### Page 3 of 36

handler and post

- application assessment may be required under 2,4

- D registration review if there

are an y significant changes to the current exposure assessment methodology, toxicological points of departure

, or uncertainty factors.

In addition, quantitative residential post

- application assessment s have not been performed for

exposure s potentially result ing from pesticide drift or volatilization from neighboring 2,4

- D

treated agricultural fields; these assessments may be necessary under registration review. Any assessments would consider all 2,4

- D forms

.

In 2005 there were no aggregate (food, water, and residential exposure combined ) risk estimates of concern for 2, 4

- D for adults or children

. During registration review, updated aggregate

assessments may be conducted as needed if , in the interim, there are any significant changes to the following: toxic ological PODs, FQPA and other uncertainty factors, dietary exposure estimates, and the methods or data HED uses to calculate residential exposure estimates. Any significant changes to the estimated drinking water concentrations (EDWCs), which are under

EF ED purview, may also necessitate changes to the dietary assessment

.

There are no outstanding worker exposure data requirements for 2,4

- D. An updated occupational handler assessment and a dermal post

- application assessment may be performed if warranted by significant changes to the current exposure assessment methodology, PODs, or uncertainty factors

. A quantitative occupational post

- application inhalation exposure assessment for 2,4

- D, including assessment of field volatilization, may be n ecessary under registration
review.

Polychlorinated dibenzo dioxins (PCDD) and polychlorinated dibenzo furans (PCDF) may be formed during the manufacture of 2,4

- D and can remain in the 2,4

- D technical products as impurities. According to 2,4

- D registrant s, since the 1990’s, the manufacturing processes for 2,4

- D and its chemical intermediate dichlorophenol (DCP) , have been modified to reduce concentrations of PCDD and PCDF in the technical 2,4

- D products. The 2005 RED concluded that, based on a worst

- case scenario screen which included early 1990’s data on 2,4

- D manufacturing impurities

, both the cancer and non

- cancer risks from dietary exposure to dioxins
and furans as contaminants of 2,4

- D acid were considered to be of no toxicological concern.
HED will continue to monitor data on the impurities and reassess any potential risk s as

necessary.

Chemical Use Profile

2,4

- Dichlorophenoxyacetic acid (2,4

- D) is an alkylchlorophenoxy herbicide used to control a
varie ty of broadleaf weeds. It is registered for use on many agricultural use sites including cereal grains, field, pop and sweet corn, sorghum, soybeans, sugarcane, rice, pome fruits, stone fruits, nut orchards, potatoes, hops, asparagus, strawberries, blueberries, grapes, cranberries, an d citrus. 2,4

- D is also registered for use on a variety of non

- agricultural uses including residential turf, for industrial and commercial areas, on golf courses, non

- cropland and for aquatic weed control

. P ermanent tolerances for 2,4

- D are established und er 40 CFR 180.142 for a wide variety of crops
and livestock commodities.

### Page 4 of 36

There are eleven a ctive ingredients (a.i.s) that are components of currently registered pesticide products. The list of active ingredients covered by the 2,4

- D case ( Case No. 0073 ) can be found in Appendix 1 and includes 2, 4

- D acid, its sod ium, choline, and amine salts, and its esters. It is to be noted that the choline salt was not in the reregistration case previously. The nomenclature
and physiochemical properties of the 2,4

- D a.i.s can be found in Appendix 2

.

Hazard Identification/Toxicology

2, 4

- D is a phenoxy herbicide and a plant growth regulator. Since toxicity following exposure of rats and dogs to the amine salts and esters of 2, 4

- D was similar to that observed following 2, 4

- D acid exposure, the acid has been selected as being representative of all members of the 2,4

- D reregistration case including 2, 4

- D acid, the sodium, choline, and amine salts, and esters.

In the acute lethality studies with 2, 4

- D and its salts and esters, the clinical signs of toxicity consistently observed in rats following oral administration were ataxia, myotonia, and decreased limb tone. Following dermal administration, no dermal or systemic toxicity was observed in
rabbits. Clinica l signs of toxicity observed in rats during inhalation exposure were decreased activity and closed eyes. The acid and salt forms are severe eye irritants.

The subchronic database provides evidence that the kidney [increased kidney weight, histopathologic al lesions], thyroid [decreased thyroxine, increased thyroid weight, hypertrophy of follicular cells], liver [increased liver weight, increased ALT, and AST, histopathological lesions, including hypertrophy], adrenal [increased adrenal weight, histopatholo gical lesions], eye [retinal degeneration, cataract formation], and ovaries/testes [atrophy] are target organs in the rat following exposure to 2,4

- D via the oral route at dose levels above the threshold of
saturation of renal clearance. No systemic toxic ity was observed in rabbits following repeated

exposure via the dermal route at dose levels up to the limit dose [1000 mg/kg/day]. In the dog, the kidney, thyroid, and testis are target organs [elevated blood urea nitrogen and creatinine, decreased gluco se, decreased T4, increased kidney and thyroid weights, cellular alterations of the proximal tubule, decreased testes weight and hypospermatogenesis/juvenile testis] following

exposure via the oral (diet and capsule) route at dose levels above the threshol d of saturation of
renal clearance. Effects in dogs were observed at lower dose levels than those observed in rodents, and this is attributed to the dog’s limited capacity to eliminate 2,4

- D and other organic acids. Subchronic toxicity following exposure of rats and dogs to the amine salts and esters of 2,4

- D was similar to that observed following 2,4

- D acid exposure.

Chronic toxicity studies indicate that the kidney [increased kidney weight, proximal tubule degeneration], thyroid [increased thyroid we ight, decreased T4, hyperplasia, hypertrophy], testes [decreased testes weight, atrophy], ovaries [decreased ovarian weight], and eyes [lens opacity, cataracts, retinal degeneration] are target organs in the rat following exposure to 2,4

- D at dose
levels a t or above the threshold of saturation of renal clearance. In the dog, decreased brain weight [females], increased incidence of kidney lesions, and aspermatogenesis and testes degeneration were observed.

In general, 2,4

- D undergoes limited metabolism in mammalian systems, although the metabolism that does occur primarily involves minor conjugation of the parent acid, which results in a more

### Page 5 of 36

water soluble compound that is then excreted in the urine. No detectable metabolites of 2, 4

- D have been reported in the rat, i.e. only the parent acid was detected in rat urine. 2, 4

- D conjugates have been found in the urine of dogs, humans, mice, and hamsters following oral exposure. In other metabolism studies, 2, 4

- D was the predominant residue found in ruminant
ti ssue, milk, poultry tissue, eggs, and fish.

2,4

- D is classified as a Group D chemical [not classifiable as to human carcinogenicity]. Based on the overall pattern of responses observed in both in vitro and in vivo genotoxicity tests and a weight

- of

- evid ence assessment, 2,4

- D is not mutagenic, although some cytogenic effects were
observed.

In the previous human health risk assessment (T. Dole, D316597, 5/12/2005 ) , the subchronic inhalation toxicity study was identified as a data requirement for 2,4

- D. Additionally, there was evidence for neurotoxicity (clinical signs and neuropathology) in adult animals (rats and dogs) with 2,4

- D a cid as well as evidence of increased susceptibility (qualitative) in the prenatal developmental toxicity study in rabbits w ith the diethylamine salt of 2,4

- D. To address the potential neurotoxicity concerns in the offspring, the Agency required a developmen tal neurotoxicity (DNT) study. Additionally, it was determined that a two

- generation reproduction study using the post

- 1 998 protocol (OCSPP 890.3800)

, designed to provide general information concerning the effects of a 2,4

- D on the integrity and performance of the male and female

rep roductive system

, was required. T o account for the lack of these studies, the Agency retain ed

a 10X FQPA safety factor in the 2005 human health risk assessment

.

After the RED was completed, t he Agency issued a Data Call

- in Notice (DCI) for the subchronic inhalation, DNT

, and the t wo

- g eneration r eproduction studies. In response to the latter two study requirements, the 2,4

- D Task Force with approval from the Agency conducted an Extended One Generation Reproductive Toxicity (EOGRT) study (MRID 47972101 ; TXR Nos. 0055341 and
0050697 ). T his study included an evaluation of potential effects on p arental male and female reproductive function, reproductive organ weight evaluations, and detailed histopatho logy of the reproductive organs. The study also evaluated potential effects in offspring on survival, growth,
and the development of the immune, n ervous, and reproductive systems

. In addition, the study
examined various endocr ine

- related parameters including estrous cycle evaluation (female adult
rats and F 1 offspring), qualitative ovarian follicle count (F1 females), evaluation of sperm
parameter s, anogenital distance, nipple retention, puberty onset (vaginal opening and balano

preputial separation) , and thyroid effects (weight, hormone, and histopathological).

In the EOGRT, clear NOAELs and LOAELs were identified for systemic, thyroid, and

repro ductive effects in adult animals, as well as for growth and development of offspring, developmental neurotoxicity, and developmental immunotoxicity in the offspring. The EOGRT neither identified a more sensitive endpoint n or a lower Point of Departure ( POD ) than those used in the existing 2,4

- D risk assessments

. ( See App endix 3, Tables A3.1 and A3.2 for a summary of the most recent toxicological endpoints and PODs. )

In response to the subchronic inhalation study requirement, the 2,4

- D Task Force conducted a 28

- day inhalation study (MRID 47398701; TXR No. 0054870). Following repeat dose nose

- only inhalation exposure of rats to 2,4

- D

, the incidence and severity of the portal

- of

- entry effects

### Page 6 of 36

( squamous metaplasia and epithelial hyperplasia with increased mixed inflammatory cells within the larynx ) were increased in a dose

- related manner. Clinical signs associated with inhalation exposure at the high dose included excessive salivation, labored breathing, and chromodacryorrhea. A NOAEL for portal

- of

- entry effec ts was not determined. The LOAEL is 0.05 mg/L, based on squamous metaplasia and epithelial hyperplasia with increased mixed inflammatory cells within the larynx

.

