OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION 

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

September 1, 2015

PC Code: 085712 DP Barcode: 427301

MEMORANDUM

SUBJECT: Registration Review: Problem Formulation for Nicarbazin (OvoControl P) for

R edu cin g Hatchability in Pigeons.
FROM: Christina Wendel, Biologist Richard Shamblen, Biologist Environmental Risk Branch 2 Environmental Fate and Effects Division (7507P)

REVIEWED BY: Nick Federoff, Wildlife Biologist R. David Jones, PhD., Senior Agronomist Environmental Risk Branch 2 Environmental Fate and Effects Division (7507P)
THROUGH: Brian Anderson, Branch Chief Elyssa Arnold, Risk Assessment Process Leader Environmental Risk Branch 2 Environmental Fate and Effects Division (7507P)
TO: Bonnie Adler, Chemical Review Manager Jill Bloom, Team Leader Linda Arrington, Branch Chief Risk Management and Implementation Branch 5 Pesticide Re-evaluation Division (7508P) 

### RICHARD SHAMBLEN Digitally signed by RICHARD SHAMBLEN DN: c=US, o=U.S. Government, ou=USEPA, ou=Staff, cn=RICHARD SHAMBLEN, dnQualifier=0000051207 Date: 2015.09.01 12:16:46 -04'00'



### 2015.09.01 13:28:28 -04'00'

ROBERT JONES 2015.09.02 15:15:36 -04'00'

2015.09.02 16:36:43 -04'00'

2015.09.03 13:52:45 -04'00'

### 2 

## 

1. Executive summary ............................................................................................................. .... 3 2. Introduction .................................................................................................................. ........... 6
a. Mode of Action ................................................................................................................ .... 6 3. Use Characterization .......................................................................................................... ..... 7 4. Conclusions from Previous Risk Assessments ....................................................................... 8
a. Ecological Risk Assessment ................................................................................................ 8 b. Drinking Water Exposure Assessments ............................................................................. 10
c. Clean Water Act Programs ................................................................................................ 10 5. Environmental Fate and Transport Characteristics ............................................................... 10
a. Physical Properties ........................................................................................................... .. 10 b. Degradation Characteristics ............................................................................................... 12
c. Study Waiver requests ....................................................................................................... 1 4 d. Degradates..................................................................................................................... ..... 14 6. Receptors...................................................................................................................... ......... 14
a. Effects to Aquatic Organisms ............................................................................................ 15 b. Effects to Terrestrial Organisms ........................................................................................ 16
c. Ecological Incidents .......................................................................................................... . 16 7. Exposure Pathways of Concern ............................................................................................ 17
a. Background .................................................................................................................... .... 18 b. Potential Exposure to Terrestrial Wildlife ......................................................................... 18
c. Secondary Exposure by Predators and Scavengers ........................................................... 19 d. Potential Exposure to Aquatic Environments .................................................................... 19
e. Ecological Drinking Water Exposure Pathways ................................................................ 19 8. Analysis Plan ................................................................................................................. ....... 21
a. Stressors of Concern .......................................................................................................... 22 b. Measures of Exposure ........................................................................................................ 2 2
c. Measures of Effect ............................................................................................................ . 23 d. Endangered Species Assessments ...................................................................................... 24
e. Endocrine Disruptor Screening Program ........................................................................... 24 9. Preliminary Identification of Data Gaps ............................................................................... 24
a. Environmental Fate ............................................................................................................ 25 b. Effects ....................................................................................................................... ......... 27 10. References .................................................................................................................... ...... 31
a. Submitted Environmental Fate Studies .............................................................................. 33 b. Submitted Ecological Toxicity Studies .............................................................................. 35 APPENDIX A. SIP Inputs and Outputs for Nicarbazin (DNC & HDP components) .................. 39

### 3 

## 1. Executive summary
The Environmental Fate and Effects Division (EFED) has completed the problem formulation for the ecological risk, environmental fate, endangered species, and drinking water assessments to be conducted as part of the registration review of nicarbazin (PC code 085712). The problem formulation describes the methods planned to be used during the completion of drinking water and ecological risk assessments in support of registration review and provides an overview of the environmental fate, ecological effects, potential risks associated with the use, and uncertainties unique to the risk assessment of nicarbazin. This document also identifies additional studies that would be beneficial to the conduct of an ecological risk assessment. Nicarbazin is made up of two components, DNC and HDP (see Section 2 for further details). HDP acts as the synergist that aids absorption of the toxicant, DNC. Ecological risk assessments have been conducted on nicarbazin, for both OvoControl G (no longer registered) and OvoControl P (currently registered). Conclusions from the previous assessments determined that based on very limited guideline and literature data for birds and mammals, nicarbazin posed both an acute risk (RQ = 1.4 for mortality) and chronic risk (RQ >500 for reproductive/chronic effects) to non-target listed and non-listed birds. This is not unexpected given its intended use as a bird reproduction inhibitor. At 1% of the diet, the chronic risk (RQ 5) still exceeded the Level of Concern (LOC)

. Currently, two labels (OvoControl P: EPA Registration No. 80224-1 and SLN Registration No. 15000-1 (for Puerto Rico only)) are registered as a control agent (treated bait) for pigeons, with use limited to urban communities. Based on an application rate for flocks of 2,400 pigeons, more than 10,000 pounds of the OvoControl P control agent, containing nearly 55 pounds of nicarbazin, will be applied at each treatment site. The number of treatment sites per urban area, or treatment density, is undefined.
The formation of the vitelline membrane is common in animals, and the mode of action of nicarbazin is to reduce the viability and hatchability of eggs by interfering with the formation of the vitelline membrane. Therefore, reproductive effects in animals other than birds, including aquatic animals, are possible. However, no adequate studies that evaluated reproductive effects of nicarbazin in species other than birds have been submitted or identified in the open literature. Exposure to aquatic environments may occur if nicarbazin is used in close proximity of water, orthrough feces of target animals because nicarbazin appears to pass through birds largely unmetabolized. In addition, the nicarbazin components DNC and HDP, present in pigeon feces, are stable to hydrolysis. HDP is soluble in water, whereas DNC has a calculated Koc of 1650 and log Kow of 3.6. Thus, with continuous feeding, biomagnification and food-chain exposure to predators is possible. Based on the mode of action and the potential exposures, data that allow for toxicity thresholds for reproductive effects to be defined are critical for risk assessment, including:

x Fish full-life cycle (OCSPP guideline no. 850.1500)

x Aquatic invertebrate life-cycle (OCSPP guideline no. 850.1300);

x Chronic sediment toxicity (Non-guideline).

### 4 Since DNC and HDP essentially work as a toxicant and synergist, respectively, data on both chemicals together will likely result in the most conservative analysis. However, studies of DNC with and without HDP would allow for an evaluation of the toxicity enhancement of HDP on DNC. Therefore, if there are differences in the environmental fate, metabolism, and exposure potential of the two chemicals, then the resulting differences in the risk profile can be described only if data on each component are available. Past assessments have also noted these data gaps. In addition, acute toxicity to aquatic organisms using the chemicals together is not known and toxicity to aquatic plant species in general is not known. Although nicarbazin has not shown high acute toxicity to other organisms, these data are needed for risk assessment if there is potential exposure to aquatic and saltwater environments. The freshwater species acute toxicity data can be used as a surrogate for the saltwater species. No toxicity data is available for terrestrial plants or terrestrial invertebrates; however, based on the current use pattern and available information, additional data is not needed at this time.

Data Needs The specific recommended studies are summarized in Tables 1 and 2 . For the acute aquatic freshwater invertebrate and fish studies listed in Table 1 , acceptable studies already have been submitted for the individual nicarbazin components, but testing is recommended in these same species for the nicarbazin complex (DNC + HDP). The submitted ecotoxicity studies conducted with DNC and HDP are discussed in Table 7and 8 below. Table 1: Recommended Ecotoxicity Guideline and Non-Guideline Studies for Nicarbazin OCSPP Guideline Study Study Description Test Species Test Material Aquatic 850.1010 Freshwater invertebrate acute toxicity Waterflea (Daphnia magna ) Nicarbazin complex 850.1075 Freshwater fish acute toxicity e.g., Rainbow trout ( Oncorhynchus mykiss )
orBluegill sunfish (Lepomis macrochirus ) 850.1300 Freshwater invertebrate life-cycle D. magna

DNC; and Nicarbazin

complex 850.1500 Freshwater fish full lifecycle e.g., Rainbow trout ( O. mykiss )

Non

- Guideline Chronic Sediment Toxicity Midge ( Chironomus dilutes ); freshwater amphipod (Hyalella azteca ); and estuarine amphipod (Leptocheirus plumulosus ) 850.4400 Aquatic vascular plant toxicity Duckweed (Lemna spp.)
850.4500 Aquatic non

- vascular plant toxicity 3 algal species 850.4550 Cyanobacteria Terrestrial

850.2100 Avian acute oral toxicity with passerine species Passerine species ( e.g., house sparrow ( Passer domesticus ) , z ebra finch ( Taeniopygia guttata ), red-wing blackbird ( Agelaius phoeniceus ); canary ( Serinus canaria )) Nicarbazin complex (As Current

Product; OvoControl P) 850.2300 Avian reproduction Currently being conducted by registrant; (protocol review D424098, USEPA 2015 b )

### 5 Despite its history of use in the poultry industry, little is known about the environmental fate of nicarbazin (WHO, 1998; Boxall et al., 2003a, b; EFSA, 2003). To conduct drinking water and ecological risk assessments for nicarbazin, EFED recommends the registrant submit seven (7) OCSPP environmental fate, transport and transformation test guideline studies. These guideline studies, by test material, are summarized in Table 2 . Recommendations are consistent with previous risk assessments, data evaluation records, and responses to data waiver requests (DP312669, DP313794; USEPA, 2005a and b; and DP328803; USEPA, 2007a). Table 2: Recommended Environmental Fate, Transport and Transformation Guideline Studies OCSPP Guideline OCSPP Guideline Description Comments Test Material 835.1230 Adsorption/ Desorption Batch equilibrium DNC; HDP; and Nicarbazin complex 835.1240 Leaching None 835.2120 Hydrolysis Will be used to evaluate the need for fish BCF study. Nicarbazin complex

835.2240 Aqueous Photolysis Chemical properties indicate nicarbazin is likely to photolyze in water. DNC; HDP; and Nicarbazin complex 835.4100 Aerobic Soil Metabolism None 835.4300 Aerobic Aquatic Metabolism None
835.4400 Anaerobic Aquatic Metabolism None

850.1730 Fish bioconcentration A fish bioconcentration study is needed based on

the high K ow of DNC

(MRID 46416410). DNC; and Nicarbazin complex

850.6100 Analytical methods in soil Must include ECM and ILV DNC; HDP; and Nicarbazin complex 850.6100 Analytical methods in water Must include ECM and ILV 830.7550 830.7560 830.7570 Octanol- Water Partitioning (Kow) Study Will be used to evaluate the need for fish BCF study. Nicarbazin complex

Abbreviations: ECM = environmental chemistry methods; ILV = independent laboratory validation


### Label and Use Clarification Issues

To better understand the manner in which nicarbazin is used or intended to be used would be beneficial for the subsequent risk assessment, especially for modeling purposes. The following information would help the Agency conduct a realistic risk assessment:

x Clarify the term “urban areas

. ”Although the labels provides examples of site types ( e.g., office parks, malls, etc.), in this context, how are “urban areas” identified? For example, are these use sites limited to within an urban area as defined by the U.S. Census Bureau? 1 

### See footnote below for more information about the U.S. Census Bureau classification.

1 https://www.census.gov/geo/reference/urban-rural.html

### 6 x Clarify the number of treatment sites within the urban area, or define the maximum treatment density.

x Usage data (none are available at this time) . “Usage” is the number of lbs of the active ingredient used, typically on an annual basis, over the course of several years. Details on where this use occurs geographically, what sites represent what portion of overall usage, average and maximum application rates, etc., are also useful.

x Maximum and typical flock count. The product application rate is based on an estimated flock count, which must be performed just prior to the intended time of application. The product labels do not limit the total amount of product to be used daily or annually at a given site. The labels provide examples of the application rate for different flock sizes, up to 2,400 pigeons, but there is no explicit information about the maximum number of pigeons to be treated at any one site. It would also be useful to get an idea of the typical flock size or range of sizes applicators are attempting to control with a given application method ( e.g., bait pans, mechanical feeders, etc.).


