### Di ca mb a Human H e alth Ri s k A sses sm e nt DP No

. 0 378366

, 0 4049 1 7



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D

. C

. 20460



### M E M ORA N D UM

D a te : Ma r c h 29

, 2 01 6 O F F I CE OF
CHEMICAL SAF E TY AND
POLL UTI O N PR E VE NTI O N



### SU BJ EC T : Di ca mb a an d Di ca m ba B A P MA Sa lt: H u m a n-H ea lth R i s k Asse ss m e n t fo r Pr o p ose d Sect i o n 3 Ne w Uses o n Dicamb a -t o l e r a nt C o tto n a nd Soybea n

P C C od e : 0 2 980 1. 1289 3 1. 0 2 98 02, 0 2 9 8 0 6

. 12 894 4.

029 8 03. I 0009 -1 & 1290 4 3 OP B a r c o d e: 0 37 8 366. 04 0 491 7, 04 02 514

. 04 2 1 306

. 040 25 5 1

D ec i s i o n No. : 43 27 52. 4 6 799 7. 4 637 10

P e tit i o n N o

. : 2F8067 & O F 7725 R e gi s trati o n N o.: 5 24 -58 2

- M l 69 1. 5 24

- ANO & 7969

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R e g ul at o r y A ct i o n: Se c ti on 3 & R 1 70

R i s k A ss e s s m en t T y pe: Sin g l e Ch e mi c al. A g g r ega t e T X R No. : NA C a se No

. : 006 5

C A S No.: 1 9 1 8-00

- 9

40 CFR: § 1 80

. 227 M RID No

. : N A



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### Dicarnba Human Health Ri sk Ass e ssment DP No. 0 37 8 366, 0404 9 1 7

1 .0 Execut i ve Summary

.................................................................................................................. .. ................... 4

2.0 HED R ecom m e ndation s

....................................................... .. ................. . ... ... . ...... ..... ... . .. .............................. 7

2. 1 Data D e fi cie nci es

........................................................................................................................................ 7

2.2 Tolerance Co n siderat ion s

.................................................................... ... ................................................... 7

2.2. 1 E nforc e m e nt A nal ytica l Met h o d

...................................................................................................... 7

2

. 2.2 Recommended Toleranc es

........................................................................... .. ................... . ............... 7

2.2.3 Revisions to Petitioned-For Tolcrance s

.......................................................................... ...... ........... 8

2.2.4 In ternationa l H a rm on i zation

... .. .................................... . ................................................................. 8

2.3 Label Recomm e ndatio n s

............................................................................... . ............................. .. ... ....... . . 8

2.3.1 Recommendations fr o m Res idu e R ev i cws

................ .. .. .. ... .... .......................................................... 8

2

. 3.2 Recommendation s from Occupati o nal Assessme nt

........................................................................ 9

2.3.3 Recommendations fr o m Re s ident i a l A ssess ment

.. ....... .. . ...... ........................... . ............................. 9

3. 0

3. 1

3.2

3.3

3 ..t
3.5 

### 4.0

4.1

4.2 In troduction

......................................................................... . ........ .. ......................................... . ...................... 9

C h em i cal Id c ntit y

............................................................................................. . ....... . ................................. 9

Ph ys ical / C h e 1 n i ca l C har ac t erist i cs

........... . ............. . ....... . ................................................... . ...... .. ........... I 0

P est i c id e Use Pattern

................................................................. ............................. ................. .... . ........... 11

A nticip ate d Expos ur e P a th ways

.. .. .... .. ..... .. ............................................................................................ 1 7

Co n s ideratio n or E n viro nm enta l Ju s ti ce

................................................................................................ 1 8

H azard C h aracteriza ti on a nd Do se- Resp o nse Assessmen t

.................... .. .. . .............................................. 1 8

T ox icol ogy St udie s Ava il ab l e for A n a l ys i s

........ .... ... .. ..... ............ .... ....................................................... 1 9 Absorpt i on , Di s tribution

, Metabol i s m , & Eliminat i on (ADME)

................. .................... . ................... 20

4.2. 1 Dermal Ab so rpti o n

... ............ ......... .................................................................................................. 20

4.3 Tox i co l ogica l Effects

.............. ... . ... . ..... ..................................................................................................... 20

4.4 Safe t y Fac t or for In fa n t s an d Ch i ldre n (FQ P A Sa f ety Factor)

........................................ .. .. . .............. 22

4.4.1 Co mpl ete n ess or the To x i co l ogy Database

... ... .............................................................................. 23

4.4.2 Evidence or Ne u roto x i c it y

.... .. .. .. ..................................................................................................... 24

4.4.3 Ev i dence o f Sens i ti v i t y / Susce p tibilit y in th e Developing or You n g Animal..

............................. 24

4.4.4 Re s idu al U n ce rt a int y in t h e Expos ur e Databa se

.......................................................................... 24

4 .5 Toxicity E n dpoint and P o int of D epa rtur e Se lection s

......................................... .. ............................... 24

4.5. 1 D ose- Response Assess m e n t

..... .. ....... . .................................... .. . . ... . ... . ... ... ........ ...... .... .. .................... 24

4.5.2 Recommendati o n for Co m b inin g R o ut es of Exposu r es for Ri s k Asses s m e n t

............................ 26

4.5.3 Ca n ce r C l ass ifi ca ti on a nd Ri s k Assessme nt R eco mm e n datio n

................................................... 26

4.5.4 S umm a r y or Poi nt s or Departure and Toxicit y E n d p oin t s Used in Hum a n Risk Assessme nt.. 27

5.0 Dietar y Exposure a nd Risk Assessme n t

............................................................................. .. ......... . ............ 30

5. 1 Metabol it e / Degradate R es idu e P rofi l e

................................................ ... ................................................ 30

5. 1

. 1 S umm a r y o r Plant and Ani m a l Metaboli s m S tu die s

......................... . .......................................... 30

5. 1 .2 Summa r y o r E n viron m en tal Degradation

........................................................ .. ........................... 3 1
5.1.3 Comparison of M e t abo li c Pathwa ys

........................................................ .. .................................... 3 1

5 .1 .4 Re s idu es o f Concern Sum m a r y and Ratio n ale

............................................................................. 32

5.2 Fo o d Re s id ue Pr o fil c

....................................................... . ........................................................................ 33

5.3 Water R esid u e P r ofile

.................................................. ... .................. .................................... ........... .. ...... 34

5.4 Di etary Ri s k A ssess m e nt

......................................................................................................................... 36

5.4

. 1 De sc ripti o n or R esid u e Data Used in Dietary Assess m e nt

...................................................... . .... 36

5.4.2 Percent C r o p Treat ed U se d in D ietary Assessme nt

.......................... ........................... ................ 36

5.4.3 A c ut e Dietar y Ri s k Assess m ent

......................................................... . .......... . ...... . .......................... 36

5.4.4 Ch r o ni c Di etary R i s k Assess rn e n t

...................... ........... ... .............................................. . .. ..... . ...... . 37

S..t.5 Ca n cer Di etary Ri sk Assessme nt

................................................................................................... 37

S.4.6 S umm a r y Table

....... .... .... .... ......... ..... ........ .. .... ......... ... ...... ...... .. ...................................................... 37

6.0 Res i d e ntial (No n -Occ up atio n a l ) Ex p os ure / Ri s k Charac t erizat i on

...... . ................................................... 37

6. 1 Re s i dent i al H andler Exposure

................................. . ....... . ........ . ............................................................. 38

6.2 Po s t- A ppli ca ti o n Exposure

......................................... ............ . .................. . .. ... . . ... . ...... . ........................... 39

6.3 Re s id e ntial Risk Estimates for Use in Aggregate A ssess ment.

........... .. ................................................ 4 1

6.4 Reside n tia l By s ta n der P ost-ap pli cat i on I nhalation Ex p os ur e

.. ... . ........................................................ 41

6.4.1 Flux Dat a

..... .. ...... . ............................................ . ............................................................................... 42

6.4.2 Vo l a tili za ti on Mod e li ng an d Ri s k As sess ment

................................................................ .. .. ..... ..... 43

Page 2of105Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 3 of 105 6.4.3 Volatilization Risk Estimates

................................ ................................ ................................ .......... 43
6.5 Non

- Occupational Spray Drift Exposure and Risk Estimates

................................ ............................. 44
7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ............................... 46
7.1 Acute Aggregate Risk

................................ ................................ ................................ .............................. 46
7.2 Short

- Term Aggregate Risk

................................ ................................ ................................ .................... 46
7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ................................ ........ 47
7.4 Chronic Aggregate Risk

................................ ................................ ................................ .......................... 47

7. 5 Cancer Aggregate Risk

................................ ................................ ................................ ............................ 47
8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ............................ 48
9.0 Occupational Exposure/Risk Characterization

................................ ................................ ......................... 48
9.1 Short

- /Intermediate

- Term/ Handler Risk

................................ ................................ .............................. 48
9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ ................................ ................. 52
9.2.1 Dermal Post

- application Risk

................................ ................................ ................................ ......... 52
9.2.2 Inhalation Post

- application Risk

................................ ................................ ................................ .... 53
10.0 References

................................ ................................ ................................ ................................ ..................... 53 Appendix A. Toxicology Profile

................................ ................................ ................................ ............................... 55 Appendix B. Physical/Chemical Properties

................................ ................................ ................................ .......... 104 Appendix C. Review of Human Research

................................ ................................ ................................ ............. 104 Appendix D. International Residue Limits Summary

................................ ................................ ......................... 105Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 4 of 105 

### 1.0 Executive Summary

Monsanto has submitted petitions PP# 0F7725 and PP#2F8067 requesting Section 3 registration
for the use of dicamba on dicamba

- tolerant soybean and cotton. For these petitions, Monsanto is requesting to establish new tolerances for dicamba

- tolerant soybean forage at 45 ppm and for dicamba tolerant soybean hay at 70 ppm as a joint work

- share project with Canada and Japan

. Monsanto is also requesting to amend the cotton un

- delinted seed tolerance from 0.2 ppm to 3.0 ppm and establish a new tolerance for cotton gin byproducts at 70.0 ppm. The proposed application is for pre

- and post

- emergence uses of dicamba on these dicamba

- tolerant crops.

BASF has also submitted R170 new food

- use registration requests for the dicamba BAPMA ( N,

N

- Bis

- (3

- aminopropyl) methylamine ) product on conventional crops as well as on dicamba

tolerant cotton and soybean

. In support of this request, bridging data were provided to demonstrate equivalency of residues resulting from the BAPMA salt product with respect to the registered diglycolamine (DGA) salt. Included in the BASF petition are bridging data for another new formulation of dicamba which contains the diethylenetriamine (DETA) salt ;

r egistration of the DETA formulation of dicamba is not being requested at this time

.

Dicamba ( benzoic acid, 3,6

- dichloro

- 2

- methoxy

- , aka 3,6

- dichloro

- o

- anisic acid) is a selective systemic herbicide belonging to the benzoic acid chemical family and is currently registered for use on both soybeans and cotton as pre

- plant applications and not as post emergence applications because crop injury could occur if it wer e to come in contact with roots, stems, or foliage. Dicamba is available for use in either acid or salt forms with registered uses being maintained on a wide variety of crop and livestock feed items

. Dicamba also has registered uses for treatment
on turf

. Permanent tolerances are established under 40 CFR §180.227(a)(1) for dicamba and its 3,6

- dichloro

- 5

- hydroxybenzoic acid (5

- hydroxydicamba) metabolite. Additional tolerances are established under 40 CFR §180.227(a)(2) for dicamba and its 3,6

- dichloro

- 2

- h ydroxybenzoic acid (aka 3,6

- diclorosalicyclic acid or DCSA) metabolite, as well as under 40 CFR §180.227(a)(3) for dicamba, 5

- hydroxydicamba, and the DCSA metabolite.

The residue chemistry database for dicamba is complete. The nature of residues for dic amba

tolerant soybean and cotton is understood. N o new revised tolerances on livestock commodities are required to support this petition. A number of enforcement methods exist for the determination of dicamba and its metabolites in soybean and cotton as well as in animal
matrices.

Using the OECD calculation procedures, tolerances of 60 ppm for soybean forage and 100 ppm for soybean hay are recommended. The current tolerances of 10 ppm in soybean seed and 30 ppm in soybean hull are adequate. For cotton , the recommended tolerances of 3.0 ppm for
cotton undelinted seed and 7 0 ppm for cotton gin byproducts are appropriate.

BASF has submitted new toxicology studies for the dicamba BAPMA salt (rat developmental,

rat 28

- day inhalation and rat 90

- day oral s tudies) and a 28

- day inhalation study on the dicamba acid, as well as an OECD 422 developmental/reproduction study for the BAPMA base.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 5 of 105 

### N eurotoxic signs (e.g., ataxia, decreased motor activity, impaired righting reflex and gait) were
observed in studies i n rats and rabbits at doses over 150 mg/kg/day . The rat reproduction study
and the d evelopmental studies in rats and rabbits showed no evidence (qualitative or quantitative) for increased susceptibility following in utero or postnatal exposure of dicamba
acid or its salts

. In the rabbit developmental toxicity study, an increased incidence of abortion (1/20 does) was seen at doses that also caused maternal toxicity, as evidenced by clinical signs of neurotoxicity. In a two

- generation dicamba acid reproduc tive toxicity study, offspring toxicity
was manifeste d as decreases in pup weight at a dose where parental toxicity was also observed. Dicamba is classified as “not likely to be carcinogenic to humans”

. Mutage nicity studies did not demonstrate mutagenic concern for dicamba. There was no evidence of dermal or systemic toxicity following repeated dermal application of dicamba acid or the salts at the limit dose (1000 mg/kg/day). There is no concern for immunotoxicity following exposure to dicamba

. Followin g oral administration, dicamba is rapidly absorbed and rapidly excreted in urine and feces without significant metabolism. Dicamba has a low acute toxicity via the oral, dermal or inhalation route (Acute Toxicity Categories III or IV ). It is an eye and de rmal irritant but it is not
a skin sensitizer.

An acute dietary risk assessment was conducted for the general population including infants and children based on clinical signs of neurotoxicity (ataxia, unsteady gait and convulsions) observed
in maternal animals in a developmental toxicity study in rats with the dicamba BAPMA salt

. An acute Reference Dose (RfD) of 0.29 mg/kg/day was established based on a Point of Departure (POD) of 29 mg/kg/day and the application of the conventional 100 inter

- and intr a

- sp ec ies uncertainty factor s (UF s ). An acute dietary risk assessment was not conducted for females 13

- 49 since toxicity endpoints of concern attributable to a single dose (exposure) w ere not identified in the database. A chronic dietary risk assessment wa s conducted based on decreased body weights
in the off spring in a two

- generation reproduction toxicity study with the DCSA metabolite. A chronic RfD of 0.04 mg/kg/day was established based on a POD of 4 mg/kg/day and the application of the conventional 10 0 UF s . The POD selected would address the suite of toxic effects seen with the acid, salts and the metabolite s of dicamba. Risk assessment for incidental oral exposure for children is based on a decreased pup weight in the reproduction study with
dicamba a cid. The Level of Concern (LOC) for this scenario is a target Margin of Exposure (MOE) of 100

, which includes the conventional 100 UF

. A quantitative dermal assessment is not required for dicamba acid or the BAPMA salt since no systemic toxicity was seen at the limit
dose in rats and/or rabbits with dicamba or its salts and there was no concern for susceptibility
based on the findings of the developmental and reproduction studies

. Potential risks from occupational and residentia l exposure via the inhalation route will be assessed using PODs and endpoints of concerns derived from route

- specific inhalation toxicity studies conducted with the
dicamba acid and dicamba BAPMA salt

.

The acute and chronic dietary (food and drinking wa ter) exposure estimates are not of concern for the U.S. population or any population sub

- group. For the acute dietary assessment, the most highly

- exposed population sub

- group is all infants (<1 year old) at 31% of the aPAD. For the chronic dietary assessme nt, the most highly

- exposed population sub

- group is children 1

- 2 years
old at 42% of the cPAD.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 6 of 105 

### There are no proposed residential uses at this time for either dicamba or the dicamba BAPMA
salt ; however, there are existing residential turf uses of dicamba t hat have been reassessed in this document to reflect updates to HED’s 2012 Residential Standard Operating Procedures (SOPs). There is no potential hazard via the dermal route for dicamba ; therefore

, the handler assessment
include s only the inhalation route of exposure

, and the post

- application assessment includes only
the incidental oral route s of exposure. The residential handler (adult) and post

- application (children 1 to <2 years old ) risk estimates are not of concern for dicamba for all scenarios (i.e., all inhalation MOEs ≥ 30 and incidental oral MOEs ≥ 100)

.

A quantitative assessment of non

- occupational exposure and risk resulting from spray drift was conducted for the BAPMA salt, which results in no risk estimates of concern (i.e., all MOEs ≥ 100) at the field edge for aerial and ground boom applications at the maximum agricultural application rate of 1 lb ae/A. Since the dicamba residential turf application rate is equal to or higher than the proposed uses of dicamba on agricultural crops, the res idential turf scenario is protective of any exposure via spray drift from the proposed agricultural dicamba applications.

The potential non

- occupational exposure to vapor phase dicamba and BAPMA residues emitted from treated fields from the proposed uses has been evaluated in this assessment. Volatilization modeling was completed using PERFUM as well as chemical

- and formulation

- specific flux
data. The results indicate that volatilization of dic amba and BAPMA from treated crops does
occur and could result in bystander exposure ; however, results of PERFUM modeling indicate that airborne concentrations, even at the edge of the treated fields, are not of concern.

The acute and chronic aggregate e xposure estimates are equal to the acute and chronic dietary
assessments and are not of concern for the U.S. population or any population sub

- group. The
short

- term aggregate (food, water, and residential) assessment for children is not of concern
since the MOE is 36 00 ( LOC = 100 ). For adults, there is no short

- term aggregate assessment since there is no dermal hazard identified and the inhalation effects are not systemic. Dicamba is not likely to be carcinogenic to humans, thus a quantitative cancer risk is not applicable and not
assessed.

Occupational handler and post

- application exposures are anticipated from the proposed uses. For the proposed uses of dicamba, t he label

- required personal protective equipment (PPE) for mixers, loaders, applicators and other handlers includes a long

- sleeved shirt and long pants, socks, shoes, and chemical

- resistant gloves (except for applicators using ground boom equipment, pilots or flaggers). For the proposed uses of dicamba BAPMA salt , the label

- required PPE for mixer, loaders, applicators and other handlers includes long

- sleeved shirt and long pants, shoes plus socks. The restricted entry interval (REI) on the proposed label s is 24 hours. The occupational handler inhalation risk esti mates are not of concern for dicamba (i.e., MOEs ≥ 30 ). Most occupational handler inhalation risk estimates are of concern for dicamba BAPMA salt (inhalation MOEs < LOC of 300) based on the label

- required PPE (i.e., no respiratory protection). Some handl er risk estimates are still of concern with the maximum respiratory protection/engineering controls. Since there is no potential hazard via the dermal route for dicamba, a quantitative occupational post

- application dermal risk assessment was not completed

. The REI on the proposed labels (24 hours) is based on WPS requirements.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 7 of 105 

### 2.0 HED Recommendations

HED has no objection to the registration and establishment of tolerances for dicamba uses requested by Monsanto on dicamba

- tolerant cotton and soyb e an provided the label modifications
are made as outlined in Section 2.3 below. There are also no residue chemistry considerations that would preclude registration of the new BAPMA salt formulation of dicamba requested by

BASF . HED has no objection for estab lishing the use of the BAPMA end

- use product on conventional crops as well as on dicamba

- tolerant cotton and soybean. The specific tolerance recommendations are provided in Section 2.2.2

.

2.1 Data Deficiencies

Provided a revised Section F reflecting the recommended tolerance levels listed in Table 2.2.2, is provided, there are no residue chemistry , toxicology or exposure data deficiencies that preclude establishing permanent tolerances on soybean and cotton raw agricultural commodities (RACs)
for dicamba.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods are available for the enforcement of the newly proposed cotton seed and cotton gin byproducts as well as soybean seed, forage and hay tolerances. The existing analytical method AM

- 0691B

- 0297

- 4 is the latest revision of the Agency validated method AM

0691B

- 0297

- 2 which was submitted to FDA for inclusion into PAM volume II.

A n independent laboratory validation of the liquid chromatography/mass spectrometer/mass
spectrometer (LC/MS/MS) method, BASF Method D0902, used for analyzing the field trial samples in the bridging studies has also been provided for assessment. BASF Analytical Method
D0902 meets these conditions depicting the suitability of an enforcement methodology. Pending editorial revisions recommended by the independent validation laboratory, HED determines the
BASF method to be adequate for the tolerance enforcement of crops.

Dicamba is completely recover ed through the FDA multi

- residue method (MRM) testing protocols using Section 402 E2 of Protocol B

, but is partially recovered using Section 402 E1 of Protocol B (Appendix II of PAM Volume I). BASF Corporation has recently submitted multi

residue testing data for the dicamba metabolites of concern 5

- OH dicamba and DCSA (MRID 48001304) and is currently under review by the Agency.

An alytical standards for dicamba and its metabolites of concern are currently available in the
EPA National Pesticide Standards Repository (personal communication with Theresa Cole, BEAD, 0 8 /3 1 /201 5 ). The current stock of standards is set to expir e on 02 /0 1 /201 7

.

2.2. 2 Recommended TolerancesDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 8 of 105 

### The current tolerance expression is compliant with HED’s Interim Guidance on Tolerance Expressions (05/27/2009, S. Knizner). The newly proposed tolerances should be established
under 40 CFR §180.227(a)(3) as noted below in Table 2.2.2. The 40 CFR §180.227(a)(1) citation for dicamba currently lists a 0.2 ppm tolerance for cotton, undelinted seed. This entry in the CFR should be removed, and replaced with the tolerances shown above under 40 CFR §180.227(a)(3).

Table 2.2.2 . Tolerance Summary for Dicamba

. Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition ) Cotton, gin byproducts 70.0 70 Cotton, undelinted seed 3.0 3.0 Soybean, forage 45.0 60 Soybean, hay 70 .0 100



### 2.2. 3 Revisions to Petitioned

- For Tolerances

Tolerances for soybean forage and hay proposed by the petitioner were estimated using the NAFTA MRL calculator. EPA’s recommended tolerances, which differ from the proposed tolerances, were derived using the OECD MRL calculation procedures, which is the Agency’s

current standard for determination of tol erances

.

2.2.4 International Harmonization

The review of dicamba

- tolerant soybean studies is a global joint review led by the U.S. with Canada and Japan as participating reviewers. US EPA and PMRA (Canada) previously established a harmonized tolerance (M RL) for soybean on seed at 10 ppm. There are currently no Mexican, Canadian or Codex MRLs established for soybean forage and hay or for cotton gin byproducts. There are MRLs of 0.2 ppm in Mexico and 0.04 ppm established by Codex on
cotton seed. Mexico a dopts existing U.S. crop tolerances for export purposes

, which in this
instance

, is the current cotton undelinted seed tolerance of 0.2 ppm. Because the registrant is now requesting a late season use of dicamba on dicamba

- tolerant cotton, the currently

es tablished international tolerances are not adequate to cover residues likely from the newly proposed use in the U.S. In addition, the dicamba residues of concern for dicamba

- tolerant cotton also include the DCSA metabolite which is not found nor regulated in the other common varieties of cotton. Therefore, harmonization with respect to the tolerance expression is not possible at this time for cotton seed. Since there are no international tolerances on cotton gin byproducts, there is no issue of internati onal harmonization relevant to that tolerance (Appendix D)

.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

An amended Section B for the Monsanto c otton petition (PP#2F8067) is required noting that no more than two (2) post

- emergence applications may be made past the first open boll stage whenDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 9 of 105 

### treating dicamba

- tolerant cotton. This also requires BASF to provide an amended Section B noting this same restriction for the post

- emergence treatment of dicamba

- tolerant cotton on the
dicamba BAPMA product label as well.

2.3.2 Recommendations from Occupational Assessment

Most occupational handler inhalation risk estimates are of concern for dicamba BAPMA salt
based o n the label

- required PPE (i.e., no respiratory protection). Some handler risk estimates are still of concern with the maximum respiratory protection (i.e., PF10 respirator) / engineering
controls (see Table 9.1.3)

.

2.3.3 Recommendations f rom Residential Assessment

None.

3.0 In troduction

Dicamba, 3,6

- dichloro

- 2

- methoxybenzoic acid, is a selective benzoic acid herbicide registered for controlling a wide variety of broadleaf weeds and woody plants prior to their emergence. It
has similar signaling properties to natural auxins which induce abnormal and uncontrollable growth to disrupt normal plant functions at high concentrations. Dicamba end

- use products are available as either acid or salt formulations with registered uses being maintained on a w ide variety of crop

, livestock feed commodities and turf

.

Monsanto has developed dicamba

- tolerant variet ies of soybean and cotton seed s capable of receiving dicamba treatments up to seven days before harvest. A dicamba mono

- oxygenase (DMO) gene is intro duced into dicamba

- tolerant seed s to encode the enzyme dicamba O

demethylase to convert dicamba into the non

- herbicide metabolite 3,6

- dichlorosalicylic acid (DCSA ) , thus causing the plant to tolerate the herbicidal effect of dicamba. Tabl e 3.1 shows the

c hemical names and structures of dicamba and its residues of concern.

3.1 Chemical Identity

Table 3.1. Test Compound Nomenclature: Dicamba and its Residues of Concern. Compound Chemical Structure

Common name Dicamba

IUPAC name 3,6

- Dichloro

- o

- anisic acid

CAS name Benzoic acid, 3,6

- dichloro

- 2

- methoxy

CAS # 1918

- 00

- 9

End

- use product/EP M1691 H erbicide ( EPA Reg. No. 524

- 582) and Engenia Herbicide (EPA Reg.

No. 7969

- GUL)Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 10 of 105 Compound

Common name 5

- Hydroxy

- dicamba

IUPAC name 2,5

- dichloro

- 3

- hydroxy

- 6

- methoxybenzoic acid

CAS name Benzoic acid, 2,5

- dichloro

- 3

- hydroxy

- 6

- methoxy

CAS registry number 7600

- 50

- 2 Compound

Common name DCSA; 3,6

- dichlorosalicylic acid

IUPAC name 3,6

- dichloro

- 2

- hydroxybenzoic acid

CAS name Benzoic acid, 3,6

- dichloro

- 2

- hydroxy

CAS registry number 3401

- 80

- 7 Compound

Common name DCGA; 3,6

- dichlorogentisic acid

IUPAC name 2,5

- dichloro

- 3,6

- dihydroxybenzoic acid

CAS name Benzoic acid, 2,5

- dichloro

- 3,6

- dihydroxy

CAS registry number 18688

- 01

- 2



### 3.2 Physical/Chemical Characteristics

Technical dicamba is a light cream/tan colored solid composed of granules, lumps, flakes. Dicamba has a vapor pressure of 3.4 x 10

- 5 

### mm Hg at 25 ° C and is known to volatize in the field. Dicamba is not expected to bi oaccumulate in aquatic organisms because it is an anion at environmental pH value s (pK a 

### =1.9). Dicamba is not significantly broken down by water or light. Aerobic soil metabolism is the main degradative process for dicamba. A single observed half

life for dicamba was six (6) days with the formation of the intermediate degradate 3,6

- dichloro

2

- hydroxybenzoic acid (aka 3,6

- diclorosalicyclic acid or DCSA). DCSA was found to degrade roughly at the same rate as dicamba. Dicamba was found to be very soluble (6100 ppm) and very mobile (K OC 

### =13.4) in the laboratory. Results from two acceptable fi e ld dissipation studies conducted with the dimethylamine salt of dicamba indicated it dissipated with a half

- life of 4.4 to 19.8 days. DCSA was the major degradate in both studies with both DCSA and dicamba being found in soil segments deeper than 10 cm. If any dicamba did reach anaerobic groundwater, it would be somewhat persistent due to its observed anaerobic half

- life of 141 days. Given these
factors dicamba and the DCSA metabolite may remain evident in water to reach water supplies for human consumption. See Appendix B for a table of physio

- chemical properties of dicamba.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 11 of 105 

### 3.3 Pesticide Use Pattern

The dicamba product used for treating dicamba

- tolerant soybean and cotton proposed by

Monsanto for registration is the M1691 Herbicide (EPA Reg. No. 524

- 582) which is a soluble (flowable) concentrate formulation. This end

– use product contains 56.8% active ingredient in
the form of the DGA salt of dicamba (equivalent to 4.0 lb acid equivalents (ae) /gal). A summary of the proposed directions for use taken directly from the supplemental M1691 herbicide label provided by the registrant are presented below in Table 3.3.1.

The submitted data are adequate and reflect the maximum use rates listed in M1691 Herbicide Supplemental labeling.

Table 3.3. 1

. Summary of Directions for Use of Dicamba.

Formulation [EPA Reg. No.] Applic.

Timing, Type, and Equip. Max.

Applic.

Rate (lb ae 1 /A) Max.

No. Applic.

per Season Max.

Seasonal Applic. Rate (lb ae/A) Combined

Max. Seasonal Applic. Rate (lb ae/A) RTI 2

(days) PHI 3 (days) Use Directions
and Limitations 4

MON 88701 Cotton

M1691 4.0 lb ae/gal

SL [524

- 582] Pre

- plant,

at planting,
and Pre

emergence Broadcast (20 gal/A) 1.0 NS 5 1.0 2.0 7 7 Use of a COC or
MSO is not
recommended with Roundup
branded
herbicides. These adjuvants are only
used when other products require
them. For best results apply at min spray rate of

10 GPA. Apply with ground equipment only; aerial application is prohi bited. Post

emergence, Broadcast (20 gal/A) 0.5 NS 2.0

Soybean

M1691 4.0 lb ae/gal
SL [524

- 582] Pre

- plant,

at plant ing

, and Pre

emergence Broadcast (20 gal/A) 1.0 NS 1.0 2.0 7 7 The maximum rate for any single, in

- crop (post

- emergence) application must
not exceed 0.5 lbDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 12 of 105 Table 3.3. 1

. Summary of Directions for Use of Dicamba.

Formulation [EPA Reg. No.] Applic.

Timing, Type, and Equip. Max.

Applic.

Rate (lb ae 1 /A) Max.

No. Applic.

per Season Max.

Seasonal Applic. Rate (lb ae/A) Combined

Max. Seasonal Applic. Rate (lb ae/A) RTI 2

(days) PHI 3 (days) Use Directions
and Limitations 4

Post

emergence, Broadcast (20 gal/A) 0.5 NS 1 .0 dicamba a.e. per

acre. A second post

emergence application may follow up to the R1 reproductive
stage . Apply with ground equipment only; aerial application is

pro hibited.

1 ae = Acid Equivalents

2 RTI = Re

- Treatment Interval

3 PHI = Pre

- Harvest Interval

4 COC = Crop Oil Concentrate; MSO = Methylated Seed Oil.

5 NS = Not Specified



### For treating dicamba

- tolerant cotton, the M1691 Herbicide (EPA Reg. No. 524

- 582) product label allows growers flexibility in the application of dicamba to control weeds. The residue data provided examining this broad pattern of use shows that later post

- emergence trea tments give much higher residues then those made at earlier growth stages. Following the pattern of late season use demonstrated by the field trial data, no more than two (2) post

- emergence applications may be made after the first open boll stage when tre ating dicamba

- tolerant cotton. Therefore, the registrant should amend the product label to include this restriction since the data provided only support this pattern of use.

In regard to the Engenia Herbicide (EPA Reg. No. 7969

- GUL) , this end

- use product is a new BAPMA salt formulation of dicamba developed by the BASF Corporation. It is an SL product proposed for use in treating conventional crops, as well as dicamba/glufosinate

- tolerant cotton
and dicamba

- tolerant soybean. This end

– use product contains 48.38% active ingredient in the form of the BAPMA salt of dicamba (equivalent to 5.0 lb ae/gal). The proposed BAPMA label depicts the same pattern of use found on the labels of the many other registered salts of dicamba which allows growers great flexibi lity for application to control weeds when cultivating crops.
Table 3 .3.2 provides a summary of the use directions taken directly from the proposed BAPMA product label.

Table 3.3. 2

. Summary of Directions for Use of the Engenia 5.0 lb ae/gal SL Herbicide Formulation of Dicamba (EPA Reg. No. 7969

- GUL).

Application. Timing, Type, and Equip. Max.

Applic.

Rate (lb ae 1 /A) Max.

No. Applic

. per Season Max.

Seasonal Applic.

Rate (lb ae/A) Combined

Max.
Seasonal Applic. Rate (lb ae/A) RTI 2

(days) PHI 3

(days) Use Directions and

Limitations 4

Asparagus

Post

- emergence 0.5 NS 5 0.5 NA 6 1 1Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 13 of 105 Table 3.3. 2

. Summary of Directions for Use of the Engenia 5.0 lb ae/gal SL Herbicide Formulation of Dicamba (EPA Reg. No. 7969

- GUL).

Application. Timing, Type, and Equip. Max.

Applic.

Rate (lb ae 1 /A) Max.

No. Applic

. per Season Max.

Seasonal Applic.

Rate (lb ae/A) Combined

Max.
Seasonal Applic. Rate (lb ae/A) RTI 2

(days) PHI 3

(days) Use Directions and

Limitations 4

Broadcast (40

- 60 gal/A) - Apply in combination with glyphosate (Roundup).

- Do not harvest 24
hours after treatment.

- Do not use in the Coachella Valley of CA. Post

- harvest,
Broadcast (Burndown Treatment) 1.0 2.0

Corn (field, seed, silage) and Popcorn Preplant

- Pre

emergence Broadcast 0.5 NS 0.5 1.5 14 NS

- Engenia is not registered on sweet corn.

- Do not contact seeds.

- Application rates vary by soil texture and growth stage.

- Adjuvants may be used
and it can be mixed with other herbicide products. Pre

- emergence Broadcast

Post

Emergence
Broadcast

Cotton (non

- dicamba

- tolerant)

Pre

- emergence Broadcast (Preplant Burndown) 0.25 NS 0.25 0.25 NA NA

- Adjuvants may be used
and it can be mixed with other herbicide products.

