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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, Fungicide, and Rodenticide Act 

(FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA). FIFRA sets forth a federal 

licensing scheme for the sale, distribution and use of pesticides; FFDCA establishes the 

mechanism and standards by which EPA sets tolerances establishing allowable levels for 

pesticide residues in food. As a general matter, under FIFRA Section 3, before a pesticide can be 

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

FIFRA Section 6 authorizes EPA to cancel pesticide registrations that do not comply with 

FIFRA and, in certain circumstances, to suspend those registrations pending the completion of 

cancellation proceedings. Registration decisions, insofar as non-dietary risks are concerned, are 

governed by a “risk-benefit” standard. In order for EPA to register a pesticide, it must not pose 

“any unreasonable risk to man or the environment, taking into account the economic, social, and 

environmental costs and benefits of the use of any pesticide.” FIFRA §§ 2(bb) and 3(c)(5). This 

response only addresses NRDC’s assertions of unreasonable adverse effects on the environment 

and occupational exposures (dietary risk issues are addressed in EPA’s response 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 whether those risks are 

reasonable in light of the benefits associated with use of the pesticide. In making both initial 

registration decisions and decisions as to whether products should remain registered, EPA first 

typically looks to determine whether 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 determines that the use does 

pose a risk of concern (either based on an initial 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 the risk to levels that do not exceed levels of 

concern. These changes can include changes to the directions for use on the product’s label 

(such as changes in application rates and methods, extending restricted entry levels, requiring 

protective clothing or equipment, etc.), or they can include changes to the pesticide’s formulation 

or packaging. If these changes are adopted voluntarily by a registrant, the use is then generally 

found to be acceptable. 

If a registrant does not agree to changes to the terms and conditions 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 the benefits associated with that use. If the 

Agency determines the risks associated with the use are not justified by the benefits associated 

with that use without changes to the terms and conditions of the registration, the Agency will, in 
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the case of a not-yet-registered pesticide, deny registration under FIFRA section 3(c)(6) or, in the 

case of a registered pesticide, initiate appropriate regulatory action under FIFRA section 6 unless 

the necessary changes (if any are possible) are made by the registrant. If, on the other hand, the 

Agency determines that the risks associated with a use are justified by the benefits, the use would 

continue to meet the FIFRA 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 health 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 ecological exposures, the Agency concluded 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” standard applicable to registration decisions under 

FIFRA Section 3(c)(5). 

Specifically in the RED, to address concerns regarding ecological risks to fish, aquatic 

invertebrates, birds, mammals, and non-target terrestrial and aquatic 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 risks 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 reduction 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 causes unreasonable adverse 

effects on the environment and, therefore, must cancel all 2,4-D registrations. As mentioned 

earlier, that portion of NRDC’s Petition that seeks either cancellation of registrations or 

revocation of tolerances based on issues related to dietary or residential risks are being addressed 

separately in an Order to be published in the Federal Register pursuant to section 408(d)(4) of the 

FFDCA. 

EPA considers this portion of the response to NRDC’s petition 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. Because, as explained below, EPA is today denying 

petitioners’ request to cancel on the basis of endocrine effects on ecological species and the 

adequacy of personal protective equipment for workers, 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 section 408 of the FFDCA. 

In terms of the issues addressed in this portion of EPA’s response 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 
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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 sufficient grounds for cancellation of the 2,4-D 

registrations. The statutory standard for cancellation of a pesticide is that the pesticide “when 

used in accordance with widespread and commonly recognized practice, 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 “risk-benefit” standard that requires consideration of benefits 

before a use can be found not to meet the standard. 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 level of human exposure to the pesticide, and the 

benefits the pesticide’s use provides. 

The flaw in NRDC’s petition with regard to its request to cancel all 2,4-D registrations is that it 

addresses only 2,4-D’s potential harm 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 “potential to cause endocrine disrupting effects . . . [and] EPA should 

have quantitatively incorporated [this information on 2,4-D’s harmful effects] in its risk 

assessment of 2,4-D.” While the reference to endocrine effects clearly addresses the first 

element of the risk assessment process – identification of a harm or toxic effect, NRDC’s 

assertion that EPA should quantitatively incorporate the 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. Similarly, NRDC alleges that factors EPA did not consider would 

enhance the exposure of 2,4-D to workers. Again, 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 quantitative incorporation of the studies it cites would alter EPA’s 

prior conclusion regarding whether risks of concern exist or how they would compare to benefits 

for 2,4-D. At best, NRDC is asking EPA to take a revised look at the 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 ecological 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 statutory standard for cancellation. 

