Bromacil Registration Review Human

- Health Assessment Scoping Document

Page 3 of 19 neurotoxicity battery (acute and subchronic) and an immunotoxicity study are required

. In addition, HED has determined that a 90

- day inhalation toxicity study is required to asses s potential risk via the inhalation route from occupational exposures

. When these studies are submitted, the current points of departure (PODs) may need to be re

- evaluated along with the Food Quality Protection Act (FQPA) Safety Factor (SF) for future risk assessments.

The residue chemistry database is sufficient to support the current registrations. However, the following residue chemistry data items should be addressed : (1) all citrus and pineapple labels should be up dated to include preharvest intervals (PHIs) of 7 days and 125 days, respectively; (2) new livestock dietary burdens that include parent and Metabolite D should be calculated based on current Agency policy; (3) the tolerance expression for bromacil in 40 C FR §180.210 should be updated to reflect current Agency policy; and 4) the commodity definition for citrus may be updated to reflect the current Citrus 10

- 10 crop group definition. No additional citrus field trials are required to update the commodity def inition.

The qualitative nature of bromacil residues in the registered primary crops and ruminants is adequately understood based on acceptable orange, pineapple, and goat metabolism studies. The residue of concern in citrus and pineapple fruit for tol erance expression is bromacil per se. For risk assessment purposes, the residues of concern in orange are also only parent and in pineapple are parent and Metabolite D with Metabolite D residue estimated by multiplying the parent residue by 12 X

. Adequate analytical enforcement methods are available. Additionally, adequate field trial, processing factor, and storage stability data are available. HED notes that if other major uses are registered in the future, additional plant or livestock metabolism stud ies, rotational crop studies, and/or regulation /consideration of other residues in addition to the parent and Metabolite D may be required.

The dietary exposure database is adequate to support existing registrations; however
, revis ed

a ssessment s are required using the most recent dietary exposure model, a 12X residue factor to account for the higher levels of Metabolite D residues measured in pineapple, and updated estimated drinking water concentrations ( EDWCs) provided by the Environmental Fate and Effects Division (EFED). The dietary exposure assessments may also need to be updated if toxicological endpoints change

. The occupational exposure database is adequate to support the Registration Review process for bromacil. Updated occupational handle r exposure assessments may be required under Registration Review based upon revisions to the Agency’s s cenario

- specific surrogate handler exposure data ( http://www.epa.gov/pesti cides/science/handler

- exposure

- table.pdf ). Recommended unit exposures for occupational handler assessments have generally been derived only from the Pesticide Handler Exposure Database (PHED )

. However, recently both the Outdoor Residential Exposure Task Force (ORETF) and Agricultural Handler Exposure Task Force (AHETF) have submitted pesticide handler exposure monitoring data that the Agency is using in place of PHED. As more reliable data become available (such as that from the AHETF and ORETF), the Agency will continue to replace existing data. N ew exposure monitoring data may be incorporated , as necessary, during Registration Review. In addition, an occupational handler exposure assessment may be required for the reg istered post

- harvest use on pineapple.

In the 1996 RED, HED expressed concern about potential post

- application exposure arising from

re

- entering treated turf areas ( i.e. , recreational areas). Since the completion of the RED, all of the products registere d for use in recreational areas have been cancelled ( p ersonal communication between J. Tyler and S. Snyderman, 14

- FEB

- 2012). However, there is theBromacil Registration Review Human

- Health Assessment Scoping Document

Page 4 of 19 potential for occupational post

- application exposures to individuals entering fields treated with bromacil. Therefore, a quantitative post

- application exposure assessment will be required for the post

- application scenarios associated with the registered agricultural uses of bromacil (citrus and pineapples). Post

- application data for brush control and weed cont rol are not required since there are no reentry tasks associated with these registered nonagricultural uses of bromacil.

In addition, revised occupational handler and post

- application assessments may also be needed if toxicological endpoints change or oth er new data are received by the Agency that impact exposure estimates.

Hazard Identification/Toxicology

Bromacil is a member of the substituted uracil family of herbicides whose pesticidal mode of action involves inhibition of photosynthesis. Based on the results of acute toxicity studies in rats, brom acil was classified as Category IV, the lowest category for acute toxicity via the oral, dermal
, and inhalation routes . It was found to cause mild eye and skin irritation (Categories III and IV, respectively) but not to be a skin sensitizer.

Following oral administration of radiolabeled bromacil to rats, absorption from the gastrointestinal tract was rapid with peak blood levels (t max ) measured at 1 and 2 hours for males and females, respect ively. Distribution, particularly at a high dose level, was more pronounced at 1 h ou r in the thyroid, adrenal, liver, and kidneys, although there was no evidence of bioaccumulation by 120 hours. Urine was the primary route of excretion, except in pre

conditioning, where repeated low dosing studies with males resulted in fecal and urinary excretion that were about equal. Based on the urinary excretion profile, an elimination half

- life of about 13 hours was estimated for both sexes.

