Federal Register / Vol. 77, No. 75 / Wednesday, April 18, 2012 / Rules and Regulations 23135 

copy of the rule, to each House of the 

Congress and to the Comptroller General 

of the United States. EPA will submit a 

report containing this action and other 

required information to the U.S. Senate, 

the U.S. House of Representatives, and 

the Comptroller General of the United 

States prior to publication of the rule in 

the Federal Register. A major rule 

cannot take effect until 60 days after it 

is published in the Federal Register. 

This action is not a ‘‘major rule’’ as 

defined by 5 U.S.C. 804(2). 

Under section 307(b)(1) of the Clean 

Air Act, petitions for judicial review of 

this action must be filed in the United 

States Court of Appeals for the 

appropriate circuit by June 18, 2012. 

Filing a petition for reconsideration by 

the Administrator of this final rule does 

not affect the finality of this action for 

the purposes of judicial review nor does 

it extend the time within which a 

petition for judicial review may be filed, 

and shall not postpone the effectiveness 

of such rule or action. Parties with 

objections to this direct final rule are 

encouraged to file a comment in 

response to the parallel notice of 

proposed rulemaking for this action 

published in the Proposed Rules section 

of today’s Federal Register, rather than 

file an immediate petition for judicial 

review of this direct final rule, so that 

EPA can withdraw this direct final rule 

and address the comment in the 

proposed rulemaking. This action may 

not be challenged later in proceedings to 

enforce its requirements (see section 

307(b)(2)). 

List of Subjects in 40 CFR Part 52 

Environmental protection, Air 

pollution control, Incorporation by 

reference, Intergovernmental relations, 

Particulate matter, Reporting and 

recordkeeping requirements. 

Dated: March 8, 2012. 

Jared Blumenfeld, 

Regional Administrator, Region IX. 

Part 52, Chapter I, Title 40 of the Code 

of Federal Regulations is amended as 

follows: 

PART 52—[AMENDED] 

■ 1. The authority citation for Part 52 

continues to read as follows: 

Authority: 42 U.S.C. 7401 et seq. 

Subpart F—California 

■ 2. Section 52.220, is amended by 

adding paragraphs (b)(11)(ii), 

(c)(21)(xiv)(D) and (c)(381)(i)(I) to read 

as follows: 

§ 52.220 Identification of plan. 

* * * * * 

(b) * * * 

(11) * * * 

(ii) Previously approved on May 31, 

1972 in paragraph (b) of this section and 

now deleted without replacement, Rule 

2.7. 

* * * * * 

(c) * * * 

(21) * * * 

(xiv) * * * 

(D) Previously approved on June 14, 

1978 in paragraph (c)(21)(xiv)(A) of this 

section and now deleted without 

replacement, Rule 2.4. 

* * * * * 

(381) * * * 

(i) * * * 

(I) Yolo-Solano Air Quality 

Management District. 

(1) Rule 2.3, ‘‘Ringelmann Chart,’’ 

revised on January 13, 2010. 

(2) Rule 2.11, ‘‘Particulate Matter 

Concentration,’’ revised on January 13, 

2010. 

(3) Rule 2.12, ‘‘Specific 

Contaminants,’’ revised on January 13, 

2010. 

* * * * * 

[FR Doc. 2012–8947 Filed 4–17–12; 8:45 am] 

BILLING CODE 6560–50–P 

ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Part 180 

[EPA–HQ–OPP–2008–0877; FRL–9344–1] 

2,4-D; Order Denying NRDC’s Petition 

To Revoke Tolerances 

AGENCY: Environmental Protection 

Agency (EPA). 

ACTION: Order. 

SUMMARY: In this Order, EPA denies a 

petition requesting that EPA revoke all 

pesticide tolerances for 2,4- 

dichlorophenoxyacetic acid (2,4-D) 

under section 408(d) of the Federal 

Food, Drug, and Cosmetic Act (FFDCA). 

The petition was filed on November 6, 

2008, by the Natural Resources Defense 

Council. 

DATES: This Order is effective April 18, 

2012. Objections and requests for 

hearings must be received on or before 

June 18, 2012, and must be filed in 

accordance with the instructions 

provided in 40 CFR part 178 (see also 

Units I.B and I.C. of the SUPPLEMENTARY

INFORMATION.) 

ADDRESSES: EPA has established a 

docket for this action under docket 

identification (ID) number EPA–HQ– 

OPP–2008–0877. All documents in the 

docket are listed in the docket index 

available at http://www.regulations.gov. 

Although listed in the index, some 

information is not publicly available, 

e.g., Confidential Business Information 

(CBI) or other information whose 

disclosure is restricted by statute. 

Certain other material, such as 

copyrighted material, is not placed on 

the Internet and will be publicly 

available only in hard copy form. 

Publicly available docket materials are 

available either in the electronic docket 

at http://www.regulations.gov, or, if only 

available in hard copy, by appointment 

at One Potomac Yard (South Bldg.), 

2777 S. Crystal Dr., Arlington, VA, 

between 9 a.m. to 3 p.m., Monday 

through Friday, excluding legal 

holidays. To schedule an appointment, 

call (703) 305–5805. 

FOR FURTHER INFORMATION CONTACT: 

Cathryn Britton, Pesticide Re-evaluation 

Division, Office of Pesticide Programs, 

Environmental Protection Agency, 1200 

Pennsylvania Ave. NW., Washington, 

DC 20460–0001; telephone number: 

(703) 308–0136; fax number: (703) 308– 

8005; email address: 

britton.cathryn@epa.gov. 

SUPPLEMENTARY INFORMATION: 

I. General Information 

A. Does this action apply to me? 

In this document EPA denies a 

petition by the Natural Resources 

Defense Council (NRDC) to revoke 

pesticide tolerances. This action may 

also be of interest to agricultural 

producers, food manufacturers, or 

pesticide manufacturers. Potentially 

affected entities may include, but are 

not limited to: 

• Crop production (North American 

Industrial Classification System 

(NAICS) code 111), e.g., agricultural 

workers; greenhouse, nursery, and 

floriculture workers; farmers. 

• Animal production (NAICS code 

112), e.g., cattle ranchers and farmers, 

dairy cattle farmers, livestock farmers. 

• Food manufacturing (NAICS code 

311), e.g. agricultural workers; farmers; 

greenhouse, nursery, and floriculture 

workers; ranchers; pesticide applicators. 

• Pesticide manufacturing (NAICS 

code 32532), e.g. agricultural workers; 

commercial applicators; farmers, 

greenhouse, nursery, and floriculture 

workers; residential users. 

This listing is not intended to be 

exhaustive, but rather provides a guide 

for readers regarding entities likely to be 

affected by this action. Other types of 

entities not listed in this unit could also 

be affected. NAICS codes have been 

provided to assist you and others in 

determining whether this action might 

apply to certain entities. If you have any 

questions regarding the applicability of 

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23136 Federal Register / Vol. 77, No. 75 / Wednesday, April 18, 2012 / Rules and Regulations 

this action to a particular entity, consult 

the person listed under FOR FURTHER

INFORMATION CONTACT. 

B. Can I file an objection or hearing 

request? 

Under section 408(g) of FFDCA, any 

person may file an objection to any 

aspect of this order and may also 

request a hearing on those objections. 

You must file your objection or request 

a hearing on this order in accordance 

with the instructions provided in 40 

CFR part 178. To ensure proper receipt 

by EPA, you must identify docket ID 

number EPA–HQ–OPP–2008–0877 in 

the subject line on the first page of your 

submission. All objections and requests 

for a hearing must be in writing, and 

must be received by the Hearing Clerk 

on or before June 18, 2012. Addresses 

for mail and hand delivery of objections 

and hearing requests are provided in 40 

CFR 178.25(b). 

In addition to filing an objection or 

hearing request with the Hearing Clerk 

as described in 40 CFR part 178, please 

submit a copy of the filing that does not 

contain CBI for inclusion in the public 

docket that is described in ADDRESSES. 

Information not marked confidential 

pursuant to 40 CFR part 2 may be 

disclosed publicly by EPA without prior 

notice. Submit this copy, identified by 

docket ID number EPA–HQ–OPP–2008– 

0877, by one of the following methods: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the on-line 

instructions for submitting comments. 

• Mail: U.S. Environmental 

Protection Agency, Office of Pesticide 

Programs (OPP) Public Regulatory 

Docket (7502P), 1200 Pennsylvania Ave. 

NW., Washington, DC 20460–0001. 

• Delivery: OPP Regulatory Public 

Docket (7502P), Environmental 

Protection Agency, Rm. S–4400, One 

Potomac Yard (South Bldg.), 2777 S. 

Crystal Dr., Arlington, VA. Deliveries 

are only accepted during the Docket 

Facility’s normal hours of operation 

(8:30 a.m. to 4 p.m., Monday through 

Friday, excluding legal holidays). 

Special arrangements should be made 

for deliveries of boxed information. The 

Docket Facility telephone number is 

(703) 305–5805. 

C. What should be included in 

objections? 

The objection stage is the second stage 

in the multi-stage petition process under 

FFDCA section 408. This multi-stage 

process is initiated by a petition 

requesting establishment, modification, 

or revocation of a tolerance. In the 

petition, the petitioner has the 

opportunity to make its best case for 

why its request should be granted. 

Notice and comment on the petition 

gives interested parties the chance to 

express views or provide information on 

the subject matter of the petition. 

Once EPA makes a decision on a 

petition, and publishes its decision in 

the Federal Register, the second stage of 

the petition process is triggered. At this 

point, parties who disagree with EPA’s 

decision, whether it is a decision to 

grant or deny the petition, may file 

objections with EPA to the decision 

made. The objection stage gives parties 

a chance to seek review of EPA’s 

decision before the Agency. This is an 

opportunity for parties to contest the 

conclusions EPA reached and the 

determinations underlying those 

conclusions. As an administrative 

review stage, it is not an opportunity to 

raise new issues or arguments or present 

facts or information that was available 

earlier. On the other hand, parties must 

do more than repeat the claims in the 

petition. The objection stage is the 

opportunity to challenge EPA’s decision 

on the petition. An objection fails on its 

face if it does not identify aspects of 

EPA’s decision believed to be in error 

and explain why EPA’s decision is 

incorrect. 

This two-stage process ensures that 

issues are fully aired before the Agency 

and a comprehensive record is compiled 

prior to judicial review. The sequential 

nature of the petition and objection 

process is essential for two reasons. The 

availability of administrative review 

before EPA gives EPA, as well as other 

parties, an opportunity to clearly define 

and articulate the complex science, 

policy, and legal issues involved in 

tolerance decisions. The two-stage 

process also is designed to make the 

administrative process as efficient as 

possible while still providing parties an 

opportunity for an adjudicatory hearing 

if needed. In the first stage, EPA is given 

the opportunity to resolve the issues 

raised by petition through a process 

similar to informal notice-and-comment 

rulemaking. Only material, factual 

issues that remain disputed following 

this first stage may be raised in a 

hearing request. Under this scheme, 

hearings, if needed, can focus on the key 

areas of factual dispute. Of course, the 

first stage of the petition process can 

only serve its winnowing function if 

parties are restricted at the second 

(objection) stage from raising new 

issues. 

II. Background 

A. What action is the agency taking? 

On November 6, 2008, the Natural 

Resources Defense Council (NRDC) filed 

with EPA a petition that, among other 

things, requested that EPA revoke all 

tolerances for the pesticide 2,4- 

dichlorophenoxyacetic acid (2,4-D) 

established under section 408 of the 

Federal Food, Drug, and Cosmetic Act 

(FFDCA), 21 U.S.C. 346a (Ref. 1). NRDC 

claims that EPA’s conclusion outlined 

in the 2005 Reregistration Eligibility 

Decision (RED) for 2,4-D, which allowed 

2,4-D to be reregistered and its 

tolerances retained, was based on a risk 

assessment that was deficient in regard 

to the toxicity of 2,4-D and the amount 

of human exposure to the chemical. 

Specific to 2,4-D tolerances, NRDC 

asserts that EPA failed to incorporate 

information on the endocrine disrupting 

effects of 2,4-D into its human health 

risk assessments; EPA disregarded data 

on neurotoxicity related to 2,4-D; EPA 

disregarded information showing that 

2,4-D is mutagenic; EPA ignored data 

showing that dermal absorption of 2,4- 

D is enhanced by alcohol consumption, 

sunscreen, and DEET; and that EPA 

ignored the exposure of 2,4-D via breast 

milk to infants. Numerous studies are 

cited in the petition that NRDC claims 

supports its assertions. EPA has 

reviewed all of the studies cited by 

NRDC. 

In this order, EPA is denying NRDC’s 

petition to revoke 2,4-D’s tolerances in 

full. Many of NRDC’s claims fail to state 

a sufficient ground for revocation and 

instead merely critique the manner in 

which the risk assessment underlying 

the 2,4-D RED was conducted. Those 

claims that do allege relevant statutory 

grounds for revocation EPA finds to be 

without merit. The other aspects of 

NRDC’s petition not concerning the 2,4- 

D tolerances are addressed in another 

EPA action. 

B. What is the agency’s authority for 

taking this action? 

Under section 408(d)(4) of the 

FFDCA, EPA is authorized to respond to 

a section 408(d) petition to revoke 

tolerance either by issuing a final rule 

revoking the tolerances, issuing a 

proposed rule, or issuing an order 

denying the petition. (21 U.S.C. 

346a(d)(4)). 

III. Statutory and Executive Order 

Reviews 

A. FFDCA/FIFRA and Applicable 

Regulations 

1. In general. EPA establishes 

maximum residue limits, or 

‘‘tolerances,’’ for pesticide residues in 

food and feed commodities under 

section 408 of the FFDCA. (21 U.S.C. 

346a). Without such a tolerance or an 

exemption from the requirement of a 

tolerance, a food containing a pesticide 

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Federal Register / Vol. 77, No. 75 / Wednesday, April 18, 2012 / Rules and Regulations 23137 

residue is ‘‘adulterated’’ under section 

402 of the FFDCA and may not be 

legally moved in interstate commerce. 

(21 U.S.C. 331, 342). Monitoring and 

enforcement of pesticide tolerances are 

carried out by the U.S. Food and Drug 

Administration (FDA) and the U.S. 

Department of Agriculture (USDA). 

Section 408 was substantially rewritten 

by the Food Quality Protection Act of 

1996 (FQPA), which added the 

provisions discussed below establishing 

a detailed safety standard for pesticides, 

additional protections for infants and 

children, and the estrogenic substances 

screening program. (Pub. L. 104–170, 

110 Stat. 1489 (1996)). 

EPA also regulates pesticides under 

the Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA), (7 U.S.C. 136 

et seq). While the FFDCA authorizes the 

establishment of legal limits for 

pesticide residues in food, FIFRA 

requires the approval of pesticides prior 

to their sale and distribution, (7 U.S.C. 

136a(a)), and establishes a registration 

regime for regulating the use of 

pesticides. FIFRA regulates pesticide 

use in conjunction with its registration 

scheme by requiring EPA review and 

approval of pesticide labels and 

specifying that use of a pesticide 

inconsistent with its label is a violation 

of federal law. (7 U.S.C. 136j(a)(2)(G)). 

2. Safety standard for pesticide 

tolerances. A pesticide tolerance may 

only be promulgated or left in effect by 

EPA if the tolerance is ‘‘safe.’’ (21 U.S.C. 

346a(b)(2)(A)(i)). This standard applies 

when responding both to petitions to 

establish and petitions to revoke 

tolerances. ‘‘Safe’’ is defined by the 

statute to mean that ‘‘there is a 

reasonable certainty that no harm will 

result from aggregate exposure to the 

pesticide chemical residue, including 

all anticipated dietary exposures and all 

other exposures for which there is 

reliable information.’’ (21 U.S.C. 

346a(b)(2)(A)(ii)). Section 408 includes 

numerous provisions directing how EPA 

should quantitatively assess the risks of 

pesticides in determining whether a 

tolerance meets the safety standard. For 

example, section 408 either authorizes 

or requires EPA to consider safety 

factors appropriate to use of animal 

experimentation data, 21 U.S.C. 

346a(b)(2)(D)(ix), aggregate and 

cumulative exposures to the pesticide in 

question and other related substances, 

21 U.S.C. 346a(b)(2)(D)(v) and (vi), 

anticipated or actual pesticide residue 

levels as compared to the maximum 

levels permitted by tolerances, 21 U.S.C. 

346a(b)(2)(E), and the percentage of 

crops that bear pesticide residues, 21 

U.S.C. 346a(b)(2)(F). See 21 U.S.C. 

346a(b)(2)(B)(iv) (limiting an exception 

to the safety standard to pesticides 

posing risks that do not exceed ‘‘10 

times the yearly risk’’ allowed under the 

safety standard). 

Risks to infants and children are given 

special consideration. Providing 

additional protection to infants and 

children was a particular focus of the 

FQPA. Section 408(b)(2)(C) requires 

EPA to make a specific determination 

regarding the safety of tolerances to 

infants and children and to consider, 

among other things, information 

‘‘concerning the special susceptibility of 

infants and children to the pesticide 

chemical residues * * *.’’ (21 U.S.C. 

346a(b)(2)(C)(i)(II) and (ii)(II)). This 

provision also creates a presumptive 

additional safety factor for the 

protection of infants and children. 

Specifically, it directs that ‘‘[i]n the case 

of threshold effects, * * * an additional 

tenfold margin of safety for the pesticide 

chemical residue and other sources of 

exposure shall be applied for infants 

and children to take into account 

potential pre- and post-natal toxicity 

and completeness of the data with 

respect to exposure and toxicity to 

infants and children.’’ (21 U.S.C. 

346a(b)(2)(C)). EPA is permitted to ‘‘use 

a different margin of safety for the 

pesticide chemical residue only if, on 

the basis of reliable data, such margin 

will be safe for infants and children.’’ 

(Id.). Due to Congress’ focus on both 

pre- and post-natal toxicity, EPA has 

interpreted this additional safety factor 

as pertaining to risks to infants and 

children that arise due to pre-natal 

exposure as well as to exposure during 

childhood years. For convenience’s 

sake, the legal requirements regarding 

the additional safety margin for infants 

and children in section 408(b)(2)(C) are 

referred to throughout this Order as the 

‘‘FQPA safety factor for the protection of 

infants and children’’ or simply the 

‘‘FQPA safety factor.’’ ’ 

3. Procedures for establishing, 

amending, or revoking tolerances. 

Tolerances are established, amended, or 

revoked by rulemaking under the 

unique procedural framework set forth 

in the FFDCA. Generally, a tolerance 

rulemaking is initiated by the party 

seeking to establish, amend, or revoke a 

tolerance by means of filing a petition 

with EPA. (See 21 U.S.C. 346a(d)(1)). 

EPA publishes in the Federal Register a 

notice of the petition filing and requests 

public comment. (21 U.S.C. 346a(d)(3)). 

After reviewing the petition, and any 

comments received on it, EPA may issue 

a final rule establishing, amending, or 

revoking the tolerance, issue a proposed 

rule to do the same, or deny the 

petition. (21 U.S.C. 346a(d)(4)). 

Once EPA takes final action on the 

petition by establishing, amending, or 

revoking the tolerance or denying the 

petition, any party may file objections 

with EPA to EPA’s decision on the 

petition and seek an evidentiary hearing 

on those objections. (21 U.S.C. 

346a(g)(2)). Objections and hearing 

requests must be filed within 60 days. 

(Id.). The statute provides that EPA shall 

‘‘hold a public evidentiary hearing if 

and to the extent the Administrator 

determines that such a public hearing is 

necessary to receive factual evidence 

relevant to material issues of fact raised 

by the objections.’’ (21 U.S.C. 

346a(g)(2)(B). EPA regulations make 

clear that hearings will only be granted 

where it is shown that there is ‘‘a 

genuine and substantial issue of fact,’’ 

the requestor has identified evidence 

‘‘which, if established, resolve one or 

more of such issues in favor of the 

requestor,’’ and the issue is 

‘‘determinative’’ with regard to the relief 

requested. (40 CFR 178.32(b)). Further, 

a party may not raise issues in 

objections unless they were part of the 

petition and an objecting party must 

state objections to the EPA decision and 

not just repeat the allegations in its 

petition. Corn Growers v. EPA, 613 F.2d 

266 (D.C. Cir. 2010), cert. denied, 131 S. 

