EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Maggie Rudick,<PHONE_NUMBER>

TEMPLATE:

Bayer CropScience

(5E8431)

EPA has received a pesticide petition (5E8431) from Bayer CropScience, P.O. Box 12014, 2 T.W. Alexander Drive, Research Triangle Park, NC 27709 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by:

1.  Establishing a tolerance for residues of Deltamethrin, IUPAC chemical name:

(S)-α-cyano-3-phenoxybenzyl (1R,3R)-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate in or on the raw or processed agricultural commodity orange, dried pulp at 3 parts per million (ppm), orange, oil at 50 parts per million (ppm)

2.	Amending existing tolerance for residues of Deltamethrin, IUPAC chemical name: (S)-α-cyano-3-phenoxybenzyl (1R,3R)-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate in or on the raw or processed agricultural commodity orange, fruit at 0.3 parts per million (ppm).

EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant and livestock metabolism.  The metabolism of deltamethrin in plants is adequately understood for purposes of establishing these proposed tolerances.  In plants, cis-deltamethrin undergoes isomerization to form trans- and α-R-deltamethrin.  Each of these isomers can undergo cleavage at the ester linkage to yield 3-phenoxybenzaldehyde and cis- or trans-Br2CA metabolites that can be further oxidized, reduced, and/or conjugated.  Deltamethrin is also directly hydroxylated to 4(-hydroxydeltamethrin or the nitrile group can be hydrolyzed to form an amide metabolite.  Deltamethrin (cis-deltamethrin) and its isomers alpha-R-deltamethrin, and trans-deltamethrin were the major residues found in all crops.  Smaller amounts of several minor components were present at <0.01 mg/kg and <10% of the TRR.  Deltamethrin (cis-deltamethrin) and its isomers alpha-R-deltamethrin, and trans-deltamethrin are the relevant residues of concern for tolerance enforcement in crop commodities.

The nature of residues in animal commodities is also adequately understood.  The metabolism of deltamethrin in rats, lactating cows and laying hens dosed orally shows similar pathways.  Deltamethrin is readily metabolized and excreted with half-lives of less than 24 hours.  The basic metabolic reactions involve cleavage of the ester bond by oxidation and/or hydrolysis, followed by oxidation of the released acid and alcohol moieties. The acid moiety (Br2CA) is transformed into conjugates, chiefly the glucuronide, and excreted in urine. It can also be hydroxylated at one of the gem-methyl groups, which is in turn conjugated and excreted. The unstable alcohol moiety is transformed via the aldehyde into the acid (mPB acid), which undergoes further oxidation by hydroxylation on aromatic rings and then is extensively excreted in urine, mainly as the 4'OH sulfate conjugate.

Deltamethrin (cis-deltamethrin) and its isomers alpha-R-deltamethrin, and trans-deltamethrin are the relevant residues of concern for tolerance enforcement in livestock commodities.

	2. Analytical method.  Analytical methods based on a gas chromatography equipped with an electron capture detector (GC/ECD) are available for enforcing tolerances for residues of deltamethrin.  These methods are used for the determination of cis-deltamethrin, alpha-R-deltamethrin, and trans-deltamethrin in crop and animal matrices.  The total residue reported is the sum of residues of three isomers.

3. Magnitude of residues.  Residue trials were conducted on orange in the United States and Brazil in accordance with the EPA and PMRA guidelines for crop field trials (OCSPP 860.1500; OCSPP 860.1520; OCSPP-170005; FRL-6559-3 Import Tolerance Guidance; DACO 7.4.1; DACO 7.4.2; DACO 7.4.5) to support the tolerances requested.

B. Toxicological Profile

1. Acute toxicity.  The acute oral toxic potency of deltamethrin depends on the vehicle that is used, with an LD50 in rats that ranges from 66.7 mg/kg (males) when administered in sesame oil to >5000 mg/kg (both sexes) in an aqueous methylcellulose suspension.  Deltamethrin technical is classified in Category II for acute oral and inhalation toxicity, Category III for dermal toxicity and eye irritation and Category IV for skin irritation.  Deltamethrin is not a skin sensitizer but can cause transient paresthesia (a local itching, burning or tingling sensation of the skin) following skin contact to sensitive individuals.

