### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 3 of 71 5.4.4 Chronic Dietary Risk Assessment

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

5.4.5 Cancer Dietary Risk Assessment

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

5.4.6 Summary Table

................................ ................................ ................................ ........... 24 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Residential Handler Exposure

................................ ................................ .................... 25

6.2 Post

- Application Exposure

................................ ................................ .......................... 27

6.3 Combined Exposure

................................ ................................ ................................ ..... 28

6.4 Residential Bystander Postapplication Inhalation Exposure

................................ ... 29

6.5 Spray Drift

................................ ................................ ................................ .................... 29

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 29

7.1 Acute Aggregate Risk

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

7.2 Short

- Term Aggregate Risk

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

7. 3 Chronic Aggregate Risk

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

7.4 Cancer Aggregate Risk

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

8.0 Cumulative Exposure/Risk Characterization

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

9.0 Occupational Exposure/Risk Characterization

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

9.1 Short

- /Intermediate

- Term Handler Risk

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

9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ ................... 46

9.2.1 Dermal Post

- application Risk

................................ ................................ .................. 46

9.2.2 Inhalation Postapplication Risk

................................ ................................ .............. 48

10.0 References

................................ ................................ ................................ ......................... 49 Appendix A. Toxicology Profile and Executive Summaries

................................ ................. 50

A.1 Toxicology Data Requirements

................................ ................................ ................... 50

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 51

A.3 Hazard Identification and Endpoint Selection

................................ .......................... 54

A.4 Executive Summaries

................................ ................................ ................................ ... 57 Appendix B. International Residue Limits

................................ ................................ .............. 69 Appendix C. Physical/Chemical Properties

................................ ................................ ............. 70 Appendix D. Review of Human Research

................................ ................................ ................ 71

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 4 of 71 1.0 Executive Summary

Pendimethalin (N

- (1

- ethylpropyl)

- 3,4

- dimethyl

- 2,6

- dinitrobenzenenamine) is a selective herbicide used for controlling annual grass and broadleaf weeds. It is a meristematic inhibitor that interferes with the plant’s cellular division of mitosis and is gene rally applied early in the growing season as a pre

- emergent and early post

- emergent herbicide . Pendimethalin is currently formulated into a variety of product form ulation s including; aqueous capsule suspension, granular, em ulsifiable concentrate, and liqui d formulations . Five new agricultural uses of

p endimethalin have been proposed for the aqueous capsule suspension formulation of the end

use product Prowl ® 

### H 2 

### O (38.7 % a.i.; EPA Reg istration Number: 241

- 418), a 3.8 lb s ai /gallon liquid formulation. The new uses include the following crops; leaf lettuce, leafy brassica greens, melons, vegetable soybean (edamame), kiwi and other small fruit vines. The maximum single proposed application rate is 1.0 lb s ai/A for leaf lettuce , leafy brassica greens, and melon production; 1.43 lbs ai/A for vegetable soybean (edamame); and 6.0 lb ai/A for kiwi and small

fruit vines. Prowl ® 

### H 2 

### O can be applied via ground or aerial application methods.

Use Profile

E nd

- use products containing p endimethalin are currently registered for use on the follow ing

crops : alfalfa, artichoke, asparagus, bearing fruit and nut trees, brassica head and stem vegetables, carrots, carrots grown for seed, clover, corn, cotton, edible beans, fallow, forage legumes, fruiting vegetables, garlic, grain sorghum, grape, green onions, lentil and peas, mint,

non

- bearing fruit trees, olive trees, onions, peanuts, potatoes, rice, soybeans, strawberry,

sugarcane, sun flowers, tobacco and wheat. In addition to agricultural crops, p endimethalin is registered for northern and southern grasses, for use on sod farms and for seed production. Additionally, p endimethalin is registered for use by commercial applicators and ho meowners on lawns, parks, golf courses, in and around ornamentals , and weed control in non

- cropland areas, such as landscape ground covers. Pendimethalin is also registered for use on container grown and field grown ornamentals, however, it is not to be u sed in greenhouses, shade houses, or other

enclosed structures.

