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March 20, 2017
RE: Proposed Rule: Procedures for Chemical Risk Evaluation Under the Amended Toxic Substances
Control Act, Docket ID EPA–HQ–OPPT–2016–0654
The Humane Society of the United States (HSUS) and Gradient have collaborated to provide comments to
the US Environmental Protection Agency (EPA) on the implementation of the provisions under the Toxic
Substances Control Act (TSCA), as amended by the Frank R. Lautenberg Chemical Safety for the 21st
Century Act (LCSA).
These comments are being submitted on behalf of members and supporters of HSUS (the nation's largest
animal protection organization), who share the common goal of promoting the use of reliable and relevant
regulatory chemical testing methods and strategies that protect human health and the environment while
reducing, and ultimately eliminating, the use of animal testing to determine chemical toxicity. Gradient, an
environmental and risk sciences consulting firm that shares HSUS's commitment to the protection of human
health and the environment, worked jointly with HSUS to promote innovative toxicology strategies that
will both improve chemical safety assessment as well as minimize the use of animal testing in such
assessments.
We thank EPA for this opportunity to comment on the Proposed Rule. The amended TSCA is an important
development for chemical regulation in the US. Under the new TSCA, EPA is tasked with performing
affirmative safety evaluations for both new and existing chemicals. In order to meet the new requirements,
it will be necessary for companies to produce data that inform toxicity determinations for thousands of
chemicals that are currently being manufactured and imported in the US. While we realize that, in the short
term, it will be impossible to fully eliminate animal testing and still meet these data needs, we assert that
industry, the general public, and animals are best served when the use of animal testing in chemical toxicity
evaluations is minimized. The implementation of all aspects of the Proposed Rule offers a tremendous
opportunity to advance toxicological analysis through the use of alternative testing methods, including
targeted in vitro testing, quantitative structure-activity relationship (QSAR) analysis, read-across, and high-
throughput screening. Our comments are focused on emphasizing the need for thoughtful chemical
characterization strategies that promote the use of non-animal testing alternatives without compromising
the reliability of chemical safety evaluations.
In the Proposed Rule (US EPA, 2017a), EPA describes three groups of chemicals that will undergo risk
evaluation: (1) chemicals designated as "high-priority" substances, (2) chemicals for which manufacturers
request that EPA perform risk evaluations, (3) the first 10 chemicals from the 2014 TSCA work plan
selected by the Agency to undergo evaluation. Conducting these risk evaluations will be an extensive, 3-
year process that considers the full life cycle of each chemical substance (from manufacturing to disposal).
The process will include public comment periods on both the scope of the evaluations and the draft
evaluations. In these risk evaluations, particular consideration will be given to potentially exposed and
susceptible sub-populations (e.g., workers, children), and EPA must specifically consider the best available
science and apply a weight-of-evidence (WoE) approach. Interested parties may submit draft risk
evaluations of the chemicals undergoing review for EPA to consider. If EPA determines that a chemical
presents an "unreasonable risk," that chemical must be controlled with risk management measures. In the
Proposed Rule, EPA states that it is soliciting specific input on whether terms such as "best available
science," "weight-of-the-evidence," "sufficiency of information," "unreasonable risk," and "reasonably
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available information" should be codified or should be provided in guidance that can be updated as the
definitions of these terms evolve (US EPA, 2017a).
Our comments on the "Procedures for Chemical Risk Evaluation Under the Amended Toxic Substances
Control Act" are summarized below.
General Comment
Overall, EPA should develop clearer guidelines for the risk evaluation process described in the Proposed
Rule, specifically for:
how exposures and risks will be evaluated across the full life cycle of the substance being evaluated
(i.e., manufacturing, processing, distribution, use, and disposal),
how exposures for the many possible uses of a chemical will be considered in the evaluation,
how susceptible sub-populations will be evaluated,
what data will be considered "sufficient" for the evaluation,
what constitutes the "best available science,"
how systematic reviews and WoE evaluations will be conducted, and
what constitutes "unreasonable risk."