2. Genotoxicity.  There was no evidence of mutagenicity in a battery of in vitro and in vivo studies with technical-grade deltamethrin. Therefore, deltamethrin is classified as non-mutagenic.

3. Reproductive and developmental toxicity.  A rat development toxicity study conducted with deltamethrin indicated a maternal NOEL of 3.3 mg/kg/day based on clinical signs, decreased weight gain and mortality. The developmental NOEL was 11 mg/kg/day (HDT).

In a rabbit development toxicity study with deltamethrin, the maternal NOEL was considered to be 32 mg/kg/day (HDT).  The developmental NOEL was > 32 mg/kg/day.

In a developmental neurotoxicity study, the maternal NOAEL was 6.8 mg/kg bw/day, based on decreased body weight, weight gain and food consumption during gestation and decreased body weight and food consumption during lactation noted at 16 mg/kg/day. The offspring NOAEL was 6.8 mg/kg bw/day, based on delayed balanopreputial separation, reduced body weight and weight gain before weaning for both sexes, with recovery after weaning. There was no evidence of neurodevelopment effects at any dose level.

In a two-generation rat reproduction study with deltamethrin, the parental NOAEL was 5.4 mg/kg/day based on clinical signs and increased mortality. The offspring NOAEL was 5.8 mg/kg/day based on decreased body weights, body weight gain and increased pup mortality. The reproductive NOAEL was 24.9 mg/kg/day (HDT). Deltamethrin was not a developmental or reproductive toxicant.

4. Subchronic toxicity.  A 90-day rat oral toxicity study was conducted with deltamethrin administered by gavage. The NOEL was 2.5 mg/kg/day based on reduced body weight gain and slight hypersensitivity to sound.  In another 90-day rat dietary study with deltamethrin, the NOEL was 300 ppm (23.9 mg/kg/day for males, 30.5 mg/kg/day for females) based on uncoordinated movement, unsteady gait, tremors, increased sensitivity to sound, shakes and spasmodic convulsions.  The difference in the NOEL between the two studies is attributed to the different means of exposure (oral gavage as a bolus dose vs. dietary administration).

A 12-week study was conducted with deltamethrin in mice. The NOEL was 300 ppm (61.5 mg/kg/day in males and 77.0 mg/kg/day in females) based on clonic contractions, convulsions, poor condition, decreased weight gain and mortality.

Two 13-week dog studies were conducted with deltamethrin.  In the first study, beagle dogs were administered deltamethrin by capsule using PEG 200 as a vehicle.  The NOEL for this study was 1 mg/kg/day based on tremors, unsteadiness, jerking movements, salivation, vomiting, liquid feces and/or dilation of the pupils.  In the second study, deltamethrin was administered by capsule without a vehicle to beagle dogs. The NOEL for this study was 10 mg/kg/day based on unsteady gait, tremors, head shaking, vomiting and salivation. The difference in toxicity between the two studies is attributed to the enhanced absorption resulting from the use of PEG 200 as a vehicle in the first study.

A 21-day dermal toxicity study was conducted with deltamethrin in rats. The NOEL for systemic toxicity was determined to be 1000 mg/kg/day (HDT).  In a subchronic inhalation study, rats were exposed to aerosolized deltamethrin for 6 hours per day, 5 days per week, for a total of 14 days over 3 weeks. Based on slightly decreased body weight and neurological signs at 2.5 mg/kg/day, it was concluded that 0.003 mg/L (0.783 mg/kg/day) was the NOEC (NOEL) for systemic effects in this study.

5. Chronic toxicity.	Deltamethrin was administered in the diet to beagle dogs for 2 years.  No treatment-related effects were observed and the NOEL was judged to be 40 ppm (1.1 mg/kg/day). In another study, deltamethrin was administered by capsule (without a vehicle) to beagle dogs for 1 year. The NOEL in this study was determined at 1 mg/kg/day based on neurologic signs, decreased food consumption and changes in several hematology and blood chemistry parameters.

