Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 3 of 36 

## Table of Contents 1.0 EXECUTIVE SUMMARY

................................ ................................ ..................... 4 2.0 INGREDIENT PROFILE

................................ ................................ ..................... 10 2.1 S UMMARY OF P ROPOSED U SES

................................ ................................ ................................ .. 10 2.2 S TRUCTURE AND N OMENCLATURE

................................ ................................ .............................. 11 2. 3 P HYSICAL AND C HEMICAL P ROPERTIES

................................ ................................ .................... 11 

### 3.0 HAZARD CHARACTERIZAT ION/ASSESSMENT

................................ ........ 12 3.1 H AZARD AND D OSE

- R ESPONSE C HARACTERIZATION

................................ ............................... 12 3.2 FQPA C ONSIDERATIONS

................................ ................................ ................................ .............. 14 3.3 D OSE

- R ESPONSE A SSESSMENT

................................ ................................ ................................ .. 15 

### 4.0 DIETARY EXPOSURE/RIS K CHARACTERIZATION

................................ . 18 4.1 P ESTICIDE M ETABOLISM AND E NVIRONMENTAL D EGRADATION

................................ ............. 18 4.2 D IETARY E XPOSURE AND R ISK

................................ ................................ ................................ . 22 

### 5.0 RESIDENTIAL (NON

- OCCUPATIONAL) EXPOSU RE/RISK CHARACTERIZATION

................................ ................................ ............................... 23 5.1 O THER (S PRAY D RIFT , ETC .)

................................ ................................ ................................ ...... 23 

### 6. 0 AGGREGATE RISK ASSESSMENT AND RISK CHARACTERIZ ATION

. 23 6.1 A CUTE A GGREGATE R ISK

................................ ................................ ................................ .......... 24 6.2 S HOR T

- AND I NTERMEDIATE

- T ERM A GGREGATE R ISK

................................ ............................. 24 6.3 L ONG

- T ERM A GGREGATE R ISK

................................ ................................ ................................ . 24 6.4 C ANCER R ISK

................................ ................................ ................................ ............................. 24 

### 7.0 CUMULATIVE RISK CHARACTERIZATIO N/ASSESSMENT

................... 24 8.0 OCCUPATIONAL EXPOSUR E/RISK PATHWAY

................................ ......... 24 8.1 H ANDLER E XPOSURE AND R ISK E STIMATES

................................ ................................ ............. 25 8.2 P OST

- APPLICATION E XPOSURE AND R ISK E STIMATES

................................ .............................. 29 8.3 R ESTRICTED E NTRY I NTERVAL (REI)

................................ ................................ ....................... 30 

### 9.0 DATA NEEDS AND LABEL RECOMMENDATIONS

................................ .... 30 9.1 T OXICOLOGY

................................ ................................ ................................ ............................. 30 9.2 R ESIDUE C HEMISTRY

................................ ................................ ................................ ................. 30 9 .3 O CCUPATIONAL AND R ESIDENTIAL E XPOSURE

................................ ................................ ......... 31 

### APPENDIX A: TOXICIT Y PROFILE TABLES.

................................ ...................... 32 APPENDIX B: METABOL ISM ASSESSMENT.

................................ ...................... 35 APPENDIX C: TOLERAN CE SUMMARY FOR PYRIM ETHANIL.

.................... 36Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 4 of 36 1.0 Executive Summary

IR

- 4 has submitted a petition for the use of Scala TM 

### SC Fungicide (EPA Reg. No. 264

- 788), an
aqueous SC formulation containing 5.0 lbs/gal of pyrimethanil. The petitioner requests that the following tolerances be established as a result of the proposed uses for the residues of pyrimethanil (4,6

- dimethyl

- N

- phenyl

- 2

- pyrimidinamine) in/on:

Ginseng

................................ ................................ ................................ ................................ 2.5 ppm Onion, bulb, subgroup 3

- 07A

................................ ................................ ............................... 0.10 ppm Onion, green, subgroup 3

- 07B

................................ ................................ ............................. 2.0 ppm Berry and small fruit, small fruit vine climbing subgroup, except fuzzy kiwifruit 13

- 07F

.. 5.0 ppm Berry and small fruit, low growing b erry subgroup 13

- 07G

................................ ................ 3.0 ppm



### Pyrimethanil is an amino acid synthesis inhibitor that inhibits the secretion of fungal enzymes necessary for fungal infection. Pyrimethanil is currently registered in the U.S. for use on almonds, pome fruit, citrus fruit, st one fruit (except cherry), bananas, grapes, onions, pistachios, strawberries, tomatoes

, and tuberous and corm vegetables. Permanent tolerances have been established for residues of pyrimethanil per se in/on plant commodities at levels ranging from 0.05 pp m 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 Uses : The proposed use to the subject crops is as a foliar application three times at 0.35

- 0.70 lb ai/A with a maximum of 1.4

- 2.1 lb ai/A/season and a preharvest interval (PHI) of 1

- 30 days.

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 neurotox icity, 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. Exposure to pyrimet hanil in oral toxicity studies primarily resulted in decreased body weights and body

- weight gain , often accompanied by decreases in food consumption. The major target organs of repeated oral exposure were the liver and the thyroid. No reproductive toxici ty was 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 tr ansferase (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 wer e mediated via disruption of the thyroid/pituitary axis. There were no concerns for mutagenicity.

Dose

- response and Food Quality Protection Act ( FQPA ) Assessment : The toxicity database for pyrimethanil is adequate for risk assessment and tolerance setti ng. Appropriate endpoints were identified for exposures t o pyrimethanil. The identified endpoints for pyrimethanil are as follows:Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 5 of 36 The Agency has selected the no

- observed

- adverse

- effect level ( NOAEL ) of 100 mg/kg/body weight for the acute dietary risk assessment for the general population including infants and children. The endpoint of concern is neurotoxicity (decreased motor activity, ataxia, decreased body temperature, hind

- limb grip strength, and dilated pupils) observed in an acute neurotoxicity study at 1000 mg/kg/day [lowest

- observed

- adverse

- effect level (LOAEL) ]

. The Agency has selected the developmental NOAEL of 45 mg/kg/day for the acute dietary risk assessment for pregnant females (13

- 49). The endpoint of concern is skeletal variations (increases in fetuses with 13 thoracic vertebrae and 13 pairs of ribs) observed in a pre

- natal developmental toxicity study in rabbits at 300 mg/kg/day (LOAEL). The in utero effects are the most sensitive en dpoint for this sub

- population (potentially pregnant females). The Agency has selected the NOAEL of 17 mg/kg/day for chronic dietary risk assessment for general population including infants and children. The endpoint of concern is systemic toxicity manif ested as decreased body

- weight gains; increased serum cholesterol and gamma

- glutamyl transferase (GGT), increased relative liver/body

- weight ratios, necropsy and histopathological findings in the liver and thyroid observed in a chronic toxicity/carcinogeni city study in rats at 221 mg/kg/day (LOAEL). The pyrimethanil data base 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 co ncern is decreases in body weight and body

- weight gain observed in the two

- generation reproduction study in rat at 294 mg/kg/day (LOAEL). The use of this NOAEL will also address the concern for the toxicity seen in the target organs (liver and thyroid) se en at a comparable dose (221 mg/kg/day) in the chronic toxicity/carcinogenicity study in rats as well as the developmental toxicity study in rabbits. Since an oral dose was selected a dermal

- absorption factor of 51% should be use for route

- to

- route extrap olation which yields a dermal

- equivalent dose of 45 mg/kg/day (23 mg/kg/day ÷ 0.51 dermal

- absorption factor = 45 mg/kg/day). The p yrimethanil database does not contain an inhalation 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 decreases in body weight and body

- weight gain observed in the two

- generation reproduction study in rat at 294 mg/kg/day (LOAEL). Since an oral dose was selected

, a 100% absorption factor (i.e., equivalent to oral absorption) should be use for route

- to

- route extrapolation.



