### UN IT ED STATES ENVIRONMENTAL PROTECTION AGENCY W ASHTNGTON, D .C. 20460

OFF I CE OF C HEMICAL SAFETY AND P OLLU TION PREVENTION



### MEMORANDUM

Date:

S ubject:

P C Code: Deci s i on Nos.: P et i tion Nos.: 

### 22-SEP-2015

Pyrimethanil. Human Health Ri s k Assessme nt for Propo se d Uses on Gre e nhou se -Grown Cucumbers

, Tomato Subgro up 8-IOA

, Lemon S ubgroup 10- l OB

, Orange Subgroup I 0-1 OA

, Grapefruit Subgroup l 0-1 OC, Pome Fruit Group 11-10

, Stone Fruit Group 1 2- 12 Ca n eberry Subgroup 13-07 A

, and Bushberry Subgroup l 3-07B.

28820 1 4 9239 1 & 4 93 5 05 4F829 1 & 4E8302 DP B arcode: Registration Nos.: Regulatory Ac ti o n : 0428262 264-788 & 43813-32 Section 3 Ri s k A ss essme n t Type: Single Chemical/Aggregate Assessment None Case No.: 7059 TXR No.: MRID No.:



### From:

Through:

To: No n e


### George F. Kramer
, Ph.D.

, Senior Chemis CASNo.: 40CFR 53 112-28- 0 § 1 80.5 1 8



### Jennifer R. T y ler

, Chemist /} / Anwar Y. Dunbar

, Ph.D

. , Ph ar m aco l og i st

## ~**~Y~** Ri s k Assessment Branch 1 ( RAB I )/ Health

### Effectffii**ion** ( HED; 7509P)

Thur s ton G. Morton
, Acting Branch C hief !"'/} /

# !~ 

# /r

RAB l / HED (7509P)

# ~V/)/'t 

# /

Hope Johnson/Cynthia Giles-Parker

, RM 2 1 Registration Division (RD; 7505P)

The HED of the Offic e of P es ticide Programs (OPP) i s charged with est imating the risk to human health from exposure t o p es ticides. The RD of OPP ha s requested that HED eva l uate hazard and
expos ure data and co nduct di e tar y, occupational

, residential and aggregat e exposure assessments , as needed

, to esti m ate th e ri s k to human health that will result from propo se d and curren tl y

r eg i s tered uses of th e active ingredient 

### (ai) p y rim e thanil ( 4

, 6-dimethyl- N -ph e n y l-2-
pyr imidinamin e). Th e Int erregional Res e arch Project No. 4 (IR-4) and Bay e r CropScience have

s ubmitted petitions for th e use of pyrim et h anil o n c ucumbers (greenhouse-grown)

, tomato

s ubgroup 8-1 OA

, lemon s ub g roup 10-1 OB

, orange s ub gro up 10-1 OA, g rap efr uit subgroup 10- l OC

, pome fruit g roup l l -10, s tone fruit group 12-1 2, caneberry s ubgroup 1 3-07 A

, and bushberry s ub grou p l 3-07 B. The risk assessm e nt , residue chemistr y review

, and dietary
expos ure assessment were conducte d b y Georg e Kramer ( RABI ); occupational/res idential
expos ure assessment were pro v ided b y J enn i fer T y l e r ( RAB I ); th e hazard characterization b y Anwar Dunbar ( RAB I ); and the drinking water assessment b y Jame s W o lf of the E n v iron.m ental Fate and Effects Divi s ion ( EFED )

.



### NOTE : A human h ea lth ri sk assessme nt was comp l eted on 28-JAN-2015 by HED (Memo

, J. Ty l er e l al.

, 

### D417167). In th e present m emo, di e tary , occupat i onal, and aggregate risks were rePa ge I of32Pyrimethanil Human Health Risk Assessment D P# 428262

eva lu ated ba se d o n th e addition of the propo sed ne w u ses to th e p y r i methanil use pattern.



### Table of Contents 1.0 Exec uti ve S umm ary 2.0 HED R eco mmendations 2.1 Data Deficiencies / Cond ition s of Registration 2.2 Tole r ance Co nsiderations 3.0 Introduction 3.1 C h e mical I den tit y 3. 2 P h ysica l /C hemical Cha ract er i stics 3.3 P es ti c i de Use Pattern 3.4 An ti cipa t e d Exposu r e Pathwa ys 3.5 C onsideration of Environmental Ju s tic e 4.0 Ha za rd C h aracte ri za tion and Do se Re s pon se Assessment 4. 1 Summaty of Toxicological Effects 4.2 Safetyfac tor for Infants and Ch ildr en (F QPA Safety Factor) 4.3 Toxicity E ndpoint and POD Selection s 5.0 Di e t ary Ex p osure and Risk Assessme nt 5.1 R es i dues of Conce r n Su mm01 y and Rational e 5.2 Food Residu e Profil e 5.3 Wate r R esidue Profile 5.4 Diet01y Ri sk Assessmen t 6

. 0 R es id entia l (No n-O ccupatio nal ) Exposure/Risk C har ac t erizat i o n 6.1 Sp ra y Drift 6.2 R es id en ti al Bystander Post-Application Inhalation Exposure 7 .0 Agg r ega t e Ex posure / Risk Charac t erizatio n 7. 1 Ac ut e Aggrega t e Ri sk 7.2 Sho rt- and Int e rm ed iat e-Te rm Aggrega t e Ri sk 

### 7. 3 Chronic Aggregate Ri sk 

### 7. 4 Ca nc e r Ri sk 8.0 C umulati ve Ri s k Character i zation/Assessme nt 9.0 Occupatio n a l Exposure / Risk Path way 9. 1 Handl e r Exposu r e and Ri sk Estimates 9.2 Po s t -appl i ca tion Exposure and Ri sk Est im a t es 9.3 R es tri c t ed -Entry Interval (REI) 1 0.0 R efe r e nce s A pp endix A: To x icity P rofile Tabl es. A p pendix B: Metabo li sm Assess ment.

Pa ge 2 of32 3 

### 6 6 6 

### 8 8 9 

### 9 JO 

### 10 10 

### JI
12 

### 13 16 16 

### 16 1 7 18 1 9 19 20 20 20 21 21 21 21 2 1 21 

### 26 27 

### 28 

### 29 32P yrimethanil Human Health Risk Assessment DP# 428262

Page 3 of 32 

### 1.0 Executive Summary

IR

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

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

- 788), an aqueous suspension

- concentrate (SC) formulation containing 5.0 lbs/gal of pyrimethanil on the cucumbers (greenhouse

- grown), tomato subgroup 8

- 10A, lemon subgroup 10

- 10B, orange subgroup 10

- 10A, grapefruit subgroup 10

- 10C, pome fruit group 11

- 10, and stone fruit group 12

- 12 (PP# 4E8302)

. . No new data were submitted to support tolerances on tomato s ubgroup 8

- 10A, lemon subgroup 10

- 10B, pome fruit group 11

- 10, orange subgroup 10

- 10A, grapefruit subgroup 10

- 10C, and stone fruit group 12

- 12 . The petitioner has requested that existing tolerances be expanded to their respective crop groups or crop subgro ups. Bayer CropScience has submitted a petition for the use of Scala ® 

### SC Fungicide on caneberry subgroup 13

- 07A and bushberry subgroup 13

- 07B (PP# 4F8291)

. Pyrimethanil is an amino acid synthesis inhibitor that inhibits the secretion of enzymes necessa ry for fungal infection. Pyrimethanil is currently registered in the U.S. for use on several raw agricultural commodities (RACs) . Permanent tolerances have been established for residues of pyrimethanil per se in/on plant commodities at levels ranging fro m 0.05 ppm in/on vegetable, tuberous and corm, subgroup 1C to 150 ppm in/on citrus oil [40 CFR §180.518(a)(1)]. Tolerances have also been established for pyrimethanil residues and its metabolite 4

- [4,6

- dimethyl

- 2

- pyrimidinyl)amino]phenol in fat (0.01 ppm) , kidney (2.5 ppm) and byproducts (except kidney) (0.01 ppm) of cattle, goats, horses and sheep and in milk (0.05 ppm) [40 CFR §180.518(a)(2)]. There are no registered or proposed residential uses.

Proposed New Use s : The proposed new use on greenhouse

- grown cucumbers is as a foliar application three times per season at 0.70 lbs ai/A with a maximum of 2.1 lbs ai/A/season and a preharvest interval (PHI) of 1 day. The proposed new use to caneberries and bushberries is as a foliar application 2

- 4 times per season at 0.35

- 0.70 lbs ai/A with a maximum of 1.4 lbs ai/A/season and a PHI of 1 day.

