TSCA Section 5(a)(3) Determination for Premanufacture Notice (PMN) P-18-0391

Number: P-18-0391

TSCA Section 5(a)(3) Determination: The chemical substance is not likely to present an
unreasonable risk (5(a)(3)(C))

Chemical Name:

Specific: 1-Propanaminium, N-(carboxymethyl)-N, N-dimethyl-3-[(3,5, 5-trimethyl-l-oxohexyl),
amino]- inner salt

Conditions of Use (intended, known, or reasonably foreseen)1:

Intended conditions of use (specific): Manufacture and process for use and use as a liquid

laundry detergent, consistent with the manufacturing, processing, use, distribution, and
disposal information described in the PMN.

Known conditions of use: Applying such factors as described in footnote 1, EPA evaluated

whether there are known conditions of use and found none.

Reasonably foreseen conditions of use: Applying such factors as described in footnote 1, EPA
has identified, based on information in another TSCA submission, that it is reasonably
foreseen that the chemical could be used such that there could be inhalation exposures.

Summary: The chemical substance is not likely to present an unreasonable risk of injury to
health or the environment, without consideration of costs or other nonrisk factors, including an
unreasonable risk to a potentially exposed or susceptible subpopulation identified as relevant by
the Administrator under the conditions of use, based on the risk assessment presented below and
the terms of the proposed Significant New Use Rule (SNUR) signed by EPA. Although EPA

1	Under TSCA § 3(4), the term "conditions of use" means "the circumstances, as determined by the Administrator,
under which a chemical substance is intended, known, or reasonably foreseen to be manufactured, processed,
distributed in commerce, used, or disposed of." In general, EPA considers the intended conditions of use of a new
chemical substance to be those identified in the section 5(a) notification. Known conditions of use include activities
within the United States that result from manufacture that is exempt from PMN submission requirements.

Reasonably foreseen conditions of use are future circumstances, distinct from known or intended conditions of use,
under which the Administrator expects the chemical substance to be manufactured, processed, distributed, used, or
disposed of. The identification of "reasonably foreseen" conditions of use will necessarily be a case-by-case
determination and will be highly fact-specific. Reasonably foreseen conditions of use will not be based on
hypothetical or conjecture. EPA's identification of conditions of use includes the expectation of compliance with
federal and state laws, such as worker protection standards or disposal restrictions, unless case-specific facts indicate
otherwise. Accordingly, EPA will apply its professional judgment, experience, and discretion when considering such
factors as evidence of current use of the new chemical substance outside the United States, evidence that the PMN
substance is sufficiently likely to be used for the same purposes as existing chemical substances that are structurally
analogous to the new chemical substance, and conditions of use identified in an initial PMN submission that the
submitter omits in a revised PMN. The sources EPA uses to identify reasonably foreseen conditions of use include
searches of internal confidential EPA PMN databases (containing use information on analogue chemicals), other
U.S. government public sources, the National Library of Medicine's Hazardous Substances Data Bank (HSDB), the
Chemical Abstract Service STN Platform, REACH Dossiers, technical encyclopedias (e.g., Kirk-Othmer and
Ullmann), and Internet searches.

2	Reasonably foreseen conditions of use subject to a proposed SNUR are not likely to present an unreasonable risk
of injury to health or the environment. Based on EPA's experience, it is the Agency's judgment that a new use
would not commence during the pendency of a proposed SNUR because web posting of a proposed SNUR serves as
the cut-off date for a significant new use. Therefore, manufacturers and processors would not commence a
prohibited new use that would be legally required to cease upon the finalization of the SNUR. Once a SNUR is final
and effective, no manufacturer or processor - including the PMN submitter - may undertake the conditions of use

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TSCA Section 5(a)(3) Determination for Premanufacture Notice (PMN) P-18-0391

estimated that the new chemical substance could be very persistent, the substance has a low
potential for bioaccumulation, such that repeated exposures are not expected to cause food-chain
effects via accumulation in exposed organisms. Based on test data submitted on the new
chemical substance and analogue data, EPA estimates that the chemical substance has low
environmental hazard and potential for the following human health hazards: lung effects (lung
surfactancy), systemic (maternal) and developmental effects, and irritation to skin and eyes. The
PMN describes conditions of use that mitigate the human health risks. Therefore, EPA concludes
that the new chemical is not likely to present unreasonable risk to human health or the
environment under the intended conditions of use.

