By Lisa M. Campbell and Timothy D. Backstrom
In July 2018, the California Environmental Protection Agency’s Department of Pesticide Regulation (DPR), Human Health Assessment (HHA) Branch, issued its final toxic air contaminant (TAC) evaluation of chlorpyrifos. This final TAC evaluation updates the December 2017 draft evaluation of chlorpyrifos as a TAC for the Scientific Review Panel (SRP) which updated the August 2017 draft and was reviewed by the SRP on TACs, and incorporates certain changes based on SRP recommendations. As part of their review of the December 2017 draft, the SRP recommended “additional and detailed review of developmental neurotoxicity studies, in particular recent in vivo animal studies as well as a more in depth analysis of human effects of chlorpyrifos” and “that DPR reevaluate the critical endpoints, the associated [(uncertainty factors (UF)], and the resulting [reference concentrations (RfC)] and [reference doses (RfD)] for each endpoint.”
DPR determines that a pesticide is a TAC for a non-cancer adverse effect if the projected air concentrations associated with use of the pesticide are more than one tenth of the inhalation RfC established based on animal toxicity and epidemiology data. In the draft TAC evaluation for chlorpyrifos, DPR utilized the threshold for red blood cell acetylcholinesterase (AChE) inhibition in humans and a target margin of exposure (MOE) of 100, including a factor of 10 intended to account for potential neurodevelopmental effects below the threshold for RBC AChE inhibition. In the final TAC evaluation for chlorpyrifos, DPR increased the MOE for AChE inhibition to 300, based on deficiencies in the human inhalation parameters used to model the threshold for AChE inhibition.
In addition, the final TAC evaluation establishes a new No Observed Effect Level (NOEL) for neurodevelopmental effects in animal studies with chlorpyrifos reported at exposure levels well below the threshold for AChE inhibition. Based on this NOEL, DPR has derived a new inhalation RfC for neurodevelopmental effects, using a standard MOE of 100 consisting of 10X for interspecies sensitivity and 10X for intraspecies variability. This new inhalation RfC based on neurodevelopmental effects in animal studies is about one-half the revised inhalation RfC based on the threshold for AChE inhibition. Because the modeled spray drift air concentrations for chlorpyrifos are more than one tenth of this new inhalation RfC, DPR concludes “that chlorpyrifos meets the criteria to be listed as a TAC pursuant to the law of California.”
In the final TAC evaluation for chlorpyrifos, DPR concluded that there is sufficient evidence from animal studies to establish a new NOEL for neurodevelopmental effects, which is well below the level that has been shown to cause AChE inhibition in the same animals. Although the U.S. Environmental Protection Agency (EPA) has previously issued a determination that the default 10X safety factor for infants and children established by the Food Quality Protection Act (FQPA) should be retained for chlorpyrifos, this determination was based on epidemiology studies that purported to show adverse neurodevelopmental outcomes in humans at exposure levels below the threshold for AChE inhibition. The methodology used in these epidemiology studies has been harshly criticized by the pesticide industry. DPR views these epidemiology studies as providing corroboration, but the new DPR risk assessment is predicated instead on DPR’s view that animal studies with chlorpyrifos report neurodevelopmental effects below the threshold for AChE inhibition. The DPR risk assessment based on these animal studies uses a standard MOE of 100. How EPA may or may not view DPR’s conclusion is not known. In light of the August 9, 2018, decision by the U.S. Court of Appeals for the Ninth Circuit (Ninth Circuit) directing EPA to proceed with revocation of all tolerances and cancellation of all registrations for chlorpyrifos, the effect of the DPR conclusion on EPA actions is not clear. Nevertheless, it is worth noting that, because the mechanism by which chlorpyrifos would cause such neurodevelopmental effects is unknown and is below the level that causes AChE inhibition, any presumption by EPA that other organophosphate (OP) pesticides may cause the same type of effects will likely be vigorously disputed by industry on scientific grounds.
Please see our blog item Ninth Circuit Directs EPA to Revoke all Tolerances and Cancel All Registrations for Chlorpyrifos for more information on the Ninth Circuit’s August 9, 2018, decision.
