UNITED STA TES ENVIRONMENTA L PROTECTION AGENCY

MEMORANDUM Date : 4 /20 /11 SUBJECT: Bromoxynil: Human Hea

Grown for Seed, Conservation Reserve Program Areas, PC Code: 035301 , 035302 Decision No.: 425581 Petition No . : 9F7678 Risk A ss essment Type : Single Chemical/Aggregate T XR No.: NA MRID No . : NA FROM: Cassi L .Walls, Ph.D.,

My ron S. Ottley , Ph.D., Toxicologist Nancy Dodd, Chemist Kristin Rury , Biologist Risk Assessment Branch III (RAB3) Health Effects Division (HED) (7509P) THROUGH: Paula Deschamp, Branch Chief

RAB3/HED (7509P) TO: Bethany Benbow, RM#23

Registration Division (7505P)

Page 1 of 72 UNITED STA

TES ENVIRONMENTA L PROTECTION AGENCY WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

Human Hea lth Risk Assessment for Amended Uses on Grown for Seed, Conservation Reserve Program Areas, and Grain Sorghum DP Barcode: D 374609 Re gistration No. : 264
- 1023 Regulatory Action: Section 3 Registration Case No.: 2070 CAS No.: 1689
- 84
- 5, 1689
- 99 40 CFR: 180.324 Cassi L .Walls, Ph.D., Risk Assessor

, Ph.D., Toxicologist Chemist Biologist Risk Assessment Branch III (RAB3) Health Effects Division (HED) (7509P) Paula Deschamp, Branch Chief RAB3/HED (7509P) Bethany Benbow, RM#23 Registration Division (7505P) UNITED STA

TES ENVIRONMENTA L PROTECTION AGENCY

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

Uses on Grass and Grain Sorghum
. Section 3 Registration
99
- 2Page 2 of 72

1.0 Executive Summary
................................ ................................ ................................ ........... 4 2.0 Regulatory Conclusions and Recommendations
................................ ............................. 8 2.1 Data Deficiencies/Conditions of Registration
................................ .............................. 9 2.2 Tolerance Considerations
................................ ................................ .............................. 9 2.2.1 Enforcement Analytical Method
................................ ................................ ............... 9 2.2.2 International Harmonization
................................ ................................ ................... 10 2.2.3 Recommended Tolerances
................................ ................................ ....................... 10 2.2.4 Revisions to Petitioned - For Tolerances
................................ ................................ .. 11 2.3 Label Recommendations
................................ ................................ .............................. 12 2.3.1 Recommendations from Residue Reviews
................................ .............................. 12 2.3.2 Recommendations for Worker Safety
................................ ................................ .... 12 2.3.3 Recommendations for Residential Safety
................................ ............................... 12 3.0 Ingredient Profile
................................ ................................ ................................ ............. 12 3.1 Structure and Nomenclature
................................ ................................ ....................... 13 3.2 Physical/Chemical Characteristics
................................ ................................ ............. 14 3.3 Summary of Existing/Amended Uses
................................ ................................ ......... 14 4.0 Hazard Characterization and Dose - Response Assessment
................................ .......... 17 4.1 Toxicology Studies Available for Analysis
................................ ................................ . 17 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)
............................. 18 4.2.1 Dermal Absorption
................................ ................................ ................................ ... 18 4.3 Toxicological Effects
................................ ................................ ................................ .... 19 4.4 Safety factor for Infants and Children (FQPA Safety Factor)
................................ 20 4.4.1 Completeness of the Toxicology Database
................................ .............................. 20 4.4.2 Evidence of Neurotoxicity
................................ ................................ ........................ 21 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal
........ 21 4.4.4 Residual Uncertainty in the Exposure Database
................................ ................... 21 4.5 Toxicity Endpoint and Point of Departure Selections
................................ .............. 22 4.5.1 Dose - Response Assessment
................................ ................................ ...................... 22 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment
..... 22 4.5.3 Cancer Classification and Risk Assessment Recommendation
............................ 22 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment
................................ ................................ ................................ ............................... 22 4.6 Endocrine Disruption
................................ ................................ ................................ ... 24 5.0 Dietary Exposure and Risk Assessment
................................ ................................ ......... 25 5.1 Metabolite/Degradate Residue Profile
................................ ................................ ....... 25 5.1.1 Summary of Plant and A nimal Metabolism Studies
................................ ............. 25 5.1.2 Summary of Environmental Degradation
................................ .............................. 26 5.1.3 Comparison of Metabolic Pathways
................................ ................................ ....... 27 5.1.4 Residues of Concern Summary and Rationale
................................ ...................... 27 5.2 Food Residue Profile
................................ ................................ ................................ .... 28 5.3 Water Residue Profile
................................ ................................ ................................ .. 30 5.4 Di etary Risk Assessment
................................ ................................ .............................. 31 5.4.1 Description of Residue Data Used in Dietary Assessment
................................ .... 31 5.4.2 Percent Crop Treated Used in Dietary Assessment
................................ .............. 32 5.4.3 Acute Dietary Risk Assessment
................................ ................................ ............... 33 5.4.4 Chronic Dietary Risk Assessment
................................ ................................ ........... 33Page 3 of 72

5.4.5 Cancer Dietary Risk Assessment
................................ ................................ ............. 34 5.4.6 Summary Table
................................ ................................ ................................ ......... 34 6.0 Residential (Non - Occupational) Exposure/Risk Characterization
............................. 34 6.1 Spray Drift
................................ ................................ ................................ .................... 34 7.0 Aggregate Exposure/Risk Characterization
................................ ................................ .. 35 7.1 Acute Aggregate Risk
................................ ................................ ................................ ... 35 7.2 Shor t - and Intermediate - Term Aggregate Risk
................................ ....................... 35 7.3 Chronic Aggregate Risk
................................ ................................ .............................. 35 7.4 Cancer Aggregate Risk
................................ ................................ ................................ 35 8.0 Cu mulative Exposure/Risk Characterization
................................ ............................... 35 9.0 Occupational Exposure/Risk Characterization
................................ ............................ 35 9.1 Short -/Intermediate Term Non - Cancer & Cancer Risk For Pesticide Handlers
.. 36 9.2 Short -/Intermediate - Term Post - Application Risks
................................ ................... 43 10.0 Environmental Justice Considerations
................................ ................................ .......... 47 11.0 References
................................ ................................ ................................ ......................... 48 Appendix A. Toxicology Profile and Executive Summaries
................................ .................. 49 A.1 Toxicology Data Requirements
................................ ................................ ................... 49 A.2 Toxicity Profiles
................................ ................................ ................................ ............ 50 A.3 HAZARD IDENTIFICATION AND ENDPOINT SELECTION
........................... 66 A.3.2 Chronic Reference Dose (cRfD)

– All Populations
................................ ............ 67 A.3.3 Dermal Short - Term (1 - 30 days) and Intermediate - Term (1 - 6 Months)
.......... 68 A.3.3 Inhalation Short - Term (1 - 30 days) and Intermediate - Term (1 - 6 Months)
..... 69 Appendix B. Chemical Names and Structures of Bromoxynil, its Esters and Metabolite
. . 70 Appendix C. Review of Human Research
................................ ................................ ................ 71 Appendix D. International Residue Limit Status Sheet
................................ ......................... 72Page 4 of 72

1.0 Executive Summary Use Profile : Baye r CropScience (BCS) has proposed a new product, HUSKIETM Herbicide (EPA Registration No. 264
- 1023), that contains bromoxy nil octanoate, bromoxy

nil heptanoate, and py rasulfotole as the active ingredients. The adequacy of the proposed uses of py rasulfotole will be addressed in a separate document. The bromoxy nil octanoic and heptanoic esters are rapidly converted to the bromoxy nil phenol ( 3,5
- dibrom o - 4
- hydrox ybenz onitrile)
. Therefore, the exposure and tolerances are based on bromox ynil phenol (from here on out will be referred to as bromox yn il)
. BCS has proposed amended uses for bromoxy nil formulated in the HUSKIETM Herbicide product. Bromoxy

nil is currentl y registered for use on grass and grain sorghum; however, BSC is proposing to amend the use pattern b y shorten ing the preharvest interval ( PHI ) which subsequently

will result in an increase in the tolerance. Bromox ynil i s a contact h erbicide which is registered for application as the octanoic and/ or heptanoic acid esters for control of broadleaf weeds in v arious crops. Bromox ynil inhibits photosynthetic electron transport and oxidative phosphorylation in mitochondria
. The previous b rom o x yn il risk assessment was conducted to support the Reregistration Eligibility Decision (RED) in December 1998. HUSKIETM Herbicide is an emulsifiable concentrate which contains 13.4% bromoxy nil octanoate, 12.9% bromoxy nil heptanoate, 3.3% py

rasulfotol e, and 70.4% inerts. The formulation contains 1.75 lbs bromox yn il active ingredient per gallon. HUSKIETM Herbicide foliar spray

may be applied to conservation reserve program acres ( CRP ) and grasses grown for seed from preemergence to established grasses. A maximum of two applications with a re treatment interval (RTI) of 30 day s can be made with a maximum rate of 0. 41 lb ai/A/ye ar for CRP and grasses grown for seed. The preharvest intervals (PHI) are 7 day s for forage and 30 day s for hay ; the restricted entry interval (REI) is 12 hours. HUSKIETM Herbicide is applied as a postemergence foliar spray to grain sorghum using ground application equipment. Application through any ty pe of irrigation s ys tem is prohibited. A maximum of two applications with an RTIof 11 day s can be made for a maximum rate of 0. 4 4 lb ai/A/ye ar for grain sorghum
. The preharvest interval s (PHI) are 7 day s for forage and 60 day s for grain or stover; the restricted entry interval (REI) is 12 hours. Human Health Risk Asses sment : Bromox ynil phenol has moderate acute toxicity via the oral and inhalation routes and low acute toxicity via the dermal route. Bromox ynil octanoate has moderate acute toxicity via the oral and dermal routes and low acute toxicity via the inhalation route. Due to rapid conversion of the ester forms of the chemical (heptanoate and octanoate) to the phenol, toxicity testing was conducted with both phenol and octanoate material , and the risk assessment is based on exposure to the phenol. In the repeated dos e studies of the mammalian toxicology database, the liver was the primary target organ of bromox ynil toxicity . Across species, duration and gender, changes in weight, clinical chemistry

and pathology

indicated treatment
- related perturbations in and advers e effectsPage 5 of 72

on liver function. Treatment
- related effects were also observed on body weight and body weight gain changes (rats, mice, dogs, rabbits)
. Subchronic and chronic studies in dogs showed that bromox y ni l elevated body

temperature, manifested by incr eased panting at lower dose levels, and hy perthermia and death as dose levels increased. Bromox ynil produced developmental toxicity across all tested species. The consistent effect seen at the 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. Bromox ynil is classified as “possible human carcinogen.” This was based on the presence of hepatocellular tumors in male and female mice. There is no concern for mutagenicity
. The unit risk, Q 1 * , of bromox yn il based upon male mouse hepatocellular tumors rates is 0.103 (mg/kg/day) - 1 in human equivalents. Dietary Exposure (Food/Water): The residue chemistry

data and environmental fate data are adequate to assess human exposure. Although somewhat refined, the acute, chronic and cancer dietary food exposure assessments are based on reliable data and will not underestimate exposure/risk. Acute : A refined acute dietary assessment was conducted. The assumptions of this dietary assessment included average field trial residues for all grains; tolerance level residues for cotton, garlic, onio n, peppermint and spearmint; anticipated residues in livestock; and maximum crop treated (CT) estimates for all crops . Empirical or DEEMTM default processing factors were used
. Potential residues in drinking water were included in the anal ys es based on surface water results from the Tier I FIRST model. The acute dietary

(food and drinking water) exposure to bromoxy nil is below HED’s level of concern [i.e., <100% of the acute Population Adjusted Dose (aPAD)] for the general U.S. population and all population subgroups. At the 99.9 th percentile of the exposure distribution, the US population occupied just 3.3% of the aPAD , while the most highly exposed population subgroup, all infants (< 1 year old), occupied 7.4% of the aPAD. Chronic : A refined chronic dietary assessment was conducted. The assumptions of this dietary assessment included average field trial residues for all crops except for spearmint and peppermint where tolerance values were used; anticipated residues in livestock; and average CT estim ates for all crops . Empirical or DEEMTM default processing factors were used
. Potential residues in drinking water were included in the analy ses based on surface water results from the Tier I FIRST model. The non
- cancer chronic dietary (food and drinkin g water) exposure to bromoxy nil is below HED’s level of concern [i.e., <100% of the c hronic 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 g eneral U.S. population as well as for Children 1
- 2 years old, the most highly

exposed population subgroup.Page 6 of 72

Cancer: The cancer dietary (food and drinking water) risk estimate for the general U.S. population is 1.5 x 10 - 6 , which is below HED’s level of concern ( generally in the range of 10 - 6 ). Residential Exposure: There are no residenti al uses of bromoxy nil; therefore, a residential exposure assessment was not necessary to conduct. Aggregate Risk: Acute: Aggregate a cute risk is equivalent to acute dietary risk. There is potential acute exposure (7.4 % of the aPAD) via the diet (food and drinking water) as determined in Section 5.3
. Chronic: Aggregate chronic risk is equivalent to chronic dietary risk. There is p otential chronic exposure ( ≤1% of the cPAD) via the diet (food and drinking water) as determined in Section 5.4
. Short
- and Intermediate Term: Since there are no residential uses for bromoxy nil, short
- and intermediate
- term aggregate assessments were not conducted. Cancer: The aggregate cancer risk (food and drinking water) is 1.5 x 10 - 6

. Occupational Exposure/Risk: This risk assessment evaluated the occupational handler and post
- application scenarios for both the amended uses and existing uses of bromox ynil. Bromox ynil is currentl y registered for use on grass and grain sorghum; however, B CS is proposing to shorten the PHI which subsequently will result in an increase in the tolerance. The existing uses assessed in 1998 were reassessed because a higher dermal absorption factor was identified fo r route - to - route extrapol ation and an inhalation endpoint was selected for inhalation exposure risk assessment. Agricultural Handlers: Occupational short
- term (1
- 30 day s) and intermediate
- term (1
- 6 months) dermal and inhalation exposure s are expected from bromox ynil handler activities associated with both the proposed and existing agricultural uses. HED used data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in the PHED Surrogate Exposure Guide (8/98) to assess handler exposures (HED Science Advisory Council for Exposure (ExpoSAC) Standard Operating Procedure (SOP) No. 7, dated 01/28/1999). A Margin of Exposure (MOE) greater than 100 for the inhalation , dermal, and combined route s is deemed adequate to p rotect occupational bromoxy nil handlers. Amended uses The results indicate that the MOEs for the amended uses for occupational handler scenarios were not of concern (i.e., an MOE > 100) at some level of personal pro tection (gloves). The dermal MOE was 12 with baseline attire for mixer/loaders, and the dermal MOEs ranged from 2,400 to 2,600 for applicators. The dermal MOEs with baseline attire plus gloves (PPE
- G) ranged from 1,500 to 1, 6 00 for mixer/loaders and from 2,400 to 2, 6 00 for applicators. Inhalation MOEs ranged from 11 , 0 00 to 12,000 for mixer/loaders and from 18,000 to 19,000 for applicators. ThePage 7 of 72

c ombined (dermal + inhalation) MOE with baseline attire was 12 for mixer/loaders and the MOEs ranged from 2,200 to 2 3 00 for applicators. Combined (dermal + inhalation) MOEs with baseline attire plus gloves (PPE
- G) ranged from 1,300 to 1,400 for mixer/loaders and from 2,200 to 2, 3 00 for applicators. The results indicate that estimated cancer risks were not of concern (i.e., in the 10 - 6 range or lower) for both commercial and private users at some level of personal protection (gloves). At baseline attire, estimated risk for commercial users of bromox ynil is in the 10 - 4 range for mixer/loaders and 10 - 6 range for applicators; at baseline plus gloves (PPE
- G), estimated risk is in the 10 - 6 range for mixer/loaders and applicators. At baseline attire, estimated risk for private users of bromox ynil is in the 10 - 5 range for mixer/loaders and in the 10 - 7 range for appli cators; at baseline plus gloves (PPE
- G) estimated risk is in the 10 - 6 range for mixer/loaders and 10 - 7 range for applicators. Reevaluation of Existing Bromoxynil Uses The results indicate that the mixing/loading MOEs for the existing use sites were not of concern (i.e., an MOE > 100) at some level of personal protection (gloves) for all crops and application methods, except mixing/loading for aerial application to corn and wheat, which requires a closed sy stem. The results indicate that MOEs for application of bromoxy nil to all existing use sites were not of concern at some level of personal protection (gloves). Flagging for bromoxy nil application was not of concern at baseline attire. The dermal MOEs at baseline attire range from 0.3 4 (risks of conc ern) to 160 for mix ing/loading for application to corn and wheat , from 1.2 (risks of concern) to 1,400 for mixing/loading for application to all other crops, from 200 to 6,000 for applicators, and from 310 to 620 for flaggers. Inhalation MOEs at baseline attire were >330 for mixer/loaders, applicators and flaggers and are not of concern. Combined (dermal + inhalation) MOEs at baseline plus gloves ranged from 38 to 2 ,900 for mixer/loaders, 380 to 4,900 for applicators, and from 270 to 530 for flaggers. Mixing and loading scenarios for bromoxy nil application to corn and wheat were below HED’s LOC=100 at baseline and PPE
- G. With coveralls, mixing/loading for application to corn and wheat, the d ermal MOE was 57 and the c ombined d ermal and inhalation MOEs ranged from 55 (risk of concern) to 190
. In a closed system, the dermal MOE for mixing/loading for application to corn & wheat was 120 and was 4,800 for inhalation exposure ; the combined dermal + inhalation MOE was 110 , and there fore not of concern
. The results indicate that estimated cancer risks were not of concern (i.e., in the 10 - 6 range or lower) for both commercial and private users at some level of personal protection (gloves) for all scenarios except aerial application to corn and wheat, which requires a closed sy stem
. At baseline attire, estimated risks for commercial users of bromox ynil are in the 10 - 5 to 10 - 2 range (depending on the use site) for mixer/loaders, in the 10 - 7 to 10 - 5 range for applicators and 10 - 6 and 10 - 5 range for flaggers. At baseline attire plus gloves , estimated risk is in the 10 - 4 or 10 - 7 range for mixer/loaders, in the 1 0 - 5 and 10 - 7 for applicators and in the 10 - 5 or 10 - 6 for flaggers. With PPE
- G and the addition of coveralls , estimated risk is in the 10 - 4 and 10 - 7 range for mixer/loaders, in the 1 0 - 5 and 10 - 7 range for applicators, and in the 1 0 - 5 or 10 - 6 range for flaggers. With a closed sy stem, estimated risk is in the 10 - 5 or 10 - 7 range (depending on the use site).Page 8 of 72

