                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
\* MERGEFORMAT

                                                                     	OFFICE OF
                                                           	CHEMICAL SAFETY AND
                                            	              POLLUTION PREVENTION

MEMORANDUM

Date: 		28-JAN-2015

Subject:	Pyrimethanil.  Human Health Risk Assessment for Proposed Post-Harvest Use on Pomegranates.

PC Code:
288201
DP Barcode:
D417167
Decision No.:
484376
Registration No.:
43813-32
Petition No.:
3F8213
Regulatory Action:
Section 3
Risk Assessment Type:
Single Chemical/Aggregate Assessment
Case No.:
7059
TXR No.:
None
CAS No.:
53112-28-0
MRID No.:
None
40 CFR
§180.518

From:		Jennifer R. Tyler, Chemist
      Jaclyn Pyne, Biologist
		Anwar Y. Dunbar, Ph.D., Pharmacologist
		Risk Assessment Branch 1 (RAB1)/Health Effects Division (HED; 7509P)

Through:	Charles W. Smith III, Branch Chief
		George F. Kramer, Ph.D., Senior Chemist
		RAB1/HED (7509P)

To:		Hope Johnson/Cynthia Giles-Parker, RM 21
      Registration Division (RD; 7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides.  The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from proposed and currently registered uses of the active ingredient (ai) pyrimethanil (4,6-dimethyl-N-phenyl-2-pyrimidinamine).  Bayer CropScience has submitted a petition for the post-harvest use of pyrimethanil on pomegranates.  The risk assessment and occupational/residential exposure assessment were provided by Jennifer Tyler (RAB1); the residue chemistry review and dietary exposure assessment by Jaclyn Pyne (RAB1); the hazard characterization by Anwar Dunbar (RAB1); and the drinking water assessment by James Wolf of the Environmental Fate and Effects Division (EFED).

NOTE:  A human health risk assessment was completed on 22-MAY-2013 by HED (Memo, J. Tyler et al., D389923).  In the present memo, dietary, occupational, and aggregate risks were re-evaluated based on the addition of pomegranates to the pyrimethanil use pattern.

                               Table of Contents
1.0	Executive Summary	3
2.0	HED Recommendations	5
2.1	Data Deficiencies/Conditions of Registration	5
2.2	Tolerance Considerations	6
3.0	Introduction	6
3.1	Chemical Identity	7
3.2	Physical/Chemical Characteristics	7
3.3	Pesticide Use Pattern	7
3.4	Anticipated Exposure Pathways	8
3.5	Consideration of Environmental Justice	8
4.0	Hazard Characterization and Dose Response Assessment	9
4.1	Summary of Toxicological Effects	9
4.2	Safety factor for Infants and Children (FQPA Safety Factor)	10
4.3	Toxicity Endpoint and POD Selections	11
5.0	Dietary Exposure and Risk Assessment	14
5.1	Residues of Concern Summary and Rationale	14
5.2	Food Residue Profile	14
5.3	Water Residue Profile	15
5.4	Dietary Risk Assessment	16
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	17
7.0	Aggregate Exposure/Risk Characterization	17
7.1	Acute Aggregate Risk	17
7.2	Short- and Intermediate-Term Aggregate Risk	17
7.3	Chronic Aggregate Risk	18
7.4	Cancer Risk	18
8.0	Cumulative Risk Characterization/Assessment	18
9.0	Occupational Exposure/Risk Pathway	18
9.1	Handler Exposure and Risk Estimates	18
9.2	Post-application Exposure and Risk Estimates	20
10.0	References	21
Appendix A:  Toxicity Profile Tables.	22
Appendix B:  Metabolism Assessment.	26

1.0	Executive Summary
Bayer CropScience has submitted a petition for the post-harvest use of Penbotec[(R)] 400 Soluble Concentrate (SC) (EPA Reg. No. 43813-32), a SC formulation containing 3.27 pounds (lb) ai/gallon (gal) [400 grams (g) ai/liter (L)] on pomegranates.  The petitioner requests the establishment of a 5.0-ppm tolerance for residues of pyrimethanil in/on pomegranate.

Pyrimethanil is an amino acid synthesis inhibitor that inhibits the secretion of enzymes necessary for fungal infection.  Pyrimethanil is currently registered in the U.S. for use on several raw agricultural commodities (RACs).  Permanent tolerances have been established for residues of pyrimethanil per se in/on plant commodities at levels ranging from 0.05 ppm in/on vegetable, tuberous and corm, subgroup 1C to 150 ppm in/on citrus oil [40 CFR §180.518(a)(1)].  Tolerances have also been established for pyrimethanil residues and its metabolite 4-[4,6-dimethyl-2-pyrimidinyl)amino]phenol in fat (0.01 ppm), kidney (2.5 ppm) and byproducts (except kidney) (0.01 ppm) of cattle, goats, horses and sheep and in milk (0.05 ppm) [40 CFR §180.518(a)(2)].  There are no registered or proposed residential uses.

Proposed Use:  The proposed use to the subject crops is as a single post-harvest application at 0.82 lb ai/100 gal via in-line dip/drench wash tanks.  Applications can be made to the fruit on the same day as sold or consumed.

Toxicity Profile:  Pyrimethanil is of low acute lethality by the oral, dermal, and inhalation routes. It is a slight eye irritant, is not irritating to the skin, and it is not a dermal sensitizer.  A single oral dose of 1000 mg/kg produced a number of acute signs of neurotoxicity, including ataxia, dilated pupils, and decreases in motor activity, hind limb grip strength, and body temperature.  However, there was no evidence of neurotoxicity with repeated dosing in a subchronic neurotoxicity study in rats.  The major target organs of repeated oral exposure were the liver and the thyroid.  These effects were accompanied by decreased body weight.  Reproductive toxicity was not observed, and developmental effects (e.g., decreased fetal weight, retarded ossification, extra ribs) were observed only at maternally toxic doses.  Special short-term exposure studies demonstrated increased liver uridine diphosphate glucuronosyl transferase (UDPGT) activity leading to decreases in thyroid hormones (T3, T4) and compensatory increases in thyroid-stimulating hormone (TSH) in adult rats.  Thyroid adenomas were seen in rats following long-term exposure, and it was concluded that they were mediated via disruption of the thyroid/pituitary axis.  There were no concerns for mutagenicity.

Dose-response and Food Quality Protection Act (FQPA) Assessment:  The pyrimethanil risk assessment team has evaluated the hazard and exposure data; and, based on these data, recommended that the FQPA Safety Factor (SF) be reduced to 1X.  The toxicological is complete and there is no evidence of increased offspring susceptibility.  The exposure databases are sufficient to determine the nature/magnitude of the residue in food and dietary analyses are unlikely to underestimate risk of exposure from pyrimethanil.  Although there is evidence of neurotoxicity in the acute neurotoxicity study, concern is low since effects were only seen at the limit dose, effects are well-characterized with clearly established no-observed adverse effect level/lowest observed adverse effect level (NOAEL/LOAEL) values, and the selected endpoints are protective for the observed effects.

Residue Chemistry:  The qualitative nature of the pyrimethanil residue in plant commodities is adequately understood based on acceptable metabolism studies in lettuce, grapes, and tomatoes.  The HED Metabolism Assessment Review Committee (MARC) has determined that for risk assessment and tolerance expression, parent only is the residue of concern.  The data-collection method used to generate pomegranate residue data in conjunction with magnitude of the residue study associated with this petition was a gas chromatography method with mass-selective detection (GC/MSD).  There are also adequate methods available to enforce tolerances for residues of pyrimethanil in/on pomegranate.  The submitted field trial residue data for pomegranate are adequate.  The field trial data reflect the proposed use pattern, an adequate number of trials were conducted, and samples were analyzed for the residue of concern using validated data-collection methods.  Using the Organization for Economic Co-operation and Development (OECD) tolerance calculation procedures for the residue data set indicates that the requested tolerance of 5.0 ppm for residues of pyrimethanil in/on pomegranates is appropriate.  For plant commodities, the U.S., Canadian, and Codex residue definitions are harmonized.  There are currently no established Codex or Canadian MRLs for residues of pyrimethanil in/on pomegranates; therefore, harmonization is not an issue for this petition.

