/kg/day, respectively. A 
Histopathology Peer Review and Pathology Working Group (Ref. 67) 
independently evaluated the liver slides from rats chronically treated 
with DINP (Refs. 5 and 7) and confirmed that the incidence of 
spongiosis hepatis was increased in male rats in each study.
    There is general agreement that spongiosis hepatis develops from 
the perisinusoidal (Ito) cells of the liver. The existing data support 
the conclusion that the increased incidence of spongiosis hepatis in 
dosed rats is clearly related to DINP treatment. In evaluating the data 
for hepatic spongiosis, EPA considered (1) the possibility that 
occurrence of spongiosis hepatis and induction of peroxisome 
proliferation were related; (2) the possibility that the occurrence of 
spongiosis hepatis was a consequence of MNCL; (3) the relationship of 
spongiosis hepatis to hepatocellular cancer; and (4) the human 
relevance of hepatis spongiosis.
    The occurrence of spongiosis hepatis and peroxisome proliferation 
in the livers of rats exposed to DINP are likely to be unrelated due to 
two different MOAs. Although peroxisome proliferation appeared to occur 
in both sexes of rats and mice, the incidence of spongiosis hepatis was 
increased only in male rats. In addition, spongiosis hepatis occurred 
in control animals and in treated animals at doses that did not induce 
peroxisome proliferation. These data indicate that induction of 
peroxisome proliferation per se is not a prerequisite for induction of 
spongiosis hepatis.
    The increased incidence of spongiosis hepatis observed in rats 
exposed to DINP is not due to MNCL. This conclusion is based on the 
findings of the Experimental Pathology Laboratories (Ref. 67), which 
noted that only about 50% of the animals with spongiosis hepatis also 
had MNCL and that the incidence of spongiosis hepatis increased in some 
rats that did not show signs of MNCL.
    Spongiosis hepatis may be associated with or located within foci of 
cellular alteration or hepatocellular neoplasms. This association has 
prompted questions regarding the relationship of this lesion to 
carcinogenic processes in the liver. EPA considers the relationship 
between spongiosis hepatis and hepatic carcinogenesis to be two 
independent events. There does not appear to be strong correlation 
between the induction of spongiosis hepatis and the occurrence of 
hepatocellular neoplasms in rats treated with DINP. In addition, 4 of 
the 12 studies reviewed by Karbe and Kerlin (Ref. 68) reported 
spongiosis hepatis in the absence of hepatocellular neoplasms while a 
fifth study observed hepatocellular cancer in females only.
    Spontaneous and induced spongiosis hepatis lesions have been 
observed in fish as well as rats, but the existence of the lesion in 
humans and other species is less well supported (Ref. 68). It is 
unknown whether human Ito cells are capable of developing spongiosis 
hepatis as observed in rats. In the absence of information that clearly 
indicates a species-specific MOA for development of spongiosis hepatis, 
the occurrence of this lesion in rats is assumed to be relevant to 
humans (Ref. 68).
    Based on the available data, the WoE indicates that the spongiosis 
hepatis is a treatment-related lesion in rats treated with DINP and 
that the occurrence of this lesion in animals is relevant to human 
health. EPA has identified NOAEL and LOAEL values of 15 and 152 mg/kg/
day, respectively, for the Lington study (Ref. 7) and 88 and 359 mg/kg/
day, respectively, for the Moore study (Ref. 5) based on indications of 
serious liver damage (i.e., a statistically significant increased 
incidence of spongiosis hepatis and increased liver weight and liver 
enzyme activities) in male rats chronically exposed to DINP for 2 
years.
    In summary, the available literature as discussed above and in the 
updated hazard assessment (Ref. 3), provides evidence that DINP can be 
reasonably anticipated to cause chronic liver toxicity in humans. EPA 
proposes to conclude that the available liver toxicity data provides a 
sufficient basis for listing DINP on the EPCRA section 313 toxic 
chemicals list pursuant to EPCRA section 313(d)(2)(B)(ii) because it 
demonstrates that DINP can reasonably be anticipated to cause serious 
or irreversible chronic effects on the liver.