T he E OG RT study satisfies the DCI requirements for OCSPP 870.3800 (Reproduction and Fertility Effects), OCSPP 870.6300 (Developmental Neurotoxicity), and OCSPP 870.7800 (Immunotoxicity) studies for 2,4

- D. The 28

- day subchronic inhalation toxicity study satisfies the

DCI requirement for OCSPP 870.3465 (90

- Day Inhalation) study for 2,4

- D

. (See Appendix 4 for a summary of the toxicology data requirements and Appendix 5 for study profiles .)

The National Resources Defense Council (NRDC) filed a petition on November 6, 2008

r equesting that EPA revoke all tolerances for 2,4

- D. The petition raised a number of technical issues primarily pertaining toxicology, but also to exposure, epidemiology, and pet incidents. HED responded to issues specifically pertaining to the 2,4

- D huma n health risk assessment (L. Taylor et al , 3/27/12, D392844). EPA concluded that the NRDC petition did not raise sufficient grounds for concern, and the petition was denied. [Federal Register/Vol. 77, No. 75; Wednesday, April 18, 2012/Rules and Regulation s. EPA

- HQ

- OPP

- 2008

- 0877; FRL

- 9344

- 2 (23135

- 23158)]. The petition issues did not warrant any changes to the 2005 human health risk assessment.

In 201 2 , EPA re

- examined the risks of 2,4

- D in response to an application to amend a 2,4

- D FIFRA registration. The re

- examination took into account the newly submitted extended one

generation reproduction study evaluating 2,4

- D’s potential for causing endocrine, neurotoxic, or

immunot oxic effects. As part of that 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

, neurotoxic , and reproductive effects and those data requirements had been met, EPA determined that the 10X FQPA safety factor shou ld be re duced to 1X ( D 398209)

.

Conclusion : T he 2,4

- D toxicity database is complete. A ll of the required toxicity data have been
received and reviewed. U nder registration review the toxicological endpoints and PODs for use in 2,4

- D risk assessments will b e re evaluated taking into account all studies, including those received since the 2005 RED (EOGRT and inhalation).

Dietary Exposure

Residue Chemistry

T he magnitude of the residue database is complete

. The nature of the residue is understood based
on the available metabolism and residue studies ; the residue of concern for tolerance regulation and risk assessment is 2,4

- D per se (MARC 10/13/04, TXR. No. 0052264)

.

The 2005 2,4

- D risk assessment requested field trial data on wheat hay and limi ted irrigated crop studies ( strawberry and sugar beet). Those data requirements have since been waived (T.

### Page 7 of 36

Goodlow, D336596, 4/16/07 and D340921, 10/18/07 ). The 2007 waiver memos also recommended or reassessed several 2,4

- D tolerances which are not currently reflected 40 CFR §180.142 : In D340921 it was determined that a tolerance value of 50 ppm is appropriate for hay,
and should be established for residues of 2,4

- D in/on wheat hay, barley hay, millet hay and oat hay under 40 CFR §180.142(a ) . In D3 36596 it was recommended that a tolerance value of 0.1 ppm be established under 40 CFR §180.142(a ) for residues of 2,4

- D in/on strawberries, grapes, Crop Groups 11 (pome fruit) and 12 (stone fruit), and on Crop Groups 1 and 2, root and tuber vegetables (excluding potatoes) and the leaves of root and tuber vegetables, respectively.

Dietary Assessment

Food Only

The 2005 acute dietary assessment (T. Jimerson, 4/18/05, D315512) was slightly refined with the following assumptions : tolerance

- level exposure values for most commodities, the highest field trial residue value for citrus commodities, and 100% crop treated (%CT). Hal f the average Limit of Detection ( LOD ) from Pesticide Data Program ( PDP ) monitoring data was used as the milk
value as no milk sample s contained detectable 2,4

- D residues over several years of PDP sampling. The assessment was conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID , Version 1.33), which incorporates consumption data from USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII),

1994

- 1996 and 1998. The acute dietary (food only) risk estimates were below the Agency’s level of concern (100% of the aPAD) at the 95 th 

### exposure percentile for the general U.S. population and all population subgroups. The most highly exposed population subgroup was children 1

- 2 years
old at 33% aPAD.

The 2005 chronic dietary asse ssment was moderately refined, making use of the following:
tolerance

- level exposure values for most commodities; averages of field trial data and processing study factors for small grains, citrus, and sugarcane sugar and molasses; %CT information for all commodities. As in the case of the acute assessment, 1⁄2 of the average LOD from PDP monitoring data was used for milk. The chronic dietary (food only) risk estimates were below the Agency’s level of concern

. Chronic dietary (food) r isk estimates to child ren 1

- 2 years of age, the most highly exposed population subgroup, w ere 8.5% of the cPAD.

Water

In the 2005 RED

, the Environmental Fate and Effects Division ( EFED ) derived Estimated Environmental Concentrations (EECs) i n water through an evaluation of monitoring data and modeling. A number of di fferent scenarios were assessed and EECs provided for each. Scenarios evaluated included the direct application of 2,4

- D to water bodies for aquatic weed control, a rice use scenario, and terrestrial uses including food and nonfood uses. The EFED EECs for drinking water used in the 2005 human health risk assessment are listed below . As the direct aquatic uses and the terrestrial uses of 2,4

- D are distinctly different, risk estimate s

a ssociated with both of these major use patterns were assessed

. The 2,4

- D degradates detected in the various laboratory environmental fate studies were 1,2,4

- benzenetriol, 2,4

- dichlorophenol (2,4

- DCP), 2,4

- dichloroanisole (2,4

- DCA), 4

- chlorophenol, chlorohy droquinone (CHQ), volatile

### Page 8 of 36

organics, bound residues, and carbon dioxide. The OPP Metabolism Assessment Review Committee (MARC) determined that all residues other than 2,4

- D are not of risk concern due to low occurrence under environmental conditions, compa ratively low toxicity, or a combination
thereof. The residue of concern in drinking water for human health assessment is 2,4

- D (MARC memo, 10/13/04, TXR No. 0052264)

.

EECs selected for use in 2005 RED :

Acute EECs : Surface Water (aquatic applications; Maximum Contaminant Level, Office of Water MCL) = 70 ug/liter
Surface water ( worst case terrestrial use PRZM

- EXAM ; NC apple) = 118 ug/liter
Ground Water (the highest monitored value from the USGS NAWQA database) = 15 ug/liter

Chron ic EECs : Surface Water (maximum time weighted annual mean from the NAWQA database) = 1.5 ug/liter Surface Water (dissipation modeling of aquatic application when 70 ppb occurs at time zero) = 11 ug/liter Surface Water (worst case terrestrial use PRZM

- EXAMs ; NC apple) = 23 ug/liter Ground Water (the highest monitored value from the NAWQA database) = 15 ug/liter

Short

- and Intermediate

- Term EECs : Surface Water (aquatic applications; Maximum Contaminant Level, MCL) = 70 ug/liter
Surface Water (worst case terrestrial use PRZM

- EXAMs, 1 in 10 year average; NC apple) = 64 ug/liter Ground Water (the highest monitored value from the NAWQA database) = 15 ug/liter

Food plus Water

Previously, estimated d rinking water concentrations were not directly incorporated into DEEM
in the 2,4

- D dietary assessment. At the time of the latest risk assessment, HED was calculating drinking water levels of comparison (DWLOCs) and comparing them to the estimated EECs (also called EDWCs, estimated drinking water conce ntrations) provided by EFED to determine
whether or not the risk estimates were of concern. See the section of this document titled Aggregate Risk Assessment for a description of the DWLOC approach and aggregate dietary (food and water) risk s estimate d i n the 2005 RED, which were not of concern for 2,4

- D.

Conclusions: The 2,4

- D residue chemistry database is complete No new data are needed to assess potential dietary exposure and risk for 2,4

- D. During registration review, updated dietary
food assessmen ts may be conducted as needed to include any significant changes that might be made to toxicological PODs, FQPA and uncertainty factors, dietary exposure estimates, and

EDWCs. If a revised drinking water assessment is warranted, EFED will conduct a drinkin g water assessment to support future human health dietary risk assessments of 2,4

- D. The drinking water assessment will be performed based on EFED’s current guidance using appropriate surface and groundwater models.

### Page 9 of 36

Residential (Non

- Occupational) Expos ure

There are products containing 2,4

- D registered for residential use or that may be applied by residential applicators or by commercial applicators to residential sites. The maximum application rate is 1.5 lb acid equivalent ( ae ) of 2,4

- D /acre

. 2,4

- D is formulated with other
herbicides such as MCPP

- p and 2,4

- DP. Products can be applied to ornamental turf, including golf courses, cemeteries, parks, sports fields, turfgrass , lawns and other grass areas . Residential handler exposure may occur . I n addition, post

- application exposure can result when people enter parks and athletic fields that have been treated with 2,4

- D, or when golfers play golf on courses
that have been treated

. 2,4

- D can also be used for aquatic weed control of surface weeds

, which could potentially lead to recreational swimmer exposure

.

