                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                         WASHINGTON, D.C. 20460      

                                                    	OFFICE OF CHEMICAL SAFETY 
                                                                                                        AND POLLUTION PREVENTION
                                                                              	



MEMORANDUM

Date:  4/20/11

SUBJECT:	Bromoxynil: Human Health Risk Assessment for Amended Uses on Grass Grown for Seed, Conservation Reserve Program Areas, and Grain Sorghum.
 
PC Code:  035301, 035302
DP Barcode:   D374609
Decision No.: 425581
Registration No.: 264-1023
Petition No.: 9F7678
Regulatory Action: Section 3 Registration
Risk Assessment Type: Single Chemical/Aggregate
Case No.: 2070
TXR No.:  NA
CAS No.: 1689-84-5, 1689-99-2
MRID No.: NA
40 CFR: 180.324


FROM:	Cassi L.Walls, Ph.D., Risk Assessor 
		Myron S. Ottley, Ph.D., Toxicologist
		Nancy Dodd, Chemist
		Kristin Rury, Biologist
		Risk Assessment Branch III (RAB3)
		Health Effects Division (HED) (7509P)

THROUGH:	Paula Deschamp, Branch Chief 
		RAB3/HED (7509P)

TO:		Bethany Benbow, RM#23
		Registration Division (7505P)





1.0	Executive Summary	4
2.0	Regulatory Conclusions and Recommendations	8
2.1	Data Deficiencies/Conditions of Registration	9
2.2	Tolerance Considerations	9
2.2.1	Enforcement Analytical Method	9
2.2.2	International Harmonization	10
2.2.3	Recommended Tolerances	10
2.2.4	Revisions to Petitioned-For Tolerances	11
2.3	Label Recommendations	12
2.3.1	Recommendations from Residue Reviews	12
2.3.2	Recommendations for Worker Safety	12
2.3.3	Recommendations for Residential Safety	12
3.0	Ingredient Profile	12
3.1	Structure and Nomenclature	13
3.2	Physical/Chemical Characteristics	14
3.3	Summary of Existing/Amended Uses	14
4.0	Hazard Characterization and Dose-Response Assessment	17
4.1	Toxicology Studies Available for Analysis	17
4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)	18
4.2.1	Dermal Absorption	18
4.3	Toxicological Effects	19
4.4	Safety factor for Infants and Children (FQPA Safety Factor)	20
4.4.1	Completeness of the Toxicology Database	20
4.4.2	Evidence of Neurotoxicity	21
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	21
4.4.4	Residual Uncertainty in the Exposure Database	21
4.5	Toxicity Endpoint and Point of Departure Selections	22
4.5.1	Dose-Response Assessment	22
4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment	22
4.5.3	Cancer Classification and Risk Assessment Recommendation	22
4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	22
4.6	Endocrine Disruption	24
5.0	Dietary Exposure and Risk Assessment	25
5.1	Metabolite/Degradate Residue Profile	25
5.1.1	Summary of Plant and Animal Metabolism Studies	25
5.1.2	Summary of Environmental Degradation	26
5.1.3	Comparison of Metabolic Pathways	27
5.1.4	Residues of Concern Summary and Rationale	27
5.2	Food Residue Profile	28
5.3	Water Residue Profile	30
5.4	Dietary Risk Assessment	31
5.4.1	Description of Residue Data Used in Dietary Assessment	31
5.4.2	Percent Crop Treated Used in Dietary Assessment	32
5.4.3	Acute Dietary Risk Assessment	33
5.4.4	Chronic Dietary Risk Assessment	33
5.4.5	Cancer Dietary Risk Assessment	34
5.4.6	Summary Table	34
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	34
6.1	Spray Drift	34
7.0	Aggregate Exposure/Risk Characterization	35
7.1	Acute Aggregate Risk	35
7.2	Short- and Intermediate- Term Aggregate Risk	35
7.3	Chronic Aggregate Risk	35
7.4	Cancer Aggregate Risk	35
8.0	Cumulative Exposure/Risk Characterization	35
9.0	Occupational Exposure/Risk Characterization	35
9.1	Short-/Intermediate Term Non-Cancer & Cancer Risk For Pesticide Handlers	36
9.2	Short-/Intermediate-Term Post-Application Risks	43
10.0	Environmental Justice Considerations	47
11.0	References	48
Appendix A.  Toxicology Profile and Executive Summaries	49
A.1	Toxicology Data Requirements	49
A.2	Toxicity Profiles	50
A.3	HAZARD IDENTIFICATION AND ENDPOINT SELECTION	66
A.3.2	Chronic Reference Dose (cRfD)  -  All Populations	67
A.3.3	Dermal Short-Term (1-30 days) and Intermediate-Term (1-6 Months)	68
A.3.3	Inhalation Short-Term (1-30 days) and Intermediate-Term (1-6 Months)	69
Appendix B.  Chemical Names and Structures of Bromoxynil, its Esters and Metabolite.	70
Appendix C.  Review of Human Research	71
Appendix D.  International Residue Limit Status Sheet	72

1.0	Executive Summary

Use Profile:  Bayer CropScience (BCS) has proposed a new product, HUSKIE(TM) Herbicide (EPA Registration No. 264-1023), that contains bromoxynil octanoate, bromoxynil heptanoate, and pyrasulfotole as the active ingredients.  The adequacy of the proposed uses of pyrasulfotole will be addressed in a separate document.  The bromoxynil octanoic and heptanoic esters are rapidly converted to the bromoxynil phenol (3,5-dibromo-4-hydroxybenzonitrile).  Therefore, the exposure and tolerances are based on bromoxynil phenol (from here on out will be referred to as bromoxynil).  

BCS has proposed amended uses for bromoxynil formulated in the HUSKIE(TM) Herbicide product.  Bromoxynil is currently registered for use on grass and grain sorghum; however, BSC is proposing to amend the use pattern by shortening the preharvest interval (PHI) which subsequently will result in an increase in the tolerance.  Bromoxynil is a contact herbicide which is registered for application as the octanoic and/or heptanoic acid esters for control of broadleaf weeds in various crops.  Bromoxynil inhibits photosynthetic electron transport and oxidative phosphorylation in mitochondria.  The previous bromoxynil risk assessment was conducted to support the Reregistration Eligibility Decision (RED) in December 1998.  

HUSKIE(TM) Herbicide is an emulsifiable concentrate which contains 13.4% bromoxynil octanoate, 12.9% bromoxynil heptanoate, 3.3% pyrasulfotole, and 70.4% inerts.  The formulation contains 1.75 lbs bromoxynil active ingredient per gallon.  HUSKIE(TM) Herbicide foliar spray may be applied to conservation reserve program acres (CRP) and grasses grown for seed from preemergence to established grasses.  A maximum of two applications with a retreatment interval (RTI) of 30 days can be made with a maximum rate of 0.41 lb ai/A/year for CRP and grasses grown for seed.  The preharvest intervals (PHI) are 7 days for forage and 30 days for hay; the restricted entry interval (REI) is 12 hours.  

HUSKIE(TM) Herbicide is applied as a postemergence foliar spray to grain sorghum using ground application equipment.  Application through any type of irrigation system is prohibited. A maximum of two applications with an RTI of 11 days can be made for a maximum rate of 0.44 lb ai/A/year for grain sorghum.  The preharvest intervals (PHI) are 7 days for forage and 60 days for grain or stover; the restricted entry interval (REI) is 12 hours.  

Human Health Risk Assessment:

Bromoxynil phenol has moderate acute toxicity via the oral and inhalation routes and low acute toxicity via the dermal route.  Bromoxynil octanoate has moderate acute toxicity via the oral and dermal routes and low acute toxicity via the inhalation route.  Due to rapid conversion of the ester forms of the chemical (heptanoate and octanoate) to the phenol, toxicity testing was conducted with both phenol and octanoate material, and the risk assessment is based on exposure to the phenol.  

In the repeated dose studies of the mammalian toxicology database, the liver was the primary target organ of bromoxynil toxicity.  Across species, duration and gender, changes in weight, clinical chemistry and pathology indicated treatment-related perturbations in and adverse effects on liver function.  Treatment-related effects were also observed on body weight and body weight gain changes (rats, mice, dogs, rabbits).  Subchronic and chronic studies in dogs showed that bromoxynil elevated body temperature, manifested by increased panting at lower dose levels, and hyperthermia and death as dose levels increased.

Bromoxynil produced developmental toxicity across all tested species.  The consistent effect seen at the LOAEL, was supernumerary ribs in rats, mice and rabbits. In addition, supernumerary ribs occurred in rats exposed by both the oral and dermal routes.

Bromoxynil is classified as "possible human carcinogen."  This was based on the presence of hepatocellular tumors in male and female mice.  There is no concern for mutagenicity.  The unit risk, Q1[*], of bromoxynil based upon male mouse hepatocellular tumors rates is 0.103 (mg/kg/day)[-1] in human equivalents. 

	Dietary Exposure (Food/Water):

The residue chemistry data and environmental fate data are adequate to assess human exposure.  Although somewhat refined, the acute, chronic and cancer dietary food exposure assessments are based on reliable data and will not underestimate exposure/risk.

Acute:  A refined acute dietary assessment was conducted.  The assumptions of this dietary assessment included average field trial residues for all grains; tolerance level residues for cotton, garlic, onion, peppermint and spearmint; anticipated residues in livestock; and maximum crop treated (CT) estimates for all crops.  Empirical or DEEM(TM) default processing factors were used.  Potential residues in drinking water were included in the analyses based on surface water results from the Tier I FIRST model. 

The acute dietary (food and drinking water) exposure to bromoxynil is below HED's level of concern [i.e., <100% of the acute Population Adjusted Dose (aPAD)] for the general U.S. population and all population subgroups.  At the 99.9[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 estimates for all crops.  Empirical or DEEM(TM) default processing factors were used.  Potential residues in drinking water were included in the analyses based on surface water results from the Tier I FIRST model. 

The non-cancer chronic dietary (food and drinking water) exposure to bromoxynil is below HED's level of concern [i.e., <100% of the chronic Population Adjusted Dose (cPAD)] for the general U.S. population and all population subgroups.  The chronic dietary exposure estimates are <1% of the cPAD for the general U.S. population as well as for Children 1-2 years old, the most highly exposed population subgroup. 

Cancer:  The cancer dietary (food and drinking water) risk estimate for the general U.S. population is 1.5 x 10[-][6], which is below HED's level of concern (generally in the range of 10[-6]).

	Residential Exposure:

There are no residential uses of bromoxynil; therefore, a residential exposure assessment was not necessary to conduct.

	Aggregate Risk:

Acute:  Aggregate acute risk is equivalent to acute dietary risk.  There is potential acute exposure (7.4% of the aPAD) via the diet (food and drinking water) as determined in Section 5.3.  

Chronic:  Aggregate chronic risk is equivalent to chronic dietary risk.  There is potential chronic exposure (<=1% of the cPAD) via the diet (food and drinking water) as determined in Section 5.4.  

Short- and Intermediate Term:  Since there are no residential uses for bromoxynil, short- and intermediate-term aggregate assessments were not conducted.

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

	Occupational Exposure/Risk:

This risk assessment evaluated the occupational handler and post-application scenarios for both the amended uses and existing uses of bromoxynil.  Bromoxynil is currently registered for use on grass and grain sorghum; however, BCS is proposing to shorten the PHI which subsequently will result in an increase in the tolerance.  The existing uses assessed in 1998 were reassessed because a higher dermal absorption factor was identified for route-to-route extrapolation and an inhalation endpoint was selected for inhalation exposure risk assessment.

Agricultural Handlers:  Occupational short-term (1 - 30 days) and intermediate-term (1 - 6 months) dermal and inhalation exposures are expected from bromoxynil handler activities associated with both the proposed and existing agricultural uses.  HED used data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in the PHED Surrogate Exposure Guide (8/98) to assess handler exposures (HED Science Advisory Council for Exposure (ExpoSAC) Standard Operating Procedure (SOP) No. 7, dated 01/28/1999).  A Margin of Exposure (MOE) greater than 100 for the inhalation, dermal, and combined routes is deemed adequate to protect occupational bromoxynil handlers.

Amended uses
The results indicate that the MOEs for the amended uses for occupational handler scenarios were not of concern (i.e., an MOE > 100) at some level of personal protection (gloves).  The dermal MOE was 12 with baseline attire for mixer/loaders, and the dermal MOEs ranged from 2,400 to 2,600 for applicators.  The dermal MOEs with baseline attire plus gloves (PPE-G) ranged from 1,500 to 1,600 for mixer/loaders and from 2,400 to 2,600 for applicators.  Inhalation MOEs ranged from 11,000 to 12,000 for mixer/loaders and from 18,000 to 19,000 for applicators.  The combined (dermal + inhalation) MOE with baseline attire was 12 for mixer/loaders and the MOEs ranged from 2,200 to 2300 for applicators.  Combined (dermal + inhalation) MOEs with baseline attire plus gloves (PPE-G) ranged from 1,300 to 1,400 for mixer/loaders and from 2,200 to 2,300 for applicators.  
	
The results indicate that estimated cancer risks were not of concern (i.e., in the 10[-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 bromoxynil 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 bromoxynil is in the 10[-5] range for mixer/loaders and in the 10-7 range for applicators; at baseline plus gloves (PPE-G) estimated risk is in the 10-6 range for mixer/loaders and 10[-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 system.  The results indicate that MOEs for application of bromoxynil to all existing use sites were not of concern at some level of personal protection (gloves).  Flagging for bromoxynil application was not of concern at baseline attire.  

The dermal MOEs at baseline attire range from 0.34 (risks of concern) to 160 for mixing/loading for application to corn and wheat, from 1.2 (risks of concern) to 1,400 for mixing/loading for application to all other crops, from 200 to 6,000 for applicators, and from 310 to 620 for flaggers.  Inhalation MOEs at baseline attire were >330 for mixer/loaders, applicators and flaggers and are not of concern. Combined (dermal + inhalation) MOEs at baseline plus gloves ranged from 38 to 2,900 for mixer/loaders, 380 to 4,900 for applicators, and from 270 to 530 for flaggers.  Mixing and loading scenarios for bromoxynil application to corn and wheat were below HED's LOC=100 at baseline and PPE-G.  With coveralls, mixing/loading for application to corn and wheat, the dermal MOE was 57 and the combined dermal and inhalation MOEs  ranged from 55 (risk of concern) to 190. In a closed system, the dermal MOE for mixing/loading for application to corn & wheat was 120 and was 4,800 for inhalation exposure; the combined dermal + inhalation MOE was 110, and therefore not of concern.  

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

At baseline attire, estimated risks for commercial users of bromoxynil 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 10[-]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 10[-][5] and 10[-][7] range for applicators, and in the 10[-][5] or 10[-]6 range for flaggers. With a closed system, estimated risk is in the 10-5 or 10[-7] range (depending on the use site).  

Agricultural Post-application:  Occupational short-term (1 - 30 days) and intermediate-term (1 - 6 months) dermal exposures are expected for worker re-entering bromoxynil treated fields and performing post-application activities such as scouting and harvesting.  All post-application dermal exposures were evaluated using surrogate data and default assumptions

Amended uses 
The dermal non-cancer short- and intermediate-term post-application MOEs ranged from 150 to 1,500 on the day of application.  The estimated cancer risks for agricultural workers on the day of application ranged from 1.4x10[-6] to 1.1x10[-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 days after application, risk from sod harvesting is not of concern 5 days after application, and risk from occupational contact with full foliage corn, sorghum and cotton is not of concern 4 days after application.  The estimated cancer risks on the day of application ranged from 2.3x10[-6] to 1.4x10[-4].  

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for bromoxynil at this time.    

Environmental Justice Considerations:  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment.  Dietary and 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 by the Human Studies Review Board.  All of the listed studies have received the appropriate review.

2.0	Regulatory Conclusions and Recommendations

Provided revised Sections B (OPPTS 860.1200) and F (OPPTS 860.1550) are submitted, HED can recommend permanent tolerances for the uses of bromoxynil on grass and grain sorghum commodities and conditional registration for the requested uses on annual and perennial grasses grown for seed, conservation reserve program acres, and grain sorghum.
Additional data are needed as conditions of registration as outlined in Section 2.1 below.  The specific tolerance recommendations are discussed in Section 2.2, and label modifications are discussed in Section 2.3.




2.1	Data Deficiencies/Conditions of Registration

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

      860.1200 Directions for Use
      A revised Section B is requested to include an "APPLICATION METHODS" section for grass specifying type of application, method of application, and minimum gallons sprayed per acre for each method; clarify method of application for sorghum; and include rotational crop plantback intervals for all crops which are not primary (treated) crops on the label or are not already listed in the Crop Rotation Guidelines section of the label.

      860.1550 Proposed Tolerances
      A revised Section F must be submitted to reflect the tolerances and correct commodity definitions as listed in Table 2.2.4.

The following data are required as a condition of registration:

TOXICOLOGY

      870.6200 Neurotoxicity Battery (Acute and Subchronic Studies) 
      The acute and subchronic neurotoxicity screening battery is required to fulfill current 40 CFR Part 158 data requirements. 