In repeated chronic dietary dosing studies in rats and dogs, the most sensitive toxic effect reported was d ecreased body

- weight gain . The high dose (103 and 144 mg/kg bw/day for males and females, respectively) effects reported in the rat consisted of cystic follicles and ultimobranchial cysts of the thyroid in males and epithelial hyperplasia of the thymus in females

. The thyroid effects in male rats progressed to dose

- related trends in thyroid C

- cell adenomas and/or carcinomas. In a carcinogenicity study in mice, liver lesions were reported at all dose levels in males. Liver effects also included hepatocel lular hypertrophy, single cell and centrilobular vacuolation and necrosis, and hepatocellular lysis with red blood cell accumulation. There was a significant increase in combined hepatocellular adenomas and/or carcinomas at the high dose (871 mg/kg bw/day) in males only. Based on the increased incidence of liver tumors in male mice and the positive trends in thyroid tumors in male rats, the Carcinogenicity Peer Review Committee classified bromacil as Group C

– “possible human carcinogen,” and recommended t he RfD approach for quantification of human risk. There is no evidence that bromacil is mutagenic or genotoxic.

In a developmental toxicity study in rats where oral gavage dosing was performed on gestation days (GD) 7

- 16 , maternal toxicity was manifested as decreased body

- weight gain and food consumption. Developmental toxicity was observed at a dose higher than that caused maternal toxicity and included increased incidences of rudimentary lumbar ribs and extra thoracic vertebrae

. At the next higher dos e level, more significant skeletal developmental variations due to retarded development were reported including partial ossification of the axial skeleton ( interparietal, parietal, and supraoccipital skull bones, bipartite and dumbbelled centrum of theBromacil Registration Review Human

- Health Assessment Scoping Document

Page 5 of 19 ver tebrae, sternum
, and hyoid ) and the partial ossification of the appendicular skeleton ( pubis and ischium ).

In a rabbit developmental toxicity where dosing was performed on GD 7

- 19, developmental toxicity was reported in the form of an increase in late pos t

- implantation loss and a decrease in the number of female pups. At the next higher dose level, there was an increase in the mean percentage of skeletal variations.

In a 2

- generation toxicity study in rats, there were no effects on reproductive performan ce. The parental effects were based on an increased incidence of hydroephrosis (obstruction of urine flow from the kidneys).

In the last HED chapter for the RED ( J. Redden 31

- May

- 1995) , the following toxicity studies were reported as data gaps: a 21

- day dermal toxicity (guideline 82

- 2), and a dermal sensitization study (82

- 1). Subchronic toxicity studies were noted as missing but not required since chronic toxicity data was available. Since then, a 28

- day dermal toxicity study (MRID# 44172401) and dermal sensitization studies (MRID#s: 46626906, 46882106, and 46882208) have been submitted.

According to the 2007 40 CFR Part 158 requirements, the following studies are required: neurotoxicity studies (acute and subchronic) and an immunotoxicity study. In addition , a 28

- day inhalation toxicity study is required to assess potential risks via the inhalation route from occupational exposures

. On March 01, 2012 HED’s Hazard Science Policy Council (HASPOC) confirmed the need for the neurotoxicity ba ttery and the immune

- and the inhalation toxicity studies listed above (TXR No. 0054237 )

. Once all data have been received and reviewed, the bromacil Registration Review Team recommends that the PODs and SFs used for risk assessment purposes be re

- examine d and a new risk assessment be completed, if necessary.

Endocrine Disruption

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA) , EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic, and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproducti ve, and general or systemic toxicity

. These studies include endpoints that may be susceptible to endocrine influence , including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rate s, reproductive loss, and sex ratios in offspring

. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of the reregistration decision , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), bromacil is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occ urring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily requiredBromacil Registration Review Human

- Health Assessment Scoping Document

Page 6 of 19 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 r elationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which c ontains 58 pesticide active ingredients and 9 inert ingredients

. Bromacil is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of Registration Review , EPA will issue future EDSP orders/data call

- ins, requiring the submission of EDSP screening assays fo r bromacil. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening bat tery, please visit our website: http://www.epa.gov/endo/

Conclusions The toxicity database for bromacil is inadequate to support current registration requirements due to the following critical studies currently miss ing in the database:

870.6200 Neurotoxicity Screening Battery (Acute and Subchronic) 870.3465 90

- day inhalation toxicity 870. 7800 Immunotoxicity

When the required studies are submitted, the current toxicity endpoint/dose selection may need to be re

- evalu ated along with the FQPA SF for future risk assessments.

Residue Chemistry

Bromacil is registered for application to two agricultural crops: citrus and pineapple. Tolerances are established for residues of bromacil in/on these crops at 0.1 ppm in 40 CFR §180.210. There are no tolerances established for secondary residues of bromacil in/on livestock commodities.

There are no registered uses of lithium bromacil on food crops. Previously, bridging field trials for citrus were required for lithium bromacil; however, the registrant requested the cancellation of their food

- use lithium bromacil product in 1994, so no chemistry data for lithium bromacil are required at this time.

Acceptable orange and pineapple metabolism studies are available . Results from the orange metabolism study indicate that bromacil undergoes hydroxylation at the 6

- methyl group to produce Metabolite A (5

- bromo

- 3

- secbutyl

- 6

- hydroxy

- methylur acil), which is readily conjugated with glucose and is converted to malonyl ester of glucose conjugate of Metabolite A. In pineapple, the metabolism of bromacil proceeds from hydroxylation of the sec

- butyl side chain followed by conjugation of the hydroxy lated metabolites. The compound 5

- bromo

- 3

- (2

- hydroxy

- 1

- methylpropyl)

- 6

- methyluracil (Metabolite D) comprised a significant portion of the residue in pineapple fruit and was observed at a level 12 times that of the bromacil concentration.Bromacil Registration Review Human