The residential products are typically formulated as dry weed and feed products or as liquids in concentrates or ready

- to

- use sprays. Both spot and broadcast treatments are included on the
la bels. Exposures are expected to be short

- term in duration for broadcast treatments because the label allows only two broadcast treatments per year. Exposures are also expected to be short

term in duration for spot treatments because the labels recommend repeat applications for hard to
kill weeds in two to three weeks. Liquid and granular formulations can be used to control aquatic weeds as well.

Residential Handler Exposure

A short

- term residential handler exposure assessment for residential application of granules, spray, and ready

- to

- use products to lawns using handheld equipment was performed in the 2005 RED using the maximum application rate; combined dermal and inhalatio n risks were not of concern (MOEs > LOC of 1000 ). Short

- term residential handler MOEs range from 1,800 to 29,000. Since the RED, t he level of concern has been reduced to100 with the removal of the 10X safety factor

.

The Health Effects Division’s 2012 Sta ndard Operating Procedures for Residential Pesticide Exposure Assessment has updated exposure assessment methodology for residential exposure scenarios, including methodology for adult handler exposure assessment. A screening level
residential handler ass essment for 2,4

- D, considering updated exposure methodology

, indicates
that handler risk estimates are not likely to be of concern. An updated residential handler assessment may be required under registration review if warranted by significant changes in exposure assessment methodology, toxicological points of departure or uncertainty fa ctors.

Residential Post

-

Application Exposure

Residential post

- application exposure may occur after products containing 2,4

- D have been applied to residential turf sites

, including ornamental lawns and turf . Similar exposures may occur when people ente r parks and athl etic fields that have been treated wit h 2,4

- D, or when golfers play golf on courses that have been treated . Chemical

- specific turf transferable residue ( TTR) data are available for 2,4

- D. Acute and short

- term adult dermal exposure to treated turf (including golfers) and child dermal and incidental oral exposure to treated turf were assessed in the 2005 RED. Risks were not of concern for all routes of exposure (MOEs > LO C of 1000 ).

### Page 10 of 36

The acu te child total MOE was 1,100; the short

- term child total MOEs ranged from 1,200 to 3,900. The adult dermal acute and short

- term MOE was 1,000 for heavy yardwork activities on
treated turf and 15,000 for golfing activities. A biomonitoring study was also used to ca lculate
risk estimates for post

- application exposure on turf in the 2005 RED. MOEs based on the biomonitoring data were not of concern and were greater than the modeled estimates from the

RED.

2,4

- D can be used for aquatic weed control of surfa ce weeds and submersed weeds. According to
the 2005 RED, many herbicide treatments are applied to aquatic areas where recreational swimming is not likely to occur; however, post

- application scenarios for recreational swimmers (dermal and ingestion exposure for adults and children) were assessed in the RED. B ecause the 2,4

- D water concentrations can vary depending upon the application rate and site conditions, the maximum swimming water concentration (MSWC) was calculated . The MSWC is the water concentration at which the combined dermal and ingestion MOE met or exceed ed the LOC of

1000 ( that is, the maximum water concentration where swimmer exposure did not pose a risk of

concern )

. MSWCs were calculated for adults and children for acute and short

- term durations for all 2,4

- D forms

. The maximum application rate for subsurface treatments is 4 ppm. Initial and average 2,4

- D (acids and amines) and 2,4

- D BEE (butoxyethyl ester) concentrations following application were determined in th e 2005 RED. A lthough some concentrations exceed ed MSWCs for certain forms and under certain conditions, it was concluded that , overall, the
concentrations were unlikely to be of concern. Current l abels restrict swimming in treated water
for at least 24 h ours after application , as indicated in the RED . In addition

, because the LOC is

now 100, MSWCs will increase . Thus, 2,4

- D levels in water are expected to be lower than the MSWCs 24 hours after application

, and would not be expected to be of concern for swimmer

exposure.

Three turf transferable residue (TTR) studies specific for 2,4

- D were submitted by the Broadleaf
Turf Herbicide TTR Task Force and served as the data source for the RED assessment

. A summary of the data used for exposure assessment can be found in the 2005 RED. These studies satisfy the turf transferable residue data requirement under 40 CFR Part 158.

The Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessmen t has updated exposure assessment methodology for residential exposure scenarios, including adult and children exposure to treated turf

, and also for golfers on treated golf courses

. Based on previous findings, the new SOPs, and the change in the FQPA safety factor, a screening level assessment would not likely indicate that these exposures result in risks
of concern. An updated residential post

- application assessment may be required under registration review if warranted by any significant changes in exposure assessment method ology, toxicological points of departure or uncertainty factors

.

Pesticide drift is always a potential source of exposure for residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method s employed for 2,4

- D . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at

### Page 11 of 36

http://www.epa.gov/opp00001/factsheets/spraydrift.htm ). The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT ® 

### computer model to its risk assessments for pesticides applied by air, orchard airblast

, and ground hydraulic methods. After the policy is in place, the Agency may impose further
refinements in drift

- management practices to reduce off

- target drift with specific products with signif icant risks associated with drift.

A quantitative residential post

- application dermal and inhalation exposure assessment has not been performed for pesticide drift from neighboring 2,4

- D

- treated agricultural fields; a drift

assessment may be necessary dur ing registration review. Risk estimates for post

- application residential dermal exposure to treated turf may be considered protective of residential dermal exposure via drift from agricultural 2,4

- D applications.

Volatilization of pesticides also may be a potential source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and
Rodenticide A ct (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). A quantitative post

application inhalation exposure assessment for field volatilization of 2,4

- D has not been performed and may be necessary under registration review. A volatilization assessment would include all registered forms of 2,4

- D.

Conclusions: The residential exposure database for 2,4

- D is complete

. Previous residential
handler and related post

- application exposure assessments (for the turf and aquatic uses) did not
result in risk estimates of concern. The LOC (target MOE) was previously 1000 for residential

assessments. The LOC for residential assessments has since been revised to 100 ( a 10X FQPA factor has been removed). A screening level assessment indicates that residential handler and
post

- application exposures are not likely to be of concern when considering the updated

exp osure methodologies. An updated residential handler and post

- application assessment may be required under 2,4

- D registration review if there are any significant additional changes in exposure assessment methodology, toxicological points of departure

, or u ncertainty factors.

In addition, a quantitative residential post

- application exposure assessment has not been performed for exposures representing pesticide drift or volatilization from neighboring 2,4

- D

treated agricultural fields; these assessment s may be necessary under registration review.

Aggregate Risk Assessment

For aggregate risk assessment, risk estimates resulting from food, drinking water, and residential
uses are combined.

In the 2005 2,4

- D RED drinking water levels of concern ( DWLOCs ) were calculated for comparison to the EECs

. The respective DWLOCs and aggregate risk estimates were calculated for acute, short

- term , and chronic (non

- cancer) exposures.

### Page 12 of 36

A DWLOC is the water concentration (ppb or ug/liter) that is associated with the dri nking water exposure portion of the risk cup that remains after estimated dietary and residential exposures have been subtracted. This concentration value (DWLOC) represents the available or allowable exposure through drinking water. Estimated Drinking Water Concentrations (EDWCs) in drinking water that are less than the DWLOCs do not exceed HED’s level of concern. DWLOC values vary for population subgroups depending on dietary exposure through foods for each subgroup, assumptions made about the volume of drinking water consumed, and default body weights for each subgroup.

Acute

The previous a cute aggregate risk assessments address ed exposure to 2,4

- D residues in food and water using the DWLOC approach

. The acute DWLOCs were 432 ppb or greater with t he most sensitive population being females 13

- 49 years old. The EECs of 118 ug/liter for surface water
and 15 ug/liter for groundwater we re substantially less than the DWLOCs which indicate d that
the acute aggregate risk estimate s we re not of concern.

Short

- Term

Short

- term aggregate risk assessments were conducted by c alculating DWLOCs based upon
short

- term turf exposures, chronic food exposures and short

- term endpoints. Short

- term exposures from swimming in treated water bodies were not included beca use these exposures

represe nt high

- end unlikely scenarios. The short

- term DWLOCs were calculated only for females

13

- 49 and children 1

- 6 because these population subgroups have the highest exposure and are protective of the other subgroups. The DWLOCS ran ge from 24 to 54 ug/liter. These DWLOCs

were all greater than the E EC s, which range from 15 to 23 ug/liter, and indicate d that short

- term aggregate risk estimates were not of concern.

Chronic

Chronic DWLOCs were calculated based upon chronic dietary exposures. As there are no chronic residential exposures, residential exposures were not included in the chronic DWLOC
calculations. The chronic DWLOCs were 47 ug/liter or greater with the most sen sitive populations being infants and children. The E ECs , which range from 1.5 to 23 ug/liter, were less
than the DWLOCs . Chronic aggregate risk estimate s were not of concern. It should be noted that the master label indicates that potable water consumpti on from a treated water body cannot begin until the 2,4

- D concentration is 70 ug/liter or below, therefore an annual average exposure at the MCL of 70 ug/liter would not occur because dissipation would reduce the initial concentration of 70 ug/liter to an annual average concentration of 11 ug/liter.