- After application, wait
for 1” of rainfall/irrigation and a

21

- day interval before planting.

- For MO and TN only,
wait for 1” of rainfall/irrigation and a

14

- day inter val before planting. Cotton (dicamba/glufosinate

- tolerant)

Pre

- emergence Broadcast 1.0 NS 1.0 2.0 14 7

- Use of a COC or MSO adjuvants are only used when other products require them. For best results apply at min spray rate of 10 GPA. Post

emergence, Broadcast 0.5 NS 2.0

Grass Grown for Seed

Post

Emergence
Broadcast 1.0 NS 2.0 NA NS 37

- 51

- Apply with recommended adjuvants to seedling grasses when the crop reaches the 3

- 5 leaf stage.

- Follow listed grazing restrictions; 7 days for 0.5 lb ae/A applicationsDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 14 of 105 Table 3.3. 2

. Summary of Directions for Use of the Engenia 5.0 lb ae/gal SL Herbicide Formulation of Dicamba (EPA Reg. No. 7969

- GUL).

Application. Timing, Type, and Equip. Max.

Applic.

Rate (lb ae 1 /A) Max.

No. Applic

. per Season Max.

Seasonal Applic.

Rate (lb ae/A) Combined

Max.
Seasonal Applic. Rate (lb ae/A) RTI 2

(days) PHI 3

(days) Use Directions and

Limitations 4

and 21 days for 1.0 lb ae/A applications.

- Follow listed PHI restrictions; 37 days for 0.5 lb ae/A applications and 51 days for 1.0 lb ae/A applications. Pasture, Hay, Rangeland, and Farmstead (non

- cropland)

Broadcast
treatment of

non

- cropland 0.5 NS 1.0 NA NA NA

- Engenia can be applied using water, oil

- in

- water emulsions including invert systems, or sprayable fluid fertilizer
as a carrier.

- Follow listed grazing restrictions; 7 days for 0.5 lb ae/A applications and 21 days for 1.0 lb ae/A applications. Broadcast
treatment of small grain grown for pasture & newly seeded

grass 0.5 0.5

Spot Treatment 0.001

-

5ft

canopy 0.04

– 10 ft canopy
0.09

– 15ft

canopy NS

- Apply as a cut surface
treatment for unwanted trees and prevention of sprouts of cut trees.

- Apply as an undiluted spot treatment directly to
the soil or as a Lo

- Oil
basal bark treatment using an oil

- in

- water
emulsion solution when plants are dormant.

Proso Millet

Broadcast and
spot treatment for broadleaf
weed control 0.125 NS 0.125 NA NS NS

- Apply to actively growing weeds when proso millet is in the

- 2
to 5

- leaf stage.

- Apply only if proso millet injury is acceptable.

- Follow listed grazing restrictions; 7 days for
0.5 lb ae/A. Small Grain (Barley, Oats, Triticale & Wheat)Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 15 of 105 Table 3.3. 2

. Summary of Directions for Use of the Engenia 5.0 lb ae/gal SL Herbicide Formulation of Dicamba (EPA Reg. No. 7969

- GUL).

Application. Timing, Type, and Equip. Max.

Applic.

Rate (lb ae 1 /A) Max.

No. Applic

. per Season Max.

Seasonal Applic.

Rate (lb ae/A) Combined

Max.
Seasonal Applic. Rate (lb ae/A) RTI 2

(days) PHI 3

(days) Use Directions and

Limitations 4

Post

emergence, Broadcast

- Barley 0.094

–

up to 4

- leaf stage NS 0.34

spring
seeded barley NA NS 7

and

37

- hay - May be applied before,

during or after planting.

- Do not apply pre

harvest in CA.

- Do not use a COC for
post

- emergence application.

- Application in periods of rapid growth may result in temporary crop leaning.

- Do not apply if there potential for crop injury is unacceptable.

- Do not graz e small grain within 7 days of

treatment. 0.38 fall
seeded barley

Post

emergence, Broadcast

- Oats 0.125

–

up to 5

- leaf stage 0.125

Post

emergence, Broadcast

– Wheat &
Triticale 0.125

–

up to the

6

- leaf
stage 0.5

Post

emergence, Broadcast

– Fall Seeded
Wheat 0.25

–

after the

3

- leaf
stage

Sorghum

Pre

- emergence Broadcast 0.25 NS 0.5 0.5 NS 30

- May be used pre

- plant,
post

- emergence or pre

harvest in split applications.

- Pre

- plant treatments are
to be made 14

- days before planting.

- Application in periods of rapid growth may result in temporary crop leaning.

- Do not graze before mature grain stage or
within 7

– days of

treatment. Post

emergence, Broadcast

Soybean (non

- dicamba

- tolerant)

Pre

- plant
Broadcast Spray 0.25 @ a

14

- day

pre

- plant
Interval NS 0.5 2.0 NS 7

- Application can be
made with other
herbicides.

- Pre

- plant application
cannot exceed 0.5 lbs ae/A per season. 0.5 @ a

28

- day

pre

- plant
IntervalDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 16 of 105 Table 3.3. 2

. Summary of Directions for Use of the Engenia 5.0 lb ae/gal SL Herbicide Formulation of Dicamba (EPA Reg. No. 7969

- GUL).

Application. Timing, Type, and Equip. Max.

Applic.

Rate (lb ae 1 /A) Max.

No. Applic

. per Season Max.

Seasonal Applic.

Rate (lb ae/A) Combined

Max.
Seasonal Applic. Rate (lb ae/A) RTI 2

(days) PHI 3

(days) Use Directions and

Limitations 4

Pre

- harvest
Broadcast Spray 1.0 2.0

- Do not apply in areas
where annual rainfall is
below 25 inches.

- Pre

- harvest applications are only made when pods are a
mature brown color.

- Do not make pre

harvest applications in
CA.

- Do not feed pre

- harvest treated fodder and hay. Soybean (dicamba

- tolerant)

Pre

- emergence Broadcast 1.0 NS 1.0 2.0 NS 7

- forage
And

14

- hay - Application can be
made with other
herbicides.

- Pre

- emergent applications can be made
at 1.0 lbs ae/A to
medium to fine texture
soils and at 0.5 lbs ae/A to course and sandy
soils.

- Do not apply after first
bloom.

- Post

- emergent treatments may cause wilting for 24

- 72 hours
afterwards.

- Do not apply post

emergent treatments by aerial application.

- Do not apply with ammonium containing
additives. Post

emergence, Broadcast 0.5 2 1.0

Sugarcane

Post

emergence, Broadcast 1.0 NS 2.0 NA NS 87

- Application can be
made with other
herbicides.

- Application may be made any time after weed emergence.

- When possible spray beneath the sugarcane canopy to minimize the likelihood of crop injury. Farmstead Turf (non

- cropland) and Sod FarmsDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 17 of 105 Table 3.3. 2

. Summary of Directions for Use of the Engenia 5.0 lb ae/gal SL Herbicide Formulation of Dicamba (EPA Reg. No. 7969

- GUL).

Application. Timing, Type, and Equip. Max.

Applic.

Rate (lb ae 1 /A) Max.

No. Applic

. per Season Max.

Seasonal Applic.

Rate (lb ae/A) Combined

Max.
Seasonal Applic. Rate (lb ae/A) RTI 2

(days) PHI 3

(days) Use Directions and

Limitations 4

Broadcast

treatment 0.5 NS 1.0 NA NS NS

- To avoid injury to newly seeded grasses, delay application until after the second mowing.

- Application may cause stunting and
discoloration in sensitive grasses (bentgrass, buffalograss, carpetgrass & St. Augustinegrass).

- Do not use on
residential sites.

- Applications can be
made at 0.25 lbs ae/A to
medium to fine texture
soils and at 0.125 lbs ae/A to course and sandy
soils.

1 ae = Acid Equivalents

2 RTI = Re

- Treatment Interval

3 PHI = Pre

- Harvest Interval

4 COC = Crop Oil Concentrate; MSO = Methylated Seed Oil.

5 NS = Not Specified

6 NA = Not Applicable



### The proposed use directions for the new BAPMA salt formulation of dicamba are adequate to
allow evaluation of the submitted bridging study data. The residue data provided examine the broad use pattern of dicamba using post

- emergence broadcast treatments m ade at the maximum application rate following the specified minimum pre

- harvest interval (PHI). Prior residue data
submitted for dicamba

- tolerant cotton shows that later post

- emergence treatments give much higher residues then those made at earlier growth stages. Following the pattern of late season use demonstrated by the field trial data, no more than two (2) post

- emergence applications may be made after the first open boll stage when treating dicamba

- tolerant cotton. Therefore, the BAPMA product label must be amended to include this restriction since the data provided only support this pattern of use.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use of dicamba on dicamba

- resistant soybeans and cotton , and the proposed use of the BAPMA salt on various agricultural crops

. Dicamba is currently registered for use on agricultural crops and for use on turf. Humans may be exposed to dicamba

, including the
counter io ns of its various salt forms such as the BAPMA salt

, in food and drinking water, since
dicamba and BAPMA salt may be applied directly to growing crops and app lication may result
in dicamba and BAPMA salt reaching surface and ground water sources of drinking water.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 18 of 105 

### Additionally, humans may be exposed to the plant metabolite, DCSA, via dietary exposures. There are residential uses of dicamba, but not the dicamba BAPMA salt

. A dults may be exposed to dicamba during pesticide applications in residential settings, and both adults and children may be exposed dermally in pos t

- application scenarios on turf. C hildren may also have incidental oral exposure in post

- application scenarios for turf to dicamba acid

. Non

- occupational exposures from spray drift may occur from both dicamba acid and the BAPMA salt. In an occupational setting, applicators may be exposed during application of dicamba acid and the BAPMA salt

. There is a potential for post

- application exposure for worke rs re

- entering treated fields.

Ri sk assessments have been previously prepared fo r the existing uses of dicamba . This risk assessment considers all of the aforementioned exposure pathways based on th e proposed new
uses of dicamba , including the counter ions of its various salt forms such as the BAPMA salt , but also considers the existing uses as well, particularly for the dietary exposure assessment. There are several compounds that have been consider ed , including dicamba acid, the dicamba metabolites (DCSA, 5

- OH dicamba, and DCGA), and t he dicamba BAPMA counter ion. Separate assessments of dicamba acid, the dicamba metabolites (DCSA, 5

- OH dic amba, and DCGA), and the BAPMA counter ion were not needed because the selected endpoints are protective of all forms

.

3.5 Consideration of Envir onmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered 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.archives.gov/federal

- register/executive

- orders/pdf/12898.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 data from the U.S. Department of Agriculture’s (USDA’s) Nati onal Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) 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 y ear, 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 exposu res 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 bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific sub

- groups.

4.0 Hazard Characterization and Dose

- Response Assessment

Dicamba ( 3, 6

- dichloro

- 2

- methoxybenzoic acid ) is a selective benzoic acid herbicide registered
for controlling a wide variety of broadleaf weeds and woody plants prior to their emergence forDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 19 of 105 

### conventional crops

. It is an auxin ag onist and has similar signaling properties to natural plant
auxins

, which induce abnormal and uncontrollable growth to disrupt normal plant functions at high concentrations. The pesticidal mode of action of dicamba is not known to be relevant to
mammals. D icamba

- tolerant plants convert dicamba in to the non

- herbicidal metabolite 3, 6

- dichlorosalicylic acid (DCSA ), thus causing the plant to tolerate the herbicidal effect of dicamba for post

- emergence applications

.

4.1 Toxicology Studies Available for Analysis

The toxicology database on dicamba is extensive and complete with respect to 870 guideline requirements for characterizing the hazard of dicamba , with routes of administration that are consistent with potential exposure scenarios

. The toxicology studies for dicamba acid, its salts [isopropylamine (IPA) and diglycolamine (DGA)], the currently proposed N, N

- Bis

- (3

- aminopropyl) methylamine (BAPMA) salt, and the plant metabolites DCSA (3, 6

- dichlorosalicylic acid) and DCGA (3, 6

- dichlorogentisic acid) are summarized in Appendix A. The data from the following studies were used to evaluate the hazard potential of dica mba acid
and dicamba BAPMA salt:

Dicamba Acid, IPA and DGA Salts : Sub

- chronic Oral Study: 90

- day oral toxicity (rat),
Dermal Studies: 28

- day dermal toxicity (rat), 21

- day dermal toxicity (rabbit) Developmental Studies: rat and rabbit developmental toxicity studies Reproduction Study: 2

- generation reproduction study (rat) Chronic Studies: combined oral chronic toxicity/carcinogenicity (ra t), carcinogenicity (mouse), chronic oral toxicity (dog) Neurotoxicity Studies: acute and subchronic neurotoxicity (rat) Inhalation Study: 28

- d ay i nhalation s tudy (rat) Immunotoxicity Study: Immunotoxicity (rat) Mutagenicity battery
Metabolism

DCSA M etab olite : Subchronic Studies: 90

- day oral toxicity (rat), 90

- day oral toxicity (dog) Developmental Studies: rat and rabbit developmental toxicity studies Reproduction Study: 2

- generation reproduction study (rat) Chronic Study: combined oral chronic toxicity/c arcinogenicity (rat) Mutagenicity battery
Metabolism

DCGA M etabolite : Sub

- chronic Study: 28

- day oral toxicity (rat) Mutagenicity battery

Dicamba BAPMA Salt Inhalation Study: 28

- d ay i nhalation s tudy (rat)
90

- Day Oral Study in RatsDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 20 of 105 

### Developmental Study (rat) Mutagenicity battery

BAPMA Cation Base OECD 422 Reproduction/Developmental Study

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

The metabolism study in rats showed that following oral gavage administration at 400 mg/kg

, dicamba is rapidly absorbed within a few hours and rapidly excreted . The phase I plasma half

life is less than 4 hours at doses of 400 mg/kg or lower and essentially all of the radio

- labelled
dicamba is eliminated in 48 hours . Over 95% of the administered dose is e xcreted in the urine.
The compound is not metabolized n or accumulated by the tissues in adult, non

- pregnant rats

. However, a pproximately 13% of dicamba in the urine is conjugated as the glucuronide. In plants,
dicamba is converted to the DCSA and DCGA meta bolites, which have dietary exposures.

The gavage plasma pharmacokinetic studies in rats showed that absorption of radiolabeled dicamba was rapid, with peak plasma concentrations foun d within 2 hours of treatment. Absorption was not saturated, even at the highest dose (800 mg/kg) , as indicated by increasing plasma concentrations with doses. However, the increase in plasma c oncentration was non

linear/ disproportionate from one dose to the next dose and serum half

- life increased with dose

, which is consiste nt with saturation of excretion. Another plasma pharmacokinetic s tudy suggests
that dicamba i s an inhibitor of renal anion transport (i.e. urinary excretion) since co

- dosing with an inhibitor of this process (i.e. probenecid) increased plasma levels of di camba and decreased its
clearance rate. No significant treatment

- relat ed differences between the genders were found. A
DCSA study demonstrates that DCSA has a similar structure and metabolism as dicamba, with rapid absorption and rapid elimination. DCSA i s poorly metabolized (except for some glucuronide conjugates) and predominantly excreted in the urine as the parent compound.

4.2.1 Dermal Absorption

An acceptable guideline dermal absorption study is not available for dicamba. The lack of a dermal absorption study is not a concern since quantification of dermal risk is not required due to lack of dermal or systemic toxicity at the limit dose (1000 mg/ kg/day) following repeated application to rats and/or rabbits with the dicamba acid and the IPA and DGA salts.

4.3 Toxicological Effects

Reviewing the various toxicity studies on the different forms of dicamba acid, BAPMA salt, and DCSA plant metabolite , it appears that the mode of administration (i.e. gavage vs. dietary) had an impact on the type of toxicity observed for these compounds. For example, the repeat dietary administration have effects occurring at higher doses than the acute gavage dosing. Following gavage administration, there were rapid onset of clinical signs as seen in the metabolism study at lower doses in the gavage studies. The dicamba acid and dicamba BAPMA studies indicate that the nervous system is the major target following gavag e exposure. These clinical signs include ataxia, decreased foot splay, decrease d arousal and rears/minutes and decreased motor activity.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 21 of 105 

### For dicamba acid and the BAPMA salt, signs consistent with neurotoxicity were observed in several gavage studies in rat s and rabbits without accompanying histopathology. For dicamba acid, when comparing the gavage acute neurotoxicity (ACN) study with the dietary sub

- chronic neurotoxicity (SCN) study, the acute effect level was over 2.5X lower than the subchronic effect
lev el for the same endpoints of rigidity and impaired gait and impaired righting reflex. The DCSA metabolite is less neurotoxic than dicamba acid. For DCSA, clinical signs were only evident at gavage doses of 1000 mg/kg or greater in the mouse micronucleus st udy (hypo

activity, squinted eyes, hunched posture) or the rat acute oral toxicity study at 2000 mg/kg (wobbly gait), while clinical signs for dicamba acid (hypo

- activity, ataxia) were apparent at gavage doses of 250 mg/kg or greater in the mouse micronucl eus assay. DCSA caused decreased body weight and increased creatinine levels (a measure of renal deficiency) in the rat 90

- day dietary study at 659 mg/kg/day. DCSA produced decreased body weight, emesis, and an increase in clotting time in the dog sub

- chro nic 90

- day oral study only at the highest doses tested (HDT, capsule, 150 mg/kg/day). Dicamba BAPMA caused increased clotting time and increased
creatinine levels in the rat 90

- day dietary study at the limit dose. However in the gavage rat developmental st udy, dicamba BAPMA caused ataxia, unsteady gait and convulsions at 86 mg/kg/day. The creatinine effects, along with the pharmacokinetics/excretion data, suggests that the kidney is also a target organ and that adverse effects begin to occur at doses where kidney
clearance starts to become non

- linear. There was no evidence of immunotoxicity with the acid
form.

Pre

- natal developmental gavage toxicity studies in rats and rabbits, and two

- generation reproduction studies in rats were available with the dicamb a acid and the DCSA plant
metabolite. T he d evelopmental studies in rats and rabbits showed no evidence (qualitative or quantitative) for increased susceptibility following in utero exposure of dicamba acid or the dicamba BAPMA salt. In the rat developmenta l studies for dicamba acid or dicamba BAPMA, there was no developmental toxicity up to the highest dos e tested , but the BAPMA salt was approximately 4 times more toxic to the dams than dicamba acid based on the common effect of
ataxia

. A single incidence o f abortion in the dicamba rabbit developmental toxicity study (1 in 20
does , 4 days after dosing ceased ) occurred at a maternally toxic dose ( manifested as ataxia and decreased motor activity ) . For the DCSA metabolite, there was no developmental toxicity up to the highest doses tested in the definitive studies in rats and rabbits. At higher doses in the DCSA developmental range

- finding studies, there w ere decreased fetal weights in rats at the same dose
that caused rales in the dams and dam deaths occurred at the highest dose tested in rabbits. In the OECD 422 reproduction/developmental screening study (870.3650) with the BAPMA base, decreased motor activity and water consumption were observed in dams at the mid dose while pronounced toxicity and deaths wer e observed in the dams at the highest dose tested (HDT) . This OECD 422 study did not identify developmental toxicity. However, dicamba product exposure is not to the pure BAPMA base and the base composition in the dicamba BAPMA salt is only one

fourth that of the dicamba component in this salt form . Thus, the dicamba BAPMA salt rat developmental study PODs will be protective for the BAPMA base effects.

In contrast, following pre and/or post

- natal exposures in the two

- generation reproduction studies,
the DCSA metabolite was more toxic to the offspring than the acid form . In the reproduction study with DCSA , offspring toxicity manifested as decreases in body weight at a dose (37 mg/kg/day) that is approximately 10

- fold lower than the dose (362 mg/kg/day) tha t causedDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 22 of 105 

### parental / systemic toxicity (decreased body weight ) demonstrating increased susceptibility in the

young

. Furthermore, when the adverse effects observed in the offspring were compared for the two compounds ( i.e. LOAEL comparison), the DCSA dose (3 7 mg/kg/day) at which decreased pup weight was observed was approximately 12

- fold lower than the dicamba acid dose (450 mg/kg/day) that caused the same effect

.

Conversely, in the reproduction study with dicamba acid there was no evidence (qualitative or quantitative) for increased susceptibility following pre and/or or postnatal exposure

. D ecreased pup body weights were observed in all generations and matings at the mid (136 mg/kg/day) (86

- 90% of control) and at the high (450 mg/kg/day) (74

- 94% of control) dose groups throughout lactation, relative to the concurrent controls. Based on detailed statistical analysis (multivariate) comparison with the MARTA historical control data (M iddle

- A tlantic R eproduction and

T eratology As sociation, Appendix 6), it was concluded that there was no adverse effect on pup body weights during the F1 generation lactation period or post

- weaning phase at the low and mid dose groups. The offspring NOAEL was established at 136 mg/kg/day and the offsp ring LOAEL was 450 mg/kg/day based on decreased pup weights in the F1 and F2B generations. At the 450 mg/kg/day dose, there were adverse decreases in the F1 pup body weights at PND 0 before the lactation phase.

In the dicamba acid, dicamba IPA and dicamb a DGA salts sub

- chronic dermal toxicity studies,
there were no adverse effects observed up to the limit dose (1000 mg/kg/day). However, t he
dicamba BAPMA salt was demonstrated to be more toxic than dicamba acid via the inhalation
route. The inhalation stud y for dicamba acid revealed hyperplasia in the lung with a clear no observed adverse effect level (NOAEL), while the dicamba BAPMA salt produced hyperplasia and ulceration of the larynx at a dose approximately 35 times lower than dicamba acid effects
and a NOAEL was not established. The inhalation effects for both dicamba acid and the BAPMA
salt were local and non

- systemic.

Dicamba is classified as “not likely to be carcinogenic to humans” based on the lack of evidence of carcinogenicity in mice and rats w ith the acid form and in rats with DCSA

. Mutagenicity
studies generally did not demonstrate evidence of mutagenic potential for dicamba although some positive results were reported in vitro

. Dicamba acid and the dicamba BAPMA salt both
induced chromosomal aberrations in human lymphocytes in vitro , however

, genotoxicity was negative in vivo in the mouse micronucleus assay, thus the concern for genotoxicity for dicamba
or its salts is low. The BAPMA base was negative for genotoxicity in bacteria, but positiv e for genotoxicity based on in vitro mammalian cell culture

.

Dicamba acid has a low ac ute toxicity via oral, dermal and inhalation ro ute (Acute Toxicity Categories III or IV ). It is an eye and dermal irritant but it is not a skin sensitizer. BAPMA base is Category II or III toxicity via oral, dermal or inhalation routes, but it is corrosive to the eyes
and a dermal irritant and sensitizer. The d icamba BAPMA salt has a low acute toxicity via oral,
dermal or inhalation ro ute (Acute Toxicity Categories III or IV). The dicamba BAPMA salt is not an eye or dermal irritant, but it is a skin sensitizer.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 23 of 105 

### The FQPA Saf

ety Factor (SF) may be reduced (i.e. 1X) for acute and c hronic dietary risk

assessments for the following reasons:

1. The toxicity database for dicamba is complete with respect to required 870 guideline
studies

. 2. For the dicamba acid, there is no evidence of increased susceptibility following in utero exposures to rats and rabbits an d following pre and/or post

- natal exposure to rats in a

two

- generation reproduction study. For the dicamba acid and BAPMA salt, no developmental toxicity was seen at the highest doses tested in the prenatal developmental
studies with rats. Although quantit ative offspring susceptibility was observed in the 2

- generation reproduction study for the DCSA metabolite based on decreased pup weights,

t he degree of concern for the susceptibility is low because there is a well

- established
NOAEL for offspring t oxicity in that study and DCSA has rapid clearance. Additionally, the current points of departure are health protective and therefore address the concern for offspring toxicity observed in this reproduction study.

3. Consistent neurotoxic signs (e.g., ataxia, decreas ed motor activity, impaired righting reflex and gait) were observed in multiple studies i n rats and rabbits . After considering the available toxicity data, EPA determined that there is no need for a developmental neurotoxicity study or additional UFs to a ccount for neurotoxicity for the following reasons: (1) although clinical signs of neurotoxicity were seen in pregnant animals, no evidence of developmental anomalies of the fetal nervous system were observed in the prenatal developmental toxicity studies, in either rats or rabbits, at maternally toxic doses up to 300 or 400 mg/kg/day, respectively; (2) there was no evidence of behavioral or neurological effects on the offspring in the two

- generation reproduction study in rats; (3)
the ventricular dilation of the brain in the combined chronic toxicity and carcinogenicity study in rats was only observed in females at the high dose after two years of exposure at doses of 127 mg/kg/day . The significance of this observation is questionable, since no
similar his topathological finding was seen in t wo sub

- chronic neurotoxicity study at the
limit dose or other chronic studies.

4. There are no residual uncertainties identified in the exposure databases. The dietary food

exposure assessme nts were performed based on toler ance

- level residues for the acute dietary, average field trial data for the chronic dietary and available % crop

- treated
information . Conservative ground and surface water modeling estimates were used. Similarly, conservative r esidential SOPs were used to assess post

- application exposure of children as well as incidental oral exposure of toddlers. These assessments will not
under

- estimate the exposure and risks posed by dicamba.

However, the 10X FQPA SF is retained f or assessing inhalation risk s for th e dicamba BAPMA
salt , the FQPA SF is retained in the form of a LOAEL to NOAEL factor (UF L 

### ) since the POD
used was a LOAEL (See Table 4.5.4.1 )

.

4.4.1 Completeness of the Toxicology Database

The toxicity database for dicamba is adequate in terms of endpoint selection and dose response information to characterize the potential for dietary prenatal or postnatal risk to infants andDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 24 of 105 

### children. Available studies include acceptable rat and rabbit developmental toxicity studies, two

rat 2

- generation reproduction studies, and acute/subchronic neurotoxicity studies in rats.

4.4.2 Evidence of Neurotoxicity

There is evidence of neurotoxicity resulting from exposure to dicamba throughout the toxicology
database (i.e. impaired gait, impaired righting reflex, ataxia, decreased motor activity, rigi dity upon handling, etc)

. After considering the available toxicit y data, the agency determined th at a DNT is not required, as described previously.

4.4.3 Evidence of Sensitivity/Susceptibili ty in the Developing or Young Animal

There is no evidence of susceptibility to the young following in utero exposure to dicamba acid, dicamba BAPMA or DCSA. However, quantitative offspring susceptibility was observed in the

2

- generation repro duction study for the DCSA metabolite based on decreased pup weights. T he degree of concern for the susceptibility is low because there is a well

- established NOAEL for offspring t oxicity in that study and DCSA has rapid clearance

. Additionally, the current point of dep artures are health protective and therefore address the concern for offspring toxicity observed in the reproduction studies.

4.4.4 Residual Uncertainty in the Exposure Database

The residential exposure assessment assumes maximum label use rate as well as other conservative assumptions. The acute dietary exposure assessment is based on an exaggerated exposure scenario whic h assumes that all commodities being consumed retain tolerance level
residues. The drinking water estimates utilized conservative mode ls. Therefore, the A gency does not believe that exposure to dicamba will be under

- estimated.

4.5 Toxicity Endpoint and Point of Departure Selections

The toxicology endpoints and points of departure selections have been updated since the last risk

assessm ent (D 340156, 2008) 

### to consider new toxicology data for the dicamba BAPMA salt, as
well as the route

- specific inhalation study results for dicamba acid (see Appendix A.3)

.

4.5.1 Dose

- Response Assessment

Dicamba acid has dietary, dermal, inhalation and incidental oral exposure scenarios. The dicamba BAPMA salt has no residential uses, thus there is no incidental oral exposures. The DCSA metabolite is not formed in mammals and is generated within plants, th us its main exposure is for chronic dietary scenarios. The DCSA reproduction study POD was not selected
for non

- dietary endpoints, since the residue present on foliar surfaces to which people may be exposed is the parent compound rather than the DCSA metab olite. The detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in appendix A.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 25 of 10 5 

### Acute Dietary Scenario s : The rat developmental study for the dicamba BAPMA s alt was selected to assess a single oral exposure of the general population

, including infants and children, to dicamba acid or its BAPMA salt. The NOAEL is 29 mg/kg/day, and the LOAEL is 86 mg/kg/day based on ataxia, unsteady gait and convulsions in the dams ( considered a single

- dose effect since the signs occurred within 3 hours after dosing ) . This study was selected because it represents the most sensitive endpoint in the dicamba database for exposure to the parent
dicamba acid or its BAPMA salt demonst rating an acute response with a well

- defined NOAEL
value

. The decreases in the pup body weights in the reproduction studies are not considered single dose effects. The selected POD will be protective of the effects of dicamba acid and the
BAPMA salt via th e oral route. A separate acute dietary assessment for females 13

- 49 was not performed since no there was no developmental toxicity attributed to a single dose in the toxicology data bas e. The single incidence of abortion in the rabbit developmental study

o ccurred late gestation and therefore likely not from a single exposure.

An uncertainty factor of 100X (10X to account for interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF) is applied t o the NOAEL to obtain a n acute RfD of
0.29 mg/kg/ day. Since the FQPA SF is reduced, the acute Population Adjusted Dose ( PAD ) is equivalent to the acute R fD ( 0.29 mg/kg/ day )

.

Chronic Dietary Scenario s : The chronic dietary scenario for dicamba acid and all of its salt forms is based on decreased pup weights observed at 37 mg/kg/day (LOAEL) in a reproduction study on the DCSA plant metabolite ; the NOAEL of 4 mg/kg/day is selected for deriving the
chronic R fD. This POD will be the most protective of all toxic effects seen following exposure to
dicamba acid or dicamba BAPMA salt. An uncertainty factor of 100X (10X to account for interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF) i s applied to the

NOAEL to obtain a chronic RfD of 0.04 mg/kg/day. Since the FQPA SF was reduced, the chronic PAD is equivalent to cRfD ( 0.04 mg/kg/ day )

.

Short and Intermediate Term Incidental Oral Scenario s : The toxicology studies on the plant
metabolite s are not appropriate for this scenario since these metabolites are generated inside the plants and unavailable for incidental oral expos ure. The developmental studies are not appropriate for incidental oral scenarios involving hand

- to

- mouth behavior. The dicamba
BAPMA salt has no residential uses other than potential for spray drift

. T he most appropriate study was the multi

- generation reproductive toxicity study in rats dosed with parent compound was selected based on impaired pup growth at 450 mg/kg/day ( LOAEL); the NOAEL of 136 mg/kg/day was selected as the POD for this scenario. The Level of Concern (LOC) is a Margin of Exposure (MOE) of 100 which includes the 10X factor account s for interspecies extrapolation, a 10X factor accounts for intraspecies variation, and a 1X FQPA S F.

Short, Intermediate and Long

- Term Inhalation Scenario s : The dose and endpoint selected for
dicamba acid and dicamba BAPMA risk assessment utilized the route

- specific aerosol inhalation
studies for each AI. Fo r dicamba acid in halation risk assessment for short and intermediate term
durations , the POD was based on the route

- specific dicamba acid inhalation toxicity study in Wistar rats with a LOAEL of 0.050 mg/L based on local effects of hyperplasia in the lungs and lymph nodes (NOAEL = 0.005 mg/L, non

- systemic , pulmonary RDDR = 0.590 ).Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 26 of 105 

### The dose and endpoint selected for the dicamba BAPMA salt in halation risk assessment for short
and intermediate term durations w ere based on the dicamba BAPMA salt inhalation t oxicity study in rats with a LOAEL of 0.0014 mg/L based on local effects of hyperplasia and ulceration of the larynx ( no NOAEL, non

- systemic , extra

- thoracic RDDR = 0.190 ).

The standard interspecies extrapolation UF can be reduced from 10X to 3X for dica mba acid and
BAPMA salt due to the calculation of human equivalent concentrations ( HECs ) accounting for pharmacokinetic (not pharmacodynamic) interspecies differences. Therefore, the LOC for
dicamba acid inhalation exposures is for MOEs less than 30 (3X f or interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF when applicable ). For BAPMA salt, an
additional 10X UF L 

### is applied due to lack of a NOAEL; therefore, the LOC for BAPMA salt inhalation exposures is for MOEs less than 300. The inhalation HEC/HED results are listed in Appendix A. 5

.

Short, Intermediate, and Long

- term Dermal Scenario s : A dermal assessment is not required for dicamba acid or its BAPMA salt since no effects were detected up to the limit dose (1000 mg/kg/day) in the dermal studies for dicamba acid, IPA salt and DGA salt. Additionally, the dicamba anion is the major componen t in t he BAPMA salt and t he BAPMA base component of
the dicamba BAPMA salt is o nly 20% of the salt mass (and 28% on a molar basis) , t hus, the dicamba BAPMA salt is unlikely t o have adverse dermal effects. In support, t he acute dermal toxicity for the dicam ba BAPMA salt is low ( Category IV )

.

The BAPMA amine base does not require a separate assessment since the OCED 422 developmental/reproduction toxicity screening study on the pure compound had a LOAEL of 100 mg/kg/day based on decreased motor activity and water consumption with a NOAEL of 25 mg/kg/day. Thus, the dicamba BAPMA rat developmental study will be protective for its exposure and considering the BAPMA composition in this salt is 4 times less than the dicamba acid composition. Furthermore, the BAPM A cation is predicted to degrade much faster than the
dicamba anion.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Based upon different toxicological effects and/or target organs observed in the selected endpoints
for risk as sessment, incidental oral, dermal, and inhalation routes of exposure should not be combined for dicamba acid or dicamba BAPMA salt. Therefore, the dicamba salt weights will be utilized for regulation, not the dicamba acid equivalents.