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

- 6 months) dermal exposures are expected for worker re
- entering bromoxy nil treated fields and performing post - application activities such as scouting and harvesting
. A ll post - ap plication dermal exposure s were evaluated using surrogate data and default assumptions Amended uses The dermal non
- cancer short
- and intermediate
- term post - application MOEs ranged from 150 to 1,500 on the day

of application. The estimated cancer risks for agricultural workers on the day of application ranged from 1.4 x10 - 6 to 1. 1 x10 - 5

. Reevaluation of Existing Bromoxynil Uses The short
- and intermediate
- term dermal non
- cancer MOEs for all existing occupational post
application scenarios ranged from 45 to 1,400 on the day of application; and therefore, some post - application activities are of concern. Risk from occupational contact with full foliage wheat, small grains and mint is not of concern 8 day s after application, risk from sod harvesting is not of concern 5 day s after application, and risk from occupational contact with full foliage corn, sorghum and cotton is not of concern 4 day s after application. The estimated cancer risks on the day

of application ranged from 2.3 x10 - 6 to 1.4x10 - 4

. Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for bromox ynil at this time. Environmental Justice Considerations : Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment . Dietary and non
dietary exposures were considered. Review of Human Research: This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies (listed in Appendix C) have been determined to require a review of their ethical conduct, and one of these studies is also subject to review b y the Human Studies Review Board. All of the listed studies have received the appropriate review. 2.0 Regulatory Conclusions and Recommendations Provided revised Sections B (OPPTS 860.1200) and F (OPPTS 8 60.1550) are submitted, HED can recommend permanent tolerances for the uses of bromox yn il on grass and grain sorghum commodities and conditional registration for the requested uses on annual and perennial grasses grown for seed, conservation reserve program acres, and grain sorghum. Additional data are needed as condition s of registration as outlined in Section 2.1 below. The specific tolerance recommendations are discussed in Section 2.2, and label modifications are discussed in Section 2.3.Page 9 of 72

2.1 Data Deficiencies/Conditions of Registration The following must be provided prior to a tolerance being established or registration allowed: 860.1200 Directions for Use A revised Section B is requested to include an “ APPLI CATION METHODS ” section for gras s specifying type of application, method of application, and minimum gallons sprayed per acre for each method; clarify me thod of application for sorghum; and include rotational crop plantback intervals for all crops which are not primary (treated) crops on the label or are not already listed in the Crop Rotation Guidelines section of the label. 860.1550 Proposed Tolerances A revised Section F must be submitted to reflect the tolerances and correct commodity definitions as listed in Table 2.2.4. The following d ata are required as a condition of registration : TOXICOLOGY 870.6200 Neurotoxicity

Battery (Acute and Subchronic Studies) The acute and subchronic neurotoxicity screening battery

is required to fulfill current 40 CFR Part 158 data requirement s. 870.7800 Immunotoxic i ty The immunotoxic i ty study is required to fulfill current 40 CFR Part 158 data requirements. In a letter dated June 23, 2010, BCS acknowledged the data deficiency for immunotoxicity

testing on bromoxy

nil and notified EPA that the conduct of this study is in the process of being scheduled for 2011. OCCUPATI ONAL EXPOSURE 875.2100 Dislodgeable Foliar Residue Study To characterize post
- application exposure and reduce uncertainty for late applications of bromox yn il, HED is requesting the registrant submit a dislodgeable foliar residue (DFR) study on a repres entative row crop (e.g. corn). 2.2 Tolerance Considerations 2.2.1 Enforcement Analytical Method Multiresidue methods data for bromox ynil butyr ate and bromox ynil octanoate have been submitted. R ecovery

of bromoxy

nil octanoate and bromoxy nil buty rate using FDA Multiresidue Me thod 303: Method II for Nonfatty Foods (Mills, Onley, Gaither Method) is variable.Page 10 of 72

B romox ynil was not detected through Flo risil elution. The data have been forwarded to FDA and included in the PESTDATA database. Adequate residue anal ytical methodology is available for tolerance enforcement for bromox ynil per se in grass and grain sorghum commodities. Method Iin PAM , Vol. II, is a gas liquid chromatograph y/microcoulometric detection ( GLC/MCD ) method that has undergone a successful EPA method validation on wheat grain. Method Ia is the same method except that it uses gas chromatograph y/electron capture detection ( GC/ECD ) for determination of methylated bromox yn il. Adequate residue anal ytical methodology is available for tolerance enforcement for bromox ynil per se in livestock commodities. M ethod A is a GC/MCD or GC/ECD method for the analysis of bromox yn il per se re sidues in livestock tissues and is essentially the same as Method I. Method B is a GC/ECD method that is also similar to Method I, with modifications to the cleanup procedures
. Adequate residue anal ytical methodology is available for tolerance enforcement for parent and 3,5
- dibromo
- 4
- hydrox yb enzoic acid (DBHA) in cottonseed and gin trash samples. The method is a gas chromatograph y/mass spectrometric detection (GC/MSD) method , “Bromox ynil: Method of Anal ys is for Bromox ynil and its Metabolite, 3,5
- Dibrom o - 4
- hydrox yb enzoic Acid in Cottonseed, Gin Trash, and Seed Processed Fractions using GC/MSD.” The method (Method RES9603) has been the subject of an independent laboratory validation (ILV) and an Agency petition method validation (PMV). 2.2.2 Internation al Harmonization There are currently

no maximum residue limits (MRL s) established b y C odex, Canada, or Mexico for bromox yn il
. Tolerances have been established by Canada for grain of sorghum grain at 0.1 ppm and for milk at 0.1 ppm. The Canadian toleranc e expression is “ 3,5
- dibromo
- 4
- hydrox yb enzonitrile, including the metabolite 3,5
- dibromo
- 4
- hydrox ybenz oic acid”; however, c ompliance with the tolerance levels in the U.S. will be determined b y measuring onl y bromox yn il (3,5
- dibromo
- 4
- hydrox ybenzonitrile). An International Residue Limit Status sheet is attached (Appendix D ). 2.2.3 Recommended Tolerances HED recommends for the following tolerances and residue definition s : 40 CFR § 180.324(a)(1): Tolerances are established for residues of bromoxy nil, inclu ding its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined b y measuring only bromox ynil (3,5
- dibromo
- 4
- hydrox yb enzonitrile) resulting from application of its o ctanoic and/or heptanoic acid ester. Grass, forage
................................ ................................ ..................... 18 ppm Grass, hay
................................ ................................ ........................ 5.0 ppmPage 11 of 72

Grain, aspirated grain fractions
................................ ........................ 1.2 ppm Milk
................................ ................................ ................................ . 0.4 ppm Sorghum, grain, grain
................................ ................................ ...... 0.2 ppm Sorghum, grain, forage
................................ ................................ .... 0.8 ppm Note: The established tolerance of 0.2 ppm on sorghum, grain, stover is to remain unchanged. 40 CFR § 180.324(a)(2): Tolerances are established for residues of bromoxy nil, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined b y measuring only bromox ynil (3,5
- dibromo
- 4
- hydrox yb enzonitrile) and its metabo lite 3,5
- dibromo
- 4
- hydroxy benzoic acid (DBHA) resulting from application of its octanoic and/or heptanoic acid ester. All livestock commodities should be moved from 40 CFR § 180.324(a)(2) to 40 CFR § 180.324(a)(1), leaving only cotton, gin byproducts ; cotton, hulls ; and cotton, undelinted seed in 40 CFR § 180.324(a)(2). 2.2.4 Revisions to Petitioned - For Tolerances Table 2.2.4 compares proposed and recommended tolerance levels. The recommended tolerance levels , including an increase for sorghum , grain , forage , are based on the submitted magnitude of the residue data and the Agency ’s tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP. Because the tolerance on the grain of grain sorghum is being increased from 0.05 ppm to 0.2 ppm, higher residues may occur in aspirated grain fractions. HED has determined that a higher tolerance of 1.2 ppm is needed for grain, aspirated grain fractions
. Based on calculated residues in dairy cattle for the tolerance assessment, the established tolerance on milk must be increased from 0.1 ppm to 0.4 ppm. Other livestock tolerances remain unchanged. Table 2.2.4. Tolerance Summary for Brom oxynil Comm odity Tolerance (ppm) Comments Correct Commodity Definition Established Proposed Recommended Grass, forage 3.0 18 18 Grass, hay 3.0 5.0 5.0 Grain, aspirated fractions 0.3
-- 1.2 Grain, aspirated grain fractions Milk 0.1
-- 0.4 Sorghum, grain 0.05 0.2 0.2 Sorghum, grain, grain Sorghum, grain, forage 0.5
-- 0.8 Sorghum, grain, stover 0.2
-- 0.2Page 12 of 72

2.3 Label Recommendations 2.3.1 Recommendations from Residue Reviews A revised Section B/label must be submitted with the following revisions: a) The grass section of the HUSKIE TM Herbicide label should have an “APPLI CATION METHODS” section which states the type(s) of application (e
. g. , foliar spray , broadcast spray , etc.), the method(s) of application (i.e., ground, air, or both), and the minimum gallons spray per acre for each method. b) The sorghum section should state that aerial applications are not to be made. c) The label contains rotational crop plantback intervals for some crops but not all crops. A 30
- day rotational crop restriction is adequate for bromox yn il. The petitioner must consider rotational crop plantback requirements for all active ingredients on the label and then indicate a plantback interval for all crops which are not primary (treated) crops on the label or are not already listed in the Crop Rotation Guidelines section of the label. 2.3.2 Recommendations for Worker Safety Based on email correspondence with the registrant (dated 11/01/2010), HuskieTM Herbicide (EPA Reg. No. 264
- 1023) is not intended for application with chemigation or aerially to grain sorghum, grass grown for seed and CRP areas. The label should restrict aerial and chemigation explicitly from these use sites. A closed sy stem is required for mixers/loaders for existing corn and wheat applications. Although, a 12
- hr REI was proposed, under the WPS for Agricultural Pesticides, a 24
- hr REI is required for chemicals classified under Toxicity Category II. Therefore, a REIof 24 hours is required on the HuskieTM Herbicide label. Other bromoxy nil product labels should also require a 24
- hr REI, except for specific the use sites wheat, small grains and mint which require an REI of 8 days, sod harvesting which require an REI of 5 days, and corn, sorghum and cotton which require an REI of 4 days. 2.3.3 Recommendations f or Residential Safety There are currently no registered or proposed residential uses of bromox yn il. However, existing labels should clarify

that products containing bromoxy nil are restricted from use on golf course turf. 3.0 Ingredient Profile Bromox ynil is registered for the application as the octanoic and/or heptanoic esters which rapidl y convert t o the phenol (bromoxy nil). The bromoxy

nil esters and phenol are chemicall y and phy sicall y similar which allows the risk assessment to be based on bromoxynil. Bromoxy nil is a selective contact foliage applied herbicide used to control a variety of broadle af weeds.Page 13 of 72

Bromox ynil inhibits photosynthetic electron transport and also uncouples oxidative phosphorylation in mitochondria, thereby stopping energy

production and negativel y affecting plant respiration. Baye r CropScience has proposed uses for HUSKIETM H erbicide (EPA Registration No. 264
- 1023) containing bromoxy nil as one of the active ingredients on annual and perennial grasses grown for seed , conservation reserve program acres (CRP) , and grain sorghum
. HUSKIETM Herbicide is an emulsifiable concentrate which contains 13.4% bromoxy nil octanoate, 12.9% bromox yn il heptanoate, 3.3% py rasulfotole, and 70.4% inerts. The formulation contains 1.75 lbs bromox yn il active ingredient per gallon. HUSKIETM Herbicide foliar spray may be applied to CRP and grasses grown for seed from preemergence to established grasses. A maximum of two applications with a re treatment interval (RTI) of 30 day s can be made for in a maximum rate of 0.41 lb ai/A/ye ar for CRP and grasses grown for seed. The preharvest intervals (PHI) are 7 day s for forage and 30 day s for hay ; the restricted entry interval (REI) is 12 hours. The adequacy of the proposed uses of p yr asulfotole will be addressed in a separate document. HUSKIETM Herbicide is applied as a postemergence foliar spray to grain sorghum using ground application equipment. Application through any ty pe of irrigation s ys tem is prohibited. A maximum of two applications with an RTIof 11 day s can be made for a maximum rate of 0.44 lb ai/A/ye ar for grain sorghum. The preharvest intervals (PHI) are 7 day s for forage and 60 day s for grain or stover; the restricted entry interval (REI) is 12 hours. 3.1 Structure and Nomenclature Appendix B provides structures and nomenclature for the bromox ynil esters. Table 3.1 Brom oxynil Nomenclature. Chemical Structure

Em pirical Formula C 7 H 3 Br2NO Common Name bromoxynil or bromoxynil phenol Com pany Experimental Name AE F025943 IUPAC Name 3,5
- dibromo
- 4
- hydroxybenzonitrile CAS Name 3,5
- dibromo
- 4
- hydroxybenzonitrile CAS Registry Number 1689
- 84
- 5 (phenol) 1689
- 99
- 2 (octanoate) 56634
- 95
- 8 (heptanoate) End
- use Product/EP HuskieTM Herbicide Chemical Class Benzonitrile HerbicidePage 14 of 72

Table 3.1 Brom oxynil Nomenclature. Known impurities of concern None

3.2 Physical/Chemical Characteristics Table 3.2 Physicochemical Properties of Brom oxynil (Brom oxynil Phenol) Param eter Value Reference (MRID) Molecular Weight 276.9 47815001 Melting point/range 190.5°C 47815001 pH @ ambient 3.68 47815001 Density 2.31 g/cm3 at 20°C 47815001 Water solubility 0.090 g/L at 25oC 47815001 Solvent solubility (20oC) Heptane Xylene Methanol Octanol Acetone Ethyl acetate Acetonitrile 0.15 g/L 8.8 g/L 80.5 g/L 46.7 g/L 186 g/L 97.7 g/L 51.1 g/L 47815001

Vapor pressure 1.4 Pa at 20  C 47815001 Dissociation constant, pKa 3.86 47815001 Octanol/water partition coefficient, Log(KOW) 2.90 (K ow = 794) 47815001 UV/visible absorption spectrum Primary λmax = 221.2 Primary λmax = 286.8 47815001
3.3 Summary of Existing/Amended Uses Currently bromoxy nil 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 alf alfa, forage/hay , and grass. Current, n on - food uses include outdoor industrial areas, nonagricultural uncultivated areas/soil, non - residential commercial/industrial lawns, and sod farms. Baye r CropScience has proposed amendments to the existing use patterns of annual and perennial grasses grown for seed , conservation reserve program acres (CRP) , and grain sorghum on the HUSKIETM Herbicide label
. HUSKIETM Herbicide (EPA Registration No. 264
- 1023) controls broadleaf weeds and mannagrass in grasses and broadl eaf weeds in grain sorghum. HUSKIETM Herbicide is an emulsifiable concentrate which contains 13.4% bromoxy nil octanoate, 12.9% bromoxy nil heptanoate, 3.3% py

rasulfotole, and 70.4% inerts. The formulation contains 1.75 lbs bromox yn il per gallon. The submitted label for HUSKIETM Herbicide (EPA Registration No. 264
- 1023) is adequate to allow evaluation of the residue data relative to the proposed uses. Refer to Section 2.3 for recommended modifications to the proposed labels.Page 15 of 72

