UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES July 27, 2004 MEMORANDUM SUBJECT: PENTACHLORONITROBENZENE ( PCNB): Revised HED Chapter of the Reregistration Eligibility Decision Document ( RED). PC Code: 056502. Case# 0128 List A. DP Barcode D291281.

FROM: Diana Locke, Ph. D. Toxicologist Reregistration Branch II Health Effects Division ( 7509C)

THRU: Alan Nielsen, Branch Senior Scientist Reregistration Branch II Health Effects Division ( 7509C)

TO: Margaret Rice, Chief Reregistration Branch II Special Review and Reregistration Division ( 7508W)

Attached is the revised Human Health Assessment for PCNB. The assessment has been revised according to the " error only" comments submitted jointly by Amvac Chemical Corporation and Crompton Corporation, registrants of PCNB manufacturing use and end use products. The Agency solicited these comments from the registrants as part of procedures to ensure transparency and public participation in reregistration eligibility decision making. The Agency specifically solicited comments on errors in the original risk assessment, " such as those that are mathematical, computational, or typographical" rather than comments pertaining to " matters of policy, interpretation, or applicability of data." This revised assessment accounts for errors of the first type as submitted by the registrants, and does not address comments of the second type. We believe that this revised assessment is suitable now for public review and comment. This document will be made available to the public at the same time as the revised " Environmental Fate and Ecological Risk Assessment for the Re registration of Pentachloronitrobenzene." The environmental fate and ecological risk assessment also has been revised pursuant to the " error only" comments submitted jointly by Amvac Chemical Corporation and Crompton Corporation. While examining the comments of these registrants, the Agency became aware of, and corrected, some errors in the models for estimating environmental concentrations of PCNB and its metabolites. The corresponding corrections have not been made to the revised Human Health Assessment for PCNB at this time, but it has been determined that the changes, when incorporated, will not have a significant impact on drinking water exposures or on the risk profile for PCNB health effects as a whole. Changes to the health risk assessment pursuant to the revised estimated environmental concentrations will be incorporated in the final risk assessment.

The revised Human Health Assessment for the PCNB RED document was generated as part of Phase 3 of the Interim Public Participation Process. The Health Effects Division's ( HED) chapter reflects the Agency's current guidelines concerning the retention of the Food Quality Protection Act ( FQPA) factor and risk assessment. This chapter includes a summary of the product chemistry from Ken Dockter, residue chemistry and dietary risk assessment from Mohsen Sahafeyan, toxicology review from Laurence Chitlik, occupational and residential exposure assessment from Seyed Tadayon, incidence review from Ruth Allen, drinking water exposures from Cheryl Sutton [ Environmental Fate and Effects Division ( EFED)], as well as risk assessment and characterization from Diana Locke.

This assessment provides information to support the issuance of a risk management decision document known as a Reregistration Eligibility Decision ( RED) Document for PCNB. EPA's pesticide reregistration process provides for the review of older pesticides ( those initially registered prior to November 1984) under the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) to ensure that they meet current scientific and regulatory standards. The process considers the human health and ecological effects of pesticides and incorporates a reassessment of tolerances ( pesticide residue limits in food) to ensure that they meet the safety standard established by the Food Quality Protection Act ( FQPA) of 1996.

cc: Margaret Stasikowski Debbie Edwards William Hazel Jill Bloom Tom Myers TABLE OF CONTENTS 1.0 EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION . . . . . . . . . . . . . . . . . . . 5 3.0 HAZARD CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.1 Hazard Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.2 FQPA Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.3 Dose Response Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.4 Endocrine Disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.5 Potential Hexachlorobenzene and Pentachlorobenzene Contamination . . . . . . . . . . 14 3.6 Residues of Pentachlorophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . 16 4.1 Summary of Registered Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4.2 Tolerance Reassessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 4.3 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.3.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.3.2 Dietary Exposure Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 <IP_ADDRESS> Acute Dietary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 <IP_ADDRESS> Chronic Dietary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 <IP_ADDRESS> Cancer Dietary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4.4 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4.4.1 Environmental Fate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4.4.2 Estimated Drinking Water Concentrations ( EDWCs) . . . . . . . . . . . . . . . . 26 4.4.3 Monitoring Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.5 Residential and Other Non occupational Exposure/ Risk Pathways . . . . . . . . . . . . . 27 4.5.1 Home Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 <IP_ADDRESS> Handler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 <IP_ADDRESS> Residential Postapplication . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.5.2 Recreational . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 4.6 Other ( Spray Drift; Farm Worker Children, etc.) . . . . . . . . . . . . . . . . . . . . . . . . . . 31 5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATIONS . . . . . . . . 32 5.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 5.2 Acute Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 5.3 Short Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 5.4 Intermediate Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 5.5 Chronic Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 5.6 Cancer Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 6.0 CUMULATIVE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 7.0 OCCUPATIONAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 7.1 Agricultural, Seed Treatment, and Non crop/ Utility Uses . . . . . . . . . . . . . . . . . . . . 35 7.1.1 Handler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 <IP_ADDRESS> Exposure and Risk Estimates for Agricultural Uses . . . . . . . . . . 36 <IP_ADDRESS> Exposure and Risk Estimates for Seed Handlers . . . . . . . . . . . . 38 7.1.2 Postapplication Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 <IP_ADDRESS> Noncancer Postapplication Exposure and Risk Estimates . . . . . . 40 7.2 Incident Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 8.0 DATA NEEDS/ LABEL REQUIREMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 8.1 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 8.2 Product Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 8.3 Residue Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 ATTACHMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 APPENDIX 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 APPENDIX 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 1 PENTACHLORONITROBENZENE 1.0 EXECUTIVE SUMMARY PCNB is an organochlorine used mainly as a soil applied, contact ( non systemic), fungicide for soil treatment around vegetables, field crops, turf, and ornamentals. PCNB has agricultural, non food/ feed, and residential uses. As a fungicide, PCNB is effective in retarding germination and colony growth, and suppressing sporulation. PCNB is also used as a seed treatment for the control of soil and seed borne diseases of root, leafy, and row crops, as well as turf. It is primarily applied as a spray, through sprinkler irrigation systems or granular preparations to soil, though it has many other methods of application. It is formulated as a flowable concentrate ( FlC), water dispersible granular ( WDG), wettable powder ( WP), emulsifiable concentrate ( EC), granular ( G), dust ( D), and ready to use ( RTU) formulations. These products may be applied as pre plant incorporated applications, in furrow applications, broadcast applications, or banded applications using ground equipment, or as seed treatments.

Hazard Summary Generally, PCNB has low acute toxicity, with most study results in Toxicity Categories III or IV, although one study identified PCNB as a weak sensitizer. Subchronic and chronic studies indicate that the thyroid and liver are the target organs for PCNB. Limited evidence, such as increased thyroid stimulating hormone ( TSH), and thyroid and liver hypertrophy, suggest that the thyroid effects may be due, at least in part, to a disturbance of thyroid homeostasis. Aminotransferase activities ( AST/ ALT, particularly ALT) decrease in a dose dependent manner by as much as 30 80% in rats and dogs. However there are no data to evaluate the toxicological significance of the these findings. The Agency has requested that the registrants address these issues of thyroid activity and transaminase enzymatic activity. National Toxicology Program ( NTP) genetic toxicology testing indicates that PCNB is not mutagenic in bacteria or in cultured mammalian cells. PCNB was negative for the induction of Sister Chromatid Exchanges ( SCE) in vitro. PCNB is classified as a Group C possible human carcinogen and the HIARC recommended that for risk assessment purposes, the Reference Dose ( RfD) approach should be used for quantification of human risk.

There was no quantitative or qualitative evidence of increased susceptibility of rat or rabbit fetuses after in utero exposure, or after pre or postnatal exposure to rats in multigeneration reproduction studies. Therefore, the HIARC determined that the special FQPA factor can be reduced to 1X because there are no residual uncertainties for pre and/ or postnatal toxicity. No findings of significant toxicological concern were identified in the submitted developmental or reproductive toxicity data. No neurobehavioral alterations nor evidence of neuropathological effects were observed in the available data. Based on the weight of evidence, the HIARC concluded that a developmental neurotoxicity ( DNT) study is not required for PCNB. However, data gaps were identified concerning thyroid hormone levels, the significance of ALT/ AST enzyme levels, and pharmacokinetics. The absence of the comparative thyroid study resulted in a 2 database uncertainty factor of 10X ( UFDB of 10X) which was applied to the dietary, as well as all residential/ recreational exposure ( incidental oral, dermal and inhalation) scenarios.

Residue Chemistry The tolerance expression for PCNB includes parent and the metabolites, pentachloroaniline ( PCA) and pentachlorothioisole ( PCTA). However, neither of the two major food monitoring programs analyzes for both metabolites in every sample consistently or the number of samples that are analyzed for more than one metabolite is generally insufficient (< 100) for use in the risk assessment according to HED guidelines. Eighty four polychlorinated phenyl metabolites of concern have been identified in animal and plant metabolism, and environmental degradate data. The Agency maintains that due to insufficient toxicity data on the metabolites of PCNB, and due to the polychlorinated nature of the PCNB metabolites, these metabolites cannot be comfortably ruled out as being toxic unless proven otherwise through suitable toxicity data, which may be generated by the registrant. All these metabolites are included in the dietary risk assessment. In order to estimate the total residues of concern ( i. e., include residues of all 84 metabolites), it was assumed that the Total Toxic Residue ( TTR) would be equal to or less than the estimated Total Radioactive Residues ( TRR) in each crop, which includes extractable as well as unextractable residues. To estimate the TTR for each crop, the monitoring data for that crop and the ratio of TRR to PCNB observed in the metabolism studies were used. The available monitoring data also showed detected residues of PCNB and/ or its metabolites in/ on a number of crops for which there is no registration. Additional data are required for a number of crops. Data on plant and animal metabolism studies are required. Tolerances on livestock commodities need to be established.

Dietary Exposure and Risk Estimates No adverse effects attributed to a single exposure ( dose) were identified. Therefore, no acute dietary risk assessment was conducted.

The chronic dietary risk assessment is considered to be a highly refined assessment using all available monitoring data, % crop treated (% CT) information, and processing factors. However, because monitoring data did not analyze for all PCNB metabolites of concern ( 84), the ratio of TRR to PCNB from available metabolism studies in combination with monitoring residue data on PCNB, or TRR values directly, were used to estimate the total residues of concern. Since residues of PCNB and/ or its metabolites were detected in monitoring data for some unsupported ( not registered/ without tolerances) food uses, assessments using the Dietary Exposure Evaluation Model Food Consumption Intake Database ( DEEM FCID) and Lifeline, with and without unsupported food uses, were performed. The chronic dietary risk assessment, for food alone, shows that the risks for all population subgroups are below the level of concern; i. e., 100% chronic Population Adjusted Dose ( cPAD), with and without nonregistered crops. The highest estimated risks are for children 1 2 years of age ( 34% cPAD). The major contribution to the risk came from milk fat, followed by brassica vegetables. 3 Residential/ Recreational Exposure and Risk Estimates  Handlers and Postapplication In residential settings, the Agency does not use personal protective equipment ( PPE) to limit exposures, because they are viewed as impractical and not enforceable. Risk estimates are based on handlers wearing short sleeved shirts, short pants, shoes, and socks. No chemicalspecific data are available for residential/ recreational scenarios so, estimates from available databases and standard assumptions were used to calculated potential exposures along with using maximum application rates and a dermal absorption factor selected from a submitted dermal toxicity study. The residential scenarios where Margins of Exposure ( MOEs) do not meet the Agency's target MOE of 1000, and therefore are of concern, include dermal risk for mixing/ loading/ applying liquids with low pressure handwand ( 280) and dermal and inhalation risks for garden hose end sprayer and belly grinder ( 12).

Short term postapplication risk estimates resulting from dermal contact with treated turf during high contact lawn activities at application rates of 32.67 lbs active ingredient per acre ( ai/ A) and 43.56 lbs ai/ A exceeded the level of concern for adults ( MOE 30 40) and for children ( MOE 82 110). Activities such as golfing and mowing lawns treated with PCNB at application rates of 32.67 and 43.56 lbs ai/ A resulted in MOEs of 575 430 for golfing and 1145 860 for mowing, and exceed HED's level of concern. Aggregating, or adding residential handler exposure and postapplication exposure also results in MOEs below 1000. The risk estimates for toddler's non dietary ingestion of PCNB on treated turf indicate that risks exceed HED's level of concern for hand to mouth transfer ( MOE 2), incidental turfgrass mouthing ( MOE 6 8), and incidental ingestion of soil ( MOE 460 612).

Aggregate Risk Estimates For PCNB and its metabolites, quantitative aggregate exposure assessments that include food + drinking water + incidental oral/ dermal/ inhalation exposures were not performed since potential exposures and their associated risks from individual sources of exposures were already of concern, particularly for children. However, chronic dietary aggregate exposures were estimated by combining food and estimated drinking water exposures ( provided by EFED) directly in the DEEM FCID program. They showed chronic aggregate risks of concern for most exposed population subgroups, particularly infants ( 313% cPAD) and children 1 2 years old ( 173% cPAD).

Occupational Exposure and Risk Estimates  Handlers and Postapplication No chemical specific data are available for occupational exposure scenarios so, estimates from available databases and standard assumptions were used to calculated potential exposures. The results of the short and intermediate term occupational handler assessments indicate that for the dry flowable formulation, the majority of the potential exposure scenarios result in total MOE( s) > the target MOE of 100 at the baseline clothing attire of long pants, long sleeved shirts, no gloves, and no respirator while using open systems. For the liquid formulation, the risk 4 estimates indicate that in order for the mixer/ loaders to achieve MOEs of 100 for all uses at both the short and intermediate term exposure durations that minimum PPE clothing attire be required ( i. e., long pants, long sleeved shirts, chemical resistant gloves, and a dust/ mist respirator while using open systems). This is consistent with the current label except for the need, in some scenarios, to add an organic vapor respirator. The risk estimates for the majority of uses with the wettable powder formulation are not of concern ( clothing attire of long pants, long sleeved shirts, chemical resistant gloves, and no respirator). However, the risk estimates indicate that in order for the mixer/ loaders of wettable powders to achieve MOEs of 100 for all uses at both the shortand intermediate term durations that, for some uses, PCNB should be packaged in water soluble packets. The dust formulation was only used for seed treatment and has acceptable risks.