4.5.3 Cancer Classif

ication and Risk Assessment Recommendation

In accordance with the EPA Final Guidelines for Carcinogen Risk Assessment (March 29, 2005),
dicamba is classified as “ n ot likely to be carcinogenic to humans ” . This decision was based on the lack of findings in the cancer studies in rats and mice which were tested at adequate dose levels to assess the carcinogenicity of dicamba (TXR No. 0053647). Mutagenicity studies generally did not demonstrate evidence of mutagenic potential for dicamba although some positive results were reported in vitro

. Dicamba acid and the dicamba BAPMA salt both inducedDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 27 of 105 

### chromosomal aberrations in human lymphocytes in vitro , however

, genotoxicity was negative in

vivo in the mouse micronucleus assay, thus the concern for genotoxicity for dicamba or its salts
is low. The BAPMA base was negative for genotoxicity in bacteria, but positive for genotoxicity
based on in vitro mammalian cell culture

. Additionally, the D CSA metabolite also had a lack of findings in a chronic/carcinogenicity study in rats.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

Table 4.5.4.1 Toxicological Doses and Endpoints for Dicamba Acid and Dicamba BAPMA Salt for use in
Human Health Risk Assessments

Exposure
Scenario Point of Departure FQPA SF and Level of
Concern for Risk

Assessment Study and Toxicological Effects

Acute Dietary (General population including infants and
children ) NOAEL = 29 mg/kg/day UF A =10 X

UF H =10 X FQPA SF = 1X

Acute RfD = 0.29 mg/kg/day

aPAD = 0.29 mg/kg/day Dicamba BAPMA Rat Developmental Study

Maternal NOAEL is 29 mg/kg/day in dams
LOAEL is 86 mg/kg/day in dams, based on ataxia, unsteady gait and convulsions observed shortly after dosing

Developmental NOAEL > 288 mg/kg/day (200 mg/kg/ day as acid equivalent)

Acute Dietary (Females 13

- 49 years of age) N/A N/A No developmental toxicity attributed to acute exposure in the toxicology
database . The abortions in the rabbit developmental st udy occurred at gestation day 22

. Chronic Dietary (All populations) Offspring NOAEL= 4

mg/kg/day UF A =10 X

UF H =10 X FQPA SF = 1X

Chronic RfD = 0.04 mg/kg/day

cPAD = 0.04 mg/kg/day Reproductive study in rats with
DCSA metabolite.

Offspring LOAEL = 37 mg/kg/day based on decreased pup weights in

F1 generation on PN D 14 and 21 (both sexes) and week 18 (females)

Short

- (1

- 30 Days)
and Intermediate

- (1

- 6 months) Term
Incidental Oral Offspring NOAEL= 136

mg/kg/day Residential

LOC for MOE = 100

UF A =10 X

UF H =10 X

FQPA SF = 1X Reproductive study in rats with
Dicamba Acid

.

Offspring LOAEL=450 mg/kg/day based on decreased pup weights.

No dermal assessment for dicamba acid since the dermal toxicology studies for dicamba acid, IPA and DGA salts all had NOAELs of 1000 mg/kg/day

.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 28 of 105 Table 4.5.4.1 Toxicological Doses and Endpoints for Dicamba Acid and Dicamba BAPMA Salt for use in
Human Health Risk Assessments

Exposure
Scenario Point of Departure FQPA SF and Level of
Concern for Risk

Assessment Study and Toxicological Effects

Dicamba Acid
Short

- , Intermediate

and Long

- Term
Inhalation NOAEL=0.005/0.005 mg/L

(M/F)

Residential Handler

HED= 0.07 mg/kg/day HEC=0.00295 mg/L Residential Bystander HEC=0.00053 mg/L Occupational Handler

HED=0.21 mg/kg/day HEC=0.00221 mg/L Residential
LOC for MOE = 30

Occupational
LOC for MOE = 30

UF A = 3X

UF H =10X

FQPA SF = 1X Aerosol i nhalation study in rats
with Dicamba Acid

.

NOAEL=0.005/0.005 mg/L (M/F) LOAEL=0.050/0.050 mg/L (M/F),
based on minimal multifocal
bronchiole

- alveolar hyperplasia in males; multiple microscopic findings in the lung and associated lymph nodes in females

Dicamba BAPMA Salt
Short

- , Intermediate

and Long

- Term
Inhalation LOAEL = 0.0014 mg/L

Occupational Handler

HED=0.020 mg/kg/day HEC=0.0002 mg/L

Residential Bystander HEC=0.00005 mg/L Residential
LOC for MOE = 300

Occupational
LOC for MOE = 300

UF A = 3X

UF H =10X

UF L = 10X Dicamba BAPMA Rat Inhalation Study

NOAEL=NA LOAEL=0.0014 mg/L (LDT), based

on ulcers in epithelial tissues of the larynx and single/multi

- focal hyperplasia in the larynx

Cancer (Oral, dermal, inhalation) Dicamba is classified as “not likely to be carcinogenic to humans”.

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 adver se 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). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessme nt. 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.



### 4.6 Public Health, Incidents and Epidemiology Information

The incident review identified a relatively high frequency of cases reported for dicamba in both the Incidents Data System ( IDS ) and SENSOR

- Pesticides (Evans, S. and Recore, S., D427231)

. While the majority of case reports are low in severity in both data bases, there are a number of
mode rate severity cases reported and f urther review of dicamba may be warranted.

The Agricultural Health Study (AHS) includes dicamba and the study authors conclude that there were not significant associations with cancer ov erall or strong associations with any specific type of cancer.

4.6.1 Incidents

For the M ain IDS, from January 1, 2010 to May 27, 2015, there were 309 incidents reported involving dicamba

. Fourteen of these incidents were classified as major severity, 292 incidentsDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 29 of 105 

### were classified as moderate severity, three were classified as minor severity, and two were classified as having no or unknown effects.

In Aggregate IDS, from January 1, 2010 to May 27, 2015 , there were 2032 incident reported involving di camba. Forty one incidents were classified as having no or unknown effects and 1991 incidents were classified as minor severity. Minor severity means that a person alleged or exhibited some symptoms, but they were minimally traumatic, the symptoms resolv ed rapidly and usually involved skin, eye or respiratory irritation.

The top five implicated dicamba products in IDS are all products for use by homeowners to treat lawns. These products are all co

- formulated with additional active ingredients. Four of these products are ready to use formulations and the other two are soluble concentrate formulations
that can be used with a hose

- end sprayer or a tank sprayer.

A query of SENSOR

- Pesticides 1998

- 2011 identifies 2 90 cases, stemming from 270 events, involving dicamba. Six cases are single ai products and the remaining 284 cases are multiple ai products

.

A total of 252 cases were low in severity, 36 cases were moderate in severity, and two cases were high severit y. Both of the high severity incidents involved intentional ingestion for self

harm and will not be further analyzed.

The majority of cases were non

- occupational (62%) and occurred in private residences (51%). 41% of cases were applying the product at the time of exposure and another 40% of cases were residential bystanders, such as family members, who were in the residence during or after the application at the time of the exposure. Occupational cases comprise 28% of total case reports, including half of the moderate severity cases.

Symptoms most commonly reported for dicamba cases involved the nervous system (n=144), primarily headache and dizziness; the respiratory system (n=125), primarily upper respiratory pain and shortness of breath, followed b y gastrointestinal system (n=117) and dermatological system (n=109).

Cases occurred in a variety of settings, with 179 cases were not work

- related (residential), 80
cases were work

- related, and 31 cases had unknown work status. Most cases (n=150) occurr ed in private residences and 50 cases occurred on a farm. Nine cases, stemming from four events,
occurred at schools.

4.6.2 Epidemiology Data

In an AHS paper entitled “Cancer Incidence among Pesticide Applicators Exposed to Dicamba in the Agricultura l Health Study” authors found no strong association between dicamba exposure and cancer risk. (Samanic, et al. 2006) . In this study, Samanic et al. incorporated incident

cancers diagnosed between enrollment (generally between 1993 and 1997) and December 3 1,
2002 by linkage to state cancer registries

. Poisson regression was used to estimate rate ratios andDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 30 of 105 

### associated confidence intervals by tertiles of dicamba exposure. The authors concluded that

“ Exposure was not associated with overall cancer incidence nor were there strong associations with any specific type of cancer”

. More specifically, no stati stically significant associations were seen using intensity

- weighted lifetime exposure days and the “No exposure” group as a referent category. While a trend was apparent (p = 0 .02), none of the individual point estim ates was significantly elevated and the authors state that this result is due largely due to elevated risk at the highest exposure level.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies
Tier II summary review section 6.2.1 “Metabolism, distribution and expression of residues in plants” Reregistration Eligibility Decision Memo, D317699, 12/20/2005, C. L. Olinger Residue Chemistry Summary, D408384, A. Kamel, 4/18/2013 48728701.der, P. Savoia, 03/25/2013 (or Residue Chemistry Summary)



### For non

- dicamba

- resistant plants, the nature of the residue was previously determined to be understood (D317699, C. L. Olinger, 12/20/2005). Prior plant metabolism studies were reviewed in part with the 1983 residue chemistry chapter of the dicamba registration standard. The studies demonstrate that dicamba is rapidly absorbed and translocated by grasses, grapes,
black valentine beans, wheat and bluegrass, as well as in soybeans. Dicamba is metabolized in plants mainly by demethylation and hydroxylation.

A new metabolism study submitted by the registrant on dicamba resistant soybean shows that the identified dicamba metabolites were DCSA glucoside (60.32

- 74.48% of TRR), which was the major component in dicamba

- tolerant soybean, DCSA HMGglucoside (1.14

- 7.62% of TRR), DCGA glucoside (0.75

- 4.32%), DCGA malony lglucoside (0.73

- 5.46% of TRR), DCSA (1.54

- 4.08% of TRR), in addition to two minor un

- identified metabolites characterized as mixtures of unknown DCSA and DCGA conjugates, each constituted less than 2.0% of the TRR. The
metabolite 5

- OH dicamba, which is p art of the current tolerance expression, has not been
detected.

The petitioner has also submitted a new metabolism study for dicamba

- tolerant cotton (48728701.der, P. Savoia, 03/25/2013). M etabolism was found to occur at an appreciable rate
with the first step in the process being demethylation of parent into the DCSA metabolite. Residue levels were considerably lower for the pre

- emergence samples in comparison to those obtained following post

- emergence treatment . Parent dicamba was identified in al l the matrices tested which include both gin byproducts and in seed at lower levels. Its metabolites DCSA glucoside, DCSA, and DCGA glucoside were found to be present in all matrices as well. The 5

- OH dicamba metabolite was not identified in any matrix. For dicamba

- tolerant cotton, DCSA glucoside was the major metabolite obtained with the highest levels being found in the gin byproducts samples.

The nature of dicamba residues in animals was previously determined based on acceptable
metabolism studie s conducted on ruminants and poultry (MRID 43245201

- 2). The residues ofDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 31 of 105 

### concern in meat, milk, poultry and eggs consisted of dicamba and 3,6

- dichloro

- 2

- hydroxybenzoic acid (DCSA) [40 CFR §180.227 (a)(2)].

The nature of the dicamba residue in rotational crops was previously reviewed. It has been
concluded that limited and/or extensive field accumulation studies with dicamba were not necessary and rotational crop tolerances need not be established provided the registrants amended all dicamba labels to sp ecify a 120

- day plant

- back interval (PBI) when dicamba is applied at a maximum seasonal rate of 0.75 lb ae/A or less . At application rates of 0.75

- 2.0 lb ae/A, only crops with established tolerances can be rotated for planting.

5.1.2 Summary of Environ mental Degradation

Dicamba is very soluble in water (6100 ppm) and very mobile (K oc 

### = 13.4) in the laboratory. Because dicamba is not persistent under aerobic conditions, very little dicamba could be expected to leach to groundwater. If any dicamba did reach anaerobic ground water, it would be somewhat persistent (due to its anaerobic half

- life of 141 days); any DCSA that reached ground water would be expected to persist. Results from two acceptable field dissipation studies conducted with dimethylamine salt of dicamba, indicated that dicamba dissipated with a half

- life range of 4.4 to 19.8 days. The DCSA was the major degradate in both studies. Both, dicamba and its degradate (DCSA) were found in soil segments deeper than 10 cm.

Aerobic soil metabolis m is the main degradative process for dicamba. A single observed half

life for dicamba was six days; with formation of the intermediate non

- persistent degradate DCSA. DCSA degraded at roughly the same rate as dicamba; the final metabolites were carbon
di oxide and microbial biomass. Dicamba is stable to abiotic hydrolysis at all pH's and photodegrades slowly in water and on soil. Dicamba is more persistent under anaerobic soil:water systems in the laboratory, with a half

- life of 141 days. The major degr adate under anaerobic conditions was DCSA, which was persistent, comprising > 60% of the applied dose after 365 days of anaerobic incubation. No other anaerobic degradates were present at > 10% during the incubation. There are no acceptable data for the aerobic aquatic metabolism of dicamba; supplemental information indicates that dicamba degrades more rapidly in aquatic systems when sediment is present (Memo, Ibrahim Abdel

- Saheb, D317705, 5/31/2005).

Dicamba is not expected to bioaccumulate in aquatic organisms because it is an anion at environmental pHs (pKa = 1.9).

5.1.3 Comparison of Metabolic Pathways

The metabolism of dicamba is qualitatively similar in all plants. Dicamba is metabolized in plants mainly by demethylation and hydroxylation. The main metabolites are 5

- hydroxydicamba and DCSA. The metabolite 2,5

- dichloro

- 3,6

- dihydroxybenzoic acid (DCGA) has been recently
identified in dicamba

- tolerant plants. DCGA is formed by the hydroxylation of DCSA. In dicamba tolerant plants, the relative amounts of the metabolites DCSA, 5

- OH dicamba and DCGA vary significantly when compared to the corresponding dicamba non

- tolerant plants. Metabolism in ruminants was similar to poultry, the metabolism proceeds in a similar fashion to that seen in plants d escribed above, however, an additional metabolite, 2

- amino

- 3,6

-Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 32 of 105 

### dichlorophenol has been identified in low amounts only in hen liver. In rat, dicamba is rapidly absorbed and excreted. The compound is not metabolized or accumulated by the tissues.

5.1.4 Re sidues of Concern Summary and Rationale

The r isk assessment team for dicamba

- tolerant cotton and soybean met in consultation with the

co

- chairs of the HED Residues of Concern Knowledgebase Sub

- committee (ROCKS) on March 18, 2013 to discuss determining the residues of concern (ROC) for tolerance and risk assessment.
The team concluded that parent dicamba, DCSA , and 5

- OH dicamba were residues of concern in
cotton for both tolerance expression and risk assessment , while they were t he ROC in soybean for tolerance setting only. The ROC for soybean for risk assessment were parent dicamba,

DCSA , DCGA and 5

- OH dicamba (D410934, A. Kamel & P. Savoia, 06/03/2013)

.

Based on the results obtained from the metabolism and field trial studies, t he residues present in both soybean and dicamba

- tolerant soybean were comprised of dicamba, 5

- hydroxydicamba,
DCSA and DCGA. HED and PMRA evaluated both the exposure and hazard profiles for dicamba, 5

- OH dicamba, DCSA and DCGA. Based on available toxi city studies and structural similarities, HED considers the parent and all three metabolites to be of comparable toxicity. The submitted data supported the existing tolerance expression for dicamba on soybean which includes parent dicamba, the DCSA metabo lite and the 5

- OH dicamba metabolite found in non

resistant varieties as the residues monitored in the tolerance expression. Since dicamba, 5

- OH dicamba, and DCSA account for the majority of residues in tolerant and /or non

- tolerant soybean,
this tolerance expression provides sufficient residues to monitor for misuse for both tolerant and

non

- tolerant soybean; therefore the ROC for tolerance setting purposes is dicamba, 5

- OH
dicamba and DCSA. DCGA was not considered necessary for determining misuse; and th us was not added to the tolerance expression. T he DCGA metabolite was included because it is present in appreciable concentrations up to 7.6 ppm (mean = 2.66 ppm) in feed items and in quantifiable amounts up to 0.14 ppm (mean = 0.032 ppm) in the seed in t he registrant’s submitted field trial data. In addition, amounts of DCGA found in soybean processed seed fractions were comparable to the amounts of DCSA.

The newly submitted data for dicamba

- tolerant cotton supports including parent and the DCSA
metabol ite, along with the 5

- OH dicamba metabolite found in non

- resistant varieties as the residues of concern in cotton for tolerance expression and risk assessment. The rationale for this decision follows that residues present in both cotton and dicamba

- tolera nt cotton were comprised of dicamba, and its metabolites, 5

- OH dicamba, DCSA, and DCGA. However, dicamba, 5

- OH dicamba, and DCSA account for the majority of the residues in both tolerant and non

- tolerant cotton and will provide sufficient residues with wh ich to monitor for misuse for both tolerant and

non

- tolerant cotton; therefore, the ROC for tolerance setting purposes is dicamba, 5

- OH dicamba, and DCSA.

For the purpose of risk assessment, HED considered both the exposure and hazard profiles for
dicamba , 5

- OH dicamba, DCSA, and DCGA and is including dicamba, 5

- OH dicamba, and
DCSA as the ROC for tolerant and non

- tolerant cotton. While DCGA may be of comparable toxicity, it was present in the cotton metabolism studies at less than 10% of the total radioa ctive residue (TRR), and is only detected in livestock feed items, not in human food items. Further,Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 33 of 105 

### inclusion of this metabolite as a ROC in feed items would have no material impact on the livestock dietary burden since calculation of the reasonably bala nced livestock diets are driven by other feed items with far higher residues. Therefore, HED is not including the DCGA
metabolite as a ROC on cotton for risk assessment.

The residues of concern that are i ncluded for tolerance expression and risk assess ment based on all the available data for dicamba are presented below in Table 5.1.4.

Table 5. 1. 4

. Dicamba Residues of Concern.

Matrix Tolerance Expression Residues for Risk Assessment
Barley, corn, grasses, oats, proso millet, sorghum, sugarcane, and
wheat Dicamba + 5

- OH dicamba Dicamba + 5

- OH dicamba

Asparagus Dicamba + DCSA 1 Dicamba + DCSA

Cotton Dicamba + 5

- OH dicamba + DCSA Dicamba + 5

- OH dicamba + DCSA Soybeans, and aspirated grain fractions (AGFs) Dicamba + 5

- OH dicamba + DCSA Dicamba + 5

- OH dicamba + DCSA

+ DCGA 2

Livestock Dicamba + DCSA Dicamba + DCSA Drinking Water NA 3 Dicamba + DCSA

1 DCSA also referred to as 3,6

- dichloro

- 2

- hydroxybenzoic acid or as 3,6

- dichlorosalicylic acid.

2 DCGA is also referred to as 2,5

- dichloro

- 3,6

- dihydroxybenzoic acid.

3 NA

– Not Applicable.



### 5 .2 Food Residue Profile

The application of dicamba to crops primarily results in surface residues being found. For the proposed uses on dicamba

- tolerant soybean and cotton, adequate crop field trial data were provided. These data are used to provide the basis for determining th e recommended tolerances, as well as constructing the supporting dietary risk assessment.

The residue chemistry database for dicamba is adequate to support the proposed new uses on
dicamba

- tolerant soybeans and cotton. The nature of the residue is adequ ately understood based on prior metabolism studies made on wheat, grape, asparagus, sugarcane, cotton, and soybean, as well as on new ones provided for dicamba

- tolerant soybean and cotton. Data on the metabolism
of dicamba in dicamba

- tolerant soybean and cotton demonstrate that dicamba is rapidly absorbed and translocated in the plants

. The nature of the residue is adequately understood in livestock based on previous metabolism studies made on ruminants and poultry. The highest levels of
dicamba residues in beef accumulated in kidney and liver tissues

. The occurrence of quantifiable residues of dicamba or DCSA in poultry eggs and meat as a result of treating crops with poultry feed items at the maximum use patterns are not anticipated. There are adequate methods available for the enforcement of tolerances established on all plant and livestock commodities. Adequate storage stability data are available which demonstrate residues of dicamba are stable
when stored frozen in dicamba

- tolerant soybeans for up to 9.6 months, and dicamba

- tolerant cotton for up to 6 months.

In the submitted field trials made on dicamba

- tolerant soybeans, there were detectable levels of
dicamba and its metabolites found in seed. Levels were found above the limits of de tection at concentrations well below the previously established 10.0 ppm tolerance for non

- resistantDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 34 of 105 

### soybean seed; therefore, the 10.0 ppm tolerance for soybean seed remains adequate. For the field trials provided on dicamba

- tolerant cotton, detectable le vels were found above the 0.2 ppm tolerance previously established for non

- resistant cotton seed. Using the Organization for Economic Cooperation and Development (OECD) calculation procedures and inputting the total residues, a tolerance of 3.0 ppm is rec ommended for cotton seed.

Tolerances are recommended of 60 ppm on soybean forage, 100 ppm on soybean hay, and 70 ppm on cotton gin byproducts

, which are livestock feed items. However, these tolerances will not increase livestock dietary burden; therefore, no new revised tolerances on livestock commodities are required.

For the registration of the new BAPMA salt formulation of dicamba, side

- by

- si de field trials on representative crops were made to show product equivalency. Bridging studies provided for pasture grasses, wheat, field corn, and soybeans show that the average combined residues of dicamba are similar in the new BAPMA product with resp ect to the registered DGA salt
formulation with all results falling well below established tolerance limits.

No new rotational crop data have since been submitted; therefore, the plant back restrictions noted in the 2005 RED are appropriately specified on the proposed product label for treating
these dicamba

- tolerant crops. Specifically, that a 120

- day PBI is followed when dicamba is applied at a maximum seasonal rate of 0.75 lb ae/A or less . At seasonal application rates of
0.75

- 2.0 lb ae/A, only crops w ith established tolerances can be rotated for planting.

Processing study data were provided and r esidues of dicamba were found not to concentrate in the processed commodities of dicamba

- tolerant cotton , but slightly concentrated in soybean hull (1.4 × ), flour (1.2 × ) and meal (1.3 × ) fractions

. Based on the maximum residues found in soybean seeds and processed fractions using a 50% exaggerated application rate , the existing tolerances for soybean seed of 10 ppm and soybean hull at 30 ppm are adequate.

5.3 Water Residue Profile

Residues of dicamba and its DCSA degradate are known to be persistent in the environment and can reach drinking water supplies for human consumption. As a result, the Environmental Fate and Effects Division (EFED) provided dr inking water exposure estimates for risk assessment (D404824, R. Baris, 03/28/2013). This assessment remains current since no new fate data have been submitted and it was derived with the latest models used by EFED for estimating pesticide
residues in dri nking water (personal communication, M. Corbin, 08/19/2015). For this determination, EFED conducted a Tier I PRZM GW drinking water assessment from groundwater sources for the proposed new uses. Residues of concern for drinking water for risk

assessment purposes were the parent and its DCSA metabolite. Table s 5.3.1

– 5.3.4 provide the modeling estimates for drinking water summarized from surface water and ground water sources. For the purposes of this assessment, the highest (most conservative) PRZM

- GW values were used for the acute (329 ppb parent + 0.041 ppb DCSA) and chronic (187 ppb parent + 0.041 ppb DCSA) assessments. The combined estimated drinking water residues (parent + DCSA) for peak
concentration used in the acute assessment and chronic were 329 and 187 u g /L ( pp b ),Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 35 of 105 

### respectively. The model and its description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

Table 5.3.1. DICAMBA (parent only) Preliminary Cotton Runs for Dicamba (PCA corrected

– 0.87)

Model Use/Scenario Acute (ug/L) Chronic (ug/L) 30

- year average (ug/L)

SW (PRZM/EXAMS) CAcotton_wirrgSTD.txt 7.72 6.62 1.07

MScottonSTD.txt 53.37 44.5 6.52

NCcottonSTD.txt 32.14 27.32 4.24

Table 5.3.2 DICAMBA (parent only) Preliminary Cotton Runs for Dicamba (PCA corrected

– 0.87)

Groundwater Peak (ug/L) Post breakthrough

average (ug/L) 30

- year average (ug/L)

PRZM

- GW (no pca applied) GAcoastal 41.9 28.2 24.9

DELMARVA 192 121 117
FLCitrus 238 161 155

FLPotato 56.8 19.2 18.1

NCcoastal 65.3 32.6 29.3

WIsands 329 187 158

SCIGROW

-- 0.0015

-- -- Note: the highest estimates are in bold.

Table 5.3.3 DCSA (PCA corrected

– 0.87)

Model Use/Scenario Acute (ug/L) Chronic (ug/L) 30

- year average (ug/L)

SW (PRZM/EXAMS) MScottonSTD.txt 2.97 2.59 0.63

Table 5.3. 4 DCSA (PCA corrected

– 0.87)

Groundwater Peak (ug/L) Post breakthrough

average (ug/L) 30

- year average (ug/L)

PRZM

- GW (no pca applied) GAcoastal* 4.47E

- 5 3.93E

- 5 2.38E

- 5

DELMARVA 1.94E

- 4 1.65E

- 4 4.45E

- 5

FLCitrus 0.041 0.041 0.018

FLPotato* 5.71E

- 11 3.67E

- 11 3.114E

- 11

NCcoastal 7.31E

- 5 3.64E

- 5 2.59E

- 5

WIsands* 8.3E

- 4 7.66e

- 4 3.67E

- 4

SCIGROW

-- 0.0059

-- -- *100 year simulation Note: the highest estimates are in bold.



### In regard to the registration of the new Engenia herbicide, the BAPMA counter ion is known to have greater toxicity than the dicamba active ingredient. Because it is not possible to delineate exposure between the dicamba and BAPMA portion of the salt when this end

- use product is applied, drinking water estimates must be adequately protective. To ensure the dicamba drinking water estimates are protective, EFED has examined drinking water exposures for dicamba versus the BAPMA counter ion (personal communication, W. Eckel, 07/15/2015). EFED used the Mississippi (MS) cotton scenario, a benchmark high

- runoff scenario, to compare exposures fromDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 36 of 105 

### applications of the BAPMA end

- use product. This modeling found t he 365

- day average
concentrations for dicamba

- acid and BAPMA were comparable at 11 ppb and 11.8 ppb, respectively, for the Index Reservoir. The drinking water estimates provided are considered to be protective since the lowest adverse effect doses were selected for assessment.

5.4 Dietary R isk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute and chronic aggregate dietary food and drinking water exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16. This software uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).

For this a ction there are several compounds to consider which include dicamba acid, the dicamba metabolites (DCSA, 5

- OH dicamba, and DCGA), and the dicamba BAPMA counter ion. The toxicological database is sufficient for assessing the toxicity of and characterizing the hazards of
dicamba. D icamba acid, the dicamba metabolites (DCSA, 5

- OH dicamba, and DCGA), and the
dicamba BAPMA counter ion are all considered because the lowest adverse effect doses were selected for dietary assessment.

The acute and chronic aggrega te dietary risk assessments were conducted incorporating all current and proposed uses. Tolerance level residues for all commodities along with 100% CT were used in the acute dietary exposure assessments. A refined chronic dietary exposure

assessment was performed which used average residues from field trial studies for crops, tolerance levels for livestock commodities, and relevant %CT data. Modeling estimates for ground water (PRZM

- GW ) were used to estimate residue concentrations in drinking water for both the acute and chronic assessments. The use of anticipated residues, empirical processing factors, and additional %CT data would refine further HED’s exposure and risk estimates for

dicamba.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Fo r the existing uses attributed to dicamba, BEAD provided a compilation of percent crop treated (%CT) data presented in Attachment 1 to aid in the refinement of the chronic dietary risk assessment ( D427534, J. Alsadek, 06/25/2015). The following average p ercent crop treated estimates were used in the chronic dietary risk assessment for the following crops that are currently registered for dicamba: asparagus: 5%; barley: 5%; corn: 10%; oats: 2.5%; sorghum: 15%; sugarcane: 20%; sweet corn: 1%; and wheat: 10 %. One hundred percent crop treated was assumed for all other applicable crops (100 %CT).

5.4.3 Acute Dietary Risk Assessment

The acute analysis was an unrefined determination which used tolerance levels and 100 %CT for all existing and proposed uses

. The dietary exposure analyses that were performed result inDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 37 of 105 

### acute dietary risk estimates that are below the Agency’s level of concern for both food and water. For the U.S. population the exposure was 0.042760 mg/kg/day, which utilized 15% of the acute

p opulation adjusted dose (aPAD) at the 95 th 

### percentile. The highest exposure and risk estimates
were for all infants. At the 95 th 

### percentile, the exposure for all infants was 0.088733 mg/kg/day,
which utilized 31% of the aPAD.

5.4.4 Chronic Dietary Risk Assessment

The chronic analysis was a refined determination which used average residues based on field trial studies for crops, tolerance levels for livestock commodities, and relevant %CT data for several existing uses. The chronic risk estimates f or dicamba are below the Agency’s level of concern for the general U.S. population and all population subgroups. The most highly exposed population subgroup is children ages 1

- 2 with a risk estimate for dicamba for food and water of
42% of the cPAD.

5.4.5 Cancer Dietary Risk Assessment

Dicamba is classified as not likely to be carcinogenic to humans; therefore, a quantitative cancer dietary assessment was not performed.

5.4.6 Summary Table

Table 5.4.6 Summary of Dietary (Food and Drinking Water) Exposure and Risk for Dicamba.

Population Subgroup Acute Dietary 1 (95 th Percentile) Chronic Dietary 2

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD

General U.S. Population 0.042760 15 0.006319 16

All Infants (< 1 year old) 0.088733 31 0.014024 35

Children 1

- 2 years old 0.075295 26 0.016988 42

Children 3

- 5 years old 0.065788 23 0.011948 30

Children 6

- 12 years old 0.047142 16 0.007618 19

Youth 13

- 19 years old 0.032166 11 0.004936 12

Adults 20

- 49 years old 0.035172 12 0.005526 14

Adults 50

- 99 years old 0.029776 10 0.005340 13

Females 13

- 49 years old N/A 3 N/A 0.005465 14

1 Acute dietary analysis derived from a 0.29 mg/kg/day aPAD for the general population.

2 Chronic dietary analysis derived from a 0.04 mg/kg/day cPAD for the general population.

3 N/A

– not applicable, no endpoint was concluded for this population subgroup.

4 Highest exposures found for each assessment are noted in bold.



### 6.0 Residential (Non

- O ccupational) Exposure/Risk CharacterizationDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 38 of 105 

### There are no proposed residential uses at this time for either dicamba or the BAPMA salt ; however, there are existing residential uses of dicamba that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs 1 

### along with policy changes for body weight assumptions. The revision of residential exposures will impact the human health aggregate risk assessment for dicamba. The proposed new BAPMA salt of dicamba does not impact the resid ential assessment as there are no proposed uses of dicamba BAPMA that would result in residential exposure; therefore, only the registered uses of dicamba have been reassessed
in this document. Registered uses of dicamba include solid products or liquid p roducts in concentrates or ready

- to

- use sprays for use as spot and broadcast treatments on turf.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handlers are addressed somewhat differently by HED as homeowners are assumed to complete all elements of an

app lication without use of any protective equipment.

The quantitative exposure/risk assessment developed for residential handlers is based on the following lawn/turf application scenarios:

 Mix/Load/Apply Liquid with Hand

- held Equipment

 Apply Ready

- To

- Use with Hand

- held Equipment

 Load/Apply Granule with Hand

- held Equipment

Residential Handler Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. Each assumpt ion and factor is detailed below.

Application Rate: The maximum application rate for residential products on turf is 1 lb ae/acre.

Unit Exposures and Area Treated or Amount Handled: Unit exposure values and estimates for area treated or amount handled w ere taken from HED’s

2012 Residential SOPs 1



### .

Exposure Duration: Residential handler exposure is expected to be short

- term in duration. Interme diate

- term exposures are not likely because of the intermittent nature of applications by homeowners.

Residential Handler Non

- Cancer Exposure and Risk Estimate Equations

1 Available: http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/standard

- operating

- procedures

- residential

pesticideDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 39 of 105 

### The algorithms used to estimate exposure and dose for residential handlers can be f ound in the
2012 Residential SOPs 2



### .

Combining Exposures/Risk Estimates:
There is n o potential hazard via the dermal route f or dicamba. Only inhalation risk estimates were quantitatively assessed.

Summary of Residential Handler Non

- Cancer Exposure and Risk Estimates The residential handler risk estimates are not of concern for dicamba (Inhalation MOEs > LOC of 30) for all scenarios.

Table 6 .1.1. Residential Handler Non

- cancer Exposure and Risk Estimates for Dicamba Acid.

Exposure Scenario Level of

Concern Inhalation Unit

Exposure (mg/lb ai) Maximum

Application

Rate 1 Area Treated or

Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 5 MOE 6

Mixer/Loader/Applicator

Lawns/Turf, Liquid, Hose

- end Sprayer

30 0.022 1 lb ae/acre 0.5 acres 0.00014 510

Lawns/Turf, Liquid, Sprinkler Can 0.000023 lb
ae/ft 2 1000 ft 2 0.0000063 11 ,000

Lawns/Turf, Liquid, Manually

pressurized handwand 0.018 0.05 lb ae/gallon 5 gallons 0.000056 1, 2 00

Lawns/Turf, Liquid, Backpack 0.14 0.00044 16 0

Lawns/Turf, RTU, Hose

- end Sprayer 0.034 1 lb ae/acre 0.5 acres 0.00021 330

Lawns/Turf, Granule, Push

- type rotary

spreader 0.0026 1 lb ae/acre 0.5 acres 0.000016 4,300

Lawns/Turf, Granule, Belly grinder 0.039

0.000023 lb
ae/ft 2 1200 ft 2 0.000013 5 ,200

Lawns/Turf, Granule, Spoon 0.087

100 ft 2 0.0000025 28 ,000

Lawns/Turf, Granule, Cup/Shaker Can 0.013 0.00000037 190 ,000

Lawns/Turf, Granule, Hand Dispersal 0.38 0.000011 6,400
Liquid = Liquid concentrate; RTU = Ready

- to

- use 1 Based on registered uses. Application rate is 1 lb ae/acre. 1 lb ae per acre with an assumed minimum of 20 gallons used per acre = 0.05 lb ae/gal; 1 lb ae/acre * 1 acre/43560 ft 2 = 0.0000344 lb ae/ft 2

2 Based on HED’s 2012 Residential SOPs ( http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/standard

operating

- procedures

- residential

- pesticide ).
5 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/ area or volume ) × Area Treated or Amount Handled ( area

/day or volume /day) ÷ Body Weight ( 80 k g).

