UN ITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON. D.C. 20460 

MEMORANDUM 

DATE: December 2, 2015 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Nicarbazin. Human Health Draft Risk Assessment for Registration Review. 

PC Codes: 085712 

Decision No.: 505004, 505007 

Petition No.: NIA 

Risk Assessment Type: Single Chemical Aggregate 

TXR No.: N/A 

MRID No.: NIA 

DP Ba rcode: 0427303, 0427299 

Registration No.: 80224-1 , 80224-2 

Regulatory Action: Registration Review 

Case No.: 7628 

CAS Nos.: 330-95-0 

40 CFR: NA 

FROM: Matthew Crowley, Biologist/Risk Assessor 

Risk Assessment Branch J [ 

Health Effects Division (7509P) 

Office of Pesticide Programs 

Christopher Schlosser, Toxicologist 

Risk Assessment Branch Vf 

Health Effects Division (7509P) 

Office of Pesticide Programs 

THROUGH: Christina Swartz, Branch Chief 

Risk Assessment Branch 11 

Health Effects Division (7509P) 

Office of Pesticide Programs 

TO: Bonnie Adler, Chemical Review Manager 

Risk Management and Implementation Branch 5 

Pesticide Re-evaluation Division 

Office of Pesticide Programs 

As part of Registration Review, the Pesticide Re-evaluation Division (PRD) of the Office of 

Pesticide Programs (OPP) has requested that the Health Effects Division (HED) determine the 

hazard and exposure data as well as the assessments needed to estimate human health risk that 

will result from the currently registered uses of pesticides. In the case of nicarbazin, a pigeon 

contraceptive, HED has determined that no additional data are needed, and therefore this 

memorandum serves as both HED's scoping document and draft risk assessment (DRA) for 

nicarbazin. The risk assessment was provided by Matthew Crowley (RABii) with hazard 

characterization by Christopher Schlosser (RAB VI). 
Nicarbazin Draft Risk Assessment DP No. D427303 

Table of Contents 

1.0 Executive Sununary ............................................................................................................... 3 

2.0 11 ED Recommendations ......................................................................................................... 4 

2.1 Data Deficiencies/Conditions of Registration ................................................................ 4 

2.2 Tolerance Considerations ............................................................................................... 4 

2.3 Label Recommendations .......................................................................... ....... ....... ........ 5 

3.0 Introduction ...................................................................................................... ....... ....... ........ 5 

3.1 Chemical Identity and Physical/Chemical Characteristics ................... .......................... 5 

3.2 Pesticide Use Pattern ................................................................................ ... .... .... ... ........ 6 

3.3 Anticipated Exposure Pathways .. .... .... ................................................................... .... .... 6 

3.4 Consideration of Environmental Justice ...... .... .... ............... .... ... .... ....... ...................... .... 6 

4.0 l lazard Characterization and Dose-Response Assessment .............................. ... ........ ... .... ... . 7 

5.0 Endocrine Disruptor Screening Program ................... .... .... ............... .... ... ... .... ....... .... ............ 9 

6.0 Dietary Exposure and Risk Assessment .... .... .... .... ........ .... ....... .... ... .... ...................... ... .... ... I 0 

7 .0 Residential (Non-Occupational) Exposure/Risk Characterization ............................... ....... I 0 

8.0 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk Estimates .. I 0 

9.0 Non-Occupational Spray Drift Exposure and Risk Estimates ............................................. 11 

I 0.0 Aggregate Exposure/Risk Characterization ....................................................................... 11 

11.0 Cumulative Exposure/Risk Characterization ..................................................................... 11 

12.0 Occupational Exposure/Risk Characterization .................................................................. 11 

12.1 Occupational Handler Exposure/Risk Estimates ............................................. ............. 12 

12.2 Occupational Post-application Exposure/Risk Estimates ................................ ............. 15 

13.0 Public Health and Pesticide Epidemiology Data ............................................................... 15 

14.0 References ..................... .... .... ........ ................................................................................ ..... 15 

14.1 HED Memoranda .... ................... ........................................... ............................. ........ .. 15 

14.2 Published Literature and Other Documents ................................................ ... .... .... ...... 16 

Appendix A: Toxicity Profile and Executive Summaries ................................ ....... .... ................. 17 

A. I Toxicology Data Requirements ...... .... .............................................. ... .... ... .... .............. 17 

A.2 "foxieity Profiles ..... ... ........ .... .... .... .... ................................... .... ....... ...................... .... ... 18 

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Nicarbazin Draft Risk Assessment DP No. 0427303 

1.0 Executive Summary 

Use and Exposure Profile 

Nicarbazin is the active ingredient in one registered end-use product, OvoControl P (EPA Reg. 

No. 80224-1 ), a 0.5% active ingredient granule/bait pigeon contraceptive packaged in a 30 lb 

bag. Use sites are limited to paved/concrete areas or rooftops of office parks, malls, hospitals, 

schools, bridges, airports, other commercial/industrial buildings/structures. The label specifies 

use in secured areas with limited public access and for applicators to remove excess/uneaten bait 

one how- after application. 

Based on this use pattern, only dermal and inhalation exposures are anticipated for occupational 

handlers (mixer/loaders and applicators); fo llowing removal of excess/uneaten bait, occupational 

post-application exposures are not expected. Additionally, no dietary exposures via food and/or 

water nor any non-occupational/residential exposures via application, post-application, spray 

drift, or volatilization are expected. 