The results of the short and intermediate term seed handler assessments indicate that, for all formulations, the majority of the potential exposure scenarios result in total MOEs > 100 with long pants, long sleeved shirts, gloves, and no respirator while using open systems. Seed handlers working in a smaller facility, performing multiple activities, might require a respirator to reduce exposures so that potential risks ( MOEs) would be > 100 and not of concern.

There is a low potential for occupational postapplication exposure when used as a preplant or at planting fungicide. Therefore, HED does not require a postapplication assessment for seed treatment or agricultural uses. However, the Agency has determined that there are potential postapplication exposures to individuals re entering PCNB treated areas for the purpose of golf course and turf maintenance. Available databases, standard assumptions, and submitted transferable residue values were used, and adjusted when needed, to estimate potential postapplication exposures. The short and intermediate term estimated risks to golf course workers or sod growers doing hand harvesting on day zero result in MOEs > the target MOE of 100 and do not exceed HED's level of concern at the 32.67 and 43.56 lb ai/ A application rates.

A number of accidental human poisonings from exposure to PCNB in both occupational and residential settings have been reported. Though the data from these sources often lacked specific information on the extent of exposure and the circumstances of exposure, the incidence information indicate definite poisoning risks from misuse of products that contain PCNB, or from not wearing PPE. 5 Cl Cl Cl Cl Cl NO 2 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION ( Revised Reregistration Eligibility Decision Document ( RED) of Pentachloronitrobenzene ( PCNB, PC Code 056502): Product and Residue Chemistry Considerations. Reregistration Case 0128. DP Barcode. D305653. Mohsen Sahafeyan and Kenneth W. Dockter. July 21, 2004)

Chemical Name: Pentachloronitrobenzene, PCNB CAS Number: 82 68 8 Empirical Formula: C 6 Cl 5 NO 2 Molecular Weight: 295.3 Specific Gravity: 1.718 Boiling Point: 328

C Melting Point: 142 145

C Vapor Pressure: 1.13 x 10 4 mmHg Water solubility: 440 ppb 3.0 HAZARD CHARACTERIZATION [ PCNB  Report of the Hazard Identification Assessment Review Committee. Elizabeth A. Doyle. April 9, 2003; PCNB ( PC Code 056502) Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision ( RED). Laurence D. Chitlik, December 15, 2003; Pentachloronitrobenzene ( PCNB). ( List A, Case No. 0128) Briefing Memorandum to Metabolism Assessment Review Committee to discuss PCNB residues of concern for inclusion in dietary risk assessment. Chemical 056502. Mohsen Sahafeyan & Larry Chitlik. April 8th, 2003]

3.1 Hazard Profile Generally, PCNB has low acute toxicity, with most study results in Toxicity Categories III or IV, but in one study ( Uniroyal) PCNB was identified as a weak sensitizer. Though information in the published literature indicates that PCNB undergoes extensive biotransformation in mammals, there is an uncertainty as to its biological half life and thus as to its potential for bioaccumulation. Data in the literature suggest that its half life might be relatively short at low doses and higher at higher doses. The registrants have been asked to address the issue of biological half life and therefore, the potential for bioaccumulation. 6 Table 1a. Acute Toxicity ( Uniroyal/ Crompton)

Guideline No. Study Type MRIDs # Results Toxicity Category 870.1100 Acute Oral 43198201 LD 50 = > 5000 mg/ kg IV 870.1200 Acute Dermal 43198202 LD 50 = > 5000 mg/ kg IV 870.1300 Acute Inhalation 43118201 LC 50 = > 1.7 mg/ L III 870.2400 Primary Eye Irritation 43198203 Slight irritant III 870.2500 Primary Skin Irritation 43198204 Non irritant IV 870.2600 Dermal Sensitization 40609001 Weak sensitizer 870.6200 Acute Neurotoxicity NA Table 1b. Acute Toxicity ( Amvac)

Guideline No. Study Type MRIDs # Results Toxicity Category 870.1100 Acute Oral 41443101 LD 50 = > 5050 mg/ kg IV 870.1200 Acute Dermal 41443102 LD 50 = > 2020 mg/ kg III 870.1300 Acute Inhalation 41443103 LC 50 = > 6.49 mg/ L III 870.2400 Primary Eye Irritation 41443104 Slight irritant III 870.2500 Primary Skin Irritation 41443105 Non irritant IV 870.2600 Dermal Sensitization 45236401 Non sensitizer 870.6200 Acute Neurotoxicity NA Subchronic and chronic studies indicate that the thyroid and liver are target organs for PCNB. Limited evidence ( increased TSH, and thyroid and liver hypertrophy) suggest that the thyroid effects may be due, at least in part, to a disturbance of thyroid homeostasis. Aminotransferase activities ( AST/ ALT, particularly ALT) decrease in a dose dependent manner by as much as 30 80% in rats and dogs. However, the available data are inadequate to evaluate the toxicological significance of these findings. The registrants are requested to address these issues of thyroid activity and transaminase enzymatic activity. 7 TABLE 2. SUBCHRONIC/ CHRONIC TOXICITY PROFILE DER# MRID/ SPONSOR Study Type & Dose Levels * NOAEL ( mg/ kg/ day) ** LOAEL ( mg/ kg/ day)

1 41987301 UNIROYAL 2 Yr. Chronic Toxicity/ Carcinogenicity Feeding  Rat ( 1991) 0, 1, 150, 300 mg/ kg/ day (

/  ) Systemic: 1 Systemic: 150 Based on an increase in hepatocellular hypertrophy, hepatocellular hyperplasia (  ) & thyroid hypertrophy & hyperplasia Increase in thyroid follicular cell adenomas & carcinomas in

at 150 & 300 ( p< 0.05) &  trend only.

2 43015801 AMVAC 2 Yr. Chronic Toxicity/ Carcinogenicity Gavage  Rat ( 1993) 0, 3.6, 36, 357, 714 mg/ kg/ day (

/  ) 3.6

36  36

, 357  Hepatocellular hypertrophy & the thyroid follicular cell hypertrophy/ hyperplasia. Negative for neoplasia.

3 45609101 NTP TR325 2 Yr. Carcinogenicity in Mice ( 1987). 0, 400, & 1000 mg/ kg/ day

0, 600 & 1400 mg/ kg/ day  No increased neoplasia but reduced survival decreased sensitivity of study.

4 41718600 & 41718601 UNIROYAL 1 Yr. Chronic Toxicity Feeding  Dog ( 1993). 0, 0.375, 3.75, & 37.5 mg/ kg/ day ( used dog conversion factor) (

/  ) 3.75 37.5 based on increased serum ALP and cholesterol, increased liver weight and hepatocellular hypertrophy.

5 43469301, 43469302, 43469303 AMVAC 2 Generation Reproduction  Rat ( 1994) 0, 10, 100, 1000 mg/ kg/ day 10

100  100

, 1000  based on increases in hepatocellular hypertrophy & thyroid follicular cell hypertrophy/ hyperplasia.

6 41918701 UNIROYAL 2 Generation Reproduction  Rat ( 1991). 0, 1.2, 169, 344 (

) & 0, 1.5, 218, 455 (  ) Parental: 1.2

, 1.5  Repro/ Dev: 1.2 Parental: 169

, 218  based on decreased body weight and weight gain. Repro/ Dev: 169 based on decreased mean pup weights.

7 40588601 UNIROYAL Developmental Tox Gavage  Rat ( 1988). 0, 30, 600, 1200 mg/ kg/ day Maternal: > 1200 Develop: > 1200 Maternal > 1200 ( HDT) Develop > 1200 ( HDT)

8 41361301 AMVAC Developmental Tox Gavage  Rabbit ( 1989). 0, 100, 300, & 900 mg/ kg/ day Maternal: 300 Develop: > 900 Maternal: 900 based on clinical signs of toxicity, decreased body weight gain & food consumption, abortions & premature delivery Develop: > 900 ( HDT)

9 40717102 UNIROYAL Developmental Tox Gavage  Rabbit ( 1988). 0, 6.25, 12.5, 125, & 250 mg/ kg/ day Maternal: 12.5 Develop: 125 Maternal: 125 based on decreased maternal body weight & body weight gain. Develop: 250 based on decreased fetal weights. 8 10 41361201 AMVAC Developmental Tox Gavage  Rat ( 1989). 0, 250, 750, & 1500 mg/ kg/ day Maternal: > 1500 Develop: > 1500 Maternal: > 1500 Develop: > 1500 Small increases in incidences of thoracic vertebrae/ fetus seen at 750 but, no doseresponse not considered biologically significant & not seen in any other study.

11 42630801 UNIROYAL 7, 14, 30 or 90 Day Subchronic  Male Rat ( 1993). Non guideline 0, 1.0, & 333 mg/ kg/ day < 1.0 ( 90 days) 1.0 ( 90 days) based on liver & thyroid hypertrophy. After 14 & 30 days: thyroid follicular epithelial hypertrophy observed at 333 ( HDT).

12 42416001 AMVAC 13 Week Subchronic Gavage  Rat ( 1992). 0, 5, 10, 100, or 1000 mg/ kg/ day

/  100 (

/  ) 1000 (

/  ) based on increased relative ( to body) liver wt. & histopathological changes in the liver & thyroid.

13 42413901, 42713401 & 42713402 UNIROYAL 21 Day Dermal  Rat ( 1992). 0, 30, 300, or 1000 mg/ kg/ day (

/  ) Systemic: > 1000 Systemic: > 1000 ( HDT)

14 42416002 AMVAC 21 Day Dermal  Rat ( 1992). 0, 100, 300 & 1000 (

/  ) 300 1000 based on the increased incidences of dilatation of the thyroid follicles & hypertrophy of the thyroid follicular epithelium in

. No reported treatment related effects in  .

15 255226/ 250698 OLIN/ UNIROYAL Skin Penetration Study of Olin's Terraclor Formulations ( 1983). ( 20% Dust & 75% WP) Approx. 30% recovery after 5 days & only 1 2% after 4 hr. exposure N/ A 16 44096601 UNIROYAL Metabolism  Special Non Guideline  Rat ( 1996). N/ A N/ A 17 44096602 UNIROYAL Metabolism  Special Non Guideline  Rat ( 1996). N/ A N/ A * NOAEL = No Observable Adverse Effect ** LOAEL = Lowest Observable Adverse Effect HDT = Highest Dose Tested In a 21 day dermal toxicity study in rats, dilation of the thyroid follicles and hypertrophy of the thyroid follicular epithelium were observed at the highest dose tested ( 1000 mg/ kg/ day) in males only. These changes were not observed in any of the other dose groups, including controls, or in any females, nor were any other treatment related effects observed. The NOAEL is 300 mg/ kg/ day. 9 No inhalation toxicity studies are available. Absorption by the inhalation route is considered to be equivalent to absorption by the oral route.

No findings of significant toxicological concern were identified in the submitted developmental or reproductive toxicity data. No neurobehavioral alterations nor evidence of neuropathological effects were observed in the available data. There was no indication of increased susceptibility in these studies. Due to concerns for the potential impact of PCNB exposure on the function of the thyroid as evidenced by the increases in thyroid weights and the changes noted in TSH, T3, and T4, noted in the PCNB database, the HIARC is requiring a comparative thyroid assay in young and adult rats which includes hormonal measurements for thyroid function. This request stems from concerns regarding the possible impact of perturbations of thyroid function on the development of the young.

There is no indication of immunotoxicity at this time. However, effects on thyroid function have been reported in a number of studies submitted to the Agency. Data are required. There is no evidence that PCNB is neurotoxic. Therefore, acute delayed neurotoxicity, acute and subchronic neurotoxicity studies, and a DNT study are not required ( at this time).

Although it has been suggested that there may be a hormonal mechanism of action for PCNB, there is insufficient evidence to make a definitive finding. Results from the NTP genetic toxicology testing ( NTP TR 325, 1987 submitted as MRID# 45609101), indicate that PCNB ( lot and % ai not specified) is not mutagenic in bacteria or in cultured mammalian cells. There is suggestive in vitro evidence showing that PCNB is clastogenic in the absence of S9 activation and equivocal in the presence of S9 activation. However, in a more definitive erythrocyte mouse micronucleus assay ( MRID# 45539601), PCNB was not shown to be clastogenic. PCNB was also negative for the induction of SCEs in vitro. The carcinogenicity of PCNB was assessed in reviews of 1977 ( special review), and in 1986 and 1992 ( Second Carcinogenicity Peer Review of PCNB. Pamela Hurley and Esther Rinde. December 18, 1992). In 1992, the Cancer Peer Review Committee ( CPRC) classified PCNB as a Group C possible human carcinogen and recommended that for the purpose of risk characterization, the RfD approach should be used for quantification of human risk.

Although the HIARC has identified the rat metabolism study as a significant data gap, several non guideline and unacceptable ( but potentially upgradable) rat metabolism studies have been submitted to the Agency. Both the guideline metabolism and special bioaccumulation studies are required and are considered data gaps. Data from a series of limited single and repeated dose Rhesus monkey studies suggest that PCNB bioaccumulates in mammals. In this same series, it was noted that both the biliary fecal and renal urinary routes were utilized for the excretion of PCNB and its metabolites, with a slight preference for the fecal route. The limited data in rats, monkeys, and dogs that are available suggest that generally it is the metabolites that are accumulated within tissues to a greater extent than parent PCNB itself. 10 3.2 FQPA Considerations ( PCNB  Report of the Hazard Identification Assessment Review Committee. Elizabeth A. Doyle. April 9, 2003)

The HIARC concluded that there was no quantitative or qualitative evidence of increased susceptibility of rat or rabbit fetuses after in utero exposure, or after pre or postnatal exposure to rats in multigeneration reproduction studies. Therefore, the special FQPA factor was reduced to 1X because there are no residual uncertainties for pre and/ or postnatal toxicity.

Acceptable developmental toxicity studies in rats and rabbits, and reproductive toxicity studies are available and adequate for FQPA considerations. Based on the weight of evidence, the HIARC concluded that a DNT study is not required for PCNB. However, data gaps were identified concerning thyroid hormone levels, the significance of ALT/ AST enzyme levels, and pharmacokinetics. Specifically, HIARC is requiring a comparative thyroid assay in young and adult rats which includes hormonal measurements for thyroid function, since thyroid weights were increased in a number of chronic and subchronic studies in rats, and TSH, T3, and T4 levels were affected in a 90 day special oral study in male rats.