Ct. 2931 (2011). EPA’s final order on the 

objections is subject to judicial review. 

(21 U.S.C. 346a(h)(1)). 

4. Tolerance reassessment and FIFRA 

reregistration. The FQPA required that 

EPA reassess the safety of all pesticide 

tolerances existing at the time of its 

enactment. (21 U.S.C. 346a(q)). EPA was 

given 10 years to reassess the 

approximately 10,000 tolerances in 

existence in 1996. In this reassessment, 

EPA was required to review existing 

pesticide tolerances under the new 

‘‘reasonable certainty that no harm will 

result’’ standard set forth in section 

408(b)(2)(A)(ii). (21 U.S.C. 

346a(b)(2)(A)(ii)). This reassessment was 

substantially completed by the August 

3, 2006 deadline. Tolerance 

reassessment was generally handled in 

conjunction with a similar program 

involving reregistration of pesticides 

under FIFRA. (7 U.S.C. 136a–1). 

Reassessment and reregistration 

decisions were generally combined in a 

document labeled a Reregistration 

Eligibility Decision (RED). 

5. Estrogenic substances screening 

program. Section 408(p) of the FFDCA 

creates the estrogenic substances 

screening program. This provision 

directed EPA to ‘‘develop a screening 

program to determine whether certain 

substances may have an effect in 

humans that is similar to an effect 

produced by a naturally occurring 

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23138 Federal Register / Vol. 77, No. 75 / Wednesday, April 18, 2012 / Rules and Regulations 

estrogen, or such other endocrine effect, 

as the Administrator may designate.’’ 

This screening program must use 

‘‘appropriate validated test systems and 

scientifically relevant information.’’ (21 

U.S.C. 346a(p)(1)). 

Pursuant to the Administrator’s 

discretionary authority, EPA adopted a 

two-tiered screening and testing strategy 

and expanded the EDSP to include the 

androgen and thyroid hormonal 

pathways and ecological effects. (63 FR 

71542, 71544, December 28, 1998). The 

first tier involves screening ‘‘to identify 

substances that have the potential to 

interact with the endocrine system’’ and 

the second tier involves testing ‘‘to 

determine whether the substance causes 

adverse effects, identify the adverse 

effects caused by the substance, and 

establish a quantitative relationship 

between the dose and the adverse 

effect.’’ (Id. at 71545). Tier 1 screening 

is limited to evaluating whether a 

substance is ‘‘capable of interacting 

with’’ the endocrine system, and is ‘‘not 

sufficient to determine whether a 

chemical substance may have an effect 

in humans that is similar to an effect 

produced by naturally occurring 

hormones.’’ (Id. at 71550). Based on the 

results of Tier 1 screening, EPA will 

decide whether Tier 2 testing is needed. 

Importantly, ‘‘[t]he outcome of Tier 2 is 

designed to be conclusive in relation to 

the outcome of Tier 1 and any other 

prior information. Thus, a negative 

outcome in Tier 2 will supersede a 

positive outcome in Tier 1.’’ (Id. at 

71554–71555). 

In 2008, after an extensive validation 

process, including peer review of 

individual assays, EPA notified the 

public of the EDSP proposed Tier 1 

battery of screening assays in a Federal 

Register Notice issued January 24, 2008 

(73 FR 4216). EPA submitted the 

proposed battery for peer review by 

FIFRA Scientific Advisory Panel (SAP). 

A final report of the peer review is 

available. (Ref. 2). EPA announced the 

issuance of orders for Tier 1 Screening 

on October 21, 2009 for 67 chemicals 

including 2,4-D. (74 FR 54422, 54425). 

With regard to endocrine effects on 

humans, EPA has designated the 1998 

rat two-generation reproduction study 

(870–3800) as the applicable Tier 2 

study for the Endocrine Disruptor 

Screening Program. In this reproduction 

study, potential hormonal effects can be 

detected through behavioral changes, 

ability to become pregnant, duration of 

gestation, signs of difficult or prolonged 

parturition, apparent sex ratio (as 

ascertained by anogenital distances) of 

the offspring, feminization or 

masculinization of offspring, number of 

pups, stillbirths, gross pathology and 

histopathology of the vagina, uterus, 

ovaries, testis, epididymis, seminal 

vesicles, prostate, and any other 

identified target organs. EPA concluded 

that the rat two-generation reproduction 

study is valid for the identification and 

characterization of reproductive and 

developmental effects, including those 

due to endocrine disruption, based on 

the long history of its use, the 

endorsement of the 1998 test guideline 

by the FIFRA SAP, and acceptance by 

member countries of the Organisation 

for Economic Cooperation and 

Development (OECD). 

In addition to the 1998 test guideline 

for the mammalian two-generation 

reproductive toxicity study, EPA has 

proposed the new OECD test guideline 

for the extended one-generation 

reproductive toxicity study as an 

alternate EDSP Tier 2 test. The extended 

one-generation reproductive toxicity 

study was not only designed to provide 

the traditional spectrum of information 

from a reproductive study, but was also 

enhanced to evaluate reproductive and 

developmental endpoints associated 

with the endocrine, nervous, and 

immune systems in male and female 

adult rodents and offspring at birth, 

weaning, and puberty, which may not 

necessarily be covered in other 40 CFR 

part 158 test guideline studies. 

EPA has received all required final 

study reports and data from the Tier 1 

battery of tests for 2,4-D. (Refs. 

3,4,5,6,7,8, and 9). EPA waived the in 

vivo mammalian Tier 1 tests for 2,4-D 

due to the availability of a newlysubmitted extended one generation 

reproduction study with 2,4-D. (Ref. 10). 

The submitted EDSP Tier 1 assays will 

be considered with regard to potential 

ecological effects and the need for Tier 

2 in vivo studies for effects in wildlife. 

Although the submitted Tier 1 in vitro 

studies may inform EPA on mechanistic 

issues in mammalian systems (e.g., 

whether 2,4-D can bind to the estrogen 

or androgen receptor in mammals), the 

studies will not affect EPA’s 

conclusions on the quantitative 

endocrine risks posed by 2,4-D for 

humans given the availability of the 

extended one-generation reproduction 

study (an in vivo study in rats) that 

comprehensively examined the risks to 

human health from 2,4-D’s interaction 

with endocrine system endpoints. (See 

discussion in Unit VII.A.1.c.). 

B. EPA Risk Assessment for 

Tolerances—Policy and Practice 

1. The safety determination—risk 

assessment. To assess risk of a pesticide 

tolerance, EPA combines information on 

pesticide toxicity with information 

regarding the route, magnitude, and 

duration of exposure to the pesticide. 

The risk assessment process involves 

four distinct steps: 

• Identification of the toxicological 

hazards posed by a pesticide; 

• Determination of the ‘‘Level of 

Concern (LOC)’’ with respect to human 

exposure to the pesticide; 

• Estimation of human exposure to 

the pesticide; and 

• Characterization of risk posed to 

humans by the pesticide based on 

comparison of human exposure to the 

LOC. 

a. Hazard identification. In evaluating 

toxicity or hazard, EPA reviews toxicity 

data, typically from studies with 

laboratory animals, to identify any 

adverse effects on the test subjects. 

Where available and appropriate, EPA 

will also take into account studies 

involving humans, including human 

epidemiological studies. For most 

pesticides, the animal toxicity database 

usually consists of studies investigating 

a broad range of endpoints including 

gross and microscopic effects on organs 

and tissues, functional effects on bodily 

organs and systems, effects on blood 

parameters (such as red blood cell 

count, hemoglobin concentration, 

hematocrit, and a measure of clotting 

potential), effects on the concentrations 

of normal blood chemicals (including 

glucose, total cholesterol, urea nitrogen, 

creatinine, total protein, total bilirubin, 

albumin, hormones, and enzymes such 

as alkaline phosphatase, alanine 

aminotransferase and cholinesterases), 

and behavioral or other gross effects 

identified through clinical observation 

and measurement. EPA examines 

whether adverse effects are caused by 

different durations of exposure ranging 

from short-term (acute) to long-term 

(chronic) pesticide exposure and 

different routes of exposure (oral, 

dermal, inhalation). Further, EPA 

evaluates potential adverse effects in 

different age groups (adults as well as 

fetuses and juveniles). (Ref. 11 at 8–10). 

EPA also considers whether the 

adverse effect has a threshold—a level 

below which exposure has no 

appreciable chance of causing the 

adverse effect. For effects that have no 

threshold, EPA assumes that any 

exposure to the substance increases the 

risk that the adverse effect may occur. 

b. LOC/dose-response analysis. Once 

a pesticide’s potential hazards are 

identified, EPA determines a 

toxicological LOC for evaluating the risk 

posed by human exposure to the 

pesticide. In this step of the risk 

assessment process, EPA essentially 

evaluates the levels of exposure to the 

pesticide at which effects might occur in 

the toxicity studies. An important 

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1 Different terminology has been used to label 

factors used in calculating safe doses of chemical 

substances. At first, they were frequently referred to 

as ‘‘safety’’ factors. The terminology has evolved 

over the decades, however, such that what was once 

generally called a safety factor has come to be 

generally referred to as an uncertainty factor. (Ref. 

12 at A–3). The rationale for the change was that 

although the use of such factors does promote 

safety, the factors actually address uncertainty 

issues (e.g., uncertainty about the differences in 

sensitivities of animals and humans, uncertainty 

concerning variation inhuman sensitivities, 

uncertainty created by missing data, etc.). The 

FQPA reintroduced the term ‘‘safety’’ factors with 

its reference to a ‘‘margin of safety.’’ Subsequent to 

the passage of FQPA, the Office of Pesticide 

Programs has used the terms safety factor and 

uncertainty factor interchangeably. 

aspect of this determination is assessing 

the relationship between exposure 

(dose) and response (often referred to as 

the dose-response analysis). EPA 

follows differing approaches to 

identifying a LOC for effects that only 

occur above a threshold (‘‘threshold 

effects’’) and those for which a 

threshold dose cannot be determined 

(‘‘non-threshold effects’’). Because EPA 

identified only threshold effect risks for 

2,4-D, only EPA’s risk assessment 

procedures for threshold risks are 

discussed in this Order. 

In examining the dose-response 

relationship for a pesticide’s threshold 

effects, EPA evaluates an array of 

toxicity studies on the pesticide. Two 

critical parts of this evaluation involve 

identification of a quantitative dose 

level(s) from these studies to be used in 

assessing the pesticide’s safety to 

humans (referred to as the Point of 

Departure) and selection of appropriate 

safety factors for translating the results 

of toxicity studies in relatively small 

groups of animals or humans to the 

overall human population, including 

major identifiable subgroups of 

consumers. The Point of Departure is 

used in conjunction with identified 

safety factors to calculate a Level of 

Concern for a pesticide. 

i. Point of Departure. A Point of 

Departure (POD) is the dose serving as 

the ‘starting point’ in extrapolating a 

risk to the human population. In 

selecting the POD, EPA first evaluates 

all relevant available toxicity data and 

conducts a weight of the evidence 

analysis, considering consistency, 

reproducibility, temporal and dose 

concordance, and biological plausibility 

of the effects reported. EPA then selects 

a value from a dose-response curve that 

is at the low end of the observable data 

(the no observed adverse effect level, or 

NOAEL, the lowest-observed adverse 

effect level, or LOAEL, or an 

extrapolated benchmark dose) as the 

POD. Doses in toxicology studies are 

generally expressed in terms of 

milligrams of the test substance per 

kilogram of body weight of the test 

subject per day (mg/kg/day). EPA will 

make separate determinations as to the 

Points of Departure for both short and 

long exposure periods as well as for the 

different routes of exposure (oral, 

dermal, and inhalation). 

ii. Safety factors. It has long been a 

standard risk assessment practice, to use 

numerical factors—variously referred to 

over time as either uncertainty or safety 

factors 1 in conjunction with 

experimental toxicity data in assessing 

risk to humans. The two most common 

safety/uncertainty factors are the factors 

used to address the potential difference 

in sensitivity between humans and 

experimental animals (i.e., inter-species 

sensitivity) and within the human 

population (i.e., intra-species 

sensitivity). Generally a factor of tenfold 

(10X) is used as a default for both the 

inter-species and intra-(human) species 

safety factors. When EPA bases its POD 

on a dose level from experimental 

animal data, it will generally use both 

factors so that it accounts both for the 

fact that it is extrapolating a dose level 

in animals to humans and that there 

may be a wide variation in human 

response to the compound. This would 

result in a total safety factor of 100X 

because each factor indicates that the 

potential variations addressed constitute 

a multiple of 10X. When EPA bases its 

POD on a dose level from human data, 

only the intra-species factor would be 

needed because EPA is not extrapolating 

a dose used in an animal study. 

In addition to the inter- and intraspecies factors, risk assessors also apply 

‘‘additional’’ or ‘‘modifying’’ safety/ 

uncertainty factors based on specific 

circumstances related to the toxicity 

data, particularly with regard to 

deficiencies in that data. Additional 

factors are applied to address: (1) An 

absence of critical toxicity data; (2) the 

failure of a study to identify a NOAEL; 

(3) the necessity of using a sub-chronic 

data to choose a POD for estimating 

chronic risk; and (4) results in a study 

that suggest the inter- or intra-species 

factors may not be sufficient. Generally, 

a safety factor value of 10X or 3X (which 

is considered to be one-half of 10X on 

the logarithmic scale) is used to address 

these concerns. 

EPA’s safety/uncertainty factor 

practice with regard to pesticides was 

altered to a degree by the Food Quality 

Protection Act (FQPA). (Ref. 12). That 

Act established a presumptive 

additional ‘‘safety’’ factor of 10X to 

protect infants and children. The 

additional factor was designed to 

account for the completeness of the 

toxicity and exposure databases and the 

potential for pre- and post-natal toxicity. 

EPA has interpreted this legislation as 

both a ‘‘codification and expansion’’ of 

prior EPA practice with regard to 

additional safety/uncertainty factors. 

(Ref. 12 at A–4–A–5). It codified EPA’s 

prior practice by requiring the 

additional presumptive factor to address 

toxicity data completeness issues (i.e., 

absence of a particular study, a NOAEL 

in a completed study, or chronic data). 

These traditional additional uncertainty 

factors became FQPA safety factors for 

the protection of infants and children. 

EPA concluded that Congress had not 

intended EPA to double-up on safety 

factors by, for example, applying an 

‘‘additional’’ uncertainty factor due to 

missing data, and apply a FQPA safety 

factor as well to address the same 

missing data. (Ref. 12 at A–5). Congress 

expanded EPA’s prior practice by 

providing that the additional FQPA 

safety factor for the protection of infants 

and children was designed to address 

not just toxicity data deficiencies but 

exposure data deficiencies as well and 

by its emphasis on protecting against 

potential pre- and post-natal toxicity. In 

theory, EPA could have, prior to the 

enactment of the FQPA, used an 

‘‘additional’’ or ‘‘modifying’’ factor to 

address health risks to children not 

otherwise protected by the inter-species, 

intra-species, or data deficiency safety 

factors, but use of such a factor was not 

common. The FQPA also modified the 

status quo by making the additional 

safety factor for infants and children 

presumptive in nature. 

The narrowly-focused and highlyprescriptive nature of the FQPA safety 

factor provision has created some 

practical problems for EPA in 

integrating the new statutory 

requirements with pesticide risk 

assessment approaches and, more 

generally, with Agency risk assessment 

practices. As noted above, the FQPA 

essentially codified EPA’s prior risk 

assessment practice as to ‘‘additional’’ 

uncertainty factors and it expanded the 

use of additional uncertainty factors 

into new areas. The FQPA, however, did 

not speak to use of traditional (nonadditional) uncertainty factors. Thus, 

the end result was that some uncertainty 

factors for FFDCA pesticides remained 

unaffected by the new statutory 

requirements (the inter- and intraspecies factors), some uncertainty 

factors became FQPA safety factors 

(additional uncertainty factors that 

addressed toxicity data deficiencies), 

and some safety factors that either had 

previously never existed or were at least 

extremely rare were created as a 

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23140 Federal Register / Vol. 77, No. 75 / Wednesday, April 18, 2012 / Rules and Regulations 

statutory phenomenon (a factor to 

address exposure data base deficiencies 

and a factor to address potential preand post-natal toxicity). This selective 

inter-weaving of statutory requirements 

with Agency science policy made 

FFDCA risk assessments for pesticides 

unique compared to general Agency risk 

assessment practice. 

Pesticide risk, however, is not 

regulated under a single statute. Risks to 

workers or the environment from 

pesticide use are regulated by EPA 

under FIFRA not the FFDCA. Further, 

EPA may address risks posed by 

pesticide contamination of the 

environment under several other 

statutes, including the Safe Drinking 

Water Act, 42 U.S.C. 300f et seq., the 

Resource Conservation and Recovery 

Act, 42 U.S.C. 6901 et seq., and the 

Comprehensive Environmental 

Response, Compensation, and Liability 

Act, 42 U.S.C. 9601 et seq. Prior to 

enactment of the FQPA’s specific 

provisions on pesticide risk assessment, 

a pesticide risk assessment performed 

by EPA’s Office of Pesticide Programs 

under the aegis of FFDCA section 408 

could generally be easily translated for 

use by the Office of Pesticide Programs 

under FIFRA, or by the other media 

offices within EPA for use under other 

statutes. However, once pesticide risk 

assessment under the FQPA became not 

simply a matter of good scientific 

practice but was channeled by explicit 

statutory requirements, it became 

incumbent upon the Office of Pesticide 

Programs to prepare its FFDCA 

pesticide risk assessments in a manner 

that clearly delineated what aspects of 

the assessment were driven solely by 

science and what aspects primarily by 

FQPA statutory requirements. 

Specifically, the Office of Pesticide 

Programs had to be transparent with 

regard to whether it was relying on 

FQPA safety factors based on unique 

FQPA requirements (exposure database 

deficiencies and potential pre- and postnatal toxicity) or FQPA safety factors 

that are essentially a codification of 

prior general EPA ‘‘additional’’ safety/ 

uncertainty factor practice. 

EPA addressed these ‘‘transparency’’ 

issues at length in its 2002 policy 

statement on the FQPA safety factor. To 

clarify how the FQPA safety factor 

provision left a portion of prior safety/ 

uncertainty practice unchanged, 

codified another portion, and also 

expanded the use of safety factors, EPA 

explained the overlap between the 

FQPA safety factor and ‘‘additional’’ 

safety factors in depth and included the 

following figure to graphically illustrate 

the issue: 

With regard to providing transparency 

on the FQPA safety factor decisions, 

EPA took two steps. First, it adopted a 

new term, the ‘‘special’’ FQPA safety 

factor, for children safety factors that 

were based solely on the new FQPA 

requirements. Second, it adopted the 

approach of calculating two different 

safe doses for a pesticide: One that 

excluded any ‘‘special’’ FQPA safety 

factors and one that included them. (See 

discussion of reference doses and 

population-adjusted doses in Unit 

III.B.1.b.iii, below). Introducing the new 

terminology on FQPA safety factors into 


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long-established safety factor practice 

has proved challenging. EPA staff 

frequently drafted documents that (1) 

claimed no FQPA safety factor was 

needed but applied an additional 

uncertainty factor to address the 

completeness of the data base or 

reliance on a LOAEL; or (2) treated the 

‘‘special’’ FQPA safety factor as the only 

type of FQPA safety factor. Such 

misstatements did not substantively 

change risk assessment outcomes but 

they did raise the confusion level on an 

already complex topic. Eventually, EPA 

determined that the term ‘‘special’’ 

FQPA safety factor caused more 

problems than it solved and abandoned 

it. However, EPA has retained the 

approach of continuing to calculate both 

a safe dose with, and without, what was 

once referred to as ‘‘special’’ FQPA 

safety factors. 

