UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: May 10,2013 

SUBJECT: 2,4-D: HED Response to Comments Submitted on the Human Health 

Assessment Scoping Document in Support of Registration Review. 

PC Codes: 03000 I [and including 030004, 

030016,030019,030025,030035, 030053,030063, 

030066, 051505] 

DP Barcode: 040990 I 

Decision No.: 476131 Registration No.: NA 

Petition No.: NA 

Risk Assessment Type: NA 

TXR No.: NA 

MRIDNo.:NA 

Regulatory Action: Registration Review Scoping 

Case No.: 0073 

CAS No.: 94-75-7 

40 CFR: §180.142 

FROM: Danette 

Risk Assessment 

Drew, Chemi Branch ~ 

V Nil 

Health Effects Division (7509P) 

and 

Shanna Recore, Industrial Hygienist 

Carol H. Christensen, Ph.D., MPH, Eptoemiolog·st 

Toxicology and Epidemiology Branch 

Health Effects Division (7509P) 

THROUGH: Michael S. Metzger, Branch Chief f J 4 /.I J / /-

Risk 

Health 

Assessment 

Effects Division 

Branch 

(7509P) 

V /VII IV{ ~tf.( "A' ' ~ 

TO: Garland Waleko, Review Manager 

Risk Management and Implementation Branch 2 

Pesticide Re-Evaluation Division (7508P) 

Office of Pesticide Programs 

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This document was written in response to public comments for the 2,4-D Human Health 

Assessment Scoping Document in Support of Registration Review (D. Drew, 0402411, 12/2112) 

which was prepared as part ofthe 2,4-D Preliminary Work Plan (PWP) (Docket No. EPA-HQOPP-2012-0330). The comments relating to the human health assessment seeping document, and 

HED's responses, are shown below: 

Comments from Industry Task Force II on 2,4-D Research Data, Technical 

Committee 

Comments regarding the 2,4-D Human Health Assessment Seeping Document in Support 

of Registration Review appear on pages 38 to 50 of the Task Force II submission 

Registrant's Comments to the initial docket opening for Registration Review of 2, 4-

Dichlorophenoxyacetic acid (2,4-D), 2114/13. HED-relevant comments are labeled as 

number 63 through 82. Comments generally pertain to typographical, grammatical or 

citation errors. A few comments (numbers 68, 77, 78, and 79) also suggest minor 

changes to the toxicology text and tables. Under registration review of2,4-D, HED will 

consider the suggested corrections, additions and deletions, and will incorporate them 

where warranted. 

Comments from The Center for Food Safety (CFS) 

Comments regarding the 2,4-D Seeping Document appear on pages 6 to 11 of the CFS 

submission Comments on Registration Review of the Herbicide 2,4-D, 2/12/13. The 

comments appear to be primarily focused on applications that have been submitted to the 

EPA requesting the registration of new uses of2,4-D. HED is only responding to 

comments that may apply to the registration review of2,4-D based on currently 

registered uses and is not responding at this time to comments pertaining to any proposed 

or unregistered uses. HED has specifically responded to issues raised in the CFS 

submission regarding epidemiological data, human incident data, and dioxin assessment. 

Epidemiology 

In this section HED is addressing the comments raised in CSF's comment letter and in 

the associated Appendix A (pp.51-61) regarding the evaluation of open literature 

observational epidemiology studies. The herbicide 2,4-D is a widely used herbicide 

product in the U.S. with both agricultural and non-agricultural uses on current labels. 

Hazard and exposure information gained through epidemiological evaluation of exposed 

populations and sub-populations such as agricultural workers and professional pesticide 

applicators are an important stream of evidence to consider. As EPA moves towards a 

weight of the evidence consideration of 2,4-D hazard, exposure, and risk issues during 

the registration review process, it will consider epidemiology studies such as those cited 

by commenters, per the draft Policy on Incorporation of Epidemiology and Human 

Incident Data into Human Risk Assessment (White Paper, February 2010 at EPA-HQPage 2 of6 
OPP-2009-0851) and the Office ofPesticide Program's Open Literature Guidance 

(http://www. epa. gov /pesti ci des/science/literature-studies .html). 