Drinking Water Exposure and Risk:  Based on the information provided, EFED considers the proposed post-harvest dip use of pyrimethanil as an indoor use that would pose minimal exposure to the environment, provided that release of the chemical and contaminated water are controlled.  Therefore, EFED concluded that an updated drinking water assessment is not needed for the proposed use.  HED used estimated drinking water concentrations (EDWCs) provided by EFED in conjunction with the most-recent human health risk assessment.  Surface and ground EDWCs were generated by EFED using the Pesticide Root Zone Modeling/Exposure Analysis Modeling System (PRZM/EXAMS) and the Screening Concentration in Ground Water Model (SCI-GROW) models, respectively.  The EDWCs for the combined total residues (pyrimethanil + 2-amino-4,6-dimethylpyrimidine) in ground water are not expected to exceed 4.8 μg/L based on the registered seasonal application rate of 2.1 lb ai/A on strawberry in Florida.  The EDWCs for combined residues of pyrimethanil (parent + 2-amino-4,6-dimethylpyrimidine) in raw surface source water are not expected to exceed 86.5 μg/L for the peak 1-in-10-year concentration; and 29.4 μg/L for the 1-in-10-year annual mean concentration.

Dietary Exposure and Risk:  Acute and chronic dietary exposure assessments were conducted using the using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID) Version 3.16.  The acute and chronic dietary analyses assumed default processing factors (as necessary), empirical processing factors for orange and apple juice, tolerance-level residues, 100% crop treated (CT) for all commodities and EDWCs (acute 86.5 ppb, chronic 29.4 ppb) for direct and indirect water sources.  The resulting acute dietary risk estimates (food and drinking water) were <=38% of the acute population-adjusted dose (aPAD) and are not of concern to HED (<100% aPAD; children 1-2 years old were the most highly exposed population subgroup).  The resulting chronic dietary risk estimates (food and drinking water) were <=76% of the chronic population-adjusted dose (cPAD) and are not of concern to HED (<100% cPAD; children 1-2 years old were the most highly exposed population subgroup).

Residential Exposure:  Currently, there are no registered/proposed uses of pyrimethanil that result in residential exposures.  Therefore, a residential exposure assessment was not performed.

Aggregate Risk:  The Agency conducts aggregate exposure assessments by summing dietary (food and water) and residential exposures (residential or other non-occupational exposures).  Since there are no registered/proposed uses of pyrimethanil that result in residential exposures, the acute and chronic aggregate risk assessments are equal to the acute dietary and chronic dietary estimates (food and water only), respectively.  The acute and chronic aggregate exposures to the general U.S. population and all other subpopulations from the uses of pyrimethanil do not exceed HED's level of concern (LOC).

Occupational Exposure/Risk:  Based on the anticipated use patterns and current labeling, dermal and inhalation exposure occupational pesticide handlers are expected to be mixer/loaders using open-pour loading of liquids for automated systems.  Occupational handler dermal and inhalation risk estimates were calculated.  An MOE >=100 is adequate to protect occupational pesticide handlers from dermal and inhalation exposures.  Dermal and inhalation risks for occupational handlers are above the LOC (100) with label-required personal-protective equipment (PPE) (i.e., long-sleeved shirt, long pants, shoes plus socks and chemical-resistant gloves); and, therefore, are not of concern.

Based on the proposed use pattern, HED expects post-application dermal and inhalation exposure for workers while sorting and packing treated pomegranates, as well as indirect inhalation exposure for workers present in the warehouse, but not directly involved in the treatment process.  The short- and intermediate-term risk estimates are not of concern (i.e., MOEs >=100) at baseline (i.e., t-shirt and no gloves and no respirator) for all post-application exposure activities.

Environmental Justice Considerations:  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf.

Review of Human Research:  This exposure/risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Re-entry Task Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  For certain studies, that review may have included review by the Human Studies Review Board.  Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.
2.0	HED Recommendations

HED concludes that the toxicological, residue chemistry and occupational/residential databases support a Section 3 registration and establishment of the tolerances listed in Section 2.2.2.  HED is not recommending for any additional data or label modifications in conjunction with this petition.
2.1	Data Deficiencies/Conditions of Registration

No additional data are required to support the proposed use.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

A residue analytical method entitled "Analytical Method for the Determination of Residues of ZK 100309 in Vines, Strawberries, and Apples by HPLC" was submitted in conjunction with an earlier pyrimethanil petition, PP#4E4384, for the establishment of a tolerance on imported wine grapes.  The method has been subjected to a successful petition method validation (PMV) by Analytical Chemistry Branch (ACB)/Biological and Economics Analysis Division (BEAD) (DP# 288256, E. Kolbe, 7/7/04).  In addition, the QuEChERS method has been shown to adequately quantify residues of pyrimethanil (http://www.crl-pesticides.eu/library/docs/fv/CRLFV_Multiresidue_methods.pdf).

2.2.2	Recommended Tolerances

Table 2.2.2.  Tolerance Summary for Pyrimethanil.
Commodity
                           Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
Comments; Correct Commodity Definition
                            40 CFR §180.518 (a)(1)
Pomegranate
                                      5.0
                                      5.0

2.2.3	Revisions to Petitioned-For Tolerances

HED is not recommending for any changes to the proposed tolerance.

2.2.4	International Harmonization

For plant commodities, the U.S., Canadian, and Codex residue definitions are harmonized.  There are currently no established Codex or Canadian MRLs for residues of pyrimethanil in/on pomegranates; therefore, harmonization is not an issue for this petition.

2.3	Label Recommendations

HED is not recommending for any changes to Penbotoc[(R)] 400 SC (EPA Reg. No. 43813-32) label.

3.0	Introduction

Pyrimethanil is an anilinopyrimidine fungicide that inhibits the secretion of fungal enzymes that are required during the infection process.  Pyrimethanil blocks the ability of the fungus to degrade and digest the plant tissues, thus stopping penetration and development of the disease.  The precise mechanism of inhibition of enzyme secretion has not been fully established.  Protein synthesis is not inhibited, and evidence suggests that extracellular enzymes accumulate inside the fungus, their release being blocked in the presence of the fungicide.  Pyrimethanil penetrates rapidly into the plant tissues, where it stops the development of the disease, providing a significant curative action.  In vitro, germ tube extension and mycelial growth are inhibited.

Pyrimethanil does not exhibit cross-resistance to sterol-inhibitors, dicarboximides, benzimidazoles, quinone outside inhibitors, or phenylamides, but may exhibit cross-resistance in certain plant pathogenic fungi including anilinopyridine (AP) compounds such as cyprodinil and mepanipyrim.

3.1	Chemical Identity

Table 3.1.  Test Compound Nomenclature.
Chemical structure

Common name
Pyrimethanil
IUPAC name
N-(4,6-dimethylpyrimidin-2yl)aniline
CAS name
4,6-dimethyl-N-phenyl-2-pyrimidinamine
CAS #
53112-28-0
End-use product/(EP)
Penbotoc[(R)] 400 SC (EPA Reg. No. 43813-32)
3.2	Physical/Chemical Characteristics

Table 3.2.  Physicochemical Properties of the Technical Grade Test Compound.
Parameter
                                     Value
                                  References
Melting point
                                    96[o]C
The Pest Manual.  British Crop Protection Council.  Twelfth Edition, Editor: C.D.S. Tomlin.
pH (water solution at 25[o]C)
                                      6.1

Specific gravity at 20[o]C
                                     1.15

Water solubility (g/l at 25[o]C)
                                    0.121

Solvent solubility (g/l at 20[o]C)
acetone  -  389, ethyl acetate  -  617, methanol  -  176, methylene chloride  -  1000, n-hexane  -  23.7, toluene  -  412

Vapor pressure at 25[o]C
                                    2.2 mPa

Octanol/water partition coefficient log (KOW)
                                     2.84

UV/visible absorption spectrum
                         No UV absorption above 290 nm
Pest Management Regulatory Agency Health, Canada, 2006.

3.3	Pesticide Use Pattern

Table 3.3 provides a summary of the proposed use patterns.  Penbotec[(R)] 400SC is formulated as a SC, and is proposed at a maximum application rate of 32 fl oz formulation/100 gal water, water-wax, or wax-oil emulsion (0.82 lb ai/100 gal) via in-line dip/drench wash tanks to harvested pomegranates.  A single post-harvest application is permitted.  There is no post-treatment interval prior to human consumption.  The product label requires applicators and other handlers to wear PPE which consists of long-sleeved shirt, long pants, shoes plus socks and chemical-resistant gloves.