As set forth below, the information available to EPA is sufficient to permit the Agency to
conduct a reasoned evaluation of the health and environmental effects of the chemical substance
under the conditions of use that are not subject to the proposed SNUR, in order to determine that
the chemical substance is not likely to present an unreasonable risk under those conditions of
use. As such, EPA does not need to impose testing requirements to conduct this evaluation.
Whether testing is needed to evaluate the effects of the intended, known, or reasonably foreseen
conditions of use of a chemical substance subject to a PMN is determined on a case-by-case
basis. To the extent that testing may be necessary to conduct a reasoned evaluation of the health
or environmental effects of the reasonably foreseen conditions of use that are subject to the
proposed SNUR, EPA will make the appropriate determination if a SNUN is submitted
following finalization of the SNUR.

EPA found no known conditions of use, assessed the intended conditions of use, and addressed
reasonably foreseen conditions of use by proposing a SNUR. Therefore, EPA determines the
new chemical substance is not likely to present unreasonable risk to human health or the
environment.

Fate: Environmental fate is the determination of which environmental compartment(s) a
chemical moves to, the expected residence time in the environmental compartment(s) and
removal and degradation processes. Environmental fate is an important factor in determining
exposure and thus in determining whether a chemical may present an unreasonable risk. EPA
estimated physical/chemical and fate properties of the new chemical substance using data
submitted for the new chemical substance and EPI (Estimation Program Interface) Suite™
(http://www.epa.gov/tsca-screening-tools/epi-suitetm-estimation-program-interface). In
wastewater treatment, the new chemical substance is expected to be removed with an efficiency
of 0% due to low biodegradability, low sorption, and low stripping. Removal of the new
chemical substance by biodegradation is negligible. Sorption of the new chemical substance to
sludge, soil, and sediment is expected to be low. Migration of the new chemical substance to

identified as a significant new use of the PMN substance in the SNUR. EPA must first evaluate the new use in
accordance with the requirements of TSCA Section 5 and (a) either conclude that the new use is not likely to present
an unreasonable risk under the conditions of use; or (b) take appropriate action under section 5(e) or 5(f). If EPA
were not to finalize the proposed SNUR, then that decision would be based on information and data provided to the
Agency during the comment period demonstrating that the reasonably foreseen conditions of use subject to the
proposed SNUR are not likely to present an unreasonable risk. Under either scenario, the reasonably foreseen
condition of use is not likely present an unreasonable risk.

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TSCA Section 5(a)(3) Determination for Premanufacture Notice (PMN) P-18-0391

groundwater is expected to be rapid due to low sorption to soil and sediment. Due to low
estimated vapor pressure and Henry's law constant, the new chemical substance is expected to
undergo negligible volatilization to air. Overall, these estimates indicate that the new chemical
substance has low potential to volatilize to air and has high potential to migrate to groundwater.

•j

Persistence : Persistence is relevant to whether a new chemical substance is likely to present an
unreasonable risk because chemicals that are not degraded in the environment at rates that
prevent substantial buildup in the environment, and thus increase potential for exposure, may
present a risk if the substance presents a hazard to human health or the environment. EPA
estimated degradation half-lives of the new chemical substance using data submitted for the new
chemical substance. EPA estimated that the new chemical substance's aerobic and anaerobic
biodegradation half-lives are > 6 months. These estimates indicate that the new chemical
substance may be very persistent in aerobic environments (e.g., surface water) and anaerobic
environments (e.g., sediment).

Bioaccumulation4: Bioaccumulation is relevant to whether a new chemical substance is likely
to present an unreasonable risk because substances that bioaccumulate in aquatic and/or
terrestrial species pose the potential for elevated exposures to humans and other organisms via
food chains. EPA estimated the potential for the new chemical substance to bioaccumulate using
EPI Suite™. EPA estimated that the new chemical substance has low bioaccumulation potential
based on BCFBAF model result < 1000 (bioconcentration factor = 3 (estimated) and
bioaccumulation factor = 1 (estimated)). Although EPA estimated that the new chemical
substance could be very persistent, the substance has a low potential for bioaccumulation, such
that repeated exposures are not expected to cause food-chain effects via accumulation in exposed
organisms.