EPA is requesting that stakeholders submit as much information as possible on the chemicals that will be
undergoing risk evaluations. It is critical that stakeholders have a clear understanding of the risk evaluation
process so that they are able to provide EPA with as much information as possible to help the Agency
conduct thorough evaluations.
Comment #1: EPA should better describe the term "weight of evidence."
Issue: EPA explicitly states in the Proposed Rule that it will not define the term "weight of evidence," but
will rely on the use of the term in general EPA procedures (i.e., other risk assessment guidelines and
policies) (US EPA, 2017a). Because the term "weight of evidence" is vague in many of these other EPA
contexts, it is unclear how it will be applied in the implementation of the new TSCA.
Suggestion: Conducting a WoE evaluation is a critical component of the risk evaluation process.
Therefore, the process, content, and standards for a "weight of evidence" evaluation should be described
in: 1) Rule-specific guidance that EPA will follow during the risk evaluation process; and 2) Risk evaluation
guidance documents intended for "interested persons," as described in the Rule (US EPA, 2017a, p. 7,566
). In addition to a description of the process in the guidance documents, EPA needs to clearly describe the
specific steps it will carry out in order to adhere to the TSCA's requirement that the Agency make decisions
about chemical safety based on "the weight of the scientific evidence."
The LCSA statute states that "[t]he Administrator shall make decisions under sections 4, 5, and 6
based on the weight of the scientific evidence" (US Congress, 2016). The Proposed Rule states
that a risk evaluation must "describe the weight of scientific evidence for the identification of
hazards and exposure' 15 U.S.C. 2605(b)(4)(F)(i),(iii)–(v)" (US EPA, 2017a, p. 7,563). The Rule
goes on to provide a fairly good discussion of the key components of a WoE evaluation. For
example, the Proposed Rule states that "WoE is not a simple tallying of the number of positive and
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negative studies, but rather relies on professional judgment" (US EPA, 2017a, p. 7,564), and
describes that study quality needs to be evaluated as part of a WoE evaluation, and that a WoE
evaluation should also involve "assembling and assessing [data for] the individual lines of evidence
and then performing an integrated analysis of those lines of evidence" (US EPA, 2017a, p. 7,564).
However, Rule-specific guidance is needed to explicitly describe how EPA will conduct an
integrated analysis of all the data for a chemical and how the data integration process will be
communicated in a transparent fashion, so that all parties can understand the basis of the Agency's
WoE conclusions. The following are suggestions that EPA should consider in development of
guidance documents for its own implementation of the Rule and for risk evaluations conducted by
"interested persons."
WoE Framework
Examples: The Agency should point to specific WoE frameworks it will follow in its
WoE evaluations and describe how the results of these evaluations will be communicated.
We recommend that EPA review several recent articles on best practices for WoE
evaluations (e.g., Rhomberg et al., 2013; Rhomberg, 2014). Rhomberg et al. (2013)
surveyed 50 WoE frameworks, which EPA could consider when identifying frameworks
to follow in its evaluations. Additionally, the Agency could review Bailey et al. (2015),
which presents a recent example of a WoE evaluation for naphthalene carcinogenesis.
Clear Presentation of Hypothesis and Alternative Hypotheses: EPA should provide a
"narrative" of the WoE evaluation process, as well as a summary table of the key pieces of
evidence that are the basis of the WoE conclusion. The WoE framework that the Agency
plans to follow should be presented in the Rule-specific guidelines. The Agency should
then apply this framework in each of its chemical risk evaluations. In addition, in its risk
evaluations, EPA should apply a framework that includes a discussion of any evidence that
seems to contradict its WoE conclusion, why that evidence was given less weight in the
overall risk evaluation, and why a potential alternative hypothesis (e.g., a hypothesis for a
different mode of action) was rejected. Table 3 in Bailey et al. (2015) provides a good
example of how competing accounts of the available data can be compared and clearly
presented.
