UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

Date: October 31 , 2012 

SUBJECT: Bromoxynil. Human Health Assessment Seeping Document in Support of 

Registration Review. 

PC Code: 035301, 035302, 128920 

Decision No.: 4113.5..5 

DP Barcode: DP 406426 

Registration No.: NA 

Petition No.: NA Regulatory Action: Registration Review 

Risk Assessment Type: NA Case No.: 2070 

TXRNo.:NA 

MRIDNo.:NA 

CAS No.: 1689-84-5, 1689-99-2 

40 CFR: 180.324 

FROM: 

THRU: 

TO: 

Cassi Walls, Ph.D., Senior Biologist (Y~ .1. U~ Myron Ottley, Ph.D., Senior Scientist /J1AA1J ~ 

Meheret Negussie, Chemist ~ftet,eJ ~r~~ Kristin Rury, Biologist \(_ 

Risk Assessment Branch III (RA ) 

Health Effects Division (7509P) 

Office of Pesticide Programs 

JeffDawson, 

Risk Assessment 

Acting 

Branch 

Chief 

III t!A{ J-~-6~ 

Health Effects Division (7509 

Office of Pesticide Programs 

Jill Bloom, Chemical Review Manager 

Risk Management and Implementation Branch 2 

Pesticide Re-Evaluation Division (PRD) 

Office of Pesticide Programs (7508P) 

Page 1 of37 
Page 2 of 37

Executive Summary

The HED Registration Review Team has evaluated the most recent human health assessments 

and database for the herbicides bromoxynil octanoate, bromoxynil heptanoate, and bromoxynil 

phenol (3,5-dibromo-4-hydroxybenzonitrile) to determine whether sufficient data are available 

and whether any updates are needed to support Registration Review. HED has considered the 

most recent human-health risk assessments for bromoxynil, updates to the toxicity, exposure, and 

usage databases, and current Agency science policy and risk assessment methodologies to 

determine the scope of work necessary to support Registration Review. In addition, HED 

conducted an open literature search to look for new literature relevant to the human health risk 

assessment. The results of the literature search showed that no new information relevant to the 

human health risk assessment has been published.

Since the bromoxynil octanoic and heptanoic esters are rapidly converted to the bromoxynil 

phenol, the exposure and tolerances are based on bromoxynil phenol (referred to as bromoxynil

in the remainder of this document). Bromoxynil is a contact herbicide which is registered for 

application as the octanoic and/or heptanoic acid esters for control of broadleaf weeds. 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, nonfood uses include outdoor industrial areas, nonagricultural uncultivated areas/soil, nonresidential commercial/industrial lawns, and sod farms. Bromoxynil inhibits photosynthetic 

electron transport and oxidative phosphorylation in mitochondria. 

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. 

With repeated dosing, the liver was the primary target organ of bromoxynil toxicity. Changes in 

weight, clinical chemistry and pathology indicated treatment-related perturbations in and adverse 

effects on liver function across species, durations, and genders. Treatment-related decreases in 

body weight and decreases in body weight gain were observed in rats, mice, dogs, and 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 lowest observed adverse effect level (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 a “possible human carcinogen” based on the presence 

of hepatocellular tumors in male and female mice. The unit risk, Q1

*

, of bromoxynil based upon 

male mouse hepatocellular tumors rates is 0.103 (mg/kg/day)-1in human equivalents. There is 
Page 3 of 37

no concern for mutagenicity. The FQPA Safety Factor is reduced (i.e.,1X) since there no residual 

uncertainties for pre-and or post natal toxicity. 

Sufficient data are available to assess the toxicity of bromoxynil, with the possible exception of 

immunotoxicity data, which is currently under review. Once the immunotoxicity data have been 

reviewed, the bromoxynil Registration Review Team recommends that the points of departure 

and safety factors used for risk assessment purposes for bromoxynil be re-examined.

The residue chemistry database is sufficient to support current registrations of bromoxynil. The 

nature of the residue in plants and livestock has been defined. Adequate field trial, rotational 

crop, and storage stability data are available. 