Hazard/Toxicology Assessment 

Based on the available data submitted to the Agency and an available European Food Safety 

Authority (EFSA) report, the toxicology database for nicarbazin is sufficient for assessing risk. 

Nicarbazin has low acute toxicity, is a moderate eye irritant, and is not a dermal irritant or 

sensitizer. Available studies did not indicate any concerns for neurotoxicity or immunotoxicity. 

No evidence of mutagenicity was observed. 

The lowest observed adverse effect level (LOAEL) of 181 mg/kg/day from the 90-day rat oral 

toxicity study is considered appropriate for assessing risk for all exposure scenarios. A I OX 

database uncertainty factor was applied for a LOAEL to no observed adverse effect level 

(NOAEL) extrapolation, resulting in a 1000-fold UF (1 OX for interspecies extrapolation, IOX for 

intraspecies variation, and 1 OX Ufdb) for all exposure scenarios. Nicarbazin is a non-food use 

chemical with no residential uses; exposure to children is not expected. Therefore, additional 

safety factors according to the Food Quality Protection Act (FQPA) do not apply. 

Aggregate Exposure and Risk 

In accordance with the FQPA, HED must consider all routes of exposure, including from nonpesticidal sources, to estimate aggregate exposure (i .e., dietary (food and/or drinking water) plus 

non-dietary/residential). Based on the use pattern for nicarbazin, dietary and nondietary/residential exposures from its pesticidal use are not expected; thus an aggregate 

assessment is not applicable. 

Occupational Exposure and Risk 

The quantitative exposure/risk assessment developed for occupational handlers of nicarbazin is 

based on applications of granules by hand or with hand-operated equipment such as a belly 

grinder or rotary spreader. There were no combined (de1mal + inhalation) risks of concern with 

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Nicarbazin Draft Risk Assessment DP No. D427303 

label-specified work attire and personal protective equipment (PPE) (long sleeve shirt, pants, 

shoes. socks, gloves). 

Environmental .Justice Considerations 

Potential areas of environmental justice concerns. to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, ''Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations." 

Review r~( I !uman Research 

This risk assessment relies in part on data from studies in whi ch adult human subjects were 

intentionall y exposed to a pesticide or other chemical. These data, which include studies from 

the Pesticide llandlers Exposure Database Version I. I (PH ED I.I ) and the Outdoor Residential 

Exposure Task Force (ORETF) database are (1) subject to ethics review pursuant to 40 CFR 26, 

(2) have received that review, and (3) are compliant with applicable ethics requirements. For 

certain studies, the ethics review may have included review by the Human Studies Review 

Board. Descriptions of data sources, as well as guidance on the ir use, can be found at the 

Agency websites: http://www2.epa.gov/pesticidc-scicncc-and-asscssing-pcsticiderisks/occupational-pesticide-handler-exposure-data and hnp://ww'.v2.epa.gov/pesticide-scienceand-assessi n g-pcst ic idc-risks/occu pational-pest icide-post-app I icat ion-ex po sure. 

2.0 HED Recommendations 

HED has examined all applicable databases for nicarbazin, and concludes that there are no 

residue chemistry, occupational/residential, or toxicology data deficiencies that would preclude 

the continuation of its registration. 

In terms of human health risk concerns, only occupational handler exposures are expected and no 

risks of concern were identified assuming label-specified wo rk attire and personal protective 

equipment (PPE) of long-sleeve shirt, long pants, and gloves. The lack of any risk concerns in 

this assessment was pa11ially due to the assumption that the label-required gloves are chemicalresistant, despite the label onl y specifying ''gloves". Thus, HED recommends confirming and 

revising the label to specify use of '·chemical-resistant gloves" during application and removal of 

excess/uneaten bait, in addition to any other PPE requirements based on the end-use product 

acute toxicity profile. 

2.1 Data Deficiencies/Conditions of Registration 

There arc no data deficiencies for nicarbazin. 

2.2 Tolerance Considerations 

There are no pesticide tolerances for nicarbazin. 

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Nicarbazin Draft Risk Assessment DP No. 0427303 

2.3 Label Recommendations 

The product label specifies wearing a long-sleeved shirt, long pants, shoes, socks, and gloves - it 

does not specify whether the gloves should be chemical-resistant. This should be confirmed, 

both in terms of risk estimates described in this assessment assuming the exposure reduction 

provided by chemical-resistant gloves, as well as any other PPE requirements based on the enduse product acute toxicity profile. 

3.0 Introduction 

Nicarbazin was first registered as a pesticide by EPA in 2005 to reduce egg hatching in Resident 

Canada Geese. Nicarbazin interferes with the formation of the vitelline membrane, separating 

the egg yolk and egg white. The exact mode of action is unknown, although it is thought 

nicarbazin interferes with cholesterol metabolism in the formation of the membrane. Eggs from 

treated birds are described as mottled in appearance, reflecting a porous vitelline membrane. The 

effect on hatchability is a function of time and dose and the effect is reversible. 

Nicarbaz in has been a Food and Drug Administration (FDA) approved veterinary drug for use as 

an anticoccidial agent in broiler chickens since 1955. FDA has established a tolerance of 4 parts 

per million for nicarbazin residues in uncooked chicken muscle, skin, liver, and kidney (21 Code 

of Federal Regulations 556.445). FDA has also established its use as a feed additive to prevent 

outbreaks of fecal and intestinal coccidiosis (21 Code of Federal Regulations 558.366) (US EPA, 

2005). 