Conclusions: In 2005 there were no aggregate (food, water, and residential) risk estimates of concern for 2, 4

- D. During registration review, updated aggregate assessments m ay be conducted as needed to include any significant changes that might be made to toxicological PODs

, FQPA and uncertainty factors, dietary exposure estimates , methods or data HED uses to calculate

### Page 13 of 36

residential exposure estimates , or EDWCs

. Emerging policie s related to pesticide drift and
volatilization assessment s may dictate further changes to the existing aggregate risk assessment.

Cumulative Risk Assessment

The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. 2,4

- D is a member of the alkylphenoxy herbicide class of pesticides. This class also includes MCPA, 2,4

- DB, and 2,4

- DP. Although the various phenoxy herbicides have similar structural components, HED ha s no data indicating that they have a common mode of toxic action. Therefore, a cumulative risk assessment has not been performed for these compounds.

Occupational Exposure

Occupational Handler Exposure

The active ingredient 2,4

- D , including its choline, sodium, and amine salts, and esters are herbicides registered for preplant, preemergence, postemergence or preharvest use a variety of agricultural crops

. Formulations include wettable powder, liq uid, and granule formulations. Occupational handl er exposure scenarios include mixing/loading all formulations ; applying formulations by aerial, groundboom, airblast, or handheld equipment ; mixing/loading/applying with handheld equipment ; flagging ; and applying product to submersed and floating aquatic

w eeds. Short

- and intermediate

- term occupational handler scenarios for all formulations, application rates and application methods have been previo usly assessed in the 2005 RED. Combined (dermal and inhalation) r isk estimates (MOEs) ranged from >1 to > 1000 for mixing/loading scenarios, from 78 to >1000 for applicators, from 500 to >1000 for mixer/loader/applicators, and 210 to >1000 for flaggers, depending on exposure scenario and
level of PPE. T he short

- term and intermediate

- term MOEs for all occupati onal handler scenarios except wettable powders exceed ed the LOC of 100 with baseline or single

- la yer PPE and are not
of concern. The MOEs for handling wettable powders we re acceptable with engineering controls (i.e. water

- soluble bags).

Recommended unit exposures for occupational handler assessments have generally been derived only from the Pesticide Handlers Exposure Database ( PHED )

. However, recently both the Outdoor Residential Exposure Task Force ( ORETF ) and the Agricultural Handler Exposure Task

For ce ( AHETF ) have produced pesticide handler exposure monitoring data that the Agency is using in place of PHED ( http://www.epa.gov/pesticides/science/handler

- exposure

- data.html ). As more reliable data become available, the Agency will cont inue to replace existing data.
Reviewers will incorporate new exposure monitoring data, as necessary, during r egistration

r eview.

An updated occupational handler assessment may be required unde r registration review if warranted by any significant changes in exposure assessment methodology, toxicological points of departure

, or uncertainty factors.

Occupational Post

- application Exposure

### Page 14 of 36

Occupational post

- application dermal exposure is possible from post

- emergent, broadcast foliar

uses. Pre

- emergent, ground directed uses would not result in significant occupational post

application exposure.

A short

- and intermediate

- term occupational post

- application exposure assessment wa s completed in the 2005 RED; only uses resulting in significant foliar residue (not minimal exposure due to application timing or method) and post

- application activities applicable based on application timing were assessed ; uses likely to have limited expo sure potential due to application timing or method were not assessed . Chemical

- specific turf transferrable residue ( TTR ) data are available for 2,4

- D and were used for the occupational post

- application exposure
assessment for turf uses. Chemical

- specific dislodgeable foliar residue (DFR) data we re not available for 2,4

- D; default dislodgeable residue inputs were used for foliar post

- application exposure scenarios. All assessed short

- and intermediate

- term post

- application scenario s were not of concern (M OEs > LO C of 100 ). Post

- application dermal short

- term MOEs using maximum application rates range d from 210 to 17,000; intermediate

- term MOEs using average application rates range d from 300 to 13,000.

Recommended transfer coefficients for occupational pos t

- application assessments are derived
from Agricultural Reentry Task Force ( ARTF) exposure monitoring studies ( http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html ). These transfer coefficients have been updated in 2012 based on a reanalysis and submission of new monitoring
data. Reviewers will incorporate new exposure monitoring d ata, as necessary , during

r egistration r eview.

Volatilization of pesticides may be a potential source of post

- application inhalation exposure to individuals nearby pesticide applications. A quantitative post

- application inhalation exposure

assessment for field volatilization of 2,4

- D and its formulations has not been performed and may
b e necessary under registration review. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ).

In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has residential or occupational uses that could result in post

application dermal exposure. As part of the recent revision to the Healt h Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessmen t , HED analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be dislodged after a foliar a pplication (F AR 

### ). This default value is 25%. Of the analyzed DFR studies, the maximum F AR 

### value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, a calculated MOE of approximate ly 4 times higher than the LOC, i.e. an M OE > 400 if the LOC = 100, using the default dislodged residue value would provide an adequate margin of safety for any potentially higher residues seen in a
chemical

- specific DFR study ( Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and D islodgeable Foliar Residue (DFR) Studies . 6/7/2012, Exposure Science Advisory

### Page 15 of 36

Council ). Based on a screening level assessment, a lthough some of the dermal post

- application

MOEs for 2,4

- D were less than 4 x the LOC (<400), there are no risks of concern; che mical specific DFR data are not being required at this time. Because of the conservative nature of the dermal endpoint and point of departure selected for 2,4

- D , the MOEs calculated using default

DFR data in the previous dermal assessments may be consider ed very conservative ; there are no
dermal risks of concern for 2,4

- D when using the default DFR data.

An updated post

- application occupational assessment may be required under registration review if warranted by any significant changes in exposure assessment methodology, toxicological endpoints or points of departure

, or uncertainty factors.

Restricted Entry Interval (REI)

The WPS Restricted Entry Interval (REI) for 2,4

- D is 12 hours for the ester and sodium salt
forms and is 48 hours for the acid and amine salt forms.

All forms of 2,4

- D are Acute Toxicity Category III or IV for acute dermal, inhalation and oral toxicity and primary skin irritation. The acid and amine salt forms of 2,4

- D Toxicity Category I for primary eye ir ritation; therefore, based on the acute toxicity category the acid and amine salt
forms of 2,4

- D, a restricted entry interval ( REI) of 48 hours is required under the Worker Protection Standard ( WPS). The ester forms are toxicity Category III or IV for pri mary eye irritation; therefore a 12 hour REI is appropriate under WPS. For 2,4

- D end use products where other active ingredients are included, the acute toxicity profile of the other ingredients should be checked to ensure the label lists the appropriate REI.

Conclusions: The occupational exposure database is complete f or 2,4

- D. There were no occupational handler or post

- application exposure estimates of concern. A quantitative occupational post

- application inhalation exposure assessment for 2,4

- D, including assessment of volatilization, may be necessary under registration review. An updated handler assessment and a dermal post

- application assessment may also be necessary if wa rranted by any significant changes in exposure assessment methodology, toxicological points of departure, or uncertainty
factors

.

Public Health and Pesticide Epidemiology Data

HED has evaluated the OPP Incident Data System (IDS) and the publications f rom the Agricultural Health Study (AHS). In general, there were few incidents reported for 2,4

- D as a single chemical only, but there is a high absolute number of incidents reported involving 2,4

- D with another active ingredient

. Although vast majority o f these incidents w ere of low severity, several high severity outcomes are reported in the IDS database. It is important to note that since most of these reported incidents involve more than one active ingredient (i.e. 2,4

- D and another active ingredient) , the incidents that were reported were not necessarily attributable to 2,4

- D. Further, while incident information can be an important source of feedback to the Agency, reports of adverse health effects allegedly due to a specific pesticide exposure ( i.e

. , an “incident”) are largely self

- reported and therefore, generally speaking, neither exposure to a pesticide or reported symptom (or the connection between the two) is validated or otherwise

### Page 16 of 36

confirmed. Typically, causation cannot be determined based on incident data. Nevertheless, based on the absolute number of incidents and the few high severity outcomes that are reported, these incident data warrant further analysis in the preliminary risk assessment phase of Registration Review. Obtaining additional information on current usage data for 2,4

- D would improve future assessments. Additionally, any follow

- up studies from the AHS will be
evaluated if available at the time of the risk assessment.

Tolerance Assessment and International Harmonization

Tolerances are established for residues of 2,4

- D in a variety of food and feed, fish, and livestock
commodities [40 CFR §180.142(a), (c) and (d)]. The residue of concern for tolerance enforcement and risk assessment (plants and livestock) is 2,4

- D, both free and conjugated,
determined as the acid. Adequate analytical methodology is available for data collection and 2,4

- D tolerance enforcement purposes.

The U

. S

. tolerance definition is expressed as “ 2,4

- D (2,4

- dichlorophenoxyacetic acid), both free and conjugated, determined as the acid ”. T he definition for Canada is “ (2,4

- dichlorophenoxy)
acetic acid” and for C odex is “2,4

- D”

. A summary of the U

. S

. tolerances

, and Canadian and Codex MRLs is presented in Appendix 6

. Canadian MRLs are harmonized with the US
tolerance levels , with the exception of citrus. Several of the U

. S

. tolerances are harmonized with Codex MRLs, but there are many that are not harmonized. During registration review the Agency will further evalu ate the tolerance levels to determine if they can be harmonized with
Codex and/or Canada.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the

most recent human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.epa.gov/fedreg/eo/eo12898.htm . The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S. (inc luding different ages, regions, and ethnicities), and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further
refines the risk assessments to ensure that the risk estimates are based on the best available
information.