Two rat chronic toxicity/oncogenicity studies were conducted with deltamethrin.  In the first study, the test substance was administered via the diet to rats for 2 years.  The NOEL for this study was 20 ppm (1 mg/kg/day) based on slightly decreased weight gain.  In a more recent study, deltamethrin was administered to rats in the diet for 2 years. The NOEL for this study was 25 ppm (1.1 and 1.5 mg/kg/day for males and females, respectively) based on neurological signs, weight gain effects and increased incidence of histopathological changes to the liver.  No evidence of carcinogenicity was noted in either study.

Two mouse oncogenicity studies were conducted with deltamethrin.  In the first study, deltamethrin was administered in the diet for two years.  No adverse effects were observed and the NOEL was 100 ppm (12 and 15 mg/kg/day, respectively, for males and females). In another study, deltamethrin was administered in the diet to mice for 97 weeks. The NOEL was 1000 ppm (15.7 and 19.6 mg/kg/day) based on a higher incidence of poor physical condition and a slight transient weight reduction.  There was no evidence of oncogenicity in either study.

6. Neurotoxicity.  Deltamethrin was administered in a single dose by gavage in rats. The NOAEL was 5 mg/kg/day, based on salivation, soiled fur, impaired mobility, no response to approach or touch in several animals at the time of peak effect at 15 mg/kg. There was no evidence of neuropathology at any dose.

In a subchronic neurotoxicity study, deltamethrin was administered in the diet of rats for 13 weeks. The NOAEL was 15 mg/kg/day, based on mortality, clinical signs of toxicity, FOB findings, and decreased body weights, body weight gains, and food consumption at 56 mg/kg/day. There was no evidence of neuropathology at any dietary level.

7. Animal metabolism.  The absorption of deltamethrin is highly dependent upon the route and vehicle of administration. Once absorbed, deltamethrin is rapidly and extensively metabolized and excreted, primarily within the first 48 hours, in feces and an approximately equal amount in urine. Absorbed deltamethrin is cleaved by hydrolysis at the ester site followed by rapid sulfate and glucuronide conjugation.

8. Endocrine disruption.  No special studies have been conducted to investigate the potential of deltamethrin to induce endocrine effects. However, the standard battery of required toxicity studies includes an evaluation of the potential effects on reproduction and development, and an evaluation of the pathology of the endocrine organs following repeated or long-term exposure. There is no evidence that deltamethrin induces endocrine disruption.

C. Aggregate Exposure

1. Dietary exposure.  The proposed new import tolerance use of deltamethrin on oranges and processed orange commodities has minor effects on the previous dietary aggregate risk assessment conducted for all existing registered uses (EPA, D423638, December 4, 2014).  Residues for the additional crop group were based on field trials on orange fruit.  Assessments, using the DEEM FCID Version 4.02 software, were conducted to evaluate potential risks due to chronic and acute dietary exposure of the U.S. population and selected population subgroups to residues of deltamethrin.  Consumption data used in this program were taken from NHANES WWEIA 2005-2010.

The acute toxicity endpoint used in the acute assessment was the Bench Mark Dose Level of 1.49 mg/kg/day from the deltamethrin acute neurotoxicity study as described in the Agency’s HED risk assessment (EPA, D417556, February 24, 2015).  A 100X uncertainty factor was applied for all populations > 6 yrs. old results in an acute population reference dose (aPAD) of 0.015 mg/kg/day.  An additional FQPA Safety Factor of 3X was applied to children under 6 yrs. resulting in a aPAD of 0.005 mg/kg/day.

EPA determined that a chronic dietary endpoint is not required because repeated exposure to deltamethrin does not result in a lower point of departure. Therefore, the acute dietary endpoint is protective of chronic exposure scenarios.  Chronic dietary exposure was estimated in order to address aggregate exposure.