Data Gaps: EPA should state clearly in its risk evaluations whether there are data gaps,
as well as whether any gaps need to be filled. For example, it may not be necessary to
collect more data to fill a data gap for a particular part of a proposed biological pathway
for a chemical if there are enough data for another part of the biological pathway to strongly
suggest a particular mode of action or process exists (or does not exist) for a chemical. If
data gaps are identified in a WoE evaluation, EPA should include a discussion about the
types of data that will be accepted to fill these gaps. As required in the LCSA, EPA should
clearly "explain the basis for any decision that requires the use of vertebrate animals" (US
Congress, 2016). It is critical that, whenever possible, EPA accept the use of non-animal
testing methods (e.g., in vitro, read-across, QSAR, high-throughput, and genomic response
assays) listed in the Rule to fill any identified data gaps.
WoE for Exposure Assessment
In a risk evaluation, the LCSA requires the Administrator to "describe the weight of the
scientific evidence for the identified hazard and exposure" (US Congress, 2016, emphasis
added). However, the Proposed Rule does not discuss how a WoE approach will be used
in the exposure assessments EPA performs as part of its chemical risk evaluations. The
LCSA states that the Administrator shall "address risks from the manufacture, processing,
distribution in commerce, use, or disposal of a chemical substance or mixture, or any
combination of those activities" (US Congress, 2016). In the Proposed Rule, EPA
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interprets that to mean "all conditions of use" (US EPA, 2017a). However, because it may
be very difficult to evaluate exposures from all the possible uses of a chemical, EPA should
use a WoE approach to describe which exposures/uses were considered and why, and
explain whether aggregate or sentinel exposures were considered and why. In this way,
EPA can make clear that although all the uses of a chemical may not have been fully
evaluated, they were considered in the risk assessment. It is important that EPA clearly
illustrate the decision process for how particular exposures are chosen within their
chemical risk evaluations. We recommend organizing the available exposure information
for a chemical in a table, describing why some information may not be needed (e.g., if it is
covered by another exposure) what information may still be necessary to obtain, what
assumptions were made to fill in gaps about possible exposures, and the basis for choosing
aggregate or sentinel exposures for the risk evaluation.
WoE for Hazard and Exposure Combined
It would then be helpful to present exposure and hazard information together in a WoE
table to provide bounds on the possible risk posed by a chemical. For example, for a
specific chemical, EPA could provide a matrix combining its hazard estimate with low-
exposure/low-frequency estimates up to high-exposure/high-frequency estimates to
provide a semi-quantitative, but risk-based, justification of why some exposures are
considered and others are not. This WoE table should also illustrate why an aggregate or
sentinel exposure assessment is needed.
Lastly, Comment #2 provides a list of additional peer-reviewed articles and government reports
that EPA should review that describe the importance of systematic review and WoE evaluations
in risk assessment and provide example frameworks that EPA should consider following.
Comment #2: EPA should better describe the term "best available science."
Issue: EPA explicitly states in the Proposed Rule that it will not define the term "best available science,"
but will rely on the use of the term in general EPA procedures (i.e., other risk assessment guidelines and
policies) (US EPA, 2017a). Because the term "best available science" is vague in many of these EPA
contexts, it raises issues about how it will be applied in the implementation of the new TSCA.
Suggestion: EPA should describe the term "best available science" in: 1) Rule-specific guidance that EPA
will follow during the risk evaluation process; and 2) Risk evaluation guidance documents intended for
"interested persons," as described in the Rule (US EPA, 2017a, p. 7,566 ).. Although we propose a
definition for "best available science," it is our suggestion that the process for how to determine what is the
"best available science" is more important. Any definition of the "best available science" should include
the information derived from a systematic review of the available data for a chemical and a WoE evaluation
of that data. One possible definition could be: "all of the data obtained via systematic review that were
determined to be of high quality via standard data quality methodology." Note that the WoE evaluation for
a chemical should consider all the data available for that chemical, including low-quality data. However,
EPA should describe why certain low-quality data would not be considered as part of the "best available
science."
