- 2 - background for 2,4-D. The fourth section contains EPA’s response to those FIFRA claims made

in the Petition. The final section is the conclusion.

I. Legal Framework

EPA regulates pesticides under the Federal Insecticide, Fung icide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA). FIFRA sets forth a federal licensing scheme for the sale, distribution a nd use of pesticides; FFDCA establishes the mechanism and standards by which EPA sets to lerances establishing allowable levels for pesticide residues in food. As a general matter, under FIFRA Section 3, befo re a pesticide can be

distributed or sold in th e United States, it must be registered by EPA.

FIFRA Section 6 authorizes EPA to cancel pestic ide registrations that do not comply with FIFRA and, in certain circumstances, to suspend those registrations pend ing the completion of cancellation proceedings. Registration decisions, in sofar as non-dietary risks are concerned, are governed by a “risk-benefit” standard. In order fo r EPA to register a pesticide, it must not pose “any unreasonable risk to man or the environmen t, taking into account the economic, social, and

environmental costs and benefits of the use of a ny pesticide.” FIFRA §§ 2(bb) and 3(c)(5). This response only addresses NRDC’s assertions of unreasonable adve rse effects on the environment and occupational exposures (dietary risk issues ar e addressed in EPA’s res ponse to the Petition to revoke 2,4-D tolerances).

Because FIFRA imposes a risk-benefit standard for dealing with risks which occur because of exposures other than through the diet, whether to grant or retain a registration is not simply a matter of whether there are risks of concern, but rather wh ether those risks are reasonable in light of the benefits associated wi th use of the pesticide. In making both initial registration decisions and decisi ons as to whether products shoul d remain registered, EPA first typically looks to determine whethe r a particular use of a pesticide poses a meaningful risk (often referred to as a “risk of concern”).

If a use does not pose a risk of concern, EPA generally finds the use to be an acceptable one without regard to the benefits associated with the use. If EPA dete rmines that the use does pose a risk of concern (either based on an ini tial examination or upon further refinement of the risk), EPA then looks to determine whether changes to the terms and conditions of use of the pesticide can feasibly and effectively mitigate th e risk to levels that do not exceed levels of concern. These changes can include changes to the directions for us e on the product’s label (such as changes in applicati on rates and methods, extending rest ricted entry levels, requiring protective clothing or equipment, et c.), or they can include change s to the pesticide’s formulation or packaging. If these changes are adopted voluntarily by a regist rant, the use is then generally found to be acceptable.

If a registrant does not agree to changes to the terms and cond itions of a registration, or if effective changes cannot reasonably be implemented, the Agency then must determine whether the risks associated with the use are justified by th e benefits associated with that use. If the Agency determines the risks associated with the use are not justified by th e benefits associated with that use without changes to the terms and c onditions of the registration, the Agency will, in- 3 - the case of a not-yet-registered pesticide, deny re gistration under FIFRA sec tion 3(c)(6) or, in the case of a registered pesticide, initiate appropr iate regulatory action unde r FIFRA section 6 unless the necessary changes (if any are possible) are ma de by the registrant. If, on the other hand, the Agency determines that the risks associated with a use are justified by th e benefits, the use would

continue to meet the FIFR A standard for registration.

II. Background

On June 30, 2005, EPA issued a Reregistration Eligibility Decision (RED) for 2,4-D. In the RED for 2,4-D, EPA evaluated the human hea lth and ecological risks associated with all registered uses of 2,4-D. EPA determined that there is a reasonable certainty that no harm will result to human health from exposure to the food uses of the pesticide. In considering all potential occupational and ecologi cal exposures, the Agency concl uded that with the adoption of the risk mitigation measures identified in the 2,4-D RED, all of the registered uses for 2,4-D

meet the “no unreasonable adverse effects” standa rd applicable to registration decisions under FIFRA Section 3(c)(5).