Human Health Hazard5: Human health hazard is relevant to whether a new chemical substance

3	Persistence: A chemical substance is considered to have limited persistence if it has a half-life in water, soil or
sediment of less than 2 months or there are equivalent or analogous data. A chemical substance is considered to be
persistent if it has a half-life in water, soil or sediments of greater than 2 months but less than or equal to 6 months
or if there are equivalent or analogous data. A chemical substance is considered to be very persistent if it has a half-
life in water, soil or sediments of greater than 6 months or there are equivalent or analogous data. (64 FR 60194;
November 4, 1999)

4	Bioaccumulation: A chemical substance is considered to have a low potential for bioaccumulation if there are
bioconcentration factors (BCF) or bioaccumulation factors (BAF) of less than 1,000 or there are equivalent or
analogous data. A chemical substance is considered to be bioaccumulative if there are BCFs or BAFs of 1,000 or
greater and less than or equal to 5,000 or there are equivalent or analogous data. A chemical substance is considered
to be very bioaccumulative if there are BCFs or BAFs of 5,000 or greater or there are equivalent or analogous data.
(64 FR 60194; November 4 1999)

5	A chemical substance is considered to have low human health hazard if effects are observed in animal studies with
a No Observed Adverse Effect Level (NOAEL) equal to or greater than 1,000 mg/kg/day or if there are equivalent
data on analogous chemical substances; a chemical substance is considered to have moderate human health hazard if
effects are observed in animal studies with a NOAEL less than 1,000 mg/kg/day or if there are equivalent data on
analogous chemical substances; a chemical substance is considered to have high human health hazard if there is
evidence of adverse effects in humans or conclusive evidence of severe effects in animal studies with a NOAEL of
less than or equal to 10 mg/kg/day or if there are equivalent data on analogous chemical substances. EPA may also
use Benchmark Dose Levels (BMDL) derived from benchmark dose (BMD) modeling as points of departure for
toxic effects. See https://www.epa.gov/bmds/what-benchmark-dose-software-bmds. Using this approach, a BMDL

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TSCA Section 5(a)(3) Determination for Premanufacture Notice (PMN) P-18-0391

is likely to present an unreasonable risk because the significance of the risk is dependent upon
both the hazard (or toxicity) of the chemical substance and the extent of exposure to the
substance. EPA estimated the human health hazard of this chemical substance based on its
estimated physical/chemical properties and by comparing it to structurally analogous chemical
substances for which there is information on human health hazard. Absorption of the new
chemical substance is expected to be poor through the skin, moderate through the gastrointestinal
(GI) tract, and good through the lung based on physical/chemical properties and analogue test
data. EPA identified lung effects (lung surfactancy) based on potential interference with natural
lung surfactants and systemic (maternal) and developmental effects, based on structure
(quaternary amine) and analogue data. Data submitted on the new chemical substance indicate it
is not irritating to the skin (OECD 439) or eyes (OECD 492) in vitro; however, these studies
were performed with the test substance at concentration approximately three times lower than
recommended in the test guidelines. Therefore, EPA based its hazard conclusions for skin and
eye irritation on in-vivo data for an analogue. EPA quantitatively assessed the new chemical
substance using analogue data and identified a no-observed-adverse-effect-level (NOAEL) of
330 mg/kg-bw/day (95 mg active substance/kg-bw/day) based on systemic (maternal) toxicity
and developmental effects in an oral prenatal developmental toxicity study in rats (OECD 414),
which were used to derive exposure route- and population-specific points of departure (POD) for
quantitative risk assessment, described below. EPA qualitatively evaluated dermal irritation
hazards.

Environmental Hazard6: Environmental hazard is relevant to whether a new chemical
substance is likely to present unreasonable risk because the significance of the risk is dependent
upon both the hazard (or toxicity) of the chemical substance and the extent of exposure to the
substance. EPA determined environmental hazard for this new chemical substance based on
acute toxicity data submitted for the new chemical substance. Acute toxicity values measured for
fish, aquatic invertebrates, and algae are > 983 mg/L, 384 mg/L, and 159 mg/L, respectively.
Chronic toxicity values measured for fish, aquatic invertebrates, and algae are > 98.3 mg/L (test
data with an acute-to-chronic ratio (ACR) of 10), 38.4 mg/L (test data with an ACR of 10), and

is associated with a benchmark response, for example a 5 or 10 % incidence of effect. The aforementioned
characterizations of hazard (low, medium, high) would also apply to BMDLs. In the absence of animal data on a
chemical or analogous chemical substance, EPA may use other data or information such as from in vitro assays,
chemical categories (e.g., Organization for Economic Co-operation and Development, 2014 Guidance on Grouping
of Chemicals, Second Edition. ENV/JM/MONO(2014)4. Series on Testing & Assessment No. 194. Environment
Directorate, Organization for Economic Co-operation and Development, Paris, France.

