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Dossier for Candidate Low-Priority Substance Propanedioic
acid, 1,3-diethyl ester
(CASRN 105-53-3)
(Diethyl Malonate)
For Release at Proposal
August 9, 2019
Office of Pollution Prevention and Toxics
U.S. Environmental Protection Agency
1200 Pennsylvania Avenue
Washington, DC 20460
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Contents
1. Introduction 1
2. Background on Diethyl Malonate 3
3. Physical-Chemical Properties 4
3.1 References 6
4. Relevant Assessment History 8
5. Conditions of Use 9
6. Hazard Characterization 13
6.1 Human Health Hazard 16
6.1.1 Absorption, Distribution, Metabolism, and Excretion 17
6.1.2 Acute Toxicity 18
6.1.3 Repeated Dose Toxicity 19
6.1.4 Reproductive and Developmental Toxicity 19
6.1.5 Genotoxicity 20
6.1.6 Carcinogenicity 20
6.1.7 Neurotoxicity 20
6.1.8 Skin Sensitization 21
6.1.9 Skin Irritation 21
6.1.10 Eye Irritation 21
6.1.11 Hazards to Potentially Exposed or Susceptible Subpopulations 22
6.2 Environmental Hazard 22
6.2.1 Acute Aquatic Toxicity 22
6.2.2 Chronic Aquatic Toxicity 22
6.3 Persistence and Bioaccumulation Potential 23
6.3.1 Persistence 23
6.3.2 Bioaccumulation Potential 23
7. Exposure Characterization 24
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7.1 Production Volume Information 24
7.2 Exposures to the Environment 24
7.3 Exposures to the General Population 25
7.4 Exposures to Potentially Exposed or Susceptible Subpopulations 25
7.4.1 Exposures to Workers 25
7.4.2 Exposures to Consumers 26
8. Summary of Findings 27
8.1 Hazard and Exposure Potential of the Chemical Substance 27
8.2 Persistence and Bioaccumulation 28
8.3 Potentially Exposed or Susceptible Subpopulations 28
8.4 Storage near Significant Sources of Drinking Water 29
8.5 Conditions of Use or Significant Changes in Conditions of Use of the Chemical Substance 30
8.6 The Volume or Significant Changes in Volume of the Chemical Substance Manufactured or Processed.... 31
8.7 Other Considerations 31
9. Proposed Designation 32
Appendix A: Conditions of Use Characterization I
A.1 CDR Manufacturers and Production Volume I
A.2. Uses II
A.2.1 Methods for Uses II
A.2.2 Uses of Diethyl Malonate IV
A.3 References XI
Appendix B: Hazard Characterization XIV
B.1 References: XXVI
Appendix C: Literature Search Outcomes XXIX
C.1 Literature Search and Review XXIX
C.1.1 Search for Analog Data XXIX
C.1.2 Search Terms and Results XXX
C.2 Excluded Studies and Rationale XXXVIII
C.2.1 Human Health Hazard Excluded References XXXVIII
C.2.2 Environmental Hazard XLIV
C.2.3 Fate XLVII
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Tables
Table 1: Diethyl Malonate at a Glance 3
Table 2: Physical-Chemical Properties for Diethyl Malonate 4
Table 3: Conditions of Use for Diethyl Malonate 11
Table 4: Low-Concern Criteria for Human Health and Environmental Fate and Effects 13
Table 5: Diethyl Malonate and Analog Structures 17
Table A.1:1986-2015 National Production Volume Data for Diethyl Malonate (Non-Confidential Production ^
Volume in Pounds)
Table A.2: Sources Searched for Uses of Diethyl Malonate II
Table A3: Uses of Diethyl Malonate IV
Table B.1: Human Health Hazard XIV
Table B.2: Environmental Hazard XXIII
Table B.3: Fate XXIV
Table C.1: Sources Used for Analog Search XXX
Table C.2: Search Terms Used in Peer-Reviewed Databases XXX
Table C.3: Search Terms Used in Grey Literature and Additional Sources XXXVII
Table C.4: Off-Topic References Excluded at Title/Abstract Screening for Human Health Hazard XXXVIII
Table C.5: Screening Questions and Off-Topic References Excluded at Full Text Screening for Human
Health Hazard
Table C.6: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for ^
Human Health Hazard - Animal
Table C.7: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for
Human Health Hazard - In Vitro
Table C.8: Off-Topic References Excluded at Title/Abstract Screening for Environmental Hazard XLIV
Table C.9: Screening Questions and Off-Topic References Excluded at Full Text Screening for
Environmental Hazard XLV
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Table C.10: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for
Environmental Hazard XLVI
Table C.11: Off-Topic References Excluded at Initial Screening for Fate XLVII
Table C.12: Screening Questions and Off-Topic References Excluded at Full Text Screening for Fate XLVI 11
Table C.13: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for
_ XLVI 11
Fate
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1. Introduction
In the Lautenberg amendments to the Toxic Substances Control Act (TSCA) (section 6(b)(1)(B)) and
implementing regulations (40 CFR 702.3), a low-priority substance is described as a chemical
substance that the Administrator concludes does not meet the statutory criteria for designation as a
high-priority substance, based on information sufficient to establish that conclusion, without
consideration of costs or other non-risk factors. A high-priority substance is defined as a chemical
substance that the Administrator concludes, without consideration of costs or other non-risk factors,
may present an unreasonable risk of injury to health or the environment because of a potential hazard
and a potential route of exposure under the conditions of use, including an unreasonable risk to
potentially exposed or susceptible subpopulations identified as relevant by the Administrator.
Propanedioic acid, 1,3-diethyl ester, referenced as diethyl malonate for the remainder of this
document, is one of the 40 chemical substances initiated for prioritization as referenced in a March
21, 2019 notice (84 FR 10491).1
Before determining low or high prioritization status, under EPA's regulations at 40 CFR 702.92 and
pursuant to section 6(b)(1)(A) of the statute, EPA will generally use reasonably available
information to screen the candidate chemical substance under its conditions of use against the
following criteria and considerations:
the hazard and exposure potential of the chemical substance;
persistence and bioaccumulation;
potentially exposed or susceptible subpopulations;
storage near significant sources of drinking water;
conditions of use or significant changes in the conditions of use of the chemical substance;
the chemical substance's production volume or significant changes in production volume; and
other risk-based criteria that EPA determines to be relevant to the designation of the chemical
substance's priority.
Designation of a low-priority substance indicates that the chemical does not meet the statutory criteria
for a high-priority substance and that a risk evaluation is not warranted at the time.
This risk-based, screening-level review is organized as follows:
Section 1 (Introduction): This section explains the requirements of the Lautenberg
amendments to the Toxic Substances Control Act (TSCA) and implementing regulations -
including the criteria and considerations ~ pertinent to prioritization and designation of low-
priority substances.
Section 2 (Background on the Proposed Low-Priority Substance): This section includes
information on attributes of the chemical substance, including its structure, and relates them
to its functionality.
1 https://www.federalregister.gov/documents/2019/03/21/2019-05404/imtiation-of-prioritization-under-tlie-toxic-substances-
control-act-tsca
2 The prioritization process is explained in the Procedures for Prioritization of Chemicals for Risk Evaluation Under the
Toxic Substances Control Act (82 FR 33753).
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Section 3 (Physical-Chemical Properties) : This section includes a description of the physical-
chemical properties of the chemical substance and explains how these properties lead to the
chemical's fate, transport, and exposure potential.
Section 4 (Relevant Assessment History): This section includes an overview of the outcomes
of other governing entities" assessments of the chemical substance.
Section 5 (Conditions of Use): This section presents the chemical substance's known,
intended, and reasonably foreseen conditions of use under TSCA.
Section 6 (Hazard Characterization): This section summarizes the reasonably available
hazard information and benchmarks the information against low-concern thresholds.
Section 7 (Exposure Characterization): This section includes a qualitative summary of
potential exposures to the chemical substance.
Section 8 (Summary of Findings): In this section, EPA presents information pertinent to
prioritization against each of the seven statutory and regulatory criteria and considerations,
and proposes a conclusion based on that evidence.
Section 9 (ProposedDesignation): In this section, EPA presents the proposed designation for
this chemical substance.
Appendix A (Conditions of Use Characterization): This appendix contains a comprehensive
list of TSCA and non-TSCA uses for the chemical substance from publicly available
databases.
Appendix B (Hazard Characterization): This appendix contains information on each of the
studies used to support the hazard evaluation of the chemical substance.
Appendix C (Literature Search Outcomes): This appendix includes literature search outcomes
and rationales for studies that were identified in initial literature screening but were found to
be off-topic or unacceptable for use in the screening-level review.
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2. Background on Diethyl Malonate
Table 1 below provides the CAS number, synonyms, and other information on diethyl malonate.
Table 1: Diethyl Malonate at a Glance
Chemical Name
Diethyl Malonate
CASRN
105-53-3
Synonyms
Ethyl Malonate; Diethyl Propanedioate; Malonic Ester; Propanedioic acid, diethyl ester;
Dicarbethoxymethane; Carbethoxyacetic ester;
Trade Name(s)
Molecular Formula
C7H12O4
Representative Structure
° \ 0
0 0
Diethyl malonate is a diester derivative of malonic acid, a dicarboxylic acid with two carboxyl groups
(-COO-) separated by one methylene group (-CH2-). Diethyl malonate is formed by the replacement
of the hydroxyl groups (-OH) of malonic acid with ethoxy groups (-OCH2CH3). The hydrogen atoms
on the methylene carbon between the two carboxyl groups make this compound acidic. Because of its
unique structure, diethyl malonate is reactive and functions as a reagent for organic synthesis and to
make products such as barbiturates, pigments, and agrochemicals. Volatile esters are known to have
fruity scents and are often used as fragrances and flavorings. Diethyl malonate is a volatile diester that
occurs naturally in fruits such as grapes, strawberries, guava, melon, pineapple, and blackberries.
Section 5 includes conditions of use for this chemical.
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3. Physical-Chemical Properties
Table 2 lists physical-chemical properties for diethyl malonate. A chemical's physical-chemical properties provide a basis for understanding a
chemical's behavior, including in the environment and in living organisms. These endpoints provide information generally needed to assess
potential environmental release, exposure, and partitioning as well as insight into the potential for adverse toxicological effects.
Table 2: Physical-Chemical Properties for Diethyl Malonate
Source/
Model
Data Type
Endpoint
Endpoint value
Notes
PubChem 2019
Experimental
State at room
temperature
Liquid
ChemlDPIus 2019; OECD
SIDS 2005; ECHA2019;
EPISuite v.4.113
Estimated
Molecular weight
160 g/mol
EPISuite v.4.11
Calculated
Molecular weight
160.17 g/mol
Lyman etal. 1990
Estimated
Molar volume
183 cm3/mol
ChemlDPIus 2019
Experimental
Melting Point
o
o
O
LO
ChemlDPIus 2019; EPISuite
v.4.11
Experimental
Boiling Point
200 °C
OECD SIDS 2005
Experimental
Water solubility
2.00E+04 mg/L
ChemlDPIus 2019; ECHA
2019; EPISuite v.4.11
Experimental
Water solubility
2.32 E+04 at 37 °C
mg/L
EPISuite v.4.11
Estimated
Water solubility
2.97E+04 mg/L
Kow method
David etal., 2012
Experimental
Vapor pressure
1 mm Hg at 40 °C
ChemlDPIus 2019; OECD
SIDS 2005; ECHA 2019
Experimental
Vapor pressure
0.27 mm Hg (0.36
hPa) at 25 °C
EPISuite v.4.11
Estimated
Vapor pressure
3.61 E-01 mm Hg
EPISuite v.4.11
Experimental
Henry's Law
constant
2.1E-06 atm-m3/mol
Experimental value identified in EPISuite's internal database
3 All EPI Suite estimates used the following physical property inputs: BP = 200 deg C, MP = -50 deg C, VP = 0.269 mm Hg, WS = 23,200 mg/L, log P = 0.96; SMILES:
0=C(0CC)CC(=0)0CC
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Table 2: Physical-Chemical Properties for Diethyl Malonate
Source/
Model
Data Type
Endpoint
Endpoint value
Notes
ChemlDPIus 2019; OECD
SIDS 2005; ECHA2019;
EPISuite v.4.11
Experimental
Log Kow
0.96
EPISuite v.4.11
Estimated
Log Kow
0.9
EPISuite v.4.11
Estimated
Log Koa
5.026
EPISuite v.4.11
Estimated
Log Koc
1 (MCI); 1.325 (Kow)
Cataldoetal. 1990; Fellows
etal. 1990
Experimental
Volatilization (T
1/2)
From soil: 1.2-2
hours
Cataldoetal. 1990; Fellows
etal. 1990
Experimental
Volatilization (T
1/2)
From foliar surfaces:
1.3-242 hours
Foliar surface composition affects sorption and volatilization
EPISuite v.4.11
Estimated
Volatilization
(T1/2)
From river: 14.76
days; from lake:
165.4 days
OECD SIDS 2005
Experimental
Photolysis (T1/2)
35 minutes
EPISuite v.4.11
Estimated
Indirect
photolysis (T1/2)
3.13 days
From OH rate constant 3.41 E-12 cm3/molecules-second (12 hour
day; 1.5E6 OH/cm3)
EPISuite v.4.11
Estimated
Hydrolysis (T1/2)
Half-life at pH=7:
16.198 days
Half-life at pH=8:
1.620 days
EPISuite v.4.11
Estimated
BAF
1.058
EPISuite v.4.11
Estimated
BCF
3.162
EPISuite v.4.11
Estimated
Biodegradability
Ready
biodegradability
prediction: Yes
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Based on its reported physical form (PubChem, 2019) and measured melting point (ChemlDPlus,
2019), diethyl malonate is a liquid under ambient conditions. Liquids have the potential for exposure
via direct dermal contact with the substance, and through ingestion or by inhalation of aerosols if they
are generated. Exposure through direct dermal contact with this substance is expected to result in poor
to moderate dermal absorption based on experimental data (discussed further in Section 6.1.1) and its
molecular weight, water solubility and log Kow. Based on its measured vapor pressure (ChemlDPlus,
2019), diethyl malonate is expected to volatilize at ambient temperatures, and therefore has the
potential for inhalation exposure to vapor-phase material. The estimated Henry's Law constant (EPI
Suite, 2019) for diethyl malonate indicates slow volatilization from water and aqueous solutions,
which can also result in inhalation exposure to volatilized material. Based on measured solubility data
(ChemlDPlus, 2019), diethyl malonate is considered water soluble, indicating the potential for this
substance to dissolve in water and form an aqueous solution. Water soluble substances have an
increased potential for absorption through the lungs; therefore, if inhalation of vapors or aerosols
occurs, absorption through the lungs is likely. Based on its estimated log K0W(EPI Suite, 2019),
diethyl malonate is unlikely to cross lipid membranes. Absorption and sequestration in fatty tissues
are unlikely, as reflected in the estimated BCF and BAF values for this compound (EPI Suite, 2019).
The estimated log Koc (EPISuite) indicates diethyl malonate is highly mobile in soils, increasing its
potential for leaching into groundwater, including groundwater sources of drinking water. If oral
exposure occurs via ingestion of contaminated drinking water absorption through the gastrointestinal
tract is expected to be poor based on the log Kow (EPI Suite, 2019). Measured and estimated data
(discussed further in Section 6.3.1) indicate diethyl malonate is readily biodegradable, meaning that it
has the potential to break down in the environment into carbon dioxide and water.
3.1 References
Cataldo, D. A., Ligotke, M. W., Harvey, S. D., Fellows, R. J., Li, S. W. (1990). Acute environmental
toxicity and persistence of DEM, a chemical agent simulant: Diethyl malonate. Final report.
Technical Report, Department of Energy
ChemlDplus. (2019). Diethyl malonate. Retrieved from https://chem.nlm.nih.gov/chcmidplus/rn/112-
92-5
David, R. M., Bachman, A. N., Butala, J. H., Piper, J. T. (2012) Esters of Mono-, Di-, and
Tricarboxylic Acids. Patty's Toxicology, Sixth Edition. Volume 4, John Wiley & Sons, Chapter 58,
Page 147.
European Chemicals Agency (ECHA). (2019). Diethyl malonate. Retrieved from
https://echa.europa.eu/substance-information/-/substanceinfo/100.003.006
Fellows, R. J., Harvey, S. D., Ligotke, M. W., Cataldo, D. A., Li, S. W. (1990) Environmental
persistence and toxicity of dimethyl malonate and methyl salicylate. Technical Report,
Department of Energy
Lyman, Warren J., Reehl, W. F., Rosenblatt, D. H. (1990). Handbook of chemical property estimation
methods: environmental behavior of organic compounds. American Chemical Society
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OECD (2005). Malonic acid diesters. Retrieved from
https://heronet.epa.gov/heronet/index.cfm/reference/download/reference_id/4935263
PubChem. (2019). Diethyl malonate. Retrieved from
https: //pubchem .ncbi .nlm .nih. gov/compound/8221
U.S. EPA. (2019). Estimation Programs Interface Suite, v 4.11. United States Environmental
Protection Agency, Washington, DC, USA
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4. Relevant Assessment History
EPA assessed the toxicological profile of diethyl malonate and added the chemical to the Safer
Choice Program's Safer Chemical Ingredients List (SCIL) in July 2013 under the functional class of
fragrances. The SCIL4 is a continuously updated list of chemicals that meet low-concern Safer Choice
criteria.5
EPA also reviewed international assessments of diethyl malonate. EPA identified assessments by the
Organisation for Economic Co-operation and Development (OECD) and Canadian, Germany, and
New Zealand government agencies.
The OECD SIAM discussed the SIDS Initial Assessment Report (SIAR) on malonic acid diesters,
including diethyl malonate, in April 2005. The SIAM determined this chemical to be "low priority for
further work" for human health and the environment.6
The Canadian Government, through an assessment of toxicity and exposure as part of its
categorization of the Domestic Substance List, found that diethyl malonate did not meet its criteria for
further attention.7
The German Environment Agency (UBA) designated diethyl malonate as "low hazard to waters" in
August 2017 based on an assessment of ecotoxicity and environmental fate.8
New Zealand's Environmental Protection Authority lists diethyl malonate in its Chemical
Classification and Information Database (CCID), which includes hazard and physical information
about single chemicals for use in hazard classifications and safety information. For diethyl malonate,
the CCID includes the classification description "acutely toxic."9 This classification is based on
information in Chemwatch1" from 2006 that classified this chemical as R65, "Harmful: may cause
lung damage if swallowed." Section 6.1 of this screening review contains a summary of the
reasonably available information on acute toxicity in 2019 and an explanation of why EPA does not
believe acute toxicity is a concern for this chemical.
4 https://www.epa.gov/saferchoice/safer-ingredients
5 https://www.epa.gov/sites/production/files/2013-12/documents/dfe master criteria safer ingredients v2 l.pdf
0 https://lipvchemicals.oecd.org/ui/handler.axd?id=66A562AA-27EC-4AlB-B87D-637A7DA9E162
7 https://canadacheniicals.oecd. org/CheniicalDetails.aspx?CheniicalID=8443FA36-2730-44AE-ADlE-EDD461C2026F
8 https://webrigoletto.uba.de/rigoletto/public/searcliDetail.do7kennuninieF 1188
9 https://www.epa.govt.nz/database-searcli/cheniical-classification-and-infoniiation-database-ccid/view/14427
10 https://www.cheniwatch.net
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5. Conditions of Use
Per TSCA section 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. EPA assembled information
on all uses of diethyl malonate (Appendix A) to determine conditions of use.11 One source of
information that EPA used to help determine conditions of use is 2016 Chemical Data Reporting
(CDR). The CDR rule (previously known as the Inventory Update Rule, or IUR), under TSCA
section 8, requires manufacturers (including importers) to report information on the chemical
substances they produce domestically or import into the U.S., generally above a reporting threshold of
25,000 lb. per site per year. CDR includes information on the manufacturing, processing, and use of
chemical substances with information dating to the mid-1980s. CDR may not provide information on
other life-cycle phases such as the chemical substance's end-of-life after use in products (i.e.,
disposal).
According to CDR, diethyl malonate is manufactured domestically and imported. It is used in
processing (incorporation into formulation, mixture or reaction and processing as a reactant) for
construction, odor agents manufacturing, and other applications. Industrial uses include automotive
paint and cleaning and washing agents. Consumer and commercial uses include washing and cleaning
products, polishes and wax blends, and air care products, among others. Based on the known
manufacturing, processing, and uses of this chemical substance, EPA assumes distribution in
commerce. According to CDR, five facilities reported that the chemical substance was not recycled
(e.g., not recycled, remanufactured, reprocessed, or reused). For another three facilities, this
information was withheld. For an additional facility, information was not known or reasonably
ascertained. No information on disposal is found in CDR or through EPA's Toxics Release Inventory
(TRI) Program12 since diethyl malonate is not a TRI-reportable chemical. Although reasonably
available information did not specify additional types of disposal, for purposes of this proposed
prioritization designation, EPA assumed end-of-life pathways that include releases to air, wastewater,
surface water, and land via solid and liquid waste based on the conditions of use (e.g., incineration,
landfill).
To supplement CDR, EPA conducted research through the publicly available databases listed in
Appendix A (Table A.2) and performed additional internet searches to clarify conditions of use or
find additional occupational13 and consumer uses. This research improved the Agency's
understanding of the conditions of use for diethyl malonate. Although EPA identified uses of diethyl
malonate in personal care products, this screening review covers TSCA conditions of use for the
chemical substance and personal care products are not considered further in EPA's assessment.
Exclusions to TSCA's regulatory scope regarding "chemical substance" can be found at TSCA
section 3(2). Table 3 lists the conditions of use for diethyl malonate considered for chemical
11 The prioritization process, including the definition of conditions of use, is explained in the Procedures for Prioritization
of Chemicals for Risk Evaluation Under the Toxic Substances Control Act (82 FR 33753).
12 https://www.epa.gov/toxics-release-inventorv-tri-program
13 Occupational uses include industrial and/or commercial uses
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substance prioritization, per TSCA section 3(4). Table 3 reflects the TSCA uses determined as
conditions of use listed in Table A.3 (Appendix A).
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Table 3: Conditions of Use for Diethyl Malonate
Life Cycle
Stage
Category
Subcategory of Use
Source
Manufacturing
Domestic manufacture
Domestic manufacture - information on whether
domestically manufactured was not reported
EPA (2017b)
Import
Import- multiple sites report import
Processing
Processing- incorporation into formulation, mixture or
reaction
Other-construction
EPA (2017b)
Pharmaceutical and medicine manufacturing
Odor agents-miscellaneous manufacturing
EPA (2017b), CPCat (2019)
Processing as a reactant
Other-pharmaceutical and medicine manufacturing
EPA (2017b)
Other
Automotive manufacturing
CPCat (2019)
Chemical manufacturing
CPCat (2019), ECHA (2018)
Toilet preparation manufacturing
CPCat (2019)
Recycling
Recycling
EPA (2017b)14
Distribution
Distribution
Distribution
EPA (2017b)
Industrial Uses
Other
Automotive paint
CPCat (2019)
Chemical warfare agents
CPCat (2019)
Cleaning and washing agents
CPCat (2019), ECHA (2018)
Motor vehicle care
CPCat (2019)
Isocyanate blocking agent
Synapse Information Resources (n.d.);
Special Chem (2018)
Paints, lacquers, varnishes - possibly
industrial/consumer/ commercial.