Currently there is only one registered end-use product, OvoControl P (EPA Reg. No. 80224-1 , 

Innolytics, LLC), a 0.5% active ingredient granule/bait, used as a contraceptive for pigeons. Use 

sites are limited to paved/concrete areas or rooftops of office parks, malls, hospitals, schools, 

bridges, a irports, or other commercial/industrial buildings/structures. The label specifies use in 

secured areas with limited public access. 

3.1 Chemical Identity and Physical/Chemical Characteristics 

Nicarbaz in (Cl 9H l 8N606) is a complex of two compounds, 4,4'-dinitrocarbanilide (DNC, 

302.25 molecular weight) and 4,6-dimethyl-2-pyrimidinol (HOP, 124.14 molecular weight). 

DNC is considered to be the active component, while HOP aids in absorption. Additional 

nomenclature and physical/chemical properties are provided below. 

Table 3.1.1 C hemical Nomenclatu re a nd Physical/Chemical Properties of Nicar bazin (US EPA, 2005) 

CAS # 330-95-0 

Molecular weight (g/mole) 426.38 

Physical state Yellow, fine powder 

Melting point 265-275 °C 

slightly soluble in dimethylsulphoxide (DMSO) and dimethylformamide (DMF); 

Aqueous solubility insoluble in water and methanol, however it decomposes slowly when mixed with 

them 

pH 5-7 (I % suspension in water) 

Density (g/mL) 0.5 

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Nicarbazin Draft Risk Assessment DP No. D427303 

3.2 Pesticide Use Pattern 

Table 3.3. 1 below outlines the use profile for OvoControl P, the only end use product registered 

containing nicarbazin as the active ingredient. The manufacturing/formulating use product is 

EPA Reg. No. 80224-2. 

Table 3.3.1 Nicarbazin Use Profile (EPA Reg. No. 80224-1) 

Application 

Work Use Directions a nd Use Sitcffarget Formulation Equipment Attire/ Rate PPE Limitations 

Commercial and 0.5%ai - Hand I ounce of Long - Use only in secured 

industrial granule/bait dispersal product per 5 sleeved areas with limited 

buildings (e.g., - Rotary pigeons shirt. long public access. 

office parks, spreader pants, - Condition pigeons over 

malls, hospitals. - Belly I o'Zi5 pigeons shoes, a period of 5 to 14 days. 

schools, bridges, grinder * 1 lb/ 16oz* socks, starting with small 

airports): 0.5% = gloves. amounts of bait and 

rooftops or 0.0000625 lb visually observing paved/concrete ai/pigeon whether the pigeons are 

areas of limited feeding. 

public access Product is a 30 Remove excess bait lb bag, enough -

to treat 2400 after each feeding. 

pigeons - Discontinue use after 14 

days if conditioning 

fails. 

3.3 Anticipated Exposure Pathways 

Based on the use pattern, dermal and inhalation exposures are anticipated for occupational 

handlers only (i.e., those who individuals who load/apply the product and remove excess/uneaten 

bait). After application and bait removal, no occupational post-application exposures are 

expected, nor are any non-occupational/residential exposures expected via application, postappl ication, spray drift, or volatilization. For occupational handler scenarios, short- and 

intermediate-term durations are expected; long-term exposures are not anticipated. 

3.4 Consideration of Environmental .Justice 

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human hea lth risk assessment. in accordance with U.S. Executive Order 12898, ·'Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,'· 

(http://www.archi\'cs.go\'/federal-reuister/executive-orders/pdf/J 2898.pdl). As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup's food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

serting. Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture under the National Health and Nutrition Examination Survey, '·What We Eat in 

America,'' (NJ lANES/WWEIA). These food consumption patterns are used in pesticide risk 

assessments for all registered food uses of a pesticide. These data are analyzed and categorized 

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Nicarbazin Draft Risk Assessment DP No. D427303 

by subgroups based on age, season of the year, ethnic group, and region of the country. 

Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups, and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for children, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development, as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups. 

4.0 Hazard Characterization and Dose-Response Assessment 

The toxicology database for nicarbazin is sufficient for assessing risk (See Appendix A). In its 

previous registration, three non-guideline toxicity studies on a 3: 1 mixture of DNC to HOP 

(chronic dog, chronic rat, and two-generation reproduction) and one non-guideline study on 

nicarbazin (developmental rat) were submitted to the Agency. A metabolism study and 

mutagenicity battery are also available. Since that time, additional studies have been identified 

as part of a 2010 European Food Safety Authority (EFSA) evaluation for the use ofnicarbazin as 

a feed additive for chickens including: a 90-day oral toxicity study on nicarbazin; a 90-day oral 

toxicity study on DNC; and a developmental toxicity study in rabbits on nicarbazin (EFSA, 

2010). 

Although the current 40 CFR Part 158 Toxicology Data Requirements include a 90-day oral, 90-

day dermal, subchronic inhalation, developmental rabbit, neurotoxicity (acute and subchronic), 

and immunotoxicity studies, these studies were not submitted for nicarbazin. However, based on 

a weight-of-evidence (WOE) approach, using all hazard and exposure information available to 

the Agency and contained within the EFSA evaluation, the Hazard and Science Policy Council 

(HASPOC) determined these studies are not required to support the registered uses of nicarbazin 

(Bever, R, I 0/21 /2015; TXR #0057261 ). Additionally, an acute dermal toxicity study is also 

required per 40 CFR Part 158, but is not needed for Registration Review (personal 

communication with John Redden, Registration Division, 12/2/ 15). 