Table 3.3. Summary of Directions for Use of Bromoxynil. Applic. Timing, Type, and Equipment Formulation

[EPA Reg. No.] Applic. Rate

(lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations 1,2,3
Grass (Grasses Grown for Seed and Conservation Reserve Program Acres) (Perennial Ryegrass, Annual Ryegrass, Tall Fescue, Fine Fescue, Kentucky Bluegrass, Orchardgrass, and Timothy) Pre
- emergence and/or post
emergence HUSKIETM

Herbicide (EPA Reg. No. 264
- 1023) 13.5
- 15 oz/A

(0.18
- 0.205 lb ai/A) 2 30 oz (0.41 lb ai/A) Forage: 7

Hay: 30 Use in annual and perennial

grasses grown for seed and conservation reserve program acres (CRP). Apply from pre
- emergence to established perennial ryegrass, annual ryegrass, tall fescue, fine fescue, Kentucky bluegrass and orchardgrass. Apply to established timothy. Observe an interval of at least 30 days between applications. HUSKIETM Herbicide may be tank mixed with herbicides, insecticides, fungicides, and spray additives.* The restricted entry interval is 12 hours. Sorghum, GrainPage 16 of 72

Table 3.3. Summary of Directions for Use of Bromoxynil. Applic. Timing, Type, and Equipment Formulation

[EPA Reg. No.] Applic. Rate

(lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations 1,2,3 Postemergence, Foliar spray, Ground equipment HUSKIETM

Herbicide (EPA Reg. No. 264
- 1023) 12.8
- 16 oz/A

(0.18
- 0.22 lb ai/A) 2 32 oz (0.44 lb ai/A) Forage: 7

Grain: 60 Stover: 60 Apply to sorghum between

the 3 leaf stage of growth up to 12 inches. Apply in minimum of 10
- 15 gallons of water per acre, as needed to obtain thorough spray coverage. Do not apply through any type of irrigation system. Observe an interval of at least 11 days between applications. HUSKIETM Herbicide may be tank mixed with herbicides and insecticides.** Do not apply HUSKIETM Herbicide in a tank mix with Lorsban as an unacceptable crop response may occur. One pound of ammonium sulfate per acre may be added to optimize herbicidal ac tivity. The restricted entry interval is 12 hours. 1 Crop Rotation Plantback Intervals: 1 month: wheat, barley, oats, rye, and triticale 4 months: alfalfa, millet, grain sorghum, and soybeans 9 months: canola, canaryseed, chickpeas, corn, dry beans, flax, field peas, green beans, green peas, lentils (except in MN, MT, ND, and SD), mustards, potatoes, safflower, sunflowers, and sugarbeets 18 months: lentils in MN, MT, ND and SD 2 Grass: For weed control, HUSKIETM Herbicide may be tank mixed with Pum a®, Nortron, Rely, 2.4
- D ester/amine, AimTM, Bronate AdvancedTM, Buctril®, Curtail M/Curtail®, Dicamba, Goal, Glean, MCPA ester/MCPA amine, Sencor®, Starane®/Starane NXT/Starane Ultra, or WideMatchTM. For insect control, HUSKIETM Herbicide may be tank mixed with Baythroid®XL, Capture, Lorsban®, Mustang MaxTM, or Warrior® Insecticides. For disease control, HUSKIETM Herbicide may be tank mixed with fungicides such as Absolute, Tilt®, Quadris®, QuiltTM, or Bravo. Some tank mix options require the use of a non - ionic surfactant (NIS). Use the amount of the NIS recommended on the tank mix partner label or at a concentration of 0.25
- 0.5% v/v (1
- 2 qt per 100 gallons of spray solution). At least 80% of the surfactant product must be active non
- ionic surfactant.Page 17 of 72 3 Grain Sorghum: For grass control, HUSKIETM Herbicide may be tank mixed with 0.25
- 1.0 lb atrazine per acre. For weed control, HUSKIETM Herbicide plus atrazine may be tank mixed with phenoxy broadleaf herbicides such as 2,4
- D or dicamba. For insect c ontrol, HUSKIETM Herbicide may be tank mixed with Baythroid®XL An unacceptable crop response may occur if HuskieTM Herbicide is applied to acreage that has been previously treated with mesotrione. Sensitivity of sweet sorghum (sorgo), sudangrass, sorghum
- sudangrass hybrids, or dual
-purpose sorghum varieties to HUSKIETM Herbicide is not known and the use of HUSKIETM Herbicide on these sorghum ty pes is not recommended. 4.0 Hazard Characterization and Dose - Response Assessment Bromox ynil is a selective contac t foliage applied herbicide used to control broadleaf weeds. Bromox ynil inhibits photosynthetic electron transport and also uncouples oxidative phosphorylation in mitochondria, thereby stopping energy

production and negativel y affecting plant respiration. A correlation between this mode of action in plants and observed toxicity in the available toxicity

studies in mammals was not identified. 4.1 Toxicology Studies Available for Analysis The existing database includes acceptable toxicity studies on both bromoxy nil phenol and bromox yn il ocatanoate and it has been established that these two compounds are toxicologicall y equivalent on a molar basis (G. Ghali, 4/12/1996, TXR 011886). The exis ting database is deemed sufficient for characterizing the hazard of bromox yn il. As outlined in the table below, the database contains studies evaluating toxicity following oral and dermal exposure in rats and rabbits and oral exposure in mice and dogs, whi ch help to characterize toxicity associated with oral, dermal, and inhalation exposure routes in humans. Study Brom oxynil phenol Brom oxynil Octanoate Ac ute toxicity battery √ √ Oral subchronic toxicity
-- rats √ √ Oral subchronic toxicity
-- mice √ Oral subchronic toxicity
-- dogs √ √ Dermal subchronic toxicity
-- rabbits √ √ Oral chronic/Carcinogenicity
-- rats √

-- Oral carcinogenicity

– mice √

-- Oral chronic
-- dogs √

-- Oral developmental toxicity
-- rats √ √ Oral developmental toxicity
-- mice √

-- Oral developmental toxicity
-- rabbits √ √ Dermal developmental toxicity
-- rats √ √ Dermal developmental toxicity
-- rabbits √ √Page 18 of 72 Study Brom oxynil phenol Brom oxynil Octanoate Oral multigen
- reproduction study
-- rats √

-- Dermal special reproduction study
-- rats -- √ Mutagenicity Battery √ √ Ac ute Neurotoxicty Battery
-- -- Subchronic Neurotoxicity
-- -- Immunotoxicity
-- -- Dermal Absorption √ √ √ = available
-- = not available 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) The available data show that once absorbed, bromoxy nil octanoate is converted to bromoxy nil phenol. The absorption, distribution, excretion and metabolism of bromoxy nil octanoate were studied in male and female Sprague Dawley rats given single oral doses of 14 C
- bromox yn il octanoate b y gavage at dose levels of 2 or 20 mg/kg or at a dose level of 2 mg/kg following 14 day s of unlabeled bromoxy nil octanoate administered b y oral gavage at a dose level of 2 mg/kg/day
. Results were similar regardless of dosing regimen. The rate of absorption in both sexes was such that peak plasma concentrations of radioactivity were not reached until 7
- 10 hours after dosing. Radioactivity was distributed in most tissues; highest concentrations were observed in blood, plasma, liver, kidney s and th yr oid (especiall y 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 day s) and considerabl y l esser amounts in the feces (about 6
- 10% in both males and females at 7 day s). Excretion was more rapid in males than in females. Retention of radioactivity in tissues after 7 day s was about 2
- 3% in males and 7
- 9% in females. Essentiall y all bromox yn il o ctanoate was rapidl y and nearl y completely

converted to bromoxy

nil phenol via ester hydroly sis. In special distribution studies, the only chemical species identified in tissues was bromoxy nil phenol per se ; no bromoxy nil octanoate was identified in tissue s. In urine, the only major species was free and conjugated bromox yn il phenol with no bromoxy nil octanoate being present. In feces, however, some bromox yn il octanoate was identified. (MRID 00154756, 00154757, 42901001). 4.2.1 Dermal Absorption The pre vious risk assessment utilized a dermal absorption factor of 10.32% (excluding post
- wash residue), based on the highest absorption value obtained after 10 hours of exposure to bromox yn il octanoate, the compound to which exposure is expected. Current HED p olicy is to derive a dermal absorption factor b y combining the material remaining on the skin after skin washing to the s ys temically absorbed dose, if the material remaining on the skin is bioavailable. In the absence of bioavailability data, HED has made the assumption that the material remaining on the skin is bioavailable. Therefore, the dermal absorption value for this risk assessment is the sum of the absorption value and post
- wash residue for the 10
- hour period for bromoxy nil octanoate, or 10.32% + 6.46% ≈ 17%.Page 19 of 72

4.2.2 Other Toxicological Concerns A metabolite of bromox ynil, 3,5
- dibromo
- 4
- hydroxy benzoic acid (DBHA) has been found to be a major metabolite in cotton. HED previousl y concluded that bromox ynil and DBHA are extremely similar in structure, and since DBHA is likely to be more water soluble than bromox yn il, it should be absorbed less and eliminated faster than bromoxynil, thereby reducing its toxicity

relative to bromoxy

nil. Since adequate data were not available which indicate DBHA is l ess toxic than the parent compound, HED assumed that DBHA had the same toxicity as the parent compound bromox yn il (D246944.mem, B. Madden 6/24/1998). Since then, additional DBHA toxicity data (four acute studies, a mutagenicity study , a 90
- day

rat study and a rat developmental toxicity study) have been submitted to the Agency but have not all undergone review within HED. A preliminary examination of these data indicate that BDHA is less toxic than bromox yn il which is consistent with the expected effect that conversion of the nitrile group to a carbox y group reduces toxicity relative to bromoxy

nil. The diminished concern for DBHA toxicity

is also applicable to carcinogenicity : Ionization of the carboxyl group at phy siological pH leads to rapid excretion of DBHA and retards cellular uptake and migration of DBHA through intracellular membranes to interact with receptors associated with carcinogenicity . However, pending final review of the DBHA toxicity data, HED will continue to assume that DBHA toxicity is the same as (or less than) the parent compound, and is not expected to be more toxic than bromox ynil and to include it as a residue of concern for risk assessment 4.3 Toxicological Effects With repeated dosing in rats and mice, frequentl y observed effects were on the liver (increased liver weight, hepatocellular hypertroph y) and body weight changes. In dogs, bromox yn il appeared to affect body t emperature control. Besides decreased body weight, the treated dogs showed increased panting at low dose levels, and increased panting with elevated rectal temperatures at higher dose levels. At the highest dose levels tested, elevated body temperatures and death occurred. Developmental toxicity

was manifested in rats, mice and rabbits via the oral and derm al 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, scoliosis, misshapen thoracic centrum and incomplete ossification of sternebrae were observed in rabbits. In reproduction studies, delayed development manifested as decreased body weight and body weight gain, and delayed eye opening. In addition to the developmental toxicity observed a fter bromox ynil and bromox yn il octanoate exposure, liver toxicity

was also observed (beginning at 5 mg/kg/day in dogs and rats) in males and females in the subchronic, chronic, developmental and reproduction studies, including liver weight increases and adverse histopathological effects such as hepatocellular hy pertroph y, vacuolization and degeneration in rats, mice, and dogs, and liver tumors (beginning at 13 mg/kg/day) in chronic studies in mice. Adverse effects (beginning at 5 mg/kg/day in dogs) onPage 20 of 72

body weight and body weight gain changes were also observed in rats, mice, dogs, and rabbits. Other less widespread effects, such as salivation, increased panting , and unsteady gait occurred in dogs; blood effects such as decreases in serum protein and globul ins; increased th ym ic ly mphocy te necrosis; increased degeneration/necrosis of cardiac myofibers occurred in rats
. The increased panting in dogs occurred at 5 mg/kg/day, and increased panting with elevated rectal temperatures at 12 mg/kg/day
. Bromox ynil phenol and/or octanoate was positive in a mouse ly mphoma forward mutation assay with metabolic activation, a bacterial DNA repair assay with and without S9 activation, and in a CHO chromosomal aberration assay with activation. These mutagenic e ffects all occurred at cy totoxic dose levels and in in vitro studies only . The cancer classification of Group C Human Carcinogen with low
- dose extrapolation (Q 1 *) was assigned b y HED’s Cancer Peer Review Committee (E. Budd, 3/12/1997, TXR 0050045) based o n mouse hepatocellular tumors. 4.4 Safety factor for Infants and Children (FQPA Safety Factor) In HED’s risk assessment conducted in 1998, acute dietary risks for females 13+ utilized a NOAEL of 4 mg/kg/day

and LOAEL of 5 mg/kg/day based increased incide nce of supernumerary

ribs seen in two rat developmental toxicity studies. Based on the combined evaluation of these studies, the 10X FQPA SF was retained for concerns over the apparent steepness of the dose
- response curve. In an effort to better characte rize the dose response relationship for supernumerary ribs, a BMD analy sis has been conducted using the fetal and/or litter data available from the two rat developmental studies, plus a third developmental study which demonstrated similar results at similar dose levels. The results of the BMD anal ys is indicate that the dose response curves are not as steep as previously assumed and HED has concluded that there is high confidence that the NOAEL of 4 mg/kg/day is a protective point of departure without the n eed to retain a 10X FQPA SF (J. Kidwell, 035301TS.001.docx. Final Report of the ToxSAC. January 13, 2011). Based on the hazard and exposure data, the bromox yn il risk assessment team has recommended that the FQPA Safety

Factor be reduced to 1X. Although the presence of quantitative susceptibility

has been established (based on supernumerary ribs occurring at dose levels below the maternal LOAEL in rats), the NOAELs and LOAELs for this effect are well defined, and Benchmark Dose (BMD) anal ys is has indicated that the NOAEL of 4 mg/kg/day for supernumerary

ribs (which is the point of departure for the Females 13+ endpoint) is sufficiently protective of the fetus. Both the BMD (which represents 5% increased risk of incidence of this effect above the normal bac kground incidence) of 13.66 mg/kg/day and its lower limit (BMDL) of 8.34 mg/kg/day

are above the NOAEL of 4 mg/kg/day . The completeness and good quality of the available data used for the BMD anal ys is produced results with a high reliability factor, which is fully

presented and discussed in a separate document (M. Ottley TXR 0055648). The data base is considered complete (refer to next section) and there are no residual uncertainties. 4.4 .1 Completeness o f the Toxicology Database The toxicity

database fo r bromoxy

nil is complete except for an immunotoxicity study (OPPTS Guideline 870.7800), and acute and subchronic neurotoxicity studies (OPPTS GuidelinePage 21 of 72

870.6200a and 870.6200b). These studies are now requirements under 40 CFR §158 .500 for pesticide registration. In the absence of specific immunotoxicity , acute and subchronic neurotoxicity

studies, HED has evaluated the available bromoxy nil toxicity

database to determine whether an additional database uncertainty factor is needed to ac count for potential immunotoxicity