Specifically in the RED, to address concerns regarding ecological ri sks to fish, aquatic invertebrates, birds, mammals, and non-target terrestrial and aquati c plants, EPA required mitigation measures which included reducing the maximum application rate and measures to control spray drift in order to reduce 2,4-D risks to wildlife and non-target plants. In order to address concerns regarding risk s to workers associated with the handling of 2,4-D products, the Agency prescribed new personal protective equipment (PPE) requirements in the RED, which replaced the PPE requirements prescribed in the 1992 exposure re duction plan. These requirements are reflected on product labels.

III. Petition Response

For the reasons set forth below, EPA denies the NRDC Petition insofar as NRDC seeks to have EPA make a finding under FIFRA section 2(bb)(1) that 2,4-D cause s unreasonable adverse effects on the environment and, therefore, must cancel all 2,4-D registra tions. As mentioned earlier, that portion of NRDC’s Petition that seeks either can cellation of registrations or

revocation of tolerances based on is sues related to dietary or resi dential risks are being addressed separately in an Order to be published in the Fede ral Register pursuant to section 408(d)(4) of the

FFDCA.

EPA considers this portion of the response to NRDC’s petit ion to be final action, and believes the petitioner may challenge now this portion of the Agency ’s petition denial in federal court pursuant to section 16 of FIFRA. Becau se, as explained below, EPA is today denying petitioners’ request to cancel on the basis of endocrine effect s on ecological species and the adequacy of personal protective equipment for work ers, this letter will constitute a final Agency action as it relates to those specific issues. As noted, the remaining issues are subject to review as provided in secti on 408 of the FFDCA.

In terms of the issues addressed in this portion of EPA’s respons e to NRDC’s Petition, NRDC raises a number of generic concerns as to why EPA cannot make the FIFRA determination that 2,4-D does not cause unreasonable adverse effects on the environment. In- 4 - general, NRDC asserts that EPA cannot make its FIFRA determination based upon inadequately supported assumptions, ignored data, and reliance on inadequate studies.

These claims by NRDC do not allege suffi cient grounds for cancellation of the 2,4-D registrations. The statutory sta ndard for cancellation of a pesticide is that the pesticide “when used in accordance with widespread and commo nly recognized practi ce, generally causes

unreasonable adverse effects on the environment.” 7 U.S.C. 136d(b). As explained in Unit I above, EPA this standard is a “r isk-benefit” standard that requ ires consideration of benefits

before a use can be found not to meet the sta ndard. Thus, whether a pesticide should be cancelled is not simply a question of a pesticide’ s potential to cause harm but an issue involving a combination of factors including the pesticide’s potential harms, the pesticide’s potency (i.e. at what exposure levels will it cause harm), the le vel of human exposure to the pesticide, and the benefits the pestic ide’s use provides.

The flaw in NRDC’s petition with regard to its request to cancel a ll 2,4-D registrations is that it addresses only 2,4-D’s potential ha rm without addressing whether that harm is likely to occur or whether it would be unreasonable when weighed against 2,4-D’s benefits. For example, NRDC claims that 2,4-D has the “poten tial to cause endocrine disrupti ng effects . . . [and] EPA should have quantitatively incorporated [this inform ation on 2,4-D’s harmful effects] in its risk assessment of 2,4-D.” While the reference to endocrine effects clearl y addresses the first element of the risk assessment process – iden tification of a harm or toxic effect, NRDC’s assertion that EPA should quantit atively incorporate th e endocrine studies cited by NRDC in its

risk assessment falls far short of addressing the other elements of the risk assessment process or a risk-benefit balancing. Simila rly, NRDC alleges that factor s EPA did not consider would enhance the exposure of 2,4-D to workers. Agai n, NRDC’s assertion falls short of addressing other elements necessary for a complete risk assessment process or risk-benefit balancing.

NRDC does not allege that quantita tive incorporation of the studi es it cites would alter EPA’s prior conclusion regarding whether risks of concern exist or how th ey would compare to benefits for 2,4-D. At best, NRDC is asking EPA to ta ke a revised look at th e toxicity of 2,4-D for ecological effects and the exposure to 2,4-D for occupational risk. Yet, the ground for cancelation is a finding that risks outweigh benefits . Accordingly, NRDC’s claims that the 2,4-D registrations should be cancelled due to 2,4-D’s ecol ogical effects or worker risk is denied due to a failure to make a proper claim for cancellation by, at the very least, alleging facts that, if proven, would meet the statutor y standard for cancellation.