The EPA supporting document "2,4-D: Review oflncidents" (S. Recore, 9/4/12, DP 

Barcode D403874) provides a summary of recent epidemiological investigations in the 

National Cancer Institute's Agricultural Health Study {AHS) concerning 2,4-D. For 

purposes of the registration review scoping documents, EPA routinely summarizes 

chemical-specific evidence of cancer and non-cancer health effects observed in the AHS 

cohort. The AHS is a prospective cohort study of approximately 90,000 professional 

pesticide applicators and their spouses. The sample size, study design, and extensive and 

validated pesticide exposure assessment characterize the AHS as an exemplary 

epidemiology study and highly relevant for pesticide health outcome information. 

In the 2,4-D: Review of Incidents Memorandum, EPA preliminarily concluded that: 

"Overall, the AHS database lacks evidence that 2,4-D is related to any cancer 

outcome evaluated [including breast, prostate, lung, pancreas, colon or cutaneous 

melanoma]. There is some information to suggest an influence of2,4-D exposure 

on upper respiratory immune response, however only in the presence of other 

herbicide, glyphosate. The association with fatal injury is unexpected and may be 

explained by frequent use of application equipment, or both; further research is 

needed to disentangle the role of multiple farm-related occupational exposures 

with risk of fatal injury." 

EPA will perform additional evaluation of human epidemiology studies as part of the 2,4-

D registration review process in which epidemiology studies from the open literature 

including but not limited to the AHS will be identified, reviewed, evaluated and 

integrated with other streams of scientific evidence to support the human health risk 

assessment of the herbicide. 

Human Incident Data 

CFS comment: EPA reports 2,202 human health incidents involving 2,4-D in the 5.5 

years from 2007 to mid-2012 recorded in its Aggregate Incident Data System (IDS) 

(Health Incidents, p. 3). Though most are said to be of low severity, ''the high absolute 

number of incidents (relative to other pesticides in IDS) reported involving 2,4-D may 

suggest the need for a more in depth Tier II analysis during the Preliminary Risk 

Assessment of Registration Review." Unfortunately, EPA provides absolutely no 

description of these reports. It would be interesting to know how many involve 

neuromuscular symptoms, such as those described above, or other symptoms that might 

help explain Waggoner et al (2013)'s results. EPA is urged to draft a much fuller account 

of these 2,4-D exposure incidents and make it available in the registration review docket; 

EPA should also provide public access to the IDS database, if it does not already do so. 

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HED Response: The Aggregate IDS contains incidents resulting in less severe human 

incidents (minor, unknown, or no effects outcomes). These incidents are reported by 

registrants only as counts in what are aggregate summaries. These aggregate summaries 

do not include any description of symptoms or circumstances of exposure. However, 

incidents classified as minor severity are determined to be minimally traumatic; the 

symptoms usually involve skin, eye or respiratory irritation that resolve rapidly. The 

public can access incident information from the Aggregate IDS database by submitting a 

FOIA request 

(https://foiaonline.regulations.gov/foialaction/public/request/publicPreCreate#). 

CFS comment: EPA registered 459 2,4-D-related incidents in its Main IDS module, 

which is reserved for "higher severity outcomes," over the same 5.5-year period. Here, 

too, next to no information is provided on the nature of these more serious health 

impacts. EPA should make descriptions of these incidents available to the public, and 

provide a much fuller summary of them in the registration review docket. Six incidents 

issued in death. In the one incident described by EPA, "a 41 year old male sprayed 

diluted product earlier in the day. Later that day he experienced confusion, dizziness, 

conductive disturbance, and hypoglycemic shock. He was taken to the ER" (Human 

Incidents, Table 1, p. 7). Confusion or dizziness is consistent with some of the 

chlorophenoxy herbicide effects noted above, and could be related to increased incidence 

of serious accidents, for instance in operation of farm machinery. 

HED Response: For the seeping phase of registration review, EPA reviews and 

documents in detail and on an individual basis, only incident cases associated with a 

single active ingredient that resulted in major severity or death. Incidents involving one 

pesticide are typically focused on because they are considered to provide more certain 

information about the potential effects of the particular pesticide. However, all the 

incidents with higher severity outcomes, housed in the Main IDS module, will be 

reviewed and documented in more detail during registration review. This includes the six 

incidents that resulted in death that implicate 2,4-D, as well as other chemicals. A review 

of these deaths shows that they are due to suspected suicide, misuse, and exposure to 

multiple chemicals and these incidents cannot clearly be connected to 2,4-D. The public 

can access incident information from the Main IDS database by submitting a FOIA 

request (https :/ /foiaonline.regulations. gov /foial action/public/reg uest/publicPreCreate#). 

