Dicamba Human Health Risk Assessment DP No. 0 378366, 0 4049 17 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: March 29, 201 6 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Dicamba and Dicamba BAPMA Salt: Human-Health Risk Assessment for 

Proposed Section 3 New Uses on Dicamba-tolerant Cotton and Soybean 

PC Cod e: 02980 1. 128931. 029802, 029806. 128944. 

029803. I 0009-1 & 129043 

OP Barcode: 0 378366. 040491 7, 0402514. 042 1306. 

0402551 

Decision No.: 43 2752. 467997. 4637 10 

Petition No.: 2F8067 & OF7725 

Registration No.: 524-582-M l69 1. 524-ANO & 7969-GUL 

Regulatory Action: Section 3 & R 170 

Risk Assessment Type: Single Chemical. Aggregate 

TXR No.: NA 

Case No.: 0065 

CAS No.: 19 18-00-9 

MRID No.: NA 40 CFR: § 180.227 

FROM: Wi lliam Jrwin, PhD, DABT, To~.-·c ~~t/Ri 

Alexandra Gavelek, Biologist ;( fl-_ · 

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Jess Rowland, Risk se ~~ (RARC) Reviewer 

Jeff Dawson, RARC Reviewer CJA/L. __ Jf. ____-

Grant Rowland f vr-yv------ Registration Division 

Herbicide Branch (7505P) 

Page I of 105 
Dicarnba Human Health Risk Assessment DP No. 0 378366, 04049 17 

1.0 Executive Summary ....................................................................................................................................... 4 

2.0 HED Recommendations ................................................................................................................................. 7 

2. 1 Data Deficiencies ........................................................................................................................................ 7 

2.2 Tolerance Considerations .......................................................................................................................... 7 

2.2. 1 Enforcement Analytical Method ...................................................................................................... 7 

2.2.2 Recommended Tolerances ................................................................................................................ 7 

2.2.3 Revisions to Petitioned-For Tolcrances ........................................................................................... 8 

2.2.4 In ternational Ha rmonization ........................................................................................................... 8 

2.3 Label Recommendations ........................................................................................................................... 8 

2.3.1 Recommendations from Residue Revicws ....................................................................................... 8 

2.3.2 Recommendations from Occupational Assessment ........................................................................ 9 

2.3.3 Recommendations from Residentia l Assessment ........................................................................... 9 

3.0 

3. 1 

3.2 

3.3 

3..t 

3.5 

4.0 

4.1 

4.2 

Introduction .................................................................................................................................................... 9 

C hemical Idcntity ....................................................................................................................................... 9 

Physical/Che1n ical Characteristics ......................................................................................................... I 0 

Pesticide Use Pattern ............................................................................................................................... 11 

Anticipated Exposure Pa thways ............................................................................................................. 17 

Consideration or Environmental Justice ................................................................................................ 18 

Hazard C haracterization a nd Dose-Response Assessment ....................................................................... 18 

T oxicology Studies Ava ilable for Ana lysis ............................................................................................. 19 

Absorption, Distribution, Metabolism, & Elimination (ADME) ......................................................... 20 

4.2. 1 Dermal Absorption .......................................................................................................................... 20 

4.3 Toxicological Effects ................................................................................................................................ 20 

4.4 Safety Factor for In fa nts and Children (FQPA Safety Factor) ........................................................... 22 

4.4.1 Completeness or the Toxicology Database .................................................................................... 23 

4.4.2 Evidence or Neurotoxicity ............................................................................................................... 24 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or You ng Animal.. ............................. 24 

4.4.4 Residual Uncerta inty in the Exposure Database .......................................................................... 24 

4.5 Toxicity Endpoint and Point of Departure Selections .......................................................................... 24 

4.5. 1 Dose-Response Assessment ............................................................................................................. 24 

4.5.2 Recommendation for Combining Routes of Exposu r es for Risk Assessment ............................ 26 

4.5.3 Cancer Classification a nd Ris k Assessment Recommendation ................................................... 26 

4.5.4 Summa ry or Points or Departure and Toxicity End points Used in Huma n Risk Assessment.. 27 

5.0 Dietary Exposure a nd Risk Assessment ..................................................................................................... 30 

5. 1 Metabolite/Degradate Residue Profile ................................................................................................... 30 

5. 1.1 Summa r y or Plant and Animal Metabolism Studies .................................................................... 30 

5. 1.2 Summar y or Environmental Degradation ..................................................................................... 3 1 

5.1.3 Comparison of Metabolic Pathways .............................................................................................. 31 

5.1 .4 Residues of Concern Summa ry and Rationale ............................................................................. 32 

5.2 Food Resid ue Profilc ................................................................................................................................ 33 

5.3 Water Residue Profile .............................................................................................................................. 34 

5.4 Dietary Risk Assessment ......................................................................................................................... 36 

5.4. 1 Description or Residue Data Used in Dietary Assessment ........................................................... 36 

5.4.2 Percent C rop Treated Used in Dietary Assessment ..................................................................... 36 

5.4.3 Acute Dietary Risk Assessment ...................................................................................................... 36 

5.4.4 Ch ronic Dietary Risk Assessrnent .................................................................................................. 37 

S..t.5 Cancer Dietary Risk Assessment ................................................................................................... 37 

S.4.6 Summa ry Table ............................................................................................................................... 37 

6.0 Residential (Non-Occupationa l) Exposure/Risk Characterization .......................................................... 37 

6. 1 Residential Handler Exposure ................................................................................................................ 38 

6.2 Post-Application Exposure ...................................................................................................................... 39 

6.3 Residential Risk Estimates for Use in Aggregate Assessment. ............................................................. 4 1 

6.4 Residential Bystander Post-application Inhalation Exposure .............................................................. 41 