Most importantly, a full description of the process, content, and standards that need to be considered in
determining what is the "best available science" need to be outlined in risk evaluation guidelines. Below,
we list several government reports and peer-reviewed articles that describe the importance of systematic
review and WoE in risk assessment, and provide example frameworks for these procedures that EPA should
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consider in development of guidance documents for its own implementation of the Rule and for risk
evaluations conducted by "interested persons."
The Office of Management Budget (OMB) and Office of Science and Technology Policy
(OSTP) joint memorandum to the Executive Departments and Agencies on "Updated Principles
in Risk Analysis" (Dudley and Hays, 2007);
"Review of the EPA Draft Integrated Risk Information System (IRIS) Assessment for
Formaldehyde" by the National Academy of Science (NAS) (NRC, 2011);
The Research Integrity Roundtable (RIR) Keystone Report on "Improving the Use of Science
in Regulatory Decision-Making: Dealing with Conflict of Interest and Bias in Scientific
Advisory Panels, and Improving Systematic Scientific Reviews" (RIR, 2012);
"Review of EPA's IRIS Process" by NAS (NRC, 2014);
"Systematic Comparison of Study Quality Criteria" by Lynch et al. (2016); and
"Key Elements in Judging the Quality of a Risk Assessment" by Fenner-Crisp and Dellarco
(2016).
Comment #3: EPA should clearly present its approach to determining that a chemical poses an "unreasonable risk."
Issue: EPA explicitly states in the Proposed Rule that it will not define "unreasonable risk" in its TSCA-
specific guidance, but will rely on the use of this terms in general EPA procedures. Because the meaning
of "unreasonable risk" in other settings does include considerations of costs, alternatives, and benefits, and
because cost considerations are explicitly excluded from TSCA's determinations of risk (as stated in the
statute), the new TSCA-specific meaning of "unreasonable risk" is unclear. Third-party risk assessments
(or risk evaluations by "interested persons" as described in the Rule) and data-gathering exercises for the
chemicals undergoing EPA evaluation will be very difficult if the risk target for these chemicals is not clear.
Suggestion: If "unreasonable risk" will not be quantitatively defined in the Final Rule, EPA should
describe their approach to determining that a chemical poses an "unreasonable risk." The general approach
should be described in the Rule, with specific guidelines described in guidance documents for EPA's own
implementation of the Rule and for risk evaluations conducted by "interested persons."
Non-cancer Risks: The Proposed Rule states that a margin of exposure (MOE) could be
considered in the presentation of non-cancer risks in the risk evaluation. The Agency requests
comments on the strengths and weaknesses of this approach. This approach seems reasonable,
provided that EPA also describes the scientific basis for an acceptable MOE, which will vary across
chemicals and for different populations (e.g., workers vs. children) and will depend on the level of
uncertainty in potential toxicity and exposures for different chemicals. EPA should also plan to
present a range of exposures (i.e., include a central tendency exposure estimate) and MOE values
for the different populations evaluated in each chemical risk assessment. In addition, EPA should
take into account any industry-standard practices to mitigate exposure and releases, so that the risk
estimates for a chemical reflect actual exposures to that chemical. EPA should consider providing
a range of MOEs that would be considered acceptable for different exposure populations. This
would be extremely helpful for those conducting third-party risk assessments of chemicals for
which EPA has not yet published a draft risk evaluation.
Cancer Risks: An MOE approach could be used for evaluating the risks posed by those
carcinogens for which a threshold mode of action and exposure concentration has been identified.