Despite the inadequacy of petitioner’s clai ms regarding 2,4-D’s endocrine effects on ecological species and occupational exposure, th e following is EPA’s response to the specific

issues raised in the Pe tition relevant to NRDC’s contention that all 2,4-D registrations should be cancelled for reasons unrelated to whether the 2, 4-D tolerances meet the safety standard of

FFDCA section 408.- 5 - A. Endocrine effects on ecological species

NRDC accuses the Agency of failing to cons ider endocrine disrupting effects during reregistration of 2,4-D. 3 NRDC further contends that EPA ignored adverse effects to aquatic species from 2,4-D, yet approved 2,4-D for use in or near water. To support its claims against the Agency, NRDC cited to various studies. 4

Specifically, NRDC cited a study by Xie et al. (2005) 5 to support its claim that 2,4-D has an estrogenic effect in fish. 6 In the study, juvenile rainbow trout were exposed to 2,4-D for 7 days and produced a 93-fold in crease in an egg hormone (vitell ogenin) compared to untreated fish. While NRDC cites these findings as highlig hting the ecological risk to fish when 2,4-D is applied to water bodies for c ontrolling weeds, EPA evaluate d the study and found important deficiencies with the study such that th e results could not be considered reliable. 7

In particular, EPA determined that the Xie et al. study lacked detail s regarding the sex of the sample set of rainbow trout. 8 Knowing the sex of the trout is important because male fish maintain null or very low levels of vitellogenin in their natural st ate and when in the presence of endocrine disruptors, male fish ha ve significant levels of vitelloge nin in their blood. In contrast, female fish have naturally increasing levels of vitellogenin as they approach maturity and maintain those levels upon matura tion. Without knowing the fish se x it is not possible to make the appropriate inferences regarding vitellogenin levels. Additionally, the sample size was very small, with only six fish used per test concentrat ion. This small sample size, combined with the lack of details regarding the fi sh sex, minimizes the reliability of the study. Due to these deficiencies, EPA believes it would be inappropriate to rely on the study to alter the Agency’s

risk assessment conclusions.

NRDC also cited a study by Rawlings et al. (1998) 9 to support its claim of the endocrine disruptive effect of 2,4-D on ecological species. 10 NRDC referenced this study to demonstrate that thyroid hormone levels ar e significantly suppressed in ew es dosed with 2,4-D, thus, supporting its claim that 2,4-D interferes with neurological function in fish because NRDC claims that slight thyr oid suppression affects neurological development. 11 EPA, in analyzing the Rawlings et al. study, determined that the study could not be directly incorporated into the

3 Petition of Natural Resources Defense Council to Revoke All Tolerances and Cancel All Registrations for the Pesticide 2,4-D (November 6, 2008) at 2, 4 (hereinafter Petition).

4 For EPA’s analysis of all studies cited in the Petition and public comments see 2,4-D: Evaluation of Data Identified In NRDC Petition and Associated Documents (March 27, 2012) (h ereinafter HED).

5 Xie, L., K. Thrippleton, M.A. Irwin, G.S. Siemering, A. Mekebri, D. Crane, K. Berry, and D. Schlenk. 2005. Evaluation of Estrogenic Activities of Aquatic Herbicid es and Surfactants Using a Rainbow Trout Vitellogenin Assay. Toxicological Sciences. 87: 391-398.

6 Petition at 4.

7 U.S. EPA Review of Selected Studies in Support of NRDC Petition for Tolerance Revocation and Cancellation of
2,4-D at 3 (February 24, 2011) (hereinafter EFED).

8 EFED at 3.

9 Rawlings, N.C., S.J. Cook, and D. Waldbillig, 1998. Effect s of the pesticides carbofuran, chlorpyrifos, dimethoate, lindane, triallate, trifluralin, 2,4-D, and pentachlorophenol on the metabolic endocrine and reproductive endocrine system in ewes. Journal of toxicology and Environmental Health, Part A, 54:1, 21-36.