6 Inhalation MOE = Inhalation NOAEL ( 0.084 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).



### 6.2 Post

- Application Exposure

There is the potential for post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with dicamba. The quantitative exposure/risk assessment for residential post

- application exposures is based on the following scenari os:

 Children (1 to < 2 years old) incidental oral exposure to treated turf.

2 Available: http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/standard

- operating

- procedures

- residential

pesticideDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 40 of 105 

###  Children (1 to < 2 years old) episodic granular ingestion exposure.

Assessment of post

- application exposure to liquid formulations is protective of exposure to solid
formulatio ns, except for the episodic granular ingestion scenario which was quantitatively
assessed.

The lifestages selected for each post

- application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs 3 

### . These lifestages are no t the only lifestages that could be potentially exposed for these post

- application scenarios; however, the assessment of these lifestages is health protective for the exposures and risk estimates for any other potentially exposed lifestages.

Residential P ost

- application Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential
post

- application risk assessment. Each assumption and factor is detailed in the 2012 Residential

SOPs.

Turf Transferable Residue Data
There are chemical

- specific turf transferable residue (TTR) data available for dicamba. Based on a review of all available data, TTR residues from MRID 44959001 were used to assess post

application exposure since the study was co nducted at the maximum application rate being assessed, and predicted residues were consistent in three different site locations . T herefore, HED
has use d the predicted residue value of 0.15 μg/cm 2 

### from MRID 44959001 for risk assessment

purposes.

Reside ntial Post

- application Non

- Cancer Exposure and Risk Equations The algorithms used to estimate residential post

- application exposure and dose can be found in
the 2012 Residential SOPs.

Combining Exposure and Risk Estimates
There is n o potential hazard via the dermal route f or dicamba. Only incidental oral risk estimates were quantitatively assessed. The incidental oral scenarios (i.e., hand

- to

- mouth and object

- to

mouth) should be considered inter

- related and it is likely that they occur interspersed among st
each other across time , therefore, these scenarios are not combined

. The g ranular ingestion scenario is not combined as this exposure would not occur as a result of routine behavior and is considered an episodic event related to poisoning. 

### Therefore, no post

- application exposure scenarios were combined for children 1 < 2 years old.

Summary of Residential Post

- application Non

- Cancer Exposure and Risk Estimates The residential post

- application risk estimates are not of concern for dicamba (MOEs are gr eater than the level of concern of 100) for all incidental oral scenarios. All scenarios are short

- term exposures, except episodic granular ingestion which is an acute scenario. Incidental soil

3 Available: http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/standard

- operating

- procedures

- residential

pesticideDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 41 of 105 

### ingestion scenario is short

- term exposure only as the soil h alf

- life for dicamba is 18 days (EFED memo, I. Maher, D378447, 11/22/10).

Table 6 .2.1. Residential Post

- application Non

- cancer Exposure and Risk Estimates for Dicamba.

Lifestage Post

- application Exposure Scenario Application

Rate 1 TTR

(ug/cm 2 ) 2 Dose

(mg/kg/day) MOE

(LOC = 100) 3 Use Site Route of Exposure

1 to < 2 years old Turf

- liquid Hand

- to

- Mouth

1 lb ae/acre 0.15 0.02055 6,600 Object

- to

- Mouth 0.00062 220 ,000 Soil Ingestion 0.000034 4,0 00,000

Turf

- Granular Episodic Granular Ingestion 1% ai 0.09 320 A

1 Based on registered uses (reference: 2005 RED).

2 TTR based on MRID 44959001

. 3 MOE = Incidental oral POD ( 136 mg/kg/day) ÷ Dose (mg/kg/day) for hand

- to

- mouth, object

- to

- mouth, and soil ingestion scenarios

. LOC = 100

. A Ingestion of granules is considered episodic in nature; MOE was calculated using the acute dietary POD (29 mg/kg/day) and LOC (100).



### 6.3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6. 3 .1 reflects the residential risk estimates that are recommended for use in the aggregate assessment for dicamba. Inhalation exposures are not included in the aggregate assessment since effects from the inhalation route are not systemic/cannot be aggregated. Post

- application episodic granular ingestion following applications to lawns and turf are not included in the aggregate assessment as this exposure would not occur as a result of routine behavior and is considered an episodic event related to poisoning. T here is no recommended residential exposure for use in the adult aggregate assessment since there is no hazard via the dermal route of exposure and inhalation exposures are not included in the aggregate assessment, as described above. Therefore, the only residential exposures recommended for the dicamba aggregate assessment are the following:

 The recommended residential exposure for use in the children (1 to <2 years old) aggregate assessment reflects hand

- to

- mouth exposures from post

- application turf scenario (i.e., post

- application exposure to treated turf).

Table 6.3.1. Recommendations for the Residential Exposures for the Dicamba Aggregate Assessment.

Lifestag

e Exposure

Scenario Dose (mg/kg/day) 1 MOE (LOC = 100) 2

Dermal Inhalation Incidenta

l Oral Total Dermal Inhalation Incidental
Oral Total

Child Hand

- to

Mouth Post

application Exposure

– Treated Turf N/A N/A 0.02055 0.02055 N/A N/A 6,600 6,600

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed

. Total = dermal + inhalation + incidental oral

(where applicable)

. 2 MOE = the MOEs associated with the highest residential doses . Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental

Oral MOE), where applicable

.



### 6. 4 Residential Bystander Post

- application Inhalation ExposureDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 42 of 105 

### The potential exposure to bystanders from vapor phase dicamba and BAPMA salt residues emitted from treated fields has been evaluated for the proposed uses of dicamba on dicamba

tolerant corn and soybean, and for the pr oposed uses of BAPMA on various agricultural crops. Bystander exposure to dicamba and BAPMA emitted from treated fields depends on two main factors: 1) the rate at which these chemicals volatilize from a treated field (described as the off

gassing, emissio n or flux), and 2) how those vapors are dispersed in the air over and around the
treated field. Volatilization can occur during the application process or thereafter. It can result from aerosols evaporating during application, while deposited sprays are s till drying (possibly
via co

- distillation), or after as dried deposited residues volatilize.

This assessment employs approaches EPA has used previously to assess inhalation exposures to fumigant pesticides 4 

### and is also consistent with the recommendation s of the December 2009 Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) 5 

### meeting on the scientific issues associated with field volatilization of conversional (semi

- volatile) pesticides

.

6.4.1 Flux Data

A submitted flux study 6 

### was reviewed by the Environmental Fate and Effects Division (EFED), which estimated the flux of dicamba vapors after spray application of the DGA salt formulation. The dicamba DGA salt formulation was used alone without any tank adjuvants, and the test surface was zoysiagrass. The trial was performed in August 2012 near Columbia, IL, and experienced minimum and maximum temperatures of 21.1 o 

### C and 26.2 o 

### C, respectively.

A circle in the zoysiagrass with a diameter of 40 m (~131 ft) was sprayed wi th a tank mix of 32 oz/A (1.0 lb a.e./A) Clarity ® 

### (EPA Reg. # 7969

- 137) . Herbicide treatments were applied using a nitrogen pressurized backpack sprayer calibrated to deliver 10 gallons per acre (GPA) at 50 PSI using TeeJet ® 

### TTI 110015 spray tips. Applica tion of the test substance was made approximately perpendicular to the prevailing wind direction. In the test plot, three air samplers and an anemometer were placed in the treatment area after post

- application drift was allowed to settle (typically 2

- 5 mi nutes). Data were collected for 0

- 6 hours after application.

The field test method employed was the Theoretical Profile Shape (TPS) method which requires circular spray plots of a certain diameter, with air sampling and wind velocity measurements

acqu ired at the center of the circle at a certain, single height determined by the circle size and the surface roughness. A short description of the TPS method and calculations is provided in an Appendix of the study report.

4 U.S. EPA 2004d. FIFRA Science Advisory Panel Meeting Minutes

- Fumigant Bystander Exposure Model Review: Probabilistic Exposure and Risk Model for Fumigants (PERFUM) Using Iodomethane as a Case Study. Available at http://www.epa.gov/scipoly/sap/meetings/2 004/august1/august2425minutes.pdf

5 U.S. EPA 2009. FIFRA Science Advisory Panel Meeting Minutes

- Scientific Issues Associated with Field Volatilization of Conventional Pesticides. Available at http://www.epa.gov/scipoly/sap/meetings/2009/december/120309m eetingminutes.pdf

6 Memo, D 411382 , W. Eckel. MRID 49022501. Sall, E.; Smith, H.; Findley, D.; et al. (2013) Measurement of the Volatile Flux
of Dicamba under Field Conditions using the Theoretical Profile Shape Method. Project Number: RPN/2012/0662,

MSL002 4798. Unpublished study prepared by Monsanto Company. 52p.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 43 of 105 

### The estimated 6 hr average flux f rom the Clarity ® 

### application on zoysiagrass was 0.4 (+/

- 0.1) ng/m 2 

### /sec, representing 0.008% of the application rate. Quantitative analysis using the estimated flux rate derived from this study is described below.

While the flux data are specific to the DGA salt of dicamba, it is considered protective for the
BAPMA salt form of dicamba as well. BAPMA is considered less volatile than the DGA salt and, therefore, would be expected to result in lower air concentrations as a result of flux from a
treated fi eld. Based on modeling data using EPISuite and information provided in a BASF
patent 7 

### , the volatility of the BAPMA salt is lower than that of the DGA salt . EPISuite estimated the vapor pressure of the DGA salt as 1.48 E

- 11 mmHg at 25 o 

### C, and for BAPMA as 1.10E

- 21 mmHg at 25 o 

### C. The BASF patent provides a relative ranking of the volatility of the various
forms of dicamba (compared to the acid at 100%) , with the BAPMA salt being 0.5% of the volatility of the dicamba acid and the DGA salt being 5.4% of the di camba acid . Therefore, HED believes that the volatilization assessment conducted using the flux data for the DGA salt is protective of the BAPMA salt.

6.4.2 Volatilization Modeling and Risk Assessment

Exposure modeling for a single day was completed using Probabilistic Exposure and Risk model for FUMigants ( PERFUM). There are a variety of factors that potentially affect the emission
rates of dicamba and subsequent offsite transport including: field condition (bare soil, growing or

mature cr op canopy), field parameters (soil type, moisture, etc.) , formulation type, meteorological conditions, and application scenario (rate, method)

. The flux estimate from the study ( 0.0004 ug/m 2 

### /s) , a single 40A field, and the Bradenton, FL meteorological data were used with PERFUM to estimate risk based on the dicamba field volatility study summarized in
Section 6.4.1.

The short

- term residential inhalation endpoint s for dicamba and BAPMA were used in the
volatilization assessment (dicamba acid: 530 ug/m 3 

### an d LOC of 30; BAPMA salt: 50 ug/m 3 

### ; LOC = 300). This is considered a conservative assumption to compare the day 1 volatilization exposure to a short

- term HEC. Furthermore, a 6

- hour exposure averaging period was used in the model; it is a conservative assum ption to compare the 6 hour average exposure from the model to the HEC calculated for 24 hours of exposure especially sin c e the 6 hour exposure period used as the basis for the comparison represents the peak emissions period after application.

All of the files associated with the use of PERFUM in this assessment can be provided upon request. These files could be used to examine the detailed input and output files for each permutation of the model completed for this analysis.

6.4.3 Volatiliz ation Risk Estimates

The field volatility study suggest s that volatilization of dicamba from treated crops does occur

, and it has been assumed that is true also for the BAPMA salt, which could result in bystander

7 Low volatile amine salts of anionic pesticides

. USPTO Applicat i on: #20150210723.
http://images3.freshpatents.com/pdf/US20150210723A1.pdfDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 44 of 105 

### exposure . Results of PERFUM modeling, how ever, indicate that airborne concentrations, even at the edge of the treated fields, are not of concern. The maximum proposed application rate of 1
lb a e /A was assessed. There were no whole field and maximum field buffers estimated using PERFUM (i.e., ri sks were acceptable at all percentiles of exposure at the edge of a treated field).

6. 5 Non

- Occupational Spray Drift Exposure and Risk Estimates

Off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of fa ctors. Sprays that are released and do not deposit in the application area end up off

target and can lead to exposures to those it may directly contact. They can also deposit on surfaces where contact with residues can eventually lead to indirect exposure s ( e.g. , children playing on lawns where residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling coupled with methods employed for residential risk assessments for turf produc ts.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label language and other regulatory requirements intended to prevent them. 8 

### Direct exposures would include inhalation of the spray plume or being sprayed directly. Rather, the exposures addressed here are thought to occur indirectly through contact with impacted areas, such as residential lawns, when compliant applications are conducted. Given this premise, exposures for children (1 to 2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an indirect exposure are the focus of this analysis analogous to how exposures to turf products are
considered in risk assessment.

Dicamba: Several dicamba products have existing labels for use on turf, thus it was considered whether the risk assessment for that use may be considered protective of any type of exposu re that would be associated with spray drift. It should be noted that t he registered residential uses on turf result in exposure greater than potential exposure from spray drift; therefore, no new
residential assessment needs to be completed. If the maxi mum application rate on crops adjusted by the amount of drift expected is less than or equal to existing turf application rates, the existing turf assessment is considered protective of spray drift exposure. The proposed maximum single application rate of dicamba is 1 lb ae/A

. The highest degree of spray drift noted for any application method immediately adjacent to a treated field (Tier 1 output from the aerial application using fine to medium spray quality) results in a deposition fraction of 0.26 of th e application rate. A quantitative spray drift assessment for dicamba is not required because the

max imum application rate to a crop/ta rget site multiplied by the adjustment factor for drift of
0.26 is less than the maximum direct spray residential turf a pplication rate 1 lb ae/A 9 

### for any
dicamba products . The turf post

- application MOEs have been previously assessed and are based on the revised SOPs for Residential Exposure Assessment (i.e., see above in Section 6 .2).

8 

### This approach is consistent with the requirements of the EPA’s Worker Protection Standard which, when included on all labels, precludes direct exposure pathways.

9 1 lb ae/A x 0.26 ≤ 1 lb ae/ADicamba Human Health Risk Assessment DP No. D378366, D404917

Page 45 of 105 

### BAPMA salt: In order to evaluate the drift potential and associated risks for the BAPMA salt, an approach based on drift modeling coupled with techniques used to evaluate residential uses of pesticides was utilized . Essentially, a residential turf assessment based on exposure to deposited residues has been completed to address drift from the agricultural applications of the BAPMA
salt

. In the spray drift scenario, the deposited residue value was determined based on the amount of spray drift that may occur at varying distances from the edg e of the treated field using the AgDrift ( v2.1.1) model and the Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift Policy

. Once the deposited residue values were determined, the remainder of the spray drif t assessment was based on the algorithms and input values specified in the recently revised (2012) Standard Operating Procedures For
Residential Risk Assessment (SOPs)

.

A screening approach was developed based on the use of the AgDrift model in situation s where specific label guidance that defines application parameters is not available. 10 

### AgDrift is appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier 1 option) were incorporated into the model and represent each equipment type and use under varied conditions. The screening options specifically recommended in this methodology were selected because they are plausible and represent a reasonable upper bound level of drift for common application methods in agriculture. These screening options are consistent with how spray drift is considered in a number of ecological risk assessments and in the process used to develop drinki ng water concentrations used for risk assessment. In all cases, each scenario is to be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides are not typically applied to tree canopies) or specific label prohibitions ( e.g., aerial applications are not allowed).

The spray drift risk estimates are based on an estimated deposited residue concentration as a result of the screening level agricultural application scenarios. BAPMA salt is proposed for use

on numerous agricultural crops and can be applied via aerial and ground boom equipment. The recommended drift scenario screening level options are listed below:

 Groundboom applications are based on the AgDrift option for high boom height and using very fine to fine spray type using the 90 th 

### percentile results.

 Aerial applications are based on the use of AgDrift Tier 1 aerial option for a fine to medium spray type and a series of other parameters which will be described in more detail below (e.g., wind vector assumed to be 10 mph in a downwind direction for entire application/drift event).

Only incidental oral risk estimates were estimated since there is not dermal hazard for the BAPMA salt. The total applicable LOC is 100 so MOEs < 100 would be of concern. Children’s (1<2 year old) incidental oral risk estimates from indirect exp osure to dicamba BAPMA salt related to spray drift result in no risk estimates of concern at the field edge for groundboom and
aerial applications (i.e., all MOEs ≥ 35 ,000)

.

10 http://www.agdrift.com/Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 46 of 105 Table 6.5.1. Non

- occupational Risk Estimates Resulting from Spray Drift for BAPM A Salt.

Crop/Rate Group Spray Type/ Nozzle Configuration Application Rate (lb ai/A) Estimated

TTR t (ug/cm 2 ) a HtM MOE

at Field Edge (LOC = 100)

Aerial Fine to Medium 1 0.11115 35,000

Ground boom High Boom Very fine to Fine 48,000

a. TTR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2

.



### 7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard, or the risks themselves can be aggregated. When aggregating exposures and
risks from variou s sources, HED considers both the route and duration of exposure. Since residential exposure is expected, aggregate exposure consists of exposure from residential, food and drinking water sources.

Acute and chronic aggregate risks include only dietary exposure from food and drinking water sources. Since there are residential uses, short

- term aggregate risks were assessed which include contributions from food, drinking water, and residential exposure. I ntermediate

- term aggregate risks were not considered as residential exposure is not expected to occur for more than 30 days. Cancer aggregate risk was not quantified since dicamba is not a carcinogen. A common toxicological endpoint (decreased pup growth) of concern was not identified for short

- , intermediate

- and long

- term durations via the oral, dermal (oral equivalent) and inhalation (oral equivalent) routes. Therefore, the aggregate exposure risk assessment should include exposure
across the oral routes as appropriate for the populations of concern (i.e. food and water for adult s and food

, water and incidental oral for children)

.

7.1 Acute Aggregate Risk

It is HED policy not to aggregate non

- distributional acute residential exposures with acute dietary exposures, since it is unlikely that these types of exposures would occur in the same day. Thus, the acute dietary (food and drinking water) assessment in Section 5.4 represents acute aggregate risk. T he acu te dietary exposure assessment was conducted using tolerance

- level residues, DEEM default processing factors and 100% crop

- treated information for all registered and proposed use sites. Drinking water values were incorporated directly into the assessment.

The most highly exposed population subgroup is all infants (<1 year old; 31 % of the aPAD).

T he acute and chronic dietary exposure estimates are not of concern for the general U.S. population or any population subgroup

.

7.2 Short

- Term Aggregate RiskDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 47 of 105 

### The short term aggregate assessment is comprised of exposure from food, drinking water and residential activities (handler and post

- application). Average food and water exposure estimates
were used in the assessment. The residential scenario that resulte d in the highest exposures for
children was the post

- application exposure on turf

.

The results of the short

- term aggregate assessments for children is presented in Table 7.2. T he

MOE is greater than 100 for children scenario, thus are not of concern to HED. For adults

, there
is no short

- term aggregate assessment, since there was no dermal hazard identified in the route

specific dermal studies and the inhalation effects were not systemic. As stated in the previous section, these res ults are likely to be over

- estimates and the actual exposures are likely to be
much lower.

Table 7.2. Short

- Term Term Aggregate Risk Calculations

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Child (1

- 2 years) 136 100 0.45 0.016988 0.02055 0.037538 3600

1 LOC is 100 (10X for inter

- species and 10X for intra

- species)

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. See Table 5.4.1

4 Total Exposure = ( Avg Food & Water Exposure + Residential Exposure)

5 Aggregate MOE = [ NOAEL / (Avg Food & Water Exposure + Residential Exposure)]



### 7.3 Intermediate

- Term Aggregate Risk

Not Applicable

7.4 Chronic Aggregate Risk

Since the residential uses of dicamba are not expected to occur over the long

- term (or chronic) duration, chronic aggregate ri sk is comprised of dietary exposure only, from food and drinking water sources. The chronic dietary assessment in Section 5.4 represents chronic aggregate risk.

T he chronic dietary exposure assessment was con ducted using average field trial data , DEEM default processing factors and available % CT information for all registered and proposed use sites. Drinking water values were incorporated directly into the assessment.

The most highly exposed population sub

- group is children 1

- 2 years old ( 42 % of the cPAD). Chronic aggregate risk is not of concern for any population.

7.5 Cancer Aggregate Risk

Dicamba is classified as n ot likely to be carcinogenic to humans , thus a quantitative aggregate cancer risk is not applicable and not assessed . This c onclusion was based on the lack of findings

in cancer studies in rats and mice which were tested at adequate dose levels to assess theDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 48 of 105 

### carcinogenicity of dicamba (TXR No. 0053647). Additionally, the DCSA metabolite had a lack
of cancer findings in its ra t carcinogenicity study.

8.0 Cumulative Exposure/Risk Characterization

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 for dicamba and any other substance, and dicamba does not appear to produce a tox ic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assumed that dicamba does not have 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 cumulating effect s from substances found to have a common
mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short

- /Intermediate

- Term/ Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application e vent.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers for the dicamba DGA salt uses is based on the following scenarios:

 Mixing/loading liquid in support of ground boom application to high

- acreage crops (cotton and soybean)

 Applying spray by ground boom equipment to high acreage crops (cotton and soybean)

The quantitative exposure/risk assessment developed for occupational handlers for the dicamba BAPMA salt uses is based on the following scenarios:

 Mixing/loading liquid in support of aerial application to sod, typical field crops (asparagus), and high

- acreage crops (corn, soybean, cotton, sugarcane)

 Mixing/loading liquid in support of ground boom application to sod, typical field crops (asparagus), and high

- acreage crops (corn, soybean, cotton, sugarcane)

 Applying spray by aerial e quipment to sod, typical field crops, and high

- acreage crops

 Applying spray by ground boom equipment to sod, typical field crops, and high

- acreage

cropsDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 49 of 105 

###  Flagging in support of aerial application to sod, typical field crops, and high

- acreage

crops

Occupati onal Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate : See Section 3 for a summary of use directions and application rates

.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) 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 FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 11 

### ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 12



### .

Area Treated or Amount Handled: Based on ExpoSAC Policy 9.1:

 The area treated for g round boom application to sod and typical field crops is 80 acres per day and to high acreage crops is 200 acres per day.

 The area treated for aerial application to sod and typical field crops is 350 acres per day and to high acreage crops is 1200 acres per day.

Exposure Duration: HED classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months
as intermediate

- term. Exposure duration is determined by many factors , including the exposed population, the use site, the pest pr essure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one

- month
time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region).

For dicamba, based on the proposed use, short

- and intermediate

- term exposures are expected as the product can have multiple applications to the crop throughout the season and applicators may apply the product to multiple farms throughout the growing season.

11 Available http://www2.epa.gov/sites/production/files/2015

- 09/documents/handler

- exposure

- table

- 2015.pdf

12 Available: http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- handler

- exposure

- dataDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 50 of 105 

### Mitigation/Personal Protective Equipment: Estimates of inhalation exposure were calculated for various levels of personal protective equipment (PPE) or engineering controls. Results are presented for “baseline,” defined as no respirator, as well as with various levels of respiratory protection. The dicamba product labels currently do not require respiratory protection.

Occupational Handler Non

- Cancer Exposure and Risk Estimate Equations The algorithms used to estimate non

- cancer exposure and dose for occupational handlers can be found in Append ix A of the ORE document

.

Combining Exposures/Risk Estimates:
There is n o potential hazard via the dermal route f or dicamba. Only inhalation risk estimates were quantitatively assessed.

Summary of Occupational Handler Non

- Cancer Exposure and Risk Esti mates

DGA salt of dicamba : The occupational handler risk estimates are not of concern for dicamba acid (inhalation MOEs > LOC of 30) for all scenarios with label required PPE (i.e., no respiratory protection) . See Table 9 .1.1 below.

Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Dicamba acid (DGA salt)

.

Exposure Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1 Maximum

Applicatio

n Rate 2 Area
Treated or

Amount
Handled Daily 3 Inhalation

Baseline Mitigation Level (No Respiratory Protection) Dose (mg/kg/day) 4 MOE

(LOC = 30) 5

Mixer/Loader

Mixing/Loading Liquid in Support of Ground boom Application High Acreage Crops 0.219 1 lb

ae/acre 200 acres 0.000548 380

Applicator

Applying Spray by Ground boom Application High Acreage Crops 0.34 1 lb

ae/acre 200 acres 0.00085 250

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrog ate Reference Table” (March 2016 ).

2 Based on proposed label (Reg. No. 524

- 582).
3 Exposure Science Advisory Council Policy #9.1.

4 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal ) × Area Treated or Amount Handled (A or gal/day) ÷ BW (kg).
5 Inhalation MOE = Inhalation POD ( 0.21 mg/kg/d ay) ÷ Inhalation Dose (mg/kg/day).



### BAPMA salt of dicamba : Most occupational handler risk estimates are of concern for dicamba BAPMA salt (inhalation MOEs < LOC of 300) based on label

- required PPE (i.e., no respiratory protection) . See Table 9 .1.2 for a summary of handler risk estimates below. A summary of handler risk estimates with additional inhalation PPE/ engineering controls to mitigate risks is provided in Table 9 .1.3; some handler risk estimates are still of concern with the maximum PP E/ engineering controls

. Note that HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits (i.e., engineering controls) . Therefore, in both tables, aerial applicator risk estimates are shown representing the use of engineering controls

.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 51 of 105 Table 9 .1.2. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Dicamba BAPMA (Label Required PPE = No Respirator)

.

Exposure Scenario Crop or Target Inhalation Unit Exposur e (μg/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or

Amount
Handled Daily 3 Inhalation

Baseline Mitigation Level (No Respiratory
Protection Unless Otherwise Specified) Dose (mg/kg/day) 4 MOE

(LOC = 300) 5

Mixer/Loader

Mixing/Loading Liquid

in Support of Aerial Application Sod

0.219 0.5 lb ae/A 350 acres 0.000479 42

Typical Field Crops

1 lb ae /A 350 acres 0.000959 21

High Acreage Field Crops 1200 acres 0.00329 6.1

Mixing/Loading Liquid in Support of Ground boom Application Sod 0.5 lb ae/A 80 acres 0.00011 180

Typical Field Crops 1 lb ae/A 80 acres 0.000219 91

High Acreage Crops 200 acres 0.000548 36

Applicator

Applying Spray via Aerial Application Sod

Engineering Control:

0.0049 0.5 lb ae/A 350 acres 0.0000107 1, 9 00

Typical Field Crops

1 lb ae/A 350 acres 0.0000215 930

High Acreage Field Crops 1200 acres 0.0000735 270

Applying Spray by
Ground boom Application Sod

0.34 0.5 lb ae/A 80 acres 0.00017 120

Typical Field Crops 1 lb ae/A 80 acres 0.00034 59

High Acreage Crops 200 acres 0.00085 24

Flagger

Flagging in support of Aerial Application Sod

0.35 0.5 lb ae/A

350 acres 0.000766 26

Typical Field Crops

1 lb ae/A 0.00154 13

High Acreage Field Crops 0.00154 13

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 201 6 ).

2 Based on proposed label (7969

- GUL)

. 3 Exposure Science Advisory Council Policy #9.1.

4 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Ra te (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (kg).
5 Inhalation MOE = Inhalation POD ( 0.02 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

Table 9 .1.3. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Dicamba BAPMA (with additional respiratory protection)

.

Exposure Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 Area
Treated or

Amount
Handled Daily 3 Inhalation MOE

(LOC = 300) 4

Mitigation Level PF5 PF10 Eng.
Control

Mixer/Loader

Mixing/Loading Liquid Sod PF5: 0.0438 0.5 lb ae/A 350 acres 210 420 110Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 52 of 105 Table 9 .1.3. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Dicamba BAPMA (with additional respiratory protection)

.

Exposure Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 Area
Treated or

Amount
Handled Daily 3 Inhalation MOE

(LOC = 300) 4

Mitigation Level PF5 PF10 Eng.
Control in Support of Aerial Application Typical Field Crops PF10: 0.0219

EC: 0.083 1 lb ai/A 350 acres 100 210 55

High Acreage Field Crops 1200

acres 30 61 16

Mixing/Loading Liquid in Support of Ground boom Application Sod 0.5 lb ae/A 80 acres 910 1.800 480

Typical Field Crops 1 lb ae/A 80 acres 460 910 240

High Acreage Crops 200 acres 180 360 96

Applicator

Applying Spray via Aerial Application Sod

EC: 0.0049 0.5 lb ae/A 350 acres NA NA 1,900

Typical Field Crops

1 lb ae/A 350 acres NA NA 930

High Acreage Field Crops 1200

acres NA NA 270

Applying Spray by
Ground boom Application Sod PF5: 0.068

PF10: 0.034

EC: 0.043 0.5 lb ae/A 80 acres 590 1,200 930

Typical Field Crops 1 lb ae/A 80 acres 290 590 470

High Acreage Crops 200 acres 120 240 190

Flagger

Flagging in support of Aerial Application Sod

PF5: 0.07

PF10: 0.035 0.5 lb ae/A

350 acres 130 260 NA

Typical Field Crops

1 lb ae/A 65 130 NA

High Acreage Field Crops 65 130 NA

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 201 6 )

2 Based on proposed label (7969

- GUL)

. 3 Exposure Science Advisory Council Policy #9.1.

4 Inhalation MOE = Inhalation POD ( 0.02 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).



### 9.2 Short

- /Intermediate

- Term Post

- Application Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests

o r harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9.2.1 Dermal Post

- application Risk

Occupational Post

- application Dermal ExposureDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 53 of 105 

### There is no potential hazard via the dermal route for dicamba; therefore, a quantitative occupational post

- application dermal risk assessment was not completed.

Restricted Entry Interval

The REI specified on the proposed label s is based on the acute toxicity of dicamba. Dicamba is classified as Toxicity Category III via the dermal route, Toxicity Category II for skin irritation potential, and Toxicity Category II for eye irritation. It is not a skin sensitizer. Short

- and
intermediate

- term post

- application risk estimates were not a concern on day 0 (12 hours following application) for all post

- application activities. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute II for acute dermal, eye irritation or primary skin irritation are assigned a 24

- hour REI. Therefore , the [156 subpart K] Worker Protection Statement interim REI of 24 hours is adequate to protect agricultural workers from post

- application exposures to dicamba

.

9.2.2 Inhalation Post

- application Risk

There are multiple potential sources of post

- appl ication inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www .regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2009

- 0687

- 0037 ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological stu dies) or further analysis is required for dicamba

.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will contin ue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the agency's risk assessments.

10.0 References

Van Alstine, J., Dicamba: Summary of Hazard and Science Policy Council (HASPOC) Meeting of February 14, 2013: Recommendations on the Requirement of a Subchronic Inhalation Study ( T XR No.: 0056589)

Clock

- Rust, M, Dicamba: Human

- Health Risk Assessment for Proposed Section 3 New Uses on Sweet Corn (D340156)

Savoia, P, Dicamb a. Acute and Chronic Dietary Exposure Assessments of Food and Drinking Water to Support the Use of Dicamba on Dicamba

- Tolerant Cotton and Soybean for AmendedDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 54 of 105 

### Section 3 Registration, and Registration of the New N,N

- Bis

- (3

- aminopropyl) methylamine (BAPMA) S alt Formulation. ( D408386 & D410346)

Savoia, P, Dicamba. Section 3 Registration for the Amended Use of Dicamba on Dicamba

Tolerant Cotton. Summary of Analytical Chemistry and Residue Data ( D408384)

Kamel, A. Dicamba. New use of dicamba on dicamba

- tol erant soybean. Petition for establishment of new tolerances for soybean forage and soybean hay. (D 384422 )

Savoia, P, Dicamba. Bridging Data Demonstrating DGA ( diglycolamine ) , BAPMA (N,N

- Bis

- (3

- aminopropyl) methylamine) and DETA ( diethylenetriamine) Salt Product Equivalency, and the Independent Laboratory Validation of the BASF Method Developed for Determining Dicamba Residues in Crops.

Gavelek , A and Lowe, K. , Dicamba. Occupational and Residential Exposure Assessment for a Proposed Use on Herbicide

- Tolerant Soybean and Cotton . (D429870)

Lang, PL, Historical Control Data for Development and Reproductive Toxicity Studies, Middle Atlantic Reproduction and Teratology Association, Charles River, 1993

Evans, S. and Recore, S., Dicamba: Tier I (Scoping) Review of Human Incidents and Epidemiology (Nov. 10, 2015, D427231 )Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 55 of 105 

### Appendix A. Toxicology Profile

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for dicamba are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1 Toxicology Requirements for Dicamba

Guideline Number and Toxicity Study 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 Sub

- chronic (Rodent)

................................ ........... 870.3150 Oral Sub

- chronic (Non

- Rodent)

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

- Day Dermal

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

- Day Dermal

................................ ............................. 870.3465 90/28

- Day Inhalation

................................ .................... yes yes+
yes CR

yes yes

yes
yes

-- yes

870.3700 Developmental Toxicity (Rodent)

............................... 870.3700 Developmental Toxicity (Non

- rodent)

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

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

yes
yes

870.4100 Chronic Toxicity (Rodent)

................................ ............ 870.4100 Chronic Toxicity (Non

- rodent)

................................ ..... 870.4200 Oncogenicity (Rat)

................................ ....................... 870.4200 Oncogenicity (Mouse)

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

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

no
yes
yes
yes yes

yes
yes
yes
yes

870.5100 Mutagenicity: Gene Mutation

- bacterial

...................... 870.5395 Mutagenicity: Cytogenetics 870.5500 Mutagenicity: Other Genotoxic Effects

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

yes
yes

870.6100 Acute Delayed Neurotoxicity (Hen)

............................. 870.6100 90

- Day Neurotoxicity (Hen)

................................ ......... 870.6200 Acute Neurotoxicity Screening Battery (Rat)

............... 870.6200 90

- Day Neurotoxicity. Screening Battery (Rat)

........... 870.6300 Developmental Neurotoxicity

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

no
yes
yes CR -

- yes
yes

-

870.7485 General Metabolism

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

................................ ....................... 870.7800 Immunotoxicity............................................................. yes CR

yes yes

no

yes

+ Requirements are satisfied by chronic oral toxicity studies. CR: Conditionally RequiredDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 56 of 105 

### A.2 Toxicity Profiles

The study NOAELs and LOAELs may not reflect current HED policies , but the updates would not impact endpoint selection or PODs, which are protective of all effects observed in the
database.