CPCat (2019)
Absorbents and adsorbentspossibly
industrial/commercial/consumer
CPCat (2019)
14 In the 2016 CDR, five facilities reported that the chemical substance was not recycled (e.g., not recycled, remanufactured, reprocessed, or reused). For three facilities, this
information was withheld. For one facility, information was not known or reasonably ascertained. No further information about recycling or disposal was found.
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Table 3: Conditions of Use for Diethyl Malonate
Life Cycle
Stage
Category
Subcategory of Use
Source
Commercial/
Consumer
Building/construction materials not elsewhere covered
EPA (2017b)
Washing and cleaning products
ECHA (2018)
Polishes and wax blends
ECHA (2018)
Commercial
Coatings
ECHA (2018)
Consumer
Air care products
Air fresheners (oil diffusion, pluggable aerosol,
pluggable liquid dispenser, scented candle, wax
melts
EPA (2017b), CPCat (2019), P&G
(2015), DeLima Associates (2015 a,b),
DeLima Associates (2016a,b)
Car air freshener
P&G (2016), CPCat (2019)
Cleaning and washing agents
Specific proprietary uses identified in
Safer Choice program's Salesforce
database
Disposal
Releases to air, wastewater, solid and liquid wastes
Though not explicitly identified, releases
from disposal are assumed to be
reasonably foreseen15
15 See Section 5 for a discussion on why releases are assumed to be reasonably foreseen for purposes of this proposed prioritization designation.
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6. Hazard Characterization
EPA reviewed primary literature and other data sources to identify reasonably available information.
This literature review approach16 is tailored to capture the reasonably available information associated
with low-hazard chemicals. EPA also used this process to verify the reasonably available information
for reliability, completeness, and consistency. EPA reviewed the reasonably available information to
identify relevant, quality studies to evaluate the hazard potential for diethyl malonate against the
endpoints listed below. EPA's New Chemicals Program has used these endpoints for decades to
evaluate chemical substances under TSCA17 and EPA toxicologists rely on these endpoints as key
indicators of potential human health and environmental effects. These endpoints also align with
internationally accepted hazard characterization criteria, such as the Globally Harmonized System of
Classification and Labelling of Chemicals18 as noted above in Section 4 and form the basis of the
comparative hazard assessment of chemicals.
Human health endpoints evaluated: Acute mammalian toxicity, repeated dose toxicity,
carcinogenicity, mutagenicity/genotoxicity, reproductive and developmental toxicity, neurotoxicity,
skin sensitization, and eye and skin irritation.
Environmental fate and effects endpoints evaluated: Aquatic toxicity, environmental persistence,
and bioaccumulation.
The low-concern criteria used to evaluate both human health and environmental fate and effects are
included in Table 4 below.
Table 4: Low-Concern Criteria for Human Health and Environmental Fate and Effects
Human Health
Acute Mammalian
Toxicity19
Very High
High
Moderate
Low
Oral LDso (mg/kg)
<50
> 50 - 300
> 300 - 2000
>2000
Dermal LD50 (mg/kg)
<200
> 200- 1000
> 1000 -2000
>2000
Inhalation LC50
(vapor/gas) (mg/L)
<2
>2-10
>10-20
>20
Inhalation LC50
(dust/mist/fume)
(mg/L)
<0.5
>0.5-1.0
>1.0-5
>5
'"This process is further discussed in the document "Approach Document for Screening Hazard Information for Low-
Priority Substances Under TSCA."
17 https://www.epa. gov/sustainable-futures/sustainable-futures-p2-framework-manual
18 https://www.unece.org/fileadmin/DAM/trans/danger/publi/ghs/ghs rev07/English/ST SG AC10 30 Rev7e.pdf
19 Values derived from GHS criteria (Chapter 3.1: Acute Toxicity. 2009, United Nations).
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Table 4: Low-Concern Criteria for Human Health and Environmental Fate and Effects
Repeated Dose
Toxicity (90-day
study)20
High
Moderate
Low
Oral (mg/kg-bw/day)
< 10
10-100
>100
Dermal (mg/kg-
bw/day)
<20
20 - 200
>200
Inhalation
(vapor/gas)
(mg/L/6h/day)
<0.2
0.2-1.0
>1.0
Inhalation
(dust/mist/fume)
(mg/L/6h/day)
<0.02
0.02-0.2
>0.2
Reproductive
Toxicity21
High
Moderate
Low
Oral (mg/kg/day)
<50
50 - 250
>250
Dermal (mg/kg/day)
< 100
100-500
>500
Inhalation (vapor,
gas, mg/L/day)
< 1
1-2.5
>2.5
Inhalation
(dust/mist/fume,
mg/L/day)
<0.1
0.1-0.5
>0.5
Developmental
Toxicity21
High
Moderate
Low
Oral (mg/kg/day)
<50
50 - 250
>250
Dermal (mg/kg/day)
< 100
100-500
>500
Inhalation (vapor,
gas, mg/L/day)
< 1
1-2.5
>2.5
Inhalation
(dust/mist/fume,
mg/L/day)
<0.1
0.1-0.5
>0.5
Mutagenicity/
Genotoxicity22
Very High
High
Moderate
Low
Germ cell
mutagenicity
GHS Category 1A
or 1B: Substances
known to induce
heritable mutations
or to be regarded
as if they induce
heritable mutations
in the germ cells of
humans.
GHS Category 2:
Substances which
cause concern for
humans owing to the
possibility that they
may induce heritable
mutations in the germ
cells of humans.
Evidence of
mutagenicity support by
positive results in vitro
OR in vivo somatic cells
of humans or animals
Negative for
chromosomal
aberrations and gene
mutations, or no
structural alerts.
20 Values from GHS criteria for Specific Target Organ Toxicity Repeated Exposure (Chapter 3.9: Specific Target Organ
Toxicity' Repeated Exposure. 2009, United Nations).
21 Values derived from the U.S. EPA's Office of Pollution Prevention & Toxics criteria for HPV chemical categorizations
(Methodology* for Risk-Based Prioritization Under ChM tP), and the EU REACH criteria for Annex IV (2007).
22 From GHS criteria (Chapter 3.5: Germ Cells Mutagenicity'. 2009, United Nations) and supplemented with considerations
for mutagenicity and genotoxicity in cells other than germs cells.
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Table 4: Low-Concern Criteria for Human Health and Environmental Fate and Effects
Mutagenicity and
genotoxicity in
somatic cells
OR
Evidence of
mutagenicity
supported by positive
results in in vitro AND
in vivo somatic cells
and/or germ cells of
humans or animals.
Carcinogenicity23
Very High
High
Moderate
Low
Known or
presumed human
carcinogen (GHS
Category 1Aand
1B)
Suspected human
carcinogen (GHS
Category 2)
Limited or marginal
evidence of
carcinogenicity in
animals (and
inadequate24 evidence
in humans)
Negative studies or
robust mechanism-
based structure
activity relationship
(SAR)
Neurotoxicity
(90-day study)20
High
Moderate
Low
Oral (mg/kg-bw/day)
< 10
10-100
>100
Dermal (mg/kg-
bw/day)
<20
20 - 200
>200
Inhalation
(vapor/gas)
(mg/L/6h/day)
<0.2
CD
CM
CD
>1.0
Inhalation
(dust/mist/fume)
(mg/L/6h/day)
<0.02
0.02-0.2
>0.2
Sensitization25
High
Moderate
Low
Skin sensitization
High frequency of
sensitization in
humans and/or high
potency in animals
(GHS Category 1A)
Low to moderate
frequency of
sensitization in human
and/or low to moderate
potency in animals
(GHS Category 1B)
Adequate data
available and not
GHS Category 1Aor
1B
Respiratory
sensitization
Occurrence in
humans or evidence
of sensitization in
humans based on
animal or other tests
(equivalent to GHS
Category 1A or 1B)
Limited evidence
including the presence
of structural alerts
Adequate data
available indicating
lack of respiratory
sensitization
23 Criteria mirror classification approach used by the IARC (Preamble to the L4RC Monographs: B. Scientific Review and
Evaluation: 6. Evaluation and rationale. 2019) and incorporate GHS classification scheme (Chapter 3.6: Carcinogenicity.
2009, United Nations).
24 EPA's approach to determining the adequacy of information is discussed in the document "Approach Document for
Screening Hazard Information for Low-Priority Substances Under TSCA."
25 Incorporates GHS criteria (Chapter 3.4: Respiratory or Skin Sensitization. 2009, United Nations).
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Table 4: Low-Concern Criteria for Human Health and Environmental Fate and Effects
Irritation/
Corrosivity26
Very High
High
Moderate
Low
Eye irritation/
corrosivity
Irritation persists
for >21 days or
corrosive
Clearing in 8-21
days, severely
irritating
Clearing in 7 days or
less, moderately
irritating
Clearing in less than
24 hours, mildly
irritating
Skin irritation/
corrosivity
Corrosive
Severe irritation at 72
hours
Moderate irritation at 72
hours
Mild or slight irritation
at 72 hours
Environmental Fate and Effects
Acute Aquatic
Toxicity Value
(L/E/ICso)27
Chronic Aquatic
Toxicity Value
(L/E/ICso)27
Persistence (Measured in terms of level of
biodegradation)28
Bioaccumulation
Potential29
May be low concern
if <10 ppm...
...and <1 ppm...
...and the chemical meets the 10-day window as
measured in a ready biodegradation test...
Low concern if >10
ppm and <100
ppm...
...and >1 ppm and
<10 ppm...
...and the chemical reaches the pass level within
28 days as measured in a ready biodegradation
test
...and BCF/BAF <
1000.
Low concern if >100
ppm...
...and > 10 ppm...
... and the chemical has a half-life < 60 days...
6.1 Human Health Hazard
Below is a summary of the reasonably available information that EPA included in the hazard
evaluation of diethyl malonate. In many cases, EPA used analogous chemicals to make findings for a
given endpoint. Where this is the case, use of the analog is explained. If the chemical studied is not
named, the study is for diethyl malonate. Appendix B contains more information on each study.
EPA used best professional judgement to select analogs for diethyl malonate based on similarity in
structure, physical-chemical properties, and functionality, with the assumption that these chemicals
will have similar environmental transport and persistence characteristics, bioavailability and toxicity
profiles. Diethyl malonate is the diethyl ester of propanediol acid. EPA is using two analogs for
diethyl malonate. The first is dimethyl malonate, the dimethyl ester of propanediol acid. The second
is dimethyl glutarate, which varies from dimethyl malonate by only its carbon chain length.
Other possible analogs for diethyl malonate are dimethyl succinate (DMS, CASRN 106-65-0) and
dimethyl adipate (DMA, CASRN 627-93-0). These are all aliphatic diesters like diethyl malonate,
20 Criteria derived from the Office of Pesticide Programs Acute Toxicity Categories (U.S. EPA. Label Review Manual.
2010).
27 Derived from GHS criteria (Chapter 4.1: Hazards to the Aquatic Environment. 2009, United Nations), EPA OPPT New
Chemicals Program (Pollution Prevention (P2) Framework, 2005) and OPPT's criteria for HPV chemical categorization
(Methodology> for Risk Based Prioritization Under C1l4MP. 2009).
28 Derived from OPPT's New Chemicals Program and DIE Master Criteria and reflects OPPT policy on PBTs (Design for
the Environment Program Master Criteria for Safer Chemicals, 201).
29 Derived from OPPT's New Chemicals Program and Arnot & Gobas (2006) [Arnote, J.A. and F,A. Gobas, A review of
bioconcentration factor (BCF) and bioaccimndation factor (B*4F) assessments for organic chemicals in aquatic organisms.
Environmental Reviews, 2006. 14: p. 257-297.]
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except that the aliphatic chain lengths separating the esters groups are longer. There is a large amount
of data available for the commercial mixture commonly known as dibasic esters (DBE- mixture of
DMS, DMA and DMG, CASRN 95481-62-2); however, this CASRN was excluded as a potential
analog based on its variable composition. EPA did not identify relevant, quality studies3" for these
other possible analogs, resulting in the selection of dimethyl malonate and dimethyl glutarate as
appropriate analogs for this screening review.
Table 5: Diethyl Malonate and Analog Structures
CASRN
Name
Structure
105-53-3
Diethyl malonate
0 0
1 i
HjC O 0 CH3
108-59-8
Dimethyl malonate
O O
1119-40-0
Dimethyl glutarate
0 0
6.1.1 Absorption, Distribution, Metabolism, and Excretion
Absorption
To assess the substance's dermal absorption potential, EPA relied on experimental data. An in vivo
dermal absorption study using diethyl malonate showed that approximately 2.5% to 15% of the
applied dose penetrated through the skin of several animal species (mice, human or pig skin grafted
on mice, pig, and dog) following a 24- to 48-hour exposure period (Reifenrath et al.. 1984).
Several in vitro skin absorption and penetration studies have been conducted using diethyl malonate.
Approximately 16% of the applied dose penetrated through human cadaver skin following a 24-hour
exposure period, with a maximum penetration rate of approximately 350 (.ig/cnr/hour (CIR Expert
Panel. 2010; OECD. 2005). In one study using pig skin, approximately 3% to 10% of the applied
dose was absorbed or found in the receptor fluid and approximately 8% to 30% of the applied dose
remained in the skin following a 50-hour exposure period (CIR Expert Panel. 2010; OECD. 2005). In
another study using pig skin, approximately 0.2 to 1.6% of the applied dose was found in the receptor
fluid, 0.2-0.9% of the applied dose remained in the skin, and 0.2 to 0.7% of the applied dose remained
on the skin surface following a 24-hour exposure period (CIR Expert Panel. 2010; OECD. 2005;
30 This process is further discussed in the document "Approach Document for Screening Hazard Information for Low-
Priority Substances Under TSCA."
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Chellquist and Reifenrath. 1988). These results demonstrate poor to moderate dermal absorption of
diethyl malonate.
If ingested orally, diethyl malonate is expected to have poor absorption from the gastrointestinal tract
based on its molecular weight, water solubility, and log Kow (Section 3).
If inhaled as a vapor or aerosol, absorption from the lungs is likely based on diethyl malonate "s water
solubility (Section 3).
Distribution
Based on its water solubility and log Kow (Section 3), diethyl malonate is likely to be distributed
mainly in aqueous compartments of an organism, and absorption and sequestration in fatty tissues is
unlikely.
Metabolism
Because quality experimental data31 on diethyl malonate metabolite formation were limited, the
Quantitative Structure-Activity Relationship (QSAR) toolbox32 was used to run the rat liver S9
metabolism simulator, the skin metabolism simulator, and the in vivo rat metabolism simulator. The
QSAR toolbox was used to identify putative diethyl malonate metabolites. All three metabolism
simulators predicted ethanol and 2-ethoxycarbonyl-acetic acid as metabolites of diethyl malonate.
The rat liver S9 and in vivo rat metabolism simulators predicted acetic acid, acetaldehyde and malonic
acid as metabolites of diethyl malonate.
Excretion
Based on diethyl malonate "s lower molecular weight and high water solubility, it is likely to be
excreted via urine. Because of its low vapor pressure, excretion via gas exchange is unlikely.
6.1.2 Acute Toxicity
EPA assessed toxicity from acute exposures to diethyl malonate using read-across from dimethyl
malonate. A study on rats exposed to dimethyl malonate in their diet reported no effects at the single
dose tested (2000 mg/kg), resulting in an LD50 greater than 2000 mg/kg (ECHA. 1992b). Another
study on rats exposed to dimethyl malonate by oral gavage also reported an LD50 greater than 2000
mg/kg (OECD. 2005; ECHA. 1992c). These studies indicate low concern for acute toxicity from oral
exposures based on these results exceeding the low-concern criteria threshold of 2000 mg/kg.
A study on rats exposed to dimethyl malonate via dermal application for 24 hours demonstrated no
effects at the single dose tested (2000 mg/kg), resulting in an LD50 greater than 2000 mg/kg (OECD.
2005; ECHA. 1992a). This study indicates low concern for acute toxicity from dermal exposure based
on these results exceeding the low-concern criteria threshold of 2000 mg/kg.
31 This process is further discussed in the document "Approach Document for Screening Hazard Information for Low-
Priority Substances under TSCA."
32 https://www.oecd.org/chemicalsafetv/risk-assessment/oecd-qsar-toolbox.htm
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6.1.3 Repeated Dose Toxicity
EPA assessed toxicity from sub-chronic exposures to diethyl malonate using read-across from an
analog, dimethyl malonate. In an OECD Guideline 422 study, rats were exposed to dimethyl malonate
via oral gavage for 39 days for males and 51 days for females (OECD. 2005; ECHA. 2003). A no
observed adverse effect level (NOAEL) of 300 mg/kg-day and a lowest observed adverse effect level
(LOAEL) of 1000 mg/kg-day based on hepatocellular hypertrophy were reported. EPA considered
this effect reversible because there was not a significant increase in hypertrophy in the recovery
groups. The study results indicate low-concern for toxicity from sub-chronic exposures because the
effects were reversible and the NOAEL and LOAEL meet the low-concern criteria threshold of 300
mg/kg-day for a ~30-day repeated dose study.33
6.1.4 Reproductive and Developmental Toxicity
EPA assessed the potential for diethyl malonate to induce developmental toxicity using read-across
from dimethyl malonate. In the same OECD Guideline 422 study, rats were exposed to dimethyl
malonate via oral gavage for 39 days for males and 51 days for females (OECD. 2005; EC'HA. 2003).
Reproductive parameters including fertility indices, duration of gestation, number of corpora lutea,
pre and post-implantation loss, numbers of pups born and live litters, mean litter size, sex, ratio, pup
viability, and pup survivability were recorded. Pups from each litter were examined for external
deformities, malformations and gross pathologies. No adverse effects were noted on any of these
parameters, resulting in a NOAEL of 1000 mg/kg-day. This result, taken with the low-concern criteria
oral threshold of 250 mg/kg-day, indicates low concern for reproductive and developmental toxicity.
EPA also used read-across from an analog to assess developmental toxicity from inhalation
exposures. A study in rabbits exposed to vapors of the analog dimethyl glutarate from gestation day 7
to 28 reported a no observed adverse effect concentration (NOAEC) of 1.0 mg/L based on no adverse
effects noted related to developmental toxicity (Munlev. 2003). EPA calculated a saturation vapor
concentration of 1.55 mg/L for dimethyl glutarate. While the NOAEC of 1.0 mg/L is below the low-
concern criteria threshold of 2.5 mg/L, because of limited dosing in the study and because no adverse
effects were observed close to the calculated saturation vapor concentration for dimethyl glutarate,
EPA uses best professional scientific judgement to conclude that these results indicate low concern
for developmental toxicity for diethyl malonate.
33
Although EPA did not identify any repeated dose inhalation studies that meet the data quality criteria (see Appendix C)
for assessment against the low-concern criteria, commercial, variable mixtures of dibasic esters are known to irritate the
respiratory tract in rodents during repeated exposures. Following inhalation of dibasic ester mixtures, absorption and
metabolism occurs within the upper respiratory tract. Specifically, the esters are hydrolyzed by carboxylesterases to the
corresponding aliphatic alcohols and carboxylic acids. The observed effects are localized to the upper respiratory tract
during repeated exposures, with some studies demonstrating tissue repair and regeneration following a recovery period,
indicating reversibility. The human relevance of dibasic ester-induced nasal irritation in rodents is not clearly understood
because rodents are obligatory nose breathers, while humans breathe through both the mouth and nose. Therefore, the
concentration of a chemical impacting tissues in the rodent nose is proportionally greater than that for humans. Though these
results suggest respiratory irritation may be possible in humans, the studies did not meet the data quality criteria for this
chemical substance's screening review for prioritization.
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6.1.5 Genotoxicity
EPA assessed diethyl malonate's potential to induce genotoxicity using experimental data. Diethyl
malonate was negative for inducing gene mutations in bacteria in two studies (OECD. 2005). EPA
also used read-across from dimethyl malonate to assess genotoxicity. Human peripheral lymphocytes
exposed to dimethyl malonate were negative for chromosomal aberrations, with and without
metabolic activation (OECD. 2005; ECHA. 2003).
An in vivo study on rats exposed to dimethyl glutarate also reported negative results for chromosomal
aberrations (SOCMA. 2002). These data indicate low concern for diethyl malonate to induce
genotoxicity.
6.1.6 Carcinogenicity
Because quality experimental data on diethyl malonate were limited, EPA relied on publicly available
quantitative structure activity relationship (QSAR) models and structural alerts (SA) to assess the
carcinogenic potential for diethyl malonate. Structural alerts represent molecular functional groups or
substructures that are known to be linked to the carcinogenic activity of chemicals. The most common
structural alerts are those for electrophiles (either direct acting or following activation). Modulating
factors that will impact the carcinogenic potential of a given electrophile will include its relative
hardness or softness, its molecular flexibility or rigidity, and the balance between its reactivity and
stability.34 For this chemical and its metabolites, there is an absence of the types of reactive structural
features that are present in genotoxic carcinogens. Diethyl malonate is not an electrophile. ISS
profiler, a QSAR model35, did not identify any structural alerts for diethyl malonate or its metabolites.
Further, the Virtual models for property Evaluation of chemicals within a Global Architecture
(VEGA) models"36 results indicate diethyl malonate has low potential to be carcinogenic or
mutagenic.
Diethyl malonate's metabolism, lack of structural alerts, and experimental genotoxicity studies
indicate that this chemical is unlikely to be carcinogenic or mutagenic.
6.1.7 Neurotoxicity
While no traditional neurotoxicity studies were available for diethyl malonate or its analogs, EPA
assessed the potential for neurotoxicity using relevant endpoints measured in repeated dose studies
and searching predictions by U.S. EPA's ToxCast.37
34 "Fundamental and Guiding Principles for (Q)SAR Analysis of Chemical Carcinogens with Mechanistic Considerations:
Series on Testing and Assessment, No. 229." 2015. Environment Directorate, Joint Meeting of the Chemicals Committee
and the Working Party on Chemicals, Pesticides and Bio techno logy.
35 Carcinogenicity alerts by ISS 2.4 profiler as encoded in the QSAR Toolbox 4.3 (qsartoolbox.org) and the 4
carcinogenicity models housed within the VEGA 1.1.4 software tool available from https://www.vegahub.eu. A summary
of the results from these models is provided in Appendix B.