10 Petition at 4.

11 Id. at 4, 5.- 6 - Agency risk assessment process because the study endpoints could not be related in a

mathematical fashion to a corres ponding level of effect for an apical endpoint in the whole organism. 12

Nevertheless, comparing the effects endpoint (10 mg/kg-bw) reported by Rawlings with

the chronic mammalian effects threshold used by the Agency for mammalian wildlife risk assessment (2-generation rat reproduction NOEL of 5 mg/kg-bw) suggests that the Agency risk assessment for mammalian wildlife is adequately protective even if the Rawlings’ study had

been considered in the assessment. 13 Therefore, the Rawlings study has no impact on the Agency’s current risk assessment conclusions.

NRDC claims that the two studies addressed ab ove, which deal specifically with fish, and

several other studies it cited (Haddow et al., 199 9; Charles et al., 1996; Liu et, 1996; Kim et al., 2005; Kim et al., 2002, Dufford et al., 1995; Lerd a et al., 1991; and Garry et al., 1996), 14 which

deal with rodents and humans , show that EPA should not a llow applications of 2,4-D to waterways where fish may be exposed because of endocrine disrupting e ffects. While NRDC’s claims that studies showing possi ble endocrine effects in humans and rodents indicate the same effects for fish, the Agency believes that a ny confident extrapolati on across broad taxonomic groups must be mindful of othe r lines of evidence, notably th e comparative metabolism of the chemical in question. The NRDC petition does not make a case that the distribution and fate of 2,4-D in other animals such as mammals follows th e same patterns as in fish. Therefore, based upon the Agency’s analysis, the studies cited by NRDC do not impact the Agency’s quantitative ecological risk assessments or alter its conclusions.

Additionally, during th e public comment period, several other studies were cited in support of NRDC’s claims (see Filkowski et al., 2003, cited by Beyond Pesticides and the State of New York) as well as to counter its claims (see Hurst and Sheahan, 2003; Petit et al., 1997; Schubert et al., 2008; Spiteri et al., 1999; and Vonier et al., 1 996 cited by the Industry Task Force II on 2,4-D Research Data). As with th e studies cited by NRDC in its petition, EPA analyzed each study to determine whether the st udies met the basic scientific quality criteria outlined in the Agency’s data evaluation guidance, whether acceptable study results could be translatable to an exposure of 2,4-D in whole or ganisms, whether any resulting effects could be clearly and quantitatively related to apical adve rse outcomes in those organisms, and ultimately

whether the results would alte r the Agency’s ecological risk assessments for 2,4-D.

Based upon EPA’s analysis, one study was found to be unacceptable for risk assessment use because of a lack of measured 2,4-D exposure that would allow for an establishment of 2,4-D as the source of any observabl e effects (Schubert et al.). 15 This study would therefore have no impact on the quantitative risk a ssessment performed by the Agency.

12 EFED at 3.

13 Id.

14 Collectively addressed separately in 2,4-D; Order Denying NRDC's Petition to Re voke Tolerances, EPA-HQOPP-2008-0877; FRL-9344-1

15 EFED at 1.- 7 - Three other studies EPA evaluated examined the effects of 2,4-D in yeast cells, brown trout or alligator tissue isolates (Hurst and Sheahan, 2003; Pe tit et al., 1997; and Vonier et al., 1996). The Hurst and Sheahan and Petit et al. st udies reported no estrogenic response for 2,4-D in yeast cells. Vonier et al. reported no stat istically significant competitive binding of 2,4-D for

estrogen receptors. 16 Moreover, these three studies cannot be related in a mathematical fashion to responses in whole higher organism and do not establish effects endpoints based on exposure routes and levels translatable to whole organism exposure routes. Therefore, these studies have no impact on the quantitative risk assessment performed by the Agency.

The Spiteri et al. study that EPA evaluated, involved dire ct application of 2,4-D to alligator eggs, involved whole or ganisms and had a relevant re lationship between the exposure

route and the measurements for risk assessmen t exposure calculations. However, this study showed no statistically significant effects associ ated with 2,4-D exposure relative to controls. 17
Therefore, the results of this study support the Agency’s previous risk assessment conclusions.

