UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

 

MEMORANDUM

Date: 4/20/11

SUBJECT: Bromoxynil: Human Hea

Grown for Seed, Conservation Reserve Program Areas, 

PC Code: 035301, 035302

Decision No.: 425581

Petition No.: 9F7678

Risk Assessment Type: Single 

Chemical/Aggregate

TXR No.: NA

MRID No.: NA

FROM: Cassi L.Walls, Ph.D., 

Myron S. Ottley, Ph.D., Toxicologist

Nancy Dodd, Chemist

Kristin Rury, Biologist

Risk Assessment Branch III (RAB3)

Health Effects Division (HED) (7509P)

THROUGH: Paula Deschamp, Branch Chief 

RAB3/HED (7509P)

TO: Bethany Benbow, RM#23

Registration Division (7505P)

Page 1 of 72

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

 AND POLLUTION PREVENTION

Human Health Risk Assessment for Amended Uses on

Grown for Seed, Conservation Reserve Program Areas, and Grain Sorghum

DP Barcode: D374609

Registration No.: 264-1023

Regulatory Action: Section 3 Registration

Case No.: 2070

CAS No.: 1689-84-5, 1689-99

40 CFR: 180.324

Cassi L.Walls, Ph.D., Risk Assessor

, Ph.D., Toxicologist

Chemist

Biologist

Risk Assessment Branch III (RAB3)

Health Effects Division (HED) (7509P)

Paula Deschamp, Branch Chief 

RAB3/HED (7509P)

Bethany Benbow, RM#23

Registration Division (7505P)

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION

Uses on Grass 

and Grain Sorghum.

Section 3 Registration

99-2
Page 2 of 72

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

2.0 Regulatory Conclusions and Recommendations............................................................. 8

2.1 Data Deficiencies/Conditions of Registration .............................................................. 9

2.2 Tolerance Considerations.............................................................................................. 9

2.2.1 Enforcement Analytical Method ............................................................................... 9

2.2.2 International Harmonization................................................................................... 10

2.2.3 Recommended Tolerances....................................................................................... 10

2.2.4 Revisions to Petitioned-For Tolerances.................................................................. 11

2.3 Label Recommendations.............................................................................................. 12

2.3.1 Recommendations from Residue Reviews.............................................................. 12

2.3.2 Recommendations for Worker Safety .................................................................... 12

2.3.3 Recommendations for Residential Safety............................................................... 12

3.0 Ingredient Profile............................................................................................................. 12

3.1 Structure and Nomenclature....................................................................................... 13

3.2 Physical/Chemical Characteristics ............................................................................. 14

3.3 Summary of Existing/Amended Uses......................................................................... 14

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 17

4.1 Toxicology Studies Available for Analysis................................................................. 17

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)............................. 18

4.2.1 Dermal Absorption................................................................................................... 18

4.3 Toxicological Effects .................................................................................................... 19

4.4 Safety factor for Infants and Children (FQPA Safety Factor) ................................ 20

4.4.1 Completeness of the Toxicology Database.............................................................. 20

4.4.2 Evidence of Neurotoxicity........................................................................................ 21

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 21

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 21

4.5 Toxicity Endpoint and Point of Departure Selections.............................................. 22

4.5.1 Dose-Response Assessment...................................................................................... 22

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment..... 22

4.5.3 Cancer Classification and Risk Assessment Recommendation............................ 22

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

Assessment............................................................................................................................... 22

4.6 Endocrine Disruption................................................................................................... 24

5.0 Dietary Exposure and Risk Assessment......................................................................... 25

5.1 Metabolite/Degradate Residue Profile ....................................................................... 25

5.1.1 Summary of Plant and Animal Metabolism Studies............................................. 25

5.1.2 Summary of Environmental Degradation.............................................................. 26

5.1.3 Comparison of Metabolic Pathways....................................................................... 27

5.1.4 Residues of Concern Summary and Rationale ...................................................... 27

5.2 Food Residue Profile .................................................................................................... 28

5.3 Water Residue Profile.................................................................................................. 30

5.4 Dietary Risk Assessment.............................................................................................. 31

5.4.1 Description of Residue Data Used in Dietary Assessment.................................... 31

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 32

5.4.3 Acute Dietary Risk Assessment............................................................................... 33

5.4.4 Chronic Dietary Risk Assessment........................................................................... 33
Page 3 of 72

5.4.5 Cancer Dietary Risk Assessment............................................................................. 34

5.4.6 Summary Table......................................................................................................... 34

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 34

6.1 Spray Drift.................................................................................................................... 34

7.0 Aggregate Exposure/Risk Characterization.................................................................. 35

7.1 Acute Aggregate Risk................................................................................................... 35

7.2 Short- and Intermediate- Term Aggregate Risk....................................................... 35

7.3 Chronic Aggregate Risk .............................................................................................. 35

7.4 Cancer Aggregate Risk ................................................................................................ 35

8.0 Cumulative Exposure/Risk Characterization ............................................................... 35

9.0 Occupational Exposure/Risk Characterization ............................................................ 35

9.1 Short-/Intermediate Term Non-Cancer & Cancer Risk For Pesticide Handlers .. 36

9.2 Short-/Intermediate-Term Post-Application Risks................................................... 43

10.0 Environmental Justice Considerations.......................................................................... 47

11.0 References......................................................................................................................... 48

Appendix A. Toxicology Profile and Executive Summaries .................................................. 49

A.1 Toxicology Data Requirements................................................................................... 49

A.2 Toxicity Profiles............................................................................................................ 50

A.3 HAZARD IDENTIFICATION AND ENDPOINT SELECTION ........................... 66

A.3.2 Chronic Reference Dose (cRfD) – All Populations............................................ 67

A.3.3 Dermal Short-Term (1-30 days) and Intermediate-Term (1-6 Months).......... 68

A.3.3 Inhalation Short-Term (1-30 days) and Intermediate-Term (1-6 Months)..... 69

Appendix B. Chemical Names and Structures of Bromoxynil, its Esters and Metabolite.. 70

Appendix C. Review of Human Research................................................................................ 71

Appendix D. International Residue Limit Status Sheet......................................................... 72
Page 4 of 72

1.0 Executive Summary

Use Profile: Bayer CropScience (BCS) has proposed a new product, HUSKIETM Herbicide 

(EPA Registration No. 264-1023), that contains bromoxynil octanoate, bromoxynil heptanoate, 

and pyrasulfotole as the active ingredients. The adequacy of the proposed uses of pyrasulfotole 

will be addressed in a separate document. The bromoxynil octanoic and heptanoic esters are 

rapidly converted to the bromoxynil phenol (3,5-dibromo-4-hydroxybenzonitrile). Therefore, the 

exposure and tolerances are based on bromoxynil phenol (from here on out will be referred to as 

bromoxynil). 

BCS has proposed amended uses for bromoxynil formulated in the HUSKIETM Herbicide 

product. Bromoxynil is currently registered for use on grass and grain sorghum; however, BSC 

is proposing to amend the use pattern by shortening the preharvest interval (PHI) which 

subsequently will result in an increase in the tolerance. Bromoxynil is a contact herbicide which 

is registered for application as the octanoic and/or heptanoic acid esters for control of broadleaf 

weeds in various crops. Bromoxynil inhibits photosynthetic electron transport and oxidative 

phosphorylation in mitochondria. The previous bromoxynil risk assessment was conducted to 

support the Reregistration Eligibility Decision (RED) in December 1998. 

HUSKIETM Herbicide is an emulsifiable concentrate which contains 13.4% bromoxynil 

octanoate, 12.9% bromoxynil heptanoate, 3.3% pyrasulfotole, and 70.4% inerts. The 

formulation contains 1.75 lbs bromoxynil active ingredient per gallon. HUSKIETM Herbicide

foliar spray may be applied to conservation reserve program acres (CRP) and grasses grown for 

seed from preemergence to established grasses. A maximum of two applications with a 

retreatment interval (RTI) of 30 days can be made with a maximum rate of 0.41 lb ai/A/year for 

CRP and grasses grown for seed. The preharvest intervals (PHI) are 7 days for forage and 30 

days for hay; the restricted entry interval (REI) is 12 hours. 

HUSKIETM Herbicide is applied as a postemergence foliar spray to grain sorghum using ground

application equipment. Application through any type of irrigation system is prohibited. A 

maximum of two applications with an RTI of 11 days can be made for a maximum rate of 0.44 lb 

ai/A/year for grain sorghum. The preharvest intervals (PHI) are 7 days for forage and 60 days 

for grain or stover; the restricted entry interval (REI) is 12 hours. 

Human Health Risk Assessment:

Bromoxynil phenol has moderate acute toxicity via the oral and inhalation routes and low acute 

toxicity via the dermal route. Bromoxynil octanoate has moderate acute toxicity via the oral and 

dermal routes and low acute toxicity via the inhalation route. Due to rapid conversion of the 

ester forms of the chemical (heptanoate and octanoate) to the phenol, toxicity testing was 

conducted with both phenol and octanoate material, and the risk assessment is based on exposure 

to the phenol. 

In the repeated dose studies of the mammalian toxicology database, the liver was the primary

target organ of bromoxynil toxicity. Across species, duration and gender, changes in weight, 

clinical chemistry and pathology indicated treatment-related perturbations in and adverse effects 
Page 5 of 72

on liver function. Treatment-related effects were also observed on body weight and body weight 

gain changes (rats, mice, dogs, rabbits). Subchronic and chronic studies in dogs showed that 

bromoxynil elevated body temperature, manifested by increased panting at lower dose levels, 

and hyperthermia and death as dose levels increased.

Bromoxynil produced developmental toxicity across all tested species. The consistent effect 

seen at the LOAEL, was supernumerary ribs in rats, mice and rabbits. In addition, supernumerary

ribs occurred in rats exposed by both the oral and dermal routes.

Bromoxynil is classified as “possible human carcinogen.” This was based on the presence of 

hepatocellular tumors in male and female mice. There is no concern for mutagenicity. The unit 

risk, Q1

*

, of bromoxynil based upon male mouse hepatocellular tumors rates is 0.103 

(mg/kg/day)

-1

in human equivalents.

Dietary Exposure (Food/Water):

The residue chemistry data and environmental fate data are adequate to assess human exposure. 

Although somewhat refined, the acute, chronic and cancer dietary food exposure assessments are

based on reliable data and will not underestimate exposure/risk.

Acute: A refined acute dietary assessment was conducted. The assumptions of this dietary

assessment included average field trial residues for all grains; tolerance level residues for cotton, 

garlic, onion, peppermint and spearmint; anticipated residues in livestock; and maximum crop 

treated (CT) estimates for all crops. Empirical or DEEMTM default processing factors were used. 

Potential residues in drinking water were included in the analyses based on surface water results 

from the Tier I FIRST model. 

The acute dietary (food and drinking water) exposure to bromoxynil is below HED’s level of 

concern [i.e., <100% of the acute Population Adjusted Dose (aPAD)] for the general U.S. 

population and all population subgroups. At the 99.9th percentile of the exposure distribution, 

the US population occupied just 3.3% of the aPAD, while the most highly exposed population 

subgroup, all infants (< 1 year old), occupied 7.4% of the aPAD. 

Chronic: A refined chronic dietary assessment was conducted. The assumptions of this dietary

assessment included average field trial residues for all crops except for spearmint and 

peppermint where tolerance values were used; anticipated residues in livestock; and average CT 

estimates for all crops. Empirical or DEEMTM default processing factors were used. Potential 

residues in drinking water were included in the analyses based on surface water results from the 

Tier I FIRST model. 

The non-cancer chronic dietary (food and drinking water) exposure to bromoxynil is below 

HED’s level of concern [i.e., <100% of the chronic Population Adjusted Dose (cPAD)] for the 

general U.S. population and all population subgroups. The chronic dietary exposure estimates 

are <1% of the cPAD for the general U.S. population as well as for Children 1-2 years old, the 

most highly exposed population subgroup. 
Page 6 of 72

Cancer: The cancer dietary (food and drinking water) risk estimate for the general U.S. 

population is 1.5 x 10-6, which is below HED’s level of concern (generally in the range of 10-6).

Residential Exposure:

There are no residential uses of bromoxynil; therefore, a residential exposure assessment was not 

necessary to conduct.

Aggregate Risk:

Acute: Aggregate acute risk is equivalent to acute dietary risk. There is potential acute exposure 

(7.4% of the aPAD) via the diet (food and drinking water) as determined in Section 5.3. 

Chronic: Aggregate chronic risk is equivalent to chronic dietary risk. There is potential chronic 

exposure (≤1% of the cPAD) via the diet (food and drinking water) as determined in Section 5.4. 

Short- and Intermediate Term: Since there are no residential uses for bromoxynil, short- and 

intermediate-term aggregate assessments were not conducted.

Cancer: The aggregate cancer risk (food and drinking water) is 1.5 x 10-6. 

Occupational Exposure/Risk:

This risk assessment evaluated the occupational handler and post-application scenarios for both 

the amended uses and existing uses of bromoxynil. Bromoxynil is currently registered for use on 

grass and grain sorghum; however, BCS is proposing to shorten the PHI which subsequently will 

result in an increase in the tolerance. The existing uses assessed in 1998 were reassessed 

because a higher dermal absorption factor was identified for route-to-route extrapolation and an 

inhalation endpoint was selected for inhalation exposure risk assessment.

Agricultural Handlers: Occupational short-term (1 - 30 days) and intermediate-term (1 - 6 

months) dermal and inhalation exposures are expected from bromoxynil handler activities 

associated with both the proposed and existing agricultural uses. HED used data from the 

Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in the PHED Surrogate 

Exposure Guide (8/98) to assess handler exposures (HED Science Advisory Council for 

Exposure (ExpoSAC) Standard Operating Procedure (SOP) No. 7, dated 01/28/1999). A Margin 

of Exposure (MOE) greater than 100 for the inhalation, dermal, and combined routes is deemed 

adequate to protect occupational bromoxynil handlers.

Amended uses

The results indicate that the MOEs for the amended uses for occupational handler scenarios were 

not of concern (i.e., an MOE > 100) at some level of personal protection (gloves). The dermal 

MOE was 12 with baseline attire for mixer/loaders, and the dermal MOEs ranged from 2,400 to 

2,600 for applicators. The dermal MOEs with baseline attire plus gloves (PPE-G) ranged from 

1,500 to 1,600 for mixer/loaders and from 2,400 to 2,600 for applicators. Inhalation MOEs 

ranged from 11,000 to 12,000 for mixer/loaders and from 18,000 to 19,000 for applicators. The 
Page 7 of 72

combined (dermal + inhalation) MOE with baseline attire was 12 for mixer/loaders and the 

MOEs ranged from 2,200 to 2300 for applicators. Combined (dermal + inhalation) MOEs with 

baseline attire plus gloves (PPE-G) ranged from 1,300 to 1,400 for mixer/loaders and from 2,200

to 2,300 for applicators. 

The results indicate that estimated cancer risks were not of concern (i.e., in the 10-6range or 

lower) for both commercial and private users at some level of personal protection (gloves). At 

baseline attire, estimated risk for commercial users of bromoxynil is in the 10-4range for 

mixer/loaders and 10-6 range for applicators; at baseline plus gloves (PPE-G), estimated risk is in 

the 10-6 range for mixer/loaders and applicators. At baseline attire, estimated risk for private 

users of bromoxynil is in the 10-5range for mixer/loaders and in the 10-7 range for applicators; at 

baseline plus gloves (PPE-G) estimated risk is in the 10-6 range for mixer/loaders and 10-7range 

for applicators. 

Reevaluation of Existing Bromoxynil Uses

The results indicate that the mixing/loading MOEs for the existing use sites were not of concern 

(i.e., an MOE > 100) at some level of personal protection (gloves) for all crops and application 

methods, except mixing/loading for aerial application to corn and wheat, which requires a closed 

system. The results indicate that MOEs for application of bromoxynil to all existing use sites 

were not of concern at some level of personal protection (gloves). Flagging for bromoxynil 

application was not of concern at baseline attire. 

The dermal MOEs at baseline attire range from 0.34 (risks of concern) to 160 for mixing/loading 

for application to corn and wheat, from 1.2 (risks of concern) to 1,400 for mixing/loading for 

application to all other crops, from 200 to 6,000 for applicators, and from 310 to 620 for 

flaggers. Inhalation MOEs at baseline attire were >330 for mixer/loaders, applicators and 

flaggers and are not of concern. Combined (dermal + inhalation) MOEs at baseline plus gloves

ranged from 38 to 2,900 for mixer/loaders, 380 to 4,900 for applicators, and from 270 to 530 for 

flaggers. Mixing and loading scenarios for bromoxynil application to corn and wheat were 

below HED’s LOC=100 at baseline and PPE-G. With coveralls, mixing/loading for application 

to corn and wheat, the dermal MOE was 57 and the combined dermal and inhalation MOEs 

ranged from 55 (risk of concern) to 190. In a closed system, the dermal MOE for mixing/loading 

for application to corn & wheat was 120 and was 4,800 for inhalation exposure; the combined 

dermal + inhalation MOE was 110, and therefore not of concern. 

The results indicate that estimated cancer risks were not of concern (i.e., in the 10-6range or 

lower) for both commercial and private users at some level of personal protection (gloves) for all 

scenarios except aerial application to corn and wheat, which requires a closed system. 

At baseline attire, estimated risks for commercial users of bromoxynil are in the 10-5to 10-2

range (depending on the use site) for mixer/loaders, in the 10-7to 10-5range for applicators and 

10-6and 10-5range for flaggers. At baseline attire plus gloves, estimated risk is in the 10-4or 10-7

range for mixer/loaders, in the 10

-5 and 10-7

for applicators and in the 10-5 or 10-6for flaggers. 

With PPE-G and the addition of coveralls, estimated risk is in the 10-4and 10-7 range for 

mixer/loaders, in the 10

-5

and 10-7range for applicators, and in the 10

-5

or 10-6 range for flaggers.

With a closed system, estimated risk is in the 10-5 or 10-7range (depending on the use site). 
Page 8 of 72

Agricultural Post-application: Occupational short-term (1 - 30 days) and intermediate-term (1 

- 6 months) dermal exposures are expected for worker re-entering bromoxynil treated fields and 

performing post-application activities such as scouting and harvesting. All post-application 

dermal exposures were evaluated using surrogate data and default assumptions

Amended uses

The dermal non-cancer short- and intermediate-term post-application MOEs ranged from 150 to 

1,500 on the day of application. The estimated cancer risks for agricultural workers on the day

of application ranged from 1.4x10-6to 1.1x10-5.

Reevaluation of Existing Bromoxynil Uses

The short-and intermediate-term dermal non-cancer MOEs for all existing occupational postapplication scenarios ranged from 45 to 1,400 on the day of application; and therefore, some 

post-application activities are of concern. Risk from occupational contact with full foliage 

wheat, small grains and mint is not of concern 8 days after application, risk from sod harvesting 

is not of concern 5 days after application, and risk from occupational contact with full foliage 

corn, sorghum and cotton is not of concern 4 days after application. The estimated cancer risks 

on the day of application ranged from 2.3x10-6to 1.4x10-4. 

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for bromoxynil at this time. 

Environmental Justice Considerations: Potential areas of environmental justice concerns, to 

the extent possible, were considered in this human health risk assessment. Dietary and nondietary exposures were considered.

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 studies 

(listed in Appendix C) have been determined to require a review of their ethical conduct, and one 

of these studies is also subject to review by the Human Studies Review Board. All of the listed 

studies have received the appropriate review.

2.0 Regulatory Conclusions and Recommendations

Provided revised Sections B (OPPTS 860.1200) and F (OPPTS 860.1550) are submitted, HED

can recommend permanent tolerances for the uses of bromoxynil on grass and grain sorghum 

commodities and conditional registration for the requested uses on annual and perennial grasses 

grown for seed, conservation reserve program acres, and grain sorghum.

Additional data are needed as conditions of registration as outlined in Section 2.1 below. The 

specific tolerance recommendations are discussed in Section 2.2, and label modifications are 

discussed in Section 2.3.
Page 9 of 72

2.1 Data Deficiencies/Conditions of Registration

The following must be provided prior to a tolerance being established or registration 

allowed:

860.1200 Directions for Use

A revised Section B is requested to include an “APPLICATION METHODS” section for 

grass specifying type of application, method of application, and minimum gallons 

sprayed per acre for each method; clarify method of application for sorghum; and include 

rotational crop plantback intervals for all crops which are not primary (treated) crops on

the label or are not already listed in the Crop Rotation Guidelines section of the label.

