### Page **1** of **21 UNITED STA** **TES ENVIRONMENTA L PROTECTION A**  **GENCY**

**WA SHINGTON, D.C. 20460**  **OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION**  

### MEMORANDUM **DATE:** December 14 , 201 5 **SUBJECT: Chlorophacinone**  **.** Human Health Scoping Document in Support of Registration Review. **PC Code:** 06770 7 **DP Barcode:** D 426549 **Decision No.:** 502937 **Registration No. :**  NA **Petition No.:** NA **Regulatory Action:** Registration Review Scoping Document **Risk Assessment Type:** NA **Case No.:** 2100 **T XR No.:**  NA **CAS No.:** 3691

- 35

- 8 **MRID No.:** NA **40 CFR:** NA **FROM:** Barry

O’Keefe , Senior Biologist Vincent Chen, Toxicolo gist Risk Assessment Branch III (RAB 3 ) Health Effects Division (7509P) **THR OUGH**  **:** M atthew Crowley , Biologist

Chemistry

and Exposure Branch (CEB) Health Effects Division (7509P) Chris Schlosser, Biologist Risk Assessment Branch V I (RAB6) Health Effects Division (7509P) Christine Olinger, Branch Chief Risk Assessment Branch III (RAB3) Health Effects Division (7509P) **TO:** Christina Motilall , Chemical Review Manager

Thomas Moriart y , Team Leader Neil Anderson , Branch Chief Risk Management and Implementation Branch 1 (RMIB 1 ) Pesticide Re

- Evaluation Division ( PRD ) (7508P)

### Page **2** of **21 Executive Summary**  Following is the Health Effects Division’s (HED ’s ) human health scoping document for the rodentic ide chlorophacinone to support Registration Review. To evaluate the scope of work necessary to support Registration Review, HED has considered previous risk assessments for chlorophacinone ; updates to its toxi city, exposure , and usage databases ; and the latest Agency science policy

and risk assessment methodologies. The most recent HED assessment for chlorophacinone is the HED Chapter of the Reregistration Eligibility Decision (RED) Document co mpleted in 1997 ( J. Redden, 04/25/1997 ). Chlorophacinone, an indandione, is a first generation anticoagulant rodenticide that disrupts the vitamin K cycle necessary for blood

- clotting factors to function. The toxicity database supports the mechanism of action by demonstrating that animals exposed to chlorophacinone have increased blood coagulation times and mortality . Chlorophacinone is highly toxic through oral, dermal, and inhalation routes of exposure. Chorophacinone is formulated into numerous baits in packs, blocks, granulars, pellets, tablets, grains, granules, tracking powders/dusts, and impregnated materials. The toxicology

database is adequate for risk assessment of most currentl y registered formulations and use patterns, with the exception of tracking powder formulation uses. A 90

- day subchronic inhalation toxicity study is still required , due to expected higher exposures from the tracking powder formulation products. For the tracking powder products, it is difficult to determine the specific use pattern and maximum application rates from the registered labels. It is therefore difficult to assess and estimate the inhalation exposure risks from these products. As part of Registration Review, toxicity endpoints, PODs, and uncertainty factors will be re

evaluated according to current HED approaches in hazard characterization

. Occupational and residential handler dermal and inhalation exposures are possible from existing uses of chlorophacinone. Residential post

- application exposures to small children should not be possible for those products that are in childproof tamper resistant packaging; however, a few products are not in tamper resistant packaging and tracking powder products may be an exposure concern for small children

. Dermal and inhalation exposure s are possible for occupational and/or residential handlers as they refill bait stations, distribute products into rodent burrows, as they apply tracking powders, or as they load and apply broadcasted products to orchards. At the time of Registration Review, HED will reevaluate the points of departure , toxicity endpoints, and uncertainty factors u sed for risk assessment purposes

. Based upon that reevaluation, HED will determine if occupational and residential handler exposure risk assessments are needed

. Additionally , in order to adequatel y and appropriately assess occupational exposures from the use of tracking powders at the time of Registration Review, the registrant will need to provide more information on the use pattern
.

### Page **3** of **21 I**  **ntroduction** Chlorophacinone, an indandione, is a first generation anticoagulant rodenticide that disrupts the vitamin K cycle necessary for blood

- clotting factors to function. Chl orophacinone is formulated into numerous baits in packs, blocks, granul e s, pellets, tablets, grains, tracking powders/dusts, and impregnated materials (e.g., EPA Reg. Nos
. 7173

- 287 and 7173

- 289)

. Most of the end

- use products contain 0.005% active ingredient (ai). However, the two tracking powder products contain 0.2% ai. The labelled target pests are rats, mice, and pocket gophers . Use sites include in and around residential, industrial, and agricultural buildings; rangeland ; residential lawns ; golf courses ; orchards ; and non- crop areas. Application equipment include s spoons, scoops, probe dispensers, burrow builders, dusters

. Application rates are numerous and vary widely depending upon formulation and product ty pes. The most recent HED assessment for chlorophacinone is the HED Chapter of the Reregistration Eligibility

D ecision (RED) Document co mpleted in 1997 (J. Redden, 04/25/1997). In 2008, the Agency

issued a risk mitigation decision for ten rodenticides, of which chlorophacinone was included. The mitigation decision set restrictions in order to minimize exposure to children, wildlife and domestic animals. The risk mitigation decision does not appl y to rodenticide field (non

- commensal rodents) uses or tracking powder products.

 Consumer

- based products (≤ 1 lb.), o Second

- generation anticoagulants are prohibited as well as loose baits/pellets/meal as a form for above ground outdoor uses. o 

### When applied outdoors above ground and in areas accessible to children, non - target wildlife or domestic animals, baits must be contained in bait stations. o 

### Products for use outdoors and above

- ground must be placed within 50 feet of a building.  