EPA evaluated the Filkowski et al. study, wh ich reported that 2,4-D produced mutagenic

effects in Arabidopsis thaliana . However, in the absence of a quantitative peer-reviewed relationship linking mutation to adverse apical e ffects on plant fitness (survival, growth, or reproduction), the Agency cannot quantitatively assess the whole organism consequences of genotoxic measurement endpoints. 18 Therefore, this study would not influence the Agency’s risk assessment because genotoxic endpoints in this case are not considered to be quantifiably

relatable to an adverse outc ome in the whole organism.

In summary, the Agency concl uded that none of the cited st udies would have a material impact on the conclusions of the current ecological risk assessment. Additionally, EPA utilizes conservative exposure scenarios when assess ing ecological risk generally. While these conservatisms are not expressly employed in EPA’ s assessment to address the uncertainties in relying on surrogate species data, they ultimately serve the same purpose; they add a measure of protection to account for uncertainti es in EPA’s assessment. Theref ore, EPA is confident that its assessment is protective of aquatic species.

For the discussion regarding the Agency’s e ndocrine disruptor screening program, see the separate Order that will be published in the Fede ral Register pursuant to section 408(d)(4) of the

FFDCA.

B. Personal Protective E quipment (PPE) for workers

NRDC, in its petition, questioned the adequacy of the Agency’s evaluation of worker exposure and PPE. 19 In support of its assertions regard ing worker exposure, NRDC cited three studies in its petition (Riviere et al., 2003; Moody et al., 199 2; and McDuffie et al., 2005). 20
Additionally, NRDC claims the Agency did not address the potential enhancement of 2,4-D

16 Id. at 1-2.

17 Id. at 2.

18 Id.

19 Petition at 13.

20 Id. at 13.- 8 - absorption due to alcohol consumption, DEET exposure, and sunscreen. 21 Because it is relevant to residential risk, NRDC’s dermal absorption claim regarding 2,4-D, and the additional studies cited to support the claim, are addressed in a sepa rate Order that will be published in the Federal Register pursuant to sect ion 408(d)(4) of the FFDCA.

For its claim regarding 2,4-D and worker expos ure issues, NRDC cited the Riviere et al. study to claim that occlusion can signif icantly enhance skin absorption of 2,4-D. 22 The stated goal of the Riviere study was to determine the impact of co-exposure factors that could modulate transdermal flux of topically applied DEET. Resu lts suggest that co-expo sure to a number of chemicals that potentially could be encountered in a military environment may modulate the percutaneous absorption of topically applied DEET beyond that seen for normal vehicles, at typically applied concen trations. Also observed was that covering DEET dose areas with an occlusive dressing, or even fa bric, enhances absorption.

The Agency is aware that occlusive cove rings increase skin hydration status by preventing water loss, and that hydrated skin is generally more permeable to pesticides than unhydrated skin. Therefore, occlus ive coverings would be expected to increase exposure via the dermal route, resulting in increased risk. Ho wever, in EPA’s evalua tion of this study, it found that the Agency’s risk assessment already accounts for any uncertainty raised by NRDC relative to the findings of Riviere et al. 23

In the 2005 risk assessment, it should be not ed that EPA used a protective value for quantifying dermal absorption from a human volunt eer study. EPA derived an initial dermal absorption factor of 5.8%, based upon the mean-p ercent absorbed value from four different human dermal absorption studies. However, EPA ultimately used a value of 10%, in order to be protective, based on the upper ra nge of the variability obser ved in the results.

EPA believes that its use of a 10-percent derm al absorption value for 2,4-D is protective. EPA’s conclusion is supported by an extensive set of high quality human research results. EPA principally relied on an in vivo human study which showed average human dermal absorption at 5.8 percent. 24 EPA also considered four other in vivo human studies. 25 These studies involved

21 Id. at 2.

22 Id. at 13.

23 HED at 36.

24 Feldmann, R.J., Maibach, H.I., 1974. Percutaneous penetration of some pesticides and herbicides in man. Toxicol. Appl. Pharmacol. 28, 126–132.