(http://www.oecd.org/officialdocuments/publicdisplavdocumentpdf/?cote=env/im/mono(2014)4&doclanguage=en)).
structure-activity relationships, and/or structural alerts to support characterizing human health hazards.

6 A chemical substance is considered to have low ecotoxicity hazard if the Fish, Daphnid and Algae LC50 values are
greater than 100 mg/L, or if the Fish and Daphnid chronic values (ChVs) are greater than 10.0 mg/L, or there are not
effects at saturation (occurs when water solubility of a chemical substance is lower than an effect concentration), or
the log Kow value exceeds QSAR cut-offs. A chemical substance is considered to have moderate ecotoxicity hazard
if the lowest of the Fish, Daphnid or Algae LC50s is greater than 1 mg/L and less than 100 mg/L, or where the Fish
or Daphnid ChVs are greater than 0.1 mg/L and less than 10.0 mg/L. A chemical substance is considered to have
high ecotoxicity hazard, or if either the Fish, Daphnid or Algae LC50s are less than 1 mg/L, or any Fish or Daphnid
ChVs is less than 0.1 mg/L (Sustainable Futures https://www.epa.gov/sustainable-futures/sustainable-futures-p2-
framework-manual).

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TSCA Section 5(a)(3) Determination for Premanufacture Notice (PMN) P-18-0391

41.7 mg/L for fish, aquatic invertebrates, and algae, respectively. These toxicity values indicate
that the new chemical substance is expected to have low environmental hazard. Application of
assessment factors of 4 and 10 to acute and chronic toxicity values results in an estimated acute
concentration of concern (COC) of 39.75 mg/L (39,750 ppb) and a chronic COC of 3.84 mg/L
(3,840 ppb).

Exposure: The exposure to a new chemical substance is potentially relevant to whether a new
chemical substance is likely to present unreasonable risks because the significance of the risk is
dependent upon both the hazard (or toxicity) of the chemical substance and the extent of
exposure to the substance.

EPA estimates occupational exposure and environmental release of the new chemical substance
under the intended conditions of use described in the PMN using ChemSTEER (Chemical
Screening Tool for Exposures and Environmental Releases; https://www.epa.gov/tsca-screening-
tools/chemsteer-chemical-screening-tool-exposures-and-environmental-releases). EPA uses
EFAST (the Exposure and Fate Assessment Screening Tool; https://www.epa.gov/tsca-
screening-tools/e-fast-exposure-and-fate-assessment-screening-tool-version-2014) to estimate
general population, consumer, and environmental exposures.

EPA considers workers to be a potentially exposed or susceptible subpopulation (PESS) on the
basis of greater exposure potential compared to the general population. EPA also considers PESS
in conducting general population drinking water exposures by evaluating risks associated with
water intake rates for multiple age groups, ranging from infants to adults. EPA considers
consumers of specific products to be a potentially exposed or susceptible subpopulation on the
basis of greater exposure potential compared to the general population who do not use specific
products.

For this new chemical assessment, EPA assessed worker exposure via dermal contact; inhalation
exposures to workers are expected to be negligible. Releases to air, water, and landfill were
estimated. Exposure to the general population was assessed via ingestion of drinking water, fish,
and groundwater impacted by landfill leachate. Exposures were not assessed for the general
population via inhalation because releases to air were expected to be negligible (below modeling
thresholds). Consumer exposures were assessed via dermal contact for general purpose cleaner
and laundry detergent scenarios.