Table 3.3.  Summary of Proposed Directions for Use of Pyrimethanil.[1]
                                   Commodity
                           Trade Name (EPA Reg. No.)
                      Application Timing, Type, Equipment
                               Application Rate
                                (lb ai/100 gal)
                       Maximum Seasonal Application Rate
                                (lb ai/100 gal)
                                      PHI
                                    (days)
                                      RTI
                                    (days)
                                   Min. GPA
Pomegranate
Penbotec[(R)] 400 SC (43813-32)
In-line dip/drench
0.82
0.82
NA
NA
NA
1.  PHI = preharvest interval; RTI = retreatment interval; GPA = gallons of water per acre; NA = not applicable.

HED Conclusions:  The submitted label is adequate to allow evaluation of the residue data relative to the proposed post-harvest use on pomegranates.

3.4	Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new post-harvest use of pyrimethanil on pomegranates.  Humans may be exposed to pyrimethanil in food and drinking water since pyrimethanil may be applied directly to growing crops, and applications may result in pyrimethanil reaching surface and ground water sources of drinking water.  There are no registered residential uses of pyrimethanil; therefore, human exposure in residential or non-occupational settings are expected.  In an occupational setting, workers may be exposed while handling the pesticide prior to application as well as when performing sorting and packing tasks.  Additionally, there is a potential for indirect inhalation exposure for workers in the warehouse or packaging facility not directly involved in the automated treatment process.

A human health risk assessment was completed on 22-MAY-2013 by HED (Memo, J. Tyler et al., D389923).  This risk assessment considers all of the aforementioned exposure pathways based on the proposed new use of pyrimethanil, but also considers the existing uses as well, particularly for the dietary exposure assessments.

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose Response Assessment

Since the last risk assessment, the conclusions and study classification for the subchronic neurotoxicity study have been revised so that no LOAEL was observed, and so that it is now an acceptable/guideline study (Memo, A. Dunbar, 14-AUG-2014; TXR# 0057032).  The toxicology database for pyrimethanil is therefore now complete.  The HED HASPOC looked at all existing hazard and exposure data, and current use patterns for pyrimethanil; and, using a weight-of-evidence (WOE) approach, concluded that subchronic inhalation and  dermal toxicity studies are not required for pyrimethanil at this time (Memo, J. Van Alstine, 8-FEB-2013; TXR# 0056470).

4.1	Summary of Toxicological Effects

Pyrimethanil is of low acute lethality by the oral, dermal, and inhalation routes.  It is a slight eye irritant, is not irritating to the skin, and it is not a dermal sensitizer.

Through the oral route, pyrimethanil was well absorbed from the gastrointestinal tract.  Following a single oral dose of 10 mg/kg, pyrimethanil was eliminated within 24 hours, and the major route of elimination was via the urine (72%).  Approximately 17-18% of the dose was eliminated via the feces.  Detectable levels of pyrimethanil were found in the adrenals, blood, kidney, liver, spleen, and thyroid less than 24 hours post dosing.  The chemical was detected only in the liver, kidney, thyroid, and blood at 24 hours post dose.  Four days post-dose, detectable levels of the chemical were found only in the liver, kidney, and thyroid.  Regarding the total detectable levels per tissue, the highest levels of the chemical were detected in the liver in both sexes.  There were no significant sex differences in metabolites generated.

Pyrimethanil was well absorbed through the dermal route.  In a dermal penetration study, the compound was applied to the shaved dorsal skin of male Sprague Dawley rats.  Total absorbed dose (based on the sum of urine, feces, cage wash, blood, carcass, and non-treated skin) for the low, intermediate, and high doses at 10 hours post-treatment were 37.22, 35.77, and 20.39%, respectively.  The "potentially absorbable" dose (combined tape stripping excluding first two tape strips and treated skin after tape stripping) for low, intermediate, and high dose at 10 hours post-treatment was 13.95, 5.55, and 4.80%, respectively.  Absorption increased with greater exposure time, and the percent of dose absorbed increased with lower doses.  The value ultimately used for risk assessment was calculated by combining the absorbed dose (37.22%) with the potentially absorbable dose (13.95%) from the study, which would be equal to 51.2%.  Use of the 51% dermal absorption value for dermal exposure assessment for human risk is considered conservative and protective.

By the oral route of exposure, the rat was the most sensitive species to pyrimethanil toxicity followed by the dog and then the mouse.  The major target organs of repeated oral exposure were the liver, kidney, and the thyroid, and effects observed were manifested as some clinical signs (vomiting, diarrhea, and salivation in the dog for example), changes in clinical chemical parameters (liver enzymes), changes in organ weights (mostly relative), and finally macroscopic and microscopic organ changes.  There were also decreased body weights throughout the database.  No reproductive toxicity was observed, and developmental effects (e.g., decreased fetal weight, retarded ossification, extra ribs) were observed only at maternally toxic doses.  There was no evidence of neurotoxicity in either of the acute or subchronic studies.  There were no indicators of targeted effects on the immune system in the guideline Immunotoxicity study..

Special short-term exposure studies demonstrated increased liver UDPGT activity leading to decreases in thyroid hormones (T3, T4) and compensatory increases in TSH in adult rats.  Thyroid adenomas were seen in rats following long-term exposure, and it was concluded that they were mediated via disruption of the thyroid/pituitary axis.  In the newly submitted mouse carcinogenicity study, there was no evidence of thyroid tumors up to the highest dose tested.  There are no concerns for mutagenicity.

The thyroid has been shown to be one of the target organs in adult animals for pyrimethanil-induced toxicity thus raising a potential concern for thyroid toxicity in the young.  However, HIARC previously concluded that there is no concern for thyroid toxicity in the young based on the following weight of evidence considerations the effects seen on the thyroid and the liver in the database, while treatment-related, are not severe in nature; and in each of the studies that show an effect on thyroid hormone levels, as well as in all studies chosen for points of departure (PODs) selection, there is a wide dose spread (~10-fold difference between NOAELs and LOAELs) which provides a measure of protection for any potential effects linked to decreased thyroid hormone levels in offspring.

4.2	Safety factor for Infants and Children (FQPA Safety Factor)

The pyrimethanil risk assessment team has evaluated the hazard and exposure data; and, based on these data, recommended that the FQPA SF be reduced to 1X.  The toxicological is complete and there is no evidence of increased offspring susceptibility.  The exposure databases are sufficient to determine the nature/magnitude of the residue in food and dietary analyses are unlikely to underestimate risk of exposure from pyrimethanil.  Although there is evidence of neurotoxicity in the acute neurotoxicity study, concern is low since effects were only seen at the limit dose, effects are well-characterized with clearly established NOAEL/LOAEL values, and the selected endpoints are protective for the observed effects.

4.2.1	Completeness of the Toxicology Database

The toxicology database for pyrimethanil is adequate for FQPA consideration.  The following studies are available: Developmental toxicity studies in rats and rabbits, a two-generation reproduction toxicity study, and both acute and subchronic neurotoxicity studies.

4.2.2	Evidence of Neurotoxicity

Clinical signs of neurotoxicity (ataxia, decreased motor activity, decreased body temperature, decreased hind limb grip strength in males, and dilated pupils) were observed in females in the acute neurotoxicity study in rats at the highest dose tested only (1000 mg/kg).  Although the limit dose was not tested in the subchronic neurotoxicity study, no clinical signs, behavioral changes or neuropathology were seen at 1/2 limit dose (up to 430 mg/kg/day).  In addition, no neurotoxic signs were seen in the rest of the database and the target organ for toxicity for pyrimethanil is the thyroid.  The concern for neurotoxicity therefore is low.

4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of qualitative or quantitative increased susceptibility following pre-/post-natal exposure to pyrimethanil in the developmental toxicity studies in rats and rabbits or in the two-generation reproduction study in rats.

4.2.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties with respect to exposure data.  The dietary food exposure assessment utilizes tolerance-level residues (established or recommended) and 100% CT for all proposed/established commodities.  By using these assumptions, the acute and chronic exposures/risks will not be underestimated.  The dietary drinking water assessment utilizes water concentration values generated by models and associated modeling parameters that are designed to provide conservative, health-protective, high-end estimates of water concentrations that will not likely be exceeded.  There are no residential uses.

4.3	Toxicity Endpoint and POD Selections

The selected toxicity endpoints are summarized in Tables 4.3.1 and 4.3.2.

