### UNITED STATES ENV IRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

MEMORANDUM

Date: December 5, 2013 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: 2,4-DP-p (dichloroprop-p). Human Health Assessment Scoping Document in Support of Registration Review.

PC Code: 031402 (2,4DP-p acid)

, 031403 (2

, 4- DP Barcode: D413488 DP-p amine salt), and 031465 (2

, 4-DP-p 2

- ethylhexyl ester) Decision No.: 481240 Registration No.: NA Petition Nos.: NA Regulatory Actio n: Registration Review Risk Assess Type: Scopi n g Document CaseNo.: NA T XRNo.: NA CAS Nos.: 15165-67-0 (2

, 4D P -p)

, 10 4786-87-0 (2,4-DP-p amine s alt), 53404-32-3 (2

, 4-DP amine salt) and 865363-39-9 (2,4-DP-p 2-ethyl he xyl ester) MRIDNo.: NA



### FROM: Id eliz Negr6n-Encamac i6n

, Ph.D., Risk Assessor 

# :Jd.[.q L

# ~ j
Ronnie Bever
, Jr., Ph.D.,

# ~-i~~**~** 

# 9

- \l"CV 

# fJ Seyed Tadayon,**Chemist~~~** 

### Risk Assessment Branch V

THRU: Health Effects Division (7509P) Office of Pesticide Programs

Linda Tay l or , Ph.D., To xicologis 

# yc._
Michael Metzger, Branch Chief Risk Assessment Branch V Hea lth Effects Division (7509P) Office of Pesticide Programs

TO: Kaitlin Keller

, Chemical Review Manager Tracy Perry, Risk Manager Pesticide Re-evaluation Division (7508P) Office of Pest i cide Programs

Page 

### 1 of30EXECUTIVE SUMMARY



### The HED Regist ra

tion Review Team h as evalua t ed th e most recent hum an health assessments and database for the herb i cide

, 2,4 -D P-p [2-(2,4-dichlorophenoxy)propanoic acid] ( includi ng da ta on it amine salt and ethy l hexy l es t e r )

, to determine whet h er sufficient data are available and whether any updat es are n eeded to s u pport Registration Review. Sin c e 2001, there has been a comp l ete transition o f technical 2,4-DP acid product regi strat ions from th e r ace mic (mixed i somer) form (w ritt en as 2

, 4-D P) to th e enriched isomer form of2,4 -DP (written as 2,4-DP-p). O nl y the R i so mer of2

, 4-DP is herbicidally act i ve. HED has considered the most r ecent humanhe a l th risk assessments for 2

, 4-DP -p ; updates to the toxicity

, exposure, and usage databases ; and

c u rrent Agency science policy and risk assessmen t methodologies to d e t ermine the scope of

wo rk n ecessary to support Registration Review. In addition, HE D conducted an open lit erature search to look for new lit era ture relevant to the human h ea lth risk asses s m e n t. The result s of the lit e ratur e sea r c h showed that no new inf ormation relevant to the human health ri s k assessment has bee n published.

2,4 -DP- p is a ch l orophenoxy h erbicide used primarily in comb in at i on with o th e r h e rbic ides for controlling broadleaf weeds in resid e ntial a nd co mmer c ial turf grass, golf courses, on sod farms

as well as for noxiou s weed and bru s h control on uncultiv a t ed nonagricultura l areas such as roadsides a nd r ight s -of- way. There are no registered food or feed uses for 2

, 4

- DP-p acid or its amines or esters in the U.S. that re qu ire the es tabli shmen t of tolerances. Uses of2,4

- DP-p on pasture (m uni c ipal

, state and fede ra l l a n ds) we r e ide ntifi ed by BEAD. Agricu l tura l uses o n pasture are co nsider ed a foo d use w hi ch is not supported by the database. The 2,4 -DP- p Task force h as indicated th at there is not use on pas ture land

, and h as ex pres sed a w illingness to modify l a b els to prohibit this use

. Toxicity / Hazard Conside r at i ons The tox i city database for 2

, 4-DP-p is incomplete

. A 90-day subchronic inhalation toxicity i s requir ed. The toxicity profile of 2,4-DP-p shows that the princ ip a l toxic effects are nephr otoxic it y and h epatotoxici t y. There were a l s o rep orted clinica l chemistry a nd hema to l ogy changes assoc iated with th e n ep hrotoxicity and hepatotoxicity. 2,4 -DP-p h as been classified as "not like l y to be carcinogenic t o human s." 2,4 DP-p was a l so ge n era ll y not mutagenic. In the
acute neurotoxicity study in ra t s, 2

, 4 -D P-p caused various abno rmaliti es noted dur i ng the functional observa t ional battery (FOB) and caused a decrease in motor activity; however

, no

ev id e n ce of neu r opa th ology was observed. In the combine d subc hroni c oral tox i c i ty and
neurot ox i city study, d ec r eased fore- and hindlimb grip strength were noted in fema le s. No evidence of increas ed s u scep tibility was observe d followin g in utero exposure in rats and rabbit s

or fo ll owi n g pre- and/or postnata l exposure in ra ts. Developmental to xici t y was o b served in the
rat and rabbit at dose levels a t and above those causing maternal toxicity. Reproductive toxic i ty

was observed in th e rat. T h e ava ilabl e toxicity data in d i cate low acute oral, dermal, inhalation

, and primary dermal irritation toxicity for 2,4-DP-p, 2,4-DP-p EHE (2,4 -DP -p ethy l h exy l ester)

, and 2,4-DP-p DMAS (2,4-DP -p dimethylamine s alt ; to xici t y categories III and IV). 2 ,4-DP-p is

a se v e r e eye irritant (toxicity category 1 ). 2,4-DP -p i s not a dermal se nsiti zer; however

, 2,4-DP-p EHE a nd 2,4-DP- p DMAS are dermal sens iti zers.

Page 2 of30

### Page 3 of 30

Dietary Exposure and Risk 2,4

- DP

- p products are used outdoors on turf and for woody plant control in non

- crop areas

. Provided label modifications are made to prohibit use on past ure, there are no uses that would result in dietary exposure . Therefore

, the dietary risk assessment considers drinking water
exposures only . In the most recent dietary risk assessment, a cute and chronic r isks were below the HED level of concern , <16% aRfD and <1% cRfD, respectively (D342620; 08/13/2007)

. Updated d ietary exposure assessments for 2,4

- DP

- p may be necessary to consider the most
recent drinking water consumption data, and to include newly estimated drinking water concentrations.

Residen tial Handler and Post Application Exposure and Risk The residential exposure database is adequate to support registration review for 2,4 DP

- p

. Since 2,4

- DP

- p, its salts, and esters are not restricted use pesticides, HED previously conducted a residential handler exposure assessment for lawn use (D342620; 08/13/2007). Risk estimates

were not of concern. The MOEs ranged from 44,000 to 7,700,000.

Previous residential post

- application assessments, which assessed incidental oral exposures only, relied on def

ault assumptions for turf transferrable residues following treatments. Chemical

specific TTR data is not required to assess exposure to residues following 2,4 DP

- p treatments. For the residential postapplication assessment, the following incidental oral exposures: hand

- to

mouth; object

- to

- mouth; incidental soil ingestion; and episodic ingestion of granules may need to be included in the registration review assessment, reflecting any updated doses and endpoints for risk assessment, HED’s Residential SOPs, and current policies.