### Professional

- based products o 

### Must be sold in quantities of ≥ 4 lbs. (first

- generation anticoagulants/non

anticoagulants), ≥ 8 lbs. (second

- generation anticoagulants; agricultural building use) and ≥ 16 lbs. (second generation anticoagulants; above ground outdoor use) o 

### May not be offered for sale in consumer stores (hardware, grocery , etc.). o 

### Must also be placed within 100 feet of a structure (fence and perimeter baiting beyond 100 feet of a man

- made s tructure are prohibited) when used outdoors and above ground, see 50 foot Document Clarification Letter to Bell (03.20.12) (signed) in docket number EPA

- HQ

- OPP

- 2006

- 0955

- 0820 found at www.regulations.gov. o 

### For uses of first

- generation or non

- anticoagulants, product labels require bait stations if children, wildlife or domestic animals may be exposed. o 

### For uses of second

- generation anticoagulants, labels require bait stations for all outdoors above grounds placements and/or indoor placements where children, wi ldlife or domestic animals may be exposed.

### Page **4** of **21** Several of the chlorophacinone products are currently registered as restricted use pesticides (RUPs). Products intended for occupational use are packaged as 4 pounds (lbs) or more. The majority of chlorophacinon e products are applied using tamper resistant bait stations, which are required for all rodenticides where children and pets may be present per 2008 anticoagulant rodenticide mitigation. This is , however, one chlorophacinone end use product that is applie d to orchards b y ground broadcast equipment at a maximum rate of 2 0 lb of product per acre or 0
. 0 0 1 lb active ingredient (ai) per acre in post

- harvest fruit tree orchards. Also, tamper resistant bait stations are not required for burrow, canop y, and tracking powder applications. Inaddition, for chlorophacinone, there are two registered products, EPA Reg. Nos. 7173

- 287 and 7173

- 289, that do not appear to adhere to these mitigation stipulations, since they are labelled for non

- tamper resistant bait station s. See use profile table in the appendix (Attachment 1 ) for more information on application rate and application methods of chlorophacinone products. Refer to Attachment 2 (Table A.2 ) for the chemical identity and Attachment 3 (Table A.3 ) for the physiochemical properties of chlorophacinone

. **Hazard Identification/Toxicology** The toxicology

studies available for risk assessment include an acute toxicity battery ; subchronic oral toxicity

studies in rats; a subchronic dermal toxicity study in rabbits; prenatal developmental toxicity studies in rats and rabbits; a battery of mutagenicity

studies; a companion animal safety study in rats; and a metabolism and pharmacokinetic study in rats. The available absorption , distribution , metabolism , an d excretion (ADME ) database enabled evaluation of s ys temic availability ; the database included evaluations of rats exposed to single or repeated oral doses. In the single oral dose evaluation, chlorophacinone absorption peaked between 4 and 6 hours with a half

- life (T 1⁄2 

### ) of ~10 hours; additionally , chlorophacinone was sy stemicall y distributed and found in the highest concentration within the liver and kidneys. In the repeat oral dose evaluation, blood concentration measurements indicate that chlorophacinone bioaccumulation occurred in the test animals; additionally, chlorophacinone excretion evaluated over 4 days was predominately through feces (94.7

- 108.6% administered dose) with a far lesser excretion (<1% administered dose) through urine and respiration. In a biliary excretion assay , chlorophacinone excretion evaluated for 8 hours post

- dosing through bile was significant (~26% administered dose). In the repeat ed dose oral and dermal toxicity studies with rats, the most sensitive effect was an increase in coagulation times observed at the lowest dose with mortality occurring at higher doses. In the oral toxicity study, treated animals exhibited dose

- related increases in coagulation times starting at 10 mg/kg/day (28% increased coagulation time) and led t o mortality . In the dermal toxicity

study , treated animals exhibited dose

- related increases in coagulation times (i.e., PT and APTT) starting at 0.4 mg/kg/day (28% increase in PT and 61% increase in APTT). The toxicity in both the oral and dermal toxicity studies support the pesticide’s mechanism of action as an anticoagulant. In the rat prenatal developmental toxicity study , there was evidence for increased susceptibility ; developmental toxicity

(i.e., increased incidences of hydroureter, distended ureter , and total

### Page **5** of **21** ureter anomalies) occurred at doses lower than those that caused maternal toxicity (i.e., dose

related increases in mortality). In the rabbit prenatal developmental toxicity study, there was no evidence for increased susceptibility ; maternal toxicity (i.e., increased coagulation times) occurred at doses lower than those that caused developmental toxicity

. Although increased susceptibi li ty

was seen in the developmental rat study , there is no residual uncertainty for pre and/or post

- natal toxicity since there are no food uses for chlorophacinone, and thus no potential for human dietary

exposure. There is no concern for mutagenicity as demonstrated b y in vivo and in vitro assays. Chlorophacinone has high acute toxicity via the oral (Toxicity

Category I), dermal (Toxicity Category I), and inhalation (Toxicity Category I) routes of exposure; is not a dermal irritant (Toxicity Category IV) or eye irritant (Toxicity Category IV); and i s not a dermal sensitizer. Please refer to Attachment 4 for the summary of the toxicity

endpoints and points of departure (PODs) and Attachment 5 for the complete toxicity profile table. HED ’s Hazard and Science Policy Council (HASPOC) based on hazard and exposure considerations has granted waiver to the following studies: 1) the 90

- day oral toxicity

in non

rodents study : 2) the reproduction and fertility effects study ; 3) the acute neurotoxicity screen battery ; 4) the subchronic neurotoxicity screening battery ; and 5) the immunotoxicity study since chlorophacinone is acutely toxic at low doses with a distinct mechanism of action (i.e., disrupting blood clotting) that is unlikely to have different toxicity in repeat oral dose studies ( TXR# 0057326 , U. Ha

biba, 12/15/2015 )

. However, the HASPOC has determined that a 90

- day subchronic inhalation toxicity study ( OCSPP 870.3465) is required based on the current use profile of chlorophacinone (TXR# 0057326 , U. Habiba, 12/15/2015 ) . Specifically , the 90

- day inhalation study will be used to assess potential risk from inhalation exposure to occupational handlers from the use of registered tracking p owder end use products

. Conclusions : The toxicology database is adequate for risk ass essment of most currently registered formulations and use patterns, with the exception of tracking powder formulation uses . A 90

- day subchronic inhalation toxicity study is required to assess risk via inhalation exposure from occupational use (i.e

. , tracking powder endues products)

. As part of Registration Review, toxicity endpoints, PODs, and uncertainty factors will be re

- evaluated according to current HED approaches in hazard characterization. **Residue Chemistry and Dietary Exposure**  All uses of chlorophacinone are non - food uses ; therefore, no tolerances are established or needed. In addition , a dietary exposure assessment from food is not needed. However, the broadcast application to orchards may result in the need for a drinking water assessment in Registration Review. Conclusions : A dietary

exposure assessment is not anticipated to be needed during Registration Review unless there are drinking water exposure estimates.