(iii). Level of Concern. By Level of 

Concern (LOC), EPA means a numerical 

value that separates exposures that 

would generally be regarded as raising 

health concerns from those that do not. 

The POD (see Unit III.B.1.b.i. above) is 

used in estimating and describing the 

LOC; however, the LOC is expressed 

differently depending on whether the 

risk assessment addresses dietary or 

non-dietary exposures. The use of 

different approaches is due to the fact 

that non-dietary exposure assessments 

often involve combining exposures from 

multiple pathways. 

For dietary risks, EPA uses the POD 

to calculate an acceptable LOC that is 

referred to as a reference dose (RfD). The 

RfD is calculated by dividing the POD 

by all applicable safety or uncertainty 

factors with one exception (see below). 

(Ref. 12 at 4–11). Safety/uncertainty 

factors are divided separately and 

sequentially into the POD. Thus, for 

example, if the POD is 1 milligram/ 

kilogram/day (mg/kg/day) and there are 

two applicable 10X safety/uncertainty 

factors, then the reference dose would 

be 0.01 mg/kg/day (i.e., 1 mg/kg/day 

divided twice by 10). For convenience’s 

sake, safety factors are often combined 

by multiplying them by each other. This 

product when divided into the POD 

would, of course, produce the same 

result as sequential division. For 

reduction of a safety factor, a similar 

process is followed. For example, if a 

safety factor is to be reduced by half, 

this is done by taking the square root of 

the factor rather than dividing by two. 

See 73 FR 42683, 42696 (July 23, 2008). 

In implementing FFDCA section 408, 

EPA’s Office of Pesticide Programs, also 

calculates a variant of the RfD referred 

to as a Population Adjusted Dose (PAD). 

A PAD is the RfD divided by any 

portion of the FQPA safety factor that 

does not correspond to one of the 

traditional additional safety factors used 

in general Agency risk assessments. 

(Ref. 12. at 13–16). As noted above, the 

reason for calculating PADs is so that 

other parts of the Agency, which are not 

governed by FFDCA section 408, can, 

when evaluating the same or similar 

substances, easily identify which 

aspects of a pesticide risk assessment 

are a function of the particular statutory 

commands in FFDCA section 408. 

Today, RfDs and PADs are generally 

calculated for both acute and chronic 

dietary risks although traditionally RfDs 

and PADs were only calculated for 

chronic risks. RfDs/PADs for acute and 

chronic risks will generally have 

different Points of Departure (because 

they are generally based on studies of 

different duration) and may be based on 

different safety factors as well 

depending on the characteristics of the 

studies relied on in choosing the POD. 

For example, if the study used to pick 

the POD for acute risk identified a 

NOAEL but the study used for chronic 

risk did not, any additional safety factor 

used to address this lack of a NOAEL in 

calculating the RfD/PAD for chronic risk 

would not be applicable to the acute 

RfD/PAD derivation. 

For non-dietary, and combined 

dietary and non-dietary, risk 

assessments of threshold effects, the 

toxicological LOC is not expressed as an 

RfD/PAD but rather in terms of an 

acceptable (or target) Margin of 

Exposure (MOE) between human 

exposure and the POD. The ‘‘margin’’ 

that is being referred to in the term MOE 

is the ratio between human exposure 

and the POD which is calculated by 

dividing human exposure into the POD. 

An acceptable MOE is generally 

considered to be a margin at least as 

high as the product of all applicable 

safety factors for a pesticide. For 

example, if a pesticide needs a 10X 

factor to account for potential interspecies differences, 10X factor for 

potential intra-species differences, and 

10X factor for the FQPA children’s 

safety provision, the safe or target MOE 

would be a MOE of at least 1,000. What 

that means is that for the pesticide in 

the example to meet the safety standard, 

human exposure to the pesticide would 

generally have to be at least 1,000 times 

smaller than the POD. Like RfD/PADs, 

specific target MOEs are selected for 

exposures of different durations and 

routes. For non-dietary exposures, EPA 

typically examines short-term, 

intermediate-term, and long-term 

exposures. Additionally, target MOEs 

may be selected based on both the 

duration of exposure and the various 

routes of non-dietary exposure—dermal, 

inhalation, and oral. Target MOEs for a 

given pesticide can vary depending on 

the characteristics of the studies relied 

upon in choosing the POD for the 

various duration and route scenarios. 

c. Estimating human exposure. Risk is 

a function of both hazard and exposure. 

Thus, equally important to the risk 

assessment process as determining the 

hazards posed by a pesticide and the 

toxicological LOC for those hazards is 

estimating human exposure. Under 

FFDCA section 408, EPA is concerned 

not only with exposure to pesticide 

residues in food but also exposure 

resulting from pesticide contamination 

of drinking water supplies and from use 

of pesticides in the home or other nonoccupational settings. (See 21 U.S.C. 

346a(b)(2)(D)(vi)). Additionally, EPA 

must take into account nonoccupational exposure from ‘‘other 

related substances.’’ (Id.). 

i. Exposure from food. There are two 

critical variables in estimating exposure 

in food: (1) The types and amount of 

food that is consumed; and (2) the 

residue level in that food. 

Consumption is estimated by EPA 

based on scientific surveys of 

individuals’ food consumption in the 

United States conducted by the USDA. 

(Ref. 11 at 12). Information on residue 

values comes from a range of sources 

including crop field trials; data on 

pesticide reduction (or concentration) 

due to processing, cooking, and other 

practices; information on the extent of 

usage of the pesticide; and monitoring 

of the food supply. (Id. at 17). 

In assessing exposure from pesticide 

residues in food, EPA, for efficiency’s 

sake, follows a tiered approach in which 

it, in the first instance, assesses 

exposure using the worst case 

assumptions that 100 percent of the 

crop or commodity in question is 

treated with, or exposed to, the 

pesticide and 100 percent of the food 

from that crop or commodity contains 

pesticide residues at the tolerance level. 

(Id. at 11). When such an assessment 

shows no risks of concern, a more 

complex risk assessment is unnecessary. 

By avoiding a more complex risk 

assessment, EPA’s resources are 

conserved and regulated parties are 

spared the cost of any additional studies 

that may be needed. If, however, a first 

tier assessment suggests there could be 

a risk of concern, EPA then attempts to 

refine its exposure assumptions to yield 

a more realistic picture of residue values 

through use of data on the percent of the 

crop or commodity actually treated 

with, or exposed to, the pesticide and 

data on the level of residues that may be 

present on the treated crop or 

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commodity. These latter data are used to 

estimate what has been traditionally 

referred to by EPA as ‘‘anticipated 

residues.’’ More information on refining 

estimates of pesticide exposure can be 

found at Ref. 11; 70 FR 46706, 46732, 

August 10, 2005). 

ii. Exposure from water. EPA may use 

either or both field monitoring data and 

mathematical water exposure models to 

generate pesticide exposure estimates in 

drinking water. Monitoring and 

modeling are both important tools for 

estimating pesticide concentrations in 

water and can provide different types of 

information. Monitoring data can 

provide estimates of pesticide 

concentrations in water that are 

representative of specific agricultural or 

residential pesticide practices and 

under environmental conditions 

associated with a sampling design. 

Although monitoring data can provide a 

direct measure of the concentration of a 

pesticide in water, it does not always 

provide a reliable estimate of exposure 

because sampling may not occur in 

areas with the highest pesticide use, 

and/or the sampling may not occur 

when the pesticides are being used. 

In estimating pesticide exposure 

levels in drinking water, EPA most 

frequently uses mathematical water 

exposure models. EPA’s models are 

based on extensive monitoring data and 

detailed information on soil properties, 

crop characteristics, and weather 

patterns. (69 FR 30042, 30058–30065, 

May 26, 2004). These models calculate 

estimated environmental concentrations 

of pesticides using laboratory data that 

describe how fast the pesticide breaks 

down to other chemicals and how it 

moves in the environment. These 

concentrations can be estimated 

continuously over long periods of time, 

and for places that are of most interest 

for any particular pesticide. Modeling is 

a useful tool for characterizing 

vulnerable sites, and can be used to 

estimate peak concentrations from 

infrequent, large storms. 

iii. Exposure from residential use of 

pesticides. Residential assessments 

examine exposure to pesticides in nonoccupational or residential settings (e.g., 

homes, parks, schools, athletic fields or 

any other areas frequented by the 

general public). Exposures to pesticides 

may occur to persons who apply 

pesticides or to persons who enter areas 

previously treated with pesticides. Such 

exposures may occur through oral, 

inhalation, or dermal routes. 

Residential assessments are 

conducted through examination of 

significant exposure scenarios (e.g., 

children playing on treated lawns or 

homeowners spraying their gardens) 

using a combination of generic and 

pesticide-specific data. To regularize 

this process, OPP has prepared Standard 

Operating Procedures (SOPs) for 

conducting residential assessments on a 

wide array of scenarios that are 

intended to address all major possible 

means by which individuals could be 

exposed to pesticides in a nonoccupational environment (e.g. homes, 

schools, parks, athletic fields, or other 

publicly accessible locations). The SOPs 

identify relevant generic data and 

construct algorithms for calculating 

exposure amounts using these generic 

data in combination with pesticidespecific information. The generic data 

generally involve survey data on 

behavior patterns (e.g., activities 

conducted on turf and time spent on 

these activities) and transfer coefficient 

data. Transfer coefficient data measure 

the amount of pesticide that transfers 

from the environment to humans from 

a defined activity (e.g., hand contact 

with a treated surface or plant). Specific 

information on pesticides can include 

information on residue levels as well as 

information on environmental fate such 

as degradation data. 

d. Risk characterization. The final 

step in the risk assessment is risk 

characterization. In this step, EPA 

combines information from the first 

three steps (hazard identification, LOC/ 

dose-response analysis, and human 

exposure assessment) to quantitatively 

estimate the risks posed by a pesticide. 

Separate characterizations of risk are 

conducted for different durations of 

exposure. Additionally, separate and, 

where appropriate, aggregate 

characterizations of risk are conducted 

for the different routes of exposure 

(dietary and non-dietary). 

For threshold risks, EPA estimates 

risk in one of two ways. Where EPA has 

calculated a RfD/PAD, risk is estimated 

by expressing human exposure as a 

percentage of the RfD/PAD. Exposures 

lower than 100 percent of the RfD/PAD 

are generally not of concern. 

Alternatively, EPA may express risk by 

comparing the MOE between estimated 

human exposure and the POD with the 

acceptable or target MOE. As described 

previously, the acceptable or target MOE 

is the product of all applicable safety 

factors. To calculate the actual MOE for 

a pesticide, estimated human exposure 

to the pesticide is divided into the POD. 

In contrast to the RfD/PAD approach, 

higher MOEs denote lower risk. 

Accordingly, if the target MOE for a 

pesticide is 100, MOEs equal to or 

exceeding 100 would generally not be of 

concern. As a conceptual matter, the 

RfD/PAD and MOE approaches are 

fundamentally equivalent. For a given 

risk and given exposure of a pesticide, 

if exposure to a pesticide were found to 

be acceptable under an RfD/PAD 

analysis it would also pass under the 

MOE approach, and vice-versa. 

2. EPA policy on the FQPA safety 

factor for the protection of infants and 

children. As the previous brief summary 

of EPA’s risk assessment practice 

indicates, the use of safety factors plays 

a critical role in the process. This is true 

for traditional 10X safety factors to 

account for potential differences 

between animals and humans when 

relying on studies in animals (interspecies safety factor) and potential 

differences among humans (intraspecies safety factor) as well as the 

FQPA’s additional 10X safety factor. 

In applying the FQPA safety factor 

provision, EPA has interpreted it as 

imposing a presumption in favor of 

applying an additional 10X safety factor. 

(Ref. 12 at 4, 11). Thus, EPA generally 

refers to the additional 10X factor as a 

presumptive or default 10X factor. EPA 

has also made clear, however, that this 

presumption or default in favor of the 

additional 10X is only a presumption. 

The presumption can be overcome if 

reliable data demonstrate that a different 

factor is safe for children. (Id.). In 

determining whether a different factor is 

safe for children, EPA focuses on the 

three factors listed in FFDCA section 

408(b)(2)(C)—the completeness of the 

toxicity database, the completeness of 

the exposure database, and potential 

pre- and post-natal toxicity. In 

examining these factors, EPA strives to 

make sure that its choice of a safety 

factor, based on a weight-of-theevidence evaluation, does not 

understate the risk to children. (Id. at 

24–25, 35). 

IV. 2,4-D Regulatory Background 

2,4-D is a phenoxy herbicide, plant 

growth regulator, and fungicide that has 

been used in the United States since the 

mid 1940s. It comes in multiple 

chemical forms and is currently found 

in approximately 600 end-use products 

registered for agricultural, residential, 

industrial, and aquatic uses. It is 

formulated primarily as an amine salt in 

an aqueous solution or as an ester in an 

emulsifiable concentrate. There are 85 

tolerances for 2,4-D listed in the Code of 

Federal Regulations. 

1. Special review based on human 

carcinogenicity. On September 22, 1986, 

the Agency issued a preliminary 

notification of Special Review of 2,4-D 

because of concerns for epidemiological 

links of 2,4-D to non-Hodgkin’s 

lymphoma from both occupational and 

residential exposure. In 1987, EPA 

requested that the FIFRA SAP examine 

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Federal Register / Vol. 77, No. 75 / Wednesday, April 18, 2012 / Rules and Regulations 23143 

the evidence bearing on 2,4-D’s 

carcinogenicity. The Panel concluded 

that the present data for animals and 

humans were inadequate for 

determining carcinogenicity and that 

2,4-D should be classified under Group 

D of EPA’s cancer guidelines—Not 

Classifiable as to Human 

Carcinogenicity. (Refs. 13 and 14). 

Based upon findings that existing data 

did not support a link between 2,4-D 

and carcinogenicity, the Agency 

published a proposed decision Not to 

Initiate Special Review on March 23, 

1988 (53 FR 9590) and deferred a final 

decision until reregistration. 

To further address the potential link 

of non-Hodgkin’s lymphoma to 2,4-D 

exposure, a joint Science Advisory 

Board (SAB)/SAP Special Joint 

Committee was convened to review 

available epidemiological and other data 

on 2,4-D. In 1994, the Committee 

concluded that ‘‘the data are not 

sufficient to conclude that there is a 

cause and effect relationship between 

exposure to 2,4-D and non-Hodgkin’s 

lymphoma.’’ (Ref. 15). In 1997, EPA reexamined the weight of the evidence on 

cancer taking into account two new 

cancer bioassays in mice and rats. (Ref. 

16). These new bioassays showed no 

statistically significant tumor response 

in either species. Although EPA 

concurred with the Joint Committee’s 

recommendation to classify 2,4-D under 

Group D, EPA requested further 

histopathological examinations of 

mouse and rat tissue from previously 

conducted studies to further inform its 

decision. These exams showed no 

evidence to alter the prior findings, and 

on March 16, 1999, the Agency notified 

the 2,4-D Task Force that the EPA 

would continue to classify 2,4-D under 

Group D. (Ref. 17). 

Since the March 16, 1999 decision, 

the Agency has twice reviewed 

epidemiological studies linking cancer 

to 2,4-D exposure during the 

reregistration process of 2,4-D. In the 

first review, completed January 14, 

2004, EPA concluded there was no 

additional evidence that would 

implicate 2,4-D as a cause of cancer. 

(Ref. 14). The second review of available 

epidemiological studies occurred in 

response to comments received during 

development of the 2,4-D RED. EPA’s 

report, dated December 8, 2004, found 

that none of the more recent 

epidemiological and animal studies 

supported a conclusion that 2,4-D was 

a likely human carcinogen. (Ref. 15). 

Because the Agency determined that the 

existing data did not support a 

conclusion that links human cancer to 

2,4-D exposure, it decided not to initiate 

a Special Review of 2,4-D in 2007. (72 

FR 44510, August 8, 2007). 

A part of this cancer assessment was 

the review of data bearing on 2,4-D’s 

potential mutagenicity. EPA has 

consistently found that these data do 

not support classification of 2,4-D as a 

carcinogen. This view was concurred in 

by the Joint Committee of SAB/SAP. 

2. FFDCA tolerance reassessment and 

FIFRA pesticide reregistration. As 

required by the Food Quality Protection 

Act of 1996, EPA reassessed the safety 

of the 2,4-D tolerances under the safety 

standard established in the FQPA. In the 

June 2005 RED for 2,4-D, EPA evaluated 

the human health risks associated with 

all registered uses of 2,4-D and 

determined that there is a reasonable 

certainty that no harm will result from 

aggregate non-occupational exposure to 

the pesticide chemical residue. (Refs.18 

and 19). In making this determination, 

EPA considered dietary exposure from 

food and drinking water and all other 

non-occupational sources of pesticide 

exposure for which there is reliable 

information. The Agency concluded that 

with the adoption of the risk mitigation 

measures identified in the 2,4-D RED, 

all of the tolerances for 2,4-D meet the 

safety standard as set forth in section 

408(b)(2)(D) of the FFDCA. Therefore, 

the tolerances established for residues of 

2,4-D were considered reassessed as safe 

under section 408(q) of FFDCA. 

At the time of 2,4-D reregistration, 

there were no available studies on 2,4- 

D that adequately assessed its endocrine 

disruption potential, and the Agency 

determined that a repeat 2-generation 

reproduction study should be 

conducted to evaluate comparative 

thyroid effects in young and adult 

animals as well as the gonads and 

reproductive/developmental endpoints 

more thoroughly. The 2,4-D RED 

indicated that a new reproduction study 

using the revised 2-generation 

reproduction study protocol and 

measurement of additional parameters 

was needed to address these data gaps. 

EPA also required submission of a 

developmental neurotoxicity study. 

Although these data were needed, EPA 

concluded that the toxicology database 

was adequate for identification of doses 

and endpoints of concern for risk 

assessments. The values selected for risk 

assessments were protective of all 

observed adverse effects. Additionally, 

EPA retained the additional FQPA 10X 

safety factor for the protection of infants 

and children to address the uncertainty 

raised by the missing data. Finally, 2,4- 

D toxicity generally occurs at doses 

above renal saturation, i.e., doses above 

which the excretory processes could 

readily eliminate the chemical; the 

Agency’s risk assessment regulated at 

doses below this level. Consequently, 

the Agency had high confidence that the 

risk assessment did not underestimate 

risks from exposure to 2,4-D. 

On February 28, 2006, EPA issued a 

data call-in for 2,4-D that, among other 

things, required submission of the 

reproduction and developmental 

neurotoxicity studies mentioned above. 

In February 2010, in response to the 

data call-in, the Industry Task Force II 

on 2,4-D Research Data submitted a 

state-of-the-science extended onegeneration reproduction toxicity study 

to fulfill these requirements. The 2,4-D 

extended one-generation reproductive 

toxicity study included a detailed 

assessment of endocrine endpoints 

(thyroid, estrus cyclicity, sexual 

maturation (animals were observed for 

delays in vaginal opening and preputial 

separation), andrology, and ovarian 

staging), in addition to reproductive 

function, developmental neurotoxicity, 

and immunotoxicity endpoints. 

3. More recent actions. EPA has 

conducted a number of rulemakings 

with respect to 2,4-D tolerances since 

completion of tolerance reassessment. In 

July, 2005, EPA established new 2,4-D 

tolerances on hops, soybeans, and wild 

rice. (70 FR 43298, July 27, 2005). This 

action was based on the safety 

determination in the 2,4-D tolerance 

reassessment. No comments were 

received. In June 2007, EPA proposed 

numerous changes to the 2,4-D 

tolerances to implement determinations 

made in the 2,4-D tolerance 

reassessment (72 FR 31221). These 

proposed changes included 

modification of the chemical terms used 

in the tolerance expression, the 

amendment of various tolerance levels, 

and removal of certain tolerances. No 

comments relevant to 2,4-D tolerances 

were received and EPA finalized the 

tolerance actions on September 12, 2007 

(72 FR 52013). 2,4-D tolerances have 

been modified three times since 2007. In 

2008, minor changes were made to 

correct errors in the 2007 rulemaking. 