### The pyrimethanil ris k assessment team has evaluated the hazard and exposure data; and, based on these data, recommended that the FQPA S afety F actor (SF) be reduced to 1X . The recommendation is based on the following:

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 r abbits or in the
two

- generation reproduction study in rats. There are no residual uncertainties concerning pre

- and post

- natal toxicity. A guideline immunoto xicity study has been submitted; and

, there is no evidence for immunotoxicity due to pyrimethanil t reatment. Evidence of neurotoxicity was observed at a very high dose (the limit dose) in the acute neurotoxicity study in rats. However, the study has a clear NOAEL, which is being utilized as the point of departure (POD) for the acute dietary exposure

s cenario; and

, there was no evidence of neurotoxicity observed in the subchronic neurotoxicity study in rats. A developmental neurotoxicity (DNT) study is not required. The thyroid has been shown to be one of the target organ s in adult animals for p yrimethanil

induced toxicity thus raising a potential concern for thyroid toxicity in the young. The Hazard Identification Assessment Review Committee ( HIARC ) , however, concluded that there is no concern for thyroid toxicity in the young based on the foll owing weight of evidence considerations: the effects seen on the thyroid and the liver in the database, while treatment

-Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 6 of 36 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 c hosen for endpoint 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. In addition, the decrease i n thyroid hormone in the special 14

- day study was relatively mild (≤24%), statistically significant at only one time point, observed at a high dose (379 mg/kg./day), and compensated for by an increase in TSH. Any possible decrease in thyroid hormone level s at the POD s chosen for risk assessmen t would be undetectable. T here was no indication of any offspring toxicity in offspring, except for decr eased body weight, in the two

- generation reproduction toxicity study. There are no residual uncertainties with r espect to exposure data. The dietary food exposure assessment utilizes tolerance

- level residues (established or recommended) and 100% crop treated (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, which are designed to provide conservative, health

- protective, high

- end estimates of water concentrations that will not likely be exceeded. There are no residential uses.



### P yrimethanil was reclassified as “ Not Likely To Be Carcinogenic to Humans at Doses That Do Not Alter Rat Thyroid Hormone Homeostasis

. ” Therefore, q uantification of carcinogenic risk is not required

. The Cancer Assessment Review Committee (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 chronic reference d ose (cRfD) is not expected to alter thyroid hormone homeostasis nor result in thyroid tumor formation.

Residue Chemistry : No new data were submitted to support tolerances on onion, bulb, subgroup 3

- 07A ; onion, green, subgroup 3

- 07B; low

- growing berry 13

- 07G crop subgroup; or small fruit vine climbing subgroup 13

- 07F, except fuzzy kiwifruit. The petitioner has requested that existing tolerances be expanded to their respective crops or crop groups.

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 ginseng residue data in conjunction with the magnitude of the residue study associated with this petition was gas chromatography/mass

selective detector (GC/MSD) Method 140/01/012. The lowest level of method val idation (LLMV) was 0.05 ppm. This method was adequate for data collection. There are also adequate methods available to enforce pyrimethanil tolerances on the subject crops.

The submitted field trial residue data for ginseng are adequate. The field t rial data reflect the proposed use pattern, an adequate number of trials were conducted in the appropriate geographic regions, and samples were analyzed for the residue of concern using validated data

- collection methods. Per

- trial

- average

- residues of pyri methanil residues ranged from 0.099 to 0.585 ppm in/on three ginseng trials with samples harvested at a 29

- day PHI (highest individual residue of 0.69 ppm) from the three trials. Using the Organization for Economic Co

- operation and Development (OECD) tole rance calculation procedures for the residue data set indicates that the requested tolerance of 2.5 ppm for residues of pyrimethanil in/on ginseng is too high; a tolerance of 1.5 ppm is appropriate. A revised Section F is requested.Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 7 of 36 For plant commodities , the U.S., Canadian, and Codex residue definitions are harmonized. The U.S. and Codex tolerances/maximum residue limits (MRLs) for residues of pyrimethanil in/on the bulb onion subgroup 3

- 07A, green onion subgroup 3

- 07B, and grapes (small vine climbing f ruit subgroup 13

- 07F) are not harmonized. For grapes, the European PHI is 21 days; the U.S., 7 days. Residues were thus higher in U.S. residue trials, necessitating a higher tolerance, and precluding harmonization. For the bulb onion subgroup 3

- 07A and green onion subgroup 3

- 07B, HED recommends that the U.S. tolerances be increased in order to harmonize with Codex; bulb onion subgroup 3

- 07A from 0.10 to 0.20 ppm and green onion subgroup 3

- 07B from 2.0 to 3.0 ppm. The U.S. tolerances and Codex MRLs for s trawberries (low

- growing berry subgroup 13

- 07G) are harmonized. There are currently no established Codex, Canadian, or Mexican MRLs for pyrimethanil in/on ginseng.

Drinking Water Exposure and Risk : Surface and ground estimated drinking water concentra tions (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 (py rimethanil + 2

- amino

- 4,6

- dimethylpyrimidine) in groun d 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 concent ration

. Dietary Exposure and Risk : Acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

FCID , ver. 2.03), which incorporates consumption data from the United States Department of Agriculture (USDA) Continuing Survey of Food Intake by Individuals (CSFII; 1994

- 1996 and 1998). A cancer dietary assessment was not conducted because pyrimethanil is classified as “not likely to be carcinogenic to humans.”

The acute and chronic dietary analyses assumed DEEM

- FCID TM 

### (ver. 7.81) default pro cessing factors (as necessary), empirical processing factors for orange and apple juice, tolerance

- level residues, 100% 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 ≤35% of the a cute population

- adjusted dose (aPAD) and are not of concern to HED (<100% aPAD; all infants <1 year old were the most highly exposed population subgroup). The resulting chronic dietary risk estima tes (food and drinking water) were ≤64% 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 re gistered/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 assessment s were equal to the acute dietary and chronic dietary estimate s (food and water only) , respectively

. The acute and chronic aggregate exposure to the U.S. population and all other subpopulations from the uses of p yrimethanil does not exceed HED ’s level of concern (LOC)

.Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 8 of 36 Occupational Exposure/Risk : Based on the proposed new uses, the most highly exposed occupational pesticide handlers are expected to be mixer/loaders usin g open

- pour loading of liquids in support of aerial and groundboom applications, aerial applicators, applicators using
open

- cab ground boom equipment, and flaggers. Occupational handler dermal and inhalation risk estimates were calculated. An MOE ≥100 is adequate to protect occupational pesticide handlers from dermal and inhalation exposures. Airblast applicator dermal MOEs are >100 with a baseline protection plus gloves and headgear. All other estimated dermal and inhalation MOEs are >100 with baseline protection, and these proposed uses are not of concern for HED . The proposed label requires applicators and other handlers to wear a long

- sleeved shirt and long pants, shoes plus socks, and chemical

- resistant gloves. The label should be amended to speci fy the use of chemical

- resistant headgear for overhead exposure. RD should ensure the appropriate personal

- protective equipment ( PPE ) is listed on the label.

HED expects that post

- application dermal exposure will occur since pyrimethanil is applied post

emergence as a foliar spray. HED has determined that short

- and intermediate

- term risk estimates are not of concern (i.e., MOEs ≥100) on the day of treatment (i.e., Day 0) for all post

application exposure activities

. Based on the Agency's current practi ces, a quantitative occupational post

- application inhalation exposure assessment was not performed for pyrimethanil at this time.