- Health Assessment Scoping Document

Page 7 of 19 Based on the orange and pineapple metabolism studies, HED concluded that the residues of concern in orange and pineapple for purposes of tolerance expression is bromacil only. The residues of concer n for risk assessment in orange is also parent only and the residues o f concern in pineapple for risk assessment are parent and metabolite D with residues of metabolite D estimated by multiplying parent residues by 12X

.
The nature of the residue in ruminants is adequately understood based on an acceptable ruminant metabol ism study in goats reflecting oral dosing. In ruminants, bromacil is hydroxylated at the 6

- methyl and the sec

- butyl side chains and the 6

- hydroxymethyl derivative is further conjugated. The primary route of elimination was through excretion. When the di et of the goat included 9.2 ppm of bromacil, the maximum transfer of radioactivity was 0.04 ppm to milk and 0.02 ppm to kidney, the tissue with the highest concentration of residues. Previously, the Agency concluded that additional ruminant feeding studie s and livestock tolerances are not required because the residues of bromacil expected in milk and meat would be <0.0001 ppm, a level that could not be quantitated by the available analytical method. This conclusion was based on the following: 1) a maximu m theoretical dietary burden of 0.033 ppm for cattle calculated by assuming 33% of the diet consisting of dried citrus pulp; 2) the level of bromacil fed to the animals in the ruminant metabolism study (9.2 ppm; 280 X ); and 3) the low total radioactive resi due ( TRR ) levels in milk (0.04 ppm) and tissue samples (0.02 ppm) from the metabolism study. The guidelines for calculating livestock dietary burdens have changed since the RED. As part of Registration Review, new livestock dietary burdens that include p arent and Metabolite D should be calculated to confirm that tolerances for residues of bromacil in livestock commodities are not required

. Since bromacil is not registered for use on crops that are fed to poultry, a poultry metabolism study is not require d at this time.

HED notes that if other major uses are registered in the future, then additional plant or livestock metabolism studies, rotational crop studies, and/or regulation of other residues in addition to the parent may be required.

Adequate m ethods are available for tolerance enforcement and data collection. A gas

- liquid chromatography (GLC) method with microcoulometric detection is available for tolerance enforcement and is listed in Pesticide Analytical Method (PAM) Vol. II as Method I. Additional methods include a GLC method with electron

- capture detection (ECD), published in PAM Vol. II as Method B, and an improved GLC method using a thermionic nit rogen/phosphorus detector (GLC/NPD ) used for data collection. These methods have not unde rgone validation by the Agency ( MRID#s 013999, 014217, 019944, 42967301, and 43078801).

The registrant submitted data on a GLC/ NPD method for determining residues of bromacil per se in/on oranges and pineapple. The submitted method is a modification of M ethod B published in PAM Vol. II and has a more sensitive limit of detection (LOD = 0.01 ppm) than any of the enforcement methods. In addition, the registrant has submitted data on a confirmatory GLC/ mass

- selective detector (MSD) data collection method fo r citrus and pineapple that may be used if bromacil residues are present at or above a level of 0.01 ppm.

Enforcement analytical methods for residues in livestock are not required as no tolerances exist for residues of bromacil in livestock commodities

. The FDA PESTDATA data base dated 1/94 (PAM Vol. I, Appendix II) indicates that bromacil is completely recovered (>80%) using PAM, Vol. I Multiresidue Protocol D and not recovered using Protocol E Sections 211.1 or 212.1. Analytical standards with an expir ation date of 13

- JUL

- 2015 are available for bromacil (personal communication with T. Cole, 25

- JAN

- 2012).Bromacil Registration Review Human

- Health Assessment Scoping Document

Page 8 of 19 The requirements for storage stability data were previously satisfied for the purposes of reregistration. The submitted storage stability data indica te that residues of bromacil per se are stable at

- 15 oC for up to 18 months in citrus and pineapple fruits and in pineapple beverage juice and bran at 15 oC for 99 and 139 days, respectively. The registrant did not provide information regarding the durat ion of storage of citrus samples that were used for tolerance assessment; however, since residues of bromacil were not observed in the citrus metabolism study and residue samples used for tolerance assessment bore non

- detectable (<0.05 ppm) residues of bro macil per se , it can be concluded that the citrus fruit field trials are validated by acceptable storage stability data (MRID 42967401, 43461601). Additional storage stability data are not required for Registration Review.

As part of the RED, the Agenc y concluded that acceptable data on citrus (oranges, lemons, grapefruit, and tangelos) are available. Residues of bromacil per se were <0.05 ppm in/on citrus harvested up to 8 months after treatment with 3.2

- 8.0 lbs ai/A/season of bromacil in tests perfor med in CA, TX, and FL. Additional data on citrus were also submitted in support of an amended use to increase the maximum seasonal use rate from 6.4 lb ai/A/season to 8.5 lb ai/A/season in FL. Residues of bromacil per se were <0.05 ppm in/on citrus harve sted 7, 14, 21, and 28 days after the last treatment with 6.4

- 8.5 lb ai/A/season of bromacil in four trials performed in FL. Although field trial data requirements have changed since the citrus data was submitted, additional field trial data are not requi red since all residues were less than the limit of detection at the time of the studies and the 2009 Pesticide Data program (PDP) data indicated that residues of bromacil were not detected in the 210 orange samples analyzed for residues of bromacil (LOD = 0.030 ppm). All labels should, however, be updated to include a 7

- day PHI for citrus. As stated in the RED, the available data support the established 0.1

- ppm crop group tolerance for residues of bromacil in/on citrus fruits.