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

- but not the incidence
- of thy mic l ymphocy

te necrosis at otherwise toxic dose levels in a subchronic rat study. The NOAEL and LOAEL for these thym ic effects were 91 mg/kg/day and 45 mg/kg/day . It is anticipated that the points of departure selected for bromoxy nil (see table 4.5.4) will be protective of this adverse effect, There is no evidence of neuroto xicity in the database. Consequently , HED believes the existing data are sufficient for endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements under FQPA, and an additional database uncertainty factor does not n eed to be applied. 4.4.2 Evidence of N eurotoxicity There are currently

no acute or subchronic neurotoxicity studies available, and the available subchronic and chronic data did not raise concern for potential neurotoxicity associated with bromox yn il or bromoxy

nil octanoate exposure. Though panting and elevated rectal temperature are observed in the subchronic dog study , these effects are not considered to be indicative of neurotoxicity

but rather generalized s ys temic toxicity
. 4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal The available data indicate that bromox yn il produces developmental effects (supernumerary ribs) in rats and rabbits at or below the maternal NOAELs in both oral and dermal studies, and that bromox yn il octanoate produces supernumerary ribs at the maternal NOAEL in a dermal study
. Supernumerary

ribs were observed in rats, mice and rabbits after oral and/or dermal administration, and more severe developmental effects were seen at the maternal LOAEL and higher doses. Therefore, there is evidence of quantitative susceptibility in the data base. However, clear NOAELs for the developmental effects, and basing the point of departure on these effects addresses HED concerns for quantitative susceptibility
. 4.4. 4 Residual Uncertainty in the Exposure Datab ase There are no residual uncertainties in the exposure database. Although the dietary assessments conducted with DEEM
- FCID were refined, HED does not believe that the exposure estimates are underestimated beca

use the data were based on reliable and acceptable field trial and feeding studies and estimates of percent crop treated . The assessment utilized anticipated residues for all livestock commodities, average field trial residues for all grains in the acute assessment, average field trial residues for all crops except spearmint and peppermint in the chronic assessment , average estimates of percent crop treated in the chronic assessment and, maximum estimates of percent crop treated in the acute assessment . In addition, default processing factors were assumed for all commodities. The DEEM anal ys is also assumed that all drinking water willPage 22 of 72

contain bromox yn il at the highest EDWC levels modeled by EFED for surface water. For these reasons it can be conclude d that the DEEM
- FCID anal ys is does not underestimate risk from acute or chronic exposure to bromoxy nil. In addition , there are no registered residential uses. 4.5 Toxicity Endpoint and Point of D eparture Selections 4.5.1 Dose - Response Assessment In th e previous risk assessment (D246944, B. Madden, 6/24/1998), the FQPA 10X uncertainty factor was retained for the Acute Dietary Females 13+ endpoint despite the point of departure being an adverse effect (supernumerary ribs) in the fetus. The primary reaso n for the retention was an apparent steepness of the dose
- response curve (NOAEL = 4 mg/kg/day , LOAEL = 5 mg/kg/day) derived b y combining the results of two co
- critical studies. However, a more refined data evaluation tool, benchmark dose (BMD) analysis, h as become available and HED has been using it in the risk assessment process. As mentioned in Section 4.4, the results returned by the BMD anal ys is (D 386424, M. Ottley , TXR 0055648 ) suggest a point of departure substantially higher than the NOAEL of 4 mg/kg/day , which supports the position that the NOAEL of 4 mg/kg/day is adequatel y protective of this adverse effect in rat fetuses without an addition safety factor . Secondly , the BMD anal ys is results, which took into consideration all the doses and respons es in the studies, indicate that the dose
- response curve is not steep as previously thought. As such, there remained no basis for retention of the 10X, and for this risk assessment it has been removed. 4.5.2 Recommendation for Combining Routes of Expo sures for Risk Assessment There is no potential for residential exposure from the proposed and existing uses of bromoxynil. However, occupational workers will be exposed from dermal and inhalation routes. Effects of supernumerary

ribs were observed in bo th dermal and oral developmental studies. Since a common toxicological effect was identified, these routes of exposure can be combined to estimate combined occupational risk. 4.5.3 Cancer Classification and Risk Assessment Recommendation Bromox ynil phenol has been classified b y the HED Cancer Assessment and Review Committee as a Group C, possible human carcinogen, based on a treatment
- related increased incidence of hepatocellular adenomas, carcinomas and adenomas/carcinomas combined in mice (E. Budd and E. Rinde, 3/12/1997, TXR 0050045). 4. 5 . 4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment The details for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in Appendix A. The following table provides the information in summary form.Page 23 of 72

Table 4.5.4 a Summary of Toxicological Doses and Endpoints for Brom oxynil for Use in Dietary and Non Occupational Hum an Health Risk Assessments Exposure/ Scenario Point of

Departure Uncer tainty/FQ

PA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects
Ac ute Dietary (General Population, including Infants and Children) NOAEL= 8

mg/kg/day UF A= 10 x

UF H =10 x FQPA SF=1x Ac ute 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 Ac ute Dietary (Females 13
- 49 years of age) NOAEL 4

mg/kg/day UF A= 10 x

UF H =10x FQPA SF=1x Ac ute 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 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 res ult 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 extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAE L = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD =Page 24 of 72

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. Table 4.5.4 b Summary of Toxicological Doses and Endpoints for Brom oxynil for Use in Occupational Hum a n 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 establish ed). Both studies showed a dose
related 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, T XR 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 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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human po pulation (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. Based on the available toxicity database an d the Agency's current practices, the inhalation risk for bromox ynil was assessed using an oral toxicity study . The Agency

sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studie s for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory

Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/1201 09meeting.html ). The Agency

is in the process of evaluating the SAP report and may , as appropriate, re
- examine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data. If any

new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for bromoxy

nil and/or a re
examination of the inhalation toxicity risk assessment. 4.6 Endocrine Disruption As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an eff ect produced b yPage 25 of 72

a “naturally

occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening as say s to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal s ys tems will proceed to the next stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose
- response relationship between the dose and the E, A, or T effect. Between October 2009 and February 2010, EPA has issued test orders/data call
- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathway s such as food and water, residential activity , and certain post
- application agricultural scenarios. This list should not be construed as a l ist of known or likely endocrine disruptors. Bromox ynil is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingl y, EPA anticipates issuing future EDSP test orders/data call
- ins for all pesticide active ingredients
. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/
. 5.0 Dietary Exposure and Risk Assessment Sources : Bromoxynil. Petition for Tolerances in Support of New Uses on Grass and Grain Sorghum. Summary ofAnalytical Chemistry and Residue Data. D378614, N. Dodd, 2/15/11

. Bromoxynil: Acute, Chronic, and Cancer Aggregate Dietary (Food and Drinking W ater) Exposure and Risk Assessments for the New Uses on Grass and Grain Sorghum

. D378615, C. Walls, 3/22

/11. Drinking W

ater Assessment for Ground and Aerial Applications of Bromoxynil on Grass Grown for Seed and Ground Application of Sorghum. D374620, T. Mason , 12/16/10

. 5.1 Metabolite/Degradate Residue Profile 5.1.1 Summary of Plant and Animal Metabolism Studies P RIMARY CROPS: The nature of the residue in alfalfa , sweet corn, and cotton following application of 14 C
- bromox yn il octanoate is adequately understood. The metabolic pathway involves hydrol ys is of the ester, oxidation of the nitrile group to the acid via the amide, and conjugation; debromination occurs in a parallel pathway.Page 26 of 72

The translocation of bromoxy nil octanoate in cotton is extremely minimal. Bromox ynil octanoate ( 14 C
- labelled) was applied to a single leaf or boll and harvested after 7 day s (from leaves) or 47 day s (from bolls). A very small amount (0.15% or less of the total radioactive residue [TRR]) was translocated to adjacent leaves. No residues were found in cottonseed. However, transgenic cotton metabolizes bromoxy nil primarily to 3,5
- dibromo
- 4
- hydroxy benzoic acid (DBHA) [78.6% of the tot al radioactive residues (TRR)]. ROTATIONAL CROPS: A confined rotational crop study was conducted on spinach, beets, and wheat with 14 C
- bromox ynil octanoate. Low level residues of multiple, p olar components were found in the rotational crops. The field rotational crop studies in winter wheat, collard greens and radishes are adequate to demonstrate that detectable bromox ynil residues would not be expected in crops rotated at 30 day s (or more) following application of bromoxy nil octanoate to primary crops. RUMI NANTS: The nature of the residue in ruminant s is adequ atel y understood for bromox yn il. When 14 C
- bromox yn il octanoate was administered to lactating goats, 90% of the TRR was recovered as bromox ynil per se . The parent compound was found onl y in milk (1.7% of the TRR). DBHA was found only in liver (4% of the TRR). POUL TRY: The nature of the residue in poultry is adequ atel y understood for bromox ynil. When 14 C
- bromox yn il octanoate was administered to laying hens, 73
- 100% of the TRR was recovered as bromox ynil per se . The parent compound was found onl y in eggs (4
- 6% of the TRR). Polar unknowns accounted for 3% of the TRR in liver. RAT: Bromox ynil heptanoate and octanoate are rapidly absorbed and widely distributed in most tissues. Most of the radioactivity was excreted in the urine, mostly in the form of bromox yn il phenol. There was no significant retention in tissues after 7 day s. Bromoxy nil heptaonate and octanoate were metaboli zed to bromoxy nil phenol via ester hydrol ys is. 5.1.2 Summary of Environmental Degradation Bromox ynil octanoate is chemicall y and ph ys ically similar to bromoxy

nil heptanoate. Both esters rapidl y degrade to bromox yn il phenol (bromoxy nil). Bromoxy

nil octanoate is mobile and non - persistent . It dissipates in the environment b y abiotic hydrol ys is, photoly tic degradation, and microbial
- mediated metabolism in both the aerobic and anaerobic environments. Bromox ynil octanoate readily hydrol yz es to bromoxy ni l phenol and then further degrades to CO 2 . B romox ynil phenol is more persistent in the environment than bromoxy nil octanoate. Residues of bromox yn il are moderately to highl y mobile in soils and do not break down by abiotic processes, such as h ydrolysis and photol ys is. However, bromox yn il rapidly degrades under aerobic and anaerobic conditions. Bromox ynil may

move from the treated field to surface water or ground water through run
- off shortly after application. The field dissipation studies show that bromox yn il residues dissipated with half
- lives of 1 to 14 day s and were not detected below 15 cm soil depth indicating thatPage 27 of 72

leaching is not an anticipated route of dissipation , likely du e to the rapid degradation rate. Although, bromox ynil is mobile , it has a short metabolic half
- life in soil under aerobic conditions and it should not be a ground water concern in most environments. In the event that bromoxy nil did reach ground water , it is expected to degrade slowly due to microbial activity (faster under aerobic conditions than anaerobic conditions) but is rather persistent otherwise. 5.1.3 Comparison of Metabolic Pathways In primary

crops, bromoxy

nil phenol was the major residue identified in various matrices. Transgeni c cotton metabolizes bromoxy nil primarily

to 3,5
- dibromo
- 4
- hydroxy benzoic acid (DBHA)
. In rotational crops, bromoxy nil phenol was not identified. Only low level residues of multiple, polar components were found in the rotational crops In drinking water, th e residue of concern for risk assessment is bromoxy nil phenol. In ruminants, the primary residue identified in milk was bromox ynil phenol. The m etabolite DBHA was also identified as a minor residue in liver
. In the rat, the metabolism of bromox yn il heptanoate and octanoate proceeded via ester h ydroly sis to bromox yn il phenol. 5.1.4 Residues of Concern Summary and Rationale Table 5.1.4 Summary of Metabolites and Degradates to be included in th e Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression
Plants Primary Crop (except cotton)

Cotton Bromoxynil (phenol ) Bromoxynil (phenol) + DBHA Bromoxynil (phenol) Bromoxynil (phenol) + DBHA Rotational Crop Bromoxynil (phenol) Bromoxynil (phenol) Livestock Ruminant Bromoxynil (phenol) + DBHA Bromoxynil (phenol)

Poultry Bromoxynil (phenol) + DBHA Bromoxynil (phenol) Drinking Water Bromoxynil (phenol) Not Applicable Rationale: Plants Primary Crops : The nature of the residue in plants is adequatel y understood for the presently proposed crops based on metabolism studies on alfalfa , sweet corn , and cotton
. In all primary crops except cotton , bromoxy nil phenol is the residue of concern for the tolerance expression andPage 28 of 72

for risk assessment since it was the major residue detected
. Because 78.6% of the bromox ynil residues in transgenic cotton are metabolized to DBHA, the cotton residues of concern for the tolerance expression and for risk assessment are bromoxy nil and its metabolite DBHA
. Rotational Crops : Th e nature of the residue in rotational crops is adequately understood based on an acceptable confined rotational crop study conducted on winter wheat, collard greens and radishes. Residues were less than the limit of quantitation ( <0.02 ppm) in winter wheat forage, radish tops and roots, and in collard greens harvested from the 30
- day plantback plots; residues were less than the limit of detection (<0.01) in wheat grain and straw harvested from the 30
- day interval. Based on the rotational crop data, plant
- back intervals of 30 day s are adequate for all rotational crops planted after application of bromoxy nil octanoate and heptanoate. Livestock Ruminants: The nature of the residue in ruminants is adequatel y understood based on an acceptable study conducted on lactating goats with 14 C
- bromox yn il octanoate
. 90% of the TRR was recovered as bromoxynil per se . The parent compound was found only in milk (1.7% of the TRR). DBHA was found on ly in the liver (4% of the TRR). Since the metabolite DBHA is found in commodities considered to be livestock feed items, the potential for transfer of secondary residues to livestock exists. The HED Metabolism Committee has concluded that DBHA could transfer to livestock tissues in proportion to the parent but is no more toxic than parent
. Thus, the residues of concern in ruminants for risk assessment are bromoxy nil phenol and DBHA. The residue of concern for the tolerance expression is bromoxy nil phenol. Poultry : The nature of the residue in poultry is adequatel y understood based on an acceptable study conducted on laying hens with 14 C
- bromox ynil octanoate
. 73
- 100% of the TRR was recovered as bromox ynil per se . The parent compound was found onl y in eggs (4
- 6% of the TRR). Polar unknowns accounted for 3% of the TRR in liver. Because the metabolite DBHA is found in commodities considered to be livestock feed items, residues of concern in poultry for risk asses sment are bromoxy nil and DBHA. The residue of concern for the tolerance expression is bromox yn il
. Drinking Water Bromox ynil octanoate is chemicall y and ph ys ically similar to bromoxy

nil heptanoate. Since both esters rapidl y degrade to bromox yn il phenol , the drinking water resi due of concern for risk assessment is bromoxy

nil
. 5 .2 Food Residue Profile Crop Field Trials The submitted magnitude of the residue data , summarized in Table 5.2.1, are adequate for risk assessment and tolerance assessment. For all crops, the number and locations of field trials are adequate and the field trials reflect the proposed use patterns
. Two spray applications of the formulated HUSKIE product were made to each crop . No adjuvants were used. The Agency ’sPage 29 of 72

tolerance spre adsheet, as specified b y the Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP, was used to determine appropriate tolerance levels. Based on the available data and estimated residue values , all proposed tolerances are adequate . Howe ver, HED is recommending that the established tolerance of 0.5 ppm on the forages of grain sorghum be increased to 0.8 ppm.

TABLE 12. Summ ary of Residue Data fromCrop Field Trials with Brom oxynil
Matrix Total Applic. Rate lb a.i./A (kg a.i./ha) PHI (days) Residue Levels 1 (ppm)

n Min. Max. HAFT 2 Median (STMdR) Mean

(STMR) Std.

Dev. Grass (proposed use = 0. 44 lb ai/A total application rate, 7 - day PHI forage; 30 - day PHI hay) Grass Forage 0.43
- 0.51 (0.48
- 0.57) 0 24 3.37 37.8 37.1 18.2 18.9 11.6

7
- 11 24 0.0921 14.2 13.7 0.520 2.81 5.03 Grass Hay 0.43
- 0.45 (0.48
- 0.50) 28
- 31 24 <0.01 2.26 2.05 0.089 0.333 0.58 Grain Sorghum (proposed use = 0.44 lb ai/A total application rate, 7 - day PHI forage; 60 - day PHI grain and stover ) Sorghum Forage 4 0.431
- 0.442 (0.482
- 0.498) 0 24 4.16 27.2 25.2 11.1 12.0 5.21

5 to 8 24 0.072 0.61 0.58 0.28 0.30 0.16 ECH 3 ( 32 to 82) 24 <0.01 0.30 0.30 <0.01 0.037 0.081 Sorghum Grain4 56 to 60 24 <0.01 0.11 0.103 0.011 0.028 0.030 Sorghum Stover4 56 to 60 24 0.011 0.11 0.097 0.060 0.061 0.032 1 Grass LLMV = 0.01 ppm for grass forage and grass hay. LOD = 0.00531 ppm for forage and 0.00287 ppm for hay; Grain Sorghum LLMV = 0.01 ppm for forage, grain, and stover. LOD = 0.00246 ppm for forage, 0.00379 ppm for grain, or 0.00315 for stover. LLMV (0.01 ppm) was used when values were <LLMV. 2 HAFT = Highest Average Field Trial. 3 ECH = Earliest commercial harvest 4 Residues reported as bromoxynil phenol. Processing Studies There are no processed commodities associated with use on grass. The processed commodity associated with use on grain sorghum is flour; however, residue data are not needed on sorghum flour at this time since it is used exclusively in the United States a s a component for dry

wall, and not as either a human food or feedstuff. Residues in aspirated grain fractions must be determined for uses on corn, sorghum, so ybeans, and wheat. Studies on residues in aspirated grain fractions of barley , corn, sorghum, an d wheat have been previousl y reviewed and deemed adequate to support a tolerance on aspirated grain fractions (grain dust). The studies all indicate that residues concentrate in aspirated grain fractions. Because the tolerance on the grain of grain sorghum is being increased from 0.05 ppm to 0.2 ppm, higher residues may occur in aspirated grain fractions. Therefore, HED is recommending that the established tolerance of 0.3 ppm grain, aspirated grain fractions be increased to 1.2 ppm based on the new sorghum grain field trial data and established concentration factor
.Page 30 of 72