IV. What is EPA's rationale for listing the DINP category?

    Based on EPA's review of the available carcinogenicity data, EPA 
proposes to conclude that DINP can reasonably be anticipated to cause 
cancer in humans. In addition, based on EPA's review of the available 
chronic toxicity data, EPA proposes to conclude that DINP can 
reasonably be anticipated to cause serious or irreversible chronic 
human health effects at moderately low to low doses including 
developmental effects, kidney toxicity, and liver toxicity. The data 
for DINP

[[Page 48137]]

demonstrates that DINP has moderately high to high human health 
toxicity based on the available animal studies. Therefore, EPA proposes 
to conclude that, based on the available toxicity data summarized above 
and in the updated hazard assessment, DINP meets the criteria in EPCRA 
section 313(d)(2)(B) for listing on the EPCRA section 313 toxic 
chemicals list.
    EPA is proposing to add DINP to the EPCRA section 313 list as a 
chemical category under the name ``Diisononyl Phthalates (DINP): 
Includes branched alkyl di-esters of 1,2 benzenedicarboxylic acid in 
which alkyl ester moieties contain a total of nine carbons.'' As 
explained in Unit III.A., DINP includes the branched alkyl di-esters of 
1,2 benzenedicarboxylic acid in which the alkyl ester moieties contain 
a total of nine carbons and there is no single generic CAS number that 
represents all DINPs. This category includes the four CAS numbers that 
represent the DINP esters identified in Unit III.A., as well as any 
other branched alkyl di-ester of 1,2-benzenedicarboxylic acid in which 
the alkyl ester moieties contain a total of nine carbons. As EPA has 
explained in the past (see 59 FR 61442-61443, November 30, 1994)(FRL-
4922-2), EPCRA allows the Agency, in its discretion, to add a chemical 
category to the list, where EPA identifies the toxic effect of concern 
for at least one member of the category and then shows why that effect 
can reasonably be expected to be caused by all other members of the 
category. Given the structural similarities of the members of the 
proposed DINP category, it is reasonable to anticipate that all members 
of the DINP category as described will exhibit similar toxicity. For 
this reason, creating a category of DINP is the most appropriate way to 
list this class of chemicals.
    EPA has concluded that it is not appropriate to consider exposure 
for chemicals that are moderately high to highly toxic based on a 
hazard assessment when determining if a chemical should be added for 
chronic human health effects pursuant to EPCRA section 313(d)(2)(B) 
(see 59 FR 61440-61442). Therefore, in accordance with EPA's standard 
policy on the use of exposure assessments (see November 30, 1994 (59 FR 
61432, FRL-4922-2), an exposure assessment is neither necessary nor 
appropriate for determining whether DINP meets the criteria of EPCRA 
section 313(d)(2)(B).

V. References

    The following is a listing of the documents that are specifically 
referenced in this document. The docket includes these documents and 
other information considered by EPA, including documents that are 
referenced within the documents that are included in the docket, even 
if the referenced document is not itself physically located in the 
docket. For assistance in locating these other documents, please 
consult the person listed under FOR FURTHER INFORMATION CONTACT.

