### UNITED STATES ENVIRONMENTAL PROTECTIONAGENCY WASHINGTON, D.C. 20460 OFFICE OFCHEMICAL SAFETY AND POLLUTION PREVENTION

September 19, 2012 

### MEMORANDUM SUBJECT: Ammonium Bromide: Human Health Registration Review Seeping Document

PC Code: 000352 DP Barcode: 401466 DecisionNo.: RegistrationNo.: NA PetitionNo.: NA Regulatory Action: Registration Review Risk Assess Type: Single Chemical Case No.: 5002 TXRNo.:NA MRIDNo.: NA 

### FROM:

THROUGH:

TO: CAS No.: 12124-97-9 40CFR: NA (}."'' Timothy C. Dole, CIH, Industnal

## Hygte~ 'l 

### 1

## ·~ Jenny Tao, Senior Toxicologist

## c)~ 

# , .- / William Hazel, Ph. D., SeniorCliemist

## d:/"~ Risk Assessment and Science Support Branch (RASSB) Antimicrobials Division (751OP)



# ---- Timothy Leighton, Senior Scientist {

- Risk Assessment and Science Support Branch (RA Antimicrobials Division (7510P)**<'~I I~**  Steve Weiss, Acting Branch Chief**~** {.;V.e Risk Assessment and Science Support Branch (RASSB) Antimicrobials Division (751OP) Rebecca von dem Hagen, Chemical Review Manager Regulatory ManagementBranch II (RMBII) Antimicrobials Division (751OP)

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# ~.**~**EXECUTIVE SUMMARY Ammonium bromide is registered for use inpaper mills, recirculating cooling water systems and sewage systems. Itis used in conjunction with a chlorine source (sodium hypochlorite or chlorine gas) in a closed systemto produce bromide activated monochloramine. The specified dose onproduct labels is 1to 5 ppm available chlorine for both initial and subsequenttreatments. The toxicology database includes a 13 week oral study in rats with neurological observations, a 4 week oral range finding study inrats, a developmental oral study inrats, and a one generation reproductive toxicity study inrats. The most significant finding from these studies is a LOAEL of 100 mg/kg/day for displaced testes inmale fetuses inthe developmental study. As this was the lowest dose, the NOAEL could notbe determined. The acute toxicity studies indicate that ammonium bromide is oflowacute oral, dermal, and inhalation toxicity (all are Toxicity Category III). Itis irritatingto the eyes (Toxicity Category II) butnotto the skin (Toxicity Category IV) and is not a dermal sensitizer. The mutagenicity studies, which include the Ames test, the in vivo mouse micronucleus test and the mouse lymphomamutation assay, indicate that ammonium bromide is not mutagenic. No dietary (food) ordrinking waterrisks are expectedto be associated withthe existing uses ofammonium bromide. The onlypotentially toxic compound resulting in the water system from the ammonium bromide uses is monochloramine, however, any monochloramine not consumed inthe water system is expectedto degrade under the hightemperature conditions ofthe paper drying process (110 °C) and itis not expected to remain inthe paperto migrate to food. Itis also highly unlikely that monochloramine drinking water exposures will result inrisks ofconcern (i.e. exposures are not anticipated to exceedthe maximum residual disinfectant level (MRDL) of4.0 ppm) because the maximum application rate is 5.0 ppm and most ofthe monochloramine will be consumed during the treatmentprocess. Occupational exposures to the products formulated as liquids are not anticipated to result in risks ofconcern for ammonium bromide because the label requires thatthese products be handled in a closed system. Occupational exposures to the products formulated as solids, however, may result inrisks ofconcern depending upon the physical properties ofthese products and howthey are handled. Although information in the acute toxicity study for one ofthe products suggests thatthe product is notreadily inhalable, specific product chemistry studies, such as particle size analysis or attrition testing, are needed to confirm this finding. Althoughthe label specifies that the Fuzzicide feeder/delivery system, which is a closed system, is used to mix a solution ofammonium bromide withthe oxidantto produce the biocide (i.e. bromine activated monochloramine) the label does not indicate how the ammoniumbromide solution is mixed and the possibility exists thatthis process involves openpouring ofammonium bromide into a premixtank. Therefore, unless it canbe proventhat inhalation exposures will not occur, inhalation toxicity (Guideline #870.3465) and exposure (Guideline #875.1400) studies will be required. Itis understood thatthe reaction ofammonium bromide with the chlorine source is controlled to enhance the production ofmonochloramine, whichis non-volatile, while minimizing the production oftrichloramine, which is volatile. It is recommended that the conditions needed to preventthe production oftrichloramine be stated on the labels.

