_ _ _**···- ----** **~~?!~P.i ~!~~Registration**  Review !2uman-Health**Assessmen~ Sc~_e~-~~?~~** **~~.!2 !**  _ _

____ _ _____ __ _

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON

, D.C. 20460

MEMORANDUM

Date: September 3, 2013 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Chloropicrin. Human-Health Assessment Scoping Document in Support of Registration Review.

PC Code: 081501 DP Barcode: 0410119
Decision No

. : Lf7C.'I31 Registration No.: N / A
Petition No.: N / A Regulatory Action: Registration Review Scoping Document
Risk Assessment Type: N /A Case No.: 0040

TX R No

. : N / A CAS No.: 76-06-2**MIDD~:NM ~cr~NM** 

FROM: CharlesSmi th ,B ranchChief /'

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### >/!: ? Shalu Shelat, I ndustr i a l Hygienis t**-10~** '- Nancy McCarroll, Toxicologist

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### ~~,... ......... Chr i stopher Schlosser, Toxicologist

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Health Effects Division (7509P)



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Nath an Mottl, Biologist 

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Antimicrobials Division (751 OP)

THROUGH: Felecia Fort, Branch Chief



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R i sk Assessment Branch 6 (RABV 1)

## ~ Health Effe cts Division (7509P)

Steve Weiss, Branch Chief

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, Senior Scientist 

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Antimicrobials Division (751 OP)



### TO: Carolyn Schroeder, Chemical Review Manager
Risk Management and Implemen tat ion Branch IV
Pesticide Re-Evaluation Division (7508P)

Attached i s the combined HED and AD human-hea l th risk assessment seeping document for chloropicrin to support registrat ion rev iew.

Page I of 19..**S:~~?! opicrin** **Re ~~** **~~!ion** Rev i ew**Hu_!ll ~!l_-Hea** **lth Asse_s.~~nt** **Scoe in** **~_!) ()~U~~~!**  _________ ____ _ Executive Summary

Ch l o r opicr in is a non-selective pre-plant soil fumigant with fungicidal, herbicidal, insecticidal,
and nematicidal propert i es. Chloropicrin is also an act i ve ingredient in antimicrobial wood preservat i ve products. The Health Effects Di vision (HED) and the Antimicrobial Division (AD)
ha ve evaluated the status of the human-health assessme nt s for chloropicrin to determi n e whether
sufficient da ta a re available to support Registration Review. HED and AD h ave also considered
the most recent huma n-h ealt h r isk assessments for ch l o r opicrin with respect to toxicity,

exposure, and usage databases, and the most updated Agency science policy and risk assessmen t methodologies to dete rmin e the scope of work necessary to support Registration Review.

The Amended Chlorop icrin Re registration Elig i bility Decision ( RED ) document was issued in May 2009. The Amended RED focused on th r ee main use categories of ch l oropicrin: ( 1) preplant soil fum i ga tio ns (e.g., agr i cultural and commerc ial green h ouse); (2) residential uses (warning agent for sulfuryl fluoride); and (3) other specialized fumiga t ions (e.g

. , spot tree replant
sites and remedial wood t re atments)

. Chloropicrin use i n empty grain bins and empty potato storage/house cellars were voluntarily cancelled as part of the chloropicrin RED process. Since
th e Amended RED was issued, no new uses of chlo r opicr in ha ve been registered and the Agency
determined that the use o f chloropicrin as a warning agent prior to sulfury l fluoride residential fumigations is not a pesticidal use

.

The toxicity database for chloropicrin is adequate for Registration Review. HED's Hazard and
Science Policy Council ( H ASPOC) has determined that a neurotoxici t y battery is not required
for chloropicrin. An Immuno toxicity study was required as part of the 2009 Amended RED but
this req ui rement was subsequently waived (Reaves; D382316 ; 4/27/201 1 ). The focal poin t s for
the assessment of chloropicrin are occupational and res iden tia l inhalation exposure

. There is no

r oute specific dermal study avai l able for chloropicrin; however, HED has not previously performed a d e rmal exposure assessment fo r chloropicrin since it is category I for primary skin
ir

ritation and acute dermal toxicity and significant dermal exposure is not expected. Th ere are a number of route spec i fic i nhalation studies available for chloropicrin including an acute inhalation/irritation study in humans, an acute inhalat i on study in rats, developmental inhalation
stud i es in rats and rabbits, a 2-generation repr oduction inhalation study in rats, 13-week
inhalation studies in rats and mice, a 78-week inh alation cancer study in mice, and a 2-year
i n halation cancer study in rats. The Agency does not anticipate the need to reevaluate the points
of departure (PODs) and uncertainty factors (UFs) for the residen t ial and occupationa l exposure

assessme n ts during Registration Review.

The residue chem i stry and dietary -e xposure database is adequate to support current registration requirements. The current uses of chloropicrin have previously been determined to be non-food

uses. In addition, based on envi r onmenta l fate data, the residual conten t s in soils, and monitoring data, chloropicrin is not expec t ed to adversely impact the drinki n g water sources such

as surface water and ground water. The Agency does not anticipate th e need to perform dietary

or drinking water assessments during Registration Review.

The residentia l exposure database for chloropicrin is adequate for Re g i stration Review with the

excep t ion of a n ambient air study measuring c hlor opicrin from soil fumigant applications. The Agency does not anticipate the need t o perform additional or updated PERF UM modeling during Registration Review unless new field volati li ty studies become available or poin ts of departure (PODs) or uncerta i nty factors (UFs) for the residential exposu re assessment change.

Page 2 of 19Chloropicrin Registration Review Human

- Health Assessment Scoping Document

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Page 3 of 19 

### The occupational exposure database for chloropicrin is adequate for Registration Review. The Agency does not anticipate the need to perform additional or updated occup ational exposure assessments during Registration Review unless new occupational exposure studies become available or points of departure (PODs) or uncertainty factors (UFs) for the occupational exposure assessment change.

No new data deficiencies outside those previously required through reregistration were identified for chloropicrin

.

HED and AD anticipate conducting the following risk assessment updates during Registration
Review: Toxicology: None Residue Chemistry: None Dietary Exposure: None
Occ upational/Residential Exposure:

o HED will be required to perform a n ambient air assessment during Registration Review once the chloropicrin ambient air study is submitted to the Agency.