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.hss.energy.gov/nuclearsafety/env/guidance/jus tice/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 estimate s risks to population subgroups from pesticide exposures t hat are based on patterns of that subgroup’s food consumption. Extensive data on food consumption patterns are compiled by the USDA under the CSFII and are used in pesticide risk assessments for all proposed/registered food uses/tolerances 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. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure from traditional dietary patterns amon g specific subgroups.

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 Pesti cide 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 a re 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

.Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 9 of 36 Regulatory Recommen dations and Data Deficiencies

Recommendations

Pending submission of revised Sections B and F as specified below, t he residue chemistry, toxicology, and occupational exposure databases support conditional registration and establishment of permane nt tolerances as listed below.

Ginseng

................................ ................................ ................................ ........... 1.5 ppm Onion, bulb subgroup 3

- 07A

................................ ................................ ......... 0. 2 0 ppm Onion, green subgroup 3

- 07B

................................ ................................ ........ 3 .0 ppm Fruit, small, vine climbing, subgroup 13

- 07F, except fuzzy kiwifruit

........... 5.0 ppm Low growing berry subgroup 13

- 07G

................................ ............................ 3.0 ppm Note to RD: With the establishment of these tolerances, the following tolerances should be removed: strawberry; grape; onion, bulb; and onion, green.



### In accordance with current Agency practice to describe more clearly the measurement and scope

o r coverage of tolerances, HED recommends for the following revisions to the pyrimethanil tolerance expressions:

40 CFR §180.518 (a)(1) “Tolerances are established for residues of the fungicide pyrimethanil, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only pyrimethanil (4,6

- dimethyl

- N

- phenyl

- 2

- pyrimidinamine).”

40 CFR §180.518 (a)(2) “Tolerances are established for residues of t he fungicide pyrimethanil, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring is to be determined by measuring only the sum of pyrime thanil and its metabolite 4

- [4,6

- dimethyl

- 2

- pyrimidinyl)amino]phenol, calculated as the stoichiometric equivalent of pyrimethanil.”

40 CFR §180.518 (a)(3) “Tolerances are established for residues of the fungicide pyrimethanil, including its metabolites an d degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring is to be determined by measuring only the sum of pyrimethanil and its metabolite 4,6

- dimethyl

- 2

- (phenylamino)

- 5

- pyrimidinol, calculated as the stoichiometric equivalent of pyrimethanil.”

Data Deficiencies

/Requirements

Toxicology : A 90

- d ay inhalation study (870.3465 )

Residue Chemistry : Adjuvants were not used in any of the submitted residue field trials. Since adjuvants were not used in the submitted residue field trials, the label should prohibit such uses on ginseng; onion, bulb, subgroup 3

- 07A ; onion, green, subgroup 3

- 07B; low

- growi ng berry 13

- 07G crop subgroup; or small fruit vine climbing subgroup 13

- 07F, except fuzzy kiwifruit.Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 10 of 36 A summary of the recommended tolerances along with recommendations for commodity definitions are presented in Appendix C . The petitioner is required to su bmit a revised Section F to reflec t the recommendations in Appendix C

.

ORE : The label should be amended to specify the use of chemical

- resistant headgear for overhead exposure. RD should ensure the appropriate PPE is listed on the label.

2.0 Ingredient Profile

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 pene tration 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 relea se 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 inhib ited.

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.

2.1 Summary of Proposed Uses

Table 2.1 provides a summary of the proposed use patterns. Scala TM 

### SC is formul ated as a SC, and is proposed at a maximum application rate of 0.70 lb ai/A via ground and aerial applications to ginseng, bulb vegetables 03

- 07A and 03

- 07B, small fruit, vine climbing 13

- 07B, and low

growing berry 13

- 07G. The proposed PHIs range from 1 t o 30 days. The label requires applicators and other handlers to wear a long

- sleeved shirt and long pants, shoes plus socks, and chemical

- resistant gloves. The proposed label specifies a 12

- hour restricted

- entry interval (REI).Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 11 of 3 6 Table 2.1. Summary of Dir ections for Use of Pyrimethanil. 1 Applic. Timing, Type, and Equip. Formulation

(EPA Reg. No.) Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations
Bulb Vegetables Do not apply this product for more than 2 sequential applications before rotating to a fungicide from a different functional
group.

Minimum application

vo lume: 50 GPA ground and 15 GPA aerial for vine crops, and 15 GPA ground and 5 GPA aerial for field crops.

R TI : 7

- 14 days.

PBI: 30 days for all non

labeled crops. Ground, air, or chemigation Scala TM SC Fungicide (264

- 788) 0.35

- 0.70 3

- 6 2.1 7

Ginseng Ground, air, or chemigation Scala TM SC Fungicide (264

- 788) 0.70 3 2.1 30

Small Fruit Vine

- Climbing Subgroup Except Fuzzy Kiwifruit
Ground, air, or chemigation Scala TM SC Fungicide (264

- 788) 0.35

- 0.70 2

- 4 1.4 7

Low

- Growing Berry Subgroup

Ground, air, or chemigation Scala TM SC Fungicide (264

- 788) 0.35

- 0.70 3

- 6 2.1 1

1. PHI = preharvest interval. GPA = gallons per acre. RTI = retreatment interval. PBI = plantback interval.



### HED Conclusions : The submitted label is adequate to allow evaluation of the residue data relative to the proposed uses. Adjuvants were not used in any of the submitted residue field trials (48421101.der.doc, 45657111.der.wpd, 45657112.der.wpd, and 45657123.der.wpd). Since adjuvants were not used in the submitted residue field trials, the label should prohibit such uses on ginseng; onion, bulb, su bgroup 3

- 07A; onion, green, subgroup 3

- 07B; low

- growing berry 13

- 07G crop subgroup; or small fruit vine climbing subgroup 13

- 07F, except fuzzy kiwifruit. In addition, RD should ensure the appropriate PPE is listed on the label.

2.2 Structure and Nomenclature

Table 2.2 . 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) Scala TM SC Fungicide (EPA Reg. No. 264

- 788)



### 2.3 Physical and Chemical Properties

Table 2 .3

. 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) 0.121Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 12 of 36 Table 2 .3

. Physicochemical Properties of the Technical Grade Test Compound

. Solvent solubility (g/l at 20 o C) acetone

– 389, ethyl acetate

– 617, methanol

– 176, methylene chloride

– 1000, n

- hexane

– 23.7, toluene

– 412 Vapo r pressure at 25 o C 2.2 mPa Octanol/water partition coefficient log (K OW ) 2.84

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



### 3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose

- Response Characterization

3.1.1 Adequacy of the Toxicity Databas e and Hazard Profile

The toxicology database for pyrimethanil is complete. Since the completion of the previous risk assessment, the previously requested guideline mouse carcinogenicity study has been submitted ( Memo, J. Kidwell, 24

- APR

- 2003, TXR# 0050408), and the cancer classification has been changed ( Memo, J. Rowla nd , 23

- DEC

- 2011

, TXR#0056151). A guideline immunotoxicity study has also been submitted. HED’s Hazard Assessment and Policy Committee (HASPOC)

, looked at all existing hazard and exposure data, and current use patterns for p yrimethanil, and used a weight

- of

- evidence approach to require a 90

- day inhalation study and to not require a 28

- day dermal toxicity study (Memo, D. Smegal, 23

- FEB

- 12, TXR# 0054040). This weight

- of

evidence approach for the inhalation study considered all of the available hazard and ex pos ure information including: (1) the use of an oral POD that results in MOEs as low as 110 (the lowest MOE) for risk via the inhalation route resulting fr om occupational and residential exposures; (2) the physical/chemical properties; (3) the toxicologi cal profile of pyrimethanil; and (4) there is repeated inhalation exposure based on the use pattern and method of application (i.e., greenhouses ). The committee further concluded that u nder the current uses, a 28

- day dermal study is not required pending t he use of headgear in occupational scenarios of concern. This 28

- day study is required for any future residential uses , and the registrant is welcome to submit a study to further refine dermal risk assessments.