Occupational exposure assessments may need to be reassessed based on current Occupational 

and Residential Exposure (ORE) policies and exposure data and to consider the results of the 

immunotoxicity study, which has not been reviewed The restricted entry intervals (REIs) for the 

registered uses of bromoxynil should be reevaluated during Registration Review. A residential 

handler assessment is not required; however, the Agency may need to consider off-target 

movement of pesticides into residential settings.

Introduction

HED has evaluated the existing human health risk assessments for bromoxynil to determine 

whether sufficient data are available and whether a new human health risk assessment is needed 

to support Registration Review. HED has considered the most recent risk assessments for 

bromoxynil, updates to its toxicity, exposure and usage databases, and current Agency science 

policies and risk assessment methods. The most recent risk assessment for bromoxynil was 

conducted in 2011 (D374609, C. Walls, 4/20/11). 

Hazard Identification/Toxicology

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. 

The toxicology database for bromoxynil is complete. The principal toxicities of concern 

following bromoxynil exposure are developmental and liver effects. There is no evidence of 

neurotoxicity in the bromoxynil data base, and HED’s Hazard Science and Policy Council 

(HASPOC) has waived the neurotoxicity battery and subchronic inhalation toxicity study (TXR 

0056526, K. Rury 12/00/12) because that data from such tests is not necessary for conducting an 

updated risk assessment.

Bromoxynil phenol, bromoxynil heptanoate and bromoxynil octanoate have been determined by 

HED to be toxicologically equivalent (TXR 011886, G. Ghali, 4/12/96). The available toxicity 

database for bromoxynil and bromoxynil octanoate show a pattern of toxicity that goes across the 

two chemicals (as expected), across species, sexes, routes of administration, durations of 
Page 4 of 37

exposure, and generations. The latest risk assessment was based on the available toxicity data 

(D374609, C. Walls, 04/20/2011).

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 

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

gain changes (rats, mice, dogs, and rabbits). Studies in dogs showed that bromoxynil elevated 

body temperature, manifested by increased panting at lower dose levels, and incidents of 

hyperthermia and death increased as dose levels increased. Based on a preliminary review of the 

data, there was no evidence of immunotoxicity at the highest dose tested in male C57BL/6J 

mice.

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, thoracic centrum, and misshapen 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.

Bromoxynil is classified as a “possible human carcinogen” based on the presence of 

hepatocellular tumors in male and female mice. The unit risk, Q1

*

, of bromoxynil based upon 

male mouse hepatocellular tumors rates is 0.103 (mg/kg/day)-1in human equivalents. (TXR 

0050045, E. Budd and E. Rinde. 03/12/1997) Mutagenicity tests were largely negative and did 

not raise a concern. 

Bromoxynil phenol has moderate acute toxicity (Toxicity Category II) via the oral and inhalation 

routes and low acute toxicity (Toxicity Category III) via the dermal route. It is a moderate eye 

irritant (Toxicity Category II) and is not a dermal irritant (Toxicity Category IV) or skin 

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

(Toxicity Category II) and low acute toxicity (Toxicity Category III) via the inhalation route. It 

is a moderate eye irritant (Toxicity Category II) and is not a dermal irritant (Toxicity Category 

IV); it is a skin sensitizer. 

The available data indicate that bromoxynil (and/or the octanoate) produces developmental 

effects (supernumerary ribs) in rats and rabbits at or below the maternal No Observed Adverse 

Effect Levels (NOAELs) in both oral and dermal studies, and that bromoxynil octanoate 

produces supernumerary ribs at the maternal NOAEL in a rat 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 

substantial and consistent evidence of quantitative susceptibility in the database. However, the 

concern is low for the observed susceptibility since clear NOAELs/LOAELs were established for 

the developmental effects and the endpoints of concern and Points of Departure were used for 

overall risk assessments.
Page 5 of 37

Toxicity endpoints, Points of Departure, and safety factors for bromoxynil risk assessment were 

selected by HED in 2011 (Attachment 3). 