1.0 Introduction

Chloropicrin is a non

- selective pre

- plant soil fu migant with fungicidal, herbicidal, insecticidal, and nematicidal properties. Chloropicrin is also an active ingredient in antimicrobial wood preservative products. The Health Effects Division (HED) and the Antimicrobial Division (AD)
have evaluated the status of the human

- health assessments for chloropicrin to determine whether sufficient data are available to support Registration Review. HED and AD have also considered
the most recent human

- health risk assessments for chloropicrin with respect to toxic ity, exposure, and usage databases, and the most updated Agency science policy and risk assessment methodologies to determine the scope of work necessary to support Registration Review.

The Amended Chloropicrin Reregistration Eligibility Decision (RED) do cument was issued in May 2009. The Amended RED focused on three main use categories of chloropicrin: (1) pre

plant soil fumigations (e.g., agricultural and commercial greenhouse); (2) residential uses (warning agent for sulfuryl fluoride); and (3) other s pecialized fumigations (e.g., spot tree replant sites and remedial wood treatments). Chloropicrin use in empty grain bins and empty potato storage/house cellars were voluntarily cancelled as part of the chloropicrin RED process (75 FR 24699)

. Since the Am ended RED was issued, no new uses of chloropicrin have been registered and the agency determined that the use of chloropicrin as a warning agent prior to sulfuryl fluoride residential fumigations is not a pesticidal use.

2.0 Hazard Identification/Toxicology

The toxicity database for chloropicrin is adequate for Registration Review

. HED’s Hazard and Science Policy Coun cil (HASPOC) has determined that a neurotoxicity battery is not required for chloropicrin ( Dunbar; 5/22 /13; TXR 0056 662 )

. The 2009 Amended RED required a n Immunotoxicity study for chloropicrin but this requirement was subsequently waived (Reaves; D382316; 4/27/2011). Attachment 2 provides a summary of the acute, subchronic, and chronic toxicity profile for chloropicri n . Attachment 3 provides a summary of the relevant toxicological endpoints used in the chloropicrin 2009 risk assessment.Chloropicrin Registration Review Human

- Health Assessment Scoping Document

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Page 4 of 19 

### No inhalation pharmacokinetic or metabolism studies are available at this time for chloropicrin and the metabolic pathway has not be en determined. However, studies from the open literature indicate glutathione and thiol proteins may play a role in the metabolism of chloropicrin. Chloropicrin is a sensory irritant with a clear mode of action and target. Stimulation of the trigeminal nerve mediates sensations in the nose, eyes, throat, and upper respiratory tract. Furthermore, a human sensory irritation study for chloropicrin revealed that eye irritation was the most sensitive endpoint. Specifically, phase three of the human study id entified a range of concentrations in which sensitive subjects (e.g., young adults) were capable of detecting chloropicrin in the eyes without changes in the upper respiratory tract. The human study also suggests that the transient eye irritation experien ced from an hour of exposure does not carry over from day to day. Protection of eye irritation therefore likely protects against changes in upper respiratory parameters. The Human Studies Review Board (HSRB) concluded the human study was conducted under ethical standards and is scientifically robust for estimating a safe level of inhalation exposure.

The robust animal database for chloropicrin provides insight into the dose

- response and progression of respiratory irritation that occurs at higher concentrations. Chloropicrin is classified as category I (highly toxic) for acute inhalation, primary skin irritation, and acute dermal toxicity. There is no route specific dermal study available for chloropicrin however, HED has not previously performed a dermal exposure assessment for chloropicrin since it is category I for primary skin irritation and acute dermal toxicity and significant dermal exposure is not expected. For the major route of concern, the inhalation rodent database is robust with a number of route specific inhalation studies available for chloropicrin including an acute
inhalation/irritatio n study in humans, an acute inhalation study in rats, developmental inhalation studies in rats and rabbits, a 2

- generation reproduction inhalation study in rats, 13

- week inhalation studies in rats and mice, a 78

- week inhalation cancer study in mice, and a 2

- year inhalation cancer study in rats. In developmental inhalation toxicity studies with chloropicrin (MRID 42740601, 42740602), no evidence of quantitative or qualitative susceptibility in developing animals was observed.

There is no quantitative or qualitative susceptibility observed in the developmental and reproductive inhalation toxicity studies with chloropicrin . All of the developmental NOAELs are equal to or larger than the NOAELs for maternal toxicity.

In vitro mutagenicity assays for ch loropicrin have mixed positive and negative results; however,
in vivo data for chloropicrin are negative. C urrently

, chloropicrin is not considered a carcinogen by the inhalation route of exposure since there were no treatment

- related increases in tumor
i ncidence when compared to control animals in two acceptable inhalation carcinogenicity studies
in the mouse and rat.

Conclusions: The toxicity database for chloropicrin is adequate for Registration Review

. The Agency does not anticipate the need to reev aluate the points of departure (PODs) and uncertainty factors (UFs) for the residential and occupational exposure assessments during Registration
Review.

3.0 Residue Chemistry

The residue chemistry database for chloropicrin is adequate for Registration R eview. The qualitative nature of the residue in plants is adequately understood based on an acceptable plant metabolism study (S. Knizner, D200326 and D202185, 8/25/94). The plant metabolism andChloropicrin Registration Review Human

- Health Assessment Scoping Document

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Page 5 of 19 

### environmental fate studies demonstrated that when used as a preplant soil fumigant, chloropicrin is degraded in both aerobic and anaerobic soil to carbon dioxide (CO 2 

### ). The CO 2 

### generated from the chloropicrin is subsequently taken up by the plant and incorporated into starch, proteins, pectin, lignin, hemicellulo se, and cellulose. Therefore, the use of chloropicrin as a preplant soil fumigant is considered to be a non

- food use and tolerances are not needed (J. Abbots, Memo, 8/15/96).

Conclusions: The residue chemistry database for chloropicrin is adequate fo r Registration
Review.

4.0 Dietary Exposure

The dietary exposure database for chloropicrin is adequate for Registration Review. As described in Section 3.0, the Agency previously decided that the currently registered uses of chloropicrin are non

- food uses

.