Storage Stability Adequate storage stability data are available to support the storage durations and conditions of samples from the submitted crop field trial studies on grain sorghum and grass. Storage stability data are available that demonstrate that bromox yn il residues are stable in the f orage, grain , and stover of grain sorghum and in the forage, hay , and seed of grass stored frozen at
- 10°C for 12 months
. Meat, Milk, Poultry, and Egg s Livestock feed items associated with grass are forage, hay , and silage and the livestock feed items associated with grain sorghum are grain, forage/silage, stover and aspirated grain fractions ( Table 1 Feedstuffs , June 2008). M aximum reasonably balanced dietary burden s (MRBDB) of bromox yn il were updated for beef cattle, dairy cattle, swine, and poultry
. The resulting dietary burdens are now 1.6 ppm for beef cattle, 32.7 ppm for dairy cattle, 0.48 ppm for poultry , and 0.39 ppm for swine. Followi ng re - evaluation of the available animal feeding studies in consideration of the recalculated dietary burdens, HED concludes that the established tolerance for residues of bromox yn il for milk should be increased from 0.1 ppm to 0.4 ppm. Other livestock to lerances remain unchanged. Rotational Crops No tolerances are required for rotational crops. The confined rotational crop study indicated that no residues of concern are expected to occur in rotational crops with appropriate plant
- back intervals. 5.3 Water Residue Profile Estimated surface water and groundwater concentrations are shown in Table 5.3.1. The di etary

exposure assessment used value s of 11.5 ppb for acute and 0.19 ppb for chronic (non
- cancer and cancer) assessments. Th e drinking water assessment is based on Tier I surface water model simulations for the proposed sorghum bromox yn il use . S ince bromoxy nil heptanoate is chemicall y and phy sically similar to bromoxy

nil octanoate and both esters rapidl y degrade to brom oxy

nil phenol , all calculations were performed in terms of bromoxy nil phenol
. Table 5. 3 .1 Summary of Estimated Surface Water and Groundwat er Concentrations

for Bromoxynil . a Scenario Surface Water Conc., ppb b Groundwater Conc., pp t c Ac ute 11.5 3.26 Chronic (non
- cancer) 0.19 3.26 Chronic (cancer) 0.19 3.26
a DP#3 74620 , Tiffany Mason , 12/16/2010. b From the Tier I FIRST mo del (FQPA I ndex Reservoir S creening T ool)
. I nput parameters are based on 2 applications at 0.305 lbs ai/A on sorghum 11 days apart c From the SC I
- GROW mo del ( Screening Concentration in Groundwater)Page 31 of 72

M onitoring data for bromoxy nil are available from the USGS NAWQA surface and ground water database and California Department of Pesticide Regulation ( CDPR) surface water database . The NAWQA database had taken 7,218 samples for bromoxy nil across the United States. It is believed that these samples represent bromoxy nil phenol, but cannot be verified since USGS did not differentiate between bromoxy nil phenol, bromoxy

nil octanoate, b romox ynil heptanoate, or bromox yn il buty rate. Out of 7, 218 samples, there were 54 confirmed detections ranging in concentration from 0.001 μg/L to 6.1 μg/L . Of those 54 detections, 40 were samples taken from streams, 8 from ground water sources, 4 from waste water treatment effluent, and 1 from a water distribution sy stem. The rest of the samples were below the detection limit. The CDPR database looked for both bromox ynil and bromox yn il octanoate. Out of 531 samples and approximately

29 sites, taken f

rom February

8, 1993 to January

6, 2005, 192 were for bromox yn il octanoate, and 339 were for bromoxy nil. There were two detections, one for bromox yn il and one for bromoxy nil octanoate. Both occurred on May 9, 1997 in Yolo County , CA with a concentration of 0.06 μg/L . It is possible these two detections at the same location, date, and concentration could be the same bromoxy nil compound. 5.4 Dietary Risk Assessment 5.4.1 Description of Residue Data Used in Dietary Assessment Refined dietary

acute and chronic analy ses were conducted for bromoxy nil. The acute assessment used average field trial values for all grains since they are considered to be blended commodities. Italso utilized tolerance levels for cotton, garlic, onion, peppermint and spearmint as well as anticipated residues for l ivestock commodities based on the results from the crop field trials and animal feeding studies (D 3 78614 , Nancy Dodd, 17
-NOV
- 2010). Default processing factors were used. The chronic and cancer analy ses used averag e field trial residues for all commodities except spearmint and peppermint where tolerance values were used. Livestock anticipated residues were estimated using average percent crop treated data, average field trial residue values, and results from the animal feeding studies (D 3 78614 , Nancy Dodd, 17
-NOV
- 2010). Default processing factors were used. Tabl e 5.4.1 summarizes the bromoxy nil residue levels and processing factors for all crops and livestock commodities used in the acute, chronic and cancer dietary assessments. Table 5.4. 1. Summary of Brom oxynil Residue Levels For All Crops Used in Acute, Chronic, and Cancer Analyses. Matrix Anticipated Residue [Acute] (ppm) Anticipated Residue

[Chronic/Cancer] (ppm) Processing Factors Alfalfa 0.13 0.13 Cereal grains Barley Corn Oats Rye Wheat 0.01 0.01 Corn Syrup: 1.5
Flax, seed 0.01 0.01Page 32 of 72

Table 5.4. 1. Summary of Brom oxynil Residue Levels For All Crops Used in Acute, Chronic, and Cancer Analyses. Matrix Anticipated Residue [Acute] (ppm) Anticipated Residue

[Chronic/Cancer] (ppm) Processing Factors Sorghum 0.028 0.028 Cotton 1.5 0.3 Garlic 0.1 0.01 Onion 0.1 0.01 Dried: 9.0 Mint (peppermint and spearmint) 0.1 0.1 Cattle, goat, horse, sheep; Fat 0.13 0.0024 Cattle, goat, horse, sheep; meat byproducts Kidney: 0.43 Liver: 0.38 Kidney: 0.0081 Liver: 0.0070 Cattle, goat, horse, sheep Meat 0.070 0.0013 Dried:1.92 Egg 0.0038 0.000078 Hog, fat 0.0062 0.00015 Hog, meat byproducts Kidney: 0.020 Liver: 0.018 Kidney: 0.00051 Liver: 0.00044 Hog, meat 0.0033 0.000083 Milk 0.0032 0.00054 Poultry, fat 0.0061 0.00013 Poultry, meat byproducts Liver: 0.048 Liver: 0.00099 Poultry, meat 0.0038 0.000078 The drinking water residue levels used in the dietary assessment were estimated using Tier I FIRST Version 1.1.1 (FQPA Index R eservoir S creening T ool) modeling . The Estimated Drinking Water Concentration (EDWC) for bromoxy nil residues are surface water re sidues based on applications to sorghum . The EDWC for total bromox yn il residues is 11.5 ppb for the acute and 0.19 ppb for both the chronic and cancer assessment s. T he water residues were directly incorporated in the DEEM
- FCID into the categories “water, direct, all sources” and “water, indirect, all sources.” 5.4.2 Percent Crop Treated Used in Dietary Assessment Actual bromox ynil percent crop treated data provided in the Screening Level Usage Anal ys es (SLUA) from the Biological and Economic Anal ysis Division (BEAD) were used in the acute, chronic and cancer dietary assessments (D 382833 , Arthur Grube, 22
- OCT
- 2010) and (D 378991 , Jihad Alsadek, 08
- July
- 2010). The followin g maximum percent crop treated estimates were used in the acute dietary risk assessment for the following crops that are currently registered for bromoxy

nil: alfalfa: 2.5 %; barley : 35%; corn: 5%; oats: 5%; rye: 1%; wheat: 35%; flax: 35%; cotton: 5%; sorghum: 2.5%; garlic: 70%; onion: 70%; and mint: 25%. The following average percent crop treated estimates were used in the chronic and cancer dietary risk assessments for the following crops that are currentl y registered for bromox yn il: alfalfa: 1%; barley : 20%; corn: 2.5%; oats: 5%; rye: 1%; wheat: 15%; flax: 35%; cotton: 2.5%; sorghum: 2.5%; garlic: 50%; onion: 55%; and mint: 25%.Page 33 of 72

It should be noted that the sorghum percent crop treated values used in the acute and chronic assessments were based o n existing uses. Because there is a proposed change in the sorghum use pattern (i.e., shorter PHI), there is a potential for a change in the percent crop treated value. However, grain sorghum is a small contributor to the overall livestock dietary burden estimate. If the percent crop treated value for sorghum was assumed to be 100%, the overall impact to the dietary exposure and risk assessment would be negligible. 5.4.3 Acute Dietary Risk Assessment A refined dietary

acute analy sis was conducted for bromox yn il. For all grains, average field trial values were used since grains are considered to be blended commodities. Tolerance levels were used for cotton, garlic, onion, peppermint and spearmint. Li vestock anticipated residues were estimated using r esults from the crop field trials and animal feeding studies. Additionally , maximum percent crop treated estimates provided by BEAD were used for all crop commodities. Default processing factors were used. A c onservative EDWC derived through EFED modelin g which is unlikely

to underestimate the concentration of bromox yn il in drinking water was utilized. The surface water EDWC (11.5 μ g/L) was incorporated directly into the dietary assessment
. As shown in Table 5.4. 6 , the acute dietary (food and drinking water) exposure to bromox ynil is below HED’s level of concern [i.e., <100% of the c hronic Population Adjusted Dose (cPAD)] for the general U.S. population and all po pulation subgroups at the 99.9 th percentile of the exposure distribution. The acute dietary exp osure estimates are 3.3% of the aPAD for the general U.S. population and 7.4% of the aPAD for all infants (<1 ye ar old), the most highly exposed population subgroup. 5.4.4 Chronic Dietary Risk Assessment Refined dietary

chronic and cancer an aly ses were conducted for bromoxy nil. Average field trial residues were used for all commodities except for spearmint and peppermint where tolerance values were used. Livestock anticipated residues were estimated using average percent crop treated data, average field trial residue values, and results from the animal feeding studies. Additionally , average percent crop treated estimates provided b y BEAD were used for all crop commodities. Default processing factors were used. A c onservative EDWC derived through EFED modeling which is unlikely to underestimate the concentration of bromoxy nil in drinking water was utilized. The surface water EDWC (0.19 μ g/L) was incorporated directly into the dietary assessment
. As shown in Table 5.4.3 , the non
- cancer chronic dietary (food and drinking water) exposure to bromox yn il is below HED’s level of concern [i.e., <100% of the c hronic Population Adjusted Dose (cPAD)] for the general U.S. population and all population subgroups. The chronic dietary exposure estimates are 0. 1% of the cPAD for the general U.S. population and 0.3% of the cPAD for children 1
- 2 years old, the most highly exposed population subgroup.Page 34 of 72

5.4.5 Cancer Dietary Risk Assessment Bromox ynil is a possible human carcinogen and requires a quantitative cancer risk assessment. The unit risk, Q 1 * = 0.103 (mg/kg/day) - 1 , of bromoxy nil is based upon on male mouse hepatocellular tumors . The surface water EDWC (0.19 μ g/L) was incorporated directl y into the dietary a ssessment
. As shown in Table 5.4 .6, the cancer dietary (food and drinking water) exposure estimate for the general U.S. population is 1.5 x 10 - 6 , which is below HED’s level of concern ( generall y in the range of 1 0 - 6 ). 5.4.6 Summary Table
Table 5.4.6. Summary of Dietary ( Food and Drinking Water) Exposure and Risk for Brom oxynil
Population Subgroup Acute Dietary ( 99.9th Percentile) Chronic Dietary Cancer Dietary Exposure (m g/kg/day) % aPAD Dietary Exposure (m g/kg/day) % cPAD Dietary Exposure (m g/kg/day) Risk General U.S. Population 0.002639 3.3 0.000014 ‹1% 0.000014 1.5 x 10 - 6 All Infants (< 1 year old) 0.005892 7.4 0.000024 ‹1%

N/A N/A Children 1
- 2 years old 0.003714 4.6 0.000040 ‹1% Children 3
- 5 years old 0.003527 4.4 0.000032 ‹1% Children 6
- 12 years old 0.002151 2.7 0.000021 ‹1% Youth 13
- 19 years old 0.002507 3.1 0.000013 ‹1% Adults 20
- 49 years old 0.001965 2.5 0.000011 ‹1% Adults 50+ years old 0.001482 1.9 0.000010 ‹1% Females 13
- 49 years old 0.001756 4.4 0.000011 ‹1% 6.0 Residential (Non - Occupational) Exposure/Risk Characterization There are no currently

registered or proposed residential uses of bromox yn il. 6.1 Spray Drift Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application metho d employed for bromox ynil . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placedPage 35 of 72

on product labels/labeling. The Agency has completed its evaluation of the new database submitted by

the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy

on how to appropriatel y apply the data and the AgDRIFT computer model to its risk ass essments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy

is in place, the Agency

may impose further refinements in spray drift management practices to reduce off
- target drift with specific products with signi ficant risks associated with drift. 7.0 Aggregate Exposure/Risk Characterization Under FQPA, HED must consider and aggregate pesticide exposures and risk from three major sources: food, drinking water, and residential exposures. 7.1 Acute Aggregate Risk There is potential acute exposure via the diet (food and drinking water). Refer to Section 5.3
. 7.2 Short - and Intermediate - Term Aggregate Risk Since there are no residential uses for bromox ynil, short
- and intermediate
- term aggregate assessments were not conducted. 7.3 Chronic Aggregate Risk There is potential chronic exposure via the diet (food and drinking water). Refer to Section 5.4. 7.4 Cancer Aggregate Risk There is potential chronic cancer exposure via the diet (food and drinking water). Refer to Sectio n 5.5
. 8.0 Cumulative Exposure/Risk Characterization Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to bromox yn il and any other substances and bromoxy nil does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that bromox yn il has a common mechanism of toxicity with other substances. Fo r 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 mech anism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. 9.0 Occupational Exposure/Risk Characterization Source: Bromoxynil: Occupational and Residential Exposure Assessment for Proposed Field Uses of Bromoxynil on Grain Sorghum (to include grain and forage), Grass Grown for Seed,Page 36 of 72

Conservation Reserve Program Areas and Existing Use Sites of Bromoxynil. D378616, K. Rury, 4/7 /11. Bromox ynil is formulated as an emulsifiable concentrate, soluble concentrate , and as a wettable powder in water soluble packets (WSB ) and can be applied with aerial equipment, chemigation, and groundboom sprayer s . Application rates for bromox yn il range from 0.21 to 0.5 lb bromox yn il per acre. Currentl y registered bromoxynil agricultural use sites include: corn, sorghum, transgenic cotton, seedling alfalfa, flax, garlic, small grains (wheat, barley , oats, and rye ), onions , grasses grown for seed and sod production, conservation reserve program (CRP) areas, non - residential turfgrass, non cropland/industrial sites, and mint. The proposed formulated end
- use product evaluated in this assessment is labeled under the trade name HUSKIETM Herbicide (EPA Reg. No. 264
- 1023) (Huskie) containing 26.3% bromox yn il and 3.3% py rasulfotole. A separate ORE assessment has been conducted for py rasulfotole ( D375392, A. Nowotarski, 09/03/ 10). This assessment was completed to incorporat e amended uses of bromox yn il on grain sorghum (to include grain and forage) , grass grown for seed, and conservation reserve program areas (CRP). This document also reassesses existing uses of bromox yn il as the dermal absorption factor ha s increased and an inhalation endpoint was added to the bromoxy

nil toxicity

database. 9.1 Short -/Intermediate Term Non - Cancer & Cancer Risk For Pesticide Handlers There is a potential for short
- and intermediate
- term occupational exposure to bromoxy nil during mixing, loading , and applying, and for short
- and intermediate
- term post - application activities. Chronic exposure is not expected for the proposed use patterns associated with bromoxy nil. Estimated short
- and intermediate
- term dermal exposures were compared to the NOAE L of 10 mg/kg/day

from a dermal developmental study in which increased incidence of supernumerary ribs were seen. Estimated short
- and intermediate
- term inhalation exposures were compared to the NOAEL of 4 mg/kg/day from an oral developmental toxicity stu dy in the rat based on increased incidence of supernumerary ribs. Chemical
- specific data for assessing exposure during pesticide handling activities (mixing/loading, appl yi ng, and flagging) were not submitted to the Agency in support of this Section 3 a

pplication. It is HED policy to use data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 to assess handler exposures for regulatory actions when chemical
specific data are not available (HED Science Advisory Council for Exposure, SOP No.7 , January 1999). 9.1.1 Occupational Handler Non - Cancer Risk Estimates Daily dermal exposures (assuming 100% absorption and a 60 kg body weight) were compared to the NOAEL of 10 mg/kg/day from a dermal developmental study to determine the risk for short
and i ntermediate
- term dermal exposures. Daily inhalation exposures (assuming 100% absorption and a 60 kg body weight were compared to the NOAEL of 4 mg/kg/day from an oral developmental toxicity

study to determine the risk for short
- and intermediate
- term expo sures. The MOEs for short
- term and intermediate
- term dermal and inhalation non
- cancer risk estimates for the proposed and currently registered use sites o f bromox yn il are shown in Table 9.1.1.1
.Page 37 of 72