The Bromacil Guidance Doc ument (9/82) concluded that acceptable data on pineapple were available and that no additional data were required. Residues of bromacil were non

- detectable (<0.04 ppm) in/on one sample each of pineapple fruit and forage from plants treated at 8 lb ai/A/se ason and harvested at a 396 post

- treatment interval (PTI). However, the 1989 Second Round Review ( SRR ) noted that the submitted data did not reflect residues in pineapple harvested at the minimum inferred PHI of 150 days and that no tolerance had been est ablished for residues of bromacil in/on pineapple forage. Data depicting bromacil residues in/on pineapple and pineapple forage were required. In 1995, the Agency received additional pineapple f

ield data for three field trials in HI that indicated that r esidues of bromacil will not exceed the established tolerance of 0.1 ppm in/on pineapples harvested 125

- 215 days following the last of two applications of the bromacil 80% WP formulation at 10 lb ai/A (1.25 X the maximum seasonal rate) or 20 lb ai/A (2.5x). Residues of bromacil per se were non

- detectable (<0.04 ppm) in/on five control samples and seven treated samples. No additional data are required; however, as indicated in the RED, the registrant must specify a PHI of 125 days in all relevant labels. A s pineapple forage is no longer listed as a regulated commodity (“Agency guidance on calculating reasonably balanced diets for livestock” (Memo J. Stokes, 30

- JUN

2008) , data in/on pineapple forage are no longer required. The pineapple field trial data are acceptable and no additional field trials are required at this time.

As indicated in the RED, adequate processing studies have been submitted and residues of bromacil per se do not concentrate in citrus and pineapple processed commodities. Residues of bromacil per se were <0.04 ppm in/on citrus dried pulp. Data for citrus molasses were not submitted but the Agency concluded that if residues do occur in dried citrus pulp and molassesBromacil Registration Review Human

- Health Assessment Scoping Document

Page 9 of 19 they will not exceed the tolerance for the raw agricultural commodity. In addition, additional data on citrus processed commodities were submitted in support of an amended use to increase the maximum seasonal use rate of bromacil in FL. Residue s of bromacil in orange fruit, peel, pulp, and juice were non

- detectable (<0.05 ppm) at PHIs of 8, 15, 23, and 30 days. In a pineapple processing study (MRID 43461601), residues of bromacil per se were non

- detectable (<0.04 ppm) in/on pineapple harvested 215 days after two broadcast applications of bromacil (80% WP), first at 12 lb ai/A before planting followed by a second application prior to floral induction at 8 lb ai/A for a total seasonal rate of 20 lb ai/A (2.5 X ). Residues were also non

detectable i n/on juice and bran processed from the pineapples. Although the pineapple fruit used to obtain processing data did not bear measurable residues, the Agency concluded that the pineapple processing study is adequate because the registrant indicated that the plants treated at 2.5X exhibited signs of phytotoxicity. No food/feed additive tolerances are required for pineapple juice or bran.

As part of Registration Review, the tolerance expression for bromacil (40 CFR §180.210) should be updated as follows:

(a) General. Tolerances are established for residues of the herbicide bromacil, 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 bromacil, 5

- bromo

- 6

- methyl

- 3

- (1

- methylpropyl)

- 2,4(1 H ,3 H )

- pyrimidinedione , in or on the commodity.

Additionally, the citrus commodity definition should be updated to reflect the Citrus 10

- 10 crop group commodities as part of Registration Review. N o additional field trials are required for this updated commodity definition because field trial data are available f or oranges, lemons, and grapefruit, the representative crops of the citrus 10

- 10 crop group.

Conclusions The qualitative nature of broma cil residues in plants and livestock is adequately understood based on acceptable orange, pineapple, and goat metabolism studies. The residue of concern and the residue to be regulated in citrus and pineapple fruit is bromacil per se. For risk assessment purposes, an additional 12X factor should be used for pineapple to account for residues of Metabolite D observed in the pineapple metabolism study. Adequate analytical enforcement methods are available. Additionally, adequate field trial, processing factor, and storage stability data are available. HED notes that if other major uses are registered in the futu re, additional plant or livestock metabolism studies, rotational crop studies, and/or regulation of other residues in addition to the parent may be required.

The following residue chemistry data items should be addressed as part of Registration Review:

All citrus and pineapple labels should be updated to include PHIs of 7 days and 125 days, respectively. New livestock die tary burdens that include parent and Metabolite D should be calculated based on current Agency policy. The tolerance expression for bromacil in 40 CFR §180.210 should be updated to reflect current Agency policy. The commodity definition for citrus should b e updated to reflect the current Citrus 10

- 10 crop group definition. No additional citrus field trials are required to update the commodity definition.Bromacil Registration Review Human

- Health Assessment Scoping Document

Page 10 of 19 Dietary Exposure

An acute dietary assessment has not been conducted for bromacil because an endpoint of concern attributable to a single dose was not identified. The results of the most recent chronic dietary exposure assessment for bromacil were included in the 1996 RED. A Dietary Risk Evaluation System (DRES) chronic exposure analysis was performed u sing tolerance

- level residues and 100 percent crop treated information for all commodities to estimate the Theoretical Maximum Residue Contribution (TMRC) for the general population and 22 subgroups. The analysis used existing tolerances and resulted in a TMRC that represented <1% of the RfD for the U.S. general population. Children 1

- 6 years old were the subgroup with the highest exposure, and occupied 1% of the RfD. Based on the analysis, it appeared that chronic and cancer dietary risk estimates for t he uses recommended through reregistration were not of concern.