No clear target organ could be identified fo llowing exposure to nicarbazin in the current toxicity 

database. Decreased body weight was identified in both the 90-day oral study and 

developmental toxicity studies in rats. Additionally, following 90 days of exposure, effects 

included: decreases in body weights, erythrocytes, hemoglobin, and hematocrit; increases in 

blood urea nitrogen and plasma creatinine; increases in several relative organ weights; and 

tubular degeneration in the kidney and degeneration in the seminiferous tubule. Based on the 

available data, while all effects at 90 days appear to be of minimal severity, an increase in 

toxicity over time is suggested when comparing the 90-day and developmental studies in rats. In 

rabbits, lobulation of the liver was observed in the maternal animals. However, due to low 

incidence and absence of corresponding effects, the toxicological significance of this effect is 

unclear. 

No effects were observed in studies using the 3: 1 mixture of DNC to HOP or using DNC alone 

including: the chronic oral toxicity studies with a NOAEL of 400 mg/kg in both dogs and rats; 

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Nica rbazin Draft Risk Assessment DP No. 0 427303 

the reproductive toxicity study with no parental or reproductive effects observed up the highest 

dose tested of 400 mg/kg/day in rats; and the 90-day oral gavage study with DNC showing no 

effects up to 709 mg/kg/day in rats. Therefore, based on the available data, nicarbazin appears to 

be more toxic than both DNC alone and the 3: I DNC to HOP mixture. 

In developmental toxicity studies, no developmental toxicity was observed in the rabbit. In rats. 

decreased fetal weights were observed in the presence of maternal toxicity (decreased body 

weights in dams). Therefore, there is no concern for pre-natal susceptibility. 

The available studi es did not indicate any concerns for neurotoxicity or immunotoxicity. 

Carcinogenicity studies are not required for a non-food use chemical. No evidence of 

mutageni city was observed. 

Nicarbazin has low acute toxicity (Category TV), is a moderate eye irritant (Category (Ill), and is 

not a dermal irritant (Category IV) or sensitizer. 

The LOA EL of 181 mg/kg/day from the 90-day toxicity study is considered appropriate for 

assessing risk for all exposure scenarios. A I Ox database uncertainty factor was applied for a 

OAEL to LOAEL extrapolation. However, it should be noted that this LOAEL is derived from 

the EfSA evaluation and does not reflect current Agency policy, and therefore, may be 

considered to be conservative. 

For all exposure scenarios, a 1000-fold UF ( lOX for interspecies extrapolation, I OX for 

intraspecies variation. and !OX UFdb) was applied. Nicarbazin is a non-food use chemical with 

no residential uses and exposure to children is not expected; therefore, Food Quality Protection 

Act (FQPA) safety factor considerations do not apply. 

Table 4.1 Nica rbazin: Summa ry of Toxicological Doses and Endpoints fo r Non-Occupational Human Health 

Risk Assessments. 

Level of 

Exposure Point of Uncertainty Concern for Study a nd Tox icological Effects Scenario Departure Factors Risk 

Assessments 

Dermal Short- LOAEL = 18 1 UFA= 10 LOC for MOE = 90-Dav Oral Toxicitv 

Term(! to30 mg/kg/day UF11= 10 1000 (EFS/\ 20 I 0) 

days), UFdb = 10 

LOAEI.= 181 mg/kg/day based on Intermediate Term 

( l 10 6 momhs), decreases in body weights. 

erythrocytes. hemoglobin. and 

and Long Tenn hcmatocrit. Increases in blood urea 

(>6 monlhs) nitrogen and plasma creatinine. 

Increases in several relative organ 

\\eights. Tubular degeneration in the 

kidney and degeneration in the 

semini ferous tubule. 

No NOAEL wa;; idemified. 

Inhalation Short- LOAEL = 181 UFA = 10 LOC for MOE = 90-Day Oral Toxicitv 

Tenn (I to 30 mg/kg/day UFH = 10 1000 (EFSA 2010) 

days). UFdb = 10 

Intermed iate Term 

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Nicarbazin Draft Risk Assessment DP No. 0427303 

T a ble 4.1 Nicar baz in: Summary of Toxicological Doses and Endpoints fo r Non-Occupational Human Health 

Ris k Assessments. 

Level of 

Expos u re Point of Uncertainty Concern for Study a nd Toxicological E ffects Scenario Departure Factors R is k 

Assessments 

( I to 6 months), LOA EL= 181 mg/kg/day based on 

and Long Term decreases in body weights. 

(>6 months) erythrocytes. hemoglobin. and 

hcmatocrit. Increases in blood urea 

nitrogen and plasma ereatinine. 

Increases in several re lative organ 

weights. Tubular degeneration in the 

kidney and degeneration in the 

seminifcrous tubule. 

No NOAEL was identified. 

Point of Departure (POD)= A data point or an estimated point that is derived from observed dose-response data and used to mark 

the beginning of extrapolation to determine risk associated with lower environmentally re levant human exposures. NOAEL = no 

observed adverse effect level. LOA EL = lowest observed adverse effect level. UF = uncertainty factor. UFA= extrapolation from 

an imal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). 