860.1550 Proposed Tolerances

A revised Section F must be submitted to reflect the tolerances and correct commodity

definitions as listed in Table 2.2.4.

The following data are required as a condition of registration:

TOXICOLOGY

870.6200 Neurotoxicity Battery (Acute and Subchronic Studies) 

The acute and subchronic neurotoxicity screening battery is required to fulfill current 40 

CFR Part 158 data requirements. 

870.7800 Immunotoxicity 

The immunotoxicity study is required to fulfill current 40 CFR Part 158 data 

requirements. 

In a letter dated June 23, 2010, BCS acknowledged the data deficiency for 

immunotoxicity testing on bromoxynil and notified EPA that the conduct of this study is 

in the process of being scheduled for 2011.

OCCUPATIONAL EXPOSURE

875.2100 Dislodgeable Foliar Residue Study

To characterize post-application exposure and reduce uncertainty for late applications of 

bromoxynil, HED is requesting the registrant submit a dislodgeable foliar residue (DFR) 

study on a representative row crop (e.g. corn). 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Multiresidue methods data for bromoxynil butyrate and bromoxynil octanoate have been 

submitted. Recovery of bromoxynil octanoate and bromoxynil butyrate using FDA Multiresidue 

Method 303: Method II for Nonfatty Foods (Mills, Onley, Gaither Method) is variable. 
Page 10 of 72

Bromoxynil was not detected through Florisil elution. The data have been forwarded to FDA 

and included in the PESTDATA database. 

Adequate residue analytical methodology is available for tolerance enforcement for bromoxynil 

per se in grass and grain sorghum commodities. Method I in PAM, Vol. II, is a gas liquid 

chromatography/microcoulometric detection (GLC/MCD) method that has undergone a 

successful EPA method validation on wheat grain. Method Ia is the same method except that it

uses gas chromatography/electron capture detection (GC/ECD) for determination of methylated 

bromoxynil.

Adequate residue analytical methodology is available for tolerance enforcement for bromoxynil 

per se in livestock commodities. Method A is a GC/MCD or GC/ECD method for the analysis 

of bromoxynil per se residues in livestock tissues and is essentially the same as Method I. 

Method B is a GC/ECD method that is also similar to Method I, with modifications to the 

cleanup procedures.

Adequate residue analytical methodology is available for tolerance enforcement for parent and 

3,5-dibromo-4-hydroxybenzoic acid (DBHA) in cottonseed and gin trash samples. The method 

is a gas chromatography/mass spectrometric detection (GC/MSD) method , “Bromoxynil: 

Method of Analysis for Bromoxynil and its Metabolite, 3,5-Dibromo-4-hydroxybenzoic Acid in 

Cottonseed, Gin Trash, and Seed Processed Fractions using GC/MSD.” The method (Method 

RES9603) has been the subject of an independent laboratory validation (ILV) and an Agency

petition method validation (PMV).

2.2.2 International Harmonization

There are currently no maximum residue limits (MRLs) established by Codex, Canada, or

Mexico for bromoxynil. Tolerances have been established by Canada for grain of sorghum grain 

at 0.1 ppm and for milk at 0.1 ppm. The Canadian tolerance expression is “3,5-dibromo-4-

hydroxybenzonitrile, including the metabolite 3,5-dibromo-4-hydroxybenzoic acid”; however, 

compliance with the tolerance levels in the U.S. will be determined by measuring only 

bromoxynil (3,5-dibromo-4-hydroxybenzonitrile). An International Residue Limit Status sheet 

is attached (Appendix D).

2.2.3 Recommended Tolerances

HED recommends for the following tolerances and residue definitions:

40 CFR §180.324(a)(1):

Tolerances are established for residues of bromoxynil, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance levels 

specified below is to be determined by measuring only bromoxynil (3,5-dibromo-4-

hydroxybenzonitrile) resulting from application of its octanoic and/or heptanoic acid ester.

Grass, forage .....................................................................................18 ppm

Grass, hay........................................................................................ 5.0 ppm
Page 11 of 72

Grain, aspirated grain fractions........................................................1.2 ppm

Milk................................................................................................. 0.4 ppm

Sorghum, grain, grain ......................................................................0.2 ppm

Sorghum, grain, forage ....................................................................0.8 ppm

Note: The established tolerance of 0.2 ppm on sorghum, grain, stover is to remain 

unchanged.

 

40 CFR §180.324(a)(2):

Tolerances are established for residues of bromoxynil, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance levels 

specified below is to be determined by measuring only bromoxynil (3,5-dibromo-4-

hydroxybenzonitrile) and its metabolite 3,5-dibromo-4-hydroxybenzoic acid (DBHA) 

resulting from application of its octanoic and/or heptanoic acid ester.

All livestock commodities should be moved from 40 CFR §180.324(a)(2) to 40 CFR 

§180.324(a)(1), leaving only cotton, gin byproducts; cotton, hulls; and cotton, undelinted seed in 

40 CFR §180.324(a)(2). 

2.2.4 Revisions to Petitioned-For Tolerances

Table 2.2.4 compares proposed and recommended tolerance levels. The recommended tolerance 

levels, including an increase for sorghum, grain, forage, are based on the submitted magnitude of 

the residue data and the Agency’s tolerance spreadsheet as specified by the Guidance for Setting 

Pesticide Tolerances Based on Field Trial Data SOP. Because the tolerance on the grain of 

grain sorghum is being increased from 0.05 ppm to 0.2 ppm, higher residues may occur in 

aspirated grain fractions. HED has determined that a higher tolerance of 1.2 ppm is needed for 

grain, aspirated grain fractions. Based on calculated residues in dairy cattle for the tolerance 

assessment, the established tolerance on milk must be increased from 0.1 ppm to 0.4 ppm. Other 

livestock tolerances remain unchanged.

Table 2.2.4. Tolerance Summary for Bromoxynil

Commodity

Tolerance (ppm) Comments

Established Correct Commodity Definition Proposed Recommended 

Grass, forage 3.0 18 18

Grass, hay 3.0 5.0 5.0

Grain, aspirated fractions 0.3 -- 1.2 Grain, aspirated grain fractions

Milk 0.1 -- 0.4

Sorghum, grain 0.05 0.2 0.2 Sorghum, grain, grain

Sorghum, grain, forage 0.5 -- 0.8

Sorghum, grain, stover 0.2 -- 0.2 
Page 12 of 72

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

A revised Section B/label must be submitted with the following revisions:

a) The grass section of the HUSKIE TM Herbicide label should have an “APPLICATION 

METHODS” section which states the type(s) of application (e.g., foliar spray, broadcast 

spray, etc.), the method(s) of application (i.e., ground, air, or both), and the minimum gallons 

spray per acre for each method.

b) The sorghum section should state that aerial applications are not to be made.

c) The label contains rotational crop plantback intervals for some crops but not all crops. A 

30-day rotational crop restriction is adequate for bromoxynil. The petitioner must consider 

rotational crop plantback requirements for all active ingredients on the label and then indicate 

a plantback interval for all crops which are not primary (treated) crops on the label or are not 

already listed in the Crop Rotation Guidelines section of the label.

2.3.2 Recommendations for Worker Safety

Based on email correspondence with the registrant (dated 11/01/2010), HuskieTM Herbicide 

(EPA Reg. No. 264-1023) is not intended for application with chemigation or aerially to grain 

sorghum, grass grown for seed and CRP areas. The label should restrict aerial and chemigation 

explicitly from these use sites. 

A closed system is required for mixers/loaders for existing corn and wheat applications.

Although, a 12-hr REI was proposed, under the WPS for Agricultural Pesticides, a 24-hr REI is 

required for chemicals classified under Toxicity Category II. Therefore, a REI of 24 hours is 

required on the HuskieTM Herbicide label. Other bromoxynil product labels should also require a 

24-hr REI, except for specific the use sites wheat, small grains and mint which require an 

REI of 8 days, sod harvesting which require an REI of 5 days, and corn, sorghum and 

cotton which require an REI of 4 days.

2.3.3 Recommendations for Residential Safety

There are currently no registered or proposed residential uses of bromoxynil. However, existing 

labels should clarify that products containing bromoxynil are restricted from use on golf course 

turf. 

3.0 Ingredient Profile

Bromoxynil is registered for the application as the octanoic and/or heptanoic esters which rapidly 

convert to the phenol (bromoxynil). The bromoxynil esters and phenol are chemically and 

physically similar which allows the risk assessment to be based on bromoxynil. Bromoxynil is a 

selective contact foliage applied herbicide used to control a variety of broadleaf weeds. 
Page 13 of 72

Bromoxynil inhibits photosynthetic electron transport and also uncouples oxidative 

phosphorylation in mitochondria, thereby stopping energy production and negatively affecting 

plant respiration.

Bayer CropScience has proposed uses for HUSKIETM Herbicide (EPA Registration No. 264-

1023) containing bromoxynil as one of the active ingredients on annual and perennial grasses 

grown for seed, conservation reserve program acres (CRP), and grain sorghum. HUSKIETM 

Herbicide is an emulsifiable concentrate which contains 13.4% bromoxynil octanoate, 12.9% 

bromoxynil heptanoate, 3.3% pyrasulfotole, and 70.4% inerts. The formulation contains 1.75 lbs 

bromoxynil active ingredient per gallon. HUSKIETM Herbicide foliar spray may be applied to 

CRP and grasses grown for seed from preemergence to established grasses. A maximum of two 

applications with a retreatment interval (RTI) of 30 days can be made for in a maximum rate of 

0.41 lb ai/A/year for CRP and grasses grown for seed. The preharvest intervals (PHI) are 7 days 

for forage and 30 days for hay; the restricted entry interval (REI) is 12 hours. The adequacy of 

the proposed uses of pyrasulfotole will be addressed in a separate document. 

HUSKIETM Herbicide is applied as a postemergence foliar spray to grain sorghum using ground 

application equipment. Application through any type of irrigation system is prohibited. A 

maximum of two applications with an RTI of 11 days can be made for a maximum rate of 0.44 lb 

ai/A/year for grain sorghum. The preharvest intervals (PHI) are 7 days for forage and 60 days 

for grain or stover; the restricted entry interval (REI) is 12 hours. 

3.1 Structure and Nomenclature

Appendix B provides structures and nomenclature for the bromoxynil esters.

Table 3.1 Bromoxynil Nomenclature.

Chemical Structure

Empirical Formula C7H3Br2NO

Common Name bromoxynil or bromoxynil phenol

Company Experimental 

Name

AE F025943 

IUPAC Name 3,5-dibromo-4-hydroxybenzonitrile

CAS Name 3,5-dibromo-4-hydroxybenzonitrile

CAS Registry Number 1689-84-5 (phenol)

1689-99-2 (octanoate)

56634-95-8 (heptanoate)

End-use Product/EP HuskieTM Herbicide

Chemical Class Benzonitrile Herbicide
Page 14 of 72

Table 3.1 Bromoxynil Nomenclature.

Known impurities of 

concern

None

3.2 Physical/Chemical Characteristics

Table 3.2 Physicochemical Properties of Bromoxynil (Bromoxynil Phenol)

Parameter Value Reference (MRID)

Molecular Weight 276.9 47815001

Melting point/range 190.5°C 47815001

pH @ ambient 3.68 47815001

Density 2.31 g/cm3at 20°C 47815001

Water solubility 0.090 g/L at 25oC 47815001

Solvent solubility (20oC) Heptane

Xylene

Methanol

Octanol

Acetone

Ethyl acetate

Acetonitrile

0.15 g/L

8.8 g/L

80.5 g/L

46.7 g/L

186 g/L

97.7 g/L

51.1 g/L

47815001

Vapor pressure 1.4 Pa at 20C 47815001

Dissociation constant, pKa 3.86 47815001

Octanol/water partition coefficient, 

Log(KOW)

2.90 (Kow = 794) 47815001

UV/visible absorption spectrum Primary λmax = 221.2

Primary λmax = 286.8

47815001

3.3 Summary of Existing/Amended Uses

Currently bromoxynil is used on agricultural food crops including garlic and onions; food and 

feed crops including mint, flax, spearmint, peppermint, barley, oats, rye, triticale, wheat, 

sorghum, cotton, and field and pop corn; and feed crops including alfalfa, forage/hay, and grass. 

Current, non-food uses include outdoor industrial areas, nonagricultural uncultivated areas/soil, 

non-residential commercial/industrial lawns, and sod farms.

Bayer CropScience has proposed amendments to the existing use patterns of annual and 

perennial grasses grown for seed, conservation reserve program acres (CRP), and grain sorghum 

on the HUSKIETM Herbicide label. HUSKIETM Herbicide (EPA Registration No. 264-1023) 

controls broadleaf weeds and mannagrass in grasses and broadleaf weeds in grain sorghum. 

HUSKIETM Herbicide is an emulsifiable concentrate which contains 13.4% bromoxynil 

octanoate, 12.9% bromoxynil heptanoate, 3.3% pyrasulfotole, and 70.4% inerts. The 

formulation contains 1.75 lbs bromoxynil per gallon.

The submitted label for HUSKIETM Herbicide (EPA Registration No. 264-1023) is adequate to 

allow evaluation of the residue data relative to the proposed uses. Refer to Section 2.3 for 

recommended modifications to the proposed labels. 
Page 15 of 72

Table 3.3. Summary of Directions for Use of Bromoxynil.

Applic. 

Timing, Type, 

and Equipment

Formulation

[EPA Reg. 

No.]

Applic. Rate

(lb ai/A)

Max. No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations1,2,3

Grass

(Grasses Grown for Seed and Conservation Reserve Program Acres)

(Perennial Ryegrass, Annual Ryegrass, Tall Fescue, Fine Fescue, Kentucky Bluegrass, Orchardgrass, and Timothy)

Pre-emergence 

and/or postemergence

HUSKIETM 

Herbicide 

(EPA Reg. 

No. 264-

1023)

13.5-15 oz/A

(0.18-0.205 lb 

ai/A)

2 30 oz

(0.41 lb 

ai/A)

Forage: 7

Hay: 30

Use in annual and perennial 

grasses grown for seed and 

conservation reserve 

program acres (CRP). 

Apply from pre-emergence 

to established perennial 

ryegrass, annual ryegrass, 

tall fescue, fine fescue, 

Kentucky bluegrass and 

orchardgrass. Apply to 

established timothy.

Observe an interval of at 

least 30 days between 

applications.

HUSKIETM Herbicide may 

be tank mixed with 

herbicides, insecticides, 

fungicides, and spray 

additives.*

The restricted entry interval 

is 12 hours.

Sorghum, Grain
Page 16 of 72

Table 3.3. Summary of Directions for Use of Bromoxynil.

Applic. 

Timing, Type, 

and Equipment

Formulation

[EPA Reg. 

No.]

Applic. Rate

(lb ai/A)

Max. No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations1,2,3

Postemergence,

Foliar spray, 

Ground 

equipment

HUSKIETM 

Herbicide 

(EPA Reg. 

No. 264-

1023)

12.8-16 oz/A

(0.18-0.22 lb 

ai/A)

2 32 oz

(0.44 lb 

ai/A)

Forage: 7

Grain: 60

Stover: 60

Apply to sorghum between 

the 3 leaf stage of growth 

up to 12 inches.

Apply in minimum of 10-

15 gallons of water per 

acre, as needed to obtain 

thorough spray coverage.

Do not apply through any 

type of irrigation system.

Observe an interval of at 

least 11 days between 

applications.

HUSKIETM Herbicide may 

be tank mixed with 

herbicides and 

insecticides.** 

Do not apply HUSKIETM 

Herbicide in a tank mix 

with Lorsban as an 

unacceptable crop response 

may occur.

One pound of ammonium 

sulfate per acre may be 

added to optimize 

herbicidal activity.

The restricted entry interval 

is 12 hours.

1 Crop Rotation Plantback Intervals: 

1 month: wheat, barley, oats, rye, and triticale

4 months: alfalfa, millet, grain sorghum, and soybeans

9 months: canola, canaryseed, chickpeas, corn, dry beans, flax, field peas, green beans, green peas, lentils 

(except in MN, MT, ND, and SD), mustards, potatoes, safflower, sunflowers, and sugarbeets

18 months: lentils in MN, MT, ND and SD

2 Grass:

For weed control, HUSKIETM Herbicide may be tank mixed with Puma®, Nortron, Rely, 2.4-D 

ester/amine, AimTM, Bronate AdvancedTM, Buctril®, Curtail M/Curtail®, Dicamba, Goal, Glean, MCPA 

ester/MCPA amine, Sencor®, Starane®/Starane NXT/Starane Ultra, or WideMatchTM.

For insect control, HUSKIETM Herbicide may be tank mixed with Baythroid®XL, Capture, Lorsban®, 

Mustang MaxTM, or Warrior® Insecticides.

For disease control, HUSKIETM Herbicide may be tank mixed with fungicides such as Absolute, Tilt®, 

Quadris®, QuiltTM, or Bravo.

Some tank mix options require the use of a non-ionic surfactant (NIS). Use the amount of the NIS 

recommended on the tank mix partner label or at a concentration of 0.25-0.5% v/v (1-2 qt per 100 gallons 

of spray solution). At least 80% of the surfactant product must be active non-ionic surfactant.
Page 17 of 72

3 Grain Sorghum:

For grass control, HUSKIETM Herbicide may be tank mixed with 0.25-1.0 lb atrazine per acre. For weed 

control, HUSKIETM Herbicide plus atrazine may be tank mixed with phenoxy broadleaf herbicides such as 

2,4-D or dicamba.

For insect control, HUSKIETM Herbicide may be tank mixed with Baythroid®XL

An unacceptable crop response may occur if HuskieTM Herbicide is applied to acreage that has been 

previously treated with mesotrione.

Sensitivity of sweet sorghum (sorgo), sudangrass, sorghum-sudangrass hybrids, or dual-purpose sorghum 

varieties to HUSKIETM Herbicide is not known and the use of HUSKIETM Herbicide on these sorghum 

types is not recommended.

4.0 Hazard Characterization and Dose-Response Assessment

Bromoxynil is a selective contact foliage applied herbicide used to control broadleaf weeds. 

Bromoxynil inhibits photosynthetic electron transport and also uncouples oxidative 

phosphorylation in mitochondria, thereby stopping energy production and negatively affecting 

plant respiration. A correlation between this mode of action in plants and observed toxicity in 

the available toxicity studies in mammals was not identified. 

4.1 Toxicology Studies Available for Analysis

The existing database includes acceptable toxicity studies on both bromoxynil phenol and 

bromoxynil ocatanoate and it has been established that these two compounds are toxicologically 

equivalent on a molar basis (G. Ghali, 4/12/1996, TXR 011886). The existing database is 

deemed sufficient for characterizing the hazard of bromoxynil. As outlined in the table below, 

the database contains studies evaluating toxicity following oral and dermal exposure in rats and 

rabbits and oral exposure in mice and dogs, which help to characterize toxicity associated with 

oral, dermal, and inhalation exposure routes in humans.