Amended Bromoxynil Uses The results indicate that the MOEs for the proposed uses for occupational handler scenarios were not of concern (i.e., an MOE > 100) at some level of personal protection (gloves). The dermal MOE was 12 with baseline attire for mixer/loaders, and the dermal MOEs ranged from 2,400 to 2,600 for applicators. The dermal MOEs with baseline attire plus gloves (PPE
- G) ranged from 1,300 to 1,400 for mixer/loaders and from 2,400 to 2,600 for applicators. Inhalation MOEs ranged from 11,000 to 12,000 for mixer/loaders and from 18,000 to 19,000 for applicators. The combined (dermal + inhalation) MOE with baseline attire was 12 for mixer/loaders and ranged from 2,200 to 2,300 for applicators. Combined (dermal + inhalation) MOEs with baseline attire plus gloves (PPE
- G ) ranged from 1,300 to 1,400 for mixer/loaders and from 2,200 to 2,300 for applicators. Reevaluation of Existing Bromoxynil Uses The results indicate that the mixing/loading MOEs for the existing use sites were not of concern (i.e., an MOE > 100) at som e level of personal protection (gloves) for all crops and application methods, except mixing/loading for aerial application to corn and wheat, which requires a closed sy stem. The results indicate that MOEs for application of bromoxy nil to all existing use sites were not of concern at some level of personal protection (gloves). Flagging for bromoxy nil application was not of concern at baseline attire. The dermal MOEs at baseline attire range from 0.34 (risks of concern) to 160 for mixing/loading for application to corn and wheat, from 1.2 (risks of concern) to 1,400 for all other crops, from 200 to 6,000 for applicators, and from 310 to 620 for flaggers. Inhalation MOEs at basel ine attire were >330 for mixer/loaders, applicators and flaggers and are not of concern. Combined (dermal + inhalation) MOEs at baseline plus gloves ranged from 38 to 2,900 for mixer/loaders, 380 to 4,900 for applicators, and from 270 to 530 for flaggers. Mixing and loading scenarios for bromox yn il application to corn and wheat were below HED’s LOC=100 at baseline and PPE
- G. With coveralls, mixing/loading for application to corn and wheat, the dermal MOE was 57 and the combined dermal and inhalation MOEs for ranged from 55 (risk of concern) to 190. In a closed system , the dermal MOE for mixing/loading for application to corn & wheat was 120 and was 4,800 for inhalation exposure; the combined dermal + inhalation MOE was 110, and therefore not of concern.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 38 of 72 Table 9.1.1. 1 Summary of Occupational (Non Cancer) Risks of Bromoxynil to Am ended and Existing Use Sites
Handler Scenario Dermal MOE Inhalation MOE Combined Dermal/Inhalation MOE

Baseline Baseline +

Gloves Coveralls Closed System Baseline Respirator Closed System Baseline Baseline + Gloves Coveralls +

Respirator Closed

System Amended Uses Mixer/loader 12 1,300
- 1,400 Not Needed 11,000
- 12,000 Not Needed 12 1,300
- 1,400 Not Needed Applicator 2,400
-

2,600 2,400
-

2,600 18,000
- 19,000 2,200
- 2,300 2,200
- 2,300 Existing Uses Mixer/loader (Corn & wheat) 0.34

– 160 43
- 350 57 120 330
- 5,700 1 , 700
- 5 , 700 4 , 800 0.34
- 160 38
- 330 55
- 190 110 Mixer/loader (all other crops) 1.2
- 1,400 150
- 3,100 200 11,000
- 50,000 Not Needed 1.2
- 1,400 130
- 2,900 Not Needed Flagger 310
- 620 290
- 570 Not Needed 3,900
- 7,800 290
- 580 270
- 530 Liquid Application 200
- 6,000 430
- 6,000 3,200
- 40,000 190
- 4,900 380
- 4,900Bromox ynil Human Health Risk Assessment DP No. 374609

Page 39 of 72 9.1.2 Occupational Handler Cancer Risk Estimates For the proposed use sites of bromox yn il, HED assumed 10 days of bromoxy nil exposure per ye ar to assess cancer risks to commercial agricultural handlers and 2 day s of bromoxy nil exposure per year to assess risks to private agricultural handlers based on use pattern information and maximum treatments per year. For the existing use sites, HED a ssumed 30 day s of bromox yn il exposure per year for high acreage crops (corn and wheat), while 10 day s of exposure per year for all other use sites. Based on the use profile and the maximum number of applications allowed per year (1

– 3 applications) these estimates are expected to be a conservative representation of expos ure to bromox yn il per ye ar. EPA conducted an assessment of the carcinogenic risk estimates associated with bromoxy nil following exposures to occupational handlers. The minimum level of PPE for handlers is based on acute toxicity for the end
- use product. The Registration Division (RD) is responsible for ensuring that PPE listed on the label is in compliance with the Worker Protection Standard (WPS) for Agricultural P esticides. The Agency generall y considers occupational cancer risk estimates within the range of 1 to 3x10 - 6 (approximately

1
- 3 in 1 million persons) or less to be negligible, but may accept risk estimates as high as 1x10 - 4 when all mitigation measures th at are feasible and practical have been applied, particularl y when there are critical pest management needs associated with the use of the pesticide. Exposure assumptions and canc er estimates for occupational handlers are summarized in Tables 9.1.2.1 and 9.1.2.2. Amended Uses (EPA Reg. No. 264

- 1023) The results indicate that estimated cancer risks were not of concern (i.e., in the 10 - 6 range or lower) for both commercial and private users at some level of personal protection (gloves). The cancer ris k estimates at baseline attire for commercial users of bromoxy nil ranged from 1.7x10 - 4 to 1.8x10 - 4 for mixer/loaders and was 1.1x10 - 6 for applicators. The cancer risk estimates at baseline plus gloves (PPE
- G) for commercial handlers ranged from 2.0x10 - 6 t o 2.1x10 - 6 for mixer/loaders and was 1.1x10 - 6 for applicators. The cancer risk estimates with coveralls for commercial handlers ranged from 1.4x10 - 6 to 1.5x10 - 6 for mixer/loaders, and from 8.8x10 - 7 to 9.2x10 - 7 for applicators. The cancer risk estimates at baseline attire for private users of bromox yn il was 3.5x10 - 5 for mixer/loaders and ranged from 2.1x10 - 7 to 2.2x10 - 7 for applicators. The cancer risk estimate s at baseline plus gloves (PPE
- G) for private applicators ranged from 4.0x10 - 7 to 4.2x10 - 7 for mixer/loaders and from 2.1x10 - 7 to 2.2x10 - 7 for applicators. The cancer risk estimate s for private applicators with coveralls ranged from 2.8x10 - 7 to 3.0x10 - 7 for mixer/loaders and the risk was 1.8x10 - 7 for applicators. Reevaluation of Existing Bromoxynil Uses The results indicate that estimated cancer risks were not of concern (i.e., in the 10 - 6 range or lower) for both commercial and private users at some level of personal protection (gloves) for all scenarios except aerial application to corn an d wheat, which requires a closed sy stem. The cancer risk estimate s at baseline attire for bromoxy nil use on currentl y registered use sites ranged from 4.0x10 - 5 to 1.8x10 - 2 for mixing/loading for application to corn & wheat, from 1.5x10 - 6 to 6.0x10 - 3 for mixing/loading to all other use sites, from 3.6x10 - 7 to 3.3x10 - 5 for applicators and 3.9x10 - 6 to 1.8x10 - 5 for flaggers. The cancer risk estimate s at baseline attire plusBromox ynil Human Health Risk Assessment DP No. 374609

Page 40 of 72 gloves ranged from 2.0x10 - 5 to 1.9x10 - 4 for mixing/loading for application to corn & wheat, from 7.7x10 - 7 to 6.9x10 - 5 for mixing/loading for application to all other use sites, from 6.4x10 - 7 to 1.6x10 - 5 for applicators and from 6.3x10 - 6 to 1.9x10 - 5 for flaggers. The cancer risk estimate s with PPE
- G and coveralls ranged from 1.3x10 - 5 to 1 .5x10 - 4 for mixing/loading for application to corn & wheat, from 4.9x10 - 7 to 4.4x10 - 5 for mixing/loading for application to all other use sites, from 5.0x10 - 6 to 2.0x10 - 5 for flaggers, and from 2.7x10 - 7 to 1.6x10 - 5 for applicators. The cancer risk estimate s with PPE
- G, coveralls and a respirator ranged from 1.1x10 - 5 to 1.2x10 - 4 for mixing/loading for application to corn & wheat, from 4.1x10 - 7 to 3.4x10 - 5 for mixing/loading for application to all other use sites, from 4.3x10 - 6 to 1.7x10 - 5 for flagg ers, and from 2.5x10 - 7 to 1.2x10 - 5 for applicators. With a closed system, the cancer risk estimate s ranged from 9.3x10 - 6 to 5.6x10 - 5 for mixing/loading for application to corn & wheat, and from 6.2x10 - 7 to 5.4x10 - 6 for application to all other use sites.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 41 of 72 Table 9.1.2.1. Summary Table Occupational Cancer Risk Estimates of Bromoxynil for Commercial Applicators to Amended and Existing Use Sites Handler Scenario Cancer Risk Estimate Baseline Baseline + Gloves Coveralls & Baseline Inhalation Coveralls + Respirator Closed System Amended Uses Mixer/loader 1.7x10 - 4

- 1.8x10 - 4 2.0x10 - 6

– 2.1x10 - 6 1.4x10 - 6

– 1.5x10 - 6 Applicator 1.1x10 - 6 1.1x10 - 6 8.8x10 - 7

– 9.2x10 - 7 Existing Uses Mixing/loading (corn & wheat) 4.0x10 - 5

- 1.8x10 - 2 2.0x10 - 5

- 1.9x10 - 4 1.3x10 - 5

– 1.5x10 - 4 1.1x10 - 5

– 1.2x10 - 4 9.3x10 - 6

- 5.6x10 - 5 Mixing/Loading (all other crops) 1.5x10 - 5

- 6.0x10 - 3 7.7x10 - 7

- 6.9x10 - 5 4.9x10 - 7

– 4.4x10 - 5 4.1x10 - 7

– 3.4x10 - 5 6.2x10 - 7

– 5.4x10 - 6 Flagger 3.9x10 - 6

– 1.8x10 - 5 4.2x10 - 6

– 1.9x10 - 5 5.0x10 - 6

– 2.0x10 - 5 4.3x10 - 6

– 1.7x10 - 5 Applicator 3.6x10 - 7

– 3.3x10 - 5 3.7x10 - 7

– 1.9x10 - 5 2.7x10 - 7

- 1.6x10 - 5 1.2x10 - 5

– 2.5x10 - 7Bromox ynil Human Health Risk Assessment DP No. 374609

Page 42 of 72 Table 9.1.2.2. Summary Table Occupational Cancer Risk Estimates of Bromoxynil for Private Applicators to Amended Use Sites
Handler Scenario Cancer Risk Estimate Baseline Baseline + Gloves Coveralls

Amended Uses Mixer/loader 3.5x10 - 5 4.0x10 - 7

- 4.2x10 - 7 2.8x10 - 7 3.0x10 - 7 Applicator 2.1x10 - 7

- 2.2x10 - 7 2.1x10 - 7

- 2.2x10 - 7 1.8x10 - 7Bromox ynil Human Health Risk Assessment DP No. 374609

Page 43 of 72 9.2 Short -/Intermediate - Term Post - Application Risks HED uses the term post
- application to describe exposures that occur when individuals are present in an environment that has been previousl y treated with a pesticide. Such exposures may occur when workers enter previously

treated areas to perform job funct ions, including activities related to crop production, such as scouting for pests or harvesting. Post
- application exposure levels vary over time and depend on the typ e of activity , the nature of the crop or target that was treated, the typ e of pesticide a

pplication, or the pesticide’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post
- application exposure. 9.2.1 Post -Application Exposure and Cancer Risks Chemical
- specific residue data were not submitted for bromox ynil , therefore, the standard assumption regarding dislodgeablity was used to estimate post - application exposure (i.e. HED uses 20% of the application rate was used as the initial dislodgeable foliar res idue (DFR) ). The transfer coefficients (TC) used in this assessment are from an interim transfer coefficient policy developed by HED’s ExpoSAC (Ag Default Transfer Coefficients, Policy 3.1 ). It is the intention of HED’s ExpoSAC that this policy will be p eriodicall y updated to incorporate additional information about agricultural practices in crops and new data on transfer TCs
. The default TCs used in this assessment represent a wide range of possible activities at the highest exposure levels. HED used extremely conservative inputs to estimate the post
- application risk of bromox yn il: the assessment of post
- application exposure represents high
- end, worst
- case scenarios. For example, full foliage TCs were used for corn, sorghum, wheat, small grains, and mint as the use directions allow for later
- stage application to the crops. However, b romoxy nil is likely

to be applied more frequently

in the early

stages of plant growth to be the most effective against competing weeds, representing minimal foliage expos ure for post
- application workers (however the labels do not clearl y specify

earl y application timing for all crops, so full foliage was still assessed in certain scenarios). Additionally , post - application exposure was estimated using default, conservative residue values representative of the day of application. Exposure is expected to diminish over time, because bromox yn il residues eventually dissipate in the environment . With chemical
- specific residue data, the residue values could be averaged seasonall y to provide a more refined assessment of bromoxy nil post - application exposure potential. Uncertainty surrounding bromoxy

nil residues available on foliage for transfer could be reduced with chemical
- specific DFR studies. A summary

of the occupational post - application dermal exposure and risk for post
- emergent application of bromox yni l is provided in Table s 9.2.1.1, 9.2.1.2, 9.2.1.3, and 9.2.1.4. The Agency

assumed post
- application exposure to treated crops could occur 30 day s per ye ar for high acreag e crops (corn and wheat) and 10 day s for all other crops. Post
- application cancer risk estimates assume contact with bromox yn il 30 and 10 day s per year over a 35 year lifespan and are considered a worst case, extremely conservative estimation based on the bromox yn il use pattern. As stated above, the Agency generall y considers occupational cancer risks in the general range of 1x10 - 6 to be negligible, but may

accept risks as high as 1x10 - 4 when all mitigation measures that are feasible and practical have be en applied.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 44 of 72 Amended Use Sites (EPA Reg. No. 264

- 1023) The dermal non
- cancer short
- and intermediate
- term MOEs ranged from 150 to 1,500 on the day of application. The estimated occupational post
- application cancer risks on the day of application ranged from 1.4x10 - 6 to 1. 1 x10 - 5

. Under the WPS for Agricultural Pesticides, a 24 - hr REI is required for chemicals classified under Toxicity Category II. Therefore , the REI on the HuskieTM Herbicide label should be 24 hours
.