30 There are four carcinogenicity models housed within the VEGA 1.1.4 software tool available from
https://www.vegahub.eu. A summary of the results from these models is provided in Appendix B.
37 https://actor.epa.gov/dashboard/. Chemical specific assay list can be found at
https://actor.epa.gOv/dashboard/#chemical/55934-93-5.
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No treatment-related effects in functional observation battery tests were reported in a combined
repeated dose and reproduction/developmental screening test in rats exposed to the analog dimethyl
malonate at gavage doses up to 1000 mg/kg-day (OECD. 2005).
EPA also considered mechanistic studies to assess neurotoxicity. Dimethyl malonate was not
cytotoxic to striatal neurons in an in vitro cytotoxicity study in primary culture neurons from the fetal
rat ganglionic eminence (Mclaughlin et al.. 1998). Dimethyl malonate exposure caused selective
motor neuron death to primary neuronal cells isolated from rat spinal cord tissue (Kanki et al.. 2004)
and other mechanistic studies indicate malonate may be involved in oxidative stress that contributes
to dopamine efflux (Mov et al.. 2007; Zeevalk et al.. 1998). However, these effects do not appear to
translate into adverse outcomes, as noted in the functional observation battery results. Further,
ToxCast results for dimethyl malonate and diethyl malonate included 27 in vitro high-throughput
biochemical assays and 15 cell-based assays related to neurological functions.38 Neither dimethyl
malonate nor diethyl malonate induced bioactivity in any of the assays.
Based on the functional observation battery results and low-hazard results for other endpoints,
including, but not limited to acute, reproductive and developmental toxicity, EPA anticipates low
concern for neurotoxicity.
6.1.8 Skin Sensitization
EPA assessed diethyl malonate "s potential to act as a skin sensitizer using read-across from dimethyl
malonate. An OECD Guideline 406 study in guinea pigs exposed to dimethyl malonate reported it as
negative for inducing skin sensitization (ECHA. 1992g). These results indicate low concern for skin
sensitization.
6.1.9 Skin Irritation
EPA assessed diethyl malonate "s potential to act as a skin irritant using read-across from dimethyl
malonate. In a study following OECD Guideline 404, rabbits exposed dermally to dimethyl malonate
had slight erythema 30 to 60 minutes after the patch was removed, but there were no other signs of
irritation (OECD. 2005; ECHA. 1992f). Dimethyl malonate was considered to be non-irritating.
These results indicate low concern for skin irritation.
6.1.10 Eye Irritation
EPA assessed diethyl malonate "s potential to act as an eye irritant using experimental data. In a study
following OECD Guideline 405, rabbits exposed to diethyl malonate displayed slight to moderate
chemosis, irritation of the conjunctivae and iris, and cornea opacity with all effects reversible within
21 days (OECD. 2005). Because these results indicate moderate to high potential for eye irritation,
EPA considered additional information on a closely-related analog to determine the potential for eye
irritation. A study following OECD Guideline 405 (OECD. 2005; ECHA. 1992d. e), with rabbits
38 Identified by supplemental infonnation in Chushak Y., Shows H., Gearhart J., Pangbum H. 2018. In silico identification
of protein targets for chemical neurotoxins using Toxcast in vitro data and read-across within the QSAR toolbox.
Toxicology Research issue 3. Supplemental files:
https://pubs.rsc.Org/en/content/articlelanding/2018/tx/c7tx00268h#idivAbstract.
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exposed to dimethyl malonate reported similar effects, but all effects were reversible within 8 days.
Read-across from dimethyl malonate confirms the irritation effects are slight to moderate and could
clear faster than 21 days. EPA interprets the slight to moderate results from both chemicals to indicate
diethyl malonate has moderate concern for eye irritation.
6.1.11 Hazards to Potentially Exposed or Susceptible Subpopulations
The above information supports a low human health hazard finding for diethyl malonate based on
low-concern criteria. This finding includes considerations such as the potential for developmental
toxicity, reproductive toxicity, and acute or repeated dose toxicity that may impact potentially
exposed or susceptible subpopulations. Based on the hazard information discussed in Section 6, EPA
did not identify populations with greater susceptibility to diethyl malonate.
6.2 Environmental Hazard
EPA assessed environmental hazard for diethyl malonate based on available acute experimental data
and estimated chronic toxicity values using the Ecological Structure Active Relationships (ECOSAR)
predictive model.39 Appendix B contains a summary of the reasonably available environmental
hazard data.
6.2.1 Acute Aquatic Toxicity
EPA assessed environmental hazard from acute exposures using experimental data. Five studies in
aquatic vertebrates exposed to diethyl malonate resulted in LC50S ranging from 11.8 mg/L to 17 mg/L
(QECD. 2005: Geigeretal.. 1986; Call et al.. 1981). Invertebrates exposed to diethyl malonate had an
EC50 of 202 mg/L (QECD. 2005) and algae had an EC50 greater than 800 mg/L (QECD. 2005). For a
chemical with acute aquatic toxicity values between 10 ppm to 100 ppm to be considered low concern
for environmental hazard, the chemical must reach 60% degradation within 28 days. These aquatic
toxicity values indicate low concern for acute aquatic exposure due to aquatic toxicity values greater
than 10 mg/L coupled with biodegradation (discussed in Section 6.3.1).
6.2.2 Chronic Aquatic Toxicity
Chronic toxicity values were estimated using the ECOSAR predictive model. Chronic effects are
predicted to occur at 8.1 mg/L for aquatic vertebrates, 190 mg/L for aquatic invertebrates, and 18
mg/L for algae. For a chemical with chronic aquatic toxicity values between 1 ppm and 10 ppm to be
considered low concern for environmental hazard, the chemical must reach 60% degradation with 28
days. Given the toxicity values estimated for diethyl malonate's and its ability to biodegrade within
28 days (Section 6.3.1), this chemical is expected to have low concern for chronic aquatic toxicity..
39 https://www.epa. gov/tsca-screenmg-tools/ecological-structure-activitv-relationships-ecosar-predictive-model
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6.3 Persistence and Bioaccumulation Potential
6.3.1 Persistence
EPA assessed environmental persistence for diethyl malonate using an experimental study following
OECD Guideline 301A (OECD. 2005). Diethyl malonate degraded 92% in 7 days and 98% in 28
days. This result indicates low concern for persistence based on the low-concern threshold of a half-
life less than 28 days given the aquatic toxicity values (discussed in Section 6.2). Furthermore, a
microbial inhibition test indicates diethyl malonate is non-toxic to microbial populations found in
sewage treatment plants (Fellows etal.. 1990).
Anaerobic biodegradation data were not available for diethyl malonate or closely-related analogs.
EPA predicted anaerobic biodegradation for diethyl malonate using BioWin4" models which
predicted diethyl malonate will degrade fast in anaerobic environments. No degradation products of
concern were identified for this chemical substance.
Therefore, the available biodegradation results meet the low-concern threshold, and indicate this
chemical will have low persistence.
6.3.2 Bioaccumulation Potential
Based on the estimated bioaccumulation factor (BAF) value of 1.06, using the Estimation Programs
Interface (EPI) Suite models,41 diethyl malonate is expected to have low potential for
bioaccumulation in the environment based on the low-concern threshold of less than 1000.
40 https://envirosim.com/products/biowin
41 https://www.epa.gov/tsca-screening-tools/epi-suitetm-estimation-program-interface
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7. Exposure Characterization
EPA considered reasonably available information on exposure for diethyl malonate. In general, there
is limited information on exposure for low-hazard chemicals. EPA determined the CDR database and
certain other sources of diethyl malonate use information are sources of information relevant to
diethyl malonate's exposure potential. Of these sources, EPA determined that the CDR database
contained the primary source of information on the conditions of use for this exposure
characterization. EPA also consulted sources of use information from other databases and public
sources (listed in Table A.2). EPA used these sources only where they augmented information from
the CDR database to inform intended, known, or reasonably foreseen uses (Section 5).
As shown in Tables 3 and A.3, diethyl malonate is used as a processing aid for construction and other
applications, as well as in various industrial, commercial, and consumer uses. Non-TSCA uses are
beyond the scope of this assessment because of the exclusions under TSCA section 3(2) (See Table
A.3).
Under the conditions of use identified in Table 3, EPA assessed the potential exposure to the
following categories: the environment, the general population, and potentially exposed or susceptible
subpopulations including workers and consumers.
7.1 Production Volume Information
Production volume information for diethyl malonate is based on an analysis of CDR data reported
from 1986 to 2015.42 The CDR database indicates that for reporting year 2015, 15 companies
manufactured or imported diethyl malonate at 16 sites. In 1986, 1990, 1998, and 2006 reporting
years, aggregate production volume for diethyl malonate was between 500,000 and 1,000,000 lbs. In
the 1994 reporting year, aggregate production volume was between 1,000,000 and 10,000,000 lbs.,
and in the 2002 reporting year was between 10,000 and 500,000 lbs. For the 2012 to 2015 reporting
years aggregate production volume was between 100,000 and 500,000 lbs., and for 2011, the exact
amount was reported at 385,876 lbs. In general, since 2011, production volume has remained
relatively stable.
7.2 Exposures to the Environment
EPA expects most exposures to the environment to occur during the manufacture, processing, import,
and industrial, commercial, and consumer use of diethyl malonate. Exposure is also possible from
other uses, such as distribution and disposal. These activities could result in releases of diethyl
malonate to media including surface water, landfills, and air.
EPA expects high levels of removal of diethyl malonate during wastewater treatment (either directly
from the facility or indirectly via discharge to a municipal treatment facility or Publicly Owned
Treatment Works (POTW)). Further, diethyl malonate is expected to have low persistence (aerobic
42 The CDR requires manufacturers (including importers) to report information on the chemical substances they produce
domestically or import into the U.S. above 25,000 lb. per site per year.
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and anaerobic biodegradation are discussed in Section 6.3.1) and has the potential to breakdown in
the environment to carbon dioxide and water. Therefore, any release of this chemical is expected to
break down, reducing exposure to aquatic organisms in the water column and groundwater sources of
drinking water, including well water. Based on the estimated log Koc (Section 3), diethyl malonate is
expected to have negligible adsorption to sediment, reducing the potential for toxicity to benthic
organisms. Diethyl malonate's biodegradability and removal during treatment processes will reduce
the exposure potential to aquatic organisms.
If disposed of in a landfill, this chemical is expected to degrade under aerobic and anaerobic
conditions (aerobic and anaerobic biodegradation are discussed in Section 6.3.1).
If incineration releases during manufacturing and processing occur, EPA expects significant
degradation of diethyl malonate to the point that it will not be present in air.
7.3 Exposures to the General Population
EPA expects the general population is unlikely to be exposed to diethyl malonate from the potential
environmental releases described above. Air exposure is unlikely from incineration. If diethyl
malonate is present in the air from volatilization, it is expected to be reduced significantly by
photolysis, with a half-life of 35 minutes (see Table 2 in Section 3). Diethyl malonate is also unlikely
to be present in surface water because it will degrade, reducing the potential for the general
population to be exposed by oral ingestion or dermal exposure. Given the low bioaccumulation and
bioconcentration potential of diethyl malonate, oral exposure to diethyl malonate via fish ingestion is
unlikely.
7.4 Exposures to Potentially Exposed or Susceptible Subpopulations
EPA identified workers as a potentially exposed or susceptible subpopulation based on greater
exposure to diethyl malonate than the general population during manufacturing, processing,
distribution, use, and disposal. EPA also identified consumers as a population that may experience
greater exposure to diethyl malonate than the general population through use of washing and cleaning
products, polishes and wax blends, and air care products, for example.
7.4.1 Exposures to Workers
Based on its reported physical form and measured melting point (Table 2), diethyl malonate is a
liquid under ambient conditions. Based on diethyl malonate's conditions of use (Table 3), workers
may be exposed to liquids through direct dermal contact with the substance and inhalation of aerosols
if generated. Based on its measured vapor pressure, diethyl malonate is expected to be volatile at
ambient temperatures, and therefore workers may be exposed through inhalation of vapors. If diethyl
malonate is in a dilute form, the estimated Henry's Law constant for diethyl malonate indicates
volatilization from water and aqueous solutions is possible. Workers may be exposed to diethyl
malonate in manufacturing, processing, distribution, use, and disposal.
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7.4.2 Exposures to Consumers
Consumers may be exposed to diethyl malonate through the use of washing and cleaning products,
polishes and wax blends, and air care products, for example. For all these uses, if dermal contact does
occur, diethyl malonate is expected to have poor to moderate absorption through the skin based on its
molecular weight, water solubility and partitioning coefficients (Section 3) and on experimental
dermal absorption studies (Section 6). If the chemical is in an aerosol product and inhalation exposure
occurs, diethyl malonate's absorption from the lungs is likely. EPA does not include intentional
misuse, such as people drinking products containing this chemical, as part of the known, intended, or
reasonably foreseen conditions of use that could lead to an exposure (82 FR 33726). Diethyl
malonate's metabolism and excretion is expected to further reduce the duration of exposure.
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8. Summary of Findings
EPA has used reasonably available information on the following statutory and regulatory criteria and
considerations to screen diethyl malonate against each of the priority designation considerations in 40
CFR 702.9(a), discussed individually in this section, under its conditions of use:
the hazard and exposure potential of the chemical substance (See Sections 6 and 7);
persistence and bioaccumulation (See Section 6.3);
potentially exposed or susceptible subpopulations (See Section 7.4);
storage near significant sources of drinking water (See Section 8.4);
conditions of use or significant changes in the conditions of use of the chemical substance
(See Section 5);
the chemical substance's production volume or significant changes in production volume
(See Section 7.1); and
other risk-based criteria that EPA determines to be relevant to the designation of the chemical
substance's priority.
EPA conducted a risk-based screening-level review based on the criteria and other considerations
above and other relevant information described in 40 CFR 702.9(c) to inform the determination of
whether the substance meets the standard of a high-priority substance. High-priority substance means
a chemical substance that EPA determines, without consideration of costs or other non-risk factors,
may present an unreasonable risk of injury to health or the environment because of a potential hazard
and a potential route of exposure under the conditions of use, including an unreasonable risk to
potentially exposed or susceptible subpopulations identified as relevant by EPA (40 CFR 702.3). This
section explains the basis for the proposed designation and how EPA applied statutory and regulatory
requirements, addressed rationale, and reached conclusions.
8.1 Hazard and Exposure Potential of the Chemical Substance
Approach: EPA evaluated the hazard and exposure potential of diethyl malonate. EPA used this
information to inform its proposed determination of whether diethyl malonate would meet the
statutory criteria and considerations for proposed designation as a low-priority substance.
Hazard potential:
For diethyl malonate's hazard potential, EPA gathered information for a broad set of human health
and environmental endpoints described in detail in Section 6 of this document. EPA benchmarked this
information against low-concern thresholds. EPA found that diethyl malonate is of low concern for
human health and environmental hazard across the range of endpoints in this low-concern criteria.
Exposure potential:
To understand exposure potential, EPA gathered information on physical-chemical properties,
production volumes, and the types of exposures likely to be faced by workers, the general population,
consumers, and children (discussed in Sections 3 and 7). EPA also gathered information on
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environmental releases. EPA identified the general population, workers, consumers, and the
environment as most likely to experience exposures. EPA determined that while the general
population, workers, and consumers may be exposed to diethyl malonate, exposure by the dermal and
ingestion pathways are limited by diethyl malonate "s physical-chemical properties. If inhalation
occurs, diethyl malonate is expected to be metabolized and excreted, reducing the duration of
exposure. If diethyl malonate is released into the environment, its exposure potential will be reduced
through biodegradation under aerobic and anaerobic conditions.
Rationale: Although diethyl malonate may cause moderate eye irritation, the effects are reversible,
thereby reducing concern for longer-term effects. Workers could be exposed during manufacturing,
processing, distribution, use, and disposal, splashing of solutions, or hand-to-face and eye
contact. Other uses covered under TSCA, especially consumer uses in washing and cleaning products,
would be unlikely to result in more than incidental eye exposure. Eye irritation resulting from
exposure in occupational and consumer settings is mitigated by the reversible nature of the effect and
addressed by rinsing with water.
Proposed conclusion: Based on an initial analysis of reasonably available hazard and exposure
information, EPA proposes to conclude that the risk-based, screening-level review under 40 CFR
702.9(a)(1) does not support a finding that diethyl malonate meets the standard for a high-priority
substance. The reasonably available hazard and exposure information described above provides
sufficient information to support this proposed finding.
8.2 Persistence and Bioaccumulation
Approach: EPA has evaluated both the persistence and bioaccumulation potential of diethyl
malonate based on a set of EPA and internationally accepted measurement tools and thresholds that
are indicators of persistence and bioaccumulation potential (described in Section 6). These endpoints
are key components in evaluating a chemical's persistence and bioaccumulation potential.
Rationale: EPA review of experimental data indicates diethyl malonate is biodegradable under
aerobic conditions and predicted to be degradable under anaerobic conditions (discussed in Section
6.3.1). EPA's EPI Suite models indicate a low potential for bioaccumulation and bioconcentration
(Section 6.3.2).
Proposed conclusion: Based on an initial screen of reasonably available information on persistence
and bioaccumulation, EPA proposes to conclude that the screening-level review under 40 CFR
702.9(a)(2) does not support a finding that diethyl malonate meets the standard for a high-priority
substance. The reasonably available persistence and bioaccumulation information described above
provides sufficient information to support this proposed finding.
8.3 Potentially Exposed or Susceptible Subpopulations
Approach: TSCA Section 3(12) states that the "term 'potentially exposed or susceptible
subpopulation' means a group of individuals within the general population identified by the
Administrator who, due to either greater susceptibility or greater exposure, may be at greater risk than
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the general population of adverse health effects from exposure to a chemical substance or mixture,
such as infants, children, pregnant women, workers, consumers, or the elderly." EPA identified
workers engaged in the manufacturing, processing, distribution, use, and disposal of diethyl malonate
as a potentially exposed or susceptible subpopulation (described in more detail in Section 7).
Consumers are also a potentially exposed subpopulation because of their use of products such as
washing and cleaning products, polishes and wax blends, and air care products, as shown in Table 3.
Rationale: EPA did not identify hazard effects for this chemical that would make any population
susceptible. EPA expects workers and consumers to have a higher exposure to diethyl malonate than
the general population. Because of the chemical's low-concern hazard properties and reversibility of
effects, exposure does not pose a significant increase in risk for consumers or workers.
Proposed conclusion: Based on the Agency's understanding of the conditions of use and expected
users such as potentially exposed or susceptible subpopulations, EPA proposes to conclude that the
screening-level review under 40 CFR 702.9(a)(3) does not support a finding that diethyl malonate
meets the standard for a high-priority substance. While the conditions of use will result in an increase
in exposures to certain populations, the consistently low-concern hazard profile of diethyl malonate
provides sufficient evidence to support a finding of low concern. The reasonably available
information on conditions of use, hazard, and exposure described above provides sufficient
information to support this proposed finding.
8.4 Storage near Significant Sources of Drinking Water
Approach: In Sections 6 and 7, EPA explains its evaluation of the elements of risk relevant to the
storage of diethyl malonate near significant sources of drinking water. For this criterion, EPA focused
primarily on the chemical substance's potential human health hazards, including to potentially
exposed or susceptible subpopulations, and environmental fate properties, and explored a scenario of
a release to a drinking water source. EPA also investigated whether the chemical substance was
monitored for and detected in a range of environmental media. The requirement to consider storage
near significant sources of drinking water is unique to prioritization under TSCA Section 6(b)(1)(A).
Rationale: In terms of health hazards, diethyl malonate is expected to present low concern to the
general population, including susceptible subpopulations, across a spectrum of health endpoints.
In the event of an accidental release into a surface drinking water source, diethyl malonate is expected
to be water soluble (see Section 3) and not expected to persist (see Section 6) in the drinking water
supply. In the event of an accidental release to land, the estimated log Koc indicates this substance is
highly mobile in soils, increasing its potential for leaching into groundwater, including well water.
The fate and transport evaluation indicates diethyl malonate is unlikely to partition into sediment,
predicted to biodegrade under aerobic and anaerobic conditions (see Section 3), and unlikely to
bioaccumulate (see Section 6), minimizing the likelihood that the chemical would be present in
sediment or groundwater to pose a longer-term drinking water contamination threat.
A sudden release of large quantities of the chemical near a drinking water source could have
immediate effects on the usability of a surface drinking water source. If such a release were to occur,
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two primary factors would operate together to reduce concern. First, the chemical would be expected
to present low concern to the general population, including susceptible subpopulations, across a
spectrum of health endpoints (see Section 6). Second, diethyl malonate would degrade in aerobic and
anaerobic environments (see Section 6). Together, these factors mean that any exposures to this
chemical through drinking water sources would be short-lived, and that if ingestion were to take
place, concern for adverse health effects would be low.
EPA also explored whether the chemical had been identified as a concern under U.S. environmental
statutes in the past. EPA searched lists of chemicals and confirmed that diethyl malonate does not
appear on these lists. The lists reviewed include EPA's List of Lists
(https://www.epa.gov/sites/production/files/2015-03/documents/list of lists.pdf). EPA also searched
the lists of chemicals included in the National Primary Drinking Water Regulations and the
Unregulated Contaminant Monitoring Rule (UCMR) under the Safe Drinking Water Act (SDWA).
Proposed conclusion: Based on a qualitative review of a potential release near a significant source of
drinking water, EPA proposes to conclude that the screening-level review under 40 CFR 702.9(a)(4)
does not support a finding that diethyl meets the standard for a high-priority substance. The
reasonably available information on storage near significant sources of drinking water described
above provides sufficient information to support these proposed findings.
8.5 Conditions of Use or Significant Changes in Conditions of Use of the
Chemical Substance
Approach: EPA evaluated the conditions of use for diethyl malonate and related potential exposures
and hazards.
Rationale: EPA evaluated the conditions of use of diethyl malonate (see Section 5 and Appendix A)
and found it to have a narrow range of conditions of use. EPA expects that even if the conditions of
use were to expand beyond activities that are currently known, intended, or reasonably foreseen, the
exposure outcome of the screening review would likely not change and would not alter the Agency's
conclusion of low concern. EPA bases this expectation on diethyl malonate's consistently low-
concern hazard characteristics across the spectrum of hazard endpoints and regardless of a change in
the nature or extent of its use and resultant increased exposures.
Proposed conclusion: EPA's qualitative evaluation of potential risk does not support a finding that
diethyl malonate meets the standard for a high-priority substance, based on its low-hazard profile
under the current conditions of use. EPA proposes to find that even if conditions of use broaden,
resulting in an increase in the frequency or amount of exposures, the analysis conducted to support
the screening-level review under 40 CFR 702.9(a)(5) would not change significantly. In particular,
the analysis of concern for hazard, which forms an important basis for EPA's findings, would not be
impacted by a change in conditions of use. Therefore, such changes would not support a finding that
diethyl malonate meets the standard for a high-priority substance. The reasonably available
information on conditions of use or significant changes in conditions of use described above provides
sufficient information to support this proposed finding.