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### 1.0 BACKGROUND 1.1 Chemical Identity The chemical identity ofammonium bromide is listed inTable 1. 

### Table 1 - Chemical Identity ofAmmonium Bromide ChemicalName Ammonium Bromide CommonName Ammonia Salt Synonym N/A PC Code 000352 CAS Registry Number 12124-97-9 Case No. N/A Empirical Formula (NH4)2 Br



### 1.2 Chemical and Physical Properties The physical and chemical properties ofammonium bromide that are relevant for human health risk assessment are listed in Table 2. 

### Table2 - Physical and Chemical Properties ofAmmoniumBromide Property Value Reference Molecular Weight 98 gm/mole Hazardous Substances Databank (HSDB) Physical State Solid HSDB Melting Point 452 C (sublimes) HSDB Boiling Point N/A N/A Water Solubility 764 gm/liter at 20 C HSDB VaporPressure 9.8 x 10-7 mm Hg PMRA,2007 Henry's Law Constant 1.3 X 10-IO atm 

### *m3/mol PMRA,2007



### 1.3 Use Information According to OPPIN, there are five productsthat contain ammonium bromide as an active ingredient (ai). These products are listed inTable 3. 

### Table 3 -AmmoniumBromide Products EPAReg. Year ProductName Percent Formulation Number Re2istered a.i. 8622-58 2008 Fuzzicide-Comp. 99% EUP- Solid 8622-76 2008 Fuzzicide SP 99% EUP- Solid 8622-64 2003 Fuzzicide Solution 35% EUP- Liquid 8622-59 2003 Ammonium Bromide

- Comp. 99% MUP-Solid 8622-75 2003 Ammonium Bromide -SP 99% MUP-Solid

Page 3 of 12Ammonium bromide is registered for use inpapermills, recirculating cooling water systems and sewage systems. The papermill uses include influentwater systems, cooling water systems, waste water systems, mill water systems, non-potable water systems, starch slurries and process waters. The recirculating water uses include industrial cooling towers, evaporative condensers, industrial water scrubbing systems, brewerypasteurizers and industrial air washing systems and the sewage systems uses include septic tanks, leach fields, tank lines, sewers, lagoons and sewage effluent water. Ammonium bromide is used inconjunction with a chlorine source (12.5 percent sodiumhypochloride or 99 percent chlorine gas) in a closed metered chemical feed systemto produce bromide activated monochloramine

. The treatment canbe administered using the slug, intermediate or continuous feed methods. The specified dose is 0.5 to 5 ppmresidual biocide expressed as total chlorine. 

### 1.4 Previous Human Health RiskAssessments An occupational risk assessment (US EPA, 2002) was written to support the registration of ammonium bromide as a liquid product. The conclusions ofthis assessment were as follows: • No significant dermal or inhalation exposure potential exists during mixing and loading because closed systems are used. • Although dermal exposure to treated water can occur during application, these exposures are not expected to result in risks ofconcern because the application rate is very low and the rate ofdermal absorption is also very low. • Inhalation exposures are negligible because the biocide is diluted in water and the exposure time is limited. A humanhealthrisk assessment was not written for the registration ofammonium bromide used as a solid in 2006. 

### 2.0 TOXICOLOGY Atthe time that ammonium bromide was registered, the toxicology databases were considered to be complete and no additional studies were required. 

### 2.1 Acute Toxicity A summary ofthe acute toxicity findings for ammonium bromide is included in Table 4. Ammonium bromide, whentested as the technical ingredient (99% ofa.i.), is oflow acute oral, dermal, and inhalationtoxicities (all are Toxicity Category III). Itis irritating to the eyes (Toxicity Category II) butnotto the skin (Toxicity Category IV) and is not a dermal sensitizer. 