Human Studies

Past 2,4

- D risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide

expo sure databases such as the PHED, the Agricultural Reentry Task Force (ARTF) Database

, and the Outdoor Residential Exposure Task Force (ORETF) Database . EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and

### Page 17 of 36

convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevail ing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued
reliance on these studies.

A huma n dermal absorption ( in vivo ) stud y (Maibach and Feldman, 1974) w as considered for determining the dermal absorption factor in previous 2,4

- D risk assessments. EPA has reviewed this study and determined that there was no clear evidence that the conduct wa s fundamentally
unethical (J. Carley, 2006).

Endocrine Disruption

EPA has received all required final study reports and data from the Tier 1 battery of tests for 2,4

- D. EPA waived the in vivo mammalian Tier 1 tests for 2,4

- D due to the availability of a newly

- submitted extended one generation reproduction study with 2,4

- D. The submitted EDSP Tier 1 tests will be considered with regard to potential environmental 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 EP A’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 interacti on with endocrine system endpoints.

Data Requirements

None

References

S. Recore, 9/4/12

, 2,4

- D : Review of Human Incidents

, D403874

.

L. Taylor et al , 3/27/12, 2, 4

- D: Revised Evaluation of Data Identified in NRDC Petition and Associated Documents, D392844.

A

. LaMay et al., 2/22/12, Amended Petition for the Establishment of a New Formulation of 2,4

- D Choline on Herbicide Tolerant Field Corn Containing the Aryloxyalkan oate Dioxygenase

- 1 (ADD

- 1) Gene, D398209

.

T. Goodlow, 10/18/07, 2,4

- D: HED Response to Wheat Hay Waiver Request, D340921.

T. Goodlow, 4/16/07, 2,4

- D: HED Response to Irrigated Crop Waiver Request, D336596.

J. Carley, 7/27/06, Initial Ethics Review of Study of Percutaneous Penetration of Severa l
Pesticides .

### Page 18 of 36

USEPA, June 2005, Reregistration Eligibility Decision for 2

, 4

- D

.

T

. Dole et al , 5/12/2005, 2,4

- D. HED’s Revised Human Health Risk Assessment for the Reregistration Eligibility Decision (RED) Rev ised to Reflect Public Comments

, D316597.

T. Jimerson, 4/18/05, 2,4

- D. Revised Acute and Chronic Dietary Exposure Assessments Including Proposed New Uses Hops and Potatoes for the Reregistration Eligibility Decision,

D315512

.

T. Jimerson, 10/13/04, 2,4

- D: Health Effects Division (HED) Metaboli sm Assessment Review Committee (MARC) Decision Document

- Revised. DP Barcodes D309452 Chemical I.D. No. 030001. Case No. 0073. Meeting date: 9/3/03. TXR No. 0052264

Maibach, HI; Feldman, RJ. (1974) Systemic absorption of pesticides through the skin of man. In: Occupational Exposure to Pesticides: Report to the Federal Working Group on Pest Management from the Task Group on Occupational Exposures to Pesticides. Appendix B. US Government Printing Office, 0

- 551

- 026, Washington, DC, pp120

- 127 . MRID 4685910 2.

### Page 19 of 36

Appendix 1

2,4

- D A CTIVE INGREDIENTS IN 

### C ASE 

### N O



### . 00 73 Active ingredient name PC code 2,4

- D acid 030001 2,4

- D sodium salt 030004 2,4

- D diethanolamine salt 030016 2,4

- D, dimethylamine salt 030019 2,4

- D, isopropylamine salt 030025 2,4

- D, triisopropanolamine salt 030035 2,4

- D, butoxyethyl ester or 2,4

- D, b utoxyethanol ester 030053

2,4

- D, 2

- ethylhexyl ester 030063 2,4

- D, isooctyl (2

- ethyl

- 4

- methylpentyl) ester 030064 2,4

- D, isooctyl (2

- octyl) ester 030065* 2,4

- D, isopropyl ester 030066 2,4

- D choline salt (choline) 051505

*No currently registered products

### Page 20 of 36

Appendix 2

The chemical structure and physiochemical properties of 2,4

- D acid is found in Table A 2 .1 and

A 2 .2 below.

TABLE A 2 .1. Compound Nomenclature.

Compound

Common name 2,4

- D

IUPAC name (2,4

- dichlorophenoxy)acetic acid

CAS name 2,4

- dichlorophenoxy acetic acid

CAS registry number 94

- 75

- 7

TABLE A 2 .2. Physicochemical Properties of Technical Grade 2,4

- D.

Parameter Value Reference

Melting point/range 138

- 141 °C Revised Product Chemistry Chapter of the 2,4

- D RED (DP# 309451, 10/12/04, T. Jimerson)

pH 2.7 at 25 °C DP# 167302, 9/25/91, R. Perfetti
Density 1.416 at 25 °C (specific gravity) Revised Product Chemistry Chapter of the 2,4

- D RED (DP# 309451, 10/12/04, T. Jimerson) Water solubility 569 mg/L ( 20 °C)
Solvent solubility g/100 g ( 25 °C )

acetone 85.0

benzene 1.07 diethyl ether 220
ethanol 130 isopropanol 31.6

toluene 0.067 xylene 0.58

Vapor pressure 1.4 x 10
- 7 mm Hg ( 25 °C)

Dissociation constant, pK

a 3.0 at 25.2 °C DP#s 186542 & 190622, 6/1/93, W. Smith
Octanol/water partition coefficient, Log(K OW ) 2.14 at pH 5; 0.177 at pH 7; 0.102 at pH 9 (0.001 M solution) Revised Product Chemistry Chapter of the 2,4

- D RED (DP# 309451, 10/12/04, T. Jimerson)
UV/visible absorption spectrum Maxima at 208, 228.3 and 283.3 nm RD Memo DP# 245940, 6/9/98, S. Mathur

### Page 21 of 36

Appendix 3

Toxicological Doses and Endpoints for 2,4

- D

Table A3.1

. Summary of Current Toxicological Doses and Endpoints for 2,4

- D for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Acute Dietary (General Population, including

Infants and Children) NOAEL=

67 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Acute RfD =

0.67 mg/kg/day

aPAD = 0.67 mg/kg/day Acute Neurotoxicity

- Rat

LOAEL = 227 mg/kg/day, based on gait

abnormalities

Acute Dietary (Females 13

- 49 years of age) NOAEL =

25 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Acute RfD =

0.25 mg/kg/day

cPAD = 0.25 mg/kg/day Developmental Toxicity

- Rat

LOAEL = 75 mg/kg/day, based on fetal
skeletal abnormalities

Chronic Dietary (All Populations) NOAEL= 5

mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Chronic RfD

= 0.05 mg/kg/day

cPAD = 0.05 mg/kg/day Combined Chronic

Toxicity/Carcinogenicity

- Rat

LOAEL = 75 mg/kg/day, based on decreased body

- weight gain (females) and food consumption (females), alterations in hematology [decreased RBC, HCT, and HGB (females), platelets (both sexes)] and clinical chemistry parameters [increased creatinine (both sexes), alanine and aspartate aminotransferases (males), alkaline phosp hatase (both sexes), decreased T4 (both sexes), glucose (females), cholesterol (both sexes), and triglycerides (females)], increased thyroid weights (both sexes at study termination), and decreased testes and ovarian weights .

Incidental Oral
Short

- Term ( 1

- 30 days) NOAEL=

25 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for

MOE = 100 Developmental toxicity

- Rat

LOAEL = 75 mg/kg/day based, on decreased maternal body weight gain

Incidental Oral

Intermediate

Term (1

- 6 months) NOAEL=

15 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for

MOE = 100 Subchronic Oral Toxicity

- Rat

LOAEL = 100 mg/kg/day based on 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.

### Page 22 of 36

Table A3.1

. Summary of Current Toxicological Doses and Endpoints for 2,4

- D for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Dermal Short

Term (1

- 30 days) NOAEL=

25 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for

MOE = 100 Rat developmental toxicity study

LOAEL = 75 mg/kg/day based, on decreased maternal body weight gain and

the increased incidence of skeletal
malformations and variations

Dermal

Intermediate

Term (1

- 6 months) NOAEL=

15 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for

MOE = 100 Subchronic oral toxicity study in rats

LOAEL = 100 mg/kg/day based on 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.

Dermal Long

Term (>6 months) NOAEL= 5

mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Residential

LOC for

MOE = 100 Rat chronic oral toxicity study in rats

LOAEL = 75 mg/kg/day, based on decreased body

- weight gain (females) and food consumption (females), alterations in hematology [decreased RBC, HCT, and HGB (females), platelets (both sexes)] and clinical chemistry parameters [increased creatinine (both sexes), alanine and aspartate aminotransferases (males), alkaline phosp hatase (both sexes), decreased T4 (both sexes), glucose (females), cholesterol (both sexes), and triglycerides (females)], increased thyroid weights (both sexes at study termination), and decreased testes and ovarian weights .

Inhalation
Short

- Term (1

- 30 days) NOAEL=

25 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for

MOE = 100 Developmental toxicity

- Rat

LOAEL = 75 mg/kg/day based, on decreased maternal body weight gain

Inhalation
Intermediate

Term (1

- 6 months) NOAEL=

15 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for

MOE = 100 Subchronic Oral toxicity

- Rat

LOAEL = 100 mg/kg/day based on 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.