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8.6 The Volume or Significant Changes in Volume of the Chemical
Substance Manufactured or Processed
Approach: EPA evaluated the current production volumes of diethyl malonate (Section 7.1) and
related potential exposures (Sections 7.2 through 7.4).
Rationale: EPA used reasonably available information on production volume (see Appendix A) in
considering potential risk. It is possible that designation of diethyl malonate as a low-priority
substance could result in increased use and higher production volumes. EPA expects, however, that
any changes in diethyl malonate's production volume would not alter the Agency's assessment of low
concern given the chemical's low-hazard profile. EPA bases this expectation on diethyl malonate's
consistently low-concern hazard characteristics across the spectrum of hazard endpoints. This
expectation would apply, even with a significant change in the volume of the chemical manufactured
or processed and resultant increased exposures.
Proposed conclusion: Based on this screening criteria under 40 CFR 702.9(a)(6), EPA proposes to
find that even if production volumes increase, resulting in an increase in the frequency or level of
exposure, diethyl malonate does not meet the standard for a high-priority substance. The reasonably
available information on production volume or significant changes in production volume described
above provides sufficient information to support this proposed finding.
8.7 Other Considerations
EPA did not identify other considerations for the screening review to support the proposed
designation of diethyl malonate as a low-priority substance.
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9. Proposed Designation
Based on a risk-based- screening-level review of the chemical substance and, when applicable,
relevant information received from the public and other information as appropriate and consistent
with TSCA section 26(h) and (i), EPA is proposing to designate diethyl malonate as a low-priority
substance as it does not meet the statutory criteria for a high-priority substance.
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Appendix A: Conditions of Use Characterization
EPA gathered information on and related to conditions of use including uses of the chemical,
products in which the chemical is used, types of users, and status (e.g., known, regulated).
A.1 CDR Manufacturers and Production Volume
The Chemical Data Reporting (CDR) rule (previously known as the Inventory Update Rule, or IUR),
under TSCA section 8, requires manufacturers (including importers) to report information on the
chemical substances they produce domestically or import into the U.S., generally above a reporting
threshold of 25,000 lb. per site per year. According to the 2016 CDR database, 9 companies
manufactured or imported diethyl malonate at 9 sites for reporting year 2015. Individual production
volumes were withheld, but may be available in later releases of the 2016 CDR.
Table A.l presents the historic production volume of diethyl malonate from the CDR (previously
known as the Inventory Update Rule, or IUR) from 1986-2015. In 1986, 1990, 1998, and 2006
reporting years, aggregate production volume for diethyl malonate was between 500,000 and
1,000,000 lbs. In the 1994 reporting year, aggregate production volume was between 1,000,000 and
10,000,000 lbs., and in the 2002 reporting year was between 10,000 and 500,000 lbs. For the 2012 to
2015 reporting years aggregate production volume was between 100,000 and 500,000 lbs., and for
2011, the exact amount was reported at 385,876 lbs. In general, since 2011, production volume has
remained relatively stable without significant increases or decreases.
Table A.1:1986-2015 National Production Volume Data for Diethyl Malonate (Non-Confidential Production
Volume in Pounds)
1986
1990
1994
1998
2002
2006
2011
2012
2013
2014
2015
500 K-
1 M
500 K-
1 M
1 M-
10 M
500 K-
1 M
10 K -
500 K
500 K-
1M
385,876
100 K
-500
K
100 K -
500 K
100 K
-500
K
100 K
-500
K
Source(s):
EPA (2018a; 2017b; 2006; 2002)
Note(s):
K = Thousand; M
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A.2. Uses
A.2.1 Methods for Uses
Section A.2 provides a list of known uses of diethyl malonate, organized by category of use. To
compile the uses, EPA searched publicly available databases listed in Tables A.2 and conducted
additional Google searches to clarify uses. Search terms differed among databases because of
different search term requirements for each database (i.e., some databases search by CASRN while
others search by chemical name).
Table A.2: Sources Searched for Uses of Diethyl Malonate
Title
Author and Year
Search Term(s)
Found Use
Information?1
Sources searched for all use reports
California Links to
Pesticides Data
California Dept of Pesticide
Regulation (2013)
105-53-3
No
Canada Chemicals
Management Plan
information sheets
Government of Canada
(2018)
105-53-3
No
Chemical and Product
Categories (CPCat)
CPCat (2019)
105-53-3
Yes
ChemView2
EPA (2018a)
105-53-3
Yes
Children's Safe Product
Act Reported Data
Washington State Dept. of
Ecology (2018)
105-53-3
No
Consumer Product
Information Database
(CPID)
DeLima Associates (2018)
105-53-3
Yes
Danish surveys on
chemicals in consumer
products
Danish EPA (2018)
Diethyl malonate
No
Datamyne
Descartes Datamyne
(2018)
Diethyl malonate
No
DrugBank
DrugBank (2018)
105-53-3; Diethyl malonate
No
European Chemicals
Agency (ECHA)
Registration Dossier
ECHA (2018)
105-53-3
Yes
eChemPortal2
OECD (2018)
105-53-3
Yes
Envirofacts2
EPA (2018b)
105-53-3
No
Functional Use Database
(FUse)
EPA (2017a)
105-53-3
Yes
Kirk-Othmer Encyclopedia
of Chemical Technology
Kirk-Othmer (2006)
Diethyl malonate
No
Non-Confidential 2016
Chemical Data Reporting
(CDR)
EPA (2017b)
105-53-3
Yes
PubChem Compound
Kimetal. (2016)
105-53-3
Yes
Safer Chemical Ingredients
List (SCIL)
EPA (2018d)
105-53-3
Yes
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Table A.2: Sources Searched for Uses of Diethyl Malonate
Title
Author and Year
Search Term(s)
Found Use
Information?1
Synapse Information
Resources2
Synapse Information
Resources (2009)
Diethyl malonate
Yes
Resource Conservation
and Recovery Act (RCRA)
EPA (2018c)
Diethyl malonate
No
Scorecard: The Pollution
Information Site
GoodGuide (2011)
105-53-3
No
Skin Deep Cosmetics
Database
EWG (2018)
105-53-3
No
Toxics Release Inventory
(TRI)
EPA (2018e)
Diethyl malonate
No
TOXNET2
NLM (2018a)
105-53-3
Yes
Ullmann's Encyclopedia of
Industrial Chemistry
Ullmann's (2000)
Diethyl malonate
No
Additional sources identified from reasonably available information
Procter & Gamble
P&G (2015)
Incidentally identified while
researching into details of this
chemical's uses and products.
Yes
Special Chem
Special Chem (2018)
Note(s):
1. If use information was found in the resource, it will appear in Table unless otherwise noted.
2. This source is a group of databases; thus the exact resource(s) it led to will be cited instead of the database as whole.
The U.S. Patent and Trademark Office has an online database that shows 6,038 patents referencing
"diethyl malonate" (USPTO 2018). Although patents could be useful in determining reasonably
foreseen uses, it is difficult to confirm whether any of the patented technologies are currently in use.
Uses inferred from patents containing diethyl malonate were not included in Table A.3. Note that the
uses in Table A.3 that are covered under TSCA are included in Section 5, Table 3 of this document.
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A.2.2 Uses of Diethyl Malonate
Table A.3: Uses of Diethyl Malonate |
Use
Expected Users
Description of Use and References
TSCA Conditions of Use: Air Scent and Fragrance Products
EPA (2017b); CPCat (2019); ECHA (2018)
Air care products
Consumer
CDR identified the use of diethyl malonate in air care products. CDR does not provide further details, however, this
category generally includes products such as air fresheners, candles, and scented gels. Air care products currently
available for use are listed elsewhere in this report, but CDR does not state the manufacturers of these products.
CPCat lists the use of diethyl malonate in "air fresheners and deodorizer." The ECHA registration dossier reports the
use of diethyl malonate in European countries in air care products.
Expected users are based on CDR's consumer/commercial classification.
P&G (2015)
Air freshener (oil
diffusion)
Consumer
Diethyl malonate is listed as an ingredient for one oil diffusing air freshener product. The product releases scent by
exposing scented oil to open air.
Expected users are consumer as the product is intended for consumer use only.
DeLima Associates (2015b)
Air freshener refills
(pluggable aerosol)
Consumer
Air freshener pluggable aerosol products are devices that contain refillable aerosol inserts, which plug into wall
outlets and automatically releases aerosol scented spritzes.
CPID generally includes products for consumer use; therefore, the expected user is a consumer.
DeLima Associates (2015a)
Air freshener refills
(pluggable liquid
dispenser)
Consumer
Air freshener pluggable liquid products are devices that contain scented liquid, which plug into wall outlets and
automatically releases liquid scented spritzes.
CPID generally includes products for consumer use; therefore, the expected user is a consumer.
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Table A.3: Uses of Diethyl Malonate
Use
Expected Users
Description of Use and References
EPA (2017b)
Aroma chemicals
Consumer, commercial
CDR identified the use of diethyl malonate in aroma chemicals used in various products using fragrance.
Expected users are based on CDR's consumer/commercial classification.
P&G (2016); CPCat (2019)
Car air freshener
Consumer
Diethyl malonate is listed as an ingredient for one car air freshener product. CPCat lists the use of diethyl malonate
in a car air freshener product.
Expected users are consumer as the product is intended for consumer use only.
CPCat (2019)
Perfumes
Industrial
CPCat lists the use of diethyl malonate in industrial perfumes.
Expected users are industrial based on CPCat's user classification.
Scented candle
Consumer
DeLima Associates (2016a)
CPID generally includes products for consumer use; therefore, the expected user is a consumer.
DeLima Associates (2016b)
Wax melts (scented)
Consumer
Wax melts are used to insert into devices that heat and melt the wax pellets to release scent.
CPID generally includes products for consumer use; therefore, the expected user is a consumer.
TSCA Conditions of Use: Industrial Uses
CPCat (2019); ECHA (2018)
Adhesive
Consumer, industrial
CPCat lists the use of diethyl malonate as a resin for industrial adhesive hardener, a type of bonding agent and an
adhesive for consumer use. The ECHA registration dossier reports the use of diethyl malonate in adhesives.
Expected users are industrial based on CPCat's user classification, and inclusion in ECHA's uses at industrial sites.
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Table A.3: Uses of Diethyl Malonate
Use
Expected Users
Description of Use and References
CPCat (2019)
Automotive paint
Industrial
CPCat lists the use of diethyl malonate in paint for automotive care including "bodywork repair."
Expected users are industrial based on CPCat's user classification.
CPCat (2019)
Chemical warfare
agents
Industrial
CPCat lists the use of diethyl malonate in chemical warfare agents. No further information could be found on the use
of diethyl malonate in chemical warfare agent.
Expected user is not stated, but it is most likely industrial for use of chemical warfare agents.
CPCat (2019); ECHA (2018)
Cleaning and washing
agents
Industrial
CPCat lists the use of diethyl malonate in industrial cleaning and washing. No further information could be found on
this use. The ECHA registration dossier reports the use of diethyl malonate in European countries in industrial
washing and cleaning products.
Expected users are industrial based on inclusion in ECHA's uses at industrial sites.
EPA (2017b)
Construction/ building
materials
Consumer, commercial,
industrial
CDR identified the use of diethyl malonate in processing - incorporation into formulation, mixture, or reaction product
in construction, and in "building/ construction materials not covered elsewhere." CPCat lists the use of diethyl
malonate in the "building of complete construction and parts thereof civil."
Expected users are consumer, commercial, and industrial based on identification in CDR's consumer/commercial
classification and industrial processing and use report.
CPCat (2019)
Motor vehicle care
Industrial
CPCat lists the use of diethyl malonate in the "maintenance and repair of motor vehicles" and "other motor vehicle
services." Other automotive uses in automotive paint, car air fresheners, and automotive manufacturing are recorded
elsewhere.
Expected users are industrial based on CPCat's user classification.
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Table A.3: Uses of Diethyl Malonate |
Use
Expected Users
Description of Use and References
TSCA Conditions of Use: Manufacturing
CPCat (2019]
Automotive
manufacturing
Industrial
CPCat lists the use of diethyl malonate in the "manufacture of motor vehicles, trailers, and semi-trailers."
Expected users are industrial based on CPCat's user classification.
CPCat (2019); ECHA (2018)
Chemical
manufacturing
Industrial
CPCat lists the use of diethyl malonate in the "manufacture of chemicals and chemical products." The ECHA
registration dossier reports the use of diethyl malonate in European countries as an intermediate in chemical
synthesis.
Expected users are industrial based on CPCat's user classification, and inclusion in ECHA's uses at industrial sites.
Synapse Information Resources (2009); Special Chem (2018)
Isocyanate blocking
agent
Industrial
Synapse Information Resources lists use of diethyl malonate as an isocyanate blocking agent. One press release
from a materials science company reports the development of a diethyl malonate-based isocyanates, which allows
"a significant reduction in the curing temperature of powder coatings formulated with it." This allows for easier
coating of wood and plastic objects in the manufacturing process. Current use of this method is unknown.
Expected users are unknown but are likely industrial for using an isocyanate blocking agent.
EPA (2017b); CPCat (2019)
Odor agent in
manufacturing
Industrial
CDR identified the use diethyl malonate as an odor agent in "miscellaneous manufacturing." CPCat lists the use
diethyl malonate as an odor agent "to change the way a product smells."
Expected users are industrial based on identification in CDR's industrial processing and use report.
CPCat (2019)
Toilet preparation
manufacturing
Industrial
CPCat lists the use of diethyl malonate in the "manufacturing of perfumes and toilet preparations."
Expected users are industrial based on CPCat's user classification.
VII
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table A.3: Uses of Diethyl Malonate |
Use
Expected Users
Description of Use and References
TSCA Conditions of Use: Cleaning Products
ECHA (2018)
Washing and cleaning
products
Consumer, commercial
The ECHA registration dossier reports the use of diethyl malonate in European countries in washing, cleaning, and
maintenance products. No further information about this specific use could be found and it is unknown whether this
is an ongoing use in the United States.
Expected users are consumer and commercial based on inclusion in ECHA's consumer uses and uses by
professional workers.
TSCA Conditions of Use: Paints and Coatings
ECHA (2018)
Coatings
Commercial
The ECHA registration dossier reports the use of diethyl malonate in European countries in coatings. No further
information about this specific use could be found and it is unknown whether this is an ongoing use in the United
States.
Expected users are commercial based on inclusion in ECHA's uses by professional workers.
CPCat (2019)
Paints, lacquers, and
varnishes
Industrial
CPCat lists the use diethyl malonate in paints, lacquers, and varnishes, and in paint primers. Use of paint for
vehicles is listed elsewhere.
Expected users are assumed to be industrial.
ECHA (2018)
Polishes and wax
blends
Consumer, commercial
The ECHA registration dossier reports the use of diethyl malonate in European countries in polish and wax blend
products. No further information about this specific use could be found and it is unknown whether this is an ongoing
use in the United States.
Expected users are consumer and commercial based on inclusion in ECHA's consumer uses and uses by
professional workers.
TSCA Conditions of Use: Miscellaneous
VIII
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table A.3: Uses of Diethyl Malonate
Use
Expected Users
Description of Use and References
CPCat (2019)
Absorbents and
adsorbents
Industrial
CPCat lists the use of diethyl malonate as absorbent and adsorbent. No further information could be found on this
use.
Expected users are assumed to be industrial.
Non-TSCA Uses
Synapse Information Resources (2009)
Barbiturates
Unknown
Synapse Information Resources lists use of diethyl malonate as an intermediate in barbiturates. Barbiturates refer to
any sedatives derived from barbituric acid.
Expected users are unknown, due to the limited availability of information.
ECHA (2018)
Biocides
Unknown
The ECHA registration dossier reports the use of diethyl malonate in European countries in biocides. No further
information about this specific use could be found and it is unknown whether this is an ongoing use in the United
States.
Expected users are consumer based on inclusion in ECHA's consumer uses.
CPCat (2019)
Cigarettes
Unknown
CPCat lists the use diethyl malonate as an additive in cigarettes. No further information could be found on this use.
Expected users are unknown, due to the limited availability of information.
Synapse Information Resources (2009)
Flavoring agent in
pharmaceuticals
Industries
Synapse Information Resources lists the use of diethyl malonate as a synthetic flavoring agent in pharmaceuticals.
Expected users are unknown but are likely industrial for use of a flavoring agent in pharmaceuticals.
IX
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table A.3: Uses of Diethyl Malonate
Use
Expected Users
Description of Use and References
Synapse Information Resources (2009); CPCat (2019); ECHA (2018)
Fragrance in
cosmetics and
personal care
products
Consumer, commercial
Synapse Information Resources lists the use of diethyl malonate as a fragrance in cosmetics. CPCat lists the use
diethyl malonate as a fragrance in personal care products. The ECHA registration dossier reports the use of diethyl
malonate in European countries in cosmetics as a perfume/ fragrance.
Expected users are consumer and commercial based on inclusion in ECHA's consumer uses and uses by
professional workers.
ECHA (2018)
Perfume/ fragrance in
pharmaceuticals
Consumer
The ECHA registration dossier reports the use of diethyl malonate in European countries in pharmaceuticals as a
perfume/ fragrance. No further information about this specific use could be found and it is unknown whether this is
an ongoing use in the United States.
Expected users are consumer based on inclusion in ECHA's consumer uses.
EPA (2017b); CPCat (2019); ECHA (2018)
Pharmaceutical and
medicine
manufacturing
Industrial
CDR identified the use diethyl malonate as an intermediate for pharmaceuticals in pharmaceutical and medicine
manufacturing. CPCat lists the use diethyl malonate in drug manufacturing. The ECHA registration dossier reports
the use of diethyl malonate in European countries as an intermediate in pharmaceuticals.
Expected users are industrial based on identification in CDR's industrial processing and use report.
Synapse Information Resources (2009); CPCat (2019)
Synthetic flavoring
agent in foods
Unknown
Synapse Information Resources lists the use of diethyl malonate as a synthetic flavoring agent in foods, described
as a "fruity flavor". CPCat lists the use of diethyl malonate as a food additive flavoring.
Expected users are unknown, due to the limited availability of information.
Children's Products
CDR reports did not include any uses in children's products.
Recycling and Disposal
In the 2016 CDR, five facilities reported that the chemical was not recycled (e.g., not recycled, remanufactured, reprocessed, or reused). For three facilities, this information
was withheld. For one facility, information was not known or reasonably ascertained. No further information about recycling or disposal was found.
X
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
A.3 References
California Dept of Pesticide Regulation. (2013). DPR Databases. Retrieved from
httos: //www. cdpr. ca. gov/dprdatabase .htm
Danish EPA. (2018). Danish surveys on chemicals in consumer products. Retrieved from
https://cng.mst.dk/chcmicals/chcmicals-in-products/consumcrs-consumcr-products/danish-
survevs-on-consumer-products/
DeLima Associates. (2015a). Febreze Noticeables Linen & Sky: Fresh Linen-Fluffy Clouds. Retrieved
from
https://www.whatsinproducts.com/tvpes/tvpe detail/1/1806 l/standard/p%20class=%22pl%22%3
EFebreze%20Noticeables%20Linen%20&%20Skv:%20Fresh%20Linen-
Fluff\%20Clouds.%20Sccntcd%20Qil%20Rcfills-04/l 5/2015/p%3E/l 6-033-426
DeLima Associates. (2015b). Glade Sense and Spray Refill, Apple Cinnamon, Aerosol. Retrieved from
https://www.whatsinproducts.com/tvpes/tvpe detail/l/16662/standard/p%20class=%22pl%22%3
EGlade%20Sense%20and%20Sprav%20Refill.%20Apple%20Cinnamon.%20Aerosol-
02/24/2015/p%3E/19-001-685
DeLima Associates. (2016a). Glade Endless Color Candle, Adventurous Orange. Retrieved from
https://www.whatsinproducts.com/tvpes/tvpe detail/l/16690/standard/p%20class=%22pl%22%3
EGladc%20Endlcss%20Color%20Candlc.%20Advcnturous%200rangc-02/24/2015/p%3E/l 9-
001-713
DeLima Associates. (2016b). Glade Wax Melts, Apple Cinnamon. Retrieved from
https://www.whatsinproducts.com/tvpes/tvpe detail/1/16718/standard/p%20class=%22pl%22%3
EGlade%20Wax%20Melts.%20Apple%20Cinnamon-02/24/2015/p%3E/l 9-001 -742
DeLima Associates. (2018). Consumer Product Information Database. Retrieved from
https: //www. whatsinproducts. com/
Descartes Datamyne. (2018). Descartes Datamyne Import-Export Database.
Dionisio, K. L., Frame, A. M., Goldsmith, M.-R., Wambaugh, J. F., Liddell, A., Cathey, T., . . . Judson,
R. S. (2015). Exploring consumer exposure pathways and patterns of use for chemicals in the
environment. Toxicology! Reports, 2, 228-237. doi:http://dx.doi.org/10.1016/i.toxrep.2014.12.009
DrugBank. (2018). DrugBank Database. Retrieved from https://www.drugbank.ca/
European Chemicals Agency (ECHA). (2018). Diethyl malonate. Retrieved from
https://echa.europa.eu/registration-dossier/-/registered-dossier/5774/3/l/6
EWG. (2018). Skin Deep Cosmetics Database. Retrieved from
https: //www.ewg. org/skindeep/#. W4RpIPlKiUk
GoodGuide. (2011). Scorecard: The Pollution Information Site. Retrieved from
http://scorecard.goodguide.com/chemical-profiles/index.tcl
Government of Canada. (2018). Chemical Substances: Services and Information. Retrieved from
https://www.canada.ca/en/health-canada/services/chemical-substances.html
XI
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Kim, S., Thiessen, P. A., Bolton, E. E., Chen, J., Fu, G., Gindulyte, A., . . . Bryant, S. H. (2016).
PubChem Substance and Compound databases. Nucleic Acids Research, -/-/(Database issue),
D 1202-D 1213. doi: 10.1093/nar/gkv951
Kirk-Othmer. (2006). Kirk-Othmer Encyclopedia of Chemical Technology.
Organisation for Economic Cooperation and Development (OECD). (2018). eChemPortal: Global Portal
to Information on Chemical Substances. Retrieved from
https: //www .echemportal. org/echemportal/index. action
P&G. (2015). Safety Data Sheet Febreze Set & Refresh. Retrieved from
https://www.pg.com/productsafetv/sds/SDS 2015/FEBREZE SET & REFRESH -
FROSTED PINE.pdf
P&G. (2016). Safety Data Sheet. Retrieved from
https://www.pg.com/productsafetv/sds/SDS 2016/Febreze Car vent clips Fresh Cut Pine.pdf
Special Chem. (2018). Bayer Polymers Develops Diethyl Malonate-Blocked Isocyanate Crosslinker for
Powder Coatings. Retrieved from https://coatings.specialchem.com/news/product-news/baver-
polvmers-develops-diethvl-malonate-blocked-isocvanate-crosslinker-for-powder-coatings
Synapse Information Resources. (2009). Specialty Chemicals Source Book. Fourth Edition. Volume 1.