### Table 4. Acute Toxicity Studies for Ammonium Bromide Test Guideline Guideline MRID Result Toxicity Numbers Category Acute Oral Toxicity (rat) 870.1100 44721303 LD50 (combined)= 2714 mg/kg III Acute Dermal Toxicity (rat) 870.1200 44721304 LD50 (combined) > 2000 mg!kg III Acute Inhalation Toxicity (rat) 870

. 1300 44721305 LC50 (combined)> 0.10 mg/1* III* Primary Eye Irritation (rabbit) 870.2400 44721306 Irritating II Primary Dermal Irritation (rabbit) 870.2500 44721307 Non Irritating IV Dermal Sensitization (guinea pig) 870.2600 44721308 Not a sensitizer N/A Page 4 of12

### *Maximum attainable concentration. Category III is assigned for regulatory purposes based on the National Library ofMedicine's (NLM) Hazardous Substances Data Bank (HSDB) and the Vermont Safety Information Resources, Inc. (SIRI) MSDS Collection's description ofammonium bromide as moderately toxic

. 

### 2.2 Repeat Dose Toxicity The following is a briefsummary ofthe currently available repeat dose toxicology studies for ammonium bromide. All ofthese studies were done with technical a.i. containing at least 98.5% percent ammonium bromide. More detailed information is included inUS EPA, 2012. MRID 

### 45139301 - 4 WeekRange Finding Study Ammonium bromide was administered viathe diet to 4 groups of5 male and 5 female rats at doses ofO, 100, 500, and 1000 mg/kg/day. Rats were monitored daily for clinical signs of toxicity, and weekly for body weight, and food and water consumption. There were no premature deaths. Mid and high dose animals ofboth sexes had agitated behavior, subdued behavior, a rolling gait, hunchedposture and eyes partially closed. All other animals were normal throughout the study. Body weight gain and food consumption was decreased inthe high dose males ( 49% and 24%, respectively). High dose females showed a body weight decrease of31%. Water consumption was similarbetween all groups. Under the conditions ofthis study, the LOAEL for both sexes is 500 mg/kg/day, based on adverse clinical signs and decreased bodyweight/body weight gains and food consumption. A NOAEL of 100 mg/kg/day was observed for both males and females. This is an acceptable/non-guideline range-finding study for the subchronic toxicity study. MRID 

### 45210801-13 WeekToxicity Study with Neurotoxicity Screening Battery Ammonium bromide was administered to rats in a powdered diet for 13 weeks. Control and high-dose groups included 25 rats per sex. Low- and mid-dose groups consisted of 15 rats per sex. The doses for the control, low, and mid dose groups were 0, 100, and 230 mg!kg/day, respectively. The dose for the high-dose group was 518 mg!kg/day for males and 785 mg/kg/day for females. Fifteen animals ofeach sex in the control and high-dose groups were sacrificed and necropsied at 13 weeks. Ofthese, 5 were examined for neurohistopathology. The other 10 animals per sex were examined for gross pathology and histopathology. The additional10 animals in the control and high-dose treatment groups (recovery group) were retained on study, withouttreatment, for an additional 4 weeks after which they were sacrificed for gross pathology only. Neurotoxicityparameters were measured during the pretrial week and inWeeks 4 and 8 on 5 animals per sex inthe control and high dose groups. At week 13, fifteen animals per sex in the control and high dose groups were evaluated for these parameters. These animals were then necropsied. At the end ofthe recovery period (week 17), the remaining 10 animals per sex in the control and high dose levels were evaluated. Ophthalmoscopic examinations, motor activity, and neurohistopathology were not remarkable in the treated animals vs. the controls. Organweight