### Page **6** of **21 Residential Exposure**  Several chlorophacinone end use products are labelled for use in residential settings. Some of these products are labelled as restricted use pesticides (RUP) , but some are not. Based upon existing labels , residential handlers can be exposed to chlorophacinone b y the dermal and inhalation routes during the refi lling of bait stations with pelleted, tableted, or granular products

. Residential handler exposures have not previously been quantitativel y assessed. However, for tracking powders , post
- application episodic incidental oral exposure may be possible. There is no residential handler exposure for tracking powders because they are RUPs. Residential exposure is expected to be short

- term onl y; intermediate

- term exposures are not likely because of the intermittent nature of applications in residential settings

. For short

- term inhalation exposures, the 1997 HED RED chapter did not establish a point of departure for use in computing risk estimates. Therefore, as a point of reference for short

- term inhalation exposures HED recommends the point of departure and endpoints from an oral study, the rabbit developmental toxicity study ; i.e. a POD of 0.005 mg/kg/day (maternal NOEL) based on elevated prothrombin and activated partial thromboplastin times seen at 0.01 mg/kg/day

. Use of this POD may

result in risk estimates of concern for the tracking powder products. During Registration Review, residential handler exposure from loading loose formulations into bait stations will need to be assessed. Additionally , f or tracking powders, an episodic incidental oral post
- application assessment may be needed during Registration Review ; however, further investigation/information should be considered for these scenarios to determine if the assessment is indeed applicable. Non Occupational Spray

Drift or Volatilization Residential by stander exposures resulting from off

- site transport (i.e., spray

drift or volatilization) is unlikely due to how chlorophacinone is formulated and used except for the granular broadcast applications of chlorophacinone in commercial orchards ( and others as appropriate). The approach is outlined in the revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs)

– Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This guidance indicates that drift is not a concern when solid materials are applied (e.g., b y aerial equipment). Therefore, onl y the potential for volatilization will be evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrentl y. In terms of volatilization, the agency has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the Agency will utilize this anal ys is to determine if data (e.g., flux studies or route

- specific inhalation toxicological studies) o r further anal ys is is required for diphacinone. Conclusions: Short

- term residential handler dermal and inhalation exposures from loading loose formulations into bait stations will need to be assessed during Registration Review. At the time of Registrati on Review, HED will reevaluate the points of departure , toxicity endpoints, and uncertainty factors currently u sed for risk assessment purposes

. Based upon that reevaluation, HED will determine if a risk assessment is necessary for residential handler exp osure s .

### Page **7** of **21** Additionally , at the time of Registration Review, HED will determine if an episodic incidental oral post

- application assessment is needed for tracking powder products. **Aggregate Risk Assessment**  In accordance with the Food Quality Protection Act , HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. For chlorophacinone, there are no dietary food exposure . However, drinking water exposure may be a possibility

due to the ground broadcast applications to fruit tree orchards. For adults, the pathways leading to exposure are residential handler dermal and inhalation exposure s. Residential handler exposure and quantitative drinking water estimates for chlorop hacinone may be aggregated if deemed appropriate at the time of Registration Review. A short

- term aggregate risk assessment is not anticipated for children , unless there is drinking water exposure, and/or if it is determined that an episodic incidental oral post

- a pplication assessment is needed for tracking powders. Whether this post

- application assessment is needed for tracking powders, or not, must be determined during Registration Review through further investigation/information. Chronic exposure from the resi dential pathway is not anticipated based on the current chlorophacinone use pattern (i.e., tamper resistant packaging)

. Conclusions : If computing drinking water estimates is deemed appropriate from the ground broadcast use in fruit orchards, then a short

- term a ggregate assessment s would be needed during the Registration Review. Additionally , if an episodic incidental oral post

- application assessment is needed for tracking powder products, then a short

- term a ggregate assessment for small children would be needed during the Registration Review. **Occupational Exposure** Occupational Handler Exposure O ccupational handler exposure s have not previously been quantitatively assessed. H andler s can be exposed by

the dermal and inhalation routes at short

- or interm ediate

- term durations. As detailed above in the residential exposure section, the 1997 HED RED chapter did not establish a point of departure to estimate handler risks . Therefore, HED recommends using the POD and endpoints from the oral rabbit developmental toxicity study ; i.e. a POD of 0.005 mg/kg/day

(maternal NOEL) based on elevated prothrombin and activated partial thromboplastin times seen at 0.01 mg/kg/day

. For the tracking powder products, it is difficult to determine the specific use pattern and maximum application rates from the registered labels. Itis therefore difficult to assess and estimate the dermal and inhalation exposure risk s from these products . These are restricted use products. In order to adequately and appropriatel y assess these exposures at the time of Registration Review, the registrant will need to provide information on use pattern , including application rate s . Additionally , based upo n the tracking powder registrations of chlorophacinone , HED still requires a 90

- day inhalation toxicity study (TXR# 0057326 , U. Habiba, 12/15/2015 )

.