U.S. Environmental Protection Agency (EPA). (2002). 1986-2002 Historical IUR Data. Retrieved from
Excel File
U.S. Environmental Protection Agency (EPA). (2006). 2006 IUR Public Database.
U.S. Environmental Protection Agency (EPA). (2017a). Functional Use Database (FUse). Retrieved
from: https://catalog.data.gov/dataset/functional-use-database-fuse
U.S. Environmental Protection Agency (EPA). (2017b). Non-Confidential 2016 Chemical Data Reporting
(CDR). Retrieved from https://www.epa.gov/chemical-data-reporting
U.S. Environmental Protection Agency (EPA). (2018a). ChemView. Retrieved from
https: //chemvie w .epa. gov/chemview
U.S. Environmental Protection Agency (EPA). (2018b). Envirofacts Multisystem Search. Retrieved from
https://www3.epa.gov/enviro/facts/multisvstem.html
U.S. Environmental Protection Agency (EPA). (2018c). Look up table for BR Waste Code (National
Biennial RCRA Hazardous Waste Report). Retrieved from
https://iaspub.epa.gov/enviro/brs codes v2.waste lookup
U.S. Environmental Protection Agency (EPA). (2018d). Safer Chemical Ingredients List. Retrieved from
https://www.epa.gov/saferchoice/safer-ingredients
U.S. Environmental Protection Agency (EPA). (2018e). TRI-Listed Chemicals. Retrieved from
https://www.epa.gov/toxics-release-inventorv-tri-program/tri-listed-chemicals
XII
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
U.S. National Library of Medicine (NLM). (2018a). ChemlDplus, a TOXNET Database. Retrieved from
httos: //chem .nlm .nih. gov/chemidplus/
U.S. National Library of Medicine (NLM). (2018b). Haz-Map. Retrieved from
https://hazmap.nlm .nih. gov/categorv-details?id=8344&table=copvtblagents
U.S. Patent and Trademark Office (USPTO). (2018). USPTO Patent Full-Text and Image Database.
Retrieved from http: //patft .uspto. gov/netacgi/nph-
Parser?Sectl=PT02&Sect2=HIT0FF&p=l&u=%2Fnetahtml%2FPTQ%2Fsearch-
bool ,html&r=0&f=S&l=5 O&TERM 1 =diethvl+malonate&FIELD 1=&co 1 =AND&TERM2=&FIE
LD2=&d=PTXT
Ullmann's. (2000). ULLMANN'S Encyclopedia of Industrial Chemistry.
Washington State Dept. of Ecology. (2018). Children's Safe Product Act Reported Data. Retrieved from
https://fortress.wa.gov/ecv/cspareporting/
XIII
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Appendix B: Hazard Characterization
Table B.1: Human Health Hazard
ADME
Source
Exposure Route
Species & Strain (if
available)
Duration
Doses and
Replicate Number
Effect
Study Details
1141389,
4939812
Dermal (in vitro)
Human cadaver
24 hours
Dose: 4 uL/0.8 cm2
skin
16% of applied dose
penetrated through
skin
Method:
Test substance reported as
CASRN 105-53-3
Purity: 99% purity
Guideline study and GLP not
reported
Results:
Mean penetration rate: 120
|jg/cm2/hour; max flux rate:
350 |jg/cm2/hour
45-50% of applied substance
evaporated, and 34-39%
remained on skin
1141389,
4939812
Dermal (in vitro)
Yorkshire pig
50 hours
Dose: 100|jg/cm2;
100|jg diluted in
ethanol (12.5 mg/mL)
/cm2; 4|jg in ethanol
(0.5 mg/mL)/cm2
3-10% of applied dose
was absorbed; 8-30%
of applied dose
remained in skin
Method:
Test substance reported as
CASRN 105-53-3
Purity > 95%
Method and GLP not
reported
Results:
100 |jg group: 3% ± 1 % of
dose was absorbed with 8%
± 0.5% remained in skin
100 |jg diluted group: 6% ±
3% of dose was absorbed
with 13% ± 2% remaining in
skin
4 |jg diluted group: 10 ± 3%
of dose was absorbed with
30 ± 10% remaining in skin
25-50% loss of radioactivity
due to evaporation
XIV
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table B.1: Human Health Hazard
1141389,
4923746
Dermal (in vitro)
Yorkshire pigs
24 hours
Dose: 1 mg/cm2 in
10 |jL acetone
0.2-16% applied dose
in acceptor cell, 0.2-
0.9% in skin, and 0.6-
0.7% on surface
Method:
Test substance reported as
CASRN 105-53-3 (DEM)
Purity: 98%
Method and GLP compliance
not reported
Results:
Radiolabeled hydrolysis
products (monomethyl
malonate and malonic acid)
were 15-35% (total) with 20-
21 % in the acceptor cell, 3-
5% in the skin, and 2-4% on
the surface
Heat treated skin samples
had increased absorption of
radiolabeled DEM and
decreased hydrolysis
products
Total recovery of radiolabel
was 50-80%; some radiolabel
lost to volatilization
94897
Dermal
Athymic nude
mice
Yorkshire pigs
Hairless dog
Human skin
grafted on
athymic nude
mice
Pig skin grafted
on athymic nude
mice
24-48 hours
Dose: 0.1 mg/cm2
2.5% to 15%
penetration of the
applied dose
Method:
Test substance reported as
CASRN 105-53-3
Purity > 98%
Method and GLP compliance
not reported
Results:
Athymic nude mice: 15 ± 2%
penetration
Yorkshire pigs: 2.5 ± 0.2%
penetration
Hairless dog: 4 ± 2%
penetration
XV
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table B.1: Human Health Hazard
human skin grafted on
athymic nude mice: 4 ± 2%
penetration
Pig skin grafted on athymic
nude mice: 6 ± 1 %
penetration
Acute Mammalian Toxicity
Source
Exposure Route
Species & Strain (if
available)
Duration
Doses and
Replicate Number
Effect
Study Details
4940215
Oral (feed)
WISW rats
Single
exposure
Dose: 2000 mg/kg
Replicates: 5
per sex
LDso > 2000 mg/kg
Methods:
Test substance reported as
CASRN 108-59-8
Purity not reported
OECD Guideline 401
GLP compliant
4940413,
1141389
Oral (gavage)
WISW rats
Single
exposure,
observed for 14
days
Dose: 2000 mg/kg
Replicates: 5 per
sex
LD50 > 2000 mg/kg
Methods:
Test substance reported
as CASRN 108-59-8
Purity: 99%
OECD Guideline 401
GLP compliant
1141389,
4940412
Dermal
WISW rats
24 hour
exposure,
observed up to
14 days
Dose: 2000 mg/kg
Replicates: 5 per
sex
LD50 > 2000 mg/kg
Methods:
Test substance reported as
CASRN 108-59-8
Purity: 99%
OECD Guideline 402
GLP compliant
Repeated Dose Toxicity
Source
Exposure Route
Species & strain (if
available)
Duration
Doses and replicate
number
Effect
Study Details
1141389,
4940227
Oral (gavage)
Wistar rats
39 days
(males), 51
days (females)
Doses: 0,100, 300,
and 1000 mg/kg-
day
NOAEL: 300 mg/kg-
day;
LOAEL: 1000 mg/kg-
day based on
hepatocellular
hypertrophy
Methods:
Test substance reported
as CASRN 108-59-8
Purity 99.8%
OECD Guideline 422
GLP compliant
Endpoints:
XVI
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table B.1: Human Health Hazard
Replicates: 10 per
Significantly increased
sex per group in main
incidences of hepatocellular
group, 5 per sex per
hypertrophy in highest
dose in recovery
dose. The effect was
group
reversible as the effect was
not increased in recovery
group animals.
Reproductive Toxicity
Source
Exposure Route
Species & Strain (if
available)
Duration
Doses and replicate
number
Effect
Study Details
1141389
Oral (gavage)
Wistar rats
39 days
Doses: 0,100, 300,
NOAEL: 1000 mg/kg-
Methods:
(males), 51 day
(females)
and 1000 mg/kg-
day
Replicates: 10 per
sex per group in main
group, 5 per sex per
dose in recovery
group
day
Test substance reported as
CASRN 108-59-8
Purity 99.8%
OECD Guideline 422
GLP compliant
Developmental Toxicity
Source
Exposure Route
Species & Strain (if
available)
Duration
Doses and replicate
number
Effect
Study Details
1141389
Oral (gavage)
Wistar rats
39 days
Doses: 0,100, 300,
NOAEL: 1000 mg/kg-
Methods:
(males), 51 day
(females)
and 1000 mg/kg-
day
Replicates: 10 per
sex per group in main
group, 5 per sex per
dose in recovery
group
day
Test substance reported as
CASRN 108-59-8
Purity 99.8%
OECD Guideline 422
GLP compliant
5097463
Inhalation
Hra(NZW) SPF rabbits
Gestation Day
7 to 28
Doses: 0, 0.03, 0.10,
0.30, and 1 mg/L-day
Replicates: 22 per
group
NOAEC: 1 mg/L-day
Methods:
Test substance reported as
CASRN 1119-40-0
Purity 99.61%
OPPTS 870.3700
GLP compliant
Cancer
XVII
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table B.1: Human Health Hazard
Source
Effect
Study Details
OncoLogic v8.0
OncoLogic currently has no assessment criteria
regarding diesters.
Structure could not be evaluated by Oncologic
ISS v2.443
Negative (estimated)
Diethyl malonate does not contain any structural
features indicative of electrophilic potential.
Methods:
Carcinogenicity alerts by ISS profiler
Results:
No alerts were identified for the parent structure (an aldehyde
alert is flagged for its primary aldehyde metabolite)
VEGA 1.1.4"
Diethyl malonate was processed through all 4 models. 3
of the models predicted it to be non-carcinogenic with
low-moderate reliability. 1 model predicted it to be
carcinogenic with low reliability.
Methods:
VEGA 1.1.4 contains 4 models for carcinogenicity - CAESAR
2.1.9, ISS 1.0.2, IRFMN/Antares 1.0.0, IRFMN/ISSCAN-GX
1.0.0
Overall, diethyl malonate is expected not to be
carcinogenic on the basis of the VEGA predictions.
Results:
CAESAR 2.1.9: Predicted to be Carcinogenic with low
reliability (diethyl malonate lies outside of the applicability
domain (AD) of the model)
ISS 1.0.2: Predicted to be Non-carcinogenic with low
reliability (diethyl malonate lies outside of the AD)
IRFMN/Antares 1.0.0: Predicted to be Possible Non-
carcinogen with low reliability (diethyl malonate lies outside
of the AD)
IRFMN/ISSCAN-GX 1.0.0: Predicted to be Possible Non-
carcinogen with moderate reliability (diethyl malonate
could be outside of the AD)
43 Carcinogenicity alerts by ISS profiler comprises 55 structural alerts for genotoxic and non-genotoxic carcinogenicity. The alerts have been compiled upon existing knowledge of
the mechanism of action of carcinogenic chemicals that have been published elsewhere (Benigni andBossa (2011) Chem Rev 111: 2507-2536 andBenigni R et al. (2013) Chew
Rev. 113: 2940-2957).
44 VEGA 1.1.4 contains 4 different models to facilitate an in silico assessment of carcinogenicity potential. The models are summarized in Golbamaki et al. (2016) J Environ Sci
and Health Part C http://dx.doi.org/10.1080/10590501.2Q16.1166879 as well as in documentation that is downloadable from within the VEGA tool itself
(https: //www. vegahub. eu/).
CAESAR 2.1.9 is a classification model for carcinogenicity based on a neural network.
ISS 1.0.2 is a classification model based on the ISS ruleset (as described above for the OECD Toolbox).
IRFMN/Antares 1.0.0 and IRFMN/ISSCAN-GX 1.0.0 are classification models based on a set of rules built with SARpy software (part of the same suite of VEGA tools
https://www.vegahub.eu/) extracted from the Antares and ISSCAN-CGX datasets respectively.
XVIII
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table B.1: Human Health Hazard
Genotoxicity
Source
Exposure Route
Species & Strain (if
available)
Duration
Doses and replicate
number
Effect
Study Details
1141389
Gene mutation (in
Salmonella
With and
Doses: 8, 40, 200,
Negative
Methods:
vitro)
typhimurium strains
TA98, TA100, TA1535,
TA1537, TA1538
without
1000, and 5000
|jg/plate
Test substance reported as
CASRN 105-53-3
Purity not reported
Directive 84/449/EEC B.14
GLP compliant
1141389
Gene mutation (in
Salmonella
With and
Doses: up to 5000
Negative
Methods:
vitro)
typhimurium strains
TA97, TA98, TA100
without
|jg/plate
Test substance reported as
CASRN 105-53-3
Purity not reported
GLP compliance not
reported
1141389,
Chromosomal
Human peripheral
With and
Doses: 0, 312.5,
Negative
Methods:
4940224
aberrations (in vitro)
lymphocytes
without
625, 1250,
2500, and 5000
Ijg/mL
Test substance reported as
CASRN 108-59-8
Purity: 99.8%
OECD Guideline 473
GLP compliant
5097466
Chromosomal
Fischer 344 Albino
With
Doses: 0, 0.5,1.0,
Negative
Methods:
aberrations (in
Rats
and 2.0 mg/L
Test substance reported as
vivo), inhalation
Replicates: 5 per
CASRN 1119-40-0
sex per dose
Purity: 99.61%
OECD Guideline 474
GLP compliant
Sensitization I
Source
Exposure Route
Species & Strain (if
available)
Duration
Doses and replicate
number
Effect
Study Details
4940214
Dermal
Dunkin Hartley guinea
Observed for
Doses: 0.4 to
Negative
Methods:
pigs
72 hours
0.46 g of test
substance
Replicates: 10
animals per dose
Test substance reported as
CASRN 108-59-8
Purity not reported
OECD Guideline 406
GLP compliant
XIX
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table B.1: Human Health Hazard
Irritation
Source
Exposure Route
Species & Strain (if
Duration
Doses and replicate
Effect
Study Details I
available)
number
1141389
Ocular
White Russian rabbits
Observed for
Dose: 0.1 mL of
Positive
Methods: I
21 days
undiluted substance
Replicates: 6 total
rabbits
Test substance reported as
CASRN 105-53-3
Purity not reported
GLP compliant
Results:
Average irritation scores for
cornea, iris, conjunctivae
redness and chemosis were
0.6,0.8,1.7, and 1.3,
respectively, with an overall
irritation (Draize) score of
25.8 out of 110
All effects were fully
reversible within 21 days
1141389,
Dermal
White Russian rabbits
4 hour
Dose: 0.5 mL of
Negative
Methods: I
4940218
exposure,
observed for 72
hours
undiluted substance
Replicates: 1 male a
nd 2 females
Test substance reported as
CASRN 108-59-8
Purity: 99%
OECD Guideline 404
GLP compliant
Results:
Slight erythema was
observed in all animals 30-60
minutes after removal of the
patch, but no other signs of
irritation
Considered to be non-
irritating
Neurotoxicity
Source
Exposure Route
Species & Strain (if
Duration
Doses and replicate
Effect
Study Details I
available)
number
L_
XX
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table B.1: Human Health Hazard
1141389,
4940227
Oral (gavage)
Wistar rats
39 days
(males), 51
days (females)
Doses: 0,100, 300,
and 1000 mg/kg-day
Replicates: 5 per
sex per dose
NOAEL: 1000 mg/kg-
day
Methods:
Test substance reported as
CASRN 108-59-8
Purity 99.8%
OECD Guideline 422
GLP compliant
Endpoints:
No effects were noted for
functional observational
battery test
4923714
Neuron cytotoxicity (In
vitro)
Fetal Sprague-Dawley
rat primary culture
neurons
72 hours
Dose: 50 pM
Negative
Methods:
Test substance reported as
CASRN 108-59-8
Purity not reported
GLP compliance not
reported
4933586
Electron transport
chain assays
Wistar rat cerebral
cortex homogenates
Single
exposure
Doses: 1, 2.5, and 5
mM
Significant inhibition
of Complex I, Complex
II, Complex l+lll, and
Complex I l+lll
activities, but not
Complex III or
Complex IV activities
Methods:
Test substance reported as
CASRN 108-59-8
Purity not reported
GLP compliance not
reported
4926318
Neuron cytotoxicity (In
vitro)
Primary neuronal cells
isolated
from rat spinal cord tis
sue
48 hours
Doses: 0,10, 20, 30,
50, and 100 mM
Causes selective
motor neuron death at
lower doses. The
toxicity is mediated by
ionotropic glutamate
receptors
Methods:
Test substance reported as
CASRN 108-59-8
Purity not reported
GLP compliance not
reported
XXI
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Table B.1: Human Health Hazard
4931886
Neuron cytotoxicity (In
vitro)
Mesencephalic culture
from embryonic day 15
rats
24 hours
Dose: 50 pM
Suggests that
glutamate receptors
become involved after
the interruption of
energy metabolism
and contributes to
irreversible cell
damage
Methods:
Test substance reported as
CASRN 108-59-8
Purity not reported
GLP compliance not
reported
4933534
Neuron, IP injection
Male Swiss
Webster mice
15 minutes
Via striatal
microdialysis,
24 hour
observation
Doses: 4 pM to 2.67
M
Suggests that
dopamine efflux via the
dopamine transporter
plays a role in neuronal
cell damage
Methods:
Test substance reported as
CASRN 108-59-8
Purity not reported
GLP compliance not
reported
4933481
Mechanistic
neurological
Brain homogenate
from adult Wistar rats
Doses: 1, 2 and 4
mmol/L
Direct interactions of
malonate with NMDA
receptors are not
involved in malonate
pro-oxidative activity in
vitro
Methods:
Test substance reported as
CASRN 108-59-8
Purity not reported
GLP compliance not
reported
XXII
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Table B.2: Environmental Hazard
Aquatic Toxicity: Experimental
Source
Species & strain (if
available)
Duration
Doses and
replicate number
Effect
Study Details
4939286
Pimephales promelas
96 hours
Doses: 0, 5.06,
9.51, 17.2, 34.3,
and 64.1 mg/L
LCso: 14.9 mg/L
Methods:
Test substance reported as CASRN 105-53-3
Purity: 99%
GLP compliant
Results:
EC50:14.8 mg/L
4939288
Pimephales promelas
96 hours
Doses: 0.22,
6.78, 9.59, 16.3,
24.6, and 33.5
mg/L (measured)
LCso: 11.8 mg/L
Methods:
Test substance reported as CASRN 105-53-3
Purity: 99%
GLP compliant
4935263
Pimephales promelas
96 hours
Doses: 2.8,10.4,
13.2, 20.6, 33.3,
and 54.6 mg/L
(measured)
LCso: 17 mg/L
Methods:
Test substance reported as CASRN 105-53-3
Purity: 99%
OECD Guideline 203
GLP compliance not reported
4935263
Pimephales promelas
96 hours
Doses: 0, 5.1-
5.4, 9.0-10.4,
17.4-18.3, 33.2-
37.5, and 63.6-
67.5 mg/L
(measured)
LCso: 15.4 mg/L
Methods:
Test substance reported as CASRN 105-53-3
Purity: 99%
OECD Guideline 203
GLP compliance not reported
4935263
Pimephales promelas
96 hours
Doses: 0, 6.78,
9.59, 16.3, 24.6,
and 33.5 mg/L
(measured)
LCso: 12 mg/L
Methods:
Test substance reported as CASRN 105-53-3
Purity not reported
GLP compliance not reported
4935263
Daphnia magna
48 hours
Doses: 0,100,
140, 200, 280,
400, 560, and 800
mg/L (nominal)
ECso: 202 mg/L, 95%
confidence limit: 175.2 -
233.6
Methods:
Test substance reported as CASRN 105-53-3
Purity: 99.5%
Test method 84/449/EC C.2
GLP compliant
Results:
ECo: 100 mg/L (nominal
EC100: 400 mg/L (nominal)
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4935263
Scenedesmus subspicatus
72 hours
Doses: 0,12.5,
25, 50, 100, 200,
400, and 800
mg/L (nominal)
ECso > 800 mg/L
Methods:
Test substance reported as CASRN 105-53-3
Purity not reported
Guideline 88/302/EEC
GLP compliance not reported
Results:
EC10:115 mg/L (nominal)
NOEC: 25 mg/L (nominal)
Aquatic Toxicity: Estimated
Model
Endpoint
Species
Predicted Effect
Level
Notes
ECOSAR
v2.0 (Class:
Esters)
Estimated
Freshwater
fish
8.1 mg/L
Input SMILES: 0=C(0CC)CC(=0)0CC. Experimental input values: logKow = 0.96; WS
= 23200 mg/L; MP = -50°C.
ECOSAR
v2.0 (Class:
Esters)
Estimated
Daphnia
magna
190 mg/L
Input SMILES: 0=C(0CC)CC(=0)0CC. Experimental input values: logKow = 0.96; WS
= 23200 mg/L; MP = -50°C.
ECOSAR
v2.0 (Class:
Esters)
Estimated
Green algae
18 mg/L
Input SMILES: 0=C(0CC)CC(=0)0CC. Experimental input values: logKow = 0.96; WS
= 23200 mg/L; MP = -50°C.
Table B.3: Fate
Environmental Fate: Experimental
Source
Endpoint
Duration
Doses and number of
replicates
Results
Study Details
4935263
Biodegradation
28 days
Dose: 9.56 mg/L
Readily biodegradable
Methods:
Test substance reported as CAS RN 105-53-3
Purity > 99%
OECD Guideline 301A
GLP compliant
Biodegradation kinetics:
92% in 7 days
98% in 28 days
4935263
Photolysis
35 minutes
Dose: 5 mg/L
Readily photolyzes
Methods:
Test substance reported as CAS RN 105-53-3
Purity not reported
XXIV
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Photolytic Ozonation
GLP compliance not reported
Results:
100% in 35 minutes
4923463
Photooxidation
N/A.