Page 5 of 12changes were considered to be ofno toxicological significance and histopathology ofthese organs was notremarkable. Gross and histopathology were notremarkable. Two males inthe main studyhigh-dose group (500 mg/kg/day), and a single male inthe high dose recovery group were sacrificed inWeeks 6, 9, and 13, respectively, due to intractable conditions, notrelated to the administration ofthe test compound. Body weight gain inmales showed a decrease inthe high (23%) and mid (10.5%) dose bythe end ofthe study. Females showed a decrease inthe high (22.2%) dose by the end ofthe study. Duringthe 4 weekrecovery period, although a 45% increase inthe rate ofweight gain occurred, body weight still showed a significant decrease of 11% and 8% in males and females, respectively. Food consumption inmales was generally decreased starting on day 28 inthe high dose and day 42 inthe intermediate dose when compared to the controls. No change was seen in the food consumption during the 4 week recovery period inmales and infemales at all dose levels during the main and the recovery study. After 12 weeks exposure at the high dose, there were minor, but statistically significant increases inhemoglobin and hematocrit for both sexes. In the high dose female, increases in neutrophils and monocytes were noted. After the 4-week recovery period, total and differential white cell counts in males showed a significantly, although slight decrease vs. the controls. Meanphosphate levels inthe blood increased 15% and 10% inmales exposed at 225 (P<0.01) and 500 (P<0.05) mg/kg/day, respectively, relative to controls. Inthe high dose females atthe recovery period, clinical chemistry changes were noted, butwere slight and not considered of anytoxicological importance. Duringthe recovery period, the high dose females showed a 62% increase in alkaline phosphatase values vs. the control, but such change was probably oflittle toxicological importance. Atthe high dose, clinical observations included nasal bleeding, claws longer than normal, rolling gait, staggering, subdued behavior, reduced activity and hind limp splaying inbothmale and female animals. The functional neurobehavioral findings (FOB) recorded a high incidence of decreases inboth fore andhindlimb grip strength, limpness and postural/rolling gait abnormalities. A slight increase inthe incidence ofdecreased alertness, and increased landing foot splay was also seen. The reduced hindlimb grip strength ofthe high-dose females (butnot high-dose males) remained through the 4-week recovery period. Males at the mid dose exhibited the clinical observations similarto the high dose, except for reduced activity. Correlation was afforded in the FOB tests and included limpness, decreased hindlimb grip strength, postural/rolling gait abnormalities and slight increases inthe incidence of increased landing foot splay. Atthe low dose, limpness was observed in 3/10 males, but only 1110 showed limpness onmore than one occasion. Females exhibited a very low incidence of general clinical observations. The FOB findings included limpness and a slight increase in increased landing foot splay. Atthe lowdose, generally no clinical observations or abnormalities inthe FOB were noted. The LOAEL for both sexes is 225 mg/kg/day, based ondecrease inbody weight gain and food consumption in males, neurobehavioral findings oflimpness, reduced hindlimb grip

Page 6 of 12strength, and increased landing foot splay, which was more pronounced in the males. A NOAEL of 100 mg/kg/day was observed for bothmales and females. This study is classified as ACCEPABLE for a 90-day subchronic study. However, the neurotoxicity screening assessment portion ofthe study is UNACCEPTABLE, butupgradable. This assessment can be upgraded ifthe following data are submitted and found to be acceptable: 1. Additional details onhow individual neurobehavioral parameters were evaluated (e.g. criteriaused to score the different endpoints and description ofmethods ofstatistical analysis). 2. A description ofthe neurotoxicity screening battery positive control or some other demonstration ofthe laboratory's experience withthese tests. MRID 45139302- Developmental Toxicity Study in Rats Ammonium bromide was administeredby oral gavage to 4 groups of24 mated female rats at doses of0, 100, 300, and 1000 mg/kg/day from days 6 - 19 inclusive ofgestation where Day 0 was the day ofdetection ofmating. One high dose level female was sacrificed on day 10 ofgestationbecause ofsevere clinical signs. Maternal toxicity at 1000 mg/kg/day included abnormal clinical observations such as rolling gait, animal limp whenhandled, piloerection, subdued behavior, hunched posture, eyes dark and slowrespiration which were generally noted throughout the treatment period. Virtually no effects were seen at the lower dose levels comparedto the controls. At 1000 mg/kg/day, a statistically significant depression in body weight gain was seen from gestational days 6- 12 (57%) and 6- 20 (18%) were noted. The lower dose levels were not remarkable comparedto the controls. Food consumption at all dose levels was equivalentto the control group. Interuterine mortality was unaffected at 1000 mg/kg/day. A reduction (14.5%; p<0.001) in mean fetal weight ofmales and females combined was noted. At 1000 mg/kg/day fetal abnormalities included reduced/absent leftkidney, often associated with absences ofthe left adrenal and/or ureter. Many animals also showed narrowing ofthe left uterine hom and abnormalities ofthe spleen. There was a dose-related increase in the incidence offetuses and litters with kinked ribs, often associated with incomplete ossification ofthe ribs at all dose levels vs. the control. These animals also showed an increased incidence ofcurved scapula at 1000 mg/kg/day. The incidence ofanimals with slightly kinked ribs was also increased at 300 and 1000 mg/kg/day. There was a slight increase in the incidence offetuses withreduction inthe size ofthe 13thrib(s) at 1000 mg/kg/day with a marginal increase occurring at 300 mg/kg/day. Anincrease incidence ofdilated renal pelvis, dilated ureter was seen at 1000 mg/kg/day. A displacement ofthe testes was seen at all dose levels, and was in a dose-related trend (low: 11