Toxicity/ Hazard The risk assessment for pendimethalin is based on a well

- characterized and complete toxicology database. In repeat

- dose oral studies, the thyroid was consistently the targe t organ for pendimethalin toxicity. No developmental effects were seen in rabbit or rat developmental toxicity studies and no reproductive or offspring effects were seen in the 2

- generation rat reproduction study. Based on the effects of hormonal changes (alterations in thyroid weights and histopathological lesions) observed in several studies following oral administration of pendimethalin

, HED had a strong indication that pendimethalin may cause disruption to the endocrine system. Consequently, HED recom mended that a developmental thyroid assay be conducted to evaluate the impact of pendimethalin on thyroid hormones, structure, and/or thyroid hormone homeostasis during development. A developmental thyroid study (MRID 48695603)

was submitted and demonstra ted no developmental thyroid effect was observed

. Pendimethalin is classified as a “possible human carcinogen.”

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 5 of 71 Pendimethalin has a low order of acute toxicity via oral, dermal and inhalation routes of exposure as demonstrated by the toxicity cat e gories (III & IV). Pendimethalin is not an eye or

skin irritant and is not a skin sensitizer.

HED’s level of concern includes a 10X uncertainty factor (UF) for intraspecies extrapolation. This factor is used to account for human variability in toxicoki netics and toxicodynamics. However, the interspecies UF (used to account for animal to human differences in toxicokinetics and toxicodynamics) may be reduced to 3X with respect to obse rved thyroid effects in the rat because of several important quantitat ive dynamic differences between rats and humans with respect to thyroid function (Interim Guidance on Thyroid Disrupting Pesticides, dated 11/ 0 1/05). Additionally, HED has recommended the 10X FQPA safety factor be removed (reduced to 1X)

due to no evidenc e of susceptibility. NOAELs were used for short

- term, intermediate

- term, and

chronic risk assessments. The selected toxicity endpoints and PoDs for risk assessment are

based on the most sensitive and relevant data.

Dietary Exposure (Food and Water)

Th e residue chemistry data and environmental fate data are adequate to assess human exposure. The assessments are based on reliable data and will not underestimate exposure or risk. Estimated drinking water concentrations (EDWCs) were incorporated directly into the dietary exposure assessments. A n unrefined acute dietary assessment was conducted assuming 100% crop treated (CT), tolerance

- level residues

, Dietary Exposure Evaluation Model (DEEM TM) default processing factors or empirical processing factors when available

. The results of the acute dietary analysis for food and drinking water show that the acute dietary risk estimates are below the Agency’s level of concern (<100% of the acute population adjusted dose (aPAD)) for all population subgroups and were estimated at <1% of the aPAD for the U.S. general population

and 2.0 % of the aPAD for the most highly exposed population subgroup ( infants < 1 years old ).

A n un refined chronic dietary assessment using tolerance

- level residues, assuming 100% crop treated (CT) estimates and default DEEMTM processing factors or empirical processing factors

were also conducted. The results of the chronic dietary analysis for food and drinking water indicate that the chronic dietary risk es timates are below the Agency’s level of concern (<100% of the chronic population adjusted dose (cPAD)) for all population subgroups and were estimated at <1% of the cPAD for the U.S. general population and 1.6% of the cPAD for the most highly exposed popul ation subgroup (children 1

- 2 years old). Pendimethalin is classified as a “possible human carcinogen;” h owever, the chr onic dietary risk assessment is considered to be protective of any cancer effects; therefore, a separate quantitative cancer aggregate r isk assessment is not required

Residential Exposure Although the proposed labels do not contain residential uses, p endimethalin is currently registered for use on lawns, landscape ornamentals , weed control non

- cropland areas by commercial applicators and homeowners

. Residential exposures were assessed in this document because changes in Standard Operating Procedures, body weight parameters, and toxicological information has changed since the last residential assessment (M. Collantes, Z. Fig ue r oa ;
D 325175; 0 4/ 0 2/07). Updated residential handler and post

- application risk estimates do not exceed HED’s level of concern (MOEs ≥ 30). Updated residential exposure risk estimates are also considered in the aggregate risk assessment.