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 gastrointe stinal 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, kid ney, thyroid, and blood at study termination 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 chem ical 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 ski n of male Sprague Dawley rats. Total absorbedPyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 13 of 36 dose for the low, intermediate, and high dose s at 10 hours post

- treatment w ere 37.22, 35.77, and 20.39%, respectively. The “potentially absorbable” dose (combine 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. Subchronic and chronic exposure to pyrimethanil in oral toxicity studies primarily resulted in decreased body weights and body

- weight gain , often accompanied by decreases in food consumption. The major target organs of repeated oral exposure were the liver, kidney

, and the thyroid, and effects observed w ere manifested as some

c linical signs (vomiting, diarrh ea , 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. No reproductive toxicity was observed, and developmental effects (e.g., decreased fetal weight, retarded ossification, extra ribs) were observed only at maternally toxic doses. Pyrimethanil wa s not immunotoxic.

There are currently no dermal or inhalati on toxicity studies available for pyrimethanil.

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 for the thyroid tumors up to the highest dose tested

. There are no concerns for mutagenicity.

3.1.2 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 fem ales 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 was seen at 1/2 limit dose (4 30 mg/kg/day) in the subchronic neurotoxicity study. In addition, no neurotoxic signs were seen in the rest of the database and the target organ for toxicity for pyrimethanil is the thyroid ; therefore

, neurotoxicity is not a primary concern.

3.1.2.1 Determination of Susceptibility

There is no evidence for increased susceptibility following in utero exposure in the rat and rabbit or following pre

- and post

- natal exposure in the 2

- generation reproduction study in rats.

3.1.2.2 Degree

- of

- Concern Analys is

There are no concerns or residual uncertainties for pre

- and/or postnatal toxicity following exposure to pyrimethanil.Pyrimethanil Human

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### Page 14 of 36 3.1.3 Recommendation for a DNT Study

There are no neurotoxicity concerns and no evidence for increased susceptibility; therefore, there is no concern for potential neurodevelopmental effects from exposure to pyr i methanil. A developmental neurotoxicity study is not required.

3.2 FQPA Considerations

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 study, Acute and subchronic (unacceptable) neurotoxicity studies

, An immunotoxicity study

. 

### Based on previous HIARC conclusions (2003) and the pyrimethanil risk assessment team’s re

evaluation of the hazard and exposure data, the FQPA SF can be reduced to 1X . The recommendation is based on the following:

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. There are no residual uncertainties concerning pre

- and postnatal toxicity. A guideline immunotoxicity s tudy has been submitted, and there is no evidence for immunotoxicity due to pyrimethanil treatment. Evidence of neurotoxicity was observed at a very high dose (the limit dose) in the acute neurotoxicity study in rats. However, the study has a clear NOAEL , which is being utilized as the POD for the acute dietary exposure scenario, and there was no evidence of neurotoxicity observed in the subchronic neurotoxicity study in rats up to the highest dose tested in that study (430 mg/k/day). A DNT study is not required. Thyroid has been shown to be one of the tar get organs in adult animals for p yrimethanil

- induced toxicity thus raising a potential concern for thyroid toxicity in the young. HIARC, however, 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 thyro id hormone levels, as well as in all studies chosen for 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. There are no residual uncertainties with respect to exposure data. The dietary food exposure

a ss essment utilizes tolerance

- level residues (established or recommended) and 100% CT for all proposed/established commodities. By using these assu mptions, 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

- p rotective, high

- end estimates of water concentrations that will not likely be exceeded. There are no residential uses.



### The FQPA SF recommended by the pyrimethanil review team assumes that the exposure databases (dietary food, drinking water, and resident ial) are complete and that the risk assessment for each potential exposure scenario includes all metabolites and/or degradates of concern and does not underestimate the potential risk for infants and children.Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 15 of 36 3.3 Dose

- Response Assessment

3.3.1 Acute Po pulation

- Adjusted Dose (a PA D)

- Females A ge 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 develop mental 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.

3.3.2 Acute Population

- Adjusted Dose (a PA D)

- General 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 int er

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

. Th e effects were seen after a single oral dose and thus appropriate for this exposure scenario and the population of concern.

3.3.3 Chronic Population

- Adjusted Dose (c PA D)

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 decreased body

- weight g ains, increased serum cholesterol and GGT, increased relative liver/body

- weight ratios, necropsy, and histopathological find ings 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 v ia chronic dietary exposure to p yrimethanil.

3.3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

There are no residential uses for pyrimethanil. Therefore, an incidental oral endpoint was not chosen.

3.3.5 Dermal Absorption

A dermal

- absorption study was submitted (MRID No. 46630101) and reviewed ( Memo, P.V. Shah, 23

- FEB

- 2009, D 322065 ). A dermal

- absorption factor of 51% was chosen based on results from the in vivo dermal

- absorption study in rats. Previously, HED used a dermal

- absorption factor of 37.2% ( Memo, K. Lowe, 04

- JAN

- 20 0 7, D322065). This dermal

- absorption factor was based on preliminary review of the MRID 46630101; however, subsequent to a detailed review HED concluded that the dermal

- absorption factor of 51% is more appropriate for this dermal exposure assessment.Pyrimethanil Human

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### Page 16 of 36 3.3.6 Dermal Exposure (Short

- and Intermediate

- Term)

The p yrimethanil data base does not contain a dermal toxicity study. Therefore, the Agency has selected an ora l NOAEL of 23 mg/kg/day for short and intermediate term dermal risk assessments. The endpoint of concern is decreases in body weight and body

- weight gain observed in the two

- generation reproduction study in rat at 294 mg/kg/day (LOAEL). The use of this N OAEL will also address the concern for the toxicity seen in the target organs (liver and thyroid) seen at a comparable dose (221 mg/kg/day) in the chronic toxicity/carcinogenicity study in rats as well as the developmental toxicity study in rabbits. Since an oral dose was selected a dermal

- absorption factor of 51% should be use for route

- to

- route extrapolation which yields a dermal

- equivalent dose of 45 mg/kg/day (23 mg/kg/day ÷ 0.51 dermal

- absorption factor = 45 mg/kg/day).

3.3.7 Inhalation Exposure (S hort

- and Intermediate

- Term )

An inhalation toxicity study was not submitted. The short

- and intermediate

- term inhalation endpoints are based upon the parental effe cts observed in the 2

- generation reproduction study

. The NOAEL is 23.1 mg/kg/day. The ef fect observed at the LOAEL of 294 mg/kg/day was decreased parental mean body weights and body

- weight gains. This endpoint is appropriate for the duration of exposure and the populations of concern. The Agency has assumed that absorption via the inhalatio n route is complete (100%). The LOC for occupational dermal exposure is a MOE <100.

3.3. 8 Level of Concern for Margin of Exposure

The target MOEs for occupational and non

- dietary residential exposure risk assessments are as follows:

Table 3.3.8. Summary of L O C s for Risk Assessment.

Route Duration Short

- Term (1

- 30 days) Intermediate

- Term (1

- 6 Months) Occupational (Worker) Exposure Dermal 100 100 Inhalation 100 100 Residential (Non

- Dietary) Exposure Oral NA NA Dermal NA NA Inhalation NA NA



### 3.3.9 Classification of Carcinogenic Potential

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March 2005), the 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;Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 17 of 36 iii) There is no mutagenicity concern and there is no evidence for thyroid carcinogenesis mediated thro ugh 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 c onsidered sufficient to indicate that Pyrimethanil induced thyroid follicular tumors through an antithyroid mode of action; and v) Rats are substantially more sensitive than humans to the development of thyroid follicular cell tumors in response to thyroid ho rmone 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 t he cRfD is not expected to alter thyroid hormone homeostasis nor result in thyroid tumor formation.