### Page **8** of **21** Occupational Post

- Application Exposure There is no anticipated occupational post

- application exposure to the current use pattern of chlorophacinone. Conclusions : Occupational handler dermal and inhalation exposures are possible from existing uses of chlorophacinone. During Registration Review, HED will reevaluate the points of departure , toxicity

endpoints, and uncertainty factors u sed for risk assessment purposes

. Based upon that reevaluation, HED will update the occupational handler risk assessments. Additionally , in order to adequatel y and appropriately assess exposures from the use of tracking powders at the time of Registration Review, the registrant will need to provide information on the use pattern and application rate s . **Public Health and Pesticide Epidemiology Data** As part of the Rodenticide Risk Mitigation Decision (RMD), and the subsequent Notice of Intent to Cancel (NOI C), the Environmental Protection Agency ’s Office of Pesticide Programs’ Pesticide Re

- evaluation Division requested an analy sis of human incidents involving exposure to rodenticides in 2011 (D395567, S. Recore , 10/28/2011) and then updated in 2015 ( D 426573 , S. Recore, 11/24/2015 ). S ummary report s listing incidents for chlorophacinone are reported to the OPP Incident Data S ys tem (IDS), the National Pesticide Information Center (NPI C ), the Centers for Disease Co ntrol and Prevention/National Institute for Occupational Safety and Health (CDC/NI OSH), Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR), and Agricultural Health Study (AHS) databases. For the M ain OPP Incident Data Sy stem (IDS) , from January 1, 2010 to May

27, 2015, there was 1 incident reported for chlorophacinone in the database. This incident involved an adult female suicide attempt and was classified as moderate severity

. In Aggregate IDS, from January 1, 2010 to May 27, 2015 , there was 1 incident reported involving chlorophacinone

. This incident was classified as having no or unknown effects. Overall, there are few incidents reported to IDS involving chlorophacinone. A query of the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification Sy stem for Occupational Risk

Pesticides (SENSOR)

- Pesticides from 1998

- 2011 , identifies 12 cas es involving chlorophacinone

. Of these, nine cases involv e d chlorophacinone alone, as opposed to incidents involving chlorophacinone in combination with other active ingredients . One case was moderate in severity and eight cases were low in severity. Eight of the nine cases involved inhalation of the product “ dust

. ” The moderate severity

case occurred after an insulation worker was working in a school attic. The insulation work was generating dust in the attic. That evening the case experience d shakiness, fever and vomiting but felt better after a few hours. The case experienced respiratory , neurological, gastrointestinal, renal, and cardiovascular

### Page **9** of **21** sy mptoms following exposure. “Rat pellets” were found throughout the attic and the school but the workers were not notified of this. Eight cases experienced respiratory s ymptoms after exposure, and eight cases experienced neurological sy mptoms after exposure. Five cases experienced gastrointestinal s ymptoms. Eight cases were occupational and one case was a homeowner. The homeowner case occurred when the case opened a can of gopher bait and inhaled it, experienced shortness of breath and coughing and called Poison Control. The American Association of Poison Control Centers (AAPCC) is a non

-profit , national organization founded in 1958 that represents the poison control centers of the United States and the interests of poison prevention and treatment of poisoning. All of the calls to a poison control center are managed by

a medical professional trained to answer questions about poisons. AAPCC produces an annual summary report giving statistics and information on all the poisonings reported to PCCs in a calendar ye ar. Although AAPCC data was reviewed b y HED for the 2011 human incidents report ( D 395567 ) anal yz ing exposure to commensal rodenticides , it was not reviewed for this incident anal ys is. At the time of this report there is insufficient information available to determine if the mitigations have impacted the frequency of incidents occurring

. The most current AAPCC annual report available is for ye ar 2013 and the phase out of the remaining non

- compliant products began in June 2014 and was complete as of March 31, 2015

. However , AAPCC data is reviewed annuall y for reduction in reported rode nticide incidents as a Strategic Measure. For FY 2014 (using the 2013 AAPCC annual report data), there was a reduction of 17% incidents reported to the AAPCC annual reports compared to the number of rodenticide exposures to children ages 1 to 6 ye ars old in 2011. The reductions in child exposures are expected to become more prominent beginning in the 2016 AAPCC annual report; which will be reflected in the FY 2018 Strategic Measure. The target reduction for FY 2018 is to reduce rodenticide exposure incidents b y 75% in children ages 1 to 6 ye ars old. The Agricultural Health Study (AHS) is a high quality , prospective epidemiology study evaluating the link between pesticide use and various health outcomes , including cancer. The AHS includes private and commercial pesticide applicators and their spouses

. The commensal rodenticides are not included in the AHS. In order to minimize children and wildlife exposure to rodenticide products the 2008 RMD included risk mitigation measures requiring rodenticide products used in homes and marketed to general residential consumers be sold only with bait stations. Most rodenticide products complied with the mitigation measures required in the RMD as of June 4, 2011. The phase out production of the final 12 non

- compliant products began in June 2014 and production of these products stopped on December 31, 2014. Distribution to retailers ended March 31, 2015. Due to the fact that these safety mea sures were only recentl y full y implemented , there is insufficient information available to determine if the mitigations have impacted the frequency of incidents occurring. However, the Agency will continue to monitor the incident information and

### Page **10** of **21** during Registration Review provide an updated review of incidents, considering pre

- and post

mitigation incidents separatel y, when the information becomes available. **Tolerance Assessment and International Harmonization** There are no tolerances for chlorop hacinone. **Environmental Justice** 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 L o w - Income Populations," http://www.epa.gov/compliance/environmentaljustice/resources/policy /exec_order_12898.pdf

. As a part of every

pesticide risk ass essment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy , HED estimates risks to pesticide exposures that are based on activities in and around the home that involve pesticide use in a residential setting. Whenever appropriate, these non

- dietary exposures are calculated based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. **Cumulative** 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 chlorophacinone and any other substances and chlorophacinone does not appear to produce a toxic metabolite produced by 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 chemical s, 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/. **Human Studies** The risk assessment s HED anticipates being conducted during Registration Review for chlorophacinone will rel y in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED) , the Agricultural Handler Exposure Task Force (AHETF) database , and the Outdoor Residential Exposure Task Force (ORETF)

. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of

### Page **11** of **21** EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied , and there is no regulatory barrier to continued reliance on these studies

. **Data Defic**  **i e**  **ncies** The following toxicology data are needed to support the registered uses of chlorophacinone: 870.3465 Subchronic Inhalation Study A 90

- day subchronic inhalation study is required in order to adequatel y assess inhalation exposures from the use of tracking powders. **References Recent**  **Mem oranda Relevant to Registration Review of**  **Chlorophacinone. Author**  **DP/TXR # Date**  **Title Hum**  **an Health Risk Assessment**  **s** J. Redden Not Available 04/25/1997 HED Chapter of the Reregistration Eligibility Decision Document (RED) for Chlorophacinone (Case No. 2100) **Incident Report** S. Recore D 426573 11 /24 /2015 Rodenticide: Tier I (Scoping) Revie w of Human Incidents and Epidemiology Assessment S. Recore D395567 10 /28 /20 1 1 Rodenticides Tier II : Review of Human Incidents **Hazard and Science Policy Council** U. Habiba TXR# 0057326 12/15/2015 Rodenticides: Summary of Hazard and Science Policy Council (HASPOC) Meeting on October 1, 2015: Recommendations on Data Requirements for Rodenticides. 