Toxicity Profile : Pyrimethanil is of low acute lethality by the oral, dermal, and inhalation routes. It is a slight eye irritant, is not irritating to the skin, and it is not a dermal sensitizer. A single oral dose of 1000 mg/kg produced a number of acute signs of neurotoxicity, including ataxia, dilated pupils, and decreases in motor activity, hind limb grip strength, and body temp erature. However, there was no evidence of neurotoxicity with repeated dosing in a subchronic neurotoxicity study in rats. The major target organs of repeated oral exposure were the liver and the thyroid. These effects were accompanied by decreased body weight. R eproductive toxicity

was not observed, and developmental effects (e.g., decreased fetal weight, retarded ossification, extra ribs) were observed only at maternally toxic doses. Special short

- term exposure studies demonstrated increased liver ur idine diphosphate glucuronosyl transferase (UDPGT) activity leading to decreases in thyroid hormones (T3, T4) and compensatory increases in thyroid

stimulating hormone (TSH) in adult rats. Thyroid adenomas were seen in rats following long

term exposure, a nd it was concluded that they were mediated via disruption of the thyroid/pituitary axis. There were no concerns for mutagenicity.

Dose

- response and Food Quality Protection Act ( FQPA ) Assessment : The pyrimethanil risk assessment team has evaluated the h azard and exposure data; and, based on these data, recommended that the FQPA Safety Factor (SF) be reduced to 1X. The toxicological database is complete and there is no evidence of increased offspring susceptibility. The exposure databases are sufficient to determine the nature/magnitude of the residue in food and dietary analyses areP yrimethanil Human Health Risk Assessment DP# 428262

Page 4 of 32 

### unlikely to underestimate risk of exposure from pyrimethan il. Although there is evidence of potential neurotoxicity in the acute neurotoxicity study, concern is low since effects were only seen at the limit dose, effects are well

- characterized with clearly established no

- observed adverse

- effect level/lowest

- obse rved adverse

- effect level (NOAEL/LOAEL) values, and the selected endpoints are protective for the observed effects.

Residue Chemistry : The qualitative nature of the pyrimethanil residue in plant commodities is adequately understood based on acceptable metabolism studies in lettuce, grapes, and tomatoes. The HED Metabolism Assessment Review Committee (MARC) has determined that for risk assessment and tolerance expression, parent only is the residue of concern. The data

- collection method used to generat e pomegranate residue data in conjunction with magnitude of the residue study associated with this petition was a high

- performance liquid chromatography (HPLC) with tandem mass spectroscopy (MS/MS) Method 140/01/012. There are also adequate methods availa ble to enforce tolerances for residues of pyrimethanil in/on crops

. The submitted field trial residue data for the subject crops are adequate. The field trial data reflect the proposed use pattern, an adequate number of trials were conducted, and samples were analyzed for the residue of concern using validated data

- collection methods.

Drinking Water Exposure and Risk : Su rface and ground estimated drinking water concentrations (EDWCs) for combined residues of pyrimethanil (parent + 2

- amino

- 4,6

- dimethyl pyrimidine) were generated by EFED using the Surface Water Concentration Calculator (SWCC) and Pesticide Root Zone Model

- Ground Water (PRZM

- GW) models, respectively. In this assessment, the 1

- in

- 10

- year annual average surface water concentration (27.9 ppb ) and the 1

- in

10

- year acute peak surface water concentrations (156 ppb) were used for chronic and acute dietary exposure assessments, respectively.

Dietary Exposure and Risk : Acute and chronic dietary exposure assessments were conducted using the Dieta ry Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16. The acute and chronic dietary analyse s assumed default processing factors (as necessary), empirical processing factors for orange and apple juice, tolerance

- level residues, 100% crop treated ( CT ) for all commodities and EDWCs for direct and indirect water sources. The resulting acute dietary risk esti mates (f ood and drinking water) were ≤ 40 % of the a cute population

- adjusted dose (aPAD) and are not of concern to HED (<100% aPAD; children 1

- 2 years old were the most highly exposed population subgroup). The resulting chronic dietary risk estimates (f ood and drinking water) were ≤ 80 % of the chronic population

adjusted dose ( cPAD ) and are not of concern to HED (<100% cPAD; children 1

- 2 years old were the most highly exposed population subgroup).

Residential Exposure : Currently, there are no registered/p roposed 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 expo sures, the acute and chronic aggregate risk assessment s ar e equal to the acute dietary and chronic dietary estimate s (food and water only) , respectively

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

.P yrimethanil Human Health Risk Assessment DP# 428262

Page 5 of 32 

### Occupational Exposure/Risk : Based on the anticipated use patterns and current labeling, short

and intermediate

- term dermal and inhalation exposures occupational handler exposures are expected from the proposed uses. A margin of exposure (MOE) ≥ 100 is adequate to protect occupational pesticide handlers from dermal and inhalation exposures. Risk estimates for all scenarios are not of concern at either baseline or with the additio n of person al

- protective equipment (PPE; up to and including label

- prescribed PPE which includes chemical

- resistant gloves and headgear), except for applying broadcast sprays via mechanically

- pressurized handguns to greenhouse

- grown cucumbers. For this sc enario, risk estimates are not of concern assuming a double layer of clothing and chemical

- resistant gloves are worn, which is the highest level of PPE for which exposure data are available for this scenario. Exposure data are not available to assess the impact of chemical

- resistant headgear for handheld equipment.

HED expects that post

- application dermal exposure will occur since pyrimethanil is applied as a foliar spray. An occupational post

- application dermal exposure assessment was conducted previo usly in conjunction with a request for the use of pyrimethanil on small fruit, vine climbing 13

- 07F and low growing berry 13

- 07G (Memo, J. Tyler, 0 8

- MAY

- 2012; D389987) . The post

application dermal exposures in the 08

- MAY

- 2012 assessment were calculated for post

application activities with the highest (i.e., most conservative) transfer coefficients (TCs) (girdling and turning of grapes). In addition, the proposed use pattern for caneberry crop group 13

- 07A, bushberry crop subgr oup 13

- 07B are identical to that of small fruit, vine climbing 13

- 07F and low growing berry 13

- 07G. Therefore, the 5/8/2012 post

- application dermal exposure assessment is adequate to cover the proposed uses on caneberry

, crop group 13

- 07A

, and bushberry

, crop subgroup 13

- 07B. In that assessment, the 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.

For greenhouse cucumbers, the occupationa l post

- application risk estimates are of concern (i.e., MOEs < 100) on the day of application (12 hours after application) for high

- contact activities such as hand harvesting, pinching, hand pruning, tying, etc. These activities are not of concern at 48 ho urs after application. For low

- contact activities (such as transplanting and irrigation), risk estimates are not of concern on the day of application.

Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhal ation exposure assessment was not performed for pyrimethanil at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for pyrimethanil.

The Worker Protection Standard (WPS) for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)]

.

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 1289 8, "Federal Actions to Address Environmental Justice in Minority Populations and Low

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

. Review of Human Research : This exposure/risk assessment re lies in part on data from studies inP yrimethanil Human Health Risk Assessment DP# 428262

Page 6 of 32 

### which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Reentry T ask Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies

, that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.

2.0 HED Recommen dations

Pending submission of a revised Section s B and F, HED concludes that the toxicologi cal, residue chemistry and occupational/residential databases support a Section 3 registration and establishment of the tol erances listed in Section 2.2.2

.

2.1 Data Deficiencies/Conditions of Registration

No additional data are required to support the proposed use.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

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

pesticides.eu/library/docs/fv/CRLFV_Multiresidue_methods.pdf ).

2.2.2 Recommended Tolerances

Table 2.2.2. Tolerance Summary for Pyrimethanil.

Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition
40 CFR §180.518 (a)(1)
Cucumber 1.5 1.5 Orange subgroup 10

- 10A 10 10 Harmonization with Canada. Fruit, citrus, group 10

- 10 Lemon subgroup 10

- 10B 11 Grapefruit subgroup 10

- 10C 10 Fruit, pome, group 11

- 10 14 15 Harmonization with Codex. Fruit, stone, group 12

- 12 10 10 Tomato, subgroup 8

- 10A 0.50 0.50 Caneberries subgroup 13

- 07A 15.0 15 Caneberry, subgroup 13

- 07A Bushberries subgroup 13

- 07B 8.0 8.0 Bushberry, subgroup 13

- 07BP yrimethanil Human Health Risk Assessment DP# 428262

Page 7 of 32 

### Note to RD : With the establishment of these tolerances, the following tolerances should be removed from 40 CFR §180.518 (a)(1): "Fruit, citrus, group 10, except lemon, postharvest," "Lemon, preharvest and postharvest," "Fruit, pome, group 11 (pre

- harvest and post

- harvest)," "Fruit, stone, group 12," and "Tomato." Also, the tolerance in 40 CFR §180.518(a)(1) for residues of pyrimethanil in/on onion, bulb, subgroup 3

- 07A (2.0 ppm) does not match the recommended tolerance from a previous assessment (Memo, Tyler et al. , 22

- MAY

- 2013; D389923). HED recommended for a to lerance of 0.20 ppm for residues of pyrimethanil in/on onion, bulb, subgroup 3

- 07A.

2.2.3 Revisions to Petitioned

- For Tolerances

For some commodities, the proposed tolerance levels differ slightly from those being recommended by HED. In the case of pome fruit, HED is recommending a higher tolerance level in order to harmonize with the established Canadian maximum residue limit (MRL). In the case of citrus fruit, HED is recommending for a single crop

- group tolerance, instead of the individual subgroups i n order to harmonize with the established Canadian MRL. In addition, HED is recommending a change in the numerical expression of the caneberry subgroup 13

- 07A tolerance value in order to conform to current HED policy on significant figures.