3.3. 1 0 Recommendation for Aggregate Exposure Risk Assessments

As per FQPA, 1996, when there are potential residential exposures to the pesticide, aggregat e risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. An aggregated exposure risk assessment is not required since there are no residential uses for pyrimethanil at this time.

3.3.1 1 Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Human Health Risk Assessments

The selected toxicity endpoints ar e summarized in Tables 3.3.11. a and 3.3.11 .b.

Table 3.3.11. a. Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Dietary and Non

Occupational Human

- Health Risk Assessments.
Exposure/ Scenario Point of

Departure Uncertainty/FQ

PA Safety Factors RfD, PAD,

LOC Study and Toxicological Effects

Acute Dietary (Females 13

- 49 years of age) NOAEL =

45 mg/kg/day UF A = 10X

UF H = 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 UF A = 10X

UF H = 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 UF A = 10X

UF H = 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 gain s; increased serum cholesterol and GGT, increased relative liver/body weight ratios, necropsy and histopathological findings in the liver and thyroid. Cancer (oral, dermal, inhalation) In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March 2005), the 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 ).Pyrimethanil Human

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### Page 18 of 36 Table 3 .3.11. b. Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Occupational Human

- Health Risk Assessments

. Exposure Scenario Dose Used in Risk

Assessment, UF FQPA SF and 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) In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March 2005), the 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 ). Point of d eparture (POD) = A data point or an estimated point that is derived from o bserved dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL =

no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapo lation from animal to human (intraspecies). UF H = 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 .0 Dietary Exposure/Risk Characterization

The residue chemistry data submitted in support of proposed uses were evaluated by HED on 08

- MAY

- 2012 (Memo, G. Kramer; D 389985 ) . The drinking water assessment was completed by EFED on 26

- SEP

- 2011 (Memo, J. Wolf; DP389925). The dietary exposure assessmen t was completed in a HED memorandum dated 08

- MAY

- 2012 (Memo, G. Kramer; D 389986 ).

4 .1 Pesticide Metabolism and Environmental Degradation

4 .1.1 Metabolism in Crops

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 MARC has determined that for risk assessment and tolerance expression, parent only is the residue of concern. Future new uses on root crops whose tops are significant food/feed items will require the analysis of samples for metabolite AEC614278.

4 .1.2 Metabolism in Livestock

None of the subject crops have livestock food/feed ite ms of regulatory interest; therefore, issues pertaining to livestock metabolism, analytical methods and storage stability data for and residues in livestock commodities are not addressed in the current petition.

4 .1.3 Analytical Methodology

A residue ana lytical 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 imp orted wine grapes. The method has been subjected to a successful petition method validation (PMV) byPyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 19 of 36 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 ).

4 .1.4 Environmental Degrada tion

EFED studies indicated that pyrimethanil is expected to be moderately persistent in the environment. Aerobic metabolism is expected to be the major route of degradation for pyrimethanil in the environment. The only major degradate is 2

- amino

- 4,6

- di methylpyrimidine (degradate 1). Although it may be less toxic than the parent, degradate 1 is expected to be more mobile and more persistent in the environment than the parent. MARC recommended that parent and degradate 1 are the residues of concern for drinking water.

4 .1.5 Comparative Metabolic Profile

The major route of dissipation for pyrimethanil is expected to be aerobic metabolism for both aqueous and terrestrial environments. Pyrimethanil partitions into the sediment, but is stable to anaerobic (total system) degradation in both soil and sediment systems. Pyrimethanil is stable to both hydrolysis and aqueous photolysis at environmental pHs, but is susceptible to photolysis in soil.

In plants, pyrimethanil is the only significant residue rangin g from essentially all of the total radioactive residues (TRR) in carrots and tomatoes to 44% in lettuce. Limited metabolism of pyrimethanil occurs with minor amounts (less than 10%) of the phenyl and pyrimidyl hydroxylated metabolites (AE C614276, AE C61 4277, AE C614278, and AE C621312) being released after acid hydrolysis. Analysis of the foliage from apples and carrots confirmed that the metabolism of pyrimethanil in plants proceeded primarily via hydroxylation of the aromatic ring structures as well a s the methyl groups.

In livestock, pyrimethanil is rapidly metabolized and excreted from lactating dairy cows. The observed total radioactive residues in edible tissues and milk were as follows: milk maximum residue of 0.069 ppm; liver

- 0.363 ppm; kidne y 0.249 ppm, and muscle 0.017 ppm. The metabolic pathway is similar to that of plants involving hydroxylation of the phenyl and pyrimidine rings as well as hydroxylation of the methyl substituents. Further metabolic reactions occur including cleavage of the phenyl ring to produce substituted pyrimidines. The major metabolite was AE C614276 (46% of the kidney residues, 63% of the milk residues resulting from hydroxylation of the phenyl ring ) . Hydroxylation of the pyrimidinyl ring of pyrimethanil resulted in formation of minor amounts of AE C614277. Hydroxylation of the methyl groups of pyrimethanil resulted in formation of minor amounts of AE C614278. Hydroxylation of the methyl groups of AE C614276 resulted in formation of minor amounts of AE C614800.

In rats, when pyrimethanil was administered orally, it was absorbed rapidly and eliminated within 24 hours. The major routes of elimination were the urine (approximately 72% of the administered dose), and the feces (17

- 18% of the administered dose). The main pathways of metabolism involved oxidation to phenols in either or both aromatic rings. The minor pathways of metabolism involved oxidation of the methyl group to the corresponding alcohol.Pyrimethanil Human

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### Page 20 of 36 4 .1.6 Toxicity Profile of Major Metabolites and Degradates

The primary residue of concern in both crop and animal commodities is pyrimethanil. In the animal metabolism, since major metabolites are produced following the oral administration of pyrimethanil, toxicology data for metabolites are completely supported by data obtained for pyrimethanil.

4 .1.7 Pesticide Metabolites and Degradates of Concern

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) py rimethanil 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

- a mino

- 4,6

- dimethylpyrimidine )

.

Table 4 .1.7 . 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,
p yrimethani l + AEC614277. Pyrimethanil + AEC614276 for muscle, fat, and byproducts. Pyrimethanil + AEC614277 for milk. Poultry Not Applicable Not Applicable Drinking Water Parent (Pyrimethanil) + Degradate 1 (2

- a mino

- 4,6

- dimethylpyrimidine) Not Applicable



### 4 .1.8 Drinking Water Residue Profile

EFED reassessed pyrimethanil for the proposed n ew uses presented in this memo . 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 ( Memos, 22

- OCT

- 2003, D 283999 and D 290313; 08

- JAN

- 2009, D 353180 ).

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 conce ntration. These EDWCs correspond to the FL/strawberries (acute) and NY/grapes (chronic) scenarios.Pyrimethanil Human

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### Page 21 of 36 Table 4 .1.8

. Estimated Drinking Water Concentrations for Combined Total Residues, Parent (Pyrimethanil) Plus Major Degradate (2

- amino

- 4,6

- dimethylpyrimidi ne).

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.

4 .1.9 Food Residue Profile

No new data were submitted to support tolerances on onion, bulb, subgroup 3

- 07A ; onion, green, subgroup 3

- 07B; low

- growing berry 13

- 07G crop subgroup; or small fruit vine climbing subgroup 13

- 07F, except fuzzy kiwifruit. The petitioner has requested that existing tolerances be expanded to their respective crops or crop groups.