Conclusions: HED’s Hazard Science and Policy Council (HASPOC) has assessed the need for 

the newly required neurotoxicity battery a subchronic inhalation toxicity study and has waived 

the requirements for these studies at this time (TXR 0056526, K. Rury 12/00/12). Thus, the 

toxicity database is considered complete and adequate for risk assessment, with the exception of 

the immunotoxicity study. Once the submitted immunotoxicity data have been reviewed, the 

bromoxynil Registration Review Team recommends that the toxicological endpoints, points of 

departure, and safety factors used for risk assessment purposes for bromoxynil be re-examined.

Dietary Exposure

The residue chemistry and drinking water data are adequate to assess dietary exposure. The most 

recent dietary (food and drinking water) exposure assessment was conducted in 2011 (D378615, 

C. Walls, 3/22/11) using the Dietary Exposure Evaluation Model DEEM-FCIDTM, Version 2.03. 

This assessment was conducted to support the amended use pattern on grass and grain sorghum. 

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

will not underestimate exposure/risk.

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. Maximum crop treated estimates were used for all 

crops and empirical or DEEMTM default processing factors were used. 

The chronic assessment used 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.

The estimated drinking water concentration (EDWC) of bromoxynil was provided by the 

Environmental Fate and Effects Division (EFED) and incorporated directly into the acute and 

chronic assessments. EFED estimated residues of bromoxynil in surface water and groundwater 

using the FIRST Version 1.1.1 (FQPA Index Reservoir Screening Tool) and SCIGROW 

(Screening Concentrations in Groundwater) models, respectively. The acute surface water 

EDWC (11.5 ppb) was higher than the groundwater EDWC (3.26 ppt); therefore, the surface 

water value of 11.5 ppb was used in the acute dietary assessment. The chronic (non-cancer and 

cancer) surface water EDWC (0.19 ppb) was higher than the groundwater EDWC (3.26 ppt); 

therefore, the surface water value of 0.19 ppb was used in the chronic (cancer and non-cancer)

dietary assessments. The assessments are based on reliable data and will not underestimate 

exposure/risk.

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

concern (LOC) [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, 
Page 6 of 37

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. 

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

HED’s LOC [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. 

The cancer dietary (food and drinking water) risk estimate for the general U.S. population is 1.5 

x 10-6.

The residue chemistry database is sufficient to support current registrations. The nature of the 

residue in plants and livestock has been defined. The residue of concern in plants other than 

cotton is bromoxynil. The residues of concern in cotton are bromoxynil and the metabolite 3,5-

dibromo-4-hydroxybenzoic acid (DBHA). Bromoxynil is the residue of concern in livestock 

commodities for the tolerance expression while bromoxynil and DBHA are the residues of 

concern in livestock commodities for the risk assessment. 

Adequate residue analytical methodology is available for tolerance enforcement for bromoxynil 

per se in agricultural crops and livestock commodities. 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. Multiresidue methods data 

for bromoxynil butyrate and bromoxynil octanoate have been submitted and were deemed not 

adequate. Adequate storage stability data are available to support storage durations for 

bromoxynil. 

Conclusions: If EFED drinking water estimates do not need revision, a new dietary assessment 

for bromoxynil may not be required for the purpose of registration review. Furthermore, 

although a new version of DEEM (Version 3.16) has been released, a new dietary risk 

assessment may not be needed since it is anticipated that the changes in the model will not affect 

the risk conclusion. Additionally, BEAD has provided Screening Level Usage Analysis (SLUA) 

(Nov 2, 2011) of Bromoxynil and its esters on alfalfa, barley, corn, cotton, fallow, garlic, oats, 

onions, pastureland, sorghum (milo), soybeans, sweet corn, and wheat. Based on the available 

data, BEAD determined that the usage of bromoxynil for some crops has slightly changed since 

the most recent assessment was conducted. However, these marginal changes of %CT estimates

will have minimal impact on the dietary exposure and will not affect the overall risk conclusion. 

