[Federal Register Volume 87, Number 151 (Monday, August 8, 2022)]
[Proposed Rules]
[Pages 48128-48140]
[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:<PHONE_NUMBER>; 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<PHONE_NUMBER> 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

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-

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

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

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.

    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

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

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.

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

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#<PHONE_NUMBER>8. 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#<PHONE_NUMBER>6. 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.

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

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

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