2.2. 4 Inter national Harmonization

For plant commodities, the U.S., Canadian, and Codex residue definitions are harmonized. The proposed tolerances for residues in/on caneberry, crop subgroup 13

- 07A and bushberry, crop subgroup 13

- 07B are harmonized with the establi shed Canadian MRLs

. The U.S. tolerance for residues in/on tomato ( 0.50 ppm for the tomato subgroup 8

- 10A) is harmonized with the Canadian MRL, while the Codex MRL is established at a higher level (0.7 ppm). However, Bayer CropScience has requested that E PA not harmonize with Codex in order to prevent the creation of a trade barrier with Canada. The U.S. and Codex tolerances/MRLs for residues of pyrimethanil in/on citrus are not harmonized. Residues in the U.S. residue trials (maximum of 8.43 ppm) were h igher than the Codex MRL of 7 ppm, precluding harmonization. The U.S. and Canadian tolerances/MRLs for residues of pyrimethanil in/on citrus are harmonized, except for the lemon subgroup 10

- 10B. In order to harmonize with Canada, HED recommends that the U.S. tolerance for residues in/on the lemon subgroup 10

- 10B be reduced from 11 to 10 ppm. As this value is the same as that recommended for the other citrus subgroups, a single tolerance of 10 ppm is appropriate for residues in/on fruit, citrus, group 10

- 10. The U.S. and Codex tolerances/MRLs for residues of pyrimethanil in/on stone fruit are not harmonized. Residues were higher in the U.S. residue trials (maximum of 6.5 ppm) than the Codex MRLs of 2

- 4 ppm, precluding harmonization. The U.S. and Canadia n tolerances/MRLs for residues of pyrimethanil in/on stone fruit are harmonized at 10 ppm. The U.S. and Codex tolerances/MRLs for residues of pyrimethanil in/on the pome fruit group are not harmonized. As the difference in values is minimal, HED recommen ds that the U.S. tolerance be increased from 14 to 15 ppm in order to harmonize with Codex. There are currently no established Codex, Canadian, or Mexican MRLs for pyrimethanil in/on cucumber.

2.3 Label Recommendations

Short

- and intermediate

- term pos t

- application risk estimates were not a concern on day 0 (12 hours following application) for low

- contact activities, such as transplanting and irrigation.P yrimethanil Human Health Risk Assessment DP# 428262

Page 8 of 32 

### However, there were risk estimates of concern related to high

- contact activities up until 48 hours after application; therefore, HED is recommending that the REI be revised on the label to address th e se concerns. In addition

, there are risk estimates of concern for applicators mixing/loading/ applying broadcast sprays via a mechanically

- pressurized handgun to greenhouse

- grown cucumbers assuming the label

- prescribed PPE
, which included chemical

resistant gloves and headgear

. For this scenario, risk estimates are not of concern assuming a double layer of clothing and chemical

- resistant gloves are wor n

. Even though the label also requires chemical

- resistant headgear , there are no exposure data available to assess the reduction in exposure for handheld equipment. HED is thus recommending that the mechanically

pressurized handgun application scenario f or greenhouse

- grown cucumbers be revised on the label to address these concerns.

3 .0 I ntroduction

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

Pyrimethanil does not exhibit cross

- resistance to sterol

- inhibitors, dicarboximides, benzimidazoles, quinone outside inhibitors, or phenylamides, but may exhi bit cross

- resistance in certain plant pathogenic fungi including anilinopyridine (AP) compounds such as cyprodinil and mepanipyrim.

3.1 Chemical Identity

Table 3. 1 . Test Compound Nomenclature. Chemical structure

Common name Pyrimethanil IUPAC name N

- (4,6

- dimethylpyrimidin

- 2yl)aniline CAS name 4,6

- dimethyl

- N

- phenyl

- 2

- pyrimidinamine CAS # 53112

- 28

- 0 End

- use product/(EP) Scala ® SC Fungicide (EPA Reg. No. 264

- 788)P yrimethanil Human Health Risk Assessment DP# 428262

Page 9 of 32 

### 3.2 Physical/Chemical Characteristics

Table 3.2. Physicochemical Properties of the Technical Grade Test Compound. Parameter Value References Melting point 96 o C

The Pest Manual. British Crop Protection Council. Twelfth Edition, Editor: C.D.S. Tomlin. pH (water solution at 25 o C) 6.1 Specific gravity at 20 o C 1.15 Water solubility (g/l at 25 o C) 0.121 Solvent solubility (g/l at 20 o C) acetone

– 389, ethyl acetate

– 617, methanol

– 176, methylene chloride

– 1000, n

- hexane

– 23.7, toluene

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

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



### 3.3 Pesticide Use Pattern

Table 3. 3 provides a summary of the proposed new use patterns. Pyrimethanil is currently registered for use on tomato; citrus fruit, group 10, except lemon (postharvest); lemon (preharvest and postharvest); pome fruit group 11 (preharvest and postharvest); and stone fruit group 12 (preharvest and postharvest) . The pe titioner has requested that the existing uses be expanded to tomato subgroup 8

- 10A, lemon subgroup 10

- 10B, pome fruit group 11

- 10, orange subgroup 10

- 10A, grapefruit subgroup 10

- 10C, and stone fruit group 12

- 12 . The existing directions for use for these c rops are unchanged, other than the additional crops covered by the updated groups/subgroups. Detailed reviews of the directions for use for these crops can be found in previous HED reviews (D361363, 08

- APR

- 2009, G. Kramer; D347247, 17

- JUL

- 2008, G. Kramer; D369788, 08

- DEC

- 2009 , G. Kramer; and D284001, 12

- JAN

- 2004, J. Morales and G. Kramer).

Table 3. Summary of Directions for Use of Pyrimethanil. Applic. Timing, Type, and Equip. Formulation

(EPA Reg. No.) Applic.

Rate (lbs ai/A) Max. No.

Applic. per Season Max. Seasonal

Applic. Rate (lbs ai/A) PHI

(days) Use Directions and

Limitations
Cucumber

Greenhouse only Scala ® SC

Fungicide (EPA Reg. No. 264

- 788) 0.70 3 2.1 1 Retreatment interval: 7

- 14 days.

Small Berries (caneberries and bushberries)

Ground or air Scala ® SC

Fungicide (EPA Reg. No. 264

- 788) 0.35

- 0.70 4 1.4 0 Retreatment interval: 7

- 14 days.



### HED Conclusions : The submitted label is adequate to allow evaluation of the cucumber, caneberry, and bushberry residue data relative to the new proposed uses

.P yrimethanil Human Health Risk Assessment DP# 428262

Page 10 of 32 

### 3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new use s of pyrimethanil on cucumber, caneberry, and bushberry . Humans may be exposed to pyrimethanil in food and drinking wate r since pyrimethanil may be applied directly to growing crops, and applications may result in pyrimethanil reaching surface and ground water sources of drinking water. There are no r egistered residential uses of pyrimethanil ; therefore, human exposure in residential or non

- occupational settings is not expected

. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is also a potential for post

- application exposure for workers re

- entering treated fields.

This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of pyrimethanil and considers the existing registered uses as well for the dietary and residential exposure assessments.

3.5 Consideration of Envir onmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf ) . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA); 2003

- 2008 and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based

on a ge, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in deve lopment as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4 .0 Hazard Cha racterization and Dose Response Assessment

The toxicology database for pyrimethanil is complete. T he HED HASPOC looked at all existing hazard and exposure data, and current use patterns for pyrimethanil; and, using a weight

- of

evidence (WOE) approach, co ncluded that subchronic inhalation and dermal toxicity studies are not required for pyrimethanil at this time (Memo, J. Van Alstine, 0 8

- FEB

- 2013; TXR# 0056470).P yrimethanil Human Health Risk Assessment DP# 428262

Page 11 of 32 

### 4.1 Summary of Toxicological Effects

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

Through the oral route, pyrimethanil was well absorbed from the gastrointestinal tract. Following a single oral dose of 10 mg/k g, pyrimethanil was eliminated within 24 hours, and the major route of elimination was via the urine (  72%). Approximately 17

- 18% of the dose was eliminated via the feces. Detectable levels of pyrimethanil were found in the adrenals, blood, kidney, liver , spleen, and thyroid less than 24 hours post dosing. The chemical was detected only in the liver, kidney, thyroid, and blood at 24 hours post dose. Four days post

- dose, detectable levels of the chemical were found only in the liver, kidney, and thyroid. Regarding the total detectable levels per tissue, the highest levels of the chemical were detected in the liver in both sexes. There were no significant sex differences in metabolites generated.

Pyrimethanil was well absorbed through the dermal route. In a dermal penetration study, the compound was applied to the shaved dorsal skin of male Sprague Dawley rats. Total absorbed dose (based on the sum of urine, feces, cage wash, blood, carcass, and non

- treated skin) for the low, intermediate, and high do ses at 10 hours post

- treatment were 37.22, 35.77, and 20.39%, respectively. The “potentially absorbable” dose (combined tape stripping excluding first two tape strips and treated skin after tape stripping) for low, intermediate, and high dose at 10 hours post

- treatment was 13.95, 5.55, and 4.80%, respectively. Absorption increased with greater exposure time, and the percent of dose absorbed increased with lower doses. The value ultimately used for risk assessment was calculated by combining the absorbed dose (37.22%) with the potentially absorbable dose (13.95%) from the study, which would be approximately 51%. Use of the 51% dermal absorption value for dermal exposure assessment for human risk is considered conservative and protective.