Study Bromoxynil phenol Bromoxynil Octanoate

Acute toxicity battery √ √

Oral subchronic toxicity -- rats √ √

Oral subchronic toxicity -- mice √

Oral subchronic toxicity -- dogs √ √

Dermal subchronic toxicity -- rabbits √ √

Oral chronic/Carcinogenicity -- rats √ --

Oral carcinogenicity – mice √ --

Oral chronic -- dogs √ --

Oral developmental toxicity -- rats √ √

Oral developmental toxicity -- mice √ --

Oral developmental toxicity -- rabbits √ √

Dermal developmental toxicity -- rats √ √

Dermal developmental toxicity -- rabbits √ √
Page 18 of 72

Study Bromoxynil phenol Bromoxynil Octanoate

Oral multigen-reproduction study -- rats √ --

Dermal special reproduction study -- rats -- √

Mutagenicity Battery √ √

Acute Neurotoxicty Battery -- --

Subchronic Neurotoxicity -- --

Immunotoxicity -- --

Dermal Absorption √ √

√ = available -- = not available

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

The available data show that once absorbed, bromoxynil octanoate is converted to bromoxynil 

phenol. The absorption, distribution, excretion and metabolism of bromoxynil octanoate were 

studied in male and female Sprague Dawley rats given single oral doses of 14C-bromoxynil 

octanoate by gavage at dose levels of 2 or 20 mg/kg or at a dose level of 2 mg/kg following 14 

days of unlabeled bromoxynil octanoate administered by oral gavage at a dose level of 2 

mg/kg/day. Results were similar regardless of dosing regimen. The rate of absorption in both 

sexes was such that peak plasma concentrations of radioactivity were not reached until 7-10 

hours after dosing. Radioactivity was distributed in most tissues; highest concentrations were 

observed in blood, plasma, liver, kidneys and thyroid (especially in females). Levels of 

radioactivity in tissues were generally higher in females than in males. Most radioactivity was 

excreted in the urine (about 84-89% in males and 76-80% in females at 7 days) and considerably 

lesser amounts in the feces (about 6-10% in both males and females at 7 days). Excretion was 

more rapid in males than in females. Retention of radioactivity in tissues after 7 days was about 

2-3% in males and 7-9% in females. Essentially all bromoxynil octanoate was rapidly and nearly 

completely converted to bromoxynil phenol via ester hydrolysis. In special distribution studies, 

the only chemical species identified in tissues was bromoxynil phenol per se; no bromoxynil 

octanoate was identified in tissues. In urine, the only major species was free and conjugated 

bromoxynil phenol with no bromoxynil octanoate being present. In feces, however, some 

bromoxynil octanoate was identified. (MRID 00154756, 00154757, 42901001).

4.2.1 Dermal Absorption

The previous risk assessment utilized a dermal absorption factor of 10.32% (excluding post-wash 

residue), based on the highest absorption value obtained after 10 hours of exposure to 

bromoxynil octanoate, the compound to which exposure is expected. Current HED policy is to

derive a dermal absorption factor by combining the material remaining on the skin after skin 

washing to the systemically absorbed dose, if the material remaining on the skin is bioavailable. 

In the absence of bioavailability data, HED has made the assumption that the material remaining 

on the skin is bioavailable. Therefore, the dermal absorption value for this risk assessment is the 

sum of the absorption value and post-wash residue for the 10-hour period for bromoxynil 

octanoate, or 10.32% + 6.46% ≈ 17%.
Page 19 of 72

4.2.2 Other Toxicological Concerns

A metabolite of bromoxynil, 3,5 - dibromo-4-hydroxybenzoic acid (DBHA) has been found to be 

a major metabolite in cotton. HED previously concluded that bromoxynil and DBHA are 

extremely similar in structure, and since DBHA is likely to be more water soluble than 

bromoxynil, it should be absorbed less and eliminated faster than bromoxynil, thereby reducing 

its toxicity relative to bromoxynil. Since adequate data were not available which indicate DBHA 

is less toxic than the parent compound, HED assumed that DBHA had the same toxicity as the 

parent compound bromoxynil (D246944.mem, B. Madden 6/24/1998). 

Since then, additional DBHA toxicity data (four acute studies, a mutagenicity study, a 90-day rat

study and a rat developmental toxicity study) have been submitted to the Agency but have not all 

undergone review within HED. A preliminary examination of these data indicate that BDHA is 

less toxic than bromoxynil which is consistent with the expected effect that conversion of the 

nitrile group to a carboxy group reduces toxicity relative to bromoxynil. The diminished concern 

for DBHA toxicity is also applicable to carcinogenicity: Ionization of the carboxyl group at 

physiological pH leads to rapid excretion of DBHA and retards cellular uptake and migration of 

DBHA through intracellular membranes to interact with receptors associated with 

carcinogenicity. However, pending final review of the DBHA toxicity data, HED will continue 

to assume that DBHA toxicity is the same as (or less than) the parent compound, and is not 

expected to be more toxic than bromoxynil and to include it as a residue of concern for risk 

assessment

4.3 Toxicological Effects

With repeated dosing in rats and mice, frequently observed effects were on the liver (increased 

liver weight, hepatocellular hypertrophy) and body weight changes. In dogs, bromoxynil 

appeared to affect body temperature control. Besides decreased body weight, the treated dogs 

showed increased panting at low dose levels, and increased panting with elevated rectal 

temperatures at higher dose levels. At the highest dose levels tested, elevated body temperatures 

and death occurred.

Developmental toxicity was manifested in rats, mice and rabbits via the oral and dermal routes 

by increased incidence of supernumerary (13th and/or 14th) ribs at dose levels as low as 5 

mg/kg/day in rats. At higher dose levels, malformations such as hydrocephalus, enophthalmia, 

micropththalmia, fused ribs, scoliosis, misshapen thoracic centrum and incomplete ossification 

of sternebrae were observed in rabbits. In reproduction studies, delayed development manifested 

as decreased body weight and body weight gain, and delayed eye opening.

In addition to the developmental toxicity observed after bromoxynil and bromoxynil octanoate 

exposure, liver toxicity was also observed (beginning at 5 mg/kg/day in dogs and rats) in males 

and females in the subchronic, chronic, developmental and reproduction studies, including liver 

weight increases and adverse histopathological effects such as hepatocellular hypertrophy,

vacuolization and degeneration in rats, mice, and dogs, and liver tumors (beginning at 13 

mg/kg/day) in chronic studies in mice. Adverse effects (beginning at 5 mg/kg/day in dogs) on 
Page 20 of 72

body weight and body weight gain changes were also observed in rats, mice, dogs, and rabbits. 

Other less widespread effects, such as salivation, increased panting, and unsteady gait occurred 

in dogs; blood effects such as decreases in serum protein and globulins; increased thymic 

lymphocyte necrosis; increased degeneration/necrosis of cardiac myofibers occurred in rats. The 

increased panting in dogs occurred at 5 mg/kg/day, and increased panting with elevated rectal 

temperatures at 12 mg/kg/day.

Bromoxynil phenol and/or octanoate was positive in a mouse lymphoma forward mutation assay

with metabolic activation, a bacterial DNA repair assay with and without S9 activation, and in a 

CHO chromosomal aberration assay with activation. These mutagenic effects all occurred at 

cytotoxic dose levels and in in vitro studies only. The cancer classification of Group C Human 

Carcinogen with low-dose extrapolation (Q1*) was assigned by HED’s Cancer Peer Review 

Committee (E. Budd, 3/12/1997, TXR 0050045) based on mouse hepatocellular tumors.

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

In HED’s risk assessment conducted in 1998, acute dietary risks for females 13+ utilized a 

NOAEL of 4 mg/kg/day and LOAEL of 5 mg/kg/day based increased incidence of 

supernumerary ribs seen in two rat developmental toxicity studies. Based on the combined 

evaluation of these studies, the 10X FQPA SF was retained for concerns over the apparent 

steepness of the dose-response curve. In an effort to better characterize the dose response 

relationship for supernumerary ribs, a BMD analysis has been conducted using the fetal and/or 

litter data available from the two rat developmental studies, plus a third developmental study

which demonstrated similar results at similar dose levels. The results of the BMD analysis 

indicate that the dose response curves are not as steep as previously assumed and HED has 

concluded that there is high confidence that the NOAEL of 4 mg/kg/day is a protective point of 

departure without the need to retain a 10X FQPA SF (J. Kidwell, 035301TS.001.docx. Final

Report of the ToxSAC. January 13, 2011).

Based on the hazard and exposure data, the bromoxynil risk assessment team has recommended 

that the FQPA Safety Factor be reduced to 1X. Although the presence of quantitative 

susceptibility has been established (based on supernumerary ribs occurring at dose levels below 

the maternal LOAEL in rats), the NOAELs and LOAELs for this effect are well defined, and 

Benchmark Dose (BMD) analysis has indicated that the NOAEL of 4 mg/kg/day for 

supernumerary ribs (which is the point of departure for the Females 13+ endpoint) is sufficiently

protective of the fetus. Both the BMD (which represents 5% increased risk of incidence of this 

effect above the normal background incidence) of 13.66 mg/kg/day and its lower limit (BMDL) 

of 8.34 mg/kg/day are above the NOAEL of 4 mg/kg/day. The completeness and good quality of 

the available data used for the BMD analysis produced results with a high reliability factor, 

which is fully presented and discussed in a separate document (M. Ottley TXR 0055648). The 

data base is considered complete (refer to next section) and there are no residual uncertainties.

4.4.1 Completeness of the Toxicology Database

The toxicity database for bromoxynil is complete except for an immunotoxicity study (OPPTS 

Guideline 870.7800), and acute and subchronic neurotoxicity studies (OPPTS Guideline 
Page 21 of 72

870.6200a and 870.6200b). These studies are now requirements under 40 CFR §158.500 for 

pesticide registration. In the absence of specific immunotoxicity, acute and subchronic 

neurotoxicity studies, HED has evaluated the available bromoxynil toxicity database to 

determine whether an additional database uncertainty factor is needed to account for potential 

immunotoxicity or neurotoxicity. 

There is no evidence of immunotoxicity, with the exception of a marginal increase in the severity

- but not the incidence - of thymic lymphocyte necrosis at otherwise toxic dose levels in a 

subchronic rat study. The NOAEL and LOAEL for these thymic effects were 91 mg/kg/day and 

45 mg/kg/day. It is anticipated that the points of departure selected for bromoxynil (see table 

4.5.4) will be protective of this adverse effect, There is no evidence of neurotoxicity in the 

database. 

Consequently, HED believes the existing data are sufficient for endpoint selection for 

exposure/risk assessment scenarios and for evaluation of the requirements under FQPA, and an 

additional database uncertainty factor does not need to be applied.

4.4.2 Evidence of Neurotoxicity

There are currently no acute or subchronic neurotoxicity studies available, and the available 

subchronic and chronic data did not raise concern for potential neurotoxicity associated with 

bromoxynil or bromoxynil octanoate exposure. Though panting and elevated rectal temperature 

are observed in the subchronic dog study, these effects are not considered to be indicative of 

neurotoxicity but rather generalized systemic toxicity.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The available data indicate that bromoxynil produces developmental effects (supernumerary ribs) 

in rats and rabbits at or below the maternal NOAELs in both oral and dermal studies, and that 

bromoxynil octanoate produces supernumerary ribs at the maternal NOAEL in a dermal study. 

Supernumerary ribs were observed in rats, mice and rabbits after oral and/or dermal 

administration, and more severe developmental effects were seen at the maternal LOAEL and 

higher doses. Therefore, there is evidence of quantitative susceptibility in the data base. 

However, clear NOAELs for the developmental effects, and basing the point of departure on 

these effects addresses HED concerns for quantitative susceptibility.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. Although the dietary assessments 

conducted with DEEM-FCID were refined, HED does not believe that the exposure estimates are 

underestimated because the data were based on reliable and acceptable field trial and feeding 

studies and estimates of percent crop treated. The assessment utilized anticipated residues for all 

livestock commodities, average field trial residues for all grains in the acute assessment, average 

field trial residues for all crops except spearmint and peppermint in the chronic assessment, 

average estimates of percent crop treated in the chronic assessment and, maximum estimates of 

percent crop treated in the acute assessment. In addition, default processing factors were 

assumed for all commodities. The DEEM analysis also assumed that all drinking water will 
Page 22 of 72

contain bromoxynil at the highest EDWC levels modeled by EFED for surface water. For these 

reasons it can be concluded that the DEEM-FCID analysis does not underestimate risk from 

acute or chronic exposure to bromoxynil. In addition, there are no registered residential uses.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

In the previous risk assessment (D246944, B. Madden, 6/24/1998), the FQPA 10X uncertainty

factor was retained for the Acute Dietary Females 13+ endpoint despite the point of departure 

being an adverse effect (supernumerary ribs) in the fetus. The primary reason for the retention 

was an apparent steepness of the dose-response curve (NOAEL = 4 mg/kg/day, LOAEL = 5 

mg/kg/day) derived by combining the results of two co-critical studies. However, a more refined 

data evaluation tool, benchmark dose (BMD) analysis, has become available and HED has been 

using it in the risk assessment process.

As mentioned in Section 4.4, the results returned by the BMD analysis (D386424, M. Ottley, 

TXR 0055648) suggest a point of departure substantially higher than the NOAEL of 4 

mg/kg/day, which supports the position that the NOAEL of 4 mg/kg/day is adequately protective 

of this adverse effect in rat fetuses without an addition safety factor. Secondly, the BMD 

analysis results, which took into consideration all the doses and responses in the studies, indicate 

that the dose-response curve is not steep as previously thought. As such, there remained no basis 

for retention of the 10X, and for this risk assessment it has been removed. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

There is no potential for residential exposure from the proposed and existing uses of bromoxynil. 

However, occupational workers will be exposed from dermal and inhalation routes. Effects of 

supernumerary ribs were observed in both dermal and oral developmental studies. Since a 

common toxicological effect was identified, these routes of exposure can be combined to 

estimate combined occupational risk.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Bromoxynil phenol has been classified by the HED Cancer Assessment and Review Committee 

as a Group C, possible human carcinogen, based on a treatment-related increased incidence of 

hepatocellular adenomas, carcinomas and adenomas/carcinomas combined in mice (E. Budd and 

E. Rinde, 3/12/1997, TXR 0050045).

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

Assessment

The details for selecting toxicity endpoints and points of departure for various exposure 

scenarios are presented in Appendix A. The following table provides the information in 

summary form.
Page 23 of 72

Table 4.5.4a Summary of Toxicological Doses and Endpoints for Bromoxynil for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQ

PA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

NOAEL= 8 

mg/kg/day

UFA= 10 x

UFH=10 x

FQPA SF=1x

Acute RfD = 

0.08 

mg/kg/day

aPAD = 0.08 

mg/kg/day

Subchronic Study in Dogs

The LOAEL for effects attributed to a 

single dose was 12 mg/kg based on 

panting. In addition to panting, elevated 

rectal temperatures occurred at 16 mg/kg 

and above, and death occurred at 30 

mg/kg and above after a single dose on 

day 1

Acute Dietary

(Females 13-

49 years of 

age)

NOAEL 4 

mg/kg/day

UFA= 10 x

UFH=10x

FQPA SF=1x

Acute RfD = 

0.04 

mg/kg/day

aPAD = 0.04 

mg/kg/day

Developmental Studies in Rats 

The LOAEL of 5 mg/kg/day is based on 

an increase of supernumery ribs from 

MRID 00116558. The NOAEL is derived 

from a co-critical study (MRID 40466802)

Chronic 

Dietary (All 

Populations)

NOAEL= 1.5 

mg/kg/day

UFA= 10 x

UFH=10 x

FQPA SF=1x

Chronic RfD 

= 0.015

mg/kg/day

cPAD = 0.015 

mg/kg/day

Chronic (1 year) Study in dogs

The LOAEL of 7.5 mg/kg/day, M & F is 

based on increased incidences of 

salivation, panting, liquid feces and pale 

gums; statistically significant decreased 

body weight gain over entire duration of 

study, but particularly during first 8 weeks 

of study; statistically significant decreased 

erythrocytes (RBC), hemoglobin (Hb) and 

packed cell volume (PCV); statistically 

significant increased urea nitrogen; 

increased absolute liver weights and

liver/body weight ratios. 

Incidental 

Oral, Dermal, 

and Inhalation 

Short-Term

(1-30 days)

and 

Intermediate 

Term

(1-6 months)

Points of Departure for these exposure scenarios were not selected because there are no proposed 

or established uses which result in residential exposure. 

 

Cancer (oral, 

dermal, 

inhalation)

Bromoxynil phenol has been classified by the HED Carcinogenicity Peer Review Committee (E. 

Budd and E. Rinde, 3/12/1997, TXR 0050045) as a Group C, possible human carcinogen, based 

on male mouse hepatocellular tumors. The committee also recommended that a low dose 

extrapolation model (Q1*) be applied to the experimental animal tumor data for quantification of 

human risk. Q1* = 0.103 (mg/kg/day)-1

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). FQPA SF = FQPA Safety Factor. PAD = 
Page 24 of 72

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable.

Table 4.5.4b Summary of Toxicological Doses and Endpoints for Bromoxynil for Use in Occupational Human 

Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal Shortand 

IntermediateTerm (1-30 

days)

NOAEL= 

10 

mg/kg/day 

UFA= 10 x

UFH=10 x

Occupational LOC 

for MOE = 100

Dermal developmental toxicity study –

Rats

The LOAEL of 15 mg/kg/day based on 

increased incidence of supernumerary 

(14th) ribs.

Inhalation 

Short- and 

IntermediateTerm (1-30 

days)

NOAEL= 4 

mg/kg/day

UFA= 10 x

UFH=10 x

Occupational LOC 

for MOE = 100

Oral developmental toxicity study in rats. 

NOAEL of 4 mg/kg/day was selected from 

one study (MRID 40466802, LOAEL = 

mg/kg/day) and the LOAEL of 5 

mg/kg/day was selected from another 

study (MRID 00116558, NOAEL not 

established). Both studies showed a doserelated increased incidence of 

supernumerary ribs at the LOAEL. 

Cancer (oral, 

dermal, 

inhalation)

Bromoxynil phenol has been classified by the HED Carcinogenicity Peer Review Committee (E. 

Budd and E. Rinde, 3/12/1997, TXR 0050045) as a Group C, possible human carcinogen, based 

on male mouse hepatocellular tumors. The committee also recommended that a low dose 

extrapolation model (Q1*) be applied to the experimental animal tumor data for quantification of 

human risk. Q1* = 0.103 (mg/kg/day)-1

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). 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.

Based on the available toxicity database and the Agency's current practices, the inhalation risk 

for bromoxynil was assessed using an oral toxicity study. The Agency sought expert advice and 

input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity

studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide 

Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final 

report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). 

The Agency is in the process of evaluating the SAP report and may, as appropriate, re-examine 

and develop new policies and procedures for conducting inhalation risk assessments, including 

route to route extrapolation of toxicity data. If any new policies or procedures are developed, the 

Agency may revisit the need for an inhalation toxicity study for bromoxynil and/or a reexamination of the inhalation toxicity risk assessment.

4.6 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by 
Page 25 of 72

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA has issued test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Bromoxynil is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

5.0 Dietary Exposure and Risk Assessment 

Sources: Bromoxynil. Petition for Tolerances in Support of New Uses on Grass and Grain 

Sorghum. Summary of Analytical Chemistry and Residue Data. D378614, N. Dodd, 2/15/11.

Bromoxynil: Acute, Chronic, and Cancer Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessments for the New Uses on Grass and Grain Sorghum. D378615, C. 

Walls, 3/22/11. 

Drinking Water Assessment for Ground and Aerial Applications of Bromoxynil on Grass Grown 

for Seed and Ground Application of Sorghum. D374620, T. Mason, 12/16/10. 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

PRIMARY CROPS: The nature of the residue in alfalfa, sweet corn, and cotton following 

application of 14C-bromoxynil octanoate is adequately understood. The metabolic pathway

involves hydrolysis of the ester, oxidation of the nitrile group to the acid via the amide, and 

conjugation; debromination occurs in a parallel pathway. 
Page 26 of 72

The translocation of bromoxynil octanoate in cotton is extremely minimal. Bromoxynil 

octanoate (14C-labelled) was applied to a single leaf or boll and harvested after 7 days (from 

leaves) or 47 days (from bolls). A very small amount (0.15% or less of the total radioactive 

residue [TRR]) was translocated to adjacent leaves. No residues were found in cottonseed.

However, transgenic cotton metabolizes bromoxynil primarily to 3,5-dibromo-4-hydroxybenzoic 

acid (DBHA) [78.6% of the total radioactive residues (TRR)]. 

ROTATIONAL CROPS: A confined rotational crop study was conducted on spinach, beets, and 

wheat with 14C-bromoxynil octanoate. Low level residues of multiple, polar components were 

found in the rotational crops. The field rotational crop studies in winter wheat, collard greens 

and radishes are adequate to demonstrate that detectable bromoxynil residues would not be 

expected in crops rotated at 30 days (or more) following application of bromoxynil octanoate to 

primary crops.

 

RUMINANTS: The nature of the residue in ruminants is adequately understood for bromoxynil. 

When 14C-bromoxynil octanoate was administered to lactating goats, 90% of the TRR was 

recovered as bromoxynil per se. The parent compound was found only in milk (1.7% of the 

TRR). DBHA was found only in liver (4% of the TRR).

