Page 1 of 6 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

DATE: April 14 , 2016

SUBJECT: Response to Comments Related to the Draft Abamectin Human Health Risk Assessment in Support of the Draft Pesticide Cumulative Risk Assessment: Framework for Screening Analysis Purpose

PC Code: 122804 , 122806 DP No.: D432515 Decision No.: 495169 Registration No. : NA Petition No.: NA Regulatory Action: NA Risk Assessment Type: Cumulative Case No.: NA T XR No.: NA CAS No.: 71751

- 41

- 2

, 155569

- 91

- 8

, 119791

- 41

- 2 MRID No.: NA 40 CFR: §180.449

, §180.505

FROM: Laura Nollen, Biologist Risk Assessment Branch III (RAB3) Health Effects Division (7509P) Office of Pesticide Programs

THROUGH : Dana Vogel

, Director Health Effects Division (7509P) Office of Pesticide Programs

TO: Susan Lewis

, Director Barbara Madden, Minor Use Team Leader Registration Division (750 5 P) Office of Pesticide ProgramsPage 2 of 6 Introduction:

The Environmental Protection Agency ( EPA ) issued a notice in the Federal Register of July 29, 2015, announcing the availability of draft guidance entitled : Pesticide Cumulative Risk Assessment: Framework for Screening Analysis

. In association with this notice, the Agency sought comments on a draft human health risk assessment that utilized the draft guidance to conduct a cumulative assessment

. Th at assessment, entitled: Draft

- Abamect in. Human Health Risk Assessment for Uses on the Caneberry Subgroup 13

- 07A, Soybeans, Sweet Corn, Ear Tags for Lactating Dairy Cattle, and Golf Course Turf

, is publically available at www.regulations.gov by the document identification number (ID) EPA

- HQ

- OPP

- 2015

- 0422

- 0005

. The p urpose of the subject document is to provide the EPA response to public comments received specifically to the draft cumulative risk assessment for the avermectin macrocyclic lactone s candidate common mechanism group

. The Agency received several comme n ts from two submitters related to the draft cumulative risk
assessment . These comments are summarized and individually addressed below . T he full
comments are publically available at www.regulations.gov in docket EPA

- HQ

- OPP

- 2015

- 0422 by the document ID cited below

. All comments in response to the cumulative framework are presented a separate document 1

.

EPA

- HQ

- OPP

- 2015

- 0422

- 0013 (S. Kunickis, United States Department of Agriculture):

Comment Summary : USDA requested to review three documents associated with the Draft Abamectin Human Health Risk Assessment: 1. The P ercent Crop Area (P CA ) guidance; 2. D. Atwood, 7/23 / 14 and S. Haddad, 11/6/13 percent crop

- treated (PCT) estimates and PCT values for proposed new uses (PCTn) for abamectin; and 3. The DEEM Critical Exposure Commodi ty (CEC) analysis for abamectin.

EPA Response :

1. The PCA Guidance document is publically available 2

. 2. The PCT estimates for abamectin have been updated to provide current information for risk assessment purposes ( D. Atwood, D428074, 08/27/2015 and J. Alsadek, No DP number, 07/01/2015)

. Detailed information as to the assumptions for the PCT and PCTn is provided in section III.C.iv. of the final rule associated with abamectin, available via www.regulations.gov in docket EPA

- HQ

- OPP

- 2013

- 0428

.

3. Abamectin

- specific CEC information is available to the public as supporting and related materials for the abamectin final rule

, via www.regulations.gov

, docket ID EPA

- HQ

- OPP

- 2013

-

1 U.S. Environmental Protection Agency. 2016. Response to Comments on the Pesticide Cumulative Risk Assessment: Framework for Screening Analysis Purpose.

2 https://www.epa.gov/pesticide

- science

- an d

- assessing

- pesticide

- risks/development

- community

- water

- system

drinking

- waterPage 3 of 6 0428, in the document entitled Abamectin : PP# 4E8309, 3E8175, and 3F8184 Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Section 3 Registration Actions for Four Separate New Use Actions and Tolerance Petitions: (1) New Uses on Bean, Papaya, Star Apple, Black Sapote, Sapodilla, Canistel, Mamey Sapot e, Guava, Feijoa, Jaboticaba, Wax Jambu, Starfruit, Passionfruit, Acerola, Lychee, Longan, Spanish Lime, Rambutan, Pulasan, Pineapple; Onion, Green, Subgroup 3