## 2. Introduction
Nicarbazin was previously assessed at the time of the Proposed Registrations of OvoControl G for Geese in 2005 (DP312669, DP313794; USEPA, 2005a and b), and OvoControl P for pigeons on 2007 (DP328803; USEPA, 2007a), as well as a Section 24c risk assessment on pigeons in Hawaii in 2007 (DP344692; USEPA, 2007c), and a new use risk assessment for non-native hybrid, domestic and Muscovy ducks completed in 2007 (DP340973, DP335890; USEPA, 2007b). In addition to risk assessments that were completed, supplemental reviews and follow up waiver requests have also been completed for nicarbazin (DP363859, DP363860, USEPA 2009; DP372345, DP372348, DP349126, USEPA 2010; DP396672, USEPA 2011; D400098, USEPA 2012; DP415695, USEPA 2014 a ). 

## a. Mode of Action Nicarbazin (C 19 

### H 18 

### N 6 

### O 6 

### , MW 426.38 g/mol) is a 1:1 complex of two compounds, 4,4'- dinitrocarbanilide (DNC, 70.89% by weight) and 4,6-dimethyl-2-pyrimidinol (HDP, 29.11% by weight). DNC is considered to be the active component, and HDP aids in its absorption. The potency of DNC is reported to be increased tenfold when it is mixed with HDP (Chapman 1994). Nicarbazin is fed to pigeons to reduce the viability and hatchability of eggs by interfering with the formation of the vitelline membrane, which separates the egg yolk and the egg white. Historically, nicarbazin has been used since the mid-1950s as an anticoccidial agent to control intestinal protozoan parasites in the poultry industry. The Federal Drug Administration (FDA) currently approves the use of nicarbazin as a 125-ppm food additive for broiler chickens, but not for layers 2



### .

2 http://www.accessdata.fda.gov/scripts/animaldrugsatfda/details.cfm?dn=009-476

### 7 Figure 1: Chemical structures of HDP (left) and DNC (right) 3



### .



## 3. Use Characterization
There are no agricultural pesticidal uses for nicarbazin. Through the OvoControl P label (EPA Reg. No: 80224-1), nicarbazin is currently registered for use as a ready-to-use control agent (treated bait) for pigeons. Limited to urban areas, specific use sites include: office parks, malls, institutions, bridges, airports, and other commercial and industrial buildings or structures. OvoControl P may be applied via managed bait stations to flat rooftops, or other flat paved or concrete surfaces in secured areas that limit public access. Nicarbazin is not registered for use in Guam, American Samoa, Northern Mariana Islands, and the U.S. Virgin Islands. A Special Local Needs (SLN) 24(c) (EPA SLN No. 150001) was approved for Puerto Rico in May, for distribution and use of OvoControl P within Puerto Rico until January 15, 2020. Prior to application, applicators within Puerto Rico must contact the Pesticides Regulatory Office of the Puerto Rico Department of Agriculture to obtain a permit. The label follows the OvoControl P label (EPA Reg. No: 80224-1), with some additionsspecific to Puerto Rico. There are restrictions regarding application in areas of non-target birds cooccurrence ( i.e., Scaly-naped pigeon (Patagioenas squamosa ), Plain pigeon ( Columba inornata wetmorei ), Ringneck dove ( Streptopelia risoria ), Zenaida dove (Zenaida aurita ), White-winged dove (Zenaida asiatica ) and Common Ground dove ( Columbina passerina )), and some urban areas (Baxter Company Pharmaceuticals Installations located in Guayama, and Cabo Rojo and the delimited area for the protection of the Plain Pigeon at Cidra, Comerio, Caguas, Cayey and Aguas Buenas municipalities). As an anticoccidial agent, nicarbazin has been used to control intestinal protozoan parasites in the poultry industry since the mid- 1950’s . The Federal Drug Administration (FDA) approves the use of nicarbazin as a food additive for broiler chickens, but not for layers 4



### . Unlike use tables that typically summarize maximum use rates, Table 3 summarizes the year-round minimum application rate scenario by urban use sites. This is provided because the OvoControl P

3 http://pubchem.ncbi.nlm.nih.gov/compound/Nicarbazin#section=Top 4 http://www.accessdata.fda.gov/scripts/animaldrugsatfda/details.cfm?dn=009-476

### 8 labels do not limit the maximum daily or annual application rates. Pursuant to the labels, once pigeons are conditioned to the daily baiting program, feeding must continue daily during the entire nesting season. Depending on the climatic zone and habitat, nesting, and corresponding baiting could last year-round. The minimum single daily application rate on the labels are 2 ounces of product for every 10 pigeons. The maximum daily application rate is not specified on the labels; however, the labels provide an example of bait for 2,400 pigeons. For the example rates provided on the labels, the daily application rate could range from 0.01 ounces (oz.) of active ingredient (a.i.) to 2.4 oz. a.i. per day, or more. Annual application rates could exceed 10,000 pounds treated bait, or 54 lbs active ingredient. However, usage data is not currently available for nicarbazin (USEPA, 2015 a ). Table 3: Use summary of nicarbazin for OvoControl P labels (EPA Reg. No. 80224-1 & SLN No. 150001).

Use Sites (Urban) Minimum Single Application Rate Application Interval

(d aily) Maximum Number of

Annual Applications Minimum Annual Application Rate (oz. product/ 10 pigeons) (oz. a.i./10 pigeons (oz. product/ 10 pigeons) ( oz. a.i./ 10 pigeons) Office Parks

2 0.0 1 1 365 730 3.65 Malls Institutions ( e.g. hospitals and schools) Bridges Airports Commercial buildings or structures Industrial buildings or structures



## 4. Conclusions from Previous Risk Assessments a. Ecological Risk Assessment
A number of ecological risk assessments have been conducted on nicarbazin. The conclusions from the past assessments are summarized in Figure 2and Table 4below.

### 9 Figure 2: Graphic Summary of Potential Risks of Current Uses of Nicarbazin Table 4: Evidence of Risk to Taxonomic Groups from Assessed Nicarbazin Uses Conclusion: No Risks of Concern Certainty: High Conclusion: Risks of Concern Identified Certainty: High

Terrestrial Invertebrates: Minimal potential for exposure , no data is needed. Terrestrialplants: Minimal potential for exposure , no data is needed. Birds (surrogates for reptiles and terrestrial-phase amphibians) : Based on very limited guideline and literature data for environmental fate and effects, acute risk (RQ = 1.4 for mortality) and chronic risk (RQ > 500 for reproductive/chronic effects) to non -target listed and non-listed birds. Based on the information av ailable, at 1% of the diet, the chronic risk (RQ  5) still exceeded the LOC. Adverse effects may not be limited to egg production and hatching, but may also include other effects yet to be evaluated in other bird species. Conclusion: No Risks of Concern Certainty: Low Conclusion: Risks of Concern Identified Certainty: Low Fish & Aquatic Invertebrates: Acute effects in fish (surrogates for aquatic -phase amphibians) and aquatic invertebrates are not anticipated based on submitted data and dissolved -phase exposures; however, the greater exposures in sediments cannot be assessed due to lack of chronic sediment toxicity data. Adverse reproductive effects in exposed egglaying aquatic organisms are anticipated, based on the mode of action in birds. These effects cannot be quantified due to lack of reproduction data. Aquatic Plants: No toxicity data is available for aquatic plants; however, there is the potential for exposure to occur. Data is needed to evaluate and characterize the risk potential. Mammals: Mammalian toxicity data are available ; however, the registrant did not sub mit guideline studies. The acute and reproductive/chronic data available to the Agency have not beenassessed in past assessments. There is the potential for both primary and/or secondary exposure to occur. Any relevant information available to the Heal th Effect Division (HED); EFED will review and consider it.

### 10 

## b. Drinking Water Exposure Assessments
EFED has not conducted a drinking water exposure assessment for nicarbazin, labeled as OvoControl P. 

## c. Clean Water Act Programs
The Clean Water Act requires the Agency to publish water quality criteria that accurately reflect the latest scientific knowledge on the kind and extent of all identifiable effects on health and welfare that might be expected from the presence of pollutants in any body of water, including ground water. While these recommended criteria do not, in themselves, impose any requirements, states and authorized tribes can use them to develop water quality standards. An Aquatic Life Ambient Water Quality Criteria document has not been published for nicarbazin (see url: http://www.epa.gov/waterscience/criteria/ ). The Office of Pesticide Programs (OPP) publishes aquatic life benchmarks for freshwater species based on toxicity values for the most sensitive species from the most recent risk assessments. The aquatic life benchmarks have not been published for nicarbazin. Nicarbazin is not identified as a cause of impairment for any water bodies listed as impaired under section 303(d) of the Clean Water Act 5 

### . No Total Maximum Daily Load (TMDL) criteria have been developed for nicarbazin 

## 5. Environmental Fate and Transport Characteristics
Despite its history of use in the poultry industry, little is known about other effects or the environmental fate of nicarbazin (WHO, 1998; Boxallet al. , 2003; EFSA, 2003). Environmental fate and transport characteristics have been explored in several previous risk assessments (DP312669, 313794, 2005; and DP328803, 2007 a ). Chemical, physical, and environmental fate and transport properties presented in this problem formulation were used in these previous assessments, and are reiterated below. 

## a. Physical Properties
Nicarbazin (C 19 

### H 18 

### N 6 

### 0 6 

### , MW 426.38) is a 1:1 complex of two compounds, 4,4'-dinitrocarbanilide (DNC, 70.89% by weight) and 4,6-dimethyl-2-pyrimidinol (HDP, 29.1 1% by weight). It is crystalline or a yellow powder. The nicarbazin complex is characterized as “inherently very stable material”, where only acidic or basic conditions led to “some” degradation, into the DNC and HDP components (MRID 46416407). The degradation of the nicarbazin complex is likely biologically mediated since DNC and HDP are detected in organism’s feces. DNC and HDP have differing physical properties such that once in the environment, they will likely have different fate profiles.

5 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885

.

### 11 DNC, also known as N,N'-bis(4-nitropheny1)urea or BNPU, has the formula C 13 

### H 10 

### N4 

### O 5 

### and molecular weight of 302.25 g mol -1 

### . Its low solubility has been reported as 20 ppb (EFSA, 2003), 28 ppb (pH5), 52 ppb (pH7) and 76 ppb (pH9). It has a log octanol-water partition coefficient (log Kow) of 3.6 which suggests that DNC could bioaccumulate. HDP, also known as 4,6-dimethyl-2(1 H)-pyrimidinone, has the formula C 6 

### H 8 

### N 2 

### O, and molecular weight of 124.14 g mol -1 

### . HDP melts at approximately 200 to 205°C, and has a log octanol-water partition coefficient (log Kow) of -0.94. Its solubility in water has been reported as greater than 10,000 ppm (EFSA, 2003). HDP ’s log Kow of -0.94 indicates that it is highly hydrophilic.

Table 5 summarizes the physical/ chemical properties of nicarbazin and its constituents DNC and HDP. There are a number of data gaps, including data for solubility of the nicarbazin complex, octanol-water partition coefficient (log Kow), vapor pressure, and Henry's Law constants. Table 5: Physical/Chemical properties of nicarbazin complex, DNC and HDP.