The absence of the comparative thyroid study resulted in a database uncertainty factor of 10X ( UFDB of 10X) which was applied to the dietary, as well as all residential/ recreational exposure ( incidental oral, dermal and inhalation) scenarios. The HIARC determined that the 10X UF DB is required since the available data provide no basis to support reduction or removal of the default 10X factor.

3.3 Dose Response Assessment No adverse effects attributed to a single exposure ( dose) were identified, including in the rat or rabbit developmental toxicity studies. Therefore, no acute dietary endpoint was selected. Subchronic and chronic studies indicate that the thyroid and liver are target organs for PCNB.

The chronic dietary, long term dermal, and long term inhalation endpoints were selected from the chronic/ oncogenicity feeding study in rats based on hepatocellular hypertrophy, hepatocellular hyperplasia, and thyroid hypertrophy observed at 150 mg/ kg/ day ( NOAEL 1.0 mg/ kg/ d). Though the FQPA factor was reduced to 1X, a UF DB of 10X was applied, as well as 10X for interspecies extrapolation and 10X for intraspecies variability, for a total UF of 1000. Therefore, the chronic reference Dose ( RfD) is 1 mg/ kg/ day ÷ 1000 = 0.001 mg/ kg/ day.

The short term ( 1 30 days) incidental oral and inhalation endpoints were selected from the 90 day subchronic feeding study in male rats based on thyroid follicular epithelial hypertrophy observed at 333 ( HDT) mg/ kg/ day after 14 and 30 days ( NOAEL = 1.0 mg/ kg/ day). The residential/ recreational Level of Concern ( LOC) is 1000 based on UF DB of 10X, 10X for interspecies extrapolation, and 10X for intraspecies variability. An LOC of 100, based on 10X for interspecies extrapolation and 10X for intraspecies variability, is adequate for occupational exposures. 11 The intermediate term ( 1 6 months) incidental oral and inhalation endpoints were also selected from the subchronic feeding study in male rats. The LOAEL is1.0 mg/ kg/ day based on liver and thyroid hypertrophy seen at 90 days ( NOAEL = < 1.0 mg/ kg/ day). For a summary of the LOCs, or target margins of exposure ( MOEs) for risk assessment, see the table below.

The short and intermediate term dermal endpoints were selected from the 21 day dermal toxicity study in rats based on hypertrophy of the thyroid follicular epithelium and dilation of the thyroid follicles in males only observed at 1000 mg/ kg/ day ( NOAEL = 300 mg/ kg/ day).

TABLE 3 Route Duration Short Term ( 1 30 Days) Intermediate Term ( 1  6 Months) Long Term (> 6 Months)

Occupational ( Worker) Exposure Dermal 100 100 100 Inhalation 100 100 100 Residential ( Non Dietary) Exposure Oral 1000 1000 N/ A Dermal 1000 1000 1000 Inhalation 1000 1000 1000 Current HED policy requires that FQPA safety factors be retained for dietary and nonoccupational exposures, when appropriate, not occupational exposures ( Memorandum, Special Report of the FQPA Safety Factor Committee, B. Tarplee and J. Rowland, April 15, 1998). Therefore, an MOE of > 100 is needed in the occupational exposure risk assessment.

Though a dermal penetration study was available, it was not considered acceptable for risk assessment purposes. An estimation of dermal absorption of 33% was extrapolated using the systemic LOAEL of 333 mg/ kg/ day from the subchronic oral toxicity study in male rats and the LOAEL of 1000 mg/ kg/ day from the 21 day dermal toxicity study in the rat: the ratio is 333/ 1000 or 33%. It was noted that thyroid toxicity was the common toxic effect seen via both routes in the same species. Absorption by the inhalation route was considered to be equivalent to absorption by the oral route. 12 Table 4. Summary of Toxicology Endpoint Selection EXPOSURE SCENARIO DOSE ( mg/ kg/ day) ENDPOINT STUDY Acute Dietary No appropriate endpoint attributed to a single dose was identified. Therefore, an acute RfD was not established.

Chronic Dietary NOAEL = 1.0 UF = 100 FQPA SF = 1X UFDB = 10X Systemic toxicity LOAEL = 150 mg/ kg/ day, based on hepatocellular hypertrophy, hepatocellular hyperplasia ( females) and thyroid hypertrophy and hyperplasia. Combined chronic toxicity/ carcinogenicity study in rats MRID# 41987301 Chronic RfD = 0.001 mg/ kg/ day cPAD1= 0.001 mg/ kg/ day Incidental Oral, Short ( 1 30 days) Term NOAEL= 1.0 UF = 100 FQPA SF = 1X UFDB = 10X Based on thyroid follicular epithelial hypertrophy observed at 333 ( LOAEL) after 14 & 30 days. Nonguideline 90 day subchronic oral toxicity study in male rats MRID# 42630801 LOC for residential MOE = 1000 Incidental Oral, Intermediate ( 1 6 months) term NOAEL= < 1.0 UF = 100 FQPA SF = 1X UFDB = 10X LOAEL is 1.0 mg/ kg/ day based on liver & thyroid hypertrophy at 90 days. Nonguideline 90 day subchronic oral toxicity study in male rats MRID# 42630801 LOC for residential MOE = 1000 Dermal, Short ( 1 30 days) & Intermediate ( 1 6 months) Term NOAEL = 300 UF = 100 FQPA SF = 1X UFDB = 10X LOAEL is 1000 mg/ kg/ day based on hypertrophy of the thyroid follicular epithelium and dilation of the thyroid follicles in males only. 21 Day dermal toxicity study in male and female rats MRID# 42416002 LOC for residential MOE = 1000 LOC for occupational MOE = 100 Dermal, Long Term ( 6 months to life time)

Absorption factor 33% used for conversion from oral to dermal route NOAEL = 1.0 UF = 100 FQPA SF = 1X UFDB = 10X Systemic toxicity LOAEL = 150 mg/ kg/ day, based on hepatocellular hypertrophy, hepatocellular hyperplasia ( females) and thyroid hypertrophy and hyperplasia. Chronic toxicity/ carcinogenicity study in rats MRID# 41987301 LOC for residential MOE = 1000 LOC for occupational MOE = 100 13 Inhalation, Short ( 1 30 days) Term NOAEL= 1.0 UF = 100 FQPA SF = 1X UFDB = 10X Based on thyroid follicular epithelial hypertrophy observed at 333 ( LOAEL) after 14 & 30 days. Nonguideline 90 day subchronic oral toxicity study in male rats MRID# 42630801 LOC for residential MOE = 1000 LOC for occupational MOE = 100 Inhalation, Intermediate ( 1 6 months) Term NOAEL= < 1.0 UF = 100 FQPA SF = 1X UFDB = 10X LOAEL is 1.0 mg/ kg/ day based on liver & thyroid hypertrophy at 90 days. Nonguideline 90 day subchronic oral toxicity study in male rats MRID# 42630801 LOC for residential MOE = 1000 LOC for occupational MOE = 100 Inhalation, Long Term ( 6 months to life time) NOAEL = 1.0 UF = 100 FQPA SF = 1X UFDB = 10X Systemic toxicity LOAEL = 150 mg/ kg/ day, based on hepatocellular hypertrophy, hepatocellular hyperplasia ( females) and thyroid hypertrophy and hyperplasia. Chronic toxicity/ carcinogenicity study in rats MRID# 41987301 LOC for residential MOE = 1000 LOC for occupational MOE = 100 Cancer Group C  Possible human carcinogen Combined incidence of thyroid follicular cell adenomas & carcinomas significantly increased in males but not females, with a significant trend in both sexes. Chronic toxicity/ carcinogenicity study in rats MRID# 41987301 Q1* not calculated 1 PAD = acute or chronic RfD Special FQPA factor 3.4 Endocrine Disruption EPA is required under the Federal Food, Drug, and Cosmetic Act ( FFDCA), as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following recommendations of its Endocrine Disruptor and Testing Advisory Committee ( EDSTAC), EPA determined that there was scientific bases for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening 14 Program ( EDSP). In the available toxicity studies on PCNB, the data are inadequate to make a determination about the thyroid effects observed in animal studies. Comparative thyroid data are requested. When additional appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, PCNB may be subjected to further screening and/ or testing to better characterize effects related to endocrine disruption.

3.5 Potential Hexachlorobenzene and Pentachlorobenzene Contamination Hexachlorobenzene ( HCB) and pentachlorobenzene ( PCB) are manufacturing impurities in technical pentachloronitrobenzene ( PCNB). During a special review in the 1980s of PCNB, it was concluded that the most likely cause of any adverse effects of PCNB was due to the presence of the impurities. The Agency entered into an agreement with the manufacturers to reduce the amount of HCB in the technical grade PCNB to 0.5% by April 1983, and to 0.1% by April 1988 ( 47 FR 18177). HCB is also an impurity in other pesticides; dacthal, chlorothalonil, picloram, and pentachlorophenol ( PCP).

In 1994, the Agency expressed its concern to Amvac and Uniroyal [ Letters dated October 4, 1994. Jack Housenger to Jeannie K. Smith ( Amvac), Jack Housenger to W. F. Cummings ( Uniroyal)] about cancer risks from the manufacturing impurities, HCB and PCB. The Agency sought to establish a maximum allowable level of HCB at 0.05% and 0.01% for PCB. Both registrants complied with the changes and subsequent formulations of PCNB contained HCB and PCB contamination levels at or below the new allowable limits.

Both HCB and PCB are considered by the Agency to be possible human carcinogens ( B2 carcinogens). Agricultural use of PCNB poses a potential source of human dietary exposure to HCB and PCB and, therefore, poses a potential source of cancer risk. HCB itself was once registered in the United States as a pesticide active ingredient. The use of HCB in the United States as a pesticide a. i. was canceled in 1984 ( USEPA. 1985). In 1998 the Agency assessed the cancer risks posed by dietary exposure to HCB and PCB from the use of PCNB and other pesticide a. i. s ( Assessment of the Dietary Cancer Risk of Hexachlorobenzene and Pentachlorobenzene as impurities in Chlorothalonil, PCNB, Picloram, and several other pesticides. William Smith. February 26, 1998) and concluded that the cancer risk to humans from all pesticidal sources of dietary exposure to the combined residues of HCB and PCB was 1.81 x 10 6. The Agency generally regards risk estimates that are greater than 1 x 10 6 to be risks of concern. While the estimated cancer risk posed by dietary exposure to HCB and PCB from use of pesticides that contain these substances is slightly greater than 1 x 10 6, the Agency believes that its cancer risk estimate is an overestimate of actual cancer risk. This is largely because the cancer risk assessment was based on several worst case assumptions regarding the concentrations of HCB and PCB in the pesticide a. i. s and in foods. Experimental data show that the actual concentrations of HCB and PCB in the pesticide a. i. s are much lower than the concentrations used in the dietary exposure calculations. 15 3.6 Residues of Pentachlorophenol Revised Reregistration Eligibility Decision Document ( RED) of Pentachloronitrobenzene ( PCNB, PC Code 056502): Product and Residue Chemistry Considerations. Reregistration Case 0128. DP Barcode. D305653. Mohsen Sahafeyan and Kenneth W. Dockter. July 21, 2004; Pentachloronitrobenzene: Tier I Drinking Water EDWCs for Use in the Human Health Risk Assessment. Cheryl A. Sutton. November 12, 2003; Pentachloronitrobenzene, Revised Drinking Water Assessment: Tier 2 Drinking Water EDWCs for Use in the Human Health Risk Assessment. Cheryl A. Sutton. December 22, 2003; Environmental Fate and Ecological Risk Assessment for the Re registration of Pentachloronitrobenzene. Cheryl Sutton. February 3, 2004; Pentachlorophenol  Report of the Hazard Identification Assessment Review Committee. Jess Rowland. December 8, 1997.

Residues of free PCP, a known carcinogen, and conjugated PCP were found in some crops, and were detected in a submitted anaerobic soil metabolism study and a submitted terrestrial field dissipation study. With one exception, the conjugated PCP residues in crops were thiol compounds that are not expected to form the phenol during metabolism/ degradation. Of potential concern, because it may cleave to form PCP, is PCP glycoside ( PCP Gly) that was found in potato callus and peels in an early, inadequate, metabolism study ( MRID# 41562903). In a more recent, adequate, potato metabolism study, callus and peels were not sampled separately, but no PCP Gly was found in any potato samples. Although, PCP Gly was not found in the later, submitted adequate potato metabolism study, the first study can not be dismissed since the inadequacy of the study was decided on based on other aspects of that study, and the second study did not sample callus or peels separately. Free PCP was detected in a rotational crop study on turnip one year following soil treatment at 10 or 2 lbs ai/ A. The concentrations were < 0.001 ppm in tops and < 0.004 ppm in roots. In the case of the rotational crop study, PCNB is not registered for use on turnips, but turnips were rotated into a field where crops were treated with PCNB. Free PCP was not found in any other crop studies nor in any other environmental fate studies. Its source is unknown though, it has been speculated that it could be a minor metabolite or a manufacturing contaminant. PCP is a general biocide which is used extensively in the United States as a wood preservative. Submitted data on PCP ( specifically, as a degradate of PCNB) are lacking. While it appears from the published literature that PCP can be formed from PCNB during microbial degradation in soil, the weight of evidence is not substantial and conclusions on when ( i. e., under what environmental conditions) PCP can be expected to form in the environment cannot be validly drawn. Based on the currently available information, EFED believes that there is not sufficient evidence that PCP will routinely be formed from PCNB in the environment. Information on the microbial metabolism of PCNB in both aerobic and anaerobic soil/ water systems is necessary for a more complete evaluation of the potential for the formation of PCP resulting from the use of PCNB. Also of potential use would be additional field dissipation studies in which PCP is actually monitored as a potential degradate. Though it has been suggested that detection of PCP in field studies is due to historical use, this theory is not supported by the data. In a terrestrial field dissipation study ( MRID 43061501) submitted to EFED, a clear pattern of increasing and decreasing levels of PCP was seen, which does not support the notion that residues were present prior to the time the study was conducted. Based on both HED's and EFED's analysis of the PCP related data, there is insufficient information or cause to conduct a robust quantitative risk assessment for PCP at this time. However, a " worst case" analysis was conducted assuming potential residues of PCP in all tuber crops and using the 16 recently revised Q 1* ( 3/ 4 scaling factor) of 0.07 x 10 1 mg/ kg day. Under these circumstances, the potential risk may be 5 x 10 8 ( general population), which is not of concern.