UFdb = NOA EL to LOAEL extrapolation. MOE = margin of exposure. LOC = level of concern. N//\ = not applicable. 

5.0 Endocrine Disruptor Screening Program 

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal 

Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential 

adverse outcomes from exposure to chemicals. Collectively, these studies include acute, 

subchronic, and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, 

developmental, reproductive, and general or systemic toxicity. These studies include endpoints 

which may be susceptible to endocrine influence, including effects on endocrine target organ 

histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, 

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

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

different taxonomic groups. As part of its reregistration decision for nicarbazin, EPA reviewed 

these data and selected the most sensitive endpoints for relevant risk assessment scenarios from 

the existing hazard database. However, as required by FFDCA section 408(p), nicarbazin is 

subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate." The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

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

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

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

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

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

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

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Nicarbazin Draft Risk Assessment DP No. D427303 

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

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

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list 

of chemicals identified for EDSP screening was published on June 14, 2013 1 and includes some 

pesticides scheduled for registration review and chemicals found in water. Neither of these lists 

should be construed as a list of known or likely endocrine disruptors. 

For further information on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website.

2 

6.0 Dietary Exposure and Risk Assessment 

Nicarbazin is not registered for use in or on and food or feed crops, and though contamination of 

water bodies is possible from target animal feces, the limited and targeted use of the single 

registered product does not warrant estimation of concentrations in drinking water; therefore, a 

dietary exposure assessment is not applicable. 

7.0 Residential (Non-Occupational) Exposure/Risk Characterization 

The product is labeled for use only on the roofs or paved surfaces of and around commercial 

structures and buildings; consumer/residential applicator exposure is not expected. Additionally. 

because the label specifies use in secured areas of limited public access and directs applicators to 

observe the pigeon feeding and remove excess bait after each feeding, exposures to adults or 

children following applications are likewise not expected. 

8.0 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk 

Estimates 

Volatilization of pesticides may be a source of post-appli cation inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on 

March 2, 2010 (http:l/w\\rw.regulations.!!ov/#!documcntDetail:D=EPA-HQ-OPP-2009-0687-

0037). The agency has evaluated the SAP report and has deve loped a Volatilization Screening 

Tool and a subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-20 14-02 19). 

During Registration Review, the Agency will utilize this analysis to detem1ine if data (i.e., flux 

studies) or further analysis are required for nicarbazin. 

1 Sec hnp://www.rcgulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals 

~ hnp://www2.epa.gov/endocrine-disruption/endocrine-disruptor-scrccning-prograrn-edsp-overview 

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Nicarbazin Draft Risk Assessment DP No. 0427303 

9.0 Non-Occupational Spray Drift Exposure and Risk Estimates 

Off-target movement of pesticides can occur via many types of pathways and it is governed by a 

variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those it may directly contact. They can also deposit on 

surfaces where contact with residues can eventually lead to indirect exposures (e.g., children 

playing on lawns where residues have deposited next to treated fields). The potential risk 

estimates from these residues can be calculated using drift modeling coupled with methods 

employed for residential risk assessments for turf products. 

Because nicarbazin is both a granule and applied by hand or hand-operated equipment, exposure 

via drift is unlikely to occur. 

10.0 Aggregate Exposure/Risk Characterization 

In accordance with the FQPA, HED must consider all routes of exposure, including from nonpesticidal sources, to estimate aggregate exposure (i.e., dietary (food and/or drinking water) plus 

non-dietary/residential). Nicarbazin is a veterinary drug approved by the FDA with a tolerance 

of 4 ppm in uncooked chicken muscle, skin, liver and kidney. Such a use might be applicable to 

an aggregate exposure assessment, however, it is not registered as a pesticide for use in or on and 

food or feed crops, and the limited and targeted use of the single registered pesticide product 

does not warrant estimation of concentrations in drinking water. Additionally, because the 

product is registered for use in commercial/industrial sites and the label allows use only in 

secured areas of limited public access, neither consumer/residential applicator exposure nor 

exposures to adults or children followi ng applications are expected. 

Given that no dietary and/or non-dietary/residential exposures are expected from its pesticidal 

uses, an aggregate exposure assessment is not applicable. 

11.0 Cumulative Exposure!Risk Characterization 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to nicarbazin and any other substances, and nicarbazin does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this risk assessment, therefore, 

EPA has not assumed that nicarbazin has a common mechanism of toxicity with other 

substances. For information regarding EPA's efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA' s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/. 

12.0 Occupational Exposure/Risk Characterization 

As a granulefbait pigeon contraceptive used on paved/concrete areas or rooftops of offi ce parks, 

malls, hospitals, schools, bridges, airports, other commercial/industri al buildings/structures, 

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Nicarbazin Draft Risk Assessment DP No. D427303 

dermal and inhalation exposures to nicarbazin are anticipated for individuals who load, apply, 

and remove any excess/uneaten bait. After application and bait removal, post-application 

exposure is not expected because residues on concrete/paved areas are expected to be limited, 

nor are any worker activities in areas previously treated with nicarbazin expected that would 

involve significant hand or body contact with any residues. 

12.1 Occupational Handler Exposure/Risk Estimates 

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

The quantitative exposure/risk assessment developed for occupational handlers of nicarbazin is 

based on applications of granules by hand or with hand-operated equipment such as a belly 

grinder or rotary spreader and, as specified on the label, removal of any excess/uneaten bait after 

each feeding. 