Physical Property Nicarbazin Complex DNC HDP Source (MRID) CAS Reg No. 330-95 -0 587-90-6 108-79-2 -- Molecular weight, (g mol -1 ) 426.38 302.25 124.14

Molecular Formula C 19 H 18 N 6 0 6 C 13 H 10N 4 0 5 C 6 H 8 N 20

Structure NA

Melting point (°C) 265- 275 312 200-205

UV/VIS absorption Max (nm) 298 No data 300

Aqueous solubility (ppm) No data pH5: 0.028 pH7: 0.052 pH 9: 0.076 >10,000 (EFSA, 2003)
logKow No data 3.6 - 0.94 46416410 Vapor Pressure No data No data No data -- Henry's Law constant No data No data No data -- Hydrolysis No data Stable Stable 46445305 Abbreviations: °C = degree Celsius; g = grams; mol = mole; NA = not applicable; nm = nanometers; ppm = parts per million

### 12 

## b. Degradation Characteristics Little is known about the environmental fate and transport characteristics of the nicarbazin complex, or its components DNC and HDP. Few OSCPP guideline compliant studies have been submitted to adequately characterize the environmental fate, and no new environmental fate studies have been submitted since the previous risk assessments. Table 6summarizes the chemical properties and environmental fate parameters of the nicarbazin complex and the DNC and HDP components, when data are available. Table 6: Environmental fate characteristics of nicarbazin complex and its components, DNC and HDP.
Parameter Value Description Source (MRID) Persistence Hydrolysis half -life (d) Complex: No data DNC: Stable HDP: Stable MRID did not evaluate the nicarbazin complex. 46445305
Aqueous photolysis half-life (d) No data Waiver denied 46416445 2) Soil photolysis half-life (d) No data -- -- 1) Aerobic soil metabolism half-life (d) Invalid data Unacceptable 46416446
Anaerobic soil metabolism half-life (d) No data -- -- 1) Aerobic aquatic metabolism half-life (d) No data -- -- 1)Anaerobic aquatic metabolism halflife (d) No data -- -- 1) Mobility Freundlich soil-water partition coefficients (KF); organic carbon -normalized Freundlich coefficients (K FOC ) Complex: No data DNC: 1650 HDP: No data Unacceptable: Value calculate d 46416447 3)

Field Dissipation Terrestrial field dissipation: half-life (d); leaching depth 28 days 0-15 cm -- 46445306 4) Terrestrial field dissipation: half-life (d); leaching depth 301 days 0-15 cm -- 46416449 4) Aquatic field dissipation half-life (d) No data -- --
Fish Bioconcentration Fish bioconcentration factors; depuration rate (d) No data Waiver denied 46497102 2)
Abbreviations: a.i. = active ingredient; d = days; oz. = ounces Notes: 1) No OCSPP guideline study submitted.

### 13 2) MRID represents a waiver request; subsequently denied. 3) Unacceptable data; value presented for DNC was calculated using EPISuite software. 4) Supplemental data used for characterization purposes only. 

### Of the five (5) OCSPP guideline studies submitted for nicarbazin, only one MRID is acceptable, two are supplemental, and two are unacceptable. From the only acceptable guideline compliant study( 

### hydrolysis half-life), both DNC and HDP are classified as stable and do not undergo hydrolysis in sterile water at pH 5 to 9 (MRID 46445305). A study of mobility in soil 

### ( MRID 46416447) was classified as unacceptable because of the obsolete methodologies and inadequate documentation (DP312669, 2005a and b). For purposes of aqueous fate modeling in previous risk assessments (DP312669, 313794; 2005a and b; and DP328803, 2007a), EFED used EPISuite software to estimate the organic carbon partitioning coefficient (Koc) at 1650 mL/kg for the DNC component. Two supplemental field studies were reviewed as non-guideline studies due to numerous deviations from the terrestrial field dissipation guideline. One field study 

### (MRID 46445306) was conducted in a greenhouse using confined bare soil flats of silt loam (Greenfield, 

### IN). The soil flats were confined in plastic bags to reduce volatilization, and lined with aluminum foil to reduce leaching. Approximately 80 to 102% of the radioactivity applied was accounted for over a 1-year span, with a slight downward trend. The observed DT 50

### was about 28 days, however 28-30% of the applied radiation was still present as nicarbazin at 364 days, indicating that first-order kinetics were not followed. The second field study (MRID 46416449 and 46416446) was conducted in a 3-ft diameter enclosedbare plot of silt loam soil in Greenfield, Indiana. Nicarbazin fortified soil, consisting of milled, airdried top soil (3 inches) blended with non-sterile greenhouse potting soil and chicken excreta, was incorporated at a target application rate of 2.47 kg a.i./ha in a single 3-ft diameter (7.07 sq ft) test plot surrounded by a metal culvert extending 38 cm into the soil and 23 cm above the soil. The total recovery of radioactivity from the soil (measured as DNC) was initially 111.3% at time-0 andranged from 112.3-142.6% throughout the remainder of the study period through 377 days posttreatment. The reviewer-calculated half-life of 14C nicarbazin in soil was 301 days (r2 = 0.80), calculated using log-linear regression analysis. A DT90 value was not determined. At the end of the study period, 377 days post-treatment, the total carryover of residues of nicarbazin was 47.3% of the applied. The major route of dissipation of nicarbazin under terrestrial field conditions is likely transformation; however, samples were not analyzed for degradates. Loss from other dissipation routes (leaching, volatilization) can all be assumed to be minimal because the material balance did not decrease below the time-0 recovery of radioactivity. Dissipation due to runoff was prevented due to the design of this study (culvert around soil plot). Runoff of DNC and HDP, in either the dissolved phase or attached to soil particles or feces is expected to be a major route of dissipation and transport to water bodies.From the available information, it can be deduced that the DNC degrades slowly in soil with a halflife of about 300 days, does not volatilize substantially, or leach through the soil. It may run-off with storm water when sorbed to soil particles.

### 14 

## c. Study Waiver requests
The registrant has requested waivers for two studies associated with the initial registration of nicarbazin; both have been denied. A request for a waiver of aqueous photolysis 

### (MRID 46416445) was denied because there is evidence that nicarbazin absorbs light in the visible range, which makes photolysis a possible route of degradation (DP312669, 2005). A waiver request for the fish bioaccumulation study (MRID 46497102) was also denied pending information on the log Kow of nicarbazin (the complex), and a study of its hydrolysis behavior (DP312669, 2005). 

## d. Degradates
Degradates have not been identified in any of the submitted environmental fate studies. However, new studies are being requested, and if degradates are observed in any of the requested environmental fate studies in great enough quantities; it could potentially trigger the need for degradate toxicity data for those identified degradates. If we do not get adequate degradate data, EFED will have to make conservative assumptions that could result in greater risk concerns. 

## 6. Receptors
Toxicity endpoints from currently available studies on nicarbazin are presented in Table 7 through Table 8 below.For the available aquatic studies DNC and HDP were tested separately. HDP is practically nontoxic to freshwater fish and invertebrates on an acute basis. Acute toxicity tests for freshwater fish (warm water and cold water species) and daphnids using DNC were conducted at or above the limit of solubility. There were no mortality or sublethal effects reported for the freshwater fish studies, however, in both the DNC and HDP bluegill studies, smaller than recommended fish were used and those studi es were classified as “supplemental” rather than “acceptable.” For daphnids, mortality/immobilization and sublethal effects (lethargy) were both observed in multiple test concentrations in the DNC study, minimal effects were observed in the HDP study. No acute toxicity data are available for estuarine/marine fish or invertebrates; no chronic toxicity data are available for any aquatic animals or plants. For terrestrial organisms, the test material was the nicarbazin complex. Nicarbazin was practically non-toxic to mammals on an acute oral basis. The data indicate that nicarbazin is slightly to practically non-toxic to birds on an acute dietary basis and practically non-toxic on an acute oral basis. No mortality or clinical signs of toxicity were observed in the available avian acute oral toxicity study. Some clinical signs of toxicity (mortality, and sublethal effects) were observed in both dietary studies, with greater effects observed in the mallard study. Although this chemical is registered as an egg-hatchability control agent, no guideline avian reproduction studies have been submitted to the Agency yet. Non-guideline studies and numerous open literature studies have been submitted on multiple species including chickens ( Gallus gallus ), and Japanese quail ( Coturnix japonica ). However, the data previously submitted and reviewed do not provide sufficient information on reproductive endpoints to meet guideline requirements (see DP363859, DP363860, USEPA 2009; DP372345, DP372348, DP349126, USEPA 2010; DP396672, USEPA 2011;

### 15DP400098, USEPA 2012; and DP415695, USEPA 2014a for more detailed analysis). The twogeneration mammalian reproduction study using a 3:1 ratio of DNC:HDP showed no effects on adult rats, but some effects on offspring; however, these were not considered significant to reproduction. In the developmental study there were increased mortality to adults and decreased food intake and body weight gain of females at the high test concentration. In addition, the fetal body weight was also decreased at the highest test concentration. The fetuses of the dams in the highest test concentration also showed signs of delayed ossification, hyperplastic and bent ribs (4 fetuses), sacralization of the 6 th

### or 7 th

### lumbar vertebrae (two fetuses), cleft palate (two in the same litter), subcutaneous odema (three in the same litter), hydronephrosis (five fetuses), cryptorchismus (one fetus), and remained Merkel’s diverticulum (one fetus). No toxicity data are available for honeybees or terrestrial plants. 

## a. Effects to Aquatic Organisms Table 7: Summary of the Most Sensitive Toxicity Data Currently Available for Aquatic Animals Exposed to Nicarbazin.

Test Species Test Substance

(% a.i.) Acute Toxicity LC 50/EC 50 (mg a.i./L) (Toxicity Classification) MRID (Study Classification)

Rainbow trout DNC (98% a.i.) >0.069 46416432 (Acceptable) HDP (99.4% a.i.) >110 (practically non-toxic) 46416431 (Acceptable)

Bluegill sunfish DNC (98% a.i.) >0.072 46416434 (Supplemental) HDP (99.4% a.i.) >122 (practically non-toxic) 46416433 (Supplemental)

Waterflea DNC (98% a.i.) >0.093 46416436 (Acceptable) HDP (99.4% a.i.) >107 (practically non-toxic) 46416435 (Acceptable)

### 16 

## b. Effects to Terrestrial Organisms Table 8: Summary of the Most Sensitive Acute and Chronic Toxicity Data Currently Available for Terrestrial Animals Exposed to Nicarbazin.

Test Species Test substance

(% a .i.) Acute Toxicity Chronic Toxicity
LD 50 (mg a .i./kg bw) (Toxicity Classification) LC 50 (mga.i./kg diet (ppm)) (Toxicity Classification) MRID (Study Classification) NOAEC/ LOAEC (mg a.i./kg diet (ppm)) (Endpoints) MRID (Study Classification)

Bobwhite Quail ( Colinus virginianus ) Nicarbazin complex (>99% a.i.) >2250 ( practically
non- toxic) >5720 ( practically
non- toxic) 46416426 (Acceptable) & 46416427 (Acceptable) ND Mallard Duck ( Anas platyrhynchos ) Nicarbazin complex (>99% a.i.) ND 3680 (slightly toxic) 46445302 (Acceptable)

Laboratory rat (Rattus norvegicus ) Acute: >95% a.i.; Chronic: 3:1 ratio of DNC:HDP

(Repro.) 1:1 ratio of DNC:HDP (Develop.) >10,000 (practically
non- toxic) -- 46416413 (Acceptable) 400/>400 (No effects on adults; decreased

bw F 1b ; fewer pups in F 2a & F 3a litters , but not in F 2b& F 3b litters) 46416422 (Acceptable) Reproductive

200/600 (Increased adult mortality; decreased bw gain ; decreased fetal bw; fetuses

showed add’l physical effects) 46416421 (Acceptable) Developmental

ND = No Data; -- = Not applicable 

## c. Ecological Incidents
The Ecological Incident Information System (EIIS) is an OPP database that houses ecological incidents that have been reported to the Agency. When available, EIIS includes date and location of an incident, type and magnitude of effects observed in various species, use(s) of pesticides known or suspected of contributing to the incident, and results of any chemical residue analysis or other analyses conducted during incident investigation. EIIS incidents are categorized according to the certainty that the incident resulted from pesticide exposure. The Avian Monitoring System (AIMS) is a database administered by the American Bird Conservancy that contains publicly available data on reported avian incidents involving pesticides. Many of the incidents listed in this database are also in the EIIS. The Aggregate Incident Reports database is an Agency database that may contain minor wildlife and plant incidents for chemicals.

### 17 Reviews of the Ecological Incident Information System (EIIS, version 2.1.1), the Avian Incident Monitoring System (AIMS) 6 

### , and the EPA Incident Data System (IDS, Aggregate Incident Reports database) were conducted on April 7, 2015 for nicarbazin. There were no reported incidents in the EIIS, AIMS, or the Aggregate Incident Reports databases for nicarbazin. It should be noted, that the lack of reported incidences should not be construed as the absence of incidents. Incident reports for non-target organisms typically provide information only on mortality events and plant damage. Sublethal effects in organisms such as abnormal behavior, reduced growth and/or impaired reproduction are rarely reported, except for phytotoxic effects in terrestrial plants. Incidents often are not seen, due to scavenger removal of carcasses, decay in the field, or simply because carcasses may be hard to see on many sites and/or few people are systematically looking. Poisoned animals may also move off-site to less conspicuous areas before dying. Incidents may not get reported to appropriate authorities capable of investigating the incident for a variety of reasons including the finder may not know of the importance of reporting incidents, may not know who to call, may not feel they have the time or desire to call, or may hesitate to call because of their own involvement in the kill. Incidents reported may not get investigated if resources are limited or may not get investigated thoroughly, with residue analyses, for example. Also, if kills are not reported and investigated promptly, there will be little chance of documenting the cause, since tissues and residues may deteriorate quickly. Reports of investigated incidents often do not get submitted to EPA, since reporting by states is voluntary. 