6.4.1 Flux Data .......................................................................................................................................... 42 

6.4.2 Vola tilization Modeling and Ris k Assessment .............................................................................. 43 

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Dicamba Human Health Risk Assessment DP No. D378366, D404917

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

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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 dicambatolerant 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;

registration 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 were 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-hydroxybenzoic 

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 dicambatolerant soybean and cotton is understood. No 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 70 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 studies) and a 28-day inhalation study on the dicamba 

acid, as well as an OECD 422 developmental/reproduction study for the BAPMA base.
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Neurotoxic signs (e.g., ataxia, decreased motor activity, impaired righting reflex and gait) were 

observed in studies in rats and rabbits at doses over 150 mg/kg/day. The rat reproduction study 

and the developmental 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 reproductive toxicity study, offspring toxicity 

was manifested 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”. Mutagenicity 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. 

Following 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 dermal 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 intra-species 

uncertainty factors (UFs). An acute dietary risk assessment was not conducted for females 13-49 

since toxicity endpoints of concern attributable to a single dose (exposure) were not identified in 

the database. A chronic dietary risk assessment was conducted based on decreased body weights 

in the offspring 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 100 UFs. The POD selected would address the suite of toxic 

effects seen with the acid, salts and the metabolites of dicamba. Risk assessment for incidental 

oral exposure for children is based on a decreased pup weight in the reproduction study with 

dicamba acid. 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 residential 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 water) 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 assessment, the most highly-exposed population sub-group is children 1-2 years 

old at 42% of the cPAD.
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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 that 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 

includes only the inhalation route of exposure, and the post-application assessment includes only 

the incidental oral routes 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 residential 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 dicamba 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 exposure 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 3600 (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, the 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 labels is 24 hours. The 

occupational handler inhalation risk estimates 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 handler 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. 
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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 soybean 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 establishing 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 AM0691B-0297-2 which was submitted to FDA for inclusion into PAM volume II.

An 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 recovered 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 multiresidue testing data for the dicamba metabolites of concern 5-OH dicamba and DCSA (MRID 

48001304) and is currently under review by the Agency. 

Analytical standards for dicamba and its metabolites of concern are currently available in the 

EPA National Pesticide Standards Repository (personal communication with Theresa Cole, 

BEAD, 08/31/2015). The current stock of standards is set to expire on 02/01/2017. 

2.2.2 Recommended Tolerances
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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 tolerances.

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 (MRL) 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 adopts 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 

established 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 international 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 cotton petition (PP#2F8067) is required noting that no 

more than two (2) post-emergence applications may be made past the first open boll stage when 
Dicamba Human Health Risk Assessment DP No. D378366, D404917

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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 on 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 from Residential Assessment

None.

3.0 Introduction

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 wide 

variety of crop, livestock feed commodities and turf.

Monsanto has developed dicamba-tolerant varieties of soybean and cotton seeds capable of 

receiving dicamba treatments up to seven days before harvest. A dicamba mono-oxygenase 

(DMO) gene is introduced into dicamba-tolerant seeds to encode the enzyme dicamba Odemethylase to convert dicamba into the non-herbicide metabolite 3,6-dichlorosalicylic acid 

(DCSA), thus causing the plant to tolerate the herbicidal effect of dicamba. Table 3.1 shows the 

chemical 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-methoxyCAS # 1918-00-9

End-use product/EP M1691 Herbicide (EPA Reg. No. 524-582) and Engenia Herbicide (EPA Reg. 

No. 7969-GUL)
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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-methoxyCAS 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-hydroxyCAS 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-dihydroxyCAS 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 bioaccumulate in aquatic organisms because it is an anion at 

environmental pH values (pKa=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 halflife for dicamba was six (6) days with the formation of the intermediate degradate 3,6-dichloro2-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 (KOC=13.4) in the laboratory. Results from two acceptable field 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. 
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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 ae1/A)

Max. 

No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ae/A)

Combined 

Max. Seasonal 

Applic. Rate

(lb ae/A)

RTI2

(days)

PHI3

(days)

Use Directions 

and Limitations4

MON 88701 Cotton

M1691

4.0 lb ae/gal 

SL

[524-582]

Pre-plant, 

at planting, 

and Preemergence

Broadcast 

(20 gal/A)

1.0 NS5 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 prohibited.

Postemergence, 

Broadcast

(20 gal/A)

0.5 NS 2.0

Soybean

M1691

4.0 lb ae/gal 

SL

[524-582]

Pre-plant, 

at planting, 

and Preemergence

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 lb 
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Table 3.3.1. Summary of Directions for Use of Dicamba.

Formulation 

[EPA Reg. 

No.]

Applic. 

Timing, 

Type, and 

Equip.

Max. 

Applic. 

Rate

(lb ae1/A)

Max. 

No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ae/A)

Combined 

Max. Seasonal 

Applic. Rate

(lb ae/A)

RTI2

(days)

PHI3

(days)

Use Directions 

and Limitations4

Postemergence, 

Broadcast

(20 gal/A)

0.5 NS 1.0 dicamba a.e. per 

acre.

A second postemergence 

application may 

follow up to the 

R1 reproductive 

stage. Apply with 

ground equipment 

only; aerial 

application is 

prohibited.

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 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 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 flexibility 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 ae1/A)

Max. 

No. 

Applic

. per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ae/A)

Combined 

Max. 

Seasonal 

Applic. Rate

(lb ae/A)

RTI2

(days)

PHI3

(days)

Use Directions and 

Limitations4

Asparagus

Post-emergence 0.5 NS5 0.5 NA6 1 1
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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 ae1/A)

Max. 

No. 

Applic

. per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ae/A)

Combined 

Max. 