- 07B; Fruit, Pome, Group 11

- 10; Fruit, Small Vine Climbing, except Fuzzy Kiwifruit, Subgroup 13

- 0 7F; Berry, Low Growing, Subgroup 13

- 07G; and Conversion of Existing Crop Groups to Vegetable, Fruiting, Group 8

- 10 (and Addition of Greenhouse

- grown Tomato); Fruit, Citrus, Group 10

- 10; Fruit, Stone, Group 12

- 12; and Nut, Tree, Group 14

- 12. (2) New Uses on Caneberry Subgroup 13

- 07A. (3) Sweet Corn and Soybeans. And (4) Cattle Ear Tag on Lactating Cattle

. Comment Summary : USDA has requested additional information as to why the combined dietary and residential cumulative exposure assessment for abamectin and emamectin did not provide screening

- level total exposure estimates for the age group of children younger than six.

EPA Response : T he residential uses of abamectin relevant for the aggregate assessment and cumulative screen are from th e proposed use on golf courses. According to the 2012 Residential Standard Operating Procedures (SOPs) 3 , the lifestages applicable for post

- application exposure on golf courses are adults, children 11 to < 16 years old, and children 6 to < 11 years old.  These lifestages were chosen according to the available data as well as the behavioral characteristics of potentially exposed lifestages (Section 3.2.8 of the Residential SOPs). Residential exposures are expected to be negligible to infants and young children. Therefore, children younger than age six were not assessed for residential exposures.

EPA

- HQ

- OPP

- 2015

- 0422

- 0015 (National Resource Defense Council):

The National Resource Defense Council (NRDC) provided several comments, along with suggested recommendations

, for each of the following comments. The Agency response to each of the se comments follows.

Comment Summary: EPA did not follow any documented systematic review process , and there is no documentation to show whether or not the O ffice of Pesticide Programs ( OPP ) conducted a comprehensive literature search

. EPA Response : In 2012, OPP published a guidance document to provide guidance procedures for considering and using open literature toxicity studies to support human health risk
assessment 4

. This guidance assists OPP scientists in their judgement of the scientific quality of open literature publications. More specifically, the document discusses how to screen open literature studies for journal articles/publications that are relev ant to risk assessment, how to

3 Available: http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/standard

- operating

- procedures

residential

- pesticide

4 U.S. EPA. 2012. Guidance for considering and using open literature toxicity studies to support human health risk
assessment

. http://www.epa.gov/pesticides/science/lit

- studies.pdfPage 4 of 6 review potentially useful journal articles/publications and categorize them as to their usefulness in risk assessment, and how the studies may be used in the risk assessment. In recent years, the National Academies’ Natio nal Research Council (NRC) has encouraged EPA to move towards systematic review processes to enhance the transparency of scientific literature reviews that support chemical

- specific risk assessments to inform regulatory decision making 5

. The EPA’s Office o f Chemical Safety and Pollution Prevention (OCSPP) is currently developing policies and procedures in order to employ fit

- f or

- purpose systematic reviews. OPP’s approach to reviewing scientific data include: data collection, data revie w, and integration procedures. Therefore, OPP’s standard review approaches for assessing toxicology data submitte d by registrants and for integrating the registrant supported data with information from the open literature are consistent with the NRC’s reco mmen dations for systematic review. As such, although the terminology may differ, the approaches are consistent and similar.

Specifically for abamectin and emamectin, OPP worked with the Office of Research and Development on the literature search and inter pretation of the scientific literature. The Agency has re

- evaluated the entire abamectin and emamectin toxicological database, along with currently available literature information, in order to ensure consistent hazard ev aluation for these structurally

- rel ated pesticides. Literature data have been evaluated in order to enhance the characterization of studies reviewed by the Agency

, and several literature studies were used to enhance the characterization of the abamectin and emamectin toxicological database. F or purposes of screening , the current literature search is sufficient. In the future, i f the A gency were to move toward the determination of common mechanism group (as opposed to the ‘candidate’ mechanism group ), more information would be needed and a systematic review documenting search terms and inclusion/exclusion criteria would be useful

.

OPP also notes that f or on

- going and future cumulative screening toxicology evaluations, t he Agency is working with EPA reference librarian s in order to develop a systematic review for other groups

.

Comment Summary : All endpoints are based on unpublished industry

- sponsored studies.

