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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 assess

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 updated 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 CFR §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 definition. 

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 tolerance 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 12X. 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 studies, 

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, revised

assessments 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 handler exposure assessments may be required under 

Registration Review based upon revisions to the Agency’s scenario-specific surrogate handler 

exposure data (http://www.epa.gov/pesticides/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. New exposure monitoring data

may be incorporated, as necessary, during Registration Review. In addition, an occupational 

handler exposure assessment may be required for the 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 registered for use in recreational areas have been cancelled (personal 

communication between J. Tyler and S. Snyderman, 14-FEB-2012). However, there is the 
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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 control 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 other 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, bromacil 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 (tmax) measured at 1 and 2 hours for 

males and females, respectively. Distribution, particularly at a high dose level, was more 

pronounced at 1 hour 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 preconditioning, 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 decreased 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 hepatocellular 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 the 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 dose 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 the 
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vertebrae, 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 post-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 performance. 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 battery 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-examined 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, reproductive, 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 rates, 

reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates 

acute tests and chronic studies that assess growth, developmental and reproductive effects in 

different taxonomic groups. As part of the 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 occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 
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determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

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

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

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 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 for 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 battery, 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 missing 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-evaluated 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-methyluracil), 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 hydroxylated 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. 
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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 concern for risk assessment in orange is also parent only and the residues of 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 

metabolism 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 diet 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 studies 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 maximum 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; 280X); and 3) the low total radioactive residue (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 parent 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 required 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 methods 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 nitrogen/phosphorus detector 

(GLC/NPD) used for data collection. These methods have not undergone 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 Method 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 for 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 expiration date of 13-JUL-2015 are available for bromacil (personal 

communication with T. Cole, 25-JAN-2012).
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The requirements for storage stability data were previously satisfied for the purposes of 

reregistration. The submitted storage stability data indicate 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 duration 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 

bromacil 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 Agency 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 

performed 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 harvested 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 required 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 Document (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/season 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 established 

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 field data for three field trials in HI that indicated that residues 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 (1.25X 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. As pineapple forage is no longer listed as a regulated commodity (“Agency 

guidance on calculating reasonably balanced diets for livestock” (Memo J. Stokes, 30-JUN2008), 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 molasses 
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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. Residues 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 (2.5X). Residues were also nondetectable in/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(1H,3H)-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. No additional field trials are required for this 

updated commodity definition because field trial data are available for oranges, lemons, and 

grapefruit, the representative crops of the citrus 10-10 crop group. 

Conclusions

The qualitative nature of bromacil 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 future, 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 dietary 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 be updated to reflect the current Citrus 10-10 

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

commodity definition. 
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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 using 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 the uses recommended through reregistration were not of concern. 

There is the potential for dietary exposure to bromacil through consumption of drinking water 

that contains bromacil residues. At the time of the RED, the data available to the Agency 

indicated that bromacil had 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 average 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 water 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 reaches <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-contaminated 

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 rapidly 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 exposure 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 available. 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 products 
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registered for use in recreational 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 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 bromacil. 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-driftmanagement practices to reduce off-target drift with specific products with significant risks 

associated with drift.

Aggregate 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 population 

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 registered 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 uncultivated 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 or tablets, 

pressurized liquid, SC, WP, and WDG (or DF). Bromacil is applied by groundboom sprayers-
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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 exposure from entering into areas previously treated with 

bromacil. The bromacil RED included quantitative risk estimates for occupational handler 

scenarios, but not for occupational post-application scenarios (Memos, J. Redden, 31-MAY1995, 29-JAN-1996, 26-APR-1996).

Occupational Handlers: The 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/applying 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, engineering 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 application 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 completion 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 mitigation, 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 exposures 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):

Requirements for post-application exposure studies are addressed by Subdivision K of 

the Pesticide Assessment Guidelines. Post-application exposure data were not required 
Bromacil Registration Review Human-Health Assessment Scoping Document

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previously by the Agency. In light of toxicological concerns, i.e., developmental toxicity, 

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 treating 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 studies 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

*133-3 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/reentry 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 scenario-specific surrogate handler 

exposure data (http://www.epa.gov/pesticides/science/handler-exposure-table.pdf). 

Recommended unit exposures for occupational handler assessments 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 the 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 registered 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 

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 control are not required since 

there are no reentry tasks associated with the registered nonagricultural uses of bromacil.
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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-FEB12; D399205). The report represents incidents occurring in the U.S. from 2006 to the present.

Human Incident Data: OPP IDS (2012)

For this evaluation, the OPP IDS was utilized to retrieve pesticide incident 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 severity 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 environmental 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 reports 

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 process 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 outcomes 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 pesticide 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 incidents 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. The Agency will continue to monitor the 
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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 §180.210) 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 established 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 use 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 crops. 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 potential 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 other 

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 risk 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 generic 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 and 
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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.

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 include 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:

An occupational handler exposure assessment may be required for the registered postharvest 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. 
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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; 

2528421 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: RAB1
Bromacil Registration Review Human-Health Assessment Scoping Document

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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(1H,3H)-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 consumption 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 quantification of risk.
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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 Mexico2 Codex3

40 CFR § 180.210:

Plants: Bromacil (5-bromo-3- sec -butyl-6-

methyluracil)

None None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

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.