Seasonal 

Applic. Rate

(lb ae/A)

RTI2

(days)

PHI3

(days)

Use Directions and 

Limitations4

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-Preemergence 

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

PostEmergence 

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 interval 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.

Postemergence, 

Broadcast 

0.5 NS 2.0

Grass Grown for Seed

PostEmergence 

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 applications 
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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 ae1/A)

Max. 

No. 

Applic

. per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ae/A)

Combined 

Max. 

Seasonal 

Applic. Rate

(lb ae/A)

RTI2

(days)

PHI3

(days)

Use Directions and 

Limitations4

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)
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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 ae1/A)

Max. 

No. 

Applic

. per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ae/A)

Combined 

Max. 

Seasonal 

Applic. Rate

(lb ae/A)

RTI2

(days)

PHI3

(days)

Use Directions and 

Limitations4

Postemergence, 

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 preharvest 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 graze small 

grain within 7 days of 

treatment.

0.38 fall 

seeded 

barley

Postemergence, 

Broadcast -

Oats

0.125 –

up to 5-

leaf stage

0.125

Postemergence, 

Broadcast –

Wheat & 

Triticale

0.125 –

up to the 

6-leaf 

stage

0.5

Postemergence, 

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 preharvest 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.

Postemergence, 

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 

Interval
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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 ae1/A)

Max. 

No. 

Applic

. per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ae/A)

Combined 

Max. 

Seasonal 

Applic. Rate

(lb ae/A)

RTI2

(days)

PHI3

(days)

Use Directions and 

Limitations4

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 preharvest 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 postemergent treatments by 

aerial application.

- Do not apply with 

ammonium containing 

additives.

Postemergence, 

Broadcast 

0.5 2 1.0

Sugarcane

Postemergence, 

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 Farms
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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 ae1/A)

Max. 

No. 

Applic

. per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ae/A)

Combined 

Max. 

Seasonal 

Applic. Rate

(lb ae/A)

RTI2

(days)

PHI3

(days)

Use Directions and 

Limitations4

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 made 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 ions 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 application may result 

in dicamba and BAPMA salt reaching surface and ground water sources of drinking water. 
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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. Adults may be exposed 

to dicamba during pesticide applications in residential settings, and both adults and children may 

be exposed dermally in post-application scenarios on turf. Children 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 workers re-entering treated fields. 

Risk assessments have been previously prepared for the existing uses of dicamba. This risk 

assessment considers all of the aforementioned exposure pathways based on the 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 considered, including dicamba acid, the dicamba 

metabolites (DCSA, 5-OH dicamba, and DCGA), and the dicamba BAPMA counter ion. 

Separate assessments of dicamba acid, the dicamba metabolites (DCSA, 5-OH dicamba, and 

DCGA), and the BAPMA counter ion were not needed because the selected endpoints are 

protective of all forms. 

3.5 Consideration of Environmental 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) National 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 year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to 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 for 
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conventional crops. It is an auxin agonist 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. Dicamba-tolerant plants convert dicamba into 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 dicamba 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 (rat), carcinogenicity 

(mouse), chronic oral toxicity (dog)

Neurotoxicity Studies: acute and subchronic neurotoxicity (rat)

Inhalation Study: 28-day inhalation study (rat)

Immunotoxicity Study: Immunotoxicity (rat)

Mutagenicity battery 

Metabolism

DCSA Metabolite:

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/carcinogenicity (rat) 

Mutagenicity battery

Metabolism

DCGA Metabolite:

Sub-chronic Study: 28-day oral toxicity (rat)

Mutagenicity battery

Dicamba BAPMA Salt

Inhalation Study: 28-day inhalation study (rat)

90-Day Oral Study in Rats
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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 halflife 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 excreted in the urine. 

The compound is not metabolized nor accumulated by the tissues in adult, non-pregnant rats.

However, approximately 13% of dicamba in the urine is conjugated as the glucuronide. In plants, 

dicamba is converted to the DCSA and DCGA metabolites, which have dietary exposures.

The gavage plasma pharmacokinetic studies in rats showed that absorption of radiolabeled 

dicamba was rapid, with peak plasma concentrations found 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 concentration was nonlinear/disproportionate from one dose to the next dose and serum half-life increased with dose, 

which is consistent with saturation of excretion. Another plasma pharmacokinetic study suggests 

that dicamba is 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 dicamba and decreased its 

clearance rate. No significant treatment-related 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 is 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 gavage exposure. These clinical signs include

ataxia, decreased foot splay, decreased arousal and rears/minutes and decreased motor activity. 
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For dicamba acid and the BAPMA salt, signs consistent with neurotoxicity were observed in 

several gavage studies in rats 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 

level 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 study (hypoactivity, 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 micronucleus 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-chronic 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 study, 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 dicamba acid and the DCSA plant 

metabolite. The developmental 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 developmental studies for dicamba acid or dicamba BAPMA, 

there was no developmental toxicity up to the highest dose 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 of 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 were 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 were 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 onefourth 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 approximately10-fold lower than the dose (362 mg/kg/day) that caused 
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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 (37 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. Decreased 

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 (Middle-Atlantic Reproduction and 

Teratology Association, 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 offspring 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 dicamba DGA salts sub-chronic dermal toxicity studies, 

there were no adverse effects observed up to the limit dose (1000 mg/kg/day). However, the 

dicamba BAPMA salt was demonstrated to be more toxic than dicamba acid via the inhalation 

route. The inhalation study 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 with 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 positive for 

genotoxicity based on in vitro mammalian cell culture. 