## 7. Exposure Pathways of Concern
In order for a chemical to pose an ecological risk, it must reach ecological receptors in biologically significant concentrations. An exposure pathway is the means by which a contaminant moves in the environment from a source to an ecological receptor. For an ecological exposure pathway to be complete, it must have a source, a release mechanism, an environmental transport medium, a point of exposure for ecological receptors, and a feasible route of exposure. The assessment of ecological exposure pathways, therefore, includes an examination of the sources and potential migration pathways for constituents, and the determination of potential exposure routes ( e.g., ingestion, inhalation, dermal absorption). Chemical properties and the registered OvoControl P use patterns indicate that non-target species, both terrestrial and aquatic, may be exposed to the nicarbazin complex, and the DNC and HDP components. A conceptual model discussing and illustrating exposure pathways had been developed in several previous risk assessments for nicarbazin (DP312669, 313794, 2005; and DP328803, 2007), which remain valid. Exposure pathways presented in this problem formulation were used in these previous assessments, and are reiterated below.

6http://www.abcbirds.org/abcprograms/policy/pesticides/aims/aims/index.cfm

### 18 

## a. Background
Applications of bait will be made directly to terrestrial environments, either in bait pans, bowls or trays, or by broadcast application via hand or mechanical feeders onto rooftops, other flat paved or concrete surfaces (only). As applied according to the proposed labels, nicarbazin bait may beavailable to non-target organisms. On the labels there is precautionary language concerning nontarget species: “Do not apply more OvoControl P than the pigeons will eat in a single feeding, as this may result in non-target species' exposure to leftover bait. Do not apply in urban areas where the product may be consumed by federally listed Threatened and Endangered birds. Daily observations for non-target species must be conducted for the entire five (5) to fourteen (14) day conditioning period after feeding begins. Do not apply if non-target feeding persists and/or cannot be prevented. English house sparrows (Passer domesticus ) and European starlings ( Sturnus vulgaris ) are exempt from this restriction. It is a violation of state and federal law to intentionally feed treated bait to non- target species, including protected species.”However, data have not been provided to demonstrate that pigeons will exclude non-target animals from feeding and consume all bait that is applied. The primary source of exposure of non-target terrestrial animals is likely to be consumption of the formulated food bait. Consumption of eggs and tissues of target and non-target animals that have eaten bait is a potential source of exposure to predators and scavengers. As discussed above, biomagnification and food-chain exposure of predators is possible if exposure is continuous. Dermal and inhalation routes of exposure occur for some pesticides but are not likely to be significant for the grain-based nicarbazin food bait. Potential exposure routes are discussed in the following sections and include potential exposures to terrestrial and aquatic environments.


## b. Potential Exposure to Terrestrial Wildlife
Data are available demonstrating that non-target species of birds and mammals consumed nicarbazin bait in a field study designed to test efficacy in Canada geese (not a currently registered use) (Bynum et al. , 2005 [MRID 46497103]). Although the application conditions in the field study were different than actual label-compliant use for the control of pigeons, it can be concluded that direct exposure to the nicarbazin complex by non-target species through the consumption of treated bait is not precluded by any characteristics of the bait itself ( i.e. , the bait can be consumed by a variety of organisms). The degree to which non-target species may be directly exposed to nicarbazin depends upon, but is not limited to, the applicator’s compliance with label use directions and prohibitions, the presence of mixed flocks, the amount of treated bait consumed, and if the unconsumed bait is adequately monitored and removed from the treatment site. EFED will consider the extent to which current product labeling could impact the exposure of non-target wildlife through direct consumption of bait. In addition, nicarbazin and/or DNC may be indirectly released into terrestrial and aquatic environments through defecation by pigeons and non-target animals or by accidental release or spillage of unconsumed bait where it may accumulate and be available to soil organisms or in puddles used for drinking water by wildlife. Based on the product formulation, the inhalation exposure pathway is not a potential exposure pathway of concern, and no further analysis was needed.

### 19 

## c. Secondary Exposure by Predators and Scavengers
Secondary exposure is also possible (EFSA 2003), but the extent to which this may occur is unknown. Nicarbazin and DNC released into the terrestrial environment from bait or feces will be available to soil macroinvertebrates for uptake or consumption. Terrestrial animals that feed on soil macroinvertebrates may receive exposure via this pathway. Secondary exposure may also occur to predators and scavengers consuming tissues and/or eggs of animals that have ingested bait. This exposure may occur in both the aquatic and terrestrial environment and may raise the potential for risk to species that consume eggs of target and non-target birds ( e.g ., birds and reptiles). As discussed above, biomagnification and food-chain exposure of predators is possible if exposure is continuous. 

## d. Potential Exposure to Aquatic Environments
The proposed labels prohibits application to areas within 20 feet of water bodies, which may restrict incidental deposition in water from application of Ovocontrol P. However, the bait trays or bowls are made of durable plastic or metal, and are perforated to allow for drainage, and depending on the use site there could be exposure to water bodies. The labels do note that if rain is a factor, the bait should be located under partial cover or a canopy, and the bait should not be applied where water may accumulate. Although the labels specifically prohibits application of nicarbazin bait to standing water, the presence, frequency, and size of areas with standing water are expected to vary throughout the year. Unless bait sites are monitored regularly throughout the application period, applicators may be unable to prevent incidental deposition of bait into standing water ( e.g., from automated/mechanical feeders). Also, OvoControl P is registered for use on bridges and used on roof tops or other flat paved or concrete surfaces, which may drain into water bodies. Therefore, washoff or overflow from rainfall events may occur resulting in direct exposure to water bodies. DNC is expected to primarily partition to sediments in aquatic environments where it is expected to persist; therefore, potential reproductive effects to sediment organisms are of concern.DNC and HDP are not fully metabolized by target or non-target species. Thus, these unmetabolized components embedded in species feces are likely to be deposited to an array of objects. EFED plans to evaluate potential exposures to aquatic environments from: 1) direct deposition into receiving water body ( e.g., registered use of OvoControl P on bridges); 2) deposition onto impermeable surfaces ( e.g., rooftop, pavement, etc., typical of urban environments); and 3) deposition onto permeable surfaces representative of soils or turf matrices. EFED will examine these three exposure pathways to establish a range of estimated environmental concentrations (EECs). 

## e. Ecological Drinking Water Exposure Pathways
The drinking water exposure pathway was screened using the SIP (Screening Imbibition Program, version 1.0) screening methods. As previously described the aquatic exposure of nicarbazin would likely occur through the DNC and/or HDP components, and therefore the SIP model was run for both components. For the DNC and HDP components, it was determined that drinking water exposure alone was is NOT a potential concern for mammalian species on an acute and chronic basis ( Tables 9 and 11 ). For birds, it was determined that the drinking water exposure alone was also NOT a potential concern on an acute basis for the DNC component ( Table 10 ); however, there

### 20 was not enough data to preclude chronic exposure for either DNC or HDP components ( Tables 10 and 12 ). The HDP component of nicarbazin drinking water exposure alone was determined to be a potential pathway of concern for birds on an acute basis ( Table 12 ). Outputs for the model are located in Appendix A . SIP is described in detail at: http://www.epa.gov/oppefed1/models/terrestrial/index.htm

. Table 9: SIP Mammalian Results (DNC component)

Parameter Acute Chronic Upper bound exposure (mg/kg-bw) 0.013 0.013 Adjusted toxicity value (mg/kg-bw) 7692 154 Ratio of exposure to toxicity 0.000 0.0001

Conclusion* Drinking water exposure alone is NOT a potential

concern for mammals Drinking water exposure alone is NOT a potential

concern for mammals 

### Table 9: SIP Avian Results (DNC component)

Parameter Acute Chronic Upper bound exposure (mg/kg-bw) 0.062 0.062 Adjusted toxicity value (mg/kg-bw) 20025 0.00 Ratio of exposure to acute toxicity 0.00 0.00

Conclusion* Drinking water exposure alone is NOT a potential concern for birds Due to insufficient data, risk cannot be precluded *Conclusion is for drinking water exposure alone. This does not combine all routes of exposure. Therefore, when aggregated with other routes ( i.e ., diet, inhalation, dermal), pesticide exposure through drinking water may contribute to a total exposure that has potential for effects to non-target animals. 

### Table 10: SIP Mammalian Results (HDP component)

Parameter Acute Chronic Upper bound exposure (mg/kg-bw) 1720 1720 Adjusted toxicity value (mg/kg-bw) 1730 154 Ratio of exposure to toxicity 0.994 11.18

Conclusion* Exposure through drinking water alone is a potential

concern for mammals Exposure through drinking water alone is a potential

concern for mammals


### Table 11: SIP Avian Results (HDP component)

Parameter Acute Chronic Upper bound exposure (mg/kg-bw) 

### 8100 8100 Adjusted toxicity value (mg/kg-bw) 

### 20025 0.000 Ratio of exposure to acute toxicity 

### 0.405 0.000

Conclusion* Exposure through drinking water alone is a potential concern for birds Due to insufficient data, risk cannot be precluded
*Conclusion is for drinking water exposure alone. This does not combine all routes of exposure. Therefore, when aggregated with other routes ( i.e ., diet, inhalation, dermal), pesticide exposure through drinking water may contribute to a total exposure that has potential for effects to non-target animals. 

### There are substantial uncertainties concerning the ecological effects of nicarbazin, in part due to the extremely limited ecotoxicity data that are available. Reduction in egg hatchability is a primary

### 21 concern for non-target birds that are exposed to nicarbazin; however other effects including mortality and reproductive effects in male birds have been recorded (Chapman 1994, EFSA 2003). Few data exist for reptiles ( e.g., USDA/APHIS National Wildlife Research Center; Mathies and Miller 2005 and Primus et. al. , 2003), which may also be affected if they consume bait or target birds. Folliculogenesis and the vitelline membrane are features common to egg laying birds, reptiles, amphibians, mammals, and aquatic animals including fish and invertebrates. However, the toxicity database for aquatic species, especially on a chronic exposure basis, is very limited. Therefore, the evaluation of risk to various taxonomic groups has been based on very limited toxicity data. 

## 8. Analysis Plan
Although the DNC and HDP components are practically non-toxic to freshwater fish and invertebrates on an acute basis, the reproductive toxicity of these individual components to fish and aquatic invertebrates are not known. The formation of the vitelline membrane is common to many animals, and the mode of action of nicarbazin is to reduce the viability and hatchability of eggs by interfering with the formation of the vitelline membrane. As discussed previously, the contamination of water bodies with nicarbazin and its components is possible given the vicinity of the home range, the size of the home range of pigeons relative water bodies, and the excretion of waste products. EFED concludes that reproductive effects in egg laying animals other than birds, include reptiles, terrestrial-phase amphibians, mammals, fish, aquatic-phase amphibians, and aquatic invertebrates, are possible. So that reproductive effects in other potentially exposed animals may be assessed, EFED recommends that the following studies be required: a fish full-life cycle (guideline no. 850.1500), an aquatic invertebrate life-cycle (guideline no. 850.1300), and chronic sediment toxicity (non-guideline) studies with DNC alone and the nicarbazin complex (HDP+DNC). These types of studies have also been identified as data gaps in previous assessments. The nicarbazin assessment will be based on the following use presumptions, based on the current product labels:

· bait will be applied daily for many weeks (up to 52 weeks in some areas) in specific urban areas inhabited by pigeons

· spilled bait and bait not eaten by pigeons may pose a risk to diurnal and nocturnal non-target animals, if not cleaned up as specified on label

· bait applied on the ground (“other flat paved or concrete surfaces”poses risks to more wildlife than does bait applied on suitable elevated sites (roof tops)

· broadcast applications pose higher risks to non-target animals than do placements in trays or pans that are removed immediately after pigeons have fed

· the failure to define “urban” on the product label s allow widespread use and more potential non-target exposure

### 22 

## a. Stressors of Concern
i. Ecological Risk Assessment
For the nicarbazin ecological risk assessment, the stressors of concern are nicarbazin, and the individual DNC and HDP components. ii. Drinking Water
The EPA Office of Water has not made a determination regarding nicarbazin in water supply. EFED has not previously conducted a drinking water exposure assessment for nicarbazin, labeled as OvoControl P. However, EFED will consult with HED to determine if a drinking water exposure assessment will be needed for nicarbazin as a part of registration review , based on HED’s needs

. A formal determination of the residues of concern for drinking water will be made prior to the conduct of the risk assessment.