There is the potential for dietary exposure to bromacil through consumption of drinking water that contain s bromacil residues. At the time of the RED, the data available to the Agency indi cated that bromacil ha d been detected in ground water in five states, with concentrations in many Florida wells exceeding 100 ppb. Additional bromacil surface water residue data for South Florida suggested that it was probably unlikely that the annual ave rage concentrations of bromacil would exceed the lifetime health advisory or that peak or short term average concentrations would exceed the 1

- day and 10

- day health advisory in surface water sources for drinking water in South Florida. No other surface wa ter data were available at that time. The RED concluded that although bromacil residues in water were found above the health advisory limit (HAL; 90 ppb), an adult drinking 2 liters of water that contains 100 ppb of bromacil per day over a lifetime reache s <4% of the RfD, and a 10 kilogram child drinking 1 liter of water that contains 100 ppb of bromacil reaches 10% of the RfD. Additionally, as the infant/child’s body weight increases with age, the percent of the RfD for consumption of bromacil

- contaminat ed water decreases. The assessment indicated that drinking water exposures were not of concern.

EFED has indicated that 3

- sec

- butyl

- 6

- methyluracil (Metabolite F) is a major and persistent anaerobic aquatic degradate. Since this metabolite is not rapid ly formed, and was only found in the anaerobic studies , it is not expected to be present in drinking water supplies. An updated dietary exposure assessment is required as part of Registration Review. This assessment will incorporate revised EDWCs provided by EFED.

Conclusions The most recent chronic and cancer dietary exposure assessments were below HED’s level of concern (LOC) for the general U.S. population and all population subgroups examined. Although no new tolerances have been established for residues of bromacil and the analyses did not indicate any risks of concern, updated chronic and cancer dietary expo sure and risk assessments for bromacil are required as part of Registration Review. These assessments should be completed using the most up

- to

- date dietary exposure and risk assessment model, the 12X factor for pineapple, and updated EDWCs from EFED, as a vailable. Additionally, the assessment should take into account any changes to the toxicological endpoints or other new data received by the Agency that impact dietary exposure estimates.

Residential Exposure

There are currently no registered uses of bromacil and its lithium salts that would result in residential exposure. It should be noted that bromacil was previously registered for use in recreational areas. However, since the completion of the 1996 RED, all of the productsBromacil Registration Review Human

- Health Assessment Scoping Document

Page 11 of 19 registered for use in r ecreational areas have been cancelled (personal communication between J. Tyler and S. Snyderman, 14

- FEB

- 2012). Therefore, a residential exposure assessment is not needed to support Registration Review

. Spray Drift Spray drift is always a potential sourc e 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 bromacil . The Agency ha s 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 che mical

- 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 o f 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.

Ag gregate Risk Assessment

The most recent aggregate assessment was completed as part of the RED in 1996. Bromacil has no residential or other non

- occupational uses that might result in exposure to adults or children; therefore, the only exposures that need to be aggregated are food and drinking water exposures.

The RED considered chronic exposures from all sources of bromacil (food residues and drinking water residues) and determined that aggregate risks will be <6% of the RfD for the general population (<2% from food and <4% from water), and <11% of the RfD for infants and children (1% from food and 10% from water). The Agency concluded that aggregate risk estimates for bromacil exposure for the general U.S. population and the infants and children popul ation subgroup were not of concern.

Conclusions There is sufficient information available to assess aggregate exposure. A new aggregate exposure risk assessment that incorporates the updated dietary exposure assessment may be required during Registration Review. This assessment should also take into account any changes to the toxicological endpoints or any other new data received by the Agency that impact exposure estimates.

Occupational Exposure

Bromacil is broad

- spectrum herbicide regist ered for use on agricultural and nonagricultural areas. The agricultural uses of bromacil include a soil treatment on citrus; and a pre

- emergent, post

- emergent, or post

- harvest application to pineapple. The registered nonagricultural uses include unculti vated agricultural areas, commercial, industrial and institutional maintenance, refuse storage areas, and rights

- of

- way for weed and brush control and as a total vegetation management tool. Registered formulations of bromacil include EC, G, RTU, pellets o r tablets, pressurized liquid, SC, WP, and WDG (or DF). Bromacil is applied by groundboom sprayers

-Bromacil Registration Review Human

- Health Assessment Scoping Document

Page 12 of 19 band treatments, power sprayers, manually pressured handwands, belly grinder, and push

- type spreaders. Based on these uses, there is a potential for dermal and inhalation exposure to bromacil in occupational scenarios from handling bromacil products during the application process (i.e., mixer/loaders, applicators, and mixer/loader/applicators). In addition, there is a potential for post

- application worker e xposure from entering into areas previously treated with bromacil. The bromacil RED included quan ti tative risk estimates for occupational handler scenarios, but not for occupational post

- application scenarios (Memos, J. Redden, 31

- MAY

1995, 29

- JAN

- 1996, 2 6

- APR

- 1996).

Occupational Handlers : T he RED evaluated the occupational handler scenarios to represent the major bromacil occupational handler scenarios based on application equipment and formulation (Memos, J. Redden, 31

- MAY

- 1995, 29

- JAN

- 1996, 26

- APR

- 1996). The major exposure scenarios identified for bromacil were as follows:

Mixing/loading the liquid flowable formulation ; Applying the liquid with groundboom equipment; Applying the liquid with power sprayer equipment (i.e., rights

- of

- way sprayers and under toxic

- waste holding

- pond liners); Mixing/loading/applying granulars with a whirly bird spreader; Mixing/loading/applyi ng liquids with a low pressure handwand; and, Mixing/loading/applying with a drop spreader.