By Timothy D. Backstrom and Lisa M. Campbell
On June 19, 2018, 16 federal agencies, including the U.S. Environmental Protection Agency (EPA), issued a final rule delaying until January 21, 2019, the general compliance date for 2017 revisions to the policy governing studies with human subjects that are sponsored or utilized for regulatory purposes by the federal government (83 Fed. Reg. 28497). These revisions to the human testing policy were adopted on January 19, 2017, in a final rule (82 Fed. Reg. 7149) that amended and expanded the “Common Rule” governing human testing originally promulgated in 1991. The 2017 revisions to the human testing policy were originally scheduled to take effect on January 19, 2018, but the agencies published an interim final rule on January 22, 2018, that delayed the effective date for the new policy until July 19, 2018. Thereafter, on April 20, 2018, the same 16 agencies published a proposed rule (83 Fed. Reg. 17595) to delay the general compliance date for an additional six-month period, and to allow regulated entities to implement certain burden-reducing provisions during this interim period.
The rule delaying the effective date of the 2017 revisions for an additional six months takes effect on July 19, 2018. In the period between July 19, 2018, and January 21, 2019, regulated entities must continue to comply with the requirements of the human testing policy as it was in effect prior to the 2017 revisions. Notwithstanding this general rule, affected institutions will be permitted (but not required) to implement, for certain research, three burden-reducing provisions. Those three provisions are:
- The revised definition of “research,” which deems certain activities not to be research covered by the Common Rule;
- The elimination of the requirement for annual continuing review with respect to certain categories of research; and
- The elimination of the requirement that institutional review boards (IRB) review grant applications or other funding proposals related to the research.
The principal purposes of the additional delay in implementation of the 2017 revisions to the human testing Common Rule are to allow more time for affected institutions to prepare for compliance and for the federal agencies that have adopted the new policy to issue further guidance. The final rule states that the agencies do not expect that any additional delay in the implementation of the policy will be needed.
More information on the federal policy for the protection of human subjects is available in our blog under key phrases human subjects and common rule.
By Carla N. Hutton
On April 10, 2018, the U.S. Environmental Protection Agency (EPA) announced the availability of a draft Science Policy document intended to reduce the use of animals in testing chemicals to evaluate whether they cause an allergic reaction, inflammation, or sensitization of the skin. According to EPA, the document, Draft Interim Science Policy: Use of Alternative Approaches for Skin Sensitization as a Replacement for Laboratory Animal Testing, “describes the science behind the non-animal alternatives that can now be used (in vitro, in silico, in chemico) to identify skin sensitization.” The draft Science Policy states that the Office of Pesticide Programs (OPP) and Office of Pollution Prevention and Toxics (OPPT) will immediately begin to accept submissions of new approach methodologies (NAM) and defined approaches (DA) as described in the draft Science Policy. EPA notes that there are multiple domestic and international activities ongoing that will allow for refinement and expansion of this draft Science Policy to other DAs and additional NAMs and support global harmonization of DAs for skin sensitization. According to the draft Science Policy, OPP and OPPT “will continue to be active participants in these activities to ensure regulatory acceptance and will continue to support cross-sector collaborations that enhance animal welfare, and accelerate the implementation of NAMs.” Comments on the draft Science Policy document must be submitted to Docket Number EPA-HQ-OPP-2016-0093 by June 9, 2018.
The draft Science Policy is the result of national and international collaboration between the Interagency Coordinating Committee on the Validation of Alternative Methods, the National Toxicology Program’s Interagency Center for the Evaluation of Alternative Toxicological Methods, the European Union Reference Laboratory for Alternatives to Animal Testing, and Health Canada’s Pest Management Regulatory Agency.
By Heather F. Collins, M.S. and Margaret R. Graham
On February 28, 2018, the U.S. Environmental Protection Agency (EPA) announced the availability of three Group B -- Antimicrobial Efficacy Test Guidelines, under Series 810, Product Performance Test Guidelines. The guidelines provide recommendations for the design and execution of laboratory studies to evaluate the effectiveness of antimicrobial pesticides against public health microbial pests. 83 Fed. Reg. 8666. The three final guidelines are:
EPA states these “test guidelines are part of a series of test guidelines established by the Office of Chemical Safety and Pollution Prevention (OCSPP) for use in testing pesticides and chemical substances. The test guidelines serve as a compendium of accepted scientific methodologies and protocols for testing that is intended to provide data to inform regulatory decisions.”