Occupational Handler Exposure Data and Assumptions 

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. Each assumption and factor is detailed below on an individual basis. 

For more detai ls, see the HED occupational and residential exposure assessment (Crowley, 2015 

- 0429981). 

Application Rate and Amount of Product Handled: 

As outlined in Table 3.3. l, the application rate used in this assessment is based on the product 

label specifying a maximum rate of 1 ounce of product per 5 pigeons. Applying 0.5% nicarbazin 

will result in an application rate of approximately 0.0000625 lb ai per pigeon. For the purposes 

of risk assessment it is assumed that an entire single product (i.e., a 30 lb bag) is used per day, or 

approximately 0.15 lb nicarbazin. This would treat approximately 2,400 pigeons. 

Unit Exposures: 

It is the policy of HED to use the best available data to assess handler exposure. Sources of 

generic handler data, used as surrogate data in the absence of chemical-specific data, include 

PH ED 1.1 and the ORETF database. Some of these data are proprietary (e.g., ORETF data) and 

subject to the data protection provisions of FIFRA. The standard values recommended for use in 

predicting handler exposure that are used in this assessment, known as "unit exposures", are 

outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table3

", 

3 Available: http://www2.epa.gov/sites/production/files/20 15-09/documents/handler-exposure-table-20 15.pdf 

Page 12of19 
Nicarbazin Draft Risk Assessment DP No. 0427303 

which, along with additional information on HED policy on use of surrogate data, including 

descriptions of the various sources, can be found at the Agency website4. 

Exposure Duration: 

HED typically classifies exposures from 1 to 30 days as short-term and exposures 30 days to six 

months as intermediate-term. Exposure duration is determined by many things, including the 

exposed population, the use site, the pest pressure triggering the use of the pesticide, and the 

cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe 

that occupational handlers will not apply the same chemical every day for more than a onemonth time frame; however, there may be a large agribusiness and/or commercial applicators 

who may apply a product over a period of weeks (e.g., completing multiple applications for 

multiple clients within a region). Thus, both short- and intermediate-term exposures are 

anticipated for nicarbazin; long-term exposures are not expected. 

Mitigation/Personal Protective Equipment: 

The nicarbazin label requires a long-sleeved shirt, long pants, shoes, socks and gloves. For the 

purposes of risk assessment, the gloves are assumed to be chemical-resistant, although, per 

standard HED practice, risk estimates are also provided at baseline work attire (i.e., no chemicalresistant gloves or other PPE). Inhalation exposure is assessed assuming no respiratory 

protection. 

Occupational Handler Non-Cancer Exposure and Risk Estimate Equations 

For the algorithms used to estimate non-cancer exposure and dose for occupational handlers see 

Crowley, 2015 (0429981). 

The standard body weight for the general population (80 kg) was used for all exposure scenarios 

covered in this risk assessment since the endpoints selected were not developmental and/or fetal 

effects. 

Combining Exposures/Risk Estimates 

Dermal and inhalation risk estimates were combined in this assessment, since the toxicological 

effects for these exposure routes were similar. Dermal and inhalation risk estimates were 

combined using the following formula: 

Tola/ MOE = Point of Departure (mg/kg/day) 7 Combined Dermal + Inhalation dose (mg/kg/day) 

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates 

Based on the label-required work attire and PPE, and the assumption that the required gloves are 

chemical-resistant, no risk estimates of concern from combined dermal and inhalation exposure 

were identified (i.e., all MO Es are 2'.. 1000). 

4 A vai lab le: http:/ /www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupat ional-pesticide-hand lerexposure-data 

Page 13of19 
Nicarbazin Draft Risk Assessment DP No. 0427303 

Table 12.1.1 presents detailed exposure and risk calculations. 

F 12. 1. 1. Summar)'. of Occuoational Handler Risk Estimates fo r Nicarbazin - - --

I Dermal Inhalation Combined 

Amount Unit Exposure ' MOE5 

Exposure Equipment App Rate 1 Handled/Area _ (ug/lb ai)3 Dose (mg/kg/day)4 Un it Dose (LOC = 1000) Scenario Exposure Treated2 

SL/NG SL/G SL/NG I SL/G (ug/lb ai)3 (mg/kg/day)4 SL/NG/ SL/G/NR NR 

Hand I I I Loading I dispersal 104000 71000 0.195 0.134 470 0.00088 930 1.400 

applying I I -

10,.lof Belly 0.0000625 2400 pigeons 10000 9300 0.0 188 0.0175 62 0.00012 9,500 9.900 nulcs to grinder _ lb ai/pigcon (entire 30 lb 

paved bag) -- -

oncrctc Rotary 440 240 0.00083 0.00045 10 0.0000 19 220,000 380,000 

areas spreader ·- I Based on registered label on registered labels ouilincd in Table 3.3.1. 

2 Exposure Science Advisory Council Policy #9.1 and infom1ation provided on labels 

3 13ased on the ··occupational Pesticide I landler Unit Exposure Surrogate Reference Table"" (September 20 I 5). SL = single layer (long-slec\le shin. pants. shoes/socks NG = no gloves. G = glO\ cs. 

NR = no c~pirator. 