CFS comment: EPA notes that the great majority of these more serious incidents involve 

exposures to 2,4-D as well as other chemicals, and suggests that these much more 

numerous incidents will be discounted and perhaps ignored in the course of the 

registration review (Human Incidents, p. 3). This would be a grave mistake. The ultimate 

goal of EPA's analysis should be to safeguard the health of farmers and the public from 

the toxic effects of2,4-D in whatever form it is used, not to mechanically complete a 

product database. 2,4-D is increasingly used in conjunction with other herbicides; one 

new use application pending before the Agency is for use of a 2,4-D-glyphosate premix 

formulation. The trend to increasing use of multiple herbicides in premix formulations 

must not be used as an excuse to ignore health effects from exposure to them. While 

adverse effects from exposure to product mixtures may occasionally be neatly 

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"disentangled" as attributable to only component A or component B, there is growing 

recognition that disease and acute health effects are often multifactorial, attributable to 

more than one cause or agent. EPA is urged to fully assess all serious health incidents 

related to 2,4-D, whether the exposure is to 2,4-D alone, or to 2,4-D in combination with 

additional products. Given the results of Waggoner et al (2013), particular attention 

should be paid to patterns of adverse effects that could contribute to increased rates of 

accidents and fatal injuries. 

HED Response: EPA notes that incidents involving one pesticide are typically focused 

on because they are considered to provide more certain information about the potential 

effects of the particular pesticide. In general, there were few incidents reported for 2,4-D 

as a single chemical only, but there is a high absolute number of incidents reported 

involving 2,4-D with another active ingredient. It is important to note that since most of 

these reported incidents involve more than one active ingredient (i.e. 2,4-D and another 

active ingredient), the incidents that were reported were not necessarily attributable to 

2,4-D. In addition, typically, causation cannot be determined based on incident data. 

Nevertheless, EPA agrees that these incident data, both those implicating only 2,4-D and 

those implicating 2,4- D and other active ingredients, warrant further analysis in the 

preliminary risk assessment phase of registration review. 

Dioxin Assessment 

CFS comment: In February 2012, EPA issued Part I of its long-awaited assessment of 

dioxin toxicity, that pertaining to non-cancer risks (EPA 2012). EPA established a low 

chronic oral reference dose for dioxins of 7.0 x l 0·

11' mg/kg-day for non-cancer risks. The 

chronic oral reference dose is defined as: "An estimate of a daily oral exposure for a chronic 

duration (up to a lifetime) to the human population (including susceptible subgroups) that is 

likely to be without an appreciable risk of adverse health effects over a lifetime." The 

assessment of cancer risks posed by dioxins is still underway. 

It is essential that EPA conduct an assessment of the greatly increased exposure to dioxins 

that would be enabled by the proposed registrations in light of its review of dioxin toxicity, 

both cancer and non-cancer risks. As indicated above, the assessment should include 

collection of re liable data on dioxin contaminants in a broad range of2,4-D formulations, and 

associated exposure; assessment of dioxin emissions from manufacturing faci lities that 

produce 2,4-D; and dioxin emissions from incineration of2,4-D containers with 2,4-D 

residues. The assessment should take parti cular account of increased exposure of farmers and 

pesticide applicators to dioxins in 2,4-D (e.g. from mixing and otherwise handling 2,4-D 

concentrate) and associated with 2,4-D (from incineration of containers with 2,4-D residues). 

EPA is scheduled to begin a registration review of2,4-D late this year or early next year. The 

registration review will give EPA the opportunity to examine 2,4-D in light ofthe latest 

science on its human toxicity, and to collect and evaluate data to assess the dioxin-related 

concerns in light of the Agency's ongoing review of dioxin toxicity. The registration review 

also will involve a detailed assessment of use patterns, without which human health and other 

risks cannot be adequately evaluated. 

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HED Response: Future risk assessments for the polychlorinated dibenzo dioxin (PCDD) 

and furan (PCDF) contaminants from the uses of 2,4-D will consider updated use patterns 

and any revisions to the toxicological points of departure. 

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