Page 7 of 12fetuses of7 litters, mid: 15 fetuses of 10 litters, high: 20 fetuses of 10 litters vs. the control: 3 fetuses of3 litters). A dose-related increase inthe incidence ofsubcutaneous hemorrhage affecting the limbs and the cranium also occurred. Hemorrhage affecting the brain ventricles and the surrounding tissues was also seen in a dose-related manner. The number ofsmall fetuses was increased at 1000 mglkg/ day. The maternal LOAEL was 1000 mglkg/day based on abnormal clinical observations, including rolling gait, animal limp when handled, piloerection, subdued behavior, hunched posture, eyes dark and slowrespiration, and a decrease in weight gain during the first 6 days of the study. The maternal NOAEL was 300 mg!kg/day. The developmental LOAEL was 100 mglkg/day based ondisplaced testes in the male fetuses. The developmental NOAEL could not be determined. The developmental toxicity study with ammonium bromide in the rat is classified as Acceptable/Guideline. MRID 45579201 -RangeFinding Reproduction Study in Rats Ammonium bromide was administered viathe diet to 4 groups of 1 0 rats/sex randomly selected at doses at 0, 1600, 3200, and 6400 ppm for the premating interval. The low dose of 1600 ppmis equivalentto 151/176 mglkg/day for males/females, the mid dose of3200 ppm is equivalentto 277/347 mg/kg/day for males/females, and the high dose of6400 ppm is equivalent to 591/717 mglkg/day for males/females. The parent (PO) animals received treated diet for 2 weeks priorto mating and throughoutthe mating, gestation and lactation periods for both sexes until termination after the first generation (F1) had been weaned. Atthe high dose (5911717 mglkg/day) parental toxicity was demonstrated byreduced body weight gain overthe treatmentperiod and reduced food consumption after cohabitation. Clinical signs includedrolling gait, piloerection, hunched posture and unkempt coat. In addition, females showed hyperactive behavior. Reduced body weight gain (16%) in males overthe treatment period was noted. Forthe one female thatproduced a litter; the litter died before Day 4 of lactation. The high dose, therefore, produced both mating performance and fertility effects. Atthe mid dose (277/347 mglkg/day), clinical signs for both sexes were similarto, but less severe thanthose described for animals atthe high dose. Unkempt coat was not noted. Reduced body weight gain (13%) in males overthe treatmentperiod was noted. Bodyweight gain in the female was not affected. There was an increased incidence oftotallitterloss and a slight increase inpup mortality for surviving litters. Mean litter and pup weights were reduced throughoutthe Day 21 oflactation, except on day 4 when compared to the Control. The parental toxicity LOAEL is 277/347mg!kg!day for males/females based on clinical signs inboth sexes and reduced body weight gain (13%) in males. The NOAEL is 1511176 mg!kg!day. The reproductive toxicity LOAEL is 277/347 mg!kg!day for females/males based on an increased incidence oftotal litter loss and a slight increase inpup mortality for surviving litters.