POULTRY: The nature of the residue in poultry is adequately understood for bromoxynil. 

When 14C-bromoxynil octanoate was administered to laying hens, 73-100% of the TRR was 

recovered as bromoxynil per se. The parent compound was found only in eggs (4-6% of the 

TRR). Polar unknowns accounted for 3% of the TRR in liver.

RAT: Bromoxynil heptanoate and octanoate are rapidly absorbed and widely distributed in 

most tissues. Most of the radioactivity was excreted in the urine, mostly in the form of 

bromoxynil phenol. There was no significant retention in tissues after 7 days. Bromoxynil 

heptaonate and octanoate were metabolized to bromoxynil phenol via ester hydrolysis. 

5.1.2 Summary of Environmental Degradation

Bromoxynil octanoate is chemically and physically similar to bromoxynil heptanoate. Both 

esters rapidly degrade to bromoxynil phenol (bromoxynil). Bromoxynil octanoate is mobile and 

non-persistent. It dissipates in the environment by abiotic hydrolysis, photolytic degradation, 

and microbial-mediated metabolism in both the aerobic and anaerobic environments. 

Bromoxynil octanoate readily hydrolyzes to bromoxynil phenol and then further degrades to 

CO2. 

Bromoxynil phenol is more persistent in the environment than bromoxynil octanoate. Residues 

of bromoxynil are moderately to highly mobile in soils and do not break down by abiotic 

processes, such as hydrolysis and photolysis. However, bromoxynil rapidly degrades under 

aerobic and anaerobic conditions. 

Bromoxynil may move from the treated field to surface water or ground water through run-off 

shortly after application. The field dissipation studies show that bromoxynil residues dissipated 

with half-lives of 1 to 14 days and were not detected below 15 cm soil depth indicating that 
Page 27 of 72

leaching is not an anticipated route of dissipation, likely due to the rapid degradation rate. 

Although, bromoxynil is mobile, it has a short metabolic half-life in soil under aerobic conditions

and it should not be a ground water concern in most environments. In the event that bromoxynil 

did reach ground water, it is expected to degrade slowly due to microbial activity (faster under 

aerobic conditions than anaerobic conditions) but is rather persistent otherwise. 

5.1.3 Comparison of Metabolic Pathways

In primary crops, bromoxynil phenol was the major residue identified in various matrices. 

Transgenic cotton metabolizes bromoxynil primarily to 3,5-dibromo-4-hydroxybenzoic acid 

(DBHA). 

In rotational crops, bromoxynil phenol was not identified. Only low level residues of multiple, 

polar components were found in the rotational crops

 

In drinking water, the residue of concern for risk assessment is bromoxynil phenol.

In ruminants, the primary residue identified in milk was bromoxynil phenol. The metabolite 

DBHA was also identified as a minor residue in liver. 

In the rat, the metabolism of bromoxynil heptanoate and octanoate proceeded via ester hydrolysis 

to bromoxynil phenol.

5.1.4 Residues of Concern Summary and Rationale

Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment 

and Tolerance Expression

Matrix Residues included in Risk 

Assessment

Residues included in Tolerance 

Expression

Plants

Primary Crop (except cotton)

Cotton

Bromoxynil (phenol)

Bromoxynil (phenol)+ DBHA

Bromoxynil (phenol)

Bromoxynil (phenol)+ DBHA

Rotational Crop Bromoxynil (phenol) Bromoxynil (phenol)

Livestock

Ruminant Bromoxynil (phenol)+ DBHA Bromoxynil (phenol)

Poultry Bromoxynil (phenol) + DBHA Bromoxynil (phenol)

Drinking Water Bromoxynil (phenol) Not Applicable

Rationale:

Plants

Primary Crops: The nature of the residue in plants is adequately understood for the presently 

proposed crops based on metabolism studies on alfalfa, sweet corn, and cotton. In all primary

crops except cotton, bromoxynil phenol is the residue of concern for the tolerance expression and 
Page 28 of 72

for risk assessment since it was the major residue detected. Because 78.6% of the bromoxynil 

residues in transgenic cotton are metabolized to DBHA, the cotton residues of concern for the 

tolerance expression and for risk assessment are bromoxynil and its metabolite DBHA.

Rotational Crops: The nature of the residue in rotational crops is adequately understood based 

on an acceptable confined rotational crop study conducted on winter wheat, collard greens and 

radishes. Residues were less than the limit of quantitation (<0.02 ppm) in winter wheat forage, 

radish tops and roots, and in collard greens harvested from the 30-day plantback plots; residues 

were less than the limit of detection (<0.01) in wheat grain and straw harvested from the 30-day

interval. Based on the rotational crop data, plant-back intervals of 30 days are adequate for all 

rotational crops planted after application of bromoxynil octanoate and heptanoate.

Livestock 

Ruminants: The nature of the residue in ruminants is adequately understood based on an 

acceptable study conducted on lactating goats with14C-bromoxynil octanoate. 90% of the TRR 

was recovered as bromoxynil per se. The parent compound was found only in milk (1.7% of the 

TRR). DBHA was found only in the liver (4% of the TRR). Since the metabolite DBHA is 

found in commodities considered to be livestock feed items, the potential for transfer of 

secondary residues to livestock exists. The HED Metabolism Committee has concluded that 

DBHA could transfer to livestock tissues in proportion to the parent but is no more toxic than 

parent. Thus, the residues of concern in ruminants for risk assessment are bromoxynil phenol 

and DBHA. The residue of concern for the tolerance expression is bromoxynil phenol.

Poultry: The nature of the residue in poultry is adequately understood based on an acceptable 

study conducted on laying hens with14C-bromoxynil octanoate. 73-100% of the TRR was 

recovered as bromoxynil per se. The parent compound was found only in eggs (4-6% of the 

TRR). Polar unknowns accounted for 3% of the TRR in liver. Because the metabolite DBHA is 

found in commodities considered to be livestock feed items, residues of concern in poultry for 

risk assessment are bromoxynil and DBHA. The residue of concern for the tolerance expression 

is bromoxynil.

Drinking Water

Bromoxynil octanoate is chemically and physically similar to bromoxynil heptanoate. Since 

both esters rapidly degrade to bromoxynil phenol, the drinking water residue of concern for risk 

assessment is bromoxynil.

5.2 Food Residue Profile

Crop Field Trials

The submitted magnitude of the residue data, summarized in Table 5.2.1, are adequate for risk 

assessment and tolerance assessment. For all crops, the number and locations of field trials are 

adequate and the field trials reflect the proposed use patterns. Two spray applications of the 

formulated HUSKIE product were made to each crop. No adjuvants were used. The Agency’s 
Page 29 of 72

tolerance spreadsheet, as specified by the Guidance for Setting Pesticide Tolerances Based on 

Field Trial Data SOP, was used to determine appropriate tolerance levels. Based on the 

available data and estimated residue values, all proposed tolerances are adequate. However, 

HED is recommending that the established tolerance of 0.5 ppm on the forages of grain sorghum 

be increased to 0.8 ppm. 

TABLE 12. Summary of Residue Data from Crop Field Trials with Bromoxynil

Matrix

Total 

Applic. 

Rate

lb a.i./A

(kg a.i./ha)

PHI (days)

Residue Levels1(ppm)

n Min. Max. HAFT2 Median

(STMdR)

Mean

(STMR)

Std. 

Dev.

Grass (proposed use = 0.44 lb ai/A total application rate, 7-day PHI forage; 30-day PHI hay)

Grass Forage

0.43 - 0.51

(0.48 -

0.57)

0 24 3.37 37.8 37.1 18.2 18.9 11.6

7-11 24 0.0921 14.2 13.7 0.520 2.81 5.03

Grass Hay

0.43 - 0.45

(0.48 -

0.50)

28-31 24 <0.01 2.26 2.05 0.089 0.333 0.58

Grain Sorghum (proposed use = 0.44 lb ai/A total application rate, 7-day PHI forage; 60-day PHI grain and stover)

Sorghum Forage 4 0.431 -

0.442

(0.482 -

0.498)

0 24 4.16 27.2 25.2 11.1 12.0 5.21

5 to 8 24 0.072 0.61 0.58 0.28 0.30 0.16

ECH3(32 to 82) 24 <0.01 0.30 0.30 <0.01 0.037 0.081

Sorghum Grain456 to 60 24 <0.01 0.11 0.103 0.011 0.028 0.030

Sorghum Stover456 to 60 24 0.011 0.11 0.097 0.060 0.061 0.032

1 Grass LLMV = 0.01 ppm for grass forage and grass hay. LOD = 0.00531 ppm for forage and 0.00287 ppm for hay;

Grain Sorghum LLMV = 0.01 ppm for forage, grain, and stover. LOD = 0.00246 ppm for forage, 0.00379 ppm for 

grain, or 0.00315 for stover. LLMV (0.01 ppm) was used when values were <LLMV.

2 HAFT = Highest Average Field Trial.

3 ECH = Earliest commercial harvest

4 Residues reported as bromoxynil phenol.

Processing Studies

There are no processed commodities associated with use on grass. 

The processed commodity associated with use on grain sorghum is flour; however, residue data 

are not needed on sorghum flour at this time since it is used exclusively in the United States as a 

component for drywall, and not as either a human food or feedstuff.

Residues in aspirated grain fractions must be determined for uses on corn, sorghum, soybeans, 

and wheat. Studies on residues in aspirated grain fractions of barley, corn, sorghum, and wheat 

have been previously reviewed and deemed adequate to support a tolerance on aspirated grain 

fractions (grain dust). The studies all indicate that residues concentrate in aspirated grain 

fractions. Because the tolerance on the grain of grain sorghum is being increased from 0.05 ppm 

to 0.2 ppm, higher residues may occur in aspirated grain fractions. Therefore, HED is 

recommending that the established tolerance of 0.3 ppm grain, aspirated grain fractions be 

increased to 1.2 ppm based on the new sorghum grain field trial data and established 

concentration factor.
Page 30 of 72

Storage Stability

Adequate storage stability data are available to support the storage durations and conditions of 

samples from the submitted crop field trial studies on grain sorghum and grass. Storage stability

data are available that demonstrate that bromoxynil residues are stable in the forage, grain, and 

stover of grain sorghum and in the forage, hay, and seed of grass stored frozen at -10°C for 12 

months.

Meat, Milk, Poultry, and Eggs

Livestock feed items associated with grass are forage, hay, and silage and the livestock feed 

items associated with grain sorghum are grain, forage/silage, stover and aspirated grain fractions

(Table 1 Feedstuffs, June 2008). Maximum reasonably balanced dietary burdens (MRBDB) of 

bromoxynil were updated for beef cattle, dairy cattle, swine, and poultry. The resulting dietary

burdens are now 1.6 ppm for beef cattle, 32.7 ppm for dairy cattle, 0.48 ppm for poultry, and 

0.39 ppm for swine. Following re-evaluation of the available animal feeding studies in 

consideration of the recalculated dietary burdens, HED concludes that the established tolerance

for residues of bromoxynil for milk should be increased from 0.1 ppm to 0.4 ppm. Other 

livestock tolerances remain unchanged. 

Rotational Crops

No tolerances are required for rotational crops. The confined rotational crop study indicated that 

no residues of concern are expected to occur in rotational crops with appropriate plant-back 

intervals. 

5.3 Water Residue Profile

Estimated surface water and groundwater concentrations are shown in Table 5.3.1. 

The dietary exposure assessment used values of 11.5 ppb for acute and 0.19 ppb for chronic 

(non-cancer and cancer) assessments. The drinking water assessment is based on Tier I surface 

water model simulations for the proposed sorghum bromoxynil use. Since bromoxynil 

heptanoate is chemically and physically similar to bromoxynil octanoate and both esters rapidly 

degrade to bromoxynil phenol, all calculations were performed in terms of bromoxynil phenol.

Table 5.3.1 Summary of Estimated Surface Water and Groundwater Concentrations 

for Bromoxynil.

a

Scenario Surface Water Conc., ppb b Groundwater Conc., ppt

c

Acute 11.5 3.26

Chronic (non-cancer) 0.19 3.26

Chronic (cancer) 0.19 3.26

a DP#374620, Tiffany Mason, 12/16/2010.

b

From the Tier I FIRST model (FQPA Index Reservoir Screening Tool). Input parameters are based on 2 

applications at 0.305 lbs ai/A on sorghum 11 days apart

c

From the SCI-GROW model (Screening Concentration in Groundwater) 
Page 31 of 72

Monitoring data for bromoxynil are available from the USGS NAWQA surface and ground 

water database and California Department of Pesticide Regulation (CDPR) surface water 

database. The NAWQA database had taken 7,218 samples for bromoxynil across the United 

States. It is believed that these samples represent bromoxynil phenol, but cannot be verified since 

USGS did not differentiate between bromoxynil phenol, bromoxynil octanoate, bromoxynil 

heptanoate, or bromoxynil butyrate. Out of 7, 218 samples, there were 54 confirmed detections 

ranging in concentration from 0.001 μg/L to 6.1 μg/L. Of those 54 detections, 40 were samples 

taken from streams, 8 from ground water sources, 4 from waste water treatment effluent, and 1 

from a water distribution system. The rest of the samples were below the detection limit.

The CDPR database looked for both bromoxynil and bromoxynil octanoate. Out of 531 samples 

and approximately 29 sites, taken from February 8, 1993 to January 6, 2005, 192 were for 

bromoxynil octanoate, and 339 were for bromoxynil. There were two detections, one for 

bromoxynil and one for bromoxynil octanoate. Both occurred on May 9, 1997 in Yolo County, 

CA with a concentration of 0.06 μg/L. It is possible these two detections at the same location, 

date, and concentration could be the same bromoxynil compound. 

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Refined dietary acute and chronic analyses were conducted for bromoxynil. The acute 

assessment used average field trial values for all grains since they are considered to be blended 

commodities. It also utilized tolerance levels for cotton, garlic, onion, peppermint and spearmint 

as well as anticipated residues for livestock commodities based on the results from the crop field 

trials and animal feeding studies (D378614, Nancy Dodd, 17-NOV-2010). Default processing 

factors were used. 

The chronic and cancer analyses used average field trial residues for all commodities except

spearmint and peppermint where tolerance values were used. Livestock anticipated residues 

were estimated using average percent crop treated data, average field trial residue values, and 

results from the animal feeding studies (D378614, Nancy Dodd, 17-NOV-2010). Default 

processing factors were used. Table 5.4.1 summarizes the bromoxynil residue levels and 

processing factors for all crops and livestock commodities used in the acute, chronic and cancer 

dietary assessments. 

Table 5.4.1. Summary of Bromoxynil Residue Levels For All Crops Used in Acute, Chronic, and Cancer 

Analyses.

Matrix Anticipated Residue

[Acute] (ppm)

Anticipated Residue

[Chronic/Cancer] (ppm)

Processing Factors

Alfalfa 0.13 0.13

Cereal grains 

 Barley

 Corn

 Oats

 Rye

 Wheat

0.01 0.01 Corn Syrup: 1.5

Flax, seed 0.01 0.01
Page 32 of 72

Table 5.4.1. Summary of Bromoxynil Residue Levels For All Crops Used in Acute, Chronic, and Cancer 

Analyses.

Matrix Anticipated Residue

[Acute] (ppm)

Anticipated Residue

[Chronic/Cancer] (ppm)

Processing Factors

Sorghum 0.028 0.028

Cotton 1.5 0.3

Garlic 0.1 0.01

Onion 0.1 0.01 Dried: 9.0

Mint (peppermint and spearmint) 0.1 0.1

Cattle, goat, horse, sheep; Fat 0.13 0.0024

Cattle, goat, horse, sheep; 

meat byproducts

Kidney: 0.43

Liver: 0.38

Kidney: 0.0081

Liver: 0.0070

Cattle, goat, horse, sheep Meat 0.070 0.0013 Dried:1.92

Egg 0.0038 0.000078

Hog, fat 0.0062 0.00015

Hog, meat byproducts Kidney: 0.020

Liver: 0.018

Kidney: 0.00051

Liver: 0.00044

Hog, meat 0.0033 0.000083

Milk 0.0032 0.00054

Poultry, fat 0.0061 0.00013

Poultry, meat byproducts Liver: 0.048 Liver: 0.00099

Poultry, meat 0.0038 0.000078

The drinking water residue levels used in the dietary assessment were estimated using Tier I

FIRST Version 1.1.1 (FQPA Index Reservoir Screening Tool) modeling. The Estimated 

Drinking Water Concentration (EDWC) for bromoxynil residues are surface water residues 

based on applications to sorghum. The EDWC for total bromoxynil residues is 11.5 ppb for the 

acute and 0.19 ppb for both the chronic and cancer assessments. The water residues were 

directly incorporated in the DEEM-FCID into the categories “water, direct, all sources” and 

“water, indirect, all sources.” 

5.4.2 Percent Crop Treated Used in Dietary Assessment

Actual bromoxynil percent crop treated data provided in the Screening Level Usage Analyses 

(SLUA) from the Biological and Economic Analysis Division (BEAD) were used in the acute, 

chronic and cancer dietary assessments (D382833, Arthur Grube, 22-OCT-2010) and (D378991, 

Jihad Alsadek, 08-July-2010). 

The following maximum percent crop treated estimates were used in the acute dietary risk 

assessment for the following crops that are currently registered for bromoxynil: alfalfa: 2.5%;

barley: 35%; corn: 5%; oats: 5%; rye: 1%; wheat: 35%; flax: 35%; cotton: 5%; sorghum: 2.5%;

garlic: 70%; onion: 70%; and mint: 25%. 

The following average percent crop treated estimates were used in the chronic and cancer dietary

risk assessments for the following crops that are currently registered for bromoxynil: alfalfa: 

1%; barley: 20%; corn: 2.5%; oats: 5%; rye: 1%; wheat: 15%; flax: 35%; cotton: 2.5%; sorghum: 

2.5%; garlic: 50%; onion: 55%; and mint: 25%.
Page 33 of 72

It should be noted that the sorghum percent crop treated values used in the acute and chronic 

assessments were based on existing uses. Because there is a proposed change in the sorghum use 

pattern (i.e., shorter PHI), there is a potential for a change in the percent crop treated value. 

However, grain sorghum is a small contributor to the overall livestock dietary burden estimate. 

If the percent crop treated value for sorghum was assumed to be 100%, the overall impact to the 

dietary exposure and risk assessment would be negligible. 

5.4.3 Acute Dietary Risk Assessment

A refined dietary acute analysis was conducted for bromoxynil. For all grains, average field trial 

values were used since grains are considered to be blended commodities. Tolerance levels were 

used for cotton, garlic, onion, peppermint and spearmint. Livestock anticipated residues were 

estimated using results from the crop field trials and animal feeding studies. Additionally, 

maximum percent crop treated estimates provided by BEAD were used for all crop commodities. 

Default processing factors were used. A conservative EDWC derived through EFED modeling 

which is unlikely to underestimate the concentration of bromoxynil in drinking water was

utilized. The surface water EDWC (11.5 μg/L) was incorporated directly into the dietary

assessment.

As shown in Table 5.4.6, the acute dietary (food and drinking water) exposure to bromoxynil is 

below HED’s level of concern [i.e., <100% of the chronic Population Adjusted Dose (cPAD)] 

for the general U.S. population and all population subgroups at the 99.9th percentile of the 

exposure distribution. The acute dietary exposure estimates are 3.3% of the aPAD for the 

general U.S. population and 7.4% of the aPAD for all infants (<1 year old), the most highly

exposed population subgroup. 

5.4.4 Chronic Dietary Risk Assessment

Refined dietary chronic and cancer analyses were conducted for bromoxynil. Average field trial 

residues were used for all commodities except for spearmint and peppermint where tolerance 

values were used. Livestock anticipated residues were estimated using average percent crop 

treated data, average field trial residue values, and results from the animal feeding studies. 

Additionally, average percent crop treated estimates provided by BEAD were used for all crop 

commodities. Default processing factors were used. A conservative EDWC derived through 

EFED modeling which is unlikely to underestimate the concentration of bromoxynil in drinking 

water was utilized. The surface water EDWC (0.19 μg/L) was incorporated directly into the 

dietary assessment.

