HQ OPPT - Gradient Corp Act, Docket ID EPA–HQ–OPPT–2016–0654 The Humane Society of the...

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\\camfs\G_Drive\Projects\B216120_Humane Society\TextProc\03202017g.docx

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.

11


References

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In NICNAS Handbook for Notifiers. 86p.

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No…/2010 of the European Parliament and of the Council concerning the placing on the market and use

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European Parliament; Council of the European Union (European Union). 2012b. "Regulation (EU) No

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Control Act (Proposed rule)." Fed. Reg. 82(10):4825-4837. 40 CFR 702, January 17. Accessed at

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chemicals-for-risk-evaluation-under-the-toxic-substances-control.

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