## b. Measures of Exposure
The degree to which non-target birds (surrogates for terrestrial-phase reptiles and amphibians), and mammals may be directly exposed to nicarbazin depends upon, but is not limited to, the presence of mixed flocks, the amount of treated bait consumed, and if the unconsumed bait is adequately monitored and removed from the treatment site. Precautionary language on the labels, to try and limit exposure to non-target animals; however, there is still the potential for non-target wildlife to be exposed through direct consumption of bait unless labels can preclude or severely limit the potential for non-target animals to gain access to baits. i. Terrestrial Exposure
Exposure of terrestrial animals can occur via several pathways, including consumption of the food bait, consumption of birds or mammals that have eaten bait and contain residues in body tissues, and consumption of eggs laid by birds exposed to the food bait. Primary exposure will be based on the daily availability of the formulated 5000 ppm a.i. food bait. Literature sources will be searched for any available nicarbazin residues in body tissues and in eggs. As discussed above, biomagnification and food-chain exposure of predators may occur if exposure is continuous. For estimating direct exposure to the nicarbazin complex by non-target species, terrestrial and aquatic, exposures will be estimated using the bait concentration and estimated feeding rates of birds. i. Aquatic Exposure
Because of the potential unique exposure pathway to aquatic environments from DNC and HDP embedded in pigeon feces (described in Chapter 7, Exposure Pathways of Concern), EFED will explore methodologies to derive an area weighted application rate ( e.g. lbs/acre). Unlike previous

### 23 risk assessments, where the application scenario was representative of turf environments, the registration review aquatic risk assessment will evaluate potential exposures from applications only to rooftops, hard structures, and concrete and paved surfaces. EFED will estimate exposure concentrations using standard exposure models for both components separately.

ii. Available Monitoring Data
Despite its long history of use in poultry production, the presence of nicarbazin in water bodies has never been studied. Environmental exposure to aquatic environments from the use of nicarbazin in poultry production is possible through land disposal of litter and droppings from treated birds. Interest in the possible adverse effects of pharmaceuticals, including those used in veterinary medicine, has increased in recent years. Two papers identify nicarbazin as a high-priority for further research into its possible environmental effects (Boxall et al ., 2003a and 2003b). For the pesticidal use of nicarbazin, environmental exposure to aquatic environments could occur via pigeon feces, by accidental release or spillage of unconsumed bait, run-off from treatment areas, or displacement of bait applied to bridge surfaces. Nicarbazin is not an analyte in any of the following water monitoring programs: the California Department of Pesticide Regulation (CDPR) surface water database - http://www.cdpr.ca.gov/docs/emon/surfwtr/surfcont.htm , the USGS NAWQA surface and ground water database - http://cida.usgs.gov/nawqa_queries_public/ , and the USEPA STORET Data Warehouse - http://www.epa.gov/storet/ . Monitoring will be considered in the assessment to the extent that any future data on nicarbazin are available. 

## c. Measures of Effect
Measures of effect are based on the toxicity values generated in the guideline toxicity studies submitted by the registrant. When more than one value is generated ( e.g. , avian LC50), the most sensitive value is used for the screening assessment. For nicarbazin, guideline studies for various acute and reproductive/chronic toxicity data are lacking. When available and deemed appropriate for the assessment, toxicity values or qualitative descriptions presented in the literature are used to assess risk. Toxicity data presented in Section 6 of this problem formulation would be used to calculate risk quotients (RQs). Any additional information submitted by the registrant or found in the open literature prior to conduct of the risk assessment would also be considered. The open literature studies are identified using EPA’ s ECOTOXicology database (ECOTOX) (USEPA, 2007 d), which employs a literature search engine for locating chemical toxicity data for aquatic life, terrestrial plants, and wildlife. The evaluation of both sources of data can also provide insight into the direct and indirect effects of pesticides on biotic communities from loss of species that are sensitive to the chemicals and from changes in structure and functional characteristics of the affected communities.

### 24 

## d. Endangered Species Assessments

Consistent with EPA’s responsibility under the Endangered Species Act (ESA), the Agency will evaluate risks to federally listed threatened and endangered (listed) species from registered uses of pesticides in accordance with the Joint Interim Approaches developed to implement the recommendations of the April 2013 National Academy of Sciences (NAS) report, Assessing Risks to Endangered and Threatened Species from Pesticides . The NAS report outlines recommendations on specific scientific and technical issues related to the development of pesticide risk assessments that EPA and the Services must conduct in connection with their obligations under the ESA and FIFRA. EPA will address concerns specific to nicarbazin in connection with the development of its final registration review decision for nicarbazin

. In November 2013, EPA, the U.S. Fish and Wildlife Service, National Marine Fisheries (the Services), and USDA released a white paper containing a summary of their joint Interim Approaches for assessing risks to listed species from pesticides. These Interim Approaches were developed jointly by the agencies in response to the NAS recommendations, and reflect a common approach to risk assessment shared by the agencies as a way of addressing scientific differences between the EPA and the Services. Details of the joint Interim Approaches are contained in the November 1, 2013 white paper , Interim Approaches for National-Level Pesticide Endangered Species Act Assessments Based on the Recommendations of the National Academy of Sciences April 2013 Report. Given that the agencies are continuing to develop and work toward implementation of the Interim Approaches to assess the potential risks of pesticides to listed species and their designated critical habitat, this ecological problem formulation supporting the Preliminary Work Plan for nicarbazin does not describe the specific ESA analysis, including effects determinations for specific listed species or designated critical habitat, to be conducted during registration review. While the agencies continue to develop a common method for ESA analysis, the planned risk assessment for the registration review of nicarbazin will describe the level of ESA analysis completed for this particular registration review case. This assessment will allow EPA to focus its future evaluations on the types of species where the potential for effects exists, once the scientific methods being developed by the agencies have been fully vetted. Once the agencies have fully developed and implemented the scientific methods necessary to complete risk assessments for listed species and their designated critical habitats, these methods will be applied to subsequent analyses of nicarbazin as part of completing this registration review. 

## e. Endocrine Disruptor Screening Program
Nicarbazin was not included in the first group of 67 chemicals issued an order to conduct Tier 1 EDSP testing. For additional information the EDSP program, visit http://www.epa.gov/endo/

. 

## 9. Preliminary Identification of Data Gaps
Several previous risk assessments have identified data gaps (DP312669, 313794, 2005; and DP328803, 2007). Adequate studies or data have not been submitted since these assessments to fill

### 25 the identified data gaps. Data gaps presented in this problem formulation are derived from these previous assessments, and are reiterated below. 

## a. Environmental Fate

Table 13 identifies environmental fate studies by OCSPP guideline, classification of MRID and if additional data are needed in order to support subsequent risk assessments. Five (5) OCSPP guideline studies were submitted by the registrant for nicarbazin. Only one study, hydrolysis (MRID 464453305), is classified as acceptable, and two terrestrial field dissipation studies are supplemental, but not upgradeable (MRID 46416449, and 46445306). Two studies are classified unacceptable and include aerobic soil metabolism (MRID 46416446), and adsorption/ desorption, leaching (MRID 46416447). Eight OCSPP guideline study types have not been submitted. EFED has determined the following studies are not needed because of the use pattern described on the currently registered OvoControl P labels:

x Aquatic field dissipation study (835.6200); and,

x Anaerobic soil metabolism (835.4200). Based on the pathways of concern and proposed analysis plan, EFED recommends the following OCSPP guideline studies and corresponding data, to complete the Registration Review program’s exposure assessments:

x Batch Equilibrium (835.1230; 835.1240) for the nicarbazin complex and the constituents (DNC and HDP);

x Hydrolysis (835.2120) on the nicarbazin complex;

x Aqueous Photolysis (835.2240) for the nicarbazin complex and the two constituents (DNC and HDP);

x Aerobic Soil Metabolism (835.4100) for the nicarbazin complex and the two constituents (DNC and HDP); and,

x Aerobic aquatic metabolism (835.4300) for the nicarbazin complex and the two constituents (DNC and HDP);

x Anaerobic aquatic metabolism (835.4400) for the nicarbazin complex and the two constituents (DNC and HDP);

x Analytical methods in soil (850.6100) for the nicarbazin complex and the two constituents (DNC and HDP);

x Analytical methods in water (850.6100) for the nicarbazin complex and the two constituents (DNC and HDP); and

x Fish bioconcentration factor (850.1730) for the nicarbazin complex and the two constituents (DNC and HDP). More information on the physical properties of the Nicarbazin complex (octanol-water partition coefficient, Kow), and results of the Hydrolysis study (835.2120) are needed to decide on the waiver of the Fish bioccumulation study (850.1730). The environmental fate assessment will consider both components of nicarbazin (DNC and HDP). Therefore, sufficient data will be needed for both components. HDP was noted to enhance

### 26 adsorption of DNC; therefore, risk of DNC may be considerably different in the presence of HDP. For this reason, quantifying the duration of potential co-occurrence of HDP and DNC in water is important to risk assessment. Table 12: Status of Environmental Fate and Transport Data.
OCSPP Guideline Data Requirement Submitted Studies (MRID) Study Classification Sufficient for risk assessment? Comments

835.1230 835.1240 Adsorption/ desorption , leaching 46416447 Unacceptable No Study used obsolete methods and was insufficiently documented.
835.1410 Volatility

– laboratory None N/A No Data not needed for current use pattern 835.2120 Hydrolysis 464453305 Acceptable No Study did not include nicarbazin complex.

835.2240 Aqueous photolysis 46416445 (waiver request) N/A No Waiver request denied (D P312669, 2005).

835.2410 Soil photolysis None N/A No Data not needed for current use pattern.

835.4100 Aerobic soil metabolism 46416446 Unacceptable No Aerobic soil metabolism was studied as part of an outdoor field study (46416449), and not a laboratory study.
835.4200 Anaerobic soil metabolism None N/A N/A Data not needed for current use pattern. 835.4300 Aerobic aquatic metabolism None N/A No Data needed for registration review risk assessment.
835.4400 Anaerobic aquatic metabolism None N/A No Data not needed for current use pattern.

835.6100 Terrestrial field dissipation 46416449 Supplemental, not upgradeable No Reviewed as non-guideline. Although individual contributions of the degradation pathways were not determined, half

- lives were estimated (301d)

835.6100 Terrestrial field dissipation 46445306 Supplemental, not upgradeable No Reviewed as non -guideline

835.6200 Aquatic field dissipation None N/A N/A Data not needed for current use pattern.

850.1730 Fish bioconcentration 46497102 (waiver request) N/A No Waiver request denied (D P312669, 2005)

850.6100 Analytical method in soil None N/A No Data needed for registration review risk assessment.
850.6100 Analytical method in water None N/A No Data needed for registration review risk assessment. Abbreviations: d = days; N/A = not applicable

### 27 More information on the physical properties of the Nicarbazin complex (octanol-water partition coefficient, Kow) and results of the Hydrolysis study (161-1) are needed to decide on the waiver of the Fish Accumulation study (165-4). 

## b. Effects Table 14through Table 15 identify ecological effects studies for nicarbazin by MRID that offer data for each guideline requirement, as well as study classifications and whether further data are needed in order to support risk assessment. The rationale for additional non-guideline data requested is presented below the tables. Table 13: Submitted Aquatic Ecological Effects Data for Nicarbazin
OCSPP Guideline Data Requirement Submitted Studies (MRID) Study Classifications Sufficient for risk assessment? Comments; Current Additional Data Need

850.1010 Freshwater invertebrate acute toxicity 46416435 Acceptable

No For the aquatic toxicity testing, data is available on the DNC and HDP components individually, not the nicarbazin complex ( HDP + DNC ). Therefore, additional data are needed for acute toxicity evaluating the nicarbazin complex to aquatic organisms. Freshwater data can be used for saltwater organism data. 46416436 Acceptable

850.1025
or 850.1035 Saltwater invertebrate acute toxicity (None) (Not applicable) No No acute saltwater invertebrate data are available; there is the potential for exposure to estuarine/marine environment. However, given the low toxicity of the individual components, freshwater data can be used in lieu of the saltwater data.