Occupational handler exposures were estimated using exposure data from PHED Ver. 1.1

. With the addition of chemical

- resistant gloves or, in one instance, engine ering controls, all occupational exposure scenarios resulted in margins of exposure (MOEs) above HED’s LOC (i.e.
, 100), with the exception of the toxic

- waste holding

- pond scenario at the maximum acreage, and the mixing/loading DFs for groundboom applicati on scenario at the maximum application rate (Memo, J. Redden, 26

- APR

- 1996).

For the toxic

- waste holding

- pond scenario at the maximum acreage (48 acres), the MOE was less than 100 with the addition of chemical

- resistant gloves. However, since the completi on of the 1996 RED, all of the products registered for use under toxic

- waste holding

- pond liners have been cancelled (personal communication between J. Tyler and S. Snyderman, 13

- MAR

- 2012).

The mixing/loading DFs for groundboom application scenario at the maximum application rate resulted in a MOE less than 100. However, all occupational handler scenarios resulted in risk estimates that did not exceed HED’s LOC after some level of risk mitig ation, including the addition of a dust mask (80% reduction) for mixers/loaders (Memo, J. Redden, 26

- APR

- 1996).

Occupational Post

- application : Based on the registered uses, HED determined that there is the potential for occupational post

- application expo sures to individuals entering fields treated with bromacil

. HED was specifically concerned about potential post

- application exposure arising from re

- entering treated turf areas ( i.e., recreational areas) and from re

- entering treated crop

areas. However, a quantitative post

- application exposure assessment was not conducted in support of the RED since no post

- application data were available at that time. HED recommended the following (Memos, J. Redden, 31

- MAY

- 1995, 29

- JAN

- 1996, 26

- APR

- 1996):

Requ irements for post

- application exposure studies are addressed by Subdivision K of the Pesticide Assessment Guidelines. Post

- application exposure data were not requiredBromacil Registration Review Human

- Health Assessment Scoping Document

Page 13 of 19 previously by the Agency. In light of toxicological concerns, i.e., developmental toxic ity, and the absence of post

- application exposure data, HED requires post

- application exposure data for the registered food uses. Post

- application data for brush control and weed control is not required since there are no reentry tasks associated with tre ating of right

- of

- way, paved areas, non

- agricultural uncultivated areas, power stations, and recreational areas.

Due to the lack of post

- application data, HED previously recommended the following:

The registrant must submit post

- application exposure stu dies as confirmatory data

. Requirements for such post

- application exposure studies are addressed by Subdivision K of the Pesticide Assessment Guidelines. Post

- application/reentry exposure studies are required as confirmatory data to determine definitive REIs for all crop sites on which bromacil is registered for use. The interim REIs established in this document will be adjusted accordingly upon submission of the additional data. The required data include:

Guidelines: 132

- 1(b) Soil Dissipation *13 3

- 3 Post

- application Dermal Passive Dosimetry Exposure *133

- 4 Post

- application Inhalation Passive Dosimetry Exposure

* Guidelines 133

- 3 and 133

- 4 may be reserved at this time pending completion of the databases on agricultural post

- application/re entry exposure currently being developed by the Agricultural Reentry Task Force (ARTF)
, provided the registrant is a member of the Task Force.

However, HED has now determined that the previously requested confirmatory post

- application studies [Guidelines 132

- 1(b), 133

- 3, and 133

- 4] are not necessary at this point considering the data that have been received in recent years from various task forces ( i.e. , ORETF, ARTF
, AHETF).

Conclusions The occupational exposure database is adequate to support the Registration Review process for bromacil. Updated occupational handler exposure assessments may be required under Registration Review based upon revisions to the Agency ’s s cenario

- specific surrogate handler exposure data ( http://www.epa.gov/pesticides/science/handler

- exposure

- table.pdf ). Recommended unit exposures for occupational handler ass essments have generally been derived only from PHED

. However, recently both the ORETF and AHETF have produced pesticide handler exposure monitoring data that the Agency is using in place of PHED. As more reliable data become available (such as that from the AHETF and ORETF), the Agency will continue to replace existing data. Reviewers should incorporate new exposure monitoring data, as necessary, during Registration Review. In addition, an occupational handler exposure assessment will be required for th e registered post

- harvest use on pineapple.

In the 1996 RED, HED expressed concern about potential post

- application exposure arising from

re

- entering treated turf areas ( i.e. , recreational areas). Since the completion of the RED, all of the products regi stered for use in recreational areas have been cancelled (Personal communication between J. Tyler and S. Snyderman, 14

- FEB

- 2012). However, there is the potential for occupational post

- application exposures to individuals entering fields treated with broma cil. Therefore, a quantitative post

- application exposure assessment will be required for the post

- application scenarios associated with the registered agricultural uses of bromacil (citrus and pineapples). Post

- application data for brush control and weed control are not required since there are no reentry tasks associated with the registered nonagricultural uses of bromacil.Bromacil Registration Review Human

- Health Assessment Scoping Document

Page 14 of 19 In addition, revised occupational handler and post

- application assessments may also be needed if toxicological endpoints change or other new data are received by the Agency that impact exposure estimates.