Aggregate Risk Assessment In the most recent risk assessment, HED provided updated aggregate exposure and risk estimates for drinking water and residential exposures. Short

- , intermediate

- and long

- term aggregate risk
assessments were conducted. The aggregate risks for this active ingredient were below HED’s level of concern (i.e. MOE > 100). Aggregate exposures of 2,4

- DP

- p may need to be revised during registration review to consider updated dietary and residential exposures estimates , as well as to consider any updated short

- or intermediate

- term endpoints

. Occupational Handler and Post Application Exposure and Risk The occupational exposure database is adequate to support registration review for 2,4 DP

- p

. All short

- and intermediate

- term MOEs for agricultural handler scenarios are assessed at baseline PPE except for aerial applicators, who were assessed with closed cockpit (i.e., engineering controls) built in. All scenarios have target MOEs above 100 and thus are not a risk concern at baseline exposure, except for the following two scenarios: mixing and loading liquids for forestry applications for short

- and intermediate

- term duration; and mixing and loading wettable powder for turfgun for intermediate

- te rm duration. However, these scenarios are not a risk concern with respiratory protection (i.e., a PF5 respirator or dust mask with a protection factor of 5 when properly fitted).

In the absence of toxicity via the dermal route, no quantitative dermal post

- application risk assessment is required for the occupational uses of 2,4

- DP

- p, its salts, and esters.

### Page 4 of 30

Spray Drift Residential exposures resulting from off

- site transport (e.g., spray drift or volatilization) might occur as a result of applications of 2,4

- DP

- p. The Agency is in the process of evaluating these types of exposures and might, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate these post

- application exposures into the Agency ’s risk assessments. The need for spray drift and volatilization risk assessment for 2 , 4

- DP

- p will be examined during registration review.

1.0 F ORMULATIONS AND 

### U SE 

### P ATTERNS



### HED used the Biological and Economics Analysis Division (BEAD) Label Data System to identify all uses of 2,4

- DP

- p. In addition, the BEAD Chemical Profile for Registration Review was used to characterize the use patterns of 2,4

- DP

- p (06/12/2013, B. Phillips et. al.). HED is currently considering products formulated with 2,4

- DP

- p (PC Code 031402), 2,4

- DP

- p dimethyl amine salt (PC Code 031403), and 2,4

- DP

- p 2

- ethylhexyl ester (PC Code 031465).

2,4

- DP

- p is a chlorophenoxy herbicide used primarily in combination with other herbicides for controlling broadleaf weeds in residential and commercial turf grass, golf courses, on sod farms

, as well as for noxious weed and brush control on uncultivated

, nonagricultural areas such as roadsides and rights

- of

- way. 2,4

- DP

- p belongs to the class of phenoxy herbicides that includes 2,4

- D
, 2,4

- D B; MCPA; MCPB; and MCPP

- p. 2,4

- DP

- p is the R

- isomer enriched form of 2,4

- D P (racemic form) which is the herbicidal active component. There are no registered food or feed uses for 2,4

- DP

- p acid or its amines or esters in the U.S. that require the establis hment of tolerances.

2,4

- DP

- p, its salts, and esters are available as soluble concentrates/solid and/or liquid, emulsifiable concentrates, granulars, and ready

- to

- use liquids. They may be applied twice per year on commercial/industrial lawns, drainage systems, golf course turf, rights

- of

- way, ornamental lawns and turf, nonagricultural uncultivated areas, paved areas (private roads and sidewalks), recreational area lawns, and residential lawns. For other uses (e.g., forest plantings)

, the maximum number of applications per year is not currently specified in the labels. Most of the registered products contain 2,4

- DP

- p DMAS.

Agricultural Uses Uses of 2,4

- DP

- p on pasture were identified by BEAD. The Task Force indicated that there are no supported broa d spectrum pasture uses for 2,4

- DP

- p end use products and label clarifications will be made, as appropriate.

Non

- Agricultural and Residential Uses 2,4

- DP

- p is registered for use on ornamental lawns, recreational turf, sports fields, sod farms, roadsides , industrial sites, rights

- of

- way, and forests.

Conclusions: Uses of 2,4

- DP

- p on pasture (municipal, state and federal lands) were identified by BEAD. HED emphasizes that agricultural uses on pasture are cons idered a food use and are not supported by the database

. The 2,4

- DP

- p Task force has indicated that there is not use on

### Page 5 of 30

pasture land, and has expressed a willingness to modify lables to prohibit this use. HED notes that if the 2,4

- DP

- p Task Force, or other end use regist rants, choose to support a pasture use, additional residue chemistry data may be required to support that food use ( see Section 12.0 Data Requirements )

.

2.0 H AZARD 

### I DENTIFICATION 

### /T OXICOLOGY



### The database for 2

- (2,4

- dichlorophenoxy) R

- propionic acid (2,4

- DP

- p) is not complete. A subchronic inhalation toxicity (OPPTS 870.3465) stud y is required and ha s not been submitted. The requirement for an i mmunotoxicity (OPPTS 870.7800) was waived by the Hazard and Science Policy Council (HASPOC; 12/04/2013 ).

The toxicology database for the active ingredient contains studies on 2,4

- DP (racemic mixture) and 2,4

- DP

- p (single R isomer). The older toxicity studies used 2,4

- DP, while the newer toxicity studies tested 2,4

- DP

- p. No new toxicity and/or metabolism data ha ve been received for 2,4

- DP

- p technical since the last risk assessment ( D342620, 2007 ). The 2,4

- DP

- p Task Force provided summaries of toxicity studies (Comparison of toxicity of racemic 2,4

- DP and optically active 2,4

- DP

- p; MRID 46856706). No significant differences in toxicity between the two isomeric forms were identified. Several acute studies of dermal irritation, eye irritation, inhalation toxicity, dermal toxicity, and oral toxicity and skin sensitization were submitted for formulations, 2D + 2DP Am ine (co

- formulation) , and 2 ,4

- D DMA.

The toxicity profile tables for 2,4

- DP

- p are included as Attachment 2. The 2,4

- DP

- p endpoints, points of departure (PoDs), and uncertainty/safety factors (UF/SFs) used in the most recent human health risk assessment are summarized in Appendix A.3. The composite uncertainty factors were 100X for all exposure scenarios. 2,4

- DP

- p does not require food tolerances and is considered to be a non

- food use chemical; therefore, it is not subject to the amendments to the Feder al Food, Drug, and Cosmetic Act (FFDCA) promulgated under the Food Quality Protection Act (FQPA) of 1996.

Nephrotoxicity and hepatotoxicity appear to be the most prevalent effects. There were also reported clinical chemistry and hematology changes assoc iated with the nephro toxicity and hepatotoxicity. Nephrot oxicity was manifested in one or more studies as tubular nephrosis, increased relative kidney weight, foci of basophilic tubules, focal hyperplasia of the transitional epithelium, papillary/medullary calculi, degenerative kidney tubular vacuolization, increased pigment in renal tubuli, increased renal calcification, chronic nephropathy, and increased lipofuscin deposition in the proximal tubular cells, as well as various clinical ch e mistry and urinalysis parameter changes suggestive of nephrotoxicity. Hepatotoxicity was manifested in one or more studies as pronounced lobular pattern, diffuse single cell degeneration, a dissociation

- like appearance of the hepatocytes, too homogeneou s cytoplasm of the hepatocytes, increased liver weights, absence of fat storage, cytoplasmic eosinophilia, granular cytoplasm, hypertrophy , focal necrosis, and bile duct hyperplasia, as well as changes in clinical chemistry parameters indicative of hepatot oxicity. 2,4

- DP

- p has been classified as “not likely to be carcinogenic to humans.” 2,4

- DP

- p was also generally not mutagenic in the various assays

### Page 6 of 30

performed; although, induction of sister chromatid exchanges in Chinese hamsters was noted in one study

. In the acute neurotoxicity study in rats, 2,4

- DP

- p caused functional observational battery (FOB) effects, which included abnormal body posture (prone/lateral), palpebral closure, hypoactivity/apathy, ataxia, hypothermia, decreased number of rearings, incre ased limb splay, retarded righting response, decreased hindlimb grip strength, and increased landing foot splay in males. In addition, 2,4

- DP

- p caused a decrease in motor activity. However, no evidence of neuropathology was observed.

