### 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 S upport of Regi st ration Review.

PC Code : 035301, 035302, 128920

Decision No.: 

### 4113.5..5 DP Barcode: DP 406426 Registration No. : NA

Petition No. : NA Regulatory Action: R egis tration Review

Case No. : 2070 Risk Assessment Type: NA

TXRNo

. :NA

MRIDNo. :N A 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, Acting Chief 

# t!A{**~-6~** Risk Assessment Branch 

### III 

# J-

Heal th Effe cts 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 herbicide s 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 i s 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, pepp ermint, 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

residentia l 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 v ia 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, tox icity 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. C hanges in weight, clinical chemistry and pathology indicated treatment

- related perturbations in and adverse

effects on liver function a cro ss species, durations, and genders . Treatment

- related decreases in body weight and decreases in body weight gain were observed in rats, mice, dogs, and ra bbits

. Subchronic and chronic studies in dogs showed that bromoxy ni l 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 ) wa s supernumerary ribs in rats, mice

and rabbits. In addition, supernumerary ribs occurred in rats exposed by both the oral and

dermal routes. Brom oxynil is classified as a “possible human carcinogen” based on the presence

of hepatocellular tumors in male and female mice. The unit risk, Q 1 * 

### , of bromoxynil based upon male mouse hepatocellular tumors rates is 0.103 (mg/kg/day) - 1 

### in 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 exceptio n o f 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 f ield trial, rotational

crop , and storage stability data are avai lable.

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 restrict ed 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 pesti cides 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 da tabases, 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 app lied 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 toxic ology 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 Counci l (HASPOC) has waived the neurotoxicity battery and subchronic inhalation toxicity study (TXR

0056526 , K. Rury 12/ 00/ 12) be cause 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 incid ents 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 an d rabbits via the oral and dermal routes by increased incidence of supernumerary (13 th 

### 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, s coliosis, 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 cl assified as a “possible human carcinogen” based on the presence of hepatocellular tumors in male and female mice. The unit risk, Q 1 * 

### , of bromoxynil based upon male mouse hepatocellular tumors rates is 0.103 (mg/kg/day) - 1 

### in human equivalents. ( TXR

005004 5, 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 (an d/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 th e 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

substant ial 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 Depa rture were used for

overall risk assessments.

### Page 5 of 37

Toxicity endpoints, P oints of D eparture, and safety factors for bromoxynil risk assessment were

se lected by HED in 2011 (Attachment 3 ).

Conclusions : HED’s Hazard Science and Policy Council (HASPOC) has assess ed 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 ad equate for risk assessment, with the exception of the immunotoxicity study. O nce the submitted immunotoxicity data have been reviewed, the bromoxynil Registration Review Team recommends that the toxicological endpoints, points of departure, and safety fact ors 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 (D 378615

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

- FCID TM 

### , 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 diet a ry 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 cot ton, 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

. M aximum crop treated estimates were used for all

crops and e mpirical or DEE MTM 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 cro ps. Empirical or DEEMTM default processing factors were used.

The e stimated drinking water concentration (EDWC) of bromoxynil was provided by the Environmental Fate and Effects Division (EFED) and incorporated directly into the acute and

chronic assessmen t s

. EFED estimated residues of bromoxynil in surface water and groundwater using the FIRST Version 1.1.1 (FQPA I ndex R eservoir S creening T ool) 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 pp t) ; therefore, the surface water value of 0.19 ppb was used in the chronic (cancer and non

- cancer) dietary assessment s

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

The acute dietary (food and drinking water) expos ure 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 99.9 th 

### percentile of the exposure distribution,

### Page 6 of 37

the US population occup ied 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 h ighly 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 pla nts 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). B romoxynil is the residue of concern in l ivestock 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 butyr ate 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 diet ary assessment for bromoxynil may not be required for the purpose of registration review. Furthermore,

a lthough a n ew version of DEEM (Version 3.16 ) has been released, a new dietary risk

assessment may not be nee ded 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, garli c, 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, t hese ma rginal changes of %CT estimates

will have minimal imp act 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

- A pplication

The Agency has not considered residential pos t

- appl ication exposure for bromoxynil since there are no registered residential uses at this time.

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

Aggregate Risk Assessment

A ggregate assessments consider expos ures from food, drinking water, and residential uses. In

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

were estimated for the acute and chronic (cancer and noncancer) (food and dr inking water) exposure duratio n s . 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 ass essment may not be needed since it is anticipated that the changes in the model will not

affect the risk conclusion.

Occupational E xpos ure

Bromoxynil is currently registered for use on several agricultural crops as well as on grasses grown for seed an d 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 expos ure 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, a nd 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 combi ned (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

MOE s 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 applicati on 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 exposur e 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 a ssumed 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) the se 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 - 7 

### to 1.9x10 - 4 

### with gloves, and from

2.7x10 - 7 

### to 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 oc cupational handler risk

assessment may be needed during Registration Review

.