Chloropicrin may potentially transport to nearby surface water through runoff and erosion, especially if an application of chloropicrin coincides with, or is closely followed by a rain event. However, rapid volatilization of chloropicrin from surface w ater is expected to be an important route of dissipation. Chloropicrin is very soluble in water and has low adsorption into soil and thus it can potentially leach into shallow ground water and leaky aquifers. Chloropicrin has beenpreviously detected in n on

- targeted monitoring wells. Based on the database of pesticides in groundwater (U.S. EPA, 1992 1 

### ), chloropicrin was found at levels less than 1.00 μg/L in three wells out of 15,175 wells in Florida and was not found at any measurable levels in 1,386 well s in
California. Based on environmental fate data, modeling estimates, and monitoring data, the Agency does not expect chloropicrin to adversely impact ground water or surface water.

Based on the discussion above, no dietary or drinking water assessments have been previouslyperformed for chloropicrin

.

Conclusions: The dietary exposure database for chloropicrin is adequate for Registration
Review. The Agency does not anticipate the need to perform dietary or drinking water assessments during Registratio n Review.

5.0 Residential Exposure

Following t he 2009 Amended RED

, the Agency required three residential exposure studies for
the conventional uses of chloropicrin , including the following: a field volatility study for shank injection, bedded, untarped applications of chloropicrin (835.8100), a field volatility study for applications of chloropicrin using a water seal (835.8100), and an ambient air monitoring study for chloropicrin (non

- guideline). Two field volatility studies (MRIDs 48033801 and 4808 7401) have been submitted to the Agency. The Agency reviewed and included these studies in a 2011 chloropicrin addendum memo (Smith; D 348650 ; 1/11/2011) and thus these requirements are considered fulfilled. The Agency has not received the ambient air mo nitoring study at this time. Once this study is completed and submitted it will also be reviewed and incorporated during Registration Review.

1 U.S. Environmental Protection Agency. 1992. Pesticides in Groundwater Database, A compilation of monitoring studies: 1971

- 199 1, National Summary. EPA 734

- 12

- 92

- 0001.Chloropicrin Registration Review Human

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Page 6 of 19 

### There are currently no registered residential uses of chloropicrin . However, there is the potential for residential bystander inhalation exposure to chloropicrin after a soil fumigation application. The Agency has specifically focus ed on assessing acute inhalation exposures resulting from chloropicrin applications beca use peak chloropicrin air concentrations typically occur in the first
24 or 48 hours after application. There is also the potential for inhalation exposure to chloropicrin via ambient air. These exposures can be acute as well as longer

- term in nature.

There are two recent document s that analyzed acute residential bystander inhalation exposure to chloropicrin based on numerous f ield volatility studies and PERFUM ( P robabilistic E xposure and R isk model for Fum igants) air modeling for a variety of chloropicrin applications ( Smith and Reaves; D 348637 ; 4/30/2009 and Smith; D 348650 ; 1/ 11 /2011). The results of these assessments show that bystander inhalation exposure to chloropicrin after a soil fumigation application can vary depending on a variety of factors such as application method, agricultural tarps, water seals, and a number of soil parameters (i.e., soil moisture, organic content, etc.). For many application scenarios, the PERFUM air modeling results showed that acceptable chloropicrin air con centrations were attainable at some distance from a treated field and thus buffer zones were required to protect residential bystanders. The 2009 Amended Reregistration Eligibility Decision (RED) Document for chloropicrin provides more information on buff er zone development.

There are two recent documents that analyzed ambient air inhalation exposure to chloropicrin using limited ambient air monitoring data from California (Smith and Reaves ; D 348637 ; 4 /30/2009 and Smith ; D 404798 ; 10 / 9 /201 2 ). The results of these assessments show that ambient air inhalation exposures to chloropicrin can occur for extended periods especially in areas of high use during the season of high use. In some cases, short

- and intermediate

- term risk s exceed HED’s level of concern for chloropicrin (MOEs < 30 for short

- and intermediate

- term). In addition, no ambient air data are available for other regions/states that have high usage of chloropicrin like the southeast (Florida, North Carolina, South Carolina and Georgia) and the northwest (Washington, Oregon, and Idaho).

Conclusions : The residential exposure database for chloropicrin is adequate for Registration Review except for the outstanding exposure study (i.e., the ambient air study). HED will review and incorpo rate the ambient air monitoring study once it is submitted during Registration Review. The Agency does not anticipate the need to perform a dditional or updated PERFUM modeling during Registration Review unless new field volatility studies become available or points of departure (PODs) or uncertainty factors (UFs) for the residential exposure assessment change

.

During Registration Review, HED also plans to update the fumigant factors document (Dawson, Smith, and Shelat; D385314; 1/11/2011) . The fumigant f actors document provides a discussion of values and parameters used as the basis for buffer reduction credits (i.e., tarps) as well as for establishing GAPs (i.e., soil moisture) for the fumigants . This document impacts all of the soil fumigants including chloropicrin

.

6.0 Aggregate

- Risk Assessment

Acute and chronic aggregate

- risk assessments were not previously performed for chloropicrin because no dietary and drinking water assessments were performed (see Section 3.0 and 4.0 above)

.Chloropicrin Registration Review Human

- Health Assessment Scoping Document

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Page 7 of 19 

### Conclusions : Acute and chronic aggregate risk assessments are not anticipated during Registration Review.

7 .0 Occupational Exposure

The occupational exposure database for chloropicrin is adequate for Registration Review. No occupational exposure data were required for chloropicrin as part of the 2009 Amended RED.

The Amended RED focused on three main use categories of chloropicrin: (1) pre

- plant soil fumigations (e.g., agricultural and commercial greenhouse); (2) residential uses (warning agent for sulfuryl fluoride); and (3) other specialized fumigations (e.g., spot tree replant sites and remedial wood treatments). Chloropicrin use in empty grain bins and empty potato storage/house cellars were voluntarily cancelled as part of the chloropicrin RED process. Since the Amended RED was issued, n o new uses of chloropicrin have been registered and the agency determined that the use of chloropicrin as a warning agent prior to sulfuryl fluoride residential fumigations is not a pesticidal use.

Occupational Handlers
Conventional Uses

There is potential for occupational handler inhalation exposure to chloropicrin to occur based on the registered conventional uses of chloropicrin

. HED has not previously performed a dermal exposure assessment for chloropicrin since it is category I for primary skin irritation and acute dermal toxicity and significan t dermal exposure is not expected (see Section 2.0 for more information). The most recent HED document that analyzed the potential occupational handler
risks to chloropicrin is the 2009 risk assessment ( Smith and Reaves; D 348637 ; 4/30/2009 ). HED
assessed the acute and short

- and intermediate

- term chloropicrin inhalation exposure for the
conventional uses of chloropicrin

.