As shown in Table 5.4.3, the non-cancer chronic dietary (food and drinking water) exposure to 

bromoxynil is below HED’s level of concern [i.e., <100% of the chronic Population Adjusted 

Dose (cPAD)] for the general U.S. population and all population subgroups. The chronic dietary

exposure estimates are 0.1% of the cPAD for the general U.S. population and 0.3% of the cPAD 

for children 1-2 years old, the most highly exposed population subgroup. 
Page 34 of 72

5.4.5 Cancer Dietary Risk Assessment

Bromoxynil is a possible human carcinogen and requires a quantitative cancer risk assessment. 

The unit risk, Q1* = 0.103 (mg/kg/day)

-1

, of bromoxynil is based upon on male mouse 

hepatocellular tumors. The surface water EDWC (0.19 μg/L) was incorporated directly into the 

dietary assessment. As shown in Table 5.4.6, the cancer dietary (food and drinking water) 

exposure estimate for the general U.S. population is 1.5 x 10-6, which is below HED’s level of 

concern (generally in the range of 10

-6

).

5.4.6 Summary Table

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

Population Subgroup

Acute Dietary

(99.9th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.002639 3.3 0.000014 ‹1% 0.000014 1.5 x 10-6

All Infants (< 1 year old) 0.005892 7.4 0.000024 ‹1%

N/A N/A

Children 1-2 years old 0.003714 4.6 0.000040 ‹1%

Children 3-5 years old 0.003527 4.4 0.000032 ‹1%

Children 6-12 years old 0.002151 2.7 0.000021 ‹1%

Youth 13-19 years old 0.002507 3.1 0.000013 ‹1%

Adults 20-49 years old 0.001965 2.5 0.000011 ‹1%

Adults 50+ years old 0.001482 1.9 0.000010 ‹1%

Females 13-49 years old 0.001756 4.4 0.000011 ‹1%

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no currently registered or proposed residential uses of bromoxynil. 

6.1 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for bromoxynil. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 
Page 35 of 72

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

7.0 Aggregate Exposure/Risk Characterization

Under FQPA, HED must consider and aggregate pesticide exposures and risk from three major 

sources: food, drinking water, and residential exposures. 

7.1 Acute Aggregate Risk

There is potential acute exposure via the diet (food and drinking water). Refer to Section 5.3.

7.2 Short- and Intermediate- Term Aggregate Risk

Since there are no residential uses for bromoxynil, short- and intermediate-term aggregate 

assessments were not conducted.

7.3 Chronic Aggregate Risk

There is potential chronic exposure via the diet (food and drinking water). Refer to Section 5.4.

7.4 Cancer Aggregate Risk

There is potential chronic cancer exposure via the diet (food and drinking water). Refer to 

Section 5.5.

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 as 

to bromoxynil and any other substances and bromoxynil does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that bromoxynil has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for 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

Source: Bromoxynil: Occupational and Residential Exposure Assessment for Proposed Field 

Uses of Bromoxynil on Grain Sorghum (to include grain and forage), Grass Grown for Seed, 
Page 36 of 72

Conservation Reserve Program Areas and Existing Use Sites of Bromoxynil. D378616, K. Rury, 

4/7/11. 

Bromoxynil is formulated as an emulsifiable concentrate, soluble concentrate, and as a wettable 

powder in water soluble packets (WSB) and can be applied with aerial equipment, chemigation, 

and groundboom sprayers. Application rates for bromoxynil range from 0.21 to 0.5 lb 

bromoxynil per acre. Currently registered bromoxynil agricultural use sites include: corn, 

sorghum, transgenic cotton, seedling alfalfa, flax, garlic, small grains (wheat, barley, oats, and 

rye), onions, grasses grown for seed and sod production, conservation reserve program (CRP) 

areas, non-residential turfgrass, non cropland/industrial sites, and mint. The proposed formulated 

end-use product evaluated in this assessment is labeled under the trade name HUSKIETM 

Herbicide (EPA Reg. No. 264-1023) (Huskie) containing 26.3% bromoxynil and 3.3% 

pyrasulfotole. A separate ORE assessment has been conducted for pyrasulfotole (D375392, A. 

Nowotarski, 09/03/10). This assessment was completed to incorporate amended uses of 

bromoxynil on grain sorghum (to include grain and forage), grass grown for seed, and 

conservation reserve program areas (CRP). This document also reassesses existing uses of 

bromoxynil as the dermal absorption factor has increased and an inhalation endpoint was added 

to the bromoxynil toxicity database. 

9.1 Short-/Intermediate Term Non-Cancer & Cancer Risk For Pesticide 

Handlers

There is a potential for short- and intermediate-term occupational exposure to bromoxynil during 

mixing, loading, and applying, and for short- and intermediate-term post-application activities. 

Chronic exposure is not expected for the proposed use patterns associated with bromoxynil. 

Estimated short- and intermediate-term dermal exposures were compared to the NOAEL of 10 

mg/kg/day from a dermal developmental study in which increased incidence of supernumerary

ribs were seen. Estimated short- and intermediate-term inhalation exposures were compared to 

the NOAEL of 4 mg/kg/day from an oral developmental toxicity study in the rat based on 

increased incidence of supernumerary ribs. 

Chemical-specific data for assessing exposure during pesticide handling activities 

(mixing/loading, applying, and flagging) were not submitted to the Agency in support of this 

Section 3 application. It is HED policy to use data from the Pesticide Handlers Exposure 

Database (PHED) Version 1.1 to assess handler exposures for regulatory actions when chemicalspecific data are not available (HED Science Advisory Council for Exposure, SOP No.7, January

1999). 

9.1.1 Occupational Handler Non-Cancer Risk Estimates 

Daily dermal exposures (assuming 100% absorption and a 60 kg body weight) were compared to 

the NOAEL of 10 mg/kg/day from a dermal developmental study to determine the risk for shortand intermediate-term dermal exposures. Daily inhalation exposures (assuming 100% 

absorption and a 60 kg body weight were compared to the NOAEL of 4 mg/kg/day from an oral 

developmental toxicity study to determine the risk for short- and intermediate-term exposures. 

The MOEs for short-term and intermediate-term dermal and inhalation non-cancer risk estimates 

for the proposed and currently registered use sites of bromoxynil are shown in Table 9.1.1.1. 
Page 37 of 72

Amended Bromoxynil Uses

The results indicate that the MOEs for the proposed uses for occupational handler scenarios were 

not of concern (i.e., an MOE > 100) at some level of personal protection (gloves). The dermal 

MOE was 12 with baseline attire for mixer/loaders, and the dermal MOEs ranged from 2,400 to 

2,600 for applicators. The dermal MOEs with baseline attire plus gloves (PPE-G) ranged from 

1,300 to 1,400 for mixer/loaders and from 2,400 to 2,600 for applicators. Inhalation MOEs 

ranged from 11,000 to 12,000 for mixer/loaders and from 18,000 to 19,000 for applicators. The 

combined (dermal + inhalation) MOE with baseline attire was 12 for mixer/loaders and ranged 

from 2,200 to 2,300 for applicators. Combined (dermal + inhalation) MOEs with baseline attire 

plus gloves (PPE-G) ranged from 1,300 to 1,400 for mixer/loaders and from 2,200 to 2,300 for 

applicators. 

Reevaluation of Existing Bromoxynil Uses

The results indicate that the mixing/loading MOEs for the existing use sites were not of concern 

(i.e., an MOE > 100) at some level of personal protection (gloves) for all crops and application 

methods, except mixing/loading for aerial application to corn and wheat, which requires a closed 

system. The results indicate that MOEs for application of bromoxynil to all existing use sites 

were not of concern at some level of personal protection (gloves). Flagging for bromoxynil 

application was not of concern at baseline attire. 

The dermal MOEs at baseline attire range from 0.34 (risks of concern) to 160 for mixing/loading 

for application to corn and wheat, from 1.2 (risks of concern) to 1,400 for all other crops, from 

200 to 6,000 for applicators, and from 310 to 620 for flaggers. Inhalation MOEs at baseline 

attire were >330 for mixer/loaders, applicators and flaggers and are not of concern. Combined 

(dermal + inhalation) MOEs at baseline plus gloves ranged from 38 to 2,900 for mixer/loaders, 

380 to 4,900 for applicators, and from 270 to 530 for flaggers. Mixing and loading scenarios for 

bromoxynil application to corn and wheat were below HED’s LOC=100 at baseline and PPE-G. 

With coveralls, mixing/loading for application to corn and wheat, the dermal MOE was 57 and 

the combined dermal and inhalation MOEs for ranged from 55 (risk of concern) to 190. In a 

closed system, the dermal MOE for mixing/loading for application to corn & wheat was 120 and 

was 4,800 for inhalation exposure; the combined dermal + inhalation MOE was 110, and 

therefore not of concern. 
Bromoxynil Human Health Risk Assessment DP No. 374609

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Table 9.1.1.1 Summary of Occupational (Non Cancer) Risks of Bromoxynil to Amended and Existing Use Sites

Handler 

Scenario

Dermal MOE Inhalation MOE Combined Dermal/Inhalation MOE

Baseline Baseline + 

Gloves Coveralls Closed System Baseline Respirator Closed System Baseline Baseline + Gloves

Coveralls + 

Respirator

Closed 

System

Amended Uses

Mixer/loader 12 1,300-

1,400

Not Needed

11,000-

12,000

Not Needed

12 1,300-1,400

Not Needed

Applicator 2,400-

2,600

2,400-

2,600

18,000-

19,000 2,200-2,300 2,200-2,300

Existing Uses

Mixer/loader 

(Corn & wheat) 0.34 – 160 43-350 57 120 330-5,700 1,700-5,700 4,800 0.34-160 38-330 55 -190 110

Mixer/loader 

(all other crops) 1.2-1,400 150-3,100 200 11,000-50,000

Not Needed

1.2-1,400 130-2,900

Flagger 310-620 290-570 Not Needed

Not Needed

3,900-7,800 290-580 270-530

Liquid 

Application 200-6,000 430-6,000 3,200-40,000 190-4,900 380-4,900
Bromoxynil Human Health Risk Assessment DP No. 374609

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9.1.2 Occupational Handler Cancer Risk Estimates 

For the proposed use sites of bromoxynil, HED assumed 10 days of bromoxynil exposure per 

year to assess cancer risks to commercial agricultural handlers and 2 days of bromoxynil 

exposure per year to assess risks to private agricultural handlers based on use pattern information 

and maximum treatments per year. For the existing use sites, HED assumed 30 days of 

bromoxynil exposure per year for high acreage crops (corn and wheat), while 10 days of 

exposure per year for all other use sites. Based on the use profile and the maximum number of 

applications allowed per year (1 – 3 applications) these estimates are expected to be a 

conservative representation of exposure to bromoxynil per year. EPA conducted an assessment 

of the carcinogenic risk estimates associated with bromoxynil following exposures to 

occupational handlers. 

The minimum level of PPE for handlers is based on acute toxicity for the end-use product. The 

Registration Division (RD) is responsible for ensuring that PPE listed on the label is in 

compliance with the Worker Protection Standard (WPS) for Agricultural Pesticides. The 

Agency generally considers occupational cancer risk estimates within the range of 1 to 3x10-6

(approximately 1-3 in 1 million persons) or less to be negligible, but may accept risk estimates as 

high as 1x10-4 when all mitigation measures that are feasible and practical have been applied, 

particularly when there are critical pest management needs associated with the use of the 

pesticide. Exposure assumptions and cancer estimates for occupational handlers are summarized 

in Tables 9.1.2.1 and 9.1.2.2. 

Amended Uses (EPA Reg. No. 264-1023)

The results indicate that estimated cancer risks were not of concern (i.e., in the 10-6range or 

lower) for both commercial and private users at some level of personal protection (gloves). The 

cancer risk estimates at baseline attire for commercial users of bromoxynil ranged from 1.7x10-4

to 1.8x10-4for mixer/loaders and was 1.1x10-6 for applicators. The cancer risk estimates at 

baseline plus gloves (PPE-G) for commercial handlers ranged from 2.0x10-6 to 2.1x10-6for 

mixer/loaders and was 1.1x10-6for applicators. The cancer risk estimates with coveralls for 

commercial handlers ranged from 1.4x10-6 to 1.5x10-6for mixer/loaders, and from 8.8x10-7 to 

9.2x10-7for applicators. The cancer risk estimates at baseline attire for private users of 

bromoxynil was 3.5x10-5for mixer/loaders and ranged from 2.1x10-7 to 2.2x10-7 for applicators. 

The cancer risk estimates at baseline plus gloves (PPE-G) for private applicators ranged from 

4.0x10-7 to 4.2x10-7for mixer/loaders and from 2.1x10-7to 2.2x10-7for applicators. The cancer 

risk estimates for private applicators with coveralls ranged from 2.8x10-7 to 3.0x10-7for 

mixer/loaders and the risk was 1.8x10-7for applicators. 

Reevaluation of Existing Bromoxynil Uses

The results indicate that estimated cancer risks were not of concern (i.e., in the 10-6range or 

lower) for both commercial and private users at some level of personal protection (gloves) for all 

scenarios except aerial application to corn and wheat, which requires a closed system. 

The cancer risk estimates at baseline attire for bromoxynil use on currently registered use sites 

ranged from 4.0x10-5to 1.8x10-2 for mixing/loading for application to corn & wheat, from 

1.5x10-6to 6.0x10-3for mixing/loading to all other use sites, from 3.6x10-7to 3.3x10-5for 

applicators and 3.9x10-6to 1.8x10-5for flaggers. The cancer risk estimates at baseline attire plus 
Bromoxynil Human Health Risk Assessment DP No. 374609

Page 40 of 72

gloves ranged from 2.0x10-5to 1.9x10-4for mixing/loading for application to corn & wheat, from 

7.7x10-7to 6.9x10-5for mixing/loading for application to all other use sites, from 6.4x10-7to 

1.6x10-5for applicators and from 6.3x10-6 to 1.9x10-5for flaggers. The cancer risk estimates

with PPE-G and coveralls ranged from 1.3x10-5 to 1.5x10-4for mixing/loading for application to 

corn & wheat, from 4.9x10-7 to 4.4x10-5for mixing/loading for application to all other use sites, 

from 5.0x10-6to 2.0x10-5for flaggers, and from 2.7x10-7to 1.6x10-5for applicators. The cancer 

risk estimates with PPE-G, coveralls and a respirator ranged from 1.1x10-5to 1.2x10-4for 

mixing/loading for application to corn & wheat, from 4.1x10-7to 3.4x10-5 for mixing/loading for 

application to all other use sites, from 4.3x10-6to 1.7x10-5for flaggers, and from 2.5x10-7 to 

1.2x10-5for applicators. With a closed system, the cancer risk estimates ranged from 9.3x10-6 to 

5.6x10-5for mixing/loading for application to corn & wheat, and from 6.2x10-7to 5.4x10-6for 

application to all other use sites. 
Bromoxynil Human Health Risk Assessment DP No. 374609

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Table 9.1.2.1. Summary Table Occupational Cancer Risk Estimates of Bromoxynil for Commercial Applicators to Amended and Existing Use Sites

Handler Scenario

Cancer Risk Estimate

Baseline Baseline + Gloves Coveralls & Baseline 

Inhalation Coveralls + Respirator Closed System

Amended Uses

Mixer/loader 1.7x10-4-1.8x10-42.0x10-6– 2.1x10-61.4x10-6 – 1.5x10-6

Applicator 1.1x10-61.1x10-68.8x10-7– 9.2x10-7

Existing Uses

Mixing/loading 

(corn & wheat) 4.0x10-5 

- 1.8x10-22.0x10-5 - 1.9x10-41.3x10-5 – 1.5x10-41.1x10-5 – 1.2x10-49.3x10-6- 5.6x10-5

Mixing/Loading 

(all other crops) 1.5x10-5 

- 6.0x10-37.7x10-7 - 6.9x10-54.9x10-7– 4.4x10-54.1x10-7 – 3.4x10-56.2x10-7– 5.4x10-6

Flagger 3.9x10-6 – 1.8x10-54.2x10-6 – 1.9x10-55.0x10-6– 2.0x10-54.3x10-6 – 1.7x10-5

Applicator 3.6x10-7– 3.3x10-53.7x10-7– 1.9x10-52.7x10-7- 1.6x10-51.2x10-5– 2.5x10-7
Bromoxynil Human Health Risk Assessment DP No. 374609

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Table 9.1.2.2. Summary Table Occupational Cancer Risk Estimates of Bromoxynil for Private Applicators to Amended Use Sites

Handler Scenario Cancer Risk Estimate

Baseline Baseline + Gloves Coveralls

Amended Uses

Mixer/loader 3.5x10-54.0x10-7- 4.2x10-72.8x10-7 3.0x10-7

Applicator 2.1x10-7-2.2x10-72.1x10-7-2.2x10-71.8x10-7
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9.2 Short-/Intermediate-Term Post-Application Risks

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. 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 the type of activity, the nature of the crop or target that was treated, the type of 

pesticide application, or the pesticide’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 Post-Application Exposure and Cancer Risks

Chemical-specific residue data were not submitted for bromoxynil, therefore, the standard 

assumption regarding dislodgeablity was used to estimate post-application exposure (i.e. HED uses 

20% of the application rate was used as the initial dislodgeable foliar residue (DFR)). The transfer 

coefficients (TC) used in this assessment are from an interim transfer coefficient policy developed 

by HED’s ExpoSAC (Ag Default Transfer Coefficients, Policy 3.1). It is the intention of HED’s 

ExpoSAC that this policy will be periodically updated to incorporate additional information about 

agricultural practices in crops and new data on transfer TCs. 

The default TCs used in this assessment represent a wide range of possible activities at the highest 

exposure levels. HED used extremely conservative inputs to estimate the post-application risk of 

bromoxynil: the assessment of post-application exposure represents high-end, worst-case scenarios. 

For example, full foliage TCs were used for corn, sorghum, wheat, small grains, and mint as the use 

directions allow for later-stage application to the crops. However, bromoxynil is likely to be applied 

more frequently in the early stages of plant growth to be the most effective against competing weeds, 

representing minimal foliage exposure for post-application workers (however the labels do not 

clearly specify early application timing for all crops, so full foliage was still assessed in certain 

scenarios). Additionally, post-application exposure was estimated using default, conservative residue 

values representative of the day of application. Exposure is expected to diminish over time, because 

bromoxynil residues eventually dissipate in the environment. With chemical-specific residue data, 

the residue values could be averaged seasonally to provide a more refined assessment of bromoxynil 

post-application exposure potential. Uncertainty surrounding bromoxynil residues available on 

foliage for transfer could be reduced with chemical-specific DFR studies. 

A summary of the occupational post-application dermal exposure and risk for post-emergent 

application of bromoxynil is provided in Tables 9.2.1.1, 9.2.1.2, 9.2.1.3, and 9.2.1.4.

The Agency assumed post-application exposure to treated crops could occur 30 days per year for 

high acreage crops (corn and wheat) and 10 days for all other crops. Post-application cancer risk 

estimates assume contact with bromoxynil 30 and 10 days per year over a 35 year lifespan and are 

considered a worst case, extremely conservative estimation based on the bromoxynil use pattern. As 

stated above, the Agency generally considers occupational cancer risks in the general range of 1x10-6

to be negligible, but may accept risks as high as 1x10-4 when all mitigation measures that are feasible 

and practical have been applied. 
Bromoxynil Human Health Risk Assessment DP No. 374609

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Amended Use Sites (EPA Reg. No. 264-1023)

The dermal non-cancer short- and intermediate-term MOEs ranged from 150 to 1,500 on the day of 

application. The estimated occupational post-application cancer risks on the day of application 

ranged from 1.4x10-6to 1.1x10-5. Under the WPS for Agricultural Pesticides, a 24-hr REI is 

required for chemicals classified under Toxicity Category II. Therefore, the REI on the HuskieTM 

Herbicide label should be 24 hours. 