The developmental studies demonstrated that rat and rabbit fetuses were no more sensitive to the effects of 2,4

- DP

- p than their dams. D evelopmental effects observed in rats were decreased fetal body weight, an increased incidence of incompletely ossified sternebra, and an increased incidence of rudimentary cervical ribs. M aternal effects observed in rats included decreased body weight, body weight gain, and food consumption. T he developmental effect observed in rabbits was an increased incidence of 13th accessory rib(s) a t the same dose where decreased body weight gains and food consumption, stomach mucosa ulceration, and clinical signs of reduced general state, lateral or abdominal position, and no defecation were observed in the maternal rabbit

. In the 2

- generation rep roduction study, 2,4

- DP caused parental, reproductive, and offspring toxicity, indicating that the offspring sensitivity to 2,4

- DP was no greater than the parents. T he reproductive effects seen were decreased mating, fertility, and gestation indices; and evidence of systemic offspring toxicity included increased gestation duration and severely decreased live birth and viability indices, as well as retarded growth and development. Parental systemic toxicity included the following findings: mortality and c linical signs of poor maternal care; decreased body weights, body weight gains, and food consumption; increased water consumption; and mild effects on the liver (increased weights, hypertrophy of the periacinar hepatocytes, focal necrosis, and bile duct hy perplasia) and kidneys (increased weights, foci of basophilic (regenerating) tubules, focal hyperplasia of the transitional epithelium and papillary/medullary calculi).

The available toxicity data indicate low acute oral, dermal, inhalation, and primary dermal irritation toxicity for 2,4

- DP

- p, 2,4

- DP

- p EHE, and 2,4

- DP

- p DMAS (toxicity categories III and IV). 2,4

- DP

- p is a severe eye irritant (toxicity category I). 2,4

- DP

- p is not a dermal sensitizer; however, 2,4

- DP

- p EHE and 2,4

- DP

- p DMAS are dermal se nsitizers.

Oral metabolism studies in rats showed that 2,4

- DP

- p was absorbed rapidly, and the majority of the administered dose was excreted in urine as unchanged parent compound. Oral metabolism studies in rats with 2,4

- DP

- p

- ethylhexyl ester (EHE) and 2,4

- DP

- p

- dimethylamine (DMAS) showed that both the ester and amine forms are quantitatively converted to the acid prior to absorption. T he metabolism of 2,4

- DP

- p EHE and 2,4

- DP

- p DMAS in rats is similar to the metabolism of 2,4

- DP

- p. T he major component in the urine was 2,4

- DP

- p, and n either 2,4

- DP

- p EHE nor 2,4

- DP

- p DMAS was detected in urine or feces. The 2,4

- DP DMAS (racemic mixture) also has registered uses that are being considered; however, the toxicity profile is expected to be similar to that of the 2,4

- DP

- p DMAS.

### Page 7 of 30

Conclusions: The database for 2,4

- DP

- p is not complete . A subchronic inhalation toxicity (OPPTS 870.3465) studies is required and ha s not been submitted. The subchronic inhalation toxicity is important because this represents a possible exposure route (aerosol application) and portal

- of

- entry effects were noted in the subchronic inhalation toxicity study on the similar chemical, 2,4

- D. The available oral toxicity studies may not be protective of these portal of entry effects , which , in the case of 2,4

- D, i nclude d squamous metaplasia and epithelial hyperplasia with increased mixed inflammatory cells within the larynx (and this condition was not tot ally resolved following a 4

- week recovery period )

. The results of the subchronic inhalation study may impact the endpoints, PODs, and UF/SFs for the inhalation exposure
assessment.

3.0 D IETARY 

### E XPOSURE



### There are no registered food or feed uses for 2,4

- DP

- p acid, its amines or esters, and thus no food

- related dietary risk assessments were conducted. However, since 2,4

- DP

- p products are used outdoors on turf (golf courses, lawns, parks, etc

. ) and for woody plant control in non

- crop areas (utilit y rights

- of

- way, firebreaks, fence rows, forests, and industrial sites), the risk assessment consider s drinking water exposures. In the most recent assessment, ground water residues were low in comparison to surface water. The conservative screening

- leve l drinking
water assessment for surface water predicted acute and chronic EDWCs using the Tier II PRZM

EXAMS

- Index Reservoir model for uses on Christmas trees , the use resulting in the highest EDWCs . Acute and chronic dietary exposure estimates were below the HED level of concern

, (i.e. < 100% of the acute and chronic reference dose)

, <16% aRfD and <1% cRfD, respectively, for the general population and all population subgroups.

Conclusions: Dietary exposure assessments for 2,4

- DP

- p may be necessar y to consider the most
recent drinking water consumption data from the 2003

- 2008 U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, and to include newly estimated drinking water concentrations. 1



### 4.0 R ESIDENTIAL 

### E XPOSURE



### Residential e xposure to 2,4

- DP may occur from uses on t urfgrass and golf courses

.

Residential Handler In the last risk assessment (D342620; 08/13/2007), the estimated residential handler risk did not exceed HED’s level of concern of 100 (MOE s >100). The MOEs ranged from 44,000 to 7,700,000. However, subsequent to that assessment substantial changes have occurred regarding the exposure methodology HED uses to conduct residential assessments; therefore, f or residential handlers, the following high

- end exposure scenarios for both broadcast and spot treatment of turf may need to be reassessed under registration review : hand application of

1 Registration Review: Preliminary Problem Formulation for Environmental Fate, Ecological Risk, Endangered Species, and Drinking Water Exposure Assessments for 2,4

- DP

- p Containing R Isomer Compounds (2,4

- DP

- p acid, 2,4

- DP

- p Amine salt, and 2,4

- DP

- p 2

- ethylhe xyl ester)

. Khan, Faruque, and Radtke, Meghan., In Progress

.

### Page 8 of 30

granules; belly grinder application; load/apply granules with a broadcast spreader; mix/load/apply with a hose

- end sprayer (mix your own); mix/load/apply with a hose

- end sprayer (ready to use); mix/load/apply with hand held pump sprayer; and mix/load/apply with ready to
use sprayer. Exposure and risk estimates may need to be assessed in registration re view in accordance with the 2012 Residential SOPs.

Residential Post Application Q uantitative residential dermal post

- application risk assessment s w ere not conducted based on the absence of toxicity via the dermal route. However, an incidental oral exposure assessment for children was conducted in the most recent risk assessment ( D342620; 08/13/2007 ). All of the short

- term MOEs for these exposures were greater than 100, and thus are not of risk concern. Exposure and risk estimates may need to be assessed in registration review in accordance with the 2012 Residential SOPs.

Spray Drift Residential exposures resulting from off

- site transport (e.g., spray drift or volatilization) might occur as a result of applications of 2,4

- DP

- p . Th e Agency is in the process of evaluating these types of exposures and might, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate these post

- application exposures into the Agency’s risk assessme nts. The need for spray drift and volatilization risk assessment for 2 , 4

- DP

- p will be examined during registration review.

Conclusions: Updated residential handler and post application exposure and risk assessments may be needed during registration revi ew in accordance with the 2012 Residential SOPs d u ring registration review. Updated assessments should consider current HED policies and procedures and include any updated endpoints as appropriate. As necessary, an inhalation post

- application risk assess ment could be conducted in accordance with the development of relevant HED policies for risk assessment (e.g., spray drift, or volatilization).