(73 FR 53732, September 17, 2008). 

NRDC commented on the proposal for 

these changes but did not raise any new 

information that had not been addressed 

in response to their comments on the 

RED. In 2009, EPA modified the 2,4-D 

tolerance for cranberries. No comments 

were received. (74 FR 48408, September 

23, 2009). In 2011, a tolerance for teff 

was established, for which EPA received 

no significant comments. (76 FR 55814, 

September 9, 2011). 

Additionally, in response to an 

application to amend the 2,4-D FIFRA 

registration, EPA, in 2011, re-examined 

the risks of 2,4-D. That re-examination 

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took into account the newly submitted 

extended one-generation reproduction 

toxicity study evaluating 2,4-D’s 

potential for causing endocrine, 

neurotoxic, or imumunotoxic effects. As 

part of that risk assessment, EPA reevaluated the decision to retain the 

FQPA safety factor. Because the FQPA 

safety factor had previously been 

retained due to the absence of data on 

endocrine and neurotoxic effects and 

those data requirements had been met, 

EPA determined that the 10X FQPA 

safety factor should be removed. (Refs. 

20 and 21). 

V. The Petition To Revoke Tolerances 

NRDC filed a petition dated 

November 6, 2008 (petition), requesting, 

among other things, that EPA revoke all 

2,4-D tolerances. (Ref. 1). In response to 

EPA’s publication of the petition 

pursuant to section 408(d) of the 

FFDCA, NRDC submitted a comment in 

support of its petition. (Ref. 22). The 

petition asserts that EPA’s conclusion 

outlined in the 2005 2,4-D RED, 

allowing 2,4-D to be reregistered and its 

tolerances retained, was based on 

incorrect information and assumptions 

related to the toxicity of 2,4-D and the 

amount of human exposure to the 

chemical. Specific to tolerances, the 

petition asserts that EPA failed to 

incorporate information on the 

endocrine disrupting effects of 2,4-D 

into its human health risk assessments; 

EPA disregarded data on neurotoxicity 

related to 2,4-D; EPA disregarded 

information showing that 2,4-D is 

mutagenic; EPA ignored data showing 

that dermal absorption of 2,4-D is 

enhanced by alcohol consumption, 

sunscreen, and DEET; and that EPA 

ignored the exposure of infants to 2,4- 

D via breast milk. Numerous studies are 

cited in the petition that NRDC says 

supports their assertions. EPA has 

reviewed all of the studies submitted by 

NRDC. NRDC also relies, in part, on 

portions of its comments submitted on 

the 2,4-D RED in support of its petition. 

(Ref. 1 at 11; Refs. 23 and 24). 

VI. Public Comment 

EPA published notice of the petition 

for comment on December 24, 2008 (73 

FR 79100). EPA received approximately 

500 comments on the petition. The vast 

majority of the comments were against 

the petition, and many discussed the 

importance of 2,4-D to various 

industries, including forestry, grains, 

landscaping, and minor use crops. (See 

e.g., Ref. 25). These issues, however, are 

irrelevant to the safety determination 

under FFDCA section 408. Two of the 

comments opposing the petition, from 

the Industry Task Force on 2,4-D 

Research Data II (Task Force), and 

National Council for Air and Stream 

Improvement (NCASI), provided 

detailed comments on the petition and 

on the studies cited in the petition. 

(Refs. 26 and 27). The Task Force and 

NCASI cited additional studies during 

the comment period for EPA to consider 

in its response to the petition. 

Twenty-three comments were in 

support of the petition and agreed with 

NRDC that 2,4-D’s tolerances should be 

revoked. Most of the comments that 

were in support of the petition assert in 

a general way that 2,4-D is ‘‘unsafe,’’ but 

provide little or no reasoning for this 

conclusion. Two of the comments in 

support of the petition, one from 

Beyond Pesticides and a combined 

comment from the New York State 

Department of Health and New York 

State Department of Environmental 

Conservation, identified additional 

studies for EPA consideration. (Refs. 28 

and 29). Additionally, the comment 

from Beyond Pesticides asserts that EPA 

ignored evidence that EPA endangers 

children by removing the FQPA 10X 

safety factor; and EPA has failed to 

perform a cumulative assessment for 

2,4-D and other phenoxy herbicides. 

Finally, NRDC submitted as a comment 

additional material in support of its 

petition. (Ref. 22). 

VII. Ruling on Petition 

This Order addresses NRDC’s petition 

to revoke 2,4-D tolerances. EPA has 

divided NRDC’s grounds for revocation 

into two main categories—toxicology 

and exposure—and addressed 

separately each claim under these 

categories. Each specific claim of NRDC 

is summarized in Unit VII immediately 

prior to EPA’s response to the claim. 

This Order also constitutes a response 

to the comments received during the 

public comment period on the petition 

as they relate to NRDC’s arguments for 

revoking tolerances. Below are the 

Agency’s responses to NRDC’s 

assertions and the related public 

comments. Detailed reviews of the 

studies cited by NRDC and commenters 

can be found in the docket. (Ref. 30). 

A. Toxicology 

NRDC has raised four toxicological 

issues regarding the safety of 2,4-D: 

Endocrine disruption, neurotoxicity, 

mutagenicity, and impacts on body 

weight. Each of these issues are 

addressed below. 

1. Endocrine Disruption—a. NRDC 

Claims. In support of their petition, 

NRDC cites several studies that it says, 

‘‘* * * establish the dangerous 

endocrine disrupting effects of 2,4-D 

and underscore the need for EPA to 

consider these impacts in its assessment 

of the health impacts of 2,4-D.’’ (Ref. 1 

at 2). NRDC asks EPA to incorporate 

information on the endocrine disrupting 

effects of 2,4-D into its human health 

risk assessments. (Id. at 2). 

Specifically, NRDC cites several 

studies, discussed below, that it 

contends show that 2,4-D is an 

endocrine disruptor. (Id. at 4–5). NRDC 

quotes a portion of the 2,4-D RED, 

which states: ‘‘Based on currently 

available toxicity data, there is evidence 

of the endocrine-disrupting effects of 

2,4-D on mammals. However, no 

specific measures of such effect have 

been attempted’’ and a statement that 

when the EDSP is underway, 2,4-D may 

be subject to additional screening or 

testing. (Id. at 5–6). NRDC argues that 

EPA has relied on the delay in 

conducting the EDSP to neglect 

analyzing the endocrine effects of 2,4-D 

despite the existence of ‘‘an entire 

category of existing scientific studies 

demonstrating adverse health effects.’’ 

(Id. at 6). It uses atrazine as an example 

of a case where EPA has considered 

endocrine disrupting effects in the 

absence of the formal screening 

program. The atrazine example, 

according to NRDC, shows that EPA 

cannot claim that the existing studies on 

endocrine disrupting effects cannot be 

considered in human health risk 

assessments. NRDC states that ‘‘EPA 

should have quantitatively incorporated 

these studies and these effects in its risk 

assessment of 2,4-D.’’ (Id.). 

b. Public comments. In its comments, 

Beyond Pesticides supports NRDC’s 

petition to cancel all 2,4-D product 

registrations due to the alleged wealth of 

relevant scientific information available 

that indicates that 2,4-D is a potential 

endocrine disruptor. (Ref. 28 at 3). 

Beyond Pesticides cites additional 

studies to those cited by NRDC. (Id. at 

3–4). 

The 2,4-D Task Force, in its 

comments, disputes NRDC’s claim that 

2,4-D is an endocrine disruptor. (Ref. 26 

at 11–18). Specifically, the Task Force 

argues that NRDC’s assertions that 2,4- 

D has been shown to be a potent 

endocrine disruptor are not supported 

by the weight of the evidence 

surrounding 2,4-D’s potential for 

endocrine disrupting effects. The Task 

Force disagrees with NRDC’s contention 

that EPA ignored endocrine disrupting 

effects given that the Agency issued a 

data call-in for a study that assesses 

thyroid, gonadal, reproductive and other 

endocrine-sensitive endpoints and 

while awaiting the study imposed an 

additional 10X uncertainty factor to 

account for the data gap. (Id. at 11–12). 

The Task Force provided detailed 

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comments on each of the studies cited 

by NRDC disputing NRDC’s 

conclusions. 

Additionally, National Council for Air 

and Stream Improvement (NCASI), in its 

comments, takes issue with NRDC’s 

characterization of various studies 

indicating that 2,4-D was an endocrine 

disruptor. (Ref. 27 at 2–3). NCASI 

indicates that studies cited by NRDC to 

support their claim for endocrine 

disruption concerns are not consistent 

with other studies of 2,4-D estrogenicity. 

(Id. at 3). 

c. EPA response. With regard to 

endocrine effects, NRDC argues that 

EPA should revoke the 2,4-D tolerances 

because EPA failed to properly assess 

2,4-D’s endocrine effects in the RED risk 

assessment. For example, NRDC 

contends that ‘‘[r]ecent studies [ ] 

establish the dangerous endocrine 

disrupting effects of 2,4-D and 

underscore the need for EPA to consider 

these impacts in its assessment of the 

health impacts of 2,4-D.’’ (Ref. 1 at 4). 

NRDC concludes this portion of its 

petition by asserting that ‘‘given the 

studies suggesting that 2,4-D has the 

potential to cause endocrine disrupting 

effects, EPA should have quantitatively 

incorporated these studies and these 

effects in its risk assessment of 2,4-D.’’ 

(Id. at 6). 

These claims by NRDC do not allege 

sufficient grounds for revocation of the 

2,4-D tolerances. The statutory standard 

for revocation of a pesticide tolerance is 

that the tolerance is not ‘‘safe.’’ 21 

U.S.C. 346a(b)(2)(A)(i). ‘‘Safe’’ is defined 

by the statute to mean that ‘‘there is a 

reasonable certainty that no harm will 

result from aggregate exposure to the 

pesticide chemical residue, including 

all anticipated dietary exposures and all 

other exposures for which there is 

reliable information.’’ 21 U.S.C. 

346a(b)(2)(A)(ii). As explained in Unit 

II.B., EPA has implemented this safety 

standard, consistent with the statute, by 

a quantitative risk assessment process 

that (1) identifies the harms or toxic 

effects caused by the pesticide, (2) 

ascertains the safe level of exposure as 

to those harms; and (3) determines 

whether aggregate exposure to the 

pesticide exceeds that safe level. Thus, 

safety 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), and the level of human 

exposure to the pesticide. 

The flaw in NRDC’s petition with 

regard to its endocrine claim is that it 

addresses only 2,4-D’s potential harm 

and not 2,4-D’s safety. 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. NRDC does 

not allege that quantitative 

incorporation of the studies it cites 

would alter EPA’s prior conclusion 

regarding the safe exposure level for 2,4- 

D. Yet, unless NRDC claims that the safe 

level of exposure should be lowered, it 

has no basis to argue that the toxicity 

data on endocrine effects it cites 

indicate a lack of safety. At best, NRDC 

is asking EPA to take a revised look at 

the toxicity of 2,4-D. Yet, the ground for 

tolerance revocation is a lack of safety. 

Accordingly, NRDC’s claim that the 2,4- 

D tolerance should be revoked due to 

2,4-D’s endocrine effects is denied due 

to a failure to make a proper claim for 

revocation by, at the very least, alleging 

facts that, if proven, would meet the 

statutory standard for revocation. 

Despite the inadequacy of petitioners’ 

endocrine claims, EPA has examined 

the evidence cited by petitioners in light 

of the most current toxicity data on 2,4- 

D for the purpose of evaluating whether 

the evidence raises sufficient grounds 

for concern that EPA should consider 

initiating action that might lead to 

revocation of the 2,4-D tolerances. 

To the extent data were available, 

EPA examined 2,4-D’s potential for 

endocrine disruption in the 2005 RED. 

However, as noted there, EPA was 

handicapped in this evaluation due to 

the fact that the otherwise acceptable 

two-generation rat reproduction study 

conducted with 2,4-D did not 

adequately address endocrine concerns. 

Although several toxicity studies 

required under 40 CFR part 158 involve 

an examination of organs or endpoints 

related to endocrine disruption, the rat 

reproduction study is the most critical 

of these required studies. In fact, the 

two-generation rat reproduction study, 

as described in the 1998 EPA guideline, 

has been designated as the study that 

will be used in Tier 2 of the EDSP for 

evaluating mammalian endocrine 

effects. As mentioned above, EPA issued 

a data call-in for a two-generation 

reproduction study in rats to address 

this data gap. In response to the data 

call-in, the Task Force submitted an 

extended one-generation reproductive 

toxicity study to fulfill this requirement. 

The 2,4-D extended one-generation 

study examined endocrine disruption as 

well as developmental neurotoxicity 

and developmental immunotoxicity. 

This extended one-generation 

reproductive toxicity study was 

conducted in accordance with OECD 

guidelines and is considered a state-ofthe-science study with regard to 

examining these toxicological and 

endocrine effects. 

As to endocrine effects, the extended 

one-generation reproduction study 

examined: Potential effects on parental 

male and female reproductive function, 

offspring survival and growth including 

endocrine and systemic toxicity 

parameters such as estrous cyclicity 

(female adult rats and offspring); sperm 

parameters; anogenital distance; nipple 

retention; puberty onset (vaginal 

opening and balano-preputial 

separation); adrenal weight, thyroid/ 

parathyroid gland weight, pituitary 

gland weight, testes and ovarian weight, 

thyroid hormone effects; and 

histopathology of a wide range of tissues 

including the thyroid, adrenal, pituitary, 

testes, and ovary. (Refs. 31 and 32). The 

endpoints examined in the extended 

one-generation reproduction study meet 

or exceed the specifications in the latest 

guideline (1998) for the two-generation 

reproduction study. (Ref. 33). 

Specifically, this extended onegeneration study included evaluation of 

sperm parameters and thyroid assays 

across various age groups, which are not 

part of the two-generation study. The 

main design difference between an 

extended one-generation study and a 

two-generation study is that the latter 

study is run for a full two generations 

no matter what results are seen in the 

first generation. On the other hand, an 

extended one-generation study is not 

continued into the second generation if 

triggers on the key endpoints do not 

indicate there is a potential concern. 

This design eliminates the needless 

destruction of animals, but does not 

reduce the scientific value of the data. 

The extended one-generation study 

for 2,4-D showed no treatment-related 

effects on potential estrogenic effects or 

androgen-sensitive endpoints (no 

adverse effects on anogenital distance, 

nipple retention, age at vaginal opening, 

estrous cycle length or pattern, mating, 

fertility, time to mating, gestation 

length, pre-implantation loss, number of 

corpora lutea, sperm parameters, 

ovarian follicle counts, and 

reproductive organ weights and 

histopathology; no evidence of 

hyposadias, ectopic tests, or treatmentrelated testicular prostate or seminal 

vesicle histopathology). Anti-androgenic 

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effects in terms of decreased male 

reproductive organ weights were 

observed in some animals but they were 

not statistically significant and were 

associated with decreased body weight. 

No treatment-related effects on 

reproductive organ histopathology were 

observed. Slight effects were seen in the 

thyroid (increases or decreases in 

thyroid weight and in T3, T4, and TSH 

hormones in some animals) but no dose 

response relationship was shown. These 

effects were more significant at the 

highest dose tested but still were 

considered adaptive and not adverse 

(i.e., the thyroid responded to insult and 

corrected itself) due to the fact that this 

dose exceeded the renal saturation level. 

Accordingly, the highest dose was 

considered a No Observed Adverse 

Effect Level (NOAEL) for thyroid effects. 

Overall, the effects observed at the 

lowest doses in the extended onegeneration reproductive study for both 

the parental rats and offspring were not 

based on endocrine-related endpoints 

but on nephrotoxicity manifested as 

increased kidney weights, and 

degenerative lesions in the proximal 

convoluted tubules in the main study in 

the first-generation adult rats (P1

generation; 45.3 mg/kg bw/day); kidney 

toxicity manifested as increased kidney 

weights and increased incidence of 

degeneration of the proximal 

convoluted tubules in the adult 

offspring (F1 adults; 55.6/46.7 (M/F) mg/ 

kg/day); and decreased body weight 

observed in the male pup offspring (F1, 

Set 1a males, PND 28–69; 76.6 mg/kg/ 

day) (see discussion in Unit VII.A.4.c.). 

The NOAEL for parents and offspring 

for these effects is approximately 20 mg/ 

kg/day, (Ref. 32), which is greater than 

the NOAEL of 5 mg/kg/day from a rat 

chronic toxicity study that was used as 

the POD in assessing chronic dietary, 

long-term dermal, and long-term 

inhalation in the human health risk 

assessment supporting the 2,4-D RED. 

(Ref. 18). In that chronic study, the 

effects seen at the LOAEL of 75 mg/kg/ 

day were decreased body-weight gain 

and food consumption, alteration in 

hematology and clinical chemistry 

parameters, decreased T4, glucose, 

cholesterol, and triglycerides. The use of 

the NOAEL from the chronic rat study 

as the POD in the RED risk assessment 

is protective of chronic effects identified 

in the extended one-generation study. 

The NOAEL found in the extended 

one-generation reproductive study is 

also similar to the NOAEL of 15 mg/kg/ 

day seen in a rat subchronic oral 

toxicity study and used to identify a 

POD for subchronic effects in the RED. 

(Ref. 18 at 22). The effects seen at the 

LOAEL of 100 mg/kg/day in the rat 

subchronic study were decreased body 

weight/body-weight gain, alterations in 

some hematology [decreased platelets 

(both sexes)] and clinical chemistry 

[decreased T3 (females) and T4 (both 

sexes)] parameters, and cataract 

formation. This study was used for the 

intermediate incidental oral and 

intermediate dermal and inhalation 

assessments. Again, the NOAEL in the 

extended one-generation study is greater 

than the NOAEL chosen as a POD for 

subchronic effects, and therefore, the 

RED assessment is protective of any 

subchronic effects identified in the 

extended one-generation study. 

As noted above, EPA concluded that 

this study showed no adverse effects on 

endocrine endpoints. Accordingly, the 

extended one-generation reproduction 

study’s comprehensive examination of 

2,4-D’s potential effect on the endocrine 

system provides no indication that EPA 

should consider initiating action to 

revoke 2,4-D tolerances. 

Nothing in the data cited by NRDC or 

other commenters contradicts this 

conclusion. For the most part, the data 

relied upon by NRDC address whether 

2,4-D is capable of interacting with the 

endocrine system. The studies do not 

provide quantitative information 

appropriate for use in risk assessment or 

the quantitative information they 

provide shows that EPA’s risk 

assessment is protective of endocrine 

effects. Many of the studies cited by 

NRDC were studies conducted to 

investigate 2,4-D’s mechanism of action 

and involved testing at a single high 

dose designed to ensure effects were 

seen. In rats, although 2,4-D is readily 

absorbed in the blood, it is not 

metabolized but removed from the 

blood by the kidneys and rapidly 

excreted through the urine. Once the 

dose of 2,4-D in rats exceeds about 50 

mg/kg/day, however, the kidney (renal) 

clearance mechanism is overwhelmed 

and 2,4-D builds up in the body 

resulting in toxic effects. The toxic 

effects seen at doses above the renal 

saturation level are generally not seen at 

lower doses. EPA has assessed the risk 

of 2,4-D based on the dose levels below 

the renal saturation level at which 

adverse effects occur. 

NRDC first cites a study in fish (Xie 

(2005)) that it contends shows that 2,4- 

D has ‘‘relatively potent estrogenic 

effects in fish.’’ (Ref. 1 at 4 and Ref. 34). 

As an initial matter, a study in fish 

would carry little weight regarding a 

safe tolerance level when compared to 

a study in mammals such as the 

extended one-generation reproduction 

study in rats. Additionally, EPA does 

not regard the Xie study as reliable due 

to a failure to identify the sex of the fish 

used. The study reported that 7-day 

exposure of rainbow trout juveniles to 

1.64 mg/L 2,4-D (active or formulated 

product undetermined) produced a 93- 

fold increase in plasma vitellogenin 

compared to untreated fish. This was a 

significant difference from the untreated 

control. Six fish were used per test 

concentration, and they were described 

as ‘‘juvenile rainbow trout (standard 

length: 11.5 ± 2.2 cm) provided by the 

California Department of Fish and Game 

Mojave River Hatchery (Victorville, 

California)’’ with no reference to their 

sex or specific age information. 