      870.7800 Immunotoxicity 
      The immunotoxicity study is required to fulfill current 40 CFR Part 158 data requirements. 
      
      In a letter dated June 23, 2010, BCS acknowledged the data deficiency for immunotoxicity testing on bromoxynil and notified EPA that the conduct of this study is in the process of being scheduled for 2011.

OCCUPATIONAL EXPOSURE

      875.2100   Dislodgeable Foliar Residue Study
      To characterize post-application exposure and reduce uncertainty for late applications of bromoxynil, HED is requesting the registrant submit a dislodgeable foliar residue (DFR) study on a representative row crop (e.g. corn). 

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

Multiresidue methods data for bromoxynil butyr - ate and bromoxynil octanoate have been submitted.  Recovery of bromoxynil octanoate and bromoxynil butyrate using FDA Multiresidue Method 303: Method II for Nonfatty Foods (Mills, Onley, Gaither Method) is variable.  Bromoxynil was not detected through Florisil elution.  The data have been forwarded to FDA and included in the PESTDATA database.  

Adequate residue analytical methodology is available for tolerance enforcement for bromoxynil per se in grass and grain sorghum commodities.  Method I in PAM, Vol. II, is a gas liquid chromatography/microcoulometric detection (GLC/MCD) method that has undergone a successful EPA method validation on wheat grain.  Method Ia is the same method except that it uses gas chromatography/electron capture detection (GC/ECD) for determination of methylated bromoxynil.

Adequate residue analytical methodology is available for tolerance enforcement for bromoxynil per se in livestock commodities.  Method A is a GC/MCD or GC/ECD method for the analysis of bromoxynil per se residues in livestock tissues and is essentially the same as Method I.  Method B is a GC/ECD method that is also similar to Method I, with modifications to the cleanup procedures.

Adequate residue analytical methodology is available for tolerance enforcement for parent and 3,5-dibromo-4-hydroxybenzoic acid (DBHA) in cottonseed and gin trash samples.  The method is a gas chromatography/mass spectrometric detection (GC/MSD) method ,  "Bromoxynil: Method of Analysis for Bromoxynil and its Metabolite, 3,5-Dibromo-4-hydroxybenzoic Acid in Cottonseed, Gin Trash, and Seed Processed Fractions using GC/MSD."  The method (Method RES9603) has been the subject of an independent laboratory validation (ILV) and an Agency petition method validation (PMV).

2.2.2	International Harmonization

There are currently no maximum residue limits (MRLs) established by Codex, Canada, or Mexico for bromoxynil.  Tolerances have been established by Canada for grain of sorghum grain at 0.1 ppm and for milk at 0.1 ppm.  The Canadian tolerance expression is "3,5-dibromo-4-hydroxybenzonitrile, including the metabolite 3,5-dibromo-4-hydroxybenzoic acid"; however, compliance with the tolerance levels in the U.S. will be determined by measuring only bromoxynil (3,5-dibromo-4-hydroxybenzonitrile).  An International Residue Limit Status sheet is attached (Appendix D).

2.2.3	Recommended Tolerances

HED recommends for the following tolerances and residue definitions:

  40 CFR §180.324(a)(1):
  Tolerances are established for residues of bromoxynil, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only bromoxynil (3,5-dibromo-4-hydroxybenzonitrile) resulting from application of its octanoic and/or heptanoic acid ester.
  
      Grass, forage	18 ppm
      Grass, hay	 5.0 ppm
      Grain, aspirated grain fractions	1.2 ppm
      Milk	 0.4 ppm
      Sorghum, grain, grain	0.2 ppm
      Sorghum, grain, forage	0.8 ppm
      
      Note:  The established tolerance of 0.2 ppm on sorghum, grain, stover is to remain unchanged.
                                                                                                                                                                                                                                                                                                                                                                                                                             
  40 CFR §180.324(a)(2):
  Tolerances are established for residues of bromoxynil, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only bromoxynil (3,5-dibromo-4-hydroxybenzonitrile) and its metabolite 3,5-dibromo-4-hydroxybenzoic acid (DBHA) resulting from application of its octanoic and/or heptanoic acid ester.

All livestock commodities should be moved from 40 CFR §180.324(a)(2) to 40 CFR §180.324(a)(1), leaving only cotton, gin byproducts; cotton, hulls; and cotton, undelinted seed in 40 CFR §180.324(a)(2).  

2.2.4	Revisions to Petitioned-For Tolerances

Table 2.2.4 compares proposed and recommended tolerance levels.  The recommended tolerance levels, including an increase for sorghum, grain, forage, are based on the submitted magnitude of the residue data and the Agency's tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP.  Because the tolerance on the grain of grain sorghum is being increased from 0.05 ppm to 0.2 ppm, higher residues may occur in aspirated grain fractions.  HED has determined that a higher tolerance of 1.2 ppm is needed for grain, aspirated grain fractions.  Based on calculated residues in dairy cattle for the tolerance assessment, the established tolerance on milk must be increased from 0.1 ppm to 0.4 ppm.  Other livestock tolerances remain unchanged.

Table 2.2.4.   Tolerance Summary for Bromoxynil
                                   Commodity
                                Tolerance (ppm)
                                   Comments
                         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
                                      --
                                     0.2 





2.3	Label Recommendations

2.3.1	Recommendations from Residue Reviews

A revised Section B/label must be submitted with the following revisions:
  
  a)  The grass section of the HUSKIE TM Herbicide label should have an "APPLICATION METHODS" section which states the type(s) of application (e.g., foliar spray, broadcast spray, etc.), the method(s) of application (i.e., ground, air, or both), and the minimum gallons spray per acre for each method.
  
  b)  The sorghum section should state that aerial applications are not to be made.
  
  c)  The label contains rotational crop plantback intervals for some crops but not all crops.  A 30-day rotational crop restriction is adequate for bromoxynil.  The petitioner must consider rotational crop plantback requirements for all active ingredients on the label and then indicate a plantback interval for all crops which are not primary (treated) crops on the label or are not already listed in the Crop Rotation Guidelines section of the label.

2.3.2	Recommendations for Worker Safety

Based on email correspondence with the registrant (dated 11/01/2010), Huskie(TM) Herbicide (EPA Reg. No. 264-1023) is not intended for application with chemigation or aerially to grain sorghum, grass grown for seed and CRP areas.  The label should restrict aerial and chemigation explicitly from these use sites.  

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

Although, a 12-hr REI was proposed, under the WPS for Agricultural Pesticides, a 24-hr REI is required for chemicals classified under Toxicity Category II.  Therefore, a REI of 24 hours is required on the Huskie(TM) Herbicide label.  Other bromoxynil product labels should also require a 24-hr REI, except for specific the use sites wheat, small grains and mint which require an REI of 8 days, sod harvesting which require an REI of 5 days, and corn, sorghum and cotton which require an REI of 4 days.
 
2.3.3	Recommendations for Residential Safety

There are currently no registered or proposed residential uses of bromoxynil.  However, existing labels should clarify that products containing bromoxynil are restricted from use on golf course turf.  

3.0	Ingredient Profile

Bromoxynil is registered for the application as the octanoic and/or heptanoic esters which rapidly convert to the phenol (bromoxynil).  The bromoxynil esters and phenol are chemically and physically similar which allows the risk assessment to be based on bromoxynil.  Bromoxynil is a selective contact foliage applied herbicide used to control a variety of broadleaf weeds.  Bromoxynil inhibits photosynthetic electron transport and also uncouples oxidative phosphorylation in mitochondria, thereby stopping energy production and negatively affecting plant respiration.

Bayer CropScience has proposed uses for HUSKIE(TM) Herbicide (EPA Registration No. 264-1023) containing bromoxynil as one of the active ingredients on annual and perennial grasses grown for seed, conservation reserve program acres (CRP), and grain sorghum.  HUSKIE(TM) Herbicide is an emulsifiable concentrate which contains 13.4% bromoxynil octanoate, 12.9% bromoxynil heptanoate, 3.3% pyrasulfotole, and 70.4% inerts.  The formulation contains 1.75 lbs bromoxynil active ingredient per gallon.  HUSKIE(TM) Herbicide foliar spray may be applied to CRP and grasses grown for seed from preemergence to established grasses.  A maximum of two applications with a retreatment interval (RTI) of 30 days can be made for in a maximum rate of 0.41 lb ai/A/year for CRP and grasses grown for seed.  The preharvest intervals (PHI) are 7 days for forage and 30 days for hay; the restricted entry interval (REI) is 12 hours.  The adequacy of the proposed uses of pyrasulfotole will be addressed in a separate document. 

HUSKIE(TM) Herbicide is applied as a postemergence foliar spray to grain sorghum using ground application equipment.  Application through any type of irrigation system is prohibited. A maximum of two applications with an RTI of 11 days can be made for a maximum rate of 0.44 lb ai/A/year for grain sorghum.  The preharvest intervals (PHI) are 7 days for forage and 60 days for grain or stover; the restricted entry interval (REI) is 12 hours.  

3.1	Structure and Nomenclature

Appendix B provides structures and nomenclature for the bromoxynil esters.

Table 3.1	  Bromoxynil Nomenclature.
Chemical Structure
                                       
Empirical Formula
C7H3Br2NO
Common Name
bromoxynil or bromoxynil phenol
Company Experimental Name
AE F025943 
IUPAC Name
3,5-dibromo-4-hydroxybenzonitrile
CAS Name
3,5-dibromo-4-hydroxybenzonitrile
CAS Registry Number
1689-84-5 (phenol)
1689-99-2 (octanoate)
56634-95-8 (heptanoate)
End-use Product/EP
Huskie(TM) Herbicide
Chemical Class 
Benzonitrile Herbicide
Known impurities of concern
None


3.2	Physical/Chemical Characteristics

Table 3.2  Physicochemical Properties of Bromoxynil (Bromoxynil Phenol)
Parameter
Value
Reference (MRID)
Molecular Weight
276.9
47815001
Melting point/range
190.5°C
47815001
pH @ ambient 
3.68 
47815001
Density
2.31 g/cm[3] 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 20C
47815001
Dissociation constant, pKa
3.86
47815001
Octanol/water partition coefficient, Log(KOW)
2.90 (Kow = 794)
47815001
UV/visible absorption spectrum
Primary λmax = 221.2
Primary λmax = 286.8
47815001

3.3	Summary of Existing/Amended Uses

Currently bromoxynil is used on agricultural food crops including garlic and onions; food and feed crops including mint, flax, spearmint, peppermint, barley, oats, rye, triticale, wheat, sorghum, cotton, and field and pop corn; and feed crops including alfalfa, forage/hay, and grass.  Current, non-food uses include outdoor industrial areas, nonagricultural uncultivated areas/soil, non-residential commercial/industrial lawns, and sod farms.

Bayer CropScience has proposed amendments to the existing use patterns of annual and perennial grasses grown for seed, conservation reserve program acres (CRP), and grain sorghum on the HUSKIE(TM) Herbicide label.  HUSKIE(TM) Herbicide (EPA Registration No. 264-1023) controls broadleaf weeds and mannagrass in grasses and broadleaf weeds in grain sorghum.  HUSKIE(TM) Herbicide is an emulsifiable concentrate which contains 13.4% bromoxynil octanoate, 12.9% bromoxynil heptanoate, 3.3% pyrasulfotole, and 70.4% inerts.  The formulation contains 1.75 lbs bromoxynil per gallon.

The submitted label for HUSKIE(TM) 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. 

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
HUSKIE(TM) 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.

HUSKIE(TM) Herbicide may be tank mixed with herbicides, insecticides, fungicides, and spray additives.*

THE RESTRICTED ENTRY INTERVAL IS 12 HOURS.
                                SORGHUM, GRAIN
Postemergence,
Foliar spray, Ground equipment
HUSKIE(TM) 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.
 
HUSKIE(TM) Herbicide may be tank mixed with herbicides and insecticides.**  

Do not apply HUSKIE(TM) Herbicide in a tank mix with Lorsban as an unacceptable crop response may occur.

One pound of ammonium sulfate per acre may be added to optimize herbicidal activity.

THE RESTRICTED ENTRY INTERVAL IS 12 HOURS.
1 Crop Rotation Plantback Intervals: 
	1 month:  wheat, barley, oats, rye, and triticale
	4 months: alfalfa, millet, grain sorghum, and soybeans
	9 months: canola, canaryseed, chickpeas, corn, dry beans, flax, field peas, green beans, green peas, lentils (except in MN, MT, ND, and SD), mustards, potatoes, safflower, sunflowers, and sugarbeets
	18 months: lentils in MN, MT, ND and SD
[2] Grass:	
	For weed control, HUSKIE(TM) Herbicide may be tank mixed with Puma(R), Nortron, Rely, 2.4-D ester/amine, Aim(TM), Bronate Advanced(TM), Buctril(R), Curtail M/Curtail(R), Dicamba, Goal, Glean, MCPA ester/MCPA amine, Sencor(R), Starane(R)/Starane NXT/Starane Ultra, or WideMatch(TM).

      For insect control, HUSKIE(TM) Herbicide may be tank mixed with Baythroid(R)XL, Capture, Lorsban(R), Mustang Max(TM), or Warrior(R) Insecticides.
      
      For disease control, HUSKIE(TM) Herbicide may be tank mixed with fungicides such as Absolute, Tilt(R), Quadris(R), Quilt(TM), 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.

 [3] Grain Sorghum:	
	For grass control, HUSKIE(TM) Herbicide may be tank mixed with 0.25-1.0 lb atrazine per acre.  For weed control, HUSKIE(TM) Herbicide plus atrazine may be tank mixed with phenoxy broadleaf herbicides such as 2,4-D or dicamba.

	For insect control, HUSKIE(TM) Herbicide may be tank mixed with Baythroid(R)XL

	An unacceptable crop response may occur if Huskie(TM) 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 HUSKIE(TM) Herbicide is not known and the use of HUSKIE(TM) Herbicide on these sorghum types is not recommended.

4.0	Hazard Characterization and Dose-Response Assessment

Bromoxynil is a selective contact foliage applied herbicide used to control broadleaf weeds.  Bromoxynil inhibits photosynthetic electron transport and also uncouples oxidative phosphorylation in mitochondria, thereby stopping energy production and negatively affecting plant respiration.  A correlation between this mode of action in plants and observed toxicity in the available toxicity studies in mammals was not identified. 

4.1	Toxicology Studies Available for Analysis

The existing database includes acceptable toxicity studies on both bromoxynil phenol and bromoxynil ocatanoate and it has been established that these two compounds are toxicologically equivalent on a molar basis (G. Ghali, 4/12/1996, TXR 011886).  The existing database is deemed sufficient for characterizing the hazard of bromoxynil. As outlined in the table below, the database contains studies evaluating toxicity following oral and dermal exposure in rats and rabbits and oral exposure in mice and dogs, which help to characterize toxicity associated with oral, dermal, and inhalation exposure routes in humans.

                                     Study
                               Bromoxynil phenol
                             Bromoxynil Octanoate
Acute toxicity battery
                                      √
                                      √

                                       
                                       
Oral subchronic toxicity -- rats
                                      √
                                      √
Oral subchronic toxicity -- mice
                                      √
                                       
Oral subchronic toxicity -- dogs
                                      √
                                      √

                                       
                                       
Dermal subchronic toxicity -- rabbits
                                      √
                                      √

                                       
                                       
Oral chronic/Carcinogenicity -- rats
                                      √
                                      --
Oral carcinogenicity  -  mice
                                      √
                                      --
Oral chronic -- dogs
                                      √
                                      --

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

                                       
                                       
Dermal developmental toxicity -- rats
                                      √
                                      √
Dermal developmental toxicity -- rabbits
                                      √
                                      √

                                       
                                       
Oral multigen-reproduction study -- rats
                                      √
                                      --
Dermal special reproduction study -- rats
                                      --
                                      √

                                       
                                       
Mutagenicity Battery
                                      √
                                      √
                                       
                                       
                                       
Acute Neurotoxicty Battery
                                      --
                                      --
Subchronic Neurotoxicity
                                      --
                                      --

                                       
                                       
Immunotoxicity
                                      --
                                      --
                                       
                                       
                                       
Dermal Absorption
                                      √
                                      √
      √ = available 		-- = not available

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

The available data show that once absorbed, bromoxynil octanoate is converted to bromoxynil phenol.  The absorption, distribution, excretion and metabolism of bromoxynil octanoate were studied in male and female Sprague Dawley rats given single oral doses of [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.  Results were similar regardless of dosing regimen.  The rate of absorption in both sexes was such that peak plasma concentrations of radioactivity were not reached until 7-10 hours after dosing.  Radioactivity was distributed in most tissues; highest concentrations were observed in blood, plasma, liver, kidneys and thyroid (especially in females).  Levels of radioactivity in tissues were generally higher in females than in males.  Most radioactivity was excreted in the urine (about 84-89% in males and 76-80% in females at 7 days) and considerably lesser amounts in the feces (about 6-10% in both males and females at 7 days).  Excretion was more rapid in males than in females.  Retention of radioactivity in tissues after 7 days was about 2-3% in males and 7-9% in females.  Essentially all bromoxynil octanoate was rapidly and nearly completely converted to bromoxynil phenol via ester hydrolysis.  In special distribution studies, the only chemical species identified in tissues was bromoxynil phenol per se; no bromoxynil octanoate was identified in tissues.  In urine, the only major species was free and conjugated bromoxynil phenol with no bromoxynil octanoate being present.  In feces, however, some bromoxynil octanoate was identified.  (MRID 00154756, 00154757, 42901001).