Dicamba acid has a low acute toxicity via oral, dermal and inhalation route (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 dicamba BAPMA salt has a low acute toxicity via oral, 

dermal or inhalation route (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)
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The FQPA Safety Factor (SF) may be reduced (i.e. 1X) for acute and chronic 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 and 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 quantitative offspring susceptibility was observed in the 2-

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

the degree of concern for the susceptibility is low because there is a well-established 

NOAEL for offspring toxicity 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, decreased motor activity, impaired righting 

reflex and gait) were observed in multiple studies in 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 account 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 histopathological finding was seen in two 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 assessments were performed based on tolerance-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 residential 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 for assessing inhalation risks for the dicamba BAPMA

salt, the FQPA SF is retained in the form of a LOAEL to NOAEL factor (UFL) 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 and 
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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, rigidity 

upon handling, etc). After considering the available toxicity data, the agency determined that a 

DNT is not required, as described previously.

4.4.3 Evidence of Sensitivity/Susceptibility 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 reproduction study for the DCSA metabolite based on decreased pup weights. The 

degree of concern for the susceptibility is low because there is a well-established NOAEL for 

offspring toxicity in that study and DCSA has rapid clearance. Additionally, the current point of 

departures 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 which assumes that all commodities being consumed retain tolerance level 

residues. The drinking water estimates utilized conservative models. Therefore, the Agency 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 

assessment (D340156, 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, thus 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 metabolite. 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.
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Acute Dietary Scenarios: The rat developmental study for the dicamba BAPMA salt 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 demonstrating 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 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 single incidence of abortion in the rabbit developmental study 

occurred 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 to the NOAEL to obtain an 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 RfD (0.29 mg/kg/day).

Chronic Dietary Scenarios: 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 RfD. 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) is 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 Scenarios: The toxicology studies on the plant 

metabolites are not appropriate for this scenario since these metabolites are generated inside the 

plants and unavailable for incidental oral exposure. 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. 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. The Level of Concern (LOC) is a Margin 

of Exposure (MOE) of 100 which includes the 10X factor accounts for interspecies 

extrapolation, a 10X factor accounts for intraspecies variation, and a 1X FQPA SF.

Short, Intermediate and Long-Term Inhalation Scenarios: The dose and endpoint selected for 

dicamba acid and dicamba BAPMA risk assessment utilized the route-specific aerosol inhalation 

studies for each AI. For dicamba acid inhalation 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). 
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The dose and endpoint selected for the dicamba BAPMA salt inhalation risk assessment for short 

and intermediate term durations were based on the dicamba BAPMA salt inhalation toxicity 

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 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 applicable). For BAPMA salt, an 

additional 10X UFL 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 Scenarios: 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 component in the BAPMA salt and the BAPMA base component of 

the dicamba BAPMA salt is only 20% of the salt mass (and 28% on a molar basis), thus, the 

dicamba BAPMA salt is unlikely to have adverse dermal effects. In support, the acute dermal 

toxicity for the dicamba 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 BAPMA 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 assessment, 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 Classification and Risk Assessment Recommendation

In accordance with the EPA Final Guidelines for Carcinogen Risk Assessment (March 29, 2005), 

dicamba is classified as “not 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 induced 
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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 DCSA 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 UFA =10X

UFH =10X

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 study occurred at 

gestation day 22.

Chronic Dietary

(All populations)

Offspring NOAEL= 4

mg/kg/day

UFA =10X

UFH =10X

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 PND 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

UFA =10X

UFH =10X

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.
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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-, Intermediateand 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

UFA = 3X

UFH =10X

FQPA SF = 1X

Aerosol inhalation 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-, Intermediateand 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

UFA = 3X

UFH =10X

UFL = 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 adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = 

use of a short-term study for long-term risk assessment. 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 databases, there are a number of 

moderate severity cases reported and further 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 overall or strong associations with any 

specific type of cancer.

4.6.1 Incidents

For the Main 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 incidents 
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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 dicamba. 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 resolved 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 290 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 severity. Both of the high severity incidents involved intentional ingestion for selfharm 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 by 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) occurred 

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 Agricultural 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 31, 

2002 by linkage to state cancer registries. Poisson regression was used to estimate rate ratios and 
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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 statistically 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 estimates 

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 malonylglucoside (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 part 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). Metabolism 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 all 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 studies conducted on ruminants and poultry (MRID 43245201-2). The residues of 
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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 specify 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 Environmental Degradation

Dicamba is very soluble in water (6100 ppm) and very mobile (Koc = 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 metabolism is the main degradative process for dicamba. A single observed halflife 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 

dioxide 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 degradate 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 described above, however, an additional metabolite, 2-amino-3,6-
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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 Residues of Concern Summary and Rationale

The risk 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 the 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, the 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 toxicity 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 metabolite and the 5-OH dicamba metabolite found in nonresistant 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 thus was 

not added to the tolerance expression. The 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 the 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 

metabolite, 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-tolerant 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 which 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 radioactive 

residue (TRR), and is only detected in livestock feed items, not in human food items. Further, 
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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 balanced 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 included for tolerance expression and risk assessment 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 + DCSA1 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 

+ DCGA2

Livestock Dicamba + DCSA Dicamba + DCSA

Drinking Water NA3 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 the 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 adequately 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 detection at 

concentrations well below the previously established 10.0 ppm tolerance for non-resistant 
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soybean seed; therefore, the 10.0 ppm tolerance for soybean seed remains adequate. For the field 

trials provided on dicamba-tolerant cotton, detectable levels 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 recommended 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-side 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 respect 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 with established tolerances can be rotated for planting. 