However, the sex of the fish is 

significant with regard to vitellogenin 

levels. Male fish generally maintain null 

or very low levels of vitellogenin in 

their natural state. In the presence of 

endocrine disruptors, male fish will 

have significant levels of vitellogenin in 

their blood. Female fish will have 

naturally increasing levels of 

vitellogenin as they approach maturity 

and maintain those levels upon 

maturation. Given the sample size and 

a failure to identify the sex of the fish, 

the results seen may be a result of 

unbalanced numbers of male and female 

fish in the control and treated groups. 

Several other difficulties with the Xie 

study, including the failure to identify 

a biologically significant effect on 

vitellogenin, are noted in the comments 

of the Task Force and NCASI. 

NRDC next relies on two studies 

(Rawlings (1998) and Charles (1996)), 

which it alleges show that 2,4-D causes 

hormone suppression in animals. (Refs. 

35 and 36). In the Rawlings study, 2,4- 

D treatment resulted in a significant (p 

<0.05) decrease in serum T4 

concentrations compared to control. No 

other significant effects were noted for 

serum cortisol, insulin, estradiol, LH 

pulse frequency (mean and amplitude), 

mean serum FSH, progesterone, or gross 

signs of toxicity or body weight change. 

In the absence of a quantifiable 

relationship between serum T4 

concentration and effects upon survival, 

growth, or reproduction, the results of 

this study do not evidence an adverse 

effect that could be incorporated 

directly into the Agency risk assessment 

process. The Charles study reports on a 

subchronic study in rats and was 

submitted to EPA and relied upon in the 

RED risk assessment. The study 

identified a NOAEL of 15 mg/kg/day 

and a LOAEL of 100 mg/kg/day. The 

effects seen at 100 mg/kg/day did 

include thyroid effects such as 

decreased thyroxine, increased thyroid 

weight, and hypertrophy of follicular 

cells. These effects were seen at a dose 

(100 mg/kg/day) that was well above the 

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renal saturation level and the NOAEL 

from the study was used to set the safe 

dose for subchronic exposures to 2,4-D 

and is protective of effects occurring at 

higher dose levels. (Ref. 18 at 36). 

NRDC also cites several studies (Liu 

(1996), Kim (2005), Kim (2002)) which 

it claims show that 2,4-D can result in 

effects on testicular cells and the 

prostate. (Refs. 37, 38, and 39). Liu is an 

in vitro study investigating possible 

mechanisms of action in relation to 

Leydig cell adenomas and peroxisome 

proliferation. 2,4-D was one of the 

peroxisome proliferators evaluated in 

the study. Kim (2005) also is an in vitro 

study investigating potential androgenic 

mechanisms. EPA could not evaluate 

the Kim (2002) study because it is 

written in Korean and not available to 

EPA in English. The Task Force argues 

that the 2002 study is irrelevant because 

it involved doses above the renal 

saturation level and thus the 2005 

study, which was designed to 

investigate the effects in the 2002 study, 

is of limited value given the high dosing 

in the 2002 study. Liu also appears to 

have shown statistically significant 

effects for 2,4-D on production of 

estradiol only at very high doses. In any 

event, EPA has adequate data in living 

animals regarding 2,4-D’s potential to 

affect testicular cells or the prostate. 

There is an adequate/guideline cancer 

study in rats that dosed at levels of 5, 

75, and 150 mg/kg/day (2-year study); 

there were no effects observed in the 

prostate, including no tumors. In fact, 

there was no increase in any tumor type 

in either the rat or mouse. (Ref. 19 at 

29). There are numerous studies in the 

rat of varying duration, and no effects 

on the prostate have been observed. In 

the studies available for the 2005 RED, 

effects on the testes and ovary were 

identified, hence the request for the 

two-generation rat reproduction study. 

The extended one-generation 

reproductive study is now available and 

it assessed the prostate. There were no 

effects on prostate weight and no 

histopathology findings in the prostate 

or other male accessory sex organs. 

Finally, NRDC argues that studies 

have shown that 2,4-D causes 

abnormalities in the estrus cycle 

(Duffard (1995)), lowers sperm counts 

and causes other sperm abnormalities 

(Lerda (1991)), and results in birth 

defects (Garry (1996)). (Refs. 40, 41, and 

42). NRDC has only cited an abstract of 

the Duffard study, which provides little 

information. It is clear, however, that 

the Duffard study used a single dose (70 

mg/kg/day) that was at or above the 

renal clearance level. Garry (1996) 

investigated the hypothesis that 

offspring of pesticide applicators might 

have increased risks of birth anomalies. 

Although the initial study found an 

apparent linkage between an area of 

high phenoxy use and birth anomalies, 

a more detailed cross-sectional analysis 

of this area showed no statistically 

significant correlations between 

phenoxy use and excess adverse birth or 

neurodevelopmental effects. (Ref. 43). 

Lerda (1991) reported an apparent link 

between exposures to 2,4-D in 32 male 

applicators and reproductive effects 

(spermatogenesis). However, these 

results have little weight for assessing 

2,4-D risk because Lerda (1991) did not 

describe the nature of applicators’ 

exposures in sufficient detail to show 

that 2,4-D was the causal agent and, if 

so, the level of that exposure. For 

example, Lerda (1991) lacked 

information on the timing/duration of 

exposure relative to sampling, the use of 

protective clothing/equipment, the 

possible presence of manufacturing 

contaminants given timeframe of study, 

and exposures to other pesticides. On 

the other hand, as noted above, the 

extended one-generation reproduction 

study assessed 2,4-D’s potential impact 

on the estrous cycle and sperm counts/ 

abnormalities, and no adverse effects 

were found in these parameters. 

Beyond Pesticides, in commenting on 

the petition, cited Garry (2001) and 

Malysheva (1997), in addition to studies 

referenced by NRDC, as supporting 

NRDC’s claim that 2,4-D is an endocrine 

disruptor. (Refs. 44 and 45). Garry 

(2001) indicated serum luteinizing 

hormone (LH) values were correlated 

with urinary 2,4-D levels in humans, but 

follicle-stimulating hormone and free 

and total testosterone were not. Garry 

(2001) also found 2,4-D levels were not 

correlated with chromosome aberration 

frequency in humans but that 

chromosome aberration frequencies 

were correlated with the total volume of 

herbicides applied, including products 

other than 2,4-D and the use of 

adjuvants. This study is of limited value 

because of the small sample size, as 

noted by the authors, and because it is 

not clear what other pesticides the 

individuals were exposed to and how 

specific components of adjuvant 

products in the pesticide may have 

impacted the findings. 

According to Beyond Pesticides, the 

Malysheva (1997) study found that the 

thyroid glands of laboratory rats were 

sensitive to 2,4-D as decreases in the 

thyroid gland transport and hormone 

production functions, and impairment 

of hormone iodination in the thyroid 

were observed after acute exposure. 

However, no information on the study 

was presented and the cited article is in 

Russian and no translation was 

available. Thyroid function was fully 

evaluated in the extended onegeneration reproduction study. As noted 

above, the extended one-generation 

reproduction study examined 2,4-D’s 

potential thyroid effects and established 

a NOAEL for such effects demonstrating 

that EPA’s prior risk assessment was 

protective. 

In sum, the data cited by NRDC, 

Beyond Pesticides, and NYDOH do not 

support changing the quantitative 

endpoints for assessing the risk posed 

by 2,4-D for potential endocrine effects 

given the equivocal results in the 

studies cited and/or the high doses 

involved in the studies. Further, the 

recently-completed extended onegeneration reproduction study that was 

specifically designed to evaluate such 

effects for the purpose of assessing 

human risks does not indicate that 

existing Points of Departure for 

assessing 2,4-D risks are under 

protective. Accordingly, EPA concludes 

that NRDC’s petition does not raise 

sufficient grounds for concern that EPA 

should consider initiating action that 

might lead to revocation of the 2,4-D 

tolerances. 

2. Neurotoxicity—a. NRDC Claims. 

NRDC asserts that ‘‘the neurotoxic and 

anti-thyroid effects of 2,4-D make it 

highly likely that fetuses, infants, and 

children will be more susceptible to 

long-term adverse health effects from 

exposure to this chemical.’’ (Ref. 1 at 7). 

It cites several studies that it claims 

provide evidence that postnatal 

exposures to 2,4-D during the critical 

period for development of the infant 

brain raise serious scientific concerns. 

The cited studies by the same group of 

authors report alterations on the 

neurotransmitters systems 

(catecholamine, indoleamine), marked 

depression in locomotor activity, and 

moderate circling towards the right side 

following exposure to 2,4-D via the diet, 

during gestation, and/or postnatally. 

NRDC also cites a study reporting 

decreased serotonin levels were found 

in various areas of the brain following 

direct injection of 2,4-D into the brain. 

Impairment of normal deposition of 

myelin in the developing brain was 

reported following exposure via the 

milk or direct subcutaneous exposure. 

Several studies were cited to show 

potential effects of 2,4-D on the brain of 

neonatal rats exposed lactationally. (Id.). 

b. Public comments. The New York 

State Department of Health (NYS DOH) 

submitted comments in support of the 

NRDC petition, stating that various 

toxicological findings associated with 

2,4-D in EPA’s RED document are weak. 

(Ref. 29 at 1). The RED, for example, 

identified specific adverse health effects 

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of concern, including developmental 

neurotoxicity and endocrine disruption, 

and required further studies from the 

registrants to evaluate these effects. NYS 

DOH identifies additional studies for 

the Agency to consider. (Id.). 

Beyond Pesticides, in its comments, 

argues that EPA has underestimated 2,4- 

D’s potential neurotoxic effects, and 

cites studies which it says show changes 

to maternal behavior in rats, along with 

increased catecholamine levels and a 

drastic decrease in indolamine levels. 

(Ref. 28 at 3). 

The 2,4-D Task Force submitted 

comments arguing that the studies cited 

by NRDC do not provide credible or 

substantive evidence that 2,4-D causes 

developmental neurotoxicity at 

exposure levels or routes of 

administration relevant to humans. (Ref. 

26 at 18–21). It notes that in response 

the reregistration data call-in issued for 

2,4-D, the 2,4-D Task Force agreed to 

conduct an extended one-generation 

reproduction study in rats of 2,4-D in 

the diet. The Task Force points out that 

this study would include assessment of 

developmental neurotoxicity endpoints, 

and states that at the time it was 

preparing comments, there were no 

dose-related statistically significant 

indications of developmental 

neurotoxicity related to 2,4-D exposures, 

even at dose levels demonstrated to be 

well above the renal clearance threshold 

in rat dams and pups. (Id. at 4). 

c. Agency response. NRDC requests 

revocation of 2,4-D tolerances because 

(1) ‘‘[t]he neurotoxic and anti-thyroid 

effects of 2,4-D make it highly likely that 

fetuses, infants, and children will be 

more susceptible to long-term adverse 

health effects from exposure to this 

chemical;’’ and (2) data cited in the 

petition ‘‘provide evidence that 

postnatal exposures to 2,4-D during the 

critical period for development of the 

infant brain raise serious scientific 

concerns.’’ (Ref. 1 at 7). However, such 

claims, as discussed in Unit VII.A.1.c., 

have the same flaw as NRDC’s 

endocrine arguments: The fact that the 

young are more susceptible to adverse 

effects of a pesticide or that data on a 

pesticide raise ‘‘serious scientific 

concerns’’ do not amount to a showing 

that aggregate exposure to the pesticide 

is unsafe, the standard for revoking 

tolerances. That the young may be more 

sensitive to a pesticide than adults may 

be irrelevant to the safety determination 

if both the young and adults have 

aggregate exposures below the safe dose. 

Similarly, that exposure to a pesticide in 

high dose testing may result in serious 

effects does not show that aggregate 

actual exposure to the pesticide, as 

opposed to exposure levels in laboratory 

testing, is unsafe. Again, NRDC has 

failed to address all the steps in the risk 

assessment process necessary to a safety 

determination. As with its endocrine 

claim, NRDC has done no more than 

allege 2,4-D has the potential to cause 

harm. Accordingly, NRDC’s claim that 

the 2,4-D tolerance should be revoked 

due to 2,4-D’s neurotoxic effects is 

denied due to a failure to allege facts 

sufficient to meet the statutory standard 

for revocation. 

Despite the inadequacy of petitioners’ 

neurotoxicity claims, EPA has examined 

the evidence cited by petitioners for the 

purpose of evaluating whether the 

evidence raises sufficient grounds for 

concern regarding 2,4-D that EPA 

should consider initiating action that 

might lead to revocation of the 2,4-D 

tolerances. 

In the 2005 RED, EPA identified 

neurotoxic effects in the acute and 

subchronic neurotoxicity studies as well 

as other studies. These effects included 

clinical signs (e.g., ataxia, tremors, 

decreased motor activity) as well as 

neuropathology (e.g., retinal 

degeneration); however, these effects 

were only seen at doses above the level 

of saturation of renal clearance. Given 

these neurotoxic effects, EPA issued a 

data call-in for a developmental 

neurotoxicity study and retained the 

FQPA safety factor for the protection of 

infants and children in the absence of 

that data. To address this data gap, the 

Task Force submitted an extended onegeneration reproduction study with a 

developmental neurotoxicity 

component. 

The extended one-generation 

reproductive toxicity study on 2,4-D 

assessed developmental neurotoxicity at 

three dose levels up to the saturation 

level for renal clearance. (Ref. 31). The 

potential for neurotoxic effects was 

assessed using numerous parameters. 

First, the study used a Functional 

Observation Battery (FOB) to evaluate 

whether there were clinical signs of 

neuorotoxicity. This FOB included cageside, hand-held, and open-field 

observations of behavior, and 

measurements of body weight, rectal 

temperature, grip performance, and 

landing foot splay. Second, the study 

used an automated system for 

measuring motor activity. Third, the 

study assessed the startle response to 

auditory stimuli. Finally, a 

neuropathological exam was conducted 

on the brain (including the cerebrum, 

thalamus/hypothalamus, cerebellum 

and medulla), spinal cord, dorsal root 

ganglia, dorsal and ventral roots, 

peripheral nerves, and skeletal muscle. 

The examination of the brain included 

assessment of brain weight and gross 

measurements, microscopic 

measurements (morphometrics), and 

brain myelin. There were no treatmentrelated adverse effects on any of the 

numerous parameters assessed across 

life stages, which included multiple 

neurotoxicity-related endpoints similar 

to those in the studies cited by NRDC 

(e.g., an assessment of motor activity, 

myelination, and maternal behavior). 

Thus, the extended one-generation 

reproduction study, in conjunction with 

all of the other data bearing on 

neurotoxicity, supports EPA’s risk 

assessment of 2,4-D and provides no 

indication that EPA should consider 

initiating action to revoke 2,4-D 

tolerances. 

The studies relied upon by NRDC in 

the portion of its petition addressing 

neurotoxicity do not suggest that EPA 

has not protected against potential 

neurotoxic effects of 2,4-D. Similar to its 

approach to endocrine effects, NRDC 

appears to take the position that the 

mere fact that 2,4-D could have a 

neurotoxic effect shows that it is unsafe. 

Consistent with this approach, NRDC, 

for the most part, relies on mechanism 

of action studies that involve a single, 

high dose as opposed to risk assessment 

studies designed to investigate a 

chemical’s dose response relationship 

across a wide range of doses. NRDC 

relies on the following 2,4-D studies: A 

study in fish showing adverse brain 

effects (Ton (2006)); a study in rats 

showing delays in brain development 

and abnormal behavior patterns 

(Evangelista (1995)); a study in rats 

showing neurotoxic effects on the basal 

ganglia in the brain (Bortolozzi (2001)); 

and three studies that appear to show 

impairment of normal deposition of 

myelin in the developing brain (Rosso 

(2000); Duffard (1996); Konjuh (2008)). 

(Refs. 46, 47, 48, 49, 50, and 51). Each 

of these studies, however, either involve 

testing at levels above the renal 

saturation dose or use routes of 

exposure or methodology inappropriate 

to human risk assessment or both. 

Ton (2006) was a research study 

investigating the use of zebrafish as a 

screening assay for identifying whether 

a chemical has the potential for 

neurotoxic effects and requires further 

testing in mammalian systems. For 2,4- 

D, appropriate testing in mammals is 

available, including a developmental 

neurotoxicity study in rats. Further, Ton 

only found potential neurotoxic effects 

at dose levels exceeding the dose 

concentration that is lethal to 50 percent 

for zebrafish (referred to as the LC50

(lethal concentration)). Other limitations 

in this study are outlined in the Task 

Force’s comments. (Ref. 26 at 18–19). 

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Evangelista (1995) used doses of 50 

and 100 mg/kg/day of 2,4-D. These 

doses meet or exceed the renal 

saturation level. Further compromising 

interpretation of this study is the fact 

that the identified neurotoxic effects 

were only detected when exposure to 

2,4-D was combined with doses of 

amphetamine. NRDC also inaccurately 

describes this study as involving young 

rats when, in fact, adult animals were 

tested. 

Bortolozzi (2001) investigated 

potential neurotoxic effects of 2,4-D by 

directly injecting 2,4-D into different 

brain areas of rats. Such a 

methodological approach is not useful 

for risk assessment because it does not 

correspond to the routes of exposure for 

humans to 2,4-D and, as noted, 

appropriate route of exposure studies 

are available for 2,4-D. Further, the Task 

Force described the doses in the study 

as being 40- to 100-fold greater than the 

concentration in the brain after systemic 

treatment. 

Rosso (2000), Duffard (1996), and 

Konjuh (2008) each involved testing at 

70 or 100 mg/kg/day. These doses 

exceed the renal saturation level. Other 

limitations in these studies are detailed 

in the Task Force’s comments. (Ref. 26 

at 20–21). 

Other studies cited by NRDC and 

Beyond Pesticides that address 

neurotoxicity have similar weaknesses. 

Ferri (2007), Garcia (2004), and Garcia 

(2008) used doses exceeding the renal 

saturation level. Sturtz (2008) found 

effects on maternal care but these effects 

were not duplicated in the extended 

one-generation reproduction study and 

the effects were not associated with any 

adverse effects in the pups. 

Studies cited by the New York State 

Department of Health in comments are 

similar to the NRDC studies in that they 

are studies investigating mechanism of 

toxicity and were conducted at doses 

exceeding the renal saturation level. 

In sum, EPA does not disagree with 

NRDC that 2,4-D, if administered at high 

enough doses, may result in neurotoxic 

effects in animals. However, the data 

regarding neurotoxicity relied upon by 

NRDC, or cited by commenters, does not 

indicate that the existing Points of 

Departure for evaluating 2,4-D risks are 

underprotective. Similarly, the extended 

one-generation reproduction study 

confirms the protectiveness of the 

existing Points of Departure as to 

neurotoxic effects. Accordingly, EPA 

concludes that NRDC’s petition does not 

raise sufficient grounds for concern that 

EPA should consider initiating action 

that might lead to revocation of the 2,4- 

D tolerances. 

3. Mutagenicity—a. NRDC claims. 

NRDC claims that in comments 

submitted to EPA on the 2004 human 

health risk assessment for 2,4-D risk 

assessment, it pointed out that EPA 

disregarded a number of studies that 

highlight the mutagenicity and 

genotoxicity of 2,4-D. (Ref. 1 at 7). 

NRDC states that at the time of the RED, 

EPA responded that it was under no 

obligation to consider these studies 

because ‘‘positive findings are always 

confined to samples of 2,4-D 

formulations and not the pure 

substance.’’ (Id. at 7). NRDC claims 

EPA’s response in 2005 was deficient 

first because nothing confines EPA only 

to consider studies that examine the 

pure substance (that is, the active 

ingredient). Second, recent studies 

involving just the active ingredient do 

indeed confirm the mutagenicity and 

cytotoxicity findings of the studies 

ignored by EPA. In light of these points, 

NRDC argues that EPA should not allow 

the continued use of 2,4-D. 