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

Special short

- term exposure studies demonstrated increased liver UDPGT activity leading to decreases in thyroid hormones (T3, T4) and compensatory increases in TSH in adult rats. Thyroid adenomas were seen in rats following long

- term exposure, and it was concluded that they were mediated via disruption of the thyroid/pituitary axis. In mice there was no evidence of thyroid tumors up to the highest dose tested. There are no concerns for mutagenicity.

The t hyroid has been shown to be one of the target organs in adult animals for pyrimethanil

induced toxicity thus raising a potential concern for thyroid toxicity in the young. However, HIARC previously concluded that there is no concern for thyroid toxicity i n the young based on the following weight of evidence considerations : the effects seen on the thyroid and the liver inP yrimethanil Human Health Risk Assessment DP# 428262

Page 12 of 32 

### the database, while treatment

- related, are not severe in nature; and in each of the studies that show an effect on thyroid hormone levels , as well as in all studies chosen for points of departure ( PODs ) selection, there is a wide dose spread (~10

- fold difference between NOAELs and LOAELs) which provides a measure of protection for any potential effects linked to decreased thyroid hormone le vels in offspring.

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

The pyrimethanil risk assessment team has evaluated the hazard and exposure data and, based on these data, recommend ed that the FQPA SF be reduced to 1X. The toxicologica l is complete and there is no evidence of increased offspring susceptibility. The exposure databases are sufficient to determine the nature/magnitude of the residue in food and dietary analyses are unlikely to underestimate risk of exposure from pyrimetha nil. Although there is evidence of potential neurotoxicity in the acute neurotoxicity study, concern is low since effects were only seen at the limit dose, effects are well

- characterized with clearly established NOAEL/LOAEL values, and the selected endpoi nts are protective for the observed effects

.

4.2.1 Completeness of the Toxicology Database

The toxicology database for pyrimethanil is adequate for FQPA consideration. The following studies are available: d evelopmental toxicity studies in rats and rabbi ts, a two

- generation reproduction toxicity study, and both acute and subchronic neurotoxicity studies.

4.2.2 Evidence of Neurotoxicity

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

. The selected endpoints for pyrim ethanil protect for any p otential signs of neurotoxicity ; t herefore, t he concern for neurotoxicity is low

.

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

There is no evidence of qualitative or quantitative increased susceptibility following pre

- /post

natal exposure to pyrimethanil in the developmental toxicity studies in rats and rabbits or in the
two

- generation reproduction study in rats.

4.2.4 Residual Uncertainty in the Exposure Database

There are no residual unc ertainties with respect to exposure data. The dietary food exposure assessment utilizes tolerance

- level residues (established or recommended) and 100% CT for all proposed/established commodities. By using these assumptions, the acute and chronic
exposure s/risks will not be underestimated. The dietary drinking water assessment utilizes water concentration values generated by models and associated modeling parameters that are designed to provide conservative, health

- protective, high

- end estimates of water concentrations that will not likely be exceeded. There are no residential uses.P yrimethanil Human Health Risk Assessment DP# 428262

Page 13 of 32 

### 4.3 Toxicity Endpoint and P O D Selections

The selected toxicity endpoints are s ummarized in Tables 4.3.1 and 4.3.2

. Acute Dietary Endpoint (Females Age 13

- 49) : The endpoint used for establishing the aPAD for females 13

- 49 years of age was selected from the prenatal developmental toxicity study in rabbits. An aPAD of 0.45 mg/kg/day was derived from a developmental NOAEL of 45 mg/kg/day and a 100

- fold factor th at included 10X for inter

- species extrapolations, 10X for intra

- species variations, and 1X FQPA SF. The endpoint of concern is a developmental effect characterized as increases in fetuses with 13 thoracic vertebrae and 13 pairs of ribs observed at 300 mg/ kg (LOAEL). These developmental anomalies are presumed to be the result of a single oral dose following in utero exposure; and, therefore, are relevant to pregnant females.

Acute Dietary Endpoint (General U.S. Population) : The endpoint used for establis hing the aPAD for the general population including infants and children was selected from the acute neurotoxicity study in rats. An aPAD of 1.0 mg/kg/day was derived from a NOAEL of 100 mg/kg/day and a 100

- fold factor that included 10X for inter

- species extrapolations, 10X for intra

- species variations, and a 1X FQPA SF. Effects at the LOAEL of 1000 mg/kg (highest dose tested) included decreased motor activity, ataxia, decreased body temperature, hind limb grip strength, and dilated pupils. The effects w ere seen after a single oral dose and thus appropriate for this exposure scenario and the population of concern.

Chronic Dietary Endpoint (All Populations) : The endpoint used for deriving the cPAD was selected from a chronic toxicity study with rats. The cPAD was derived from a NOAEL of 17 mg/kg/day and a 100

- fold factor that included 10X for inter

- species extrapolations, 10X for intra

- species variations, a nd 1X FQPA SF. The LOAEL of 221 mg /kg/day is based on increased serum cholesterol and gamma glutamyl transferase (GGT), increased relative liver/body

- weight ratios, necropsy, and histopathological findings in the liver and thyroid. The endpoint of conce rn was seen following repeated oral exposure in the most sensitive species; and, thus, is appropriate for assessing potential risk via chronic dietary exposure to pyrimethanil.

Incidental Oral [short (1

- 30 days)

- and intermediate (1

- 6 months)

- term] : The re are no residential uses for pyrimethanil. Therefore, an incidental oral endpoint was not selected

. Dermal [short (1

- 30 days)

- and intermediate (1

- 6 months)

- term] : The pyrimethanil database does not contain a dermal toxicity study. Therefore, the Ag ency has selected an oral NOAEL of 23 mg/kg/day for short and intermediate term dermal risk assessments. The endpoint of concern is based on decreased body weight s observed in the rat two

- generation reproduction toxicity study at the LOAEL of 294 mg/kg/da y. Since an oral dose was selected a dermal absorption factor of 51% should be used for route

- to

- route extrapolation which yields a dermal equivalent dose of 45 mg/kg/day (23 mg/kg/day ÷ 0.51

, DAF = 45 mg/kg/day). The LOC for occupational dermal exposure s is for MOEs less than 100 (10X for inter

- species extrapolation and 10X for intra

- species extrapolation). This study protects for the effects in the pyrimethanil hazard database. It is appropriate for the route as well as the durations of exposure in oc cupational settings.

Inhalation [short (1

- 30 days)

- and intermediate (1

- 6 months)

- term] : An inhalation toxicity study was not submitted. The short

- and intermediate

- term inhalation endpoints are based uponP yrimethanil Human Health Risk Assessment DP# 428262

Page 14 of 32 

### the parental effect of decreased body weights observed in the two

- generation reproduction toxicity study. The NOAEL is 23.1 mg/kg/day. This endpoint is appropriate for the duration of exposure and the populations of concern. Inhalation exposure is assumed to be equivalent to oral exposure. The LOC for occupational inhalation exposures is for MOEs less than 100 (10X for inter

- species extrapolation and 10X for intra

- species extrapolation). This study protects for the effects in the pyrimethanil hazard database. It is appropriate for the route as we ll as the durations of exposure in occupational settings.

Table 4.3.1. Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Dietary Exposure Risk Assessments. Exposure/ Scenario POD Uncertainty/FQPA Safety Factors RfD, PAD, LOC for

Risk Assessment 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 base d 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 gains; increased serum cholesterol and GGT, increased relative liver/body weight ratios, necropsy and histopathological findings in the liver and thyroid. Cancer (oral, dermal, inhalation) 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 h ormone homeostasis” (TXR#0056151, J. Rowland, 23

- DEC

- 2012 ). Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in

sens itivity 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.P yrimethanil Human Health Risk Assessment DP# 428262

Page 15 of 32 Table 4.3.2 . Summary of Toxicological Doses and En dpoints for Pyrimethani l for Use in Occupational Human Health Risk Assessments

. Exposure Scenario POD Uncertainty/FQPA Safety Factors 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 %) UF A = 10X

UF H = 10X FQPA SF = 1X 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 %) UF A = 10X

UF H = 10X FQPA SF = 1X 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

- 2012). Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk asso ciated with lower environmentally relevant human exposures. NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential varia tion in sensitivity among members of the human population (interspecies). FQPA SF = FQPA Safety Factor. MOE = margin of exposure. LOC = level of concern. a= dermal

- absorption factor, from MRID 46630101. b= Inhalation

absorption factor assumed.



### 4.3.1 Recommendation for Combining Routes of Exposures for Risk Assessment

HED notes that the same oral toxicity study was selected for assessment of short

- /intermediate

term dermal and inhalation exposures and thus the dermal and inhalation routes of exposure should be combined.