EPA issued draft guidelines in June 2015 and solicited comments. EPA states that some comments received on those draft guidelines have been incorporated into the final versions. EPA states that the revision “is more user friendly and clarifies topics such as confirmatory data, repeat testing, hard water formulation, wetness determination testing for towelettes, and internal toilet testing … [and] also includes information on supplemental testing policies such as lower certified limits, revision of the AOAC Use Dilution Method performance standards and clarified technical details for efficacy testing.”
Documents pertaining to the revision of the product performance guidelines, including public comment submissions, and the agency’s response to comments are available at www.regulations.gov, in Docket No. EPA-HQ-OPP-2015-0276. More information on test guidelines is available on our blog.
By Lisa M. Campbell, Lisa R. Burchi, and James V. Aidala
On February 1, 2018, the U.S. Environmental Protection Agency (EPA) announced it is publishing new guidance that sets forth a tiered approach intended to help manufacturers and EPA determine when the number of field trials necessary to register seed treatment uses can be reduced.
In its memo and attached Seed-Treatment Focus Group (STFG) Guidance Document dated January 26, 2018, EPA states that its Health Effect Divison (HED) has received “multiple waiver requests for seed-treatment field-trial residue data and has reviewed multiple field-trial datasets that indicated that there was the potential to reduce the number of field trials required to support the registration of seed-treatment uses.” EPA states that to evaluate this hypothesis, the HED Chemistry Science Advisory Council (ChemSAC), in collaboration with the Health Canada Pest Management Regulatory Agency (PMRA), in accordance with the July 11, 2017, Joint Canada/United States Field Trial Requirements “performed a retrospective analysis of all seed-treatment residue data that have been submitted to EPA/PMRA and has developed a tiered approach for determining if current crop-specific field trial data requirements are required to support new seed-treatment uses, or if a reduction in the number of required field trials is appropriate.” EPA’s announcement states that “the analysis showed that the data required to support registration could be substantially reduced and still be protective of human health.”
EPA developed two decision trees detailing the process for determining the residue chemistry field trial data requirements for seed-treatment uses: one for potato seed-piece (PSP) treatments only and another one for all remaining crops. EPA states that this case study demonstrates that application of the guidance set forth in these decision trees can, for both manufacturers and the agency, “potentially save considerable resources in terms of conducting, submitting, and reviewing the studies while still obtaining the data necessary to support seed-treatment pesticide registrations.”
The outlined procedure and memo document will supersede EPA’s previous guidance issued on October 28, 1999, entitled “Classification of Seed Treatments as Food or Nonfood Uses.”
More information is available on EPA’s Determining the Number of Field Trials Required to Register Seed-Treatment Uses webpage.
This announcement of improved review procedures allows EPA to cite both greater coordination across national borders (working with Canada), and reduce unnecessary data requirements. This would fit with the current Administration’s emphasis on reducing regulatory burdens and fostering greater innovation in regulated arenas. It also might be seen as general “good government,” as it updates guidance which is now almost twenty years old. Since seed treatment technology and associated policy issues have both evolved over the years, such a review and revision would seem timely regardless of any larger political directive.
By Lynn L. Bergeson and Margaret R. Graham
On January 22, 2018, the White House again delayed the effective date of revisions to the Federal Policy for the Protection of Human Subjects, referred to as the Common Rule. Final revisions were published on January 19, 2017. On September 8, 2015, the U.S. Department of Health and Human Services (HHS) and 15 other federal departments and agencies published a Notice of Proposed Rulemaking (NPRM) proposing revisions to each agency’s codification of the Federal Policy for the Protection of Human Subjects, originally promulgated as a Common Rule in 1991. 80 Fed. Reg. 53931. On January 19, 2017, HHS and other federal departments and agencies published a final rule revising the Federal Policy for the Protection of Human Subjects. 82 Fed. Reg. 7149. The revised policy, referred to as the “2018 Requirements,” was scheduled to become effective on January 19, 2018, with a general compliance date of January 19, 2018, with the exception of the revisions to the cooperative research provisions for which the compliance date is January 20, 2020.