Table A.2.1. Acute Toxicity of Dicamba Acid

OPPTS
Guideline Study Type MRID Results Toxicity Category

870.1100 Acute oral toxicity / rat 00078444 LD 50 = > 2740 mg/kg III

870.1200 Acute dermal toxicity / rat 00241584 LD 50 = > 2000 mg/kg III

870.1300 Acute inhalation toxicity / rat 00263861 LC 50 = > 5.3 mg/L IV

870.2400 Primary eye irritation / rabbit 00241584 Irritant II

870.2500 Primary dermal irritation / rabbit 00237955 Irritant II

870.2600 Dermal sensitization / guinea pig 00263861 Non

- Sensitizer

--

Table A.2.2

. Acute Toxicity of Dicamba BAPMA Salt

Study MRID Results Tox Cat

OPPTS 870.1100

- OECD 423

Acute oral toxicity /

rat Bioassay 48599303 LD 50 Females is >2,000 mg/kg One out of six females died on study day 5 after the administration of 2,000 mg/kg. Clinical observations in all six
animals revealed impaired general state, dyspnea, piloerection and ataxia from hour 0 until study day 3 after administration. Staggering, reduced feces and exsiccosis were observed in two animals between study day 1 and 3, while gasping was seen only in one animal on study day 1. The animal that died
showed red discoloration of the fore stomach. III

OPPTS 870.1200

- OECD 402

Acute dermal toxicity

/ rat Bioassay 48599304 LD 50 Males /females> 5000 mg/kg No mortality occurred. No signs of systemic toxicity or skin
effects were observed. Mean body weight of animals increased within the normal range throughout the study period. No macroscopic pathologic abnormalities were noted in the animals examined at the end of the study. IV

OPPTS 870.1300

- OECD 403

Acute inhalation toxicity / rat 48599305 LC 50 Males/females > 0.557 mg/L (MMAD between 1.2 and 3.8 μm , GSD 3.2 to 5.8) No animals died at 0.294 mg/L. All death occurred at 1.052 and 5.045 mg/L. On study days 1

- 3 or 7

- 9. Clinical signs included accelerated respiration, labored respiration, intermittent respiration, abdominal respiration, respiration sounds, red encrusted eye, semi

- closed eyelid, no defecation, poor general state, high stepping gait, piloerection and substance contaminated fur. In all mortalities body wei ghts decreased until death. Gross pathological abnormalities
inc luded dark

- red discoloration, lung edema, encrusted nose. IIIDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 57 of 105 OPPTS 870.2400

- OECD 405

Primary eye irritation /
rabbit 48599306 No corneal opacity or iritis. All eyes positive for conju n ctival irritation (chemosis score of 2) at 1 hr; no positive scores for conju n ctival irritation at 24 hrs or subsequently (only scores of 1 for redness and/or chemosis). All scores zero by day 7. IV

OPPTS 870.2500

- OECD 404

Primary dermal
irritation / ra bbit 48599307 Not irritating No adverse skin reactions were observed in all animals at any
examination term.

PII was 0.0. IV

OPPTS 870.2600

- OECD 429

Dermal Sensitization

Local Lymph Node Assay/ mice 48599308 Local Lymph Node Assay Ambiguous

. Positive control was appropriate. The undiluted test substance caused statistically significant
increase in 3H

- thymidine incorporation into the cells (increases slightly above S.I. of 3 for 3 H

- thymidine incorporation for undiluted material). There was a st atistically significant increase in some lymph node weights as well. Positive

Table A.2.3

. Acute Toxicity of BAPMA Base [N, N

- Bis

- (3

- aminopropyl)methylamine]

Guideline Study Type Source Results Toxicity Category

BASF Test Acute oral toxicity / rat MSDS Sheet LD 50 = 691 mg/kg III

BASF Test Acute dermal toxicity /

rabbit MSDS Sheet LD 50 = 200 mg/kg II

BASF Test Acute inhalation toxicity / rat MSDS Sheet LC 50 = 0.07 mg/L II

OECD 404 Primary eye irritation / rabbit MSDS Sheet Corrosive I

QSAR Primary dermal irritation MSDS Sheet Irritant II

OCED 429 Dermal sensitization / Mouse MSDS Sheet Sensitizer

--

Table A.2.4

. Sub

- chronic, Chronic and Other Toxicity Profile for Dicamba Acid

Guideline No./ Study Type/ MRID Nos.
Doses/Classification Results

870.3100

Sub

- chronic Oral

- Rat 44623101 (1997)

(0, 500, 3000, 6000, 12000 ppm) M:0,40.1,238.7,479.4,1000 mg/kg/day F:0,43.2,266.4,535.6,1065.3 mg/kg/day

Acceptable/Guideline NOAEL= 479.4/535.6 mg/kg/day(M/F). LOAEL= 1000/1065.3 mg/kg/day (M/F) based on clinical signs, increased liver weight and increased hepatocyte hypertrophy and hepatocellular pigmentation.

870.3200

21

- Day Dermal Study

- Rabbits 40547901 (1986)

0, 40, 200 and 1000 mg/kg/day as a
42.0% Dicamba formulation

(Lot No. 52410301)

Supplementary Systemic NOAEL > 1000 mg/kg/day: Dermal NOAEL = 40 mg/kg/day & LOAEL = 200 mg/kg/day (fissuring, acanthosis and hyperkertosis). At 1000 mg/kg/day

- desquamation, moderate erythema, edema and atonia, fissuring, acanthosis and hyprkeratosis. Classified
minimum.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 58 of 105 Table A.2.4

. Sub

- chronic, Chronic and Other Toxicity Profile for Dicamba Acid

Guideline No./ Study Type/ MRID Nos.
Doses/Classification Results

870.3200

28

- Day dermal toxicity

- Rat 45814501 (2002)

0, 30, 300, 1000 mg/kg/day (M/F)

Acceptable/Guideline NOAEL= 1000 mg/kg/day (HDT)
LOAEL= not determined.

870.3465

28

- Day Inhalation Toxicity

- Rat 49461101 (2014)0, 0.001, 0.005,

0.050 mg/L

Acceptable/Guideline NOAEL=0.005/0.005 mg/L (M/F) LOAEL=0.050/0.050 mg/L (M/F), based on minimal
multifocal bronchiole

- alveolar hyperplasia in males; multiple microscopic findings in the lung and associated lymph nodes in females

870.3700a

Prenatal developmental

- Rat 00084024 (1981)

0,64,160,400 mg/kg/day (GD 6

- 19)

Acceptable/Guideline Maternal : NOAEL= 160 mg/kg/day; LOAEL= 400 mg/kg/day based on increased mortality, clinical signs (ataxia, stiffening of body when touched,
decreased motor activity) and decreased food consumption. Developmental : NOAEL= 400 mg/kg/day (HDT),

LOAEL not established.

870.3700b

Prenatal developmental

- New Zealand
White Rabbit 42429401 (1992)

0, 30, 150, 300 mg/kg/day (GD 6

- 18)

Range

- finding study : 0, 62.5, 125, 250, 500 mg/kg/day (GD 6

- 18)

Acceptable/Guideline Maternal : NOAEL= 62.5 mg/kg/day,

LOAEL= 1 50 mg/kg/day based on increased abortion, clinical signs (decreased motor activity, ataxia). Developmental : NOAEL= 62.5 mg/kg/day,
LOAEL= 150 mg/k g/ day based on increased abortion at gestation day 22 (1 in 20 does) , after dosing ceased on day
18

870.3800

Reproduction and fertility effects

- Rat 43137101 (1993)

(0,500,1500,5000 ppm) M: 0,40,122,419 mg/kg/day F: 0,45, 136, 450 mg/kg/day

Acceptable/Guideline Parental/Systemic: NOAEL= 122/136 mg/kg/day (M/F) LOAEL= 419/450 mg/kg/day (M/F) based on clinical signs (slow righting reflex). Reproductive: NOAEL=122 mg/kg/day LOAEL= 419 mg/kg/day based on delayed sexual
maturation in F1 males.
Off spring:
NOAEL=136 mg/kg/day

LOAEL= 450 mg/kg/day based on decreased pup weights i n the F1 generation at PND0/PND21 and F2B generation at
PND21 , relative to the MARTA historical control database

. Classified minimumDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 59 of 105 Table A.2.4

. Sub

- chronic, Chronic and Other Toxicity Profile for Dicamba Acid

Guideline No./ Study Type/ MRID Nos.
Doses/Classification Results

870.4200a

Chronic Toxicity/ Carcinogenicity

- Rat 00146150 (1985)

(0,50,250,2500 ppm) M: 0,2,11,107 mg/kg/day F: 0,3,13,127 mg/kg/day

Acceptable/Guideline NOAEL= 107/127 mg/kg/day (M/F)

LOAEL was not established. Brain ventricular dilation in females at the highest dose, but not obs erved in other
studies. Not carcinogenic. The study is considered adequate for evaluating the carcinogenic potential.

870.4100b

Chronic toxicity

- Dog 40321102 (1986)

(0,100,500,2500 ppm) 0,2,11,52 mg/kg/day

Acceptable/Guideline NOAEL=52 mg/kg/day (HDT)

LOAEL= Not Achieved

870.4200b

Carcinogenicity

- Mouse 40872401 (1988)

(0,50,150,1000,3000 ppm) M: 0,5.5,17.2,108,358 mg/kg/day F: 0,5.8,18.8,121,354 mg/kg/day

Acceptable/Guideline NOAEL=358/354 mg/kg/day (M/F),

LOAEL was not established.

Not carcinogenic. The study is considered adequate for evaluating the carcinogenic potential.

870.5100

Gene Mutation
Salmonella

T yphimurium 00143001 (1979)

Acceptable/Guideline N egative, n ot mutagenic.

870.5395

Chromosome

A berration (CHO) 40321101 (1986)

0, 2330, 1170, 590, and 300 μg/mL Acceptable/Guideline Negative, c hromosome aberrations were not induced in a
cultured CHO cells at concentrations tested either with or
without S

- 9 activation.

870.5550

Unscheduled
DNA S ynthesis (UDS) 00143001 (1979)

Acceptable/Guideline N egative, n o evidence of UDS at levels 0.1 to 3000 μg/mL.

870.6200

Acute Neurotoxicity

- Rat 42774104 (1993)

0,300,600,1200 mg/kg

Acceptable/Guideline NOAEL was not established,

LOAEL=300 mg/kg based on severe neurological signs (impaired respiration, rigidity upon handling, prodding, or dropping, impaired gait and righting reflex in both sexes.

870.6200

Sub

- chronic Neurotoxicity

- Rat 43245210 (1994)

0,3000,6000,12000 ppm M:0,197.1,401.4,767.9 mg/kg/day F: 0,253.4,472.0,1028.9 mg/kg/day

Acceptable/Guideline NOAEL= 401.4/472.0 mg/kg/day (M/F); LOAEL= 767.9/1028.9 mg/kg/day (M/F) based on rigidity body tone, slightly impaired righting reflex and gait.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 60 of 105 Table A.2.4

. Sub

- chronic, Chronic and Other Toxicity Profile for Dicamba Acid

Guideline No./ Study Type/ MRID Nos.
Doses/Classification Results

870.3100 and
870.6200

Combined Sub

chronic Toxicity /
Sub

- chronic Neurotoxicity Study

- Rat 48358001 (2011)

0, 500, 3000, 6000, 12000 ppm M: 0, 34, 197, 397, 803 mg/kg/day F: 0, 39, 230, 458, 938 mg/kg/day Crl:CD® [SD] rats

Acceptable/Guideline NOAEL = 397 /458 mg/kg/day (M/F)
LOAEL = 803 /938 mg/kg/day (M/F) based on behavioral signs ( uncoordinated righting, decreased hindlimb foot splay, unkempt appearance, gasping, rales in males and impaired equilibrium, rigid muscle tone in females)

870.7485

Metabolism 44609801 (1998)

Acceptable/Non

- guideline

46022302 (2003) Acceptable/Non

- guideline

46022303 (2003) Acceptable/Non

- guideline

00028261(1967) Acceptable/guideline Rapidly absorbed and rapidly excreted in urine and feces.
Dicamba is not metabolized or bioaccumulation. Approximately 13% of dicamba in the urin e is conjugated as the glucuronide.

870.7800

Immunotoxicity

- Rat 48081601 (2010)

0, 500, 1500, or 4000 ppm (0, 37, 108, or 307 mg/kg/day)

Acceptable/Guideline Negative for immunotoxicity

The NOAEL for immunotoxicity and systemic toxicity is
307 mg/kg/day

LOAEL is undetermined

Table A.2.5

. Sub

- chronic, Chronic and Other Toxicity Profile for Dicamba Metabolites and BAPMA Salt Study Type
Chemical MRID (year) Results

870.1100

DCSA Acute Oral Toxicity 47899504 (2007)

Acceptable/Guideline LD 50 = 2641 mg/kg

wobbly gait at 2000 mg/kg

870.1100

DCGA Acute Oral Toxicity 47899505 (2009)

Acceptable/Guideline LD 50 = 1460 mg/kg

870.3050

DCGA
Subchronic Tox

- Rat (28 days) 47899506 (2009)

0, 500, 3000, 6000, 12000 ppm M: 0, 40, 240, 474, 956 mg/kg/day F: 0, 45, 265, 519, 1063 mg/kg/day for females.

Acceptable/Guideline Included FOB and motor activity NOAEL = 474 mg/kg/day LOAEL = 956 mg/kg/day based upon decr eased BW in
malesDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 61 of 105 Table A.2.5

. Sub

- chronic, Chronic and Other Toxicity Profile for Dicamba Metabolites and BAPMA Salt Study Type
Chemical MRID (year) Results

870.3100

DCSA
Subchronic Tox

- Rat (90 days) 47899507 (2009)

(0, 500, 3000, 6000, 12000 ppm). M: 0, 32, 195, 362, 659 mg/kg/day F: 0, 37, 222, 436, 719 mg/kg/day

Crl:CD ® [SD] rats

Acceptable/Guideline Included FOB and MA. NOAEL = 362 mg/kg/day LOAEL = 659 mg/kg/day based on decreased body weight, increased motor activity, decreased hematological
parameters (i.e. RBC count) , and increased serum liver

enzymes

870.3100

Dicamba BAPMA
90

- Day Toxicity Study

- Rat 49441801 (2014)

M: 0, 257, 513, 1027 mg/kg/day F: 0, 294, 589, 1178 mg/kg/day

Acceptable/Guideline NOAEL is 513/589 mg/kg/day (M/F) (357/409 as Acid form) LOAEL is 1027/1178 mg/kg/day (M/F) (714/819 as Acid Form), based on altered hematology, kidney effects,
increased clotting time and clinical chemistry parameters

870.3150

DCSA
Subchronic Tox

– Dog (90 days) 48358002 (2011)

0, 15, 50 and 150 mg/kg/day 90

- day capsule study.

Acceptable/Guideline NOAEL = 50 mg/kg/day LOAEL = 150 mg/kg/day based on mortality, decreased body weight, clinical signs (abnormal excreta and emesis), and increased clotting time.

870.3200

Dicamba DGA

21

- Day Dermal Study

-- Rabbits 43554206

Diglycolamine salt (DGA, 59%) of dicamba at 0, 100 , 500 or 1000 mg/kg, 6 hours/day

Acceptable/Guideline NOAEL = 1000 mg/kg/day (Limit

- Dose) for dermal irritation and systemic toxicity.
LOAEL: not established for either end

- point.

870.3200

Dicamba IPA

21

- Day Dermal Study

-- Rabbits 43554207

Isopropylamine salt (IPA, 41%) of dicamba at 0, 100, 500 or 1000 mg/kg, 6 hours/day, 5 days/week

Acceptable/Guideline NOAEL = 1000 mg/kg/day (Limit

- Dose) for dermal irritation and systemic toxicity.
LOAEL: not established for either end

- point.

870.3465

Dicamba BAPMA
28

- Day Inhalation Toxicity Study

- Rats 49441803 (2014)

0, 0.0014, 0.0070, 0.00352 mg/L

Acceptable/Guideline NOAEL=NA LOAEL=0.0014 mg/L (LDT), based on ulcers in epithelial tissues of the larynx and single/multi

- focal hyperplasia in the larynx

870.3650

BAPMA Base OECD 422 Developmental

Reproduction Screening

Test NA NOAEL: 25 mg/kg/day LOAEL: 100 mg/kg/day based on decreased motor activity and decreased water consumption

At 500 mg/kg/day excessive toxicity and dam deathsDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 62 of 105 Table A.2.5

. Sub

- chronic, Chronic and Other Toxicity Profile for Dicamba Metabolites and BAPMA Salt Study Type
Chemical MRID (year) Results

870.3700a

DCSA

Developmental

- Rat 47899519 (2007)

0, 10, 30, 100 mg/kg/day (GD 6

- 19). Crl:CD(SD) rats

47899518 (range

- finding study ) M aternal NOAEL: 100 mg/kg/day, highest dose tested
LOAEL: not attained Developmental NOAEL: 100 mg/kg/day, highest dose tested
LOAEL: not attained Classified acceptable/guideline when considered with

range

- finding study.

Range

- finding study : MRID 47899518. 0, 50, 200, 500 or 1000 mg/kg/day: 8 females/dose 200 mg/kg/day: clinical signs (rales, red/clear material on body), decr eased fetal weight 500 mg/kg/day: mortality, early resorptions in all
survivors

870.3700a

DCGA Developmental Rat Range

- finding study 47899520 (2009)

0, 50, 200, 500, 1000 mg/kg/day

Acceptable/Guideline Maternal : NOAEL: 50 mg/kg/day LOAEL: 200 mg/kg/day based on signs of rales, clear material on body

At 500 mg/kg/day : BW 4.0

- 6.6% lower GD 13

- 20

At 1000 mg/kg/day : Mortality. BW 4.4

- 12.1% lower GD

12

- 20 Developmental: No effects on uterine growth, survival, external
malformations or variations. Fetuses received external exam only, no skeletal examination.

870.3700a

Dicamba BAPMA Developmental Toxicity Study

- Rats 49441802 (2014)

0, 29, 86, 288 mg/kg/day

Acceptable/Guideline Maternal NOAEL is 29 mg/kg/day in dams (20 as Acid form)
LOAEL is 86 mg/kg/day in dams, based on ataxia, unsteady gait and convulsions (60 as Acid Form) Developmental NOAEL > 288 mg/kg/day (200 as acid equivalent)

870.3700b

DCSA Developmental

- Rabbit 47899522 (2009)

0, 10, 25, 65 mg/kg/day (GD 6

- 28). NZW rabbits

47899521 (2010) Range

- finding study

0, 10, 30, 100, 300 mg/kg/day

Acceptable/Guideline M aternal NOAEL: 65 mg/kg/day, highest dose tested.
LOAEL: not attained Developmental NOAEL: 65 mg/kg/day, highest dose tested.
LOAEL: not attained Classified acceptable/guideline when considered with

range

- finding study.

Range

- finding study : MRID 47899521
6 females/dose. 300 mg/kg/day was lethal doseDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 63 of 105 Table A.2.5

. Sub

- chronic, Chronic and Other Toxicity Profile for Dicamba Metabolites and BAPMA Salt Study Type
Chemical MRID (year) Results

870.3800

DCSA Reproduction and fertility
effects

- Rat 47899517 (2009)

0, 50, 500, 5000 ppm M: 0, 4, 37, 362 mg/kg/day (F 0 generation) F: 0, 4, 43, 414 mg/kg/day (F 0 generation) Crl:CD(SD) rats

Acceptable/Guideline Parental NOAEL = 37 mg/kg/day LOAEL = 362 mg/kg/day based upon decreased body weight. Reproduction NOAEL = 362 mg/kg/day, highest dose tested.
LOAEL: Not attained. Offspring NOAEL = 4 mg/kg/day LOAEL = 37 mg/kg/day based upon decreased pup body weight in F 1 pups on postnatal days 14 and 21 during
lactation and week 18 in females

. At 50 00 ppm, high incidence of pup mortality

870.4200a

DCSA Chronic Toxicity/ Carcinogenicity

- Rat 47899516 (2009)

48358003 (2011)

( 0, 10, 100, 300, 1000, 3000 ppm) M: 0.5, 5.0, 14.6, 48.8, and 150.1 mg/kg/day F: 0.6, 6.1, 18.4, 60.9, and 181.5 mg/kg/day Crl:CD®[SD] rats

Acceptable/Guideline NOAEL = 150 mg/kg/day, highest dose tested. Not carcinogenic.
LOAEL: Not established

870. 5100

DCSA Bacterial gene
mutation 47899509

Acceptable/Guideline Negative, d id not induce gene mutation

870. 5100

DCGA Bacterial gene
mutation 47899514

Acceptable/Guideline Negative, d id not induce gene mutation

870. 5100

Dicamba Acid Bacterial gene mutation 47899525

Acceptable/Guideline Negative, d id not induce gene mutation

870. 5100

Dicamba BAPMA Bacterial gene mutation 48718001

Acceptable/Guideline Negative

870. 5300

DCSA HGPRT in Chinese
hamster cells 47899512

Acceptable/Guideline Negative, d id not induce forward mutations at the HGPRT
locus in CHO cells

870. 5300

Dicamba Acid HGPRT in
Chinese hamster cells 47899526

Acceptable/Guideline Negative, d id not induce forward mutations at the HGPRT
locusDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 64 of 105 Table A.2.5

. Sub

- chronic, Chronic and Other Toxicity Profile for Dicamba Metabolites and BAPMA Salt Study Type
Chemical MRID (year) Results

870. 5300

Dicamba BAPMA
HGPRT in Chinese hamster
cells 48718002

Acceptable/Guideline Negative

870.5375

DCSA Chromosome aberration assay in human lymphocytes 47899510

Acceptable/Guideline No conclusions can be reached; the data are inconclusive.

870. 5375

Dicamba Acid

C hromosomal aberration assay in human lymphocytes 47899527

Acceptable/Guideline Positive, the S9

- activated portion of the assay should have been repeated

870. 5375

Dicamba BAPMA

C hromosomal aberration assay in human lymphocytes 48718003

Acceptable/Guideline Positive, c lastogenic +/

- S9 fraction

870.5385

DCSA
Chromosome aberrati on assay in rat bone marrow 47899513

Acceptable/Guideline Negative, d id not cause an increase in the number of
chromosome aberrations in rat bone marrow cells

870.5385

DCGA
Chromosome aberr ation assay in rat bone marrow 47899515

Acceptable/Guideline Negative, d id not cause increased numbers of chromosome
aberrations in rat bone marrow cells

870. 5395

DCSA Micronucleus assay in mice 47899511 0, 250, 500, and 1000 mg/kg by

gavage (corn oil)

Range

- finding study : 0, 500, 1000, and 2000 mg/kg

Acceptable/Guideline Negative, d id not induce a clastogenic or aneugenic response in mouse bone marrow cells of male mice

At doses above 1000 mg/kg, hypo

- activity, squinted eyes, hunched posture clinical signs

870. 5395

Dicamba Acid Micronucleus assay in mice 47899528 0, 250, 500, and 1000 mg/kg by

gavage (corn oil)

Acceptable/Guideline Negative, w as neither clastogenic nor aneugenic in mouse
bone marrow

At doses of 250 mg/kg or more

, slight hypo

- activity and
ataxia were observed

870. 5395

Dicamba BAPMA Micronucleus assay in mice 48718004 0, 500, 1000 and 2000 mg/kg by

gavage (water)

Acceptable/Guideline Negative, is neither clastogenic nor aneugenic up to the
limit dose in vivo in mice

At doses of 5 0 0 mg/kg or more, hunched posture and reduced general condition were observedDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 65 of 105 Table A.2.5

. Sub

- chronic, Chronic and Other Toxicity Profile for Dicamba Metabolites and BAPMA Salt Study Type
Chemical MRID (year) Results

870.7485

DCSA Metabolism (single dose) 47899502 ( 2006)

100 mg/kg Extensively absorbed and excreted rapidly in urine with
little metabolism.

870.7485

DCSA Metabolism (repeated doses) 47899503 (2006)

(42, 125, 250, 375, or 500 mg/kg/day Acceptable/Guideline Well absorbed and rapidly excreted in urine with minimal
metabolism.

Table A.2.6

. Dicamba BAPMA Salt Toxicity: Comparison to Dicamba Acid and DCSA Metabolite

Study Dicamba Acid

NOAEL/LOAEL Dicamba BAPMA Salt

NOAEL/LOAEL DCSA Metabolite

NOAEL/LOAEL

90

- Day Oral Rat NOAEL= 479.4/535.6 mg/kg/day (M/F)

LOAEL= 1000/1065.3 mg/kg/day (M/F), based on clinical signs, decreased BWG, increased liver weight, increased hepatocyte hypertrophy and hepatocellular pigmentation. NOAEL is 513/589 mg/kg/day (M/F) (357/409 as Acid form)
LOAEL is 1027/1178 mg/kg/day (M/F) (714/819 as Acid Form), based on altered hematology and clinical chemistry parameters NOAEL is 362 mg/kg/day LOAEL is 659 mg/kg/day , based on decreased BW, increased motor activity, decreased hematological parameters, increased liver

enzymes

Rat Developmental Study Maternal NOAEL = 160 mg/kg/day LOAEL = 400 mg/kg/day in dams, based on mortality, ataxia, decreased motor activity

Developmental NOAEL > 400 mg/kg/day Maternal
NOAEL is 29 mg/kg/day in dams (20 as Acid form)
LOAEL is 86 mg/kg/day in dams, based on ataxia, unsteady gait and
convulsions (60 as Acid Form) Developmental
NOAEL > 288 mg/kg/day (200 as acid equivalent) Maternal NOAEL > 100 (HDT) in dams Developmental NOAEL > 100 (HDT)

Range Finding Study: At 200 mg/kg/day there was decreased fetal weight and mortality/early resorptions at 500 mg/kg/day

Rat Reproduction Study Parental/Systemic: NOAEL= 122/136 mg/kg/day (M/F) LOAEL= 419/450 mg/kg/day (M/F) based on clinical signs (slow righting reflex). Reproductive: NOAEL=122 mg/kg/day; LOAEL= 419 mg/kg/day based on delayed sexual maturation
in F1 males. Offspring: NOAEL=136 mg/kg/day
LOAEL= 450 mg/kg/day based on impaired pup growth BAPMA Base Cation
OECD 422 Reproduction Study

NOAEL: 25 mg/kg/day

LOAEL: 100 mg/kg/day based on
decreased motor activity and water

consu mption

At 500 mg/kg/day dam
deaths Parental NOAEL = 37 mg/kg/day LOAEL = 362 mg/kg/day based upon decreased body weight. Reproductive NOAEL = 362 mg/kg/day (HDT)
LOAEL: Not attained. Offspring NOAEL = 4 mg/kg/day LOAEL = 37 mg/kg/day based upon decreased pup body weight in

F 1 pups on postnatal days 14 and

21. At 5000 ppm, high incidence of pup mortalityDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 66 of 105 (decr eased pup weights) in the
F1 and F2B generation s during lactation period.

28

- Day Inhalation Study NOAEL=0.005/0.005 mg/L (M/F) LOAEL=0.050/0.050 mg/L (M/F), based on minimal
multifocal bronchiole

- alveolar hyperplasia in males; multiple microscopic findings in the lung and associated lymph
nodes in females NOAEL=NA LOAEL=0.0014 mg/L (LDT), based on ulcers in epithelial tissues of the larynx and single/multi

- focal hyperplasia in the larynx NA



### A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

- Females age 13

- 49

Study Selected: An acute endpoint for women of childbearing age was not selected because there were no developmental effects attributed to an acute exposure. There was no developmental toxicity in the developmental rabbit study with DCSA, in the developmental rat study with dicamba, or in the main developmental rat study with DCSA. In the range finding rat study with DCSA, early resorptions oc curred, but this effect was only at a dose that was lethal to dams. In the developmental rabbit study with dicamba, there was one abortion out of 20 does (gestation day 22 ), but this was after last day of dosing at a dose where the majority of does were

s howing signs of neurotoxicity. Therefore, the endpoint of neurotoxicity selected for the general population will be protective of potential offspring effects.

A.3.2 Acute Reference Dose (aRfD)

- General Population : Dicamba and Dicamba BAPMA

Study Selected: Rat Developmental Toxicity

– Dicamba BAPMA

MRID No.: 49441802

Executive Summary : See Appendix A

Dose and Endpoint for Risk Assessment: NOAEL = 29 mg/kg/day. Neurological signs such as ataxia, unsteady gait and convulsions at LOAEL = 86 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: These effects are considered a single

- dose effect since the sign s occurred shortly after dosing

. This study was selected because it represents the most sensitive endpoint in the dicamba dat abase for exposure to the parent dicamba acid or its BAPMA salt demonstrating an acute response with a well

- defined NOAEL value. The dicamba BAPMA study NOAEL will be protective of the effects of dicamba acid via the oral route. The decreased body weights observed in the dicamba acid or DCSA reproduction studies were considered to be the result of multiple doses and not an acute effect, thus those studies were not appropriate for this scenario. The ACN study was considered for this scenario with a LOAEL of 300 mg/kg, however the study did not have a NOAEL value and with a 10X UF L 

### applied to this LOAEL would result in a similar POD of 30 mg/kg. The selected POD will be protective of theDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 67 of 105 

### effects of dicamba acid and the BAPMA salt via the oral route. A separate acute dietary assessment
for females 13

- 49 was not performed since no there was no developmental toxicity attributed to a single dose in the toxicology data base. The abortions in the rabbi t developmental study at the

LOAEL occurred at gesta tion day 22 or later. An uncertainty factor of 100X (10X to account for interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF) is applied to the
NOAEL to obtain an aPAD of 0.29 mg/kg/day.

A.3.3 Chronic Reference Dose (cRfD): Dicamba and Dicamba BAPMA

Study Selected: Reproductive study in rats with DCSA

.

MRID No.: 47899517

Executive Summary : See Appendix A

Dose and Endpoint for Risk Assessment: Offspring NOAEL = 4 mg/kg/day based on decreased F1 pup weight at Offspring LOAEL = 37 mg/k g/day.

Comments about Study/Endpoint/Uncertainty Factors: The endpoint was decreased pup weight in the F1 generation on postnatal days 14 and 21 (both sexes) and week 18 in females. This study had the lowest NOAEL in the database for dietary exposure to the DCSA metabolite. The NOAEL for decreased pup weight in the reproduction study with dicamba was used as point of departure in previous risk assessments (NOAEL = 45 and LO AEL = 136 mg/kg/day) for conventional crops. However, the DCSA study is more appropriate to use since people are mainly exposed to DCSA in food derived from the dicamba

- tolerant crops which generate DCSA. This endpoint is protective of neurotoxicity findi ngs in the other studies with both dicamba and DCSA, which occurred at much higher doses. An uncertainty factor of 100X (10X to account for interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF) is applied to the NOAEL to obtain a cPAD of 0.04 mg/kg/day.

A.3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term): Di camba and Dicamba
BAPMA

Study Selected: Reproductive study in rats with dicamba

.

MRID No.: 43137101

Executive Summary : See Appendix A

Dose and Endpoint for Risk Assessment: Offspring NOAEL = 136 mg/kg/day based on
decreased F1 and F2 B pup weigh t s at an Offspring LOAEL = 450 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: The endpoint was decre ased pup weight
in F1 and F2B generations of the dicamba acid reproduction study. The toxicology studies on the plant metabolites are no t appropriate for this scenario since these metabolites are generated inside the plants and unavailable for incidental oral exposure. The developmental studies are notDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 68 of 105 

### appropriate for incidental oral scenarios involving hand

- to

- mouth behavior. The dicamba
BAPMA salt has no residential uses where this scenario occurs. The dicamba acid sub

- chronic oral study in adult rats had a NOAEL of 479.4 mg/kg/day and a LOAEL of 1000 mg/kg/day and didn’t provide the most sensitive POD for the incidental oral scenario lif e stage. Consequently, the most appropriate study was the multi

- generation reproductive toxicity study in rats dosed with parent compound was selected based on impaired pup growth at 450 mg/kg/day (LOAEL); the NOAEL of 136 mg/kg/day was selected as the POD for this scenario. This POD will be protective of neurotoxicity in the othe r studies which occurred at higher doses. It is appropriate to use the reproduction study with dicamba, and not DCSA, because the population of concern, children, will be exposed mainly to dicamba through hand

- to

- mouth behaviors, and not to DCSA, which is not a mammalian metabolite. The DCSA metabolite is primarily present in
dicamba

- tolerant plants and not expected to be a concern for incidental oral scenarios. An uncertainty fac tor of 100X (10X to account for interspecies extrapolation, 10X for intraspecies variation, and an FQPA factor of 1X )

.

A.3.5 Dermal Exposure (Short

- , Intermediate

- and Long

- Term)

Dermal assessments will not be performed for dicamba or dicamba BAPMA sal t since the dermal studies for the dicamba, IPA and DGA salts all had NOAELs of 1000 mg/kg/day. The dicamba anion component is ~80% of the dicamba BAPMA salt weight, so the BAPMA composition is unlikely to significantly influence the dermal toxicity

.

A.3.6 Inhalation Exposure (Short

- , Intermediate

- and Long

- Term)

Dicamba Study Selected: Dicamba Inhalation Study

MRID No.: 49461101

Executive Summary : See Appendix A

Dose and Endpoint for Risk Assessment: NOAEL = 0.005 mg/L based on minimal multifocal
bronchiole

- alveolar hyperplasia in males with multiple microscopic findings in the lung and associated lymph nodes in females at a LOAEL = 0.05 mg/L.

Comments about Study/Endpoint/Uncertainty Factors: The endpoint was local respiratory effects which is protective of neurotoxicity in the other studies occurred at much higher doses. The dicamba inhalation study is appropriate to use since workers will be exposed to dicamba via the respiratory route.

D icamba BAPMA Salt Study Selected: Dicamba BAPMA Inhalation Study

MRID No.: 49441803

Executive Summary : See Appendix ADicamba Human Health Risk Assessment DP No. D378366, D404917

Page 69 of 105 

### Dose and Endpoint for Risk Assessment: NOAEL = NA based on ulcers and hyperplasia of the larynx at a LOAEL = 0.0014 mg/L.