Processing study data were provided and residues 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 drinking 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 drinking 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. Tables 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 ug/L (ppb), 
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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 from 
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applications of the BAPMA end-use product. This modeling found the 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 Risk 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 action 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. Dicamba 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 aggregate 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

For 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 percent 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 in 
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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 

population adjusted dose (aPAD) at the 95th percentile. The highest exposure and risk estimates 

were for all infants. At the 95th 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 for 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 Dietary1

(95th Percentile) Chronic Dietary2

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/A3 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-Occupational) Exposure/Risk Characterization
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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 SOPs1along 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 residential 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 products 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 

application 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 assumption 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 were taken from HED’s 

2012 Residential SOPs1. 

Exposure Duration: 

Residential handler exposure is expected to be short-term in duration. Intermediate-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-residentialpesticide
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The algorithms used to estimate exposure and dose for residential handlers can be found in the 

2012 Residential SOPs2.

Combining Exposures/Risk Estimates:

There is no potential hazard via the dermal route for 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 

Rate1

Area Treated or 

Amount Handled 

Daily2

Inhalation

Dose 

(mg/kg/day)5 MOE6

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/ft2 1000 ft2 0.0000063 11,000

Lawns/Turf, Liquid, Manuallypressurized handwand 0.018

0.05 lb ae/gallon 5 gallons

0.000056 1,200

Lawns/Turf, Liquid, Backpack 0.14 0.00044 160

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/ft2

1200 ft2 0.000013 5,200

Lawns/Turf, Granule, Spoon 0.087

100 ft2

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 ft2 = 0.0000344 lb ae/ft2

2 Based on HED’s 2012 Residential SOPs (http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/standardoperating-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 kg).

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 scenarios: 

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

Assessment of post-application exposure to liquid formulations is protective of exposure to solid 

formulations, 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 SOPs3. These lifestages are not 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 Post-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 postapplication exposure since the study was conducted at the maximum application rate being 

assessed, and predicted residues were consistent in three different site locations. Therefore, HED 

has used the predicted residue value of 0.15 μg/cm2from MRID 44959001 for risk assessment 

purposes. 

Residential 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 no potential hazard via the dermal route for dicamba. Only incidental oral risk estimates 

were quantitatively assessed. The incidental oral scenarios (i.e., hand-to-mouth and object-tomouth) should be considered inter-related and it is likely that they occur interspersed amongst 

each other across time, therefore, these scenarios are not combined. The granular 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 greater 

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-residentialpesticide
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ingestion scenario is short-term exposure only as the soil half-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 

Rate1

TTR 

(ug/cm2)

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 4,000,000

Turf- Granular Episodic Granular Ingestion 1% ai 0.09 320A

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. There 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-toMouth Postapplication 

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 Exposure
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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 dicambatolerant corn and soybean, and for the proposed 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 offgassing, emission 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 still 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 pesticides4and is also consistent with the recommendations 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 study6 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 21.1oC and 26.2oC, respectively. 

A circle in the zoysiagrass with a diameter of 40 m (~131 ft) was sprayed with 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. Application 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 minutes). 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 

acquired 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/2004/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/120309meetingminutes.pdf

6 Memo, D411382, 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, 

MSL0024798. Unpublished study prepared by Monsanto Company. 52p.
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The estimated 6 hr average flux from the Clarity® application on zoysiagrass was 0.4 (+/- 0.1) 

ng/m2/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 field. Based on modeling data using EPISuite and information provided in a BASF 

patent7, the volatility of the BAPMA salt is lower than that of the DGA salt. EPISuite estimated 

the vapor pressure of the DGA salt as 1.48E-11 mmHg at 25oC, and for BAPMA as 1.10E-21 

mmHg at 25oC. 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 dicamba 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 crop 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/m2/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 endpoints for dicamba and BAPMA were used in the 

volatilization assessment (dicamba acid: 530 ug/m3and LOC of 30; BAPMA salt: 50 ug/m3; 

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 assumption to compare the 6 hour average exposure from the model to 

the HEC calculated for 24 hours of exposure especially since 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 Volatilization Risk Estimates

The field volatility study suggests 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 Application: #20150210723. 

http://images3.freshpatents.com/pdf/US20150210723A1.pdf 
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exposure. Results of PERFUM modeling, however, indicate that airborne concentrations, even 

at the edge of the treated fields, are not of concern. The maximum proposed application rate of 1 

lb ae/A was assessed. There were no whole field and maximum field buffers estimated using 

PERFUM (i.e., risks 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 factors. Sprays that are released and do not deposit in the application area end up offtarget 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 exposures (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 products.

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 exposure 

that would be associated with spray drift. It should be noted that the 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 maximum 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 the 

application rate. A quantitative spray drift assessment for dicamba is not required because the 

maximum application rate to a crop/target site multiplied by the adjustment factor for drift of 

0.26 is less than the maximum direct spray residential turf application rate 1 lb ae/A9for 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/A
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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 edge 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 drift 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 situations 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 drinking 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 90th 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 exposure 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).

 

10http://www.agdrift.com/ 
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Table 6.5.1. Non-occupational Risk Estimates Resulting from Spray Drift for BAPMA Salt.

Crop/Rate Group Spray Type/ Nozzle Configuration Application 

Rate (lb ai/A)

Estimated 

TTRt (ug/cm2)

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/cm2.

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 various 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. Intermediate-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 adults 

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. The acute 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). 

The 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 Risk
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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 resulted 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. The

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 routespecific dermal studies and the inhalation effects were not systemic. As stated in the previous 

section, these results 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 LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

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 risk is comprised of dietary exposure only, from food and drinking 

water sources. The chronic dietary assessment in Section 5.4 represents chronic aggregate risk. 

The chronic dietary exposure assessment was conducted 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 not likely to be carcinogenic to humans, thus a quantitative aggregate 

cancer risk is not applicable and not assessed. This conclusion was based on the lack of findings 

in cancer studies in rats and mice which were tested at adequate dose levels to assess the 
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carcinogenicity of dicamba (TXR No. 0053647). Additionally, the DCSA metabolite had a lack 

of cancer findings in its rat 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 toxic 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 effects 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 event. 