4.2.1	Dermal Absorption

The previous risk assessment utilized a dermal absorption factor of 10.32% (excluding post-wash residue), based on the highest absorption value obtained after 10 hours of exposure to bromoxynil octanoate, the compound to which exposure is expected.  Current HED policy is to derive a dermal absorption factor by combining the material remaining on the skin after skin washing to the systemically absorbed dose, if the material remaining on the skin is bioavailable.  In the absence of bioavailability data, HED has made the assumption that the material remaining on the skin is bioavailable.   Therefore, the dermal absorption value for this risk assessment is the sum of the absorption value and post-wash residue for the 10-hour period for bromoxynil octanoate, or 10.32% + 6.46% ≈ 17%.

4.2.2	Other Toxicological Concerns
      
A metabolite of bromoxynil, 3,5 - dibromo-4-hydroxybenzoic acid (DBHA) has been found to be a major metabolite in cotton.  HED  previously concluded that bromoxynil and DBHA are extremely similar in structure, and since DBHA is likely to be more water soluble than bromoxynil, it should be absorbed less and eliminated faster than bromoxynil, thereby reducing its toxicity relative to bromoxynil.  Since adequate data were not available which indicate DBHA is less toxic than the parent compound, HED assumed that DBHA had the same toxicity as the parent compound bromoxynil (D246944.mem, B. Madden 6/24/1998).  
      
Since then, additional DBHA toxicity data (four acute studies, a mutagenicity study, a 90-day rat study and a rat developmental toxicity study) have been submitted to the Agency but have not all undergone review within HED.  A preliminary examination of these data indicate that BDHA is less toxic than bromoxynil which is consistent with the expected  effect that conversion of the nitrile group to a carboxy group reduces toxicity relative to bromoxynil.  The diminished concern for DBHA toxicity is also applicable to carcinogenicity: Ionization of the carboxyl group at physiological pH leads to rapid excretion of DBHA and retards cellular uptake and migration of DBHA through intracellular membranes to interact with receptors associated with carcinogenicity.  However, pending final review of the DBHA toxicity data, HED will continue to assume that DBHA toxicity is the same as (or less than) the parent compound, and is not expected to be more toxic than bromoxynil and to include it as a residue of concern for risk assessment

4.3	Toxicological Effects
      
With repeated dosing in rats and mice, frequently observed effects were on the liver (increased liver weight, hepatocellular hypertrophy) and body weight changes.  In dogs, bromoxynil appeared to affect body temperature control.  Besides decreased body weight, the treated dogs showed increased panting at low dose levels, and increased panting with elevated rectal temperatures at higher dose levels.  At the highest dose levels tested, elevated body temperatures and death occurred.

Developmental toxicity was manifested in rats, mice and rabbits via the oral and dermal routes by increased incidence of supernumerary (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 after bromoxynil and bromoxynil octanoate exposure,  liver toxicity was also observed (beginning at 5 mg/kg/day in dogs and rats) in males and females in the subchronic, chronic, developmental and reproduction studies, including liver weight increases and adverse histopathological effects such as hepatocellular hypertrophy, vacuolization and degeneration in rats, mice, and dogs, and liver tumors (beginning at 13 mg/kg/day) in chronic studies in mice.  Adverse effects (beginning at 5 mg/kg/day in dogs) on body weight and body weight gain changes were also observed in rats, mice, dogs, and rabbits. Other less widespread effects, such as salivation, increased panting, and unsteady gait occurred in dogs; blood effects such as decreases in serum protein and globulins; increased thymic lymphocyte necrosis; increased degeneration/necrosis of cardiac myofibers occurred in rats. The increased panting in dogs occurred at 5 mg/kg/day, and increased panting with elevated rectal temperatures at 12 mg/kg/day.

Bromoxynil phenol and/or octanoate was positive in a mouse lymphoma forward mutation assay with metabolic activation, a bacterial DNA repair assay with and without S9 activation, and in a CHO chromosomal aberration assay with activation.  These mutagenic effects all occurred at cytotoxic dose levels and in in vitro studies only.  The cancer classification of Group C Human Carcinogen with low-dose extrapolation (Q1*) was assigned by HED's Cancer Peer Review Committee (E. Budd, 3/12/1997, TXR 0050045) based on mouse hepatocellular tumors.

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

In HED's risk assessment conducted in 1998, acute dietary risks for females 13+ utilized a NOAEL of 4 mg/kg/day and LOAEL of 5 mg/kg/day based increased incidence of supernumerary ribs seen in two rat developmental toxicity studies.  Based on the combined evaluation of these studies, the 10X FQPA SF was retained for concerns over the apparent steepness of the dose-response curve.  In an effort to better characterize the dose response relationship for supernumerary ribs, a BMD analysis has been conducted using the fetal and/or litter data available from the two rat developmental studies, plus a third developmental study which demonstrated similar results at similar dose levels.  The results of the BMD analysis indicate that the dose response curves are not as steep as previously assumed and HED has concluded that there is high confidence that the NOAEL of 4 mg/kg/day is a protective point of departure without the need to retain a 10X FQPA SF (J. Kidwell, 035301TS.001.docx. Final Report of the ToxSAC. January 13, 2011).

Based on the hazard and exposure data, the bromoxynil risk assessment team has recommended that the FQPA Safety Factor be reduced to 1X.  Although the presence of quantitative susceptibility has been established (based on supernumerary ribs occurring at dose levels below the maternal LOAEL in rats), the NOAELs and LOAELs for this effect are well defined, and Benchmark Dose (BMD) analysis has indicated that the NOAEL of 4 mg/kg/day for supernumerary ribs (which is the point of departure for the Females 13+ endpoint) is sufficiently protective of the fetus.  Both the BMD (which represents 5% increased risk of incidence of this effect above the normal background incidence) of 13.66 mg/kg/day and its lower limit (BMDL) of 8.34 mg/kg/day are above the NOAEL of 4 mg/kg/day. The completeness and good quality of the available data used for the BMD analysis produced results with a high reliability factor, which is fully presented and discussed in a separate document (M. Ottley TXR 0055648).  The data base is considered complete (refer to next section) and there are no residual uncertainties.

4.4.1	Completeness of the Toxicology Database

The toxicity database for bromoxynil is complete except for an immunotoxicity study (OPPTS Guideline 870.7800), and acute and subchronic neurotoxicity studies (OPPTS Guideline 870.6200a and 870.6200b).  These studies are now requirements under 40 CFR §158.500 for pesticide registration.  In the absence of specific immunotoxicity, acute and subchronic neurotoxicity studies, HED has evaluated the available bromoxynil toxicity database to determine whether an additional database uncertainty factor is needed to account for potential immunotoxicity or neurotoxicity.  

There is no evidence of immunotoxicity, with the exception of a marginal increase in the severity - but not the incidence - of thymic lymphocyte necrosis at otherwise toxic dose levels in a subchronic rat study. The NOAEL and LOAEL for these thymic effects were 91 mg/kg/day and 45 mg/kg/day. It is anticipated that the points of departure selected for bromoxynil (see table 4.5.4) will be protective of this adverse effect, There is no evidence of neurotoxicity in the database.  

Consequently, HED believes the existing data are sufficient for endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements under FQPA, and an additional database uncertainty factor does not need to be applied.
4.4.2	Evidence of Neurotoxicity

There are currently no acute or subchronic neurotoxicity studies available, and the available subchronic and chronic data did not raise concern for potential neurotoxicity associated with bromoxynil or bromoxynil octanoate exposure.  Though panting and elevated rectal temperature are observed in the subchronic dog study, these effects are not considered to be indicative of neurotoxicity but rather generalized systemic toxicity.
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The available data indicate that bromoxynil produces developmental effects (supernumerary ribs) in rats and rabbits at or below the maternal NOAELs in both oral and dermal studies, and that bromoxynil octanoate produces supernumerary ribs at the maternal NOAEL in a dermal study. Supernumerary ribs were observed in rats, mice and rabbits after oral and/or dermal administration, and more severe developmental effects were seen at the maternal LOAEL and higher doses. Therefore, there is evidence of quantitative susceptibility in the data base.  However, clear NOAELs for the developmental effects, and basing the point of departure on these effects addresses HED concerns for quantitative susceptibility.
 
4.4.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database.  Although the dietary assessments conducted with DEEM-FCID were refined, HED does not believe that the exposure estimates are underestimated because the data were based on reliable and acceptable field trial and feeding studies and estimates of percent crop treated.  The assessment utilized anticipated residues for all livestock commodities, average field trial residues for all grains in the acute assessment, average field trial residues for all crops except spearmint and peppermint in the chronic assessment, average estimates of percent crop treated in the chronic assessment and, maximum estimates of percent crop treated in the acute assessment.  In addition, default processing factors were assumed for all commodities.  The DEEM analysis also assumed that all drinking water will contain bromoxynil at the highest EDWC levels modeled by EFED for surface water.  For these reasons it can be concluded that the DEEM-FCID analysis does not underestimate risk from acute or chronic exposure to bromoxynil.   In addition, there are no registered residential uses.

4.5	Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

In the previous risk assessment (D246944, B. Madden, 6/24/1998), the FQPA 10X uncertainty factor was retained for the Acute Dietary Females 13+ endpoint despite the point of departure being an adverse effect (supernumerary ribs) in the fetus.  The primary reason for the retention was an apparent steepness of the dose-response curve (NOAEL = 4 mg/kg/day, LOAEL = 5 mg/kg/day) derived by combining the results of two co-critical studies.  However, a more refined data evaluation tool, benchmark dose (BMD) analysis, has become available and HED has been using it in the risk assessment process.

As mentioned in Section 4.4, the results returned by the BMD analysis (D386424, M. Ottley, TXR 0055648) suggest a point of departure substantially higher than the NOAEL of 4 mg/kg/day, which supports the position that the NOAEL of 4 mg/kg/day is adequately protective of this adverse effect in rat fetuses without an addition safety factor.  Secondly, the BMD analysis results, which took into consideration all the doses and responses in the studies, indicate that the dose-response curve is not steep as previously thought.  As such, there remained no basis for retention of the 10X, and for this risk assessment it has been removed.   

4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment

There is no potential for residential exposure from the proposed and existing uses of bromoxynil. However, occupational workers will be exposed from dermal and inhalation routes.  Effects of supernumerary ribs were observed in both dermal and oral developmental studies. Since a common toxicological effect was identified, these routes of exposure can be combined to estimate combined occupational risk.

4.5.3	Cancer Classification and Risk Assessment Recommendation

Bromoxynil phenol has been classified by the HED Cancer Assessment and Review Committee as a Group C, possible human carcinogen, based on a treatment-related increased incidence of hepatocellular adenomas, carcinomas and adenomas/carcinomas combined in mice (E. Budd and E. Rinde, 3/12/1997, TXR 0050045).

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

The details for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in Appendix A.  The following table provides the information in summary form.


Table 4.5.4a Summary of Toxicological Doses and Endpoints for Bromoxynil for Use in Dietary and Non-Occupational Human Health Risk Assessments
Exposure/
Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary (General Population, including Infants and Children)
NOAEL= 8 mg/kg/day
UFA= 10 x
UFH=10 x
FQPA SF=1x


Acute RfD = 0.08  mg/kg/day

aPAD = 0.08  mg/kg/day
Subchronic Study in Dogs
The LOAEL for effects attributed to a single dose was 12 mg/kg based on panting.  In addition to panting, elevated rectal temperatures occurred at 16 mg/kg and above, and death occurred at 30 mg/kg and above after a single dose on day 1
Acute Dietary
(Females 13-49 years of age)
NOAEL 4 mg/kg/day
UFA= 10 x
UFH=10x
FQPA SF=1x


Acute RfD = 0.04  mg/kg/day

aPAD = 0.04  mg/kg/day
Developmental Studies in Rats 
The LOAEL of 5 mg/kg/day is based on an increase of supernumery ribs from MRID 00116558.  The NOAEL is derived from a co-critical study (MRID 40466802)
Chronic Dietary (All Populations)
NOAEL= 1.5 mg/kg/day
UFA= 10 x
UFH=10 x
FQPA SF=1x


Chronic RfD = 0.015
mg/kg/day

cPAD = 0.015 mg/kg/day
Chronic (1 year) Study in dogs
The LOAEL of 7.5 mg/kg/day, M & F is based on increased incidences of salivation, panting, liquid feces and pale gums; statistically significant decreased body weight gain over entire duration of study, but particularly during first 8 weeks of study; statistically significant decreased erythrocytes (RBC), hemoglobin (Hb) and packed cell volume (PCV); statistically significant increased urea nitrogen; increased absolute liver weights and liver/body weight ratios. 
Incidental Oral, Dermal, and Inhalation  Short-Term 
(1-30 days)
and Intermediate Term 
(1-6 months)
Points of Departure for these exposure scenarios were not selected because there are no proposed or established uses which result in residential exposure.  

  
Cancer (oral, dermal, inhalation)
Bromoxynil phenol has been classified by the HED Carcinogenicity Peer Review Committee (E. Budd and E. Rinde, 3/12/1997, TXR 0050045) as a Group C, possible human carcinogen, based on male mouse hepatocellular tumors.  The committee also recommended that a low dose extrapolation model (Q1*) be applied to the experimental animal tumor data for quantification of human risk.  Q1* = 0.103 (mg/kg/day)[-1]
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

Table 4.5.4b Summary of Toxicological Doses and Endpoints for Bromoxynil for Use in Occupational Human Health Risk Assessments
Exposure/
Scenario
Point of Departure
Uncertainty Factors
Level of Concern for Risk Assessment
Study and Toxicological Effects
Dermal Short- and Intermediate- Term (1-30 days)
NOAEL= 10 mg/kg/day 
UFA= 10 x
UFH=10 x

Occupational LOC for MOE = 100
Dermal developmental toxicity study  -  Rats
The LOAEL of 15 mg/kg/day based on increased incidence of supernumerary (14th) ribs.
Inhalation Short-  and Intermediate-Term (1-30 days)
NOAEL= 4 mg/kg/day
UFA= 10 x
UFH=10 x

Occupational LOC for MOE = 100
Oral developmental toxicity study in rats. NOAEL of 4 mg/kg/day was selected from one study (MRID 40466802, LOAEL =   mg/kg/day) and the LOAEL of 5 mg/kg/day was selected from another study (MRID 00116558, NOAEL not established).  Both studies showed a 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, TXR 0050045) as a Group C, possible human carcinogen, based on male mouse hepatocellular tumors.  The committee also recommended that a low dose extrapolation model (Q1*) be applied to the experimental animal tumor data for quantification of human risk.  Q1* = 0.103 (mg/kg/day)[-1]
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

Based on the available toxicity database and the Agency's current practices, the inhalation risk for bromoxynil was assessed using an oral toxicity study.  The Agency sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, re-examine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data.  If any new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for bromoxynil and/or a 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 effect produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator may designate."  The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems.  Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.
Between October 2009 and February 2010, EPA has issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients.  This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity, and certain post-application agricultural scenarios.  This list should not be construed as a list of known or likely endocrine disruptors.

Bromoxynil is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP.  Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals.  Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website:  http://www.epa.gov/endo/.

5.0	Dietary Exposure and Risk Assessment 

Sources:  Bromoxynil.  Petition for Tolerances in Support of New Uses on Grass and Grain Sorghum.  Summary of Analytical Chemistry and Residue Data. D378614, N. Dodd, 2/15/11.

Bromoxynil:  Acute, Chronic, and Cancer Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the New Uses on Grass and Grain Sorghum.  D378615, C. Walls, 3/22/11.  

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

5.1	Metabolite/Degradate Residue Profile

5.1.1	Summary of Plant and Animal Metabolism Studies

PRIMARY CROPS:  The nature of the residue in alfalfa, sweet corn, and cotton following application of [14]C-bromoxynil octanoate is adequately understood.  The metabolic pathway involves hydrolysis of the ester, oxidation of the nitrile group to the acid via the amide, and conjugation; debromination occurs in a parallel pathway.  

The translocation of bromoxynil octanoate in cotton is extremely minimal.  Bromoxynil octanoate ([14]C-labelled) was applied to a single leaf or boll and harvested after 7 days (from leaves) or 47 days (from bolls).  A very small amount (0.15% or less of the total radioactive residue [TRR]) was translocated to adjacent leaves.  No residues were found in cottonseed.  However, transgenic cotton metabolizes bromoxynil primarily to 3,5-dibromo-4-hydroxybenzoic acid (DBHA) [78.6% of the total radioactive residues (TRR)].  