Despite the inadequacy of petitioner’s claims regarding 2,4-D’s endocrine effects on 

ecological species and occupational exposure, the following is EPA’s response to the specific 

issues raised in the Petition 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 consider 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 increase in an egg hormone (vitellogenin) compared to untreated 

fish. While NRDC cites these findings as highlighting the ecological risk to fish when 2,4-D is 

applied to water bodies for controlling weeds, EPA evaluated the study and found important 

deficiencies with the study such that the results could not be considered reliable.7

 

In particular, EPA determined that the Xie et al. study lacked details 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 state and when in the presence of 

endocrine disruptors, male fish have significant levels of vitellogenin in their blood. In contrast, 

female fish have naturally increasing levels of vitellogenin as they approach maturity and 

maintain those levels upon maturation. Without knowing the fish sex 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 concentration. This small sample size, combined with the 

lack of details regarding the fish 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 are significantly suppressed in ewes dosed with 2,4-D, thus, 

supporting its claim that 2,4-D interferes with neurological function in fish because NRDC 

claims that slight thyroid 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) (hereinafter 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 Herbicides 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. Effects 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 corresponding 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 above, which deal specifically with fish, and 

several other studies it cited (Haddow et al., 1999; Charles et al., 1996; Liu et, 1996; Kim et al., 

2005; Kim et al., 2002, Dufford et al., 1995; Lerda et al., 1991; and Garry et al., 1996),14 which 

deal with rodents and humans, show that EPA should not allow applications of 2,4-D to 

waterways where fish may be exposed because of endocrine disrupting effects. While NRDC’s 

claims that studies showing possible endocrine effects in humans and rodents indicate the same 

effects for fish, the Agency believes that any confident extrapolation across broad taxonomic 

groups must be mindful of other lines of evidence, notably the 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 the 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 the 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., 1996 cited by the Industry Task 

Force II on 2,4-D Research Data). As with the studies cited by NRDC in its petition, EPA 

analyzed each study to determine whether the studies 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 organisms, whether any resulting effects could be 

clearly and quantitatively related to apical adverse outcomes in those organisms, and ultimately 

whether the results would alter 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 observable effects (Schubert et al.).15 This study would therefore have no 

impact on the quantitative risk assessment performed by the Agency. 

 

12 EFED at 3. 

13 Id. 

14 Collectively addressed separately in 2,4-D; Order Denying NRDC's Petition to Revoke 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; Petit et al., 1997; and Vonier et al., 

1996). The Hurst and Sheahan and Petit et al. studies reported no estrogenic response for 2,4-D 

in yeast cells. Vonier et al. reported no statistically 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 direct application of 2,4-D to 

alligator eggs, involved whole organisms and had a relevant relationship between the exposure 

route and the measurements for risk assessment exposure calculations. However, this study 

showed no statistically significant effects associated 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, which 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 effects 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 outcome in the whole organism. 

In summary, the Agency concluded that none of the cited studies would have a material 

impact on the conclusions of the current ecological risk assessment. Additionally, EPA utilizes 

conservative exposure scenarios when assessing 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 uncertainties in EPA’s assessment. Therefore, EPA is confident that its 

assessment is protective of aquatic species. 

For the discussion regarding the Agency’s endocrine disruptor screening program, see the 

separate Order that will be published in the Federal Register pursuant to section 408(d)(4) of the 

FFDCA. 

B. Personal Protective Equipment (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 regarding worker exposure, NRDC cited three 

studies in its petition (Riviere et al., 2003; Moody et al., 1992; 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. 
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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 separate Order that will be published in the Federal 

Register pursuant to section 408(d)(4) of the FFDCA. 

For its claim regarding 2,4-D and worker exposure issues, NRDC cited the Riviere et al. 

study to claim that occlusion can significantly 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. Results suggest that co-exposure 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 concentrations. Also observed was that covering DEET dose areas with an 

occlusive dressing, or even fabric, enhances absorption. 

The Agency is aware that occlusive coverings increase skin hydration status by 

preventing water loss, and that hydrated skin is generally more permeable to pesticides than unhydrated skin. Therefore, occlusive coverings would be expected to increase exposure via the 

dermal route, resulting in increased risk. However, in EPA’s evaluation 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 noted that EPA used a protective value for 

quantifying dermal absorption from a human volunteer study. EPA derived an initial dermal 

absorption factor of 5.8%, based upon the mean-percent 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 range of the variability observed in the results. 

EPA believes that its use of a 10-percent dermal 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 participants 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 reliance 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 generally does not rely on in vitro dermal absorption data without corroboration 

from in vivo testing. The critical 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 twice the average value seen in human testing. 

 Additionally, NRDC cited a Moody et al. study to support its claim regarding the 

permeability of worker gloves in conjunction 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 exposure to UVA, and also DEET coupled with 2,4-D and the glove’s 

composition was unclear. Current production methods 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 manufacturing process, thus making the glove UVA/UVB impervious. It 

should also be noted that 2,4-D exposures used to calculate risks have been measured under real 

world conditions with actual glove use by pesticide handlers. Consequently, 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 creates an inference that 2,4-D may be 

penetrating the skin even when workers are wearing gloves.31 The Agency noted a number of 

uncertainties with this study. Specifically, 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 assessment are based on exposures to actual workers 

using gloves under real world exposure conditions and therefore takes 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.