Acute Dietary Endpoint (Females Age 13-49):  The endpoint used for establishing the aPAD for females 13-49 years of age was selected from the prenatal developmental toxicity study in rabbits.  An aPAD of 0.45 mg/kg/day was derived from a developmental NOAEL of 45 mg/kg/day and a 100-fold factor that included 10X for inter-species extrapolations, 10X for intra-species variations, and 1X FQPA SF.  The endpoint of concern is a developmental effect characterized as increases in fetuses with 13 thoracic vertebrae and 13 pairs of ribs observed at 300 mg/kg (LOAEL).  These developmental anomalies are presumed to be the result of a single oral dose following in utero exposure; and, therefore, are relevant to pregnant females.

Acute Dietary Endpoint (General U.S. Population):  The endpoint used for establishing the aPAD for the general population including infants and children was selected from the acute neurotoxicity study in rats.  An aPAD of 1.0 mg/kg/day was derived from a NOAEL of 100 mg/kg/day and  a 100-fold factor that included 10X for inter-species extrapolations, 10X for intra-species variations, and a 1X FQPA SF.  Effects at the LOAEL of 1000 mg/kg (highest dose tested) included decreased motor activity, ataxia, decreased body temperature, hind limb grip strength, and dilated pupils.  The effects were seen after a single oral dose and thus appropriate for this exposure scenario and the population of concern.

Chronic Dietary Endpoint (All Populations):  The endpoint used for deriving the cPAD was selected from a chronic toxicity study with rats.  The cPAD was derived from a NOAEL of 17 mg/kg/day and a 100-fold factor that included 10X for inter-species extrapolations, 10X for intra-species variations, and 1X FQPA SF.  The LOAEL of 221 mg /kg/day is based on increased serum cholesterol and gamma glutanyl transferase (GGT), increased relative liver/body-weight ratios, necropsy, and histopathological findings in the liver and thyroid.  The endpoint of concern was seen following repeated oral exposure in the most sensitive species; and, thus, is appropriate for assessing potential risk via chronic dietary exposure to pyrimethanil.

Incidental Oral [short (1-30 days) - and intermediate (1-6 months)-term]:  There are no residential uses for pyrimethanil.  Therefore, an incidental oral endpoint was not chosen.

Dermal [short (1-30 days) - and intermediate (1-6 months)-term]:  The pyrimethanil database does not contain a dermal toxicity study.  Therefore, the Agency has selected an oral NOAEL of 23 mg/kg/day for short and intermediate term dermal risk assessments.  The endpoint of concern is based on decreasedbody weight observed in the rat two-generation reproduction toxicity study at the LOAEL of 294 mg/kg/day.    Since an oral dose was selected a dermal absorption factor of 51% should be used for route-to-route extrapolation which yields a dermal equivalent dose of 45 mg/kg/day (23 mg/kg/day / 0.51 DAF = 45 mg/kg/day).  The LOC for occupational dermal exposures is 100 (10X for inter-species extrapolation and 10X for intra-species extrapolation).

Inhalation [short (1-30 days) - and intermediate (1-6 months)-term]:  An inhalation toxicity study was not submitted.  The short- and intermediate-term inhalation endpoints are based upon the parental effect of decreased body weights observed in the two-generation reproduction toxicity study.  The NOAEL is 23.1 mg/kg/day.  This endpoint is appropriate for the duration of exposure and the populations of concern.  Inhalation exposure is assumed to be equivalent to oral exposure.  The LOC for occupational inhalation exposures is 100 (10X for inter-species extrapolation and 10X for intra-species extrapolation).

Table 4.3.1.  Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Dietary and Non-Occupational Human Health Risk Assessments.
Exposure/
Scenario
POD
UFs/
FQPA SF
RfD, PAD, LOC
Study and Toxicological Effects
Acute Dietary
(Females 13-49 years of age)
NOAEL = 45 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X

Acute RfD = 0.45 mg/kg/day

aPAD = 0.45 mg/kg/day
Developmental Toxicity - Rabbit:
LOAEL = 300 mg/kg/day based on increases in fetuses with 13 thoracic vertebrae and 13 pairs of ribs.
Acute Dietary (General Population, including Infants and Children)
NOAEL = 100 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X

Acute RfD = 1 mg/kg/day
Acute Neurotoxicity- Rat:  LOAEL = 1000 mg/kg/day based on decreased motor activity, ataxia, decreased body temperature, hind limb grip strength, and dilated pupils.
Chronic Dietary (All Populations)
NOAEL = 17 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X

Chronic RfD = 0.17 mg/kg/day

cPAD = 0.17 mg/kg/day
Chronic Toxicity - Rat:
LOAEL = 221 mg/kg/day based on decreased body-weight gains; increased serum cholesterol and GGT, increased relative liver/body weight ratios, necropsy and histopathological findings in the liver and thyroid.
Cancer (oral, dermal, inhalation)
CARC Classification: "Not Likely To Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thyroid Hormone Homeostasis"

Table 4.3.2.  Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Occupational Human Health Risk Assessments.
                                   Exposure
                                   Scenario
                                      POD
                            LOC for Risk Assessment
                        Study and Toxicological Effects
Short (1-30 days) and Intermediate (1- 6 months) Term Dermal
Oral NOAEL =
23.1 mg/kg/day
(dermal absorption[a] = 51%)
Occupational LOC for MOE = 100
Reproductive Toxicity - Rat
LOAEL = 294 mg/kg/day based on decreased mean body weights and body-weight gains.
Short (1-30 days) and Intermediate (1- 6 months) Term Inhalation
Oral NOAEL =
23.1 mg/kg/day
(inhalation absorption[b] = 100%)
Occupational LOC for MOE = 100
Reproductive Toxicity - Rat
LOAEL = 294 mg/kg/day based on decreased mean body weights and body-weight gains.
Cancer (oral, dermal, inhalation)
CARC Classification: "Not Likely To Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thyroid Hormone Homeostasis"
Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no-observed adverse-effect level.  LOAEL = lowest-observed adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (intraspecies).  UFH = potential variation in sensitivity among members of the human population (interspecies).  FQPA SF = FQPA Safety Factor.  PAD = population-adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.  a= dermal-absorption factor, from MRID 46630101.  b= Inhalation-absorption factor assumed.

4.3.1	Recommendation for Combining Routes of Exposures for Risk Assessment

HED notes that the same oral toxicity study was selected for assessment of short-/intermediate-term dermal and inhalation exposures and thus the dermal and inhalation routes of exposure should be combined.

4.3.2	Cancer Classification and Risk Assessment Recommendation

In accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment (March 2005), the Cancer Assessment Review Committee (CARC) classified pyrimethanil as "Not Likely To Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thyroid Hormone Homeostasis" (TXR#0056151, J. Rowland, 23-DEC-2011).  This decision was based on the following:

     i) Treatment-related increases in thyroid follicular cell tumors in male and female Sprague-Dawley rats at doses which were considered adequate to assess carcinogenicity;
     ii) No treatment-related tumors were seen in male or female CD-1 mice at doses which were considered adequate to assess carcinogenicity;
     iii) There is no mutagenicity concern and there is no evidence for thyroid carcinogenesis mediated through a mutagenic mode of action;
     iv) The non-neoplastic toxicological evidence (i.e., thyroid growth, thyroid hormonal changes) indicated that pyrimethanil was inducing a disruption in the thyroid-pituitary hormonal status.  The overall weight-of-evidence was considered sufficient to indicate that Pyrimethanil induced thyroid follicular tumors through an antithyroid mode of action; and
     v) Rats are substantially more sensitive than humans are to the development of thyroid follicular cell tumors in response to thyroid hormone imbalance.

Quantification of Carcinogenic Risk:  Quantification of carcinogenic risk is not required.  The CARC determined that the thyroid tumors arise through a non-linear mode of action and the NOAEL (17 mg/kg/day) established for deriving the cPAD is not expected to alter thyroid hormone homeostasis nor result in thyroid tumor formation.

5.0	Dietary Exposure and Risk Assessment

The residue chemistry data submitted in support of proposed uses were evaluated by HED on 12-AUG-2014 (Memo, J. Pyne; D416841).  The drinking water assessment was completed by EFED on 26-SEP-2011 (Memo, J. Wolf; DP389925).  The dietary exposure assessment was completed in a HED memorandum dated 12-AUG-2014 (Memo, J. Pyne; D417165).