Comm ents about Study/Endpoint/Uncertainty Factors: The endpoint was local respiratory effects which is protective of neurotoxicity in the other studies occurred at much higher doses.
The dicamba BAPMA inhalation study is appropriate to use since workers wi ll be exposed to
dicamba BAPMA via the respiratory route.

The standard interspecies extrapolation UF can be reduced from 10X to 3X for dicamba acid and
BAPMA salt due to the calculation of human equivalent concentrations ( HECs ) accounting for pharmacokinetic (not pharmacodynamic) interspecies differences. Therefore, the LOC for
dicamba acid inhalation exposures is for MOEs less than 30 (3X for interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF when a pplicable ). For BAPMA salt, an
additional 10X UF L 

### is applied due to lack of a study NOAEL. Therefore, the LOC for BAPMA salt inhalation exposures is for MOEs less than 300.

A.4 Executive Summaries for Dicamba , Dicamba Metabolites and Dicamba Salts

A.4.1 Sub

- chronic Toxicity

870.3100 90

- Day Oral Toxicity

- Rat

In a 13

- week sub

- chronic toxicity study (MRID 44623101), dicamba technical (89.4% a.i.) was administered to HanIbm:WIST (Wistar) rats (10 or 20 rats/sex/dose) by feeding at dose levels of 0, 500 , 3000, 6000, or 12,000 ppm (equivalent to 0/0, 40.1/43.2, 238.7/266.4, 479.4/535.6, or 1000.0/1065.3 mg/kg/day [M/F]) for 13 weeks. Following 13 weeks of treatment, 10 rats/sex/dose were sacrificed. Rats (10/sex) in the control and 12,000 ppm groups wer e maintained for a 4

- week recovery period to determine the reversibility of effects.

No treatment

- related deaths were observed in any treatment group. The liver was the target organ, as evidenced by microscopic liver changes associated with clinical serum chemistry changes and increased relative (to body) liver weights (  20

- 23%) in both sexes at the high dose. The livers of the 12,000 ppm females exhibited slight centrilobular hepatocyte hypertrophy (4/10) and an increased incidence of minimal to moderate hepatocellular pigmentation (5/10). Both sexes exhibited increased alkaline phosphatase (  62

- 76%), serum alanine aminotransferase (  59

- 66%), and serum aspartate aminotransferase (  29%) activities compared to the controls.

Females exhibited an increase in mean gamma glutamyl transferase activity (  136%) while males showed a decrease activity (  50%) compared to the controls.

Other effects observed in the 12,000 ppm rats were transient hypothermia (weeks 1

- 4), reduced activity, slower movements, decreased food consumption, and less efficient food utilization than the controls throughout the treatment period. Lower mean final body weights (  18

- 20%), body weight gains (  28

- 40%) and adipose tissue content were observed compared to the controls.

Decreases in protein (  10

- 15%) and globulin (  16

- 26%) levels were observed in both sexes. InDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 70 of 105 

### females, decreased mean hemoglobin concentration (  4%) and red blood cell counts (  4%), and decreased mean corpuscular hemoglobin concentration (  3%) were observed. Significan t (p<0.05 or p<0.01) increases of white blood cell count (  13%) and lymphocyte count (  33%) were observed in 12000 ppm females compared to the controls. Males had a lower mean platelet count (  7%) and shorter partial thromboplastin time (  11%) compared to the controls. Urinalysis showed that males excreted more triple phosphate crystals in the 12000 ppm group, whereas females excreted more uric acid crystals in the 12000 and 6000 ppm groups at week 12. Following a 4

- week recovery period, all observed effec ts were recovered.

The LOAEL for this study is 12,000 ppm (1000 mg/kg/day), based on clinical signs, reduced body weight gains, hematological and clinical serum chemistry changes in both sexes, centrolobular hepatocyte hypertrophy and hepatocellular pigme ntation in females, and increased relative (to body) liver weights for both sexes. The NOAEL is 6000 ppm (479 mg/kg/day).

870.3100 90

- Day Oral Toxicity

- Mouse

NA

870.3150 90

- Day Oral Toxicity

- Dog

NA

- See chronic dog study

870.3200 21/28

- Day Der mal Toxicity

– Rat

In a 28

- day dermal toxicity study (MRID 45814501), Dicamba (91.0% a.i., batch #B2826511) was applied to the shaved skin of 10 male and 10 female Alpk:AP f 

### SD rats /sex/dose at dose levels of 0, 30, 300 or 1000 mg/kg bw/day, 6 hours/day for 5 days/week during a 28

- day period.

Clinical observations, body weights and food consumption were measured throughout the study. Urine samples were taken for clinical pathology during week 4 of the study. A functional observational battery of all an imals consisting of: detailed clinical observations, including quantitative assessments of landing foot splay, sensory perception and muscle weakness, and assessment of motor activity was performed on day 22. At the end of the scheduled period, the
animal s were killed and subjected to a post mortem examination. Blood samples were taken for clinical pathology, selected organs and specified tissues were taken for subsequent histopathological examination.

There were no changes indicative of systemic toxicity in either sex. There were no compound related effects in mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights, or gross and histologic pathology. Histopathological changes
indicative of irritation were se en in skin from the application site in both sexes given 1000 or 300 mg/kg/day and in some males given 30 mg/kg/day. A LOAEL for systemic toxicity was not established. The NOAEL is 1000 mg/kg/day the highest dose tested.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 71 of 105 

### This 28

- day dermal toxicity study in the rat is acceptable/ guideline , and satisfies the guideline requirement for a 28

- day dermal toxicity study (OPPTS 870.3200; OECD 410) in the rat.

21/28

- Day Dermal Toxicity

– Rabbit (870.3200)

In a 21

- day dermal study (MRID 40547901), New Zealand whi te rabbits (5/sex/group) received 15 repeated dermal applications of Dicamba in deionized water at dose levels of 0, 40, 200, or 1000 mg/kg/day, 6 hours/day, 5 days/week over a three week period. No systemic toxicity was observed at any dose level. Dose

- related dermal irritation was observed at the application sites. Desquamation was seen predominantly in the 1000 mg/kg/day group while moderate erythema, moderate edema and atonia were observed exclusively in the 1000 mg/kg/day group. A dose

related incide nce of fissuring was noted in the 200 and 1000 mg/kg/day groups. The severity of acanthosis and the incidence of hyperkeratosis was increased at these sites in rabbits at 200 and 1000 mg/kg. For systemic toxicity, the NOAEL was 1000 mg/kg/day (HDT); a sys temic
LOAEL was not be established.
This 28

- day dermal toxicity study in the rat is acceptable/ guideline , and satisfies the guideline requirement for a 21

- day dermal toxicity study (OPPTS 870.3200; OECD 410) in the rabbit.

870.3465 90

- Day Inhalation

– Rat

In a nose

- only inhalation toxicity study (MRID 49461101 )

, four groups of Crl: WI(Han) rats (10/sex/group; ~7 weeks of age) were administered BAS 183 H [93.9% (Batch No. 0002B01BA

251)] as a dust aerosol at exposure concentrations of 0, 0.001, 0.005, or 0.050 mg/L for 28 days.

There were no mortalities or clinical signs observed at any exposure concentration. No
substance

- related adverse findings were observed on food consumption, hematology, clinical chemistry, or during ophthalmological examinations. Body weight was not adversely affected.. At 0.05 mg/L, l ung weight was statistically increased in both sexes, and the following lung histological lesions were increased in incidence (# affected/10 in treated vs controls) in both sexes: (i) minimal to slight alveolar histiocytosis (10 vs 4 in males; 10 vs 1 in f emales) ; (ii) minimal macrophage aggregates ( 6 vs 0 in males; 8 vs 0 in females); (iii) minimal to slight bronchial hypertrophy/hyperplasia (10 vs 0 in males and females); and (iv) minimal to slight
bronchiole

- alveolar hyperplasia (8 vs 0 in males [only m inimal]; 9 vs 0 in females). Additionally,
one female had a few macrophage aggregates in the bronchus

- associated lymphoid tissue. No adverse, treatment

- related finding was noted at 0.001 or 0.005 mg/L.

The LOAEL in male Wistar rats was 0.0 50 m g/L based on minimal multifocal bronchiole

alveolar hyperplasia in the lung, and 0.050 mg/L in females based on multiple microscopic findings in the lung and associated lymph nodes. The NOAEL was 0.00 5 m g/L in males and
0.005 m g/L in females

.

This inhalation toxicity study is classified as Acceptable (Guideline) and satisfies the guideline requirement for 4

- week inhalation toxicity study in rats (OCSPP 870.3465).

A.4.2 Prenatal Developmental ToxicityDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 72 of 105 

### 870.3700a Prenatal Developmental Toxicity Study

- Rat

In a developmental toxicity study (MRID No. 00084024), pregnant (CD Charles River) rats (25/dose group) received gavage administration of dicamba (85.3%) in corn oil at dose levels of 0, 64, 160, or 400 mg/kg/day during gestation days 6 through 19. Maternal t oxicity limited to the high dose (400 mg/kg/day) was characterized by mortality in three gravid and one non

- gravid dams that exhibited neurotoxic signs prior to death; clinical signs of nervous system toxicity that included ataxia, salivation, stiffening o f the body when held, and decreased motor activity; statistically significant (p<0.05) decreases in body weight gain during the dosing period; and concomitant decreases in food consumption. Dicamba had no effect on any of the cesarean
parameters.
For mat ernal toxicity, the NOAEL was 160 mg/kg/day and the LOAEL was 400 mg/kg/day based on mortality, clinical signs, body weight changes and decreases in food consumption.

No Treatment

- related fetal gross external, skeletal or visceral anomalies (malformations or variations) were seen at any dose level. For developmental toxicity, the NOAEL was >400 mg/kg/day; a LOAEL was not
established.

This study is classified acceptable/guideline (OPPTS 870.3700a) and satisfies the requirements for a developmental toxi city study in the rat.

870.3700b Prenatal Developmental Toxicity Study

- Rabbit

In a developmental toxicity study (MRID No. 42429401), inseminated New Zealand White rabbit (19

- 20/dose) were given oral capsules containing dicamba (90.5%) at dose levels o f 0, 30, 150, or 300 mg/kg/day from days 6 through 18 of gestation. No maternal or developmental toxicity was observed at 30 mg/kg/day. At 150 mg/kg/day, maternal toxicity was characterized by abortion (5%) at day 22 and clinical signs such as ataxia, ral es, decreased motor activity. At 300 mg/kg/day maternal toxicity was manifested by abortions (20%), clinical signs, decreased body weight and body weight gain and food consumption. Developmental toxicity at 300 mg/kg/day was manifested by irregular ossifi cation of the nasal bones of the skull. At 150 mg/kg/day, increased incidence of abortion was observed and was considered developmental toxicity. In a range

- finding study, NZW rabbits were dosed at 0, 62.5, 125, 250, or 500 mg/kg/day from days 6 through 1 8 of gestation. No maternal or developmental toxicity was observed at 62.5 mg/kg/day. Treatment

- related maternal toxicity was manifested by mortality, increased resorptions and reduction in the litter size at 500 mg/kg/day. Clinical signs occurred at 125, 250, and 500 mg/kg/day. Cesarean sections revealed no treatment

- related differences between treated and control groups, and no external malformation or variations were seen in any
of the fetuses of the treated does. The NOAEL for maternal toxicity was 62.5 mg/kg/day and the LOAEL was 150 mg/kg/day based on increased incidences of abortion and clinical signs (i.e., decreased motor activity, ataxia). For developmental toxicity, the NOAEL was 62.5 mg/kg/day and the LOAEL was 150 mg/kg/day based on increased incidence of abortion.

This study is classified acceptable/guideline (OPPTS 870.3700b; OECD 414) and satisfies the requirements for a developmental toxicity study in the rabbit.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 73 of 105 

### A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

- Rat

In a two

- generation reproduction study (MRID 43137101), Sprague

- Dawley rats (32 or 28/group) received dicamba technical (86.5%) in the diet at dose levels of 0, 500, 1500, or 5000 ppm (0, 40, 122, or 419 m g/kg/day for males and 0, 45, 136 or 450 mg/kg/day for females, respectively) for two generations. Systemic toxicity was observed at 5000 ppm, manifested as clinical signs in dams from both generations during lactation (tense/stiff body tone and slow righ ting reflex) and significantly increased relative liver to body weights (112% of control) in both generations and sexes, adults as well as weanlings. The increase (107%) in relative kidney weights observed at 1500 and/or 5000 ppm were not considered to be toxicologically significant due to lack of corroborative gross or histopathological lesions in the kidneys. Sexual maturation among male pups in the F1 generation was significantly delayed at 5000 ppm. Similar effects
were not seen in females.

Significa ntly decreased pup body weights were observed in all generations and matings at 1500 ppm (86

- 90% of control) and at 5000 ppm (74

- 94% of control) throughout lactation , relative
to the concurrent controls . There was no adverse effect on pup body weights during the F1 generation lactation period or post

- weaning phase at the low and mid doses. However, t he PND21 pup body weights f or the 1500 ppm group (i.e. 136 mg/kg/day) were within the MARTA (Middle Atlantic Reproduction and Teratology Association , 1993 ) database historical control range and above the historical control mean value. The study concurrent control groups were also within the historical control range (37.3

- 65.1 grams). However, both the 2A and 2B generation concurrent control groups PND 21 pup body weights were over 2 standard deviations above the historical control mean value (i.e. 64.95, 61.76 ve rsus 49.33 grams, respectively) , thus the MARTA historical control results were utilized for toxicology decisions

. As compared to the
MARTA historical control database, there were only adverse decreases in pup body weight with statistical significance at 5000 ppm for the F1 generation at both PND 0 (

- 7.3%) and PND 21 (

- 7.9%) and the F2B generation at PND 21 (

- 12.4%)

.

The F1 animals chosen to produce th e F2A and F2B generation offspring were not selected randomly, but rather the male and female animals with the median body weights in each litter were chosen, adding some bias to the F2 phase of the study.

For parental systemic toxicity, the NOAEL was 122 and 136 mg/kg/day for males and females, respectively, and the LOAEL was 419 and 450 mg/kg/day in males and females based on clinical signs of neurotoxicity. For reproductive toxicity, the NOAEL was 122 mg/kg/day and the LOAEL was 419 mg/kg/day based on delayed sexual maturation in F 1 

### males. For offspring toxicit y, the NOAEL was 136 mg/kg/day and the LOAEL was 450 mg/kg/day based on decreas ed pup body weight during the F1 and F2B generation s during
lactation.

This study is classified as acceptable/guid eline and satisfies the guideline requirements (OPPTS 870.3800; OECD 416) for a two

- generation reproduction study in the rat.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 74 of 105 

### A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

– Rat

See 870.4200a

870.4100b Chronic Toxicity

- Dog

In a chronic oral toxicity study (MRID 40321102), dicamba (86.8, a.i., lot # 52625110) was administered to beagle dogs (4/sex/group) in diet at dose levels of 0, 100, 500, or 2500 ppm (0, 2, 11, or 52 mg/kg/day, respectively) for one year.

The investigated par ameters in this study, which included behavior, mortality, body weight, food consumption, hematology, serum chemistry, urinalysis as well as macroscopic and histologic examination of tissues, did not reveal any apparent adverse effect from the test compoun d. Therefore, the NOAEL for dicamba was 2500 ppm in the diet (about 52 mg/kg/day), the highest dosage administered in this test. A study LOAEL was not observed. The absence of any adverse effects among treated animals indicated that the MTD was not attaine d.
This one

- year dog study is classified Acceptable/Guideline and satisfies the guideline requirement for a chronic toxicity study in dogs.

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study

- R at

In a combined chronic toxicity/carcinogenicity study (MRID 00146150), groups of 60 male and 60 female CD rats were fed diets containing dicamba (86.8% a.i.; Lot no. 52625110) at 0, 50, 250 ro 2500 ppm for 115 (males) or 117 (females) weeks. These doses correspond to 0, 2, 11 or 107 mg/kg bw/day for males a nd 0, 3, 13 or 127 mg/kg bw/day for females. Treatment had no adverse effect on survival, body weight, body weight gain, food consumption, hematology, clinical chemistry, urinalysis, organ weights or gross pathology. Histopathology revealed
increases in malignant lymphomas in males (0/60, 0/60, 4/60 and 4/60 at 0, 50, 250 and 2500 ppm, respectively) and thyroid parafollicular cell carcinomas in males (1/60, 0/60, 2/60 and 5/60 at 0, 50, 250 and 2500 ppm, respectively). The Cochran

- Armitage trend test sho wed a statistically significant (p < 0.05) tendency for the proportion of animals with tumors to increase steadily with increase in dose. Pairwise comparison (Fisher’s Exact test) showed no statistical significance. Therefore, these tumors were not considered to be toxicologically signific ant.

Under the conditions of this study, dicamba was not carcinogenic in male or female rats at the doses tested. The lack of systemic toxicity indicate that the animals may have tolerated higher doses (i.e., an MTD was not achieved). However, the doses employed in this study were approved by the Agency (Memo: S. April to R. Taylor, RD, dated 09/26/86).

The administration of dicamba to rats up to 2500 ppm (107 mg/kg/day for males, 127 mg/kg/day for females) in the diet revealed increases in malignant l ymphomas in males (0/60, 0/60, 4/60Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 75 of 105 

### and 4/60 at 0, 50, 250 and 2500 ppm, respectively) and thyroid parafollicular cell carcinomas in males (1/60, 0/60, 2/60 and 5/60 at 0, 50, 250 and 2500 ppm, respectively). The Cochran

Armitage trend test showed a stati stically significant (p < 0.05) tendency for the proportion of animals with tumors to increase steadily with increase in dose. Pairwise comparison (Fisher’s Exact test) showed no statistical significance. Therefore, these tumors were not considered to be toxicologically significant.

The Dose Adequacy Review Team (DART) reviewed the dosages of the study and concluded that the dose levels in the chronic toxicity/carcinogenicity study in rats could have been higher
based on kinetics data which indicated that saturation of excretion occurred at a dose ranging from >200 to 400 mg/kg/day. However, retesting at a dose greater than 300 mg/kg/day, for example, would not be recommended based on the saturation data, which showed evidence of
saturation of excretion a t >200 mg/kg/day. Retesting at a dose of 300 mg/kg/day would not be expected to alter the conclusion that there was no carcinogenic effect. Since the doses in the rat carcinogenicity study (107/127 mg/kg/day) were within a factor of around two fold of th e saturation point (>200

- 400 mg/kg/day), the doses were considered to be adequate for assessment of carcinogenicity. Therefore, the DART concluded that a new chronic toxicity/carcinogenicity study in the rat was not required (TXR No. 0053647).

870.4200 b Carcinogenicity (feeding)

- Mouse

In a carcinogenicity study (MRID 40872401), groups of 52 male and 52 female CD

- 1 mice were fed diets containing dicamba (86.8% a.i.; Lot no. 52625110) at 0, 50, 150, 1000 or 3000 ppm for 89 (males) or 104 (females) week s. These doses correspond to 0, 5.5, 17.2, 108 or 358 mg/kg bw/day for males and 0, 5.8, 18.8, 121 or 354 mg/kg bw/day for females. Mortality was significantly increased in males at 150 ppm and at 3000 ppm; the cause of mortality was amyloidosis. The in cidence of this lesion was higher than any other single factor among males that died in all groups especially the high dose. Except for a significant decrease at 150 ppm, survival among treated females was comparable to that of the controls. Body weight gain was higher in treated males than control males while there was a 17% decrease in body weight gain in females at 3000 ppm. No treatment

- related effects were seen in food consumption, hematology, organ weights or gross pathology. Histopathology reveal ed a statistically significant (p < 0.05) increase in lymphosarcomas in females at 150 ppm only (8/52, 15%) compared to controls (2/52, 4%). The increase was not considered to be treatment

- related due to
lack of a dose

- response and the incidences were wit hin the historical control range (6

- 33%). Additionally, the incidence in the concurrent control (4%) was below the historical range.

Under the conditions of this study, dicamba was not carcinogenic in male or female mice at the
doses tested. The lack of systemic toxicity indicate that the animals may have tolerated higher doses (i.e. and MTD was not achieved). However, the doses employed in this study were approved by the Agency (Memo: S. April to R. Taylor, RD, dated 11/15/84).

The administration of d icamba to mice up to 3000 ppm (358 mg/kg/day for males, 354 mg/kg/day for females) in the diet revealed a statistically significant (p < 0.05) increase in lymphosarcomas in females at 150 ppm only (8/52, 15%) compared to controls (2/52, 4%). The
increase was not considered to be treatment

- related due to lack of a dose

- response and theDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 76 of 105 

### incidences were within the historical control range (6

- 33%). Additionally, the incidence in the concurrent control (4%) was below the historical range.

The DART revisited t he 1995 decision by the RfD/Peer Review Committee that the mouse carcinogenicity study was not tested at a high enough doses to evaluate carcinogenicity in the mouse. The DART concluded that 3000 ppm is an adequate dose in the mouse cancer study and
decide d that a new mouse carcinogenicity study was not needed (TXR No. 0053647)

.

A.4.6 Mutagenicity

For mutagenicity results, refer to Appendix A.2.

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study

- Hen

NA

870.6200 Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID 42774104) groups of Crl:CD BR rats (10/sex/dose) received a single oral (gavage) administration of dicamba (86.9%) in corn oil at doses of 0, 300, 600, or 1200 mg/kg. Vehicle controls received corn o il only. Positive controls received acrylamide at 50 mg/kg/day by intraperitoneal injection on seven consecutive days. At 300 mg/kg, transiently impaired respiration; rigidity upon handling, prodding or dropping; freezing of movement when touched; decreas ed arousal and fewer rears/minute compared to controls; impairment of gait and righting reflex were observed in both sexes. In addition, males showed decreased forelimb grip strength. With the exception of the decrease in forelimb grip strength, which pe rsisted until day seven, these effects were observed only on the day of dosing. In addition, at 600 mg/kg, both sexes showed decreases in locomotor activity and males showed significant decreases in tail flick reflex and a raised posture when placed in an open field. These effects were also observed only on the day of dosing. At the highest dose level tested (1200 mg/kg), both males and females showed an impaired startle response to an auditory stimulus. The effect was significant in males on day seven and in females on the day of dosing. In addition, males showed decreases in body weight (5

- 9%), body weight gain (24%) and food consumption (13% between days 0 and 7). The LOAEL was 300 mg/kg based on the several neurologic signs listed above; a NOAEL
was not established.

The submitted study is classified as acceptable/guideline and satisfies the Guideline requirements (870.6200a) for an acute neurotoxicity study in rats.

870.6200 Sub

- chronic Neurotoxicity Screening Battery

In a subchronic neuro toxicity study (MRID No. 43245210), Sprague

- Dawley rats (10/sex/dose) were fed diets containing dicamba (86.9%) at 0, 3000, 6000, or 12000 ppm (0, 197.1, 401.4,Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 77 of 105 

### 767.9 mg/kg/day for males and 0, 253.4, 472.0 or 1028.9 mg/kg/day for females, respectively)
fo r 13 weeks. Neurobehavioral evaluations, consisting of FOB, locomotor activity, and auditory startle response, were conducted at pre

- study and during Weeks 4, 8 and 13. No toxicologically significant differences were noted in either the mean body weights or food consumption of the
treated animals. Neurobehavioral evaluations at the 4

- , 8

- , and 13

- week evaluations revealed abnormal FOB observations consisting of rigid body tone, slightly impaired righting reflex and impaired gait. At Week 13 the incidenc es of these findings were decreased. Rigid body tone was also noted during evaluation of the righting reflex and landing foot splay. The NOAEL was 401 mg/kg/day and the LOAEL was 768 mg/kg/day based on rigid body tone, slightly impaired righting reflex and impaired gait. The study is classified as acceptable/guideline and satisfies the guideline requirements (870.6200b) for a subchronic neurotoxicity study in the rat.

In a 90

- day oral toxicity/neurotoxicity study in Sprague

- Dawley (Crl:CD® [SD] rats (MRID
48358001 ), groups of 16 rats/sex were dosed with MON 11900 in daily diets with either 0, 500, 3000, 6000, or 12000 ppm test material, which corresponded to 0, 34, 197, 397, 803 mg/kg/day in males and 0, 39, 230, 458, 938 mg/kg/day in females. There were 6 animals /sex dose in subset A
and B and 4/sex/dose in subset C. Subsets A and B were used for the functional observational battery (FOB) and subsets B and C were use d for clinical and pathology determinations. There were small body weight changes only in males. At the end of the study, 12000 ppm males weighed 5% less than controls with a cumulative weight gain of 9% less than controls; neither
value was statistical ly significant. Other than one death in a control male; all animals survived to sacrifice. Clinical observations in 12000 ppm males included unkempt appearance (2/16 males, vs 0/16 controls) and gasping/rales (1/16 males, 4 occurrences, vs 0/16 controls ). Uncoordinated righting ability was noted in 3/12 males in the 12000 ppm group. There was also lower hindlimb footsplay in 12000 ppm males during week 7. Females in the 12000 ppm group had rigid muscle tone (6/16 females) and one of
these showed an im paired equilibrium on 2 different times. Motor activity was unaffected by

treatment. The NOAEL for MON 11900 is 397 mg/kg/day and the LOAEL is 803 mg/kg/day based on FOB and clinical observations ( rigid muscle tone, impaired equilibrium, uncoordinated

r ighting ability, and decreased lower hindlimb foot splay).

This study is classified as acceptable/guideline and satisfies the guideline requirements for a 90

- day rat toxicity study and neurotoxicity study ( OECD 408 and EPA OPPTS 870.3100/870.6200).

8 70.6300 Developmental Neurotoxicity Study

NA

A.4.8 Metabolism

870.7485 Metabolism

- Rat

In a plasma kinetics study, (MRID 44609801), [phenyl

- U

- - 14 

### C]

- dicamba ( [ 14 

### C]

- dicamba; 86.0% a.i. radiochemical purity), was administered as a dietary admix to 4 male and 4 female Wistar and Sprague

- Dawley at 900, 1500, 3000, 4500, and 12000 ppm (Wistar rats) and 900, 1500,Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 78 of 105 

### 3000, 6000 and 9000 ppm (Sprague

- Dawley rats) for fourteen days, followed by a radioactive dose of 90, 150, 300, 450 mg/kg bw (Wistar rats) and 75, 125, 250, 500 and 800 mg/kg bw by a single gavage dose (in 10 ml/kg body weight 0.5% Tylose CB 30.000 in aqua bidest). Plasma levels were measured at various time intervals following radioactive dose. A preliminary study in Wistar rats suggests exce ssive toxicity following repeated gavage doses. Therefore, the main study in both strains of rats was conducted as a dietary ad mix followed by a gavage dose of radiolabeled dicamba. In both strains of rats, the plasma levels reached a

maximum level afte r 0.5

- 1 hour following the gavage dose and declined thereafter. The AUC 0

-  

### values were calculated from the plasma concentrations versus time curves at the respective dose levels indicated linear relationship with increase in dose up to a certain dose lev els in both strains of rats indicating saturation of excretion. Initial plasma half

- life was increased with increasing dose, but terminal half

- life remains more or less constant in both strains of rats indicating
saturation of excretion. Plasma half

- life was increased with increasing dose giving no indication of saturation of oral absorption. In Wistar rats, the increase in plasma AUC was linear with dose up to a level of 150 mg/kg bw in males and 300 mg/kg bw in females. Above these dose levels, plasma AUC

- values increased more than dose. Sprague

- Dawley rats showed similar results, with the increase in AUC being linear with dose up to a level of 125 and 250 mg/kg bw in males and females, respectively. Above these dose levels, plasma AUC

- values increase d more than dose. Considering that oral absorption was not saturated and that initial plasma levels went up with dose, the disproportionate increase in plasma AUC is clearly due to saturation of renal excretion of dicamba resulting in a longer plasma half

- life. This is supported by half

- life data in both species which showed an increase in plasma half

- life with dose. This plasma kinetics study in the rats is
classified Acceptable/Non

- guideline (§85

- 1).

In a plasma pharmacokinetic study (MRID 46022302), five groups of 4 male and 4 female Wistar rats received diets containing the equivalent of 50, 100, 200, 400, or 800 mg/kg dicamba/day for 90 days (Lot No. 52103810, 87.2% a.i.) . On study days 29, 63, and 91, dietary supplementation of dicamba was stoppe d and rats in each group received an equiva lent gavage
dose of 14 

### C

- dicamba (Lot No. 787

- 0102, >99% a.i., universally labeled in the phenyl group). Blood samples were drawn 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after treatment and the plasma
radioactiv ity determined. Absorption of the radiolabeled test material was rapid, with peak plasma concentrations found within 2 hours of treatment. Absorption was not saturated, even at the highest dose, as indicated by increasing plasma concentrations with dose. However, the increase in plasma concentration was disproportionate from dose as shown by the  2

- fold increase in AUC from one dose group to the next at doses >100 mg/kg. Elimination of radiolabel from the plasma was tri

- phasic, with
the terminal

- phase c onsis tent between doses. However, the initial elimination phase increased with dose, particularly in the 400 and 800 mg/kg dose groups and is consistent with excretion
saturation . No significant treatment

- related differences between the sexes or time of radiolabel
administration were found. This plasma pharmacokinetic study in the rat is classified Acceptable/Non

- guideline and
satisfies its intent.

In a pharmacokinetic study (MRID 46022303), two groups of 3 male Wistar rats were given a single 200 mg/kg gavage dose of 14 

### C

- dicamba (Lot No. 787

- 0102, >99% a.i., universally labeledDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 79 of 105 

### in the phenyl group). One group of rats was pretreated with a 150 mg/kg IP dose of probenecid, a known competitive inhibitor of renal anion transport, 30 minutes prior to dicamb a dosing. Blood samples were drawn 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after gavage treatment and the plasma radioactivity determined. The time to peak plasma concentration in rats treated with 14 

### C

dicamba occurred within 0.5 hours while peak plasma concentration was reached at 1.0 hour in the probenecid/dicamba rats. How ever, pretreatment with probenecid increased plasma AUC by a factor of 1.54. Although the terminal phase of elimination remained relatively the same, the
initial and intermediate elimina tion phases were increased by a factor of two. These data suggest that both dicamba and probenecid, act as inhibitors of renal anion transport. This pharmacokinetic study in the rat (MRID 46022303) is classified Acceptable/Non

- guideline
and satis fies its intent

.

870.7600 Dermal Absorption

- Rat
NA

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID 48081601), BAS 183 H (Dicamba technical) (92.9% a.i., Lot No. COD 001266) was administered to 8 male Crl:WI (Han) Wista r rats/dose in the diet at dose levels of 0, 500, 1500, or 4000 ppm (equivalent to 0, 37, 108, or 307 mg/kg/day) for 28 days. The male rat has been determined as the appropriate species/sex for this study. Cyclophosphamide monohydrate in water was administ ered daily by gavage to the positive control group (8 male rats) at a rate of 4.5 mg/kg/day. On Day 23, animals were immunized with an intraperitoneal injection of 0.5 mL sheep red blood cells (SRBCs) in 0.9% saline (4 x 10 8 

### SRBCs)/mL). On Day 29, all anim als were sacrificed and T

- cell dependent antibody responses (TDAR) were evaluated with an enzyme

- linked immunosorbent assay (ELISA).

There were no treatment

- related effects on clinical signs, mean body weight, mean body weight gain, or mean food and water consumption. In the positive control group, mean body weights were lower than the control value from Day 3 through Day 28, the differences reaching statistical significance (p<=0.05) when measured on Days 24 and 28. Body weight gain in the positive

contro l group also was consistently lower than the control group throughout the study, and was statistically significant over most of the measured intervals (p<=0.05) within the study, and over the entire study (i.e., Day 0

- 28, p<=0.01). Additionally, food consu mption in the positive control group was lower than the control throughout the study; these data were not statistically analyzed. The decreases in weight, weight gain, and food consumption in the positive control group were considered to be treatment (cycl ophosphamide)

- related. No unscheduled mortalities occurred in any study group. The NOAEL for systemic toxicity related to treatment with BAS H 183 (dicamba techn.) is 4000 ppm (307 mg/kg/day), the highest dose tested. A LOAEL was not
established.

There were no treatment

- related changes in anti

- SRBC IgM titers as measured by ELISA assay. The mean absolute and relative thymus weights did not differ significantly from the control in any test substance treatment group. In the positive control group, m ean anti

- SRBC IgM titersDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 80 of 105 

### were markedly lower than the control, and absolute and relative spleen and thymus weights were significantly reduced when compared with the control (p<=0.01).

The Natural Killer (NK) cell activity was not evaluated. Evaluation o f toxicity database of
dicamba including subchronic, chronic toxicity and reproduction studies showed no treatment

related effects on spleen and thymus weights and histopathology parameters that would suggest the potential for immunotoxicity. Under the HED guidance, if the TDAR assay is negative and evaluation of observational endpoints from all available toxicology database provide no evidence of immunotoxicity, the test article is considered negative for immunotoxicity and evaluation of NK cells activity is not necessary.

Under conditions of this study, the NOAEL for immunotoxicity in male rats is 4000 ppm (307 mg/kg/day), the highest dose tested. A LOAEL was not established.

This 4

- week dietary immunotoxicity study in the rat is acceptable/guideline an d satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800)

.

A.4.9 Special Studies: Toxicity of Dicamba Metabolites or Amine Salts

870.3100 DCGA 28

- Day Oral Study in Rats

In a 28 day dietary toxicity test (MRID 47899506) gro ups of 10 rats/sex/group were exposed to DCGA (MON 52724) (Purity 98.1% Lot/batch No GLP

- 0904

- 19809

- T) at dietary concentrations of 0, 500, 3000, 6000,or 12000 ppm. The average test substance consumption over the entire study was 0, 40, 240, 474, and 956 mg/kg/day for males and 0, 45, 265, 519, and 1063 mg/kg/day for females. All animals were observed twice daily for moribundity and mortality, clinical examinations were performed daily, and individual body weights were recorded weekly. Food consumption, functional observational battery (FOB) and motor activity were recorded twice weekly. All animals survived to the scheduled necropsy. There were no adverse test substance related clinical observations, effects on organ weights or histological, or macrosc opic findings. FOB and and motor activity were unaffected by treatment. Body weights were decreased 9% in males and 6% in females (not statistically significant). The NOAEL was 474 mg/kg/day and the LOAEL was 956 mg/kg/day based upon decreased body weig ht in males.