Occupational Post

- A pplication

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

ba seline 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), r isk 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 - 6 

### to 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

- spe cific 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 rat e available to be dislodged after a foliar application (F AR 

### ). This default value is 25% and is based on an analysis of 19 DFR

studies where the F AR 

### value ranged from 2% to 89%. This value is recommended for use in both residential and occupational post

- a pplication assessments. Of the analyzed DFR studies, the

maximum F AR 

### 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 st udy 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, ba sed 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 bro moxynil 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 Rodenticid e 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 av ailable 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 inh alation 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 s ufficient information available to assess occupational handler and post

application exposures. However, not all of the occupational exposure scenarios were assessed based on current ORE policies. An up

- to

- date handler and post

- application oc cupational

as sessment 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, 200 7 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, 1 1 /1 3 / 12 ).

In the A ggregate IDS module there were 11 repor ted incidents from January 1, 200 7 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 Ri sk

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

All three cases are work

- related. One case is moder ate 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 liqui d splashed on his face and mouth. He went to the ER and reported dermal and respiratory symptoms. Another case involved a femal e 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 no t 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 Assessmen t 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 exp ression (except for dry bulb onions, pearl millet, proso millet and sorghum) . T he Canadian tolerance expression is “ 3,5

- dibromo

- 4

- hydroxybenzonitrile, including the metabolite 3,5

- dibromo

- 4

- hydroxybenzoic acid (DBHA) ”

, except dry bulb onions, pearl mille t, proso millet, and sorghum ; however, c ompliance 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

. equ ivalent s (See Attachment 2).

It should be noted that a ll 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)

, s ince 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 128 98, "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 pat terns 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 ri sks 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 spec ialized 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, neurotoxici ty, 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 maturat ion, 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 sub ject 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 simil ar 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 th e 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 r egistration review, EPA will issue future EDSP orders/data call

ins, 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 produ ce 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 chemi cals 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 fro m substances found to have a common mechanism on

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Human Studies

The previous risk assessment s rely in part on data from studies in which a dult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the

PHE D and the Agricultural Reentry Task Force (ARTF) have been determined to require a review of their ethical conduct, and have received tha t 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 Reference s below, only one human health risk assessment h as been recently

conducted for bromoxynil

.

Memoranda Relevant to Registration Review of Bromoxynil

Author Barcode

(DP#) Date Title

Dodd, N. 378614 0 2/15/2011 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 0 4/20/11 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

Attachment s 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 C 7 H 3 Br 2 NO

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

### Page 17 of 37 Attachment 2

International Residue Limits

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### 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 d ry bulb onions, pearl millet, proso millet and sorghum ) None

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

US Canada Mexico 1 

### 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 Mexico 1 

### Codex 

### Wheat, forage 1.0
Wheat, grain 0.05 0.05 Wheat, hay 4.0

US [40 CFR § 180.324 (a)(2)] Canada Mexico 1 

### 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 Mexico 1 

### 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

MRL s 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 Mexico 1 

### 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 Non

Occupational 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 UF A = 10 x

UF H =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 UF A = 10 x

UF H =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 UF A = 10 x

UF H =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 live r 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 (Q 1 *) be applied to the experimental animal tumor data for quantification of human risk. Q 1 * = 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 extrapolatio n 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. UF A = extrapolation from animal to human (interspecies) . UF H = 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 con cern. 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 Short

and

Intermediate

Term (1

- 30 days) NOAEL=

10 mg/kg/day UF A = 10 x

UF H =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

Intermediate

Term (1

- 30 days) NOAEL= 4

mg/kg/day UF A = 10 x

UF H =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 dose

related increased incidence of

supernumer ary 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 h epatocellular tumors. The committee also recommended that a low dose extrapolation model (Q 1 *) be applied to the experimental animal tumor data for quantification of human risk. Q 1 * = 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 o bserved adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = populati on adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### Page 2 2 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 LD 50 = 81 mg/kg M

LD 50 = 93 mg/kg F) II 00124758

870.1200 Acute dermal toxicity Rat LD 50 >= 2000 mg/kg (M, F) III 00124758

870.1300 Acute inhalation

toxicity Rat LC 5O = 0.269 mg/L M

LC 5O = 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 LD 50 = 400 mg/kg M

LD 50 = 238 mg/kg F II 00124112

870.1100 Acute dermal toxicity Rabbit LD 50 > 2000 mg/kg M

abraded skin.

LD 50 1310 mg/kg F

with intact skin.

LD 50 = 1660 mg/kg F

with abraded skin. II 00124112

870.1300 Acute inhalation

toxicity Rat LC 5O = 0.810 mg/L M

LC 5O = 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 NO A EL 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 (19 88 )

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 LOAEL s 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 o bserved 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 (19 92 )

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 super numerary (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 ab normalities (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 a nomalies.