4.3.2 Cancer Classification and Risk Assessment Recommendation

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March 2005), the Cancer Assessment Review Committee (CARC) classified pyrimethanil as “ Not Likely To Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thyroid Hormone Homeostasis” (TXR#0056151, J. Rowland, 23

- DEC

- 2012 ). This decision was based on the following:

i) Treatment

- related increases in thyroid follicular cell tumors in male and fe male Sprague

Dawley rats at doses which were considered adequate to assess carcinogenicity; ii) No treatment

- related tumors were seen in male or female CD

- 1 mice at doses which were considered adequate to assess carcinogenicity; iii) There is no mutagenicity concer n and there is no evidence for thyroid carcinogenesis mediated through a mutagenic mode of action; iv) The non

- neoplastic toxicological evidence (i.e., thyroid growth, thyroid hormonal changes) indicated that pyrimethanil was inducing a disruption in the thyroid

- pituitary hormonal status. The overall weight

- of

- evidence was considered sufficient to indicate that Pyrimethanil induced thyroid follicular tumors through an antithyroid mode of action; and v) Rats are substantially more sensitive than humans are to the development of thyroid follicular cell tumors in response to thyroid hormone imbalance.

Quantification of Carcinogenic Risk : Quantification of carcinogenic risk is not required. TheP yrimethanil Human Health Risk Assessment DP# 428262

Page 16 of 32 

### CARC determined that the thyroid tumors arise through a non

- line ar mode of action and the NOAEL (17 mg/kg/day) established for deriving the c PAD is not expected to alter thyroid hormone homeostasis nor result in thyroid tumor formation.

5.0 Dietary Exposure and Risk Assessment

The residue chemistry data submitte d in support of proposed uses were evaluated by HED 22

- SEP

- 2015 (Memo, G. Kramer ; D421844 ). The drinking water assessment was completed by EFED on 14

- MAY

- 2015 (Memo, J. Wolf; D422295 ). The dietary exposure assessment was completed in a HED memorandum dat ed 22

- SEP

- 2015 ( Memo, G. Kramer ; D424861 ).

5.1 Residues of Concern Summary and Rationale

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

- amino

- 4,6

- dimethylpyrimidine).

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.

Matrix Residues I ncluded in Risk Assessment Residues I ncluded in Tolerance Expression Plants Primary Crop Pyrimethanil, per se Pyrimethanil, per se

Rotational Crop Pyrimethanil, per se Pyrimethanil, per se Livestock Ruminant Pyrimethanil + AEC614276 for muscle, fat, and byproducts. For milk, pyrimethanil + AEC614277. Pyrimethanil + AEC614276 for muscle, fat, and byproducts. Pyrimethanil + AEC614277 for milk. Poultry Not Applicable Not Applicable Drinking Water Parent (Pyrimethanil) + Degradate 1 (2

- amino

- 4,6

- dimethylpyrimidine) Not Applicable



### 5.2 Food Residue Profile

No new data were submitted to support tolerances on tomato subgroup 8

- 10A, lemon subgroup 10

- 10B, pome fruit group 11

- 10, orange subgroup 10

- 10A, grapefruit subgroup 10

- 10C, and stone fruit group 12

- 12 . The petitioner has requested that existing tolerances be expanded to their respective crop groups or crop subgroups. The residue data for caneberries and bushberries were previously submitted and reviewed under PP#8F7468 (Memo, W . Cutchin, 02

- FEB

- 2010; D372647)

.

The data

- collection method used to generate the cucumber residue data was an HPLC

- MS/MS Method 140/01/012. The lowest level of method validation (LLMV) was 0.05 ppm. This method was adequate for data collection. Ther e are also adequate methods available to enforce pyrimethanil tolerances on the subject crops.

The cucumber samples analyzed in this study were held in frozen storage for a maximum of 139 days prior to analysis of pyrimethanil residues. There are adequ ate concurrent storage stabilityP yrimethanil Human Health Risk Assessment DP# 428262

Page 17 of 32 

### data to indicate that pyrimethanil residues are stable in/on cucumber for the duration of this study.

The submitted field trial residue data for greenhouse

- grown cucumbers are adequate. The field trial data reflect the pr oposed use pattern, an adequate number of trials were conducted, and samples were analyzed for the residue of concern using validated data

- collection methods. Per

trial

- average

- residues of pyrimethanil ranged 0.07 ppm to 0.82 ppm in/on five cucumber trial s with samples harvested at a 1

- day PHI (highest individual residue of 0.83 ppm) from the five trials. Using the Organization for Economic Co

- operation and Development (OECD) tolerance

calculation procedures for the residue data set indicates that the req uested tolerance of 1.5 ppm for residues of pyrimethanil in/on cucumber is appropriate.

There are no new uses proposed for crops with associated livestock food/feed items of regulatory concern; therefore, a discussion of livestock residues is not german e to these petitions.

Analytical standards for pyrimethanil, with an expiration date 13

- JUL

- 2018, are currently available in the EPA National Pesticide Standards Repository.

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

specified 30

- day plant

- back interval (PBI) for crops without uses on the Scala ® 

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

5.3 Water Residue Profile

EFED studies indicated that pyr imethanil 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

- dimethylpyrimidine. Although it may be less toxic than the parent, 2

- amino

- 4,6

- dimethylpyrimidine is expected to be more mobile and more persistent in the environment than the parent. MARC recommended that parent and 2

- amino

- 4,6

- dimethylpyrimidine are the residues of concern for drinking wate r.
EFED provided EDWCs estimated with the SWCC and PRZM

- GW using the maximum application rate and number of applications, as there are no monitoring data available for use in the human health risk assessment (J. Wolf, 14

- MAY

- 2015; D422295).

IR

- 4 has r equested to expand the citrus, pome and stone fruit crops for the existing postharvest uses for PENBOTEC ® 

### 400 SC (EPA Reg. No. 43813

- 32). Based on the information provided, EFED considers the proposed post

- harvest dip use of pyrimethanil as an indoor use that would pose minimal exposure to the environment, provided that release of the chemical and contaminated water are controlled.

The screening level drinking water concentrations for combined residues of pyrimethanil (parent + 2

- amino

- 4,6

- dimethylpyrimi dine) in surface water are not expected to exceed 156 μg/L for the peak 1

- in

- 10

- year concentration; 27.9 μg/L for the 1

- in

- 10

- year annual mean concentration; and, 21.3 μg/L for the 30

- year annual average concentration for the new uses or crop group expansi on (assuming 2 crops per year 1 

### ). The screening level drinking water concentrations for combined residues of pyrimethanil (parent + 2

- amino

- 4,6

- dimethylpyrimidine) in groundwater estimated

1 1 crop per year

– peak 68 μg/L; annual average = 18 μg/L, and 30 year average = 13 μg/L.P yrimethanil Human Health Risk Assessment DP# 428262

Page 18 of 32 

### with PRZM

- GW are 128 μg/L for the highest daily value and 117 μg/L for the post

- break

through average (Table 2). Current policy is for EFED to recommend the EDWCs for the water source with the highest EDWCs, which for pyrimethanil is surface water for acute exposure and groundwater for chronic exposure. However, due to generally low leaching (EDWCs and incomplete breakthrough) with 100

- year simulation in groundwater, the surface water EDWCs are recommended for both acute and chronic exposure assessments. The EDWCs for the combined residues are presented below in Table 5 .3.1. The models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

Table 5.3.1. Surface Water and Groundwater EDWCs for Pyrimethanil Plus the Degradate (2

- amino

- 4,6

- dimethylpyrimidine) for the Proposed New uses and Crop Group Expansions for Scala ® SC Fungicide (EPA Reg No. 264

- 788) Assuming the Maximum Application Rate (3 or 6 applications @ 0.7 lb a.i./A/year). Standard Scenarios Model Ap plication Rate 1

- in

- 10

- Year 30

- Year

Surface Water #/lb a.i./A Peak Annual Mean Mean (ug/L) Multiple Scenarios 1

- 6 SWCC 3 @ 0.7/7 per crop cycle/2 crop cycles 156 1 27.9 2 21.3 3

3 @ 0.7/7 per crop cycle/1 crop cycles 67.8 4 17.5 5 13.1 6

Groundwater Highest Daily Value Post

- breakthrough Average FL Citrus PRZM

- GW 3 @ 0.7/7 per crop cycle/2 crop cycles 128 117

FL Potato 3 @ 0.7/7 per crop cycle/2 crop cycles 25.2 22.7

1 FL Strawberry (2 crop cycles).

2 PA Tomato (2 crops cycles).
3 CA Grape (2 crops cycles).

4 FL Strawberry (1 crop cycle).

5 PA Apple (1 crop cycle).

6 GA Peach (1 crop cycle).



### In this assessment, the 1

- in

- 10

- year annual average surface water concentration (27.9 ppb) and the 1

- in

- 10

- year acute peak surface water conc entrations (156 ppb) were used for chronic and acute dietary exposure assessments, respectively.

5.4 Dietary Risk Assessment

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

- FCID Version 3.16. This software uses 2003

- 2008 food consumption data from USDA’s NHANES/WWEIA

.