This study is classified as acceptable/guideline, and it satisfies the guideline requirement for a

28

- day oral toxicity study in rodents (OECD 407, OPPTS 870.3050).

870.3100 DCSA 90

- Day Oral Study in Rats

In a 90 day dietary study (MRID 47899507), Sprague

- Dawley (Crl:CD ® 

### [SD]) (10 rats/ sex/group) were exposed to MON 52708 ( purity 97.9%; Lot/batch GLP

- 0603

- 16958

- T) for 90

- days. Final dietary concentrations were 500, 3000, 6000 and 12000 ppm. Due to potential problems with palatability o bserved in a previous range finding study, rats in the higher dose groups received slowly increasing doses during the first 1 to 2 weeks. Group 4 rats received theDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 81 of 105 

### 3000 ppm diet during week 0 and the 6000 ppm diet during weeks 1 through 12. Group 5 rats received the 3000 ppm diet during week 0, the 6000 ppm diet during week 1 and the 12000 ppm diet during weeks 2 through 12.) The control group (Group 1) received the basal diet only throughout the study. The average test substance consumption over the en tire study was 0, 32, 195, 362, or 659 mg/kg/day for males and 0, 37, 222, 436, or 719 mg/kg/day for females.

All animals were observed twice daily for mortality and morbidity. Clinical observations were made daily and detailed physical exams conducted weekly. Body weights and food consumption were measured weekly. Functional observational battery (FOB), locomotor activity and ophthalmic examination data were recorded prior to beginning exposure to MON 52708 and at the end of the study (week 12). Hemat ology, serum chemistry and urinalysis assessments were conducted during study week 13. Complete necropsies were conducted on all animals at study week 13. Selected organs were weighed at necropsy and selected tissues from all animals were
examined microsc opically. Lower body weights were noted in the 12000 ppm group males and females throughout the study after dose ramping was concluded and final dosing levels were achieved (end of study week 2). Terminal mean body weights for the 12000 ppm males and fema les were 28.1% and 29.7% lower than controls, respectively. Body weights and food consumption in the 6000 ppm group females were also statistically significantly lower compared to controls during the first few weeks of the study after ramping was conclude d and generally remained lower but were not statistically significantly different for the rest of the study. Food consumption in 12000 ppm males and females was decreased from the end of week 2 until approximately midway through the study. After approxi mately week 7, food consumption was increased in 12000 ppm males compared to controls and in 12000 ppm females was comparable to
controls.

In the functional observation battery, there were no treatment

- related effects noted during home cage, handling, o pen field, sensory, neuromuscular, or physiological observations. For the motor activity assessment, ambulatory counts were increased in 12000 ppm males by 59% (p<0.005), compared to controls, during the first 15 minute interval. Ambulatory counts were i ncreased for that group in 2 other intervals, but not with statistical significance. Hematological effects were noted in the 12000 ppm group. Effects included decreased red blood cell count, haemoglobin, MCHC, and hematocrit, and were more pronounced in females
than in males. Liver enzymes, including alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase, were increased in the 12000 ppm group. Relative liver weights were higher in the 12000 ppm group compared to controls, but absolute liver weights were not statistically different. There were no microscopic findings in the liver. Microscopic lesions included an increase of bone marrow depletion in the sternum of the 12000 ppm group males and 6000 and 12000 ppm group females and hyperplasia of the epithelium in the glandular stomach of 12000 ppm group males and females. There were also four erosions in the gla ndular stomach, one each in males from the 6000 and 12000 ppm groups and two in females from the 12000 ppm group. The NOAEL is 362 mg/kg/day and the LOAEL is 659 mg/kg/day based on decreased body weight, increased motor activity, decreased hematological parameters, and increased liver

enzymes.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 82 of 105 

### This study is classified as acceptable/guideline and satisfies the guideline requirement for a 90

- day feeding study in the rat (EPA OPPTS guideline 870.3100 and OCED guideline Section 408).

870.3100 Dicamba B APMA 90

- Day Oral Study in Rats

In a 90

- day oral toxicity study (MRID 49441801), Dicamba BAPMA Salt (69.5% a.i. Dicamba acid; batch#: 1781

- 6) was administered to 10 Wistar rats /sex/dose in the diet at dose levels of 0,

4317

, 8633 , or 17266 ppm (equivalent to 0, 257

, 513, and 1027 mg/kg bw/day in males and 0, 294, 589, and 1178 mg/kg bw/day in females). The test diets were equivalent to 0, 3000, 6000, and 12000 ppm Dicamba acid (equivalent to 0, 178

, 357

, and 714 mg/kg bw/day in males and 0, 205, 409, and 8 19 mg/kg bw/day in females). Evaluated parameters included mortality, clinical signs, body weight, food consumption, ophthalmological examinations, functional observational battery (FOB), clinical pathology, organ weight, and gross and histopathological e xamination.

There were no treatment

- related effects on mortality, clinical signs, FOB, body weights, food consumption, ophthalmoscopy, urine parameters, macroscopic findings, or histopathology.

Treatment

- related increased absolute and relative kidney wei ghts were noted in males of the high

- dose study group (absolute weight 15% greater than controls [n.s.] and relative weight 20% greater than controls). Total bilibrubin levels were significantly decreased 41

- 79% in all treated animals, and the changes wer e considered related to treatment, but were not considered adverse. In males of the high

- dose group, prolonged prothrombin time (9.5%) and increased incidence of urine triple phosphate crystals were observed. In females, creatinine levels were significan tly increased 33% at the high

- dose. In both sexes at the high

- dose, total protein and globulin levels were significantly decreased 5

- 16%. The refore, under the conditions of this study, the
LOAEL of Dicamba BAPMA Salt is 17266 ppm (1027 mg/kg bw/day in ma les and 1178 mg/kg/day in females; corresponding to 714 and 819 mg/kg bw/day Dicamba Acid in males and females, respectively) , based on kidney effects and altered hematology (increased prothrombin time in males) and clinical chemistry (increased creatinine levels in females and decreased total protein and globulin levels in both sexes) parameters . The NOAEL is 8633 ppm (513 mg/kg bw/day in males and 589 mg/kg/day in females; corresponding to 357 and 409 mg/kg bw/day Dicamba Acid in males and females, respe ctively)

.

This 90

- day oral toxicity study in the rat is Acceptable / Guideline and satisfies the guideline requirement for a 90

- day oral toxicity study (O CSPP 870.3100; OECD 408)

.

870.3150 DCSA 90

- Day Oral Study in Dogs

In a 90 day oral capsule study (MRID 48358002), Beagle dogs (5 animals/sex/group) were treated with MON 52708 (purity 97.7%; Lot/batch GLP

- 0603

- 16958

- T) 

### for 90 days with doses of 0, 15, 50 and 150 mg/kg/day.

All animals were observed twice daily for mortality and morbidity. Clinical observations were performed daily and detailed physical exams were conducted weekly. Body weights were measured weekly. Food consumption was recorded daily and reported weekly. Clinical pathology evaluations included hematology, coagulation, serum chemi stry and urinalysis andDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 83 of 105 

### were conducted prior to initiation of dosing and during study weeks 6 and 13. Ophthalmic examinations were conducted prior to initiation of dosing and during study week 12. Complete necropsies were conducted on all animals during study week 13. Selected organs were weighed at necropsy and selected tissues were examined microscopically. One female in the 150 mg/kg/day dose group was euthanized in extremis on day 50 of the study. Death was associated with repeated emesis, electrolyte imbalance, and severe dehydration. All other animals survived to the scheduled necropsy.

Statistically significant decreases were observed in cumulative body weight gains in both males and females in the 150 mg/kg/day groups. Absolute mean bo dy weights in these groups were about 11% lower than controls at the end of the study, though the differences were not statistically significant. Decreased food consumption was observed in females in the 150 mg/kg/day group during study weeks 1

- 2 and 3

- 4. Male food consumption was not different from controls. Abnormal excreta and emesis were present in the 150 mg/kg/day male and female groups. Abnormal excreta began on study day 0; emesis began on study day 2. Both effects persisted to the end of the st udy. Coagulation effects were observed in both males and females: APTT values were higher in males in the 150 mg/kg/day at study week 13 and in females in the 150 mg/kg/day group at study
week 6. Liver weights relative to body weights were higher in m ales and females in the 150 mg/kg/day groups. Hypertrophy of periportal hepatocytes was observed in the livers of both sexes in the 150 mg/kg/day groups.

The NOAEL is 50 mg/kg/day and the LOAEL is 150 mg/kg/day based on mortality, decreased body weight , clinical signs (abnormal excreta and emesis), and increased clotting
time.

This study is classified as acceptable/guideline and satisfies the guideline requirement (EPA OPPTS guideline 870.3150 and OCED guideline Section 409) for a 90

- day dog study.

870.3200 Dicamba DGA 21

- Day Dermal Study in Rabbits

In a 21

- day dermal toxicity study (MRID No. 43554206) New Zealand White rabbits [5/sex/dose] were given repeated dermal applications of the diglycolamine (DGA) salt (59%) of dicamba at 0, 100, 500 or 1000 mg/kg, 6 hours/day, 5 days/week for a total of 15 applications during a 3 week period. No treatment

- related dermal reactions or histopathological dermal lesions were seen. No systemic toxicity was seen; treatment had no adverse effect on survival, clinical signs, mean body weights, body weight gains, hematology, clinical chemistry, organ weights or gross and histopathology. A NOAEL of 1000 mg/kg/day (Limit

- Dose) was established for both dermal irritation and systemic toxicity. A LO A EL was not estab lished for either end

- point.

This study is classified as Core Guideline and satisfies the data requirement [§82

- 2] for a 21

- day dermal toxicity study in rabbits and is acceptable for regulatory purposes.

870.3200 Dicamba IPA 21

- Day Dermal Study in Rabbi tsDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 84 of 105 

### In a 21

- day dermal toxicity study (MRID No. 43554207) New Zealand White rabbits [5/sex/dose] were given repeated dermal applications of the isopropylamine (IPA) salt (41%) of dicamba at 0, 100, 500 or 1000 mg/kg, 6 hours/day, 5 days/week for a total of 15 applications during a 3 week period. No treatment

- related dermal reactions or histopathological dermal lesions were seen. No systemic toxicity was seen; treatment had no adverse effect on survival, clinical signs, mean body weights, body weight gains , hematology, clinical chemistry, organ weights or gross and histopathology. A NOAEL of 1000 mg/kg/day (Limit

- Dose) was established for both dermal irritation and systemic toxicity. A LOAEL was not established for either end

- point.

This study is classified as Core Guideline and satisfies the data requirement [§82

- 2] for a 21

- day dermal toxicity study in rabbits and is acceptable for regulatory purposes.

870.3465 Dicamba BAPMA 28

- Day Inhalation Study in Rats

In a nose

- only inhalati on toxicity study (MRID 49441803 )

, four groups of Crl: WI(Han) rats (10/sex/group;

~ 10 weeks of age) were administered Dicamba BAPMA Salt [84.7%, equivalent
to 69.5% Dicamba acid (Batch No. 1781

- 6)] as a dust aerosol at target exposure concentrations
of 0, 0.0014, 0.0072, or 0.036 mg/L (respective actual concentrations of 0, 0.0015, 0.0070, and 0.0352 mg/L) for 28 days.

There were no mortalities or clinical signs observed at any exposure concentration. No
substance

- related adverse findings were observed o n body weight, ophthalmology examinations, food consumption, or clinical pathology parameters in blood. Plasma concentrations of Dicamba acid after 22 days of exposure increased with exposure concentration, but not proportionally to
the 5

- fold increase in exposure between the mid

- and high

- exposure concentrations. The respective mean values of female animals were higher than those of the males. Mic roscopic examination of tissues showed that the test substance was a respiratory tract irritant with adverse
ef fects on the nasal cavity, larynx, trachea, lungs, and the lung

- associated lymph nodes. Nasal cavity : In Level I, focal degeneration/regeneration of the respiratory and/or transitional epithelium was observed in 1 male and 1 female from the mid exposure gr oup (minimal severity), and in 8 males and 5 females from the high exposure group (minimal to slight). Two males and two females at the high concentration showed minimal focal squamous cell metaplasia of the respiratory epithelium in the septum. In Level I I, one female at the high concentration showed an ulcer in the epithelium of the septum. Larynx : Ulcers in epithelial tissues were observed in males at incidences of 2/10, 5/10, and 8/10, respectively, in the low

- , mid

- , and

– high

- exposure groups. Minimal focal inflammation was observed in Level I or Level II in 3 males at the low concentration, 1 male and 1 female at the mid concentration, and in 1 male and 3 females at the high concentration. Single or multi

- focal hyperplasias were observed in Level I
and /or Level II in 5 males and 4 females at the low concentration, 8 males and 7 females at the mid concentration, and in 7 males and 7 females at the high concentration. Trachea : Minimal or slight focal degeneration/regeneration of the respiratory epithelium was observed in 2 males at the mid concentration, and in 5 males and 1 female at the high concentration. Lung : Minimal to slight inflammation was observed in bronchi and/or a lveoli in most to all of the males and
females at the mid

- and high

- concentration . Minimal multifocal bronchiolo

- alveolar hyperplasia was observed in 2 males at the high concentration and in 1 female at the mid concentration. Minimal hypertrophy of single terminal bronchi was observed in 6 males and 3 females at theDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 85 of 105 

### high concentration . The incidence of minimal or slight multifocal alveolar histiocytosis increased in males from all three exposed groups and in females from the mid

- and high

- concentration

grou ps. The incidence of minimal or slight alveolar macrophage aggregates was increased in
males at the mid

- and high

- concentration and in females from all three exposed groups. Tracheobronchial and mediastinal lymph nodes : Minimal to slight lympho

- reticuloce llular hyperplasia in one or both of these lymph nodes was observed in males at the mid

- and high

exposure concentrations and in females at all three concentrations. Macrophage aggregates were
observed in both sexes at the mid

- and high

- exposure concentrat ions.

The LOAEL in Wistar rats was 0.0014 m g/L based on ulcers in epithelial tissues of the larynx and single/multi

- focal hyperplasias in the larynx . A NOAEL was not identified

.

This inhalation toxicity study is classified as Acceptable (Guideline) and satisfies the guideline requirement for 4

- week inhalation toxicity study in rats (OCSPP 870.3465).

870.3650 BAPMA Base OECD 422 Developmental

- Reproduction Study

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test , N,N

- Bis(3

- aminopropyl)methylamine (99.6% a.i., Batch No. O2903) was administered to 10 Wistar rats /sex/dose by gavage in deionized water at dose levels of 0, 25

, 100

,

or 500 mg/kg bw/day for at least 14 days prior to mating, throughout mating, and up to and including the day prior to sacrifice. Terminal sacrifices took place after 28 days of treatment in males and after 56 days of treatment in females. Evaluated parameters in the parent al animals included functional observational battery (FOB), motor activity, hematology, clinical chemistry, urinalysis, organ weights, macroscopic examination, and histopathology

In the high

- dose group, there was 100% mortality (both sexes) within t he first four days of treatment. One male was found dead on study day 3 and one female was found dead on study day 1. Due to clinical signs including labored respiration, piloerection, unsteady gait, hypothermia, semiclosed eyelids, and abdominal position , all animals of the high

- dose group
were sacrificed in extremis between study days 1 and 4. Treatment

- related post mortem findings in these animals included red discoloration and lesions of the gastrointestinal track including
extensive areas of erosion and/or ulceration, hemorrhagic inflammation, and blunting and fusion of villi. Tubular necrosis of the kidney was also observed.

No treatment

- related mortality or clinical signs were observed in the low

- and mid

- dose groups.
There were no treatment

- r elated effects on mean body weight, food consumption, clinical pathology, or gross and microscopic necropsy findings of the low

- and mid

- dose groups. Motor activity was decreased by 24% at 100 mg/kg/day. Body weight loss was observed in the mid

dose group (

- 2.2 g vs. 4.6 g in control) during lactation, but was not considered adverse because it did not affect mean body weights. Water consumption was decreased by 22

- 47% during premating through GD 14 and was significantly decreased by 19% in females of the mid

- dose group at the end of gestation (GD 19

- 20). In the absence of correlated effects on clinical signs, clinical pathology, organ weights, and/or gross or microscopic findings, the toxicological significance of the decreased water consumption is unclea r. Deaths occurred in the dams at 500 mg/kg bw/day. Therefore, the parental systemic NOAEL is 25 mg/kg bw/day, and theDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 86 of 105 

### LOAEL is 100 mg/kg/day based on decreased motor activity and water consumption, results from the surviving animals.

No animals in the h igh

- dose groups were mated due to excessive toxicity and mortality during the premating period. No evidence of reproductive toxicity was found. Maternal treatment did
not result in decreased in utero or postnatal survival, altered growth, abnormal clinic al signs, or an increased incidence of gross abnormalities of the offspring. Therefore, the reproductive/developmental LOAEL is not identified, and the reproductive/developmental NOAEL is 100 mg/kg bw/day. However it must be noted that there were only si x and seven
litters with live fetuses in the low

- and mid

- dose groups, respectively . A lthough the low
numbers of litters are not treatment

- related, they still limit the sensitivity of this study to detect effects on pregnancy, maternal and suckling behavi or, and growth and development of the F 1 

### offspring from conception to day 4 post

- partum.

This study is A cceptable/ Non

- Guideline and does satisfies the guideline requiremen t for a reproductive /developmental toxicity screening study ( O CS PP 870.3 650 ; OECD 4 22) in the rat.

870.3700a Dicamba BAPMA Rat Developmental Study in Rats

In a developmental toxicity study (MRID 49441802)

, D icam b a BAPMA salt [ 84.7% w/w Dicamba BAPMA; 69.5% w/w Dicamba (acid equivalent), batch# 1781

- 6 ] was admin istered to

2 5 female Wistar rats /dose in 1% aqueous carboxymethylcellulose suspension by oral gavage at dose levels of 0, 29, 86, or 288 mg/kg bw/day (correspond ing to 20 , 60, or 200 mg/kg bw/day Dicamba acid) on gestation days ( GDs) 6 through 19, inclusive. Body weights and food consumption were monitored regularly until sacrifice on GD 20. Dams were necropsied, and gravid uterine weight, number s of corpora lutea, and numbers and distribution of live and dead fetuses and early and late resorptions were recorded . Fetuses wer e sexed, weighed

, and investigated for external findings; approximately one

- half of the fetuses of each litter were examined for soft tissue findings and the remaining fetuses for skeletal findings (inclusive of cartilage). Individual placental weights al so were recorded.

At 86 and 288 mg/kg bw /day, maternal toxicity was characterized by increased incidences of
adverse clinical signs , including unsteady gait , convulsions, and ataxia (occurrences/affected animals at 86 mg/kg/day: 114/24

, 3/2 and 4/2 ; at 288 mg/kg/day: 74/20

, 187/ 25 and 63/20

, respectively, out of 25 total animals for both groups). Observations in the mid

- dose females began after dosing and persisted for a maximum of 3 hours , with the earliest observations recorded on GD 6 (unsteady gait) or GDs 12

- 13 (convulsions/ataxia), while those in the high

dose females began after dosing, persisted for a maximum of 4 hours , and were first noted on

GDs 6

- 7

. Also in the 288 mg/kg/day females, body weight gain and food consumption was significant ly reduced compared to controls during intervals at the beginning of treatment, and

non

- statistically significantly reduced for the overall treatment period as follows: body weight gain:

- 20% during GDs 6

- 13,

- 8% during GDs 6

- 19; food consumption:

- 8% dur ing GDs 6

- 10,

- 7% during GDs 6

- 19. T he corrected (for gravid uterine weight) body weight gain was significantly lower in the high dose group by 16%, indicating that the decreased weight gain was
a maternal effect. No maternal toxicity was apparent at the low dose of 29 mg/kg/day. NoDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 87 of 105 

### treatment

- related effects on maternal cesarean section parameters were noted at any dose level for this study.

The maternal LOAEL for D icamba BAPMA salt in rats is 86 mg/kg bw/day (corresponding to 60 mg/kg bw /day D icamba a cid equivalent), based on adverse clinical signs of unsteady gait
, ataxia
, and convulsions. The maternal NOAEL is 29 mg/kg bw/day (corresponding to 20 mg/kg bw /day D icamba acid equivalent).

No developmental toxicity was evident as a result of maternal treatment with up to 288 mg/kg/day of Dicamba BAPMA salt. Fetal weights, fetal sex ratios, post implantation loss and numbers of viable fetuses, implantation sites , resorptions, and corpora lut ea in all dose groups were comparable to the control group. The infrequent occurrence and nature of fetal malformations observed in the study were not considered treatment

- related , and visceral and skeletal variations were comparable to controls and/or di d not exhibit a dose

- response relationship.

The developmental LOAEL for D icamba BAPMA salt in rats was not determined. The developmental NOAEL is greater than or equal to 288 mg/kg bw/day (200 mg/kg bw /day

D icamba acid equivalent).

The developmental to xicity study in the rat is classified Acceptable / Guideline and satisfies the guideline requirement for a developmental toxicity study (OCSPP 870.3700; OECD 414) in the

rat.

870.3700a DCSA Rat Developmental Study in Rats

In a prenatal developmental toxicity study (MRID 47899519) groups of 25 bred female Crl:CD (SD) rats were administered MON 52708 (purity 97.9%; Lot/batch# GLP

- 0603

- 16958

- T) by oral gavage at doses of 0, 10, 30 and 100 mg/kg/day from gestation days 6 thro ugh 19. The doses for this study were based on a previous prenatal developmental toxicity dose range

- finding study (MRID47899518).

All animals were observed twice daily for mortality and moribundity, and individual clinical
observations were recorded fro m gestation days 0 through 20. Animals were also observed for signs of toxicity approximately 1 hour following dose administration. Body weights and food consumption were recorded on gestation days 0 and 6

- 20. On gestation day 20, a laparohysterectomy was performed on each female. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations.

All females survived to the scheduled necropsy on gestation day 20; there were no test article

rel ated clinical or macroscopic findings at any dose level. Mean maternal body weights, body weight gains, net body weights, net body weight gains, gravid uterine weights and food consumption in all test article

- treated groups were generally similar to those in the control group.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 88 of 105 

### No test article

- related effects on intrauterine growth, survival or fetal morphology were observed at any dose level.

Doses in this study were based upon toxicity in a pilot study (MRID47899518, see Appendix). In the pilot study cl inical observations at 200 mg/kg/day included salivation, red and/or clear material around the mouth and/or nose, and yellow or brown material around the genital area. Fetal body weights were decreased 14% in the 200 mg/kg/day group compared to controls.

The maternal and developmental NOAELs are both 100 mg/kg/day, the highest dose tested.
A LOAEL was not determined

.

This study is classified totally reliable (acceptable/guideline) when considered in conjunction with the range

- finding study (MRID4789 9518) and satisfies the guideline requirements (EPA OPPTS guideline 870.3700 and OCED guideline 414).

DCSA Range

- Finding Study for Rat Developmental Study

In a prenatal development toxicity range finding test (MRID47899518) groups of 8 bred female
Crl:C D(SD) rats were administered by MON 52708 (purity 97.9%; Lot/batch no GLP

- 0603

- 16958

- T 

### ) by oral gavage at doses of 0, 50, 200, 500 or 1000 mg/kg/day from gestation days 6

- 19. All animals were observed twice daily for mortality and moribundity, and individ ual detailed clinical observations were recorded from gestation days 0 through 20. Animals were also observed for signs of toxicity at the time of dose administration and approximately 1 hour following dose administration. Body weights and food consumption were recorded on gestation days 0 and 6

- 20. On gestation day 20, a laparohysterectomy was performed on each surviving female. The fetuses were weighed, sexed and examined for external malformations and developmental variations.

In the 1000 mg/kg/day group, 7 of the females were found dead and 1 female was euthanized in extremis on gestation day 7, 8 or 9. In the 500 mg/kg/day group, 2 females were found dead, 1 each on gestation days 8 and 10. All other females survived to the sc heduled necropsy. Clinical findings for surviving females in the 200 and 500 mg/kg/day groups included salivation and red and/or clear material around the mouth and/or nose. In addition, in the 500 mg/kg/day group, excessive pawing and wiping of the mout h on the cage were noted. Mean maternal body weight losses and/or lower mean body weight gains and lower food consumption, mean gravid uterine weights, net body weights and/or net body weight gains (relative to the control group) were generally noted in the 200 and 500 mg/kg/day groups throughout the treatment period. Body weight gain for the 200 mg/kg/day group was 92 g vs 117 g in controls. Body weights were also reduced in the 500 mg/kg/day, though this was in part due to the 100% resorptions at that dose.

At the scheduled necropsy, no remarkable macroscopic findings were noted in the surviving dams at any dose level. Mean absolute liver weights in the 200 and 500 mg/kg/day groups were 7.0% and 19.0% lower than the control group value, respectively . In addition, slightly higher mean absolute spleen and kidney weights (16.7% and 11.6%, respectively) were noted in the 500 mg/kg/day group when compared to the control group values.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 89 of 105 

### Evaluation of laparohysterectomy parameters in the 1000 mg/kg/day grou p was precluded by the death of all females in this group. Surviving females in the 500 mg/kg/day group had early resorptions of all litters. In the 200 mg/kg/day group, mean fetal weight was decreased 14% compared to controls. No malformations or develop mental variations were noted in any fetuses
in the control or test article

- treated groups following an external examination.

Because this range finding study was not intended to fulfill a guideline requirement, NOAELs and LOAELs are not assigned. This s tudy is suitable for use in dose selection for a definitive guideline study.

870.3700a DCGA Developmental Study in Rats

In a dose range

- finding toxicity study (MRID 47899520) four groups of eight bred female Crl:CD(SD) rats per dose group were exposed to MON 52724 (Purity 96.3%; Lot/batch No GLP

0903

- 19699

- T ) by gavage with corn oil at doses of 0, 50, 200, 500, and 1000 mg /kg/day. Animals were observed twice daily for moribundity and mortality and individual detailed clinical observations were recorded from day 0 through gestation day 20. Body weights and food consumption were recorded from gestation days 0 and 6

- 20. On g estation day 20, a laprohysterectomy was performed on each of the surviving animals and the uteri, placentae, ovaries were examined, and the number of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Fetuses receive d an external examination but not a soft tissue or
skeletal examination.

Mean body weights were 4.0% to 6.6% lower during gestation days 13

- 20 in the 500 mg/kg/day group and 4.4% to 12.1% lower during gestation days 12

- 20 in the 1000 mg/kg/day group. Five of the eight females in the 1000 mg/kg/day group died or were euthanized in extremis during gestation days 12

- 19. Clinical findings in dams included rales and red or clear material on body surfaces at doses of 200 mg/kg/day and above. There were no e ffects observed on uterine growth, survival, external malformations or variations.

Because this range finding study was not intended to fulfill a guideline requirement, NOAELs and LOAELs are not assigned. This study is suitable for use in dose selection for a definitive guideline study.

870.3700b DCSA Developmental Study in Rabbits

In a developmental toxicity study (MRID 47899522), groups of twenty

- five mated female New Zealand white rabbits were exposed to DCSA (MON 52708) (Purity 97.7%; Lot/batch No GLP

0603

- 16958

- T ) by gavage from gestation days 6

- 28 at doses of 0, 10, 25, or 65 mg/kg/day. All animals were observed twice daily for moribundity and mortality and individual detailed clinical observations, body weights, and food consumption were rec orded. On gestation day 29, a laprohysterectomy was performed on each surviving females and the uteri, placentae, ovaries were examined, and the number of fetuses, early and late resorptions, total implantations and corpora lutea were recorded.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 90 of 105 

### One control female and one female in the 65 mg/kg/day group died with cause of death undetermined. One female in the 10 mg/kg/day group aborted. All treatment groups had decreased defecation. There were no toxicologically significant test substance rela ted effects observed on survival, clinical signs, body weight, food consumption, intrauterine growth, pup survival, external malformations or morphology of fetuses.

Although no toxicity occurred in this study at the high dose of 65 mg/kg/day, the does co uld not have tolerated a much higher dose because 100 mg/kg/day was found to be a maternally lethal dose in the range finding study (MRID 47899521).

The maternal and developmental NOAELs are 65 mg/kg/day, the highest dose tested. The
maternal and devel opmental LOAELs were not determined

.

Therefore, t

his study is classified as acceptable/guideline when considered in conjunction with the range finding study and satisfies the guideline requirements for a developmental toxicity study in rabbits (OPPTS 870. 3700, OECD 414).

870.3800 DCSA Reproduction Study in Ra ts

In a dietary two

- generation reproductive toxicity study (MRID 47899517) DCSA (MON 52708) (purity 97.7%, Lot/Batch no., GLP

- 0603

- 16958

- T) was administered continuously in the diet to groups of male and female Crl:CD(SD) rats (30/sex/group) at dose levels of 0, 50, 500 and 5000 ppm. One litter per dam was produced in each generation.

Mean test substance consumption for the F0 males was 4, 37 and 362 mg/kg/day and for F0 females was 4, 43 and 41 4 mg/kg/day during the premating period, 3, 34 and 323 mg/kg/day during gestation and 8, 78 and 610 mg/kg/day during lactation, for the 50, 500, and 5000 mg/kg/day groups, respectively. Because all surviving offspring of the F0 animals in the 5000 ppm g roup were euthanized on PND 21 due to pup mortality and a high incidence of total litter loss among the dams, no offspring of the F0 animals in the 5000 ppm group were selected for the F1 generation. Mean test substance consumption for the F1 males was 4 a nd 41 mg/kg/day and for F1 females was 5 and 52 mg/kg/day during the premating period, 3 and 34 mg/kg/day during gestation and 8 and 79 mg/kg/day during lactation, for the 50 and 500 mg/kg/day groups, respectively.

Three additional groups of female rats (10/group) were included in this study for evaluation of clinical and histological pathology parameters. These non

- mated satellite animals were administered either basal diet or the test substance in the diet for at least 90 consecutive days; dietary conce ntrations were 0, 50 and 500 ppm. No differences in clinical pathology or histological parameters were observed when comparing control and test substance

- treated animal data. Mean test substance consumption for the satellite phase females in the 50 and 500 ppm groups was 4 and 42 mg/kg/day, respectively.

F0 and F1 parental survival was unaffected by test diet administration at all exposure levels. No remarkable clinical findings were noted at any exposure level tested in the F0 or F1 generations.
Parental body weight and food consumption parameters were not adversely affected at exposureDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 91 of 105 

### levels of 50 and 500 ppm in either generation. At an exposure level of 5000 ppm (evaluated only in the F0 generation), test substance

- related reductions in mean body weigh t gain, food consumption and food efficiency were noted during the first month of test diet exposure, which resulted in lower mean body weights throughout the pre

- mating period (females) or entire generation (males). Lower mean food consumption was also no ted for the 5000 ppm group females throughout gestation and lactation.

There were no indications of adverse effects on reproductive performance in either the F0 or F1 generations. Male and female mating and fertility indices, male copulation indices, female conception indices, pre

- coital intervals, spermatogenic endpoints, lengths of the estrous cycle and gestation, and live litter size were similar in all exposure groups. No test substance

- related effects in gross pathology, organ weights or histopath ology were noted in F0 or F1 parental animals. Additionally, ovarian follicle counts for the test substance

- exposed F0 (5000 ppm, high

dose group) and F1 (500 ppm, high

- dose group) females were similar to the control group
values.

Test substance

- related e ffects on pre

- weaning offspring were noted at an exposure level of 5000 ppm (F1 pups) and included decreased pup survival during PND 0

- 1, 1

- 4 (pre

- selection),

7

- 14 and 14

- 21 (due primarily to 7 females with total litter loss), clinical signs of toxicity (p ale body, blackened ventral abdominal area, distended abdomen, uneven hair growth and desquamation) and lower body weights and weight gains during PND 1

- 21.

As a result of pup mortality and a high incidence of total litter loss among the F0 dams at 5000 ppm, all surviving offspring of the F0 animals in the 5000 ppm group were euthanized on PND 21; therefore, a dosage level of 5000 ppm group was not evaluated in the F1 generation. At 500 ppm, mean F 1 

### male and female pup body weights on postnatal days 14 a nd 21 were reduced approximately

- 6% to

- 9% of controls; female pup body weight was also reduced at week 18 (

- 7%). Hyperkeratosis was noted upon histological evaluation of the F1 pups in the 5000 ppm group that had gross skin lesions or clinical findings of desquamation or uneven hair loss/hair growth.

No test substance

- related effects on offspring survival, general physical condition, body weights, macroscopic pathology and organ weights were noted at exposure levels of 50 ppm for F1 or F2

pups. Mean ages and body weights on the day of attainment of balanopreputial separation and vaginal patency were unaffected by treatment in any group.

The parental NOAEL is 37 mg/kg/day and the parental LOAEL is 362 mg/kg/day based upon decreased body weight.

No reproductive toxicity was noted and the reproductive NOAEL is 362 mg/kg/day; the reproductive LOAEL was not attained.

The offspring NOAEL is 4 mg/kg/day and the offspring LOAEL is 37 mg/kg/day based upon decreased pup body weight in F 1 

### pups on po stnatal days 14 and 21 (both sexes) and at week 18 (females only).Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 92 of 105 

### This study is classified as acceptable/guideline and satisfies the guideline requirement for a reproduction study (OECD 416, OPPTS 870.3800, PMRA DACO 4.5.1).