25 Harris, S.A., Solomon, K.R., 1992. Percutaneous penetration of 2,4-dichlorophenoxyacetic acid and 2,4-D dimethylamine salt in human volunteers. J. Toxicol. Environ. Health 36, 233–240, MRID 48772104; Maibach, H.I., Feldmann, R.J., 1974. Systemic absorption of pesticides through the skin of man. In: Occupational Exposure to Pesticides: Report to the Federal Working Group on Pest Management from the Task Group on Occupational Exposure to Pesticides, Appendix B. US Government Printing Office, 0-551-026, Washington, DC, pp. 120–127, MIRD 46859102; Moody RP, Wester RC, Melendres JL, Maibach HI. Dermal absorption of the phenoxy herbicide 2,4-D dimethylamine in humans effect of DEET and anatomic site. J Toxicol Environ Health 36(3):241-50.,1992, 48772102; Wester, R.C., Melendres, J., Sedik, L., Maibach, H., Riviere, J.E., 1998. Percutaneous absorption of salicylic acid, theophylline, 2,4-dimethylamine, diethyl hexyl phthalic acid, and p-aminobenzoic acid in the isolated perfused porcine skin flap compared to man invivo. Toxicol. Appl. Pharmacol. 151, 159–165, MRID 48772101.- 9 - eight separate trials using a total of 34 particip ants and had an average dermal absorption value of 5.7 percent. 26 To account for potential variability EPA chose a value of 10 percent.

There are several factors that support re liance on these data and demonstrate the

reasonableness of EPA’s choice of a 10-percent dermal absorption factor. 27 First, the data relied upon by EPA are from in vivo human studies. NRDC, with one exception, has cited only to in

vitro data. EPA genera lly does not rely on in vitro dermal absorption data without corroboration

from in vivo testing. The critic al limitations with in vitro dermal absorption testing, such as the lack of an intact vasculature, make it an uncertain guide for risk assessment. Finally, the value chosen by EPA for dermal absorption was nearly tw ice the average value seen in human testing.

Additionally, NRDC cited a Moody et al. study to suppor t its claim regarding the permeability of worker gloves in conjuncti on with exposure to DEET and sunlight simultaneously. 28 However, EPA does not concur with these conclusions because the conditions of this research do not represent likely exposure conditions that would be expected in current agricultural practices. 29 This is because the study only describes the permeability changes in a single glove material after expos ure to UVA, and also DEET coupl ed with 2,4-D and the glove’s composition was unclear. Current production me thods for gloves have improved since the Moody et al. research was completed in 1992. Now, gloves most likely include UVA and UVB

stabilizers in the manufacturi ng process, thus making the glove UVA/UVB impervious. It should also be noted that 2,4-D e xposures used to calculate risks have been measured under real world conditions with actual glove use by pesticid e handlers. Consequent ly, any possible effects on glove efficacy due to field conditions would already be taken into account in the risk

assessment.

The third study cited by NRDC claiming that PPE for workers is insufficient was

McDuffie et al. 30 NRDC claims that this study crea tes an inference that 2,4-D may be penetrating the skin even wh en workers are wearing gloves. 31 The Agency noted a number of uncertainties with this study. Sp ecifically, the study investigators failed to address factors such as glove type and timing of DEET use. 32 Additionally, the study authors did not indicate if glove permeability contributed to higher exposures. 33 It should again be noted that the exposure values for users wearing gloves in the 2,4-D risk assess ment are based on exposures to actual workers using gloves under real world expos ure conditions and therefore take s into account actual field

conditions.

26 Ross RH, Driver JH, Harris SA, Maibach HI. (2005). Dermal absorption of 2, 4-D: a review of species differences. Regulatory Toxicology and Pharmacology 41: 82-91; 84, Table 2.

27 See 2,4-D; Order Denying NRDC's Petition to Revoke Tolerances, EPA-HQ-OPP-2008-0877; FRL-9344-1 for additional discussion regarding the factors supporting the Agency’s choice of a 10 percent dermal absorption factor.

28 Petition at 13.

29 HED at 59, 66.

30 Id. at 62.

31 Petition at 13.

32 HED at 62.

33 Id.