850.1075 Freshwater fish acute toxicity 46416431 Acceptable

No For the aquatic toxicity testing, data is available on the DNC and HDP components individually, not the nicarbazin complex . Therefore, additional data are needed for acute toxicity evaluating the nicarbazin complex to aquatic organisms. Fres hwater data can be used for saltwater organism data. 46416432 Acceptable

46416433 Supplemental

46416434 Supplemental

850.1075 Saltwater fish acute toxicity (None) (Not applicable) No No acute saltwater fish data are available; there is the potential for exposure to estuarine/marine environment. However, given the low toxicity of the individual components, freshwater data can be used in lieu of the saltwater data.

### 28 OCSPP Guideline Data Requirement Submitted Studies (MRID) Study Classifications Sufficient for risk assessment? Comments; Current Additional Data Need

850.1300 Freshwater invertebrate life -cycle (None) (Not applicable) No No chronic aquatic organism toxicity data are available for nicarbazin. Therefore, a freshwater invertebrate life -cycle study is needed for DNC aloneas well as the nicarbazin complex.

850.1350 Saltwater invertebrates life -cycle (None) (Not applicable) N/A No chronic aquatic organism toxicity data are available for nicarbazin. However, freshwater data can be used in lieu of the saltwater data.

850.1400 Freshwater fish early

- life stage (None) (Not applicable) See below (850.1500) No chronic aquatic organism toxicity data are available for nicarbazin. However, given the need for areproduction study, a fish full lifecycle study(OCSPP 850.1500) is being recommended instead.

850.1400 Saltwater fish early

- life stage (None) (Not applicable) N/A No chronic aquatic organism toxicity data are available for nicarbazin. However, given the need for areproduction study, a fish full lifecycle study is being re commend ed instead. Freshwater data can be used in lieu of the saltwater data.

850.1500 Fish life

- cycle (None) (Not applicable) No No chronic aquatic organism toxicity data are available for nicarbazin. Therefore, a freshwater full life -cycle study is needed for DNC alone as well as the nicarbazin.

Non

Guideline Sediment Toxicity

- Chronic (None) (Not applicable) No No sediment toxicity data are available for nicarbazin. Based on the available chemical information, chronic sediment toxicity data are needed for DNC alone as well as the nicarbazin complex.

850.4400 Aquatic plant Toxicity Test using Lemna spp. (None) (Not applicable)

No No aquatic plant toxicity data are available for nicarbazin. Therefore, data are needed for DNC alone as well as the nicarbazin complex, to evaluate toxicity to aquatic plants. The preferred v ascular aquatic plant toxicity test species is Lemna spp., and the preferred non-vascular aquatic plant species are 3 algal species plus cyanobacteria. 850.4500 Algal toxicity (None) (Not applicable)

850.4550 Cyanobacteria (None) (Not applicable)

### 29 Table 15. Submitted Terrestrial Ecological Effects Data for Nicarbazin
OCSPP Guideline Data Requirement Submitted Studies (MRID) Study Classifications Sufficient for risk assessment? Comments; Current Additional Data Need

850.2100 Avian oral toxicity 46416426 Acceptable No A study in a passerine species, with the nicarbazin complex (HDP + DNC) as the test material, is needed to fulfill guideline requirements

. The Tier 1 EEC from past avian assessments was 5000 ppm , the acute LD 50> 2250 mg/kg-bw, and the sub -acute LC 50= 3680 mg/kgdiet for the game bird species tested. The passerine LD 50 would have to be at least 23 times greater than for the other avian species tested to not result in an acute listed species LOC exceedance of 0.1.

850.2200 Avian dietary toxicity 46416427 Acceptable Yes None. 46445302 Acceptable

850.2300 Avian reproduction (None) (Not applicable) No No guideline avian reproduction study has yet to be submitted to the Agency. It was identified as a data gap beginning in the 2005 Assessment (USEPA 2005). Numerous non

- guideline studies have been submitted and reviewed over the years ( DP363859, DP 363860, USEPA 2009; DP 372345, DP372348, DP 349126, USEPA 2010; D P 396672, USEPA 2011; D P400098, USEPA 2012; DP415695, USEPA 2014). However, the registrant has agreed to , and is currently working on , an adapted avian reproduction study that will provide the needed data (protocol review: DP424098, USEPA 2015 b ).
810.4250 Avian toxicants 47556001 Supplement Info. N/A Field efficacy study in pigeons; no additional data needed.

850.2500 (form. 71-5) Field Testing for Terrestrial Wildlife 46497103 Supplemental N/A OvoControl G ready use bait field study; test efficacy of field applications of Goose product. Non -target species (including passerine species, humans, small mammals, etc .) were observed at bait stations. No data needed for current use pattern.

### 30 OCSPP Guideline Data Requirement Submitted Studies (MRID) Study Classifications Sufficient for risk assessment? Comments; Current Additional Data Need

870.1100 Mammalian acute oral 46416413 Acceptable Yes None; unless HED informs us otherwise.

870.1300 Mammalian acute inhalation None (Not applicable) No None; unless HED informs us otherwise.

870.3700 Mammalian - developmental 46416421 Acceptable Yes None; unless HED informs us otherwise.

870.3800 Mammalian 2-generation Reproduction 46416422 Acceptable Yes None; unless HED informs us otherwise.

850.3020 Honey bee adult acute contact toxicity (None) (Not applicable) Yes No potential for exposure ; therefore pollinator data are not needed at this time (USEPA, 2014 b ).

850.4100 Seedling Emergence (None) (Not applicable) Yes No potential for exposure, data are not needed at this time. 850.4150 Vegetative Vigor 

### Data Gaps

Aquatic tests are needed for DNC alone & nicarbazin complex (HDP + DNC) for the following, except the acute freshwater fish and invertebrate studies, in which tests are needed only for the nicarbazin complex.

x OCSPP 850.1010: Freshwater invertebrate acute toxicity (nicarbazin complex only)

x OCSPP 850.1075: Freshwater fish acute toxicity (nicarbazin complex only)

x OCSPP 850.1300: Freshwater invertebrate life-cycle

x OCSPP 850.1500: Freshwater fish full life-cycle

x Non-Guideline: Chronic sediment toxicity (3 species; midge, and freshwater and estuarine amphipods)

x OCSPP 850.4400: Aquatic vascular plant toxicity (duckweed)

x OCSPP 850.4500 and 850.4550: Aquatic non-vascular plant toxicity (3 algal species + cyanobacteria) Terrestrial tests are needed for the nicarbazin complex (HDP + DNC).

x OCSPP 850.2100: Avian acute oral toxicity with passerine species (nicarbazin complex (HDP + DNC; as Current Product; OvoControl P)

x OCSPP 850.2300: Avian reproduction

– modified study currently in progress as discussed with registrant (protocol review; DP424098, USEPA 2015 b )

### 31 

## 10. References
Boxall, A.B.A, et al. 2003a. Are veterinary medicines causing environmental risks? Environ. Sci. Technol. 37: 286A-294A. Boxall, ABA, et al. 2003b. Prioritisation of veterinary medicines in the UK environment. Toxicology Letters. 142: 207-218. Chapman, H.D. 1994. A review of the biological activity of the anticoccidial drug nicarbazin and its application for the control of coccidiosis in poultry. Poultry Sci. Res. 5:231-243. EFSA. 2003. Opinion of the Scientific Panel on Additives and Products or Substances Used in Animal Food on the Request From the Commission on the Efficacy and Safety of the Coccidiostat Koffogran. European Food Safety Authority, Scientific Panel on Additives and Products or Substances Used in Animal Feed (FEEDAP Panel), The EFSA Journal 16: 1-40.
Mathies, 

### T. and L.A. Miller. 2005. Nicarbazin as a potential fertility control agent in the African house snake, a model species for the brown tree snake. Lab ID No. QA-72 1. National Wildlife Research Center, Fort Collins, CO. 16 p.
Primus, T.M., Kohler, D.J., Goodall, M.A., Yoder, C., Mathies, T., Miller, L, Johnston, J.J., and Vercauteren, K. 2003. Liquid Chromatographic Determination of 4,4’ -Dinitrocarbanilide, the Active Component of the Infertility Agent Nicarbazin, in Chicken, Duck, Goose, and Snake Eggs. Journal of AOAC International. 86(6):1144-1148. United States Environmental Protection Agency (USEPA). 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide Programs . U.S. Environmental Protection Agency, Office of Pesticide Programs, Environmental Fate and Effects Division. Available at http://www.epa.gov/espp/consultation/ecorisk-overview.pdf

USEPA. 2005 a . Environmental Risk Assessment for the Proposed Registration of Nicarbazin to Reduce Egg Hatching in Resident Canada Geese. Dated October 13, 2005. PC Code: 085712; DP Barcodes: 312669, 313794.
USEPA. 2005 b . Amendment to the October 13, 2005 Environmental Risk Assessment for the Proposed Registration of Nicarbazin to Reduce Egg Hatching in Resident Canada Geese (DP Barcodes: 312669, 313794). Dated November 18, 2005. PC Code: 085712; DP Barcodes: 312669, 313794.

USEPA. 2007 a . Environmental Risk Assessment for the Proposed Registration of Nicarbazin (OvoControl P) to Reduce Egg Hatching in Pigeons. Dated April 12, 2007. PC Code: 085712; DP Barcode: 328803.

USEPA. 2007 b . Ecological Risk Assessment for the Section 3 New Use Registration of Nicarbazin on Non-Native Hybrid, Domestic and Muscovy Ducks. Dated November 8, 2007. PC Code: 085712; DP Barcodes: 340973, 335890.

### 32 USEPA. 2007 c . Section 24(c) Special Local Need Registration of Nicarbazin (OvoControl P) for use on Pigeons ( Columbia livia ) in Hawaii. Dated November 8, 2007. PC Code: 085712; DP Barcodes: 344692.

USEPA. 2007 d . ECOTOXicology Database. Office of Research and Development National Health and Environmental Effects Research Laboratory’s (NHEERL’s) Mid -Continent Ecology Division (MED). http://cfpub.epa.gov/ecotox/ USEPA. 2009. EFED Review of Request from Innolytics, LLC to Remove Restricted Use Classification for Goose and Pigeon Contraceptive Products. Dated November 20, 2009. PC Code 085712, DP Barcodes: 363859 and 363860.

USEPA. 2010. EFED Review of Rebuttal from Innolytics, LLC Regarding EFED’s Response from Innolytics, LCC to Remove Restricted Use Classification for Goose and Pigeon Contraceptive Products. Dated January 21, 2010. PC Code 085712, DP Barcodes: 372345, 372348, and 349126. USEPA. 2011. EFED Review of Innolytics, LLC Request for Waiving Avian Reproduction. Data Requirement for Nicarbazin. Dated December 23, 2011. PC Code: 085712; DP Barcode: 396672. USEPA. 2012. EFED Review of Innolytics, LLC Request for Waiving Avian Reproduction Data Requirement for Nicarbazin. Dated May 31, 2012. PC Code: 085712; DP Barcode: 400908.

USEPA. 2014 a . EFED Review of Innolytics, LLC Request for Waiving Avian Reproduction Data Requirement for Nicarbazin. Dated February 10, 2014. PC Code: 085712; DP Barcode: 415695.

USEPA. 2014 b . Guidance for Assessing Pesticide Risks to Bees. U.S. Environmental Protection Agency, Office of Pesticide Programs; Health Canada Pest Management Regulatory Agency; and California Department of Pesticide Regulation. Jun. 23, 2014. Available at http://www2.epa.gov/pollinator-protection/pollinator-risk-assessment-guidance

. USEPA. 2015 a
. Memorandum “BEAD Chemical Profile for Registration Review: Nicarbazin (PC Code 85712).” From C. Cook, Through A. Jones, BEAD; To B. Adler, PRD. Dated February 23, 2015. Office of Chemical Safety and Pollution Prevention, U.S. Environmental Protection Agency, Washington, D.C.

USEPA. 2015 b . Nicarbazin: Review of Study Protocol to fulfill Avian Reproduction Study. Dated March 4, 2015. PC Code: 085712; DP Barcode: 424098.