Table 9.2.1 . 1. Occupational Post Application Exposure to Am en ded Uses of Bromoxynil Crop Maximum

Proposed Application Rate (lb ai/A) Activity Foliage

Development TC 1 Days After Treatment Transferrable

Residue 2,3 Daily Dose

(mg/kg/d) 4 MOE 5
Sorghum2 0.22 Irrigation, Scouting Full 1000 0 0.493 0.0658 150 0.22 Scouting Low 100 0 0.493 0.0066 1,500 Grass Gro wn for Seed and CRP Areas 3 0.21 Mowing Full 500 0 0.118 0.0078 1 , 300 1 Transfer Coefficients from HED Policy No. 3.0. 2 DFR ( μg/cm2 )= application rate x 20% dissipation x 4.54 x10 8 μg/lb x 2.47 x 10 - 8 A/cm2 , 3 TTR (for Grass use sites) (μg/cm 2 )= application rate x 5% dissipation x 4.54 x10 8 μg/lb x 2.47 x 10 - 8 A/cm2 4 Dermal Dos e (mg/kg/day) = DFR(t) or TTR ( μg/cm2 ) x TC (cm2/hr)x hr/day (8 hours) x (1/1000 μg/mg) x (1/ 60 kg bw) w here DFR(t)is dislodgeable foliar residue at time t 5 Dermal Short
- Term MOE = NOAEL (10 mg/kg/day)/Dermal Daily Dose (mg/kg/day)

Table 9.2.1 . 2. Occupational Post Application Cancer Risk from Am ended Agricultural Uses of Bromoxynil
Crop Maximum

Proposed Application Rate (lb ai/A) Activity Foliage Development TC 1 Days After Treatment Transferrable

Residue 2,3 Daily Dose

(mg/kg/d) 4 LADD 5 Cancer Risk Estimate 6
Sorghum 0.18 Irrigation, Scouting Full 1,000 0 0.40 0.008 0.000107 1.1E
- 05 0.22 Scouting Low 100 0 0.49 0.0010 0.000013 1.4E
- 06 Grass Gr own for Seed and CRP Areas 0.21 Full Mowing, pruning, weeding 500 0 0.12 0.0011 0.000016 1.6E
- 06 1 Transfer Coefficients from HED Policy No. 3.0. 2 DFR ( μg/cm2 )= application rate x 20% dissipation x 4.54 x10 8 μg/lb x 2.47 x 10 - 8 A/cm2 , 3 TTR (for Grass use sites) (μg/cm 2 )= application rate x 5% dissipation x 4.54 x10 8 μg/lb x 2.47 x 10 - 8 A/cm2 4 Dermal Dos e (mg/kg/day) = DFR(t) or TTR ( μg/cm2 ) x TC (cm2/hr)x hr/day (8 hours) x (1/1000 μg/mg) x (1/ 60 kg bw) where DFR(t)is dislodgeable foliar residue at time t 5 LADD= (Dermal PPE Dose+Inhalation Baseline Dose) x average days of exposure (10/365) x (35 years/70 years). 6 Cancer Risk Estimates = LADD x Q 1 *, w here Q 1 *=1.03E
- 1 (mg/kg/day) - 1

.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 45 of 72 Existing Use Sites The short
- and intermediate
- term dermal non
- cancer MOEs for all occupational post
- application scenarios ranged from 45 to 1,400 on the day of application; and therefore, some post
- application activities are of concern. Risk from occupati onal contact with full foliage wheat, small grains and mint is not of concern 8 day s after application, risk from sod harvesting is not of concern 5 day s after application, and risk from occupational contact with full foliage corn, sorghum and cotton is no t of concern 4 day s after application. The estimated cancer risks on the day of application ranged from 2.3x10 - 6 to 1.4x10 - 4

. Table 9.2.1.3 . Post Application Exposure from Bromoxynil to Registered Use Sites Crop Maximum

Application Rate (lb ai/A) Activity Foliage Development TC 1 Transferrable Residue 2,3 Daily

Dose (mg/kg/d) 4 Day 0

MOE 5 Days

After Treatment to Reach MOE > LOC MOE 5

Corn 0.5 Irrigation, Scouting Full 1,000 1.1032 0.147096 68 4 104 0.5 Scouting Minimum 400 1.1032 0.0588384 170 N/A Sorghum 0 .5 Irrigation, Scouting Full 1,000 1.1032 0.147096 68 4 104 0.5 Scouting Low 100 1.1032 0.0147096 680 N/A Wheat 0.5 Scouting Full 1,500 1.1032 0.220644 45 8 105

0.5 Irrigation,

Scouting Min 100 1.1032 0.0147096 680 N/A Other Sma ll Grains 0.5 Scouting Full 1500 1.1032 0.220644 45 8 105

0.5 Irrigation,

Scouting Min 100 1.1032 0.0147096 680 N/A Cotton 0. 5 Scouting Full 1,000 1.1032 0.147096 68 4 104 Seedling Alfalfa 0.375 Irrigation, Scouting Min 100 0.8274 0.0110322 910 N/A Flax 0.25 Scouting Min 100 0.5516 0.0073548 1,400 Garlic 0.5 Irrigation, scouting, hand weeding Min 300 1.1032 0.0441288 230

Mint 0. 5 irrigation, scouting, weeding Full 1,500 1.1032 0.220644 45 8 105
0.5 irrigation,

scouting, weeding Minimum 100 1.1032 0.0147096 680 N/A Onions 0.375 Irrigation, scouting, hand weeding Min 300 0.8274 0.0330966 300 Grass Gr own for Sod 0.5 Harvesting Full 5800 0.275805 0.2132892 47 5 102 Grass Gr own for Seed, Non Residential Turf, Non
Industrial Sites 0.5 Mowing Full 500 0.2758 0.018387 540 N/A
1 Transfer Coefficients from HED Policy No. 3.0 2 DFR ( μ g/cm2 )= application rate x 20% dissipation x 4.54 x10 8 μg/lb x 2.47 x 10 - 8 A/cm2 , TTR (for Grass use sites) ( μ g/cm2 )= application rate x 5% dissipation x 4.54 x10 8 μg/lb x 2.47 x 10 - 8 A/cm2 3 TTR (for Grass use sites) ( μ g/cm2)= application rate x 5% dissipation x 4.54 x10 8 μg/lb x 2.47 x 10 - 8 A/cm2 4 Dermal Dose (mg/kg/day) = DFR(t) ( μ g/cm2 ) x TC (cm2/hr)x hr/day (8 hours) x (1/1000 μg/mg) x (1/ 60 kg bw) where DFR(t)is dislodgeable foliar residue at time t 5 Dermal Short
- Term MOE = NOAEL (10 mg/kg/day)/Dermal Daily Dose (mg/kg/day)Bromox ynil Human Health Risk Assessment DP No. 374609

Page 46 of 72 Table 9.2.1.4 . Post Application Exposure and Cancer Risk to Work ers from Bromoxynil Treatment to Registered Use Sites Crop Maximum

Application Rate (lb ai/A) Activity Foliage Development TC 1 Exposure Days Days

After Treatment Transferrable

Residue 2,3 Daily

Dose (mg/kg/d) 4 LADD 5 Cancer Risk Estimate 6 Corn 0.5 Irrigation, Scouting Full 1000 30 0 1.1214 0.0218 0.00090 9.2E
- 05 0.5 Scouting Minimum 400 30 0 1.1214 0.0087 0.00036 3.7E
- 05 Sorghum 0.5 Irrigation , Scouting Full 1000 10 0 1.1214 0.0218 0.00030 3.1E
- 05 0.5 Scouting Low 100 10 0 1.1214 0.0022 0.00003 3.1E
- 06 Wheat 0.5 Scouting Full 1500 30 0 1.1214 0.0327 0.00134 1.4E
- 04

0.5 Irrigation,

Scouting Min 100 30 0 1.1214 0.0022 0.00009 9.2E
- 06 Other Small Grains 0.5 Scouting Full 1500 10 0 1.1214 0.0327 0.00045 4.6E
- 05

0.5 Irrigation,

Scouting Min 100 10 0 1.1214 0.0022 0.00003 3.1E
- 06 Cotton 0.5 Scouting Full 1000 10 0 1.1214 0.0218 0.00030 3.1E
- 05 Alfalfa 0.375 Irrigation, Scouting Low 100 10 0 0.8410 0.0016 0.00002 2.3E
- 06 Flax 0.75 Scouting Min 100 10 0 1.6821 0.0033 0.00004 4.6E
- 06 Garlic 0.5 Irrigation, scouting, hand weeding Min 300 10 0 1.1214 0.0065 0.00009 9.2E
- 06

Mint 0.5 irrigation, scouting, weeding Full 1500 10 0 1.1214 0.0327 0.00045 4.6E
- 05
0.5 irrigation,

scouting, weeding Minimum 100 10 0 1.1214 0.0022 0.00003 3.1E
- 06
Onions 0.375 Irrigation, scouting, hand weeding Min 300 10 0 0.8410 0.0049 0.00007 6.9E
- 06 Grass Gr own for Sod 0.5 Harvesting Full 5800 10 0 0.2803 0.0316 0.00043 4.5E
- 05 Grass Gr own for Seed Non Residential Turf, Non
Industrial Sites 0.5 Mowing Full 500 10 0 0.2803 0.0027 0.000037 3.8E
- 06 1 Transfer Coefficients from HED Policy No. 3.0 2 DFR ( μ g/cm2 )= application rate x 20% dissipation x 4.54 x10 8 μg/lb x 2.47 x 10 - 8 A/cm2 3 TTR (for Grass use sites) ( μ g/cm2 )= application rate x 5% dissipation x 4.54 x10 8 μg/lb x 2.47 x 10 - 8 A/cm2 4 Dermal Dose (mg/kg/day) = DFR(t) ( μ g/cm2 ) x TC (cm2/hr)x hr/day (8 hours) x Dermal Absorption (17%) x (1/1000 μg/mg) x (1/ 70 kg bw) where DFR(t)is dislodgeable foliar residue at time t 5 LADD= (Dermal PPE Dose+Inhalation Baseline Dose) x average days of exposure (30/365) x (35 years/70 years) 6 Cancer Risk Estimates = LADD x Q 1 *, w here Q 1 *=1.03E
- 1 (mg/kg/day) - 1 Occupational Post
- application Inhalation Exposure Based on the Agency's current practices, a quantitative occupational post
- application inhalation exposure assessment was not performed for bromoxy nil at this time. However, there are multiple potential sources of post
- application inhalation exposure to individuals performing post
- application activities in previously

treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, andBromox ynil Human Health Risk Assessment DP No. 374609

Page 47 of 72 Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 20 10 (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 b y the Agricultural Reentry Task Force and may, as app ropriate, 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 Agenc y may revisit the need for a quantitative occupational post - application inhalation exposure assessment for bromox yn il. 9.3 O ccupational Exposure Data Requirements & Label Changes To characterize post
- application exposure and reduce uncertainty for late applications of bromox yn il, HED is requesting the registrant submit a dislodgeable foliar residue (DFR) study on a representative row crop (e.g. corn). HED suggests using corn for the study site because in the U.S., 57% of bromox ynil is applied exclusively to corn and the label allows for bromoxy nil application to corn later in the growth cycle (post emergence to tassel emergence), resulting in potentiall y higher exposures. Based on email correspondence with the registrant (dated 11/01/2010), HuskieTM Herbicide (EPA Reg. No. 264
- 1023) is not intended for application with chemigation or aerially to grain sorghum, grass grown for seed and CRP areas. The label should restrict aerial a nd chemigation explicitly from these use sites. Existing labels should clarify that products containing bromoxy nil are restricted from use on golf course turf. Under the WPS for Agricultural Pesticides, a 24 - hr REI is required for chemicals classified under Toxicity Category I I. Therefore , the REI on the HuskieTM Herbicide label should be 24 hours . Other bromox ynil product labels should also require a 24
- hr REI, excep t for the specific use sites of wheat, small grains and mint which require an REI of 8 days, sod harvesting which require an REI of 5 days, and corn, sorghum and cotton which require an REI of 4 days
. 10.0 Environmental Justice Considerations Potential areas of env ironmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - 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
- establishe d 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 res idential 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 ar e anal yzed and categorized b yBromox ynil Human Health Risk Assessment DP No. 374609

Page 48 of 72 subgroups based on age, season of the ye ar, 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 condition s or circumstances warrant. Whenever appropriate, non
- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post
- application are evalu ated. 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 by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. 11.0 References Alsadek, J., 07/08/2010, DP# 378991 , Usage Report Package in Support of Registration for the Herbicide Bromoxynil, (035302)

. Dodd, N ., 2/15/2011 , DP# 378614, Bromoxynil. Petition for Tolerances in Support of New Uses on Grass and Grain Sorghum. Summary of Analytical Chemistry and Residue Data. Goodlow, T., 8/17/20 10, DP# 380770, Bromoxynil: Review of HUSKIE HERBICIDE

– Magnitude of the Residue in/on Sorghum and Grass Grube, A., 10/22/2010, DP# 382833 , Us age Report Package in Support of Registration for the Herbicide Bromoxynil, (035301)

. Mason, T., 12/16/2010, DP# 374620 , Drinking water assessment for ground and aerial application of bromoxynil on grass grown for seed and ground application of sorghum. Rury , K ., 04/07 /2011, DP # 378616, Bromoxynil: Occupational and Residential Exposure Assessment for Proposed Field Uses of Bromoxynil on Sorghum, Grass Grown for Seed, Conservation Reserve Program Areas, and Existing Use sites of Bromoxynil. Walls, C., 0 3/22 /2011, DP#378615, Bromoxynil: Acute, Chronic, and Cancer Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the New Uses on Grass and Grain Sorghum

.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 49 of 72 Appendix A . Toxicology Profile and Executive Summaries A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for non - food use for Bromoxynil are in Table 1. Use of the new guideline numbers does not imply that the ne w (1998) guideline protocols were used. Study Technical Required Satisfied 870.1100 Acute Oral Toxicity
................................ ....................... 870.1200 Acute Dermal Toxicity
................................ .................. 870.1300 Acute Inhalation Toxicity
................................ .............. 870.2400 Primary Eye Irritation
................................ .................... 870.2500 Primary Dermal Irritation
................................ .............. 870.2600 Dermal Sensitization
................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent)
................................ ............... 870.3150 Oral Subchronic (nonrodent)
................................ ......... 870.3200 21
- Day

Dermal
................................ .............................. 870.3250 90
- Day

Dermal
................................ .............................. 870.3465 90
- Day

Inhalation
................................ .......................... yes yes yes no no yes

yes yes

-

- 870.3700a Developmental Toxicity (rodent)
................................ ... 870.3700b Developmental Toxicity (nonrodent)
............................. 870.3800 Reproduction
................................ ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent)
................................ .............. 870.4100b Chronic Toxicity (nonrodent)
................................ ........ 870.4200a Oncogenicity (rat)
................................ .......................... 870.4200b Oncogenicity (mouse)
................................ .................... 870.4300 Chronic/Oncogenicity
................................ .................... yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

—Gene Mutation
- bacterial
..................... 870.5300 Mutagenicity

—Gene Mutation
- mammalian
................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations
... 870.5xxx Mutagenicity

—Other Genotoxic Effects
....................... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotox. (hen)
................................ ..... 870.6100b 90
- Day

Neurotoxicity (hen)
................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)
................. 870.6200b 90
- Day

Neurotoxicity Screening Battery (rat)
............... 870.6300 Developmental Neurotoxicity
................................ ........ no no yes yes no -

- no no

- 870.7485 General Metabolism
................................ ...................... 870.7600 Dermal Penetration
................................ ........................ 870.7800 Immunotoxicity
................................ ............................. yes yes yes yes

yes noBromox ynil Human Health Risk Assessment DP No. 374609

Page 50 of 72 A.2 Toxicity Profile s Table A.2.1. Acute Toxicity Profile Guideline Study Species Results Tox. Category MRID No. Brom oxynil Phenol Technical 870.1100 Ac ute oral toxicity Rat LD 50 = 81 mg/kg M LD 50 = 93 mg/kg F) II 00124758 870.1200 Ac ute dermal toxicity Rat LD 50 >= 2000 mg/kg (M, F) III 00124758 870.1300 Ac ute 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 Brom oxynil Octanoate Technical 870.1100 Ac ute oral toxicity Rat LD 50 = 400 mg/kg M LD 50 = 238 mg/kg F II 00124112 870.1100 Ac ute 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 Ac ute 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

mo dified Draize test. Positive 41879801Bromox ynil Human Health Risk Assessment DP No. 374609

Page 51 of 72 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.3100 90
- Day

oral toxicity (rat) MRID 41469101 (1985 )

0, 400, 755 or 1456 ppm 0, 28, 58 , 168 mg/kg/day M 0, 35, 76 , 250 mg/kg/day F Dietary Supplementary NOAEL : M = 28 mg/kg/day , F not established LOAEL M = 58 mg/kg/day), based on decreased body weight gain, increased ALT, increased AST and increased alkaline phosphates
. F = 35 mg/kg/day), based on decreased body weight gain. This study is of limited usefulness because a NO AEL 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 mo rtality
. Toxicities o bserved during the first day of the study (single dose effects) were elevated rectal tem peratures, 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 aboveBromox ynil Human Health Risk Assessment DP No. 374609

Page 52 of 72 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.3200 21
- Day

dermal toxicity (rabbit) MRID 42272301 (19 92 )

0, 30, 300 or 1000 mg/kg/day Minimum Dermal NOAEL = not established LOAEL = 1000 mg/kg/day Sy stemic 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
- im plantation 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 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
.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 53 of 72 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.3700a Prenatal

developmental in rats - dermal MRID 40881201 ,

40883601 (1988) 0, 5, 10, 50 or 100 mg/kg/day for 6 hours/day on gestation days 6
- 15
. Sprague
- Dawley Supplementary Maternal dermal NOAEL = 100 mg/kg/day Maternal dermal LOAEL not established Maternal systemic NOAEL = 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 . At 60 mg/kg/day, the followi ng additional effects were also observed: increased post
im plantation 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 verteb ral and thoracic bone abnormalities, including fused ribs, scoliosis, extra ribs, thoracic centrum misshapen and incomplete ossification of sternebrae, were observed.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 54 of 72 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.3700b Prenatal

developmental in nonrodents (rabbit) dermal MRID 40935101,

41307801 (1988) 0, 10, 50 or 150 mg/kg/day for 6 hours/day on gestation days 6
- 18
. New Zealand White Supplementary Maternal dermal NOAEL = 150 mg/kg/day Maternal dermal LOAEL not established Maternal systemic NOAEL = 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 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
- 4300Bromox ynil Human Health Risk Assessment DP No. 374609

Page 55 of 72 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.4100b Chronic toxicity

(dog) MRID 40780301,

41304701 (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), 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 (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

pf fer 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.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 56 of 72 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.4300 Com

bined 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 Com

bined 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, TA 1535, TA1537 and TA 1538 were exposed to technical grade bromoxynil phenol without metabolic activation at concentrations ranging from 3.33 to 1000 μ g/plate and with metabolic activation (rat S9 mixture) at concentrations rangi ng from 10.0 to 3330 μ g/plate. Acceptable Negative. Bromoxynil phenol, without and with metabolic activation, did not induce a genotoxic effect in this assay system.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 57 of 72 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.5375 In vitro

mammalian chromosome aberration test MRID 00115651 (1982)

C ultures of Chinese hamster ovary (CHO) cells were exposed to technical grade bromoxynil phenol without metabolic activation at concentrations ranging from 100 to 1500 μ g/ml (8 hour exposure) and from 50 to 500 μ g/ml (20 hour exposure). Acceptable Negati ve without activation Positive with activation at >= 1200 μ g/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 wa s considered to be a positive genotoxic response.