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 6 of 71 Occupational Exposure

Short

- and intermediate

- term dermal and inhalation exposure is expected for occupational handlers. The results of the occupational handler exposure and risk assessment estimates

indicate that total short

- and intermediate

- term margins of exposure (MOEs) a re not of concern to HED (i.e. MOE > 30 ) with baseline attire and varying levels of PPE with the exception of one

use scenario. O ccupational dermal post

- application exposure is expected following foliar or

post

- emergent treatment of crops ; however

, short

- and intermediate

- term margins of exposure (MOEs) are not of concern to HED (i.e. MOE > 30) . HED assumes that post

- application inhalation exposures are minimal following applications of pendimethalin. Pendimethalin has low acute inhalation toxicity (Tox icity Category I V ) and a v apor pressure of 3 x 10 - 5 

### mm Hg @

25.0°C

, therefore

, post

- application inhalation exposures and risks were not quantitatively

assessed.

Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies (Appendix D ) have been determined to require a review of their ethical conduct, and one of th ese studies is also subject to review by the Human Studies Review Board. All of the listed studies have received the appropriate review.

2.0 HED Recommendations

HED recommen ds the registration request per the proposed labels be granted for applications of pendimethalin use on leaf lettuce, leafy Brassica greens, melon production, vegetable soybean (edamame), and kiwi and other small vine climbing fruit for the Prowl ® 

### H20 formulation of pendimethalin with the exception of one scenario: commercial impregnat ion for dry bulk fertilizer for grape, kiwi, and other small fruit vines (MOE = 26) . Commercial bulk fertilizer application for the proposed use on kiwi and other small fruits resulted in MOEs that exceed HED’s level of concern (MOEs < 30). This scenario was assessed at the highest application rate and the highest amount (960 tons) bulk fertilizer treated per day. Bulk fertilizer impregnation at the lower range of 500 tons does not exceed HED’s LOC (MOEs ≥ 30). HED also recommends

the tolerance expressi on for pe n dimethalin be updated to incorporate the tolerance revisions requested in Section 2.2.3.

Existing uses of pendim e thalin were also assessed. Most currently registered uses resulted in

MOEs ≥ 30, and therefore are not of concern to HED, with the exception of the following exposure scenarios: mixing and loading for chemigation and aerial a pplication of alfalfa and sugarcane (MOE = 24) mixing/loading/application with a handgun sprayer for drench application to turf grasses

and ornamentals (MOE = 20) These exposure scenarios were assessed with additional personal protective equipment. Risk estimates for these uses with gloves and/or respirators do not exceed HED’s level of concern (MOE ≥ 30) for the alfalfa, sugarcane, and the turf and orn amental scenario s

.

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 7 of 71 2.1 Data Deficiencies/Conditions of Registration

At this time, no data deficiencies have been noted.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate enforcement methods are available and described in det ail in the following references: 1) Residue Chemistry Memo DP#s 271502; 310793; 311825; 314085; 314093; 317047; 317053,
W. Drew, 12

- Jul

- 2006 and 2) Residue Chemistry Memo DP# 238470, William Cutchin, 02

- Aug

1999 (PP#6E4603). These methods were adequate for data collection based on acceptable method validation and concurrent recovery data, and the fortification levels used in the method validation. The concurrent method recoveries were adequate to bracket expected residue levels and briefly described below.

Enforcement Methods : PAM Volume II lists four GC/ECD, methods for the determination of pendimethalin and its 3,5

- dinitrobenzyl alcohol metabolite in plant commodities. Methods I and III determine residues of the parent, whereas Methods II and IV determi ne residues of the 3,5

- dinitrobenzyl alcohol metabolite. The LOQ of each method is 0.05 ppm. A confirmatory GC/MS method was subsequently submitted and was been found adequate (DP# 238470).