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 equipment to sod, typical field crops, and high-acreage crops

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

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

crops

Occupational 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 Table11”, 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 website12. 

Area Treated or Amount Handled: 

Based on ExpoSAC Policy 9.1:

 The area treated for ground 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 pressure 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-data
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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 Appendix A of the ORE document.

Combining Exposures/Risk Estimates:

There is no potential hazard via the dermal route for dicamba. Only inhalation risk estimates 

were quantitatively assessed. 

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

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 Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

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 Surrogate 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/day) ÷ 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 PPE/ 

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.
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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 Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

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 1,900

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 2016).

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 Rate (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 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

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 210 420 110
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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 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

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 2016)

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 reentry 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 

or 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 Exposure
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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 labels 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-application 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 studies) 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 continue 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 

(TXR No.: 0056589)

Clock-Rust, M, Dicamba: Human-Health Risk Assessment for Proposed Section 3 New Uses on 

Sweet Corn (D340156)

Savoia, P, Dicamba. Acute and Chronic Dietary Exposure Assessments of Food and Drinking 

Water to Support the Use of Dicamba on Dicamba-Tolerant Cotton and Soybean for Amended 
Dicamba 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) Salt Formulation. (D408386 & D410346)

Savoia, P, Dicamba. Section 3 Registration for the Amended Use of Dicamba on DicambaTolerant Cotton. Summary of Analytical Chemistry and Residue Data (D408384)

Kamel, A. Dicamba. New use of dicamba on dicamba-tolerant soybean. Petition for 

establishment of new tolerances for soybean forage and soybean hay. (D384422)

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

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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 Required
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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 LD50 = > 2740 mg/kg III

870.1200 Acute dermal toxicity / rat 00241584 LD50 = > 2000 mg/kg III

870.1300 Acute inhalation toxicity / rat 00263861 LC50 = > 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 LD50 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 LD50 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 LC50 Males/females > 0.557 mg/L

(MMAD between 1.2 and 3.8μm, 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 weights 

decreased until death. Gross pathological abnormalities 

included dark-red discoloration, lung edema, encrusted nose. 

III
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OPPTS 870.2400-

OECD 405

Primary eye irritation / 

rabbit 

48599306 No corneal opacity or iritis.

All eyes positive for conjunctival irritation (chemosis score of 

2) at 1 hr; no positive scores for conjunctival 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 / rabbit 

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 SensitizationLocal 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 3H-thymidine 

incorporation for undiluted material). There was a statistically 

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 LD50 = 691 mg/kg III

BASF Test Acute dermal toxicity / 

rabbit

MSDS Sheet LD50 = 200 mg/kg II

BASF Test Acute inhalation toxicity / rat MSDS Sheet LC50 = 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.
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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= 150 mg/kg/day based on increased abortion, 

clinical signs (decreased motor activity, ataxia).

Developmental:

NOAEL= 62.5 mg/kg/day, 

LOAEL= 150 mg/kg/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.

Offspring:

NOAEL=136 mg/kg/day

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

the F1 generation at PND0/PND21 and F2B generation at 

PND21, relative to the MARTA historical control database.

Classified minimum
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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 observed 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 

Typhimurium

00143001 (1979)

Acceptable/Guideline

Negative, not mutagenic.

870.5395

Chromosome 

Aberration (CHO)

40321101 (1986)

0, 2330, 1170, 590, and 300 μg/mL

Acceptable/Guideline

Negative, chromosome aberrations were not induced in a 

cultured CHO cells at concentrations tested either with or 

without S-9 activation.

870.5550

Unscheduled 

DNA Synthesis 

(UDS)

00143001 (1979)

Acceptable/Guideline

Negative, no 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.
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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 Subchronic 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 urine 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

LD50 = 2641 mg/kg

wobbly gait at 2000 mg/kg

870.1100

DCGA Acute Oral Toxicity

47899505 (2009)

Acceptable/Guideline

LD50 = 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 decreased BW in 

males
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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 DevelopmentalReproduction 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 deaths
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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)

Maternal 

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), decreased 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

Maternal 

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 dose
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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 

(F0 generation)

F: 0, 4, 43, 414 mg/kg/day 

(F0 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 F1 pups on postnatal days 14 and 21 during 

lactation and week 18 in females. 

At 5000 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, did not induce gene mutation

870.5100

DCGA Bacterial gene 

mutation

47899514

Acceptable/Guideline

Negative, did not induce gene mutation

870.5100

Dicamba Acid

Bacterial gene mutation

47899525

Acceptable/Guideline

Negative, did 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, did not induce forward mutations at the HGPRT 

locus in CHO cells

870. 5300

Dicamba Acid HGPRT in 

Chinese hamster cells

47899526

Acceptable/Guideline

Negative, did not induce forward mutations at the HGPRT 

locus
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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

Chromosomal aberration 

assay in human 

lymphocytes

47899527

Acceptable/Guideline

Positive, the S9-activated portion of the assay should have 

been repeated

870.5375

Dicamba BAPMA

Chromosomal aberration 

assay in human 

lymphocytes

48718003

Acceptable/Guideline

Positive, clastogenic +/- S9 fraction

870.5385

DCSA

Chromosome aberration 

assay in rat bone marrow 

47899513

Acceptable/Guideline

Negative, did not cause an increase in the number of 

chromosome aberrations in rat bone marrow cells

870.5385

DCGA

Chromosome aberration 

assay in rat bone marrow 

47899515

Acceptable/Guideline

Negative, did 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, did 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, was 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 500 mg/kg or more, hunched posture and 

reduced general condition were observed
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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 

consumption

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 

F1 pups on postnatal days 14 and 

21. 