870.5395 In Vivo

mammalian (mouse) erythrocyte micronucleus test MRID 00124803 (1982)

B romoxynil 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 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.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 58 of 72 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.5550 Unscheduled

DNA synthesis in mammalian cells MRID 00115646 (1982)

C ultures of primary rat hepatocytes were exposed to technical grade bromoxynil phenol at concentrations 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 concentrations 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.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 59 of 72 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870
- 5xxx Forward mutation

Mouse lymphoma cells MRID 00115649 (1982)

C ultures of L5178Y TK+/
- cells were exposed to technical grade bromoxynil phenol without metabolic activation at concentrations 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 μ g/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 concentrations 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 concentrations ranging from 1.0 to 10000 μ g/plate. Acceptable Positive without activation at >= 1000 μ g/plate Positive with activation at >= 1000 μ g/plate Bromoxynil phenol induced a positive genotoxic response in both the non
- activated and activated portions of this assay.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 60 of 72 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Bromoxynil Phenol Technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.7485 Metabolism and

pharmacokinetics (species) Please see 870.7485 data

for bromoxynil octanoate. 870.7600 Dermal

penetration (species) MRID 40854602
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.

Table A.2.3 Toxicity Profile for Brom oxynil 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 weightsBromox ynil Human Health Risk Assessment DP No. 374609

Page 61 of 72 Table A.2.3 Toxicity Profile for Brom oxynil 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 c ounts, 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/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 Sy stemic 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.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 62 of 72 Table A.2.3 Toxicity Profile for Brom oxynil 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 Dev elopmental 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 (rabbi 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 availableBromox ynil Human Health Risk Assessment DP No. 374609

Page 63 of 72 Table A.2.3 Toxicity Profile for Brom oxynil 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 b r omoxynil phenol 870.4200 Carcinogenicity

rats No study data are

currently available. Please refer to 870.4200 for b r omoxynil phenol 870.4300 Carcinogenicity

mice No study data are

currently available. Please refer to 870.4300 for b r omoxynil phenol 870.5100 Bacterial reverse

mutation test Salmonella/mamm alian microsome MRID 43022701 (1993)

S trains TA98, TA100, TA 1535, TA1537 and TA 1538 were exposed to technical grade bromoxynil octanoate without and with metabolic activation (rat S9 mixture) at concentrations 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.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 64 of 72 Table A.2.3 Toxicity Profile for Brom oxynil 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 cy totoxic. 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.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 65 of 72 Table A.2.3 Toxicity Profile for Brom oxynil 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 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.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 66 of 72 A.3 HAZARD IDENTIFICATION AND ENDPOINT SELECTION A.3.1 Acute Reference Dose (aRfD)

– General Population (Including Infants and Children) Study Selected: Subchronic Study in Dogs MRID No.: 43166701 Executive Summary : In a 13
- week range
- finding study , technical grade bromoxy nil phenol was administered orall y i n gelatin capsules to groups of 2 male and 2 female beagle dogs at dose levels of 0 (control), 1, 5, 8, 12, 16, 20, 30, 40 or 50 mg/kg/day . Treatment
- related decreased body weight gain was observed in males at all dose levels tested. At 5 mg/kg/day , occa sional panting and liquid feces were also noted and at 8 and 12 mg/kg/day , frequent panting, occasional salivation, unsteady gait, decreased ery

throcyte count, decreased hemoglobin, decreased packed cell volume, and increased urea nitrogen were observed. Dose levels of 16 mg/kg/day and higher were clearl y excessive and caused mortality and/or signs of severe toxicity . Decreased body weight gain, occasional panting and liquid feces were observed in females at 5 mg/kg/day . At 8 mg/kg/day and higher, effect s in females were the same as in males. For males, no NO AEL was determined in this study (<1 mg/kg/day). The LO AEL is 1 mg/kg/day for males, based on decreased body weight gain. For females, the NO AEL is 1 mg/kg/day and the LO AEL is 5 mg/kg/day , based o n decreased body weight gain, panting and liquid feces. This study was a range - finding study . Onl y 2 dogs/sex/dose level were used and an insufficient number of tissues was microscopicall y examined in the control group and at dose levels of 12 mg/kg/day and lower. Dose and Endpoint for Establishing aRfD: The NOAEL of 8 mg/kg/day is based on an effect attributed to a single dose (panting) at the LOAEL of 12 mg/kg/day . The study NO A ELs and LO AEL S based on decreased body weight gain are not attributable to a single dose. In addition to panting, elevated rectal temperature occurred at 16 mg/kg/day and above, and death occurred at 30 mg/kg/day

and above after a single dose on day One. UF(s): A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies variation (10X). Comments on Study/Endpoint/UFs : This study provides the lowest NOAELin the database (most sensitive endpoint) and is expected to be protective for any potential single
- dose adverse effects in humans. In the dog, increased panting can be an adaptive, compensatory response to elevated body temperature, vs. an adverse effect. In this study , the cascade of events beginning with panting on day one, followe d by

a progression of elevated rectal temperature and eventually death, were considered adverse responses.

aRfD = 8 mg/kg/day

(NOAEL) = 0.0 8 mg/kg/day 100 (UF) A.3.1a Acute Reference Dose (aRfD)

– Females 13+ Study Selected: Developmental Toxicity in Rats (Oral) MRID No.: 40466802, 00116558 Executive Summary : In an oral developmental toxicity study (MRID 40466802), technical grade bromox yn il phenol was administered to groups of 22 pregnant Sprague Dawley rats by gavage at doses of 0 (control), 4, 12 .5 or 40 mg/kg/day on gestation day s 6
- 15, inclusive. The developmental toxicity NO AEL is 4 mg/kg/day. A dose - related increased incidence of supernumerary (14th) ribs was observed at the developmental toxicity LO AEL of 12.5 mg/kg/day. In creased post
implantation loss was also observed at 12.5 mg/kg/day . At 40 mg/kg/day , the following additional effects were observed in the offspring: reduced fetal weight, increased numbers of small fetuses,Bromox ynil Human Health Risk Assessment DP No. 374609

Page 67 of 72 and increased incidences of soft tissue an d skeletal abnormalities (including anophthalmia, microphthalmia, short renal papilla, and spinal and thoracic bone abnormalities). The maternal toxicity NO AEL is 12.5 mg/kg/day and the maternal toxicity LO AEL is 40 mg/kg/day, based on decreased body weig ht gain throughout most of the treatment and post - treatment period and decreased food consumption during the treatment period. In an oral developmental toxicity study (MRID 00116558), groups of 28 pregnant Sprague Dawley rats received 0 (control), 5, 15 or 35 mg/kg/day of technical grade bromox ynil phenol by gavage on gestation day s 5
- 17, inclusive . No developmental toxicity NO AEL was determined in this study (below 5 mg/kg/day). At the LO AEL of 5 mg/kg/day, a dose - related increased incidence of 14th ribs was observed. At the high dose of 35 mg/kg/day , additional effects included an increased incidence of late intrauterine deaths, decreased fetal body weights and an increase in the total incidence of minor anomalies. The maternal toxicity NO AEL is 5 mg/kg/day

and the maternal toxicity L O AEL is 15 mg/kg/day , based on decreased body weight gain. At 35 mg/kg/day , 6/28 dams died between day s 7 and 14 of gestation. Dose and Endpoint for Establishing aRfD: The NOAEL of 4 mg/kg/day (MRID 40466802) is ba sed on an increase of supernumerary ribs seen at the L OAEL of 5 mg/kg/day in a co
- critical study (MRID 00116558). UF(s): A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies variation (10X). Comments on Study/Endpoint/UFs : These studies provide the lowest NOAELin the database (most sensitive endpoint) and is expected to be protective for any potential single
- dose adverse effects in humans. The LOAEL derived from a co
- critical study is very close to the NOAEL and sug gests a steep dose
- response curve. While the BMD data (benchmark dose = 13.66 mg/kg/day) suggest that the dose
- response curve is not as steep as the observed effects would indicate, HED has taken the most protective approach and used the observed effects in the risk assessment.

aRfD = 4 mg/kg/day

(NOAEL) = 0.04 mg/kg/day 100 (UF) A.3.2 Chronic Reference Dose (cRfD)

– All Populations Study Selected: Chronic (1
- ye ar) Study in Dogs MRID No. : 40780301 and 41304701 Executive Summary : In a 12
- month chronic oral toxicity study , technical grade bromoxy nil phenol was administered in gelatin capsules to groups of 6 male and 6 female beagle dogs at dose levels of 0 (control), 0.1, 0.3, 1.5 or 7.5 mg/kg/day. At the highest dose level tested (7.5 mg/kg/day), the following treatment
- related effects were observed in both male and female dogs: increased incidences of salivation, panting, liquid feces and pale gums; statistically significant decreased body weight gain over entire duration of study , but particularl y during first 8 weeks of study; statistically significant decreased ery

throcy tes (RBC), hemoglobin (Hb) and packed cell volume (PCV); statistically

significant increased urea nitrogen; increased absolute liver weights and liver/body weight ratios. At 1.5 mg/kg/day , a statisticall y significant decreased body weight gain over the entire duration of study was observed in the male dogs. Other "effects" at this same dose level were marginal, inconsistent and of equivocal toxicological significance. Th ese effects included panting; decreased RBC, Hb and PCV; increased urea nitrogen; and increased absolute and relative liver weights in males and panting and increased absolute and relative liver weights in females. NoBromox ynil Human Health Risk Assessment DP No. 374609

Page 68 of 72 treatment - related gross or histo
- path ological changes were observed in any organs in this study . The dose level of 1.5 mg/kg/day is considered to be a threshold NO AEL/LO AEL for both male and female dogs in this study. Dose and Endpoint for Establishing cRfD : The NOAEL of 1.5 mg/kg/day is b ased on increased incidences of salivation, panting, liquid feces and pale gums; statistically significant decreased body weight gain over the entire duration of the study, but particularl y during the first 8 weeks of the study ; statistically

significant d ecreased ery throcy tes (RBC), hemoglobin (Hb) and packed cell volume (PCV); statistically significant increased urea nitrogen; increased absolute liver weights and liver/body

weight ratios seen at the LOAEL of 7.5 mg/kg/day in both sexes. UF(s): A UF of 10 0 was applied to account for interspecies extrapolation (10X) and intraspecies variation (10X). Comments about Study/Endpoint/UF: This study provides the lowest NOAEL in the database (most sensitive endpoint) that reflects chronic (long
- term) exposure whi ch is the duration relevant to human dietary

exposure. cRfD = 1.5 mg/kg/day

(NOAEL) = 0.015 mg/kg/day 100 (UF) A.3.3 Dermal Short - Term (1 - 30 days) and Intermediate - Term (1 - 6 Months) Study Selected: Rat Dermal Developmental Toxicity Study MRID No. : 40881201, 40883601 Executive Summary : In a dermal developmental toxicity study , bromox ynil phenol (solubilized in water containing 50 mg/ml sodium hydroxide and 20% triethylene gl ycol) was applied to groups of 23 pregnant Sprague Dawley rats at dose lev els of 0 (control), 5, 10, 50 or 100 mg/kg/day for 6 hours/day on gestation day s 6
- 15, inclusive. A dose
- related increased incidence of supernumerary (14th) ribs was observed in this study at 10, 50 and 100 mg/kg/day . At 10 mg/kg/day , however, the increa sed incidence was not statistically significant compared to the concurrent control group and was within the historical control range. The developmental toxicity NO AEL is 10 mg/kg/day and the developmental toxicity LO AEL is 50 mg/kg/day , based on increased 14th ribs. The maternal toxicity NO AEL is 50 mg/kg/day and the maternal toxicity L O AEL is 100 mg/kg/day , based on decreased body weight gain and decreased food consumption during the treatment period. No deaths or clinical signs, including skin irritati on, were attributed to treatment with the test material in this study
. Dose and Endpoint for Risk Assessment : The developmental NOAEL of 10 mg/kg/day is based on increased incidence of supernumerary (14 th ) ribs seen at the LOAEL of 50 mg/kg/day
. Comm ents about Study/Endpoint/Margins of Exposure: This study provides the lowest NOAEL in the database (most sensitive endpoint) that reflects the route and duration of exposure relevant to occupational and/or residential scenarios. The reference value for t his risk assessment scenario is a margin of exposure (MOE) of 100 based on 10X interspecies and 10X intraspecies uncertainty factors. The lowest NOAEL from an oral study appropriate for use for this endpoint is 4 mg/kg/day from the developmental toxicity

s tudy (see Acute Reference Dose, Females 13+). If this study were used along with the dermal absorption factor of 17% for extrapolation between the dermal and oral routes, the extrapolated NOAEL 4.0 / 0.17) would be 23.5 mg/kg/day , which is higher and less protectiveBromox ynil Human Health Risk Assessment DP No. 374609

Page 69 of 72 than the NOAEL from the route
- specific study used. Thus, using the route
- specific study would be protective of the developmental effects noted after oral exposure A.3.3 Inhalation Short - Term (1 - 30 days) and Intermediate - Term (1 - 6 Months) Study Selected: Rat Oral Developmental Toxicity Study MRID No. : 00116558 and 40466802 Executive Summary : See above: Acute Reference Dose Females 13+ Dose and Endpoint for Risk Assessment : The NOAEL of 4 mg/kg/day (MRID 40466802) is based on an increase of supernumerary ribs seen at the L OAEL of 5 mg/kg/day in a co
- critical study (MRID 00116558). Comments about Study/Endpoint/Margins of Exposure: This study provides the lowest NOAEL in the database (most sensitive endpoint) and reflects the duration of exposure relevant to occupational and/or residential exposure scenarios. Although there are uncertainties associated with the use of an oral study

for the inhalation route of exposure, the assumption is made in this risk assessment that oral and inhalation absorption rates are equivalent (100%) (The actual absorption by the oral route is 76

– 89%). The reference value for this risk assessment scenario is a margin of exposure (MOE) of 100 based on 10X interspecies and 10X intraspecies uncertainty factors.Bromox ynil Human Health Risk Assessment

Appendix B. Chemical Names and Structures of Common name Chemical name bromoxynil 3,5
- dibromo

bromoxynil octanoate 2.6
- dibromo octanoate

bromoxynil heptanoate 2.6
- dibromo heptanoate

DBHA 3,5
- dibromo Bromox ynil Human Health Risk Assessment DP No. 374609

Page 70 of 72 Chemical Names and Structures of Bromoxynil , its Esters and Metabolite.

Chemical name Chemical structure dibromo
- 4
- hydroxybenzonitrile

dibromo
- 4
- cyanophenyl octanoate

dibromo
- 4
- cyanophenyl heptanoate

dibromo
- 4
- hydroxybenzoic acid OH Br

HO DP No. 374609 , its Esters and Metabolite.

Br

OBromox ynil Human Health Risk Assessment DP No. 374609

Page 71 of 72 Appendix C. Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED and the Outdoor Residential Exposure Task Force (ORETF). EPA has reviewed all the studies supporting these multi
- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentall y unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory bar rier to continued reliance on these studies.Bromox ynil Human Health Risk Assessment DP No. 374609

Page 72 of 72 Appendix D. International Residue Limit Status Sheet Bromox ynil (035301; 09/15/2010) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3 40 CFR 180.324: Plant: bromoxynil ( 3,5
- dibromo
- 4
- hydroxybenzonitrile ) Livestock: bromoxynil (3,5
- dibromo
- 4
- hydroxybenzonitrile) and its metabolite 3,5
- dibromo
- 4
- hydroxybenzoic acid (DBHA) 3,5
- dibromo
- 4
- hydroxybenzonitrile, including the metabolite 3,5
- dibromo
- 4
- hydroxybenzoic acid None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex Grain, aspirated grain fractions 1.2 Grass, forage 18 Grass, hay 5.0 Milk 0.4 0.1 Sorghum, grain, forage 0.8 Sorghum, grain , grain 0.2 0.1 Com pleted: M. Negussie;09/16/2010
1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.
2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated store d wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.