The acute dietary assessment for combined food and water exposure shows 96% of the aPAD for Children 1-2 years old (most sensitive) and 16% of the aPAD for US Population.  Results from the dietary exposure assessments demonstrate a reasonable certainty that no harm to the overall U.S. population or any population subgroup will result from the use of deltamethrin on the proposed crops.

i. Food.  A partially refined acute dietary (food only) risk assessment was conducted.  For the population subgroup Children 1-2 years old, the acute analysis indicates an exposure of 95% of the aPAD at the 99.9th percentile.  Acute exposure to the overall U.S. population is 16% of the aPAD.

ii. Drinking water.   In order to address drinking water, water was included in the dietary analysis for food.  DEEM analyses were performed using surface water estimates based on sweet corn application at 0.45 lbs ai/A.  The EDWC for the acute and chronic dietary assessment was 0.2 ppb.  EFED determined there was no need to conduct a PRZM-GW assessment since groundwater values are at the limit of solubility of 0.2 ppb.  For the population subgroup Children 1-2 years old, the acute analysis results in an exposure of 96% of the aPAD.  Acute exposure to the overall U.S. population is 16% of the aPAD.  Drinking water was not a significant contributor to the overall dietary exposure.

2. Non-dietary exposure.

a. Occupational exposure.

The newly proposed use of deltamethrin on oranges and process orange commodities as import tolerance would have no change to previous estimates of occupational exposure.  A previous residential handler exposure assessment for indoor, outdoor, turf, pet and paint uses was conducted by EPA (D418867, 6/11/2014).  The residential handler scenarios resulted in inhalation risk estimates (Margin of Exposure) ranging from 4,300 to 850,000.  The lowest MOE of 4,300 was associated with the use of a backpack sprayer to treat lawns with a wettable powder formulation.  These risk estimates were well above the Level of Concern of 100.

	b. Residential (Non-occupational) exposure and risk

The newly proposed use of deltamethrin on oranges and process orange commodities as import tolerance would have no change to previous estimates of residential exposure.  A previous residential post-application exposure assessment for indoor, outdoor, turf, pet and paint uses was conducted by EPA (D418867, 6/11/2014).  The residential post-application scenarios resulted in incidental oral (hand-to-mouth) risk estimates (Margin of Exposure) ranging from 630 to 400,000.  The lowest MOE of 630 was associated with exposure to children from indoor bed bug scenario.  These risk estimates were well above the Level of Concern of 300 for children younger than 6 yrs. old.

All post-application inhalation and incidental oral exposure estimates for the mosquito control scenarios resulted in MOEs greater than their respective LOCs and are not of concern.

D. Cumulative Effects

Deltamethrin is a pyrethroid insecticide. In the cumulative risk assessment for pyrethroids, the EPA determined that pyrethroids perturb the kinetics of neuronal voltage-gated sodium ion channels (VGSC) following an action potential in vertebrates as a common mode of action. However, exposure to deltamethrin according to the proposed use pattern is expected to be negligible and therefore would not contribute to aggregate exposure or cumulative exposure assessment.  The Agency currently retains a 3x FQPA safety factor for all pyrethroid insecticides, as per the Cumulative Risk Assessment for Pyrethroids (2012), based on evidence of underdeveloped clearance mechanisms in neonatal rats reported in the published literature.

E. Safety Determination

1. U.S. population.  Based on the minimal potential for exposure and completeness of the toxicology database, it can be concluded that aggregate exposure to residues of deltamethrin present a reasonable certainty of no harm.  The short-term aggregate risk estimation combining residential exposure with background exposure from dietary (chronic food and water exposure) for the US population has a Margin of Exposure (MOE) of 2,200.  This MOE is well above the Level of Concern of 100.  The proposed import tolerance for orange use pattern will produce minor dietary exposures. Thus, there is a reasonable certainty that the use of deltamethrin will present no harm from aggregate exposure.