5.0 A GGREGATE 

### E XPOSURE AND 

### R ISK 

### A SSESSMENT



### In the most recent risk assessment, HED only provided updated aggregate exposure and risk estimates for drinking water and residential exposures through the inhalation and incidental oral routes. There are two reasons. First, 2,4

- DP

- p has no food use. Second, a dermal exposure assessment was not conducted, because no systemic toxicity was seen at limit dose (1000 mg/kg) with 2,4

- DP

- p or its ester or salt in 21

- day dermal toxicity studies and no developmental toxicity was found with prenatal exposure with 2,4

- DP

- p. Acute, short

- term, and chronic aggregate
assessment s were conducted. Based on the current use

- pattern for 2,4

- DP

- p on turf, there are no intermediate

- term residential exposure scenarios; therefore, an intermediate term assessment was not required. The exposure scenarios aggregated are:

### Page 9 of 30

Acute

– drinking water only Short

- term: adults

– short

- term inhalation handler exposure with chronic (average) drinking water exposure; children

- short

- term incidental oral ingestion with chronic (average) drinking water. The combined MOE’s for the scenarios examined r anged from 360 to 29,800; therefore, below HED’s level of concern (i.e. MOE > 100)

. Chronic

– drinking water only

Conclusions: Acute, short

- term, and chronic aggregate risks are not of concern; however, updated aggregate assessments may be required to support registration review that consider updated dietary and residential exposures estimates or changes in toxicological e nd points

.

6.0 O CCUPATIONAL 

### E XPOSURE



### 2 , 4

- DP

- p, its salts, and esters may be applied using aerial (sod farms only) , groundboom, hand

held spray

, and granular spreader equipment. The personal protective equipment ( PPE) required for handlers consists of a single layer of clothing (long sleeve shirt, long pants, and socks plus shoes) and chemical resistant gloves. The restricted ent ry interval (REI) for 2,4

- DP

- p is 12 hours.

The occupational uses of 2 ,4

- DP

- p, its salts, and esters result in short

- term (1

- 30 days) and intermediate

- term (1

- 6 months) occupational exposures. Based on the current use patterns, no long

- term residenti al or occupational exposures are anticipated; therefore, no long

- term dermal or inhalation risk assessments have been conducted.

Occupational Handler Exposure The registrant has not submitted chemical

- specific exposure data to estimate handler exposures

. In the absence of chemical

- specific data, it is HED policy to use the best available data to assess handler exposures. Sources of such generic (surrogate) handler data include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricul tural Handler Exposure Task Force (AHETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of Federal Insecticide, Fungicide, and Ro denticide Act (FIFRA).

All short

- and intermediate

- term MOEs for agricultural handler scenarios are assessed at baseline PPE except for aerial applicators, who were assessed with closed cockpit (i.e., engineering

c ontrols) built in. All scenarios have target MOE s above 100 and thus are not a risk concern at baseline exposure (MOE,s ranged from 2 00 to 37,000)

, except for the following two scenarios: mixing and loading liquids for forestry applications for short

- and interm ediate

- term duration (MOE’s were 41 and 29 respectively) ; and mixing and loading wettable powder for turfgun for intermediate

- term duration (MOE was 78) . However, these scenarios are not a risk concern with respiratory protection (i.e., a PF5 respirator or dust mask with a protection factor of 5 when properly fitted).

Occupational Post

- application Exposure In the absence of toxicity via the dermal route, no quantitative dermal post

- application risk

### Page 10 of 30

assessment is required for the occupational uses of 2 ,4

- DP

- p, its salts, and esters . The REI on registered labels is considered appropriate based on the toxicity of the technical ingredient. Although HED would typically require dislodgeable foliar residue (DFR) studies based on the existing use pattern, no studies are required due to a lack of toxicity via the dermal route.

Conclusions: Updated occupational handler exposure assessments may be needed during registration review if a new inhalation dose and endpoint for risk assessment are selected and to consider the most current exposure data and SOPs

.

7.0 P UBLIC 

### H EALTH AND 

### P ESTICIDE 

### E PIDEMIOLOGY 

### D ATA



### T he OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases were consulted for pesticide incident data on the active ingredients Dichlorprop, 2,4

- DP

- p, 2,4

- DP

- p, amine salt, Dimethylamine

- 2

- (2,4

- dichlorophenoxy ) propionate, Isooctyl 2

- (2,4

- dichlorphenoxy)propionate, Propionic acid, 2

- (2,4

- dichlorophenoxy)

- , 2

- ethylhexyl ester, and 2,4

- DP

- p, 2

- ethylhexyl ester (E. Evans and S. Recore, D415950, 11/07/2013)

.

HED has evaluated the available incident data and conclu des that b ased on the low frequency and severity of incident cases reported for the active after mentioned ingredients in both IDS and SENSOR

- Pesticides, there does not appear to be a concern at this time that would warrant further investigation. The Agen cy will continue to monitor the incident information

, and if a concern is triggered, additional analysis will be included in the risk assessment.

8.0 E NVIRONMENTAL 

### J USTICE



### Potential areas of environmental justice concerns, to the extent possible, were consi dered in this 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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups

, and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to

### Page 11 of 30

bystanders and farm workers

, as well as lifestyle and traditional dietary patterns among specific subgroups.

9.0 C UMULATIVE 

### R ISK 

### A SSESSMENT



### Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to 2,4

- DP

- p and any other substances and 2,4

- DP

- p does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that 2,4

- DP

- p has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for c umulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative

.

10.0 H UMAN 

### S TUDIES



### Past 2,4

- DP

- p risk assessments rely in part on data from studies in which adult human subjects were intentiona lly exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED) and th e Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethi cal or significantly deficient relative to the ethical standards prevailing 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.

11.0 D ATA 

### R EQUIREMENTS



### A subchronic inhalation toxicity study (OPPTS Guideline 870.3465) is needed based on the requirements of 40 CFR § 158 by the decision of the HASPOC (12/04/13 )

.

Residue data and toxicity data for 2,4

- DP

- p are not available to support agricultural uses on pasture feed to livestock. In the event that the registrants want to pursue uses on pasture ( e.g. broadcast uses on federal rangeland) additional toxicity (see A ppendix A. 1 .) and residue chemistry (OPPTS Guideline 860.1500 for field trials on pasture, 860.1300 for nature of residue, determination, and if necessary OPPTS Guideline 860.1480 to determine the residue level that may incur in livestock commodities ) data requirements would apply.

Turf Transferable Residue (TTR): In accordance with the updated Part 158 data requirements (2007), a TTR study is required for all occupational (e.g., sod farms, golf courses, parks, and

### Page 12 of 30

recreational areas) or residential turf uses. At this time, 2,4 DP

- p does not have a dermal hazard/endpoint, therefore, chemical

- specific TTR data are not necessary.

### Page 13 of 30

Appendix A: Toxicology Profile

A.1 Toxicology Data Requirements

The requirements to support current uses except pasture are in the table below. The se are the requirements (40 CFR 158. 500 ) for food use for 2,4

- DP

- p . Note that although there are no food uses of 2,4

- DP

- p, dietary exposure is assessed to consider residues in drinking water. Use of the new guideline numbers d oes not imply that the new (1998) guideline protocols were used.

Test 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 Irritatio n................................... 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
no
no yes yes yes

yes yes NA 2

no 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/ Carcin ogenicity...................................... no 1

no 1

no 1

no 1

no 1 yes

yes yes yes yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial......... 870.5300 Mutagenicity

— Gene Mutation

- mammalian..... 870.5375 Mutagenicity

— Structural Chromosomal

Aberrations...................................................... 870.5385 Mutagenicity

— Mammalian Bone Marrow

Chromosomal Aberration Test.......................... 870.5395 Mutagenicity

— Mammalian erythrocyte micronucleus

test............................................. yes yes

yes

yes
yes yes

yes

yes

no 3

yes
870.6100a Acute Delayed Neurotox. (hen)........................ 870.6100b 90

- Day Neurotoxicity (hen)............................... 870.6200a Acute Neurotox. Screening Battery (rat)........... 870.6200b 90

- Day Neuro. Screening Battery (rat)............... 870.6300 Develop mental Neuro

. ................................................ no
no yes yes
no no

no yes yes
no

870.7485 General Metabolism......................................... 870.7600 Dermal Penetration.......................................... 870.7800 Immunotoxicity.......................................... yes
no
no 4 yes

no
no

1 Not required under the registered use patterns.
2 The 21

- Day dermal study is sufficient to satisfy this requirement.
3 There are mutagenicity studies which evaluate both somatic and germinal cells, which is considered sufficient to satisfy CFR requirements.
4 HASPOC waived this requirement.