4 Dcrmal/lnlmlauon Dose = Unit Exposure (11gflb a1) • Conversion Factor (O.OOl mgf11g) • Application Rate ' Arca Treated ~ 100°0 absorption + BW (kg). 

S Combmed MOE= POD (mg/kg/day) + [Dermal Dose (mg/kg/day + Inhalation Dose (mg/kg/dar)J 

Page 14of 19 
12.2 Occupational Post-application Exposure/Risk Estimates 

HED uses the tem1 post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-appli cation exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical's degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure. 

Given the uses of nicarbazin, after application and bait removal, occupational post-application 

exposure is not expected because residues on concrete/paved areas are expected to be limited, 

nor are any worker activities expected that would involve significant hand or body contact with 

any residues. Therefore, any applicable restricted-entry intervals (REls) for nicarbazin would 

default to technical grade active ingredient acute toxicity-based requirements. 

13.0 Public Health and Pesticide Epidemiology Data 

Both the OPP Incident Data System (IDS) and the Centers for Disease Control and 

Prevention/National Institute for Occupational Safety and Hea lth (CDC/NIOSH) Sentinel Event 

Notification System for Occupational Risk-Pesticides (SENSOR) databases were consulted for 

pesticide incident data on nicarbazin. The purpose of the database search is to identify potential 

patterns in the frequency and severity of the health effects attributed to nicarbazin exposure. 

Nicarbazin is not included in the Agricultural Health Study (AHS), and therefore does not 

provide additional incident information. 

For the Main IDS, from January 1, 2010 to February 4, 2015, there were no incidents reported 

involving nicarbazin. In Aggregate IDS, from January 1, 20 I 0 to February 4, 2015, there were 3 

incidents reported involving nicarbazin. These incidents were classified as minor severi ty. 

Overall, there are few incidents reported to IDS involving nicarbazin. The review of SENSORPesticides 1998-20 11 identified no cases involving nicarbazin. 

Based on the low frequency and severity of incident cases reported for nicarbazin in both IDS 

and SENSOR-Pesticides there does not appear to be a concern at this time that would warrant 

further investigation. The Agency will continue to monitor the incident infonnation and if a 

concern is triggered, additional analysis will be included in the risk assessment. 

14.0 References 

14.1 HED Memoranda 

HED Memoranda Releva nt to Registration Review. 

Author Barcode Date Title 

M. Crowley 0429981 I O-Nov-2015 Nicarbazin. Occupational and Residential Exposure and Risk 

Assessment for Registration Review. 

E. Evans and S. Recore 0427460 26-May-20 15 Niearbazin: Tier I Review of Human Incidents 
Nicarbazin Draft Risk Assessment OP No. 0427303 

HED Memoranda Relevant to Registration Review. 

Author Bar code Date Title 

R. Bever TXR# 005726 1 2 l-Oct-20 15 Nicarbazin: Summary of Hazard and Science Policy Council 

(HASPOC) Meeting of September 17. 2015: Recommendations 

on the requirement fo r a 90-day oral, 90-day dermal toxicity 

study, subchronic inhalation toxicity study. developmental 

rabbit study. neurotoxicity battery (acute and subchronic 

studies). and an immunotoxicity study 

14.2 Published Literature and Other Documents 

European Food Safety (EFSA) Journal (20 10). Scientific Opinion on the safety and efficacy of 

Koffogran (nicarbazin) as a feed additive for chickens for fattening. 8(3): 155 1. 

U.S. EPA (2005). Pesticide Fact Sheet: Nicarbazin. Office of Prevention, Pesticides, and Toxic 

Substances (750 IC). 

Page 16 of 19 
Nicarbazin Draft Risk Assessment DP No. D427303 

Appendix A: Toxicity Profile and Executive Summaries 

A.l Toxicology Data Requirements 

Study requirements (40 CFR 158.340) for nicarbazin are presented below. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used. 

T est 

Required 

870.1100 Acute Ora l Toxicity ...................................................... yes 

870.1200 Acute Dermal Toxicity .................................................. yes 

870.1300 Acute Inhalation Toxicity ............................................. yes 

870.2400 Primary Eye l1Titation ................................................... yes 

870.2500 Primary Dermal Irritation .............................................. yes 

870.2600 Dermal Sensitization ..................................................... yes 

870.3100 Oral Subchronic (rodent) .................. ............................. CR 

870.3150 Oral Subchronic (nonrodent) ......................................... no 

870.3200 28-Day Dermal .............................................................. no 

870.3250 90-Day Dermal .............................................................. yes 

870.3465 90-Day Inhalation ......................................................... CR 

870.3700a Developmental Toxicity (rodent) .................................. yes 

870.3700b Developmental Toxicity (nonrodent) ............................ yes 

870.3800 Reproduction ................................................................. yes 

870.4 lOOa Chronic Toxicity (rodent) .............................................. no 

870.4200a Oncogenicity (rat) ......................................................... no 

870.4200b Oncogenicity (mouse) ................................................... no 

870.5100 Mutageniciry- Gene Mutation - bacterial .................... yes 

870.5300 Mutagenicity- Gene Mutation - mammalian ............... yes 

870.5375 Mutagenicity- Structural Chromosomal Aberrations .. yes 

870.5395 Mutagenicity- Other Genotoxic Effects ....................... no 

870.5550 Mutag,enicity- Unscheduled DNA Synthesis no 

870.6 100a Acute Delayed Neurotox. (hen) ..................................... CR 

870.6200a Acute Neurotox. Screening Battery (rat) ....................... yes 

870.6200b 90-Day Neuro. Screening Battery (rat) ......................... yes 

870.6300 Develop. Neuro ............................................................. CR 

870.7485 General Metabolism ...................................................... yes 

870.7600 Dermal Penetration ....................................................... CR 

870.7800 lmmunotoxicity ............................................................. yes 

1

Study not required. See hazard identification/toxicology section for explanations. 