NRDC also cited four studies it claims 

confirm the mutagenicity and 

cytotoxicity of 2,4-D. (Id. at 8). Two of 

these were published since the EPA 

RED was finalized and two were 

published shortly beforehand but were 

not cited in the risk assessment. Three 

of these studies examined just the active 

ingredient 2,4-D, while the third used a 

commercial 2,4-D product containing a 

mixture of 2,4-D and various inert 

ingredients. NRDC states that these 

results must be considered in 

determining whether users of these 

products are being exposed to potential 

toxicity. 

NRDC also argues that apart from 

these new data, the discussion of the 

carcinogenicity and mutagenicity of 2,4- 

D that was provided by EPA in the 2004 

risk assessment was inadequate because 

EPA failed to acknowledge numerous 

additional positive genotoxicity studies 

in the peer-reviewed scientific literature 

that together indicate that 2,4-D 

formulations are likely to be cytotoxic 

and mutagenic. (Id. at 9). According to 

NRDC, research in the open scientific 

literature have reported oxidant effects 

of 2,4-D, indicating the potential for 

cytotoxicity or genotoxicity. NRDC 

argues that another finding that may 

provide a unifying explanation of some 

of the data on 2,4-D and lymphoma is 

that the herbicide may increase 

lymphocyte replication. (Id.) 

b. Public comments. The 2,4-D Task 

Force submitted comments stating that 

2,4-D is not mutagenic. (Ref. 26 at 4). 

The Task Force claims that for 

reregistration, 2,4-D acid, plus eight 

different 2,4-D derivatives have been 

tested in a battery of mutagenicity tests 

which are comprised of a total of 28 

studies. All of these studies were 

negative (non-mutagenic). (Id. at 22). 

While the Task Force acknowledges that 

some positive mutagenicity studies 

occur, it argues that the weight of the 

evidence overwhelmingly supports a 

conclusion of minimal or no concern for 

mammalian mutagenicity for 2,4-D. The 

Task Force notes that several inherent 

characteristics of 2,4-D suggest that 

there is a very low potential for it to 

cause mutagenic effects: The half-life of 

2,4-D in humans is less than 12 hours; 

2,4-D does not metabolize or transform; 

2,4-D is excreted unchanged; and it does 

not accumulate. (Id. at 23). 

Beyond Pesticides submitted 

comments to support the petition by 

NRDC requesting the cancellation of all 

2,4-D product registrations and the 

revocation of all tolerances, stating that 

the Agency underestimated 2,4-D’s 

mutagenic effects. (Ref. 28 at 1). Beyond 

Pesticides cites a study on plants which 

shows the induction and frequency of 

certain point mutations by 2,4-D (and 

dicamba), suggesting that these point 

mutations are important as they are 

frequently associated with various types 

of cancer. Beyond Pesticides also cites 

a study which they claim indicates 2,4- 

D is cytotoxic and induces apoptosis via 

direct effect on mitochondrial 

membranes. (Id. at 2–3). 

NCASI, in its comments, asserts that 

the overwhelming weight of evidence 

indicates that 2,4-D is neither mutagenic 

nor genotoxic. NCASI states that tests of 

mutagenicity and genotoxicity are 

important in this context as indicators 

of the potential for carcinogenicity. 

They point out that the International 

Commission for Protection Against 

Environmental Mutagens and 

Carcinogens, categorization of a 

chemical as genotoxic is not an a priori 

indication of a health hazard. They note 

that there is a large body of evidence 

and broad scientific consensus that 2,4- 

D is not a carcinogen. (Ref. 27 at 4) 

c. Agency response. NRDC’s petition 

argues that the 2,4-D tolerances should 

be revoked on several grounds related to 

mutagenicity. First, NRDC claims that 

EPA did not adequately address NRDC’s 

comments on the RED risk assessment 

regarding 2,4-D’s mutagenicity and that 

subsequent data confirm the accuracy of 

NRDC’s comments. NRDC argues that 

‘‘[i]n light of these points, EPA should 

not allow the continued use of 2,4-D.’’ 

(Ref. 1 at 7). Second, NRDC asserts that 

‘‘the discussion of the carcinogenicity 

and mutagenicity of 2,4-D that EPA does 

provide in the [RED] risk assessment is 

wholly inadequate.’’ (Id. at 8). NRDC 

argues that this inadequate discussion 

led to EPA ‘‘failing to assess fully the 

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23150 Federal Register / Vol. 77, No. 75 / Wednesday, April 18, 2012 / Rules and Regulations 

risk of cancer in humans from [2,4-D] 

exposure and failing to protect humans 

from this risk adequately.’’ (Id. at 10) 

These assertions do not, however, 

provide a sufficient basis for revoking 

the 2,4-D tolerances. The ground for 

seeking revocation of a tolerance is a 

showing that the pesticide is not ‘‘safe.’’ 

Claiming that EPA improperly 

conducted its reassessment of the 2,4-D 

tolerances by failing to consider certain 

data bearing on its decision on 

mutagenicity or carcinogenicity does 

not amount to a showing that the 

tolerance is unsafe. Neither is the 

allegation that 2,4-D is a mutagen or the 

derivative claim that EPA’s failure to 

adequately consider mutagenicity data 

results in its ‘‘failing to assess fully the 

risk of cancer’’ sufficient to show that 

the 2,4-D tolerances are unsafe. As 

explained in Unit VII.A.1.c., with regard 

to its endocrine and neurotoxic claims, 

to properly assert grounds for revocation 

of a tolerance, NRDC must allege facts 

showing that aggregate exposure to 2,4- 

D poses an unsafe mutagenic risk. That, 

it has not done. As to mutagenicity, 

NRDC merely alleges that 2,4-D can 

cause mutagenic harm. As to 

carcinogenicity, NRDC’s claims are even 

more amorphous. It argues that because 

EPA failed to consider 2,4-D’s alleged 

mutagenic effects, it thereby failed to 

‘‘assess fully,’’ and adequately protect 

against, 2,4-D’s cancer risks. As to 

neither mutagenicity nor cancer has 

NRDC addressed what the safe level of 

exposure to 2,4-D is for humans or 

alleged that the exposure levels of 

humans to 2,4-D exceed this safe level. 

Accordingly, NRDC’s claim that the 2,4- 

D tolerance should be revoked due to 

2,4-D’s mutagenic effects or its failure to 

assess 2,4-D’s cancer risk in light of 

these mutagenic effects are denied due 

to a failure to make a proper claim for 

revocation by, at the very least, alleging 

facts that, if proven, would meet the 

statutory standard for revocation. 

Despite the inadequacy of petitioners’ 

mutagenicity claims, EPA has examined 

the evidence cited by petitioners for the 

purpose of evaluating whether the 

evidence raises sufficient grounds for 

concern regarding 2,4-D that EPA 

should consider initiating action that 

might lead to revocation of the 2,4-D 

tolerances. 

EPA requires the submission of 

mutagenicity data on pesticides to 

assess a pesticide’s potential to cause 

heritable mutations that may contribute 

to cancer or other genetic diseases. 

(Refs. 52 and 53). Mutagenicity analysis 

has been directed primarily at 

investigating the mechanism of action 

with regard to toxic endpoints, 

particularly cancer. (Refs. 54 and 55). It 

should be noted that EPA’s data 

requirements on mutagenicity have 

evolved over the years. Whereas earlier 

data requirements identified a wide 

range of genotoxicity tests, EPA’s 

current testing requirements focus on 

tests for mutagenic effects, i.e., heritable 

changes in DNA that could potentially 

lead to disease. It is important to point 

out that genotoxicity assays include any 

kind of study that evaluates cellular 

functions involving gene damage, or 

interference with gene replication and 

repair. Mutagenic effects are a subset of 

genotoxic ones. The difference between 

the terms ‘‘genotoxicity’’ and 

‘‘mutagenicity’’ is that ‘‘genotoxicity 

pertains to all types of DNA damage 

(including mutagenicity), whereas 

mutagenicity pertains specifically to 

mutation induction at the gene and 

chromosome levels.’’ (Ref. 56). 

Importantly, ‘‘[w]hile genotoxic effects 

may be transient, mutagenic effects are 

persistent.’’ (Id.). So unlike mutagenic 

effects which are generally nonrepairable, and permanent, other 

genotoxic effects generally do not 

exhibit these same traits. Consequently, 

non-heritable genotoxic effects do not 

necessarily lead to adverse effects in a 

whole organism, and, for the same 

reason, are also not a reliable predictor 

of such effects. While genotoxicity data 

can help to inform an understanding of 

the adverse outcome pathway for a 

chemical, by themselves, EPA does not 

accord much weight in risk assessment 

to genotoxicity data that fail to show 

heritable effects. 

EPA’s current data regulations 

require, as to mutagenicity testing, a 

bacterial reverse mutation assay, an in 

vitro mammalian cell assay, and an in 

vivo cytogenetics test. 40 CFR 

158.500(d). The recommended study 

guidelines indicate a preference for tests 

directed at identifying not merely 

genotoxicity but mutagenic effects in 

terms of gene mutation or chromosomal 

aberrations. (40 CFR 158.500(d) (test 

notes 31 and 32); (Refs. 57, 58, 59, 60, 

and 61). Omitted from the data 

regulations is the former requirement 

pertaining to ‘‘other genotoxic effects 

* * * [such as] numerical chromosome 

aberrations, direct DNA damage and 

repair, mammalian cells transformation, 

target organ/cell analysis.’’ 40 CFR 

158.340(a) and (b)(22) (2007). The 

bacterial reverse mutation assay 

(commonly known as the Ames test) is 

designed to detect point mutations in 

genetic material. As the guideline 

indicates: ‘‘Point mutations are the 

cause of many human genetic diseases 

and there is substantial evidence that 

point mutations in oncogenes and 

tumour suppressor genes of somatic 

cells are involved in tumour formation 

in humans and experimental animals.’’ 

(Ref. 57). For the in vitro mammalian 

cell assay, the guidelines recommend 

either individual assays directed at 

detecting gene mutations, (Ref. 58), or 

structural chromosome aberrations, or 

both endpoints in a single assay. (Ref. 

59). For an in vivo cytogenetics test, the 

regulations recommend either an assay 

for the detection of structural 

chromosome aberrations in bone 

marrow cells of animals, usually 

rodents, (Ref. 60), or an assay for the 

detection of cytogenetic damage which 

results in the formation of micronuclei 

containing lagging chromosome 

fragments or whole chromosomes. (Ref. 

61). Between the in vitro and in vivo 

tests, the latter carry the greater weight 

in assessing mutagenic potential 

because in vitro tests do not capture 

how a living body responds to a toxic 

insult, including its ability to detoxify 

putative mutagens and genotoxicants. 

(Ref. 54 at 2–34; and Ref. 62). 

EPA has a large body of mutagenicity 

and genotoxicity data for 2,4-D. Those 

data show little to no concern for 

heritable mutagenic effects in mammals 

but some evidence supporting 2,4-D’s 

potential to cause genotoxic effects. 

More specifically, these data show: (1) 

That 2,4-D is negative in bacterial 

mutation assays; (2) some positive 

results for mutagenicity in assays in 

yeast, plants, and insects; (3) negative 

results for mutagenicity in in vivo 

studies in animals; and (4) mixed results 

for mutagenic and genotoxic results in 

in vitro tests in mammalian cells. EPA 

summarized the results in the last 

formal cancer assessment for 2,4-D in 

1997 as follows: 

The mutagenic potential of 2,4-D has been 

extensively evaluated in a range of in vivo 

and in vitro assays that have included tests 

with human cells. Ames tests, with and 

without metabolic activation, were 

consistently negative. Negative results were 

also seen in a mouse bone marrow 

micronucleus and UDS assays in rat 

hepatocytes. Conflicting results were 

obtained in Drosophila; positive effects were 

seen in larvae, while negative results were 

seen in adults after feeding or injection. 

Conflicting results were also seen in in vitro 

mammalian cell cytogenetics assays; 2,4-D 

was negative for structural chromosomal 

damage up to an insoluble level but positive 

in the presence of metabolic activation at 

high doses. The positive evidence, however, 

tends to be weak and generally not supported 

by the data from in vivo cytogenetic assays. 

2,4-D also was nonactive in mammalian cell 

DNA repair assays. Overall, the pattern of 

responses observed in both in vivo and in 

vitro tests indicated that 2,4-D was not 

mutagenic (although some cytogenetic effects 

were seen). 

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(Ref. 16 at 17). 

Mutagenicity was considered as part 

of the weight of the evidence 

determination on cancer. EPA 

concluded that 2,4-D should be 

classified under Category D— 

Unclassifiable as to Human 

Carcinogenicity. This determination was 

based primarily on the finding that in 

the two most recent rodent studies there 

were no compound-related statistically 

significant increases in tumors in either 

rats or mice and the conclusion that 

epidemiology data failed to show a 

cause-and-effect relationship between 

2,4-D exposure and cancer. The weak 

evidence on genotoxicity was not 

sufficient to outweigh the absence of 

positive findings on tumor development 

in rodent carcinogenicity studies or 

epidemiology studies. Similar 

conclusions on mutagenic (and 

carcinogenic) potential of 2,4-D have 

been reached by independent science 

review panels. In 1994, a joint 

committee of EPA’s SAB and SAP 

concluded that: 

The conflicting cytogenetic results do not 

provide evidence for genotoxicity of 2,4-D. 

Studies with positive results have significant 

experimental deficiencies as noted above, 

thus limiting the value of these studies for 

assessing genotoxicity. Therefore, although 

there are serious data deficiencies, the 

currently available evidence suggests that 

2,4-D is non-genotoxic. The lack of 

genotoxicity may reduce the concern for 

potential carcinogenicity of 2,4-D, but it is 

recognized that not all carcinogens are 

necessarily genotoxic. 

(Ref. 15 at 19) (See Refs. 13 and 14 

(earlier meeting of the FIFRA SAP 

disagreeing with EPA’s conclusion that 

there was limited evidence supporting a 

carcinogenic designation for 2,4-D and 

instead concluding that 2,4-D should be 

classified no higher than Category D 

because evidence was only equivocal)). 

Since the 1997 EPA cancer 

assessment, the 2,4-D registrant has 

submitted a series of mutagenicity tests 

with 2,4-D and its various metabolites. 

The tests included bacteria mutation 

assays, and in vitro mammalian assays 

investigating gene mutation and 

chromosomal aberrations. These tests 

were uniformly negative. Further, in its 

comments on the petition, the Task 

Force offers a plausible hypothesis for 

the predominantly negative findings for 

2,4-D in mutagenicity testing. The Task 

Force notes that 2,4-D does not 

metabolize or transform in the body and 

is rapidly excreted in an unchanged 

form. This lack of reactivity supports a 

conclusion of low mutagenic potential. 

NRDC in its petition has cited a 

number of positive mutagenicity and 

genotoxicity studies. Taken together, 

these studies do not have a significant 

effect on the balance of the weight of 

evidence on mutagenicity and 

genotoxicity as summarized by EPA in 

its last cancer assessment. 

Studies cited by NRDC and Beyond 

Pesticides do not significantly add to 

the weight of evidence supporting a 

mutagenicity conclusion for several 

reasons. First, NRDC only referenced 

one in vivo study (Madrigal-Bujaidar 

(2001)) and that study only looked at a 

genotoxic, as opposed to a mutagenic, 

endpoint (sister chromatid exchange). 

(Ref. 63). Further diminishing the 

weight of this study is the fact that the 

authors described it as only showing 

‘‘weak positive results,’’ and concluded 

that given the ‘‘moderate genotoxic 

effect produced by 2,4-D, * * * the 

hazard for the general population 

appears to be small.’’ (Id.). Second, 

many of the studies cited by NRDC 

looked only at DNA damage (sister 

chromatid exchange), (Refs. 64 and 65), 

not mutagenic effects, and at least two 

of these studies showed marginal 

positive results at best (Arias (2003, 

2007)). (Refs. 66 and 67). Although two 

studies cited by NRDC did show a 

mutagenic (chromosomal aberration) 

response in an in vitro mammalian cell 

assay, (Zeljezic (2004); Venkov (2000)), 

two other in vitro studies were either 

negative (Figg (2000) (authors conclude 

findings do not support a ‘‘genotoxic 

pathway’’) or marginal (Holland (2002)). 

(Refs. 68, 69, 70, 71, and 72). As noted 

above, conflicting results in in vitro 

testing for 2,4-D was previously 

recognized by EPA. Other tests (Tuschl 

(2003); Bukowska (2003)) showed 

cytotoxicity but studies on cytotoxicity 

alone do not provide evidence of 

genotoxicity. (Refs. 73 and 74). Finally, 

NRDC and Beyond Pesticides cited 

studies confirming EPA’s earlier 

conclusion regarding positive mutagenic 

effects in yeast and insects (Venkov 

(2000); Tripathy 1993). (Refs. 75 and 

76). Such studies are entitled to less 

weight compared to mammalian studies, 

particularly in vivo mammalian studies. 

Finally, NRDC’s arguments regarding 

the reported oxidant effects of 2,4-D do 

not change the weight of evidence as to 

2,4-D’s cancer classification because the 

primary evidence on cancer—rodent 

carcinogenicity studies and human 

epidemiology data—do not support a 

positive cancer finding. 

Accordingly, EPA concludes that 

NRDC’s claim concerning mutagenicity 

does not raise sufficient grounds for 

concern that EPA should consider 

initiating action that might lead to 

revocation of the 2,4-D tolerances. 

4. Body weight. a. NRDC claim. In a 

section of its petition addressing 

exposure to 2,4-D through maternal 

milk, NRDC argues that EPA chose an 

incorrect POD for addressing short-term 

oral exposure and should ‘‘redo the 

short-term oral risk assessment * * *.’’ 

(Ref. 1 at 11). NRDC cites a study 

conducted in rats by Sturtz (2006) 

which identified 15 mg/kg/day as a 

LOAEL based on ‘‘adverse effects on 

breastmilk composition and on 

bodyweight in offspring * * *.’’ (Id.; 

Ref. 77) NRDC contrasts this value with 

the 25 mg/kg/day NOAEL that EPA used 

as the POD in assessing short-term oral 

risk. 

b. Public comments. The Task Force 

responded that the results in the Sturtz 

(2006) study were not replicated in a 

recent study performed under Good 

Laboratory Practice conditions. (Ref. 26 

at 27 and Ref. 78). In this study, 

according to the Task Force, 2,4-D 

significantly decreased pup body 

weights at dose levels above the renal 

saturation level but not at lower levels. 

c. Agency response. NRDC’s request 

on pup body weight is for EPA to 

‘‘redo’’ the short-term oral risk 

assessment using a lower POD based on 

a LOAEL rather than a NOAEL. 

Although this argument, like NRDC’s 

other claims as to 2,4-D toxicity, appears 

to state an insufficient basis, on its face, 

for revoking the 2,4-D tolerances, EPA 

concludes that it is qualitatively 

different than NRDC’s claims regarding 

endocrine disruption, neurotoxicity, 

and mutagenicity. Those claims did not 

address the statutory standard for 

revocation. Although not clearly 

articulated by NRDC, EPA can piece 

together a sufficient allegation 

supporting revocation with regard to 

NRDC’s body weight claim: Namely, 

that, if EPA recalculated 2,4-D shortterm risk using a revised POD of a 

LOAEL of 15 mg/kg/day, it would find 

that short-term aggregate exposure to 

2,4-D exceeds the safe level. 