WHO. 1998. Nicarbazin - Toxicological Evaluation of Certain Veterinary Drug Residues In Food. WHO Food Additive Series 41, World Health Organization International Programme On Chemical Safety, Geneva. 9 p. http://www.inchem.org/documents/jecfa/jecmono/v041je10.htm

### 33 

## a. Submitted Environmental Fate Studies
MRID Citation Reference 46416400 Innolytics, LLC (2004) Submission of Product Chemistry, Toxicity, Fate, Efficacy and Environmental Fate Data in Support of the Application for Registrations of OvoControl -P, Nicarbazin 30% Granulated Premix, and OvoControl-G. Transmittal of 43 Studies. 46416401 Wolf, E.; MacDonald, A. (2004) Product Identity and Composition, Certification of Ingredient Limits, and Discussion of Impurities of Nicarbazin and Nicarbazin 30% Granulated Premix. Project Number: NICARBAZIN/04/22. Unpublished study prepared by Exponent. 51 p. 46416402 Wolf, E.; MacDonald, A. (2004) Product Identity and Composition, Certification of Ingredient Limits, and Discussion of Impurities of OvoControl -G and OvoControl- P. Project Number: NICARBAZIN/04/34. Unpublished study prepared by Exponent. 16 p. 46416403 Wolf, E.; MacDonald, A. (2004) Description of Materials Used to Produce the Product, Description of Production Process, Description of Formulation Process, Preliminary Analysis for Nicarbazin and the Manufacturing Use Product Nicarbazin 30% Granulated Premix. Project Number: NICARBAZIN/04/08/03. Unpublished study prepared by Exponent. 130 p. 46416404 Wolf, E.; MacDonald, A. (2004) Description of Materials Used to Produce the Product, Description of Production Process, Description of Formulation Process, and Prelimonary Analysis for OvoControl -G and OvoControl-P. Project Number: NICARBAZIN/04/37. Unpublished study prepared by Exponent. 77 p. 46416406 Wolf, E.; MacDonald, A. (2004) Description and Validation of Analytical Method for the Determination of Nicarbazin in Goose Baits by HPLC/UV. Project Number: NICARBAZIN/04/36, P0000814, P0000545. Unpublished study prepared by Exponent. 38 p. 46416407 Wolf, E.; MacDonald, A. (2004) Description of Color, Physical State, Odor, Melting Point, Specific Gravity, Solubility, Vapor Pressure, Dissociation Constant, pH, Stability, and Particle Size for Nicarbazin. Project Number: NICARBAZIN/04/31. Unpublished study prepared by Exponent. 31 p. 46416408 Wolf, E.; MacDonald, A. (2004) Description of Color, Physical State, Odor, Bulk Density, pH, Flammability, Explodability, Particle Size and Shape, Storage Stability, and Corrosion Characteristics for Nicarbazin 30% Granulated Premix. Project Number: NICARBAZIN/04/32. Unpublished study prepared by Exponent. 8 p. 46416409 Wolf, E.; MacDonald, A. (2004) Description of Color, Physical State, Odor, Bulk Density, pH, Flammability, Explodability, Particle Size and Shape, Storage Stability, and Corrosion Characteristics for OvoContr ol-G and OvoControl- P. Project Number: NICARBAZIN/04/33. Unpublished study prepared by Exponent. 6 p. 46416410 Wolf, E. (2004) The Determination of the Distribution Coefficients of the Components of Nicarbazin Between 1 -Octanol and Aqueous Buffers (ADM-56). Project Number: NICARBAZIN/04/08/05. Unpublished study prepared by Exponent. 17 p. 46416411 McCracken, B. (2004) Water Solubility of DNC and HDP. Project Number: P0000936. Unpublished study prepared by Exygen Research. 26 p. 46416412 Habig, C.; Messina, J.; Daniels, C. (2004) Nicarbazin Support Documentation. Project Number: NICARBAZIN/04/30. Unpublished study prepared by Exponent. 112 p.

### 34 MRID Citation Reference 46416445 Habig, C.; Messina, J.; Daniels, C. (2004) Nicarbazin Waiver Request from Further Testing: Aqueous Photolysis. Project Number: NICARBAZIN/04/25. Unpublished study prepared by Exponent. 10 p. 46416446 Wolf, E. (2004) A Study to Determine the Rate of Depletion of Ionophore and 14-C Nicarbazin in a Field Soil Plot. Project Number: NICARBAZIN/04/13. Unpublished study prepared by Exponent. 7 p. 46416447 Wolf, E. (2004) Mobility of 14-C DNC on Soil Thin-Layer Plates. Project Number: NICARBAZIN/04/15. Unpublished study prepared by Exponent. 8 p. 46416449 Manthey, J. (1985) A Study to Determine the Rate of Depletion of Narasin and 14-C Nicarbazin in a Field Soil Plot. Project Number: ABC/0284. Unpublished study prepared by Exponent. 55 p. 46445300 Innolytics, LLC (2005) Submission of Product Chemistry, Toxicity, Environmental Fate Data in Support of the Application for Registrations of LLC/Nicarbazin 30% Granulated Premix, Ovocontrol P and Ovocontrol G. Transmittal of 6 Studies. 46445301 Wolf, E.; MacDonald, A. (2004) Description of Analytical Methods for Nicarbazin and the Manufacturing Use Product Nicarbaz in 30% Granulated Premix, Impurities, and Quality Control Processes. Project Number: NICARBAZIN/04/24. Unpublished study prepared by Exponent. 82 p. 46445305 McCracken, B. (2004) Aqueous Hydrolysis of Nicarbazin Under Laboratory Conditions Amendment 1. Project Number: EXP/108/002, P0000693. Unpublished study prepared by Exygen Research. 55 p. 46445306 Manthey, J. (1984) A Greenhouse Study to Determine the Rate of Decline of Soil Incorporated Narasinand 14C Nicarbazin Singly and in Combination. Project Number: ABC/0209. Unpublished study prepared by Exponent. 58 p. 46459800 Innolytics, LLC (2005) Submission of Toxicity and Fate Data in Support of the Application for Registration of Nicarbazin. Transmittal of 2 Studies. 46459801 Habig, C.; Messina, J.; Daniels, C. (2005) Nicarbazin Waiver Request from Further Testing. Project Number: NICARBAZIN/04/40. Unpublished study prepared by Exponent. 10 p. 46459802 Habig, C.; Messina, J.; Daniels, C. (2005) Nicarbazin Waiver Request from Further Testing. Project Number: NICARBAZIN/04/39. Unpublished study prepared by Exponent. 11 p. 46471700 Innolytics, Inc. (2005) Submission of Environmental Fate Data in Support of the Application for Registration of Nicarbazin. Transmittal of 1 Study. 46497100 Innolytics. LLC. (2005) Submission of Toxicity and Efficacy Data in Support of the Application for Registration of Ovocontrol P. Transmittal of 3 Studies. 46497102 Habig, C.; Messina, J.; Daniels, C. (2005) Nicarbazin Waiver Request from Further Testing: Fish Accumulation. Project Number: NICARBAZIN/03/15. Unpublished study prepared by Exponent. 9 p. 46998500 Innolytics, LLC (2006) Submission of Efficacy Data in Support of the Application for Registration of OvoControl P. Transmittal of 1 Study. 46998501 Wolf, E. (2006) Italian Ministry of Health: Registration of Ovistop Brand of Nicarbazin. Project Number: NICARBAZIN. Unpublished study prepared by Innolytics, LLC. 5 p.

### 35 MRID Citation Reference 47520300 Innolytics, LLC. (2008) Submission of Product Chemistry Data in Support of the Registration of OvoControl P 0.5%. Transmittal of 1 Study. 47520301 MacDonald, A. (2008) Corrosion Characteristics and Stability of OvoControl P 0.5% (Nicarbazin). Unpublished study prepared by Innolytics, LLC. 7 p. 

## b. Submitted Ecological Toxicity Studies
MRID Citation Reference 46416426 Gallagher, S.; Beavers, J. (2004) Nicarbazin Technical: An Acute Oral Toxicity Study With the Northern Bobwhite. Project Number: 573/103. Unpublished study prepared by Wildlife International, Ltd. 30 p. 46416427 Gallagher, S.; Beavers, J. (2004) Nicarbazin Technical: A Dietary LC50 Study with the Northern Bobwhite. Project Number: 573/101, P0000736. Unpublished study prepared by Wildlife International, Ltd. 89 p. 46445302 Gallagher, S.; Beavers, J. (2004) Nicarbazin Technical: A Dietary LC50 Study with the Mallard. Project Number: 573/102, Unpublished study prepared by Wildlife International, Ltd. 47556000 Innolytics, LLC (2008) Submission of Efficacy Data in Support of the Registration of OvoControl P 0.5 percent for Pigeons. Transmittal of 1 Study. 47556001 MacDonald, A. (2008) OvoControl P 0.5 percent (Nicarbazin) Field Efficacy Study in Pigeons. ProjectNumber: NICARBAZIN, 95C, 08/034. Unpublished study prepared by Innolytics, LLC. 199p. 46416429 Habig, C.; Messina, J.; Daniels, C. (2004) Nicarbazin Waiver Request From Further Testing: Wild Mammal Toxicity. Project Number: NICARBAZIN/04/28. Unpublished study prepared by Exponent. 8p. 46445303 Messina, J. (2004) Nicarbazin Avian Reproduction. Project Number: NICARBAZIN/04/18. Unpublished study prepared by Wildlife International, Ltd. 35 p. 46497101 Wolf, E. (2005) Nicarbazin Avian Reproduction Support Documentation. Project Number: QA/737, QA/774, QA/850. Unpublished study prepared by US Dept. of Agriculture, APHIS, WS, University of Georgia and Clemson University. 115 p. 46416431 Palmer, S.; Krueger, H. (2004) 2-Hydroxy-4,6 Dimethypyrimidine (HDP): A 96-Hour Static Acute Toxicity Test With The Rainbow Trout ( Oncorhynchus mykiss ): Final Report. Project Number: 573A/109, P997, V0002054/3. Unpublished study prepared by Exponent. 90 p. 46416432 Palmer, S.; Krueger, H. (2004) 4,4'-Dinitrocarbanilide (DNC): A 96-Hour Static Acute Toxicity Test with the Rainbow Trout ( Oncorhynchus mykiss ): Final Report. Project Number: 573A/106. Unpublished study prepared by Wildlife International, Ltd. 89 p. 46416433 Palmer, S.; Krueger, H. (2004) 2-Hydroxy-4,6 Dimethylpyrimidine (HDP): A 96-Hour Static Acute Toxicity Test with the Bluegill ( Lepomis macrochirus ): Final Report. Project Number: 573A/108. Unpublished study prepared by Wildlife International, Ltd. 89 p. 46416434 Palmer, S.; Krueger, H. (2004) 4,4'-DinitroCarbanilide (DNC): A 96-Hour Static Acute Toxicity Test with the Bluegill ( Lepomis macrochirus ): Final Report. Project Number: 573A/105. Unpublished study prepared by Wildlife International, Ltd. 90 p.