ROTATIONAL CROPS:  A confined rotational crop study was conducted on spinach, beets, and wheat with [14]C-bromoxynil octanoate.  Low level residues of multiple, polar components were found in the rotational crops.  The field rotational crop studies in winter wheat, collard greens and radishes are adequate to demonstrate that detectable bromoxynil residues would not be expected in crops rotated at 30 days (or more) following application of bromoxynil octanoate to primary crops.
  
RUMINANTS:  The nature of the residue in ruminants is adequately understood for bromoxynil.  When [14]C-bromoxynil octanoate was administered to lactating goats, 90% of the TRR was recovered as bromoxynil per se.  The parent compound was found only in milk (1.7% of the TRR).  DBHA was found only in liver (4% of the TRR).

POULTRY:  The nature of the residue in poultry is adequately understood for bromoxynil.  When [14]C-bromoxynil octanoate was administered to laying hens, 73-100% of the TRR was recovered as bromoxynil per se.  The parent compound was found only in eggs (4-6% of the TRR).  Polar unknowns accounted for 3% of the TRR in liver.

RAT:   Bromoxynil heptanoate and octanoate are rapidly absorbed and widely distributed in most tissues.  Most of the radioactivity was excreted in the urine, mostly in the form of bromoxynil phenol.  There was no significant retention in tissues after 7 days.  Bromoxynil heptaonate and octanoate were metabolized to bromoxynil phenol via ester hydrolysis. 

5.1.2	Summary of Environmental Degradation

Bromoxynil octanoate is chemically and physically similar to bromoxynil heptanoate.  Both esters rapidly degrade to bromoxynil phenol (bromoxynil).  Bromoxynil octanoate is mobile and non-persistent.  It dissipates in the environment by abiotic hydrolysis, photolytic degradation, and microbial-mediated metabolism in both the aerobic and anaerobic environments.  Bromoxynil octanoate readily hydrolyzes to bromoxynil phenol and then further degrades to CO2. 

Bromoxynil phenol is more persistent in the environment than bromoxynil octanoate.  Residues of bromoxynil are moderately to highly mobile in soils and do not break down by abiotic processes, such as hydrolysis and photolysis.  However, bromoxynil rapidly degrades under aerobic and anaerobic conditions. 

Bromoxynil may move from the treated field to surface water or ground water through run-off shortly after application.  The field dissipation studies show that bromoxynil residues dissipated with half-lives of 1 to 14 days and were not detected below 15 cm soil depth indicating that leaching is not an anticipated route of dissipation, likely due to the rapid degradation rate.   Although, bromoxynil is mobile, it has a short metabolic half-life in soil under aerobic conditions and it should not be a ground water concern in most environments.  In the event that bromoxynil did reach ground water, it is expected to degrade slowly due to microbial activity (faster under aerobic conditions than anaerobic conditions) but is rather persistent otherwise.  

5.1.3	Comparison of Metabolic Pathways

In primary crops, bromoxynil phenol was the major residue identified in various matrices.  Transgenic cotton metabolizes bromoxynil primarily to 3,5-dibromo-4-hydroxybenzoic acid (DBHA).  

In rotational crops, bromoxynil phenol was not identified.  Only low level residues of multiple, polar components were found in the rotational crops
  
In drinking water, the residue of concern for risk assessment is bromoxynil phenol.

In ruminants, the primary residue identified in milk was bromoxynil phenol.  The metabolite DBHA was also identified as a minor residue in liver.  

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

5.1.4	Residues of Concern Summary and Rationale

Table 5.1.4  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression
Matrix
Residues included in Risk Assessment
Residues included in Tolerance Expression
Plants
Primary Crop (except cotton)
Cotton
Bromoxynil (phenol)
Bromoxynil (phenol)+ DBHA
Bromoxynil (phenol)
Bromoxynil (phenol)+ DBHA

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

Poultry
Bromoxynil (phenol) + DBHA
Bromoxynil (phenol)
Drinking Water
Bromoxynil (phenol)
Not Applicable


Rationale:

Plants

Primary Crops:  The nature of the residue in plants is adequately understood for the presently proposed crops based on metabolism studies on alfalfa, sweet corn, and cotton.  In all primary crops except cotton, bromoxynil phenol is the residue of concern for the tolerance expression and for risk assessment since it was the major residue detected.  Because 78.6% of the bromoxynil residues in transgenic cotton are metabolized to DBHA, the cotton residues of concern for the tolerance expression and for risk assessment are bromoxynil and its metabolite DBHA.

Rotational Crops:  The nature of the residue in rotational crops is adequately understood based on an acceptable confined rotational crop study conducted on winter wheat, collard greens and radishes.  Residues were less than the limit of quantitation (<0.02 ppm) in winter wheat forage, radish tops and roots, and in collard greens harvested from the 30-day plantback plots; residues were less than the limit of detection (<0.01) in wheat grain and straw harvested from the 30-day interval. Based on the rotational crop data, plant-back intervals of 30 days are adequate for all rotational crops planted after application of bromoxynil octanoate and heptanoate.

Livestock  

Ruminants:  The nature of the residue in ruminants is adequately understood based on an acceptable study conducted on lactating goats with[14]C-bromoxynil octanoate.  90% of the TRR was recovered as bromoxynil per se.  The parent compound was found only in milk (1.7% of the TRR).  DBHA was found only in the liver (4% of the TRR).  Since the metabolite DBHA is found in commodities considered to be livestock feed items, the potential for transfer of secondary residues to livestock exists.  The HED Metabolism Committee has concluded that DBHA could transfer to livestock tissues in proportion to the parent but is no more toxic than parent.  Thus, the residues of concern in ruminants for risk assessment are bromoxynil phenol and DBHA.   The residue of concern for the tolerance expression is bromoxynil phenol.

Poultry:  The nature of the residue in poultry is adequately understood based on an acceptable study conducted on laying hens with[14]C-bromoxynil octanoate.   73-100% of the TRR was recovered as bromoxynil per se.  The parent compound was found only in eggs (4-6% of the TRR).  Polar unknowns accounted for 3% of the TRR in liver.  Because the metabolite DBHA is found in commodities considered to be livestock feed items, residues of concern in poultry for risk assessment are bromoxynil and DBHA.  The residue of concern for the tolerance expression is bromoxynil.

Drinking Water 

Bromoxynil octanoate is chemically and physically similar to bromoxynil heptanoate.  Since both esters rapidly degrade to bromoxynil phenol, the drinking water residue of concern for risk assessment is bromoxynil.

5.2	Food Residue Profile

Crop Field Trials

The submitted magnitude of the residue data, summarized in Table 5.2.1, are adequate for risk assessment and tolerance assessment.  For all crops, the number and locations of field trials are adequate and the field trials reflect the proposed use patterns.  Two spray applications of the formulated HUSKIE product were made to each crop.  No adjuvants were used.  The Agency's tolerance spreadsheet, as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP, was used to determine appropriate tolerance levels.  Based on the available data and estimated residue values, all proposed tolerances are adequate.  However, HED is recommending that the established tolerance of 0.5 ppm on the forages of grain sorghum be increased to 0.8 ppm.  

   TABLE 12.  Summary of Residue Data from Crop Field Trials with Bromoxynil
Matrix
                              Total Applic. Rate
                                   lb a.i./A
                                 (kg a.i./ha)
PHI (days)
                            Residue 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 Grain[4]
                                       
                                   56 to 60
                                      24
                                   <0.01
                                     0.11
                                     0.103
                                     0.011
                                     0.028
                                     0.030
Sorghum Stover[4]
                                       
                                   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 as a component for drywall, and not as either a human food or feedstuff.

Residues in aspirated grain fractions must be determined for uses on corn, sorghum, soybeans, and wheat.  Studies on residues in aspirated grain fractions of barley, corn, sorghum, and wheat have been previously reviewed and deemed adequate to support a tolerance on aspirated grain fractions (grain dust).  The studies all indicate that residues concentrate in aspirated grain fractions.  Because the tolerance on the grain of grain sorghum is being increased from 0.05 ppm to 0.2 ppm, higher residues may occur in aspirated grain fractions.  Therefore, HED is recommending that the established tolerance of 0.3 ppm grain, aspirated grain fractions be increased to 1.2 ppm based on the new sorghum grain field trial data and established concentration factor.

Storage Stability

Adequate storage stability data are available to support the storage durations and conditions of samples from the submitted crop field trial studies on grain sorghum and grass.  Storage stability data are available that demonstrate that bromoxynil residues are stable in the forage, grain, and stover of grain sorghum and in the forage, hay, and seed of grass stored frozen at -10°C for 12 months.

Meat, Milk, Poultry, and Eggs

Livestock feed items associated with grass are forage, hay, and silage and the livestock feed items associated with grain sorghum are grain, forage/silage, stover and aspirated grain fractions (Table 1 Feedstuffs, June 2008).  Maximum reasonably balanced dietary burdens (MRBDB) of bromoxynil were updated for beef cattle, dairy cattle, swine, and poultry.  The resulting dietary burdens are now 1.6 ppm for beef cattle, 32.7 ppm for dairy cattle, 0.48 ppm for poultry, and 0.39 ppm for swine.  Following re-evaluation of the available animal feeding studies in consideration of the recalculated dietary burdens, HED concludes that the established tolerance for residues of bromoxynil for milk should be increased from 0.1 ppm to 0.4 ppm.  Other livestock tolerances remain unchanged.  

Rotational Crops

No tolerances are required for rotational crops.  The confined rotational crop study indicated that no residues of concern are expected to occur in rotational crops with appropriate plant-back intervals.  

5.3	Water Residue Profile

Estimated surface water and groundwater concentrations are shown in Table 5.3.1. 
The dietary exposure assessment used values of 11.5 ppb for acute and 0.19 ppb for chronic (non-cancer and cancer) assessments.  The drinking water assessment is based on Tier I surface water model simulations for the proposed sorghum bromoxynil use.  Since bromoxynil heptanoate is chemically and physically similar to bromoxynil octanoate and both esters rapidly degrade to bromoxynil phenol, all calculations were performed in terms of bromoxynil phenol.

Table 5.3.1	Summary of Estimated Surface Water and Groundwater Concentrations for Bromoxynil. [a]
Scenario
Surface Water Conc., ppb [b]
Groundwater Conc., ppt [c]
Acute
11.5
3.26
Chronic (non-cancer)
0.19
3.26
Chronic (cancer)
0.19
3.26
[a] DP#374620, Tiffany Mason, 12/16/2010.
[b] From the Tier I FIRST model (FQPA Index Reservoir Screening Tool).  Input parameters are based on 2 applications at 0.305 lbs ai/A on sorghum 11 days apart
[c] From the SCI-GROW model (Screening Concentration in Groundwater) 

Monitoring data for bromoxynil are available from the USGS NAWQA surface and ground water database and California Department of Pesticide Regulation (CDPR) surface water database.  The NAWQA database had taken 7,218 samples for bromoxynil across the United States. It is believed that these samples represent bromoxynil phenol, but cannot be verified since USGS did not differentiate between bromoxynil phenol, bromoxynil octanoate, bromoxynil heptanoate, or bromoxynil butyrate.  Out of 7, 218 samples, there were 54 confirmed detections ranging in concentration from 0.001 ug/L to 6.1 ug/L.  Of those 54 detections, 40 were samples taken from streams, 8 from ground water sources, 4 from waste water treatment effluent, and 1 from a water distribution system.  The rest of the samples were below the detection limit. 

The CDPR database looked for both bromoxynil and bromoxynil octanoate. Out of 531 samples and approximately 29 sites, taken from February 8, 1993 to January 6, 2005, 192 were for bromoxynil octanoate, and 339 were for bromoxynil.  There were two detections, one for bromoxynil and one for bromoxynil octanoate.  Both occurred on May 9, 1997 in Yolo County, CA with a concentration of 0.06 ug/L.  It is possible these two detections at the same location, date, and concentration could be the same bromoxynil compound.   

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

Refined dietary acute and chronic analyses were conducted for bromoxynil.  The acute assessment used average field trial values for all grains since they are considered to be blended commodities.  It also utilized tolerance levels for cotton, garlic, onion, peppermint and spearmint as well as anticipated residues for livestock commodities based on the results from the crop field trials and animal feeding studies (D378614, Nancy Dodd, 17-NOV-2010).  Default processing factors were used.  

The chronic and cancer analyses used average field trial residues for all commodities except spearmint and peppermint where tolerance values were used.  Livestock anticipated residues were estimated using average percent crop treated data, average field trial residue values, and results from the animal feeding studies (D378614, Nancy Dodd, 17-NOV-2010).  Default processing factors were used.  Table 5.4.1 summarizes the bromoxynil residue levels and processing factors for all crops and livestock commodities used in the acute, chronic and cancer dietary assessments.  

Table 5.4.1.  Summary of Bromoxynil Residue Levels For All Crops Used in Acute, Chronic, and Cancer Analyses.
Matrix
                              Anticipated Residue
                                 [Acute] (ppm)
                              Anticipated Residue
                            [Chronic/Cancer] (ppm)
Processing Factors
Alfalfa
                                     0.13
                                     0.13

Cereal grains 
   Barley
   Corn
   Oats
   Rye
   Wheat
                                     0.01
                                     0.01


Corn Syrup: 1.5
Flax, seed 
                                     0.01
                                     0.01

Sorghum 
                                     0.028
                                     0.028

Cotton 
                                      1.5
                                      0.3

Garlic 
                                      0.1
                                     0.01

Onion
                                      0.1
                                     0.01
Dried: 9.0
Mint (peppermint and spearmint) 
                                      0.1
                                      0.1

Cattle, goat, horse, sheep; Fat
                                     0.13
                                    0.0024

Cattle, goat, horse, sheep; 
meat byproducts
                                 Kidney: 0.43
                                  Liver: 0.38
                                Kidney: 0.0081
                                 Liver: 0.0070




Cattle, goat, horse, sheep Meat
                                     0.070
                                    0.0013
Dried:1.92
Egg
                                    0.0038
                                   0.000078

Hog, fat
                                    0.0062
                                    0.00015

Hog, meat byproducts
                                 Kidney: 0.020
                                 Liver: 0.018
                                Kidney: 0.00051
                                Liver: 0.00044

Hog, meat
                                    0.0033
                                   0.000083

Milk
                                    0.0032
                                    0.00054

Poultry, fat
                                    0.0061
                                    0.00013

Poultry, meat byproducts
                                 Liver: 0.048
                                Liver: 0.00099

Poultry, meat
                                    0.0038
                                   0.000078


The drinking water residue levels used in the dietary assessment were estimated using Tier I FIRST Version 1.1.1 (FQPA Index Reservoir Screening Tool) modeling.  The Estimated Drinking Water Concentration (EDWC) for bromoxynil residues are surface water residues based on applications to sorghum.  The EDWC for total bromoxynil residues is 11.5 ppb for the acute and 0.19 ppb for both the chronic and cancer assessments.  The water residues were directly incorporated in the DEEM-FCID into the categories "water, direct, all sources" and "water, indirect, all sources."   

5.4.2	Percent Crop Treated Used in Dietary Assessment

Actual bromoxynil percent crop treated data provided in the Screening Level Usage Analyses (SLUA) from the Biological and Economic Analysis Division (BEAD) were used in the acute, chronic and cancer dietary assessments (D382833, Arthur Grube, 22-OCT-2010) and (D378991, Jihad Alsadek, 08-July-2010).   

The following maximum percent crop treated estimates were used in the acute dietary risk assessment for the following crops that are currently registered for bromoxynil:  alfalfa: 2.5%; barley: 35%; corn: 5%; oats: 5%; rye: 1%; wheat: 35%; flax: 35%; cotton: 5%; sorghum: 2.5%; garlic: 70%; onion: 70%; and mint: 25%.  

The following average percent crop treated estimates were used in the chronic and cancer dietary risk assessments for the following crops that are currently registered for bromoxynil:  alfalfa: 1%; barley: 20%; corn: 2.5%; oats: 5%; rye: 1%; wheat: 15%; flax: 35%; cotton: 2.5%; sorghum: 2.5%; garlic: 50%; onion: 55%; and mint: 25%.

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

5.4.3	Acute Dietary Risk Assessment

A refined dietary acute analysis was conducted for bromoxynil.  For all grains, average field trial values were used since grains are considered to be blended commodities.  Tolerance levels were used for cotton, garlic, onion, peppermint and spearmint.  Livestock anticipated residues were estimated using results from the crop field trials and animal feeding studies. Additionally, maximum percent crop treated estimates provided by BEAD were used for all crop commodities.  Default processing factors were used.  A conservative EDWC derived through EFED modeling which is unlikely to underestimate the concentration of bromoxynil in drinking water was utilized.  The surface water EDWC (11.5 ug/L) was incorporated directly into the dietary assessment. 

As shown in Table 5.4.6, the acute dietary (food and drinking water) exposure to bromoxynil is below HED's level of concern [i.e., <100% of the chronic Population Adjusted Dose (cPAD)] for the general U.S. population and all population subgroups at the 99.9[th] percentile of the exposure distribution.  The acute dietary exposure estimates are 3.3% of the aPAD for the general U.S. population and 7.4% of the aPAD for all infants (<1 year old), the most highly exposed population subgroup. 