Residential Exposure

Residential Handlers

A residential handler exposure assessment is not required because bromoxynil is only applied to 

use sites that are not treated by residential handlers (e.g., grass grown for seed only, sod farms, 

non-residential turf, and non-cropland industrial sites).
Page 7 of 37

Residential Post-Application 

The Agency has not considered residential post-application exposure for bromoxynil since there 

are no registered residential uses at this time.

Conclusions: A residential handler assessment is not required during Registration Review.

Aggregate Risk Assessment

Aggregate assessments consider exposures from food, drinking water, and residential uses. In 

the most recent human health risk assessment (D374609, C. Walls, 04/20/11), aggregate risks 

were estimated for the acute and chronic (cancer and noncancer) (food and drinking water) 

exposure durations. Only the food and drinking water routes were included in the aggregate 

assessment because no residential uses exist. As previously mentioned, these aggregate dietary 

risks were below HED’s level of concern. 

Conclusions: If EFED drinking water estimates do not need revision, a new aggregate 

assessment for bromoxynil may not be required for the purpose of registration review. 

Furthermore, although a new version of DEEM (Version 3.04) has been released, a new dietary 

risk assessment may not be needed since it is anticipated that the changes in the model will not 

affect the risk conclusion. 

Occupational Exposure

Bromoxynil is currently registered for use on several agricultural crops as well as on grasses 

grown for seed and sod production, non-residential turf, CRP areas, and non-cropland industrial 

sites. There is potential for short- and intermediate-term occupational exposure to bromoxynil

during handling (mixing, loading, and applying) and post-application activities.

Occupational Handlers

Occupational handler exposure and risk assessments were recently reassessed for all registered 

use sites when assessing proposed amended uses of bromoxynil on grass grown for seed, CRP 

areas, and grain sorghum. 

Occupational exposure is expected to be short- and intermediate-term in duration. Most of the 

registered bromoxynil labels require occupational handlers to wear long-sleeved shirts, long 

pants, shoes, socks, and chemical resistant gloves and the use of a chemical resistant apron when 

mixing/loading. Additionally, some labels require a respirator only when mixing/loading for 

aerial application to rangelands, pasturelands, and non-cropland. However, some labels require 

chemical resistant gloves only when mixing, loading, and cleaning equipment (EPA Reg. Nos. 

264-699 and 264-568); and only when mixing, loading, cleaning equipment, and applying with 

handled equipment (EPA Reg. Nos. 34704-866, 37404-996, and 37404-1052). 
Page 8 of 37

Non-Cancer Risk Estimates

Most of the resulting combined (dermal and inhalation) risk estimates were not of concern (a 

Margin of Exposure; MOE < 100) with the personal protective equipment (PPE) required by 

most labels (long-sleeved shirts, long pants, shoes, socks, and chemical resistant gloves) and the 

MOEs ranged from 380-4,900. However, mixing/loading bromoxynil with gloves for aerial 

application to corn and wheat were of concern (MOE = 38 for liquids and MOE = 96 for water 

soluble bags). To be not of concern, mixing/loading liquids for aerial application requires a 

closed system (MOE = 110) and mixing/loading bromoxynil in water soluble bags requires the 

use of coveralls (MOE = 170). Details on the occupational exposure risk estimates can be found 

in the most recent occupational and residential exposure assessment (D378616, K. Rury, 

04/07/2011). 

Cancer Risk Estimates

In the most recent exposure assessment for amended uses on grass grown for seed, CRP areas, 

and grain sorghum, HED assumed 10 days of bromoxynil exposure per year for commercial 

pesticide handlers, and 2 days of bromoxynil exposure per year for private pesticide handlers. 