2.2.2 International Harmonization

No Codex MRLs are established for these current new uses of pendimethalin, and there are currently no Canadian MRLs established for the proposed crops. However, an International Residue Limit Status Sheet (IRLS) follows the references and indicates that th e MRLs on Onion, bulb, Fruit, pome group 11 and Fruit, stone group 12 is 0.1 ppm are harmonized. A table containing a summary of international tolerances and maximum residue limits can be found in Appendix B

.

2.2.3 Recommended Tolerances

Table 2.2.3 su mmarizes the registrant’s proposed tolerances and the Agency’s evaluations for tolerance recommendations. The tolerance expression for pendimethalin should read as follows:

Tolerances should be established for residues of the herbicide pendimethalin, inc luding its metabolites and degradates, in or on the commodities listed below. Compliance with the tolerance levels specified below is to be determined by measuring pendimethalin and its alcohol metabolite, N

- (1

- ethylpropyl)

- 3,4

- dimethyl

- 2,6

- dinitrobenzen amine, and its metabolite (4

- [(1

- ethyl propyl) amino]

- 2

- methyl

- 3,5

- dinitrobenzyl alcohol).

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 8 of 71 T able 2.2.3. T olerance Summary for Pendimethalin.

Commodity Proposed

Tolerance (ppm) E stablished/

Tolerance (ppm) Recommended

Tolerance (ppm) Comments [ Correct Commodity

Definition ]

Lettuce, Leaf 3.0

-- 4.0 Lettuce, leaf

Brassica, leafy greens, subgroup 5B 0.20

-- 0.20

Turnip greens 0.20

-- 0.20 Turnip, greens

Melon subgroup 9A 0.10

-- 0.10

Vegetable, soybean,

succulent 0.10

-- 0.10 Vegetable, soybean (edamame)

Small fruit vine climbing subgroup 13

- 07E, except

grape 0.10

-- 0.10 Fruit, small vine climbing, subgroup 13

- 07

E , except grape



### 2.2.4 Revisions to Petitioned

- For Tolerances

Combined residues of pendimethalin and CL 202,347 were quantifiable in/on samples of leaf lettuce and mustard greens, therefore t he OECD tolerance calculation procedures were utilized in determining appropriate tolerance level s. Using the OECD tolerance calculation procedures, the

recommended tolerances should be 4.0 ppm for leaf lettuce and 0.20 ppm for brassica leafy greens, subgroup 5B, mustard greens

. HED attributes the difference in the proposed and

recommended tolerances for leaf lettuce to the petitioner’s having used the North American Free Trade Agreement (NAFTA) tolerance calculation procedures in determining the proposed

tolerance.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

860.1200 Directions for Use

The use directions for leaf lettuce , leafy brassica greens, melon, and kiwi and other small fruit vines must be amended to specify that no adjuvants may be added to the spray mixtures for these crops.

The following revisions/clarifications are required for specific crops:

o For leafy bras sica greens, the label revision must prohibit the use on turnip green

varieties grown for roots or dual

- purpose varieties grown for roots and tops. The label revision must further clarify that Pendimethalin may be use d on cultivars of turnip green varietie s grown for leaves only; the harvest of turnip green root for food/feed purposes is no t supported by residue data or an established tolerance

.

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 9 of 71 o For applications to vegetable soybean ( edamame ), the petitioner must clarify whether aerial application is permitted (as per the supplemental label ) or not (as

per Section B ).

o A m inimum retreatment interval ( RTI ) was not specified for cantaloupe . The label should be revised to specify a minimum retreatment interval of ≥ 17 days

, based on the submitted crop fie ld trial data.

860.1550 Proposed Tolerances

The tolerance for leaf lettuce should be established at 4.0 ppm, the proposed tolerance is 3.0 ppm. The petitioner should submit a revised Section F reflecting the recommended tolerances and commodity definitio ns presented in Table 2.2.3.