Page 8 of 12Mean litter and pup weights were reduced throughoutthe Day 21 lactationperiod (except on day 4) when comparedto the control. The 

### NOAEL is 1511176 mg/Jiglday. This study is an acceptable/non-guideline range finding study for reproduction toxicity. 

### 2.3 Mutagenicity Three mutagenicity studies are available. Ammonium bromide was found to benegative in all three studies. The study results are summarized inTable 5.



### Table 5 -Ammonium Bromide Mutagenicity Studies MRID Test Results 44721309 Ames Test Not mutagenic with Salmonella typhimurium strains TA1535, TA1537, TA98, and TAIOO and E. coli strain WP2uvrA, whentestedup to viability limits of 5000 Jlg/plate with and without S9 activation. 44721310 in vivo mouse Not mutagenic in micronucleus test in bone marrow ofCD-I mice whentested micronucleus test atthe concentrations ofO, 400, 800, and 1600 (maximum tolerated dose) mg/kg/day. 44721311 mouse lymphoma Not mutagenic in mouse lymphoma (L5178Y) mutation assay at maximum mutation assay concentration (induced partial cytotoxicity) of5000 Jlg/ml with and without S9 activation. 

### 2.4 Chronic Toxicity/Carcinogenicity There are no chronic toxicity or carcinogenicity studies inthe Agency's hazard database for ammonium bromide. 

### 2.5 Toxicology Endpoints When ammonium bromide was initiallyregistered as a liquidproduct in 2003, toxicity endpoints for inhalation exposure were not selected and quantitative risk assessments were not warranted because ofthe limited use pattern that did not involve human exposure. While this rationale was valid for the liquid product it may not be valid for the solid products that were subsequently registered in 2006. Depending upon the physical properties ofthe solid products and how they are handled it may be necessary to select endpoints to evaluate occupational inhalation exposure.



### 3.0 DIETARY ASSESSMENT 3.1 Dietary Exposure No residues ofpotential toxicological concern are expectedto survive the paper or paperboard manufacturing processes. Anymonochloramine not consumed inthe water system is expectedto degrade under the high temperature conditions ofthepaper drying process (110 °C). Ofcourse, any remaining ammonium bromide will exist as the dissociated ions. The chemical species likely to remain to be incorporated into the dried/finished paper and paperboard are ammonium ion, bromide ion, nitrate ion, and chloride ion for whichthere are no dietary toxicity

Page 9 of12concerns. Itis only these benign compounds that could potentially migrate into food from foodcontactpaper orpaperboard. Therefore, dietary (food) risks neednot be calculated. 

### 3.2 Drinking Water Exposure No drinking water risks are expected from the existing uses ofammonium bromide. Very low levels ofmonochloramine may survive to the point ofdischarge. EPAhas established a maximum residual disinfectant level (MRDL) of4.0 ppm and water utilities are required to maintain total chloramines at orbelowthis MRDL. Given this limits, the fact thatthe maximum application rate is 5.0 ppm and the fact that most ofthe monochloramine will be consumed during the treatmentprocess, it is highly unlikely that drinking exposures to monochloramine will result inrisks ofconcern. 

### 4.0 OCCUPATIONAL AND RESIDENTIAL EXPOSURES Occupational exposures to the liquid product are not anticipated to result in any risks of concern for ammoniumbromide because the label requires thatthis product be handled in a closed system. Occupational exposures to the solidproducts may result inrisks ofconcern depending upon the physical properties ofthe products and howthe products are handled. Althoughthe label specifies thatthe Fuzzicide feeder/delivery system, which is a closed system, is usedto mix a solution ofammoniumbromide withthe oxidantto produce the biocide (i.e. bromine activated monochloramine) the label does not indicate howthe ammonium bromide solution is mixed and the possibility exists thatthis process involves openpouring ofammonium bromide into a mix tank. Itis also notknown exactly howthe product is formulated (i.e. powder or granule) and if it will release inhalable particles when handled. Although information in the acute toxicity study suggests that the productis notreadily inhalable, specific product chemistry studies, such as particle size analysis (Guideline #830.7520) or attrition testing, are neededto confirm this finding. Itis understood thatthe reaction ofammonium bromide withthe chlorine source is controlled to enhance the production ofmonochloramine, which is non-volatile, while minimizing the production oftrichloramine, which is volatile. Itis recommended thatthe conditions needed to preventthe production oftrichloramine be stated onthe label. Residential exposures are not anticipated for ammonium bromide and monochloramine because these products are only used in industrial areas.