5.1	Residues of Concern Summary and Rationale

The residues which are regulated in plant commodities are pyrimethanil, per se (40 CFR §180.518).  For risk assessment purposes, the residues of concern are:  1) pyrimethanil for plant commodities; 2) in livestock, pyrimethanil + metabolite AEC614276 for ruminant muscle, fat and byproducts; and 3) pyrimethanil + metabolite AEC614277 for milk.  In drinking water, residues of concern are pyrimethanil + Degradate 1 (2-amino-4,6-dimethylpyrimidine).

Table 5.1.  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.
Matrix
Residues included in Risk Assessment
Residues included in Tolerance Expression
Plants
Primary Crop
Pyrimethanil, per se
Pyrimethanil, per se

Rotational Crop
Pyrimethanil, per se
Pyrimethanil, per se
Livestock
Ruminant
Pyrimethanil + AEC614276 for muscle, fat, and byproducts.  For milk, pyrimethanil + AEC614277.
Pyrimethanil + AEC614276 for muscle, fat, and byproducts.
Pyrimethanil + AEC614277 for milk.

Poultry
Not Applicable
Not Applicable
Drinking Water
Parent (Pyrimethanil) + Degradate 1 (2-amino-4,6-dimethylpyrimidine)
Not Applicable

5.2	Food Residue Profile

The data-collection method used to generate pomegranate residue data in conjunction with magnitude of the residue study associated with this petition was a GC/MSD method.  The procedure derived from "Fruit and Vegetables: Analytical Method for the Determination of Residues (Improved Version), Pyrimethanil, Active Substance," M.H. Peatman, 15/FEB/1999, and Morse Labs' modifications to the analytical method dated 6/FEB/2012 and 10/FEB/2012.  The lowest level of method validation (LLMV) was 0.05 ppm.  This method was adequate for data collection.  There are also adequate methods available to enforce tolerances for residues of pyrimethanil in/on pomegranate.

The pomegranate samples analyzed in this study were held in frozen storage for a maximum of 92 days for the whole fruits and 93 days for flesh prior to analysis of pyrimethanil residues.  Acceptable storage stability data are available demonstrating that residues of pyrimethanil are stable under frozen storage conditions in:  carrot, lettuce, and tomato for up to 12 months; in apples for up to 676 days (22.2 months); and peaches for up to 651-658 days (21.4-21.6 months) (refer to DP#s 284001 and 284870, J. Morales and G. Kramer, 1/12/04).  The available storage stability data are adequate to support the storage conditions and durations for samples of pomegranate (whole fruit and flesh) from the submitted crop field trial study.

The submitted field trial residue data for pomegranate are adequate.  The field trial data reflect the proposed use pattern, an adequate number of trials were conducted, and samples were analyzed for the residue of concern using validated data-collection methods.  Two pomegranate field trials were submitted.  Each field trial had four samples that were treated post-harvest with an SC formulation of pyrimethanil (Penbotec[(R)] 400SC), with two samples treated at a 1X rate (1,000 ppm) and two samples treated at a 2X rate (2,000 ppm).  Per-trial-average-residues of pyrimethanil in/on pomegranate, whole fruit ranged 1.51-1.66 ppm from the 1X trial and from 2.50 to 3.01 ppm in the 2X trial.  Residues were below the limit of quantitation (LOQ; <0.05 ppm) in/on pomegranate flesh treated at a 1X rate.

The OECD tolerance-calculation procedures were used to determine the tolerance for residues of pyrimethanil in/on pomegranate.  Per-trial-average-residues from the 1,000- and 2,000-ppm trials were used to calculate the tolerance.  Since the label proposes applications of 1,000 ppm, proportionality was used for the 2,000-ppm trial residues.  The OECD tolerance-calculation procedures for the residue data set indicates that the requested tolerance of 5.0 ppm for residues of pyrimethanil from a treatment solution of 1,000 ppm in/on pomegranate is appropriate.

There are no livestock food/feed items of regulatory concern the pomegranate; therefore, a discussion of livestock residues is not germane to this petition.

5.3	Water Residue Profile

Based on the information provided, EFED considers the proposed post-harvest dip use of pyrimethanil as an indoor use that would pose minimal exposure to the environment, provided that release of the chemical and contaminated water are controlled.  Therefore, an updated drinking water assessment is not needed for this new use (Memo, J. Wolfe, 30-JUN-2014; D416873).  HED used EDWCs provided by EFED in conjunction with the most-recent human health risk assessment (Memos, J. Wolfe, 22-OCT-2003, D283999 and D290313; 08-JAN-2009, D353180).  Tier I SCI-GROW screening concentration of combined total residues (pyrimethanil + 2-amino-4,6-dimethylpyrimidine) in ground water for uses on small berries (caneberries and bushberries) are not expected to exceed 4.8 μg/L for previously estimated uses based on the registered seasonal application rate of 2.1 lb ai/A on strawberry in Florida

Tier II PRZM-EXAMS screening drinking water concentrations for combined residues of pyrimethanil (parent + 2-amino-4,6-dimethylpyrimidine) in raw surface source water are not expected to exceed 86.5 μg/L for the peak 1-in-10-year concentration; 29.4 μg/L for the 1-in-10-year annual mean concentration; and, 17.9 μg/L for the 30-year annual average concentration.  These EDWCs correspond to the FL/strawberries (acute) and NY/grapes (chronic) scenarios.

Table 5.3.  Estimated Drinking Water Concentrations for Combined Total Residues, Parent (Pyrimethanil) Plus Major Degradate (2-amino-4,6-dimethylpyrimidine).
                                   Chemical
                Acute (peak) Surface Water Concentration (ppb)
                  Annual Average Surface Water Concentration
                               1-in-10-yr (ppb)
          Average of Annual Average Surface Water Concentration (ppb)
                       Ground Water Concentration (ppb)
Pyrimethanil plus
2-amino-4,6-dimethylpyrimidine.
                                     86.5
                                     29.4
                                     17.9
                                      4.8

In this assessment, the annual average surface water concentration (29.4 ppb) and the acute peak surface water concentrations (86.5 ppb) were used for chronic and acute dietary exposure assessments, respectively.

5.4	Dietary Risk Assessment

Unrefined acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using DEEM-FCID Version 3.16.  This software uses 2003-2008 food consumption data from the U.S. Department of Agriculture's (USDA's) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).

5.4.1	Description of Residue and Percent Crop Treated Data Used in Dietary Assessment

The acute and chronic dietary exposure assessment was unrefined, using tolerance-level residues and assuming 100% CT for all registered and proposed commodities.  DEEM Version 7.81 default processing factors were used to estimate residues in processed commodities, as available, and empirical processing factors were used for orange and apple juice.  Drinking water was incorporated directly into the dietary assessment using the EDWCs generated by the PRZM/EXAMS surface water model. Based on the proposed use pattern for a postharvest dip treatment, a revised drinking water assessment was not required.

5.4.2	Acute Dietary Risk Assessment

Using the DEEM-FCID software, dietary risk is estimated at 9.8% of the aPAD for the general U.S. population and 38% of the aPAD for children 1-2 years old, the population subgroup with the highest estimated acute dietary exposure.  Therefore, the acute dietary risk assessment shows that for all included commodities plus drinking water, the acute dietary risk estimates are below HED's LOC for the general U.S. population and all population subgroups (i.e., <100% aPAD).

5.4.4	Chronic Dietary Risk Assessment

Using the DEEM-FCID software, dietary risk is estimated at 14% of the cPAD for the general U.S. population and 76% of the cPAD for children 1 to 2 years old, the population subgroup with the highest estimated chronic dietary exposure to pyrimethanil.  The chronic dietary risk assessment shows that for all included commodities plus drinking water, the chronic dietary risk estimates are below HED's LOC for the general U.S. population and all population subgroups (i.e., <100% cPAD).

5.4.5	Cancer Dietary Risk Assessment

A cancer dietary assessment was not conducted because pyrimethanil is classified as "Not Likely To Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thyroid Hormone Homeostasis."