### Attachment **s** 1. Use Profile 2. Chemical Identity

Table 3
. Phy sicochemical Properties of Technical Grade Chlorophacinone Table 4
. Endpoint Selection Table 5 . Toxicity

Profile Tables 6 . Toxicology

Data Requirements Table

### Page **12** of **21 Attachment**  **1 Use	Profile	for	Chlorophacinone**  **Table A. 1**  **. Use Profile for Chlorophacinone.** Product Name EPA

Reg. No. Form

ulation % Active

Ingredient Target Pests Application Rate Tam per Resistant Bait Station Personal

Protective Equipment 1 Restricted

Use Pesticide AC Formula 90 Rodenticide 56

- 58 Granular 0.005 Norway rats, roof rats & house mice 4 oz place packs at 1 to 4

packs per placement Yes LSS, LP, SS, WG No AC Formula 90 Ready

- to
- Use Rodenticide 56

- 70 Pelleted/Tableted 0.005 Norway rats, roof rats & house mice 1.5 oz place packs at 3 to

10 place packs per placement Yes LSS, LP, SS, WG No Rozol ® Tracking Powder 7173

- 113 Tracking Powder 0.2 Norway rats, roof rats & house mice 1 to 2 oz per 2.5 ft2

indoors & in burrows leading into buildings NA LSS, LP, SS, WG, PE, D/M FR Yes

Rozol Pellets 7173

- 151 Pelleted/Tableted 0.005 Norway rats, roof rats & house mice Mice 1⁄4 to 1⁄2 oz per

placement up to 2 oz; Rats 4 to 16 oz per placement Yes LSS, LP, SS, WG No
Rozol ® Blue Tracking Powder 7173

- 172 Tracking Powder 0.2 Norway rats, roof rats & house mice 1 to 2 oz per 2.5 ft2

indoors & in burrows leading into buildings NA LSS, LP, SS, WG, PE, D/M FR Yes Rozol Pocket Gopher Bait 7173

- 184 Granular 0.005 Pocket Gophers 1⁄2 cup of bait per hole NA S, LP, SS, WG No
Rozol Vole Bait 7173

- 242 Pelleted/Tableted 0.005 Voles in Orchards, Nurseries & Tree Pla ntations Mice 1⁄4 to 1⁄2 oz per

placement up to 2 oz; Rats 4 to 16 oz per placement NA LSS, LP, SS, WG Yes

Rozol Mini Blocks 7173

- 243 Pelleted/Tableted 0.005 Norway rats, roof rats & house mice Mice 1 block per

placement up to 2 blocks. Rats 3 to 16 blocks per placement Yes LSS, LP, SS, WG No Rozol Pocket Gopher Bait II 7173

- 244 Pelleted/Tableted 0.005 Pocket Gophers 1⁄2 cup of bait per hole, 8 lb/A NA LSS, LP, SS, WG Yes Rozol Prairie Dog Bait 7173

- 286 Granular 0.005 Black

- Tailed Prairie Dogs 1⁄4 cup per burrow NA SS, G Yes Chlorophacinone Bait Station 7173

- 287 Impregnated Material 0.005 House Mice Bait Station **No** None No Chlorophacinone Block 0803 Bait Station 7173

- 289 Impregnated Material 0.005 House Mice Bait Station **No** None No Chlorophacinone 7173

- 293 Pelleted/Tableted 0.005 House Mice Bait Station, can refill Yes WG No

### Page **13** of **21 Table A.**  **1 . Use Profile for Chlorophacinone.**  Product Name EPA

Reg. No. Form

ulation % Active

Ingredient Target Pests Application Rate Tam per Resistant Bait Station Personal

Protective Equipment 1 Restricted

Use Pesticide Refillable Bait Station with bait blocks Rozol Pocket Gopher Bait III 7173

- 294 Pelleted/Tableted 0.005 Pocket Gophers 2/3 cup of bait per hole, 8 lb/A NA LSS, LP, SS, WG Yes Chlorophacinone Block 0803 Bait Station 7173

- 295 Pelleted/Tableted 0.005 House Mice Bait Station Yes None No
Rozol Mini Blocks 0803 7173

- 299 Pelleted/Tableted 0.005 Norway rats, roof rats & house mice Mice 1 block per

placement up to 2 blocks. Rats 3 to 16 blocks per placement Yes LSS, LP, SS, WG Yes Rozol Mini Blocks 0803 Refillable Bait Station 7173

- 303 Granular 0.005 House Mice 2 Bait Stations Yes None No
1 LSS = long sleeved shirt, S = shirt, LP = long pants, SS = shoes & socks, WG = waterproof gloves, PE = protective eyewear, D/M FR = dust/mist filtering respirator

### Page **14** of **21 Attachment**  **2 Chemical Identity**  **Table TABLE**  **A.2 .**  **C hlorophacinone**  **Nom enclature** 

. Chemical structure

Common name chlorophacinone IUPAC name 2

- [2

- (4

- Chlorophenyl)

- 1

- oxo - 2

- phenylethyl]indane

- 1,3

- dione CAS name 2

- [2

- (4

- chlorophenyl)

- 2

- phenylacetyl]

- 1H

- indene

- 1,3(2H)

- dione CAS registry number 3691

- 35

- 8

### Page **15** of **21 Attachment**  **3**
**Table A.3**  **. Physicochemical Properties of**  **C hlorophacinone**  **.** Parameter Value Reference Melting point 141