After publication of the 2018 Requirements, representatives of industry, including organizations representing recipients of federal human subjects research awards, expressed concern regarding their ability to implement all of the 2018 Requirements by the scheduled general compliance date. Stakeholders requested a delay in the general compliance date of the 2018 Requirements with the exception of certain burden-reducing provisions of the 2018 Requirements, including certain carve-outs from the definition of “research” exemptions, elimination of the continuing review requirements for certain categories of research, and the elimination of the requirement that institutional review boards (IRB) review grant applications. The HHS Secretary’s Advisory Committee on Human Research Protections (SACHRP) also recommended in August 2017 that implementation of the 2018 Requirements should be delayed. The new effective date is July 19, 2018. Comments are due by March 19, 2018.
More information on the Common Rule is available on our blog.
By Heather F. Collins
On August 28, 2017, the U.S. Environmental Protection Agency (EPA) announced the first of three feature and functionality updates to the Pesticide Submission Portal (PSP) expected this year. The portal is a web-based application allowing registrants to submit pesticide application packages to EPA electronically. The PSP application is accessed through EPA’s Central Data Exchange (CDX) Network which requires user registration.
This new PSP, version 1.4, release expands the feature to allow users to submit voluntary data related to specific registration review cases. Users can submit study citations, data matrices (Form 8570-35), cover letters and studies (protocols, study profiles, supplemental study data) using the new "Voluntary Submission" link on the PSP home page. This new release also allows users to resubmit previously submitted 90-day responses. Once a 90-day response or data submission has been successfully transmitted to the Office of Pesticide Programs (OPP), users may now modify responses to data requirements, cite additional studies, upload additional documents, and change how the product registration is supported. EPA states: “This action is another step in a phased approach that will ultimately lead to EPA’s ability to accept all pesticide applications electronically, a move that will help modernize the pesticide registration process, increase operational efficiencies and reduce paper waste.” EPA indicates that in addition to these changes, this update introduces enhancements and bug fixes.
EPA also released the OPP Pesticide Submission Portal (PSP) User Guide Version 1.4 which provides detailed instructions on how to use the PSP application and guidance on how to prepare a package for electronic submission.
Applicants using PSP need not submit multiple electronic copies of any pieces of their applications; EPA states that the requirement to submit multiple copies of data in Pesticide Registration Notice 2011-3 is applicable only to paper submissions. Pesticide registrants who previously submitted information via paper, CD, or DVD may instead use the portal and forego the courier costs of sending to EPA.
More information about the Electronic Submissions of Pesticide Applications is available on EPA’s website.
By Sheryl L. Dolan and Margaret R. Graham
On August 1, 2017, the U.S. Environmental Protection Agency (EPA) announced the availability of two final test method Standard Operating Procedures (SOP) for evaluating the efficacy of antimicrobial pesticides against two biofilm bacteria, Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus):
EPA also released regulatory guidance for test criteria and pesticide claims for these products, specifically Guidance for Testing the Efficacy of Antimicrobial Products Against Biofilms on Hard, Non-Porous Surfaces. Drafts of the SOPs and the guidance were initially released in October 2016 for comment. EPA received comments from nine entities and revised the drafts to incorporate suggested changes. EPA posted its response to those comments in Docket EPA-HQ-OPP-2016-0357.
EPA states that the two methods are adapted from ASTM International (ASTM) standard methods. EPA MLB SOP MB-19 is used to generate the P. aeruginosa or S. aureus biofilm on coupons. EPA MLB SOP MB-20, the Single Tube Method, then is used to determine the effectiveness of an antimicrobial product in reducing bacteria in biofilm on the coupons.
Notable aspects of the test criteria and claims guidelines include:
- The mean log density for the test organisms of 8.0 to 9.5 for P. aeruginosa and 7.5 to 9.0 for S. aureus; and
- Product performance criterion of a minimum 6-log reduction.
The guidance lists several examples of claims for efficacy against public health biofilm that EPA states are acceptable.
EPA MLB SOP MB-20 is designed to evaluate the efficacy of antimicrobial products that are water soluble powders or liquid formulations. If a company wishes to test a different type of product formulation, or test different target microorganisms, or make any other proposed modifications, it would be well advised to submit proposed alternatives to EPA for review and approval. EPA specifically cautions that the current methodologies are intended for data development to support claims for products registered for use on hard, non-porous surfaces and are not suitable for use sites associated with water systems.
The EPA’s Office of Pesticide Programs’ (OPP) regulation of biofilms has been the subject of increasingly intense commercial interest for years and the availability of this testing guidance is welcome news. While not all will agree with the approach, the new guidance is a helpful addition to OPP’s testing guidance portfolio.