Public Health and Pesticide Epidemiology Data

A summary report listing incidents for bromacil reported to the Office of Pesticide Programs (OPP) Incident Data System (IDS) has been provided for the docket (Memo, S. Recore , 29

- FEB

12; D399205). The report represents incidents occurring in the U.S. from 2006 to the present.

Human Incident Data: OPP IDS (201 2 )

For this evaluation, the OPP IDS was utilized to retrieve pesticide inci dent data on the active ingredient bromacil. Bromacil is a broad

- spectrum herbicide used to control weeds in the agricultural food crops citrus and pineapple. The purpose of the database search is to identify potential patterns in the frequency and sever ity of the health effects attributed to bromacil exposure. The IDS includes reports of alleged human health incidents from various sources, including mandatory FIFRA Section 6(a)(2) reports from registrants, other federal and state health and environmenta l agencies, and individual consumers. Since 1992, OPP has compiled these reports in IDS. IDS contains reports from across the U.S. and most incidents have all relevant product information recorded. Reports submitted to the IDS represent anecdotal report s or allegations only, unless otherwise stated in the report. The Agricultural Health Study (AHS) is a high

- quality
, prospective epidemiology study evaluating the link between pesticide use and various health outcomes including cancer. The AHS includes private and commercial pesticide applicators and their spouses . If there are AHS findings relevant to a particular pesticide going through Registration Review , the Agency will ensure they are considered in the problem formulation/scoping phase of the proc ess and, if appropriate, fully reviewed in the risk assessment phase of the process

. The AHS includes information on use of 50 different pesticide active ingredients commonly used in agriculture.

IDS records incidents resulting in higher severity outcome s in more detail, in a module called the Main IDS module. This system stores incident data for death, major and moderate incidents, and it includes more details about the location, date, and nature of the incident. Main IDS incidents involving only one p esticide are considered to provide more certain information about the potential effects of exposure from the pesticide. The less severe human incidents (minor, unknown, or no effects outcomes) are reported by registrants as counts called aggregate summaries and are recorded in a separate module called Aggregate IDS.

In Aggregate IDS, from 01

- JAN

- 2006 to 14

- DEC

- 2011, there were 12 reported incidents involving bromacil

. For the Main IDS, from 01

- JAN

- 2006 to 14

- DEC

- 2011, there were zero inci dents reported for the single chemical only in the database and three incidents reported that involved more than one chemical. Overall, there are few incidents involving bromacil reported to IDS.

Bromacil is not included in the AHS, and therefore this study does not provide information for this report.

Based on the low frequency and severity of incident cases, there does not appear to be a concern at this time that would warrant further investigation. Th e Agency will continue to monitor theBromacil Registration Review Human

- Health Assessment Scoping Document

Page 15 of 19 incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR §180.2 10) and maximum residue limits (MRLs) are summarized in Attachment 3 . Residue definitions and MRLs for bromacil have not been established by Codex and Canada. Mexico adopts U.S. tolerances and/or Codex MRLs for export purposes. Since MRLs are not establ ished by Codex and Canada for residues of bromacil, harmonization for bromacil is not an issue at this time.

Conclusions Since Codex and Canada have not established residue definitions and MRLs for bromacil, and Mexico adopts U.S. tolerances for export purposes, harmonization is not an issue at this time.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the 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.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP typically considers the highest potential exposures from the legal us e of a pesticide when conducting human

- health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvesting cr ops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.

Cumulative

As part of the RED, the Agency assessed the pot ential risk from cumulative effects of bromacil and other pesticides and substances with a common mode/mechanism of toxicity. The Agency considered structural similarities, common effects that exist between bromacil and othe r substituted uracil compounds such as terbacil and lenacil, and other compounds which could potentially result in effects similar to those of bromacil including induced cystic thyroid follicles or bromacil induced enlargement of centrilobular cells of the liver. The available data did not suggest that bromacil has a common mode/mechanism of toxicity with any other chemical; therefore, the risk assessment took into account only exposures resulting from bromacil uses. A detailed account of the considerations can be found in the RED. Should the Agency determine that new information on bromacil is available that could potentially affect the cumulative risk assessment and result in a risk of concern, the Agency will revisit the cumulative risk assessment.

Human Studies

Past bromacil ri sk assessments rely 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 generi c pesticide exposure databases such as PHED and the ARTF Database. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear andBromacil Registration Review Human

- Health Assessment Scoping Document

Page 16 of 19 convincing evidence that the conduct of any of them was either fund amentally 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 satis fied, and there is no regulatory barrier to continued reliance on these studies.

Data Requirements and Risk Assessment Updates Required Under Registration Review

Data needs and risk assessment updates required under Registration Review for bromacil are as follows:

Toxicology :
Neurotoxicity screening battery (acute and subchronic ) (870.6200). 90

- day inhalation toxicity (870.3465). Immunotoxicity (870.7800).

Residue Chemistry/Dietary Exposure :
All citrus and pineapple labels should be updated to i nclude PHIs of 7 days and 125 days, respectively. New livestock dietary burdens that include parent and Metabolite B should be calculated based on current Agency policy. The tolerance expression for bromacil in 40 CFR §180.210 should be updated to reflect current Agency policy. The commodity definition for citrus should be updated to reflect the current Citrus 10

- 10 crop group definition. No additional citrus field trials are required to update the commodity definition.