- 145 oC Rodenticide Cluster RED, 1998 Physical State Pale Yellow Microcrystalline Powder Density 0.58 g/cm2 Solvent solubility (g/L at 25oC) Water 0.002 Dichloromethane 30.2 Chloroform 28.7 Ethyl Acetate 3.08 Acetone 1.93 Diethyl Ether 1.13 Hexane 0.113 Methanol 0.109 Ethanol 0.074 Vapor pressure Negligible at 20 oC http://pubchem.ncbi.nlm.nih.go v/compound/chlorophacinone# section=Substances Dissociation constant, pKa 3.40 at 25 oC Octanol/water partition coefficient Log(P OW) 4. 22 Rodenticide Cluster RED, 1998 Stability Stable for 14 days at 54 oC

### Page **16** of **21 Attachment**  **4 Summary of Toxicity Endpoints and Points of Departure of**  **Chlorophacinone**
**Table A.4**  **.1 .**  **Summary of Toxicological Doses and Endpoints for use in Dietary and Non**  **- Occupational Human Health** 

**Risk Assessments Exposure Scenario**  **Point of**

**Departure (P o**  **D) Uncertainty /** 

**FQPA Safety Factors**  **RfD, PAD, Level**

**of Concern for Risk Assessment**  **Study and Toxicological Effects** Dermal Short Term (1

- 30 days) N OEL =

0.08 mg/kg/day UF A = 10x

UF H = 10x FQPA = 1 x Residential LOC

for MOE = 100 21

- Day Dermal Toxicity Study

–

Rabbits LOEL = 0.4 mg/kg/day Based on increased prothrombin times in both sexes on Day 21. Inhalation Short Term (1

- 30 days) Intermediate Term (1

- 6 months) NA UF A = 10x UF H = 10x FQPA = 1 x Residential LOC

for MOE = 100 The TESC says risk via inhalation is

not likely

- but the OREB chapter is requiring a respirator.
Cancer (oral, dermal, and inhalation) Cancer risk assessment was not been conducted because long

- term studies are not available and chronic exposure is not likely to occur. Point of Departure (P o D) = 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 relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = p otential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. **Table A**  **.4 .2**  **. Summary of Toxicological Doses and Endpoints for use in Occupational Human Health Risk Assessments**  **Exposure Scenario Point of** 

**Departure (P o**  **D) Uncertainty /** 

**FQPA Safety Factors**  **Level of Concern**

**for Risk Assess**  **me nt**  **Study and Toxicological Effects** Dermal Short Term (1

- 30 days) Intermediate Term (1

- 6 months) N OEL =

0.08 mg/kg/day UF A = 10x

UF H = 10x Occupational LOC

for MOE = 100 21

- Day Dermal Toxicity Study

–

Rabbits LOEL = 0.4 mg/kg/day Based on increased prothrombin times in both sexes on Day 21. Inhalation Short Term (1

- 30 days) Intermediate Term (1

- 6 months) NA UF A = 10x UF H = 10x Occupational LOC

for MOE = 100 The TESC says risk via inhalation is

not likely

- but the OREB chapter is requiring a respirator.
Cancer (oral, dermal, and inhalation) Cancer risk assessment was not been conducted because long

- term studies are not available and chronic exposure is not likely to occur. Point of Departure (P o D) = 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 relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### Page **17** of **21 Attachment**  **5 Toxicity Profile for**  **Chlorophacinone**
**Table A.5**  **.1 .**  **Acute Toxicity Profile Guideline**  **Study Type MRID (year) / Doses /**  **Classification Results**  870.1100 Acute Oral Toxicity

(Rat) 41875301 ( 1988 )

Gavage Doses (mg/kg): M: 0, 2.0, 3.2, 5.2, 8.2, 13.2, 21.0 F: 0, 2.0, 3.2, 5.2, 8.2, 13.2, 21.0 Acceptable / Guideline Toxicity Category: I LD 50 (mg/kg) : M = 3.15

F = 10.95 Combined = 6.26 870.1200 Acute Dermal

Toxicity (Rabbit) 41702801 ( 1990 )

Applied Dose (mg/kg): M: 0.25, 0.5, 0.75 Acceptable / Guideline Toxicity Category: I LD 50 (mg/kg): M = 0.329

F = NA 870.1300 Acute Inhalation

Toxicity (Rat) 41981102 (1991)

Inhalation Dose ( g/L): M: 1.33, 10.3, 11.5, 14.5 F: 1.33, 10.3, 11.5, 14.5 Acceptable / Guideline Toxicity Category: I LC 50 ( g/L): M = 7.0

F = 12.0 Combined = 9.3 870.2400 Acute Eye Irritation

(Rabbit) 41874001 (1989)

Applied Dose ( g): F: 0.1 Acceptable / Guideline Toxicity Category: IV No eye irritation for up to 72 hours.
870.2500 Acute Dermal

Irritation (Rabbit) 41702801 (1990)

Applied Dose (mg/kg): M: 0.25, 0.5, 0.75 Acceptable / Guideline Toxicity Category: IV Primary Irritation Score (PIS) = 0
870.2600 Skin Sensitization

(Guinea Pig) 41578601 (1990)

Applied Dose ( g): 0.003, 0.005, 0.01, 0.2 Acceptable / Guideline Not a dermal sensitizer

**Table A.5**  **.2 .**  **Repeat -**  **Dose and Other Toxicity Profile Guideline**  **Study Type MRID (year) / Doses /**  **Classification Results**  870.3100 90

- Day Oral

Toxicity in Rodents (Rat) 92018013 ( 1990)

Gavage Dose ( g/kg/day) : M: 0, 5, 10, 20, 40, 80, 160 F: 0, 5, 10, 20, 40, 80, 160 Acceptable / Guideline NOEL ( g/kg/day): M = 5 F = 5 LOEL ( g/kg/day): M = 10 F = 10 B ased on increased coagulation time for both males and females, with males more sensitive than females. 870.3150 90

- Day Oral

Toxicity in Non

Rodent s NA Study not needed at this time (TX R3 0057326 , U. Habiba, 12/15/2015 ) 870.3200 21/28

- Day

Dermal Toxicity (Rabbit) 42237402 ( 1992 )

Dermal Dose (mg/kg/day) : M: 0 .08, 0.40, 2.0 F: 0 .08, 0.40, 2.0 Acceptable / G

uideline Dermal Irritation

NOAEL (mg/kg/day) : M = NA F = NA LOAEL (mg/kg/day) : M = NA F = NA Systemic NOEL (mg/kg/day) : M = 0.08 F = 0.08 LOEL (mg/kg/day) : M = 0.4 F = 0.4 Based on increased prothrombin times in both sexes on Day 21. 870.3465 90