Table 9.2.1.1. Occupational Post Application Exposure to Amended Uses of Bromoxynil 

Crop

Maximum 

Proposed 

Application 

Rate (lb 

ai/A)

Activity Foliage 

Development TC1

Days 

After 

Treatment

Transferrable 

Residue2,3

Daily Dose 

(mg/kg/d)4 MOE5

Sorghum2

0.22 Irrigation, 

Scouting Full 1000 0 0.493 0.0658 150

0.22 Scouting Low 100 0 0.493 0.0066 1,500

Grass 

Grown 

for Seed 

and CRP 

Areas3

0.21 Mowing Full 500 0 0.118 0.0078 1,300

1 Transfer Coefficients from HED Policy No. 3.0.

2 DFR (μg/cm2)= application rate x 20% dissipation x 4.54 x108μg/lb x 2.47 x 10-8A/cm2, 

3 TTR (for Grass use sites) (μg/cm2)= application rate x 5% dissipation x 4.54 x108μg/lb x 2.47 x 10-8A/cm2

4 Dermal Dose (mg/kg/day) = DFR(t) or TTR (μg/cm2) x TC (cm2/hr)x hr/day (8 hours) x (1/1000 μg/mg) x (1/ 60 kg bw) 

where DFR(t)is dislodgeable foliar residue at time t

5 Dermal Short-Term MOE = NOAEL (10 mg/kg/day)/Dermal Daily Dose (mg/kg/day)

Table 9.2.1.2. Occupational Post Application Cancer Risk from Amended Agricultural Uses of Bromoxynil 

Crop

Maximum 

Proposed 

Application 

Rate

(lb ai/A)

Activity Foliage 

Development TC1

Days 

After 

Treatment

Transferrable 

Residue2,3

Daily Dose 

(mg/kg/d)4 LADD5

Cancer 

Risk 

Estimate6

Sorghum

0.18 Irrigation, 

Scouting Full 1,000 0 0.40 0.008 0.000107 1.1E-05

0.22 Scouting Low 100 0 0.49 0.0010 0.000013 1.4E-06

Grass 

Grown for 

Seed and 

CRP Areas

0.21 Full

Mowing, 

pruning, 

weeding

500 0 0.12 0.0011 0.000016 1.6E-06

1 Transfer Coefficients from HED Policy No. 3.0.

2 DFR (μg/cm2)= application rate x 20% dissipation x 4.54 x108μg/lb x 2.47 x 10-8A/cm2, 

3 TTR (for Grass use sites) (μg/cm2)= application rate x 5% dissipation x 4.54 x108μg/lb x 2.47 x 10-8A/cm2

4 Dermal Dose (mg/kg/day) = DFR(t) or TTR (μg/cm2) x TC (cm2/hr)x hr/day (8 hours) x (1/1000 μg/mg) x (1/ 60 kg bw) 

where DFR(t)is dislodgeable foliar residue at time t

5 LADD= (Dermal PPE Dose+Inhalation Baseline Dose) x average days of exposure (10/365) x (35 years/70 years).

6 Cancer Risk Estimates = LADD x Q1*, where Q1*=1.03E-1 (mg/kg/day)-1.
Bromoxynil Human Health Risk Assessment DP No. 374609

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Existing Use Sites

The short-and intermediate-term dermal non-cancer MOEs for all occupational post-application 

scenarios ranged from 45 to 1,400 on the day of application; and therefore, some post-application 

activities are of concern. Risk from occupational contact with full foliage wheat, small grains and 

mint is not of concern 8 days after application, risk from sod harvesting is not of concern 5 days after 

application, and risk from occupational contact with full foliage corn, sorghum and cotton is not of 

concern 4 days after application. The estimated cancer risks on the day of application ranged from 

2.3x10-6to 1.4x10-4. 

Table 9.2.1.3. Post Application Exposure from Bromoxynil to Registered Use Sites

Crop

Maximum 

Application 

Rate (lb 

ai/A)

Activity Foliage 

Development TC1 Transferrable Residue2,3

Daily 

Dose 

(mg/kg/d)4

Day 0 

MOE5

Days 

After 

Treatment 

to Reach 

MOE >

LOC

MOE5

Corn 0.5 Irrigation, 

Scouting Full 1,000 1.1032 0.147096 68 4 104

0.5 Scouting Minimum 400 1.1032 0.0588384 170 N/A

Sorghum 0.5 Irrigation, 

Scouting Full 1,000 1.1032 0.147096 68 4 104

0.5 Scouting Low 100 1.1032 0.0147096 680 N/A

Wheat

0.5 Scouting Full 1,500 1.1032 0.220644 45 8 105

0.5 Irrigation, 

Scouting Min 100 1.1032 0.0147096 680 N/A

Other Small 

Grains

0.5 Scouting Full 1500 1.1032 0.220644 45 8 105

0.5 Irrigation, 

Scouting Min 100 1.1032 0.0147096 680 N/A

Cotton 0.5 Scouting Full 1,000 1.1032 0.147096 68 4 104

Seedling 

Alfalfa 0.375 Irrigation, Scouting Min 100 0.8274 0.0110322 910

N/A

Flax 0.25 Scouting Min 100 0.5516 0.0073548 1,400

Garlic 0.5

Irrigation, 

scouting, 

hand 

weeding

Min 300 1.1032 0.0441288 230

Mint

0.5

irrigation, 

scouting, 

weeding

Full 1,500 1.1032 0.220644 45 8 105

0.5

irrigation, 

scouting, 

weeding

Minimum 100 1.1032 0.0147096 680

N/A

Onions 0.375

Irrigation, 

scouting, 

hand 

weeding

Min 300 0.8274 0.0330966 300

Grass 

Grown for 

Sod

0.5 Harvesting Full 5800 0.275805 0.2132892 47 5 102

Grass 

Grown for 

Seed, Non 

Residential 

Turf, NonIndustrial 

Sites

0.5 Mowing Full 500 0.2758 0.018387 540 N/A

1 Transfer Coefficients from HED Policy No. 3.0

2 DFR (μg/cm2)= application rate x 20% dissipation x 4.54 x108μg/lb x 2.47 x 10-8A/cm2, TTR (for Grass use sites) (μg/cm2)= 

application rate x 5% dissipation x 4.54 x108μg/lb x 2.47 x 10-8A/cm2

3 TTR (for Grass use sites) (μg/cm2)= application rate x 5% dissipation x 4.54 x108μg/lb x 2.47 x 10-8A/cm2

4 Dermal Dose (mg/kg/day) = DFR(t) (μg/cm2) x TC (cm2/hr)x hr/day (8 hours) x (1/1000 μg/mg) x (1/ 60 kg bw) where 

DFR(t)is dislodgeable foliar residue at time t

5 Dermal Short-Term MOE = NOAEL (10 mg/kg/day)/Dermal Daily Dose (mg/kg/day)
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Table 9.2.1.4. Post Application Exposure and Cancer Risk to Workers from Bromoxynil Treatment to Registered Use Sites

Crop

Maximum

Application 

Rate (lb 

ai/A)

Activity Foliage 

Development TC1 Exposure Days

Days 

After 

Treatment

Transferrable 

Residue2,3

Daily 

Dose 

(mg/kg/d)4

LADD5

Cancer 

Risk 

Estimate6

Corn 0.5 Irrigation, 

Scouting Full 1000 30 0 1.1214 0.0218 0.00090 9.2E-05

0.5 Scouting Minimum 400 30 0 1.1214 0.0087 0.00036 3.7E-05

Sorghum 0.5 Irrigation , 

Scouting Full 1000 10 0 1.1214 0.0218 0.00030 3.1E-05

0.5 Scouting Low 100 10 0 1.1214 0.0022 0.00003 3.1E-06

Wheat

0.5 Scouting Full 1500 30 0 1.1214 0.0327 0.00134 1.4E-04

0.5 Irrigation, 

Scouting Min 100 30 0 1.1214 0.0022 0.00009 9.2E-06

Other Small 

Grains

0.5 Scouting Full 1500 10 0 1.1214 0.0327 0.00045 4.6E-05

0.5 Irrigation, 

Scouting Min 100 10 0 1.1214 0.0022 0.00003 3.1E-06

Cotton 0.5 Scouting Full 1000 10 0 1.1214 0.0218 0.00030 3.1E-05

Alfalfa 0.375 Irrigation, 

Scouting Low 100 10 0 0.8410 0.0016 0.00002 2.3E-06

Flax 0.75 Scouting Min 100 10 0 1.6821 0.0033 0.00004 4.6E-06

Garlic 0.5

Irrigation, 

scouting, 

hand 

weeding

Min 300 10 0 1.1214 0.0065 0.00009 9.2E-06

Mint

0.5

irrigation, 

scouting, 

weeding

Full 1500 10 0 1.1214 0.0327 0.00045 4.6E-05

0.5

irrigation, 

scouting, 

weeding

Minimum 100 10 0 1.1214 0.0022 0.00003 3.1E-06

Onions 0.375

Irrigation, 

scouting, 

hand 

weeding

Min 300 10 0 0.8410 0.0049 0.00007 6.9E-06

Grass 

Grown for 

Sod

0.5 Harvesting Full 5800 10 0 0.2803 0.0316 0.00043 4.5E-05

Grass 

Grown for 

Seed Non 

Residential 

Turf, NonIndustrial 

Sites 

0.5 Mowing Full 500 10 0 0.2803 0.0027 0.000037 3.8E-06

1 Transfer Coefficients from HED Policy No. 3.0

2 DFR (μg/cm2)= application rate x 20% dissipation x 4.54 x108μg/lb x 2.47 x 10-8A/cm2

3 TTR (for Grass use sites) (μg/cm2)= application rate x 5% dissipation x 4.54 x108μg/lb x 2.47 x 10-8A/cm2

4 Dermal Dose (mg/kg/day) = DFR(t) (μg/cm2) x TC (cm2/hr)x hr/day (8 hours) x Dermal Absorption (17%) x (1/1000 μg/mg) x (1/ 70 kg 

bw) where DFR(t)is dislodgeable foliar residue at time t

5 LADD= (Dermal PPE Dose+Inhalation Baseline Dose) x average days of exposure (30/365) x (35 years/70 years)

6 Cancer Risk Estimates = LADD x Q1*, where Q1*=1.03E-1 (mg/kg/day)-1

Occupational Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment was not performed for bromoxynil at this time. However, 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 
Bromoxynil Human Health Risk Assessment DP No. 374609

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Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the 

SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure data 

generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and 

procedures, to identify the need for and, subsequently, the way to incorporate occupational postapplication inhalation exposure into the Agency's risk assessments. If new policies or procedures are 

put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for bromoxynil.

9.3 Occupational Exposure Data Requirements & Label Changes

To characterize post-application exposure and reduce uncertainty for late applications of 

bromoxynil, HED is requesting the registrant submit a dislodgeable foliar residue (DFR) study on a 

representative row crop (e.g. corn). HED suggests using corn for the study site because in the U.S., 

57% of bromoxynil is applied exclusively to corn and the label allows for bromoxynil application to 

corn later in the growth cycle (post emergence to tassel emergence), resulting in potentially higher 

exposures. 

Based on email correspondence with the registrant (dated 11/01/2010), HuskieTM Herbicide (EPA 

Reg. No. 264-1023) is not intended for application with chemigation or aerially to grain sorghum, 

grass grown for seed and CRP areas. The label should restrict aerial and chemigation explicitly 

from these use sites. 

Existing labels should clarify that products containing bromoxynil are restricted from use on golf 

course turf. 

Under the WPS for Agricultural Pesticides, a 24-hr REI is required for chemicals classified under 

Toxicity Category II. Therefore, the REI on the HuskieTM Herbicide label should be 24 hours. 

Other bromoxynil product labels should also require a 24-hr REI, except for the specific use sites of 

wheat, small grains and mint which require an REI of 8 days, sod harvesting which require an 

REI of 5 days, and corn, sorghum and cotton which require an REI of 4 days.

10.0 Environmental Justice Considerations

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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups 

according to well-established procedures. In line with OPP policy, HED estimates risks to 

population subgroups from pesticide exposures that are based on patterns of that subgroup’s food 

and water consumption, and activities in and around the home that involve pesticide use in a 

residential setting. Extensive data on food consumption patterns are compiled by the USDA under 

the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk 

assessments for all registered food uses of a pesticide. These data are analyzed and categorized by 
Bromoxynil Human Health Risk Assessment DP No. 374609

Page 48 of 72

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 subgroups.

11.0 References

Alsadek, J., 07/08/2010, DP# 378991, Usage Report Package in Support of Registration for the 

Herbicide Bromoxynil, (035302).

Dodd, N., 2/15/2011, DP# 378614, Bromoxynil. Petition for Tolerances in Support of New Uses on 

Grass and Grain Sorghum. Summary of Analytical Chemistry and Residue Data.

Goodlow, T., 8/17/2010, DP# 380770, Bromoxynil: Review of HUSKIE HERBICIDE – Magnitude of 

the Residue in/on Sorghum and Grass

Grube, A., 10/22/2010, DP# 382833, Usage Report Package in Support of Registration for the 

Herbicide Bromoxynil, (035301).

Mason, T., 12/16/2010, DP# 374620, Drinking water assessment for ground and aerial application 

of bromoxynil on grass grown for seed and ground application of sorghum.

Rury, K., 04/07/2011, DP# 378616, Bromoxynil: Occupational and Residential Exposure 

Assessment for Proposed Field Uses of Bromoxynil on Sorghum, Grass Grown for Seed, 

Conservation Reserve Program Areas, and Existing Use sites of Bromoxynil.

Walls, C., 03/22/2011, DP#378615, Bromoxynil: Acute, Chronic, and Cancer Aggregate Dietary 

(Food and Drinking Water) Exposure and Risk Assessments for the New Uses on Grass and Grain 

Sorghum.
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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for non-food use for Bromoxynil are in Table 1. Use of the new guideline numbers 

does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

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

870.3200 21-Day Dermal ..............................................................

870.3250 90-Day Dermal ..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

no

yes

yes

yes

-

-

870.3700a Developmental Toxicity (rodent)...................................

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

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

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen).....................................

870.6100b 90-Day Neurotoxicity (hen)...........................................

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

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Developmental Neurotoxicity........................................

no

no

yes

yes

no

-

-

no

no

-

870.7485 General Metabolism ......................................................

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

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

yes

yes

yes

yes

yes

no
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A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile

Guideline Study Species Results Tox. 

Category

MRID No.

Bromoxynil Phenol Technical

870.1100 Acute oral toxicity Rat LD50 = 81 mg/kg M

LD50 = 93 mg/kg F)

II 00124758

870.1200 Acute dermal toxicity Rat LD50 >= 2000 mg/kg (M, F) III 00124758

870.1300 Acute inhalation 

toxicity

Rat LC5O = 0.269 mg/L M 

LC5O = 0.150 mg/L F

II 43014701

870.2400 Primary eye irritation Rabbit Corneal opacity resolved 

within 3 days; iritis resolved 

within 4 days; conjunctival 

irritation persisted for 10 

days.

II 00124758

870.2500 Primary skin irritation Rabbit Not an irritant IV 00124758

870.2600 Dermal sensitization Guinea 

Pig

Not a sensitizer Negative 42718701

Bromoxynil Octanoate Technical

870.1100 Acute oral toxicity Rat LD50 = 400 mg/kg M

LD50 = 238 mg/kg F

II 00124112

870.1100 Acute dermal toxicity Rabbit LD50> 2000 mg/kg M

 abraded skin.

LD50 1310 mg/kg F

 with intact skin.

LD50 = 1660 mg/kg F

 with abraded skin.

II 00124112

870.1300 Acute inhalation 

toxicity

Rat LC5O = 0.810 mg/L M 

LC5O = 0.720 mg/L F

III 42167101

870.2400 Primary eye irritation Rabbit Corneal opacity and 

irritation lasting 24-72 hrs. 

Cleared by 96 hrs.

II 00124112

870.2500 Primary skin irritation Rabbit Erythema for 72 hrs. No 

edema.,

IV 00124112

870.2600 Dermal sensitization Guinea 

Pig

Contact sensitizer in 

modified Draize test.

Positive 41879801
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat)

MRID 41469101 (1985)

0, 400, 755 or 1456 ppm 

0, 28, 58, 168 mg/kg/day 

M

0, 35, 76,250 mg/kg/day F

Dietary

Supplementary

NOAEL: M = 28 mg/kg/day, F not 

established

LOAEL 

 M = 58 mg/kg/day), based on decreased body 

weight gain, increased ALT, increased AST 

and increased alkaline phosphates. 

 F = 35 mg/kg/day), based on decreased body 

weight gain. This study is of limited usefulness 

because a NOAEL was not determined for 

females, excessive mortality occurred in males 

and females at the highest dose level tested, and 

an insufficient number of tissues was 

microscopically examined.

870.3100 90-Day oral 

toxicity (mouse)

MRID 42553401 (1992)

0, 10, 30, 100, 300, 1000 

or 3000 ppm 

0, 1.3, 3.9, 13, 39, 130 or 

390 mg/kg/day M, F

Dietary

Supplementary

(Range-finding)

NOAEL: M = 3.9 mg/kg/day, F = 13 

mg/kg/day

LOAEL:

 M = 13 mg/kg/day), based on increased liver 

weights and HC hypertrophy

 F = 39 mg/kg/day, based on increased liver 

weights, heptatocellular (HC) hypertrophy, HC 

degeneration and HC vacuolization.

870.3150 90-Day oral 

toxicity rodents 

(dog)

MRID 43166701 (1988)

1, 5, 8, 12, 16, 20, 30, 40 

or 50 mg/kg/day

Capsule

Supplementary

(Range-finding)

NOAEL: M not established, F = 1 mg/kg/day

LOAEL:

 M = 1 mg/kg/day for males, based on 

decreased body weight gain. 

 F = 5 mg/kg/day, based on decreased body 

weight gain, panting and liquid feces.

At doses above the LOAELs M and/or F, the 

following additional effects were observed: 

panting, liquid feces, salivation, unsteady gait, 

decreased erythrocyte count, decreased 

hemoglobin, decreased packed cell volume, 

increased urea nitrogen, vomiting and 

mortality.

Toxicities observed during the first day of the 

study (single dose effects) were elevated rectal 

temperatures, panting and death.

Single dose NOAEL = 8.0 mg/kg 

Single dose LOAEL = 12 mg/kg based on 

panting. Elevated rectal temperatures occurred 

at 16 mg/kg and above, and death occurred at 

30 mg/kg and above
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3200 21-Day dermal 

toxicity (rabbit)

MRID 42272301 (1992)

0, 30, 300 or 1000 

mg/kg/day

Minimum

Dermal 

 NOAEL = not established

 LOAEL = 1000 mg/kg/day

Systemic

 NOAEL = not established

 LOAEL = 1000 mg/kg/day

870.3700a Prenatal 

developmental in 

rats

(MRID 40466802 (1992)

0, 4, 12.5 or 40 mg/kg/day 

on gestation days 6-15

Gavage

Sprague-Dawley

Supplementary

Maternal NOAEL = 12.5 mg/kg/day

Maternal LOAEL = 40 mg/kg/day based on 

decreased body weight gain throughout most of 

the treatment and post-treatment period and 

decreased food consumption during the 

treatment period.

Developmental NOAEL = 4 mg/kg/day

Developmental LOAEL = 12.5 mg/kg/day 

based on increased incidence of supernumerary 

(14th) ribs and Increased post-implantation 

loss. At 40 mg/kg/day, the following additional 

effects were observed in the offspring: reduced 

fetal weight, increased numbers of small 

fetuses, and increased incidences of soft tissue 

and skeletal abnormalities (including 

anophthalmia, microphthalmia, short renal 

papilla, and spinal and thoracic bone 

abnormalities).

870.3700a Prenatal 

developmental in 

rats

MRID 00116558 (1981)

(00070894, 00071084) 

0, 5, 15 or 35 mg/kg/day 

on gestation days 5-17

Gavage

Sprague-Dawley

Supplementary

Maternal NOAEL = 5 mg/kg/day

Maternal LOAEL = 15 mg/kg/day based on 

decreased body weight gain. At 35 mg/kg/day, 

6/28 dams died between days 7 and 14 of 

gestation.

Developmental NOAEL = not established.

Developmental LOAEL = 5 mg/kg/day based 

on increased incidence of 14th ribs. At the high 

dose of 35 mg/kg/day, additional effects 

included an increased incidence of late 

intrauterine deaths, decreased fetal body 

weights and an increase in the total incidence of 

minor anomalies.

870.3700a Prenatal 

developmental in 

rats

Rogers, Francis, Barbee et 

al. (1991)

0, 1.7, 5 or 15 mg/kg/day 

on gestation days 6-15

Gavage

Sprague-Dawley

Not classified.

Maternal NOAEL = 5 mg/kg/day

Maternal LOAEL = 15 mg/kg/day, based on 

decreased body weight gain and increased liver 

weights.