More information on antimicrobial pesticides is available on our blog under key phrase Antimicrobial Pesticide. More information on the methods and guidance is available on EPA’s website and in Docket No. EPA-HQ-OPP-2016-0357.
By Lisa M. Campbell and Margaret R. Graham
On June 14, 2017, the U.S. Environmental Protection Agency (EPA) issued a Federal Register notice announcing the availability of a final test guideline, Laboratory Product Performance Testing Methods for Bed Bug Pesticide Products; OCSPP Test Guideline 810.3900, part of a series of test guidelines established by the EPA’s Office of Chemical Safety and Pollution Prevention (OCSPP) for use in testing pesticides and chemical substances. 82 Fed. Reg. 27254. EPA states that this test guideline provides “guidance for conducting a study to determine pesticide product performance against bed bugs, and is used by EPA, the public, and companies that submit data to EPA,” and “recommendations for the design and execution of laboratory studies to evaluate the performance of pesticide products intended to repel, attract, and/or kill the common bed bug (Cimex lectularius) in connection with registration of pesticide products under the [Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)].” EPA states that this guidance applies to products “in any formulation such as a liquid, aerosol, fog, or impregnated fabric, if intended to be applied to have a pesticidal purpose such as to attract, repel, or kill bed bugs.” This guideline provides appropriate laboratory study designs and methods for evaluating the product performance of pesticides against bed bugs and includes statistical analysis and reporting.
EPA issued the draft guideline on February 14, 2012. This original document was the subject of FIFRA Scientific Advisory Panel (SAP) review conducted on March 6-7, 2012. EPA indicates that the final version of the guideline reflects revisions to the original draft based on comments from the SAP and the public. EPA states that the revisions include the following:
- Decreasing the number of individuals and replicates tested;
- Rescinding the recommendation to test each field strain for its resistance ratio; and including a resistance management statement;
- Clarifying the agency's Good Laboratory Practices (GLP) requirements;
- Reducing the recommended length of time individuals are exposed to insecticides;
- Recommending individuals to be observed up to 96 hours after treatment; and
- Revising the statistical analyses recommendations.
EPA has also placed two other relevant documents in the docket:
By Lisa M. Campbell, Lara A. Hall, and Margaret R. Graham
On May 8, 2016, the U.S. Environmental Protection Agency (EPA) announced its invitation for public input regarding the “Strategic Roadmap: New Approaches to Evaluate the Safety of Chemicals and Medical Products” (Roadmap), the development of which was coordinated by the National Toxicology Program’s (NTP) Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). ICCVAM states that the vision of the Roadmap is to “establish new approaches for evaluating the safety of chemicals and medical products in the United States that will increase confidence in alternative methods and improve their relevance to human health outcomes while maximizing efficiency and maintaining a commitment to replace, reduce, and refine animal use.” ICCVAM’s Roadmap effort was introduced in March 2016. A detailed presentation on the development of the Roadmap is available here.
ICCVAM, a permanent committee of the National Institute of Environmental Health Sciences (NIEHS) under the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), is composed of representatives from 16 U.S. federal regulatory and research agencies that require, use, generate, or disseminate toxicological and safety testing information. As a participating member of ICCVAM, EPA states that its role is to “encourage the development and use of alternatives to animal test methods, ensure that new methods are valid, review test method recommendations, and as appropriate, adopt these alternatives in our own regulatory programs.”
There are also three upcoming public meetings that will provide additional opportunities to comment on topics relevant to this effort:
- ICCVAM Public Forum: May 23, 2017, National Institutes of Health (NIH), Bethesda, Maryland;
- NTP Board of Scientific Counselors meeting: June 29, 2017, NIEHS, Research Triangle Park, North Carolina; and
- Scientific Advisory Committee on Alternative Toxicological Methods meeting: September 18-19, 2017, NIH, Bethesda, Maryland.
As ICCVAM’s commitment to replace, reduce, and refine animal use continues to draw public comment and gain support, there is an increasing need to demonstrate the utility and harmonization of predictive approaches in toxicology testing with the conventional safety evaluation of chemicals and medical products. Bergeson & Campbell, P.C. (B&C®) continues to monitor the development, validation, and implementation of alternative in vitro and in silico test methods, high throughput screening assays, and computational models as they are integrated into global regulatory frameworks.