The data

- collection method used to generate ginseng residue data in conjunction with the magnitude of the residue study associated with this petition was GC/MSD Method 140/01/012. The LLMV was 0.05 ppm. This method was adequate for data collection. There are also adequate methods availab le to enforce pyrimethanil tolerances on the subject crops.

The ginseng samples analyzed in this study were held in frozen storage for a maximum of 259 days prior to analysis of pyrimethanil residues. There are adequate concurrent storage stability dat a to indicate that pyrimethanil residues are stable in/on ginseng for the duration of this study.

The submitted field trial residue data for ginseng are adequate. The field trial data reflect the proposed use pattern, an adequate number of trials were co nducted in the appropriate geographic regions, and samples were analyzed for the residue of concern using validated data

- collection methods. Per

- trial

- average

- residues of pyrimethanil residues ranged from 0.099 to 0.585 ppm in/on three ginseng trials with samples harvested at a 29

- day PHI (highest individual residue of 0.69 ppm) from the three trials. Using t he OECD tolerance calculation procedures for the residue data set indicates that the requested tolerance of 2.5 ppm for residues of pyrimethanil in/o n ginseng is too high; a tolerance of 1.5 ppm is appropriate. A revised Section F is requested.

Adequate confined and limited field rotational crop trials are available and support the label

specified 30

- day plant

- back interval (PBI) for crops without us es on the Scala TM 

### label. The available data indicate that tolerances are not currently required for rotational crops.

4 .1.10 International Residue Limits

For plant commodities, the U.S., Canadian, and Codex residue definitions are harmonized. The U.S. a nd Codex tolerances/MRLs for residues of pyrimethanil in/on the bulb onion subgroup 3

- 07A, green onion subgroup 3

- 07B, and grapes (small vine climbing fruit subgroup 13

- 07F) are not harmonized. For grapes, the European PHI is 21 days; the U.S., 7 days. R esidues were thusPyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 22 of 36 higher in U.S. residue trials, necessitating a higher tolerance, and precluding harmonization. For the bulb onion subgroup 3

- 07A and green onion subgroup 3

- 07B, HED recommends that the U.S. tolerances be increased in order to harmonize w ith Codex; bulb onion subgroup 3

- 07A from 0.10 to 0.20 ppm and green onion subgroup 3

- 07B from 2.0 to 3.0 ppm. The U.S. tolerances and Codex MRLs for strawberries (low

- growing berry subgroup 13

- 07G) are harmonized. There are currently no established Code x, Canadian, or Mexican MRLs for pyrimethanil in/on ginseng.

4 .2 Dietary Exposure and Risk

Unrefined acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using DEEM

- FCID TM 

### , Version 2.03 which use s food consumption data from the USDA ’s CSFII from 1994

- 1996 and 1998.

4 .2.1 Acute Dietary Exposure/Risk

The unrefined acute assessment assumed that pyrimethanil residues are present in all commodities at tolerance levels and that 100% of all crops are treated. DEEM

- FCID TM 

### Version 7.81 default processing factors were used as necessary when empirical processing factors were not available. Drinking water was incorporated directly into the dietary assessment using the EDWCs generated by the PRZM/EXAMS wate r model.

The resulting acute dietary risk estimates for food and water combined are below HED’s LOC (i.e., <100% of the aPAD) for the general U.S. population and all population subgroups at the 95 th 

### percentile of the exposure distribution. Using the DEEM

- FCID TM 

### software, dietary risk is estimated at 9.9% of the aPAD for the general U.S. population; 35% of the aPAD for all infants <1 years old, the population subgroup with the highest estimated acute dietary exposure to pyrimethanil ; and 13% of the aPAD for the females 13

- 49 years of age population subgroup

. 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 pop ulation subgroups ( i.e., <100% aPAD).

4 .2.2 Chronic Dietary Exposure/Risk

The unrefined chronic assessment assumed that pyrimethanil residues are present in all commodities at tolerance levels and that 100% of all crops are treated. DEEM TM 

### Version 7.81 d efault processing factors were used to estimate residues in all commodities as appropriate when empirical processing factors are not available. As in the acute scenario, drinking water was incorporated directly into the chronic dietary assessment using th e EDWC values generated by the PRZM/EXAMS water model.

The resulting chronic dietary risk estimates for food and water combined are well below HED’s LOC (i.e., <100% of the cPAD) for the overall U.S. population and all population subgroups. Using the DEE M

- FCID TM 

### software, dietary risk is estimated at 14% of the cPAD for the general U.S. population and 64% 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).Pyrimethanil Human

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### Page 23 of 36 Table 4 .2. Summary of Dietary (Food and Drinking Water) Exposure an d Risk for Pyrimethanil.

Population Subgroup Acute Dietary 1
95 th Percentile Chronic Dietary 1

aPAD (mg/kg/day) Dietary

Exposure (mg/kg/day) % aPAD cPAD (mg/kg/day) Dietary

Exposure (mg/kg/day) % cPAD

U.S. Population (total)

1.0 mg/kg bw/day 0.098872 9.9

0.17 mg/kg bw/day 0.023155 14 All Infants (<1 year old) 0.349561 35 0.092221 54
Children 1

- 2 years old 0.349561 34 0.108087 64
Children 3

- 5 years old 0.246781 25 0.074796 44
Children 6

- 12 years old 0.129627 13 0.034198 20
Youth 13

- 19 years old 0.061678 6.2 0.013698 8.1
Adults 20

- 49 years old 0.054748 5.5 0.012575 7.4 Adults 50+ years old 0.064706 6.5 0.017041 10

Females 13

- 49 years old 0.45 mg/kg bw/day 0.059322 13 0.013724 8.1

1 Population subgroups with the highest exposure and risk are in bold type

.



### 4 .2.3 Cance r Dietary Risk

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 Ra t Thyroid Hormone Homeostasis.”

5 .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.

5 .1 Other (Spray Drift, 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 the ground application metho d employed for pyrimethanil

. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical

- by

- chem ical basis, the Agency is now requiring interim mitigation measures for aerial applications that should be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership 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 airblast 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 with specific products with significant risks associated with drift.

6 .0 Aggregate Risk Assessment and Risk Characterization

The Agency conduc ts 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 exposure , the acute a nd chronicPyrimethanil Human

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### Page 24 of 36 aggregate risk assessment s are equal to the acute dietary and chronic dietary estimate s (food and water only) , respectively (see Table 4 .2)

.

6 .1 Acute Aggregate Risk

No acute residential/recreational exposures are expected. In the case of pyr imethanil, 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 S ection 4.2. As shown in Table 4 .2, the acute risk es timates do not exceed the HED ’s LOC for the general U.S. population and all population subgroups.

6 .2 Short

- and Intermediate

- Term Aggregate Risk

Pyrimethanil is not registered for residential uses. Therefore, short

- and intermediate term residential exposure s are not expected.

6

. 3 Long

- Term 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, i n the case of pyrimethanil , the c hronic aggregate risk is composed of exposures to pyrimethanil residues in food and drinking water and is equivalent to the chronic die tary risk discussed in Section 4.2. As shown in Table 4 .2, the chronic risk es timates do not exceed the HED ’s LOC for th e general U.S. population and all population subgroups.

6 .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.

7 .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 re leased 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/

.

8 .0 Occupational Exposure/Risk Pathway

Based on the proposed application scenario and toxicological considerations, non

- cancer occupational handler (dermal and inhalation) and occupational post

- ap plication (dermal ) risk assessments were conducted. The proposed new uses were evaluated in the cited memorandumPyrimethanil Human

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### Page 25 of 36 and the resulting occupational exposure/risks were reviewed by the HED Science Advisory Council for Exposure (ExpoSAC; Memo, J. Tyler, 08

- MAR

- 20 12, D389987).