870.4200a DCSA Chronic To xicity/Carcinogenicity in the Rat

In this combined chronic toxicity/carcinogenicity study (MRID 47899516, chronic toxicity and MRID 48358003, carcinogenicity), Sprague Dawley (Crl:CD®[SD]) rats were exposed to MON 52708 (purity 97.4%

- 97.7%; Lot/batch no GLP

- 0603

- 16958

- T) in the diet. Di etary concentrations were 0, 10, 100, 300, 1000 or 3000 ppm. Doses for the chronic toxicity phase were 0.6, 5.6, 16.9, 56.9, and 171.2 mg/kg/day for males and 0, 0.7, 6.9, 20.5, 68.2, and 206.2 mg/kg/day for females. Doses for the carcinogenicity phase w ere 0.5, 5.0, 14.6, 48.8, and 150.1 mg/kg/day in males and 0.6, 6.1, 18.4, 60.9, and 181.5 mg/kg/day in females. There were 50 male and 50 female rats in the 24 month carcinogenicity study and 20 male and 20 female rats in the 12 month chronic toxicity st udy.

All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed daily, and detailed physical examinations were performed weekly. Individual body weights and food consumption were recorded at least weekly fo r the first 13 weeks of the study, and at least once every four weeks thereafter. Ophthalmic examinations were performed during study weeks 2 and 51. Clinical pathology parameters were evaluated for the last 10 surviving animals/sex/group: hematology and s erum chemistry were evaluated during study weeks 12 and 25, and at the scheduled necropsy (study week 52); coagulation parameters were evaluated only at the scheduled necropsy (study week 52); and urinalysis parameters were analyzed during study week 25 an d at the scheduled necropsy (study week 52). Complete necropsies were conducted on all animals, and selected organs were weighed at the scheduled necropsy. Selected tissues were examined microscopically from animals in the control and 3000 ppm groups. Tiss ue masses (when present), pituitary glands, and gross lesions (when present)
were examined from all animals.

There were no toxicologically significant treatment related effects on mortality, clinical signs, body weight, food consumption, ophthalmology, cl inical chemistry, hematology, coagulation, urinalysis, or organ weights. There were no toxicologically significant effects noted for gross or microscopic pathology.

No significant toxicity occurred in this study and the NOAEL is 150 mg/kg/day, (1000 pp m dietary concentration) the highest dose tested. A LOAEL was not determined.

This study is classified acceptable/non

- guideline.

870.7485 DCSA Metabolism

A mixture of radio

- labelled and un

- labelled DCSA (5,560 dpm/μg) as a suspension in corn oil w as administered by oral gavage individually to six male rats (Sprague

- Dawley Crl:CD® (SD)) as a single dose at a target dose level of 100 mg/kg bw (MRID 47899502). Approximately 2 mL/kg bw of dose suspension and approximately 250 μCi/kg bw of radioactivit y were administered to
each animal. Rats were 57

- 59 days old and weighed 229

- 266 g at the time of dosing.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 93 of 105 

### DCSA was poorly metabolized in the rat and was excreted largely unchanged primarily in urine. A summary of the distribution of radioactive residu es in urine, cage wash, and faeces is given in
Table 5.8

- 5. Unchanged DCSA accounted for approximately 82% of the administered dose. Two glucuronide conjugates of DCSA were identified, differing only in the position of glucuronidation (carboxyl moiety or phenol moiety). The position of glucuronidation of the metabolites was determined by their distinctive MS/MS fragmentation patterns

– fragmentation by loss of CO 2 

### from the phenolic glucuronide indicated a free aromatic carboxyl group in that metabolite. DCSA phenolic and carboxyl glucuronides accounted for approximately 10% and 5%, respectively, of the administered dose. Several other very minor metabolites were observed, none of which constituted more than 1% of the dose. In total, more than 96% of th e dose was identified.

A. 5 Inha lation Studies HEC/HED Result s

Inhalation studies in Wistar rats for 6 hours/day for 5 days/week for 28 days

Dicamba Acid

MMAD = 1.7

- 2.1 μm, GSD = 1.8

- 1.9 μm, BW = 236 g, Pulmonary RDDR = 0.590 , NOAEL = 0.005 mg/L, LOAEL = 0.050 mg/L

Occ upational handler: HEDs = 0.21 mg/kg/day and HEC = 2.21 mg/m 3



### Res idential handler: HED = 0.084 mg/kg/day and HEC = 2.95 mg/m 3



### Res idential outdoor post

- app lication: HEC = 2.95 mg/m 3



### Res idential indoor post

- app lication: HEC= 2.21 mg/m 3



### Res idential bystander: HEC = 0.53 mg/m 3



### Dicamba BAPMA Salt

MMAD = 1.9

- 2.1 μm, GSD = 1.2

- 3.4 μm, BW = 244 g, Extra

- Thoracic RDDR = 0.190 , NOAEL = NA, LOAEL = 0.0014 mg/L

Occ upational handler: HEDs = 0.020 mg/kg/day and HEC = 0.195 mg/m 3



### Res idential handler: HED = 0.007 mg/kg/day and HEC = 0.26 mg/m 3



### Res idential outdoor post

- app lication : HEC = 0.26 mg/m 3



### Res identia l indoor post

- app lication : HEC= 0.186 mg/m 3



### Res idential bystander: HEC = 0.047 mg/m 3Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 94 of 105 

### A. 6 Statistical Analysis of the Dicamba Acid Reproduction Study Pup Body Weights

A. 6 .1 Mean and Standard Deviation of litter

- specific average pup weight (males and females combined results)

Mean and Standard Deviation of litter

- specific average pup weight of F1 generation

Dose
(ppm) N Mean (SD) (grams)

PND 0 PND 4 PND 8 PND 12 PND 16 PND 21

0 25 6.29 (0.62) 10.07 (1.67) 19.05 (2.66) 30.35 (3.37) 41.53 (4.18) 59.65 (6.24)

500 28 6.29 (0.70) 9.89 (1.94) 18.63 (3.39) 29.33 (3.99) 40.01 (4.26) 57.75 (6.37)

1500 29 6.31 (0.60) 10.26 (2.02) 19.10 (2.91) 29.68 (3.83) 40.14 (5.02) 57.30 (7.09)

5000 26 5.87 (0.58) 9.09 (1.55) 16.00 (2.92) 24.43 (4.31) 33.61 (6.02) 45.41 (8.56)

Mean and Standard Deviation of litter

- specific average pup weight of F2 generations

Age Dose (ppm) N Mean (SD) (grams)

PND 0 PND 4 PND 8 PND 12 PND 16 PND 21

F2A 0 15 6.59 (0.63) 11.59 (1.23) 21.56 (1.79) 33.06 (2.80) 44.49 (3.57) 64.95 (4.09)

500 17 6.43 (0.64) 10.75 (2.04) 20.18 (3.44) 31.12 (4.23) 42.62 (4.63) 62.48 (6.89)

1500 12 6.40 (0.67) 10.41 (2.11) 19.43 (3.46) 30.23 (3.62) 40.68 (4.43) 58.44 (6.42)

5000 19 6.10 (0.67) 10.38 (1.67) 18.06 (2.90) 26.63 (3.73) 34.06 (4.46) 47.89 (6.77)

F2B 0 14 6.56 (0.64) 10.61 (1.76) 20.05 (3.38) 31.45 (4.09) 43.30 (5.32) 61.76 (6.86)

500 16 6.61 (0.73) 10.49 (1.68) 19.13 (3.33) 30.40 (4.60) 41.69 (5.63) 59.77 (7.22)

1500 14 6.69 (0.60) 10.21 (1.24) 18.16 (2.80) 27.56 (4.62) 37.55 (5.79) 52.87 (8.42)

5000 19 6.12 (0.68) 9.69 (1.98) 16.27 (2.90) 23.82 (4.04) 30.50 (3.95) 43.22 (6.33)



### Pup Body Weight Statistical Analysis Compared to the MARTA (Middle Atlantic Reproduction and Teratology Association) Historical Control Database

The results show that the PND 0 pup body weights for the MARTA histori cal control mean of 6.33 grams are statistically different than the 95% confidence intervals for F1 generation at 5000 ppm and F2B generation at 1500 ppm. However, only in the F1 generation at 5000 ppm is the pup body weight considered adverse at PND 0 since it is a decrease of 7.2% , before the lactation phase . In the F2B generation at 1500 ppm, the pup body weight is above the historical control

average, thus not considered adverse. The concurrent control PND 0 pup body weights in the dicamba acid study were statistically identical to the MARTA historical control data base PND 0
values.

The results show that the PND 21 pup body weights for the MARTA histo rical control mean of 49.33 grams is statistically different than the 95% confidence intervals for all doses except the F2A generation at 5000 ppm and F2B generation at 1500 ppm. The pup body weights are only
considered adverse in the F1 and F2B generation s at 5000 ppm, since the pup body weights areDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 95 of 105 

### both decreased by over 5% (i.e.

- 7.9% and

- 12.4%, respectively) and statistically significant,
relative to the MARTA historical control data.

At the 5000 ppm dose, there were adverse decreases in the F1 pup bo dy weights at PND 0 before the lactation phase. The WIL Research Laboratories historical control database supported the MARTA database conclusions that the dicamba acid reproduction study pup body weights were still above average values at the 500 ppm and 1500 ppm doses and only below average weights at the 5000 ppm dose (DCSA reproduction study, MRID 47899517).Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 96 of 105 

### A. 6 .2 Statistical Report: Dicamba

- a reproduction study

– Analysis of litter

- specific average pup weight s versus study concurrent control groups

Statistical methods Repeated

- Measures Analysis of Variance (mixed

- effects models) was used to analyze the litter

specific average pup weight of F1 and F2 generations on a per dam basis. (Litters of F1 generation were identified by the F0 dams’ i dentification numbers, and litters of F2 generation were identified by the F1 dams’ identification numbers.) Since the individual pup body weights were not provided in the registrant’s submission and the body weight of each of pups may be affected by th e number of pups in a given dam’s litter, the number of live pups in a dam on each measurement day was included in the model as covariate. Also, the number of pups in a dam’s litter was standardized on post

- natal day 4, so number of pups on day 0 (i.e, nu mber of live pups born) was used as covariate for the measurement on post

natal day 4. (Results show that for each pup increase in the number of live pups in a litter, the F1
litter

- specific average pup weight decreases by 0.082 grams and F2 litter

- specif ic average pup weight decreases by 0.090 grams).

In the analysis of F1 litter

- specific average pup weight, the model incorporates dose, day, interaction between dose and day, and number of live pups in the litter on the measurement day.
To account for th e correlation between measurements on different post

- natal days of same litter, an unstructured (UN) covariance matrix was selected (which has smaller Akaike Information
Criterion or AIC value compared to compound symmetric (CS) covariance matrix and

autor egressive lag(1) correlation matrix (AR(1)).Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 97 of 105 

### In the analysis of F2 litter

- specific average pup weight, the final model includes age (young: first litter/having pups at young age and old: second litter/having pups at an older age), dose, day,
interaction b etween dose and day, interaction between age and day, and number of live pups in each specific litter on the measurement day. The three

- way interaction “age

- day

- dose” and two

way interaction between “age

- dose” were not significant and were not kept in the final model. Multiple covariance matrices were considered (UN@UN (not convergence), UN@CS, UN@AR(1), and heterogeneous/different UN for each Age). The heterogeneous covariance matrices (i.e., different UN covariance for each age) were selected based the criterion of lower
AIC value.

Results:
Table A.6.2.a presents the results of comparison of the F1 litter

- specific average pup weight.
The F1 litter

- specific average pup weight associated with the high dose (5000 ppm) was significantly lower than the co ntrol on post

- natal days 0, 4, 8, 12, 16, and 21 (

- 6.4%,

- 9.4%,

- 16.2%,

- 19.6%,

- 19.2%, and 24%, respectively). The mid

- and low

- dose groups (1500 ppm and 500 ppm, respectively) did not differ significantly from the control group. Figure 1 presents the

p redicted curves and observed means of litter

- specific average pup weight. As can be seen and was confirmed with the Dunnett’s test, the average pup weight in the high

- dose group differs significantly from that of the control group.

In the analysis of F2 litter

- specific average pup weight data in which dams gave birth at both “young” or F2A and “old” or F2B ages, the interaction “dose*age” was not significant (p

- value > 0.05 and this term was thus not kept in the final model); this indicates that the dose effect (of same dose level on same given post

- natal day) on litter

- specific average pup weight was not affected by the dam’s age . Therefore, there is a single common dose effect on litter

- specific average pup weight (on a specific post

– natal day) and th is can be used to appropriately represent the dose effect (on a specific post

– natal day) at either age (“young” vs. “old”) of the dam. However, the significant “dose*day” interaction indicates that dose effects on litter

- specific average pup weight were di fferent between post

- natal days. Therefore, it is necessary for the
dose effects to be estimated

--- and e valuated

-- separately on each post

- natal day. (The significant age*day interaction indicates that the effects of post natal day on litter

- specific average pup weight varied between the two ages of the dam (young and old). Note that this day effect is not related to dose effect).

Table A.6.2.b presents the results of comparisons of common litter

- specific average pup weight between the dosed groups and control group. The litter

- specific average pup weight in mid

- dose group was not significantly different from the control group on post

- natal day s 0, 4, and 8; however, the litter

- specific average pup weight in mid

- dose group was significantly lower compared to the control group on post

- natal days 12, 16, and 21 (

- 9.3%,

- 9.9%, and

- 11.2%, respectively). The litter

- specific average pup weight in high dose group was significantly lower than the control on post

- natal days 0, 4, 8, 12, 16, and 21 (

- 7.8%,

- 9.2%,

- 17.1%,

- 21.5%,

- 26.1%, and

- 27.4%, respectively). No significant difference was seen on any post

- natal day for
the low dose group compared to the control.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 98 of 105 Table A.6.2.a: Results of comparison of litter

- specific average pup weight of F1 generation

_Name_ DOSE day0 day4 day8 day12 day16 day21

LSMean (SE) 0 6.60 (0.10) 10.38 (0.32) 18.88 (0.60) 30.18 (0.78) 41.36 (0.98) 59.47 (1.42)

500 6.63 (0.09) 10.23 (0.31) 18.44 (0.56) 29.14 (0.73) 39.82 (0.93) 57.56 (1.35)

1500 6.75 (0.10) 10.69 (0.30) 18.93 (0.55) 29.51 (0.72) 39.97 (0.91) 57.13 (1.32)

5000 6.18 (0.10) 9.40 (0.32) 15.83 (0.58) 24.26 (0.76) 33.43 (0.96) 45.21 (1.40)

Diff (SE) 500 vs.0 0.02 (0.13)

- 0.16 (0.44)

- 0.43 (0.82)

- 1.04 (1.07)

- 1.53 (1.35)

- 1.91 (1.96)

1500 vs.0 0.15 (0.13) 0.31 (0.44) 0.05 (0.81)

- 0.67 (1.06)

- 1.38 (1.34)

- 2.34 (1.94)

5000 vs.0

- 0.42 (0.13)

- 0.98 (0.45)

- 3.05 (0.83)

- 5.92 (1.09)

- 7.93 (1.38)

- 14.26 (1.99)

Percent (%) 500 vs.0 0.36

- 1.51

- 2.30

- 3.44

- 3.71

- 3.21

1500 vs.0 2.24 2.98 0.27

- 2.22

- 3.35

- 3.94

5000 vs.0

- 6.39

- 9.43

- 16.16

- 19.60

- 19.17

- 23.98

raw p

- value 500 vs.0 0.851 0.726 0.597 0.334 0.259 0.332

1500 vs.0 0.241 0.484 0.949 0.530 0.304 0.230

5000 vs.0 0.001 0.033 0.000 0.000 0.000 0.000

Dunnett p

value 500 vs.0 0.995 0.970 0.909 0.640 0.527 0.638

1500 vs.0 0.497 0.819 1.000 0.860 0.597 0.478

5000 vs.0 0.004 0.083 0.001 < 0.001 < 0.001 < 0.001

Table A.6.2.b: Results of comparison of litter

- specific average pup weight of F2 generations

_Name_ DOSE day0 day4 day8 day12 day16 day21

LSMean (SE) 0 6.92 (0.09) 11.42 (0.28) 20.56 (0.55) 32.01 (0.73) 43.57 (0.86) 62.88 (1.21)

500 6.91 (0.09) 10.86 (0.27) 19.34 (0.52) 30.31 (0.68) 41.76 (0.81) 60.59 (1.14)

1500 6.80 (0.10) 10.69 (0.30) 18.89 (0.58) 29.05 (0.77) 39.27 (0.92) 55.86 (1.29)

5000 6.38 (0.08) 10.37 (0.25) 17.05 (0.48) 25.13 (0.64) 32.19 (0.76) 45.66 (1.06)

Diff (SE) 500 vs.0

- 0.02 (0.12)

- 0.56 (0.38)

- 1.22 (0.75)

- 1.71 (0.99)

- 1.82 (1.17)

- 2.29 (1.65)

1500 vs.0

- 0.12 (0.13)

- 0.73 (0.41)

- 1.67 (0.80)

- 2.96 (1.05)

- 4.30 (1.25)

- 7.02 (1.76)

5000 vs.0

- 0.54 (0.12)

- 1.06 (0.37)

- 3.51 (0.73)

- 6.88 (0.96)

- 11.38 (1.14)

- 17.22 (1.60)

Percent 500 vs.0

- 0.22

- 4.90

- 5.91

- 5.33

- 4.17

- 3.65

1500 vs.0

- 1.75

- 6.41

- 8.11

- 9.26

- 9.87

- 11.16

5000 vs.0

- 7.78

- 9.24

- 17.05

- 21.49

- 26.12

- 27.39

raw p

- value 500 vs.0 0.901 0.146 0.105 0.084 0.122 0.165

1500 vs.0 0.344 0.074 0.037 0.005 0.001 0.000

5000 vs.0 0.000 0.005 0.000 0.000 0.000 0.000

Dunnett p

- value 500 vs.0 0.999 0.327 0.244 0.200 0.279 0.363

1500 vs.0 0.657 0.177 0.093 0.014 0.002 < 0.001

5000 vs.0 0.000 0.013 < 0.001 < 0.001 < 0.001 < 0.001



### Supplemental Tables and Figures
Table A.6.2.c : SAS output table Type 3 Tests of Fixed Effects of the model analyzing F1 litter

specific average pup weightDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 99 of 105 Table A.6.2.c. Type 3 Tests of Fixed Effects

Effect Num DF Den DF F Value Pr > F

Dose 3 104 14.46 <.0001

Day 5 104 1584.91 <.0001

Dose*Day 15 104 13.42 <.0001

npup 1 104 79.25 <.0001

repeated Day/ subject =Dam t ype =un; [IDEALLY

– if individual pup weights were available

-- THE SUBJECT WOULD NOT BE LITTER

- SPECIFIC,

BUT PUP NESTED WITHIN LITTER

- SPECIFIC



### Table A.6.2.d. : S tatistical Analysis Software (S AS ) output table Type 3 Tests of Fixed Effects
of the mode l analyzing F2 litter

- specific average pup weight

Table A.6.2.d. Type 3 Tests of Fixed Effects

Effect Num DF Den DF F Value Pr > F

Day 5 380 1979.95 <.0001

Dose 3 76 30.38 <.0001

Age 1 45 8.71 0.0050

Dose*Day 15 380 23.67 <.0001

Age* Day 5 225 2.85 0.0161

npup 1 649 112.11 <.0001

repeated Day/ subject =dam type = un group = age;



### A. 6 .3 Dicamba

– a reproduction study a nalysis of F1 body weight post

- weaning period

Background

Table A.6.3.a below presents the available data of individual F1 generation pup body weight and
the time that the data were collected.

 The data analysis was done separately for the lactation period and post

- weaning period
because:

o body weight data were reported differently for the lactation period and post

weaning period and could not be combined (i.e., averaged male and female pup body weight per litter for the lactation period and individual body weights for each gender, but no litter information, for the post

- weaning period)

o For the statistics done for the lactation period, litter was the experimental subject, and number of live pups per litter was incorporated as a covariate into the analysis of lactation period; however

– for the post

- weaning perio d

-- each individual pupDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 100 of 105 

### served as the experimental subject (no litter and no number of live pups per litter information was made available)

 The individual body weight data of female pups and male pups in post

- weaning period should not be pooled together into one single analysis because there were two pups (1 male and 1 female) selected from each litter but the information to identify which pups were from the same litter was not available. In order to do a single analysis of both males and females, the li tter information must be available to account for the litter effects in the model. Table 1 below summarizes the key features of both data set available for the lactation period and for the post

- weaning period.

Table A.6.3.a: Available data of F1 pup body weight and the time the data were collected

Time Lactation Period (Post

- natal Day) Post

- weaning Period (Post

- natal Week)

0, 4, 8, 12, 16, and 21 4, 5, 6, 7, 8, and 9

Available
data Average pup body weight per litter

(all males and females together) Individual body weight of 1 male and 1 female per litter,
but no litter information was available The pups have median body weight within each litter

were selected



### Caution: Since pups for the post

- weaning period were not selected randomly but instead purposely selected as the pup closest to the median of body weight within each litter, there are limitations in the interpretation of the results from the analysis using post

- we aning body weight data. An effect that is statistically “not significant” at a given dose level does not necessarily mean that the dose had no significant effect on the pup body weight in general. It may be that the
animal with the lowest weigh t in a litte r which was not selected for collecting body weight data during the post

- weaning period might be the animal that is most affected by the dose level.

Statistical Methods
Linear mixed

- effects models were used to analyze the repeated

- measures body weight da ta of the pups collected during post

- weaning period. The model included Dose, Week (linear term), Week*Week (quadratic term), Week*Week*Week (cubic term), and interaction between Dose and Week. The quadratic Week*Week and cubic Week*Week*Week terms allow the models to properly account for the curvature in growth curves of the animals. Based on the AIC criterion (smaller is better), the selected models included random intercept (different pups had different body weight at beginning), random coefficient of week (different pups have different linear growth rate), and random coefficient of week*week (different pups have different curvatures between their growth curves).

Results During post

- weaning period, the F1 pups body weight of both median male and fema le in each litter in the mid dose and low dose were not significantly different from the control. However, this does not mean that the average pup body weight per litter (as in lactation period) in the mid
dose and low dose were not different from the con trol during the post

- weaning period.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 101 of 105 

### The median body weight of both male and female in each litter in the high dose group was significantly lower than the control during the post

- weaning period, except for the median body weight female in high dose group on week 9. Table A.6.3.b presents the mean and standard deviation of each group by week and gender. Table A.6.3.c and A.6.3.d present the body weight comparisons between the treated groups and the control group for male and female F1 pups, respectively. These comparisons were conducted using linear mixed

- effects models.

Table A.6.3.b: Mean (SD) of F1 body weight post

- weaning period

Gender Dose Mean (SD) (grams)

Week 4 Week 5 Week 6 Week 7 Week 8 Week 9

Female 0 91.93 (12.96) 132.46 (17.55) 170.96 (18.27) 200.43 (22.39) 229.50 (26.57) 255.32 (31.74)

500 91.11 (10.78) 134.61 (12.65) 173.68 (14.22) 203.07 (17.40) 231.96 (20.40) 254.21 (23.66)

1500 89.93 (11.48) 132.29 (13.53) 171.07 (17.17) 201.11 (19.05) 227.89 (19.98) 254.93 (20.57)

5000 75.64 (9.82) 114.79 (12.32) 155.32 (15.02) 186.86 (17.23) 216.00 (21.17) 241.29 (24.61)

Male 0 94.82 (16.78) 151.39 (23.04) 215.64 (27.06) 281.54 (32.25) 341.68 (34.98) 394.96 (40.08)

500 100.14 (12.00) 159.50 (17.92) 224.14 (19.92) 292.64 (24.37) 359.32 (27.84) 415.14 (30.58)

1500 100.39 (13.10) 157.37 (19.34) 228.74 (24.13) 297.64 (31.75) 362.29 (38.38) 419.71 (45.69)

5000 79.71 (16.49) 129.21 (22.37) 190.79 (28.79) 254.21 (35.77) 311.21 (46.56) 372.41 (42.88)

Table A.6.3.c: Results of comparison of male pup body weight post

- weaning period

_Name_ DOSE Week 4 Week 5 Week 6 Week 7 Week 8 Week 9

LSMean (SE) 0 94.60 (2.80) 150.55 (3.75) 214.38

(4.78) 280.50

(5.86) 343.32

(6.99) 397.24 (8.17)

500 100.56

(2.80) 158.80

(3.75) 224.93

(4.78) 293.34

(5.86) 358.45

(6.99) 414.67 (8.17)

1500 99.70 (2.80) 159.30 (3.75) 226.79

(4.78) 296.57

(5.86) 363.04

(6.99) 420.61 (8.17)

5000 79.58 (2.80) 131.50 (3.75) 191.31

(4.78) 253.41

(5.86) 312.21

(6.99) 362.11 (8.17)

Diff (SE) 500 vs.0 5.96 (3.96) 8.25 (5.27) 10.55 (6.74) 12.84 (8.28) 15.13 (9.87) 17.43 (11.47)

1500
vs.0 5.10 (3.96) 8.75 (5.27) 12.41 (6.74) 16.06 (8.28) 19.72 (9.87) 23.37 (11.47)

5000

vs.0 - 15.02 (3.96)

- 19.04 (5.27)

- 23.07 (6.74)

- 27.09 (8.28)

- 31.11 (9.87) - 35.13 (11.47)

Percent 500 vs.0 6.30 5.48 4.92 4.58 4.41 4.39

1500

vs.0 5.39 5.81 5.79 5.73 5.74 5.88

5000
vs.0 - 15.88

- 12.65

- 10.76

- 9.66

- 9.06

- 8.84

raw p

- value 500 vs.0 0.133 0.118 0.119 0.122 0.126 0.130

1500
vs.0 0.198 0.098 0.067 0.053 0.047 0.042

5000
vs.0 <0.001 <0.001 0.001 0.001 0.002 0.002Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 102 of 105 Table A.6.3.c: Results of comparison of male pup body weight post

- weaning period

_Name_ DOSE Week 4 Week 5 Week 6 Week 7 Week 8 Week 9

Dunnett p

value 500 vs.0 0.305 0.275 0.275 0.282 0.290 0.298

1500

vs.0 0.429 0.231 0.163 0.133 0.117 0.108

5000

vs.0 0.001 0.001 0.002 0.003 0.005 0.007

Table A.6.3.d: Results of comparison of female pup body weight post

- weaning period

_Name_ DOSE Week 4 Week 5 Week 6 Week 7 Week 8 Week 9

LSMean (SE) 0 92.00 (2.18) 134.32 (2.47) 170.76

(2.93) 202.27

(3.48) 229.83

(4.11) 254.39

(4.79)

500 90.61 (2.18) 133.45 (2.47) 170.41

(2.93) 202.45

(3.48) 230.53

(4.11) 255.61

(4.79)

1500 90.07 (2.18) 132.73 (2.47) 169.51

(2.93) 201.37

(3.48) 229.28

(4.11) 254.18

(4.79)

5000 74.75 (2.18) 117.87 (2.47) 155.10

(2.93) 187.42

(3.48) 215.77

(4.11) 241.13

(4.79)

Diff (SE) 500 vs.0

- 1.39 (3.07)

- 0.87 (3.44)

- 0.35 (4.08) 0.18 (4.89) 0.70 (5.80) 1.22 (6.76)

1500

vs.0 - 1.93 (3.07)

- 1.59 (3.44)

- 1.24 (4.08)

- 0.90 (4.89)

- 0.56 (5.80)

- 0.21 (6.76)

5000
vs.0 - 17.25

(3.07) - 16.45 (3.44)

- 15.65 (4.08)

- 14.86 (4.89)

- 14.06 (5.80)

- 13.26 (6.76)

Percent 500 vs.0

- 1.51

- 0.65

- 0.20 0.09 0.30 0.48

1500
vs.0 - 2.10

- 1.18

- 0.73

- 0.45

- 0.24

- 0.08

5000

vs.0 - 18.75

- 12.25

- 9.17

- 7.34

- 6.12

- 5.21

raw p

- value 500 vs.0 0.651 0.801 0.932 0.971 0.904 0.857

1500

vs.0 0.530 0.645 0.761 0.854 0.924 0.975

5000
vs.0 <0.001 <0.001 <0.001 0.003 0.016 0.051

Dunnett p

value 500 vs.0 0.942 0.989 >0.999 >0.999 0.999 0.996

1500
vs.0 0.865 0.939 0.981 0.996 0.999 >0.999

5000
vs.0 <0.001 <0.001 <0.001 0.007 0.042 0.127



### In the scatter

- plot of observed group means and predicted curves of each group for F1 male and F1 female, the observed group means of each dose group were close to the group predicted curve. This result indicates that the selected model was very good in its ability to accurately characterize and describe the growth of body weight of the animals during the post

- weaning period.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 103 of 105 

### Supplemental Tables and Figures

Table A.6.3.e: SAS output table of Solution Fixed Effects in the analysis of male pup data

Effect Dose Estimate Stand. Error DF t Value Pr > |t|

Intercept 61.5338 13.0441 108 4.72 <.0001

Week

- 48.5249 6.3657 108

- 7.62 <.0001

Week*Week 17.9273 0.9861 111 18.18 <.0001

Week*Week*Week

- 0.9323 0.05021 332

- 18.57 <.0001

Dose 500

- 3.2160 4.7512 332

- 0.68 0.4990

Dose 1500

- 9.5165 4.7528 332

- 2.00 0.0461

Dose 5000 1.0696 4.7516 332 0.23 0.8220

Dose 0 0

. . . . Week*Dose 500 2.2935 1.6641 332 1.38 0.1691

Week*Dose 1500 3.6541 1.6642 332 2.20 0.0288

Week*Dose 5000

- 4.0227 1.6641 332

- 2.42 0.0162

Week*Dose 0 0

. . . . Note: the linear growth rate of mid dose was significantly higher than the control and the linear growth rate of high dose was significantly

lower than the control.

Table A.6.3.f: SAS output table of Type 3 Tests of Fixed Effects in the analysis of male pup data

Effect Num DF Den DF F Value Pr > F

Week 1 108 58.46 <.0001

Week*Week 1 111 330.50 <.0001

Week*Week*Week 1 332 344.85 <.0001

Dose 3 332 2.01 0.1127

Week*Dose 3 332 8.15 <.0001

Table A.6.3.g: SAS output table of Solution Fixed Effects in the analysis of female pup data

Effect Dose Estimate Stand. Error DF t Value Pr > |t|

Intercept

- 155.24 12.8583 108

- 12.07 <.0001

Week 80.6063 6.2118 108 12.98 <.0001

Week*Week

- 5.3386 0.9758 111

- 5.47 <.0001

Week*Week*Week 0.1599 0.04982 334 3.21 0.0015

Dose 500

- 3.4838 4.9228 334

- 0.71 0.4796

Dose 1500

- 3.3088 4.9219 334

- 0.67 0.5019

Dose 5000

- 20.4414 4.9219 334

- 4.15 <.0001

Dose 10000 0

. . . . Week*Dose 500 0.5229 1.1028 334 0.47 0.6357

Week*Dose 1500 0.3440 1.1027 334 0.31 0.7552

Week*Dose 5000 0.7979 1.1027 334 0.72 0.4698

Week*Dose 10000 0

. . . .
Note: the growth curve of high dose was significantly lower (shifted down) than the control.Dicamba Human Health Risk Assessment DP No. D378366, D404917

Page 104 of 105 Table A.6.3.h: SAS output table of Type 3 Tests of Fixed Effects in the analysis of male pup data

Effect Num DF Den DF F Value Pr > F

Week 1 108 172.18 <.0001

Week*Week 1 111 29.93 <.0001

Week*Week*Week 1 334 10.31 0.0015

Dose 3 334 7.03 0.0001

Week*Dose 3 334 0.18 0.9073



### Appendix B . Physical/Chemical Properties

Table B.1. Physicochemical Properties of the Technical Grade Test Compound: Dicamba.

Parameter Value Reference
Melting point 114

- 116  C (PAI)

90

- 100  C (87% TGAI) Residue Chemistry Chapter of the Dicamba RED (D317699, C. L. Olinger, 12/20/2005). pH 2.5

- 3.0 (87% TGAI)
Density 1.57 g/mL at 25  C (87% TGAI)
Water solubility 0.5 g/100 mL at 25  C (PAI)
Solvent solubility g/100 mL at 25  C (PAI)
dioxane 118.0
ethanol 92.2 isopropyl alcohol 76.0 methylene chloride 26.0

acetone 17.0
toluene 13.0 xylene 7.8 heavy aromatic naphthalene 5.2
Vapor pressure 3.4 x 10

- 5 mm Hg at 25  C (PAI)
Dissociation constant, pK a 1.97 (PAI)
Octanol/water partition coefficient, Log(K OW ) 0.1 (PAI)
UV/visible absorption spectrum neutral: 511 (275 nm) acidic (pH 0

- 1): 1053 (281 nm) basic (pH 13

- 14): 469 (274 nm)



### Appendix C

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from
Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the ARTF database; and the Outdoor Residential Exposure Task Force (ORETF) database

, are (1) subject to ethics review pursuant to 40 CFR 26, ( 2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, ca n be found at the Agency website 13



### .

13 http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- handler

- exposure

- data and http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- post

- application

- exposureDicamba Human Health Risk Assessment DP No. D378366, D404917

Page 105 of 105 

### Appendix D

. International Residue Limits Summary

Dicamba (029801, 029802, 029806, 128931, 128944 & 129043; 01/16/2013) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex 3

40 CFR 180.227: Plant: Compliance with the tolerance levels is to be determined by measuring only the residues of dicamba, 3,6

- dichloro

- 0

- anisic acid, and its metabolites, 3,6

- dichloro

- 5

- hydroxy

- 0

- anisic acid, and 3,6

- dichloro

- 2

- hydroxybenzoic acid, calculated as the stoichiometric equivalent of dicamba benzoic acid, 3,6

- dichloro

- 2

- methoxy

- , including the
metabolite benzoic acid, 2,5

- dichloro

- 3

- hydroxy

- 6

- methoxy

Plants: Dicamba
Animals:
sum of dicamba and 3,6

- di chlorosalicylic acid (DCSA) expressed as
dicamba.
The residue is not
fat

- soluble.

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex 3
Cotton, undelinted seed 3 0.04 cotton seed (*) Cotton, gin byproducts 70 Soybean, forage 60 Soybean, hay 100

Completed: M. Negussie; 01/17/2013

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

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

3 * = absent at the limit of quan titation; 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 have n ot been finalized by the CCPR and the CAC.