### Page 14 of 30

The require ments to support uses on pasture and the current uses are in the table below. These are requirements (40 CFR 158.500) for food use for 2,4

- DP

- p . Note that although there are no food uses of 2,4

- DP

- p, dietary exposure is assessed to consider residues in drinking water. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test 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 Irritatio n................................... 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 yes yes yes

yes yes NA 1

no 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/Carcinogenicity...................................... yes yes yes yes
no yes

yes yes yes yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial......... 870.5300 Mutagenicity

— Gene Mutation

- mammalian..... 870.5375 Mutagenicity

— Structural Chromosomal

Aberrations...................................................... 870.5385 Mutagenicity

— Mammalian Bone Marrow

Chromosomal Aberration Test.......................... 870.5395 Mutagenicity

— Mammalian erythrocyte micronucleus

test............................................. yes yes

yes

yes
yes yes

yes

yes

no 2

yes
870.6100a Acute Delayed Neurotox. (hen)........................ 870.6100b 90

- Day Neurotoxicity (hen)............................... 870.6200a Acute Neurotox. Screening Battery (rat)........... 870.6200b 90

- Day Neuro. Screening Battery (rat)..........

..... 870.6300 Developmental Neuro. ................................................ no
no yes yes
no no

no yes yes
no

870.7485 General Metabolism......................................... 870.7600 Dermal Penetration.......................................... 870.7800 Immunotoxicity.......................................... yes
no
no 3 yes

no
no

1 The 21

- Day dermal study is sufficient to satisfy this requirement.
2 There are mutagenicity studies which evaluate both somatic and germinal cells, which is considered sufficient to satisfy CFR requirements.
3 HASPOC waived this requirement.

### Page 15 of 30

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile of 2,4

- DP

- p, 2,4

- DP

- p DMAS and 2,4

- DP

- p EHE (a)

Guideline No. Study Type 2,4

- DP

- p 2.4

- DP

- p DMAS 2,4

- DP

- p EHE

Results Toxicity

Category Results Toxicity Category Results Toxicity Category 870.1100 Acute Oral

– Rat 567 mg/kg III 637 mg/kg III 825 mg/kg III

870.1200 Acute Dermal

–

Rat LD50

>2000 mg/kg III >2000 mg/kg III >2000 mg/kg III

870.1300 Acute Inhalation

– Rat > 2.7 mg/L IV >5.28 mg/L IV >4.1 mg/L IV

870.2400 Primary Eye

Irritation

– Rabbit A severe

eye irritant I NA NA

870.2500 Primary Skin

Irritation

– Rabbit A slight or

mild irritant IV NA NA

870.2600 Dermal

Sensitization

– Guinea Pig Not a skin

sensitizer N/A A skin sensitizer N/A A skin sensitizer N/A

NA = Not available



### Table A.2.2 Acute Toxicity Profile of 2,4

- DP Technical a
Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute Oral

– Rat 40955602 825 < LD50 < 1,470 mg/kg III 870.1200 Acute Dermal

– Rat 40955603 LD50 > 4 g/kg III 870.1300 Acute Inhalation

– Rat 41231201 LC50 > 7.4 mg/L IV

870.2400 Primary Eye Irritation

–

Rabbit 40955605 a severe to corrosive ocular irritant I

870.2500 Primary Skin Irritation

–

Rabbit 40955604 a mild to moderate dermal irritant III

870.2600 Dermal Sensitization

–

Guinea Pig 40982202 skin sensitizer N/A
a 2,4

- DP technical (pc 031401) is a racemic mixture: 3 forms of 2,4

- DP supported by registrants in the 2,4

- DP

- p Task Force are 2,4

- DP

- p (pc code 031402); 2,4

- DP

- p EHE (pc code 031465) and 2,4

- DP DMAS (pc code 031409)

### Page 16 of 30

Table A.2.3 Acute Toxicity Profile of 2,4

- DP

- p Technical a
Guideline No. Study Type MRID(s) Results Toxicity Category
870.1100 Acute Oral

– Rat 42985308 567 mg/kg III
870.1200 Acute Dermal

– Rat 42985309 LD50 >2000 mg/kg III 870.1300 Acute Inhalation

– Rat 42985310 > 2.7 mg/L IV**

870.2400 Primary Eye Irritation

– Rabbit 42985311 A severe eye irritant I

870.2500 Primary Skin Irritation

– Rabbit 42985312 A slight or mild irritant IV

870.2600 Dermal Sensitization

– Guinea Pig 43749701 Not a skin sensitizer N/A

a The acute inhalation study report provided EAD (equivalent aerodynamic diameter).



### Table A.2.3. Acute Toxicity Profile of 2,4

- DP

- p EHE Technical Guideline No. Study Type MRIDs # Results Toxicity Category 870.1100 Acute Oral

– Rat 42614602 824 mg/kg III 870.1200 Acute Dermal

– Rat 42614604 >2000 mg/kg III 870.1300 Acute Inhalation

– Rat 42937001 >4.1 mg/L IV

870.2400 Primary Eye Irritation

– Rabbit 42729101 A mild eye irritant IV

870.2500 Primary Skin Irritation

– Rabbit 42729103 A slight or mild irritant IV

870.2600 Dermal Sensitization

– Guinea Pig 43749702 A skin sensitizer N/A



### Table A.2.4. Acute Toxicity Profile of 2,4

- DP

- p DMAS Technical Guideline No. Study Type MRIDs # Results Toxicity Category 870.1100 Acute Oral

– Rat 42614601 637 mg/kg III 870.1200 Acute Dermal

– Rat 42614603 >2000 mg/kg III 870.1300 Acute Inhalation

– Rat 42914501 >5.28 mg/L IV

870.2400 Primary Eye Irritation

– Rabbit Not submitted NA NA

870.2500 Primary Skin Irritation

– Rabbit 42729102 A very slight irritant IV

870.2600 Dermal Sensitization

– Guinea Pig 43749703 A skin sensitizer N/A

### Page 17 of 30

Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (Year)/ Classification/Doses Results

870.3100 90

- Day oral

toxicity (rat) 00250351 (1981)

Acceptable/guideline 0, 100, 300, 1000, 3000
ppm (0, 5, 15, 50, 150 mg/kg/day) 50/50 racemic mixture of 2,4

- DP NOAEL = 15 mg/kg/day LOAEL = 50 mg/kg/day based on: changes in clinical chemistry and hematology parameters

Males ↑ ALP, total bilirubin, albumin and albumin/globulin ratio ↓ globulin

Females ↑ albumin/globulin ratio ↓ hematocrit and hemoglobin concentration, erythrocyte count, and globulin

870.3100 90

- Day oral

toxicity (rat) 00116494 (1981)

Acceptable/non

- guideline 0, 100, 500, 2500 ppm (0, 5, 25, 125 mg/kg/day) 50/50 racemic mixture of 2,4

- DP NOAEL not observed LOAEL = 5 mg/kg/day (lowest dose tested) based on: ↑ Kidney lesions (slight tubular nephrosis)

Incidence of slight tubular nephrosis: 1/15, 5/15, 6/15, 4/15 in 0, low

- , mid

- , high

dose males 0/15, 3/15, 1/15, and 2/15 in 0, low

- , mid

- , high

- dose females

25 mg/kg/day liver lesions: pronounced lobular pattern (♂ only) diffuse single cell degeneration (♀ only)