For all existing agricultural uses, HED assumed 30 days of bromoxynil exposure per year for 

high acreage crops (corn and wheat) and 10 days of bromoxynil exposure per year for all other 

use sites. Based on the use profile and maximum number of applications allowed per year (1-3 

applications) these estimates are expected to be a conservative representation of bromoxynil 

exposure per year. For all use sites, occupational cancer (dermal and inhalation) risks ranged 

from 3.6x10-7 to 1.8x10-2 with baseline PPE, from 3.7x10-7to 1.9x10-4 with gloves, and from 

2.7x10-7to 1.5x10-4 with coveralls. Mixing/loading liquids for application to corn and wheat 

required a closed system to be not of concern (> 10-4); all other scenarios were not of concern 

(>1x10-4) with the addition of gloves. Details on the occupational cancer exposure risk 

estimates can be found in the most recent occupational and residential exposure assessment 

(D378616, K. Rury, 04/07/2011). 

Although an occupational exposure assessment has been conducted to estimate exposure risk for 

all existing uses of bromoxynil, the assessment was not conducted based on current occupational 

exposure policies, and does not include any future changes in toxicological endpoints with the 

submission of additional toxicological data. Therefore, a new occupational handler risk 

assessment may be needed during Registration Review. 

Occupational Post-Application

Agricultural workers may have post-application dermal exposure to bromoxynil following 

application to agricultural crops. The bromoxynil Registration Eligibility Decision (RED) 

required REI of 4 days for cotton, 26 days for sod harvesting, and 24 hours for all other crops. 

For all registered use sites on the day of application (day 0), occupational non-cancer dermal 

MOEs ranged from 45 to 1,500. The target MOE was 100; post-application activities with lower 

MOEs signify risk of concern. The assessment looked at how much time would have to pass 

after application for the risk estimates to rise above 100. 
Page 9 of 37

Most registered bromoxynil labels include an REI of 12 days for harvesting sod used for 

transplanting, while some include an REI of 26 days and some only 12 hours. For other 

occupational uses, most registered bromoxynil labels require an REI of 96 hours for cotton at 

baseline PPE and 12 hours for all other crops; turf activities; and for cotton if workers wearing 

long pants, long sleeved shirt, scout apron, shoes, and socks. However, in the most recent risk 

assessment (D374609, C. Walls, 4/20/11), risk from occupational contact with full foliage wheat, 

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

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

corn, sorghum and cotton is not of concern 4 days after application. REIs for the registered uses 

of bromoxynil should be reevaluated during Registration Review. 

The estimated occupational cancer (dermal and inhalation) risks on the day of application ranged 

from 1.4x10-6to 1.4x10-4. 

Although post-application exposure and risk estimates were conducted for all registered uses of 

bromoxynil, occupational inputs have changed since the last assessment, and therefore, a new 

post-application assessment is needed. 

Chemical-specific residue data were not submitted for bromoxynil; therefore, the standard 

assumption regarding dislodgeability was used to estimate post-application exposure (i.e. HED 

uses 25% of the application rate as the initial dislodgeable foliar residue (DFR)). As part of the 

recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for 

Residential Pesticide Exposure Assessment, HED analyzed a number of DFR studies and 

selected a new default value for the fraction of the application rate available to be dislodged after 

a foliar application (FAR). This default value is 25% and is based on an analysis of 19 DFR 

studies where the FAR value ranged from 2% to 89%. This value is recommended for use in both 

residential and occupational post-application assessments. Of the analyzed DFR studies, the 

maximum FAR value seen was 89% or 3.6 times higher than the default residue transfer value. 

Therefore, a calculated MOE of approximately 4 times higher than the LOC (i.e., an MOE > 400 

if the LOC = 100) using the default dislodged residue value would provide an adequate margin 

of safety for any potentially higher residues seen in a chemical-specific DFR study (Guidance for 

Requiring/Waiving TTR and DFR Studies, 06/07/2012). For all registered use sites on the day 

of application (day 0) occupational non-cancer dermal MOEs ranged from 45 to 1,500; therefore, 

some post-application activities were of concern. A DFR study was requested in the previous 

occupational exposure assessment for bromoxynil to characterize post-application exposure and 

reduce uncertainty for late applications of bromoxynil. HED requested the registrant submit a 

dislodgeable foliar residue (DFR) study on a representative row crop (e.g. corn). HED suggested 

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. Therefore, based on 

the MOEs of risk concern and the bromoxynil use pattern, DFR studies are required for 

bromoxynil. 