4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION 4.1 Summary of Registered Uses Pentachloronitrobenzene ( PCNB): Occupational and Residential Exposure Assessment for the Reregistration Eligibility Decision Document. Seyed Tadayon. August 31, 2003; Revised Reregistration Eligibility Decision Document ( RED) of Pentachloronitrobenzene ( PCNB, PC Code 056502): Product and Residue Chemistry Considerations. Reregistration Case 0128. DP Barcode. D305653. Mohsen Sahafeyan and Kenneth W. Dockter. July 21, 2004.

PCNB is an organochlorine fungicide used for seed and soil treatments at planting. Products containing PCNB are used in both occupational and residential/ recreational settings. Registered use sites include, beans, brassica crops, cotton, garlic, hot pepper, peanut, pepper, potato, tomatoes, seed treatment, ornamental plants, cut flowers, dormant roses and bulbs, magnolia tree, southern pine seedlings and turf.

PCNB, has trade names including Terraclor, Terraclor Super X, Quintozene, and Turfcide. The common fungi controlled by PCNB are; black root ( Corticium solani), black rot of bulbs ( Sclerotinia), Camellia flower blight ( Sclerotinia), club root ( Plasmodiophora), common bunt/ stinking smut ( Tilletia foetida/ T. caries) of wheat, leaf spots, loose smut of oat ( Ustilago avenae), melting out ( Drechslera poae), melting out ( Helminthosporium), neck rot ( Stromatinia/ sclerotinia), and needle blight ( Dothistroma).

Table 5: Use Patterns, Application Rate, and Frequency of Application for PCNB Crops Application Rate lb ai/ acre Frequency of Timing of Application Agricultural Usage Patterns Beans: Bush Beans Dry/ green + bush/ pole Dry/ succulent/ snap Not specified Pole Beans Snap/ Dry + Bush Snap/ Dry + Pole 1.5 to 2.1 lbs ai/ A 1.1 1.1 to 1.5 1.36 to 1.5 1.5 to 2.1 1.5 to 2.1 1.7 to 2.1 At planting Brassica Crops: Broccoli, Brussels Sprouts, Cabbage, Cauliflower, Chinese Broccoli, Chinese Cabbage, Collards, Kale, Mustard Greens 30 lbs ai/ A ( Transplant solutions: 4.5 lbs ai/ A) Pre planting or at planting Cotton Cotton Seedling 0.93 to 2.1 lbs ai/ A 0.3 to 1.5 At planting Garlic ( in furrow and clove mist spray) 20 to 20.6 lbs ai/ A at planting Hot peppers 1.3 to 1.5 lbs ai/ A At planting 17 Peanuts 2 to 10 lbs ai/ A ( plus: aircraft  10 lb ai/ A) At planting and early pegging Peppers 7.2 to 7.5 lbs ai/ A Transplant Solution: 3.5 lbs ai/ 100 gal At planting Potatoes 10 to 25 lbs ai/ A Preplant Tomatoes 7.2 to 21.78 lbs ai/ A Preplanting or at planting Seed Treatment 0.0375 to 0.253 lb ai/ 100 lbs seed Preplant Ornamental Usage Patterns Azalea/ Camellia Plants 217.8 to 290.4 lbs ai/ A Preplanting or at planting Bulbs Dutch Iris Easter Lily, Hyacinth, Iris, Narcissus, Tulip Gladiolus Lily  various 147 to 150 lbs ai/ A 196 to 212.4 98 to 185.1 212.4 [ Transplant solutions: 1.5 lb ai/ 100 gallons to 1.5 lb ai/ 3.2 gal] [ Bulb soak: 4.5 lb ai/ 100 gal] At planting Cut Flowers: spray/ dip 1.5 lb ai/ 100 gal Prior to storage Dormant Roses & Bulbs: spray/ dip 4.5 lb ai/ 100 gal to 1.5 lbs ai/ 3.2 gal Pre plant or pre storage Magnolia Tree: Foliar spray 1.5 lb ai/ 100 gal/ or 6 lb ai/ A At least 4 sprays at 2 weeks intervals Southern Pine Seedlings 36.8 to 38.1 lbs ai/ A ( 37.5 typical) Pre plant Ornamental Plants: Bedding Plants Calendula/ Larkspur/ Snapdragon/ Sweet Peas Dutch Iris Easter Lily Flowering Bedding  broadcast  soil drench  bench soil Flower & Foliage Flower, Foliage, Shrub, Tree Flower/ Foliage/ Woody& Bedding Foliage Gladiolus Hyacinth/ Iris/ Narcissus/ Tulip Lilies Tropical Foliage Vegetable Bedding Woody & Herbaceous 40.8 lbs ai/ A 100 to 119.6 to 375 ( 1/ 10) 16.4 to 200 200 10.2 to 87.12 10.2 to 102.1 65.3 196.0 130.7 7.14 to 114.3 87.12 ( growing media mix) 120 212 212.4 40.8 40.84 40.8 to 87.1 Pre planting or at planting Turf: Turf Home Lawns Commercial Turf: Commercial & Home 32.7 to 43.1 lbs ai/ A 21.7 to 32.7 21.3 32.7 to 43.6 More reapplication at lower rate Reapplication at 3 to 4 weeks interval Table 6 represents information on registered use sites and application rates for seed treatment uses. Application rates cover various types of commercial seed treaters and seed planters. 18 Table 6. Application Rate for seed, seed piece, and cloves Application Rate lbs ai/ 100 lbs seed ( Commercial) Application Rate lbs ai/ 100 lbs seed ( On Farm)

crop minimum typical maximum minimum typical maximum barley 0.0394 0.1045 0.1307 0.0390  0.0878 bean 0.0256 0.0523 0.0347   0.0750 corn 0.0523 0.0372  0.0558 cotton 0.0656 0.2526 0.0788 0.0750 0.0750 0.1250 0.0150 garlic

oats 0.0394 0.0977 0.1045 0.1957 0.0302   0.0604 pea 0.0523 0.1045 0.0521   0.1042 peanut 0.0305 0.0375 0.0523 0.0610 0.0375 0.0375 0.0417 0.0750 potato

rice       0.0417   0.0926 safflower

sorghum   0.0305

soybean 0.0256 0.0256 0.0525 0.1045 0.0695   0.1044 sugar beet 0.0958   0.1873 0.0313   0.0625 wheat 0.0256 0.0256 0.0523 0.0525 0.0347   0.0521 4.2 Tolerance Reassessment Permanent tolerances for PCNB residues in/ on plant commodities are currently expressed as residues of PCNB per se [ 40 CFR § 180.291( a)] or as the combined residues of PCNB, and its metabolites, PCA and methyl pentachlorophenyl sulfide ( MPCPS) [ 40 CFR § 180.291( b)]. There are also interim tolerances, which are also expressed as PCNB per se [ 40 CFR § 180.319]. There are presently no tolerances for PCNB in animal commodities.

On April 16, 2003, the MARC decided that for the risk assessment purposes, PCNB and all its metabolites ( including minor metabolites) are of concern in plant and animal commodities. However, the residues of concern for tolerance setting purposes in primary and rotational crops and livestock are PCNB, PCA, and PCTA ( also abbreviated as MPCPS). A summary of the PCNB tolerance reassessment and recommended modifications in commodity definitions are presented below. 19 Table 7. Tolerance Reassessment Summary for PCNB.

Commodity Current Tolerance ( ppm) Tolerance Reassessment ( ppm) Comment/ Correct Commodity Definition Tolerances listed under 40 CFR § 180.291( a):

Cottonseed 0.1 TBD a Residue data are required from both Uniroyal and Amvac.

Tolerances listed under 40 CFR § 180.291( b):

Collards 0.2 0.2 Residue data from IR 4 support the current regional tolerance in state of Georgia. Kale 0.2 0.2 Mustard Greens 0.2 0.2 Tolerances listed under 40 CFR § 180.319 b:

Beans 0.1 TBD Residue data are required from both Uniroyal and Amvac.

Broccoli 0.1 0.1 The available residue data from Uniroyal and Amvac on broccoli and cabbage would support a permanent 0.1 ppm tolerance for the Head and Stem Brassica Vegetable Crop Subgroup. Additional residue data for broccoli from Amvac are required. Brussels Sprouts 0.1 Cabbage 0.1 Cauliflower 0.1 Garlic 0.1 0.05 Residue data from Uniroyal indicate that the tolerance could be lowered. Residue data must be submitted by Amvac.

Peanuts 1.0 TBD Additional residue data are required from both Uniroyal and Amvac.

Potatoes 0.1 1.0 Additional residue data are required from both Uniroyal and Amvac.

Peppers 0.1 0.2 Residue data from Uniroyal on peppers and tomatoes would support a permanent 0.2 ppm tolerance for the Fruiting Vegetables ( except Cucurbits) Crop Group. Additional residue data from Amvac are required. Tomatoes 0.1 Tolerances That Need To Be Proposed under 40 CFR § 180.291( a)

Cotton gin byproducts  TBD New field trial data are required.

Potato, wet peel  7.0 Based on a 7x concentration factor and the HAFT residues ( 0.95 ppm) from Amvac's potato field trials Commodity Current Tolerance ( ppm) Tolerance Reassessment ( ppm) Comment/ Correct Commodity Definition 20 Barley, grain, hay and straw  TBD Data are required from Amvac depicting PCNB residues in/ on RACs derived from seed treated with PCNB at the maximum labeled rate. Corn, grain, forage and fodder

Oat, forage, grain, hay and straw

Peas

Rice, grain and straw

Safflower, seed

Sorghum forage, grain, and stover

Soybean, forage, hay and seeds  0.02 The available data from Amvac would support separate tolerances on soybean forage, hay, and seeds at 0.02 ppm Sugar beet, roots and tops  TBD Residue data are required.

Wheat, forage, grain, hay and straw

milk  0.05 Based on data from the cattle feeding study and assuming a dietary burden of 32.3 ppm for dairy cattle.

Cattle fat, meat, and mbyp  1.0 Based on data from the cattle feeding study and assuming a dietary burden of 32.3 ppm for beef cattle. Goat fat, meat, and mbyp  1.0 Horse fat, meat, and mbyp  1.0 Sheep fat, meat, and mbyp  1.0 Hog fat, meat, and mbyp  TBD Tolerances of hog commodities should be established at the method LOQ; however, a enforcement method has not yet been submitted for livestock commodities.

Eggs  0.05 Tolerances are based on the available feeding study and assuming a dietary burden of 0.38 ppm for poultry Poultry, fat  0.5 Poultry, mbyp   0.05 a TBD = To be determined. Tolerance cannot be determined at this time because additional data are required or are currently under review. b CFR reports these as " interim" tolerances. Tolerances listed under § 180.319 should be reassigned to § 180.291( a) as time limited or permanent tolerances. Furthermore, all the current tolerance expressions which include PCNB per se should be changed to include PCNB, PCA, and PCTA per the MARC decision on 4/ 16/ 2003.

4.3 Dietary Exposure/ Risk Pathway Pentachloronitrobenzene ( PCNB). ( List A, Case No. 0128) Briefing Memorandum to Metabolism Assessment Review Committee to discuss PCNB residues of concern for inclusion in dietary risk assessment. Chemical 056502. Mohsen Sahafeyan & Larry Chitlik. April 8th, 2003; Pentachloronitrobenzene ( PCNB). ( List A, Case No. 0128) The Outcome of the HED Metabolism Assessment Review Committee Held on April 16th, 2003 to discuss 21 residues of concern in risk assessment and tolerance expression of PCNB. Chemical 056502. Mohsen Sahafeyan & Laurence Chitlik. May 8th, 2003; Probabilistic Chronic Dietary Exposure Estimates for Pentachloronitrobenzene ( PCNB). Mohsen Sahafeyan. March 31, 2004; Revised Reregistration Eligibility Decision Document ( RED) of Pentachloronitrobenzene ( PCNB, PC Code 056502): Product and Residue Chemistry Considerations. Reregistration Case 0128. DP Barcode. D305653. Mohsen Sahafeyan and Kenneth W. Dockter. July 21, 2004; Pentachloronitrobenzene, Revised Drinking Water Assessment: Tier 2 Drinking Water EDWCs for Use in the Human Health Risk Assessment. Cheryl A. Sutton. December 22, 2003.

4.3.1 Residue Profile The nature of the residue in plants and animals is adequately understood. A submitted metabolism study in lactating goats identified the major metabolites in ruminant tissues to be PCA, PCTA, N glucuronide of PCA ( PCA Gluc), and N hydroxypentachloroaniline ( NOHPCA) Gluc. The major identified residues in poultry tissues included PCNB, PCA, PCTA sulfoxide, tetrachloroaniline methyl sulfoxide, and tetrachlorophenyl methyl sulfone. The nitro group of PCNB provides a reactive center which allows rapid metabolism via three primary routes: reduction of the nitro group, displacement of the nitro group by the sulfhydryl group of reduced glutathione to give a glutathione adduct which is metabolized further, and dechlorination. PCNB is relatively stable in soil in comparison with plants and animals.

For the primary crops, plant metabolism studies on peanuts, potato, and cabbage ( cabbage study unacceptable) indicated that the major identified radioactive residues ( i. e.

10% total radioactive residue or TRR) were PCNB, S( pentachlorophenyl) malonycysteine, N malonyl S ( tetrachloroaminophenyl) cysteine, tetrachlorophenyl sulfoxide, and tetrachlorophenyl methyl sulfone. Numerous other polychlorinated phenyl compounds were identified in both the primary crop and rotational crop ( lettuce, turnip roots and tops, and wheat) studies.

A total of 84 polychlorinated phenyl metabolites of PCNB have been identified in animal and plant metabolism, and environmental degradate data. For identification and structures of each, see APPENDIX 2. The limited data that are available suggest that generally, it is the metabolites that are accumulated within plant and animal tissues to a greater extent than the parent PCNB itself. The Agency maintains that due to insufficient toxicity data on the metabolites of PCNB, and due to the polychlorinated nature of the PCNB metabolites, these metabolites cannot be comfortably ruled out as being toxic unless proven otherwise through suitable toxicity data, which may be generated by the registrant. The Agency also maintains that the general nontoxic nature of polar metabolites can not extended to include each and every instance, particularly when 1) data on non toxicity or reduced toxicity of those metabolites are lacking, and 2) the uncertainty of such a generalization may potentially put the health of the general public at stake. As there is a likelihood of release of conjugated and bound metabolites, such compounds can not also be dismissed unless proven otherwise through suitable toxicity data. Therefore, at this time, PCNB and all its polychlorinated phenyl metabolites are of toxicological concern and will be included in the risk assessment. The metabolites are considered to be toxicologically equivalent to the parent, PCNB.