5. 4.1 Description of Residue and Percent Crop Treated Data Used in Dietary Assessment

The acute and chronic dietary exposure assessment was unrefined, using tolerance

- level residues and assuming 100% CT for all registered and proposed commodities. DEEM Version 7.81 default processing factors were used to estimate residues in processed commodities, as available, and empirical processing factors were used for orange and apple juice. Drinking water was incorporated directly into the dietary assessment using the EDWCs generated by the SWCC surface water model.P yrimethanil Human Health Risk Assessment DP# 428262

Page 19 of 32 

### 5.4.2 Acute Dietary Risk Assessment

Using the DEEM

- FCID software, dietary risk is estimated at 10 % of the aPAD for the general U.S. population and 40 % of the aPAD for children 1

- 2 years old, the population subgroup with the highest estimated acute dietary exposure. Therefore, the acute dietary risk assessment shows that for all included commodities plus drinking water, the acute dietary risk estimates are below HED’s LOC for the general U.S. population and all population subgroups (i.e., <100% aPAD).

5.4.4 Chronic Dietary Risk Assessment

Using the DEEM

- FCID software, dietary risk is estimated at 1 5 % of the cPAD for the general U.S. population and 80 % of the cPAD for children 1 to 2 years old, the population subgroup with the highest estimated chronic dietary exposure to pyrimethanil. The chronic dietary risk assessment shows that for all included commodities plus drinking water, the chronic dietary risk estimates are below HED’s LOC for the general U.S. population and all population subgroups (i.e., <100% cPAD).

5.4.5 Cancer Dietary Risk Assessment

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

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Pyrimethanil.

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary Cancer
Dietary Exposure (mg/kg/day) % aPAD 1 Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.105357 11 0.024977 15

N/A N/A All Infants (<1 year old) 0.369251 37 0.090488 53 Children 1

- 2 years old 0.401904 40 0.136305 80 Children 3

- 5 years old 0.254739 25 0.082594 49 Children 6

- 12 years old 0.137476 14 0.038145 22 Youth 13

- 19 years old 0.065147 6.5 0.016025 9.4 Adults 20

- 49 years old 0.060961 6.1 0.014440 8.5 Adults 50

- 99 years old 0.063998 6.4 0.017030 10 Females 13

- 49 years old 0.063604 14 0.015479 9.1 1. Population subgroup with the highest exposure and risk is in bold type. The aPAD for Females 13

- 49 years of age is 0.45 mg/kg/day; aPAD for general U.S. population is 1 mg/kg/day.



### 6 .0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be aP yrimethanil Human Health Risk Assessment DP# 428262

Page 20 of 32 

### potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for pyrimethanil. The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more informa tion). 2 

### The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessm ent Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non

- occupational exposure to drift.

6.2 Residential Bystander Post

- Application Inhalation Exposure

Volatilization of pesti cides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticid e Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has evaluated the SAP report and has developed a Volatilizat ion Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- spe cific inhalation toxicological studies) or further analysis is required for pyrimethanil.

7.0 Aggregate Exposure/Risk Characterization

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

7 .1 Acute Aggregate Risk

No acute residential/re creational exposures are expected. In the case of pyrimethanil, the acute aggregate risk is composed of exposures to pyrimethanil residues in food and drinking water and is equivalent to the acute dietary risk discussed in S ection 5.4.1 . As shown in Table 5. 4 .6 , the acute risk es timates do not exceed the HED ’s LOC for the general U.S. population and all population subgroups.

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmP yrimethanil Human Health Risk Assessment DP# 428262

Page 21 of 32 

### 7 .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.

7

. 3 Chronic Aggregate Risk

A long

- term aggregate risk assessment was not performed, because long

- term residential exposure to pyrimethanil (i.e., >6 months) is unlikely to occur based upon the use patterns. Specifically, i n the case of pyrimethanil , the chronic aggregate risk is composed of exposures to pyrimethanil residues in food and drinking water and is equivalent to the chronic die tary risk discussed in Section 5. 4.2. As shown in Table 5. 4 .6 , the chronic risk es timates do not exceed the HED ’s LOC for the general U.S. population and all population subgroups.

7 .4 Cancer Risk

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

8 .0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mecha nism 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, E PA 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 ch emicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

9 .0 Occupational Exposure/Risk Pathway

Based on the proposed application scenario and toxicological considerations, non

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

- ap plication (dermal) risk assessments were conducted. The proposed new uses were evaluated in the cited memorandum and the resulting occupational exposure/risks were reviewed by the HED Science Advisory Council for Exposure ( ExpoSAC; Mem o, J. Tyler, 21

- SEP

- 20 15

, D429034 ).

9.1 Handler Exposure and Risk Estimates

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupatio nal handlers is based on the following scenarios: 1) open mixing/loading SC formulations for aerial, airblast, chemigation

, and groundboom applications; 2) applying sprays via aerial, airblast and groundboom equipment ;P yrimethanil Human Health Risk Assessment DP# 428262

Page 22 of 32 

### 3) flagging to support aerial applic ations; and 4) open mixing/loading/applying SC formulations for applications via backpack, manually

- pressurized handgun, and mechanically

- pressurized handgun equipment

. For pyrimethanil, based on the proposed use pattern, short

- and intermediate

- term exposures are expected. In addition, the short

- and intermediate

- term PODs are the same; therefore, estimates for short

- term durations are protective of longer

- term exposure durations. The average adult body weight of 80 kg was used for estimating dermal and inhalation doses.

No chemical

- specific handler exposure data were submitted in support of this Section 3 registration. It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as sur rogate data in the absence of chemical

- specific data, include PHED 1.1, the Agricultural Handler Exposure Task Force (AHE TF) database , or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA . The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures

, ” are outlined in the “Occupational Pesticide Handler Unit Exposure Surro gate Reference Table” (http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

data.html

. Estimates of dermal and inhalation exposure were calculated for various levels of PPE. Results are presented for “baseline,” define d as a single layer of clothing consisting of a long

- sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc). The pyrimethanil produc t labels direct mixers, loaders, applicators and other handlers to long

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

- resistant gloves made of waterproof material, chemical

- resistant headgear for overhead exposure.

Table 9.1 provides a summary of the estimated exposures and risks to occupational pesticide handlers. A MOE ≥ 100 is adequate to protect occupational pesticide handlers from dermal and inhalation exposures. Risk estimates for all scenarios are not of concern at e ither baseline or with the addition of PPE (up to and including label

- prescribed PPE which includes chemical

resistant gloves and headgear), except for applying broadcast sprays via mechanically

pressurized handguns to greenhouse

- grown cucumbers. For this scenario, risk estimates are of not of concern assuming a double layer of clothing and chemical

- resistant gloves are worn, which is the highest level of PPE for which exposure data are available for this scenario. Exposure data are not available to asses s the impact of chemical

- resistant headgear for handheld equipment.Page 23 of 32 Table 9 .1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Proposed Uses of Pyrimethanil

.

Exposure Scenario Crop LOC Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Max. App.

Rate 2 Area Treated or Amount Handled Daily 3 Dermal Inhalation Total

Level of PPE Level of PPE Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader
Open Mixing/Loading Liquids for Aerial Applications/Chemigation Small berries (caneberries and bushberries)

100 Baseline: 220
PPE

- G: 37.6 Baseline: 0.219 0.7 lb ai/A 350 A Baseline: 0.344
PPE

- G: 0.0587 Baseline: 67

PPE

- G: 390 Baseline:

0.000671 Baseline:

34,000 Baseline: 67

PPE

- G: 390

Open Mixing/Loading for Airblast Applications Blackberries, highbush blueberries, raspberries 40 A Baseline: 0.0393 Baseline: 590 Baseline: 0.0000766 Baseline:

300,000 Baseline: 590

Open Mixing/Loading Liquids for Chemigation/Groundboom Applications Greenhouse

Cucumbers 60 A Baseline: 0.0589 Baseline: 390 Baseline: 0.000115 Baseline:

200,000 Baseline: 390

Open Mixing/Loading Liquids for Groundboom Applications Blackberries,

highbush blueberries, raspberries 40 A Baseline: 0.0393 Baseline: 590 Baseline: 0.0000766 Baseline:

300,000 Baseline: 590

Lowbush blueberries 80 A Baseline: 0.0784 Baseline: 290 Baseline: 0.000154 Baseline:

150,000 Baseline: 290

Applicator

Applying Sprays via Aerial Equipment Small berries

(caneberries and bushberries)

100 Eng. Control: 2.08 Eng. Control: 0.049

0.7 lb ai/A 350 A Eng. Control: 0.00325 Eng. Control: 7,100 Eng. Control: 0.000015 Eng.

Control: 1,500,00 0 Eng. Control:

7,100

Applying Sprays via Airblast Equipment Blackberries, highbush blueberries, raspberries Baseline: 1770
PPE

- G: 1590
PPE

- DL/G: 1480
PPE

- G/CRH: 215 Baseline: 4.71 40 A Baseline: 0.316
PPE

- G: 0.284
PPE

- DL/G: 0.264
PPE

- G/CRH: 0.0384 Baseline: 73

PPE

- G: 81
PPE

- DL/G: 88
PPE

- G/CRH: 600 Baseline:

0.0165 Baseline:

14,000 Baseline: 73

PPE

- G: 81
PPE

- DL/G: 87
PPE

- G/CRH: 580P yrimethanil Human Health Risk Assessment DP# 428262

Page 24 of 32 Table 9.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Proposed Uses of Pyrimethanil

.