Doses: 5-7 pL
Rate coefficient (k)
(3.75 ± 0.4) x 10-12
cm3/molecules-second
Methods:
Test substance reported as CAS RN 108-59-8
Purity: 98%
GLP compliance not reported
4924633
Toxicity to
3 and 28 days
Doses: 0-2500 |jg/g
Negative; ECso > 2500
Methods:
microorganisms
(nominal)
Mg/g
Test substance reported as CAS RN 105-53-3
Purity not reported
GLP compliance not reported
4924617,
Volatilization
Doses: 150 mg/m3 and
T1/2:1.2-2 hours
Methods:
4924633
(soil)
1500 mg/m3
Test substance reported as CAS RN 105-53-3
Purity not reported
GLP compliance not reported
4924617,
Volatilization
Doses: 150 mg/m3 and
T1/2: 1.29 to 242.5 hours
Methods:
4924633
(foliar surfaces)
1500 mg/m3
Test substance reported as CAS RN 105-53-3
Purity not reported
GLP compliance not reported
Results:
Foliar surface composition is likely to affect sorption and
volatilization
Environmental Fate: Modelled
Model
Data Type
Endpoint
Predicted Endpoint
Notes
EPISuite
Estimated
BAF
1.058
v.4.11
EPISuite
Estimated
BCF
3.162
v.4.11
EPISuite
v.4.11
Estimated
Anaerobic
biodegradation
Predicted to biodegrade
quickly under anaerobic
Predicted probability of 1.0986. Fragment representation is valid.
Fast degradation is defined as predicted probability > 0.5.
(BIOWIN
7)
conditions
XXV
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B.1 References:
Call. DJ; Brooke. LT; Ahmad. N; Vaishnav. DP. (1981). Aquatic pollutant hazard assessments and development of ahazard prediction technology
by quantitative structure-activity relationships: First quarterly report to EPA. (U.S. EPA Cooperative Agreement No. CR 809234010).
Superior, WI: University of Wisconsin-Superior, Center for Lake Superior Environmental Studies.
Chellauist. EM; Reifenrath. WG. (1988). Distribution and fate of diethyl malonate and diisopropyl fluorophosphate on pig skin in vitro. J Pharm
Sci 77: 850-854. http://dx.doi.org/10.1002/ips.26007710Q8
CIR Expert Panel (Cosmetic Ingredient Review Expert Panel). (2010). Pink book 3: Sebacic acid/dicarboxylic acids, https://www.cir-
safetv.org/sites/default/files/116 tent sebaci rev.pdf
EC HA (European Chemicals Agency). (1992a). Dimethyl malonate: acute toxicity: dermal. https://echa.europa.eu/registration-dossier/-/registered-
dossier/8170/7/3/4
EC HA (European Chemicals Agency). (1992b). Dimethyl malonate: acute toxicity: oral. https://echa.europa.eu/registration-dossier/-/registered-
dossier/20020/7/3/2
EC HA (European Chemicals Agency). (1992c). Dimethyl malonate: acute toxicity: oral (registration dossier 8170).
https://echa.europa.eu/registration-dossier/-/registered-dossier/8170/7/3/2
EC HA (European Chemicals Agency). (1992d). Dimethyl malonate: eye irritation: 001 key | experimental result. Helsinki, Finland.
https://echa.europa.eu/registration-dossier/-/registered-dossier/20020/7/4/3
EC HA (European Chemicals Agency). (1992e). Dimethyl malonate: eye irritation: in vivo. Helsinki, Finland, https://echa.europa.eu/registration-
dossier/-/registered-dossier/8170/7/4/3
EC HA (European Chemicals Agency). (1992f). Dimethyl malonate: skin irritation/corrosion in vivo. Helsinki, Finland.
https://echa.europa.eu/registration-dossier/-/registered-dossier/8170/7/4/2
EC HA (European Chemicals Agency). (1992g). Dimethyl malonate: skin sensitisation: in vivo (non-LLNA): 001 key | experimental result.
https://echa.europa.eu/registration-dossier/-/registered-dossier/20020/7/5/2
EC HA (European Chemicals Agency). (2003). Dimethyl malonate: repeated dose toxicity: oral. Helsinki, Finland.
https://echa.europa.eu/registration-dossier/-/registered-dossier/8170/7/6/2
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EC HA (European Chemicals Agency). (2003). Dimethyl malonate: genetic toxicity: in vitro: 002 key | experimental result. Helsinki, Finland.
https://echa.europa.eu/registration-dossier/-/registered-dossier/8170/7/7/2/?documentUUID=21a208f6-4910-498 l-b296-e2d!59e lb638
Fellows. RJ: Harvey. SD; Ligotkc. MW: Cataldo. DA; Li. SW. (1990). Environmental persistence and toxicity of dimethyl malonate and methyl
salicylate. (DE91012775; PNL-SA-19465). Washington, DC: Department of Energy.
Geiger. PL; Poirier. SH; Brooke. LT; Call. DJ. (1986). Diethyl malonate. In DL Geiger; SH Poirier; LT Brooke; DJ Call (Eds.), Acute toxicities of
organic chemicals to fathead minnows (Pimephales promelas): Volume III (pp. 177-178). Superior, WI: University of Wisconsin-Superior,
Center for Lake Superior Environmental Studies.
Kanki. R; Nakamizo. T; Yamashita. H; Kihara. T; Sawada. H; Uemura. K; Kawamata. J; Shibasaki. H; Akaike. A; Shimohama. S. (2004). Effects
of mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons. Brain Res 1015: 73-81.
http://dx.doi.Org/10.1016/i.brainres 2004.04.044
Mclaughlin. BA; Nelson. D; Erecinska. M; Chesselet. MF. (1998). Toxicity of dopamine to striatal neurons in vitro and potentiation of cell death
by a mitochondrial inhibitor. J Neurochem 70: 2406-2415. http://dx.doi.Org/10.1046/i.1471-4159.1998.70062406.x
Mov. LY; Wang. SP; Sonsalla. PK. (2007). Mitochondrial stress-induced dopamine efflux and neuronal damage by malonate involves the
dopamine transporter. J Pharmacol Exp Ther 320: 747-756. http://dx.doi.Org/10.l 124/jpet. 106.110791
Munlev. S. .A. (2003). Dimethyl glutarate (DMG): inhalation developmental toxicity study in rabbits. (Laboratory Project ID: DuPont- 10657).
Newark, Delaware: E. I. du Pont de Nemours and Company, Haskell Laboratory for Health and Environmental Sciences.
https://chemview.epa.gov/chemview/proxv?filename=l 119400 DevelopmentalTox DevclopToxInhalRabbits 04152003.pdf
OECD (Organisation for Economic Co-operation and Development). (2005). Malonic acid diesters. Dimethylmalonate, 108-59-8, and
diethylmalonate, 105-53-3. (RISKLINE/2007020012). Degussa AG, Germany: UNEP.
https://hpvchemicals.oecd.org/UI/handler.axd?id=3ale8ac2-7862-4b86-8376-ca6c61817b0e
Reifenrath. WG: Chellauist. EM; Shipwash. EA; Jederberg. WW. (1984). Evaluation of animal models for predicting skin penetration in man.
Fundam Appl Toxicol 4: S224-S230. http://dx.doi.org/10.1016/0272-0590(84)90156-8
SOCMA (Synthetic Organic Chemical Manufacturers Association). (2002). Dimethyl glutarate: rat micronucleus test. (SOA002/004851).
Washington, DC. https://chemview.epa.gov/chemview/proxv?filename=627930 Genotoxicitv Erythrocyte%20micronucleus 051601 .pdf
Zeevalk. GD; Bernard. LP; Sinha. C; Ehrhart. J; Nicklas. WJ. (1998). Excitotoxicity and oxidative stress during inhibition of energy metabolism.
Dev Neurosci 20: 444-453. http://dx.doi.org/10.1159/000Q17342
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XXVIII
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Appendix C: Literature Search Outcomes
C.1 Literature Search and Review
This section briefly describes the literature search and review process, search terms, and search outcomes
for the hazard and fate screening of diethyl malonate. Search outcomes and reference details are provided
on the candidate's HERO45 project page.
EPA created a fit-for-purpose process to transparently document the literature search and review46 of
available hazard and fate information for low-priority substance (LPS) candidates. References from peer-
reviewed primary sources, grey sources,47 and other sources were identified, screened at the title/abstract
and full text level, and evaluated for data quality based on discipline-specific criteria. An overview of the
literature search and review process is illustrated in Figure CI.
Figure C.l: Overview of the Literature Search and Review Process
References available
from primary peer-
reviewed sources
T
References available
from grey literature
and other sources
References available at
title/abstract screening
T
I
References available at full text screening
T
References available at data quality evaluation
T
References included in LPS screening reviews
References excluded at
title/abstract screening
References excluded at
full text screening
References excluded at
data quality evaluation
C.1.1 Search for Analog Data
To supplement the information on the candidate chemical, diethyl malonate, EPA identified dimethyl
glutarate (CASRN 1119-40-0) as an analog. Formore details and justification on analogs, see section
6.1.1. Analogs were used to fill data gaps on endpoints for which diethyl malonate lacked quality data,
The HERO low-priority substance candidate project pages are accessible to the public at https://hero.epa.gov/hero/.
This process is further discussed in the document "Approach Document for Screening Hazard Information for Low-Priority
Substances Under TSCA."
9 Grey literature and additional sources are the broad category of studies not found in standard, peer-reviewed literature database
searches. This includes U.S. and international government agency websites, non-government organization (NGO) websites, and
data sources that are difficult to find, or are not included, in the peer-reviewed databases, such as white papers, conference
proceedings, technical reports, reference books, dissertations, and information on various stakeholder websites.
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such as acute, repeated dose, and developmental toxicity, and to add to the weight of the scientific
evidence. EPA collected reasonably available information for these endpoints by searching specific grey
literature and other secondary sources, listed on Table C. 1. If information related to the identified analogs
were available in these sources, the references were screened and evaluated using the same process as
references on diethyl malonate described above.46 EPA also used read-across from the LPS candidate,
dimethyl malonate (CASRN 108-59-8). Both chemicals along with the analog mentioned above fall under
the malonates cluster in HERO.
Table C.1: Sources Used for Analog Search
Resource
URL
ATSDR
http://www.atsdr.cdc.gov/toxprofiies/index.asp
ChemID (EPA - HPVIS via
ChemID)
http://chem.sis.nlm.nih.gov/chemidplus/
CIR
http://www.cir-safety.org/ingredients
ECHA
http://echa.europa.eu/web/guest/information-on-chemicais/registered-substances
ECOTOX
https://cfpub.epa.gov/ecotox/quick_query.htm
EPA - ChemView (incl. TSCATS,
RBP/HC, and HPV/HPVIS)
https://chemview.epa.gov/chemview
European Food Safety Authority
(EFSA)
http://www.efsa.europa.eu/
FDA
https://www.fda.gov/defauit.htm
HERA
http://www.heraproject.com/RiskAssessment.cfm
NICNAS
http://www.nicnas.gov.au/
NITE (J-CHECK)
http://www.safe.nite.go.jp/jcheck/search.action?request_locale=en
NTP
https://ntpsearch.niehs.nih.gov/home
OECD/SIDS
https://hpvchemicals.oecd.org/UI/Search.aspx;
http://webnet.oecd.org/hpv/ui/SponsoredChemicais.aspx
C.1.2 Search Terms and Results
EPA began the literature review process for the hazard screening of diethyl malonate by developing
search terms. To gather publicly available information, specific search terms were applied for each
discipline and across databases and grey literature sources. Table C.2 lists the search terms used in the
database search of peer -reviewed literature for the malonates cluster including diethyl malonate. For grey
literature and other secondary sources, Table C.3 lists the search terms used for the LPS malonates and
analogs.
Table C.2: Search Terms Used in Peer-Reviewed Databases
Discipline
Database
Search terms48
Human health
PubMed
108-59-8[rn] OR 105-53-3[rn] OR "Carbethoxyacetic ester"[tw]
OR "Dicarbethoxymethane"[tw] OR "Diethyl malonate"[tw] OR
"Diethyl propane-1,3-dioate"[tw] OR "Diethyl
propanedioate"[tw] OR "diethylmalonate"[tw] OR "Dimethyl
1,3-propanedioate"[tw] OR "Dimethyl malonate"[tw] OR
"Dimethyl propanedioate"[tw] OR "Ethyl malonate"[tw] OR
48 Additional language or syntax such as [tw], [m], [org], and [nm] were added to search terms. These are unique to individual
databases and must be applied to search terms so that the query can run properly.
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Table C.2: Search Terms Used in Peer-Reviewed Databases
Toxline
TSCATS1
WOS
"Ethyl methanedicarboxylate"[tw] OR "Ethyl propanedioate"[tw]
OR "MALONATE, DIETHYL"[tw] OR "Malonate diethyl
ester"[tw] OR "Malonic acid, diethyl ester"[tw] OR "Malonic
acid, dimethyl ester"[tw] OR "Malonic ester"[tw] OR
"Methanedicarboxylic acid diethyl ester"[tw] OR
"Methanedicarboxylic acid, diethyl ester"[tw] OR "Methyl
malonate"[tw] OR "PROPANEDIOATE, DIETHYL"[tw] OR
"PROPANEDIOATE, DIMETHYL"[tw] OR "Propanedioic acid
diethyl ester"[tw] OR "Propanedioic acid dimethyl ester"[tw] OR
"Propanedioic acid, 1,3-diethyl ester"[tw] OR "Propanedioic
acid, 1,3-dimethyl ester"[tw] OR "Propanedioic acid, diethyl
ester"[tw] OR "Propanedioic acid, dimethyl ester"[tw]
( 108-59-8 [rn] OR 105-53-3 [rn] OR "carbethoxyacetic ester"
OR "dicarbethoxymethane" OR "diethyl malonate" OR "diethyl
propane-1 3-dioate" OR "diethyl propanedioate" OR
"diethylmalonate" OR "dimethyl 1 3-propanedioate" OR
"dimethyl malonate" OR "dimethyl propanedioate" OR "ethyl
malonate" OR "ethyl methanedicarboxylate" OR "ethyl
propanedioate" OR "malonate diethyl" OR "malonate diethyl
ester" OR "malonic acid diethyl ester" OR "malonic acid
dimethyl ester" OR "malonic ester" OR "methanedicarboxylic
acid diethyl ester" OR "methanedicarboxylic acid diethyl ester"
OR "methyl malonate" OR "propanedioate diethyl" OR
"propanedioate dimethyl" OR "propanedioic acid diethyl ester"
OR "propanedioic acid dimethyl ester" OR "propanedioic acid
1 3-diethyl ester" OR "propanedioic acid 1 3-dimethyl ester"
OR "propanedioic acid diethyl ester" OR "propanedioic acid
dimethyl ester") AND (ANEUPL [org] OR BIOSIS [org] OR
CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR
HAPAB [org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR
RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS
[org] OR PESTAB [org] OR PPBIB [org]) AND NOT PubMed
[org] AND NOT pubdart [org]
108-59-8[rn] OR 105-53-3[rn]
TS=(" 108-59-8" OR "105-53-3" OR "Carbethoxyacetic ester"
OR "Dicarbethoxymethane" OR "Diethyl malonate" OR
"Diethyl propane-1,3-dioate" OR "Diethyl propanedioate" OR
"diethylmalonate" OR "Dimethyl 1,3-propanedioate" OR
"Dimethyl malonate" OR "Dimethyl propanedioate" OR "Ethyl
malonate" OR "Ethyl methanedicarboxylate" OR "Ethyl
propanedioate" OR "MALONATE, DIETHYL" OR "Malonate
diethyl ester" OR "Malonic acid, diethyl ester" OR "Malonic
acid, dimethyl ester" OR "Malonic ester" OR
"Methanedicarboxylic acid diethyl ester" OR
"Methanedicarboxylic acid, diethyl ester" OR "Methyl
malonate" OR "PROPANEDIOATE, DIETHYL" OR
"PROPANEDIOATE, DIMETHYL" OR "Propanedioic acid
diethyl ester" OR "Propanedioic acid dimethyl ester" OR
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Table C.2: Search Terms Used in Peer-Reviewed Databases
"Propanedioic acid, 1,3-diethyl ester" OR "Propanedioic acid,
1,3-dimethyl ester" OR "Propanedioic acid, diethyl ester" OR
"Propanedioic acid, dimethyl ester") AND ((WC=("Toxicology"
OR "Endocrinology & Metabolism" OR "Gastroenterology &
Hepatology" OR "Gastroenterology & Hepatology" OR
"Hematology" OR "Neurosciences" OR "Obstetrics &
Gynecology" OR "Pharmacology & Pharmacy" OR
"Physiology" OR "Respiratory System" OR "Urology &
Nephrology" OR "Anatomy & Morphology" OR "Andrology" OR
"Pathology" OR "Otorhinolaryngology" OR "Ophthalmology"
OR "Pediatrics" OR "Oncology" OR "Reproductive Biology" OR
"Developmental Biology" OR "Biology" OR "Dermatology" OR
"Allergy" OR "Public, Environmental & Occupational Health")
OR SU=("Anatomy & Morphology" OR "Cardiovascular
System & Cardiology" OR "Developmental Biology" OR
"Endocrinology & Metabolism" OR "Gastroenterology &
Hepatology" OR "Hematology" OR "Immunology" OR
"Neurosciences & Neurology" OR "Obstetrics & Gynecology"
OR "Oncology" OR "Ophthalmology" OR "Pathology" OR
"Pediatrics" OR "Pharmacology & Pharmacy" OR "Physiology"
OR "Public, Environmental & Occupational Health" OR
"Respiratory System" OR "Toxicology" OR "Urology &
Nephrology" OR "Reproductive Biology" OR "Dermatology"
OR "Allergy")) OR (WC="veterinary sciences" AND (TS="rat"
OR TS="rats" OR TS="mouse" OR TS="murine" OR
TS="mice" ORTS="guinea" OR TS="muridae" ORTS=rabbit*
OR TS=lagomorph* OR TS=hamster* OR TS=ferret* OR
TS=gerbil* OR TS=rodent* OR TS="dog" OR TS="dogs" OR
TS=beagle* OR TS="canine" OR TS="cats" OR TS="feline"
OR TS="pig" OR TS="pigs" OR TS="swine" OR TS="porcine"
OR TS=monkey* OR TS=macaque* OR TS=baboon* OR
TS=marmoset*)) OR (TS=toxic* AND (TS="rat" OR TS="rats"
OR TS="mouse" OR TS="murine" OR TS="mice" OR
TS="guinea" OR TS="muridae" ORTS=rabbit* OR
TS=lagomorph* OR TS=hamster* OR TS=ferret* OR
TS=gerbil* OR TS=rodent* OR TS="dog" OR TS="dogs" OR
TS=beagle* OR TS="canine" OR TS="cats" OR TS="feline"
OR TS="pig" OR TS="pigs" OR TS="swine" OR TS="porcine"
OR TS=monkey* OR TS=macaque* OR TS=baboon* OR
TS=marmoset* OR TS="child" OR TS="children" OR
TS=adolescen* OR TS=infant* OR TS="WORKER" OR
TS="WORKERS" OR TS="HUMAN" OR TS=patient* OR
TS=mother OR TS=fetal OR TS=fetus OR TS=citizens OR
TS=milk OR TS=formula OR TS=epidemio* OR
TS=population* OR TS=exposure* OR TS=questionnaire OR
SO=epidemio*)) OR TI=toxic* OR TS=metaboli* OR
TS=biotransform* OR ((TS="breakdown" OR TS="break-
down") AND (TS=product OR TS=products)))
XXXII
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.2: Search Terms Used in Peer-Reviewed Databases
Environmental hazard
fate
TS=(" 108-59-8" OR "105-53-3" OR "Carbethoxyacetic ester"
OR "Dicarbethoxymethane" OR "Diethyl malonate" OR
"Diethyl propane-1,3-dioate" OR "Diethyl propanedioate" OR
"diethylmalonate" OR "Dimethyl 1,3-propanedioate" OR
"Dimethyl malonate" OR "Dimethyl propanedioate" OR "Ethyl
malonate" OR "Ethyl methanedicarboxylate" OR "Ethyl
propanedioate" OR "MALONATE, DIETHYL" OR "Malonate
diethyl ester" OR "Malonic acid, diethyl ester" OR "Malonic
acid, dimethyl ester" OR "Malonic ester" OR
"Methanedicarboxylic acid diethyl ester" OR
"Methanedicarboxylic acid, diethyl ester" OR "Methyl
malonate" OR "PROPANEDIOATE, DIETHYL" OR
"PROPANEDIOATE, DIMETHYL" OR "Propanedioic acid
diethyl ester" OR "Propanedioic acid dimethyl ester" OR
"Propanedioic acid, 1,3-diethyl ester" OR "Propanedioic acid,
1,3-dimethyl ester" OR "Propanedioic acid, diethyl ester" OR
"Propanedioic acid, dimethyl ester") AND ((WC=("Agriculture,
Dairy & Animal Science" OR "Biodiversity Conservation" OR
"Biology" OR "Developmental Biology" OR "Ecology" OR
"Entomology" OR "Environmental Sciences" OR
"Environmental Studies" OR "Fisheries" OR "Forestry" OR
"Limnology" OR "Marine & Freshwater Biology" OR
"Microbiology" OR "Mycology" OR "Oceanography" OR
"Ornithology" OR "Plant Sciences" OR "Reproductive Biology"
OR "Zoology")) OR (SU=("Agriculture" OR "Biodiversity &
Conservation" OR "Developmental Biology" OR "Entomology"
OR "Environmental Sciences & Ecology" OR "Fisheries" OR
"Forestry" OR "Marine & Freshwater Biology" OR
"Microbiology" OR "Mycology" OR "Plant Sciences" OR
"Reproductive Biology" OR "Zoology" OR "Oceanography"))
OR (TI=toxic*) OR (TS=(ecotox* OR environment* OR
phytotox* OR pollut* OR "A. platyrhynchos" OR "agnatha" OR
"agnathan" OR "alligator" OR "alligators" OR "amphibian" OR
"amphibians" OR "amphipod" OR "amphipoda" OR
"amphipods" OR "Anas platyrhynchos" OR "annelid" OR
"annelida" OR "annelids" OR "Antilocapridae" OR "apidae" OR
"Aplodontidae" OR "Apoidea" OR "aquatic" OR "archiannelid"
OR "archiannelida" OR "Arvicolinae" OR "aves" OR "avian"
OR "avians" OR "badger" OR "badgers" OR "barnacle" OR
"barnacles" OR "bass" OR "bear" OR "bears" OR "beaver" OR
"beavers" OR "bee" OR "bees" OR "bird" OR "birds" OR
"bivalve" OR "bivalves" OR "bleak" OR "bluegill" OR "bluegills"
OR "bluehead" OR "bobwhite" OR "bobwhites" OR "Bovidae"
OR "C. carpio" OR "caiman" OR "Canidae" OR "carp" OR
"Castoridae" OR "catfish" OR "cephalopod" OR "cephalopoda"
OR "cephalopods" OR "Cervidae" OR "chicken" OR "chickens"
OR "chiselmouth" OR "clam" OR "clams" OR "cockle" OR
"cockles" OR "cod" OR "copepod" OR "copepoda" OR
"copepods" OR "coturnix" OR "crab" OR "crabs" OR "crappie"
XXXIII
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.2: Search Terms Used in Peer-Reviewed Databases
OR "crappies" OR "crayfish" OR "croaker" OR "crocodile" OR
"crocodiles" OR "crustacea" OR "crustacean" OR
"crustaceans" OR "Cyprinus carpio" OR "D. magna" OR "D.