Though no residues of PCP, a known carcinogen, have been found in ruminant and poultry data, PCP was found in one plant rotational crop study ( turnip), but not in any other plant 22 study. PCP was detected in an anaerobic soil metabolism study and a terrestrial field dissipation study. The circumstances under which PCP might be present are uncertain and the submitted data in which PCP was detected are limited. Therefore, a robust quantitative exposure assessment of PCP in food or drinking water cannot be conducted at this time, but a screening level assessment was conducted for tubers ( see section 3.6). Additional data are requested.

TABLE 8 Chemical: PCNB ( pentachloronitrobenzene)

Date: 16 April 2003 MARC Residues of Concern Matrix For Risk Assessment For Tolerance Expression Plants  Primary crops Parent plus all identified metabolites Parent, PCA, PCTA Plants  Rotational crops Parent plus all identified metabolites Parent, PCA, PCTA Livestock  Ruminant Parent plus all identified metabolites Parent, PCA, PCTA Livestock Poultry Parent plus all identified metabolites Parent, PCA, PCTA Fish and Shellfish N/ A N/ A Water Parent, PCA, and PCP N/ A PCA = pentachloraniline. PCTA = pentachlorothioanisole or methyl pentachlorophenyl sulfide. PCP = pentachlorophenol 4.3.2 Dietary Exposure Assessment The tolerance expression for PCNB includes the metabolites, PCA and PCTA. Of the two major food monitoring programs, however, only Food and Drug Administration ( FDA) analyzes for the combined residues of PCNB, PCA, and PCTA, while United States Department of Agriculture's ( USDA) Pesticide Data Program ( PDP) only randomly analyzes for PCA or PCTA. Furthermore, in the monitoring data, the number of samples that are analyzed for more than one metabolite is generally insufficient (< 100) for use in the risk assessment according to HED guidelines. This is particularly true for FDA data on all PCNB registered crops; therefore, all the monitoring data that were used in this dietary risk assessment were PDP data. In particular, PDP data from the two most recent years for each crop were utilized ( spanning 1997 2002). In order to estimate the total residues of PCNB and all its metabolites of concern, it was assumed that the TTR, or total residues of concern, would be equal to or less than the estimated TRR in each crop, 23 which includes extractable as well as unextractable residues. Since the metabolites of concern are all polychlorinated phenyls and the likelihood of any unextractable residue of PCNB containing a polychlorinated phenyl structure is high; using TRR values to represent TTR does not result in underestimation of the risk. To estimate the TTR for each crop, the monitoring data for that crop and the ratio of TRR to PCNB observed in the metabolism studies were used.

The available monitoring data ( 1994 2002 PDP and FDA) show detected residues of PCNB and/ or its metabolites in/ on a number of unregistered crops. The 1994 2002 PDP data show detected residues of PCNB and/ or PCA on winter squash fresh, carrots, spinach, cucumbers, asparagus, pears and celery. The 1998 2001 FDA data on crops of domestic origin show detected residues of " Quintozene ( total)," which includes PCNB, PCA, and PCTA, on domestic head lettuce, farm raised tilapia, squash, carrot, and ginseng. The 1998 2001 FDA data on imported commodities also show a number of unregistered commodities with detected residues of " Quintozene ( total)" in/ on squash, carrots, spinach, ginger root, and ginseng, with 73% of ginseng samples in all FDA data ( and 58% in FDA surveillance data) from different countries having detected residues of " Quintozene ( total)" with a range from trace to 17.44 ppm. Detected residues of PCNB and/ or its metabolites on domestic and imported commodities can be attributed to its long half life in soil, as the available studies and literature suggest. Therefore, those crops which have a considerable number of detects in both PDP and FDA ( carrots, spinach, cucumber, ginseng) were incorporated into the chronic dietary risk assessment.

<IP_ADDRESS> Acute Dietary No adverse effects attributed to a single exposure ( dose) were identified including in the rat or rabbit developmental toxicity studies. Therefore, no acute dietary endpoint was selected so, no acute dietary risk assessment was conducted.

<IP_ADDRESS> Chronic Dietary The chronic dietary risk assessment is considered to be a highly refined assessment using all available monitoring data, % CT information, and processing factors ( submitted data and default factors). However, because monitoring data did not analyze for all PCNB metabolites of concern ( 84), the ratio of TRR to PCNB from available metabolism studies in combination with monitoring residue data on PCNB, or TRR values directly, were used to estimate the total residues of concern.

The chronic risk assessment was performed with both the DEEM FCID   ( Version 1.30) and Lifeline   ( Version 2.0) models. A detailed description of the differences between the two models can be found in Probabilistic Chronic Dietary Estimates ( March 31, 2004). The 1994 1996 and 1998 USDA's Continuing Surveys of Food Intake by Individuals ( CSFII) were used in both models for the consumption database. Since residues of PCNB and/ or its metabolites were detected in monitoring data for some unsupported ( not registered/ without tolerances) food uses, assessments using DEEM FCID and Lifeline, with and without unsupported food uses, were performed. One assessment includes all the residues associated with the registered foods/ commodities, while the other also includes residues detected on crops/ commodities for 24 which there are no registrations/ tolerances.

It is believed that the wide presence of PCNB and/ or its metabolites on unsupported crops is due to its uptake from soil by rotated crops ( rather than illegal use), which in turn is due to a very long half life ( aerobic soil t 1/ 2 > 1000 days PCNB + PCA) of PCNB and/ or its metabolites in soil. Though a rotational crop restriction would normally be addressed during the mitigation phase of this review, the length of the restriction is unlikely to be feasible for the growers. Based on the available rotational crop data, ChemSAC ( June 2003) decided that only registered crops should be rotated to PCNB treated fields. Due to the persistence of the PCNB and/ or its metabolites in soil for more than two years, ChemSAC expressed a concern even with imposing restriction of rotation only to the labeled crops. ChemSAC decided that the extension of plant back interval ( PBI) restriction to 3 or 4 years or a restriction of rotation to the labeled crops for 3 4 years could not be enforced.

The chronic dietary risk assessment shows that the risks for all population subgroups are below the level of concern; i. e. < 100% cPAD, with and without unregistered crops. The highest estimated risks are for children 1 2 years of age. The major contribution to the risk came from milk fat, followed by brassica vegetables. The high contribution of the milk to the risk is due to high consumption of this food, particularly in children, combined with the high levels of TRR found in milk in the goat metabolism study.

The major source of uncertainty in this chronic dietary risk assessment is in the residue estimates. In particular, using TRR: PCNB ratios from the metabolism study in combination with PCNB residues from the monitoring data and use of absolute TRR values from the cabbage metabolism study to estimate TTR for brassica vegetables can be significant determinants of uncertainty. In addition, uncertainties in the calculation of secondary residues can be considerable. Despite the lack of monitoring residue data on all PCNB metabolites and an incomplete metabolism study on cabbage, this assessment is considered highly refined because it includes all available residue information, % CT, and processing factor information. Future refinement of this assessment would be aided if monitoring programs used validated commonmoiety methods for detection of PCNB and all its metabolites in registered and nonregistered commodities. 25 Table 9. Result of Chronic Dietary Exposure and Risk Estimates for PCNB.

Population Subgroup cPAD mg/ kg / day Risk from all crops a Risk from registered crops only DEEM FCID Lifeline DEEM FCID Lifeline Exposure mg/ kg/ d % cPAD b Exposure mg/ kg/ d % cPAD Exposure mg/ kg/ d % cPAD Exposure mg/ kg/ d % cPAD U. S. Population 0.001 0.000121 12% 0.000252 25% 0.000102 10% 0.000229 23%

All infants (< 1 yr) 0.001 0.000072 7% 0.00002 2% 0.000057 6% 0.000014 1%

Children 1 2 yrs 0.001 0.000345 34% 0.000331 33% 0.000269 27% 0.000276 28%

Children 3 5 yrs 0.001 0.000254 25% 0.000199 20% 0.000199 20% 0.000145 14%

Children 6 12 yrs 0.001 0.000161 16% 0.00013 13% 0.000128 13% 0.000093 9%

Youth 13 19 yrs 0.001 0.000104 10% 0.000092 9% 0.000086 9% 0.000066 7%

Adults 20 49 yrs 0.001 0.000097 10% 0.000263 26% 0.000084 8% 0.000244 24%

Adults 50+ yrs 0.001 0.000104 10% 0.000303 30% 0.000094 9% 0.000286 29%

Females 13 49 yrs 0.001 0.000096 10% 0.000261 26% 0.000083 8% 0.000236 24%

a Registered crop uses plus measured PCNB residues on food crops/ commodities without tolerances b % cPAD = ( exposure mg/ kg/ d ÷ cPAD mg/ kg/ d) x 100 <IP_ADDRESS> Cancer Dietary PCNB is classified as a Group C possible human carcinogen and the HIARC recommended that for risk assessment purposes, the RfD approach should be used for quantification of human risk. Consistent with the weak evidence of carcinogenic effects in one of the 3 lifetime bioassays, the HIARC indicated that a dose response assessment for cancer ( either linear low dose extrapolation or margin of exposure calculation) was not needed.

4.4 Water Exposure/ Risk Pathway Pentachloronitrobenzene: Tier I Drinking Water EDWCs for Use in the Human Health Risk Assessment. Cheryl A. Sutton. November 12, 2003; Pentachloronitrobenzene, Revised Drinking Water Assessment: Tier 2 Drinking Water EDWCs for Use in the Human Health Risk Assessment. Cheryl A. Sutton. December 22, 2003; Environmental Fate and Ecological Risk Assessment for the Re registration of Pentachloronitrobenzene. Cheryl Sutton. February 3, 2004.

4.4.1 Environmental Fate In general, PCNB is a persistent, volatile compound that will be immobile in most soils, but may have slight or even moderate mobility in coarser ( sandy) soils, particularly those that are low in organic matter. While PCNB is expected to be persistent in aerobic environments, it is microbially degraded more rapidly in anaerobic environments. It is stable to hydrolysis and is effectively stable to photodegradation on soil, but appears ( based on two submitted studies) to photodegrade fairly rapidly in water, with half lives on the order of a few days or less. While evidence of aqueous photodegradation of PCNB was not found in the literature, EFED found the submitted studies acceptable and, therefore, used the half life values determined in those studies. The major 26 degradates of PCNB in the environment are PCA and PCTA; minor degradates are pentachlorothioanisole sulfoxide ( PCTASO), pentachlorothioanisole sulfone ( PCTASO 2), and PCB, which is also present as an impurity along with HCB. While PCP was detected in two of the submitted studies, there is not sufficient evidence ( either from the submitted data or from published literature) that the compound will routinely be formed from PCNB in the environment.

Aerobic Soil Metabolism Half life t 1/ 2 = 77, 189 days ( parent only); t 1/ 2 = 489, 1012 days ( parent plus PCA) 1; t 1/ 2 = 983, 1052 days ( total residues)

Anaerobic Soil Metabolism Half life t 1/ 2 = 9 days, < 30 ( DT 50 2; parent only); t 1/ 2 = 210, 410 days ( parent plus PCA, PCP); t 1/ 2 = 268, 334 days ( total residues)

1For the purposes of the drinking water assessment, half lives were recalculated to account for the parent plus the degradates PCA and PCP, when monitored and detected. 2 DT50 = time to disappearance or dissipation of 50% of the initial concentration of the parent compound. * More than one half life is listed when more than one study was submitted.

4.4.2 Estimated Drinking Water Concentrations ( EDWCs)

Some chemical specific water monitoring data are available but they are limited and not atthe tap data. Therefore, EDWCs were calculated by EFED to estimate the potential contribution to the acute and chronic exposure from drinking water. The chronic EDWC ( point estimate) was then incorporated directly into DEEM FCID ( see Aggregate Risk section). The drinking water exposure assessment is based on maximum application rates and use patterns. Lacking environmental fate data on the metabolites, it was assumed that their mobility into sources of drinking water is the same as the parent.

Table 10. Tier 2 EDWCs for Drinking Water Risk Assessment.

Surface water drinking water sources acute: 440 ug/ L ( ppb) 1 1 in 10 years ( chronic): 44.2 ug/ L ( ppb) 30 year average: 27.5 ug/ L ( ppb)

Groundwater drinking water sources 30.6 ug/ L ( ppb) 2 1Surface water EDWC values were generated using the PRZM/ EXAMS model with a ground spray to cabbage ( one single application at 30 lb a. i./ A) in a Florida application scenario. The actual output value from PRZM/ EXAMS was 574.5 ppb for the cabbage use acute concentration. However, as this is greater than the aqueous solubility of 440 ppb for PCNB, the solubility limit should be used instead. 2Groundwater EDWCs are based on PCNB use on bulb crops at 213.4 lb a. i./ A/ application in a single application.

Though EFED has made a preliminary assessment of the potential EDWCs for the soil drench use of PCNB, prior to a final determination of EDWC's associated with a soil drench use, it is necessary that EFED obtain additional information from the registrants on this use pattern, particularly with regard to drenching practices, time between drench and transplant, number of treatments, estimated amount of pesticide/ formulated product not retained in the drenched container, and planting densities for transplants in the field.

EFED has also made a preliminary assessment of the potential EDWCs for the turf use and 27 preliminary estimates indicate that the chronic surface water potential EDWCs may be 37.9 ppb.

4.4.3 Monitoring Data NAWQA monitoring data are not available. Updated monitoring data from STORET are also not available. To supplement the limited monitoring data that are available, EFED conducted a literature search to obtain published information ( generally post 1990 only). PCNB and its major degradates PCA and PCTA have not been detected frequently in North America. The presence of PCA and PCTA in the environment are most likely a result of the use of PCNB. Detections of the potential degradate PCP in the environment cannot necessarily be attributed to its existence as a degradate of PCNB, but can be the result of its use as a pesticide itself ( wood preservative). PCP was not found in any surface water samples. Similarly, detections of the degradate ( and impurity in PCNB) PCB in the environment are most likely a result of its existence as a byproduct in the manufacture of other compounds, its existence as a degradate of HCB, and its industrial uses. There are no drinking water standards or health advisories for PCNB.