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The short-term aggregate risk estimation combining residential exposure with background exposure from dietary (chronic food and water exposure) for the Children 1-2 yrs. old has a Margin of Exposure (MOE) of 510.  This MOE is well above the Level of Concern of 300.  The use pattern for deltamethrin on orange fruit and process commodities of oranges will have minimal exposure to infants or children.  Thus, it can be concluded that there is a reasonable certainty that no harm will result from aggregate exposure to deltamethrin residues.

F. International Tolerances

Deltamethrin is a broad spectrum insecticide used throughout the world to control pests of livestock, crops, ornamentals plants and turf, and household, commercial, and industrial food use areas. As a consequence a large number of CODEX MRLs exist for deltamethrin.  US and Canadian petitions seek to harmonize MRLs at the proposed 0.3 ppm.

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 PAGE   7


[Federal Register: April 11, 2007 (Volume 72, Number 69)]
[Notices]
[Page 18226]
[DOCID:fr11ap07-60]

-----------------------------------------------------------------------

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. EL04-49-002]

Entergy Services, Inc.; Notice of Compliance Filing

April 5, 2007.
    Take notice that on March 30, 2007, Entergy Services, Inc., acting
as agent for Entergy Louisiana, LLC filed an interconnection and
operating agreement with Quachita Power, LLC pursuant to the Federal
Energy Regulatory Commission's February 28, 2007 Order.
    Any person desiring to intervene or to protest this filing must
file in accordance with Rules 211 and 214 of the Commission's Rules of
Practice and Procedure (18 CFR 385.211, 385.214). Protests will be
considered by the Commission in determining the appropriate action to
be taken, but will not serve to make protestants parties to the
proceeding. Any person wishing to become a party must file a notice of
intervention or motion to intervene, as appropriate. Such notices,
motions, or protests must be filed on or before the comment date.
Anyone filing a motion to intervene or protest must serve a copy of
that document on the Applicant and all the parties in this proceeding.
    The Commission encourages electronic submission of protests and
interventions in lieu of paper using the ``eFiling'' link at http://www.ferc.gov.
 Persons unable to file electronically should submit an

original and 14 copies of the protest or intervention to the Federal
Energy Regulatory Commission, 888 First Street, NE., Washington, DC
20426.
    This filing is accessible on-line at http://www.ferc.gov, using the

``eLibrary'' link and is available for review in the Commission's
Public Reference Room in Washington, DC. There is an ``eSubscription''
link on the Web site that enables subscribers to receive e-mail
notification when a document is added to a subscribed docket(s). For
assistance with any FERC Online service, please e-mail
<EMAIL_ADDRESS>or call<PHONE_NUMBER> (toll free). For

TTY, call<PHONE_NUMBER>.
Comment Date: 5 p.m. Eastern Time on April 20, 2007.

Philis J. Posey,
Acting Secretary.
 [FR Doc. E7-6795 Filed 4-10-07; 8:45 am]

BILLING CODE 6717-01-P


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

                                                    	OFFICE OF CHEMICAL SAFETY
                                                       AND POLLUTION PREVENTION

MEMORANDUM

DATE: 	December 14, 2015

            SUBJECT:	Chlorophacinone.  Human Health Scoping Document in Support of Registration Review.

PC Code: 067707
DP Barcode: D426549
Decision No.: 502937
Registration No.: NA
Petition No.: NA
Regulatory Action: Registration Review Scoping Document
Risk Assessment Type: NA
Case No.: 2100
TXR No.: NA
CAS No.: 3691-35-8
MRID No.: NA
40 CFR: NA

FROM:	Barry O'Keefe, Senior Biologist
		Vincent Chen, Toxicologist
		Risk Assessment Branch III (RAB3)
		Health Effects Division (7509P)

THROUGH:	Matthew Crowley, Biologist
		Chemistry and Exposure Branch (CEB)
		Health Effects Division (7509P)

		Chris Schlosser, Biologist
		Risk Assessment Branch VI (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 Moriarty, Team Leader
		Neil Anderson, Branch Chief
      Risk Management and Implementation Branch 1 (RMIB1)
		Pesticide Re-Evaluation Division (PRD) (7508P)

Executive Summary

Following is the Health Effects Division's (HED's) human health scoping document for the rodenticide 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 toxicity, 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 completed 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 currently 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 exposures 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 used 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 adequately 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.