For soil fumigation, HED utilized a number of chloropicrin specific inhalation exposure studies to assess occupational handler inhalation exposures to chloropicrin in the 2009 assessment

. These studies examined a variety of tasks associated with soil fumigation such as loading and applying. In some cases, acute as well as short

- and intermediate

- te rm risks exceed ed HED’s
level of concern for chloropicrin at baseline (MOEs < 1 for acute and MOEs < 30 for short

- and
intermediate

- term). Even with the addition of an organic vapor respirator, some short

- and
intermediate

- term risks exceed ed HED’s level of concern for chloropicrin

.

Antimicrobial Uses

The potential for occupational dermal exposure from application of chloropicrin may occur during the injection or pouring up to 2 pints per pole of the undiluted product directly into the

pre

- drilled holes or by filling vials to be placed into holes in timber. Potential dermal exposure may also occur during the process of pouring chloropicrin from original packaging containers into smaller containers prior to injecting or pouring into the pre

- drilled holes. The most recent AD document that analyzed the potential occupational handler risks to chloropicrin is the 2007 risk assessment (Leighton and Walls; D314399; 4/20/2007). The risks associated with dermal applicator exposure are not quantified in that docu ment . The PPE on current labels such as long pants, long sleeved shirts, and chemical resistant gloves mitigate skin irritation effects resulting from potential dermal exposure to chloropicrin.Chloropicrin Registration Review Human

- Health Assessment Scoping Document

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Page 8 of 19 

### As with the dermal exposure above, the potential for inhalation exposure to chloropicrin vapor may occur during the transfer from original packaging into smaller application containers or vials and during the injection or pouring of up to 2 pints per pole of the undiluted product directly into the pre

- drille d holes. Exposure during the placement of prefilled vials into drilled holes should not occur unless the vials are accidentally damaged. Based on the use pattern (i.e., intermittent exposures throughout the work shift), the acute inhalation endpoint sele cted for chloropicrin is a good indicator of the need for respiratory and eye protection. However, ambient conditions would presumably result in a minimal concentration over a long

- term duration. Workers are expected to be exposed to various concentration s of chloropicrin throughout the workday with peak concentrations occurring during open pouring of the products. Applications are performed outdoors and the product is capped into pre

- drilled holes, thereby reducing the potential for off gassing immediate ly after the application.

To mitigate the potential inhalation risks to applicators, respiratory protection was recommended during the actual pouring of chloropicrin from containers into vials and during pouring/injecting into the pre

- drilled holes. Curre nt labels provide specific instructions for workers using (1) air

purifying respirators, (2) supplied air respirators, and (3) self contained breathing apparatuses (SCBAs). In general, applicators must wear air

- purifying respirators. However, certain exp osure scenarios such as filling vials in enclosed areas may trigger the need for the use of a supplied air
or SCBA respirators. These recommendations that were stated in the RED were based on the need to protect applicators when air concentrations are abov e the acute level

- of

- concern of 0.073 ppm and the TWA of 0.0005 ppm. The RED also states that the minimum type of respiratory protection to require is difficult to determine because the actual air concentration in the vicinity of the applicator is unknown and would be hard to quantify in the field. The current labels have been adjusted based on mitigation in the 2009 amended RED. Additional label statements for respiratory protection that are not already present in the 2009 amended RED label table are not anticipated as needed for registration review.

Occupational Post

- Application
Conventional Uses

HED previously determined there were chloropicrin inhalation risk concerns for workers reentering chloropicrin fumigated fields 48 hours after application. As part of the 2009 Amended RED, the Agency placed various restrictions on reentry of workers into fumigated fields. With these restrictions, HED believes that risks to reentry workers will not exceed the
HED ’s level of concern

.

Antimicrobial Uses

In g eneral, remedial wood treatment for poles and beams on bridges do not occur in high traffic areas for bystanders. However, distribution poles are numerous and often located in people’s front yards. Therefore, any potential bystander exposure would be bes t represented by the acute duration. The most recent AD document that analyzed the potential post

- application risks to chloropicrin is the 2007 risk assessment (Leighton and Walls; D314399; 4/20/2007). There is no air monitoring data available to determin e if chloropicrin vapor is released near treated poles. To minimize the escape of the chloropicrin gas from treated poles the 2009 amended RED specified instructions to minimize potential bystander exposures. EPA confirmed that the current labelsChloropicrin Registration Review Human

- Health Assessment Scoping Document

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Page 9 of 19 

### incorpo rated specific 2009 amended RED statements to minimize the potential for vapors. The specifications include the following instructions:

plug the pre

- drilled holes immediately after chloropicrin applications; use a barrier wrap on treated wood, where neede d, to confine the vapor; do not treat drilled holes if they intersect internal rot pockets or splits; and
do not treat structures/beams indoors.

Conclusions: The occupational exposure database is adequate to support the Registration Review process for the conventional and antimicrobial uses of chloropicrin

. HED and AD do not anticipate the need to perform additional or updated occupational exposure assessments during Registration Review unless new occupational exposure studies become available or points of departure (PODs) or uncertainty factors (UFs) for the occupatio nal exposure assessment.

8.0 Public Health and Pesticide Epidemiology Data

An updated review of chloropicrin incident reports was recently prepared by HED ( Recore and
Evans , D 414490

, 8 / 29 /20 13 )

. For this evaluation, both OPP Incident Data System (IDS) a nd 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) databases was consulted for pesticide incident data on the acti ve ingredient chloropicrin

. Chloropicrin is not included in the Agricultural Health Study ( AHS ) and therefore

no information from AHS was included in this report

.

The IDS includes reports of alleged human health incidents from various sources, including mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6 (a) (2) reports from registrants, other federal and state health and environmental agenci es and individual

consumers. IDS contain reports from across the U.S. and most incidents have all relevant product information recorded. Reports submitted to the IDS represent anecdotal reports or allegations only, unless otherwise stated in the report. IDS records incidents resulting in high er severity outcomes in more detail, in a module called the Main IDS module. This system stores incident data for death, major and moderate incidents, and it includes more details about the location, date and nature of the incident.