2.3.2 Recommendations from Occupational Assessment

No label recommendations based on the occupational assessment are required for the proposed pendimethalin uses.

2.3.3 Recommendations f rom Residential Assessment

No label recommendations based on the residential assessment are required for the proposed pendimethalin uses.

3.0 In troduction

Pendimethalin is a selective herbicide used for controlling annual grass and broadleaf weeds. It is

a meristematic inhibitor that interferes with the plant’s cellular division of mitosis and is generally applied early in the growing season as a pre

- emergent and early post

- emergent herbicide. Pendimethalin is currently formulated into a variety of product formulations including; aqueous capsule suspension, granular, em ulsifiable concentrate, and liquid formulations. Five new agricultural uses of pendimethalin have been proposed for the aqueous capsule suspension

formulation of the end

- use product Prowl ® 

### H 2 

### O (38.7 % a.i .; EPA Reg istration Number: 241

- 418), a 3.8 lb s ai/gallon liquid formulation. The new uses include the following crops; leaf lettuce, leafy brassica greens, melons, vegetable soybean (edamame), kiwi and other small fruit

vines. The maximum single proposed application rate is 1.0 lb a

. i

. /A for leaf lettuce, leafy brassica greens, and melon production; 1.43 lbs ai/A for vegetable soybean (edamame); and 6.0

lb s ai/A for kiwi and small fruit vines. Prowl ® 

### H 2 

### O can be applied via ground or aerial application me thods.

The variety of end

- use products containing pendimethalin currently registered are as follows; alfalfa, artichoke, asparagus, bearing fruit and nut trees, brassica head and stem vegetables, carrots, carrots grown for seed, clover, corn, cotton, edib le beans, fallow, forage legumes, fruiting vegetables, garlic, grain sorghum, grape, green onions, lentil and peas, mint, non

- bearing fruit trees, olive trees, onions, peanuts, potatoes, rice, soybeans, strawberry, sugarcane, sunflowers, tobacco and wheat. In addition to agricultural crops, pendimethalin is registered for

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 10 of 71 northern and southern grasses, for use on sod farms and for seed production. Pendimethalin is

also registered for use by commercial applicators and homeowners on lawns, parks, golf course s, in and around ornamentals, and weed control in non

- cropland areas, such as landscape ground covers. Pendimethalin is also registered for use on container grown and field grown ornamentals, however, it is not to be used in greenhouses, shade houses, or o ther enclosed structures.

3.1 Chemical Identity

The chemical structure and nomenclature of pendimethalin are presented in Table 3.1

.

Table 3.1 Test Compound Nomenclature and Structure for Pendimethalin and Metabolite

Empirical Formula Pendimethalin

N

- (1

- ethylpropyl)

- 3,4

- dimethyl

- 2,6

- dinitrobenzenamine Metabolite CL 202347

4

- [(1

- ethylpropyl)amino]

- 2

- methyl

- 3,5

- dinitrobenzyl alcohol

Chemical Structure

Common Name Pendimethalin

Company experimental name BAS 455H (old CL 92533)

IUPAC name N

- (1

- ethylpropyl)

- 2,6

- dinitro

- 3,4

- xylidine

CAS Name N

- (1

- ethylpropyl)

- 3,4

- dimethyl

- 2,6

- dinitrobenzenamine

CAS Registry Number 40487

- 42

- 1 ; 56750

- 76

- 6

End

- use product/EP Prowl® H 2 O Herbicide (EPA Reg. No 241

- 418)

Chemical Class Dinitroaniline Herbicides



### 3.2 Physical/Chemical Characteristics

Pendimethalin contains dinitroanilines ; therefore, a discussion of the potential for formation of nitrosamines and analysis for the presence of nitrosamines formed during manufacture and storage of the product was required. Previously submitted data indicate that no volatile nitrosamines are present (<0.5 ppm) and that total nonvolatile nitrosamines were present at less than 100 ppm. These issues are mentioned for informational purposes and are addressed either in the evaluation of the technical grade of the active ingredient (TGAI) or in the registrants

c onfidential statement of formula (CSF). Details of the physio

- chemical properties are provided in Appendix C

.