125 mg/kg/day ♂ and ♀ ↓ body wt., food consumption changes in clinical chem, hematology, and urinalysis
liver lesions: pronounced lobular pattern (♂ only) diffuse single cell degeneration (♀ only)
a dissociation

- like appearance of the hepatocytes too homogen eous cytoplasm of the hepatocytes

### Page 18 of 30

Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (Year)/ Classification/Doses Results

870.3100 90

- Day oral

toxicity (rat) 41653801 (1987)

Acceptable/guideline 0, 100, 500, 2500 ppm (0, 5, 25, 125 mg/kg/day) 2,4

- DP

- p NOAEL = 5 mg/kg/day LOAEL = 25 mg/kg/day based on: ↑ Relative kidney wt in males (dose

- related)

At 125 mg/kg/day ↓ body weight ↑ absolute liver wt ↑ relative liver and kidney wt Alterations in blood chemistry

870.3100 90

- Day oral

toxicity (mouse) 43103201 (1993)

Acceptable/guideline 0, 100, 1000, 2500 ppm (♂: 0, 20, 224, 683 mg/kg/day) (♀: 0, 33, 380, 1043 mg/kg/day) 2,4

- DP

- p NOAEL = 224 mg/kg/day LOAEL = 683 mg/kg/day based on: ↓ Body weight, body weight gain, and food efficiency

Clinical chemistry parameters: ↑ ALP ↑ cyanide

- insensitive palmitoyl

- CoA

oxidation Histopathological findings: eosinophilic hepatocytes marked cytoplasmic eosinophilia in renal tubule cells

### Page 19 of 30

Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (Year)/ Classification/Doses Results

870.3100 and 870.6200 Combined

subchronic oral toxicity and neurotoxicity (rat) 43915101 (1995)

Acceptable/guideline 0, 100, 500, 2000 ♂/3000 ♀ ppm (♂: 0, 7, 35, 144 mg/kg/day) (♀: 0, 8, 42, 245 mg/kg/day) 2,4

- DP

- p NOAEL = 35 mg/kg/day LOAEL = 144 mg/kg/day based on: ↓ Body wts, body wts gains, food consumption ↑ Water consumption ↑ Liver and relative brain wt (♀), relative liver and kidney wt (♂/♀)

↑ ALP, ALT (♀), creatinine (♂), total bilirubin (♂) ↓ globulin, triglyceride, cholesterol, ↑ WBC count, monocyte, poly

morphonuclear neutrophil counts (♀) ↑ urine volume and presence of RBCs (♀) ↓ urine spe cific gravity ↓ RBC, hemoglobin, hematocrit

Liver microscopic findings (♂/♀): Absence of fat storage Cytoplasmic eosinophilia (moderate to severe ) Granular cytoplasm (moderate to severe) Slight central hypertrophy (♀ o nly)

FOB: ↓ fore

- and hindlimb grip strength (♀)

motor activity: effects were not treatment

- related

870.3150 90

- Day oral

toxicity (dog) 43462601 (1994)

Acceptable/guideline 0, 25, 175, 525 ppm (♂: 0, 0.7, 5.1, 15.7 mg/kg/day) (♀: 0, 0.8, 5.8, 18.1 mg/kg/day) 2,4

- DP

- p NOAEL = 5.1 mg/kg/day LOAEL = 15.7 mg/kg/day based on: Frequent diarrhea (up to 11 times) occurred in 4/5 males and 2/5 females during 1 to10
weeks. ↓ red blood cell count, triglyceride levels

### Page 20 of 30

Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (Year)/ Classification/Doses Results

870.3200 21

- Day dermal

toxicity (rat) 43706401 (1995)

Acceptable/guideline 0, 15, 150, 1000 mg/kg/day 2,4

- DP

- p EHE (93.2% a.i. as EHE; 65% a.i. as acid) Systemic NOAEL = 1000 mg/kg/day (limit dose) LOAEL = Not observed
Dermal NOAEL = 120 mg/kg/day LOAEL = 1000 mg/kg/day based on: Sporadic skin irritation at 1000 mg/kg/day. No irritation was seen after cessation of treatment

870.3200 21

- Day dermal

toxicity (rat) 43634401 (1988)

Acceptable/guideline 0, 12, 120, 1000 mg/kg/day 2,4

- DP

- DMAS (75.3% a.i. as DMAS salt; 60% a.i. as acid) Systemic NOAEL = 1000 mg/kg/day (limit dose) LOAEL = Not observed
Dermal NOAEL = 120 mg/kg/day LOAEL = 1000 mg/kg/day based on: Sporadic skin irritation at 1000 mg/kg/day. No irritation was seen after cessation of treatment

870.3200 21

- Day dermal

toxicity (rabbit) 42914301 (1993)

Acceptable/guideline 0, 10, 100, 1000 mg/kg/day 2,4

- DP

- p Systemic NOAEL = 1000 mg/kg/day (limit dose) LOAEL = Not observed
Dermal NOAEL = Not determined LOAEL = 10 mg/kg/day based on: Induced slight erythema (1/5 males and 1/5 females). Microscopically, minimal diffuse acanthosis (3/5 females) accompanied by minimal diffuse inflammatory cells in the superficial dermis (1 female).

100 and 1000 mg/kg/day induced well defined dermal irritation (erythema, edem a, beige staining of the treatment site and sloughing)

870.3250 90

- Day dermal

toxicity (species) NA NA

870.3465 90

- Day inhalation

toxicity (species) NA NA

### Page 21 of 30

Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (Year)/ Classification/Doses Results

870.3700a Prenatal

developmental(rat ) 42845805 (1993)

Acceptable/guideline 0, 20, 80, 160 mg/kg/day 2,4

- DP

- p Interim report is found in MRID 42615001 (1992) Maternal NOAEL = 20 mg/kg/day LOAEL = 80 mg/kg/day based on: ↓ body wt., body wt. gain, food consumption

Developmental NOAEL = 80 mg/kg/day LOAEL = 160 mg/kg/day based on: ↓ fetal body wt ↑ incidence of incompletely ossified sternebra ↑ incidence of rudimentary cervical ribs

870.3700b Prenatal

developmental(rab bit) 42845804 (1993)

Acceptable/guideline 0, 20, 50, 100 mg/kg/day 2,4

- DP

- p Materna l NOAEL = 50 mg/kg/day LOAEL = 100 mg/kg/day based on: ↑ Clinical signs (reduced general state, lateral or abdominal position and no defecation) ↓ Body wt. gains (

- 69%) , food consumption (

- 14%) during dosing period Ulceration of the stomach mucosa.

Developmenta l NOAEL = 50 mg/kg/day LOAEL = 100 mg/kg/day based on: ↑ Incidence of 13th accessory rib(s) (9 in 6 litters vs. 1)

870.3800 Reproduction and

fertility effects ( rat ) 46721401 (1992)

Acceptable/guideline 0, 80, 400, 2000 ppm (♂: 0, 8.0, 40.1, 219.6 mg/kg/day) (♀: 0, 8.7, 43.0, 233.0 mg/kg/day) Racemic (50:50) mixture of 2,4

- DP Recent range finding study for 2,4

- DP

- p, MRID 46591904 (2001) is referenced in this DER Parental/Systemic NOAEL = 40 mg/kg/day LOAEL = 219 mg/kg/day based on: Mortality and clinical signs (poor maternal care); decreased body weights, body weight gains, and food consumption; increased water consumption; and mild effects on the liver (increased weights, hypertrophy of the periacinar hepatocytes, focal necrosis, an d bile duct hyperplasia) and kidneys [increased weights, foci of basophilic (regenerating) tubules, focal hyperplasia of the transitional epithelium and papillary/medullary calculi].