Introduction

Chlorophacinone, an indandione, is a first generation anticoagulant rodenticide that disrupts the vitamin K cycle necessary for blood-clotting factors to function.  Chlorophacinone is formulated into numerous baits in packs, blocks, granules, 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 includes spoons, scoops, probe dispensers, burrow builders, dusters.  Application rates are numerous and vary widely depending upon formulation and product types.  The most recent HED assessment for chlorophacinone is the HED Chapter of the Reregistration Eligibility Decision (RED) Document completed 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 apply to rodenticide field (non-commensal rodents) uses or tracking powder products.
 Consumer-based products (<= 1 lb.),
 Second-generation anticoagulants are prohibited as well as loose baits/pellets/meal as a form for above ground outdoor uses.
 When applied outdoors above ground and in areas accessible to children, non-target wildlife or domestic animals, baits must be contained in bait stations.
 Products for use outdoors and above-ground must be placed within 50 feet of a building.
 Professional-based products
 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)
 May not be offered for sale in consumer stores (hardware, grocery, etc.).
 Must also be placed within 100 feet of a structure (fence and perimeter baiting beyond 100 feet of a man-made structure 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.
 For uses of first-generation or non-anticoagulants, product labels require bait stations if children, wildlife or domestic animals may be exposed.
 For uses of second-generation anticoagulants, labels require bait stations for all outdoors above grounds placements and/or indoor placements where children, wildlife or domestic animals may be exposed.
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 chlorophacinone 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 applied to orchards by ground broadcast equipment at a maximum rate of 20 lb of product per acre or 0.001 lb active ingredient (ai) per acre in post-harvest fruit tree orchards.  Also, tamper resistant bait stations are not required for burrow, canopy, and tracking powder applications.  In addition, 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 stations.  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, and excretion (ADME) database enabled evaluation of systemic 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 systemically 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 repeated 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 to 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 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 susceptibility 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 by 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 is 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. Habiba, 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 powder end use products.

Conclusions: The toxicology database is adequate for risk assessment 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.

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 by the dermal and inhalation routes during the refilling of bait stations with pelleted, tableted, or granular products.  Residential handler exposures have not previously been quantitatively 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 only; 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, for 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 bystander 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., by aerial equipment).  Therefore, only 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 concurrently.  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 analysis to determine if data (e.g., flux studies or route-specific inhalation toxicological studies) or further analysis 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 Registration Review, HED will reevaluate the points of departure, toxicity endpoints, and uncertainty factors currently used for risk assessment purposes.  Based upon that reevaluation, HED will determine if a risk assessment is necessary for residential handler exposures.  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 exposures.  Residential handler exposure and quantitative drinking water estimates for chlorophacinone 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-application 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 residential 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 aggregate assessments 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 aggregate assessment for small children would be needed during the Registration Review.

Occupational Exposure

Occupational Handler Exposure
Occupational handler exposures have not previously been quantitatively assessed.  Handlers can be exposed by the dermal and inhalation routes at short- or intermediate-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.  It is therefore difficult to assess and estimate the dermal and inhalation exposure risks from these products.  These are restricted use products.  In order to adequately and appropriately assess these exposures at the time of Registration Review, the registrant will need to provide information on use pattern, including application rates.  Additionally, based upon the tracking powder registrations of chlorophacinone, HED still requires a 90-day inhalation toxicity study (TXR# 0057326, U. Habiba, 12/15/2015).

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 used for risk assessment purposes.  Based upon that reevaluation, HED will update the occupational handler risk assessments.  Additionally, in order to adequately 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 rates.