5.4.4	Chronic Dietary Risk Assessment

Refined dietary chronic and cancer analyses were conducted for bromoxynil.  Average field trial residues were used for all commodities except for spearmint and peppermint where tolerance values were used.  Livestock anticipated residues were estimated using average percent crop treated data, average field trial residue values, and results from the animal feeding studies. Additionally, average percent crop treated estimates provided by BEAD were used for all crop commodities.  Default processing factors were used.   A conservative EDWC derived through EFED modeling which is unlikely to underestimate the concentration of bromoxynil in drinking water was utilized.  The surface water EDWC (0.19 ug/L) was incorporated directly into the dietary assessment.

As shown in Table 5.4.3, the non-cancer chronic dietary (food and drinking water) exposure to bromoxynil is below HED's level of concern [i.e., <100% of the chronic Population Adjusted Dose (cPAD)] for the general U.S. population and all population subgroups.  The chronic dietary exposure estimates are 0.1% of the cPAD for the general U.S. population and 0.3% of the cPAD for children 1-2 years old, the most highly exposed population subgroup. 



5.4.5	Cancer Dietary Risk Assessment

Bromoxynil is a possible human carcinogen and requires a quantitative cancer risk assessment.  The unit risk, Q1* = 0.103 (mg/kg/day)[-1], of bromoxynil is based upon on male mouse hepatocellular tumors.  The surface water EDWC (0.19 ug/L) was incorporated directly into the dietary assessment.  As shown in Table 5.4.6, the cancer dietary (food and drinking water) exposure estimate for the general U.S. population is 1.5 x 10[-][6], which is below HED's level of concern (generally in the range of 10[-6]).

5.4.6	Summary Table

 Table 5.4.6.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Bromoxynil
                              Population Subgroup
                                 Acute Dietary
                              (99.9th Percentile)
                                Chronic Dietary
                                     Cancer
                                        
                          Dietary Exposure (mg/kg/day)
                                     % aPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                     % cPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
 General U.S. Population
                                 0.002639     
                                      3.3
                           0.000014                 
                                     ‹1%
                               0.000014         
                                 1.5 x 10[-6]
 All Infants (< 1 year old)
                                    0.005892
                                      7.4
                                   0.000024
                                     ‹1%
                                      N/A
                                      N/A
 Children 1-2 years old
                                 0.003714     
                                      4.6
                           0.000040                 
                                     ‹1%
 
 
 Children 3-5 years old
                                    0.003527
                                      4.4
                           0.000032                 
                                     ‹1%
 
 
 Children 6-12 years old
                                 0.002151     
                                      2.7
                           0.000021                 
                                     ‹1%
 
 
 Youth 13-19 years old
                                 0.002507     
                                      3.1
                           0.000013                 
                                     ‹1%
 
 
 Adults 20-49 years old
                                 0.001965     
                                      2.5
                           0.000011                 
                                     ‹1%
 
 
 Adults 50+ years old
                                 0.001482     
                                      1.9
                           0.000010                 
                                     ‹1%
 
 
 Females 13-49 years old
                                 0.001756     
                                      4.4
                           0.000011                 
                                     ‹1%
 
 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

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

      6.1 Spray Drift
Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for bromoxynil.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risks associated with drift.

7.0 Aggregate Exposure/Risk Characterization

Under FQPA, HED must consider and aggregate pesticide exposures and risk from three major sources: food, drinking water, and residential exposures.  

      7.1 Acute Aggregate Risk
There is potential acute exposure via the diet (food and drinking water).  Refer to Section 5.3.

      7.2 Short- and Intermediate- Term Aggregate Risk
Since there are no residential uses for bromoxynil, short- and intermediate-term aggregate assessments were not conducted.

      7.3 Chronic Aggregate Risk
There is potential chronic exposure via the diet (food and drinking water).  Refer to Section 5.4.

      7.4 Cancer Aggregate Risk
There is potential chronic cancer exposure via the diet (food and drinking water).  Refer to Section 5.5.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a  common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to bromoxynil and any other substances and bromoxynil does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, EPA has not assumed that bromoxynil has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Source:  Bromoxynil: Occupational and Residential Exposure Assessment for Proposed Field Uses of Bromoxynil on Grain Sorghum (to include grain and forage), Grass Grown for Seed, Conservation Reserve Program Areas and Existing Use Sites of Bromoxynil.  D378616, K. Rury, 4/7/11.  

Bromoxynil is formulated as an emulsifiable concentrate, soluble concentrate, and as a wettable powder in water soluble packets (WSB) and can be applied with aerial equipment, chemigation, and groundboom sprayers.  Application rates for bromoxynil range from 0.21 to 0.5 lb bromoxynil per acre.  Currently registered bromoxynil agricultural use sites include:  corn, sorghum, transgenic cotton, seedling alfalfa, flax, garlic, small grains (wheat, barley, oats, and rye), onions, grasses grown for seed and sod production, conservation reserve program (CRP) areas, non-residential turfgrass, non cropland/industrial sites, and mint. The proposed formulated end-use product evaluated in this assessment is labeled under the trade name HUSKIE(TM) Herbicide (EPA Reg. No. 264-1023) (Huskie) containing 26.3% bromoxynil and 3.3% pyrasulfotole.  A separate ORE assessment has been conducted for pyrasulfotole (D375392, A. Nowotarski, 09/03/10).  This assessment was completed to incorporate amended uses of bromoxynil on grain sorghum (to include grain and forage), grass grown for seed, and conservation reserve program areas (CRP).  This document also reassesses existing uses of bromoxynil as the dermal absorption factor has increased and an inhalation endpoint was added to the bromoxynil toxicity database.  

      9.1 Short-/Intermediate Term Non-Cancer & Cancer Risk For Pesticide Handlers
There is a potential for short- and intermediate-term occupational exposure to bromoxynil during mixing, loading, and applying, and for short- and intermediate-term post-application activities.  Chronic exposure is not expected for the proposed use patterns associated with bromoxynil.  Estimated short- and intermediate-term dermal exposures were compared to the NOAEL of 10 mg/kg/day from a dermal developmental study in which increased incidence of supernumerary ribs were seen.  Estimated short- and intermediate-term inhalation exposures were compared to the NOAEL of 4 mg/kg/day from an oral developmental toxicity study in the rat based on increased incidence of supernumerary ribs.  

Chemical-specific data for assessing exposure during pesticide handling activities (mixing/loading, applying, and flagging) were not submitted to the Agency in support of this Section 3 application.  It is HED policy to use data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 to assess handler exposures for regulatory actions when 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 intermediate-term dermal exposures.  Daily inhalation exposures (assuming 100% absorption and a 60 kg body weight were compared to the NOAEL of 4 mg/kg/day from an oral developmental toxicity study to determine the risk for short- and intermediate-term exposures.  The MOEs for short-term and intermediate-term dermal and inhalation non-cancer risk estimates for the proposed and currently registered use sites of bromoxynil are shown in Table 9.1.1.1.  

Amended Bromoxynil Uses
The results indicate that the MOEs for the proposed uses for occupational handler scenarios were not of concern (i.e., an MOE > 100) at some level of personal protection (gloves).  The dermal MOE was 12 with baseline attire for mixer/loaders, and the dermal MOEs ranged from 2,400 to 2,600 for applicators.  The dermal MOEs with baseline attire plus gloves (PPE-G) ranged from 1,300 to 1,400 for mixer/loaders and from 2,400 to 2,600 for applicators.  Inhalation MOEs ranged from 11,000 to 12,000 for mixer/loaders and from 18,000 to 19,000 for applicators.  The combined (dermal + inhalation) MOE with baseline attire was 12 for mixer/loaders and ranged from 2,200 to 2,300 for applicators.  Combined (dermal + inhalation) MOEs with baseline attire plus gloves (PPE-G) ranged from 1,300 to 1,400 for mixer/loaders and from 2,200 to 2,300 for applicators.  

Reevaluation of Existing Bromoxynil Uses
The results indicate that the mixing/loading MOEs for the existing use sites were not of concern (i.e., an MOE > 100) at some level of personal protection (gloves) for all crops and application methods, except mixing/loading for aerial application to corn and wheat, which requires a closed system.  The results indicate that MOEs for application of bromoxynil to all existing use sites were not of concern at some level of personal protection (gloves).  Flagging for bromoxynil application was not of concern at baseline attire.  

The dermal MOEs at baseline attire range from 0.34 (risks of concern) to 160 for mixing/loading for application to corn and wheat, from 1.2 (risks of concern) to 1,400 for all other crops, from 200 to 6,000 for applicators, and from 310 to 620 for flaggers.  Inhalation MOEs at baseline attire were >330 for mixer/loaders, applicators and flaggers and are not of concern. Combined (dermal + inhalation) MOEs at baseline plus gloves ranged from 38 to 2,900 for mixer/loaders, 380 to 4,900 for applicators, and from 270 to 530 for flaggers.  Mixing and loading scenarios for bromoxynil application to corn and wheat were below HED's LOC=100 at baseline and PPE-G.  With coveralls, mixing/loading for application to corn and wheat, the dermal MOE was 57 and the combined dermal and inhalation MOEs for ranged from 55 (risk of concern) to 190. In a closed system, the dermal MOE for mixing/loading for application to corn & wheat was 120 and was 4,800 for inhalation exposure; the combined dermal + inhalation MOE was 110, and therefore not of concern.  

                                       
Table 9.1.1.1  Summary  of Occupational (Non Cancer) Risks of Bromoxynil to Amended and Existing Use Sites
                               Handler Scenario
                                  Dermal MOE
                                Inhalation MOE
                        Combined Dermal/Inhalation MOE
                                       
                                   Baseline
                               Baseline + Gloves
                                   Coveralls
                                 Closed System
                                   Baseline
                                  Respirator
                                 Closed System
                                   Baseline
                               Baseline + Gloves
                            Coveralls + Respirator
                                 Closed System
                                 Amended Uses
                                 Mixer/loader
                                      12
                                  1,300-1,400
                                  Not Needed
                                 11,000-12,000
                                  Not Needed
                                      12
                                  1,300-1,400
                                  Not Needed
                                  Applicator
                                  2,400-2,600
                                  2,400-2,600
                                       
                                 18,000-19,000
                                       
                                  2,200-2,300
                                  2,200-2,300
                                       
                                 Existing Uses
                        Mixer/loader (Corn & wheat)
                                 0.34  -  160
                                    43-350
                                      57
                                      120
                                   330-5,700
                                  1,700-5,700
                                     4,800
                                   0.34-160
                                    38-330
                                    55 -190
                                      110
                                 Mixer/loader 
                               (all other crops)
                                   1.2-1,400
                                   150-3,100
                                      200
                                       
                                 11,000-50,000
                                  Not Needed
                                   1.2-1,400
                                   130-2,900
                                  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
                                   380-4,900
                                       











            9.1.2 Occupational Handler Cancer Risk Estimates 
For the proposed use sites of bromoxynil, HED assumed 10 days of bromoxynil exposure per year to assess cancer risks to commercial agricultural handlers and 2 days of bromoxynil exposure per year to assess risks to private agricultural handlers based on use pattern information and maximum treatments per year.  For the existing use sites, HED assumed 30 days of bromoxynil exposure per year for high acreage crops (corn and wheat), while 10 days of exposure per year for all other use sites. Based on the use profile and the maximum number of applications allowed per year (1  -  3 applications) these estimates are expected to be a conservative representation of exposure to bromoxynil per year.  EPA conducted an assessment of the carcinogenic risk estimates associated with bromoxynil following exposures to occupational handlers.  

The minimum level of PPE for handlers is based on acute toxicity for the end-use product.  The Registration Division (RD) is responsible for ensuring that PPE listed on the label is in compliance with the Worker Protection Standard (WPS) for Agricultural Pesticides.  The Agency generally considers occupational cancer risk estimates within the range of 1 to 3x10[-6] (approximately 1-3 in 1 million persons) or less to be negligible, but may accept risk estimates as high as 1x10-4 when all mitigation measures that are feasible and practical have been applied, particularly when there are critical pest management needs associated with the use of the pesticide.  Exposure assumptions and cancer estimates for occupational handlers are summarized in Tables 9.1.2.1 and 9.1.2.2.     

Amended Uses (EPA Reg. No. 264-1023)
The results indicate that estimated cancer risks were not of concern (i.e., in the 10[-6] range or lower) for both commercial and private users at some level of personal protection (gloves).  The cancer risk estimates at baseline attire for commercial users of bromoxynil ranged from 1.7x10[-4] to 1.8x10[-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 to 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 bromoxynil was 3.5x10[-5] for mixer/loaders and ranged from 2.1x10-7 to 2.2x10-7 for applicators.  The cancer risk estimates at baseline plus gloves (PPE-G) for private applicators ranged from 4.0x10-7 to 4.2x10[-7] for mixer/loaders and from 2.1x10[-7] to 2.2x10[-7] for applicators.  The cancer risk estimates 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 and wheat, which requires a closed system.  
The cancer risk estimates at baseline attire for bromoxynil use on currently registered use sites ranged from 4.0x10[-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 estimates at baseline attire plus 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 estimates  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 estimates  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 flaggers, and from 2.5x10-7 to 1.2x10[-5] for applicators.  With a closed system, the cancer risk estimates  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.  

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[-7]
                                       









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[-7]




















      9.2 Short-/Intermediate-Term Post-Application Risks
HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide.  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on the type of activity, the nature of the crop or target that was treated, the type of pesticide application, or the pesticide's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.  
            
            9.2.1 Post-Application Exposure and Cancer Risks
Chemical-specific residue data were not submitted for bromoxynil, therefore, the standard assumption regarding dislodgeablity was used to estimate post-application exposure (i.e. HED uses 20% of the application rate was used as the initial dislodgeable foliar residue (DFR)).  The transfer coefficients (TC) used in this assessment are from an interim transfer coefficient policy developed by HED's ExpoSAC (Ag Default Transfer Coefficients, Policy 3.1).  It is the intention of HED's ExpoSAC that this policy will be periodically updated to incorporate additional information about agricultural practices in crops and new data on transfer TCs.  

The default TCs used in this assessment represent a wide range of possible activities at the highest exposure levels.  HED used extremely conservative inputs to estimate the post-application risk of bromoxynil: the assessment of post-application exposure represents high-end, worst-case scenarios.  For example, full foliage TCs were used for corn, sorghum, wheat, small grains, and mint as the use directions allow for later-stage application to the crops.  However, bromoxynil is likely to be applied more frequently in the early stages of plant growth to be the most effective against competing weeds, representing minimal foliage exposure for post-application workers (however the labels do not clearly specify early application timing for all crops, so full foliage was still assessed in certain scenarios). Additionally, post-application exposure was estimated using default, conservative residue values representative of the day of application.  Exposure is expected to diminish over time, because bromoxynil residues eventually dissipate in the environment.  With chemical-specific residue data, the residue values could be averaged seasonally to provide a more refined assessment of bromoxynil post-application exposure potential. Uncertainty surrounding bromoxynil residues available on foliage for transfer could be reduced with chemical-specific DFR studies.   

A summary of the occupational post-application dermal exposure and risk for post-emergent application of bromoxynil is provided in Tables 9.2.1.1, 9.2.1.2, 9.2.1.3, and 9.2.1.4.
	
The Agency assumed post-application exposure to treated crops could occur 30 days per year for high acreage crops (corn and wheat) and 10 days for all other crops.  Post-application cancer risk estimates assume contact with bromoxynil 30 and 10 days per year over a 35 year lifespan and are considered a worst case, extremely conservative estimation based on the bromoxynil use pattern.  As stated above, the Agency generally considers occupational cancer risks in the general range of 1x10[-6] to be negligible, but may accept risks as high as 1x10[-4] when all mitigation measures that are feasible and practical have been applied.  

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 1.1x10[-5].  Under the WPS for Agricultural Pesticides, a 24-hr REI is required for chemicals classified under Toxicity Category II.  Therefore, the REI on the Huskie(TM) Herbicide label should be 24 hours.  