Nonetheless, while EPA has 

interpreted NRDC’s allegation on body 

weight as a legally sufficient ground for 

revocation, EPA denies NRDC’s claim 

on body weight because the cited 

evidence does not support NRDC’s 

allegation. EPA disagrees with NRDC’s 

allegation that EPA has misidentified 

the POD for adverse effects on pup body 

weight. The recent extended onegeneration rat reproduction study 

comprehensively evaluated effects on 

pup body weights from pre- and postnatal exposures to 2,4-D. (Refs. 31). In 

this study, intended doses were: 5 mg/ 

kg/day for the low dose; 15 mg/kg/day 

for a mid dose; and 40 mg/kg/day for 

males and 30 mg/kg/day for females for 

a high dose. Actual calculated doses in 

post-natal pups following weaning (PND 

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23152 Federal Register / Vol. 77, No. 75 / Wednesday, April 18, 2012 / Rules and Regulations 

2The study does not make clear whether it was 

reporting decrements in body weight gain (the 

amount of weight gained between designated time 

periods) or absolute body weight. Body weight is 

generally regarded as the more important measure 

because decrements in body weight gain, which is 

a calculated value and may be misleading, may 

occur even though the pup is otherwise within 

normal body weight levels. 

21) were considerably higher with four 

of the five subsets within the study (Sets 

1a, 1b, 2a, and 2b) receiving almost 

double the intended dose for the postlactation period. Actual doses can differ 

from intended doses when experimental 

animals consume different amounts of 

food than projected. Body weights were 

tracked for all pups in the study from 

PNDs 1–21. There were between 24 and 

28 litters per dose group with roughly 

10 pups per litter which translates to 

roughly 250 pups per dose group. 

Looking across all pups in the study, no 

statistically significant body weight 

decreases were seen for males or 

females at any dose level for PND 1–21. 

A smaller subset of pups (Set 1a—20 

pups per dose), was specifically 

examined as to general toxicity effects 

including body weight effects. In that 

subset, statistically significant effects 

were seen in the high dose group for 

males generally between PNDs 28 and 

69. No statistically significant body 

weight effects were seen in males at the 

low or mid doses or at the high dose 

prior to PND 28. No statistically 

significant body weight effects were 

seen in females at any dose on any day. 

Other subsets (Sets 1b, 2a, 2b, and 3) for 

which dosing continued past at least 

PND 55 showed no statistically 

significant decrease in body weight at 

the conclusion of the study. Similar 

results were found in an earlier twogeneration study with 2,4-D. (Refs. 79 

and 80). In that study, the intended 

doses were: 5 mg/kg/day for the low 

dose; 20 mg/kg/day for a mid dose; and 

80 mg/kg/day for a high dose. Actual 

calculated doses in post-natal pups after 

weaning were 7–14 mg/kg/day, 26–48 

mg/kg/day, and 76–133 mg/kg/day. 

Body weight effects were seen at the 

mid-dose at PND 28 and at the high 

dose. No effects on body weight were 

observed prior to weaning at the middose. Additionally, in the range-finding 

study for the extend one-generation 

reproduction study, similar effects 

regarding pup body weight were seen— 

namely, statistically significant body 

weight decrements were only observed 

at the high dose ((1,000 ppm) 123 mg/ 

kg/day for males (calculated on PND 35) 

and (800 ppm) 121 mg/kg/day for 

females (calculated on PND 35)). (Ref. 

78). 

The Sturtz (2006) study reports 

decreases in body weight gain or 

absolute body weight at doses as low as 

15 mg/kg/day on PNDs 6 through 16.2

These results are not consistent with the 

prior two-generation reproduction study 

and were not replicated by either the 

range-finding study for the extended 

one-generation reproduction study or 

the one-generation study itself. 

Moreover, there are several reasons to 

give the Sturtz (2006) study less weight 

than the results of the other three 

studies. First, the extended onegeneration and two-generation study 

were conducted under EPA’s Good 

Laboratory Practice Standards 

regulations, see 40 CFR part 160, and all 

underlying data for these studies are 

available for review. Further, the 

extended one-generation study is 

considered state-of-the-science because 

it considered the toxicokinetic profile of 

2,4-D as it makes its way from the 

mother to the offspring, as well as a 

variety of other endpoints that are 

considered more sensitive than body 

weight (e.g., hormones, hematology, 

clinical chemistry, etc). The 

toxicokinetic aspect is particularly 

important because, based on the 

toxicokinetic profile, the doses in the 

extended one-generation reproduction 

study were adjusted during the 

lactational period to prevent excessive 

dosing both to the maternal rat and to 

the pups during early lactation and due 

to a ‘‘double exposure’’ when pups are 

both nursing and starting to consume 

diet (as in the case on PND 16). 

Adjustments to the diet were also 

performed in the Sturtz study, although 

the procedures used were different and 

may, to some extent, explain the results 

in the Sturtz study compared to the 

extended one-generation reproduction 

study. Second, the Sturtz (2006) study 

does not show a clear dose response 

effect. Although there is a greater effect 

on body weight comparing the lowest 

and highest doses, the body weight 

effects are essentially the same in the 

lowest two doses despite significant 

differences in the doses and that same 

phenomena is seen with regard to the 

highest two doses. Third, the extended 

one-generation reproduction study 

examined a much larger sample of pups. 

Roughly four times as many pups were 

evaluated in the extended onegeneration reproduction study from 

PNDs 1–21 compared to the Sturtz 

study, and the Sturtz study evaluated no 

pups after PND 16. Finally, NRDC infers 

that the Sturtz study identified an 

‘‘adverse effect’’ on the composition of 

maternal milk. However, changes in the 

composition in maternal milk may 

provide an explanation for effects seen 

in the pups but do not constitute an 

adverse effect independent of effects in 

the pups. 

Thus, to the extent NRDC’s petition 

argues that the Sturtz study showed the 

2,4-D tolerances to be unsafe, that claim 

is denied. 

B. Exposure 

1. Aggregate exposures and risk— 

residential use—a. NRDC claims. In its 

petition, NRDC restates its comments 

submitted in 2002 and 2004 concerning 

the Agency’s aggregate assessment (Ref. 

1 at 11). In its comments submitted in 

2002 and 2004, NRDC claims that EPA 

failed to conduct adequate aggregate risk 

assessment due to outstanding data gaps 

and missing information, and that EPA 

did not consider exposure through drift, 

migration of contaminated soil, or 

residential track-in exposures. (Refs. 23 

and 24). In its comments, NRDC cites 

two studies (Nishioka (1996 and 2001)) 

in support of these comments that 

pertain to track-in exposures. (Refs. 81 

and 82). 

b. Public comments. There were no 

public comments received on this issue. 

c. Agency response. In addition to the 

generalized claims regarding inadequate 

assessment of aggregate exposure in the 

RED risk assessment, NRDC does 

specifically allege that ‘‘[t]he use of 2,4- 

D in and around the home could itself 

exceed appropriate risk levels if 

properly calculated.’’ (Ref. 24 at 28). If 

the evidence adduced by NRDC 

substantiates this point—the Nishioka 

studies (1996 and 2001)—this claim 

would be sufficient grounds for 

revocation of 2,4-D tolerances. 

In response to NRDC’s claims 

regarding the level of 2,4-D exposure 

from residential use, the Agency 

reviewed both Nishioka studies (1996 

and 2001) to ascertain if the risk 

assessment completed for 2,4-D was 

protective. (Ref. 83 at 13). 

Residential exposure to 2,4-D results 

from its use on turf in residential 

environments. In the RED risk 

assessment this use pattern was 

evaluated using a screening level 

methodology that considers direct 

contact by toddlers with treated turf. 

Toddlers are considered the most highly 

exposed group in the population to turf 

uses because their behavior patterns 

(e.g., playing on turf, mouthing of hands 

and other objects) lead to both increased 

dermal and non-dietary ingestion 

exposures. The screening methodology 

assumes that these behaviors co-occur 

and also aggregates exposures from the 

pesticide in food and water. For 2,4-D, 

this screening methodology did not 

indicate a risk of concern even taking 

into account that the RED risk 

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3 In 2011, EPA removed the FQPA safety factor 

because the data gaps were filled by submission of 

the extended one-generation rat reproduction study. 

assessment retained the full 10X FQPA 

safety factor due to missing data on preand post-natal toxicity.3

Dusts are thought by some to possibly 

contribute more than negligible levels to 

potential exposures in indoor 

environments but a methodology has 

not been developed which definitively 

establishes a link between levels in dust 

with a clearly defined exposure 

pathway. This construct was discussed 

extensively at a 2009 meeting of the 

FIFRA SAP related to the revisions of 

the EPA’s Standard Operating 

Procedures for Residential Exposure 

Assessment. (Ref. 84). The conclusions 

of that panel were that insufficient 

information is currently available to 

definitively link residues in dusts to 

specific exposure pathways. 

Nonetheless, to examine whether 2,4-D 

contamination of indoor dust might 

significantly alter the RED risk 

assessment, EPA considered how the 

indoor residue values in the Nishioka 

studies would affect the risk assessment. 

EPA assumed for screening purposes 

that toddlers consume 100 mg/day of 

dust containing the highest 2,4-D 

concentration found in Nishioka studies 

(67 micrograms/gram (mg/g)). The 2,4-D 

levels in dust in the Nishioka studies 

were generally much lower than 67 mg/ 

g (e.g., 1996 maximum is 4.85 mg/g, and 

2001 median is 10 mg/g). The value of 

100 mg/day for dust consumption is 

drawn from the EPA’s Child Specific 

Exposure Factors Handbook (Ref. 85), 

and is the same value assumed for soil 

consumption. This value was also used 

in the Nishioka studies. Additional 

conservatisms in this screening 

assessment are the assumptions that (1) 

exposures from dust residues are 

assumed despite the uncertainties noted 

in the 2009 FIFRA SAP Report; and (2) 

2,4-D residues do not decline over time 

even though 2,4-D is known to dissipate 

quickly. (Ref. 84 at 26 and Ref. 86). 

Based on these assumptions, margins of 

exposure range from approximately 

32,000 to 150,000 depending upon 

whether the duration of exposure 

considered is acute-, short- or 

intermediate-term. (Ref. 30 at 66). As 

such, use of this highest dust 

concentration value would not impact 

the findings of the current risk 

assessment. If it is further assumed that 

dusts persist in impacted residences in 

such a way that ingestion of the highest 

concentration would occur in a chronic 

exposure pattern and that the highest 

noted concentration in dust would 

never dissipate, which is counterintuitive given how 2,4-D is used and its 

known rapid dissipation characteristics, 

risks are still not of concern. In such 

situations, dust would be the 

predominant source for chronic 

exposures but margins of exposure still 

would exceed 11,000 based on the 

chronic dietary POD (5 mg/kg/day). 

(Ref. 30 at 66). It should also be noted 

that Nishioka (1996) indicated that such 

exposures could be chronic in nature 

after a single application of 2,4-D, but 

this is viewed by EPA as unlikely due 

to a lack of empirical information to 

support such a supposition. Nishioka 

(1996) projected that 2,4-D would be 

found in residential carpet dust up to 1 

year later based on short-term track-in 

sampling. However, the value estimated 

by Nishioka (0.5 mg/g) is two orders of 

magnitude less than the value used in 

the extremely conservative assessments 

described above. Given that these 

unrealistic and high-end assumptions 

yield MOEs greater than 10,000, EPA 

concludes that the cited data do not 

support NRDC’s allegation that ‘‘[t]he 

use of 2,4-D in and around the home 

could itself exceed appropriate risk 

levels if properly calculated.’’ To the 

contrary, even assessing exposure using 

unrealistic, high-end values for 2,4-D, 

levels in dust indicates that residential 

dust exposures to 2,4-D are a relatively 

minor exposure. NRDC’s claim 

regarding track-in exposures is denied. 

Finally, it should be noted that the 

Agency is currently in the process of 

evaluating the state of the science 

related to the exposure pathways from 

indoor dust as illustrated by the SAP 

review of residential methods and an 

additional review related to exposures 

from volatilization. Additionally, EPA is 

developing more definitive methods 

focused on addressing and 

characterizing potential exposures from 

chemical trespass. These efforts were 

recently described in a 2011 meeting of 

the Pesticide Program Dialogue 

Committee. (Ref. 87). Once final, any 

potential modifications to methods 

impacting residential risk assessment 

will be accounted for in the upcoming 

registration review process for 2,4-D. 

2. Exposure through maternal milk— 

a. NRDC claims. NRDC asserts that EPA 

failed to include any lactational 

exposure in its aggregate risk 

assessment, although it was aware of 

research demonstrating the potential 

exposure to 2,4-D from maternal milk. 

(Ref. 1 at 11). NRDC cites several studies 

involving lactational exposure to show 

potential effects of 2,4-D on the brain of 

neonatal rats exposed lactationally. (Id.). 

The cited studies provide an assessment 

of the levels of 2,4-D attained in the 

milk of the dams and in the plasma and 

brain of the pups. NRDC also cites 

studies that it claims ‘‘confirm the 

lactational exposure and identify 

adverse effects in the offspring.’’ (Id.) 

b. Public comments. In its comments, 

the Industry Task Force disputes 

NRDC’s allegation that EPA failed to 

address 2,4-D exposure from maternal 

milk. (Ref. 26 at 24–27). The Task Force 

comments that EPA was aware, when 

conducting the aggregate risk 

assessment, that 2,4-D may be present in 

maternal milk because of the results of 

animal feeding studies using 

exaggerated doses of 2,4-D. Further, the 

Task Force argues that NRDC’s claim 

that EPA failed to include any 

lactational exposure in its aggregate risk 

assessment is not correct. According to 

the Task Force, the Agency used half the 

limit of detection (LOD) for milk value 

in its 2005 risk assessment because no 

detectable residues were found in milk 

samples over several years of Pesticide 

Data Program (PDP) monitoring. Thus, 

the Task Force asserts that EPA assumed 

that 2,4-D would be present in milk at 

0.004 ppm for both acute and chronic 

exposure (despite it being nondetectable in PDP sampling). (Id. at 26). 

The Task Force states that large doses 

of 2,4-D administered in the Sturtz et al 

(2000) study cited by NRDC render the 

study uninformative for human health 

risk assessment. (Id. at 24). The Task 

Force cites biomonitoring data from 

farm families to support its contention 

that EPA’s exposure estimates are 

reasonable. (Id. at 25). 

c. EPA’s response. Initially, EPA 

would note that the studies NRDC cited 

to support its claim that 2,4-D exposure 

through maternal milk causes adverse 

effects were considered together with 

other studies cited by NRDC pertaining 

to toxicity issues. See Unit VII.A. above. 

With regard to human exposure to 

2,4-D through maternal milk, NRDC 

alleges that such exposure occurs and 

was ignored by EPA despite the fact that 

it could result in ‘‘potentially significant 

exposures.’’ As discussed in Unit 

VII.A.1.c., this ground for objection is 

denied because (1) the standard for 

revocation is that the tolerance is unsafe 

not that there are ‘‘potentially 

significant exposures’’ that should be 

included in an aggregate assessment; 

and (2) NRDC presents no evidence to 

support its assertion that potentially 

significant exposures were excluded 

from EPA’s risk assessment. 

Accordingly, NRDC’s claim that the 2,4- 

D tolerance should be revoked due to 

exposure to 2,4-D in human breast milk 

is denied due to a failure to allege facts 

sufficient to meet the statutory standard 

for revocation and a failure to support 

the allegations that are made. 

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Despite the inadequacy of petitioners’ 

claim regarding 2,4-D exposure in 

human breast milk, EPA has examined 

the evidence cited by petitioners for the 

purpose of evaluating whether the 

evidence raises sufficient grounds for 

concern regarding 2,4-D that EPA 

should consider initiating action that 

might lead to revocation of the 2,4-D 

tolerances. 

NRDC is incorrect in asserting that 

EPA assumed that humans are not 

exposed to 2,4-D through maternal milk. 

To the contrary, EPA assumed, in its 

RED risk assessment, that all milk— 

whether animal or human—contained 

2,4-D at levels that may be present in 

cow’s milk. This is an extremely 

conservative assumption as it pertains 

to human breast milk. 

Residues in various food forms of 

cow’s milk (e.g., milk fat, nonfat milk 

solids, etc.) have been accounted for in 

the dietary exposure assessment based 

on monitoring data from the USDA 

Pesticide Data Program (PDP). There 

were no detections of 2,4-D in any 

samples, so EPA assumed that all milk 

contains half the detection limit for 2,4- 

D. (Ref. 19 at 47). This is a very 

conservative assumption as it pertains 

to human breast milk because 2,4-D 

levels in human breast milk are 

expected to be significantly lower than 

residues in cow’s milk. Exposure of 

dairy cattle to pesticides are generally 

significantly higher than humans as 

residues in cows’ key feed items, such 

as grass forage, are generally much 

higher than in human foods. As to 2,4- 

D, this is certainly the case given that 

the 2,4-D tolerances for grass (hay) and 

grass (forage) are 300 and 360 ppm, 

respectively, while 2,4-D tolerances for 

various human foods are all much 

lower—in the single digits or less than 

1 ppm (40 CFR 180.142). Grass hay and 

forage can constitute 60 percent of the 

diets of beef and dairy cattle. (Ref. 88). 

Accordingly, EPA concludes that 

NRDC’s claim regarding exposure to 2,4- 

D through human breast milk does not 

raise sufficient grounds for concern that 

EPA should consider initiating action 

that might lead to revocation of the 2,4- 

D tolerances. 

3. Dermal absorption—a. NRDC 

claims. NRDC asserts that in the final 

risk assessment, the dermal absorption 

factor used by EPA (10 percent) was too 

low. Specifically, NRDC claims that the 

EPA failed to address the possibility of 

enhanced dermal absorption of 2,4-D 

due to the potentially interacting factors 

of alcohol consumption and application 

of sunscreen, and/or the insect repellent 

DEET. (Ref. 1 at 12; Ref. 22 at 1). In its 

exposure comments on the RED, which 

NRDC incorporates in its petition, 

NRDC argued that EPA should increase 

its dermal absorption factor to at least 

14 percent based on a human dermal 

absorption study by Moody (1992). (Ref. 

24 at 16 and Ref. 89). NRDC claimed 

that such an adjustment of the dermal 

absorption factor would result in postapplication exposures for toddlers 

exceeding the LOC. (Ref. 24 at 16). In 

addition, NRDC claims that the Agency 

did not sufficiently address that using 

rubber gloves when applying 2,4-D does 

not afford adequate dermal protection 

and the effect of 2,4-D soaking into 

clothing. (Ref. 1 at 13). 

b. Public comments. In its comments, 

the Task Force disagrees with NRDC’s 

allegation regarding enhanced dermal 

absorption due to the interacting factors 

of alcohol consumption, sunscreen, and 

DEET. The Task Force argues that the 

study on which EPA relied to estimate 

dermal absorption, Feldmann and 

Maibach (1974), used ‘‘extreme’’ 

conditions. (Ref. 26 at 28 and Ref. 90). 

According to the Task Force, in this 

study 2,4-D was applied with acetone 

which denatures skin and allows for 

increased absorption. Additionally, the 

Task Force noted that the skin was not 

protected and not washed for 24 hours 

to allow maximum absorption. That 

study showed absorption of 5.8 percent. 

The Task Force also cites a recent 

article, Ross (2005), which summarized 

numerous dermal absorption studies 

with 2,4-D. (Ref. 91). According to the 

Task Force, this study concluded that 

the available studies showed remarkable 

agreement and strongly supported the 

conclusion in the Fledmann and 

Maibach study. 

The Task Force also commented on 

other issues related to dermal exposure 

such as the use of rubber gloves by 

agricultural workers. Those comments 

are not relevant to the FFDCA portion 

of NRDC’s petition and are thus 

addressed elsewhere. 

c. EPA’s response. For the purposes of 

responding to the portion of NRDC’s 

petition that requests EPA to revoke 

tolerances, EPA will respond to issues 

related to residential exposure here. 

Concerns about occupational exposures 

will be addressed elsewhere. 

Unlike most of NRDC’s other claims, 

as to dermal absorption, NRDC alleges 

grounds that if substantiated would 

provide grounds for revoking the 2,4-D 

tolerances. As summarized above, 

NRDC alleges that EPA has understated 

dermal absorption and adjustment of 

dermal absorption factor to the degree 

supported by Moody (1992) would show 

a risk of concern (i.e., a lack of safety). 