5.4.6	Summary Table

 Table 5.4.6.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Pyrimethanil.
                              Population Subgroup
                                 Acute Dietary
                              (95[th] Percentile)
                                Chronic Dietary
                                     Cancer

                          Dietary Exposure (mg/kg/day)
                                   % aPAD[1]
                                Dietary Exposure
                                  (mg/kg/day)
                                     % cPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
 General U.S. Population
                                    0.97834
                                      9.8
                                    0.023739
                                       14
                                      N/A
                                      N/A
 All Infants (<1 year old)
                                    0.344534
                                       34
                                    0.085185
                                       50

 Children 1-2 years old
                                    0.380589
                                       38
                                    0.128860
                                       76

 Children 3-5 years old
                                    0.241219
                                       24
                                    0.078291
                                       46

 Children 6-12 years old
                                    0.131512
                                       13
                                    0.036225
                                       21

 Youth 13-19 years old
                                    0.059804
                                      6.0
                                    0.015366
                                      9.0

 Adults 20-49 years old
                                    0.056534
                                      5.6
                                    0.013819
                                      8.1

 Adults 50-99 years old
                                    0.058642
                                      5.9
                                    0.016149
                                      9.5

 Females 13-49 years old
                                    0.058418
                                       13
                                    0.014775
                                      8.7

1. Population subgroup with the highest exposure and risk is in bold type.  The aPAD for Females 13-49 years of age is 0.45 mg/kg/day; aPAD for general U.S. population is 1 mg/kg/day.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization

Currently, there are no registered/proposed uses of pyrimethanil that result in residential exposures.  Therefore, a residential exposure assessment was not performed.

7.0	Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources:  food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  In the case of pyrimethanil, aggregate risk assessments were performed for acute aggregate exposure (food + drinking water) and chronic aggregate exposure (food + drinking water).  A cancer aggregate risk assessment was not performed because imidacloprid is not carcinogenic.  All potential exposure pathways were assessed in the aggregate risk assessment.

7.1	Acute Aggregate Risk

No acute residential/recreational exposures are expected.  In the case of pyrimethanil, the acute aggregate risk is composed of exposures to pyrimethanil residues in food and drinking water and is equivalent to the acute dietary risk discussed in Section 5.4.1.  As shown in Table 5.4.6, the acute risk estimates do not exceed the HED's LOC for the general U.S. population and all population subgroups.

7.2	Short- and Intermediate-Term Aggregate Risk

Pyrimethanil is not registered for residential uses.  Therefore, short- and intermediate term residential exposures are not expected.

7.3	Chronic Aggregate Risk

A long-term aggregate risk assessment was not performed, because long-term residential exposure to pyrimethanil (i.e., >6 months) is unlikely to occur based upon the use patterns.  Specifically, in the case of pyrimethanil, the chronic aggregate risk is composed of exposures to pyrimethanil residues in food and drinking water and is equivalent to the chronic dietary risk discussed in Section 5.4.2.  As shown in Table 5.4.6, the chronic risk estimates do not exceed the HED's LOC for the general U.S. population and all population subgroups.

7.4	Cancer Risk

Pyrimethanil is classified as "Not Likely To Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thyroid Hormone Homeostasis."  Therefore, a cancer aggregate risk assessment was not conducted.

8.0	Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for pyrimethanil and any other substances, and pyrimethanil does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this action, therefore, EPA has assumed that pyrimethanil does not have a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

9.0	Occupational Exposure/Risk Pathway

Based on the proposed application scenario and toxicological considerations, non-cancer occupational handler (dermal and inhalation) and occupational post-application (dermal and inhalation) risk assessments were conducted.  The proposed new uses were evaluated in the cited memorandum and the resulting occupational exposure/risks were reviewed by the HED Science Advisory Council for Exposure (ExpoSAC; Memo, J. Tyler, 20-AUG-2014, D417166).

9.1	Handler Exposure and Risk Estimates

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses.  The quantitative exposure/risk assessment developed for occupational handlers is based on the mixing/loading liquids for automated system exposure scenario.  A separate applicator assessment was not conducted as the application of pyrimethanil is mechanically automated for the in-line dip/drench wash tanks.  A mixer/loader assessment was performed and is considered to result in a conservative estimate of handler risk.

HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months as intermediate-term.  Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site.  For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one-month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region).  For pyrimethanil, based on the proposed use pattern, short- and intermediate-term exposures are expected.  In addition, the short- and intermediate-term PODs are the same; therefore, estimates for short-term durations are protective of longer-term exposure durations.  The average adult body weight of 80 kg was used for estimating dermal and inhalation doses.

No chemical-specific handler exposure data were submitted in support of this Section 3 registration.  It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include PHED 1.1, the Agricultural Handler Exposure Task Force (AHETF) database, or other registrant-submitted occupational exposure studies.  Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA).  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures," are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html.

Estimates of dermal and inhalation exposure were calculated for various levels of PPE.  Results are presented for "baseline," defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc).  The pyrimethanil product labels direct mixers, loaders, applicators and other handlers to wear long-sleeved shirt, long pants, shoes plus socks and chemical-resistant gloves.

Table 9.1 provides a summary of the estimated exposures and risks to occupational pesticide handlers.  An MOE >= 100 is adequate to protect occupational pesticide handlers from dermal and inhalation exposure.  Dermal and inhalation risks for occupational handlers are above the LOC (100) with label-required PPE (i.e., wear long-sleeved shirt, long pants, shoes plus socks and chemical-resistant gloves).

Table 9.1.  Occupational Handler Non-Cancer Exposure and Risk Estimates for Post-harvest Use on Pomegranates.
                               Exposure Scenario
                                     Crop
                                      LOC
                      Dermal Unit Exposure (μg/lb ai)[1]
                    Inhalation Unit Exposure (μg/lb ai)[1]
                    Max. App. Rate (lb ai/gal solution)[2]
                       Amount Handled Daily (gal/day)[3]
                                    Dermal
                                  Inhalation
                                     Total

                               Mitigation Level
                               Mitigation Level

                              Dose (mg/kg/day)[4]
                                    MOE[5]
                              Dose (mg/kg/day)[6]
                                    MOE[7]
                                    MOE[8]
                                 Mixer/Loader
               Open Mixing/ Loading Liquids for Automated System
                                 Pomegranates
                                      100
                                 Baseline: 220
                                 PPE-G:  37.6
                                Baseline: 0.219
                                    0.0082
                                    25,000
                                Baseline: 0.289
                                 PPE-G: 0.0494
                                 Baseline: 80
                                  PPE-G: 470
                              Baseline:  0.000565
                               Baseline:  41,000
                                 Baseline: 80
                                  PPE-G: 460
1.	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (May 2013); Level of mitigation: Baseline = Long-sleeved shirt, long pants, shoes plus socks and no gloves (dermal); no respirator (inhalation).  PPE-G = Long-sleeved shirt, long pants, shoes plus socks and chemical-resistant gloves.
2.	Based on registered or proposed label (Reg. No. 43813-32).
3.	HED ExpoSAC Policy/Guidance "Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments."
4.	Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/gal) x Amount Handled (gal/day) x DAF (51%) / BW (80 kg).
5.	Dermal MOE = Dermal NOAEL (23.1 mg/kg/day) / Dermal Dose (mg/kg/day).
6.	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/gal) x Amount Handled (gal/day) / BW (80 kg).
7.	Inhalation MOE = Inhalation NOAEL (23.1 mg/kg/day) / Inhalation Dose (mg/kg/day).
8	Total MOE = NOAEL (23.1 mg/kg/day) / Dermal Dose + Inhalation Dose.

9.2	Post-application Exposure and Risk Estimates

During automated treatments, dermal and inhalation exposure is anticipated for workers performing sorting and packing tasks.  Since the workers experience exposure following the treatment, this is technically "post-application" exposure; however, unlike other post-application activities (e.g., harvesting, scouting, etc.), this treatment is not governed by the Worker Protection Standard (WPS) and potential restricted-entry intervals (REIs).  Additionally, for workers in the warehouse or packaging facility not directly involved in the automated treatment process, there is potential for indirect inhalation exposure.  Exposures for these various scenarios are assessed using HED ExpoSAC Policy/Guidance "Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments" (M. Crowley, 23-MAR-2012).

HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months as intermediate-term.  For pyrimethanil, based on the proposed use pattern, short- and intermediate-term exposures are expected.  In addition, the short- and intermediate-term PODs are the same; therefore, estimates for short-term durations are protective of longer-term exposure durations.

The short- and intermediate-term risk estimates are not of concern (i.e., MOEs >=100) at baseline (i.e., t-shirt and no gloves and no respirator) for all post-application exposure activities.