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

exposure assessment has not been performed for bromoxynil at this time. However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing post-
Page 10 of 37

application activities in previously treated fields. These potential sources include volatilization 

of pesticides, resuspension of dusts and/or particulates that contain pesticides, and contact with 

treated leaf surfaces. The Agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009. 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 post-application 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.

Conclusions: There is sufficient information available to assess occupational handler and postapplication exposures. However, not all of the occupational exposure scenarios were assessed 

based on current ORE policies. An up-to-date handler and post-application occupational 

assessment may be needed during Registration Review to account for the changes in these

policies and exposure inputs. Additionally, DFR studies are required for bromoxynil based on 

the updated Part 158 data requirements and the occupational post-application exposure risk 

estimates.

Public Health and Pesticide Epidemiology Data

The evaluation of the OPP Incident Data System (IDS) Main module indicated that from January 

1, 2007 to September 13, 2012, there were no incidents reported for an individual chemical only 

(e.g., bromoxynil or its esters) in the database and 4 incidents reported involving more than one 

chemical. These incidents were classified as moderate severity (D406428, S. Recore, 11/13/12). 

In the Aggregate IDS module there were 11 reported incidents from January 1, 2007 to 

September 13, 2012, involving bromoxynil and its esters. Overall, there are few incidents 

involving bromoxynil and esters reported to IDS. 

In Centers for Disease Control and Prevention/National Institute for Occupational Safety and 

Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk-Pesticides 

(SENSOR) database, there are three cases involving Bromoxynil and esters from 1999 to 2008. 

All three cases are work-related. One case is moderate in severity and two cases are low in 

severity. No narrative details were provided for the moderate severity case that occurred in 

California in 1998. One case was a Custom Pesticide Applicator who opened a container of 

Starane NXT Herbicide and liquid splashed on his face and mouth. He went to the ER and 

reported dermal and respiratory symptoms. Another case involved a female apple thinner at a 

tree fruit nursery in Washington. She reported smelling an aerial herbicide application to an 

adjacent wheat field. She was seen by a physician and reported fatigue and respiratory 

symptoms.

Bromoxynil and esters are not included in the Agricultural Health Study (AHS), and therefore 

this study does not provide information for this report.
Page 11 of 37

Based on the low frequency and severity of incident cases reported for bromoxynil and esters in 

both IDS and NIOSH SENSOR-Pesticides, there does not appear to be a concern at this time that 

would warrant further investigation. The Agency will continue to monitor the incident 

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

assessment.

 

Tolerance Assessment and International Harmonization

There are currently no maximum residue limits (MRLs) established by Codex for bromoxynil. 

Tolerances have been established by Canada. The U.S. and Canadian tolerances/MRLs are not 

compatible with regard to tolerance expression (except for dry bulb onions, pearl millet, proso 

millet and sorghum). The Canadian tolerance expression is “3,5-dibromo-4-

hydroxybenzonitrile, including the metabolite 3,5-dibromo-4-hydroxybenzoic acid (DBHA)”, 

except dry bulb onions, pearl millet, proso millet, and sorghum; however, compliance with the 

tolerance levels in the U.S. is determined by measuring only bromoxynil (3,5-dibromo-4-

hydroxybenzonitrile) except for cotton, where compliance is measured by measuring the sum of 

bromoxynil and DBHA. MRL values are harmonized for barley grain, corn grain (field and 

pop), flax seed, garlic, oat, rye, wheat, and cotton undelinted seed. MRLs were not in harmony

for dry bulb onions, sorghum grain, livestock commodities, and feed stuffs. Canada does not 

establish MRLs on feed stuffs. There are Canadian MRLs on peppermint tops, spearmint tops, 

rapeseed, and on several other cereal grains that do not have U.S. equivalents (See Attachment 

2).

It should be noted that 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), since the residue of concern for livestock is 

bromoxynil only.

Environmental Justice

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

human health risk assessment, in accordance with US Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

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

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 
Page 12 of 37

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.

Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of the most recent registration decision, EPA reviewed these data and 

selected the most sensitive endpoints for the relevant risk assessment scenarios from the existing 

hazard database. However, as required by FFDCA section 408(p), bromoxynil is subject to the 

endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the 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 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. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Bromoxynil is 

not among the group of 58 pesticide active ingredients on the initial list to be screened under the 

EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data callins, requiring the submission of EDSP screening assays for bromoxynil. For further information 

on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the 

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

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

Cumulative 

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 
Page 13 of 37

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 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/.

Human Studies

The previous risk assessments rely in part on data from studies in which adult human subjects 

were intentionally exposed to a pesticide or other chemical. These studies, which comprise the 

PHED and the Agricultural Reentry Task Force (ARTF) have been determined to require a 

review of their ethical conduct, and have received that review.

Data Requirements/ Outstanding Deficiencies

875.2100 Dislodgeable Foliar Residue Study

In accordance with the updated Part 158 data requirements (2007), one or more DFR 

studies are required when a pesticide has residential or occupational uses that could result 

in post-application dermal exposure. 

References

As shown in References below, only one human health risk assessment has been recently 

conducted for bromoxynil. 

Memoranda Relevant to Registration Review of Bromoxynil

Author Barcode 

(DP#)

Date Title

Dodd, N. 378614 02/15/2011 Bromoxynil. Petition for Tolerances in Support of New Uses on Grass 

and Grain Sorghum. Summary of Analytical Chemistry and Residue 

Data

Goodlow, T 380770 8/17/2010 Bromoxynil: Review of HUSKIE HERBICIDE – Magnitude of the 

Residue in/on Sorghum and Grass

Mason, T. 374620 12/16/2010 Drinking water assessment for ground and aerial application of 

bromoxynil on grass grown for seed and ground application of sorghum

Walls, C. 378615 03/22/2011 Bromoxynil: Acute, Chronic, and Cancer Aggregate Dietary (Food and 

Drinking Water) Exposure and Risk Assessments for the New Uses on 

Grass and Grain Sorghum

Walls, C. 374609 04/20/11 Bromoxynil: Human Health Risk Assessment for Amended Uses on 

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

Sorghum

Rury, K., 378616 04/07/2011 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
Page 14 of 37

Attachments

1. Chemical Identity Table

2. International Residue Limits

3. Endpoint Selection Table and Toxicity Profiles
Page 15 of 37

Attachment 1

Chemical Identity Table

Table 1.1. Chemical Identity of Bromoxynil phenol

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)

Chemical Class Benzonitrile Herbicide

Known impurities of 

concern

None

Table 1.2. Chemical Names and Structures of Bromoxynil, its Esters and Metabolite

Common name Chemical name Chemical structure

bromoxynil 3,5-dibromo-4-hydroxybenzonitrile
Page 16 of 37

Table 1.2. Chemical Names and Structures of Bromoxynil, its Esters and Metabolite

Common name Chemical name Chemical structure

bromoxynil octanoate 2.6-dibromo-4-cyanophenyl 

octanoate

bromoxynil heptanoate 2.6-dibromo-4-cyanophenyl 

heptanoate

DBHA 3,5-dibromo-4-hydroxybenzoic acid OH

Br Br

O

HO
Page 17 of 37

Attachment 2

International Residue Limits

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

40 CFR 180.324 (a)(1):

Plant: bromoxynil, 3,5-dibromo-4-

hydroxybenzonitrile

3,5-dibromo-4-hydroxybenzonitrile, 

including the metabolite 3,5-

dibromo-4-hydroxybenzoic acid

(except dry bulb onions, pearl millet, 

proso millet and sorghum)

3,5-dibromo-4-hydroxybenzonitrile

(For dry bulb onions, pearl millet, 

proso millet and sorghum)