1. USEPA. Economic Analysis for the Addition of Diisononyl Phthalate 
Category; Community Right-to-Know Toxic Chemical Release Reporting. 
Prepared by Abt Associates. May 4, 2022.
2. Letter to EPA Administrator Carol M. Browner, Re: Petition to Add 
Diisononyl Phthalate (DINP) to the Emergency Planning and Community 
Right-to-Know Act Section 313 List of Toxic Chemicals. From Laurie 
Valeriano, Policy Director, Wastington Toxics Coalition. February 
24, 2000.
3. USEPA. Technical Review of Diisononyl Phthalate (i.e., updated 
hazard assessment). Office Pollution Prevention and Toxics Data 
Gathering and Analysis Division and Existing Chemicals Risk 
Assessment Division. April 11, 2022.
4. USEPA. Documents available on the website: Draft Protocol for 
Systematic Review in TSCA Risk Evaluations (https://www.epa.gov/assessing-and-managing-chemicals-under-tsca/draft-protocol-systematic-review-tsca-risk-evaluations) 2022.
5. Moore, M.R. 1998. Oncogenicity study in rats with 
di(isononyl)phthalate including ancillary hepatocellular 
proliferation and biochemical analyses. TSCATS Doc# 89980000308. Old 
Doc 8EHQ099813083. Fiche # OTS05562832. Submitted by Aristech 
Chemical Corporation. Produced by Covance Laboratories 2598-104.
6. Moore M.R. 1998. Oncogenicity study in mice with 
di(isononyl)phthalate including ancillary hepatocellular 
proliferation and biochemical analyses. TSCATS Doc# 89990000046. Old 
Doc 8EHQ119813083. Fiche # OTS05562833. Submitted by Aristech 
Chemical Corp. Produced by Covance 2598-105.
7. Lington, A.W.; Bird M.G.; Plutnick, R.T.; Stubblefield, W.A.; and 
Scala, RA. 1997. Chronic toxicity and carcinogenic evaluation of 
diisononyl phthalate in rats. Fundam. Appl. Toxicol 36: 79-89.
8. Kaufmann W.; Deckardt, K.; McKee, R.H.; Butala, J.H.; Bahnemann, 
R.; 2002. Tumor induction in mouse liver: di-isononyl phthalate acts 
via peroxisome proliferation. Regul. Toxicol. Pharmacol. 36:175-183.
9. Office of Environmental Health Hazard Assessment. 2013. Evidence 
on the carcinogenicity of diisononyl phthalate (DINP). Reproductive 
and Cancer Hazard Assessment Branch. California Environmental 
Protection Agency. Available from: https://oehha.ca.gov/files/proposition-65/dinphid100413pdf-0.
10. Health Canada. 2015. Supporting documentation: carcinogenicity 
of phthalates--common MOA by tumor types. Ottawa (ON): Health 
Canada.
11. Lee, S.S.-T.; Pineau, T. Drago, J; Lee, E.J.; Owens, J.W.; 
Kroetz, D.L.; Fernando-Salguero, P.M.; Westphal, H.; Gonzalez, F.L. 
1995. Targeted disruption of the isoform of the peroxisome 
proliferator-activated receptor gene in mice results in abolishment 
of the pleiotropic effects of peroxisome proliferators. Mol. Cell. 
Biol. 15(6):3012-3022.
12. Valles, E.G.; Laughter, A.R.; Dunn, C.S.; Cannelle, S.; Swanson, 
C.L.; Cattley, R.C.; Corton; J.C. 2003. Role of the peroxisome 
proliferator-activated receptor alpha in responses to diisononyl 
phthalate. Toxicol. 191(2-3):211-225.
13. Foreman, J.E.; Koga, T.; Kosyk, O.; Kang, B.; Zhu, X,; Cohen, 
S.M.; Billy, L.J.; Sharma, A.K.; Amin, S.; Gonzalez, F.J.; Rusyn, 
I.; and Peters, J.M. 2021. Diminished Hepatocarcinogenesis by a 
Potent, High-Affinity Human PPAR[alpha] Agonist in PPARA-Humanized 
Mice, Toxicological Sciences, 183(1), 70-80.
14. Foreman, J.E.; Koga, T.; Kosyk, O.; Kang, B.; Zhu, X,; Cohen, 
S.M.; Billy, L.J.; Sharma, A.K.; Amin, S.; Gonzalez, F.J.; Rusyn, 
I.; and Peters, J.M.. 2021. Species Differences between Mouse and 
Human PPAR[alpha] in Modulating the Hepatocarcinogenic Effects of 
Perinatal Exposure to a High-Affinity Human PPAR[alpha] Agonist in 
Mice, Toxicological Sciences, 183(1), 81-92.
15. Hall, M.; Matthews, A.; Webley, L.; and Harling R. 1999. Effects 
of di-isononyl phthalate (DINP) on peroxisomal markers in the 
marmoset--DINP is not a peroxisome proliferator. J. Toxicol. Sci. 
24: 237-244.
16. Pugh, G.; Isenberg, J.S.; Kamendulis, L.M.; Ackley, DC; Clare, 
L.J.; Brown, R.; Lington, A.W.; Smith, J.H.; and Klaunig, J.E. 2000. 
Effects of di-isononyl phthalate, di-2-ethylhexyl phthalate, and 
clofibrate in cynamolgus monkeys. Toxicol. Sci. 56:181-188.
17. Benford, D.J.; Patel, S.; Reavy, H.J.; Mitchell, A.; Sarginson, 
N.J. 1986. Species differences in the response of cultured 
hepatocytes to phthalate esters. Food Chem. Toxicol. 24:799-800.
18. Shaw, D.; Lee, R.; Roberts, R.A. 2002. Species differences in 
response to the phthalate plasticizer monoisononylphthalate (MINP) 
in vitro: a comparison of rat and human hepatocytes. Arch. Toxicol. 
76:344-350.
19. Yu, S.; Cao, W.Q.; Kashireddy, P.; Meyer, K.; Jia, Y.; Hughes, 
D.E.; Tan, Y.; Feng, J.; Yeldandi, A.V.; Rao, M.S.; Costa, R.H.; 
Gonzalez, F.J.; Reddy, J.K. 2001. Human peroxisome proliferator-
activated receptor [alpha] (PPAR[alpha]) supports the induction of 
peroxisome proliferation in PPAR[alpha]-deficient mouse liver. J 
Biol Chem. 2001 Nov 9;276(45):42485-42491.
20. Palmer, C.N.; Hsu, M.H.; Griffin, K.J.; Raucy, J.L.; Johnson, 
E.F. 1998. Peroxisome proliferator activated receptor-alpha 
expression in human liver. Mol Pharmacol 53(1):14-22.
21. Tugwood, J.D.; Aldridge, T.C.; Lambe, K.G.; Macdonald, N.; 
Woodyatt, N.J.