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In these cases, EPA should use an MOE approach similar to that for non-carcinogens, as described
above. Even for carcinogens, mode-of-action considerations may indicate that the dose-response
relationship should be expected to have an exposure threshold below which additional risk is not
expected. EPA should aim for using this approach whenever the data support it. Additionally, the
consideration of this approach should be part of every evaluation of possible alternative analyses.
In defining "unreasonable risk" for each chemical risk evaluation, EPA should bear in mind the
following considerations.
Whether the risks in question are low ones experienced by a very broad population or
potentially higher ones that would only be experienced by a very narrow subset of the general
population.
Whether the risks in question are expected to occur only for a defined subpopulation.
Whether exposures are essentially voluntary and knowable versus involuntary or unknowable
by those potentially exposed.
The practical issues of avoiding or altering the exposures leading to the risks in question.
The severity of the risked impact and the background rate of the effect in unexposed individuals
who are otherwise comparable to those exposed.
Comment #4: EPA should emphasize and discuss the use of alternatives to animal testing as part of information gathering for data gaps during chemical prioritization and risk evaluation processes.
Issue: Because information gathering is an early part of the prioritization process and, as stated in the
prioritization rule, will also encompass information that will be necessary for the risk evaluation (US EPA,
2017b, p. 4,829), the comments below pertain to both the prioritization and risk evaluation Proposed Rules.
In the risk evaluation Proposed Rule (US EPA, 2017a, p. 7,565), EPA states with respect to "Other Statutory
Requirements" that:
[A]mendments to TSCA section 4 require EPA to ''...reduce and replace, to the extent
practicable, [...] the use of vertebrate animals in the testing of chemical substances...''
(ellipsis in original) and to develop a strategic plan to promote such alternative test
methods. 15 U.S.C. 2603(h). Likewise, TSCA section 26 requires, to the extent that EPA
makes a decision based on science under TSCA sections 4, 5, or 6, that EPA uses certain
scientific standards and bases those decisions on the weight of the scientific evidence. 15
U.S.C. 2625(h) and (i). While these requirements are relevant to the risk evaluation of
chemical substances, EPA is not obliged to repeat them in this proposed rule. As statutory
requirements, they apply to EPA's decisions under TSCA section 6. Moreover, in
contrast to TSCA section 6, Congress has not directed EPA to implement these other
requirements ''by rule;'' it is well-established that where Congress has declined to
require rulemaking, the implementing agency has complete discretion to determine
the appropriate method by which to implement those provisions. (emphasis added)
It may be a positive sign that EPA considers the requirement to minimize vertebrate animal testing to be
implicit in its decisions under TSCA Section 6; however, this should be explicitly stated in the risk
evaluation Proposed Rule as a reminder that it is a requirement whenever toxicological data gathering is
discussed (as it is in the risk evaluation draft Proposed Rule; US EPA, 2017a, p. 7,570). In addition,
submitters of data should be reminded that this requirement extends to them ("Testing of chemical
substances and mixtures" §2603(h)(3)(A); US Congress, 2016).
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Additionally, because EPA did not define "sufficiency of information" in the prioritization or risk
evaluation Proposed Rules, it is even more important to explain to manufacturers and third-party risk
assessors what types of data EPA will consider to be "sufficient" and what role non-animal testing strategies
play in that consideration.
Suggestion: Although it is reasonable that EPA does not describe a plan for minimizing vertebrate animal
testing in full in the prioritization and risk evaluation Proposed Rules, it would be useful to emphasize
alternatives to animal testing and discuss the types of non-animal tests that EPA will be recommending
(e.g., in vitro toxicity testing; computational toxicology; data from structure-activity relationships, high-
throughput assays, genomic response assays) and the fact that collection of these data will be encouraged
rather than the use of animal data, when possible.