Table 9.2.1.1. Occupational Post Application Exposure to Amended Uses of Bromoxynil 
                                     Crop
                  Maximum Proposed Application Rate (lb ai/A)
                                   Activity
                              Foliage Development
                                     TC[1]
                             Days After Treatment
                          Transferrable Residue[2,3]
                            Daily Dose (mg/kg/d)[4]
                                    MOE[5]
                                  Sorghum[2]
                                     0.22
                             Irrigation, Scouting
                                     Full
                                     1000
                                       0
                                     0.493
                                    0.0658
                                      150

                                     0.22
                                   Scouting
                                      Low
                                      100
                                       0
                                     0.493
                                    0.0066
                                     1,500
                     Grass Grown for Seed and CRP 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 (ug/cm[2])= application rate x 20% dissipation x 4.54 x10[8] ug/lb x 2.47 x 10[-8]A/cm[2], 
3 TTR (for Grass use sites) (ug/cm[2])= application rate x 5% dissipation x 4.54 x10[8] ug/lb x 2.47 x 10[-8]A/cm[2]
4 Dermal Dose (mg/kg/day) = DFR(t) or TTR (ug/cm[2]) x TC (cm[2]/hr)x hr/day (8 hours) x (1/1000 ug/mg) x (1/ 60 kg bw) where DFR(t)is dislodgeable foliar residue at time t
5 Dermal Short-Term MOE = NOAEL (10 mg/kg/day)/Dermal Daily Dose (mg/kg/day)


Table 9.2.1.2. Occupational Post Application Cancer Risk from Amended Agricultural Uses of Bromoxynil 
                                     Crop
                       Maximum Proposed Application Rate
                                   (lb ai/A)
                                   Activity
                              Foliage Development
                                     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 Grown for Seed and CRP Areas
                                     0.21
                                     Full
                           Mowing, pruning, weeding
                                      500
                                       0
                                     0.12
                                    0.0011
                                   0.000016
                                    1.6E-06
1 Transfer Coefficients from HED Policy No. 3.0.
2 DFR (ug/cm[2])= application rate x 20% dissipation x 4.54 x10[8] ug/lb x 2.47 x 10[-8]A/cm[2], 
3 TTR (for Grass use sites) (ug/cm[2])= application rate x 5% dissipation x 4.54 x10[8] ug/lb x 2.47 x 10[-8]A/cm[2]
4 Dermal Dose (mg/kg/day) = DFR(t) or TTR (ug/cm[2]) x TC (cm[2]/hr)x hr/day (8 hours) x (1/1000 ug/mg) x (1/ 60 kg bw) where DFR(t)is dislodgeable foliar residue at time t
5 LADD= (Dermal PPE Dose+Inhalation Baseline Dose) x average days of exposure (10/365) x (35 years/70 years).
6 Cancer Risk Estimates = LADD x Q1*, where Q1*=1.03E-1 (mg/kg/day)[-1].




Existing Use Sites
The short-and intermediate-term dermal non-cancer MOEs for all occupational post-application scenarios ranged from 45 to 1,400 on the day of application; and therefore, some post-application activities are of concern.  Risk from occupational contact with full foliage wheat, small grains and mint is not of concern 8 days after application, risk from sod harvesting is not of concern 5 days after application, and risk from occupational contact with full foliage corn, sorghum and cotton is not of concern 4 days after application.  The estimated cancer risks on the day of application ranged from 2.3x10[-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 Small Grains
                                      0.5
                                   Scouting
                                     Full
                                     1500
                                    1.1032
                                   0.220644
                                      45
                                       8
                                      105

                                      0.5
                             Irrigation, Scouting
                                      Min
                                      100
                                    1.1032
                                   0.0147096
                                      680
                                      N/A
                                    Cotton
                                      0.5
                                   Scouting
                                     Full
                                     1,000
                                    1.1032
                                   0.147096
                                      68
                                       4
                                      104
                               Seedling Alfalfa
                                     0.375
                             Irrigation, Scouting
                                      Min
                                      100
                                    0.8274
                                   0.0110322
                                      910
                                      N/A
                                     Flax
                                     0.25
                                   Scouting
                                      Min
                                      100
                                    0.5516
                                   0.0073548
                                     1,400

                                    Garlic
                                      0.5
                      Irrigation, scouting, hand weeding
                                      Min
                                      300
                                    1.1032
                                   0.0441288
                                      230

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

                                      0.5
                         irrigation, scouting, weeding
                                    Minimum
                                      100
                                    1.1032
                                   0.0147096
                                      680
                                      N/A
                                    Onions
                                     0.375
                      Irrigation, scouting, hand weeding
                                      Min
                                      300
                                    0.8274
                                   0.0330966
                                      300

                              Grass Grown for Sod
                                      0.5
                                  Harvesting
                                     Full
                                     5800
                                   0.275805
                                   0.2132892
                                      47
                                       5
                                      102
       Grass Grown for Seed, Non Residential Turf, 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 (ug/cm[2])= application rate x 20% dissipation x 4.54 x10[8] ug/lb x 2.47 x 10[-8]A/cm[2], TTR (for Grass use sites) (ug/cm[2])= application rate x 5% dissipation x 4.54 x10[8] ug/lb x 2.47 x 10[-8]A/cm[2]
3 TTR (for Grass use sites) (ug/cm2)= application rate x 5% dissipation x 4.54 x10[8] ug/lb x 2.47 x 10[-8]A/cm[2]
4 Dermal Dose (mg/kg/day) = DFR(t) (ug/cm[2]) x TC (cm[2]/hr)x hr/day (8 hours) x (1/1000 ug/mg) x (1/ 60 kg bw) where DFR(t)is dislodgeable foliar residue at time t
5 Dermal Short-Term MOE = NOAEL (10 mg/kg/day)/Dermal Daily Dose (mg/kg/day)

Table 9.2.1.4. Post Application Exposure and Cancer Risk to Workers from Bromoxynil Treatment to Registered Use Sites
                                     Crop
                      Maximum Application Rate (lb ai/A)
                                   Activity
                              Foliage Development
                                     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 Grown for Sod
                                      0.5
                                  Harvesting
                                     Full
                                     5800
                                      10
                                       0
                                    0.2803
                                    0.0316
                                    0.00043
                                    4.5E-05
       Grass Grown for Seed Non Residential Turf, 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 (ug/cm[2])= application rate x 20% dissipation x 4.54 x10[8] ug/lb x 2.47 x 10[-8]A/cm[2]
3 TTR (for Grass use sites) (ug/cm[2])= application rate x 5% dissipation x 4.54 x10[8] ug/lb x 2.47 x 10[-8]A/cm[2]
4 Dermal Dose (mg/kg/day) = DFR(t) (ug/cm[2]) x TC (cm[2]/hr)x hr/day (8 hours) x Dermal Absorption (17%) x (1/1000 ug/mg) x (1/ 70 kg bw) where DFR(t)is dislodgeable foliar residue at time t
5 LADD= (Dermal PPE Dose+Inhalation Baseline Dose) x average days of exposure (30/365) x (35 years/70 years)
6 Cancer Risk Estimates = LADD x Q1*, where Q1*=1.03E-1 (mg/kg/day)[-1]

Occupational Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative occupational post-application inhalation exposure assessment was not performed for bromoxynil at this time.  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational 
post-application inhalation exposure assessment for bromoxynil.

      9.3 Occupational Exposure Data Requirements & Label Changes
To characterize post-application exposure and reduce uncertainty for late applications of bromoxynil, HED is requesting the registrant submit a dislodgeable foliar residue (DFR) study on a representative row crop (e.g. corn).  HED suggests using corn for the study site because in the U.S., 57% of bromoxynil is applied exclusively to corn and the label allows for bromoxynil application to corn later in the growth cycle (post emergence to tassel emergence), resulting in potentially higher exposures.  

Based on email correspondence with the registrant (dated 11/01/2010), Huskie(TM) Herbicide (EPA Reg. No. 264-1023) is not intended for application with chemigation or aerially to grain sorghum, grass grown for seed and CRP areas.  The label should restrict aerial and chemigation explicitly from these use sites.  

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

Under the WPS for Agricultural Pesticides, a 24-hr REI is required for chemicals classified under Toxicity Category II.  Therefore, the REI on the Huskie(TM) Herbicide label should be 24 hours.  Other bromoxynil product labels should also require a 24-hr REI, except for the specific use sites of wheat, small grains and mint which require an REI of 8 days, sod harvesting which require an REI of 5 days, and corn, sorghum and cotton which require an REI of 4 days.

10.0 Environmental Justice Considerations
Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

11.0 References
Alsadek, J., 07/08/2010, DP# 378991, Usage Report Package in Support of Registration for the Herbicide Bromoxynil, (035302).

Dodd, N., 2/15/2011, DP# 378614, Bromoxynil.  Petition for Tolerances in Support of New Uses on Grass and Grain Sorghum.  Summary of Analytical Chemistry and Residue Data.

Goodlow, T., 8/17/2010, DP# 380770, Bromoxynil: Review of HUSKIE HERBICIDE  -  Magnitude of the Residue in/on Sorghum and Grass

Grube, A., 10/22/2010, DP# 382833, Usage Report Package in Support of Registration for the Herbicide Bromoxynil, (035301).

Mason, T., 12/16/2010, DP# 374620, Drinking water assessment for ground and aerial application of bromoxynil on grass grown for seed and ground application of sorghum.

Rury, K., 04/07/2011, DP# 378616, Bromoxynil:  Occupational and Residential Exposure Assessment for Proposed Field Uses of Bromoxynil on Sorghum, Grass Grown for Seed, Conservation Reserve Program Areas, and Existing Use sites of Bromoxynil. 

Walls, C., 03/22/2011, DP#378615, Bromoxynil:  Acute, Chronic, and Cancer Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the New Uses on Grass and Grain Sorghum.

Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements
The requirements (40 CFR 158.340) for non-food use for Bromoxynil are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity	
870.1200    Acute Dermal Toxicity	
870.1300    Acute Inhalation Toxicity	
870.2400    Primary Eye Irritation	
870.2500    Primary Dermal Irritation	
870.2600    Dermal Sensitization	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    Oral Subchronic (rodent)	
870.3150    Oral Subchronic (nonrodent)	
870.3200    21-Day Dermal	
870.3250    90-Day Dermal	
870.3465    90-Day Inhalation	
                                      yes
                                      yes
                                      yes
                                      no
                                      no
                                      yes
                                      yes
                                      yes
                                       -
                                       -
870.3700a  Developmental Toxicity (rodent)	
870.3700b  Developmental Toxicity (nonrodent)	
870.3800    Reproduction	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)	
870.4100b  Chronic Toxicity (nonrodent)	
870.4200a  Oncogenicity (rat)	
870.4200b  Oncogenicity (mouse)	
870.4300    Chronic/Oncogenicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Gene Mutation - bacterial	
870.5300    Mutagenicity -- Gene Mutation - mammalian	
870.5xxx    Mutagenicity -- Structural Chromosomal Aberrations	
870.5xxx    Mutagenicity -- Other Genotoxic Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotox. (hen)	
870.6100b  90-Day Neurotoxicity (hen)	
870.6200a  Acute Neurotoxicity Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Developmental Neurotoxicity	
                                      no
                                      no
                                      yes
                                      yes
                                      no
                                       -
                                       -
                                      no
                                      no
                                       -
870.7485    General Metabolism	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      no

A.2	Toxicity Profiles

Table A.2.1.  Acute Toxicity Profile
Guideline
Study
Species
Results
Tox. Category
MRID No.
                          Bromoxynil Phenol Technical
870.1100
Acute oral toxicity
Rat
LD50 = 81 mg/kg  M
LD50 = 93 mg/kg  F)
II
00124758
870.1200
Acute dermal toxicity
Rat
LD50 >= 2000 mg/kg (M, F)
III
00124758
870.1300
Acute inhalation toxicity
Rat
LC5O = 0.269 mg/L  M 
LC5O = 0.150 mg/L F
II
43014701
870.2400
Primary eye irritation
Rabbit
Corneal opacity resolved within 3 days; iritis resolved within 4 days; conjunctival irritation persisted for 10 days.
II
00124758
870.2500
Primary skin irritation
Rabbit
Not an irritant
IV
00124758
870.2600
Dermal sensitization 
Guinea Pig
Not a sensitizer
Negative
42718701
                        Bromoxynil Octanoate Technical
870.1100
Acute oral toxicity
Rat
LD50 = 400 mg/kg  M
LD50 = 238 mg/kg  F
II
00124112
870.1100
Acute dermal toxicity
Rabbit
LD50> 2000 mg/kg  M
  abraded skin.
LD50 1310 mg/kg  F
  with intact skin.
LD50 = 1660 mg/kg  F
  with abraded skin.
II
00124112
870.1300
Acute inhalation toxicity
Rat
LC5O = 0.810 mg/L  M 
LC5O = 0.720 mg/L  F
III
42167101
870.2400
Primary eye irritation
Rabbit
Corneal opacity and irritation lasting 24-72 hrs. Cleared by 96 hrs.
II
00124112
870.2500
Primary skin irritation
Rabbit
Erythema for 72 hrs. No edema.,
IV
00124112
870.2600
Dermal sensitization
Guinea Pig
Contact sensitizer in modified Draize test.
Positive
41879801















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

90-Day oral toxicity (rat)
MRID 41469101 (1985)

0, 400, 755 or 1456 ppm 
0, 28, 58, 168 mg/kg/day M
0, 35, 76,250 mg/kg/day F
Dietary

Supplementary
NOAEL:  M = 28 mg/kg/day,  F  not established
LOAEL 
  M = 58 mg/kg/day), based on decreased body weight gain, increased ALT, increased AST and increased alkaline phosphates.  
  F = 35 mg/kg/day), based on decreased body weight gain.  This study is of limited usefulness because a NOAEL was not determined for females, excessive mortality occurred in males and females at the highest dose level tested, and an insufficient number of tissues was microscopically examined.
870.3100

90-Day oral toxicity (mouse)
MRID 42553401 (1992)

0, 10, 30, 100, 300, 1000 or 3000 ppm 
0, 1.3, 3.9, 13, 39, 130 or 390 mg/kg/day M, F
Dietary

Supplementary
(Range-finding)
NOAEL:  M = 3.9 mg/kg/day, F = 13 mg/kg/day
LOAEL:
  M = 13 mg/kg/day), based on increased liver weights and HC hypertrophy
  F = 39 mg/kg/day, based on increased liver weights, heptatocellular (HC) hypertrophy, HC degeneration and HC vacuolization.
870.3150

90-Day oral toxicity rodents (dog)
MRID 43166701 (1988)

1, 5, 8, 12, 16, 20, 30, 40 or 50 mg/kg/day
Capsule

Supplementary
(Range-finding)
NOAEL:  M  not established, F = 1 mg/kg/day
LOAEL:
  M = 1 mg/kg/day for males, based on decreased body weight gain.  
  F = 5 mg/kg/day, based on decreased body weight gain, panting and liquid feces.

At doses above the LOAELs M and/or F, the following  additional effects were observed: panting, liquid feces, salivation, unsteady gait, decreased erythrocyte count, decreased hemoglobin, decreased packed cell volume, increased urea nitrogen, vomiting and mortality.

Toxicities observed during the first day of the study (single dose effects) were elevated rectal temperatures, panting and death.

Single dose NOAEL = 8.0 mg/kg 
Single dose LOAEL = 12 mg/kg based on panting.  Elevated rectal temperatures occurred at 16 mg/kg and above, and death occurred at 30 mg/kg and above
870.3200

21-Day dermal toxicity (rabbit)
MRID 42272301 (1992)

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

Minimum
Dermal 
  NOAEL = not established
  LOAEL = 1000 mg/kg/day
Systemic
  NOAEL = not established
  LOAEL = 1000 mg/kg/day
870.3700a

Prenatal developmental in rats
(MRID 40466802 (1992)

0, 4, 12.5 or 40 mg/kg/day on gestation days 6-15
Gavage
Sprague-Dawley

Supplementary
Maternal NOAEL = 12.5 mg/kg/day

Maternal LOAEL =  40 mg/kg/day based on decreased body weight gain throughout most of the treatment and post-treatment period and decreased food consumption during the treatment period.

Developmental NOAEL = 4 mg/kg/day

Developmental LOAEL = 12.5 mg/kg/day based on increased incidence of supernumerary (14th) ribs and Increased post-implantation loss.  At 40 mg/kg/day, the following additional effects were observed in the offspring:  reduced fetal weight, increased numbers of small fetuses, and increased incidences of soft tissue and skeletal abnormalities (including anophthalmia, microphthalmia, short renal papilla, and spinal and thoracic bone abnormalities).
870.3700a

Prenatal developmental in rats
MRID 00116558 (1981)
(00070894, 00071084) 

0, 5, 15 or 35 mg/kg/day on gestation days 5-17
Gavage
Sprague-Dawley

Supplementary
Maternal NOAEL = 5 mg/kg/day
Maternal LOAEL = 15 mg/kg/day based on decreased body weight gain.  At 35 mg/kg/day, 6/28 dams died between days 7 and 14 of gestation.

Developmental NOAEL = not established.
Developmental LOAEL = 5 mg/kg/day based on increased incidence of 14th ribs.  At the high dose of 35 mg/kg/day, additional effects included an increased incidence of late intrauterine deaths, decreased fetal body weights and an increase in the total incidence of minor anomalies.
870.3700a

Prenatal developmental in rats
Rogers, Francis, Barbee et al. (1991)

0, 1.7, 5 or 15 mg/kg/day on gestation days 6-15
Gavage
Sprague-Dawley

Not classified.
Maternal NOAEL = 5 mg/kg/day
Maternal LOAEL = 15 mg/kg/day, based on decreased body weight gain and increased liver weights.

Developmental NOAEL = 5 mg/kg/day
Developmental LOAEL = 15 mg/kg/day, based on an increased incidence of supernumerary ribs.
870.3700a

Prenatal developmental in rats - dermal
MRID 40881201, 40883601 (1988)

0, 5, 10, 50 or 100 mg/kg/day for 6 hours/day on gestation days 6-15.