[[Page 48138]]

1996. Peroxisome proliferator-activated receptors: structures and 
function. Ann N Y Acad Sci 804:252-265.
22. Walgren, J.E.; Kurtz, D.T.; McMillan, J.M. 2000. Expression of 
PPAR(alpha) in human hepatocytes and activation by trichloroacetate 
and dichloroacetate. Res Commun Mol Pathol Pharmacol 108(1-2):116-
132.
23. Klaunig, J.E.; Babich, M.A.; Baetcke, K.P.; Cook, J.C.; Corton, 
J.C.; David, R.M.; DeLuca, J.G.; Lai, D.Y.; McKee, R.H.; Peters, 
J.M.; Roberts, R.A.; Fenner-Crisp, P.A. 2003. PPAR[alpha] agonist-
induced rodent tumors: modes of action and human relevance. Crit. 
Rev. Toxicol. 33(6):655-780.
24. Corton, J.C.; Cunningham, M.L.; Hummer, B.T.; Lau, C., Meek, B.; 
Peters, J.M.; Popp, J.A.; Rhomberg, L.; Seed, J.; Klaunig, J.E. 
2014. Mode of action framework analysis for receptor-mediated 
toxicity: The peroxisome proliferator-activated receptor alpha 
(PPAR[alpha]) as a case study. Crit. Rev. Toxicol. Jan; 44(1):1-49.
25. Corton, J.C.; Peters, J.M.; Klaunig, J.E. 2018. The PPAR[alpha]-
dependent rodent liver tumor response is not relevant to humans: 
addressing misconceptions. Arch. Toxicol. Jan; 2(1):83-119.
26. Felter, S.P.; Foreman, J.E.; Boobis, A.; Corton, J.C.; Doi, 
A.M.; Flowers, L.; Goodman, J.; Haber, L.T.; Jacobs, A.; Klaunig, 
J.E.; Lynch, A.M.; Moggs, J.; Pandiri, A. 2018. Human relevance of 
rodent liver tumors: Key insights from a Toxicology Forum workshop 
on nongenotoxic modes of action. Regul. Toxicol. Pharmacol. Feb; 
92:1-7.
27. Rakhshandehroo, M.; Hooiveld G.; M[uuml]ller M.; Kersten S. 
2009. Comparative Analysis of Gene Regulation by the Transcription 
Factor PPARa between Mouse and Human. PLoS ONE 4(8): e6796. 
doi:10.1371/journal.pone.0006796.
28. Office of Environmental Health Hazard Assessment. 2013. Chemical 
listed effective December 20, 2013 as known to the state of 
California to cause cancer: Diisononyl Phthalate (DINP). Available 
from: https://oehha.ca.gov/proposition-65/crnr/chemical-listed-effective-december-20-2013-known-state-california-cause-cancer.
29. Guyton, K.Z.; Chiu, W.A.; Bateson, T.F.; Jinot, J.; Scott, C.S.; 
Brown, R.C.; Caldwell, J.C. 2009. A reexamination of the PPAR-alpha 
activation mode of action as a basis for assessing human cancer 
risks of environmental contaminants. Environ Health Perspect. Nov; 
117(11):1664-72.
30. Health Canada. 2015. State of the Science Report: the Phthalate 
Substance Grouping: 1,2-Benzenedicarboxylic acid, diisononyl ester; 
1,2-Benzenedicarboxylic acid, di-C8-10-branched alkyl esters, C9-
rich (DINP). Chemical Abstracts Service Registry Numbers: 28553-12-
0, 68515-48-0. Gatineau (QC): Environment Canada, Health Canada: 
Existing Substances Program.
31. Caldwell, D.J.; Eldridge, S.R.; Lington, A.W.; and McKee, R.H. 
1999. Retrospective evaluation of alpha 2u-globulin accumulation in 
male rat kidneys following high doses of diisononyl phthalate. 
Toxicol. Sci. 51:153-160.
32. USEPA, 1991b. Alpha-2u-globulin: Association with Chemically 
Induced Renal Toxicity and Neoplasia in the Male Rat. Risk 
Assessment Forum. EPA/625/3-91/019F.
33. IARC, 1995. International Agency for Research on Cancer. 
Peroxisome Proliferation and Its Role in Carcinogenesis. Views and 
Opinions of an IARC Working Group. IARC Technical Report No. 24. 
World Health Organization, IARC, Lyon, France.
34. Chronic Hazard Advisory Panel on Diisononyl Phthalate. Report to 
the U.S. Consumer Product Safety Commission. June 2001. U.S. 
Consumer Product Safety Commission, Bethesda, MD.
35. Chronic Hazard Advisory Panel on Diisononyl Phthalate. Report to 
the U.S. Consumer Product Safety Commission. April 2010. U.S. 
Consumer Product Safety Commission, Bethesda, MD.
36. Caldwell, D.J. 1999. Review of mononuclear cell leukemia (MNCL) 
in F-344 rat bioassays and its significance to human cancer risk: A 
case study using alkyl phthalates. Regul. Toxicol. and Pharmacol. 
30:45-53.
37. Biodynamics 1986: Daly, I. (Study Director) 1981-1983. A Chronic 
Toxicity/Carcinogenicity Feeding Study in Rats with Santicizer 900. 
Performing Laboratory: Bio/dynamics, Inc., East Millstone, NJ. 