8

. 1 Handler Exposure and Risk Estimates

Potential occupational handler exposure scenarios include: 1) mixing/loading liquids in support of aerial, airblast and groundboom applications; 2) applicators using open

- cab airblast equipment; 3) aerial applicators ; 4) applicators using open

- cab ground boom equipment; and 5) flaggers.

Handler exposure is expected to be short

- and intermediate

- term based on information provided on proposed labels (i.e., maximum of three sprays per season at a maximum rate of 0.70 lb ai/A). Typically, HED completes short

- and intermediate

- term assessments for occupational scenarios in all cases because these kinds of exposures are likely and acceptable use/usage data are not available to justify deleting intermediate

- term scenarios. Based on use data and label instructions, HED believes that occupational exposures may occur over a single day or up to weeks at a time for many of the use

- patterns and that intermittent exposure over several weeks may also occur. Some applicators may apply these products over a period of weeks, because they are commercial applicators who are completing multiple pesticide applications for multiple clients. Long

- term exposures are not expected; therefore, a l ong

- term assessment was not conducted. 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, the ORETF da tabase, 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 val ues 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

- ex posure

- 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

. For pesticide handlers, it is HED’s standard practice to present estimates of dermal exposure for “baseline” ; that is, for workers wearing a single layer of work clothing consisting of a long

sleeved shi rt, long pants, shoes plus socks and no protective gloves, as well as for “baseline” and the use of protective gloves or other PPE as might be necessary. The Scala TM 

### SC label requires applicators and other handlers to wear a long

- sleeved shirt and long pan ts, shoes plus socks, and chemical

- resistant gloves.

Table 8. 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 exposures. All estimated dermal and inhalation MOEs are >100 with baseline protection, except for airblast applicators. Airblast applicator dermal MOEs are >100 only with a baseline protection plus gloves and headgear. The proposed label requires applicators andPyrimethanil Human

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### Page 26 of 36 other handlers to wear a long

- sleeved shirt and long pant s, shoes plus socks, and chemical

resistant gloves. The label should be amended to specify the use of chemical

- resistant headgear for overhead exposure. RD should ensure the appropriate PPE is listed on the label.Pyrimethanil Human

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### Page 27 of 36 Table 8 .1. Short

- and Intermediate

- te rm Exposure & Risk to Occupational Handlers From Applying Pyrimethanil to the Proposed New Use Sites.

Crop or Target Unit Exposure 1 (mg ai/lb handled) Applic. Rate 2 (lb ai/A) Units Treated 3

(A/day) Avg. Daily Dose 4

(mg ai/kg bw/day) MOE 5 Combined MOEs 7

Mixer/Loader

–

Liquids

– Aerial Applications

Ginseng, bulb vegetables, small fruit vine climbing, low

- growing

berry Dermal Baseline 6 : 0.220 PPE

- G 6 : 0.0376 0.70 350 Dermal Baseline: 0.34 PPE

- G: 0.059 Dermal Baseline: 67 PPE

- G: 390 PPE

- G dermal +

Baseline inhalation: 390 Inhal. Baseline: 0.000219 Inhal. Baseline: 0.00067 Inhal. Baseline: 34,000 Mixer/Loader

–

Liquids

– Groundboom Applications

Ginseng, bulb vegetables, small fruit vine climbing, low

- growing

berry Dermal Baseline: 0.220 0.70 80 Dermal Baseline: 0.079 Dermal Baseline: 290 Baseline dermal + inhalation: 290 Inhal. Baseline: 0.000219 Inhal: Baseline: 0.00015 Inhal. Baseline: 150,000

Mixer/Loader

–

Liquids

– Airblast Applications

Small fruit vine climbing Dermal Baseline: 0.220 0.70 40 Dermal Baseline: 0.039 Dermal Baseline: 590 Baseline dermal + inhalation: 590 Inhal. Baseline: 0.000219 Inhal: Baseline: 0.000077 Inhal: Baseline: 300,000 Applying Sprays via Aerial Equipment

Ginseng, bulb vegetables, small fruit vine climbing, low

- growing

berry Dermal Eng. Cont 9 : 0.005 0.70 350 Dermal Eng. Cont: 0.0078 Dermal Eng. Cont: 3,0 00 Eng. Control dermal + inhalation: 2,900 Inhal. Eng. Cont: 0.000068 Inhal. Eng. Cont: 0.00021 Inhal. Eng. Cont: 110, 000
Applying Sprays via Groundboom Equipment
Ginseng, bulb vegetables, small fruit vine climbing, low

- growing

berry Dermal Baseline: 0.0786 0.70 80 Dermal Baseline: 0.028 Dermal Baseline: 820 Baseline dermal + inhalation: 820 Inhal. Baseline: 0.00034 Inhal. Baseline: 0.00024 Inhal. Baseline: 97 ,000 Applying Sprays via Airblast Equipment

Small fruit vine climbing Dermal Baseline: 1.77 PPE

- G 6 : 1.59 PPE

- G, HG 6 : 0.22 0.70 40 Dermal Baseline: 0.32 PPE

- G: 0.28 PPE

- G, HG: 0.039 Dermal Baseline: 73 PPE

- G: 81 PPE

- G, HG: 590 PPE

- G, HG dermal + Baseline inhalation: 570 Inhal. Baseline: 0.00471 Inhal. Baseline: 0.0016 Inhal. Baseline: 14,000Pyrimethanil Human

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### Page 28 of 36 Table 8.1. Short

- and Intermediate

- term Exposure & Risk to Occupational Handlers From Applying Pyrimethanil to the Proposed New Use Sites.

Crop or Target Unit Exposure 1 (mg ai/lb handled) Applic. Rate 2 (lb ai/A) Units Treated 3

(A/day) Avg. Daily Dose 4

(mg ai/kg bw/day) MOE 5 Combined MOEs 7
Flagger
Ginseng, bulb vegetables, small fruit vine climbing, low

- growing

berry Dermal Baseline: 0.011 0.70 350 Dermal Baseline: 0.017 Dermal Baseline: 1,300 Baseline dermal + inhalation: 1,300 Inhal. Baseline: 0.00035 Inhal. Baseline: 0.0011 Inhal. Baseline: 22,000 1. Unit Exposures are taken from the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table, September 2011. Inhal. = Inhalation. Units = m g ai/pound of ai handled. 2. Applic. Rate. = Taken from Scala TM SC label. 3. Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1. Revised September 2001. 4. Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated * Absorption factor (dermal only = 51%) 80 kg Body Weight. 5. MOE = Margin of Exposure = NOAEL ADD. NOAEL = 23.1 (dermal and inhalation) mg/kg bw/day. 6. Baseline = Long

- sleeve shirt, long pants, and no gloves (dermal); no respirator (inhalation). PPE

- G = Long

- sleeve shirt, long pants, and gloves. PPE

- G, HG = L ong

- sleeve, shirt, long pants, plus gloves and chemical

- resistant hat. 7. Combined MOEs= NOAEL (mg/kg/day) / Combined dermal + inhalation dose (mg/kg/day).Pyrimethanil Human

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### Page 29 of 36 8 .2 Post

- application Exposure and Risk Estimates

Dermal : HED expects that post

- application exposure will occur since pyrimethanil is applied as a foliar spray. Post

- application exposure is expected to be short

- and intermediate

- term based on informati on provided on proposed labels ( i.e., maximum of 3 sprays per season with a RT I of 1

- 2 weeks ) . Only short

- term exposure was assessed; however, the assessment is protective of intermediate

- term exposures since the dermal endpoints are the same for both durations.