rerio" OR "dace" OR "Danio rerio" OR "daphnia" OR "Daphnia
magna" OR "darter" OR "darters" OR "Dasypodidae" OR
"Dicotylidae" OR "Didelphidae" OR "Dipodidae" OR "dog" OR
"dogs" OR "dogfish" OR "duck" OR "duckling" OR "ducklings"
OR "ducks" OR "earthworm" OR "earthworms" OR "ec50" OR
"ec50s" OR "echinoderm" OR "echinoderms" OR "eel" OR
"eels" OR "elasmobranch" OR "Equidae" OR "Erethizontidae"
OR "Felidae" OR "ferret" OR "fish" OR "fisher" OR "fishers"
OR "fishes" OR "flagfish" OR "flatworm" OR "flatworms" OR
"flounder" OR "frog" OR "frogs" OR "galaxias" OR "gallus" OR
"gastropod" OR "gastropoda" OR "gastropods" OR
"Geomyidae" OR "goldfish" OR "gourami" OR "gouramy" OR
"Green Algae" OR "grunion" OR "guppies" OR "guppy" OR
"haddock" OR "hagfish" OR "haplodrili" OR "Harvest mice"
OR "Harvest mouse" OR "herring" OR "Heteromyidae" OR
"honeybee" OR "honeybees" OR "hooknose" OR "inanga" OR
"killifish" OR "L. idus" OR "L. macrochirus" OR "lamprey" OR
"lampreys" OR "Ic50" OR "Ic50s" OR "leech" OR "lemming"
OR "Lepomis macrochirus" OR "Leporidae" OR "lethal
concentration" OR "Leuciscus idus" OR "lizard" OR "lizards"
OR "lobster" OR "lobsters" OR "macroinvertebrate" OR
"macroinvertebrates" OR "mallard" OR "mallards" OR "marten"
OR "medaka" OR "menhaden" OR "Microtus" OR "milkfish"
OR "mink" OR "minnow" OR "minnows" OR "mollusc" OR
"molluscs" OR "mollusk" OR "mollusks" OR "molly" OR
"mrigal" OR "mudfish" OR "mudsucker" OR "mulles" OR
"mullet" OR "mummichog" OR "mummichogs" OR "mussel"
OR "mussels" OR "Mustelidae" OR "Myocastoridae" OR
"Mysid shrimp" OR "newt" OR "newts" OR "northern pike" OR
"0. latipes" OR "0. mykiss" OR "Ochotonidae" OR "octopi" OR
"octopus" OR "oligochaeta" OR "oligochaete" OR
"Oncorhynchus mykiss" OR "Onychomys" OR "opossum" OR
"Oryzias latipes" OR "oyster" OR "oysters" OR "P. promelas"
OR "P. reticulata" OR "P. subcapitata" OR "perch" OR
"Peromyscus" OR "Pimephales promelas" OR "pinfish" OR
"pinfishes" OR "planaria" OR "planarian" OR "Poecilia
reticulata" OR "polychaeta" OR "polychaete" OR "polychaetes"
OR "Procyonidae" OR "Pseudokirchneriella subcapitata" OR
"puffer" OR "puffers" OR "pumpkinseed" OR "pumpkinseeds"
OR "pupfish" OR "quahog" OR "quahogs" OR "quail" OR
"quails" OR "rasbora" OR "rasboras" OR "Reithrodontomys"
OR "reptile" OR "reptiles" OR "rohu" OR "S. erythrophthalmus"
OR "S. quadricauda" OR "S. subspicatus" OR "salamander"
OR "salamanders" OR "salmon" OR "scallop" OR "scallops"
OR "Scardinius erythrophthalmus" OR "Scenedesmus
quadricauda" OR "Scenedesmus subspicatus" OR "Sciuridae"
XXXIV
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.2: Search Terms Used in Peer-Reviewed Databases
Toxline
TSCATS1
Proquest
OR "sea anemone" OR "sea anemones" OR "sea cucumber"
OR "sea cucumbers" OR "sea urchin" OR "sea urchins" OR
"seabass" OR "seabream" OR "shark" OR "sharks" OR
"shiner" OR "shiners" OR "shrimp" OR "Sigmodon" OR
"Sigmodontinae" OR "silverside" OR "silversides" OR "skunk"
OR "skunks" OR "snake" OR "snakehead" OR "snakes" OR
"songbird" OR "songbirds" OR "Soricidae" OR "squid" OR
"starfish" OR "stickleback" OR "sticklebacks" OR "sting ray"
OR "sting rays" OR "sucker" OR "suckers" OR "Suidae" OR
"sunfish" OR "Talpidae" OR "teleost" OR "teleostei" OR
"teleosts" OR "terrapin" OR "terrapins" OR "tilapia" OR
"tilapiaz" OR "toad" OR "toadfish" OR "toadfishes" OR "toads"
OR "tortoise" OR "tortoises" OR "trout" OR "tubificid" OR
"tubificidae" OR "tubificids" OR "turkey" OR "turkeys" OR
"turtle" OR "turtles" OR "Ursidae" OR "vole" OR "walleye" OR
"walleyes" OR "water flea" OR "water fleas" OR "waterbird"
OR "waterbirds" OR "waterfowl" OR "waterfowls" OR
"weakfish" OR "weasel" OR "whelk" OR "whelks" OR
"wildlife")))
Same as human health strategy synonyms only
Same as human health strategy CASRN only
Title=(" 108-59-8" OR "105-53-3" OR "Carbethoxyacetic ester"
OR "Dicarbethoxymethane" OR "Diethyl malonate" OR
"Diethyl propane-1,3-dioate" OR "Diethyl propanedioate" OR
"diethylmalonate" OR "Dimethyl 1,3-propanedioate" OR
"Dimethyl malonate" OR "Dimethyl propanedioate" OR "Ethyl
malonate" OR "Ethyl methanedicarboxylate" OR "Ethyl
propanedioate" OR "MALONATE, DIETHYL" OR "Malonate
diethyl ester" OR "Malonic acid, diethyl ester" OR "Malonic
acid, dimethyl ester" OR "Malonic ester" OR
"Methanedicarboxylic acid diethyl ester" OR
"Methanedicarboxylic acid, diethyl ester" OR "Methyl
malonate" OR "PROPANEDIOATE, DIETHYL" OR
"PROPANEDIOATE, DIMETHYL" OR "Propanedioic acid
diethyl ester" OR "Propanedioic acid dimethyl ester" OR
"Propanedioic acid, 1,3-diethyl ester" OR "Propanedioic acid,
1,3-dimethyl ester" OR "Propanedioic acid, diethyl ester" OR
"Propanedioic acid, dimethyl ester")
Abstract^" 108-59-8" OR "105-53-3" OR "Carbethoxyacetic
ester" OR "Dicarbethoxymethane" OR "Diethyl malonate" OR
"Diethyl propane-1,3-dioate" OR "Diethyl propanedioate" OR
"diethylmalonate" OR "Dimethyl 1,3-propanedioate" OR
"Dimethyl malonate" OR "Dimethyl propanedioate" OR "Ethyl
malonate" OR "Ethyl methanedicarboxylate" OR "Ethyl
propanedioate" OR "MALONATE, DIETHYL" OR "Malonate
diethyl ester" OR "Malonic acid, diethyl ester")
XXXV
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.2: Search Terms Used in Peer-Reviewed Databases
Abstract=("Malonic acid, dimethyl ester" OR "Malonic ester"
OR "Methanedicarboxyiic acid diethyl ester" OR
"Methanedicarboxylic acid, diethyl ester" OR "Methyl
malonate" OR "PROPANEDIOATE, DIETHYL" OR
"PROPANEDIOATE, DIMETHYL" OR "Propanediol acid
diethyl ester" OR "Propanediol acid dimethyl ester" OR
"Propanediol acid, 1,3-diethyl ester" OR "Propanediol acid,
1,3-dimethyl ester" OR "Propanediol acid, diethyl ester" OR
"Propanediol acid, dimethyl ester")
Subject=(" 108-59-8" OR "105-53-3" OR "Carbethoxyacetic
ester" OR "Dicarbethoxymethane" OR "Diethyl malonate" OR
"Diethyl propane-1,3-dioate" OR "Diethyl propanedioate" OR
"diethylmalonate" OR "Dimethyl 1,3-propanedioate" OR
"Dimethyl malonate" OR "Dimethyl propanedioate" OR "Ethyl
malonate" OR "Ethyl methanedicarboxylate" OR "Ethyl
propanedioate" OR "MALONATE, DIETHYL" OR "Malonate
diethyl ester" OR "Malonic acid, diethyl ester" OR "Malonic
acid, dimethyl ester" OR "Malonic ester" OR
"Methanedicarboxylic acid diethyl ester" OR
"Methanedicarboxylic acid, diethyl ester" OR "Methyl
malonate" OR "PROPANEDIOATE, DIETHYL" OR
"PROPANEDIOATE, DIMETHYL" OR "Propanedioic acid
diethyl ester" OR "Propanedioic acid dimethyl ester" OR
"Propanedioic acid, 1,3-diethyl ester" OR "Propanedioic acid,
1,3-dimethyl ester" OR "Propanedioic acid, diethyl ester" OR
"Propanedioic acid, dimethyl ester")
Fate
WOS
TS=(" 108-59-8" OR "105-53-3" OR "Carbethoxyacetic ester"
OR "Dicarbethoxymethane" OR "Diethyl malonate" OR
"Diethyl propane-1,3-dioate" OR "Diethyl propanedioate" OR
"diethylmalonate" OR "Dimethyl 1,3-propanedioate" OR
"Dimethyl malonate" OR "Dimethyl propanedioate" OR "Ethyl
malonate" OR "Ethyl methanedicarboxylate" OR "Ethyl
propanedioate" OR "MALONATE, DIETHYL" OR "Malonate
diethyl ester" OR "Malonic acid, diethyl ester" OR "Malonic
acid, dimethyl ester" OR "Malonic ester" OR
"Methanedicarboxylic acid diethyl ester" OR
"Methanedicarboxylic acid, diethyl ester" OR "Methyl
malonate" OR "PROPANEDIOATE, DIETHYL" OR
"PROPANEDIOATE, DIMETHYL" OR "Propanedioic acid
diethyl ester" OR "Propanedioic acid dimethyl ester" OR
"Propanedioic acid, 1,3-diethyl ester" OR "Propanedioic acid,
1,3-dimethyl ester" OR "Propanedioic acid, diethyl ester" OR
"Propanedioic acid, dimethyl ester") AND TS=(adsorp* OR
aerob* OR anaerob* OR bioaccumulat* OR bioavail* OR
bioconcentrat* OR biodegrad* OR biomoni* OR biotrans* OR
degrad* OR dispers* OR fish* OR hydroly* leach* OR migrat*
OR partic* OR partition* OR persisten* OR photoly* OR volatil*
OR abiotic OR absorb OR absorption OR accumulation-rate
XXXVI
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.2: Search Terms Used in Peer-Reviewed Databases
OR aerosol OR aerosols OR air OR anoxic OR atm-m3/mol
OR biomagnification OR biosolids OR biota OR breakdown-
product OR breakdown-products OR chelation OR coagulation
complexation OR decay-rate OR diffusion-coefficient OR
dissolution OR dust OR effluent OR environmental-fate OR
evaporation-from-water OR excretion OR flocculation OR flux
OR fugacity OR gas-phase-mass-transfer OR ground-water
OR groundwater OR half-life OR henry's-law OR incinerate
OR incineration OR indoor-outdoor-ratio OR influent OR
ingestion OR intake OR kinetics OR liquid-phase-mass-
transfer OR mass-transfer-coefficient OR microcosm OR
modified-state-space OR particle-size OR particulate OR
pathway OR pathways OR penetration-factor OR penetration-
ratio OR photostability OR placenta OR plasma OR plume OR
point-source OR point-sources OR pore-water OR
pretreatment-program OR redox OR sediment OR serum OR
sewage-treatment OR sludge OR soil OR subsurface-intrusion
OR surface-water-concentration OR time-weighted-average
OR transfer OR transformation OR trophic-magnification OR
vapor OR wait-time OR wastewater-treatment OR weight-
fraction OR wildlife OR BAF OR BCF OR BSAF OR BSAFs
OR KAW OR Kd OR KOA OR KOC OR POTW OR SES OR
WWTP OR ((OECD OR OPPTS OR OCSPP) AND (Guideline
OR guidelines)))
Table C.3: Search Terms Used in Grey Literature and Additional Sources
Chemical
Search terms
Malonates
(dimethyl
malonate;
diethyl
malonate)
Searched as a string or individually depending on source: 108-59-8" OR "105-53-3" OR "Carbethoxyacetic
ester" OR "Dicarbethoxymethane" OR "Diethyl malonate" OR "Diethyl propane-1,3-dioate" OR "Diethyl
propanedioate" OR "Dimethyl 1,3-propanedioate" OR "Dimethyl malonate" OR "Dimethyl propanedioate" OR
"Ethyl malonate" OR "Ethyl malonate (VAN)" OR "Ethyl methanedicarboxylate" OR "Ethyl propanedioate" OR
"MALONATE, DIETHYL" OR "Malonate diethyl ester" OR "Malonic acid, diethyl ester" OR "Malonic acid,
dimethyl ester" OR "Malonic ester" OR "Methanedicarboxylic acid diethyl ester" OR "Methanedicarboxylic
acid, diethyl ester" OR "Methyl malonate" OR "PROPANEDIOATE, DIETHYL" OR "PROPANEDIOATE,
DIMETHYL" OR "Propanedioic acid diethyl ester" OR "Propanedioic acid dimethyl ester" OR "Propanedioic
acid, 1,3-diethyl ester" OR "Propanedioic acid, 1,3-dimethyl ester" OR "Propanedioic acid, diethyl ester" OR
"Propanedioic acid, dimethyl ester" OR "diethylmalonate"
Analogs
searched
dimethyl succinate (106-65-0); dimethyl adipate (627-93-0); dimethyl glutarate (1119-40-0); diethyl succinate
(123-25-1); dibasic esters (95481-62-2)
After the search terms were applied, more than 1,150 references were returned by all search efforts across
peer-reviewed databases and grey literature sources. The total number of references include database
results, additional strategies, and analog searches for the malonate cluster including diethyl malonate. All
references from the search efforts were screened and evaluated through the LPS literature search and
review process.46 Of these, 30 references were included for data evaluation and used to support the
designation of diethyl malonate as LPS. The included hazard and fate references are listed in the
bibliography of Appendix B.
XXXVII
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
C.2 Excluded Studies and Rationale
This section lists the excluded references, by HERO ID, found to be off-topic or unacceptable for use in
the hazard screening of diethyl malonate. The excluded references are organized by discipline (human
health hazard, environmental hazard, and fate), presented along with a rationale based on exclusion
criteria. The criteria46 was used to determine off-topic references in the title/abstract or full text screening
and to determine unacceptable references in the data quality evaluation are provided in the form of
questions.
C.2.1 Human Health Hazard Excluded References
For the screening review of diethyl malonate, EPA excluded a total of 540 references when assessing
human health hazard. Off-topic references (e.g., studies that did not contain information relevant to
human health) were excluded at either title/abstract screening (see Table C.4), or full-text screening (see
Table C.5). Unacceptable references (e.g., studies that did not meet data quality metrics) were excluded at
full-text screening (see Tables C.6 and C.7). Off-topic and unacceptable references are displayed next to
the corresponding exclusion criteria.
Table C.4: Off-Topic References Excluded at Title/Abstract Screening for Human Health Hazard
Reference excluded (HERO ID) because the reference did NOT contain information needs49 relevant to human health
hazard
1022206
4929206
4923743
4923477
4923618
3053987
4935828
4923841
4923552
4923669
1040619
4931325
4923744
4923478
4923619
3120733
4935831
4923843
4923553
4923670
1042992
4931453
4923747
4923479
4923620
3163278
4935835
4923844
4923554
4923671
1048932
4931491
4923750
4923480
4923622
3186448
4935836
4923845
4923555
4923672
1104864
4931882
4923751
4923481
4923623
3233658
4935837
4923846
4923557
4923673
1149967
4932500
4923752
4923482
4923625
3235030
4935838
4923847
4923558
4923674
1315937
4932525
4923753
4923483
4923626
3438987
4935839
4923848
4923559
4923675
1378092
4932620
4923754
4923484
4923627
3537907
4935842
4924289
4923560
4923676
1441881
4932898
4923756
4923485
4923628
3538154
4935845
4924291
4923562
4923678
1449817
4932902
4923757
4923486
4923629
3538342
4935846
4924292
4923563
4923679
1460212
4932934
4923758
4923487
4923630
3603771
4935847
4924293
4923566
4923680
1525969
4933183
4923760
4923488
4923631
3653305
4935851
4924294
4923567
4923681
1529848
4933274
4923761
4923489
4923633
3691713
4935855
4924295
4923568
4923682
1538279
4933275
4923764
4923490
4923634
3716147
4935856
4924296
4923569
4923683
1610851
4933315
4923765
4923491
4923635
3732842
4935857
4924297
4923570
4923684
1752669
4933402
4923788
4923492
4923636
3738490
4935858
4924298
4923571
4923702
1793913
4933404
4923790
4923493
4923637
3758890
4935859
4924299
4923572
4923703
1794243
4933405
4923792
4923494
4923638
3812332
4935860
4924300
4923573
4923705
1799722
4933410
4923796
4923495
4923639
3824612
4935865
4924301
4923574
4923706
1806144
4933412
4923798
4923496
4923640
3831063
4935868
4924302
4923575
4923707
184678
4933425
4923800
4923497
4923641
4034025
4935869
4924303
4923576
4923709
2115081
4933434
4923802
4923498
4923642
4045028
4935870
4924304
4923577
4923710
2241931
4933436
4923806
4923518
4923643
4076914
4935881
4924306
4923578
4923711
49 The information needs for human health hazard includes a list of study characteristics pertaining to the study population/test
organism, types of exposures and routes, use of controls, type and level of effects. A complete list of the information needs is
provided in Table A1 of the "Approach Document for Screening Hazard Information for Low-Priority Substances Under TSCA".
These information needs helped guide the development of questions for title/abstract and full-text screening.
XXXVIII
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*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.4: Off-Topic References Excluded at Title/Abstract Screening for Human Health Hazard
2302911
4933480
4923807
4923519
4923644
4228731
4935883
4924307
4923579
4923713
2302941
4933489
4923809
4923520
4923645
4298108
4935884
4924308
4923580
4923715
2302995
4933492
4923810
4923521
4923646
4386903
4935886
4924309
4923581
4923717
2369325
4933539
4923811
4923522
4923647
4442437
4935889
4924310
4923582
4923718
2545667
4933543
4923812
4923523
4923650
4453116
4935890
4924311
4923583
4923719
2718695
4933553
4923813
4923524
4923651
4559723
4935893
4924313
4923584
4923721
2777734
4933555
4923814
4923525
4923652
4567745
4935894
4924314
4923585
4923724
2779458
4933559
4923815
4923526
4923653
466056
4935896
4924316
4923586
4923725
2789619
4933560
4923816
4923527
4923654
4865076
4935899
4924317
4923587
4923726
2792326
4933563
4923817
4923528
4923655
4923443
4935900
4924318
4923588
4923727
2794054
4933582
4923818
4923529
4923656
4923445
4935902
4924319
4923589
4923728
2810456
4933596
4923833
4923530
4923657
4923446
4935905
4924320
4923590
4923729
2810786
4933643
4923834
4923531
4923658
4923447
4935908
4924322
4923591
4923730
2823794
4935814
4923835
4923532
4923659
4923448
4935909
4924323
4923592
4923731
2861807
4935818
4923836
4923533
4923660
4923449
4935910
4924325
4923593
4923732
2892878
4935823
4923837
4923547
4923661
4923451
4935912
4924326
4923594
4923734
2898376
4935824
4923838
4923548
4923663
4923452
4935915
4924327
4923595
4923736
2907621
4935825
4923839
4923550
4923664
4923454
4935919
4924345
4923596
4923737
2913951
4935826
4923840
4923551
4923666
4923455
4935925
4924388
4923597
4923738
4923465
4936877
4929173
4923605
659685
4923457
4935927
4924389
4923598
4923739
4923466
4936893
4929174
4923606
660376
4923459
4935928
4924390
4923599
4923741
4923467
4936899
4929192
4923607
661835
4923460
4935929
4924391
4923600
4923742
4923468
4937069
4929193
4923608
4923474
4923461
4936097
4924392
4923601
4923614
4923469
4937115
4929194
4923610
4923475
4923462
4936265
4924617
4923602
4923615
4923470
4937116
4929198
4923611
4923476
4923463
4936853
4924618
4923603
4923616
4923471
4937118
4929201
4923612
4929204
4923464
4936866
4924633
4923604
4923617
4923472
4937119
4929202
4923613
4937473
4923473
Reference excluded (HERO ID) because the reference primarily contained in silico data
2777734
Table C.5: Screening Questions and Off-Topic References Excluded at Full Text Screening for Human Health Hazard
Question
Off-topic if answer is:
References excluded (HERO ID)
Does the reference contain information
No
2282023
pertaining to a low- priority substance
2791394
candidate?
4923720
4931349
4933541
4933573
4939813
4940067
4940209
4940210
4940211
4923677
4923716
4923735
4940224
4940226
XXXIX
-------
*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.5: Screening Questions and Off-Topic References Excluded at Full Text Screening for Human Health Hazard
What type of source is this reference?
Review article or book chapter that contains
only citations to primary literature sources
4923458
4935830
What kind of evidence does this
reference primarily contain?
In silico studies that DO NOT contain
experimental verification
4931349
The following question apply to HUMAN evidence only
Does the reference report an exposure
route that is or is presumed to be by
an inhalation, oral, or dermal route?
No
N/A.
Does the reference report both test
substance exposure(s) AND related
health outcome(s)?
No
N/A.
If the reference reports an exposure to
a chemical mixture, are measures of
the test substance or related
metabolite(s) reported independently
of other chemicals?
No
N/A.
Note: If the paper does not pertain to
mixtures, choose "Not Applicable".
No
N/A.
The following question apply to ANIMAL evidence only
Does the reference report an exposure
route that is by inhalation, oral, or
dermal route?
No
4733654
4933474
4933486
4933488
4933535
4933550
4935815
Does the reference report both test
substance-related exposure(s) AND
related health outcome(s)?
No
N/A.
Does the reference report the duration
of exposure?
No
2282023
Does the reference report an exposure
to the test substance only (i.e. no
mixtures with the exception of aqueous
solutions and reasonable impurities
and byproducts)?
No
2282023
Does the paper report a negative
control that is a vehicle control or no
treatment control?
No50
2282023
4933550
The following questions apply to MECHANISTIC/ALTERNATIVE TEST METHODS evidence only
Does the reference report a negative
control that is a vehicle control or no
treatment control?