Reproductive NOAEL = 40 mg/kg/day LOAEL = 219 mg/kg/day based on: Decr eased mating, fertility, and gestation indices. Severely decreased live birth index.

Offspring NOAEL = 40 mg/kg/day LOAEL = 219 mg/kg/day based on: Severely decreased viability indices and retarded growth and development.

870.4100a Chronic toxicity

(species) NA NA

### Page 22 of 30

Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (Year)/ Classification/Doses Results

870.4100b Chronic toxicity

(dog) 44638401 (1997)

Acceptable/guideline 0, 120, 240, 720 ppm (♂: 0, 3.5, 7.0, 22.2 mg/kg/day) (♀: 0, 3.9, 7.7, 26.1 mg/kg/day) 2,4

- DP

- p NOAEL = 7 mg/kg/day LOAEL = 22 mg/kg/day based on: ↓ Body weight gain changes (16%lower than controls) in females

Microscopic changes in one male

-- epididymides (chronic inflammation of the epididymides with slight amounts of cellular debris in the lumen, moderate flattening of the epididymal duct epi thelium, and slight oligospermia)

-- kidneys (slight degenerative kidney tubular vacuolization)

-- prostate gland (moderate chronic inflammation)

870.4200b Carcinogenicity

(mouse) 44900801 (1996) and

44888201 (1998) Acceptable/guideline 0, 40, 400 ppm (♂: 0, 6, 59 mg/kg/day) (♀: 0, 8, 78 mg/kg/day)

2000 ppm males and 3500 ppm females for 9 months

0 or 800 ppm (equivalent to 0 and 143 mg/kg/day) for up to 18 months 2,4

- DP

- p NOAEL = 6 mg/kg/day LOAEL = 59 mg/kg/day based on: Decreased body weights, body weight gains, food consumption, and food efficiency in males, increased pigment in renal tubuli in males, increased renal calcification in both sexes, and increased kidney weight and chronic nephropathy in females.

Treatment related increase in tumor incidence was not found. Dosing was considered adequate based on decreases in body weights, body weight gains, food consumption, food efficiency, and nephrotoxicity. (no) evidence of carcinogenicity

870.4300 Combined chronic

toxicity/ carcinogenicity (rat) 00146394 (1984)

Acceptable/guideline 0, 100, 300, 1000, 3000
ppm (♂: 0, 3.6, 11.0, 36.5, 116 mg/kg/day) (♀: 0, 4.4, 13.1, 45.7, 147 mg/kg/day) 2,4

- DP

- p NOAEL = 3.6 mg/kg/day LOAEL = 11 mg/kg/day based on: ↓ Specific gravit y and protein in urine

Treatment related increase in tumor incidence was not found.

In 36.5 m/k/d groups, ↓ urine specific gravity and protein ↑ lipofuscin deposition in the proximal tubular cells of the kidneys (both sexes). ↑ alkaline phosphatase and SGPT

### Page 23 of 30

Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (Year)/ Classification/Doses Results

Genetic Toxicity 870.5100 Bacterial reverse

mutation test 42985313 (1990)

Acceptable/guideline
5

- 500 μg/plate ±S9 2,4

- DP

- p Not genotoxic

Genetic Toxicity 870.5300 In vitro

mammalian cell gene mutation test 42985315 (1990)

Acceptable/guideline
Trial 1: 6.4

- 4000 μg/mL ±S9
Trial 2: 7.2

- 4500 μg/mL ±S9 2,4

- DP

- p Not genotoxic

Genetic Toxicity 870.5375 In vitro

mammalian chromosome aberration test 40581901 (1988)

Acceptable/guideline 75.1, 100, 501, 751, 1000 μg/ml without S9; 1000, 1500, 2000, 2500, 3000 μg/ml with S9 racemic (50:50) mixture of 2,4

- DP Positive in the presence of S9 and only at cytotoxic concentrations Negative in the absence of S9

Genetic Toxicity 870.5375 In vitro

mammalian chromosome aberration test 42985314 (1990)

Acceptable/guideline 8, 40, 200, 1000, 5000 μg/mL (±S9) 2,4

- DP Negative for clastogenic activity

Genetic Toxicity 870.5375 In vitro

mammalian chromosome aberration test 43189401 (1994)

Acceptable/guideline 10, 30, 100, 300 μg/mL (±S9) 2,4

- DP

- p Negative response in the absence and presence of S9

Genetic Toxicity 870.5395 Mammalian

erythrocyte micronucleus test 42985316 (1991)

Acceptable/guideline 4, 20, 100 mg/kg 2,4

- DP

- p Negative for clastogenic or aneugenic effects

Genetic Toxicity 870.5550 Unscheduled

DNA synthesis in mammalian cells in culture 44900802 (1994)

Acceptable/guideline 50, 200, 500 mg/kg 2,4

- DP

- p Negative

– did not induce UDS in the hepatocytes of treated rats

### Page 24 of 30

Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (Year)/ Classification/Doses Results

Genetic Toxicity 870.5915 In vivo sister

chromatid exchange assay 41646803 (1985)

Acceptable/guideline 47, 280, 1780 mg/kg Racemic (50:50) mixture of 2,4

- DP Positive for induction of SCE’s in Chinese hamsters

870.6200a Acute

neurotoxicity screening battery 43770901 (1995)

Acceptable/guideline 0, 125, 250, 400, 500 mg/kg 2,4

- DP

- p NOAEL = 125 mg/kg/day LOAEL = 250 mg/kg/day based on: FOB findings
Males and females abnormal body posture (prone/lateral), palpebral closure, hypoactivity/apathy, ataxia, hypothermia, decreased number of rearings
Males increased limb splay, retarded righting
response, decreased hindlimb grip strength, increased landing foot splay

↓ motor activity

### Page 25 of 30

Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (Year)/ Classification/Doses Results

870.6200b and 870.3100 Combined

subchronic oral toxicity and neurotoxicity (rat) 43915101 (1995)

Acceptable/guideline 0, 100, 500, 2000 ♂/3000 ♀ ppm (♂: 0, 7, 35, 144 mg/kg/day) (♀: 0, 8, 42, 245 mg/kg/day) 2,4

- DP

- p NOAEL = 35 mg/kg/day LOAEL = 144 mg/kg/day based on: ↓ Body wts, body wts gains, food consumption ↑ Water consumption ↑ Liver and relative brain wt (♀), relative liver and kidney wt (♂/♀)

↑ ALP, ALT (♀), creatinine (♂), total bilirubin (♂) ↓ globulin, triglyceride, cholesterol, ↑ WBC count, monocyte, poly

morphonuclear neutrophil counts (♀) ↑ urine volume and pre sence of RBCs (♀) ↓ urine specific gravity ↓ RBC, hemoglobin, hematocrit

Liver microscopic findings (♂/♀): Absence of fat storage Cytoplasmic eosinophilia (moderate to severe ) Granular cytoplasm (moderate to severe)
Sl ight central hypertrophy (♀ only)

FOB: ↓ fore

- and hindlimb grip strength (♀)

motor activity: effects were not treatment

- related

870.6300 Developmental

neurotoxicity NA NA

870.7485 Metabolism and

pharmacokinetics (rat) 116493 (1978)

Acceptable/non

- guideline single oral gavage dose (117 mg/kg) or 14

- day repeated oral doses at 1 mg/kg 2,4

- DP Total radioactivity recovered within 4 days after dosing: 85

- 90% of dose. Urine accounted for 74

- 82% of dose.