CR = Conditional ly Required 

Page 17of19 

Technical 

Satisfied 

yes 

no 1 

yes 

yes 

yes 

yes 

no1 

no 

no 

no1 

no1 

yes 

no1 

yes 

yes 

no 

no 

yes 

yes 

yes 

no 

no 

no 

no 1 

no 1 

no 

yes 

no 

no 1 
Nicarbazin Draft Risk Assessment 

A.2 Toxicity Profiles 

Table A.2.1: Acute Toxicity Profile for Nicarbazin 

G uideline Study Type MRID #(S) No. 

81-1 Acute Oral [rats] 464164 13 870.1000 

81-2 Acute Inhalation [rats] 464 164 15 870.1200 

8 1-4 Primary Eye Irritation 464164 16 870.2400 [rab~ - - -- 8 1-5 Primary Dermal Irritation 464 164 17 870.2500 [rabbits] 

8 1-6 Dermal Sensitization 464 16418 870.2600 [guinea pigs] -

Ta ble A.2.2: Toxicolo!!v Profile Table: Nicarbazin 

Type of Study Title 

study/ 

G uideline 

82-l a 90-Day Oral Toxicity, Rat 

870.3100 

NIA 90-Day oral toxicity, Rat 

Nicarbazin 

NI A 90-Day ora l toxicity, Rat 

DNC 

82-2 90-Day Dermal 

870.3200 

870.3465 90-day Inha lat ion 

83-3a Developmental toxicity, Rat 

870.3700a Acceptable/Non-G uide line 

3:1 DNC: HDP 

83-3b Developmental toxicity. Rabbit 

870.3700b 

j N icarbazin 

MRID 

NI A 

EFSA 

20 10 

EFSA 

2010 

NA 

NA 

46416421 

EFSA 

20 10 

DP No. D427303 

Res ults Toxicity Category 

LDso > I 0,000 mg/kg IV 

LCso > 0.147 mg/L IV 

Moderate Irritant Ill 

Non-Irritant IV 

Not a sensitizer I I 

Results/Comments 

HED detennined that the study is not 

required. 

NOA EL not determined 

LOAEL= 181 mg/kg/day, based on decreases 

in body weights, erythrocytes, hemoglobin, 

and hematocrit. Increases in blood urea 

nitrogen and plasma creatinine. Increases in 

several relative organ weights. Tubular 

degeneration in the kidney and degeneration 

in the seminiferous tubule - NOA EL = 709 mg/kg/day 

No effects were identified. 

HED dete1mined that the study is not 

requ ired. 

HED determined that the study is not 

required. 

Maternal NOA EL = 200 mg/kg/day 

Maternal LOAEL = 600 mg/kg/day based on 

Decreased body weight in dams 

Developmental NOAEL = 200 mg/kg/day, 

developmenta l toxicity was not noted at the 

dose levels tested. 

Maternal NOAEL: 60 mg/kg/day 

Page 18 of 19 
Nicarbazin Draft Risk Assessment DP No. D427303 

Table A.2.2: Toxicolo!?.V Profile Table: Nicarbazin 

Type of Study Title MRID Results/Comments 

study/ 

Guideline 

Maternal LOAEL: 120 mg/kg/day based on 

lo bu lat ion of the Ii ver. 

Developmental NOA EL: > 120 mg/kg/day 

83-4 Reproduction (2-generation), Rat 46416422 NOAEL > 400 mg/kg/day 

870.3800 Acceptable/Non-Guideline 

No effects were identified. 

DNC:HDP 

3: I 

83-1 a I Chronic feeding, Rat 464 164 19 NOAEL > 400 mg/kg/day 

870.41 OOa Acceptable/Non-Guideline 

No effects were identified. 

DNC:HDP 

3: I 

83-lb Chronic feeding, Dog 464 16420 NOAEL > 400 mg/kg/day 

870.41 OOb Acceptable/Non-Guideline 

No effects were identified. 

DNC:HDP 

3: I 

84-2 

I 

Ames mutagenicity 46416423 Negative 

870.5100 Acceptable/Non-Guideline 

84-2(b) Micronucleus Assay (CD- I Mice) 46416424 Negative 

870.5375 Acceptable/Non-Guideline - 84-2 DNA Damage (HI 7Rec and 46416423 Negative 

870.5550 M45Rec) 

Acceptable/Guide Ii ne 

870.6200 Acute Neurotoxicity, Rat NA HED determined that the study is not 

required. 

90 day Feeding Subchronic NA HED determined that the study is not 

870.6200 Neurotoxicityscreening battery, Rat required. 

Metabolism, Rat 4315350 1 Nicarbazin did not appear to be well 

85-1 Acceptable/Guideline absorbed, and was partially metabolized as 

870.7485 both metabolites and parent compound were 

identified erimaril ~ in the feces. 

870.7800 lmmunotoxicity NA HED determined that the study is not 

required. I 

Page 19 of19