It is the policy of HED to use the best available data to assess post

- application exposure. Sources of generic post

- application data, used as surrogate data in the absence of chemical

specific data, are derived from ARTF exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting post

- application exposure that are used in this assessment, known as “transfer coefficients

, ” are presented in the “Science Advisory Council for Exposure (ExpoSAC) Policy 3” (http://www.epa.gov /pesticides/science/exposac_policy3.pdf), which, along with additional information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/post

app

- exposure

- data.html

.

Chemical

- specific dislodgeable foliar residue ( DFR ) data were available for pyrimethanil on apples, grapes, and strawberries

. Since DFR data are not available for the root vegetable crops, the available data were used as surrogates. Based on a review of the available data, it was decided that the DFR data for grapes would be used to estimate post

- application exposure for the vine trellis crop group, and the strawberry DFR data would be used to estimate post

- application exposure for the low

- gro wing berry and root vegetable groups.

Even though there are no data specifically for the root vegetable crops, it is believed that the strawberry data ar e representative of the root vegetable crops for the following reasons: (1) the data represents DFR data collected in the field, and (2) the application method, rate, and timing are similar between the DFR study and the proposed use sites. One caveat is the leaf texture of strawberries does not match the root vegetable crop s

. Based on an analysis of the data, it is proposed that predicted grape and strawberry DFR values calculated based on a linear regression of the measured data be used since the R 2



### - values are high (0.900 for grape, and 0.808

- 0.883 for strawberries).

All agri cultural crop scenarios resulted in MOEs greater than 100 on day 0, and are not of

concern.

Table 8 .2. Dermal Post

- application Exposure and Risk Using Chemical Specific Data.

Crop Group Proposed Crop Transfer Coefficients (cm 2 /hr) DAT 1 Site Predicted DFR 2 (ug/cm 2 ) Chemical

Specific Dermal Dose 3 (mg/kg/day) Chemical

Specific MOE 4

Berry, low Low

- growing

berries 1,900 (irrigation) 0 CA 0.77 0.075 310
NY 0.38 0.037 630 Vegetable,
root Bulb vegetables,

ginseng 4,200 (hand weeding) 0 CA 0.77 0.16 140 NY 0.38 0.081 250

Vine trellis Small fruit, vine

climbing 19,300 (girdling, turning) 0 CA 0.21 0.21 110

1 0.17 0.17 140 1. DAT = Days after treatment 2. Predicted DFR residuesPyrimethanil Human

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### Page 30 of 36 3. Chemical

- Specific Dermal Dose = [DFR (ug/cm 2 ) x Tc (cm 2 /hr) x 0.001 mg/ug x 8 hrs/day x dermal

- absorption factor (51%)] body weight (80 kg) 4. Chemical

- Specific MOE = NOAEL (23.1 mg/kg/day)/Adjusted Dermal Dose (mg/kg/day).



### Inhalation : Based on the Agency's current practices, a quantitative occupational post

- application inhalation exposure assessment was not performed for pyrimethanil at this time primarily because it has a low acute inhalation toxicity (Toxicity Category IV), has a low vapor pressure (<1 x 10 - 7 

### torr at 25oC), and is applied at a low use rate (0.70 lb ai/A)

. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

application activities in previously treated areas. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFR A Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final r eport on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriat e, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may r evisit the need for a quantitative occupational post

- application inhalation exposure assessment for pyrimethanil.

8 .3 Restricted Entry Interval (REI)

Short

- and intermediate

- term post

- application risks were not a concern on day 0 (12 hours following appl ication) for all post

- application activities, except for girdling, tying, and turning table grapes. For all other applications, the REI is based on the acute toxicity of pyrimethanil. Pyrimethanil is of low acute toxicity by oral, dermal, and inhalation routes (Acute Toxicity Categories III and IV), a slight eye irritant, not irritating to the skin, and not a dermal sensitizer

. Acute Toxicity Category III and IV chemicals via these routes are supported by a 12

- hour REI under the Worker Protection Standar d (WPS)

.

9 .0 Data Needs and Label Recommendations

9 .1 Toxicology

A 90

- d ay inhalation study (870.3465 )

9 .2 Residue Chemistry

Adjuvants were not used in any of the submitted residue field trials. Since adjuvants were not used in the submitted residue field trials, the label should prohibit such uses on ginseng; onion, bulb, subgroup 3

- 07A ; onion, green, subgroup 3

- 07B; low

- growi ng berry 13

- 07G crop subgroup; or small fruit vine climbing subgroup 13

- 07F, except fuzzy kiwifruit. A summary of the recommended tolerances along with recommendations for commodity definitions are present ed in Appendix C. The petitioner is required to submit a revised Section F to refl ect the recommendations in Appendix C

.Pyrimethanil Human

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### Page 31 of 36 9 .3 Occupational and Residential Exposure

The label should be amended to specify the use of chemical

- resistant headgear for overhead exposure. RD sh ould ensure the appropriate PPE is listed on the label.

Appendix A: Toxicity Profile Tables. Appendix B: Metabolism Assessment. Appendix C: Tolerance Summary for Pyrimethanil.

RDI: RAB1 review (11

- JAN

- 2012); G. Kramer ( 09

- JAN

- 2012); D. Vogel (11

- JAN

- 2012) J. Tyler:S10943:PY1:(703)

- 851

- 5825(7509P)Pyrimethanil Human

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### Page 32 of 36 Appendix A: Toxicity Profile Tables

.

Table A.1. Acut e Toxicity Profile

– Pyrimethanil

. Guideline No./Study Type MRID No. Results Toxicity Category 870.1100/Acute oral toxicity 43345002 LD 50 = 4149 mg/kg, M 5971 mg/kg, F III

870.1200/Acute dermal toxicity 43345003 LD 50 >5000 mg/kg IV 870.1300/Acute inhalation toxicity 43301604 LC 50 >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.2. 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%), cholester ol, 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) 43301 620 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 weight , 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/da y

. 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, neutrop hils, 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.Pyrimethanil Human

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### Page 33 of 36 Table A.2. Toxicity Profile for Pyrimethanil.
Guideline No./Study Type MRID, (year)/ Classification/Doses Results

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 mos], 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 abe rration 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.

87 0.5395 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) unacceptable/Guideline (inadequate dosing) 0, 60, 600, 6000 ppm 0/0, 4/4.6, 38.7/44.3, 391.9/429.9 mg/kg/day [M/F] NOAEL = 44.3 mg/kg/day [F] LOAEL = 429.9 mg/kg/day [F], >391.9 mg/kg/day [M] based on body weight (8%), body weight gain (21%), food consumption (9

- 15%) [F]. No effects in m ales.Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 34 of 36 Table A.2. Toxicity Profile for Pyrimethanil.
Guideline No./Study Type MRID, (year)/ Classification/Doses Results

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 th e 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 wa s 91%

. Detec table 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 phen ols 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% de rmal

- 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

.Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 35 of 36 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.Pyrimethanil Human

- Health Risk Assessment DP# 389923



### Page 36 of 36 Appendix C: Tolerance Summary for Pyrimethanil.

Tolerance Summary for Pyrimethanil.
Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition 40 CFR §180.518 (a)(1) Ginseng 2.5 1.5 Onion, bulb, subgroup 3

- 07A 0.10 0. 2 0 Onion, green, subgroup 3

- 07B 2.0 3 .0

Berry and small fruit, small fruit vine climbing subgroup, except fuzzy kiwifruit 13

- 07F 5.0 5.0 Fruit, small, vine climbing, subgroup 13

- 07F, except fuzzy kiwifruit

Berry and small fruit, low growing berry subgroup 13

- 07G 3.0 3.0 Low growing berry subgroup 13

- 07G