Occupational Exposure :

A n occupational handler exposure assessment may be required for the registered post

harvest use on pineapple. A quantitative post

- application exposure assessment for the post

- application scenarios associated with the registered agricultural uses (citrus and pineapples) may be required

.Bromacil Registration Review Human

- Health Assessment Scoping Document

Page 17 of 19 References

Table 6. Memoranda Relevant to Registration Review.
Author Barcode Date Title

J. Redden None 31

- MAY

- 1995 The HED Chapter of the Reregistration Eligibility Decision Document (RED) for Bromacil.

J. Redden None 29

- JAN

- 1996 The Revised HED Chapter of the Reregistration Eligibility Decision Document (RED) for Bromacil.

J. Redden None 26

- APR

- 1996 The HED response to the Registrant's proposal for mitigating the mixer

- loader exposure to Bromacil.

U.S. EPA 738

- R

- 96

-

013 AUG

- 1996 Reregistration Eligibility Document (RED): Bromacil.

L. Cheng D197454 07

- APR

- 1994 Bromacil. Case No. 0041. Goat Metabolism. MRID No. 42998901. CBRS No. 12949. L. Bradley 252942;

252842 1 30

- MAY

- 1984 EPA Reg. Nos. 352

- 351 and 352

- 352. Amended Registration Request for Krovar ® I and II in Florida.

E.I. du Pont de Nemours & Company R099922 8

- JUN

- 1966 E.I. du Pont de Nemours & Company, Incorporated. Letter to Director, Pesticides Regulation Division, Agricultural Research Service, United States Department of Agriculture. [Results of Tests on the Amount of Residue in Crops Grown on Treated Soil: Bromacil].

J. Redden NA 31

- MAY

- 1995 The HED Chapter of the Reregistration Eligibility Decision Document (RED) for Bromacil, Case # (Pesticide Chemical Code 012301; Reg. Group A).

R. B. Perfetti D208682 30

- MAR

- 1995 Bromacil Reregistration Eligibility Decision Product and Residue Chemistry Chapters (No MRID #, CBRS # 14590).

R. B. Perfetti D209884;

D209883; D208561 30

- MAR

- 1995 Response to the Bromacil Reregistration Standard: Product and Residue Chemistry Studies (MRID #’s 43460601, 43461601 and 43375001, CBRS #’s 14595, 14765 and 14766). R116150; D208561 Bromacil (Du Pont; CBRS No. 14595) Product Chemistry (Final Report) Confidential Appendix.

J. Stokes 30

- JUN

- 2008 Agency guidance on calculating reasonably balanced diets for livestock.
1 These are Accession Numbers.

Attachments

Attachment 1: Bromacil Chemical Identity Tables

. Attachment 2: Bromacil Endpoint Selection Table

. Attachment 3: Bromacil and Bromacil Lithium Salt International Residue Limit Status

.

cc: S. Levy (RAB1), C. Rodriguez, (RAB1), J. Tyler (RAB1), J. Van Alstine (RAB1) RDI: RAB1 ( 03/14 /12 ), D. Vogel ( 03/15 /12), G. Kramer (03/ 15 / 12) S. Levy : S

- 10953: Potomac Yard 1 (PY1): (703)305

- 0783: 7509P: RAB1Bromacil Registration Review Human

- Health Assessment Scoping Document

Page 18 of 19 Attachment 1: Bromacil Chemical Identity Table

.

Chemical Structure

Common name Bromacil IUPAC name ( RS )

- 5

- bromo

- 3

- sec

- butyl

- 6

- methyluracil CAS name 5

- bromo

- 6

- methyl

- 3

- (1

- methylpropyl)

- 2,4(1 H ,3 H )

- pyrimidinedione CAS # 314

- 40

- 9

Attachment 2: Bromacil Endpoint Selection Table

.
Summary of Toxicological Dose and Endpoints for Bromacil.

Exposure Scenario Dose Used in Risk

Assessment, UF Special FQPA SF and

LOC for Risk Assessment Study and Toxicological Effects Acute Dietary An endpoint of concern attributable to a single dose not identified.

Chronic Dietary (All populations) NOEL = 9.82 mg/kg/day UF = 100X cRfD = 0.1 mg/kg/day FQPA SF = None cRfD = 0.1 mg/kg/day Chronic Toxicity Study

– Rats LOEL 103 mg/kg bw based on decreased body

- weight gain

. Dermal (Short

- and Intermediate

- Term) NOEL = 20 mg/kg bw/day FQPA SF = None LOC = 100 Developmental Toxicity

– Rats

Maternal LOEL = 75 mg/kg bw/day based on deficits in body

- weight gain and food consu mption during the first 2 days of dosing. Inhalation (Short and Intermediate Term)

Cancer The Carcinogenicity Peer Review Committee classified bromacil as “ Group C

- possible

human carcinogen” based on based on the increased incidence of liver tumors in male mice, and positive trends in thyroid tumors in male rats, and on limited support from SAR compounds. The use of RfD was recommended for qua ntification of risk.Bromacil Registration Review Human

- Health Assessment Scoping Document

Page 19 of 19 Attachment 3: Bromacil International Residue Limit Status

. Bromacil and Bromacil Lithium Salt (012301 and 012302; 18

- JAN

- 2012) Summary of U.S. and International Tolerances and Maximum Residue Limits. Residue Definition : US Canada Mexico 2 Codex 3 40 CFR § 180.210:

Plants: Bromacil (5

- bromo

- 3

- sec

- butyl

- 6

- methyluracil) None None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3 Fruit, citrus 0.1 Pineapple 0.1 Completed: M. Negussie; 18

- JAN

- 2012
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.