Developmental NOAEL = 5 mg/kg/day

Developmental LOAEL = 15 mg/kg/day, based 

on an increased incidence of supernumerary 

ribs.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700a Prenatal 

developmental in 

rats - dermal

MRID 40881201,

40883601 (1988)

0, 5, 10, 50 or 100 

mg/kg/day for 6 hours/day 

on gestation days 6-15.

Sprague-Dawley

Supplementary

Maternal dermal NOAEL = 100 mg/kg/day

Maternal dermal LOAEL not established

Maternal systemic NOAEL = 50 mg/kg/day

Maternal systemic LOAEL = 100 mg/kg/day 

based on decreased body weight gain and 

decreased food consumption during the 

treatment period..

Developmental NOAEL = 10 mg/kg/day

Developmental LOAEL = 50 mg/kg/day, based 

on increased 14th ribs

870.3700b Prenatal 

developmental in 

(rats)

[MRID 00138149 (1983)

0, 15, 30 or 60 mg/kg/day 

on gestation days 5-20

Gavage

New Zealand White

Guideline

Maternal NOAEL = 15 mg/kg/day

Maternal LOAEL = 60 mg/kg/day, based on 

reduced body weight gain and reduced food 

consumption during the treatment period. 

There were no deaths or clinical signs of 

toxicity associated with treatment..

Developmental NOAEL = not established

Developmental LOAEL = 15 mg/kg/day, based 

on an increased incidence of supernumerary 

ribs. At 60 mg/kg/day, the following additional 

effects were also observed: increased postimplantation loss (due primarily to 5 totally 

resorbed litters), decreased fetal weights, and 

increased numbers of litters and numbers of 

fetuses with major malformations (including 

hydrocephalus, anophthalmia, microphthalmia 

and defects in skull ossification). The 

incidence of total minor anomalies was also 

increased at 60 mg/kg/day.

870.3700b Prenatal 

developmental in 

nonrodents 

(rabbit)

MRID 00142779 (1983)

0, 30, 45 or 60 mg/kg/day 

on gestation days 6-18

Gavage

New Zealand White

Supplementary

Maternal NOAEL = 15 mg/kg/day

Maternal LOAEL = 60 mg/kg/day, based on 

increased mortality (7/23 dams died at this dose 

level) and other clinical signs of toxicity, such 

as anorexia and discharge of blood.

Developmental NOAEL = not established

Developmental LOAEL = 15 mg/kg/day, based 

on decreased fetal body weights. At 45 and 60 

mg/kg/day, a dose-related increase in extra or 

rudimentary 14th ribs also was observed. At 60 

mg/kg/day, several vertebral and thoracic bone 

abnormalities, including fused ribs, scoliosis, 

extra ribs, thoracic centrum misshapen and 

incomplete ossification of sternebrae, were 

observed.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700b Prenatal 

developmental in 

nonrodents 

(rabbit) dermal

MRID 40935101, 

41307801 (1988)

0, 10, 50 or 150 

mg/kg/day for 6 hours/day 

on gestation days 6-18.

New Zealand White

Supplementary

Maternal dermal NOAEL = 150 mg/kg/day

Maternal dermal LOAEL not established

Maternal systemic NOAEL = 50 mg/kg/day

Maternal systemic LOAEL = 150 mg/kg/day 

based on decreased body weight gain.

Developmental NOAEL = 10 mg/kg/day

Developmental LOAEL = 50 mg/kg/day, based 

on an apparent increase in agenesis of the 

intermediate lobe of the lung and on an increase 

in holes in the parietal portion of the skull.

870.3700a Prenatal 

developmental in 

mice – oral

Rogers, Francis, Barbee et 

al. 1991

0, 11, 32 or 96 mg/kg/day 

on gestation days 6-15

Gavage

Swiss Webster (CD-1)

Not Classified

Maternal NOAEL = 11 mg/kg/day

Maternal LOAEL = 32 mg/kg/day, based on 

increased mortality and increased liver weights.

Developmental NOAEL = 32 mg/kg/day

Developmental LOAEL = 96 mg/kg/day, based 

on increased incidence of 14th ribs, decreased 

fetal weights and decreased numbers of fetuses 

with ossified vertebrae.

870.3800 Reproduction and 

fertility effects

(2-generation rat)

MRID 41149301 (1989)

0, 10, 50 or 250 ppm 

(approximately 0, 0.8, 4 

or 21 mg/kg/day during 

14 weeks prior to mating)

Sprague-Dawley

Minimum

Parental NOAEL = 4 mg/kg/day

Parental LOAEL = 21 mg/kg/day based on 

decreased body weight gain in F0 and F1 

females before mating, during gestation and 

lactation and at study termination. In addition, 

possibly increased liver weights were observed 

in both male and female adults.

Reproductive NOAEL = 21 mg/kg/day

Reproductive LOAEL = not established

Offspring NOAEL = 4 mg/kg/day

Offspring LOAEL = 21 mg/kg/day based on 

decreased body weight gain during lactation 

and delayed eye opening.

870.3800 Reproduction and 

fertility effects

(3-generation rat)

MRID 00064815 (1978)

(00242060)

0, 30, 100 or 300 ppm 

(equivalent to 0, 1.5, 5 or 

15 mg/kg/day)

Wistar

Supplementary 

Parental NOAEL = 1.5 mg/kg/day

Parental LOAEL = 5.0 mg/kg/day based on 

decreased body weight gain in F1 and F2 

parents

Reproductive NOAEL = 15 mg/kg/day

Reproductive LOAEL = not established.

Offspring NOAEL = 5 mg/kg/day

Offspring LOAEL = 15 mg/kg/day based on 

decreased body weight particularly in F2 

generation.

870.4100a Chronic toxicity

(rat)

See 870-4300
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4100b Chronic toxicity 

(dog)

MRID 40780301, 

41304701 (1988)

0, 0.1, 0.3, 1.5 or 7.5 

mg/kg/day

Capsule

Guideline

Threshold dose = 1.5 mg/kg/day, (slightly 

decreased body weight gain in males)

LOAEL = 7.5 mg/kg/day, M & F, based on 

increased incidences of salivation, panting, 

liquid feces and pale gums; statistically 

significant decreased body weight gain over 

entire duration of study, but particularly during 

first 8 weeks of study; statistically significant 

decreased erythrocytes (RBC), hemoglobin 

(Hb) and packed cell volume (PCV); 

statistically significant increased urea nitrogen; 

increased absolute liver weights and liver/body 

weight ratios.

870.4200 Carcinogenicity

(mice)

MRID 00068077 (1982)

0, 10, 30 or 100 ppm 

0, 1.3, 3.9 or 13 

mg/kg/day.

Dietary

Swiss albino

Guideline for chronic 

feeding study. 

 

NOAEL

 M = 3.9 mg/kg/day

 F = 13 mg/kg/day

LOAEL

 M = 13 mg/kg/day based on a dose-related 

increased incidence of liver 

adenomas/carcinomas combined, the incidence 

being statistically significant at 13 mg/kg/day

 F = not established. 

Carcinogenicity: 

 M Positive evidence of neoplasms in males

as stated above

 F No tumors were observed in females;

CARC (1991) concluded dose levels in females 

were not sufficiently high to assess tumorigenic 

potential.

870.4200 Carcinogenicity

(mice)

MRID 43245501 (1994)

0, 20, 75 or 300 ppm

0, 3.1, 12, 46 mg/kg/day 

M 

0, 3.7, 14, 53 mg/kg/day F

CD-1

Acceptable for chronic 

feeding and for 

oncogenicity

NOAEL = 12 mg/kg/day M, 14 mg/kg/day F

LOAEL = 46 mg/kg/day M, 53 mg/kg/day F, 

based on increased liver weights, increased 

incidences of diffusely dark livers, and 

increased incidences of non-neoplastic 

microscopic lesions in liver. Histopathologic 

lesions in the liver included hepatocellular 

centrilobular hypertrophy, hepatocellular 

degeneration/necrosis, and pigment in 

hepatocytes and Kupffer cells.

Carcinogenicity: 

 Males: treatment-related increased incidences 

of hepatocellular adenomas, carcinomas, and 

adenomas/carcinomas combined were observed 

in the male mice at all dose levels in this study.

 Females: slightly increased incidences of 

hepatocellular carcinomas and of 

adenomas/carcinomas combined was observed 

at the high dose level only. 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4300 Combined 

Chronic/Carcinog

enicity (rats)

MRID 00096521 (1982)

(00064815)

0, 10, 30,100 ppm 

0, 0.5, 1.5, 5 mg/kg/day)

Dietary

Supplementary for 

chronic feeding and for 

oncogenicity

NOAEL = 5 mg/kg/day, M & F

LOAEL = not established

Carcinogenicity: 

No evidence of an increased incidence of 

neoplasms in males or females. Dose levels 

used in this study were determined to be 

insufficiently high to assess carcinogenic 

potential. 

870.4300 Combined 

Chronic/Carcinog

enicity (rats)

MRID 40612501, 

41374801 (1988)

0, 60, 190 or 600 ppm 0, 

2.6, 8.2 or 28 mg/kg/day 

M

0, 3.3, 11.0 41 mg/kg/day 

F

Dietary

Minimum for chronic 

feeding and for 

oncogenicity

NOAEL = 2.6 mg/kg/day M, 3.3 mg/kg/day F

LOAEL:

 M = 8.2 mg/kg/day, based on an increased 

incidence of spongiosis hepatis in the liver. 

 F: 11.0 mg/kg/day, based on decreased body 

weight gain. 

Carcinogenicity: 

No evidence of an increased incidence of 

neoplasms in males or females. Dose levels 

used in this study were determined to be 

sufficiently high to assess carcinogenic 

potential. 

870.5100 Bacterial reverse 

mutation test 

(Salmonella)

MRID 41995701 (1991)

Strains TA98, TA100, 

TA1535, TA1537 and 

TA1538 were exposed to 

technical grade 

bromoxynil phenol 

without metabolic 

activation at 

concentrations ranging 

from 3.33 to 1000 

μg/plate and with 

metabolic activation (rat 

S9 mixture) at 

concentrations ranging 

from 10.0 to 3330 

μg/plate.

Acceptable

Negative.

Bromoxynil phenol, without and with 

metabolic activation, did not induce a 

genotoxic effect in this assay system.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5375 In vitro 

mammalian 

chromosome 

aberration test

MRID 00115651 (1982)

Cultures of Chinese 

hamster ovary (CHO) 

cells were exposed to 

technical grade 

bromoxynil phenol 

without metabolic 

activation at 

concentrations ranging 

from 100 to 1500 μg/ml 

(8 hour exposure) and 

from 50 to 500 μg/ml (20 

hour exposure).

Acceptable

Negative without activation

Positive with activation at >= 1200 μg/ml

Bromoxynil phenol did not induce a genotoxic 

effect in the non-activated portion of this assay, 

but the significant increase in chromosome 

damage in the activated portion of this assay at 

concentrations equal to and above 1200 μg/ml 

was considered to be a positive genotoxic 

response.

870.5395 In Vivo 

mammalian 

(mouse) 

erythrocyte 

micronucleus test

MRID 00124803 (1982)

Bromoxynil phenol was

administered orally by 

gavage on two 

consecutive days to 

groups of 5 male and 5 

female CD-1 mice at dose 

levels of 0 (control), 21.6, 

69.0 or 215.5 mg/kg/day.

Acceptable

Negative at dose levels up to 215.5 mg/kg/day 

which produced target cell toxicity as well as 

death

Bromoxynil phenol did not induce a clastogenic 

effect in this assay system.

870.5395 In vivo 

Mammalian 

erythrocyte 

micronucleus test

MRID 42092301 (1991)

Single doses of technical 

grade bromoxynil phenol 

were administered orally 

by gavage to groups of 5 

male and 5 female CD-1 

mice at dose levels of 0 

(control), 35, 70 or 105 

mg/kg.

Acceptable

Negative

Bromoxynil phenol did not induce a clastogenic 

effect in this assay system.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5550 Unscheduled 

DNA synthesis in 

mammalian cells

MRID 00115646 (1982)

Cultures of primary rat 

hepatocytes were exposed 

to technical grade 

bromoxynil phenol at 

concentrations ranging 

from 0.1 to 50 μg/ml.

Acceptable

Negative

Bromoxynil phenol did not induce a genotoxic 

effect in this assay system 

870.5xxx In vitro 

transformation 

assay

MRID 00115647 (1982)

Cultures of mouse 

C3H/10T 1⁄2 C18 cells 

were exposed to technical 

grade bromoxynil phenol 

at concentrations ranging 

from 32.5 to 390 μg/ml.

Acceptable

Negative

Bromoxynil phenol did not induce a genotoxic 

effect in this assay system.

870.5xxx Sister Chromatid 

Exchange

MRID 00115648 (1982)

Cultures of Chinese 

hamster ovary (CHO) 

cells were exposed to 

technical grade 

bromoxynil phenol 

without metabolic 

activation at 

concentrations ranging 

from 4.67 to 18.7 μg/ml 

and with metabolic 

activation (rat S9 mixture) 

at concentrations ranging 

from 500 to 900 μg/ml.

Acceptable

Negative

Bromoxynil phenol did not induce a genotoxic 

effect in this assay system.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870-5xxx Forward mutation

Mouse lymphoma 

cells

MRID 00115649 (1982)

Cultures of L5178Y 

TK+/- cells were exposed 

to technical grade 

bromoxynil phenol 

without metabolic 

activation at 

concentrations ranging 

from 15.6 to 250 μg/ml 

and with metabolic 

activation (rat S9 mixture) 

at concentrations of 3.9, 

7.8, 15.6, 31.3 or 62.5 

μg/ml.

Acceptable

Negative without activation

Positive with activation at 31.3 and 63 μg/ml.

Bromoxynil phenol did not induce a genotoxic 

effect in the non-activated portion of this assay, 

but the dose-related increase in mutant colonies 

in the activated portion of this assay was 

considered to be a positive genotoxic response. 

870-5xxx Forward mutation 

Mouse lymphoma 

cells

MRID 41995702 (1991)

Cultures of Chinese 

hamster ovary 

(CHO)/HGPRT locus 

cells were exposed to 

technical grade 

bromoxynil phenol 

without and with 

metabolic activation (rat 

S9 mixture) at 

concentrations ranging 

from 100 to 1000 μg/ml.

Acceptable

Negative

Bromoxynil phenol, without and with 

metabolic activation, did not induce a 

genotoxic effect in this assay system.

870-5xxx DNA Repair Test 

(E. coli)

MRID 00115650 (1982)

Cultures of both indicator 

strains (Escherichia coli

indicator strains pol A+ 

(W3110) and pol A-

(p3478)) on agar plates 

were exposed to technical 

grade bromoxynil phenol 

without and with 

metabolic activation (rat 

S9 mixture) at 

concentrations ranging 

from 1.0 to 10000 

μg/plate.

Acceptable

Positive without activation at >= 1000 μg/plate

Positive with activation at >= 1000 μg/plate

Bromoxynil phenol induced a positive 

genotoxic response in both the non-activated 

and activated portions of this assay.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism and 

pharmacokinetics

(species)

Please see 870.7485 data 

for bromoxynil octanoate.

870.7600 Dermal 

penetration 

(species)

MRID 40854602

14C-Bromoxynil phenol, 

solubilized in water with 

sodium hydroxide, was 

topically applied to the 

skin of male Sprague 

Dawley rats at doses of 

0.10, 1.0 or 10.0 mg/rat 

for durations of exposure 

of 0.5, 1, 2, 4, 10 or 24 

hours (4 

rats/dose/duration of 

exposure). 

Acceptable

Percent dermal absorption at 10 hours was 

1.92%, 1.74% and 1.24% for doses of 0.10, 1.0 

and 10.0 mg/rat respectively. Following a soap 

and water wash (at 10 hours), 22.64%, 10.79% 

and 3.79% of the respective doses remained 

in/on the skin.

Percent dermal absorption at 24 hours was 

3.12%, 3.24% and 3.02% for doses of 0.10, 1.0 

and 10.0 mg/rat respectively. Following a soap 

and water wash (at 24 hours), 18.99%, 7.84% 

and 2.03% of the respective doses remained 

in/on the skin.

Table A.2.3 Toxicity Profile for Bromoxynil Octanoate

Guideline 

No.

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 13-Week oral 

toxicity 

(rat)

MRID 42411901 (1992)

0, 150, 600, 1100 ppm 0, 

11, 45, 91 mg/kg/day M

0, 13, 55, 111 mg/kg/day F

Dietary

Minimum

NOAEL: M = 45 mg/kg/day, F = 13.mg/kg/day

LOAEL

M = 91 mg/kg/day, based on decreased body 

weight gain, decreased serum total protein, 

decreased globulins and increased 

degeneration/necrosis of cardiac myofibers and 

possibly increased thymic lymphocyte necrosis. 

F = 55 mg/kg/day, based on decreased body 

weight gain and increased liver weights
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Table A.2.3 Toxicity Profile for Bromoxynil Octanoate

Guideline 

No.

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3150 13-Week oral 

toxicity dog

MRID 42869701, 

43700201 (19)

0, 0.43, 1.43 or 7.14 

mg/kg/day

Capsule

Supplementary

NOAEL = 0.43 mg/kg/day, M & F

LAAEL = 1.43 mg/kg/day, M & F, based on 

decreased body weight gain

870.3150 13-Week oral 

toxicity dog

MRID 00061179 (1965)

(00090653, 00111190)

0, 1, 5 or 25 mg/kg/day

Capsule

Supplementary

NOAEL = 1.0 mg/kg/day, M & F

LOAEL = 5.0 based on occasional panting 

(considered a threshold dose). At 25 

mg/kg/day, additional signs of toxicity, 

observed in both males and females, were 

panting (after each dose) throughout the study; 

decreased body weight gain; possibly decreased 

erythrocyte counts, hemoglobin, and packed cell 

volume; and increased serum urea nitrogen.

870.3200 21-Day dermal 

toxicity (rabbit)

MRID 42346201 (19--)

0, 30, 300 or 1000 

mg/kg/day

Minimum

Dermal 

 NOAEL = 30 mg/kg/day, M & F

 LOAEL = 300 mg/kg/day, M & F, based on 

significant dermal irritation consisting of slight 

to moderate redness and swelling, cracking and 

flaking of the skin

Systemic

 NOAEL = not established

 LOAEL = 1000 mg/kg/day

870.3150 90-Day oral 

toxicity in 

nonrodents (dog)

No study data are 

currently available

870.3700a Prenatal 

developmental in 

rodents (rat) - oral

Rogers, Francis, Barbee et 

al. 1991

0, 2.4, 7.3 or 21.8 

mg/kg/day on gestation 

days 6-15

Gavage

Sprague-Dawley

Not classified

Maternal NOAEL = 7.3 mg/kg/day

Maternal LOAEL = 21.8 mg/kg/day, based on 

decreased body weight gain and increased liver 

weights.

Developmental NOAEL = 7.3 mg/kg/day

Developmental LOAEL = 21.8 mg/kg/day, 

based on an increased incidence of 14th ribs and 

on reduced fetal weights.
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Table A.2.3 Toxicity Profile for Bromoxynil Octanoate

Guideline 

No.

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700a Prenatal developmental in rodents 

(rat) - dermal

MRID 41163301 (1989)

0, 2, 5, 10, 15, 20 or 75 mg 

a.i./kg/day for 6 hours/day 

on gestation days 6-15

Gavage

Sprague-Dawley

Supplementary

Maternal dermal NOAEL = 20 mg/kg/day

Maternal dermal LOAEL = 75 mg/kg/day based 

on skin irritation, 

Maternal systemic NOAEL = 15 mg/kg/day

Maternal systemic LOAEL = 20 mg/kg/day

based on decreased body weight gain and 

decreased food consumption during the 

treatment period., 

Developmental NOAEL = 10 mg/kg/day

Developmental LOAEL = 15 mg/kg/day based 

on increased incidence of supernumerary (14th) 

ribs. At 20 and 75 mg a.i./kg/day, the incidences 

of supernumerary ribs were increased still 

further.