### Page 23 of 36

Table A3.1

. Summary of Current Toxicological Doses and Endpoints for 2,4

- D for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Inhalation Long

- Term (>6 months) NOAEL= 5

mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Residential

LOC for

MOE = 100 Combined Chronic Toxicity/

Carcinogenicity

- Rats

LOAEL = 75 mg/kg/day, based on decreased body

- weight gain (females) and food consumption (females), alterations in hematology [decreased RBC, HCT, and HGB (females), platelets (both sexes)] and clinical chemistry parameters [increased creatinine (both sex es), alanine and aspartate aminotransferases (males), alkaline phosphatase (both sexes), decreased T4 (both sexes), glucose (females), cholesterol (both sexes), and triglycerides (females)], increased thyroid weights (both sexes at study termination),
and decreased testes and ovarian weights . Cancer (oral, dermal, inhalation) Classification: Group D

- Not Classifiable as to Human Carcinogenicity. That is, the

evidence is inadequate and cannot be interpreted as showing either the presence or

absence of a carcinogenic effect. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human po pulation (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table A3.2

. Summary of Toxicological Doses and Endpoints for 2,4

- D for Use in Occupational Human
Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Dermal Short

Term (1

- 30 days)* NOAEL=

25 mg/kg/day UF A =10x

UF H =10x Occupational

LOC for MOE =

100 Rat developmental toxicity study

LOAEL = 75 mg/kg/day based, on decreased maternal body weight gain and

the increased incidence of skeletal

malformations and variations

### Page 24 of 36

Table A3.2

. Summary of Toxicological Doses and Endpoints for 2,4

- D for Use in Occupational Human
Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Dermal

Intermediate

Term (1

- 6 months)* NOAEL=

15 mg/kg/day UF A =10x

UF H =10x Occupational

LOC for MOE =

100 Subchronic oral toxicity study in rats

LOAEL = 100 mg/kg/day based on 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.

Dermal Long

Term (>6 months) * NOAEL=5

mg/kg/ day UF A =10x

UF H =10x Occupational

LOC for MOE =

100 Rat chronic oral toxicity study in rats

LOAEL = 75 mg/kg/day, based on decreased body

- weight gain (females) and food consumption (females), alterations in hematology [decreased RBC, HCT, and

HGB (females), platelets (both sexes)] and clinical chemistry parameters [increased creatinine (both sexes), alanine and aspartate aminotransferases (males), alkaline phosphatase (both sexes), decreased T4 (both sexes), glucose (females), cholesterol (both sex es), and triglycerides (females)], increased thyroid weights (both sexes at study termination), and decreased testes and ovarian weights .

Inhalation

Short

- Term (1

- 30 days)* NOAEL=

25 mg/kg/day UF A =10x

UF H =10x Occupational

LOC for MOE =

100 Rat developmental toxicity study

LOAEL = 75 mg/kg/day based, on decreased maternal body weight gain

Inhalation

Intermediate

term (1

- 6 months)* NOAEL=15

mg/kg/day UF A =10x

UF H =10x Occupational

LOC for MOE =

100 Subchronic oral toxicity study in rats

LOAEL = 100 mg/kg/day based on 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.

### Page 25 of 36

Table A3.2

. Summary of Toxicological Doses and Endpoints for 2,4

- D for Use in Occupational Human
Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Inhalation Long

- Term ( >6 months)* NOAEL=5

mg/kg/day UF A =10x

UF H =10x Occupational

LOC for MOE =

100 Rat chronic oral toxicity study in rats

LOAEL = 75 mg/kg/day, based on decreased body

- weight gain (females) and food consumption (females), alterations in hematology [decreased RBC, HCT, and HGB (females), platelets (both sexes)] and clinical chemistry parameters [increased creatinine (both sexes), alanine and aspartate aminotransferases (males), alkaline phosphatase (both sexes), decreased T4 (both sexes), glucose (females), cho lesterol (both sexes), and triglycerides (females)], increased thyroid weights (both sexes at study termination), and decreased testes and ovarian weights . Cancer (oral, dermal, inhalation) Classification: Group D (not classifiable as to human carcinoge nicity)

*The dermal absorption factor is 10 percent and the inhalation absorption factor is 100 percent. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (i nterspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### Page 26 of 36

Appendix 4

Toxicology Data Requirements

The toxicology data requirements (40 CFR 158.340) for the food uses of 2,4

- D are presented below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes

no

yes yes

yes

yes

- yes A

870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

– bacterial

.................... 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5550 Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes y es

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Develop. Neurotoxicity

................................ ................. no

no

yes

yes

yes -

-

yes

yes

yes

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no

yes yes

yes

yes

Special Studies: Extended One

- Generation Reproductive Toxicity (rat) yes yes

A 28

- day

### Page 27 of 36

Appendix 5

Table A5.1. Acute Toxicity Data on 2,4

- D.

Table A5.2. Subchronic, Chronic and Other Toxicity Profile

– 2,4

- D

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3100 90

- Day oral

toxicity ( F i s ch e r 34 4 r a ts ) MRID 41991501 (1991)

Acceptable/Guideline

0, 1, 15, 100, 300 mg/kg/day NOAEL = 15 mg / kg/day LOAEL = 100 mg/kg/day, based on decreases body weight/gain, a l t e r a tion s i n he m a t olog y

a nd c l ini c a l c he m i s tr y parame t e r s , a n d c a t a r a c t
f or m a t io n i n fem a les

. At HDT, e ff

ec ts list e d a b ove occurred more freque n tly an d /or to a greater extent, as well as hist o pat h ol o gical lesions in e y es, liver, testes,

a drenals, ki d neys, t h ymus, b o n e m arrow, spleen, t h yr o ids, l u n g s.

870.3150 Sub c hroni c or a l

( c a psu l e ) tox i c i t y

- dogs MRID 4173730 1 (1990)

A c c e pt a bl e / G uid e line

0

, 0.3

, 1

. 0

, 3.0

, a n d 1 0

m g/kg/d a y] NOAEL = 1 mg / kg/day LOAEL = 3 mg/kg/day, based on decre a sed

bod y w e i g ht/bod y

- w e i g h t g a i n a n d f oo d

c on s u m ptio n ( m a l e s ), alterations in clinical

che m istry para m

eters [ increased BUN (bot h

s e x e s )

, c r e a tin i n e ( m a l e s )]

, an d d e c r e a s e d t e s t i s

w e i g ht in m ales. A t t h e h i g h e st do se t e st e d,

m o rt a lity ( 2 m ales, 1 f e m ale sacri f

iced

m ori b u n d), he m atol o gy alterations, and

m icrosco p ic lesions of the k i dn e y s and testes [h y posp e r m a t o g en e s i s ] w e r e obs e r v ed. Guid e line

No. Stu d y Type MRID # ( S) Results Toxicity Cat e gory

870.1100 Acute O ral 00101605 rat L D 5 0 = 699 mg/kg III

870.1200 Acute D erm a l 00101596 rabbits LD 5 0 >2000 mg/kg III

870.1300 Acute I nhalation 00161660 rat L C 5 0 >1.79 mg/L III

870.2400 Primary Eye I rritation 41125302 seve r e eye irritant I

870.2500 Primary Skin Irritation 42232701 non

- irritating IV

870.2600 De r mal Sensitization 00161659 not a de r mal sensitizer

-

### Page 28 of 36

Table A5.2. Subchronic, Chronic and Other Toxicity Profile

– 2,4

- D

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3150 S u b c h r o n i c o r a l

( d i e t ) t o xi c i t y ( do g) MRID 4278000 1 (1993)

A c c ep t ab l e / G

uid e line

0

, 0.5

, 1.0

, 3.75

, a n d 7. 5

m g /kg / d a y N O A E L = 1 m g / kg / d a y LO A EL = 3.7 5 m

g / kg / d a y , b a s ed on de c r e a s e d bod y

- w e i g h t gai n (bot h s e x e s ) a n d

f ood cons u m

pti o n ( m ales), a s w ell as

a l t erati o ns in cli n ical ch em i s tr y pa r a m e t e r s [inc r e a s e d B U N

, c r e a t inin e , a n d a l a nine

a m inot r an sf e r a s e ] i n bot h s e x e s , a n d d e c r e a s e d

t e s t e s w e i g ht an d s l i g htl y h i g h e r i n c i d e n c e o f

h y p osp e r m a t o g en e s i s /

ju v en i le t e s t i s a n d

in a c t i v e / ju v en i l e pro s t a t e w e r e obs e r v ed.

870.3200 21

- Day dermal

toxicity (rabbit) MRID 41735301

, 4173530 4 (1990)

A c c e pt a bl e / G uid e line

0, 10

, 100

, 100 0 m

g/kg/d a y NOAEL = 1 0 00 mg/k g /da y

LOAEL > 1 0 00 mg/k g /da y , no adverse

effe c ts observed at the limit dose

870.3465 90

- Day inhalation

toxicity (Sprague Dawley CD®)

6 hr/day, 5 days/week for 28 days MRID 47398701 (2008)

A c c e pt a bl e / G uid e line
0, 0.05, 0.1, 0.3, 1.0 mg/L Systemic NOAEL = 0.30 mg/L/day Systemic LOAEL = 1.0 mg/L/day based on increased alkaline phosphatase and aspartate
aminotransferase levels in females and decreased spleen weights in females.

NOAEL ( portal

- of

- entry effects ) = not
determined.

LOAEL ( portal

- of

- entry effects ) 

### = 0.05 mg/L /day, based on squamous metaplasia and epithelial hyperplasia with increased mixed inflammatory cells within the larynx; not totally resolved following a 4

- week recovery period.