Table 9.2.1.  Occupational Post-application Non-Cancer Exposure and Risk Estimates for Pyrimethanil.
                                   Crop/Site
                                  Activities
                                 Max App. Rate
                              (% ai in solution)
                                    Dermal
                                  Inhalation
                                   Combined

                          Unit Exposure (μg/% ai)[1]
                                     Dose
                                (mg/kg/day)[2]
                                    MOE[3]
                          Unit Exposure (μg/% ai)[1]
                                     Dose
                                (mg/kg/day)[4]
                                    MOE[5]
                                    MOE[6]

                               Mitigation Level

                               Mitigation Level

                                 Pomegranates
                                    Sorter
                                      0.1
                              T-shirt/NG: 21,600
                              T-shirt/NG: 0.0139
                                     1,700
                                   NR 6,720
                                   NR 0.0085
                                   NR 2,700
                            T-shirt/NG and NR 1,000

                                    Packer

                              T-shirt/NG: 15,300
                              T-shirt/NG: 0.0098
                                     2,400
                                   NR 6,760
                                   NR 0.0085
                                   NR 2.700
                            T-shirt/NG and NR 1,300
1.  Based on Table 2 in ExpoSAC Policy/Guidance "Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments" (M. Crowley, 23-MAR-2012); Level of mitigation: T-shirt/NG = t-shirt and no gloves; NR = no respirator.
2.  Dermal Dose = [Unit Exposure (ug/% ai) * Application Rate (% ai in solution) * Adjustment Factor (0.001 μg/mg)] / Body Weight (80 kg).
3.  Dermal MOE = Dermal POD (23.1 mg/kg/day)/Dermal Dose.
4.  Inhalation Dose = [Unit Exposure (ug/% ai) * Application Rate (% ai in solution) * Adjustment Factor (0.001 μg/mg)] / Body Weight (80 kg).
5.  Inhalation MOE = Inhalation POD (23.1 mg/kg/day)/Inhalation Dose.
6.  Total MOE = NOAEL (23.1 mg/kg/day) / (Dermal Dose + Inhalation Dose).

Table 9.2.2.  Occupational Post-application Non-Cancer Indirect Inhalation Exposure and Risk Estimates for Pyrimethanil.
                                   Crop/Site
                                 Max App. Rate
                              (% ai in solution)
                                  Inhalation

                          Unit Exposure (μg/% ai)[1]
                                Inhalation Dose
                                (mg/kg/day)[2]
                                    MOE[3]

                               Mitigation Level

                                 Pomegranates
                                      0.1
                                    NR 307
                                   NR 0.0004
                                   NR 60,000
1.  Based on Table 4 in ExpoSAC Policy/Guidance "Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments" (M. Crowley, 23-MAR-2012); Level of mitigation: NR = no respirator.
2.  Inhalation Dose = [Unit Exposure (ug/% ai) * Application Rate (% ai in solution) * Adjustment Factor (0.001 μg/mg)] / Body Weight (80 kg)].
3.  Inhalation MOE = Inhalation POD (23.1 mg/kg/day)/Inhalation Dose.

10.0	References

   * Toxicity Profile Tables.
   * Metabolism Assessment.

RDI:  G. Kramer (21-JUL-2014); RAB1 (23-JUL-2014); C. Smith (23-JUL-2014)
J. Tyler:S10943:PY1:(703)-851-5825(7509P)
Appendix A:  Toxicity Profile Tables.

A.1	Toxicology Data Requirements
The requirements (40 CFR 158.340) for food and non-food uses for pyrimethanil are in Table A.1.  Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1.  Toxicological Data Requirements for Pyrimethanil.
                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity
870.1200    Acute Dermal Toxicity
870.1300    Acute Inhalation Toxicity
870.2400    Primary Eye Irritation
870.2500    Primary Dermal Irritation
870.2600    Dermal Sensitization
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    Oral Subchronic (rodent)
870.3150    Oral Subchronic (nonrodent)
870.3200    21-Day Dermal
870.3250    90-Day Dermal
870.3465    90-Day Inhalation
                                      yes
                                      yes
                                      no
                                      no
                                      no
                                      yes
                                      yes
                                      no
                                      no
                                      no
870.3700a  Developmental Toxicity (rodent)
870.3700b  Developmental Toxicity (nonrodent)
870.3800    Reproduction
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

870.4100b  Chronic Toxicity (nonrodent)

870.4200b  Oncogenicity (mouse)
870.4300    Chronic/Oncogenicity (rat)

                                      yes

                                      yes
                                      yes

                                      yes

                                      yes
                                      yes
870.5100    Mutagenicity -- Gene Mutation - bacterial
870.5100    Mutagenicity -- Gene Reverse Mutation - bacterial
870.5300    Mutagenicity -- Gene Mutation - mammalian
870. 5395   Mutagenicity -- Micronucleaus Assay in Bone Marrow
870. 5550    Mutagenicity -- Unscheduled DNA Synthesis
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotoxicity (hen)
870.6100b  90-Day Neurotoxicity (hen)
870.6200a  Acute Neurotoxicity Screening Battery (rat)
870.6200b  90-Day Neurotoxicity Screening Battery (rat)
870.6300    Develop. Neurotoxicity
                                      no
                                      no
                                      yes
                                      yes
                                      no
                                      no
                                      no
                                      yes
                                      yes
                                       -
870.7485    General Metabolism
870.7600    Dermal Penetration
870.7800    Immunotoxicity
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

Table A.2.  Acute Toxicity Profile  -  Pyrimethanil.
Guideline No./Study Type
MRID No.
                                    Results
                               Toxicity Category
870.1100/Acute oral toxicity
43345002
                      LD50 = 4149 mg/kg, M 5971 mg/kg, F
                                      III
870.1200/Acute dermal toxicity
43345003
                              LD50 >5000 mg/kg
                                      IV
870.1300/Acute inhalation toxicity
43301604
                              LC50 >1.98 mg/L
                                      III
870.2400/Primary eye irritation
43345004
                              slight eye irritant
                                      IV
870.2500/Primary dermal irritation
43345005
                                 non irritant
                                      IV
870.2600/Dermal sensitization
43301605
                               not a sensitizer

Table A.3.  Toxicity Profile for Pyrimethanil.
                           Guideline No./Study Type
                                 MRID, (year)/
                             Classification/Doses
                                    Results
870.3100(a)
90-Day Oral Toxicity (rat)
43345006
43301608 (1990, 1992)/
acceptable/guideline
0, 80, 800, 8000 ppm
0/0, 5.4/6.8, 54.5/66.7, 529.1/625.9 mg/kg/day [M/F]
NOAEL = 54.5 mg/kg/day [M], 66.7 mg/kg/day [F].
LOAEL = 529.1 mg/kg/day [M], 625.9 mg/kg/day [F] based on  body weights (20%), body-weight gain(30%), food consumption, brown urine,  urinary protein;  abs. heart, adrenal, spleen, thymus weights;  rel. liver, kidney, gonad weights, liver, thyroid hypertrophy.
870.3100(b)
90-Day Oral Toxicity (mouse)
43301606 (1991)
acceptable/guideline
0, 80, 900, 10,000 ppm
0/0, 12/18, 139/203, 1864/2545 mg/kg/day [M/F]
NOAEL = 139 [M] mg/kg/day, 203 [F] mg/kg/day.
LOAEL = 1864 [M] and 2545 [F] mg/kg/day based on  body-weight gain (7-12%), cholesterol, bilirubin [F/M], dark thyroids, rel. liver weights, kidney, thyroid, bladder histopathology.
870.3150
90-Day Oral Toxicity (dog)
43301610 (1991)
acceptable/guideline
0, 6, 80, 1000/800 mg/kg/day [M/F]
NOAEL = 80 mg/kg/day.
LOAEL = 1000/800 mg/kg/day based on  water consumption, vomiting, diarrhea, salivation, hypoactivity.
870.3700(a)
Developmental Toxicity (rat)
43301617
43345018
43301619 (1991)
acceptable/guideline
0, 7, 85,1000 mg/kg/day
NOAEL = Maternal: 85 mg/kg/day.
Developmental:  85 mg/kg/day.
LOAEL = Maternal: 1000 mg/kg/day based on  body weight, and body-weight gain.
Developmental:  LOAEL = 1000 mg/kg/day based on  in mean litter weight and mean fetal weight.
870.3700(b)
Developmental Toxicity (rabbit)
43301620
43301621
43301622 (1991)
acceptable/guideline
0, 7, 45, 300 mg/kg/day
NOAEL = Maternal:  45 mg/kg/day.
Developmental NOAEL = 45 mg/kg/day.
LOAEL = Maternal:  300 mg/kg/day based on deaths,  body wt, body-weight gain, food consumption, production, and size of fecal pellets.
Developmental:  300 mg/kg/day based on deaths,  body weight, body-weight gain, food consumption, production and size of fecal pellets fetal weight,  fetal runts, retarded ossification, 13 thoracic vertebrae and pairs of ribs.
870.3800
Two-Generation Reproduction and Fertility Effects (rat)
43301623 (1993)
acceptable/guideline
0, 32, 400, or 5000 ppm
0/0,1.9/2.2,23.1/27.4, 294/343 mg/kg/day [M/F]
NOAEL = Systemic:  23.1 [M] mg/kg/day, 27.4 mg/kg/day [F].
Repro:  294/343 mg/kg/day.
Offspring:  23.1 mg/kg/day [M], 27.4 mg/kg/day [F].
LOAEL = Systemic:  294 mg/kg/day [M], 343 mg/kg/day [F] based on  body weight (11-13%), and body-weight gain (11-17%).
Repro:  >294/343 mg/kg/day.
Offspring:  294 mg/kg/day based on  pup body weights on PND 21.
870.4100b
Chronic Toxicity (dog)
43345007
43301614 (1992)
acceptable/guideline
0, 2, 30, 400/250 mg/kg/day
NOAEL = 30 mg/kg/day.
LOAEL = 250 mg/kg/day based on  body weight, food & water consumption, food efficiency, neutrophils,  clotting time.
870.4200b
Carcinogenicity (mouse)