Public Health and Pesticide Epidemiology Data

As part of the Rodenticide Risk Mitigation Decision (RMD), and the subsequent Notice of Intent to Cancel (NOIC), the Environmental Protection Agency's Office of Pesticide Programs' Pesticide Re-evaluation Division requested an analysis of human incidents involving exposure to rodenticides in 2011 (D395567, S. Recore, 10/28/2011) and then updated in 2015 (D426573, S. Recore, 11/24/2015).  Summary reports listing incidents for chlorophacinone are reported to the OPP Incident Data System (IDS), the National Pesticide Information Center (NPIC), the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH), Sentinel Event Notification System for Occupational Risk-Pesticides (SENSOR), and Agricultural Health Study (AHS) databases.

For the Main OPP Incident Data System (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 System for Occupational Risk-Pesticides (SENSOR)-Pesticides from 1998-2011, identifies 12 cases involving chlorophacinone.  Of these, nine cases involved 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 experienced shakiness, fever and vomiting but felt better after a few hours.   The case experienced respiratory, neurological, gastrointestinal, renal, and cardiovascular symptoms following exposure.  "Rat pellets" were found throughout the attic and the school but the workers were not notified of this.

      Eight cases experienced respiratory symptoms after exposure, and eight cases experienced neurological symptoms after exposure.  Five cases experienced gastrointestinal symptoms.  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 year.

Although AAPCC data was reviewed by HED for the 2011 human incidents report (D395567) analyzing exposure to commensal rodenticides, it was not reviewed for this incident analysis.  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 year 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 annually for reduction in reported rodenticide 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 years 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 by 75% in children ages 1 to 6 years 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 measures were only recently fully 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 during Registration Review provide an updated review of incidents, considering pre- and post-mitigation incidents separately, when the information becomes available.

Tolerance Assessment and International Harmonization

There are no tolerances for chlorophacinone.

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 Low-Income Populations," http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf.  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 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 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/.

Human Studies

The risk assessments HED anticipates being conducted during Registration Review for chlorophacinone will rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure.  Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as 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 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 Deficiencies

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 adequately assess inhalation exposures from the use of tracking powders.

References

Recent Memoranda Relevant to Registration Review of Chlorophacinone.
                                    Author
                                   DP/TXR #
                                     Date
                                     Title
                         Human Health Risk Assessments
                                   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
                                    D426573
                                  11/24/2015
Rodenticide: Tier I (Scoping) Review of Human Incidents and Epidemiology Assessment
                                   S. Recore
                                    D395567
                                  10/28/2011
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.

Attachments
1. Use Profile
2. Chemical Identity Table
3. Physicochemical Properties of Technical Grade Chlorophacinone Table
4. Endpoint Selection Table
5. Toxicity Profile Tables
6. Toxicology Data Requirements Table

Attachment 1
                        Use Profile for Chlorophacinone

Table A.1. Use Profile for Chlorophacinone.
                                 Product Name
                                 EPA Reg. No.
                                  Formulation
                              % Active Ingredient
                                 Target Pests
                               Application Rate
                         Tamper 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[(R)] Tracking Powder
7173-113
Tracking Powder
                                      0.2
Norway rats, roof rats & house mice
1 to 2 oz per 2.5 ft[2] 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[(R)] Blue Tracking Powder
7173-172
Tracking Powder
                                      0.2
Norway rats, roof rats & house mice
1 to 2 oz per 2.5 ft[2] 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 Plantations
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 Refillable Bait Station
7173-293
Pelleted/Tableted
                                     0.005
House Mice
Bait Station, can refill with bait blocks
                                      Yes
WG
                                      No
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

Attachment 2
                            Chemical Identity Table

TABLE A.2.  Chlorophacinone Nomenclature.
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

Attachment 3

Table A.3.  Physicochemical Properties of Chlorophacinone.
Parameter
Value
Reference
Melting point
141-145ºC
Rodenticide Cluster RED, 1998
Physical State
Pale Yellow Microcrystalline Powder

Density
0.58 g/cm[2]

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 20ºC
http://pubchem.ncbi.nlm.nih.gov/compound/chlorophacinone#section=Substances
Dissociation constant, pKa
3.40 at 25ºC

Octanol/water partition coefficient Log(POW)
4.22
Rodenticide Cluster RED, 1998
Stability
Stable for 14 days at 54ºC