Laboratory Study Number: 81-2572. Sponsor: Monsanto Company, St. 
Louis, MO.
38. Barber, E.D.; Cifone, M.; Rundell, J.; Przygoda, R.; Astill, 
B.D.; Moran, E.; Mulholland, A.; Robinson, E.; Schneider, B. (2000) 
Results of the L5178Y mouse lymphoma assay and the Balb/3T3 cell in 
vitro transformation assay for eight phthalate esters. J. Appl. 
Toxicol., 20:69-80.
39. Microbiological Associates (1981b) Activity of T1677 in the in 
vitro mammalian cell transformation assay in the absence of 
exogenous metabolic activation. Unpublished laboratory report from 
Microbiological Associates submitted to Tenneco Chemicals Company, 
MA project No. T1677.108.
40. Bility, M.T.; Thompson, J.T.; McKee, R.H.; David, R.M.; Butala, 
J.H.; Vanden Heuvel, J.P.; Peters, J.M. Activation of Mouse and 
Human Peroxisome Proliferator-Activated Receptors (PPARs) by 
Phthalate Monoesters, Toxicological Sciences, Volume 82, Issue 1, 
November 2004, Pages 170-182.
41. Laurenzana, E.M.; Coslo, D.M.; Vigilar, M.V.; Roman, A.M.; 
Omiecinski, C.J. 2016. Activation of the Constitutive Androstane 
Receptor by Monophthalates. Chem. Res. Toxicol. Oct 17; 29(10):1651-
1661. doi: 10.1021/acs.chemrestox.6b00186. Epub 2016 Sep 13. PMID: 
27551952; PMCID: PMC5144158.
42. Wang, Y.C.; Chen, H.S.; Long, C.Y.; Tsai, C.F.; Hsieh, T.H.; 
Hsu, C.Y.; Tsai, E.M. 2012. Possible mechanism of phthalates-induced 
tumorigenesis. Kaohsiung J. Med. Sci. Jul; 28(7 Suppl):S22-27.
43. Bachegowda, L.; Gligich, O.; Mantzaris, I.; Schinke, C.; 
Wyville, D.; Carrillo, T.; Braunschweig, I.; Steidl, U.; Verma, A. 
2013. Signal transduction inhibitors in treatment of myelodysplastic 
syndromes. J Hematol Oncol 6:50.
44. Bennasroune, A.; Rojas, L.; Foucaud, L.; Goulaouic, S.; Laval-
Gilly, P.; Fickova, M.; Couleau, N.; Durandet, C.; Henry, S.; Falla, 
J. 2012. Effects of 4-nonylphenol and/or diisononylphthalate on THP-
1 cells: impact of endocrine disruptors on human immune system 
parameters. Int J Immunopathol Pharmacol 25:365-376.
45. Trosko, J.E.; Chang, C.C.; Madhukar, B.V. 1990. Modulation of 
intercellular communication during radiation and chemical 
carcinogenesis. Radiat Res 123:241-251.
46. Smith, J.H,; Isenberg, J.S.; Pugh Jr, G.; Kamendulis, L.M.; 
Ackley, D.; Lington, A.W.; Klaunig, J.E. 2000. Comparative in vivo 
hepatic effects of di-isononyl phthalate (DINP) and related C7-C11 
dialkyl phthalates on gap junctional intercellular communication 
(GJIC), peroxisomal beta-oxidation (PBOX), and DNA synthesis in rat 
and mouse liver. Toxicol Sci 54:312-321.
47. IARC. 2013. Di(2-ethylhexyl)phthalate. IARC Monographs on the 
evaluation of carcinogenic risks to humans. Volume 101: Some 
chemicals present in industrial and consumer products, food and 
drinking-water. Lyon, France: International Agency for Research on 
Cancer. 149-284. https://publications.iarc.fr/125. April 27, 2017.
48. IARC, 2017. Agents classified by the IARC Monographs, Volumes 1-
118. Lyon, France: International Agency for Research on Cancer.
49. IRIS, 1988. Di(2-ethylhexyl)phthalate (DEHP); CASRN 117-81-7. 
Integrated Risk Information System. Washington, DC: U.S. 
Environmental Protection Agency. https://cfpub.epa.gov/ncea/iris/iris_documents/documents/subst/0014_summary.pdf. April 27, 2017.
50. NTP. 2016. Di(2-ethylhexyl) phthalate. In: Report on 
carcinogens. 14th ed. Research Triangle Park, NC: National 
Toxicology Program, https://ntp.niehs.nih.gov/ntp/roc/content/profiles/diethylhexylphthalate.pdf. August 27, 2020.
51. Office of Environmental Health Hazard Assessment. 2003 https://oehha.ca.gov/proposition-65/chemicals/di2-ethylhexylphthalate-dehp.
52. Hellwig, J.; Freudenberger, H.; and Jackh, R. 1997. Differential 
prenatal toxicity of branched phthalate esters in rats. Food and 
Chem. Toxicol. 35:501-512.
53. Waterman, S.J.; Keller, L.H.; Trimmer, G.W.; Freeman, J.J.; 
Nikiforov, A.I.; Harris, S.B.; Nicolich, M.J.; and McKee, R.H. 2000. 
Two generation reproduction study in rats given di-isononyl 
phthalate in the diet. Reprod. Toxicol. 14(1):21-36.
54. Gray, L.E.; Jr, Ostby, J.; Furr, J.; Price, M.; Rao 
Veeramachaneni, D.N.; and Parks, L. 2000. Perinatal exposure to the