In A ggregate IDS , from January 1, 200 8 to February 19, 2013, there were 18 reported incident s involving chloropicrin

. These incidents were classified as minor severity. For the M ain IDS,
from January 1, 200 8 to February 19, 2013, there were 12 incidents reported for the single chemical only in the database. One incident was classified as major severity; six incidents were classified as moderate severity; four incidents were classified as minor severity; one incident was unspecified cla ssification. There were 30 additional incidents reported involving more than one
chemical.

The SENSOR

- Pesticides database covers 11 states from 1998

- 2009, although reporting varies from state to state. Cases of pesticide

- related illnesses are ascertain ed from a variety of sources, including: reports from local Poison Control Centers, state Department of Labor workers’ compensation claims when reported by physicians, reports from State Departments of Agriculture, and physician reports to state Department s of Health. Although both occupational
and non

- occupational incidents are included in the database, SENSOR

- Pesticides focuses on occupational pesticide incidents, and is of particular value in providing that information. The
state coordinator at the 11 r espective state Departments of Health conducts case follow

- upChloropicrin Registration Review Human

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Page 10 of 19 

### activities such as obtaining medical records to verify symptoms and severity. Using standardized protocol and case definitions derived from poison center reporting, the state SENSOR

- Pesticide

c oordinator enters the incident information into the state

- based system which is sent to NIOSH annually to be aggregated.

A query of SENSOR

- Pesticides 1998

- 2009 indentifies 78 cases, stemming from 31 events, involving chloropicrin; 10 cases are single act ive ingredient and 68 are multiple active ingredient cases. There was one case fatality; two cases were high in severity; 25 cases were moderate in severity; and 50 cases were low in severity.

Based on the number of incidents reported for chloropicrin , t he effects noted in the incidents, and the recently implemented safety measures put into place in 2012 f or all soil fumigant pesticides ; chloropicrin warrants further incident analysis during registration review . This further analysis will include reviewing chloropicrin incident data from other sources as well as cases studies and

a medical literature search on human health effects of chloropicrin

.

9 .0 Tolerance Assessment and International Harmonization

There are currently no tolerances for chloropicrin (see Section 3.0 above)

.

10 .0 Environmental Justice

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

most recent chloropicrin human

- health risk assessment, i n accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

Income Populations,” (http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP typically considers th e highest potential exposures from the legal use of a pesticide when conducting human

- health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., a nd people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk
estimates are based on the best available information.

11.0 Cumulativ e

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 chloropicrin and any other substances. For the purposes of this assessment, therefore, EPA
has not assumed that chloropicrin has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common

m echanism 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 t o have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

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Page 11 of 19 

### 12.0 Endocrine Disruption

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, includ ing effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates
acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios fr om the existing hazard database. However, as required by FFDCA section 408(p), chloropicrin is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substance s (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tie red approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemi cals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the availab le data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and
establish a dose

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Chloropicrin is not among the group of 58 pesti cide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of Registration R eview, EPA will issue future EDSP orders/data
call

- ins, requiring the submission of EDSP screening assays for chloropicrin

. For further
infor mation on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

1 3 .0 H uman Studies

Past chloropicrin risk assessments rely on an intentional dosing human sensory irritation study (Cain, 2004; MRID 46443801) as the basis for the acute chloropicrin endpoint. The Human Studies Review Board (HSRB) evaluated the ethical conduct and scientific validity of the chloropicrin human study at a June 2006 meeting . The HSRB concluded that there was not clear and convincing evidence that the conduct of the research was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing when the study was conducted. The chloropicrin human study also was considered scientifically sound for the purpose of estimating a safe level of inhalation exposure to chloropicrin (HSRB Final Report, October 2006; http://www.epa.gov/osa/hsrb/files/june2006mtgreportfinal100606 ).Chloropicrin Registration Review Human

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Page 12 of 19 

### 1 4 .0 Risk Assessment Updates and Data Deficiencies

No new data deficiencies outside those previously required through reregistration were identified for chloropicrin.

HED and AD anticipate conducting the following risk assessment updates during Registration
Review: Toxicology: None Residue Chemistry: None Dietary Exposure: None Occupational/Residential Exposure:

o HED will be required to perform a n ambient air assessment during Registration Review once the chloropicrin ambient air study is submitted to the Agency.
1 5 .0 References

Memoranda Relevant to Registration Review.

Author Barcode Date Title

S. K nizner D200326,

D202185 8/25/94 Chloropicrin. Reregistration Case No. 0040. Chemical
No. 081501. MRID #43185602

J. Abbotts None 8/15/96 Chloropicrin (081501), Reregistration Case No. 0040. Tolerances and Residue Chemistry Data Requirements.

T. Leighton and
C. Walls D314399 4/20/2007

C. Smith and E.
Reaves D 348637 4 /30/2009 Chloropicrin: Third Revision of the HED Human Health
Risk Assessment.

J. Dawson, C. Smith, and S.
Shelat D385314 1/11/2011 Methyl Bromide ( PC Code 053201), Chloropicrin (PC Code 081501), Dazomet (PC Code 035602), Metam Sodium and Potassium (PC Codes 039003 & 039002), MITC (PC Code 068103), DP Barcode 385314 , Second Update To Health Effects Division Recommendations for Good Agricultural Practi ces and Associated Buffer Credits

C. Smith D 348650 1/11/2011 Chloropicrin: Addendum to the Third Revision of the HED
Human Health Risk Assessment.

C. Smith D 404798 10/9/2012 The Health Effects Division’s Review of the Chloropicrin
Manufacturers’ Task Force Request for a Waiver for 2012 Chloropicrin Ambient Air Monitoring Study (GDCI

081501

- 1155)

A. D unbar TXR

0056662 5/22/13 Chloropicrin: Summary of Hazard and Science Policy Council (HASPOC) Meeting of May 9, 2013:
Recommendations on the need for acute and subchronic neurotoxicity studies (870.6200).
S. Recore and E.
Evans D414490 8/29/2013 Chloropicrin : Review of Human Incidents



### Attachments:

Attachment 1: Chemical Identity Table.
Attachment 2: Chloropicrin Acute, Subchronic, and Chronic Toxicity Profile
Attachment 3: Chloropicrin Endpoint Selection Tables.Chloropicrin Registration Review Human

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Page 13 of 19 

### Attachment 1: Chemical Identity Table

.