- Day

Inhalation Toxicity NA NA

### Page **18** of **21 Table**  **A.5 .2**  **. Repeat** **- Dose and Other Toxicity Profile**  **Guideline Study Type**  **MRID (year) / Doses / Classification**  **Results** 870.3700 Prenatal

Developmental Toxicity Study (Rat) 43349501 ( 1994)

Range Finding Study Gavage Dose ( g/kg/day) : F: 0 , 1, 5, 25, 50, 100, 200 Main Study Gavage Dose ( g/kg/day) : F: 0 , 12.5, 25, 50, 100 Acceptable / Guideline Maternal NO EL ( g/kg/day) = 5 0 LOEL ( g/kg/day) = 100 Based on mortality. Developmental NOEL ( g/kg/day) < 12.5 LOEL ( g/kg/day) = 12.5 Based on increased incidences of hydroureter, distended ureter, and total ureter anomaly. Prenatal Developmental Toxicity Study (Rabbit) 43570801 ( 1995)

Range Finding Study Gavage Dose ( g/kg/day) : F: 0, 1, 2, 5, 10, 50, 100 Main Study Gavage Dose ( g/kg/day) : F: 0 , 5, 10, 25, 75 Acceptable / Guideline Maternal NO EL ( g/kg/day) = 5 LOEL ( g/kg/day) = 10 Based on increased prothrombin and activated partial thromboplastin times in the preliminary range

- finding study (these measurements were not made in the main study). Developmental NOEL ( g/kg/day) = 10 LOEL ( g/kg/day) = 25 Based on the lack of sufficient fetuses/litters available for evaluation 870.3800 Rep roduction and

Fertility Effects NA Study not needed at this time (TX R# 0057326, U. Habiba, 12/15/2015) 870.4100 Chronic Toxicity in

Rodents NA Study not needed at this time (TX R# 0057326, U. Habiba, 12/15/2015) 870.4200 Carcinogenicity

(Mouse) NA Study not needed at this time (TX R# 0057326, U. Habiba, 12/15/2015) Carcinogenicity (Rat) NA Study not needed at this time (TX R# 0057326, U. Habiba, 12/15/2015) 870.5100 Bacterial Reverse

Mutation Test (Salmonella typhimurium ) 43284001 (1994)

Applied Dose ( μg/

plate ) : +S9: 1

– 5000

- S9: 0.5

– 5000 Acceptable / G

uideline Under the conditions of this assay, there was no

indication of any mutagenic activity in the test strains associated with exposure to chlorophacinone (analytically determined concentration: 101%). In the S. typhimurium strains at the highest dose levels there were adequate indications of cytotoxicity (reductions in numbers of revertants and/or reductions in the background lawn). It is concluded that there was no evid ence that chlorophacinone induced a mutagenic response in any strain at any nonactivated or S9

- activated dose level. 42937133 (1989) Applied Dose ( μg/

plate ) :  S9: 5, 16, 50, 158, 500 Acceptable / G

uideline There was no evidence of induced revertant colonies

over background at any dose tested, either with or without S9. 870.5300 in vitro Mammalian

Cell Gene Mutation Test ( Chinese Hamster Ovary (CHO) Cells ) 41611701 (1990)

Applied Dose ( g/mL) :  S9: 5

– 200 Acceptable / Guideline Test material doses ≥ 100 g/mL  S9 were cytotoxic. It is concluded that there was no indication of a mutagenic response from exposure to technical chlorophacinone under the conditions of this assay.

### Page **19** of **21 Table**  **A.5 .2**  **. Repeat** **- Dose and Other Toxicity Profile**  **Guideline Study Type**  **MRID (year) / Doses / Classification**  **Results** 870.5375 in vitro Mammalian

Chromosome Aberration Test (Human Lymphocytes) 43825601 (199 5 )

Applied Dose (μg/mL):  S9: 0, 6.25, 12.5, 25, 50 Acceptable / Guideline There were no biologically significant increases in incidences of chromosomally aberrant cells/dose level or mean number of aberrations/metaphase spread. The positive controls induced the expected high yields of metaphase spreads with chromosome aberrations. Based on the above considerations, it is concluded that chlorophacinone, at doses up to and including those as sociated with cytotoxicity (50 g/mL), di d not induce a clastogenic response in human lymphocytes under the conditions of this assay either in the presence or absence of S9. 870.5395 Mammalian

Erythrocyte Micronucleus Test (Mouse) 43285901 (1994)

Intraperitoneal Injection (mg/kg/day) : M: 0, 3.75, 7.5, 15 F : 0, 3.75, 7.5, 15 Acceptable / G

uideline There was no indication of any increased incidence of

micronucleated polychromatic erythrocytes (MPCEs) associated with exposure to chlorophacinone. Positive controls (which were sacrificed 24 hours after receiving a single oral dose of 80 mg/kg cyclophosphamide) showed significant increases in incidences of MPCEs. Although there was some variation between dose groups with respect to mean PCE:NCE ratios, this seems to have been due to considerable variation between individual animals (possibly an indication that some of these mice might have subsequently died if they had not been sacrificed) rather than a direct effect of exposure to chlorophacinone. 870.5550 Unscheduled DNA

Synthesis in Mammalian Cells in Culture (Rat Hepatocytes) 43018510 (1989)

Applied Dose (μg/mL): Run 1: 0.391, 1.24, 3.91, 12.4, 39.1 Run 2: 0.391, 1.24, 3.91, 12.4, 39.1, 124 Acceptable / Guideline There was no evidence of UDS induction at any tested concentration as measured by incorporation of tritiated thymidine into DNA (using liquid scintillation counting). 42937138 (1993) Applied Dose (μg/mL): 189.7, 600 Acceptable / Guideline The mean net nuclear grain count was below zero for both doses at both treatment times indicating no induction of UDS as tested in this study. There was a 2.5 fold increase in the proportion of cells in S