None

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

US Canada Mexico1 Codex

Alfalfa, forage 0.1

Alfalfa, hay 0.5

Barley, grain 0.05 0.05

Barley, hay 9.0

Barley, straw 4.0

Corn, field, forage 0.3

Corn, field, grain 0.05 0.05

Corn, field, stover 0.2

Corn, pop, grain 0.05 0.05

Corn, pop, stover 0.2

Flax, seed 0.1 0.1

Garlic 0.1 0.1

Grain, aspirated 

fractions

1.2

Grass, forage 18

Grass, hay 5.0

Oat, forage 0.3

Oat, grain 0.05 0.05

Oat, hay 9.0

Oat, straw 4.0

Onion, bulb 0.1 0.02 dry bulb onions

Peppermint, hay 0.1

Rye, forage 1.0

Rye, grain 0.05 0.05

Rye, straw 2.0

Sorghum, grain, forage 0.8

Sorghum, grain, grain 0.2 0.05

Sorghum, grain, stover 0.2

Spearmint, hay 0.1
Page 18 of 37

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

Wheat, forage 1.0

Wheat, grain 0.05 0.05

Wheat, hay 4.0

US [40 CFR § 180.324 (a)(2)] Canada Mexico1 Codex

Livestock and cotton: bromoxynil 

and its metabolite, 3,5-dibromo-4-

hydroxybenzoic acid (DBHA), 

resulting from application of its 

octanoic and/or heptanoic acid 

ester

Same as above Same as 

above

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

US Canada Mexico1 Codex

Cattle, fat 1

Cattle, meat byproducts 3.5 0.1

Cattle, meat 0.5 0.1

Cotton, gin byproducts 7.0

Cotton, hulls 5.0

Cotton, undelinted seed 1.5 1.5

Egg 0.05 0.1

Goat, fat 1

Goat, meat byproducts 3.5

Goat, meat 0.5

Hog, fat 1

Hog, meat byproducts 3.5

Hog, meat 0.5

Horse, fat 1

Horse, meat byproducts 3.5

Horse, meat 0.5

Milk 0.4 0.1

Poultry, fat 0.05

Poultry, meat 

byproducts

0.3 0.1

Poultry, meat 0.05 0.1

Sheep, fat 1

Sheep, meat 

byproducts

3.5

Sheep, meat 0.5

MRLs With No US Equivalent

Buckwheat 0.05

Pearl millet 0.05

Peppermint, tops 0.05

Proso millet 0.05
Page 19 of 37

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

Rapeseed (canola) 0.1

Spearmint, tops 0.05

Sweet corn kernels plus 

cob with husks 

removed

0.05

Teosinte 0.05

Triticale 0.05

Wild rice 0.05

Completed: : M. Negussie; 10/15/2012

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
Page 20 of 37

Attachment 3

Summary of Bromoxnil Endpoints Selected for Risk Assessment

Table 3.1. 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 = 
Page 21 of 37

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.

Table 3.2. 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.
Page 22 of 37

Toxicity Profiles

Table 3.3. 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
Page 23 of 37

Table 3.4. 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
Page 24 of 37

Table 3.4. 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.
Page 25 of 37

Table 3.4. 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.
Page 26 of 37

Table 3.4. 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
Page 27 of 37

Table 3.4. 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. 
Page 28 of 37

Table 3.4. 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.
Page 29 of 37

Table 3.4. 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.
Page 30 of 37

Table 3.4. 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.
Page 31 of 37

Table 3.4. 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.
Page 32 of 37

Table 3.4. Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.6200a

Acute 

neurotoxicit

y screening 

battery

No study data are 

currently available

Requirements for this study have been waived 

(TXR 0000000, K. Rury, December 2012)

870.6200b

Subchronic 

neurotoxicit

y screening 

battery

No study data are 

currently available

Requirements for this study have been waived 

(TXR0000000, K. Rury, December 2012)

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.

870.7800 

Immunotoxi

city

MRID 48540505 Study in review

Table 3.5. 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
Page 33 of 37

Table 3.5. 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.
Page 34 of 37

Table 3.5. 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
Page 35 of 37

Table 3.5. 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.
Page 36 of 37

Table 3.5. 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. 
Page 37 of 37

Table 3.5. 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.