Physical and Chemical Properties of Chloropicrin

Parameter Value /Description Reference Physical State Near colorless, oily liquid Melting point/range

- 69.2 o C Merck Index Boiling point/range 112 o C at 757 mm H Merck Index Density 1.7 g/ml at 25 o C D268927 Water Solubility Very soluble Solvent Solubility 70.5 g/mL at 25 o C in acetone, ethyl alcohol, hexane, and xylene D268927 Vapor Pressure 23.8 mm H g at 25 o C D268927 Dissociation constant (pK
a ) Not applicable, nonpolar D268927 Octanol/water partition coefficient Log (K OW ) = 2.58 D268927Chloropicrin Registration Review Human

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Page 14 of 19 

### Attachment 2: Chloropicrin Acute, Subchronic, and Chronic Toxicity Profile (as of May 2013)

Chloropicrin Toxicity Profile

Guideline No./Study Type MRID No.

(year)/Classification/Exposure

Conditions Results

Special Human Study: Odor Threshold, Nose, Eye, Throat Irritation 46443801 (2004) Acceptable/Non

- Guideline
3 Phases
Phase 1: 62 subjects (356, 533, 800, and 1200 ppb) for 1

- 2 seconds from a vapor delivery
devise
Phase 2: 62 subjects (0, 50, 75, 100, 150 ppb) for 30 minutes in
a walk

- in chamber
Phase 3: 32 subjects (100, 150 ppb) for 60 mins/day for 4 consecutive days in a walk

- in
chamber Phase I: Registrant Analysis: median odor threshold: 700 ppb; (M=590 ppb and F=810 ppb) median eye irritation: 900 ppb; (M=790 ppb and F=1010 ppb) No localization of the throat; >1200ppb HED Analysis:
Odor: 10 th percentile 216 ppb; median 406 ppb; 90 th 764 ppb Eye: 10 th percentile 37 ppb; median 242 ppb; 90 th 1565 ppb

Phase 2: 38% of subjects (8M/8F) detected chloropicrin initially at 50 ppb and consistently up to 150 ppb. Severity of eye irritation not examined

. NOAEL not determined. Nose and throat irritation not as sensitive as in eyes.

Phase 3: NOAEL not established. However, BMCL 10 of 73 ppb, based on eye irritation scores of 1.5 during the maximal response period of 30

- 55 minutes. Nasal
nitric oxide incre ased and changes in air flow both at 100 ppb and 150 ppb. Nose and throat irritation less sensitive endpoints.
870.1100
Acute Oral

- Rat 05014376 (1976) Acceptable/Guideline. LD 50 = 37.5 mg/kg Toxicity Category I
870.1200
Acute Dermal

- Rat 05014376 (1976) Acceptable/Guideline. LD 50 = 100 mg/kg Toxicity Category I
870.1300
Acute Inhalation

- Mouse 45117901 (1999) Acceptable/Non

- Guideline

Head only study, 4 Albino
Swiss

- Webster male mice/grp exposed to 0.99, 3.20, 4.20, 7.25, 10.00, 14.50 ppm (analytical concen.)or 0.00664, 0.0215, 0.0282, 0.0486, 0.0671, 0.0973 mg/L (calculated analytical concen.)of gaseous CP for 30
mins. No deaths seen at any dose level. Clinical obs. normal
before and aft er exposure. Body wt. gains may been decreased at HDT only (8% of initial body wt. in control and 2% at the HDT).

- The exposure level at 50% RD (RD 50 ) was 2.34 ppm with 95% CI of 1.84 to 2.98 ppm or RD 50 of 0.016 mg/L and 95% CI of 0.012 mg/L to 0.020 mg/L

.

- 0% depression in the respiration rate was plotted by the % depression in the respiration rate reported in the study versus log exposure level and extrapolating the graph to 0% depression. The RD 0 respiratory depression occurs around 0.0017 to 0.0019 mg/ LChloropicrin Registration Review Human

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Page 15 of 19 

### Chloropicrin Toxicity Profile

Guideline No./Study Type MRID No.

(year)/Classification/Exposure

Conditions Results

870.1300
Acute Inhalation

- Rat 45117902 (1999) Acceptable/Non

- Guideline

Whole body inhalation study, 5 Sprague Dawley rats/sex/grp were exposed to 0, 10.6, 18.0, or 28.5 ppm (analytical) or 0, 0.071, 0.121, 0.158 mg/L (calculated) of aerosolized CP
for 4

- hrs and held for 2 days after exposure. Particle sizes had
a MMAD from 4.85 ·m to 6.1·m
with a GDS of 1.4 to 1.6. LC 50 was 17 ppm (M) and 19 ppm (F). Death only occurred at 2 top dose levels up to 2 days post

- exposure. Clinical signs: obs noted at all dose levels, labored breathing, gasping, decreased activity, nasal discharge, salivation, moist rales. Top 2 levels produced gasping for last 2 hrs of exposure. Gross pathology: Liver, adrenal wts, and histological findings increased at HDT. Histological findings of respiratory tract were seen at all dose levels and damage to the lungs, such as congestion, bronchiole mucosal edema, necr osis, and cellular infiltrates.

- No NOAEL demonstrated. LOAEL = 10.6 ppm or 0.071 mg/L (LDT).

870.2400 Primary Eye Irritation

- Rabbit N/A Reserved

870.2500 Primary Skin Irritation

- Rabbit 05014376 (1976) Acceptable/Guideline Corrosive Toxicity Category I

870.2600
Dermal Sensitization N/A Reserved

870.3100 Subchronic Feeding

- Rat Not required by the Agency

870.3100 Subchronic Feeding

- Mice Not required by the Agency

870.3100 Subchronic Feeding

- Mice Not required by the Agency

870.3150 Subchronic Feeding

- Dog Not required by the Agency

870.3200
21

- Day Dermal

- Rat Reserved

870.3465
13

- Week Inhalation

- Mouse 43063201 (1993) Acceptable/Guideline
10 CD

- 1 mice/sex/concentration of 0, 0.3, 1.0, or 3.0 ppm in a
whole

- body chamber, 6 h/day, 5 days/week for 13 weeks. NOAEL = 0.3 ppm (0.002 mg/L/day) LOAEL = 1.0 ppm (0.007 mg/L/day) based on decreased body weight and food consumption, increased absolute and relative lung weights in both sexes, and histopathological lesions of the nasal cavity and lungs of females.