Sufficiency of Information
The emphasis on alternatives to animal testing will be important during the data gathering stages of both
the risk evaluation and prioritization processes. The risk evaluation Proposed Rule states that "EPA also
generally intends to use its authority under TSCA to require the development of new information, as
necessary, prior to risk prioritization" (US EPA, 2017a, p. 7,568). This Proposed Rule also states that "EPA
will exercise its TSCA information collection, testing, and subpoena authorities, including those under
TSCA sections 4, 8, and 11(c) to develop the information needed for a risk evaluation" (US EPA, 2017a,
p. 7,568). Given these statements, it is important that manufacturers and third-party risk assessors
understand the types of data that will be considered "sufficient." The current risk evaluation Proposed Rule
provides little guidance on the sufficiency of non-animal testing methods. Given that these methods are
often more efficient and cost-effective, stakeholders will need to know to what extent, and in what context,
they will also be considered "sufficient."
Note that the risk evaluation Proposed Rule indicates that if the manufacturers' request is considered
"insufficient," EPA will require that the information be made available to EPA within 60 days, and if not
submitted by then, the request will be considered withdrawn (US EPA, 2017a, p. 7,569). Given this short
timeframe to supply missing information, and the fact that it might not be possible to submit the required
information within that timeframe, EPA needs to make clear what information is considered "sufficient"
early in the process so that manufacturers can collect the relevant information before requesting a risk
evaluation.
The LCSA states that EPA:
shall reduce and replace, to the extent practicable…the use of vertebrate animals in the
testing of chemical substances or mixtures under this title by—(A) prior to making a
request or adopting a requirement for testing using vertebrate animals [emphasis
added]…reasonably available existing information, including – (i) toxicity information;
(ii) computational toxicology and bioinformatics; and (iii) high-throughput screening
methods and the prediction models of those methods; and (B) encouraging and facilitating
– (i) the use of scientifically valid test methods and strategies that reduce or replace the use
of vertebrate animals…(ii) the grouping of 2 or more chemical substances [emphasis
added] into scientifically appropriate categories…(iii) the formation of industry consortia
[emphasis added] to jointly conduct testing to avoid unnecessary duplication of tests…
(US Congress, 2016)
EPA does discuss in the "Hazard Assessment" section of the risk evaluation Proposed Rule that they will
consider "[h]uman epidemiological studies; in vivo and/or in vitro laboratory studies; mechanistic or kinetic
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studies in a variety of test systems, including but not limited to toxicokinetics and toxicodynamics,
computational toxicology; data from structure-activity relationships, high-throughput assays, genomic
response assays, and ecological field data" (US EPA, 2017a, p. 7,570). We agree that it is important to
consider all of these data sources in chemical risk evaluations, and particularly non-animal testing methods
in the context of the new TSCA's "reduce and replace" requirement for animal testing (US Congress, 2016).
There needs to be more discussion of these types of data in the sections of the Proposed Rule that discuss
the sufficiency of information for EPA's chemical risk evaluation process.
According to the LCSA, when requesting any new information, EPA "…shall employ a tiered screening
and testing process, under which the results of screening-level tests or assessments of available information
inform the decision as to whether 1 or more additional tests are necessary…" (US Congress, 2016). This
is consistent with EPA's current approach. However, the requirements to "identify the need for the new
information, describe how information reasonably available to the Administrator was used to inform the
decision to require new information, [and to] explain the basis for any decision that requires the use of
vertebrate animals" (US Congress, 2016), and to reduce and replace vertebrate animal testing, necessitates
the increased use of tiered screening and testing and the implementation of non-animal testing methods and
approaches.