Exposure Scenario Crop LOC Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Max. App.

Rate 2 Area Treated or Amount Handled Daily 3 Dermal Inhalation Total

Level of PPE Level of PPE Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Applying Sprays via Groundboom Equipment Greenhouse

grown cucumbers

Baseline: 78.6 Baseline: 0.34 60 A Baseline: 0.021 Baseline: 1,100 Baseline: 0.0179 Baseline:

130,000 Baseline: 1,100

Blackberries, highbush blueberries, raspberries 40 A Baseline: 0.014 Baseline: 1,700 Baseline: 0.000119 Baseline:

190,000 Baseline: 1,700

Lowbush blueberries 80 A Baseline: 0.0281 Baseline: 820 Baseline: 0.000238 Baseline:

97,000 Baseline: 810

Flagger

Flagger Small berries

(caneberries and bushberries) 100 Baseline: 11 Baseline: 0.35 0.7 lb ai/A 350 A Baseline: 0.0172 Baseline: 1,300 Baseline: 0.00107 Baseline:

22,000 Baseline: 1,200

Mixer/Loader/Applicator

Broadcast applications via backpack Greenhouse

grown cucumbers Baseline: 13,200
PPE

- G: 11,200 Baseline: 140

0.014 lb ai/gal solution 40 gal

solution Baseline: 0.0471 Baseline: 490 Baseline: 0.00098 Baseline:

24,000 Baseline: 480

Broadcast applications via manually pressurized handgun Baseline: 100,000
PPE

- G: 430 Baseline: 30 Baseline: 0.357
PPE

- G: 0.00154 Baseline: 65

PPE

- G: 15,00 Baseline:

0.00021 Baseline:

110,000 Baseline: 65

PPE

- G: 13,000

Broadcast applications via mechanically

- pressurized handgun Greenhouse

grown cucumbers Baseline: 3500
PPE

- G: 2500
PPE

- DL/G: 1600 Baseline: 120

1000 gal solution Baseline: 0.312

PPE

- G: 0.223
PPE

- DL/G: 0.143 Baseline: 74

PPE

- G: 100
PPE

- DL/G: 160 Baseline:

0.021 Baseline:

1,100 Basel ine: 69

PPE

- G: 92
PPE

- DL/G: 140

Blackberries, highbush blueberries, raspberries Baseline: 1300
PPE

- G: 390 Baseline: 3.9 Baseline: 0.116 Baseline: 200 Baseline: 0.000683 Baseline:

34,000 Baseline: 200P yrimethanil Human Health Risk Assessment DP# 428262

Page 25 of 32 Table 9.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Proposed Uses of Pyrimethanil

.

Exposure Scenario Crop LOC Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Max. App.

Rate 2 Area Treated or Amount Handled Daily 3 Dermal Inhalation Total

Level of PPE Level of PPE Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Broadcast applications via mechanically

- pressurized handgun Lowbush

blueberries 100 Baseline: 1300
PPE

- G: 390 Baseline: 3.9 0.047 lb ai/gal solution 1000 gal

solution Baseline: 0.39

PPE

- G: 0.117 Baseline: 59

PPE

- G: 200 Baseline:

0.00229 Baseline:

10,000 Baseline: 59

PPE

- G: 200

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( May 2013 ); Level of PPE : Baseline = Long

- sleeved shirt, long pants, shoes plus socks and no gloves (dermal); no respirator (inhalation). PPE

- G = Long

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

- resistant gloves. PPE

- DL/G = Long

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

- resistant gloves. PPE

- G/CRH = Long

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

- resistant gloves and headgear for overhead exposure (*label

- prescribed PPE)

. EC = enclosed cockpit (aerial applicators). 2 Based on registered or proposed label (Reg. No. 264

- 788). 3 HED ExpoSAC Policy 9.1. 4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/gal) × Amount Handl ed (gal/day) × DAF (51%) ÷ BW (80 kg). 5 Dermal MOE = Dermal NOAEL (23.1 mg/kg/day) ÷ Dermal Dose (mg/ kg/day). 6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/gal) × Amou nt Handled (gal/day) ÷ BW (80 kg). 7 Inhalation MOE = Inhalation NOAEL (23.1 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). 8 Total MOE = NOAEL (23.1 mg/kg/day) ÷ Dermal Dose + Inhalation Dose.P yrimethanil Human Health Risk Assessment DP# 428262

Page 26 of 32 

### 9 .2 Post

- application Exposure and Risk Estimates

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In a ddition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

Dermal : HED expects that post

- application dermal exposure will occur since pyrimethanil is applied as a foliar spray. An occupational post

- application dermal exposure assessment was conducted previously in conjunction with a request for the use of pyrimethanil on small fruit, vine climbing 13

- 07F and low growing berry 13

- 07G (Memo, J. Tyler, 08

- MAY

- 2012 ; D389987)

. In that assessment, the 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.

The post

- application dermal exposures in the 08

- MAY

- 2012 asse ssment were calculated for post

- application activities with the highest (i.e., most conservative) TCs (girdling and turning of grapes). In addition, the proposed use pattern for caneberry crop group 13

- 07A, bushberry crop subgroup 13

- 07B are identical to that of small fruit, vine climbing 13

- 07F and low growing berry 13

- 07G. Therefore, the 5/8/2012 post

- application dermal exposure assessment is adequate to cover the proposed uses on caneberry crop group 13

- 07A and bushberry crop subgroup 13

- 07B.

An ass essment was conducted for post

- application dermal exposure from applications to greenhouse

- grown cucumbers

. 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 surr ogate 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

- applicatio n 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 informa tion about the ARTF data, can be found at http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.

Chemical

- specific DFR data are available for pyrimethanil on gre enhouse cucumbers (MRID# 48823501). This study has been submitted to the Agency, and a detailed review is forthcoming. Based on a preliminary analysis of the data, it is proposed that predicted greenhouse cucumber DFR values calculated based on a linear regression of the measured data be used since the R 2



### - value is high (0.9762).

Table 9.2 provides a summary of the estimated post

- application dermal exposures and risks to occupational pesticide workers. The short

- and intermediate

- term risk estimates are of concern (i.e., MOEs ≥ 100) on the day of application for high contact post

- application exposure activities associated with greenhouse

- grown vegetables. Risk estimates are not of concern for these activities after 48 hours. Low contact activities, such as transplanting and irrigation, are not of concern on the day of application.P yrimethanil Human Health Risk Assessment DP# 428262

Page 27 of 32 Table 9.2. Dermal Post

- application Exposure and Risk Using Chemical

- Specific Data.

Crop/Site 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

Greenhouse

- grown Cucumbers 1,200 0
Greenhouse Cucumbers 4.681 0.282 82

1 0.247 93
2 0.217 110
230 0 0.054 430 1. DAT = Days after treatment

. 2. Predicted DFR residues from chemical

- specific study (MRID 48823501)

. 3. Chemical

- Specific Dermal Dose = [DFR (ug/cm 2 ) x Tc (cm 2 /hr) x 0.001 mg/ug x 8 hrs/day x DAF (51%)]  body weight (80 kg)

. 4. Chemical

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

.


### Inhalation : There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. 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 FIFRA SAP in December 2009, and received the SAP’s final report on March 2, 2010 ( http: //www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studie s) or further analysis is required for pyrimethanil.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the ARTF . Given these two efforts, the Agency will continue to identify the need f

or and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposu re assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhal ation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

The WPS for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applic ations through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)].

9.3 Restricted

- Entry Interval (REI)

The proposed label specifies a 12

- hour REI. Pyrimethanil is classified as Toxicity Category IV via the dermal route and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. Short

- and intermediate

- term post

- application risk estimates were not a concern on day 0 (12 hours following application) for low contact activities, such as transplanting and irrigation. However, there were risk estimates of concern related to high contact activities up until 48 hours after application; therefore, HED is recommending that the REI be revised on theP yrimethanil Human Health Risk Assessment DP# 428262

Page 28 of 32 

### label to address those concerns.

10.0 References

Previous Risk Assessments: J. Tyler et al.

, 28

- JAN

- 2015; D417167. J. Tyler et al.

, 22

- MAY

2013 ; D389923

.

HASPOC Memo: J. Van Alstine, 08

- FEB

- 2013; TXR# 0056470

Chemistry Memo: G. Kramer, 22

- SEP

- 2015 ; D421844

Drinking Water Memo: J. Wolf, 14

- MAY

- 2015; D422295

Dietary Memo: G. Kramer, 22

- SEP

- 2015 ; D424861

Occupational and Residential Exposure Assessment Memo: J. Tyler

, 2 1

- SEP

- 2015 ; D429034

List of Appendices: Appendix A. Toxicology Profile Appendix B. Physical/Chemical Properties Appendix C. Review of Human Research

cc: G. Kramer (RAB1) RDI: RAB1 ( 7 / 22 /15) G.F. Kramer:S10957:PY

- S:(703)305

- 5079:7509P:RAB1P yrimethanil Human Health Risk Assessment DP# 428262

Page 29 of 32 

### Appendix A: Toxicity Profile Tables

.