43301615 (1992)
unacceptable/guideline
0, 16, 160, 1600 ppm
0/0, 2/2.5, 20/24.9, 210.9/253 mg/kg/day
[M/F]
NOAEL = 210.9 mg/kg/day [M], 253.8 mg/kg/day [F].

No toxicologically significant effects were found.
870.4200b
Carcinogenicity (mouse)
 48046301 (2010)
acceptable/guideline
0 (2 groups), 3,500, or 7,000 ppm (equivalent to 0, 0, 477/594, 984/1217 mg/kg bw/day [M/F])
NOAEL = 477/594 mg/kg/day [M/F].
LOAEL = 984/ 1217 mg/kg/day based on increased livers weights (both absolute and relative) in both males and females and increased thyroid colloidal alteration mainly in males at the high dose.  There were no compound related carcinogenic effects seen in this study.
870.4300
Combined Chronic/Carcinogenicity (rat)
43301612-3 (1993)/
acceptable/guideline
0, 32, 400, 5000 ppm
0/0, 1.3/1.8, 17/22, 221/291 mg/kg/day
[M/F]
NOAEL = 17 mg/kg/day [M], 22 mg/kg/day [F].
LOAEL = 221 mg/kg/day [M], 291 mg/kg/day [F] based on  body-weight gain (5-15% [M]; 15-45% [F])
[10-15%@ 6 months], serum cholesterol, GGT, rel. liver weights; liver, thyroid histopathology [ thyroid adenomas].
870.5100
Gene Mutation
43301624 (1990);
0, 15, 50, 150, 500, or 1500 μg/plate in the presence and absence of mammalian metabolic activation (S9-mix)

Acceptable/Guideline
There was no evidence of induced mutant colonies over background.
870.5300
Gene Mutation
43301625 (1991);
0, 15, 50, 150, 500, or 1500 μg/plate in the presence and absence of mammalian metabolic activation (S9-mix)

Acceptable/Guideline
There was no clear evidence of biologically significant induction of mutant colonies over background.
870.5375
Chromosome aberration
43301627 (1990);
0, 7.8, 31.3, or 62.5 μg/mL without metabolic activation (S9-mix) and to concentrations of 0, 31.3, 125, or 250, μg/mL with S9-mix.

Acceptable/Guideline
There was no evidence of chromosome aberrations induced over background.
870.5395
Mammalian erythrocyte micronucleus test in mice
43301626 (1991);
0, 225, 450, or 900 mg/kg body weight

Acceptable/Guideline
There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in mouse bone marrow at any dose or harvest time.
870.5550
Unscheduled DNA synthesis in mammalian culture
43301628 (1991)
0, 100, 300, or 1000 mg/kg body weight
Acceptable/Guideline
Negative in inducing unscheduled DNA synthesis in rat hepatocytes as a result of in vivo gastric intubation.
870.6200a
Acute-Neurotoxicity Screening Battery (rat)
45657221
45657220 (2001)
acceptable/guideline
0, 30, 100, 1000 mg/kg/day
NOAEL = 100 mg/kg/day [M], 100 mg/kg/day [F].
LOAEL = 1000 mg/kg/day [M], 1000 mg/kg/day [F] based on  motor activity, ataxia, and body temperature  in both sexes,  hindlimb grip strength in males, and  dilated pupils in females on Day 1.
870.6200b
Subchronic-Neurotoxicity Screening Battery (rat)
45657222 (1998) Acceptable/Guideline
0, 60, 600, 6000 ppm
0/0, 4/4.6, 38.7/44.3, 391.9/429.9 mg/kg/day [M/F]
The systemic NOAEL = 6000 ppm (391.9/429.9 mg/kg/day [M/F])

A LOAEL for systemic toxicity was not observed.

The neurotoxicity NOAEL is 6000 ppm (391.9/429.9 mg/kg/day [M/F]).

A LOAEL for neurotoxicity was not observed.

870.7465
Metabolism and Pharmacokinetics
43301629 (1991),
10 mg/kg (28 days consecutive days) [M]
acceptable/guideline

43345009 (1993),
11.8 mg/kg or 800 mg/kg (single dose), 10 mg/kg/day (14 days repeated dosing) [M/F]
acceptable/guideline

43750101 (1995)
10 mg/kg [M/F] (single dose)
Acceptable/guideline
At a dose level of 10 mg/kg, pyrimethanil was eliminated within 24 hours, and the major route of elimination was via the urine [72%].  Approximately 17-18% of the dose was eliminated via the feces.  Radiolabel was detected only in the liver, kidney, and blood at study termination [24 hours post dose].  The highest residue was displayed in the liver in both sexes.  There was no significant sex difference.  The overall recovery of radiolabel was 91%.  Detectable levels of radiolabel were found in the adrenals, blood, kidney, liver, spleen, and thyroid following exposure.  Only the blood and liver displayed detectable levels of radiolabel after a single dose [24-hour sample].  Four days after the last dose, detectable levels of radiolabel were found only in the liver, kidney, and thyroids.  It appears that the levels in the blood, kidney, and thyroid would continue to increase with increased exposure time, while the level in the adrenal appears to have reached a plateau, and that in the liver appears to be declining.  The main pathways of metabolism involved oxidation to phenols in either or both aromatic rings, and the minor pathways involved oxidation of the methyl group to the corresponding alcohol.  Minor differences were observed between the high- and low-dose exposures, the single low- and repeat low-dose exposures, and between the sexes, but none appear to be of any toxicological significance.
870.7600
Dermal Penetration
46630101 (2005)
Acceptable/guideline
0.6, 6.0, and 60 μg ai/cm[2]
The dermal-absorption value at 10 hours is 51.2%.  This value is very similar to 60% absorption (57.20% absorbed dose plus 2.77% potentially absorbable dose) for which the skin site was washed after 10 hours, and which were sacrificed after 120 hrs.  Therefore, using the 51% dermal absorption value for dermal exposure assessment for human risk is conservative and considered protective.
870.7800
Immunotoxicity
48263901 (2010)
0, 80, 800, or 8000 ppm (0, 6.9, 69.5, or 652 mg/kg bw/day, respectively [F])
Acceptable/Guideline
Immunotoxicity NOAEL = 8000 ppm (652 mg/kg/day).
Immunotoxicity LOAEL is not established.

Appendix B:  Metabolism Assessment.

Table B.1.  Pyrimethanil Metabolites of Concern.
Common name/
ID No.
Chemical name
Chemical structure
AE C614276
4-[4,6-dimethyl-2-pyrimidinyl)amino]phenol

AE C614277
4,6-dimethyl-2-(phenylamino)-5-pyrimidinol

Degradate 1
2-amino-4,6-dimethylpyrimidine.