Sprague-Dawley

Supplementary
Maternal dermal NOAEL = 100 mg/kg/day
Maternal dermal LOAEL not established

Maternal systemic NOAEL = 50 mg/kg/day
Maternal systemic LOAEL = 100 mg/kg/day based on decreased body weight gain and decreased food consumption during the treatment period..

Developmental NOAEL = 10 mg/kg/day
Developmental LOAEL = 50 mg/kg/day, based on increased 14th ribs
870.3700b

Prenatal developmental in (rats)
[MRID 00138149 (1983)

0, 15, 30 or 60 mg/kg/day on gestation days 5-20

Gavage
New Zealand White

Guideline
Maternal NOAEL = 15 mg/kg/day
Maternal LOAEL = 60 mg/kg/day, based on reduced body weight gain and reduced food consumption during the treatment period.  There were no deaths or clinical signs of toxicity associated with treatment..

Developmental NOAEL = not established
Developmental LOAEL = 15 mg/kg/day, based on an increased incidence of supernumerary ribs. At 60 mg/kg/day, the following additional effects were also observed:  increased post-implantation loss (due primarily to 5 totally resorbed litters), decreased fetal weights, and increased numbers of litters and numbers of fetuses with major malformations (including hydrocephalus, anophthalmia, microphthalmia and defects in skull ossification).  The incidence of total minor anomalies was also increased at 60 mg/kg/day.
870.3700b
Prenatal developmental in nonrodents (rabbit)
MRID 00142779 (1983)

0, 30, 45 or 60 mg/kg/day on gestation days 6-18

Gavage
New Zealand White

Supplementary
Maternal NOAEL = 15 mg/kg/day
Maternal LOAEL = 60 mg/kg/day, based on increased mortality (7/23 dams died at this dose level) and other clinical signs of toxicity, such as anorexia and discharge of blood.

Developmental NOAEL = not established
Developmental LOAEL = 15 mg/kg/day, based on decreased fetal body weights. At 45 and 60 mg/kg/day, a dose-related increase in extra or rudimentary 14th ribs also was observed. At 60 mg/kg/day, several vertebral and thoracic bone abnormalities, including fused ribs, scoliosis, extra ribs, thoracic centrum misshapen and incomplete ossification of sternebrae, were observed.
870.3700b
Prenatal developmental in nonrodents (rabbit) dermal
MRID 40935101, 41307801 (1988)

0, 10, 50 or 150 mg/kg/day for 6 hours/day on gestation days 6-18.

New Zealand White


Supplementary
Maternal dermal NOAEL = 150 mg/kg/day
Maternal dermal LOAEL not established

Maternal systemic NOAEL = 50 mg/kg/day
Maternal systemic LOAEL = 150 mg/kg/day based on decreased body weight gain.

Developmental NOAEL = 10 mg/kg/day
Developmental LOAEL = 50 mg/kg/day, based on an apparent increase in agenesis of the intermediate lobe of the lung and on an increase in holes in the parietal portion of the skull.
870.3700a

Prenatal developmental in mice  -  oral
Rogers, Francis, Barbee et al. 1991

0, 11, 32 or 96 mg/kg/day on gestation days 6-15

Gavage
Swiss Webster (CD-1)

Not Classified
Maternal NOAEL = 11 mg/kg/day
Maternal LOAEL = 32 mg/kg/day, based on increased mortality and increased liver weights.

Developmental NOAEL = 32 mg/kg/day
Developmental LOAEL = 96 mg/kg/day, based on increased incidence of 14th ribs, decreased fetal weights and decreased numbers of fetuses with ossified vertebrae.
870.3800

Reproduction and fertility effects
(2-generation rat)
MRID 41149301 (1989)

0, 10, 50 or 250 ppm (approximately 0, 0.8, 4 or 21 mg/kg/day during 14 weeks prior to mating)

Sprague-Dawley

Minimum
Parental NOAEL = 4 mg/kg/day
Parental LOAEL = 21 mg/kg/day based on decreased body weight gain in F0 and F1 females before mating, during gestation and lactation and at study termination.  In addition, possibly increased liver weights were observed in both male and female adults.

Reproductive NOAEL = 21 mg/kg/day
Reproductive LOAEL = not established

Offspring NOAEL = 4 mg/kg/day
Offspring LOAEL = 21 mg/kg/day based on decreased body weight gain during lactation and delayed eye opening.
870.3800

Reproduction and fertility effects
(3-generation rat)
MRID 00064815 (1978)
(00242060)

0, 30, 100 or 300 ppm (equivalent to 0, 1.5, 5 or 15 mg/kg/day)

Wistar

Supplementary 

Parental NOAEL = 1.5 mg/kg/day
Parental LOAEL = 5.0 mg/kg/day based on decreased body weight gain in F1 and F2 parents

Reproductive NOAEL = 15 mg/kg/day
Reproductive LOAEL = not established.

Offspring NOAEL = 5 mg/kg/day
Offspring LOAEL = 15 mg/kg/day based on decreased body weight particularly in F2 generation.
870.4100a

Chronic toxicity
(rat)
See 870-4300

870.4100b

Chronic toxicity (dog)
MRID 40780301, 41304701 (1988)

0, 0.1, 0.3, 1.5 or 7.5 mg/kg/day
Capsule

Guideline
Threshold dose = 1.5 mg/kg/day, (slightly decreased body weight gain in males)
LOAEL = 7.5 mg/kg/day, M & F, based on increased incidences of salivation, panting, liquid feces and pale gums;  statistically significant decreased body weight gain over entire duration of study, but particularly during first 8 weeks of study;  statistically significant decreased erythrocytes (RBC), hemoglobin (Hb) and packed cell volume (PCV);  statistically significant increased urea nitrogen; increased absolute liver weights and liver/body weight ratios.
870.4200

Carcinogenicity
(mice)
MRID 00068077 (1982)

0, 10, 30 or 100 ppm 
0, 1.3, 3.9 or 13 mg/kg/day.

Dietary
Swiss albino

Guideline for chronic feeding study. 

  
NOAEL
   M = 3.9 mg/kg/day
   F = 13 mg/kg/day
LOAEL
   M = 13 mg/kg/day based on a dose-related increased incidence of liver adenomas/carcinomas combined, the incidence being statistically significant at 13 mg/kg/day
   F = not established.  

Carcinogenicity: 
   M  Positive evidence of neoplasms in males as stated above
   F  No tumors were observed in females; CARC (1991) concluded dose levels in females were not sufficiently high to assess tumorigenic potential.
870.4200

Carcinogenicity
(mice)
MRID 43245501 (1994)

0, 20, 75 or 300 ppm
0, 3.1, 12, 46 mg/kg/day M 
0, 3.7, 14, 53 mg/kg/day F

CD-1

Acceptable for chronic feeding and for oncogenicity

NOAEL = 12 mg/kg/day M, 14 mg/kg/day F
LOAEL = 46 mg/kg/day M, 53 mg/kg/day F, based on increased liver weights, increased incidences of diffusely dark livers, and increased incidences of non-neoplastic microscopic lesions in liver.  Histopathologic lesions in the liver included hepatocellular centrilobular hypertrophy, hepatocellular degeneration/necrosis, and pigment in hepatocytes and Kupffer cells.

Carcinogenicity: 
  Males: treatment-related increased incidences of hepatocellular adenomas, carcinomas, and adenomas/carcinomas combined were observed in the male mice at all dose levels in this study.
  Females: slightly increased incidences of hepatocellular carcinomas and of adenomas/carcinomas combined was observed at the high dose level only.  
870.4300

Combined Chronic/Carcinogenicity (rats)
MRID 00096521 (1982)
(00064815)

0, 10, 30,100 ppm 
0, 0.5, 1.5, 5 mg/kg/day)
Dietary

Supplementary for chronic feeding and for oncogenicity
NOAEL = 5 mg/kg/day, M & F
LOAEL = not established

Carcinogenicity:  
No evidence of an increased incidence of neoplasms in males or females.  Dose levels used in this study were determined to be insufficiently high to assess carcinogenic potential.   
870.4300

Combined Chronic/Carcinogenicity (rats)
MRID 40612501, 41374801 (1988)

0, 60, 190 or 600 ppm 0, 2.6, 8.2 or 28 mg/kg/day M
0, 3.3, 11.0 41 mg/kg/day F
Dietary

Minimum for chronic feeding and for oncogenicity
NOAEL = 2.6 mg/kg/day M,  3.3 mg/kg/day F
LOAEL:
   M = 8.2 mg/kg/day, based on an increased incidence of spongiosis hepatis in the liver.  
   F: 11.0 mg/kg/day, based on decreased body weight gain.  

Carcinogenicity:  
No evidence of an increased incidence of neoplasms in males or females.  Dose levels used in this study were determined to be sufficiently high to assess carcinogenic potential.   
870.5100

Bacterial reverse mutation test (Salmonella)
MRID 41995701 (1991)

Strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to technical grade bromoxynil phenol without metabolic activation at concentrations ranging from 3.33 to 1000 ug/plate and with metabolic activation (rat S9 mixture) at concentrations ranging from 10.0 to 3330 ug/plate.

Acceptable
Negative.

Bromoxynil phenol, without and with metabolic activation, did not induce a genotoxic effect in this assay system.
870.5375

In vitro mammalian chromosome aberration test
MRID 00115651 (1982)

Cultures of Chinese hamster ovary (CHO) cells were exposed to technical grade bromoxynil phenol without metabolic activation at concentrations ranging from 100 to 1500 ug/ml (8 hour exposure) and from 50 to 500 ug/ml (20 hour exposure).

Acceptable
Negative without activation

Positive with activation at >= 1200 ug/ml

Bromoxynil phenol did not induce a genotoxic effect in the non-activated portion of this assay, but the significant increase in chromosome damage in the activated portion of this assay at concentrations equal to and above 1200 ug/ml was considered to be a positive genotoxic response.
870.5395

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

Bromoxynil phenol was administered orally by gavage on two consecutive days to groups of 5 male and 5 female CD-1 mice at dose levels of 0 (control), 21.6, 69.0 or 215.5  mg/kg/day.

Acceptable
Negative at dose levels up to 215.5 mg/kg/day which produced target cell toxicity as well as death

Bromoxynil phenol did not induce a clastogenic effect in this assay system.
870.5395

In vivo Mammalian erythrocyte micronucleus test
MRID 42092301 (1991)

Single doses of technical grade bromoxynil phenol were administered orally by gavage to groups of 5 male and 5 female CD-1 mice at dose levels of 0 (control), 35, 70 or 105 mg/kg.

Acceptable
Negative

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

870.5550

Unscheduled DNA synthesis in mammalian cells
MRID 00115646 (1982)

Cultures of primary rat hepatocytes were exposed to technical grade bromoxynil phenol at concentrations ranging from 0.1 to 50 ug/ml.

Acceptable
Negative

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

870.5xxx

In vitro transformation assay
MRID 00115647 (1982)

Cultures of mouse C3H/10T (1/2) C18 cells were exposed to technical grade bromoxynil phenol at concentrations ranging from 32.5 to 390 ug/ml.

Acceptable
Negative

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

870.5xxx
	
Sister Chromatid Exchange
MRID 00115648 (1982)

Cultures of Chinese hamster ovary (CHO) cells were exposed to technical grade bromoxynil phenol without metabolic activation at concentrations ranging from 4.67 to 18.7 ug/ml and with metabolic activation (rat S9 mixture) at concentrations ranging from 500 to 900 ug/ml.

Acceptable
Negative

Bromoxynil phenol did not induce a genotoxic effect in this assay system.
870-5xxx

Forward mutation
Mouse lymphoma cells
MRID 00115649 (1982)

Cultures of L5178Y TK+/- cells were exposed to technical grade bromoxynil phenol without metabolic activation at concentrations ranging from 15.6 to 250 ug/ml and with metabolic activation (rat S9 mixture) at concentrations of 3.9, 7.8, 15.6, 31.3 or 62.5 ug/ml.

Acceptable
Negative without activation

Positive with activation at 31.3 and 63 ug/ml.

Bromoxynil phenol did not induce a genotoxic effect in the non-activated portion of this assay, but the dose-related increase in mutant colonies in the activated portion of this assay was considered to be a positive genotoxic response.    

870-5xxx

Forward mutation 
Mouse lymphoma cells
MRID 41995702  (1991)

Cultures of Chinese hamster ovary (CHO)/HGPRT locus cells were exposed to technical grade bromoxynil phenol without and with metabolic activation (rat S9 mixture) at concentrations ranging from 100 to 1000 ug/ml.

Acceptable
Negative

Bromoxynil phenol, without and with metabolic activation, did not induce a genotoxic effect in this assay system.
870-5xxx

DNA Repair Test 
(E. coli)
MRID 00115650 (1982)

Cultures of both indicator strains (Escherichia coli indicator strains pol A+ (W3110) and pol A- (p3478)) on agar plates were exposed to technical grade bromoxynil phenol without and with metabolic activation (rat S9 mixture) at concentrations ranging from 1.0 to 10000 ug/plate.

Acceptable
Positive without activation at >= 1000 ug/plate

Positive with activation at >= 1000 ug/plate

Bromoxynil phenol induced a positive genotoxic response in both the non-activated and activated portions of this assay.
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 remained in/on the skin.

Percent dermal absorption at 24 hours was 3.12%, 3.24% and 3.02% for doses of 0.10, 1.0 and 10.0 mg/rat respectively.  Following a soap and water wash (at 24 hours), 18.99%, 7.84% and 2.03% of the respective doses remained in/on the skin.















Table A.2.3 Toxicity Profile for Bromoxynil Octanoate
                                 Guideline No.
                                  Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
870.3100

13-Week oral toxicity 
(rat)
MRID 42411901 (1992)

0, 150, 600, 1100 ppm 0, 11, 45, 91 mg/kg/day M
0, 13, 55, 111 mg/kg/day F
Dietary

Minimum
NOAEL:  M = 45 mg/kg/day, F = 13.mg/kg/day
LOAEL
M = 91 mg/kg/day, based on decreased body weight gain, decreased serum total protein, decreased globulins and increased degeneration/necrosis of cardiac myofibers and possibly increased thymic lymphocyte necrosis.  F = 55 mg/kg/day, based on decreased body weight gain and increased liver weights
870.3150

13-Week oral toxicity dog
MRID 42869701, 43700201 (19)

0, 0.43, 1.43 or 7.14 mg/kg/day
Capsule

Supplementary
NOAEL = 0.43 mg/kg/day, M & F
LAAEL = 1.43 mg/kg/day, M & F, based on decreased body weight gain
870.3150

13-Week oral toxicity dog
MRID 00061179 (1965)
(00090653, 00111190)
0, 1, 5 or 25 mg/kg/day

Capsule

Supplementary
NOAEL = 1.0 mg/kg/day, M & F
LOAEL = 5.0 based on occasional panting (considered a threshold dose).  At 25 mg/kg/day, additional signs of toxicity, observed in both males and females, were panting (after each dose) throughout the study; decreased body weight gain; possibly decreased erythrocyte counts, hemoglobin, and packed cell volume; and increased serum urea nitrogen.
870.3200

21-Day dermal toxicity (rabbit)
MRID 42346201 (19--)

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

Minimum
Dermal 
  NOAEL = 30 mg/kg/day, M & F
  LOAEL = 300 mg/kg/day, M & F, based on significant dermal irritation consisting of slight to moderate redness and swelling, cracking and flaking of the skin

Systemic
  NOAEL = not established
  LOAEL = 1000 mg/kg/day
870.3150

90-Day oral toxicity in nonrodents (dog)
No study data are currently available

870.3700a

Prenatal developmental in rodents (rat) - oral
Rogers, Francis, Barbee et al. 1991

0, 2.4, 7.3 or 21.8 mg/kg/day on gestation days 6-15
Gavage
Sprague-Dawley

Not classified
Maternal NOAEL = 7.3 mg/kg/day
Maternal LOAEL = 21.8 mg/kg/day, based on decreased body weight gain and increased liver weights.

Developmental NOAEL = 7.3 mg/kg/day
Developmental LOAEL = 21.8 mg/kg/day, based on an increased incidence of 14th ribs and on reduced fetal weights.
870.3700a

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 skin irritation, 

Maternal systemic NOAEL = 15 mg/kg/day
Maternal systemic LOAEL = 20 mg/kg/day based on decreased body weight gain and decreased food consumption during the treatment period., 

Developmental NOAEL = 10 mg/kg/day
Developmental LOAEL = 15 mg/kg/day based on increased incidence of supernumerary (14th) ribs. At 20 and 75 mg a.i./kg/day, the incidences of supernumerary ribs were increased still further.
870.3700b

Prenatal 
developmental in 
non-rodents (rabbit) - dermal
MRID 41471901, 42183901 (1990)

0, 5, 10, 15, 20, 40 or 80 mg a.i./kg/day for 6 hours/day on gestation days 6-18

New Zealand White

Supplementary

Maternal dermal NOAEL = not established
Maternal dermal LOAEL = 5.0 mg/kg/day based on skin irritation. At 15 mg/kg/day and higher, a majority of treated animals manifested erythema, fissuring and desquamation.