870.3465
13

- Week Inhalation

- Rat 43063201 (1993) Acceptable/Guideline 10 CD rats/sex/concentration 0, 0.3, 1.0, or 3.0 ppm in a whole

body chamber, 6 h/day, 5 days/week for 13 weeks. NOAEL = 0.3 ppm (0.002 mg/L/day) LOAEL = 1.0 ppm (0.007 mg/L/day), based on increased lung weights of both sexes, and histopathological changes in the nose of females and lungs of males and females.Chloropicrin Registration Review Human

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Page 16 of 19 

### Chloropicrin Toxicity Profile

Guideline No./Study Type MRID No.

(year)/Classification/Exposure

Conditions Results

870.3700 Inhalation Developmental Toxicity

- Rat 42740602 (1993) Acceptable/Guideline
30 mated female Crl:CD VAP/Plus rats to 0, 0.4, 1.2, or 3.5 ppm in a whole

- body inhalation chamber, 6 h/day on
GDs 6

- 15 Maternal NOAEL = 0.4 ppm (0.003 mg/L/day) Maternal LOAEL = 1.2 ppm (0.008 mg/L/day) based on mortality, decreased b ody weight and food consumption, and signs consistent with CP toxicity. Developmental NOAEL = 1.2 ppm (0.008 mg/L) Developmental LOAEL= 3.5 ppm (0.024 mg/L), based on decreased pup body weights.

870.3700 Inhalation Developmental Toxicity

- Rabbit 42740601 (1993) Acceptable/Guideline
20 inseminated female New Zealand white rabbits/group to 0, 0.4, 1.2, or 2.0 ppm in a whole

body inhalation chamber, 6 h/day, on GDs 7

- 29 Maternal NOAEL is 0.4 ppm (0.003 mg/L) Maternal LOAEL is 1.2 ppm (0.008 mg/L), ba sed on mortality, body weight loss, and decreased food consumption. Developmental NOAEL= 0.4 ppm (0.003 mg/L) Developmental LOAEL= 1.2 ppm (0.008 mg/L), based on abortions and decreased fetal weights.

870.3800
Inhalation 2

- Generation Reproductive Toxicity

- (Main study)
Rat 43391901 (1994) Acceptable/guideline
26 Crl:CD VAF/Plus rats/sex/group to 0, 0.5, 1.0, or 1.5 ppm in whole body
inhalation chamber Note: Offspring not directly exposed until PND 28 Parental systemic NOAEL > 1.5 ppm (0.0101 mg/L) Parental systemic LOAEL not identified Offspring NOAEL > 1.5 ppm (0.0101 mg/L) Offspring LOAEL not identified Reproductive NOAEL > 1.5 ppm (0.0101 mg/L) Reproductive LOAEL not identified

870.3800 Range

- finding, Inhalation
2

- Generation Reproductive Toxicity

- Rat 46427801 (conducted 1992, study report 1996)
10 Crl:CD VAF/Plus rats/sex/group by whole body exposure 0, 0.4, 1.0, or 2.0 ppm for 6hrs/day, 7 days/week during premating (14 days) and gestation day 0

- 20 No treatment

- related mortality, clinical signs, or necropsy findings in any parental males or females,
and no treatment

- related effects on reproductive parameters. Mean body weight and weight gain decreased in high

- dose group (1

- 3% M& 5

- 6% F) beginning at we ek 1. Maternal body weight was
decreased 5

- 8% and decreased 17% during gestation. Food consumption decreased 8

- 14% in males and 14% in females during premating and 7% during gestation. Litter size decreased 33% and uterine implantation sites decreased 3 0% in the high

- dose

group.

870.4100 Chronic Feeding Toxicity

- Rat 43744301 (1995) Acceptable/guideline 30 Sprague

- Dawley Crl: CD ® BR, VAF/Plus rats/sex/dose by gavage in corn oil at dose levels at 0, 0.1, 1.0, or 10 mg/kg/day
for 104 weeks Only clinical toxicity observed was salivation after dosing in high

- dose male and female rats. Dose

related increase in incidence of subcutaneous masses
of skin of females related to the increased incidence of mammary fibroadenomas. Hyper

- keratosis and
h yperplasia of the nonglandular stomach in both
sexes. Females had dose

- related increase in incidence of fibroadenoma of the mammary gland at high

- dose.
Increased rate of C

- cell hyperplasia of the thyroid in high

- dose females. NOAEL = 0.1 mg/kg/day [F]
NOA EL = 1.0 mg/kg/day [M] LOAEL = 1.0 mg/kg/day [F], based on periportal hepatocyte vacuolation and thyroid C

- cell hyperplasia and stomach lesions at the high

- dose. LOAEL = 10 mg/kg/day [M], basedon on stomach
lesions.Chloropicrin Registration Review Human

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Page 17 of 19 

### Chloropicrin Toxicity Profile

Guideline No./Study Type MRID No.

(year)/Classification/Exposure

Conditions Results

870.4100 Chronic Feeding Toxicity

- Dog 43196301(1994) Acceptable/guideline 4 beagle dogs/sex/dose in corn oil by gelatin capsule to 0, 0.1, 1.0, or 5.0 mg/kg/day for one

year NOAEL [M] = 0.1 mg/kg/day NOAEL [F] = 1.0 mg/kg/day LOAEL [M] = 1.0 mg/kg/day, based on gastrointestinal irritation (vomiting and diarrhea), and blood chemistry alterations, LOAEL [F] = 5.0 mg/kg/day, based on gastrointestinal irritation (vomiting and diarrhea), microcytic hypochromatic anemia, and blood

c hemistry alterations.

870.4200 Carcinogenicity
Inhalation

- Mouse (78 weeks) 43632201 (1997) Acceptable/guideline
50 CD

- 1 ® mice/sex/concentration by dynamic whole body at 0, 0.1, 0.5, or 1.0 ppm for 6hrs/day, 5 days/week for 78 weeks NOAEL = 0.1 ppm (0.0007 mg/L) LOAEL = 0.5 ppm (0.0034 mg/L), based on systemic toxicity and irritation, based on decreased body weights and gains, increased lung weights, and histological changes in the nasal cavity, upper respiratory tract and lungs. No significant treat ment

- related increase in tumors.