No
1060760
4935815
4935882
4940221
50 Except for acute mammalian toxicity and skin and eye irritation studies, where the use of a negative control may not be
required (e.g., OECD 403 Acute Inhalation Toxicity Guidelines).
XL
-------
*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.5: Screening Questions and Off-Topic References Excluded at Full Text Screening for Human Health Hazard
4940211
Does the reference report an exposure
to the test substance only (i.e. no
mixtures with the exception of aqueous
solutions and reasonable impurities
and byproducts)?
No
1060760
4935815
4935882
For genotoxicity studies only: Does the
study use a positive control?
No
1060760
4940211
Table C.6: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for Human Health
Hazard - Animal
Data Quality Metric
Unacceptable if:
References excluded (HERO ID)
Metric 1:
Test substance identity
The test substance identity
cannot be determined from
the information provided
(e.g., nomenclature was
unclear and CASRN or
structure were not reported).
OR
For mixtures, the components
and ratios were not characterized or
did not include information that could
result in a reasonable approximation
of components.
N/A.
Metric 2:
Negative and vehicle controls
A concurrent negative control group
was not included or reported.
OR
The reported negative control group
was not appropriate (e.g.,
age/weight of animals differed
between control and treated
groups).
N/A.
Metric 3:
Positive controls
When applicable, an appropriate
concurrent positive control (i.e.,
inducing a positive response) was
not used.
N/A.
Metric 4:
Reporting of doses/concentrations
Doses/concentrations were not
reported and could not be calculated
using default or reported estimates
of body weight and diet/water intake
(e.g., default intake values are not
available for pregnant animals).
4939812
4940213
4940223
Metric 5:
Exposure duration
The duration of exposure was not
reported.
OR
The reported exposure duration was
not suited to the study type and/or
4939812
4940229
XLI
-------
*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.6: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for Human Health
Hazard - Animal
Data Quality Metric
Unacceptable if:
References excluded (HERO ID)
outcome(s) of interest (e.g., <28
days for repeat dose).
Metric 6:
Test Animal characteristics
The test animal species was not
reported.
OR
The test animal (species, strain, sex,
life-stage, source) was not
appropriate for the evaluation of the
specific outcome(s) of interest (e.g.,
genetically modified animals, strain
was uniquely susceptible or resistant
to one or more outcome of interest).
N/A.
Metric 7:
Number of animals per group
The number of animals per study
group was not reported.
OR
The number of animals per study
group was insufficient to
characterize toxicological effects
(e.g., 1-2 animals in each group).
4939812
Metric 8:
Outcome assessment methodology
The outcome assessment
methodology was not sensitive for
the outcome(s) of interest (e.g.,
evaluation of endpoints outside the
critical window of development, a
systemic toxicity study that
evaluated only grossly observable
endpoints, such as clinical signs and
mortality, etc.).
4939812
4940229
Metric 9:
Reporting of data
Data presentation was
inadequate (e.g., the report
does not differentiate among
findings in multiple exposure
groups).
OR
Major inconsistencies were present
in reporting of results.
4939812
4940227
Table C.7: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for Human Health
Hazard - In Vitro
Data Quality Metric
Unacceptable if:
References excluded (HERO ID)
Metric 1:
Test substance identity
The test substance identity or
description cannot be determined
from the information provided (e.g.,
nomenclature was unclear and
CASRN or structure were not
reported).
OR
1141389
4923763
XLII
-------
*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.7: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for Human Health
Hazard - In Vitro
Data Quality Metric
Unacceptable if:
References excluded (HERO ID)
For mixtures, the components and
ratios were not characterized or did
not include information that could
result in a reasonable approximation
of components.
Metric 2:
Negative controls
A concurrent negative control group
was not included or reported.
OR
The reported negative control
group was not appropriate (e.g.,
different cell lines used for
controls and test substance
exposure).
651740
1141389
4929197
4940222
Metric 3:
Positive controls
A concurrent positive control or
proficiency group was not used.
1141389
4940222
Metric 4:
Assay type
The assay type was not reported.
OR
The assay type was not appropriate
for the study type or outcome of
interest (e.g., in vitro skin corrosion
protocol used for in vitro skin
irritation assay).
N/A.
Metric 5:
Reporting of concentration
The exposure doses/concentrations
or amounts of test substance were
not reported.
625777
1141389
4935924
Metric 6:
Exposure duration
No information on exposure
duration(s) was reported.
OR
The exposure duration was not
appropriate for the study type and/or
outcome of interest (e.g., 24 hours
exposure for bacterial reverse
mutation test).
625777
1141389
4929197
4933481
4935924
4940217
4940222
Metric 7:
Metabolic activation
No information on the
characterization and use of a
metabolic activation system was
reported.
OR
The exposure duration was
not appropriate for the study
type and/or outcome of
interest (e.g., 24 hours
exposure for bacterial reverse
mutation test).
1141389
4929197
Metric 8:
Test model
The test model was not reported
OR
N/A.
XLIII
-------
*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.7: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for Human Health
Hazard - In Vitro
Data Quality Metric
Unacceptable if:
References excluded (HERO ID)
The test model was not routinely
used for evaluation of the specific
outcome of interest.
Metric 9:
Outcome assessment methodology
The outcome assessment
methodology was not reported.
OR
The assessment methodology was
not appropriate for the outcome(s) of
interest (e.g., cells were evaluated
for chromosomal aberrations
immediately after exposure to the
test substance instead of after post-
exposure incubation period).
1141389
4933534
4935924
C.2.2 Environmental Hazard
For the screening review of LPS candidate diethyl malonate, EPA excluded a total of 466 references
when assessing environmental hazard. Off-topic environmental hazard references excluded at
title/abstract screening are listed in Table C.8, and those excluded at full-text screening are listed in Table
C.9. References in Table C.10 represent unacceptable studies based on specific data quality metrics for
environmental hazard. Off-topic and unacceptable references are displayed next to the corresponding
exclusion criteria.
Table C.8: Off-Topic References Excluded at Title/Abstract Screening for Environmental Hazard
Reference excluded (HERO ID) because the reference did NOTcontain information needs51 relevant to environmental
hazard
94897
4936806
4936221
4933099
4923806
4246082
4933547
4936269
4933345
4931453
184678
4936815
4936227
4933101
4923810
4332446
4933550
4936270
4933348
4931491
625777
4936817
4936228
4933105
4923838
4381738
4933552
4936271
4933350
4931879
651740
4936820
4936229
4933106
4923841
4386903
4933553
4936273
4933352
4931880
660376
4936840
4936231
4933175
4923845
4422413
4933555
4936274
4933397
4931881
922459
4936844
4936232
4933180
4924292
4442437
4933557
4936275
4933398
4931882
1040619
4936849
4936233
4933181
4924297
4482713
4933558
4936781
4933399
4931883
1042992
4936853
4936236
4933182
4924298
4482800
4933559
4936785
4933400
4931884
1048932
4936854
4936237
4933183
4924301
4499033
4933560
4936790
4933402
4931886
1060760
4936858
4936238
4933186
4924311
4607184
4933563
4936791
4933403
4931888
1149967
4936863
4936239
4933187
4924313
4671024
4933565
4936792
4933404
4931889
1315937
4936864
4936240
4933189
4924318
4720648
4933566
4936794
4933405
4931891
1441881
4936866
4936241
4933191
4924322
4923443
4933567
4933661
4933406
4931892
1448620
4936867
4936242
4933264
4924325
4923445
4933570
4933662
4933410
4932219
1538279
4936871
4936243
4933265
4924388
4923448
4933571
4933663
4933411
4932490
1616838
4936873
4936244
4933270
4924389
4923449
4933573
4933665
4933412
4932491
1794239
4936877
4936245
4933271
4924617
4923452
4933577
4933667
4933413
4932494
51 The information needs for environmental hazard includes a list of study characteristics pertaining to the test organism/species,
type and level of effects, and use of controls. A complete list of the information needs is provided in Table A2 of the "Approach
Document for Screening Hazard Information for Low-Priority Substances Under TSCA". These information needs helped guide
the development of questions for title/abstract and full-text screening.
XLIV
-------
*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.8: Off-Topic References Excluded at Title/Abstract Screening for Environmental Hazard
2235088
4936892
4936246
4933272
4924618
4923460
4933578
4933669
4933414
4932495
2324664
4936893
4936247
4933275
4926318
4923464
4933580
4935815
4933415
4932500
2545667
4936895
4936248
4933279
4929173
4923468
4933582
4935818
4933418
4932502
2777734
4936898
4936249
4933283
4929174
4923469
4933583
4935825
4933420
4932503
2779458
4936899
4936251
4933284
4929192
4923470
4933586
4935828
4933421
4932513
2789619
4937069
4936252
4933285
4929193
4923471
4933587
4935831
4933422
4932520
2792326
4937146
4936253
4933286
4929194
4923475
4933588
4935835
4933423
4932620
2810786
4937172
4936254
4933313
4929196
4923478
4933590
4935836
4933425
4932621
2823794
4937173
4936255
4933315
4929197
4923479
4933591
4935837
4933427
4932688
3120733
4937174
4936259
4933321
4929198
4923488
4933595
4935839
4933429
4932890
3163278
4937480
4936260
4933324
4929200
4923492
4933596
4935857
4933431
4932892
3235030
4933535
4936262
4933329
4929201
4923498
4933597
4935865
4933432
4932894
3438987
4933537
4936263
4933331
4929202
4923522
4933598
4935869
4933433
4932896
3538154
4933539
4936264
4933332
4929204
4923524
4933602
4935881
4933434
4932898
3603771
4933541
4936265
4933333
4929205
4923526
4933604
4935886
4933436
4932900
3653305
4933542
4936266
4933338
4929206
4923527
4933606
4935889
4933474
4932901
3732842
4933543
4936267
4933342
4931325
4923529
4933632
4935905
4933475
4932906
4079158
4933545
4936268
4933343
4931349
4923530
4933633
4935908
4933476
4932907
4923640
4933652
4935969
4933493
4932987
4923552
4933634
4935909
4933479
4932936
4923646
4933653
4935984
4933494
4932992
4923553
4933635
4935910
4933480
4932937
4923660
4933655
4936018
4933495
4932993
4923557
4933637
4935912
4933481
4932944
4923672
4933656
4936097
4933497
4932995
4923562
4933638
4935919
4933483
4932945
4923676
4933657
4936137
4933522
4933000
4923581
4933640
4935925
4933485
4932950
4923678
4933658
4936138
4933527
4933090
4923584
4933641
4935927
4933486
4932951
4923682
4933660
4936142
4933528
4933092
4923587
4933642
4935928
4933488
4932953
4923702
4923743
4936200
4933530
4933093
4923589
4933643
4935929
4933489
4932978
4923703
4923748
4923727
4933533
4923726
4923604
4933645
4935949
4933490
4932982
4923710
4923751
4923728
4933534
4923715
4923605
4933648
4935953
4933492
4932985
4923713
4923757
4923742
4923714
4923792
Reference excluded (HERO ID
because the reference did NOT present quantitative environmental hazard data
N/A.
Table C.9: Screening Questions and Off-Topic References Excluded at Full Text Screening for Environmental Hazard
Question
Off-topic if answer is:
References excluded (HERO ID)
Does the reference contain information
No
4939897
pertaining to a low- priority substance
4951381
candidate?
4939518
What type of source is this reference?
Review article or book chapter that
contains only citations to primary literature
sources
N/A.
Is quantitative environmental hazard
No
N/A.
data presented?
Is this primarily a modeling/simulation
Yes
N/A.
study? [Note: select "No" if
experimental verification was included
in the study]
Is environmental hazard data
No
N/A.
presented for standard or non-standard
XLV
-------
*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.9: Screening Questions and Off-Topic References Excluded at Full Text Screening for Environmental Hazard
Question
Off-topic if answer is:
References excluded (HERO ID)
aquatic or terrestrial species (fish,
invertebrates, microorganisms, non-
mammalian terrestrial species)?
Is exposure measured for the target
Mixture
N/A.
substance or is the test substance a
Formulated Product
N/A.
mixture (except for reasonable
impurities, byproducts, and aqueous
solutions) or formulated product?
Does the reference report a duration of
No
N/A.
exposure?
Does the reference report a negative
No
4939816
control that is a vehicle control or no
4939817
treatment control?
4940066
Does the reference include endpoints
No
N/A.
in the information needs?
Table C.10: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for
Environmental Hazard
Question
Unacceptable if:
References excluded (HERO ID)
Metric 1:
Test substance identity
The test substance identity or description cannot be
determined from the information provided (e.g.,
nomenclature was unclear, CASRN or structure were
not reported, substance name/ description does not
match CASRN).
OR
For mixtures, the components and ratios were not
characterized or did not include information that could
result in a reasonable approximation of components.
4935613
4939694
Metric 2:
Negative controls
A concurrent negative control group was not included or
reported.
4935263
4939694
Metric 3:
Experimental system
The experimental system (e.g., static, semi-static, or
flow-through regime) was not described.
4935263
4939287
4939484
4939694
Metric 4:
Reporting of
concentrations
Test concentrations were not reported.
4935263
Metric 5:
Exposure duration
The duration of exposure was not reported.
OR
The reported exposure duration was not suited to the
study type and/or outcome(s) of interest (e.g., study
intended to assess effects on reproduction did not
expose organisms for an acceptable period of time prior
to mating).
4935263
Metric 6:
Test organism
characteristics
The test species was not reported.
OR
N/A.
XLVI
-------
*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.10: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for
Environmental Hazard
Question
Unacceptable if:
References excluded (HERO ID)
The test species, life stage, or age was not appropriate
for the outcome(s) of interest.
Metric 7:
Outcome assessment
methodology
The outcome assessment methodology was not
reported.
4935263
4939694
Metric 8:
Reporting of data
Data presentation was inadequate.
OR
Major inconsistencies were present in reporting of
results.
4935263
C.2.3 Fate
For the screening review of LPS candidate diethyl malonate, EPA excluded a total of 469 references
when assessing environmental fate. Off-topic fate references excluded at title/abstract screening are listed
in Table C.l 1, and those excluded at full-text screening are listed in Table C.12. References in Table C.13
represent unacceptable studies based on specific data quality metrics for fate. Off-topic and unacceptable
references are displayed next to the corresponding exclusion criteria.
Table C.11: Off-Topic References Excluded at Initial Screening for Fate
Reference excluded (HERO ID) because the reference did NOT contain information needs52 relevant to environmental
fate
4924311
4936179
4936039
4935967
4923550
4033388
4937141
4936111
4936159
4935825
4931883
4936180
4936040
4935969
4923557
4089130
4937142
4936112
4936160
4935826
448349
4936181
4936042
4935971
4923575
4096023
4937143
4936114
4936161
4935828
466056
4936182
4936045
4935972
4923579
4142764
4937144
4936115
4936162
4935838
488729
4936184
4936046
4935975
4923580
4182651
4937145
4936116
4936164
4935845
651740
4936185
4936047
4935977
4923581
4228731
4937146
4936117
4936165
4935886
659685
4936186
4936048
4935978
4923584
4238775
4937148
4936118
4936167
4935896
922459
4936190
4936049
4935979
4923585
4238776
4937149
4936120
4936169
4935899
1160162
4936191
4936050
4935981
4923589
4275273
4937150
4936121
4936170
4935925
1166560
4936193
4936051
4935982
4923599
4298108
4937152
4936122
4936171
4935929
1181656
4936194
4936052
4935983
4923604
4419091
4937153
4936123
4936172
4935931
1182264
4936195
4936053
4935985
4923610
4419092
4937154
4936124
4936174
4935933
1190450
4936196
4936055
4935987
4923613
4419093
4937155
4936125
4936175
4935935
1204263
4936198
4936056
4935988
4923629
4422413
4937156
4936126
4936176
4935936
1449817
4936199
4936057
4935989
4923638
4422447
4937157
4936127
4936177
4935937
1452087
4936200
4936059
4935990
4923640
4453116
4937159
4936129
4936178
4935938
1453426
4936201
4936060
4935991
4923642
4559723
4937160
4936132
4923457
4935939
1610186
4936204
4936061
4935992
4923643
4607184
4937161
4936133
4923459
4935940
1610851
4936205
4936064
4935993
4923645
4665778
4937162
4936134
4923468
4935941
1611653
4936206
4936065
4935995
4923647
4708473
4937163
4936135
4923471
4935943
52 The information needs for fate includes a list of study characteristics pertaining to the associated media and exposure
pathway s, associated processes, and use of controls. A complete list of the information needs is provided in Table A3 of the
"Approach Document for Screening Hazard Information for Low-Priority Substances Under TSCA". These information needs
helped guide the development of questions for title/abstract and full-text screening.
XLVII
-------
*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.11: Off-Topic References Excluded at Initial Screening for Fate
1752669
4936207
4936066
4935996
4923664
4709249
4937164
4936136
4923473
4935944
1792712
4936209
4936067
4935998
4923670
4711360
4937165
4936137
4923475
4935945
1793863
4936210
4936068
4935999
4923671
4720648
4937166
4936138
4923477
4935948
1794382
4936211
4936070
4936000
4923682
4721999
4937167
4936139
4923480
4935949
1941474
4936212
4936071
4936001
4923703
4722919
4937169
4936140
4923482
4935950
1949851
4936213
4936072
4936002
4923706
4761067
4937170
4936141
4923486
4935952
1950394
4936216
4936073
4936003
4923711
4789294
4937474
4936142
4923487
4935953
1951869
4936218
4936074
4936004
4923715
4830553
4937475
4936144
4923488
4935954
1954812
4936220
4936075
4936006
4923725
4866723
4937476
4936146
4923489
4935955
1965772
4936221
4936076
4936007
4923726
4882194
4937477
4936148
4923491
4935957
1967704
4936222
4936077
4936010
4923730
4923449
4937478
4936149
4923493
4935958
2241931
4936223
4936078
4936012
4923732
4923451
4937479
4936150
4923498
4935959
2324664
4936225
4936079
4936013
4923743
4923525
4935964
4935961
4923519
4935960
2369325
4936226
4936081
4936014
4923845
4923527
4935965
4935962
4923522
4923523
2791394
4936249
4936083
4936016
4924292
3738367
4937127
4936094
4936030
4929194
2792326
4936251
4936084
4936017
4924296
3751974
4937128
4936096
4936032
4931453
2810786
4936259
4936085
4936018
4924297
3753346
4937129
4936097
4936033
4932990
2879557
4936271
4936086
4936022
4924306
3754273
4937131
4936100
4936035
4933315
2904592
4936864
4936087
4936023
4924308
3757714
4937132
4936101
4936036
4933411
3002189
4937121
4936089
4936024
4924313
3758839
4937133
4936102
4936037
4933577
3537907
4937122
4936090
4936025
4924318
3763886
4937134
4936103
4936151
4933632
3538342
4937124
4936091
4936026
4924388
3765216
4937135
4936104
4936154
4933633
3603771
4937125
4936092
4936028
4924618
3830431
4937136
4936107
4936156
4933634
3705115
4937126
4936093
4936029
4929193
3830766
4937138
4936108
4936157
4935814
4923533
4033387
4937140
4936110
4936158
4935815
Reference excluded (HERO ID) because the reference did NOT present quantitative environmental fate data
N/A.
Table C.12: Screening Questions and Off-Topic References Excluded at Full Text Screening for Fate
Question
Off-topic if answer is:
References excluded (HERO ID)
Does the reference contain
No
4935968
information pertaining to a low-
4935984
priority substance candidate?
1448620
2545667
4935968
4935984
What type of source is this
Review article or book chapter that contains
N/A.
reference?
only citations to primary literature sources
Is quantitative fate data presented?
No
N/A.
Is this primarily a
Yes
N/A.
modeling/simulation study? [Note:
Select "Yes" only if there is no
experimental verification]
Table C.13: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for Fate
Data quality metric
Unacceptable if:
References excluded (HERO ID)
Metric 1:
The test substance identity or description cannot be
determined from the information provided (e.g.,
4931884
XLVIII
-------
*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.13: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for Fate
Data quality metric
Unacceptable if:
References excluded (HERO ID)
Test substance identity
nomenclature was unclear and CASRN or structure
were not reported).
OR
For mixtures, the components and ratios were not
characterized or did not include information that could
result in a reasonable approximation of components.
Metric 2:
Study controls
The study did not include or report crucial control
groups that consequently made the study unusable
(e.g., no positive control for a biodegradation study
reporting 0% removal).
OR
The vehicle used in the study was likely to unduly
influence the study results.
4935263
4939814
Metric 3:
Test substance stability
There were problems with test substance stability,
homogeneity, or preparation that had an impact on
concentration or dose estimates and interfered with
interpretation of study results.
4935263
Metric 4:
Test method suitability
The test method was not reported or not suitable for
the test substance.
OR
The test concentrations were not reported.
OR
The reported test concentrations were not measured
and the nominal concentrations reported greatly
exceeded the substances water solubility, which would
greatly inhibit meaningful interpretation of the
outcomes.
4935263
Metric 5:
Testing conditions
Testing conditions were not reported and the omission
would likely have a substantial impact on study results.
OR
Testing conditions were not appropriate for the method
(e.g., a biodegradation study at temperatures that
inhibit the microorganisms).
4935263
4939814
Metric 6:
System type and design-
partitioning
Equilibrium was not established or reported, preventing
meaningful interpretation of study results.
OR
The system type and design (e.g. static, semi-static,
and flow-through; sealed, open) were not capable of
appropriately maintaining substance concentrations,
preventing meaningful interpretation of study results.
N/A.
Metric 7: Test organism-
degradation
The test organism, species, or inoculum source were
not reported, preventing meaningful interpretation of
the study results.
N/A.
Metric 8:
Test organism-partitioning
The test organism information was not reported.
OR
The test organism is not routinely used and would
likely prevent meaningful interpretation of the study
results.
N/A.
XLIX
-------
*** Proposal Draft - Do Not Cite, Quote or Release During the Review ***
Table C.13: Data Quality Metrics and Unacceptable References Excluded at Data Quality Evaluation for Fate
Data quality metric
Unacceptable if:
References excluded (HERO ID)
Metric 9:
Outcome assessment
methodology
The assessment methodology did not address or
report the outcome(s) of interest.
2545667
4935263
Metric 10:
Data reporting
Insufficient data were reported to evaluate the outcome
of interest or to reasonably infer an outcome of
interest.
OR
The analytical method used was not suitable for
detection or quantification of the test substance.
OR
Data indicate that disappearance or transformation of
the parent compound was likely due to some other
process.
4935263
Metric 11:
Confounding variables
There were sources of variability and uncertainty in the
measurements and statistical techniques or between
study groups.
4935263
4939814
Metric 12:
Verification or plausibility
of results
Reported value was completely inconsistent with
reference substance data, related physical chemical
properties, or otherwise implausible, suggesting that a
serious study deficiency exists (identified or not).
N/A.
L
------- |