Approaches to Avoid Animal Testing
Because sufficiency of information begins during the prioritization process for chemicals undergoing EPA
risk evaluation, it might be useful for EPA to provide a set of physical-chemical properties, in vitro tests,
and QSAR methods that a company could apply to their chemical that would help them determine whether
their chemical might be considered high priority, or when they need to consider some form of animal
testing. The aim would be to provide a means to assure the public that chemicals have not been overlooked
in the prioritization process simply because of ignorance of possible effects of concern stemming from a
lack of testing. The approach would stand in contrast to the European Union (EU) Registration, Evaluation,
Authorisation and Restriction of Chemicals (REACH) approach, for which the standard and mandated set
of baseline testing includes a great deal of animal testing and considerable expense. The shortcoming of
the REACH approach is that animal testing is done, through the minimum dataset mandate, before
evaluating which specific tests are necessary to establish adequate protection of public health. A well-
thought-out minimum in vitro assay and QSAR array, however, would add the benefit of ensuring that
indicators of the major toxicity concerns are routinely considered, while leaving animal testing to those
cases in which it is absolutely necessary.
In scenarios in which new animal testing is necessary, EPA should consider requesting companies to
provide proof that they have explored alternatives to animal testing methods (i.e., in vitro, QSAR, read-
across, data-waiving), leaving animal testing as a last resort. EPA should also encourage joint data
submission (and data generation, if warranted) by companies, as indicated in LCSA §2603(h)(1)(B) (US
Congress, 2016). Lastly, EPA should encourage collaboration and data sharing among governmental
agencies (internal or domestic) for a given chemical.
In addition to saving the lives of many animals, the use of non-animal testing data (i.e., in vitro testing;
computational toxicology; data from structure-activity relationships, high-throughput assays, genomic
response assays, waiving of studies) will allow for faster data gathering and will make it easier to meet the
timeline requirements for the prioritization and risk evaluation processes. Several frameworks have
recommended approaches that limit animal testing for these reasons. EPA should consider approaches
applied by some of these frameworks, as summarized below:
Australia's National Industrial Chemicals Notification and Assessment Scheme (NICNAS) (new
chemicals, Inventory Multi-tiered Assessment and Prioritisation [IMAP] framework, Priority
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Existing Chemicals [PEC] assessments) – These frameworks specify that the use of animal testing
may be reduced through data-waiving. NICNAS only requests animal testing if potential risks
cannot be evaluated through other means (Australia NICNAS, 2009, 2016a,b).
EU REACH Existing Community Rolling Action Plan (CoRAP) and New Chemical
Registration – REACH encourages data sharing among registrants of the same substance.
In addition, REACH encourages and provides guidance documents for the use of read-across, data-
waiving, and QSAR to inform all human health and aquatic toxicological endpoints, whenever
appropriate (ECHA, 2017a,b). Under the REACH legislation, animal testing is only acceptable as
a last resort.
Similar to the Australia NICNAS and EU CoRAP approaches, we suggest that EPA require that companies
attempt to fulfill data requirements via non-animal testing methods and existing animal studies, and only
conduct new animal tests if alternative options are not appropriate or sufficient.
In addition to considering the Australia and EU approaches, see suggestions below regarding how EPA
could implement this approach.
EU REACH Annex II notes many accepted scenarios where certain tests may be waived (European
Union, 2012a):
Waiving a short-term, repeated-dose 28-day toxicity study if there is an existing or planned 90-
day study.
Waiving in vivo skin sensitization and acute dermal toxicity tests if the chemical is corrosive
or has a pH value <2 or >11.
Waiving reproductive and developmental toxicity tests if the chemical is already a genotoxic
carcinogen or a known germ cell mutagen. This approach is likely due to the fact that all
carcinogens, mutagens, or reproductive toxicants (CMRs) are regulated the same way in the
EU.
Waiving a reproductive and developmental toxicity test if the chemical has low toxicological
activity (i.e., no adverse effects seen in any of the available tests) and it can be proven from
toxicokinetic data that no systemic absorption occurs via the relevant exposure pathways.
Waiving duplicate carcinogenicity and long-term, repeated-dose studies by using a combined
carcinogenicity and long-term, repeated-dose study (Organisation for Economic Co-operation
and Development [OECD] Test Guideline 453).