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for food and non

- food uses for pyrimethanil are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1

. Toxicological Dat a Requirements for Pyrimethanil

. Study Technical Required Satisfied 870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ..................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes yes

no

no

no yes

yes

no

no

no 870.3700a Developmental Toxicity (rodent)

................................ .. 870.3700b Developmental Toxicity (nonrodent)

............................ 870.3800 Reproduction

................................ ................................ . yes yes yes yes

yes yes 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200b Oncogenicity (mouse)

................................ ................... 870.4300 Chronic/Oncogenicity (rat)

................................ ........... yes yes yes yes

yes yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5100 Mutagenicity

— Gene Reverse Mutation

- bacterial

....... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

............... 870. 5395 Mutagenicity

— Micronucleaus Assay in Bone Marrow 870. 5550 Mutagenicity

— Unscheduled DNA Synthesis

.............. yes yes yes yes yes yes

yes yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ .......... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Develop. Neurotoxicity

................................ ................. no

no yes yes

no no

no yes yes

- 870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes yes yes yes

yes yes

Table A. 2 . 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 sensitizerP yrimethanil Human Health Risk Assessment DP# 428262

Page 30 of 32 Table A.3. Toxicity Profile for Pyrimethanil. Guideline No./Study Type MRID, (year)/ Classification/Doses Results

870.3100(a) 90

- Day Oral Toxicity (rat) 43345006 43301608 (1990, 1992)/ acceptable/guideline 0, 80, 800, 8000 ppm 0/0, 5.4/6.8, 54.5/66.7, 529.1/625.9 mg/kg/day [M/F] NOAEL = 54.5 mg/kg/day [M], 66.7 mg/kg/day [F]

. LOAEL = 529.1 mg/kg/day [M], 625.9 mg/kg/day [F] based on  body weights (20%), body

- weight gain(30%), food consumption, brown urine,  urinary pr otein;  abs. heart, adrenal, spleen, thymus weights ;  rel. liver, kidney, gonad weights , liver, thyroid hypertrophy.

870.3100(b) 90

- Day Oral Toxicity (mouse) 43301606 (1991) acceptable/guideline 0, 80, 900, 10,000 ppm 0/0, 12/18, 139/203, 1864/2545 mg/kg/day [M/F] NOAEL = 139 [M] mg/kg/day, 203 [F] mg/kg/day

. LOAEL = 1864 [M] and 2545 [F] mg/kg/day based on  body

weight gain (7

- 12%),  cholesterol, bilirubin [F/M], dark thyroids,  rel. liver weights, kidney, thyroid, bladder histopathology.

870.3150 90

- Day Oral Toxicity (dog) 43301610 (1991) acceptable/guideline 0, 6, 80, 1000/800 mg/kg/day [M/F] NOAEL = 80 mg/kg/day

. LOAEL = 1000/800 mg/kg/day based on  water consumption, vomiting, diarrhea, salivation, hypoactivity.

870.3700(a) Developmental Toxi city (rat) 43301617 43345018 43301619 (1991) acceptable/guideline 0, 7, 85,1000 mg/kg/day NOAEL = Maternal: 85 mg/kg/day

. Developmental: 85 mg/kg/day

. LOAEL = Maternal: 1000 mg/kg/day based on  body weight, and body

- weight gain. Developmental: LOAEL = 1000 mg/kg/day based on  in mean litter weight and mean fetal weight.

870.3700(b) Developmental Toxicity (rabbit) 43301620 43301621 43301622 (1991) acceptable/guideline 0, 7, 45, 300 mg/kg/day NOAEL = Maternal: 45 mg/kg/day

. Deve lopmental NOAEL = 45 mg/kg/day

. LOAEL = Maternal: 300 mg/kg/day based on deaths,  body wt, body

- weight gain, food consumption, production, and size of fecal pellets. Developmental: 300 mg/kg/day based on deaths,  body weight

, body

- weight gain, food con sumption, production and size of fecal pellets  fetal weight,  fetal runts, retarded ossification, 13 thoracic vertebrae and pairs of ribs.

870.3800 Two

- Generation Reproduction and Fertility Effects (rat) 43301623 (1993) acceptable/guideline 0, 32, 400, or 5000 ppm 0/0,1.9/2.2,23.1/27.4, 294/343 mg/kg/day [M/F] NOAEL = Systemic: 23.1 [M] mg/kg/day, 27.4 mg/kg/day [F]

. Repro: 294/343 mg/kg/day

. Offspring: 23.1 mg/kg/day [M], 27.4 mg/kg/day [F]

. LOAEL = Systemic: 294 mg/kg/day [M], 343 mg/kg/day [F] ba sed on  body weight (11

- 13%), and body

- weight gain (11

- 17%)

. Repro: >294/343 mg/kg/day

. Offspring: 294 mg/kg/day based on  pup body weights on PND 21.

870.4100b Chronic Toxicity (dog) 43345007 43301614 (1992) acceptable/guideline 0, 2, 30, 400/250 mg/kg/day NOAEL = 30 mg/kg/day

. LOAEL = 250 mg/kg/day based on  body weight, food & water consumption, food efficiency,  neutrophils,  clotting time.

870.4200b Carcinogenicity (mouse) 43301615 (1992) unacceptable/guideline 0, 16, 160, 1600 ppm 0/0, 2/2.5, 20/24.9, 210.9/253 mg/kg/day [M/F] NOAEL = 210.9 mg/kg/day [M], 253.8 mg/kg/day [F]

. No toxicologically significant effects were found.

870.4200b Carcinogenicity (mouse) 48046301 (2010) acceptable/guideline 0 (2 groups), 3,500, or 7,000 ppm (equi valent 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 stud y.

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 mo nth s],  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.P yrimethanil Human Health Risk Assessment DP# 428262

Page 31 of 32 Table A.3. Toxicity Profile for Pyrimethanil. Guideline No./Study Type MRID, (year)/ Classification/Doses Results

870.5300 Gene Mutation 43301625 (1991); 0, 15, 50, 150, 500

, or 1500 μg/plate in the presence and absence of mammalian metabolic activation (S9

- mix)

Acceptable/Guideline There was no clear evidence of biologically significant induction of mutant colonies over background.

870.5375 Chromosome aberration 4330162 7 (1990); 0, 7.8, 31.3, or 62.5 μg/mL without metabolic activation (S9

- mix) and to concentrations of 0, 31.3, 125

, or 250, μg/mL with S9

- mix.

Acceptable/Guideline There was no evidence of chromosome aberrations induced over background.

870.5395 Mammalian erythrocyte micronucleus test in mice 43301626 (1991); 0, 225, 450

, or 900 mg/kg body weight

Acceptable/Guideline There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in mouse bone marrow at any dose or harvest time.

870.5550 Unscheduled DNA synthesis in mammalian culture 43301628 (1991) 0, 100, 300

, or 1000 mg/kg body weight Acceptable/Guideline Negative in inducing unscheduled DNA synthesis in rat hepatocytes as a result of in vivo gastric intubation.

870.6200a Acute

- Neurotoxicity Screening Battery (rat) 45657221 45657220 (2001) 0, 30, 100, 1000 mg/kg/day A cceptable/ G uideline 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) A cceptable/Guideline 0, 60, 600, 6000 ppm 0/0, 4/4.6, 38.7/44.3, 391.9/429.9 mg/kg/day [M/F] The systemic NOAEL = 6000 ppm (391.9/429.9 mg/kg/day [M/F])

. A LOAEL for systemic toxicity was not observed. The neurotoxicity NOAEL is 6000 ppm (391.9/429.9 mg/kg/day [M/F]). A LOAEL for neurotoxicity was not observed.

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

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

43750101 (1995) 10 mg/kg [M/F] (single dose) Acceptable /guideline At a dose level of 10 mg/kg

, pyrimethanil was eliminated within 24 hours, and the major route of elimination was via the urine [  72%]. Approximately 17

- 18% of the d ose was eliminated via the feces. Radiolabel was detected only in the liver, kidney, and blood at study termination [24 hours post dose]. The highest residue was displayed in the liver in both sexes. There was no significant sex difference

. The overall recovery of radiolabel was  91%

. 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) Ac ceptable/guideline 0.6, 6.0, and 60 μg ai/cm 2 The dermal

- absorption value at 10 hours is 51.2%. This value is very similar to 60% absorption (57.20% absorbed dose plus 2.77% potentially absorbable dose) for which the skin site was washed after 10 hours, and which were sacrificed after 120 hrs. Therefore, using the 51% dermal absorption value for dermal exposure assessment for human risk is conservative and considered protective.

870.7800 Immunotoxicity 48263901 (2010) 0, 80, 800, or 8000 ppm (0, 6.9, 69.5, or 652 mg/kg bw/day, respectively [F]) Acceptable/Guideline Immunotoxicity NOAEL = 8000 ppm (652 mg/kg/day)

. Immunotoxicity LOAEL is not established

.P yrimethanil Human Health Risk Assessment DP# 428262

Page 32 of 32 

### 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.