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phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters 
sexual differentiation of the male rat. Toxicol. Sci. 58:350-365.
55. Borch, J.; Ladefoged, O.; Hass, U.; Vingaard, A.M. 2004. 
Steroidogenesis in fetal male rats is reduced by DEHP and DINP, but 
endocrine effects of DEHP are not modulated by DEHA in fetal, 
prepubertal and adult male rats. Reprod. Toxicol. 18:53-61.
56. Clewell, R. 2011. Pharmacokinetics and Fetal Testes Effects 
after Diisononyl Phthalate Administration in Rat Gestation. 
Performing laboratory: The Hamner Institutes for Health Sciences, 
Research Triangle Park, NC. Laboratory Study Number: 09016. Sponsor: 
ExxonMobil Biomedical Sciences, Inc, Annandale, NJ.
57. Clewell, R. 2011. A Dose Response Study of the Effects on Male 
Rat Sexual Development After Administration of Diisononyl Phthalate 
to the Pregnant and Lactating Dam. Performing laboratory: The Hamner 
Institutes for Health Sciences, Research Triangle Park, NC. 
Laboratory Study Number: 10003. Sponsor: ExxonMobil Biochemical 
Sciences Inc., location not reported.
58. Waterman, S.J.; Ambroso, J.L.; Keller, L.H.; Trimmer, G.W.; 
Nikiforov, A.I.; Harris, S.B. 1999. Developmental toxicity of di-
isodecyl and di-isononyl phthalates in rats. Reprod. Toxicol. 
13(2):131-136.
59. Masutomi, N.; Shibutani, M.; Takagi, H.; Uneyama, C.; Takahashi, 
N.; Hirose, M. 2003. Impact of dietary exposure to methoxychlor, 
genistein, or diisononyl phthalate during the perinatal period on 
the development of the rat endocrine/reproductive systems in later 
life. Toxicology 192:149-170.
60. Gray, L.E, Jr; Kavlock, R.J. An extended evaluation of an in 
vivo teratology screen utilizing postnatal growth and viability in 
the mouse. Teratog Carcinog Mutagen. 1984;4(5):403-26. doi: 10.1002/
tcm.1770040504. PMID: 6150557.
61. Hack, M.; Klein, N.K.; Taylor, H.G. 1995. Long-Term 
Developmental Outcomes of Low Birth Weight Infants. The Future of 
Children, vol. 5, no. 1, 1995, pp. 176-96.
62. National Toxicology Program Center for the Evaluation of Risks 
to Human Reproduction Expert Panel Report on Diisononyl Phthalate. 
Center for the Evaluation of Risks to Human Reproduction. October, 
2000.
63. Parks, L.G.; Ostby, J.S., Lambright; C.R.; Abbott; B.D.; 
Klinefelter; G.R.; Barlow, N.J.; Gray, L.E. Jr. 2000. The 
plasticizer diethylhexyl phthalate induces malformations by 
decreasing fetal testosterone synthesis during sexual 
differentiation in the male rat. Toxicol. Sci. 58:339-349.
64. Thompson, C.J.; Ross, S.M.; Gaido, K.W. 2004. Di(n-Butyl) 
phthalate impairs cholesterol transport and steroidogenesis in the 
fetal rat testis through a rapid and reversible mechanism. 
Endocrinol. 145(3):1227-1237.
65. Wilson, V.S.; Lambright, C.; Furr, J.; Ostby, J.; Wood, C.; 
Held, G.; Gray, L.E. 2004. Phthalate ester-induced gubernacular 
lesions are associated with reduced insl3 gene expression in the 
fetal rat testis. Toxicol. Lett. 146(3):207-215.
66. The British Industrial Biological Research Association. 1986. 21 
day Feeding Study of Diisononyl Phthalate to Rats: Effects on the 
Liver and Liver Lipids, Fiche No. OTS0509544. TSCATS Doc# 40-
8626208A.
67. Experimental Pathology Laboratories. 1999. Histopathlogy peer 
review and pathology working group review of selected lesions of the 
liver and spleen in male and female F344 rats exposed to 
di(isononyl)phthalate. EPL Project number 303-013, Pathology Report.
68. Karbe, E. and Kerlin, R.L. 2002. Cystic degeneration/spongiosis 
hepatis in rats. Toxicol. Pathol. 30:216-227.