870.3700a Developmental

toxicity

Fischer 344 rats

(GD 6

- 15) MRID 00130407

, 0013040 8 (1983)

A c c e pt a bl e / G uid e line

0

, 8

, 25

, an d 7 5 m g/kg/d a y Maternal NOAEL = 25 mg / k g /day

M a t e rn a l L O A EL = 7 5 m g/kg/da y , b a s e d o n d e c r e a s e d body w e igh t ga i ns

. Su r viv a l w a s no t

a f f e c t e d b y t r e a t m en t

.

D e ve l op m en t a l N O A EL = 2 5 m g/kg/d a y Develo p mental LOAEL = 75 mg/ k g/ d ay, based on skeletal variati o ns.

870.3700b Prenatal

developmental in (New Zealand white rabbit)

GD 6

- 18 MR I D 4174760 1 [1990]

A c c e pt a bl e / G uid e line

0

, 10

, 30

, an d 9 0 m g/kg/d a y Maternal NOAEL = 30 mg / k g /day

M a t e rn a l L O A EL = 9 0 m g/kg/d a y , b a s e d o n

c lin i c a l s igns [ a t a xi a , d e c r e a s e d m oto r a c tiv i ty

, lo s s o f right i n g re f

l e x , c old extremities],

aborti o n (2 )

, decre a sed bo d y

- weig h t gains.

Surv i va l w a s no t a f

f e c t e d b y t r e a t m

en t

.

D e ve l op m en t a l N O A EL = 3 0 m g/kg/d a y Develo p mental LOAEL = 90 mg/ k g/ d ay, based

on aborti o ns.

### Page 29 of 36

Table A5.2. Subchronic, Chronic and Other Toxicity Profile

– 2,4

- D

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3800 Reproduction and

fertility effects (Fischer 344 rat) MRID 00150557 and

00163996 (19xx)

acceptable/guideline*

*new 870.3800 required (see MRID below) Parental NOAEL = 5 mg/kg/day. Parental LOAEL = 20 mg/kg/day based on

decr e ased fe m ale body w eight/bo d y weight gain ( F 1) and male renal tubu l e alt e ration ( F 0 and F1). At HDT, excess toxicity and too few pups for second litter (dose group terminated).

Reproductive N OAEL = 20 mg/kg/day. Reproductive LOAEL = 80 mg/kg/day, based

on increased gestation length.

Offspring NOAEL = 5 mg/kg/day Offspring LOAEL = 20 mg/kg/day based on pup deaths.

### Page 30 of 36

Table A5.2. Subchronic, Chronic and Other Toxicity Profile

– 2,4

- D

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3800 Reproduction and

fertility effects ( Crl:CD(SD) rat)

Extended One
Generation Reproductive Toxicity (EOGRT) study 47972101 (2010)

acceptable/non

- guideline*

*satisfies the requirement for a reproduction and fertility effects study P arental (male) systemic NOAEL = 300 ppm (16.6 mg/kg/day )

. P arental (male) systemic LOAEL = 800 ppm (45.3 mg/kg/day), based on nephrotoxicity manifested as increased kidney weights, and degenerative lesions in the proximal convoluted tubules in the main study

P1 rats. Parental (female) systemic NOAEL = 600 ppm ( 40.2 mg/kg/day ) . No toxicologically relevant effects
were identified in P1 females or in the GD 17 satellite female groups at the highest dose tested. Thyroid toxicity NOAEL = 800/600 ppm (45.3 mg/kg/day in males and /40.2 mg/kg/day in females)

, the highest dose tested . The thyroid effects noted in the database were considered to be adaptive. Offsp ring (F1 adults) NOAEL = 300 ppm (20.9/ mg/kg bw/day in males and 23.3 mg/kg/day in females). Offspring (F1 adults) LOAEL = 800/600 ppm (55.6 mg/kg bw/day in males and 46.7 mg/kg/day in females), based on kidney toxicity manifested as increased kidney wei ghts and increased incidence of degeneration of the proximal convoluted tubules

. F1 offspring NOAEL = 300 ppm. The dose on a mg/kg/day basis for the PND 22 F1 offspring was
not calculated. F1 offspring (PND 22) LOAEL = 800/600 ppm, based on decreased body weight observed throughout lactation. DNT offspring NOAEL = 800 ppm/600 ppm (81.7 mg/kg bw/day in males, 59.2 mg/kg bw/day in females) , the highest dose tested [ lack of evidence of DNT (FOB parameters, motor activity, and acoustic startle response) ]

. DIT offspring NOAEL = 800/600 ppm (71.8 mg/kg bw/day in males and 55.3 mg/kg bw/day in females), the highest dose tested [ lack of evidence of DIT [SRBC antibody

- forming cell assay (PND 66

- 70) and Natural Killer Cell assay (PND 87

- 93)]. Reproductive NOAEL = 800/600 ppm (45.3 mg/kg bw/day in males, 40.2 mg/kg bw/day in females), the highest dose tested [ lack of effect on estrous cyclicity, (P1 females, satellite GD 17 dams, Set 3 F1 offspring) or reproductive indices (mating, fertility, time to mating, gestation length, pre

- and

post

- implantation loss



### , number of corpora lutea (satellite GD 17 dams), sperm parameters, ovarian follicle counts, and reproductive organ histopathology).

### Page 31 of 36

Table A5.2. Subchronic, Chronic and Other Toxicity Profile

– 2,4

- D

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.4100a Chronic toxicity

(Fischer 344 rat) MRID 43612001 (1995)

MRID 44284501 (19xx)

0, 5, 75, or 150 mg/kg/day

Acceptable/Guideline NOAEL = 5 mg/kg/day. LOAEL = 75 mg/kg/day, based on de c r e a s e d

bod y

- w e ig h t g ain ( f e m a l e s ) an d f

o o d

c on s u m p t io n ( f

e m a l e s )

, a l ter a t io n s i n he m a t o lo g y [ d e c r e a s e d R B C ( f e m a l e s )

, H G B (f e males), platel e ts (both sexes)] and cli n ical

chemist r y parame t ers [ increas e d crea t ini n e (both sex e s), alani n e and aspartate
aminotransfe r ase (males )

, alkal i ne pho s phatase ( both sex e s), decr e ased T4 (both

sexes )

, glucose (f

e males), c holesterol ( both sexes), and triglyce r ides (fe m ales)], i n cr e ased thyroid weights ( b o t h s e x e s a t s t ud y

t e r m i na t io n )

, d e c r e a s e d t e s t e s an d o v a r ia n

w e ig h t s , an d mi c r o sc op i c l e si o n s i n t h e lu n gs (f e males). A t the high

- dose level, t h ere we r e microscopic lesio n s in the ey e s, liver, adipose
tiss u e, and l ung s

.

There was no t r eat m ent

- r elat e d i n cr e ase in

the incidence of any tumor.

870.4100b Chronic toxicity

(Beagle dog) MRID 43049001 (1993)

Acceptable/Guideline

0, 1, 5, or 7.5/10 mg/kg/day NOAEL = 1 mg/kg/day LOAEL = 5 mg/kg/day, based on decr e ased

bo d y

- w e ight gain (both sexes) and food consumption (f

e males), as well as alte r ations

in clinical chemistry para m et e rs [incr e ased

B U N

, cre a t inin e , a n d a l an i n e

a m in o t r an s f

e r a se , d e c r e a s e d gl u c os e ] i n bo t h

s e x e s , d e c r e a s e d b r ai n w e ig h t i n f e m a l e s , an d

h i s t op a t h ol o gi c a l le si o n s i n t h e li ve r an d

k i dn e y s . At the highest dose tested, aspermatogenesis and degeneration of the

testes was observed in one male and decreased brain weight was observed in both sexes.

870.4200 Carcinogenicity

(Fischer 344 rat) MRID 43612001 (1995)

MRID 44284501 (19xx)

0, 5, 75, or 150 mg/kg/day

Acceptable/Guideline See under 870.4100a above

870.4300 Carcinogenicity

(B 6 C 3 F 1 CRL BR mouse) MRID 40061801 (1993)

Acceptable/Non

- guideline

0, 1, 15, or 45 mg/kg/day NOAEL = 1 mg/kg/day LOAEL = 15 mg/kg/day, based on tre a tmen t

r e la t e d in c r e a s e in ki d ney weights in both

sexes and mic r oscopic r e nal lesio n s in males.

T h ere was no trea t ment

- rela t ed increase in

the i n cidence of any tumor type. Doses not adequate to assess carcinogenic potential.

### Page 32 of 36

Table A5.2. Subchronic, Chronic and Other Toxicity Profile

– 2,4

- D

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.4300 Carcinogenicity

(B 6 C 3 F 1 CRL BR mouse) MRID 43879801 (1995)

MRID 43597201(1995)

Acceptable/Guideline

0, 5, 62/150, or 120/300 mg/kg/day (male/female) NOAEL = 5 mg/kg/day LOAEL =62/150 mg/kg/day, based on based

on a n i n c r e a s e d ab s o l u t e a n d /o r r e la t iv e kidn e y w e ig h t s an d a n in c re a se d in c id e n c e

o f re na l m i c r o sc op i c lesions.

T here w as no trea t ment

- rela t ed increase in

the i n cidence of any tumor type.