4.5 Residential and Other Non occupational Exposure/ Risk Pathways [ Pentachloronitrobenzene ( PCNB): Revised Occupational and Residential Exposure Assessment for the Reregistration Eligibility Decision Document. Seyed Tadayon. July 15, 2004]

There is a potential for exposure in residential settings during the application process for homeowners who use products containing PCNB. There is also a potential for exposure from entering areas treated with PCNB, such as entering treated lawns, including golf courses, that could lead to exposures for both adults and children. Risk assessments have been completed for both residential handler and postapplication scenarios. For residential handler exposure assessments, HED used the Outdoor Residential Exposure Task Force ( ORETF) study data and the Residential Standard Operating Procedures ( SOPs).

4.5.1 Home Uses PCNB is registered for use on residential lawns. It is not a restricted use chemical. Therefore, homeowners may obtain and apply PCNB to the lawn to deter fungal growth. The labels recommend no more than 2 applications per year. Following application to the lawn, adults may be exposed to PCNB through dermal contact with the lawn and mowing activities. Children ( primarily toddlers) may have dermal contact with the treated lawn, as well as hand to mouth, object to mouth, and incidental ingestion exposures. Screening level assumptions are incorporated into residential exposure assessments and are therefore, high end.

<IP_ADDRESS> Handler The Agency uses the term " handlers" to describe those individuals who are involved in the pesticide application process. Residential handlers are assumed to complete all elements of an application, including mixing/ loading, with little use of any protective equipment. Residential handler exposure scenarios are only considered to be short term in nature due to the episodic uses associated with homeowner products. Area/ volumes of spray or chemical used in the risk 28 assessment are based on HED guidance specific to residential use patterns. A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. HED based its calculations on what would reasonably be treated by homeowners such as the size of a lawn, or the size of a garden. This information was used by the HED to define chemical use values for handlers which in turn were coupled with unit exposure values to calculate risks. The factors used for the PCNB assessment were those presented in the HED Science Advisory Committee Policy 12: Recommended Revisions To The Standard Operating Procedures For Residential Exposure Assessment which was completed on February 22, 2001. In addition to these factors, unit exposure values were used to calculate risk estimates. These unit exposure values were taken from the Pesticide Handlers Exposure Database ( PHED) or from ORETF data. The quantitative exposure/ risk assessment developed for residential handlers is based on these scenarios:

1. Applying Granulars for Hand application 2. Mixing/ Loading/ Applying Liquids for Low Pressure Handwand application 3. Mixing/ Loading/ Applying Liquids for Backpack sprayer application 4. Mixing/ Loading/ Applying Liquids for Garden hose end sprayer ( ORETF  RTU) application 5. Mixing/ Loading/ Applying Liquids for Garden hose end sprayer ( ORETF  conventional) application 6. Loading/ Applying Granulars for Belly Grinder application 7. Loading/ Applying Granulars for Push type spreader ( ORETF) application 8. Loading/ Applying Granulars for Push type spreader ( ORETF) application In residential settings, the Agency does not use PPE to limit exposures, because they are viewed as impractical and not enforceable. Risk estimates are based on handlers wearing shortsleeve shirts, short pants, shoes, and socks. The overall uncertainty factor applied to residential handler risk assessments is 1000. Residential risks are of concern for a few scenarios, ( i. e., MOE < 1000), including dermal risk for mixing/ loading/ applying liquids with a low pressure handwand and dermal and inhalation risk for the garden hose end sprayer and belly grinder.

Table 11: Summery Short Term Residential Handler Risk for PCNB Exposure Scenario ( Scenario #) Use1 Application Rate2 Daily Area Treated/ day3 Dermal MOE4 Inhalation MOE5 Applicator Applying Granulars for Hand application ( 1) Turf 32.67 lb ai / A 0.023 A 65 200 Mixer/ Loader/ App Mixing/ Loading/ Applying Liquids for Low Pressure Handwand application ( 2) Turf 0.15 lb ai / gal 5 gal 280 3100 Mixing/ Loading/ Applying Liquids for Backpack sprayer application ( 3) 0.15 lb ai / gal 5 gal 5500 3100 Mixing/ Loading/ Applying Liquids for Garden hose end sprayer ( ORETF  RTU) application ( 4) 32.67 lb ai / A 0.5 A 490 390 Mixing/ Loading/ Applying Liquids for Garden hose end sprayer ( ORETF  conventional) application ( 5) 32.67 lb ai / A 0.5 A 120 250 Loading/ Applying Granulars for Belly Grinder application ( 6) 32.67 lb ai / A 0.5 A 12 69 Table 11: Summery Short Term Residential Handler Risk for PCNB Exposure Scenario ( Scenario #) Use1 Application Rate2 Daily Area Treated/ day3 Dermal MOE4 Inhalation MOE5 29 Loading/ Applying Granulars for Push type spreader ( ORETF) application ( 7) 32.67 lb ai / A 0.5 A 1900 4900 Loading/ Applying Granulars for Push type spreader ( ORETF) application ( 8) 43.56 lb ai / A 0.5 A 1400 3700 1Crops and use patterns are from PCNB labels and LUIS report 2Application rates are based on maximum values found in various sources including LUIS and various labels. In most scenarios, a range of maximum application rates is used to represent the range of rates for different crops/ sites/ uses. Most application rates upon which the analysis is based are presented as lb ai/ A. In some cases, the application rate is based on applying a solution at concentrations specified by the label ( i. e., presented as lb ai/ gallon). 3Amount treated is based on the area or gallons that can be reasonably applied in a single day for each exposure scenario of concern based on the application method and formulation/ packaging type. ( Standard EPA/ OPP/ HED values). 4Dermal MOE = short term endpoint for dermal, such as oral NOAEL ( 300 mg/ kg/ day) / Daily Dermal Dose. Target Dermal MOE is 1000. 5Inhalation MOE = oral NOAEL ( 1 mg/ kg/ day) / Daily Inhalation Dose. Target Inhalation MOE is 1000.

<IP_ADDRESS> Residential Postapplication Adults and children, are potentially exposed to residues after application of PCNB products in residential settings. After application to turf, short to intermediate term dermal exposures are anticipated for adults and children. Incidental oral exposure is also expected to occur for small children and is combined with their dermal exposures, where applicable ( i. e., playing on turf). The physical and behavioral differences between adults and children are continuously being studied by the Agency, and the current standard assumptions set forth by the HED and the Science Advisory Panel ( SAP) are contained in the Residential SOPs ( revised February, 2001).

Though the label prohibits application more than 2 times per year, even with the slow dissipation rates, it is not expected that individual residential exposure duration would exceed 30 days in duration since exposure on a residential lawn would diminish continuously with time. However, short and intermediate term risks were assessed using maximum application rates for each scenario to be protective of any longer exposures/ risks. Residential postapplication exposure assessments assume residents wear the following attire: short sleeved shirt, short pants, shoes and socks, and no gloves or respirator. Negligible PCNB inhalation exposure is anticipated for nonhandlers due to the low chemical vapor pressure and dilution of vapor outdoors. The scenarios likely to result in postapplication exposures are as follows:

° dermal contact of adults and toddlers to treated turf and lawns; and ° oral exposure to toddlers from ingestion of grass, soil, or hand to mouth contact Representative turf/ lawn reentry activities include, but are not limited to:

° Adults involved in a low exposure activity, such as golfing or walking on treated turf; ° Toddlers involved in a low exposure activity, such as walking on treated turf; ° Adults mowing or other moderate contact activity, for 1 2 hours; ° Adults involved in a high exposure activity, such as heavy yard work; and 30 ° Toddlers involved in high exposure activities on turf.

Although a Turf Transferable Residue ( TTR) study ( MRID# 44687101) was submitted in support of the reregistration of PCNB, it was not acceptable for this assessment.

4.5.2 Recreational PCNB has recreational uses on golf courses. According to a 1992 report from The Center For Golf Course Management, 12.2 % of the population were golfers ( i. e., 28.5 million people). Golf is considered a lifetime sport so individuals of all ages, excluding very small children, routinely play. Potential risks to young children are difficult to assess because of the uncertainties associated with any extrapolations using adult dermal exposure data and because of the increased likelihood that other behaviors might contribute to exposure such as mouthing contaminated hands or golf balls.

The exposure duration was assumed to be 4 hours since this is the estimate of the average time it takes to play a round of golf, which is based on the report completed by the Center For Golf Course Management [ 1992 Golf Course Operations: Cost of Doing Business/ Profitability. Library of Congress GV975. G56 1992]. The dose levels calculated for adult golfers can be considered upper level estimates of exposure for several reasons including; the clothing scenario considered ( i. e., shorts and short sleeved shirts are not worn by all golfers), and because combining average values across several input parameters mathematically results in an upper percentile calculated value.

Table 12 : Summery of Risk for Residential/ Recreational Postapplication Activities on Treated Turf with PCNB Activity Application Rate ( lb ai/ acre) TTR 5% of application ratea Transfer Coefficient ( cm2/ hr) b Dermal Dose ( mg/ kg/ day) c MOEd ( day 0)

high contact lawn activities: adults 32.67 7.09 14500 2.939 40 43.56 6.89 2.856 30 high contact lawn activities: toddler 32.67 18.3 5200 2.720 110 43.56 19.77 2.938 80 mowing turf: adults 32.67 18.3 500 0.262 1145 43.56 24.4 0.349 860 golf course reentry: adult 32.67 18.3 500 0.523 575 43.57 24.4 0.698 430 a TTR source: 5% of application rate, " Residential SOP Revised February 2001 " was used for determination of MOE's. b Transfer coefficient from the Residential SOP's ( 02/ 01). c Dermal dose = normalized TTR (

g/ cm2) x TC ( cm2/ hr) x conversion factor ( 1 mg/ 1,000

g) x exposure time ( 2 hrs/ day playing or mowing; 4 hrs golfing) / body weight ( 70 kg adult or 15 kg child 1 6 yrs). d MOE = NOAEL ( 300 mg/ kg/ day; based on a dermal study) / dermal dose Note: TTR = turf transferable residue DAT = days after treatment The oral non dietary risk estimates for small children from hand to mouth and ingestion exposure while playing on PCNB treated turf are contained in Table 13. Risk estimates were combined where applicable for PCNB 31 Table 13: Residential Oral Non dietary Short and Intermediate term Postapplication Risks for PCNB Exposure Scenario Route of Exposure Population Application Ratea MOEb Short term Postapplication Exposures Hand to Mouth Activity on Turf Oral Toddler 32.67 2 43.56 2 Object to Mouth Activity on Turf Oral Toddler 32.67 8 43.56 6 Incidental Soil Ingestion Oral Toddler 32.67 612 43.56 460 Intermediate term Postapplication Exposures Hand to Mouth Activity on Turf Oral Toddler 32.67 1 43.56 1 Object to Mouth Activity on Turf Oral Toddler 32.67 8 43.56 6 Incidental Soil Ingestion Oral Toddler 32.67 612 43.56 460 a Application rates represent a range of label rates of 32.67 43.56 lb ai/ acre for all liquid and granular products which may be applied to residential and recreational lawns either professionally or by a consumer. Incidental oral doses were calculated using formulas presented in the Residential SOPs ( updated 1999 2000). Short term doses were calculated using the following formulas: ( 1) Hand to mouth oral dose to children on the day of treatment ( mg/ kg/ day) = [ application rate ( lb ai/ acre) x fraction of residue dislodgeable from potentially wet hands ( 5%) x 11.2 ( conversion factor to convert lb ai/ acre to

g/ cm2)] x median surface area for 1 3 fingers ( 20 cm2/ event) x hand to mouth rate ( 20 events/ hour) x exposure time ( 2 hr/ day) x 0.001 mg/ µ g] x 50% extraction by saliva / bw ( 15 kg child 1 6 yrs). This formula is based on proposed changes to the December 1999 Residential SOPs. ( 2) Turf mouthing oral dose to child on the day of treatment ( mg/ kg/ day) = [ application rate ( lb ai/ acre) x fraction of residue dislodgeable from potentially wet hands ( 20%) x 11.2 ( conversion factor to convert lb ai/ acre to

g/ cm2) x ingestion rate of grass ( 25 cm2/ day) x .001 mg/ µ g] / bw ( 15 kg child 1 6 yrs). Soil ingestion oral dose to child on the day of treatment ( mg/ kg/ day) = [( application rate ( lb ai/ acre) x fraction of residue retained on uppermost 1 cm of soil ( 100% or 1.0/ cm) x 4.54e+ 08

g/ lb conversion factor x 2.47e 08 acre/ cm2 conversion factor x 0.67 cm3/ g soil conversion factor) x 100 mg/ day ingestion rate x 1.0e 06 g/

g conversion factor] / bw ( 15 kg; child 1 6 yrs). Short term dose based residue on the soil on day of application. b MOE = NOAEL ( 1 mg/ kg/ day for both short and intermediate term assessments) / Oral Dose ( mg/ kg/ day). Aggregate MOEs = NOAEL / [ sum of incidental oral doses] with an target MOE of 1000.

4.6 Other ( Spray Drift; Farm Worker Children, etc.)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application but, to a lesser extent, could also be a potential source of exposure from ground application methods. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies, and other parties, for pesticide regulation to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership composed of U. S. pesticide registrants, and is developing a policy on how to appropriately apply the data, and the AgDRIFT computer model, to its risk assessments for pesticides applied by air, orchard air blast, and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off target drift and risks associated with aerial as well as other application types, where appropriate. This will include expanding the scope of the residential exposure assessments 32 by developing guidance for characterizing exposures from other sources not already addressed, such as from spray drift, residential residue track in, exposures to farm worker children, and exposures to children in schools.

Of note, measurable levels of PCNB were detected in an ambient air monitoring study conducted by CalEPA's Department of Pesticide Regulation ( CDPR) in Lompoc, California ( Santa Barbara County) in 2000 ( http:// www. cdpr. ca. gov/ docs/ dprdocs/ lompoc/ vol3_ multiple_ pest/ volume3_ march2003. pdf). PCNB was detected in 72% of the air samples taken between May August 2000. Since this information raised concerns for potential risks to by standers and workers in adjacent fields, a screening level assessment was conducted by the USEPA and determined that these potential exposures resulted in risks below the Agency's level of concern ( i. e. > MOE 1000).