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 (PoD)
                       Uncertainty / FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Dermal
Short Term
(1-30 days)

NOEL =
0.08 mg/kg/day
UFA = 10x
UFH = 10x
FQPA = 1x

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
UFA = 10x
UFH = 10x
FQPA = 1x

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 (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 relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential 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 (PoD)
Uncertainty / FQPA Safety Factors
Level of Concern for Risk Assessment
Study and Toxicological Effects
Dermal
Short Term
(1-30 days)

Intermediate Term
(1-6 months)
NOEL =
0.08 mg/kg/day
UFA = 10x
UFH = 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
UFA = 10x
UFH = 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 (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 relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

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
LD50 (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
LD50 (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
LC50 (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
Based on increased coagulation time for both males and females, with males more sensitive than females.
                                   870.3150
90-Day Oral Toxicity in Non-Rodents
NA
Study not needed at this time (TXR3 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 / Guideline
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
                                   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
NOEL (g/kg/day) =	50
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
NOEL (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
Reproduction and Fertility Effects
NA
Study not needed at this time (TXR# 0057326, U. Habiba, 12/15/2015)
                                   870.4100
Chronic Toxicity in Rodents
NA
Study not needed at this time (TXR# 0057326, U. Habiba, 12/15/2015)
                                   870.4200
Carcinogenicity
(Mouse)
NA
Study not needed at this time (TXR# 0057326, U. Habiba, 12/15/2015)

Carcinogenicity
(Rat)
NA
Study not needed at this time (TXR# 0057326, U. Habiba, 12/15/2015)
                                   870.5100
Bacterial Reverse Mutation Test
(Salmonella typhimurium)
43284001 (1994)
Applied Dose (ug/plate):
    	+S9:	1  -  5000
    	-S9:	0.5  -  5000
Acceptable / Guideline
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 evidence that chlorophacinone induced a mutagenic response in any strain at any nonactivated or S9-activated dose level.

42937133 (1989)
Applied Dose (ug/plate):
    	S9:	5, 16, 50, 158, 500
Acceptable / Guideline
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.
                                   870.5375
in vitro Mammalian Chromosome Aberration Test
(Human Lymphocytes)
43825601 (1995)
Applied Dose (ug/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 associated with cytotoxicity (50 g/mL), did 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 / Guideline
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 (ug/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 (ug/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.
                                   870.6200
Acute Neurotoxicity Screening Battery
NA
Study not needed at this time (TXR# 0057326, U. Habiba, 12/15/2015)

90-Day Neurotoxicity Screening Battery
NA
Study not needed at this time (TXR# 0057326, U. Habiba, 12/15/2015)
                                   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 K1 died. All rats treated with vitamin K1 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 K1-treated rats which had been fed the chlorophacinone-containing diet for 72 hours died.

While vitamin K1 has been shown to be a somewhat effective treatment following chlorophacinone ingestion, there were some mortalities among the rats which were given vitamin K1 at 48 hours. This suggests a potential hazard if incidents 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 / Guideline
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 residual 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 the 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 days 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 (TXR# 0057326, U. Habiba, 12/15/2015)

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
                                   Submitted
                                   Satisfied
870.1100
Acute Oral Toxicity
                                      Yes
                                      Yes
                                      Yes
870.1200
Acute Dermal Toxicity
                                      Yes
                                      Yes
                                      Yes
870.1300
Acute Inhalation Toxicity
                                      Yes
                                      Yes
                                      Yes
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)
                                      Yes
                                      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
                                      Yes
                                      Yes
                                      Yes
870.5300
870.5375
in vitro Mammalian Cell Gene Mutation Test
in vitro Mammalian Chromosome Aberration Test
                                    Yes[1]
                                      Yes
                                      Yes
                                      Yes
870.5385
870.5395
Mammalian Bone Marrow Chromosomal Aberration Test
Mammalian Erythrocyte Micronucleus Test
                                    Yes[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]

Neurotoxicity 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).