Maternal systemic NOAEL = 80 mg/kg/day
Maternal systemic LOAEL =  not established 

Developmental NOAEL = 80 mg/kg/day
Developmental LOAEL = not observed
870.3700a

Prenatal developmental in rodents (rabbit) - oral
No study available
No study is necessary (Fifth Developmental Toxicity Peer Review Committee, 4/21, 1992)
870.3800

Reproduction and fertility effects -  Rat
Oral
No study available

870.3800

Reproduction and fertility effects -  Rat
Dermal
MRID 41667401 (1990)

Male rats treated with 0, 25, 50 or 100 mg a.i./kg/day for 21 days, then mated with unexposed female rats on days 1, 7, 14, 21, 35, 56 or 113 post-exposure.

Supplementary 
Special study.
Male dermal NOAEL =50 mg/kg/day
Male dermal LOAEL = 100 mg/kg/day, based on significant skin irritation.

Male systemic NOAEL = 25 mg/kg/day
Male systemic LOAEL = 50 mg a.i./kg/day, based on decreased body weight gain.  At 100 mg a.i./kg/day, possibly increased liver weights were also observed.

Male reproductive NOAEL = 50 mg/kg/day
Male reproductive LOAEL = 100 mg a.i./kg/day (tentative), based on possibly decreased prostate gland weight.  

Offspring NOAEL =100 mg/kg/day
Offspring LOAEL = not established
870.4100b

Chronic toxicity dogs
No study data are currently available.  Please refer to 870.4100b for bromoxynil phenol

870.4200

Carcinogenicity rats
No study data are currently available.  Please refer to 870.4200 for bromoxynil phenol

870.4300

Carcinogenicity mice
No study data are currently available.  Please refer to 870.4300 for bromoxynil phenol

870.5100

Bacterial reverse mutation test
Salmonella/mammalian microsome

MRID 43022701 (1993)

Strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to technical grade bromoxynil octanoate without and with metabolic activation (rat S9 mixture) at concentrations ranging from 33 to 10000 ug/plate.

Acceptable
Negative.

Bromoxynil octanoate, without and with metabolic activation, did not induce a genotoxic effect in this assay system.

870.5395

Mammalian in vivo erythrocyte micronucleus test
MRID 41930802 (1991)

Single doses of technical grade bromoxynil octanoate were administered orally by gavage to groups of 5 male CD-1 mice at dose levels up to 183 mg/kg and to groups of 5 female CD-1 mice at dose levels up to 267 mg/kg.

Acceptable
Negative.

Bromoxynil octanoate did not induce a clastogenic effect in this assay system.

870.5550

Unscheduled DNA synthesis in mammalian cells
Cultures of primary rat hepatocytes were exposed to technical grade bromoxynil octanoate at concentrations ranging from 0.98 to 15.63 ug/ml.  Higher concentrations (> 31.25 ug/ml) were cytotoxic.

Acceptable
 Negative

Bromoxynil octanoate did not induce a genotoxic effect in this assay system.   (MRID 42078901)    

870.6300

Developmental neurotoxicity rats
No study available

870.7600

Dermal Absorption - rat
MRID 40854603 (1988)

[14]C-Bromoxynil octanoate, incorporated into the end-use product Buctril, which contained 33.4% bromoxynil octanoate as the active ingredient, was topically applied to the skin of male Sprague Dawley rats at doses of 0.08, 0.4 or 3.4 mg/rat for durations of exposure of 0.5, 1, 2, 4, 10 or 24 hours (4 rats/dose/duration of exposure).

Acceptable
Percent dermal absorption at 10 hours was 10.32%, 7.07% and 4.51% for doses of 0.08, 0.4 and 3.4 mg/rat respectively.  Following a soap and water wash (at 10 hours), 6.46%, 8.06% and 6.13% of the respective doses remained in/on the skin.  

Percent dermal absorption at 24 hours was 17.58%, 18.43% and 10.88% for doses of 0.08, 0.4 and 3.4 mg/rat respectively.  Following a soap and water wash (at 24 hours), 7.91%, 9.50% and 4.97% of the respective doses remained in/on the skin. 



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 dosing regimen.  Rate of absorption was moderate in both males and females; peak plasma concentrations of radioactivity were not reached until 7-10 hours after dosing.

Radioactivity was widely distributed in most tissues; highest concentrations were observed in blood, plasma, liver, kidneys and thyroid (especially in females).  Levels of radioactivity in tissues were generally higher in females than in males.  Most radioactivity was excreted in the urine (about 84-89% in males and 76-80% in females at 7 days) and considerably lesser amounts in the feces (about 6-10% in both males and females at 7 days).

Excretion was more rapid in males than in females.  Retention of radioactivity in tissues after 7 days was about 2-3% in males and 7-9% in females.  Essentially all bromoxynil octanoate was rapidly and nearly completely converted to bromoxynil phenol via ester hydrolysis.  

In special studies, the only chemical species identified in tissues was bromoxynil phenol per se; no bromoxynil octanoate was identified in tissues.  In urine, the only major species was free and conjugated bromoxynil phenol with no bromoxynil octanoate being present.  In feces, however, some bromoxynil octanoate was identified.



A.3	HAZARD IDENTIFICATION AND ENDPOINT SELECTION
A.3.1	Acute Reference Dose (aRfD)  -  General Population (Including Infants and Children)
Study Selected: Subchronic Study in Dogs
MRID No.:  43166701
Executive Summary:  In a 13-week range-finding study, technical grade bromoxynil phenol was administered orally in gelatin capsules to groups of 2 male and 2 female beagle dogs at dose levels of 0 (control), 1, 5, 8, 12, 16, 20, 30, 40 or 50 mg/kg/day.  Treatment-related decreased body weight gain was observed in males at all dose levels tested.  At 5 mg/kg/day, occasional panting and liquid feces were also noted and at 8 and 12 mg/kg/day, frequent panting, occasional salivation, unsteady gait, decreased erythrocyte count, decreased hemoglobin, decreased packed cell volume, and increased urea nitrogen were observed.  Dose levels of 16 mg/kg/day and higher were clearly excessive and caused mortality and/or signs of severe toxicity.  Decreased body weight gain, occasional panting and liquid feces were observed in females at 5 mg/kg/day.  At 8 mg/kg/day and higher, effects in females were the same as in males.  For males, no NOAEL was determined in this study (<1 mg/kg/day).  The LOAEL is 1 mg/kg/day for males, based on decreased body weight gain.  For females, the NOAEL is 1 mg/kg/day and the LOAEL is 5 mg/kg/day, based on decreased body weight gain, panting and liquid feces.  This study was a range-finding study.  Only 2 dogs/sex/dose level were used and an insufficient number of tissues was microscopically examined in the control group and at dose levels of 12 mg/kg/day and lower.  
Dose and Endpoint for Establishing aRfD:  The NOAEL of 8 mg/kg/day is based on an effect attributed to a single dose (panting) at the LOAEL of 12 mg/kg/day. The study NOAELs and LOAELS based on decreased body weight gain are not attributable to a single dose.  In addition to panting, elevated rectal temperature occurred at 16 mg/kg/day and above, and death occurred at 30 mg/kg/day and above after a single dose on day One. 
UF(s):  A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies variation (10X).
Comments on Study/Endpoint/UFs:  This study provides the lowest NOAEL in the database (most sensitive endpoint) and is expected to be protective for any potential single-dose adverse effects in humans.  In the dog, increased panting can be an adaptive, compensatory response to elevated body temperature, vs. an adverse effect.  In this study, the cascade of events beginning with panting on day one, followed by a progression of elevated rectal temperature and eventually death, were considered adverse responses.

      aRfD = 8 mg/kg/day (NOAEL) = 0.08 mg/kg/day
                            100 (UF)

A.3.1a	Acute Reference Dose (aRfD)  -  Females 13+
Study Selected: Developmental Toxicity in Rats (Oral)
MRID No.:  40466802, 00116558
Executive Summary:  In an oral developmental toxicity study (MRID 40466802), technical grade bromoxynil phenol was administered to groups of 22 pregnant Sprague Dawley rats by gavage at doses of 0 (control), 4, 12.5 or 40 mg/kg/day on gestation days 6-15, inclusive.  The developmental toxicity NOAEL is 4 mg/kg/day.  A dose-related increased incidence of supernumerary (14th) ribs was observed at the developmental toxicity LOAEL of 12.5 mg/kg/day.  Increased 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, and increased incidences of soft tissue and skeletal abnormalities (including anophthalmia, microphthalmia, short renal papilla, and spinal and thoracic bone abnormalities).  The maternal toxicity NOAEL is 12.5 mg/kg/day and the maternal toxicity LOAEL is 40 mg/kg/day, based on decreased body weight gain throughout most of the treatment and post-treatment period and decreased food consumption during the treatment period.    

In an oral developmental toxicity study (MRID 00116558), groups of 28 pregnant Sprague Dawley rats received 0 (control), 5, 15 or 35 mg/kg/day of technical grade bromoxynil phenol by gavage on gestation days 5-17, inclusive.  No developmental toxicity NOAEL was determined in this study (below 5 mg/kg/day).  At the LOAEL of 5 mg/kg/day, a dose-related increased incidence of 14th ribs was observed.  At the high dose of 35 mg/kg/day, additional effects included an increased incidence of late intrauterine deaths, decreased fetal body weights and an increase in the total incidence of minor anomalies.  The maternal toxicity NOAEL is 5 mg/kg/day and the maternal toxicity LOAEL is 15 mg/kg/day, based on decreased body weight gain.  At 35 mg/kg/day, 6/28 dams died between days 7 and 14 of gestation. 

Dose and Endpoint for Establishing aRfD:  The NOAEL of 4 mg/kg/day (MRID 40466802) is based on an increase of supernumerary ribs seen at the LOAEL of 5 mg/kg/day in a co-critical study (MRID 00116558).
 
UF(s):  A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies variation (10X).
Comments on Study/Endpoint/UFs:  These studies provide the lowest NOAEL in the database (most sensitive endpoint) and is expected to be protective for any potential single-dose adverse effects in humans.  The LOAEL derived from a co-critical study is very close to the NOAEL and suggests a steep dose-response curve.  While the BMD data (benchmark dose = 13.66 mg/kg/day) suggest that the dose-response curve is not as steep as the observed effects would indicate, HED has taken the most protective approach and used the observed effects in the risk assessment.
      aRfD = 4 mg/kg/day (NOAEL) = 0.04 mg/kg/day
                            100 (UF)

A.3.2	Chronic Reference Dose (cRfD)  -  All Populations
Study Selected:  Chronic (1-year) Study in Dogs
MRID No.: 40780301 and 41304701
Executive Summary:   In a 12-month chronic oral toxicity study, technical grade bromoxynil phenol was administered in gelatin capsules to groups of 6 male and 6 female beagle dogs at dose levels of 0 (control), 0.1, 0.3, 1.5 or 7.5 mg/kg/day.  At the highest dose level tested (7.5 mg/kg/day), the following treatment-related effects were observed in both male and female dogs:  increased incidences of salivation, panting, liquid feces and pale gums;  statistically significant decreased body weight gain over entire duration of study, but particularly during first 8 weeks of study;  statistically significant decreased erythrocytes (RBC), hemoglobin (Hb) and packed cell volume (PCV);  statistically significant increased urea nitrogen; increased absolute liver weights and liver/body weight ratios.  At 1.5 mg/kg/day, a statistically significant decreased body weight gain over the entire duration of study was observed in the male dogs.  Other "effects" at this same dose level were marginal, inconsistent and of equivocal toxicological significance.  These effects included panting; decreased RBC, Hb and PCV; increased urea nitrogen; and increased absolute and relative liver weights in males and panting and increased absolute and relative liver weights in females.  No treatment-related gross or histo-pathological changes were observed in any organs in this study.  The dose level of 1.5 mg/kg/day is considered to be a threshold NOAEL/LOAEL for both male and female dogs in this study.

Dose and Endpoint for Establishing cRfD:  The NOAEL of 1.5 mg/kg/day is based on increased incidences of salivation, panting, liquid feces and pale gums; statistically significant decreased body weight gain over the entire duration of the study, but particularly during the first 8 weeks of the study; statistically significant decreased erythrocytes (RBC), hemoglobin (Hb) and packed cell volume (PCV); statistically significant increased urea nitrogen; increased absolute liver weights and liver/body weight ratios seen at the LOAEL of 7.5 mg/kg/day in both sexes.
UF(s):  A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies variation (10X).
Comments about Study/Endpoint/UF:  This study provides the lowest NOAEL in the database (most sensitive endpoint) that reflects chronic (long-term) exposure which is the duration relevant to human dietary exposure.  
      cRfD = 1.5 mg/kg/day (NOAEL) = 0.015 mg/kg/day
                      100 (UF)

A.3.3	Dermal Short-Term (1-30 days) and Intermediate-Term (1-6 Months) 
Study Selected:  Rat Dermal Developmental Toxicity Study
MRID No.: 40881201, 40883601
Executive Summary:   In a dermal developmental toxicity study, bromoxynil phenol (solubilized in water containing 50 mg/ml sodium hydroxide and 20% triethylene glycol) was applied to groups of 23 pregnant Sprague Dawley rats at dose levels of 0 (control), 5, 10, 50 or 100 mg/kg/day for 6 hours/day on gestation days 6-15, inclusive.  A dose-related increased incidence of supernumerary (14th) ribs was observed in this study at 10, 50 and 100 mg/kg/day.  At 10 mg/kg/day, however, the increased incidence was not statistically significant compared to the concurrent control group and was within the historical control range.  The developmental toxicity NOAEL is 10 mg/kg/day and the developmental toxicity LOAEL is 50 mg/kg/day, based on increased 14th ribs.  The maternal toxicity NOAEL is 50 mg/kg/day and the maternal toxicity LOAEL is 100 mg/kg/day, based on decreased body weight gain and decreased food consumption during the treatment period.  No deaths or clinical signs, including skin irritation, were attributed to treatment with the test material in this study.    

Dose and Endpoint for Risk Assessment:  The developmental NOAEL of 10 mg/kg/day is based on increased incidence of supernumerary (14[th]) ribs seen at the LOAEL of 50 mg/kg/day.
Comments about Study/Endpoint/Margins of Exposure:  This study provides the lowest NOAEL in the database (most sensitive endpoint) that reflects the route and duration of exposure relevant to occupational and/or residential scenarios. The reference value for this risk assessment scenario is a margin of exposure (MOE) of 100 based on 10X interspecies and 10X intraspecies uncertainty factors.
The lowest NOAEL from an oral study appropriate for use for this endpoint is 4 mg/kg/day from the developmental toxicity study (see Acute Reference Dose, Females 13+).  If this study were used along with the dermal absorption factor of 17% for extrapolation between the dermal and oral routes, the extrapolated NOAEL 4.0 / 0.17) would be 23.5 mg/kg/day, which is higher and less protective than the NOAEL from the route-specific study used.  Thus, using the route-specific study would be protective of the developmental effects noted after oral exposure
 
A.3.3	Inhalation Short-Term (1-30 days) and Intermediate-Term (1-6 Months) 
Study Selected:  Rat Oral Developmental Toxicity Study
MRID No.: 00116558 and 40466802
Executive Summary:  See above: Acute Reference Dose Females 13+
Dose and Endpoint for Risk Assessment:  The NOAEL of 4 mg/kg/day (MRID 40466802) is based on an increase of supernumerary ribs seen at the LOAEL of 5 mg/kg/day in a co-critical study (MRID 00116558).
Comments about Study/Endpoint/Margins of Exposure:  This study provides the lowest NOAEL in the database (most sensitive endpoint) and reflects the duration of exposure relevant to occupational and/or residential exposure scenarios.  Although there are uncertainties associated with the use of an oral study for the inhalation route of exposure, the assumption is made in this risk assessment that oral and inhalation absorption rates are equivalent (100%) (The actual absorption by the oral route is 76  -  89%). The reference value for this risk assessment scenario is a margin of exposure (MOE) of 100 based on 10X interspecies and 10X intraspecies uncertainty factors. 

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

Common name
Chemical name
Chemical structure
bromoxynil
3,5-dibromo-4-hydroxybenzonitrile
                                       
                                       
                                       
bromoxynil octanoate
2.6-dibromo-4-cyanophenyl octanoate
                                       
                                       
                                       
bromoxynil heptanoate
2.6-dibromo-4-cyanophenyl heptanoate
                                       
                                       
DBHA
3,5-dibromo-4-hydroxybenzoic acid
                                       
Appendix C.  Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure.  Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED and the Outdoor Residential Exposure Task Force (ORETF).  EPA has reviewed all the studies supporting these multi-pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted.  All applicable requirements of EPA's Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.
Appendix D.  International Residue Limit Status Sheet

Bromoxynil (035301; 09/15/2010)
Summary of US and International Tolerances and Maximum Residue Limits 
Residue Definition:
US
Canada
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

                                                                               
Completed:  M. Negussie;09/16/2010
[1] Includes only commodities of interest for this action.  Tolerance values should be the HED recommendations and not those proposed by the applicant.
2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains.  PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.