-phase in cultures from treated rats of both dosage groups sacrificed at 12

- 14 hours. Only slides from the 12

- 14 hour time point were analyzed for S

- phase synthesis. 870.6 2 00 Acute N eurotoxicity

Screening Battery NA Study not needed at this time (TX R# 0057326, U. Habiba, 12/15/2015) 90

- Day Neurotoxicity Screen ing Battery NA Study not needed at this time (TX R# 0057326, U. Habiba, 12/15/2015)

### Page **20** of **21 Table**  **A.5 .2**  **. Repeat** **- Dose and Other Toxicity Profile**  **Guideline Study Type**  **MRID (year) / Doses / Classification**  **Results** 870.7200 Companion Animal

Safety (Rat) 41981101 ( 1991 )

Gavage Doses (mg/kg): M: 5.28, 4.73, 5.03 Acceptable / Guideline All rats which ate the chlorophacinone

- containing pellets and did not receive vitamin K 1 died. All rats treated with vitamin K 1 after 24

- hour exposure to the chlorophacinone diet survived, as did 3/5 rats fed the chlorophacinone

- containing diet for 48 hours. All of the vitamin K 1 - treated rats which had been fed the chlorophacinone

- containing diet for 72 hours died. While vitamin K 1 has been shown to be a somewhat effective treatment following chlorophacinone ingestion, there were some mortalities among the rats which were given vitamin K 1 at 48 hours. This suggests a potential hazard if incid ents occur involving pets or small children in which it is not known or realized that ingestion has occurred. It is noted that this antidotal study does not include prothrombin times; and that such information, while not necessary for purposes of reregistration, could be useful to the Agency in defining hazards associated with exposure to chlorophacinone. 870.7485 Metabolism and

Pharmacokinetics (Rat) 00155540 ( 1981 )

Gavage Dose (mg/kg): Single: 1 Repeated: 1.43 (3 Days) Acceptable / G

uideline Chromatography and autoradiography demonstrated

that the chlorophacinone remained unchanged in plasma, with a blood half

- life of about 10 hours. Chlorophacinone was distributed systemically (e.g., liver, kidney, lung, heart, muscle, fat, and in the residu al carcass). Urine and CO2 radioactivity were less than 1% of the total dose. Most of the radioactivity was excreted in the feces (94.7% in one rat and 108.6% in the other over the 4

- day period). Excretion reached 90% in the first two days. Two hours after administration of chlorophacinone in the duodenum, biliary elimination was constant. At the end of 8 hours, an average of 26% of the administered radioactivity was eliminated in the bile. Although it is reported that there is over 90% excretion in t

he two days following dosage, the findings in the subchronic study (MRID 92018013) indicate there is a potential for bioaccumulation (or cumulative toxicity). In the subchronic study, there were mortalities at 40 g/kg/day in 10/10 males (deaths occurred d ays 29

- 82) and 4/10 females (deaths on days 69

- 111), and there were also mortalities at 20 g/kg/day in 4/10 males (deaths on days 105

- 111). 870.7600 Dermal Penetration NA No dermal absorption data is available. Therefore, the Agency assumes that the dermal absorption factor (DAF) = 100%. 870.7800 Immunotoxicity NA Study not needed at this time (TX R# 0057326, U. Habiba, 12/15/2015)

### Page **21** of **21 Attachment**  **6 Toxicology	Data	Requirements**  The requirements (40 CFR § 158.340) for food and non

- food uses for Chlorophacinone are in Table A.6
. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.
**Table A.6**  **. Toxicology**  **Data Requirements Guideline**  **Study Type Required**  **Subm itted**  **Satisfied** 870.1100 Acute Oral Toxicity Yes Yes Yes 870.1200 Acute Dermal Toxicity Yes Yes Yes 870.1300 Acute Inhalation Toxicity Yes Yes Y es 870.2400 Acute Eye Irritation Yes Yes Yes 870.2500 Acute Dermal Irritation Yes Yes Yes 870.2600 Skin Sensitization Yes Yes Yes 870.3100 90

- Day Oral Toxicity in Rodents CR Yes Yes 870.3150 90

- Day Oral Toxicity in Non

- Rodents CR No Yes 2 870.3200 21/28

- Day Dermal Toxicity No Yes Yes 870.3250 90

- Day Dermal Toxicity Yes No NA 870.3465 90

- Day Inhalation Toxicity CR No No 3 870.3700 Prenatal Developmental Toxicity Study (Rat) Y es Yes Yes

Prenatal Developmental Toxicity Study ( Rabbit) Yes Yes Yes 870.3800 Reproduction and Fertility Effects Yes No Yes 2 870.4100 Chronic Toxicity (Rodent) CR No Yes 2 870.4200 Carcinogenicity ( Rat) CR No Yes 2

Carcinogenicity ( Mouse ) CR No Yes 2 870.5100 Bacterial Reverse Mutation Test Y es Yes Yes 870.5300 870.5375 in vitro Mammalian Cell Gene Mutation Test

in vitro Mammalian Chromosome Aberration Test Y es 1 Yes Yes Yes 870.5385 870.5395 Mammalian Bone Marrow Chromosomal Aberration Test

Mammalian Erythrocyte Micronucleus Test Y es 1 No Yes Yes 870.6100 Delayed Neurotoxicity of Organophosphorus Substances (Acute, Hen) CR No NA

Delayed Neurotoxicity of Organophosphorus Substances (28

- Day, Hen) CR No NA 870.6200 Neurotoxicity Screening Battery (Acute, Rat) Yes No Yes 2

Neuro toxicity Screening Battery (90

- Day , Rat) Yes No Yes 2 870.6300 Developmental Neurotoxicity Study CR No NA 870.7200 Companion Animal Safety CR Yes NA 870.7485 Metabolism and Pharmacokinetics CR Yes Yes 870.7600 Dermal Penetration CR No NA 870.7800 Immunotoxicity Yes No Yes 2 CR Conditionally Required NA Not Applicable 1 Either guideline study type may be used to satisfy the data requirement (e.g., 870.5300 or 870.5375) 2 Study requirements are not needed to provide further hazard characterization (TXR # 0057326, U. Habiba, 12/15/2015)

. 3 Study required due to potential exposure and risks from tracking powders (TXR# 0057326, U. Habiba, 12/15/2015)

.