Highest conc. of dichlorprop derived radioactivity was found in kidneys. No radioactivity in expired air. Urine: Major component is parent (75% of dose)
Feces: Metabolites were not analyzed

### Page 26 of 30

Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (Year)/ Classification/Doses Results

870.7485 Metabolism and

pharmacokinetics (rat) 44187601 (1996)

Acceptable/guideline single oral gavage dose (5 or 100 mg/kg) or 14

- day repeated oral doses at 5 mg/kg 2,4

- DP

- p

---------------------------

44187602 (1996) Acceptable/guideline single oral gavage dose 5 mg/kg 2,4

- DP

- p

- DMAS and 2,4

- DP

- p EHE Total radioactivity recovered within 5 days after dosing: 91

- 100% of dose.
Urine accounted for 87

- 96% of dose.
Urine and feces: Major component in urine is parent

----------------------------------------------- 2,4

- DP

- p

- DMAS and 2,4

- DP

- p

- 2EHE
Total radi oactivity recovered within 7 days after dosing: 91

- 96% of dose.
Urine accounted for 83 of dose.
Urine: Major component is 2,4

- DP

- p

870.7600 Dermal

penetration (rat) 44229301 (1997)

Unacceptable/guideline 2,4

- DP

- p

- DMAS and 2,4

- DP

- p EHE Test material migrated from the application site to the covering material in an unpredictable manner throughout the exposure duration thus making it impossible to determine the actual dose.

870.7800 Immunotoxicity NA NA

### Page 27 of 30

Appendix A. 3. 2,4

- DP

- p Endpoints and Doses for Risk Assessment

Table A.3. 1. Toxicological Doses and Endpoints for 2,4

- DP

- p for Use in Dietary and Occupational Human Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty

Factors RfD/Level of

Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary All populations including infants and children NOAEL =

5.1 mg/kg/day UF A = 10x

UF H = 10x aRfD = 0.05

mg/kg/day 90

- Day Oral Toxicity study in Dogs (MRID

43462601) LOAEL = 15.7 mg/kg/day based on frequent diarrhea in 4/5 males and 2/5 females during weeks 1

- 10

Chronic Dietary All populations including infants and children NOAEL =

3.6 mg/kg/day UF A = 10x

UF H = 10x cRfD = 0.036

mg/kg/day 2

- year Chronic Toxicity Study in rats (MRID

146394) LOAEL = 11 mg/kg/day based on decreases in specific gravity and protein in urine. Considering the kidney toxicity [increases in lipofuscin deposition in the proximal tubular cells of the kidneys] seen in the higher dose levels, this effect was considered treatment

- related. Kidney effects were also observed in the following studies: subchronic toxicity study in rats at 5 mg/kg/day (increased incidence of slight tubular nephrosis), 1

- year chronic study in dogs at 22 mg/kg/day (slight degenerative kidney tubular vacuolization), subchronic neurotoxicity study in rats at 144 mg/kg/day (d ecrease in urine specific gravity), 2

- generation reproduction study in rats at 219 mg/kg/day [increased weights, foci of basophilic (regenerating) tubules, focal hyperplasia of the transitional epithelium and papillary/medullary calculi]

Incidental Oral Short

Term (1

- 30 days) NOAEL =

5.1 mg/kg/day UF A = 10x

UF H = 10x Residential

LOC for MOE = 100 90

- Day Oral Toxicity study in Dogs (MRID

43462601) LOAEL = 15.7 mg/kg/day based on frequent diarrhea in 4/5 males and 2/5 females during weeks 1

- 10 Incidental Oral Intermediate

Term (1

- 6 months) NOAEL =

3.6 mg/kg/day UF A = 10x

UF H = 10x Residential

LOC for MOE = 100 2

- year Chronic Toxicity Study in rats (MRID

146394) LOAEL = 11 mg/kg/day based on decreases in specific gravity and protein in urine. Considering the kidney toxicity [increases in lipofuscin deposition in the proximal tubular cells of the kidneys] seen in the higher dose levels, this effect was considered treatment

- related. (See chronic dietary RfD discussion)

### Page 28 of 30

Table A.3. 1. Toxicological Doses and Endpoints for 2,4

- DP

- p for Use in Dietary and Occupational Human Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty

Factors RfD/Level of

Concern for Risk Assessment Study and Toxicological Effects

Dermal Short

and Intermediate

Term (1

- 30 days; 1

- 6 months) No quantification is required because no hazard was identified.

Inhalation Short

- Term (1

- 30 days) NOAEL =

5.1 mg/kg/day UF A = 10x

UF H = 10x Residential/

Occupational LOC for MOE = 100 90

- Day Oral Toxicity study in Dogs (MRID

43462601) LOAEL = 15.7 mg/kg/day based on frequent diarrhea in 4/5 males and 2/5 females during weeks 1

- 10 Inhalation Intermediate

Term (1

- 6 months) NOAEL =

3.6 mg/kg/day UF A = 10x

UF H = 10x Residential/

Occupational LOC for MOE = 100 2

- year Chronic Toxicity Study in rats (MRID

146394) LOAEL = 11 mg/kg/day based on decreases in specific gravity and protein in urine. Considering the kidney toxicity [increases in lipofuscin deposition in the proximal tubular cells of the kidneys] seen in the higher dose levels, this effect was considered treatment

- related. (See chronic dietary RfD discussion) Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor

increases in two adequate rodent carcinogenicity studies.

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 obs erved 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 population (intraspecies). MOE = margin of exposure. LOC = level of

concern.

### Page 29 of 30

Appendix B: Chemistry

1.0 Identification of Active Ingredient

TABLE B.1 .1 Test Compound Nomenclature

— 2,4

- DP

- p Chemical Structure

Empirical Formula C 9 H 8 Cl 2 O 3 Common name 2,4

- DP

- p or dichlorprop
IUPAC name R

- 2

- (2,4

- dichlorophenoxy)propionic acid
CAS name (2R)

- 2

- (2,4

- dichlorophenoxy)propionic acid CAS Registry Number 15165

- 67

- 0
PC Code 031402
Chemical Class Phenoxypropionic herbicide

TABLE B. 1.2 Test Compound Nomenclature

— 2,4

- DP

- p DMAS 1

Chemical Structure

Empirical Formula C 9 H 8 Cl 2 O 3 . C 2 H 7 N
Common name 2,4

- DP

- p, dimethylamine salt

IUPAC name (R)

- 2

- (2,4

- Dichlorophenoxy)propanoic acid, dimethylamine salt CAS Registry Number 104786

- 87

- 0
PC Code 031403

1 The 2,4

- DP dimethylamine salt (racemic mixture ; PC Code 031419; CAS No 53404

- 32

- 3 ) also has registered uses that are being considered under this registration review schedule

.

### Page 30 of 30

TABLE B. 1.3 Test Compound Nomenclature

- 2,4

- DP

- p - 2EHE
Chemical Structure

Empirical Formula C 17 H 24 Cl 2 O 3 Common name 2,4

- DP,2

- ethylhexyl ester

IUPAC name (R)

- (2,4

- Dichlorophenoxy)propanoic acid, 2

- ethylhexyl ester CAS Registry Number 865363

- 39

- 9
PC Code 031465



### 2.0 Physical and Chemical Properties
TABLE B.2 Physicochemical Properties for 2,4

- DP

- p
Parameter Value Reference Molecular Weight 235.1 46591916; Cornell University Cooperative Extension PMEP Melting point/range 122.5

- 124.5° C Comb 2002, MRID 45698103 Density 1.42 g/ml Water solubility (20°C) 590 mg/L 46591916 Solvent solubility (temperature not specified) Highly soluble in acetone, benzene, carbon tetrachloride, diesel oil and kerosene Henry’s Constant 2.43E

- 10 atm m 3 /mol 46591916 Vapor pressure (25°C) 4.65E

- 7 torr 46591916 Octanol/water partition coefficient, logP OW (25°C) 1.029 at pH 5

- 0.562 at pH 7

- 0.873 at pH 9 Cameron et al. 1992; MRID 42916202

pKa 3.67 EFSA 2006