Waiving a subchronic, repeated-dose 90-day toxicity study if:
A 28-day study already showed that the chemical has severe toxicity worthy of it being
classified in Globally Harmonized System of Classification and Labelling (GHS) Category
1 or 2, or
The chemical undergoes immediate disintegration and there is sufficient data on all of the
degradation products, or
The chemical is unreactive, insoluble, not inhalable, and showed no toxicity in a 28-day
test.
Waiving aquatic toxicity testing in crustacean, fish, and algae if the chemical is highly
insoluble.
Other test-waiving opportunities:
Waiving a second species (mouse) for carcinogenicity test:
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An assessment of 202 pesticide evaluations from the EU review program under former
plant protection products Directive 91/414/EEC indicated that "the mouse carcinogenicity
study contributed little or nothing to either derivation of an acceptable daily intake (ADI)
for assessment of chronic risk to humans, or hazard classification for labeling purposes.
From a pesticide approval perspective, the mouse study did not influence a single outcome"
(Billington et al., 2010). This finding echoes that of the International Life Sciences
Institute (ILSI)/Health and Environmental Sciences Institute (HESI) Agricultural Chemical
Safety Assessment Systemic Toxicity Task Force in 2006, which recommended wholesale
"elimination of the mouse carcinogenicity bioassay" (Doe et al., 2006).
Waiving an acute oral toxicity test if a 28-day oral study reported a no observed adverse effect
level (NOAEL) >1,000 mg/kg-bw:
Authors used the European Chemicals Agency (ECHA) REACH Dossier dataset and found
1,256 substances that had both a reliable 28-day oral and acute oral study. They found that
lack of subchronic oral toxicity (e.g., NOAEL >1,000 mg/kg-bw) was an excellent
predictor of low acute oral toxicity (e.g., lethal dose 50 [LD50] >2,000 mg/kg-bw). The
accuracy rate was 98%, with nine cases having an incorrect prediction. However, when
the authors looked into these nine cases, they found that the data were misrepresented in
eight cases, so there was ultimately only one true case. The predictive relationship holds
relatively stable for those subchronic studies in which the NOAEL was >500 (96%) and
>300 mg/kg-bw (94%) (Gissi et al., 2016).
Waiving an acute dermal toxicity test if an acute oral toxicity test has been performed:
A 2007 publication by the United Kingdom Pesticide Safety Directorate examined
unpublished acute oral and dermal toxicity data for 195 pesticide active (technical)
ingredients and 3,111 formulated products, concluding that "the dermal acute toxicity study
adds little if anything to the database on pesticide active substances" and that a "similar
result was indicated for formulated products" (Thomas and Dewhurst, 2007). A 2010
update to this analysis, using a slightly expanded dataset of 240 pesticide active substances
subjected to acute toxicity testing by both oral and dermal routes, found that in only two
cases (0.8%) did substances receive a more severe classification when the dermal route
was assessed rather than the oral route (Creton et al., 2010). Taken together, these analyses
clearly illustrate the limited value of acute toxicity testing via the dermal route for the
purpose of classification and labeling, and call into question the appropriateness of
regulations that continue to require redundant dermal route testing when oral data are
already available.
EU Biocidal Products Regulation 528/2012 Data Requirement 8.7.3 (Annex II) now
provides that:
Testing by the dermal route is necessary only if: inhalation of the substance is
unlikely, or skin contact in production and/or use is likely, and either the
physicochemical and toxicological properties suggest potential for a significant
rate of absorption through the skin, or the results of an in vitro dermal penetration
study (OECD 428) demonstrate high dermal absorption and bioavailability.
(European Union, 2012b).
EPA's Office of Pesticide Programs also recently published waiver guidance for acute
dermal toxicity based on oral data in its "Guidance for Waiving Acute Dermal Toxicity
Tests for Pesticide Formulations & Supporting Retrospective Analysis" (US EPA, 2016).
Although this guidance was based on a retrospective analysis of formulations, the study
and guidance provide further support for waiving dermal studies based on oral data.
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