### 36 MRID Citation Reference 46416437 Wolf, E. (2004) Nicarbazin Acute Freshwater Fish, Aquatic Invertebrates, Alga Toxicity. Project Number: NICARBAZIN/04/19. Unpublished study prepared by Exponent. 16 p. 46416435 Palmer, S.; Krueger, H. (2004) 2-Hydroxy-4,6 Dimethylpyrimidine (HDP): A 48-Hour Static Acute Toxicity Test with th e Cladoceran (Daphnia magna ): Final Report. Project Number: 573A/107C. Unpublished study prepared by Wildlife International, Ltd. 90 p. 46416436 Palmer, S.; Krueger, H. (2004) 4,4'-Dinitrocarbanilide (DNC): A 48-Hour Static Acute Toxicity Test with the Cl adoceran (Daphnia magna ): Final Report. Project Number: 573A/104A. Unpublished study prepared by Wildlife International, Ltd. 91 p. 46416438 Habig, C.; Messina, J.; Daniels, C. (2004) Nicarbazin Waiver Request from Further Testing: Acute LC50 Estuarine and Marine Organisms, Fish Early Life Stage and Aquatic Invertebrate Life -Cycle, Fish Life- Cycle, Aquatic Organism Accumulation, and Simulated or Actual Field Testing -Aquatic Organisms. Project Number: NICARBAZIN/04/21. Unpublished study prepared by Exponent. 9 p. 46416413 Messina, J. (2004) Nicarbazin Acute Oral Toxicity LD50: (Rat). Project Number: NICARBAZIN/04/12. Unpublished study prepared by Exponent. 7 p. 46416414 Messina, J.; Daniels, C. (2004) Nicarbazin Waiver Request from Further Testing: Acute Dermal Toxicity LD50. Project Number: NICARBAZIN/04/29. Unpublished study prepared by Exponent. 8 p. 46416415 Brooker, A. (2001) Koffogran: Acute (Four-Hour) Inhalation Study in Rats. Project Number: CYT/044/014207,NICARBAZIN/04/02. Unpublished study pre pared by Huntingdon Life Sciences, Ltd. 35 p. 46416416 Blanchard, E. (2001) Koffogran: Eye Irritation to the Rabbit. Project Number: NICARBAZIN/04/02, CYT/002/013543/SE. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 16 p. 46416417 Blanchard, E. (2001) Koffogran: Skin Irritation to the Rabbit. Project Number: NICARBAZIN/04/03, CYT/001/013542/SE. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 15 p. 46416418 Coleman, D. (2001) Koffogran: Skin Sensitization to the Guinea-Pig (Buehler Method - 9 Inductions). Project Number: NICARBAZIN/04/04, CYT/003/013699/SS. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 28 p. 46645600 Innolytics, LLC (2005) Submission of Toxicity Data in Support of the Application for Registration of OvoControl G. Transmittal of 1 Study. 46645601 Messina, J.; Daniels, C. (2005) Nicarbazin Waiver Request from Further Testing: Acute Inhalation Toxicity LC50. Project Number: NICARBAZIN/05/01. Unpublished study prepared by Exponent. 8 p. 46416419 Messina, J. (2004) Nicarbazin Chronic Toxicity Rat. Project Number: NICARBAZIN/04/08. Unpublished study prepared by Exponent. 184 p. 46416420 Messina, J. (2004) Nicarbazin Chronic Toxicity Dog. Project Number: NICARBAZIN/04/07. Unpublished study prepared by Exponent. 184 p. 46416421 Messina, J. (2004) Nicarbazin Developmental Toxicity. Project Number: NICARBAZIN/04/10. Unpublished study prepared by Exponent. 50 p.

### 37 MRID Citation Reference 46416422 Messina, J. (2004) Nicarbazin Multigeneration Reproduction Toxicology. Project Number: NICARBAZIN/04/05. Unpublished study prepared by Exponent. 48 p. 46416423 Messina, J. (2004) Nicarbazin Genotoxicity. Project Number: NICARBAZIN/04/09. Unpublished study prepared by Exponent. 20 p. 46416424 Innes, D. (2001) Nicarbazin: Micronucleus Test in Bone Marrow of CD-1 Mice 0 h + 24 h Oral Dosing and 48 h Sampling. Project Number: 20677, NICARBAZIN/04/11, 767115. Unpublished study prepared by Inveresk Research International. 31 p. 46416425 Messina, J. (2004) Nicarbazin Metabolism. Project Number: NICARBAZIN/04/06. Unpublished study prepared by Exponent. 252 p. 46416439 Habig, C.; Messina, J.; Daniels, C. (2004) Nicarbazin Waiver Request from Further Testing: Seedling Emergence, Vegetative Vigor and Aquatic Plant Growth. Project Number: NICARBAZIN/04/20. Unpublished study prepared by Exponent. 8 p. 46471701 Wolf, E. (2005) Determination of the Toxicity of Nicarbazin (Nicarbazin) and Supacox (Pancoxin Plus) to Eight Higher -Plant Species by Soil Application. Project Number: NICARBAZIN/04/38, WD00775/000. Unpublished study prepared by Exponent. 47 p. 46416440 Habig, C.; Messina, J.; Daniels, C. (2004) Nicarbazin Waiver Request from Further Testing: Honey Bee Acute Contact LD50, Honey Bee Toxicity of Residues on Foliage, and Field Testing for Pollinators. Project Number: NICARBAZIN/04/20. Unpublished study prepared by Exponent. 8 p. 46416441 Messina, J. (2004) Nicarbazin, HDP, and DNC Acute Earthworm Toxicity. Project Number: NICARBAZIN/04/16. Unpublished study prepared by Exponent. 58 p. 46416442 Messina, J. (2004) Nicarbazin Pigeon Efficacy Information. Project Number: NICARBAZIN/ 04/17. Unpublished study prepared by Exponent. 15 p. 46445304 Bynum, K.; Eisemann, J.; Miller, L.; et. al. (2004) Efficacy of 2500 ppm Nicarbazin for Reproductive Inhibition in Canada Geese. Unpublished study prepared by US Dept. of Agriculture, APHIS, WS. 37p. 46497103 Bynum, K.; Eisemann, J.; Weaver, G.; et al. (2005) QA-1102: Multi-center Field Study of Nicarbazin Bait for use in the Reduction in Hatching of Eggs Laid by Local Canada Goose (Branta canadensis ) Flocks. Project Number: QA/1102. Unpublished study prepared by US Dept. of Agriculture, APHIS, WS and Innolytics, LLC. 130 p. 46820700 Innolytics, LLC (2006) Submission of Toxicity Data in Support of the Application for Registration of OvoControl P. Transmittal of 1 Study. 46820701 Avery, M. (2006) Effects of Nicarbazin Bait on Pigeon Reproduction: OvoControl P. Project Number: QA/1239, WD00775/000. Unpublished study prepared by U.S. Dept. of Agriculture, A.P.H.I.S. 52 p. 46851500 Innolytics, LLC (2006) Submission of Toxicity Data in Support of the Application for Registration of OvoControl G. Transmittal of 1 Study. 46851501 MacDonald, A. (2006) Nicarbazin Support Documentation Feral Pigeons - Social and Feeding Behavior. Project Number: NICARBAZIN. Unpublished study prepared by Innolytics, LLC and Ministry of Agriculture, Fisheries and Food. 76 p.

### 38 MRID Citation Reference 46992100 Innolytics, LLC (2006) Submission of Environmental Fate Data in Support of the Application for Registration of OvoControl P. Transmittal of 2 Studies. 46992101 Avery, M.; Keacher, K.; Tillman, E. (2006) Development of Nicarbazin Bait for Managing Rock Pigeon ( Columbia livia ) Populations. Unpublished study prepared by U.S. Dept. of Agriculture, National Wildlife Research Center 29 p. 46992102 Wolf, E.; MacDonald, A. (2006) Supporting Documentation for the Use of Nicarbazin in Feral Pigeons. Unpublished study prepared by Innolytics, LLC. 43 p. 47043200 Innolytics, LLC (2007) Submission of Fate Data in Support of the Application for Registration of OvoControl P. Transmittal of 1 Study. 47043201 Wolf, E. (2007) Supporting Field Study for the Use of Nicarbazin in Feral Pigeons. Project Number: NICARBAZIN. Unpublished study prepared by Innolytics, LLC. 41 p. 48026600 Innolytics, LLC (2010) Submission of Exposure and Risk Data in Support of the Registration of OvoControl P 0.5%. Transmittal of 1 Study. 48026601 MacDonald, A. (2010) OvoControl P 0.5% (Nicarbazin): Population Dynamics in Pigeons. Unpublished study prepared by Innolytics, LLC. 10 p. 46992400 Innolytics, LLC (2006) Submission of Toxicity and Efficacy Data in Support of the Registration of OvoControl G. Transmittal of 1 Study. 46992401 Barbato, G.; MacDonald, A. (2006) Pekin Duck Model for Action of Nicarbazin on Fertility. Project Number: NICARBAZIN. Unpublished study prepared by Innolytics, LLC. 12 p. 46845800 Innolytics, LLC (2006) Submission of Efficacy Data in Support of the Amended Registration of OvoControl G. Transmittal of 1 Study. 46845801 Bynum, K.; Eisemann, J.; Weaver, G.; et. al. (2006) QA-1102: Multi-Center Field Study of Nicarbazin Bait for Use in the Reduction in Hatching of Eggs Laid by Local Canada Goose (Branta canadensis ) Flocks: Final Report. Project Number: QA/1102, QA/1345. Unpublished study prepared by US Dept. of Agriculture, APHIS, WS. 1031 p. 49474200 Innolytics, LLC (2014) Submission of Toxicity Data in Support of the Registration of Nicarbazin. Transmittal of 1 study. 49474201 Stafford, J. (2014) Nicarbazin: Reproductive NOEAC Test with the Northern Bobwhite ( Colinus virginianus ). Unpublished study prepared by Smithers Viscient. 11p.

### 39 

### APPENDIX A. SIP Inputs and Outputs for Nicarbazin (DNC & HDP components)
Table 1. Inputs Parameter Value Chemical name Nicarbazin (DNC moiety) Solubility (in water at 25 o C; mg/L) 0.076
Mammalian LD 50 (mg/kg-bw) 10000 Mammalian test species laboratory rat Body weight (g) of "other" mammalian species Mammalian NOAEL (mg/kg-bw) 200 Mammalian test species laboratory rat Body weight (g) of "other" mammalian species
Avian LD 50 (mg/kg-bw) 2250 Avian test species northern bobwhite quail Body weight (g) of "other" avian species Mineau scaling factor Mallard NOAEC (mg/kg-diet) Bobwhite quail NOAEC (mg/kg-diet) NOAEC (mg/kg-diet) for other bird species Body weight (g) of other avian species NOAEC (mg/kg-diet) for 2nd other bird species Body weight (g) of 2nd other avian species

Table 2. Mammalian Results Parameter Acute Chronic Upper bound exposure (mg/kg-bw) 0.0131 0.0131 Adjusted toxicity value (mg/kg-bw) 7691.6057 153.8321 Ratio of exposure to toxicity 0.0000 0.0001

Conclusion* Drinking water exposure alone is NOT a potential

concern for mammals Drinking water exposure alone is NOT a potential concern for mammals

Table 3. Avian Results Parameter Acute Chronic Upper bound exposure (mg/kg-bw) 0.0616 0.0616 Adjusted toxicity value (mg/kg-bw) 20025.0000 0.0000 Ratio of exposure to acute toxicity 0.0000 0.0000

Conclusion* Drinking water exposure alone is NOT a potential concern for birds Due to insufficient data, risk cannot be precluded

*Conclusion is for drinking water exposure alone. This does not combine all routes of exposure. Therefore, when aggregated with other routes ( i.e ., diet, inhalation, dermal), pesticide exposure through drinking water may contribute to a total exposure that has potential for effects to non-target animals.

### 40 Table 1. Inputs Parameter Value Chemical name Nicarbazin_HDP moiety Solubility (in water at 25 o C; mg/L) 10000
Mammalian LD 50 (mg/kg-bw) 4000 Mammalian test species other Body weight (g) of "other" mammalian species 35 Mammalian NOAEL (mg/kg-bw) 200 Mammalian test species laboratory rat Body weight (g) of "other" mammalian species
Avian LD 50 (mg/kg-bw) 2250 Avian test species northern bobwhite quail Body weight (g) of "other" avian species Mineau scaling factor Mallard NOAEC (mg/kg-diet) Bobwhite quail NOAEC (mg/kg-diet) NOAEC (mg/kg-diet) for other bird species Body weight (g) of other avian species NOAEC (mg/kg-diet) for 2nd other bird species Body weight (g) of 2nd other avian species
Enter body weight of 'other' mammalian species for LD50.

Table 2. Mammalian Results Parameter Acute Chronic Upper bound exposure (mg/kg-bw) 1720.0000 1720.0000 Adjusted toxicity value (mg/kg-bw) 1730.1231 153.8321 Ratio of exposure to toxicity 0.9941 11.1810

Conclusion* Exposure through drinking water alone is a potential

concern for mammals Exposure through drinking water alone is a potential

concern for mammals

Table 3. Avian Results Parameter Acute Chronic Upper bound exposure (mg/kg-bw) 8100.0000 8100.0000 Adjusted toxicity value (mg/kg-bw) 20025.0000 0.0000 Ratio of exposure to acute toxicity 0.4045 0.0000

Conclusion* Exposure through drinking water alone is a potential concern for birds Due to insufficient data, risk cannot be precluded

*Conclusion is for drinking water exposure alone. This does not combine all routes of exposure. Therefore, when aggregated with other routes ( i.e ., diet, inhalation, dermal), pesticide exposure through drinking water may contribute to a total exposure that has potential for effects to non-target animals.