### 5.0 AGGREGATE AND CUMULATIVE EXPOSURE As there are no dietary (food or drinking water) orresidential exposures associated withthe currently registered uses ofammoniumbromide there is no need to estimate aggregate or cumulative risks.

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### 6.0 INCIDENTS There are no hwnan incidents reported inthe OPP incident database that are associated with ammoniwn bromide exposure. 

### 7.0 TOLERANCES There are no tolerances for ammoniwn bromide. 

### 8.0 ENDOCRINE DISRUPTION EFFECTS As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments ofcarcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual 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 ofits mostrecent registration decision, EPAreviewed these data and selectedthe most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section408(p), ammoniumbromide is subjectto the endocrine screening part ofthe 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 inhumans orwildlife similar to an effect produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1consists ofa battery of 11 screening assays to identify the potential ofa chemical substance to interact withthe estrogen, androgen, orthyroid (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 ofthe EDSP where EPA will determine which, ifany, ofthe Tier 2 tests are necessary based onthe available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused bythe substance, and establish a dose-response relationship betweenthe dose and the E, A, or T effect. UnderFFDCA 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 of67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Ammoniwn bromide is not among the group of58 pesticide active ingredients onthe initial list to be screenedunder the EDSP. Accordingly, as partofregistrationreview, EPA will issue future EDSP orders/data call-ins, requiring the submission ofEDSP screening assays for ammoniwn bromide. For further information onthe status ofthe EDSP, the policies and procedures, the list of67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website at: http://www.epa.gov/endo/

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### 9.0 ANTICIPATED DATA NEEDS A listing ofthe studies required for the human health registration review ofammonium bromide is included in Table 6. The inhalation toxicity and exposure studies are needed to evaluate inhalation exposures to ammonium bromide that occur during the openpour addition of products that are formulated as solids. These studies can be waived ifit can be proventhat no exposure occurs due to the nature ofthe product (i.e. granules that are not inhalable based on particle size data) orthe manner in which it is handled (i.e. closed system addition to the premix tank used to make the ammonium bromide solution). No additional studies are needed to assess the hazards ofbromine activated monochloramine. 

### Table 6 -StudiesNeeded for the Registration Review ofAmmonium Bromide Study Needed Guideline Applicable Exposure Scenarios 90 Day Inhalation Toxicity 870.3465 Openpour solid formulations into premixtankA Indoor Exposure, Inhalation 875.1300 Open pour solid formulations into premixt:ank"B DataReporting/Calculations 875.1600 Particle Size 875.7520 Openpour solid formulations into premixtank A. These studies canbe waived ifit canbe proventhat no exposure occurs due to the nature ofthe product (i.e. granules that are not inhalable based on particle size data) orthe manner in which it is handled (i.e. closed system addition to the premixtankused to make the ammoniumbromide solution) B. Itmaybe possible to use proprietary surrogate exposure data ifdata compensation issues can be addressed.



### 10.0 REFERENCES PMRA, 2007. EvaluationReportERC2007-09 Ammonium Bromide Fuzzicide, H113-26/2007- 9E-PDF, PestManagementRegulatory Agency, Health Canada, 13 November 2007. U.S. EPA, 2002. Review oftheEvaluation ofthe Potential Exposure and Human Health Risks for Fuzzicide (Ammonium Bromide) When Used in Cooling Water Systems and Pulp and Paper Mills, D282465. June 6, 2002 U.S. EPA, 2012. Ammonium Bromide: Summary ofMammalian Toxicology Datafor the Registration Review Scoping Document. D401624.

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