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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

TXR 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 (7505P)

Office of Pesticide Programs
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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2015, announcing the availability of draft guidance entitled: Pesticide Cumulative Risk 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sought comments on a draft human health risk assessment that utilized the draft guidance to 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. That assessment, entitled: Draft- Abamectin. 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 purpose 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 lactones candidate common 

mechanism group.

The Agency received several comments from two submitters related to the draft cumulative risk

assessment. These comments are summarized and individually addressed below. The 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 document1. 

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 Percent Crop Area (PCA) 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 Commodity 

(CEC) analysis for abamectin.

EPA Response:

1. The PCA Guidance document is publically available2.

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-and-assessing-pesticide-risks/development-community-water-systemdrinking-water
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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 Sapote, 

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 13-07F; 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: The residential uses of abamectin relevant for the aggregate assessment and 

cumulative screen are from the 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 these comments follows. 

Comment Summary: EPA did not follow any documented systematic review process, and there 

is no documentation to show whether or not the Office 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 

assessment4. 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 relevant to risk assessment, how to 

 3 Available: http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/standard-operating-proceduresresidential-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.pdf
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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’ National 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 making5. 

The EPA’s Office of Chemical Safety and Pollution Prevention (OCSPP) is currently developing 

policies and procedures in order to employ fit-for-purpose systematic reviews. OPP’s approach 

to reviewing scientific data include: data collection, data review, and integration procedures. 

Therefore, OPP’s standard review approaches for assessing toxicology data submitted by 

registrants and for integrating the registrant supported data with information from the open 

literature are consistent with the NRC’s recommendations 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 interpretation 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 evaluation for these 

structurally-related 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. For 

purposes of screening, the current literature search is sufficient. In the future, if the Agency 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 for on-going and future cumulative screening toxicology evaluations, the 

Agency is working with EPA reference librarians 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 

about 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 outlined in Part 158. 

Additionally, Title 40 CFR §160 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 units 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.
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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 Summary: OPP failed to consider alternate mode of action/adverse outcome 

pathways (MOA/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 for cumulative risk assessment6. A 

significant amount of toxicology knowledge is required to fully establish key events associated 

with an adverse 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 

derivatives of avermectin. There is a wealth of data on the insecticidal MOA for avermectin: its 

insecticidal actions are mediated by interaction with the glutamate-gated chloride channels and 

GABAA-gated chloride channels. Although a proven common MOA finding consistent with 

previous Agency guidance to identify CMGs7 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 

guidance8

.

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 mechanism 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 Chronic 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 uncertainty 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 the 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-scienceand-assessing-pesticide-risks/guidance-cumulative-risk-assessment-pesticide. 7 U.S. Environmental Protection Agency. 1999. Guidance 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.
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in human-relevant studies available in the toxicology database; (2) The toxicology database for 

abamectin and emamectin is complete for human health risk assessment; (3) The 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 consistent with the proposed 

MOA; and (4) There are no residual concerns with respect to the exposure databases.