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 = 5 0 mg/kg/day

Maternal systemic LOAEL = 1 00 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 . A t 60 mg/kg/day, the followi ng additional effects were also observed: increased post

implantation 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, a nophthalmia, 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 verteb ral 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 = 5 0 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 th e 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.

Rep roductive 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

paren ts

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 (19 88 )

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), hem oglobin (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 (19 82 )

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 e vidence 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 ass ess tumorigenic potential.

870.4200 Carcinogenicity

(mice) MRID 43245501 (19 94 )

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 Ku pffer 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 incidenc es 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 (19 82 )

( 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 incr eased incidence of neoplasms in males or females. Dose levels used in this study were determined to be

insu fficiently high to assess carcinogenic potential.

870.4300 Combined

Chronic/ Carcinog enicity (rats) MRID 40612501,

41374801 (19 88 )

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.

Carcinogeni city:

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)

S trains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to technical grade bromoxynil phenol

without metabolic

activation at

concentrat ions ranging

from 3.33 to 1000

μ g/plate and with metabolic activation (rat S9 mixture) at

concentrat ions rangi ng 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)

C ultures of Chinese hamster ovary (CHO) cells were exposed to technical grade bromoxynil phenol

without metabolic

activation at

concentra tions ranging from 100 to 1500 μ g/ml (8 hou r exposure) and from 50 to 500 μ g/ml (20 hour exposure).

Acceptable Negati ve 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

co ncentr ations equal to and above 1200 μ g/ml was considered to be a positive genotoxic

response.

870.5395 In Vivo

mammalian (mouse) erythrocyte

micronucleus test MRID 00124803 (1982)

B romoxynil phenol w as 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 a s 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)

S ingle 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)

C ultures of primary rat hepatocytes were exposed to technical grade bromoxynil phenol at

concent rations ranging from 0.1 to 50 μ g/ml.

Acceptable Negative

Bromoxynil phenol did not induce a genotoxic effect in this assay system

870.5xxx In vitro

transformation

assay MRID 00115647 (1982)

C ultures of mouse

C3H/10T 1⁄2 C18 cells were exposed to technical grade bromoxynil phenol

at concentra tions ranging from 32.5 to 390 μ g/ml.

Acceptable Negative

Bromoxynil phenol did not induce a genotoxic effect in this assay system.

870.5xxx Sister Chromatid

Exchange MRID 00115648 (1982)

C ultures 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 μ g/ml

and with metabolic activation (rat S9 mixture)

at concentr ations ranging

from 500 to 900 μ g/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)

C ultures of L5178Y

TK+/

- cells were exposed to technical grade bromoxynil phenol

without metabolic

activation at

concentra tions ranging from 15.6 to 250 μ g/ml

and with metabolic activation (rat S9 mixture) at concentrations of 3.9,

7. 8, 15.6, 31.3 or 62.5

μ g/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 po sitive genotoxic respons e.

870

- 5xxx Forward mutation

Mouse lymphoma

cells MRID 41995702 (1991)

C ultures of Chinese hamster ovary (CHO)/HGPRT locus cells were exposed to technical grade bromoxynil phenol

without and with metabolic activation (rat S9 mixture) at

concentra tions ranging from 100 to 1000 μ g/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)

C ultures 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

concentrat ions ranging

from 1.0 to 10000

μ g/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

14 C

- 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 re mained

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 (19 92 )

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

870.31 5 0 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

870.31 5 0 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 42 346201 (19

-- )

0, 30, 300 or 1000 mg/kg/day

Minimum Dermal NOAEL = 30 mg/kg/da y, 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

870.370 0a Prenatal develop

mental 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 s kin 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.

870.3700 b Prenatal

developmental in

non

- rodents (ra bbit )

- 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 (ra bbi t)

- 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 b ody 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)

S trains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to technical grade bromoxynil octanoate

without and with metabolic activation (rat S9 mixture) at

concentra tions ranging from 33 to 10000 μ g/plate.

Acceptable Negative.

Bromoxynil octan oate, 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 octan oate did not induce a clastogenic effect in this assay system.

870.5550 Unscheduled DNA

synthesis in

mammalian cells C ultures of primary rat

hepatocytes were exposed to technical grade bromoxynil octanoate at

concentrati ons ranging from 0.98 to 15.63 μ g/ml. Higher concentrations ( > 31.25 μ g/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)

14 C

- Bromoxynil octanoate, incorporated into the end

use product Buctril, which

contained 33.4% bromoxynil octanoate as the active ingredient, was topically applied to the skin of male Sprague Dawley r ats 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 respec tively. 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 M etabolism

- 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 14 C

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.

Minimum Results were similar regardless of dos ing regimen. Rate of absorption was moderate in both males and females; peak plasma concentrations of radioactivity were not reached

until 7

- 10 hours after d osing.

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. Essential ly 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 i n 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.