5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATIONS 5.1 Overview Due to the availability of acceptable oral and dermal studies using PCNB, the dietary, incidental oral, and dermal risk assessments were conducted using route specific endpoints. There are no subchronic inhalation toxicity data on PCNB. Due to the greenhouse use of PCNB the HIARC requested that a 90 day inhalation toxicity study of PCNB be conducted. To fully characterize the hazard and potential risk from exposures to PCNB additional studies are requested: study to assess thyroid toxicity in adults vs. offspring development; study to address the toxicological significance of alterations in AST/ ALT activities; and a metabolism study that includes blood kinetics and half life of PCNB. No acute dietary endpoint was selected since no adverse effects attributed to a single exposure ( dose) were identified, including in the rat or rabbit developmental toxicity studies. The chronic dietary, and short, intermediate, and longterm dermal, inhalation, and incidental oral endpoints are all based on a common the toxic effect, thyroid toxicity, observed in animals following subchronic or chronic exposure. PCNB is a weak dermal sensitizer, shows evidence of being clastogenic, and is classified as a Group C carcinogen (" Possible" human carcinogen).

A common toxicological endpoint of concern ( thyroid toxicity) was identified for the oral, dermal, and inhalation ( oral equivalent) routes of exposure. Therefore, for short, intermediate and long term ( when appropriate) exposure aggregate risk assessments, these routes/ durations can be aggregated for the appropriate populations.

In assessing aggregate risks, HED has considered exposures from dietary ( food and drinking water) and non dietary ( dermal and inhalation) pathways. For residential and other nondietary exposure pathways relevant incidental oral, dermal, and inhalation ( if applicable) exposures are included to calculate short, intermediate, and long term aggregate risks. For the dietary pathway, food exposure estimates come from the dietary exposure analysis discussed above ( Section 4.3.2). Generally, when there are insufficient water monitoring data available to quantitatively include in the aggregate risk assessment as a means of assessing whether or not aggregate exposures to a chemical and its metabolites are likely to exceed levels of concern. 33 EFED has provided estimated drinking water concentrations.

For PCNB and its metabolites, quantitative aggregate exposure assessments that include dietary ( food + drinking water) + incidental/ dermal/ inhalation exposures were not performed, since potential exposures and their associated risks from individual sources of exposures were already of concern, particularly for children. However, chronic aggregate exposures were estimated by combining food and estimated drinking water exposures directly in the DEEMFCID program.

5.2 Acute Aggregate Risk No adverse effects attributed to a single exposure ( dose) were identified, no acute dietary risk assessment was conducted and therefore, no acute aggregate risk assessment was conducted.

5.3 Short Term Aggregate Risk Short term ( 1 30 days) aggregate risk includes the chronic estimated dietary exposure plus, when applicable, estimated residential/ recreational incidental oral, dermal, and inhalation exposures resulting from the registered uses of the chemical. In the case of PCNB, dietary exposures from food plus water are already of concern for infants ( 313% cPAD), children 1 2 years ( 173% cPAD), children 3 5 years ( 155% cPAD), children 6 12 years ( 105% cPAD), adults 50+ years ( 102% cPAD), and the general population ( 105% cPAD). Add to that, potential risks of concern from dermal contact with treated lawns ( MOE 40 for adults), and ingestion of granulars ( MOE < 1 for toddlers), and aggregate risks would clearly be of even greater concern. Though dietary exposures to adult homeowners from food alone, may be acceptable ( 25% cPAD or less for general population), when potential drinking water ( total 105% cPAD), and dermal ( MOE 65) and inhalation ( MOE 200) risks from applying granulars by hand, and postapplication dermal risks ( MOE 30) from high contact lawn activities on turf are considered, aggregate risks are of concern ( target MOE > 1000). When potential dietary ( food + water) risks to infants ( 313% cPAD) and children ( 173% cPAD for 1 2 yr. olds) are considered with potential residential postapplication incidental oral ( MOE 460) and hand to mouth ( MOE 1) risks, estimated aggregate risks are even greater.

5.4 Intermediate Term Aggregate Risk Intermediate term ( 1 6 months) aggregate risk includes the chronic estimated dietary exposure plus, when applicable, estimated intermediate term residential/ recreational incidental oral, dermal, and inhalation exposures resulting from the registered uses of the chemical. Residential handler exposures are generally considered to be short term only due to the episodic uses associated with the product. Though the label prohibits application more than 2 times per year, even with the slow dissipation rates, it is not expected that the individual postapplication residential exposure duration would exceed 30 days in duration since exposure on a residential lawn would diminish continuously with time. However, short and intermediate term risks were assessed using maximum application rates for each scenario to be protective of any longer 34 exposures/ risks. The potential exposures and risks from the separate sources of exposure, alone, are of concern, particularly for children. As above ( section 5.3), when these potential exposures and associated risks are layered upon each other, risk concerns are increased.

5.5 Chronic Aggregate Risk Chronic aggregate risk estimates include only dietary pathways of exposure ( food + water). Chronic aggregate exposures were estimated by combining food and estimated drinking water exposures directly in the DEEM FCID program. The chronic dietary risk without the inclusion of water is below the Agency's level of concern; i. e., < 100% cPAD. When exposures from drinking water are added, chronic aggregate risks for most of the exposed population subgroups, particularly infants ( 313% cPAD) and children 1 2 years old ( 173% cPAD) are above the Agency's level of concern.

5.6 Cancer Aggregate Risk PCNB is classified as a Group C possible human carcinogen and the HIARC recommended that for risk assessment purposes, the RfD approach should be used for quantification of human risk. Therefore, a separate assessment of aggregate cancer risk is not required.

Table 14. Result of Chronic Dietary Exposure and Risk Estimates for PCNB.

Population Subgroup cPAD mg/ kg/ day Risk from all crops ( no water) Risk from all crops Including risk from water DEEM FCID Lifeline DEEM FCID Exposure, mg/ kg/ day % cPAD Exposure, mg/ kg/ day % cPAD Exposure, mg/ kg/ day % cPAD U. S. Population 0.001 0.000121 12% 0.000252 25% 0.001052 105%

All infants (< 1 yr) 0.001 0.000072 7% .00002 2% 0.003126 313%

Children 1 2 yrs 0.001 0.000345 34% 0.000331 33% 0.001729 173%

Children 3 5 yrs 0.001 0.000254 25% 0.000199 20% 0.001549 155%

Children 6 12 yrs 0.001 0.000161 16% 0.00013 13% 0.001054 105%

Youth 13 19 yrs 0.001 0.000104 10% 0.000092 9% 0.000777 78%

Adults 20 49 yrs 0.001 0.000097 10% 0.000263 26% 0.000967 97%

Adults 50+ yrs 0.001 0.000104 10% 0.000303 30% 0.001019 102%

Females 13 49 yrs 0.001 0.000096 10% 0.000261 26% 0.000962 96%

° " Risk from all crops" indicates the risk from oral consumption of residues found in the food chain at present time, whether from registered or unregistered crops ( for details see discussion under residue section).

6.0 CUMULATIVE The Food Quality Protection Act ( 1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among 35 other things, available information concerning the cumulative effects to human health that may result from dietary, residential, or other non occupational exposure to other substances that have a common mechanism of toxicity. The reason for consideration of other substances is due to the possibility that low level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the other substances individually. A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a common toxic effect by a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe.

Guidance for conducting cumulative risk assessments on substances that have a common mechanism of toxicity is available from the OPP Website ( http:// www. epa. gov/ pesticides). In the guidance, it is stated that a cumulative risk assessment of substances that cause a common toxic effect by a common mechanism will not be conducted until an aggregate exposure assessment of each substance has been completed. Before undertaking a cumulative risk assessment, HED will follow procedures for identifying chemicals that have a common mechanism of toxicity as set forth in the " Guidance for Identifying Pesticide Chemicals and Other Substances that Have a Common Mechanism of Toxicity" ( 64 FR 5795 5796, February 5, 1999).

PCNB is a member of the substituted aromatics class of pesticides ( George W. Ware, The Pesticide Book, Fourth ed., 1994). Other members of this class include 2,6 dichloro 4 nitroaniline ( dichloran, DCNA) and chlorothalonil. HED did not perform a cumulative risk assessment as part of this risk assessment for PCNB because HED has not yet initiated a review to determine if these or any other chemical substances that have a mechanism of toxicity in humans in common with it.

7.0 OCCUPATIONAL EXPOSURE Pentachloronitrobenzene ( PCNB): Revised Occupational and Residential Exposure Assessment for the Reregistration Eligibility Decision Document. Seyed Tadayon. July 15, 2004.

7.1 Agricultural, Seed Treatment, and Non crop/ Utility Uses For agricultural uses, HED relied almost completely on surrogate data from the Pesticide Handlers Exposure Database ( PHED) Version 1.1. Chemical specific postapplication exposure data have not been submitted by the registrant in support of reregistration of PCNB. However there is a low potential for occupational postapplication exposure when a pre plant or at planting fungicide is used. Many agricultural operations mechanically plant seeds early in the season, which minimizes the potential for contact. Significant exposure during harvesting or any other late season activities, is not likely since the chemical is applied pre plant or at planting. However the Agency has determined that there are potential postapplication exposures to individuals reentering PCNB treated areas for the purpose of mowing ( roadsides, rights of way, golf course) and harvesting ( sod farms). 36 7.1.1 Handler HED determined potential exposures to handlers by identifying exposure scenarios from the various application equipment types that are recommended on PCNB labels. Based on reviewing pesticide labels and a use meeting with the registrants, agricultural use patterns specific to PCNB are associated with the following application methods/ equipment:

Agricultural Uses:

 Chemigation  Ground boom sprayer  Airblast sprayer  Push type spreader  Tractor drawn spreader  Aerial application Seed Treatment Uses:

 Commercial seed treater  On farm seed treatment  Planter/ seed box <IP_ADDRESS> Exposure and Risk Estimates for Agricultural Uses HED has determined that there are potential exposures to mixers, loaders, applicators, or other handlers during the usual use patterns associated with PCNB. The potential handler exposures to the 103 identified exposure scenarios were assessed using the toxicological endpoints and uncertainty factors associated with the a. i. Therefore, the level of PPE was determined by the assessment of the a. i. independently from the currently required risk mitigation measures on PCNB labels. This distinction of determining risk mitigation measures based on the a. i. instead of the label required PPE is important because of the nature of the end use products. For example, some end use products require additional PPE because of the end use product's potential for eye and/ or skin irritation. Conversely, HED does not want to mandate additional PPE ( e. g., heat stress issues) if it is not required based on the endpoint and uncertainty factors. There are some PPE, such as chemical resistant aprons and/ or head gear, that the HED uses as qualitative measures because there are no recognized protection factors ( PF) to assess their effectiveness.

The risks are presented separately for some scenarios and combined for others. Most of the hand held equipment such as push type granular spreaders are assessed as mixer/ loader/ applicators, a combined function. With these types of small operations the mixing, loading, and applying are almost always carried out by the same individual. There are data available to estimate exposure from these small area activities. For equipment such as groundboom tractors, or airblast sprayers, the tasks are assessed separately for mixer/ loaders and applicators. By separating the two job functions, HED can determine the most appropriate PPE or engineering controls without requiring the handler to wear PPE throughout the entire workday or engineering controls that are not needed. 37 MOEs were calculated for handlers for short ( 1 30 days) and intermediate term ( 1 6 months) durations. The assessment includes MOE calculations for various levels of PPE using the surrogate data from PHED ( V1.1). The short term duration is believed to be most representative of private growers and the intermediate term duration represents commercial applicators who may repeatedly apply PCNB for 1 to 6 months. PCNB was classified as a category C possible human carcinogen and not requiring any type of quantitative cancer risk assessment.

The risk estimates for short and intermediate term dermal exposures resulted largely in MOEs greater than or equal to the target MOE of 100, with use of PPE or engineering controls. The following scenarios did not have MOEs > 100 at any mitigation level and therefore, are of concern ( bracketed numbers correspond to those in Table 15; Appendix 1):

( 6) mixing/ loading dry flowable for chemigation application ( sod farms), ( 58) sprays for high pressure handwand application ( ornamentals), ( 94) mixing/ loading/ applying liquid for handgun ( lawn) sprayer ( ORETF) application, ( 98) mixing/ loading/ applying granular for belly grinder application ( ornamentals) ( 100) mixing/ loading/ applying wettable powders for low pressure handwand application ( ornamentals  woody shrubs and vines, and herbaceous plants), ( 101) mixing/ loading/ applying wettable powders for low pressure handwand application ( ornamentals  shade trees)

The results of the inhalation handler risk assessment for both the short and intermediateterm exposure durations are summarized in Table 15 ( Appendix 1). All inhalation scenarios had MOEs > 100, though some required the addition of PPE or engineering controls including:

( 6) mixing/ loading dry flowable for chemigation application ( sod farms), ( 16) mixing/ loading liquids for chemigation application, ( 24) mixing/ loading liquids for chemigation application, ( 25) mixing/ loading liquids for aerial application, ( 42) mixing/ loading wettable powder for chemigation application ( cole crops), ( 50) mixing/ loading wettable powder chemigation application ( sod farms), ( 51) mixing/ loading wettable powders for groundboom application, ( 58) sprays for high pressure handwand application ( ornamentals), ( 87) sprays for high pressure handwand application, ( 100) mixing/ loading/ applying wettable powders for low pressure handwand, application ( ornamentals  woody shrubs and vines, and herbaceous plants), ( 101) mixing/ loading/ applying wettable powders for low pressure handwand, application ( ornamentals  shade trees).

The results of the short and intermediate term occupational handler assessments indicate that for the dry flowable formulation, the majority of the potential exposure scenarios result in total MOE( s) > 100 at the baseline clothing attire of long pants, long sleeved shirts, no gloves, and no respirator while using open systems. For the liquid formulation, the risk estimates indicate that in order for the mixer/ loaders to achieve MOEs of 100 for all uses at both the short 38 and intermediate term exposure durations, minimum PPE clothing attire should be required ( i. e., long pants, long sleeved shirts, chemical resistant gloves, and a dust/ mist respirator while using open systems). This is consistent with the current label except for the need, in some scenarios, to add an organic vapor respirator. The risk estimates for the majority of uses with the wettable powder formulation are acceptable ( clothing attire of long pants, long sleeved shirts, chemical resistant gloves, and no respirator). However, the risk estimates indicate that in order for the mixer/ loaders of wettable powders to achieve MOEs of 100 for all uses at both the short and intermediate term durations that, for some uses, PCNB should be packaged in water soluble packets.