(Ref. 24 at 16). In the petition, NRDC’s 

focus shifts from the Moody study to a 

series of in vitro studies investigating 

the effect of the use of sunscreen and 

alcohol on 2,4-D dermal absorption. 

NRDC argues that these studies show 

that EPA has underestimated dermal 

absorption. The various combinations of 

in vitro results appear to indicate that 

dermal absorption was enhanced by up 

to a factor of about 2.5 while most tested 

scenarios indicate a factor of 2 or less. 

(Refs. 92,93,94 and 95). One study used 

human skin and the results suggest a 

factor of up to 3 depending upon 

sunscreen ingredient tested. (Ref. 92). 

NRDC also claims that use of the 

pesticide Deet increases dermal 

absorption of 2,4-D. Here, NRDC turns 

back to the Moody study but that study 

actually concluded that ‘‘Deet had no 

significant effect on total cumulative 

palmar permeability to this herbicide 

[2,4-D].’’ (Ref. 89 at 245). 

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. Ross 

(2005) notes that ‘‘the degree of 

uncertainty and variability associated 

with human dermal absorption for 2,4- 

D is better defined than for virtually any 

other pesticide * * *.’’ (Ref. 91 at 84). 

EPA principally relied on an in vivo 

human study which showed average 

human dermal absorption at 5.8 percent. 

(Ref. 90). EPA also considered four other 

in vivo human studies. (Refs. 89, 96,97 

and 98). These studies involved 8 

separate trials using a total of 34 

participants and had an average dermal 

absorption value of 5.7 percent. (Ref. 91 

at 84, Table 2) 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. 

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. The Moody 

study (1992) did involve in vivo human 

testing but the results of this study were 

similar to the higher values seen in the 

human in vivo studies considered by 

EPA. In fact, if the Moody study results 

from the trial combining 2,4-D and 

DEET are included in the overall 

average of dermal absorption from the 

human studies, the average absorption 

only increases from 5.7 percent to 6.4 

percent. (Ref. 30). Second, the studies 

considered by EPA involved exposure 

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conditions that varied based on 

application site (forearms, hands), 

topical dose rates (1.7 to 1,100 mg/cm2), 

form (acid or salt), application media 

(water, ethanol, acetone), and exposure 

time. As noted, the overall average 

dermal absorption value for all of these 

data combined (N=34), regardless of 

design, was 5.7 percent. Examination of 

these variables, particularly the use of 

different application vehicles and 

different anatomical sites, is likely to 

have captured much of the variability 

measured in the sunscreen and alcohol 

in vitro studies. On this latter point, it 

is worth noting that NRDC placed 

particular emphasis on the potential 

additive effect of sunscreen and alcohol. 

Yet, the relevant study on this point 

found that the effect from both 

sunscreen and alcohol to be no higher 

than a factor of 2.9 and that was only 

with an extremely high alcohol dose. 

(Ref. 92). At the lowest alcohol dose 

tested in the study, the researchers 

actually concluded that alcohol had an 

inhibitory effect on dermal absorption. 

This low dose, when converted to 

human consumption amounts, is the 

equivalent of 7 ounces of 100 proof 

liquor for women and just slightly less 

than 9 ounces for men. Third, the data 

considered by EPA was developed by 

different researchers at different 

laboratories. The reproducibility of 

results across these studies gives them 

enhanced reliability. As Ross (2005) 

notes: ‘‘Multiple human studies 

conducted on the forearm and hand 

provide remarkably consistent results, 

especially considering the studies were 

performed years apart in time, at 

different laboratories by different 

personnel on totally different human 

subjects.’’ (Ref. 91 at 84). On the other 

hand, the in vitro studies cited by NRDC 

all were conducted by the same group 

of researchers. Finally, the value chosen 

by EPA for dermal absorption was 

nearly twice the average value seen in 

human testing. 

Providing further support for the 

reasonableness of EPA’s assumption on 

dermal absorption are exposure 

monitoring studies (including 

epidemiological analyses, 

environmental measurements, and 

methodological analyses) cited by NRDC 

and commenters. (Ref. 30 at 65–69). In 

fact, many of these studies report 

exposure levels that are similar to or far 

below exposures estimated by EPA. For 

example, NRDC cited results from Lerda 

(1991), (Ref. 99), prior to the RED, 

which are similar to those predicted in 

the 2005 EPA risk assessment for 

applicators wearing normal work 

clothing. Current labels require the use 

of protective clothing and gloves. NRDC 

also cited median urinary values in 

children reported by Morgan (2008), 

(Ref. 100), which are lower than those 

used to establish risk estimates in the 

2005 risk assessment. Other data cited 

in comments, such as Alexander (2007), 

(Ref. 101), cited by the 2,4-D Task Force, 

(Ref. 26 at 30), indicate values much 

lower than values that would reflect a 

risk concern for both applicators and 

their family members according to the 

2005 assessment. (Ref. 19 at 57–60). 

Accordingly, NRDC’s claim regarding 

dermal absorption is denied. 

EPA is currently involved in 

processes to refine many of its exposure 

assessment inputs (http://www.epa.gov/ 

pesticides/science/handler-exposuredata.html) and to establish better 

methods for the consideration of 

epidemiological research into the 

regulatory process. (See Ref. 102). The 

Agency is also re-evaluating pesticide 

risks on a cyclical basis under its 

registration review process. Given these 

two efforts, the Agency will further 

evaluate research related to 2,4-D during 

registration review. The Agency has also 

been actively participating in 

epidemiological research efforts such as 

the Agricultural Health Study and, as 

part of this process, will pursue 

additional information related to 2,4-D 

and the potential for health effects in 

potentially exposed populations. 

C. Additional Issues Raised in Public 

Comments 

Some comments raised issues beyond 

the scope of NRDC’s petition. For 

example, Beyond Pesticides, in its 

comments, claimed that EPA was not 

justified in removing the FQPA safety 

factor and had failed to address 

cumulative effects from 2,4-D and other 

chlorophenoxy pesticides. (Ref. 28 at 5– 

6). It is not appropriate for EPA to 

consider these comments in support of 

the petition because they have not been 

subject to the public comment process 

which is critical to the EPA’s 

administrative review of the petition 

under section 408(d). 

VIII. Statutory and Executive Order 

Reviews 

This action, denies a petition to 

revoke tolerances, is in the form of an 

order and not a rule. (21 U.S.C. 

346a(f)(1)(C)). Under the Administrative 

Procedure Act (APA), orders are 

expressly excluded from the definition 

of a rule. (5 U.S.C. 551(4)). Accordingly, 

the regulatory assessment requirements 

imposed on a rulemaking do not apply 

to this action, as explained further in 

the following discussion. 

A. Executive Order 12866 and Executive 

Order 13563 

Because this order is not a ‘‘regulatory 

action’’ as that term is defined in 

Executive Order 12866 entitled 

‘‘Regulatory Planning and Review’’ (58 

FR 51735, October 4, 1993), this action 

is not subject to review by the Office of 

Management and Budget (OMB) under 

Executive Orders 12866 and 13563 

entitled ‘‘Improving Regulation and 

Regulatory Review’’ (76 FR 3821, 

January 21, 2011). 

B. Paperwork Reduction Act 

This action does not contain any 

information collections subject to OMB 

approval under the Paperwork 

Reduction Act (PRA), 44 U.S.C. 3501 et 

seq. 

C. Regulatory Flexibility Act 

Since this order is not a rule under 

the APA (5 U.S.C. 551(4)), and does not 

require the issuance of a proposed rule, 

the requirements of the Regulatory 

Flexibility Act (RFA) (5 U.S.C. 601 et 

seq.) do not apply. 

D. Unfunded Mandates Reform Act; and 

Executive Orders 13132 and 13175 

This order denies a petition to revoke 

tolerances; it does not alter the 

relationships or distribution of power 

and responsibilities established by 

Congress in the preemption provisions 

of section 408(n)(4) of FFDCA. As such, 

the Agency has determined that this 

action will not have a substantial direct 

effect on States or tribal governments, 

on the relationship between the national 

government and the States or tribal 

governments, or on the distribution of 

power and responsibilities among the 

various levels of government or between 

the Federal Government and Indian 

tribes. Thus, the Agency has determined 

that Executive Order 13132 entitled 

‘‘Federalism’’ (64 FR 43255, August 10, 

1999) and Executive Order 13175 

entitled ‘‘Consultation and 

Coordination with Indian Tribal 

Governments’’ (65 FR 67249, November 

9, 2000) do not apply to this order. In 

addition, this order does not impose any 

enforceable duty or contain any 

unfunded mandate as described under 

Title II of the Unfunded Mandates 

Reform Act (UMRA) (2 U.S.C. 1531– 

1538). 

E. Executive Orders 13045, 13211 and 

12898 

As indicated previously, this action is 

not a ‘‘regulatory action’’ as defined by 

Executive Order 12866. As a result, this 

action is not subject to Executive Order 

13045, entitled ‘‘Protection of Children 

from Environmental Health Risks and 

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23156 Federal Register / Vol. 77, No. 75 / Wednesday, April 18, 2012 / Rules and Regulations 

Safety Risks’’, (62 FR 19885, April 23, 

1997) and Executive Order 13211 

entitled ‘‘Actions Concerning 

Regulations That Significantly Affect 

Energy Supply, Distribution, or Use’’, 

(66 FR 28355, May 22, 2001). In 

addition, this order also does not 

require any special considerations 

under Executive Order 12898 entitled 

‘‘Federal Actions to Address 

Environmental Justice in Minority 

Populations and Low-Income 

Populations’’ (59 FR 7629, February 16, 

1994). 

F. National Technology Transfer and 

Advancement Act 

This action does not involve any 

technical standards that would require 

Agency consideration of voluntary 

consensus standards pursuant to section 

12(d) of the National Technology 

Transfer and Advancement Act 

(NTTAA), (15 U.S.C. 272 note). 

IX. Congressional Review Act 

The Congressional Review Act, 5 

U.S.C. 801 et seq. does not apply 

because this action is not a rule as that 

term is defined in 5 U.S.C. 804(3). 

X. References 

1. Petition of Natural Resources Defense 

Council to Revoke All Tolerances and 

Cancel All Registrations for the Pesticide 

2,4-D (November 6, 2008). 

2. Office of Prevention, Pesticides and Toxic 

Substances, EPA, Memorandum from 

Elizabeth Resek to Jim Downing, 

‘‘Transmittal of Meeting Minutes of the 

FIFRA Scientific Advisory Panel Meeting 

Held on March 25–26, 2008 to review 

and consider the Endocrine Disrupter 

Screening Program (EDSP) Proposed Tier 

1 Screening Battery.’’ (June 11, 2008). 

3. Marino, T.; Coady, K.; Sosinski, L.; et al. 

(2010) 2,4-Dichlorophenoxyacetic Acid: 

A Fish Short-Term Reproduction Assay 

Using the Fathead Minnow, Pimephales 

promelas. Project Number: 101026. 

Unpublished study prepared by Dow 

Chemical, USA. 155 p. MRID 48317001. 

4. Coady, K.; Marino, T.; Thomas, J. (2010) 

2,4-Dichlorophenoxyacetic Acid: The 

Amphibian Metamorphosis Assay Using 

the South African Clawed Frog, Xenopus 

laevis. Project Number: 101025. 

Unpublished study prepared by Dow 

Chemical, USA. 152 p. MRID 48317002. 

5. Schisler, M.; LeBaron, M.; Visconti, N. 

(2011) (Endocrine Disruptor Screening 

Program): Evaluation of 2,4- 

dichlorophenoxyacetic Acid (2,4-D) in 

an in vitro Androgen Receptor Binding 

Assay. Project Number: 111111/OCR. 

Unpublished study prepared by 

Exponent, Inc. and The Dow Chemical 

Co. 91p. MRID 48614301. 

6. Coady, K.; Sosinski, L. (2011) (Endocrine 

Disruptor Screening Program): 2,4- 

Dichlorophenoxyacetic Acid: Evaluation 

of 2,4-Dichlorophenoxy Acetic Acid in 

the Human Recombinant Aromatase 

Assay. Project Number: 111036/OCR 

31868 P803. Unpublished study 

prepared by Exponent, Inc. and The Dow 

Chemical Co. 98p. MRID 48614302. 

7. LeBaron, M.; Schisler, M.; Visconti, N. 

(2011) (Endocrine Disruptor Screening 

Program): 2,4-Dichlorophenoxyacetic 

Acid: Evaluation of 2,4- 

dichlorophenoxyacetic Acid (2,4-D) in 

an in vitro Estrogen Receptor Binding 

Assay. Project Number: 111121/OCR. 

Unpublished study prepared by The 

Dow Chemical Co., and Exponent, Inc. 

91p. MRID 48614303. 

8. LeBaron, M.; Kan, H. (2011) (Endocrine 

Disruptor Screening Program): 

Evaluation of 2,4-Dichlorophenoxy 

Acetic Acid (2,4-D) in an in vitro 

Estrogen Receptor Transcriptional 

Activation Assay in Human Cell Line 

HELA-9903. Project Number: 111043/ 

OCR. Unpublished study prepared by 

Exponent, Inc., and The Dow Chemical 

Co. 109p.MRID 48614304. 

9. LeBaron, M.; Kan, H.; Perala, A. (2011) 

(Endocrine Disruptor Screening 

Program): Evaluation of 2,4- 

Dichlorophenoxyacetic Acid (2,4-D) in 

the in vitro Steroidogenesis Assay. 

Project Number: 111038/OCR. 

Unpublished study prepared by 

Exponent, Inc., and The Dow Chemical 

Co. 78p. MRID 48614305. 

10. Office of Chemical Safety and Pollution 

Prevention, EPA, Memorandum from 

Greg Ackerman to Katie Weyrauch, ‘‘2,4- 

Dichlorophenoxyacetic Acid (2,4-D) - 

Report of the Endocrine Disruptor 

Review Team—Test Order #: EDSP– 

031001–120’’ (December 20, 2010). 

11. EPA, A User’s Guide to Available EPA 

Information on Assessing Exposure to 

Pesticides in Food (June 21, 2000). 

12. Office of Pesticide Programs, EPA, Office 

of Pesticide Programs’ Policy on the 

Determination of the Appropriate FQPA 

Safety Factor(s) for Use in the Tolerance 

Setting Process (February 28, 2002). 

13. Office of Pesticides and Toxic 

Substances, EPA, Memorandum from 

Stephen L. Johnson to Douglas D. Campt, 

‘‘Transmittal of Final FIFRA Scientific 

Advisory Panel Reports on the June 25, 

1987 meeting’’ (July 8, 1987). 

14. EPA, Scientific Advisory Panel Open 

Meeting (June 25, 1987). 

15. EPA, An SAB Report: Assessment of 

Potential 2,4-D Carcinogenicity. Review 

of the Epidemiological and Other Data 

on Potential Carcinogenicity of 2,4-D by 

the SAB/SAP Joint Committee. (March 

22, 1994). 

16. EPA, Carcinogenicity Peer Review (4th) of 

2,4-Dichlorophenoxyacetic acid (2,4-D). 

(January 29, 1997). 

17. EPA, Agency Review of Task Force II 

Study Submission: MRID 44284501 and 

MRID 44284502. (March 16, 1999). 

18. Office of Prevention, Pesticides and Toxic 

Substances, EPA, Reregistration 

Eligibility Decision for 2,4-D (June 2005). 

19. Office of Prevention, Pesticides and Toxic 

Substances, EPA, Memorandum from 

Timothy C. Dole to Katie Hall, ‘‘2,4-D. 

HED’s Revised Human Health Risk 

Assessment for the Reregistration 

Eligibility Decision (RED) Revised to 

Reflect Public Comments. PC Code 

030001; DP Barcode D316597’’ (May 12, 

2005). 

20. Office of Chemical Safety and Pollution 

Prevention, EPA, Memorandum from 

Alexandra LaMay to Michael Walsh, 

‘‘Petition for the Establishment of a New 

Formulation of 2,4-D Choline on 

Herbicide Tolerant Field Corn 

Containing the Aryloxyalkanoate 

Dioxygenase-1 (ADD–1) Gene. (October 

27, 2011). 

21. Office of Chemical Safety and Pollution 

Prevention, EPA, Memorandum from 

Alexandra LaMay to Michael Walsh, 

‘‘2,4-D: Amended Petition for the 

Establishment of a New Formulation of 

2,4-D Choline on Herbicide Tolerant 

Field Corn Containing the 

Aryloxyalkanoate Dioxygenase-1 (ADD– 

1) Gene.’’ (February 22, 2012). 

22. NRDC, ‘‘Supplement To The Natural 

Resources Defense Council Petition To 

Revoke All Tolerances And Cancel All 

Registrations For The Pesticide 2,4-D’’ 

(February 23, 2009). 

23. Boston Women’s Health Book Collective, 

et al., Objections to the establishment of 

a tolerance for pesticide chemical 

residues of 2,4-D. OPP 301219. (May 7, 

2002). 

24. Beyond Pesticides, NRDC, et. al. 

comments on RED 2004. At 

regulations.gov EPA–HQ–OPP–2004– 

0167–0072 (August 23, 2004). 

25. Agricultural Retailers Association et al. 

Docket ID number EPA–HQ–OPP–2008– 

0877. Available at regulations.gov EPA– 

HQ–OPP–2008–0877–0104. 

26. Industry Task Force II on 2,4-D Research 

Data, Comments on The Natural 

Resource Defense Council’s Petition to 

Revoke All Tolerances and Cancel All 

Registrations for the Pesticide 2,4-D’’ 

(February 23, 2009). 

27. National Council for Air and Stream 

Improvement, Inc., ‘‘Re: Docket # EPA– 

HQ–OPP–2008–0877 (February 20, 

2009). 

28. Beyond Pesticides, ‘‘Re: Petition to 

Revoke all Tolerances and Cancel all 

Registrations for the Pesticide 2,4- 

Dichlorophenoxyacetic Acid (2,4-D); 

Docket Number: EPA-OPP–2008–0877’’ 

(February 23, 2009). 

29. New York State Department of 

Environmental Conservation, New York 

State Department of Health, ‘‘RE: EPA– 

HQ–OPP–2008–0877’’ (February 23, 

2009). 

30. Office of Chemical Safety and Pollution 

Prevention, EPA, Memorandum from 

Linda Taylor, Nancy McCarroll, and 

Khin Swe Oo to Joel Wolf, ‘‘2,4-D: 

Evaluation of Data Identified in NRDC 

Petition and Associated Documents’’ 

(March 27, 2012). 

31. Risk Assessment Branch VII, Health 

Effects Division (7509P), EPA, 2,4-D: 

Review of Extended 1-Generation 

Reproduction Study and Dose-RangeFinding and Pharmacokinetic Titration 

Studies. D376556. MRID 47972101, 

47417901, 47417902. (November 30, 

2010). 

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32. Office of Chemical Safety and Pollution 

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2011). 

33. Office of Prevention, Pesticides and Toxic 

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(August 1998). 

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al. Evaluation of estrogenic activities of 

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a rainbow trout vitellogenin assay. 

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(August 1998). 

59. Office of Prevention, Pesticides and Toxic 

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Test (August 1998). 

60. Office of Prevention, Pesticides and Toxic 

Substances, EPA, Health Effects Test 

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61. Office of Prevention, Pesticides and Toxic 

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induced cytogenic damage in human 

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herbicide 2,4-dichlorophenoxyacetic and 

a commercial formulation, 2,4- 

dichlorophenoxyacetic acid 

dimethylamine salt. I. Evaluation of 

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in Chinese Hamster ovary (CHO) cells. 

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induction by the herbicide 2,4- 

dichlorophenoxyacetic acid in chick 

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2003. 

67. Arias, E. Cytogenetic Effects of Short- and 

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the Phenoxyherbicide 2,4-D. 

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em.20301. 2007. 

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Dated: April 7, 2012. 

Steven Bradbury, 

Director, Office of Pesticide Programs. 

[FR Doc. 2012–9106 Filed 4–17–12; 8:45 am] 

BILLING CODE 6560–50–P 

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