VI. Statutory and Executive Order Reviews

    Additional information about these statutes and Executive Orders 
can be found at https://www.epa.gov/laws-regulations/laws-and-executive-orders.

A. Executive Order 12866: Regulatory Planning and Review and Executive 
Order 13563: Improving Regulation and Regulatory Review

    This action is not a significant regulatory action and was 
therefore not submitted to the Office of Management and Budget (OMB) 
for review under Executive Orders 12866 (58 FR 51735, October 4, 1993) 
and 13563 (76 FR 3821, January 21, 2011).

B. Paperwork Reduction Act (PRA)

    This action does not impose any new information collection burden 
under the PRA, 44 U.S.C. 3501 et seq. Burden is defined in 5 CFR 
1320.3(b). OMB has previously approved the information collection 
activities contained in the existing regulations and has assigned OMB 
control numbers 2070-0212 and 2050-0078. Currently, the facilities 
subject to the reporting requirements under EPCRA section 313 and PPA 
section 6607 may use either EPA Toxic Chemicals Release Inventory Form 
R (EPA Form 9350-1), or EPA Toxic Chemicals Release Inventory Form A 
(EPA Form 9350-2). The Form R must be completed if a facility 
manufactures, processes, or otherwise uses any listed chemical above 
threshold quantities and meets certain other criteria. For the Form A, 
EPA established an alternative threshold for facilities with low annual 
reportable amounts of a listed toxic chemical. A facility that meets 
the appropriate reporting thresholds, but estimates that the total 
annual reportable amount of the chemical does not exceed 500 pounds per 
year, can take advantage of an alternative manufacture, process, or 
otherwise use threshold of 1 million pounds per year of the chemical, 
provided that certain conditions are met, and submit the Form A instead 
of the Form R. In addition, respondents may designate the specific 
chemical identity of a substance as a trade secret pursuant to EPCRA 
section 322, 42 U.S.C. 11042, 40 CFR part 350.
    OMB has approved the reporting and recordkeeping requirements 
related to Forms A and R, supplier notification, and petitions under 
OMB Control number 2070-0212 (EPA Information Collection Request (ICR) 
No. 2613.02) and those related to trade secret designations under OMB 
Control 2050-0078 (EPA ICR No. 1428). As provided in 5 CFR 1320.5(b) 
and 1320.6(a), an Agency may not conduct or sponsor, and a person is 
not required to respond to, a collection of information unless it 
displays a currently valid OMB control number. The OMB control numbers 
relevant to EPA's regulations are listed in 40 CFR part 9 and displayed 
on the information collection instruments (e.g., forms, instructions).

C. Regulatory Flexibility Act (RFA)

    I certify that this action will not have a significant economic 
impact on a substantial number of small entities under the RFA, 5 
U.S.C. 601 et seq. The small entities subject to the requirements of 
this action are small manufacturing facilities. The Agency has 
determined that of the 198 to 396 entities estimated to be impacted by 
this action, 181 to 362 are small businesses; no small governments or 
small organizations are expected to be affected by this action. All 
small businesses affected by this action are estimated to incur 
annualized cost impacts of less than 1%. Thus, this action is not 
expected to have a significant adverse economic impact on a substantial 
number of small entities. A more detailed analysis of the impacts on 
small entities is located in EPA's economic analysis (Ref. 1).

D. Unfunded Mandates Reform Act (UMRA)

    This action does not contain an unfunded mandate of $100 million or 
more as described in UMRA, 2 U.S.C. 1531-1538, and does not 
significantly or uniquely affect small governments. This action is not 
subject to the requirements of UMRA because it contains no regulatory 
requirements that might significantly or uniquely affect small 
governments. EPA did not identify any small governments that would be 
impacted by this action. EPA's economic analysis indicates that the 
total industry cost of this action is

[[Page 48140]]

estimated to be $920,938 to $1,839,925 in the first year of reporting 
and $438,542 to $876,155 in subsequent years (Ref. 1).