At 5000 ppm, high incidence of pup 

mortality
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(decreased pup weights) in the 

F1 and F2B generations 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 occurred, 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 

showing 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 signs occurred shortly 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 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 UFL applied to this 

LOAEL would result in a similar POD of 30 mg/kg. The selected POD will be protective of the 
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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 rabbit developmental study at the 

LOAEL occurred at gestation 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/kg/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 LOAEL = 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 findings 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): Dicamba 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 F2B pup weights at an Offspring LOAEL = 450 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: The endpoint was decreased pup weight 

in F1 and F2B generations of the dicamba acid reproduction study. The toxicology studies on the 

plant metabolites are not appropriate for this scenario since these metabolites are generated 

inside the plants and unavailable for incidental oral exposure. The developmental studies are not 
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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 life 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 other 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 factor 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 salt 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. 

Dicamba BAPMA Salt

Study Selected: Dicamba BAPMA Inhalation Study

MRID No.: 49441803

Executive Summary: See Appendix A
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Dose and Endpoint for Risk Assessment: NOAEL = NA based on ulcers and hyperplasia of the 

larynx at a LOAEL = 0.0014 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 BAPMA inhalation study is appropriate to use since workers will 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 applicable). For BAPMA salt, an 

additional 10X UFL 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 were 

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. In 
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females, decreased mean hemoglobin concentration (4%) and red blood cell counts (4%), and 

decreased mean corpuscular hemoglobin concentration (3%) were observed. Significant 

(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 effects 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 pigmentation 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 Dermal 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 fSD 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 animals 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 

animals 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 seen 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.
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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 white 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 doserelated incidence 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 systemic 

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. 0002B01BA251)] 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, lung 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 females); (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 minimal]; 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 0.050 mg/L based on minimal multifocal bronchiolealveolar 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 0.005 mg/L in males and 

0.005 mg/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 Toxicity
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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 toxicity 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 of 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 maternal 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 toxicity 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 of 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, rales, 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 ossification 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 18 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.
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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 mg/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 

righting 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. 

Significantly 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, the 

PND21 pup body weights for 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 versus 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 the 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 F1

males. For offspring toxicity, the NOAEL was 136 mg/kg/day and the LOAEL was 450

mg/kg/day based on decreased pup body weight during the F1 and F2B generations during 

lactation. 

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3800; OECD 416) for a two-generation reproduction study in the rat.
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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 parameters 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 compound. 

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 attained.

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 - Rat

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 and 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 showed 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 significant.

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 lymphomas in males (0/60, 0/60, 4/60 
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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 CochranArmitage trend test showed 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 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 at >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 the 

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).

870.4200b 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) weeks. 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 incidence 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 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 the incidences were within 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 dicamba 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 the 
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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 the 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 

decided 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 oil 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; decreased 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 persisted 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 neurotoxicity 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, 
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767.9 mg/kg/day for males and 0, 253.4, 472.0 or 1028.9 mg/kg/day for females, respectively) 

for 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 incidences 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 used 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 statistically 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 impaired 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 

righting 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). 

870.6300 Developmental Neurotoxicity Study

NA

A.4.8 Metabolism

870.7485 Metabolism - Rat

In a plasma kinetics study, (MRID 44609801), [phenyl-U-

-14C]- dicamba ( [14C]-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, 
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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 excessive 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 after 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 levels 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 increased 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 stopped and rats in each group received an equivalent gavage 

dose of 14C-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 

radioactivity 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 consistent 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 14C-dicamba (Lot No. 787-0102, >99% a.i., universally labeled 
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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 dicamba 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 14Cdicamba occurred within 0.5 hours while peak plasma concentration was reached at 1.0 hour in 

the probenecid/dicamba rats. However, 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 elimination 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 satisfies 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) Wistar 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 administered 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 108

SRBCs)/mL). On Day 29, all animals 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 

control 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 consumption 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 (cyclophosphamide)-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, mean anti-SRBC IgM titers 
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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 of toxicity database of 

dicamba including subchronic, chronic toxicity and reproduction studies showed no treatmentrelated 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 and 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) groups 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 macroscopic 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 weight 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/batchGLP-0603-16958-T) for 90-

days. Final dietary concentrations were 500, 3000, 6000 and 12000 ppm. Due to potential 

problems with palatability observed 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 the 
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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 entire 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). Hematology, 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 microscopically.

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 females 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 concluded 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 approximately 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, open 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 increased 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 glandular 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. 
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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 BAPMA 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 819 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 examination.

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 weights 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 were 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 significantly 

increased 33% at the high-dose. In both sexes at the high-dose, total protein and globulin levels 

were significantly decreased 5-16%. Therefore, under the conditions of this study, the 

LOAEL of Dicamba BAPMA Salt is 17266 ppm (1027 mg/kg bw/day in males 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, respectively).

This 90-day oral toxicity study in the rat is Acceptable / Guideline and satisfies the guideline 

requirement for a 90-day oral toxicity study (OCSPP 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/batchGLP-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 chemistry and urinalysis and 
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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 body 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 study. 

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 males 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 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.

870.3200 Dicamba IPA 21-Day Dermal Study in Rabbits
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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 inhalation 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 on 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. Microscopic 

examination of tissues showed that the test substance was a respiratory tract irritant with adverse 

effects 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 group (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 II, 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 alveoli 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 the 
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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 

groups. 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-reticulocellular 

hyperplasia in one or both of these lymph nodes was observed in males at the mid- and highexposure concentrations and in females at all three concentrations. Macrophage aggregates were 

observed in both sexes at the mid- and high-exposure concentrations. 