870.4200 Carcinogenicity/gavage

Mouse/Rat [bioassay] 05014915 (1978) supplemental

Rats: [M]: 0, 25 or 26 mg/kg/day [F]: 0, 20, or 22 mg/kg/day Mice [M]: 0, 66 mg/kg/day [F]: 0, 33 mg/kg/day High

- incidence of early death in CP dosed rats. No neoplasm observed at higher incidences in dosed rats from controls. Rapid decrease in survival after first year in both sexes of mice. Proliferative lesions of squamous epithelium of the
forestomach of mic e included two carcinomas and a papilloma. Statistical analysis did not demonstrate related to CP. Bioassay of CP did not permit evaluation of carcinogenicity due to short survival
time of mice and rats.
870.4300
Chronic Inhalation Toxicity/Carcinogenici ty

Rat. (2 year) 43755301 (1995) Acceptable/guideline 50 Sprague

- Dawley CD rats/sex/concentration 0, 0.1, 0.5, or 1.0 ppm in a whole body inhalation chamber for 6 hrs/day, 5days/week for up to 108 weeks NOAEL =0.1 ppm (0.0007 mg/L) LOAEL = 0.5 ppm (0.0034 mg/L), based on increased mortality rate and decreased mean survival time in males, and transiently decreased body weight gains in
both sexes. Port of entry NOAEL = 0.5 ppm Port of entry LOAEL = 1.0 ppm (males), based on
severe rhinitis of the anterior na sal cavity.
870.5100
Bacterial Reverse Mutation Test (Ames Assay) 41960801 (1990) Acceptable/guideline
10

- 3333 μg/plate +/

- S9 (2 independent trials) Positive: S9

- activated CP is m utagenic in Salmonella typhimurium strains TA98, and TA100.

870.5300 Mutagenic

- Lymphoma
Mutation

- Mouse 41960803 (1990) Acceptable/guideline
0.038

- 0.75 nL/mL

– S9
0.89

- 16.0 nL/mL +s9 Negative: CP ranging from 0.038 to 0.75 nL/mL

- S9 and 0.89 to 16 nL/mL +S9 did not induce a mutagenic response in two independently performed mouse lymphoma forward mutation assays up to cytotoxic
concentrations

. 870.5375
In Vitro Chromosomal
Aberration in Chinese
Hamster V79 Cells 41960802 (1990) Acceptable/guideline
0.75 to 1 nL/mL

– S9
4

- 6 nL/mL +S9 Positive: Nonactivated doses of CP from 0 .75 to 1 nL/mL induced a reproducible and significant clastogenic response in CH V79 cells harvested 12 hours post

- treatment. S9

- activated CP was negative.
Nonactivated CP was clastogenic over a narrow range of cytotoxic concentrations. CP in the absence of S9 activation is a clastogen in this mammalian test system.
870.53 95
Mammalian E rythrocyte
M icronucleus T est

Mouse 4 8067601 ( 2010 ) Acceptable/guideline 0, 62.5, 125 and 250 mg/kg(oral gavage); cell harvest at 24 Negative up to an overtly toxic dose (250 mg/kg).Chloropicrin Registration Review Human

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Page 18 of 19 

### Chloropicrin Toxicity Profile

Guideline No./Study Type MRID No.

(year)/Classification/Exposure

Conditions Results

and/or 48 hours post dosing

870.5 550
Unscheduled DNA Synthesis in mammalian
cells in culture

- Rat hepatocytes 41960804 (1990) Acceptable/guideline
0.3 to 6 nL/mL Negative: CP was not genotoxic in primary rat hepatocytes over a concentration range (0.3 to 6 nL/mL) that included moderately cytotoxic levels.

No Guideline
In vivo Unscheduled DNA Synthesis

- Rat hepatocytes 48067501 (2010) Acceptable 0, 85 sand 250 mg/kg (oral gavage); cell harvest at 2 & 14 hours postdosing Negative up to an overtly toxic dose (250 mg/kg).

870.6200
Inhalation Acute Neurotoxicity

- Rats Not required by the Agency 1

870.6200 Feeding Subchronic Neurotoxicity

- Rats Not required by the Agency 1

870.7485
Metabolism

– Rat \ Not available

870.7600
Dermal Penetration

- Rat Not required by the Agency

870.7 8 00 Immunotoxicity Not required by the Agency 2

1 HED’s Hazard and Science Policy Council (HASPOC) has determined that a neurotoxicity battery is not required for chloropicrin ( Dunbar; 5/22/13; TXR 0056662 ).

2 The 2009 Amended RED required an Immunotoxicity study for chloropicrin but this requirement was subsequently waived (Reaves; D382316; 4/27/2011).Chloropicrin Registration Review Human

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Page 19 of 19 

### Attachment 3: Chloropicrin Endpoint s from 20 09 Risk Assessment

Summary of Toxicological Dose and Endpoints for Use in Chloropicrin Human Health
Inhalation Risk Assessment

Risk Assessment Study NOAEL/LOAEL Endpoint HED HC or HEC
Acute
Inhalation Non

occupational Human Irritation

Study BMCL 10 = 73 ppb

LOAEL = 100 ppb Eye irritation, ↑ nasal

nitric oxide & change in
air flow HC = 73 ppb
UF = 1

Occupational Human Irritation

Study BMCL 10 = 73 ppb

LOAEL = 100 ppb Eye irritation, ↑ nasal

nitric oxide & change in
air flow HC = 73 ppb
UF = 1

Short

- and
Intermediate

Term
Inhalation (1

- 6 months) Non

occupational 13

- Week

Inhalation Study
in Mice NOAEL = 0.3 ppm

LOAEL = 1.0 ppm Nasal and lung damage,

increased lung weights HEC = 0.008 ppm
UF = 30

Occupational 13

- Week

Inhalation Study
in Mice NOAEL = 0.3 ppm

LOAEL = 1.0 ppm Nasal and lung damage,

increased lung weights HEC = 0.035 ppm
UF = 30

Long

- term Inhalation (> 6 months) Non

occupational 78

- Week Cancer

Study in Mice NOAEL = 0.1 ppm

LOAEL = 0.5 ppm Nasal discharge, nasal and

lung damage, increased lung weights, body weight
loss HEC = 0.004 ppm
UF = 30

Occupational 78

- Week Cancer

Study in Mice NOAEL = 0.1 ppm

LOAEL = 0.5 ppm Nasal discharge, nasal and

lung damage, increased lung weights, body weight
loss HEC = 0.015 ppm
UF = 30

Cancer Chloropicrin is currently not considered a carcinogen.