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 Regis tration 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 Drew,

## Chemi**~** Risk Assessment Branch VNil Health Effects Division (7509P) and Shanna Recore, Industrial Hygienist Carol H. Christensen, Ph.D. , MPH, Eptoemi olog ·st Toxicology and Epidemiology Branch Health Effects Division (7509P) THROUGH: Michael S. Metzger, Branch Chief 

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TO: Garland Waleko, Review Manager Risk Management and Implementation Branch 2 Pesticide Re-Evaluation Division (7508P) Office of Pe s ticide Programs

Page 1 of6This 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 li terature 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 evalua tion of exposed populations and sub-population s 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-HQ

Page 2 of6OPP

-2009-0851) and the Office ofPesticide Program's Open Literature Guidance (http ://www. epa. gov/pestici des/ science / literature-studies .html). The EPA supporting document "2,4-D : Re view oflncidents" (S. Recore, 9/4/12, DP Barcode D403874) provides a summary of recent epidemio logical 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. T he sample s ize, 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 preli minarily 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 i s some information to suggest an influenc e 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 disentang le the role of multiple farm-related occupational exposures with risk of fatal injury." EPA will perform additional evaluation ofhuman epidemio logy studies as part of the 2,4- D registration review process in which epidemiology studies from the open literature including but not lim ited to the AHS will be identified , rev iewed , evaluated and integrated with other streams of scientific evidenc e to support the human health risk assessment of the herbicide

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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 analys i s during the Preliminary Risk Assessment ofRegistration Re view." Unfortunately, EPA provides abso lutely no description of these reports. 

### It would be interesting to know how many invo lve 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 fu ll er account of the se 2,4-D exposure incidents and make it available in the reg i stration review docket; EPA should also provide public access to the IDS database, if it does not already do so.

Page 3 of6HED 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 inc lude any description of symptoms or circumstances of exposure. However, incidents classified as minor sever ity are determined to be minimally traumatic; the symptoms usuall y involve skin, eye or re spiratory irritation that resolve rapidly. The public can access incident information from the Aggregate IDS database by submitti ng a FOIA request (https://foiaonline.regulations.gov/foialaction /public/request /publicPreCreate#)

. CFS comment: EPA reg istered 459 2,4-D-related incidents in its Main IDS module, which is re served 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 summa ry 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 conf usion , 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 incidenc e of serious accidents, for instance in opera tion 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 associate d with a single active ingredient that resulted in major severity or death. Incidents involving one pesticide are typ i cally 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 ID S 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 ofthese 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 /f

oial 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). T his 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 tox ic 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 th e Agency is for use of a 2,4-D-glyphosate premix formu lation. 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 Page 4 of6"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 w ith 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 w ith another active ingredient. It i s 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 necessari ly 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 preli minary ri sk assessment phase of registration review.

Dioxin Assessment CFS comment: In February 2012, EPA issued Part I of its l ong -awaited assessment of di ox in tox ici ty, that pertain ing to non - cancer risks (EPA 2012). EPA established a low chron i c oral refe rence dose for dioxins of 7.0 x l 0 ·11' mg/kg-day for non-cance r ris ks. Th e chron i c oral reference dose is defined as: "An estimate of a daily oral exposure for a chronic duratio n (up to a lifetime) to the human population (inc lud ing susceptible subgroups) that is likely to be without an appreciable ri sk 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 ofthe greatly increased exposure to dioxins th at would be enabled by the proposed r eg istration s in light of its re view of di ox in tox icity, both cancer and non-cancer risks. As indicated above, the assessment should include collection of re liable data on d i oxin contaminants in a broad range of2,4-D formulations, and associated exposure; assess men t of dioxin emissions from manufacturing faci li ties that produce 2,4-D; and dioxin emissions from incineratio n of2,4

- D containers with 2,4

- D res id ues. The assessment should take parti cular account of increased exposure of farmers and pesticide applicators to dioxins in 2,4-D (e.g. from mix ing and otherwise handling 2,4-D concentrate) and associated with 2,4-D (from incineration of containers w ith 2,4 -D r esidues). EPA is schedu l ed to begin a r egistration review of2,4

- D late th is yea r o r early next year. The registration review will give EPA the opportunity to examine 2,4

-D in light ofthe latest science on its human tox icity, and to collect and evaluate data to assess the d i oxin-related concerns in light ofthe Agency's ongoing review of dioxin tox icity

. The registrati on review also will involve a detailed assessment of use patterns , without wh i ch human health and other risks cannot be adequately evaluated. Page 5 of6HED 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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