Risk Characterization: EPA applies a margin of exposure approach to calculate potential
human health risks of new chemicals. A benchmark (acceptable) margin of exposure is derived
by applying uncertainty factors for the following types of extrapolations: intra-species
extrapolation (UFh = 10 to account for variation in sensitivity among the human population),
inter-species extrapolation (UFA = 10 to account for extrapolating from experimental animals to
humans) and LOAEL-to-NOAEL extrapolation (UFl = 10 to account for using a LOAEL when
a NOAEL is not available). Hence, in the New Chemicals Program, a benchmark MOE is
typically 100 and 1,000 when NOAELs and LOAELs, respectively, are used to identify hazard.
When allometric scaling or pharmacokinetic modeling is used to derive an effect level, the UFH
may be reduced to 3, for a benchmark MOE of 30. The benchmark MOE is used to compare to
the MOE calculated by comparing the toxicity NOAEL or LOAEL to the estimated exposure

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concentrations. When the calculated MOE is equal to or exceeds the benchmark MOE, the new
chemical substance is not likely to present an unreasonable risk. EPA assesses risks to workers
considering engineering controls described in the PMN but in the absence of personal protective
equipment (PPE) such as gloves and respirators. If risks are preliminarily identified, EPA then
considers whether the risks would be mitigated by the use of PPE (e.g., impervious gloves,
respirator).

Risks to human health for the new chemical substance were evaluated using the points of
departure (i.e., NOAEL) described above. Risks were identified for workers for systemic and
developmental toxicity via dermal exposure based on quantitative hazard data for an analogue
(MOE = 85; Benchmark MOE = 100). Risks were not evaluated for workers via inhalation
because inhalation exposures are expected to be negligible. Irritation hazard to workers via
dermal contact was identified based on structural alerts, analogue data, and the submitter's
Safety Data Sheet (SDS). Risk for this endpoint was not quantified due to a lack of dose-
response for this hazard. However, exposures can be mitigated by the use of appropriate personal
protective equipment (PPE), including impervious gloves and eye protection. EPA expects that
employers will require and workers will use appropriate PPE consistent with the SDS prepared
by the new chemical submitter, in a manner adequate to protect them.

Risks were not identified for the general population for systemic and developmental toxicity via
ingestion of drinking water, fish, and groundwater based on quantitative hazard data for an
analogue (MOEAdultDW — 16,340, MOE[n|an||)\v — 3,890, MOE] Ingestion — 529,543, M O E (;r( mud water
= 2,192,982; Benchmark MOE = 100). Risks were not identified for the general population via
inhalation of stack/fugitive air because exposures are expected to be negligible (below modeling
thresholds). Irritation hazards to the general population are not expected via drinking water, fish
ingestion, and ground water due to dilution of the chemical substance in the media.

Risks were not identified for consumers for systemic and developmental toxicity and via dermal
contact for use as a general purpose cleaner based on quantitative hazard data for an analogue
(MOE = 1,857; Benchmark MOE = 100). Risks were not identified for consumers for systemic
and developmental toxicity via dermal contact for use as a liquid laundry detergent based on
quantitative hazard data for an analogue (MOE = 5,919; Benchmark MOE = 100). Risks were
not evaluated for consumers via inhalation because exposure is expected to be negligible.
Irritation hazards to consumers are not expected when using as general purposes cleaner or liquid
laundry detergent due to dilution of the chemical substance in the media.

Risks to the environment were evaluated by comparing estimated surface water concentrations
with the estimated acute and chronic COCs. Risk to the environment were not identified based
on low hazard.

It is reasonably foreseen, based on information in another TSCA submission, that the new
chemical substance could be used for other uses, including as a hard surface cleaner, such that
there could be inhalation exposures. The SNUR that has been proposed for this chemical
substance defines certain conditions of use as significant new uses. The proposed significant new
uses include manufacturing, processing, or use of the substance for any use that results in
inhalation exposures. Conditions of use that fall under the restrictions of the proposed SNUR are
not likely to present unreasonable risk of injury to health or the environment because (1) those

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conditions of use are not likely to be commenced during the pendency of the proposed SNUR,
and (2) upon finalization of the SNUR, those conditions of use would be prohibited unless and
until EPA makes an affirmative determination that the significant new use is not likely to present
an unreasonable risk or takes appropriate action under section 5(e) or 5(f).

2/28/2020		/s/

Date:	Tala R. Henry, Ph.D.

Deputy Director for Programs

Office of Pollution Prevention and Toxics

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