EPA Response : EPA requires that pesticide registrants provide data from studies conducted according to EPA’s testing guidelines . These guidelines meet the data requirements under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. 136 et seq.). Information abo ut the specific scientific studies required for pesticide registration is located in the Code of Federal Regulations: Title 40 CFR § 158. EPA’s test guidelines for use in data development for the assessment of pesticides are based on the data requirements o utlined in Part 158. Additionally, Title 40 CFR §1 60 provides the Good Laboratory Practice (GLP) Standards that are required for conducting studies that support applications for pesticide registrations under FIFRA and petitions requesting tolerance or tolerance exemptions under the Federal Food, Drug and Cosmetic Act (FFDCA) (21 U.S.C. 346a, 348)

. GLP standards help to ensure the quality and scientific integrity of studies developed and submitted to support these actions , and include quality assurance u nits with periodic inspections and thorough documentation. All studies

5 NRC 2011. Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde ; NRC 2014. Review of EPA's Integrated Risk Information System (IRIS) Process.Page 5 of 6 submitted to EPA that are intended to support applications for pesticide registrations or tolerances/tolerance exemptions under FFDCA are thoroughly reviewed by the Agency.

Comment S ummary : OPP failed to consi der alternate mode of action/adverse outcome pathways (M OA/AOPs ) in the cumulative assessment group and relied on a poorly understood proposed MOA/AOP with very little supporting data.

EPA Response : Under the existing cumulative risk assessment guidance, only those groups with fully established common mechanism groups are assessed f or cumulative risk assessment 6

. A significant amount of toxicology knowledge is required to fully establish key events asso ciated with an a dverse outcome. As a result, OPP has only assessed five common mechanism groups thus far

. The new screening framework guidance provides the opportunity to substantially expand the number of groups assessed for cumulative risk.

The process of collecting and evaluating existing data helps identify potential MOAs and further those which may be eliminated

. In the case of abamectin and emamectin, these pesticides are de rivatives of avermectin. T here is a wealth of data on the insecti cidal MOA for avermectin: its insecticidal actions are mediated by interaction with the glutamate

- gated chloride channels and GABA A - gated chloride channels. Although a proven common MOA finding consistent with previous Agency guidance to identify CMGs 7 has not been found, EPA has conducted a screening

- level cumulative assessment for the avermectin macrocyclic lactones of abamectin and emamectin, using conservative assumptions consistent with the new screening framework guidance 8

.

Comment Summary : EPA eliminated established default protective factors.

EPA Response : Decisions on uncertainty or safety factors for cumulative assessments reflect considerations on the complete set of chemicals under evaluation , abamectin and emamectin, and the common mecha nism of toxicity. The toxicity endpoints and points of departure (PODs) for all exposure scenarios for abamectin and emamectin were recently reevaluated and were selected from the Subchronic and C hronic oral toxicity studies in dogs. The default interspecies (10X) and intraspecies (10X) uncertainty factors have been applied for abamectin and emamectin in the avermectin macrocyclic lactones cumulative assessment in order to account for potential human variability and to account for unce rtainty in extrapolating animal data to estimate potential human risk. However, the Agency believes that data are sufficient to support the reduction of Food Quality Protection Act (FQPA) safety factor from 10X to 1X for both abamectin and emamectin for th e following reasons: ( 1 ) The POD selected from the dog studies is based on clear no observed adverse effect levels ( NOAELs ) that are protective of the adverse effects seen

6 U.S. Environmental Protection Agency. 2002a. Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity ; January 14, 2002. Available: https://www.epa.gov/pesticide

- science

and

- assessing

- pesticide

- risks/guidance

- cumulative

- risk

- assessment

- pesticide

. 7 U.S. Environmen tal Protection Agency. 1999. G uidance for Identifying Pesticide Chemicals and Other Substances That Have a Common Mechanism of Toxicity

. Environmental Protection Agency, Office of Pesticide Programs. Fed. Reg. 64:5796

- 5799.
8 U.S. Environmental Protection Agency. 2016

. Pesticide Cumulative Risk Assessment: Framework for Screening Analysis Purpose.Page 6 of 6 in human

- relevant studies available in the toxicology database; ( 2 ) T he toxicology database for abamectin and emamectin is complete for human health risk assessment; ( 3 ) T he proposed MOA is the interaction with gamma aminobutyric acid (GABA) receptors

, leading to neurotoxicity

, and the findings of neurotoxic signs observed in the database are c onsistent with the proposed MOA; and ( 4 ) T here are no residual concerns with respect to the exposure databases.