870.5 100 Salmonella

typhimurium TA98, TA100, TA1535, Ta1537,

Ta1538 MRID 41409801(1990)

Acceptable/guideline

100

- 100 0 μg /

p l a t e w / S9 ; 66

. 7

- 667 0 μg /

p l a t e w / ou t S9 N o e v i den c e of ba c t e r i a l mu t a t i o n w / a n d

w / ou t S9

870.5395 i n vivo mouse

micronucleus assay

ICR mouse (bone marrow) MRID 41409804

, 41870101 (1990)

Acceptable/guideline

40

- 40 0 μg / kg Neg a ti ve.

870.5450 Uns c hedu l e d DN A

s yn t he s i s a s s a y MRID 4 1 409807 (1990)

Acceptable/guideline N o evidenc e o f i n d uct i o n o f u n schedule d

D N A synthes i s

Literature

studies

cited by

NRDC Mutagenicity/

Genotoxicity ( in vivo and in vitro ) NA Office of Pesticide Programs, EPA, Reevaluation of the Genetic Toxicology

Profile of 2,4

- D. (December 12, 2011).

870.6200a Acute neurotoxicity

screening battery

(Fischer 344 rat) MRID 43115201 ( 1994 )

Acceptable/guideline

0, 15, 75, or 250 mg/kg/day

Achieved: 0, 13, 67, or 227 mg/kg/day N O A E L = 6 7 m g /k g. LOAEL = 227 mg/kg/day, bas e d o n a n inc r e a se d in c id e n c e o f in c o or din a t i o n a n d

s l ig h t g a i t abn o r m a li t i e s ( d e s c r ib e d a s f o r e pa w f le xi n g o r knu c klin g ) an d d e c r e a s e d

t o t a l m o t o r a c t i vi t y.

870.6200b Subchronic

neurotoxicity screening battery

(Fischer 344 rat) MRID 43293901 (1994 )

Acceptable/guideline

0, 5, 75, or 150 mg/kg/day

Males 0, 4.6, 71.2, or 141.1 mg/kg/day

Females 0, 4.6, 68, 138.9 mg/kg/day NO A E L = 71/68 m g /k g /d a y. LOAEL = 141/139 mg/kg/day

, ba se d o n i n c r e a s e d re la t iv e f

o r e li m b g r i p s t re ng t h and

increas e d i n cidence of bilateral r e tinal

d egene r ation.

870.6300 Developmental

neurotoxicity
( Crl:CD(SD) rat) MRID 47972101 (2010)

See under EOGRT DNT offspring NOAEL = 800 ppm/600 ppm (81.7 mg/kg bw/day in males, 59.2 mg/kg bw/day in females), the highest dose tested [lack of evidence of DNT (FOB parameters, motor activity, and acoustic startle response)].

870.7485 Metabolism and

pharmacokinetics ( Fischer 344 rat ) MRID 41737302 (19xx)

### Page 33 of 36

Table A5.2. Subchronic, Chronic and Other Toxicity Profile

– 2,4

- D

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.7600 Dermal penetration

( human , male) F e ld ma n

. R

. J

. a n d

Mai ba c h

, H

. I

. ( 1 9 7 4 )

. P e r c ut a n e o u s P e n e t ra ti o n

o f S ome Pesticides and

H e rbicides in Man.

Toxi c ol. Appl.

Pharmacol. 28: 126

- 132 ]

. dermal applic a tion was 5 .8 % ± 2.4 %

870.7800 Immunotoxicity

SRBC antibody

forming cell assay and
Natural Killer Cell

assay ( Crl:CD(SD) rat) MRID 47972101 (2010)

See under EOGRT DIT offspring NOAEL = 800/600 ppm (71.8 mg/kg bw/day in males and 55.3 mg/kg bw/day in females), the highest dose tested [lack of evidence of DIT [SRBC antibody

- forming cell assay (PND 66

- 70) and Natural Killer Cell assay (PND 87

- 93)].

### Page 3 4 of 36

Appendix 6

International Residue Limits : 2,4

- D (PC Code 030001; 6/14/12)

TABLE A6. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 Codex 2

40 CFR 180.142

Plant/Livestock: 2,4

- D (2,4

- dichlorophenoxyacetic acid), both free and conjugated, determined as the
acid (2,4

- dichlorophenoxy) acetic acid 2,4

- D

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex 2

Almond hulls 0.1 Asparagus 5.0 5.0 Barley, bran 4.0 Barley, grain 2.0 Barley, straw 50 Berry, group 13 0.2 0.1 berries and other
small fruits Cattle, fat 0.3 Cattle, kidney 4.0 5 Edible offal (mammalian) Cattle, meat 0.3 0.2 meat from

mammals other than
marine mammals) Cattle, meat byproducts, except kidney 0.3 5 Edible offal (mammalian) Corn, field, forage 6.0 Corn, field, grain 0.05 0.05 field corn 0.05 maize Corn, field, stover 50 40 maize fodder (dry) Corn, pop, grain 0.05 Corn, pop, stover 50 Corn, sweet, forage 6.0 Corn, sweet, kernel plus cob with husks

removed 0.05 0.05 0.05 sweet corn (corn

on

- the

- cob) (*) Corn, sweet, stover 50 Cranberry 0.5 0.5 0.1 berries and other
small fruits

Fish 0.1 Fruit, citrus, group 10 3.0 2.0 citrus fruits 1 citrus fruits Po Fruit, pome, group 11 0.05 0.05 apples, asian pears, crabapples, loquats, mayhaws, pears, quinces 0.01 pome fruits (*)

Fruit, stone, group 12 0.05 0.05 apricots, nectarines, peaches, plumcots, plums, prune plums, sweet cherries, tart cherries 0.05 stone fruits (*)

Goat, fat 0.3 Goat, kidney 4.0 5 Edible offal (mammalian) Goat, meat 0.3 0.2 meat from
mammals other than marine mammals) Goat, meat byproducts, except kidney 0.3 5 Edible offal (mammalian)

### Page 35 of 36

TABLE A6. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 Codex 2
Grain, aspirated fractions 40 Grape 0.05 0.1 berries and other
small fruits Grass, forage 360 Grass, hay 300 Hop, dried cones 0.2 Horse, fat 0.3 Horse, kidney 4.0 5 Edible offal (mammalian)
Horse, meat 0.3 0.2 meat from
mammals other than marine mammals) Horse, meat byproducts, except kidney 0.3 5 Edible offal (mammalian) Millet, forage 25 Millet, grain 2.0 Millet, straw 50

Milk 0.05 0.01 milks Nut, tree, group 14 0.2 0.2 tree nuts Oat, forage 25 Oat, grain 2.0 Oat, straw 50

Pistachio 0.05

Potato 0.4 0.2 Rice, grain 0.5 0.1 rice, husked Rice, hulls 2.0 Rice, straw 10 10 rice straw and fodder, dry Rye, bran 4.0 Rye, forage 25 Rye, grain 2.0 2 rye Rye, straw 50 Sheep, fat 0.3 Sheep, kidney 4.0 5 Edible offal (mammalian) Sheep, meat 0.3 0.2 meat from

mammals other than marine mammals) Sheep, meat byproducts, except kidney 0.3 5 Edible offal (mammalian)

Shellfish 1.0 Sorghum, grain, forage 0.2 Sorghum, grain, grain 0.2 0.01 (*) Sorghum, grain, stover 0.2 Soybean, forage 0.02 Soybean, hay 2.0 0.01 soya bean fodder (*) Soybean, seed 0.02 0.01 soya bean (dry) (*) Strawberry 0.05 0.05 Sugarcane, cane 0.05 0.05 Sugarcane, molasses 0.2 Teff, bran 4.0 Teff, forage 25.0 Teff, grain 2.0 Teff, straw 50.0

### Page 36 of 36

TABLE A6. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 Codex 2
Vegetable, leaves of root and tuber, group 2 0.1

Vegetable, root and tuber, except potato, group 1 0.1

Wheat, bran 4.0 Wheat, forage 25 Wheat, grain 2.0 2 Wheat, straw 50 100 wheat straw and fodder, dry (c) Tolerances with regional registrations. Tolerances with regional registration, as defined in §180.1(l), are established for residues of the herbicide, plant regulator, and fungicide 2,4

- D, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels is to be determined by measuring residues of 2,4

- D (2,4

- dichlorophenoxyacetic acid), both free and c onjugated, determined as the acid, in or on the follow commodities: Rice, wild, grain 0.05 (d) Indirect or inadvertent residues. Tolerances are established for indirect or inadvertent residues of the herbicide, plant regulator, and fungicide 2,4

- D, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerances levels is to be determined by measuring residues of 2,4

- D (2,4

- dichlorophenoxyacetic acid), both free and conjugated, determined as the ac id, in or on the following commodities: Animal feed, nongrass, group 18 0.2

Avocado 0.05 Cotton, undelinted seed 0.05 Dill, seed 0.05

Okra 0.05 Vegetable, brassica leafy, group 5 0.4 Vegetable, bulb, group 3 0.05 Vegetable, cucurbit, group 9 0.05 Vegetable, foliage of legume, group 7 0.2 Vegetable, fruiting, group 8 0.05 Vegetable, leafy, except brassica, group

4 0.4

Vegetable, legume, group 6 0.05 MRLs with No US Equivalent Eggs 0.01 (*) Hay or fodder (dry) of grasses 400 Poultry meat 0.05 (*) Poultry, edible offal of 0.05 (*)

Completed: M. Negussie; 06/21/2012

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed ha ve not been finalized by the CCPR and the CAC.