The LOAEL in Wistar rats was 0.0014 mg/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 parental 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 the 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-related 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 middose 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 unclear. Deaths occurred in the dams at 

500 mg/kg bw/day. Therefore, the parental systemic NOAEL is 25 mg/kg bw/day, and the 
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LOAEL is 100 mg/kg/day based on decreased motor activity and water consumption, 

results from the surviving animals. 

No animals in the high-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 clinical 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 six and seven 

litters with live fetuses in the low- and mid-dose groups, respectively. Although 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 behavior, and growth and development of the F1

offspring from conception to day 4 post-partum.

This study is Acceptable/ Non-Guideline and does satisfies the guideline requirement for a 

reproductive/developmental toxicity screening study (OCSPP 870.3650; OECD 422) in the rat. 

870.3700a Dicamba BAPMA Rat Developmental Study in Rats

In a developmental toxicity study (MRID 49441802), Dicamba BAPMA salt [84.7% w/w 

Dicamba BAPMA; 69.5% w/w Dicamba (acid equivalent), batch# 1781-6] was administered to 

25 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 (corresponding 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, numbers of corpora lutea, and numbers and distribution of live and dead 

fetuses and early and late resorptions were recorded. Fetuses were 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 also 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 highdose 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 

significantly 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% during GDs 6-10, -

7% during GDs 6-19. The 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. No 
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treatment-related effects on maternal cesarean section parameters were noted at any dose level 

for this study. 

The maternal LOAEL for Dicamba BAPMA salt in rats is 86 mg/kg bw/day 

(corresponding to 60 mg/kg bw/day Dicamba acid 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 Dicamba 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 lutea 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 did not exhibit a dose-response 

relationship. 

The developmental LOAEL for Dicamba 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 

Dicamba acid equivalent).

The developmental toxicity 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 through 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 from 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 articlerelated 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.
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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 clinical 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 (MRID47899518) 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:CD(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 individual 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 scheduled 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 mouth 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. 
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Evaluation of laparohysterectomy parameters in the 1000 mg/kg/day group 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 developmental 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 study 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 GLP0903-19699-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 gestation 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 received 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 effects 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 GLP0603-16958-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 recorded. 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. 
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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 related 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 could 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 developmental LOAELs were not determined.

Therefore, this 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 Rats

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 414 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 group 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 and 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 concentrations 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 exposure 
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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 weight 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 noted 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 histopathology were noted in F0 or F1 parental 

animals. Additionally, ovarian follicle counts for the test substance-exposed F0 (5000 ppm, highdose group) and F1 (500 ppm, high-dose group) females were similar to the control group 

values.

Test substance-related effects 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 (pale 

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 F1 male and female pup body weights on postnatal days 14 and 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 F1 pups on postnatal days 14 and 21 (both sexes) and at 

week 18 (females only).
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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 Toxicity/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. Dietary 

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 were 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 study. 

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 for 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 serum 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 and 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. Tissue 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, clinical 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 ppm 

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 was 

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 radioactivity were administered to 

each animal. Rats were 57-59 days old and weighed 229-266 g at the time of dosing. 
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DCSA was poorly metabolized in the rat and was excreted largely unchanged primarily in urine. 

A summary of the distribution of radioactive residues 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 CO2

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 the dose was identified. 

A.5 Inhalation Studies HEC/HED Results

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

 Occupational handler: HEDs = 0.21 mg/kg/day and HEC = 2.21 mg/m3

 Residential handler: HED = 0.084 mg/kg/day and HEC = 2.95 mg/m3

 Residential outdoor post-application: HEC = 2.95 mg/m3

 Residential indoor post-application: HEC= 2.21 mg/m3

 Residential bystander: HEC = 0.53 mg/m3

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

 Occupational handler: HEDs = 0.020 mg/kg/day and HEC = 0.195 mg/m3

 Residential handler: HED = 0.007 mg/kg/day and HEC = 0.26 mg/m3

 Residential outdoor post-application: HEC = 0.26 mg/m3

 Residential indoor post-application: HEC= 0.186 mg/m3

 Residential bystander: HEC = 0.047 mg/m3
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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 historical 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 historical 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 generations at 5000 ppm, since the pup body weights are 
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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 body 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).
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A.6.2 Statistical Report: Dicamba- a reproduction study – Analysis of litter-specific 

average pup weights versus study concurrent control groups

Statistical methods

Repeated-Measures Analysis of Variance (mixed-effects models) was used to analyze the litterspecific average pup weight of F1 and F2 generations on a per dam basis. (Litters of F1 

generation were identified by the F0 dams’ identification 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 the 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, number of live pups born) was used as covariate for the measurement on postnatal 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-specific 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 the 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 

autoregressive lag(1) correlation matrix (AR(1)).
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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 between 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 twoway 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 control 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 

predicted 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 this 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 different between post-natal days. Therefore, it is necessary for the 

dose effects to be estimated --- and evaluated -- 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 days 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. 
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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 pvalue

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 litterspecific average pup weight 
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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 type=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.: Statistical Analysis Software (SAS) output table Type 3 Tests of Fixed Effects

of the model 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 analysis 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 postweaning 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 period -- each individual pup 
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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 litter 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-weaning 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 weight in a litter 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 data 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 female 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 control during the post-weaning period.
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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 0.002
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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 pvalue

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 pvalue

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.
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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.
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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, pKa 1.97 (PAI)

Octanol/water partition coefficient, Log(KOW) 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, can be found at the 

Agency website13. 

 

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-exposure
Dicamba 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 Mexico2 Codex3

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-methoxyPlants: Dicamba

Animals:

sum of dicamba 

and 3,6-

dichlorosalicylic 

acid (DCSA) 

expressed as 

dicamba.

The residue is not 

fat-soluble.

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

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 quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed 

postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the 

sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.