870.3700b Prenatal 

developmental in 

non-rodents 

(rabbit) - dermal

MRID 41471901, 

42183901 (1990)

0, 5, 10, 15, 20, 40 or 80 

mg a.i./kg/day for 6 

hours/day on gestation 

days 6-18

New Zealand White

Supplementary

Maternal dermal NOAEL = not established

Maternal dermal LOAEL = 5.0 mg/kg/day 

based on skin irritation. At 15 mg/kg/day and 

higher, a majority of treated animals manifested 

erythema, fissuring and desquamation.

Maternal systemic NOAEL = 80 mg/kg/day

Maternal systemic LOAEL = not established

Developmental NOAEL = 80 mg/kg/day

Developmental LOAEL = not observed

870.3700a Prenatal 

developmental in 

rodents (rabbit) -

oral

No study available No study is necessary (Fifth Developmental 

Toxicity Peer Review Committee, 4/21, 1992)

870.3800 Reproduction and 

fertility effects - 

Rat

Oral

No study available
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Table A.2.3 Toxicity Profile for Bromoxynil Octanoate

Guideline 

No.

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3800 Reproduction and 

fertility effects - 

Rat

Dermal

MRID 41667401 (1990)

Male rats treated with 0, 

25, 50 or 100 mg 

a.i./kg/day for 21 days, 

then mated with 

unexposed female rats on 

days 1, 7, 14, 21, 35, 56 or 

113 post-exposure.

Supplementary 

Special study.

Male dermal NOAEL =50 mg/kg/day

Male dermal LOAEL = 100 mg/kg/day, based 

on significant skin irritation.

Male systemic NOAEL = 25 mg/kg/day

Male systemic LOAEL = 50 mg a.i./kg/day, 

based on decreased body weight gain. At 100 

mg a.i./kg/day, possibly increased liver weights 

were also observed.

Male reproductive NOAEL = 50 mg/kg/day

Male reproductive LOAEL = 100 mg 

a.i./kg/day (tentative), based on possibly 

decreased prostate gland weight. 

Offspring NOAEL =100 mg/kg/day

Offspring LOAEL = not established

870.4100b Chronic toxicity 

dogs

No study data are 

currently available. Please 

refer to 870.4100b for 

bromoxynil phenol

870.4200 Carcinogenicity 

rats

No study data are 

currently available. Please 

refer to 870.4200 for 

bromoxynil phenol

870.4300 Carcinogenicity 

mice

No study data are 

currently available. Please 

refer to 870.4300 for 

bromoxynil phenol

870.5100 Bacterial reverse 

mutation test

Salmonella/mamm

alian microsome

MRID 43022701 (1993)

Strains TA98, TA100, 

TA1535, TA1537 and 

TA1538 were exposed to 

technical grade 

bromoxynil octanoate 

without and with 

metabolic activation (rat 

S9 mixture) at 

concentrations ranging 

from 33 to 10000 μg/plate.

Acceptable

Negative.

Bromoxynil octanoate, without and with 

metabolic activation, did not induce a genotoxic 

effect in this assay system.
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Table A.2.3 Toxicity Profile for Bromoxynil Octanoate

Guideline 

No.

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5395 Mammalian in 

vivo erythrocyte 

micronucleus test

MRID 41930802 (1991)

Single doses of technical 

grade bromoxynil 

octanoate were 

administered orally by 

gavage to groups of 5 male 

CD-1 mice at dose levels 

up to 183 mg/kg and to 

groups of 5 female CD-1 

mice at dose levels up to 

267 mg/kg.

Acceptable

Negative.

Bromoxynil octanoate did not induce a 

clastogenic effect in this assay system.

870.5550 Unscheduled DNA 

synthesis in 

mammalian cells

Cultures of primary rat 

hepatocytes were exposed 

to technical grade 

bromoxynil octanoate at 

concentrations ranging 

from 0.98 to 15.63 μg/ml. 

Higher concentrations (>

31.25 μg/ml) were 

cytotoxic.

Acceptable

Negative

Bromoxynil octanoate did not induce a 

genotoxic effect in this assay system. (MRID 

42078901) 

870.6300 Developmental 

neurotoxicity rats

No study available

870.7600 Dermal 

Absorption - rat

MRID 40854603 (1988)

14C-Bromoxynil octanoate, 

incorporated into the enduse product Buctril, which 

contained 33.4% 

bromoxynil octanoate as 

the active ingredient, was 

topically applied to the 

skin of male Sprague 

Dawley rats at doses of 

0.08, 0.4 or 3.4 mg/rat for 

durations of exposure of 

0.5, 1, 2, 4, 10 or 24 hours 

(4 rats/dose/duration of 

exposure).

Acceptable

Percent dermal absorption at 10 hours was 

10.32%, 7.07% and 4.51% for doses of 0.08, 0.4 

and 3.4 mg/rat respectively. Following a soap 

and water wash (at 10 hours), 6.46%, 8.06% 

and 6.13% of the respective doses remained 

in/on the skin. 

Percent dermal absorption at 24 hours was 

17.58%, 18.43% and 10.88% for doses of 0.08, 

0.4 and 3.4 mg/rat respectively. Following a 

soap and water wash (at 24 hours), 7.91%, 

9.50% and 4.97% of the respective doses 

remained in/on the skin. 
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Table A.2.3 Toxicity Profile for Bromoxynil Octanoate

Guideline 

No.

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism -rat MRID 00154756, 

00154757 (1984), 

42901001 (1993)

The absorption, 

distribution, excretion and 

metabolism of bromoxynil 

octanoate were studied in 

male and female Sprague 

Dawley rats given single 

oral doses of 14Cbromoxynil octanoate by 

gavage at dose levels of 2 

or 20 mg/kg or at a dose 

level of 2 mg/kg following 

14 days of unlabeled 

bromoxynil octanoate 

administered by oral 

gavage at a dose level of 2 

mg/kg/day. 

Minimum 

Results were similar regardless of dosing 

regimen. Rate of absorption was moderate in 

both males and females; peak plasma 

concentrations of radioactivity were not reached 

until 7-10 hours after dosing.

Radioactivity was widely distributed in most 

tissues; highest concentrations were observed in 

blood, plasma, liver, kidneys and thyroid 

(especially in females). Levels of radioactivity 

in tissues were generally higher in females than 

in males. Most radioactivity was excreted in the 

urine (about 84-89% in males and 76-80% in 

females at 7 days) and considerably lesser 

amounts in the feces (about 6-10% in both

males and females at 7 days).

Excretion was more rapid in males than in 

females. Retention of radioactivity in tissues 

after 7 days was about 2-3% in males and 7-9% 

in females. Essentially all bromoxynil 

octanoate was rapidly and nearly completely 

converted to bromoxynil phenol via ester 

hydrolysis. 

In special studies, the only chemical species 

identified in tissues was bromoxynil phenol per 

se; no bromoxynil octanoate was identified in 

tissues. In urine, the only major species was 

free and conjugated bromoxynil phenol with no 

bromoxynil octanoate being present. In feces, 

however, some bromoxynil octanoate was 

identified.
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A.3 HAZARD IDENTIFICATION AND ENDPOINT SELECTION

A.3.1 Acute Reference Dose (aRfD) – General Population (Including Infants and Children)

Study Selected: Subchronic Study in Dogs

MRID No.: 43166701

Executive Summary: In a 13-week range-finding study, technical grade bromoxynil phenol was 

administered orally in gelatin capsules to groups of 2 male and 2 female beagle dogs at dose levels 

of 0 (control), 1, 5, 8, 12, 16, 20, 30, 40 or 50 mg/kg/day. Treatment-related decreased body weight 

gain was observed in males at all dose levels tested. At 5 mg/kg/day, occasional panting and liquid 

feces were also noted and at 8 and 12 mg/kg/day, frequent panting, occasional salivation, unsteady

gait, decreased erythrocyte count, decreased hemoglobin, decreased packed cell volume, and 

increased urea nitrogen were observed. Dose levels of 16 mg/kg/day and higher were clearly 

excessive and caused mortality and/or signs of severe toxicity. Decreased body weight gain, 

occasional panting and liquid feces were observed in females at 5 mg/kg/day. At 8 mg/kg/day and 

higher, effects in females were the same as in males. For males, no NOAEL was determined in this 

study (<1 mg/kg/day). The LOAEL is 1 mg/kg/day for males, based on decreased body weight gain. 

For females, the NOAEL is 1 mg/kg/day and the LOAEL is 5 mg/kg/day, based on decreased body 

weight gain, panting and liquid feces. This study was a range-finding study. Only 2 dogs/sex/dose 

level were used and an insufficient number of tissues was microscopically examined in the control 

group and at dose levels of 12 mg/kg/day and lower. 

Dose and Endpoint for Establishing aRfD: The NOAEL of 8 mg/kg/day is based on an effect 

attributed to a single dose (panting) at the LOAEL of 12 mg/kg/day. The study NOAELs and 

LOAELS based on decreased body weight gain are not attributable to a single dose. In addition to 

panting, elevated rectal temperature occurred at 16 mg/kg/day and above, and death occurred at 30 

mg/kg/day and above after a single dose on day One. 

UF(s): A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies 

variation (10X).

Comments on Study/Endpoint/UFs: This study provides the lowest NOAEL in the database (most 

sensitive endpoint) and is expected to be protective for any potential single-dose adverse effects in 

humans. In the dog, increased panting can be an adaptive, compensatory response to elevated body 

temperature, vs. an adverse effect. In this study, the cascade of events beginning with panting on 

day one, followed by a progression of elevated rectal temperature and eventually death, were 

considered adverse responses.

aRfD = 8 mg/kg/day (NOAEL) = 0.08 mg/kg/day

 100 (UF)

A.3.1a Acute Reference Dose (aRfD) – Females 13+

Study Selected: Developmental Toxicity in Rats (Oral)

MRID No.: 40466802, 00116558

Executive Summary: In an oral developmental toxicity study (MRID 40466802), technical grade 

bromoxynil phenol was administered to groups of 22 pregnant Sprague Dawley rats by gavage at 

doses of 0 (control), 4, 12.5 or 40 mg/kg/day on gestation days 6-15, inclusive. The developmental 

toxicity NOAEL is 4 mg/kg/day. A dose-related increased incidence of supernumerary (14th) 

ribs was observed at the developmental toxicity LOAEL of 12.5 mg/kg/day. Increased postimplantation loss was also observed at 12.5 mg/kg/day. At 40 mg/kg/day, the following additional 

effects were observed in the offspring: reduced fetal weight, increased numbers of small fetuses, 
Bromoxynil Human Health Risk Assessment DP No. 374609

Page 67 of 72

and increased incidences of soft tissue and skeletal abnormalities (including anophthalmia, 

microphthalmia, short renal papilla, and spinal and thoracic bone abnormalities). The maternal 

toxicity NOAEL is 12.5 mg/kg/day and the maternal toxicity LOAEL is 40 mg/kg/day, based 

on decreased body weight gain throughout most of the treatment and post-treatment period 

and decreased food consumption during the treatment period. 

In an oral developmental toxicity study (MRID 00116558), groups of 28 pregnant Sprague Dawley

rats received 0 (control), 5, 15 or 35 mg/kg/day of technical grade bromoxynil phenol by gavage on 

gestation days 5-17, inclusive. No developmental toxicity NOAEL was determined in this study 

(below 5 mg/kg/day). At the LOAEL of 5 mg/kg/day, a dose-related increased incidence of 

14th ribs was observed. At the high dose of 35 mg/kg/day, additional effects included an increased 

incidence of late intrauterine deaths, decreased fetal body weights and an increase in the total 

incidence of minor anomalies. The maternal toxicity NOAEL is 5 mg/kg/day and the maternal 

toxicity LOAEL is 15 mg/kg/day, based on decreased body weight gain. At 35 mg/kg/day, 6/28 

dams died between days 7 and 14 of gestation. 

Dose and Endpoint for Establishing aRfD: The NOAEL of 4 mg/kg/day (MRID 40466802) is 

based on an increase of supernumerary ribs seen at the LOAEL of 5 mg/kg/day in a co-critical study 

(MRID 00116558).

UF(s): A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies 

variation (10X).

Comments on Study/Endpoint/UFs: These studies provide the lowest NOAEL in the database 

(most sensitive endpoint) and is expected to be protective for any potential single-dose adverse 

effects in humans. The LOAEL derived from a co-critical study is very close to the NOAEL and 

suggests a steep dose-response curve. While the BMD data (benchmark dose = 13.66 mg/kg/day) 

suggest that the dose-response curve is not as steep as the observed effects would indicate, HED has 

taken the most protective approach and used the observed effects in the risk assessment.

aRfD = 4 mg/kg/day (NOAEL) = 0.04 mg/kg/day

 100 (UF)

A.3.2 Chronic Reference Dose (cRfD) – All Populations

Study Selected: Chronic (1-year) Study in Dogs

MRID No.: 40780301 and 41304701

Executive Summary: In a 12-month chronic oral toxicity study, technical grade bromoxynil 

phenol was administered in gelatin capsules to groups of 6 male and 6 female beagle dogs at dose 

levels of 0 (control), 0.1, 0.3, 1.5 or 7.5 mg/kg/day. At the highest dose level tested (7.5 mg/kg/day), 

the following treatment-related effects were observed in both male and female dogs: increased 

incidences of salivation, panting, liquid feces and pale gums; statistically significant decreased body 

weight gain over entire duration of study, but particularly during first 8 weeks of study; statistically 

significant decreased erythrocytes (RBC), hemoglobin (Hb) and packed cell volume (PCV); 

statistically significant increased urea nitrogen; increased absolute liver weights and liver/body 

weight ratios. At 1.5 mg/kg/day, a statistically significant decreased body weight gain over the 

entire duration of study was observed in the male dogs. Other "effects" at this same dose level were 

marginal, inconsistent and of equivocal toxicological significance. These effects included panting; 

decreased RBC, Hb and PCV; increased urea nitrogen; and increased absolute and relative liver 

weights in males and panting and increased absolute and relative liver weights in females. No 
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treatment-related gross or histo-pathological changes were observed in any organs in this study. The 

dose level of 1.5 mg/kg/day is considered to be a threshold NOAEL/LOAEL for both male and 

female dogs in this study.

Dose and Endpoint for Establishing cRfD: The NOAEL of 1.5 mg/kg/day is based on increased 

incidences of salivation, panting, liquid feces and pale gums; statistically significant decreased body 

weight gain over the entire duration of the study, but particularly during the first 8 weeks of the 

study; statistically significant decreased erythrocytes (RBC), hemoglobin (Hb) and packed cell 

volume (PCV); statistically significant increased urea nitrogen; increased absolute liver weights and 

liver/body weight ratios seen at the LOAEL of 7.5 mg/kg/day in both sexes.

UF(s): A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies 

variation (10X).

Comments about Study/Endpoint/UF: This study provides the lowest NOAEL in the database 

(most sensitive endpoint) that reflects chronic (long-term) exposure which is the duration relevant to 

human dietary exposure. 

cRfD = 1.5 mg/kg/day (NOAEL) = 0.015 mg/kg/day

 100 (UF)

A.3.3 Dermal Short-Term (1-30 days) and Intermediate-Term (1-6 Months) 

Study Selected: Rat Dermal Developmental Toxicity Study

MRID No.: 40881201, 40883601

Executive Summary: In a dermal developmental toxicity study, bromoxynil phenol (solubilized in 

water containing 50 mg/ml sodium hydroxide and 20% triethylene glycol) was applied to groups of 

23 pregnant Sprague Dawley rats at dose levels of 0 (control), 5, 10, 50 or 100 mg/kg/day for 6 

hours/day on gestation days 6-15, inclusive. A dose-related increased incidence of supernumerary

(14th) ribs was observed in this study at 10, 50 and 100 mg/kg/day. At 10 mg/kg/day, however, the 

increased incidence was not statistically significant compared to the concurrent control group and 

was within the historical control range. The developmental toxicity NOAEL is 10 mg/kg/day and 

the developmental toxicity LOAEL is 50 mg/kg/day, based on increased 14th ribs. The maternal 

toxicity NOAEL is 50 mg/kg/day and the maternal toxicity LOAEL is 100 mg/kg/day, based on 

decreased body weight gain and decreased food consumption during the treatment period. No deaths 

or clinical signs, including skin irritation, were attributed to treatment with the test material in this 

study. 

Dose and Endpoint for Risk Assessment: The developmental NOAEL of 10 mg/kg/day is based 

on increased incidence of supernumerary (14th) ribs seen at the LOAEL of 50 mg/kg/day.

Comments about Study/Endpoint/Margins of Exposure: This study provides the lowest NOAEL 

in the database (most sensitive endpoint) that reflects the route and duration of exposure relevant to 

occupational and/or residential scenarios. The reference value for this risk assessment scenario is a 

margin of exposure (MOE) of 100 based on 10X interspecies and 10X intraspecies uncertainty 

factors.

The lowest NOAEL from an oral study appropriate for use for this endpoint is 4 mg/kg/day from the 

developmental toxicity study (see Acute Reference Dose, Females 13+). If this study were used 

along with the dermal absorption factor of 17% for extrapolation between the dermal and oral routes, 

the extrapolated NOAEL 4.0 / 0.17) would be 23.5 mg/kg/day, which is higher and less protective 
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than the NOAEL from the route-specific study used. Thus, using the route-specific study would be 

protective of the developmental effects noted after oral exposure

A.3.3 Inhalation Short-Term (1-30 days) and Intermediate-Term (1-6 Months) 

Study Selected: Rat Oral Developmental Toxicity Study

MRID No.: 00116558 and 40466802

Executive Summary: See above: Acute Reference Dose Females 13+

Dose and Endpoint for Risk Assessment: The NOAEL of 4 mg/kg/day (MRID 40466802) is 

based on an increase of supernumerary ribs seen at the LOAEL of 5 mg/kg/day in a co-critical study 

(MRID 00116558).

Comments about Study/Endpoint/Margins of Exposure: This study provides the lowest NOAEL 

in the database (most sensitive endpoint) and reflects the duration of exposure relevant to 

occupational and/or residential exposure scenarios. Although there are uncertainties associated with 

the use of an oral study for the inhalation route of exposure, the assumption is made in this risk 

assessment that oral and inhalation absorption rates are equivalent (100%) (The actual absorption by

the oral route is 76 – 89%). The reference value for this risk assessment scenario is a margin of 

exposure (MOE) of 100 based on 10X interspecies and 10X intraspecies uncertainty factors.
Bromoxynil Human Health Risk Assessment

Appendix B. Chemical Names and Structures of 

Common name Chemical name

bromoxynil 3,5-dibromo

bromoxynil octanoate 2.6-dibromo

octanoate

bromoxynil heptanoate 2.6-dibromo

heptanoate

DBHA 3,5-dibromo

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Chemical Names and Structures of Bromoxynil, its Esters and Metabolite. 

Chemical name Chemical structure

dibromo-4-hydroxybenzonitrile

dibromo-4-cyanophenyl 

octanoate

dibromo-4-cyanophenyl 

heptanoate

dibromo-4-hydroxybenzoic acid OH

Br

HO

DP No. 374609

, its Esters and Metabolite. 

Br

O
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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 to determine their dermal and inhalation exposure. Many such 

studies, involving exposure to many different pesticides, comprise generic pesticide exposure 

databases such as PHED and the Outdoor Residential Exposure Task Force (ORETF). EPA has 

reviewed all the studies supporting these multi-pesticide generic exposure databases, and has found 

no clear and convincing evidence that the conduct of any of them was either fundamentally unethical 

or significantly deficient relative to the ethical standards prevailing at the time the research was 

conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of 

Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued 

reliance on these studies.
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Appendix D. International Residue Limit Status Sheet

Bromoxynil (035301; 09/15/2010)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.324:

Plant: bromoxynil (3,5-dibromo-4-

hydroxybenzonitrile)

Livestock: bromoxynil (3,5-dibromo-4-

hydroxybenzonitrile) and its metabolite 3,5-

dibromo-4-hydroxybenzoic acid (DBHA)

3,5-dibromo-4-

hydroxybenzonitrile, 

including the 

metabolite 3,5-

dibromo-4-

hydroxybenzoic acid

None

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

US Canada Mexico2 Codex

Grain, aspirated grain fractions 1.2

Grass, forage 18

Grass, hay 5.0

Milk 0.4 0.1

Sorghum, grain, forage 0.8

Sorghum, grain, grain 0.2 0.1

Completed: M. Negussie;09/16/2010

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.