<IP_ADDRESS> Exposure and Risk Estimates for Seed Handlers There are a number of methods that can be used to treat seeds both commercially and onfarm On farm seed treatment methods include concrete tumbler, drill box, duster, in furrow, mist type seed treater, planter/ seed box, seed treater and slurry type seed treater. Commercial seed treatment equipment produced by Gustafson include Computerized Seed and Chemical Proportioner, Gustafson Accu Treat Treater, Gustafson S Series and SS Series, Gustafson SSAMP Treater, and Triple Treat Seed Treater.

On farm seed treatment is considered, by most sources, to represent a relatively small proportion of the total use of treated seed in the U. S. This may be due, in large part, to the greater time investment, labor, and equipment commitment required for on farm seed treatment compared to buying the treated seed. However, some seed crops record a sizable percentage of on farm seed treatment. A risk assessment for on farm seed treatment ( planter box) was completed using a submitted dust formulation study. The dust formulation study is the only onfarm seed treatment study available, and is used as a surrogate for planter box seed treatment with a liquid formulation. The planter box seed treatment liquid formulation risk assessment is considered conservative since treatments with dust formulations usually present higher risks than liquids. There are no data for other seed treatments done on farm.

An exposure assessment was conducted for workers loading treated seed into plant hoppers and driving a closed cab tractor to pull the planter around the field. Commercial, onfarm seed treatment, and planter exposures were addressed using the Science Advisory Council Exposure Policy 14 ( May, 2003), seed treatment SOP. This database was created by USEPA, and measures exposure values for seed treaters and planters under actual field conditions. There are potential exposures to loader/ applicators, baggers, sewers, workers performing multiple activities and on farm treatment with planter boxes, and seed planters during the usual usepatterns associated with PCNB. Six exposure scenarios were identified to represent the extent of PCNB seed treatment uses. PCNB labels include a multitude of uses and a wide range of application rates. Though the seed treatment risk assessment is not all inclusive, an attempt has been made to assess a range of application rates to capture the exposures associated within each scenario. MOEs were calculated for handlers for short and intermediate term durations. The short term duration is believed to be the most representative of on farm seed treaters and the intermediate term duration represents commercial seed treaters who may repeatedly apply PCNB for 1 to 6 months. The assessment includes MOE calculations for various feasible levels of PPE 39 using the surrogate data from the seed treatment SOP.

The results of the short and intermediate term seed handler assessments indicate that, for all formulations, the majority of the potential exposure scenarios result in total MOEs > 100 with long pants, long sleeved shirts, gloves, and no respirator while using open systems. Seed handlers working in a smaller facility, performing multiple activities, might require a respirator to reduce exposures so that potential risks ( MOEs) would be > 100 and not of concern.

Table 16: Summary of Short and Intermediate term Dermal and Inhalation Risk from Seed Treatment for PCNB ( MOEs )

Crops Loader/ applicator Bagger Sewer Multiple activities On Farm ( planter box) Planters Derm Inh Derm Inh Derm Inh Derm Inh Derm Inh Derm Inh Barley 1000 200 2500 500 3600 350 550 50 300 9000 3600 900 Bean 3000 700 8000 1500 11000 1000 1500 150 550 20000 16000 4000 Corn 3200 700 8000 1500 12000 1100 1800 150 2100 73000 45000 11000 Cotton 7000 1650 18000 3500 27000 2400 4000 350 9300 330000 36000 8700 NA NA NA NA NA NA NA NA 3500 120000 13000 3300 Oats 650 150 1700 300 2400 200 360 300 400 13000 2400 600 Pea 1500 350 4000 730 5700 500 800 75 250 9000 13000 3000 Peanut 12500 2800 31500 6000 46000 4200 6800 600 240 8400 145000 3600 Rice 900 200 2300 400 3400 300 500 50 150 5300 2000 500 Safflower 2100 470 5300 1000 7700 700 1100 100 NA NA 57000 14000 Sorghum 4200 940 11000 2000 15000 1400 2300 200 NA NA 430000 110000 Soybeans 1500 350 3900 700 5700 500 800 75 3300 120000 7000 1600 Sugar beet 4100 900 10000 2000 15000 1300 2000 200 7000 230000 110000 27000 Wheat 2400 600 6000 1100 9000 800 1300 120 340 12000 7000 1600 7.1.2 Postapplication Exposures There is a low potential for occupational postapplication exposure when used as a preplant or at planting fungicide. PCNB is applied to the soil directly and is soil incorporated well before the plants are mature. Further, the timing of the application greatly reduces the potential for postapplication exposure to treated foliage and/ or soil. Also, many agricultural operations mechanically plant seeds early in the season, which minimizes the potential for contact. Significant exposure during harvesting or any other late season activities, is not likely since the chemical is applied pre plant. Therefore, HED does not require a postapplication assessment for seed treatment or agricultural uses. However, the Agency has determined that there are potential postapplication exposures to individuals re entering PCNB treated areas for the purpose of: 40 Roadsides: mowing; Bermuda grass rights of way: mowing; Sod farms: mowing and harvesting; Golf course turfgrass: mowing.

<IP_ADDRESS> Noncancer Postapplication Exposure and Risk Estimates For golf course maintenance or sod harvesting, transfer coefficients of 3400 and 6800 cm2/ hr were used, based on the Agricultural Re entry Task Force ( ARTF) data ( see HED Exposure SAC Policy guidance 3.1, 8/ 00). Transferable residue values from the submitted TTR study ( MRID# 446871 01) were used and adjusted when needed. The short and intermediateterm estimated risks to golf course workers or sod growers doing hand harvesting on day zero result in MOEs > 100 and do not exceed HED's level of concern at the 32.67 and 43.56 lb ai/ A application rates.

Table 17: Days After Treatment Target MOE Achieved ( Target MOE = 100)

Crop/ Use Pattern Application Rate ( lb ai/ acre) Postapplication Activity TTR ( sites)

g/ cm2 DAT 0a Transfer Coefficientb MOEc REI ( days)

Golf Course Turf 32.67 Mow, seed, mechanical weed, aerate, fertilize, prune 0.366 3400 2100 0 43.56 0.488 1580 0 Sod Farms 32.67 Mow, scout, mechanical weed, irrigate 0.366 6800 1120 0 43.56 0.488 790 0 a TTR source: MRID # 446871 01 turf transferable residue study. DAT 0 residue values were used for the short term assessments and DAT 7 residue values were used for the intermediate term assessments. The study was conducted in CA, OR, MO using an average application rate of 32.67lb ai/ acre for each sites. When assessing activities involving a different application rate than was used in the study, the TTR values were adjusted proportionately to reflect the different application rates. For example for an application rate of 43.56 lb ai/ acre : normalized ( adjusted) TTR = Turf study TTR x 43.56 lb ai/ A assessed rate / 32.67 lb ai/ A study rate. b Transfer coefficient from : Policy Memo # 003 .1 " Agricultural Transfer Coefficients," Revised  August 7, 2000. C MOE = NOAEL ( 300 mg/ kg/ day; based on a dermal study) / dermal dose Note: TTR = turf transferable residue DAT = days after treatment 7.2 Incident Data Review of PCNB Poisoning Incident Data Chemical: # 056502. Ruth H. Allen. February 4, 2003.

The Agency has reviewed the Incident Data System ( IDS), the Poison Control Center, the California Department of Food and Agriculture ( Department of Pesticide Regulation), and the National Pesticide Telecommunications Network ( NPTN) databases for reported human incident information for PCNB. A number of accidental human poisonings from exposure to PCNB in both occupational and residential settings have been reported. The data from these sources often lacked specific information on the extent of exposure and the circumstances of exposure. Collectively, however, the incidence information indicate definite poisoning risks from misuse of products that contain PCNB, or from not wearing PPE, especially eye protection. Most of the incidents reported were of eye and skin irritation. 41 8.0 DATA NEEDS/ LABEL REQUIREMENTS 8.1 Toxicology 1. Although the thyroid is a target organ for PCNB, thyroid hormone and TSH determinations have been performed only in one nonguideline study ( 90 day study in male rats) using an inappropriate dose spacing ( 0, 1, & 333 mg/ kg/ day) which precludes a meaningful assessment of dose response and time course features of the effect. The HIARC requests that the registrants conduct a study to assess thyroid toxicity in adults vs. offspring development. The study should include; a) assays of appropriate hormones; b) organ weights; and c) histopathology. The study should be conducted at adequate doses. The registrants are requested to consult the Agency concerning the details.

2. Aminotransferase activities ( AST/ ALT, particularly ALT) decrease in dose dependent manner by as much as 30 80% in rats and dogs. Although the literature indicates that aminotransferase inhibition may result in increases in Gamma aminobutyrate ( GABA), hepatocellular tyrosine, and other amino acid related compounds, there are insufficient data to evaluate the toxicological significance of the inhibition findings for PCNB. The registrants are requested to address the toxicological significance of these alterations in AST/ ALT activities.

3. Although information in the published literature indicates that PCNB undergoes extensive biotransformation in mammals, there is an uncertainty as to its biological half life and thus, as to its potential for bioaccumulation. Data in the literature suggest that its half life might be relatively short at low doses and higher at higher doses. It is therefore requested that the registrants perform a guideline metabolism study of PCNB ( including a mass balance of radioactivity in excreta, tissues, and carcass), including a Tier II study of blood kinetics, to determine a half life of PCNB. The registrants should consult the Agency as to the details of the protocol.

4. There are no subchronic inhalation toxicity data on PCNB. Due to the greenhouse use of PCNB, the HIARC requests that a 90 day inhalation toxicity study of PCNB be conducted. It is recommended that interim thyroid hormone analyses be made at 7, 14, 30, and 90 days.

8.2 Product Chemistry 1. Additional data are required for the Amvac 95% T concerning preliminary analysis ( OPPTS 830.1700). For specifics see Revised Reregistration Eligibility Decision Document ( RED) of Pentachloronitrobenzene ( PCNB, PC Code 056502): Product and Residue Chemistry Considerations. Reregistration Case 0128. DP Barcode. D305653. Mohsen Sahafeyan and Kenneth W. Dockter. July 21, 2004.

8.3 Residue Chemistry See Residue Chemistry chapter ( 07/ 21/ 04). 42 REFERENCES Environmental Fate and Ecological Risk Assessment for the Re registration of Pentachloronitrobenzene. Cheryl Sutton. February 3, 2004.

National Toxicology Program. 1987. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Pentachloronitrobenzene in B6C3 F1 Mice. U. S. Department of Health and Human Services. Public Health Service. National Institutes of Health ( NIH) Publication No. 87 2581. NTP TR 325.

ATTACHMENTS Assessment of the Dietary Cancer Risk of Hexachlorobenzene and Pentachlorobenzene as impurities in Chlorothalonil, PCNB, Picloram, and several other pesticides. William Smith. February 26, 1998.

PCNB  Report of the Hazard Identification Assessment Review Committee. Elizabeth A. Doyle. April 9, 2003.

PCNB ( PC Code 056502) Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision ( RED). Laurence D. Chitlik, December 15, 2003.

Pentachloronitrobenzene ( PCNB). ( List A, Case No. 0128) Briefing Memorandum to Metabolism Assessment Review Committee to discuss PCNB residues of concern for inclusion in dietary risk assessment. Chemical 056502. Mohsen Sahafeyan & Larry Chitlik. April 8th, 2003;

Pentachloronitrobenzene ( PCNB). ( List A, Case No. 0128) The Outcome of the HED Metabolism Assessment Review Committee Held on April 16th, 2003 to discuss residues of concern in risk assessment and tolerance expression of PCNB. Chemical 056502. Mohsen Sahafeyan & Laurence Chitlik. May 27th, 2003 Pentachloronitrobenzene: Tier I Drinking Water EDWCs for Use in the Human Health Risk Assessment. Cheryl A. Sutton. November 12, 2003.

Pentachloronitrobenzene, Revised Drinking Water Assessment: Tier 2 Drinking Water EDWCs for Use in the Human Health Risk Assessment. Cheryl A. Sutton. December 22, 2003.

Pentachloronitrobenzene ( PCNB): Revised Occupational and Residential Exposure Assessment for the Reregistration Eligibility Decision Document. Seyed Tadayon. July 15, 2004.

Pentachlorophenol: Report of the Hazard Identification Assessment Review Committee. Jess Rowland. December 8, 1997.

Probabilistic Chronic Dietary Exposure Estimates for Pentachloronitrobenzene ( PCNB). 43 Mohsen Sahafeyan. January 30th, 2004.

Review of PCNB Poisoning Incident Data Chemical: # 056502. Ruth H. Allen. February 4, 2003.

Revised Reregistration Eligibility Decision Document ( RED) of Pentachloronitrobenzene ( PCNB, PC Code 056502): Product and Residue Chemistry Considerations. Reregistration Case 0128. DP Barcode. D305653. Mohsen Sahafeyan and Kenneth W. Dockter. July 21, 2004.

Second Carcinogenicity Peer Review of PCNB. Pamela Hurley and Esther Rinde. December 18, 1992. 44 APPENDIX 1 Table 15: Summery of Short and Intermediate Term Occupational Risk for PCNB Exposure Scenario ( Scenario #) Crop App Rate4 lbai/ A or lb ai/ gal Daily Area Treated A or gals Dermal MOE Inhalation MOE9 Baseline PPE1 PPE2 PPE3 PPE4 PPE5 PPE6 Eng. C Baseline PPE1 PPE4 PPE2 PPE5 PPE3 PPE6 Eng. C Mixer/ Loader Dry Flowables for High Pressure HandWand application ( 1) Containerized nursery stock, soil drench ( beans, brussels sprouts, cabbage,

cauliflower) 0.0038 1000 gals 85000 85000 120000 No Data 24000 120000 240000 No Data Dry Flowables for Chemigation application ( 2) Commercial/

industrial lawns 32.67 10 970 970 1400 No Data 280 1400 2800 No Data Dry Flowables for High Pressure HandWand application ( 3) Commercial/

industrial lawns,