E. Executive Order 13132: Federalism

    This action does not have federalism implications as specified in 
Executive Order 13132 (64 FR 43255, August 10, 1999). It will not have 
substantial direct effects on the States, on the relationship between 
the national government and the States, or on the distribution of power 
and responsibilities among the various levels of government.

F. Executive Order 13175: Consultation and Coordination With Indian 
Tribal Governments

    This action does not have tribal implications as specified in 
Executive Order 13175 (65 FR 67249, November 9, 2000). This action 
relates to toxic chemical reporting under EPCRA section 313, which 
primarily affects private sector facilities. Thus, Executive Order 
13175 does not apply to this action.

G. Executive Order 13045: Protection of Children From Environmental 
Health Risks and Safety Risks

    EPA interprets Executive Order 13045 (62 FR 19885, April 23, 1997) 
as applying only to those regulatory actions that concern environmental 
health or safety risks that EPA has reason to believe may 
disproportionately affect children, per the definition of ``covered 
regulatory action'' in section 2-202 of the Executive Order. This 
action is not subject to Executive Order 13045 because it does not 
concern an environmental health risk or safety risk.

H. Executive Order 13211: Actions Concerning Regulations That 
Significantly Affect Energy Supply, Distribution, or Use

    This action is not subject to Executive Order 13211, because it is 
not a significant regulatory action under Executive Order 12866.

I. National Technology Transfer and Advancement Act (NTTAA)

    This rulemaking does not involve technical standards. As such, 
NTTAA section 12(d), 15 U.S.C. 272 note, does not apply to this action.

J. Executive Order 12898: Federal Actions To Address Environmental 
Justice in Minority Populations and Low-Income Populations

    Executive Order 12898 (59 FR 7629, February 16, 1994) directs 
federal agencies, to the greatest extent practicable and permitted by 
law, to make environmental justice part of their mission by identifying 
and addressing, as appropriate, disproportionately high and adverse 
human health or environmental effects of their programs, policies, and 
activities on minority populations (people of color) and low-income 
populations. The EPA believes that this type of action does not 
directly concern human health or environmental conditions and therefore 
cannot be evaluated with respect to potentially disproportionate and 
adverse effects on people of color, low-income populations and/or 
indigenous peoples. This regulatory action adds an additional chemical 
category to the EPCRA section 313 reporting requirements; it does not 
have any impact on human health or the environment. This action does 
not address any human health or environmental risks and does not affect 
the level of protection provided to human health or the environment. 
This action adds an additional chemical category to the EPCRA section 
313 reporting requirements which provides information that government 
agencies and others can use to identify potential problems, set 
priorities, and help inform activities.

List of Subjects in 40 CFR Part 372

    Environmental protection, Community right-to-know, Reporting and 
recordkeeping requirements, and Toxic chemicals.

    Dated: August 2, 2022.
Michal Freedhoff,
Assistant Administrator, Office of Chemical Safety and Pollution 
Prevention.

    Therefore, for the reasons set forth in the preamble, EPA proposes 
that 40 CFR chapter I be amended as follows:

PART 372--TOXIC CHEMICAL RELEASE REPORTING: COMMUNITY RIGHT-TO-KNOW

0
1. The authority citation for part 372 continues to read as follows:

    Authority:  42 U.S.C. 11023 and 11048.

0
2. In Sec.  372.65, adding in alphabetical order an entry to Table 3 in 
paragraph (c) for ``Diisononyl Phthalates (DINP)'' to read as follows:


Sec.  372.65   Chemicals and chemical categories to which this part 
applies.

* * * * *
    (c) * * *

                        Table 3 to Paragraph (c)
------------------------------------------------------------------------
                      Category name                       Effective date
------------------------------------------------------------------------
 
                              * * * * * * *
Diisononyl Phthalates (DINP): Includes branched alkyl di-       1/1/2024
 esters of 1,2 benzenedicarboxylic acid in which alkyl
 ester moieties contain a total of nine carbons. (This
 category includes but is not limited to the chemicals
 covered by the CAS numbers and names listed here)......
    28553-12-0 Diisononyl phthalate.
    71549-78-5 Branched dinonyl phthalate.
    14103-61-8 Bis(3,5,5-trimethylhexyl) phthalate.
    68515-48-0 Di(C8-10, C9 rich) branched alkyl
     phthalates.
 
                              * * * * * * *
------------------------------------------------------------------------

* * * * *
[FR Doc. 2022-16908 Filed 8-5-22; 8:45 am]
BILLING CODE 6560-50-P