3.3 Pesticide Use Pattern

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 11 of 71 IR

- 4 has submitted a Section B and draft supplemental labels for the proposed uses of the 3.8 lb s a.i. / gal CS formulation of pendimethalin (Prowl® H 2 

### O Herbicide; EPA Reg. No. 241

- 418). The

directions for use are presented in Table 3 .3 for the proposed uses of the 3.8 lbs a.i./gal CS formulation on leaf lettuce, leafy brassica greens, melon, vegetable soybe an (edamame), and

kiwi and other small fruit vines. The established use directions were obtained from labels accepted 10/31/2011 for the CS formulation and 04/03/2009 for the EC formulation. Refer to section 2.3 for the recommended modifications to the p roposed label. Table 3.3 provides the summary of the directions for use.

Table 3. 3 Summary of Directions for Use of Pendimethalin.

Applic. Timing, Type, and Equip. Formu

lation Applic. Rate (lb a.i. /A) Max. No.

Applic.

per Season Max.

Seasonal Applic. R ate (lb a.i. /A) RTI

(days) PHI (days) Use Directions and Limitations

Proposed Uses

Leaf Lettuce

Foliar, Broadcast, Ground (min. 10 gal/A) or air (min. 5 gal/A) 3.8 lb

a.i. /gal

CS 1.0 1 1.0 Not appli

cable (NA) 20 Apply to direct

- seeded or

transplanted leaf lettuce from the

3

- leaf stage until 20 days prior to

harvest.

Leafy Brassica Greens: Mustard greens, broccoli raab, Chinese cabbage (bok choy), collards, kale, mizuna, mustard spinach, rape greens, and turnip greens

Foliar, Broadcast, Ground (min. 10 gal/A) or air (min. 5 gal/A) 3.8 lb

a.i. /gal

CS 1.0 1 1.0 NA 21 Apply to direct

- seeded or transplanted Brassica leafy greens

at the 4

- leaf to 5

- leaf stage.

Melon: Cantaloupe, citron melon, muskmelon and watermelon

Preplant, retransplant,

or Preemergence [1 st
app.] or Post

emergence, prior to vine running [2 nd

app.], Shielded to row middles, Ground (min. 10 gal/A) 3.8 lb

a.i. /gal

CS 1.0 2 2.0 Not specified (NS) 35 First application: Apply before

melon transplanting, before seeded crop has emerged, or between rows covered with plastic mulch (prior to holes being punched for planting). Second application: Apply prior to vine running. Do not feed forage or graze

livestock in treated fields.

Vegetable Soybean (Edamame)

Preplant Surface, Broadcast, Ground (min. 10 gal/A) or air (min. 5 gal/A) 3.8 lb

a.i. /gal

CS Coarse soil

0.95

Medium

1.2

- 1.4

Fine soil

1.4 Heavy clay

1.5 1 Coarse soil

0.95

Medium

1.4

Fine soil

1.4 Heavy clay

1.5 NA 85 Apply up to 15 days prior to planting or up to 45 days prior to planting when used in a tank mix or applied sequentially with

postemergence

- applied herbicides.

Do not exceed 1.0 lb a.i. /A in

Southern states. Do not use in

CA.

Preplant incorporated, Broadcast, Ground (min. 10 gal/A) or air (min. 5 gal/A) Apply up to 60 days prior to planting. Do not exceed 1.0 lb

a.i. /A in Southern states. Do not

use in CA.

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 12 of 71 Table 3. 3 Summary of Directions for Use of Pendimethalin.

Applic. Timing, Type, and Equip. Formu

lation Applic. Rate (lb a.i. /A) Max. No.

Applic.

per Season Max.

Seasonal Applic. R ate (lb a.i. /A) RTI

(days) PHI (days) Use Directions and Limitations

Preemergence, Broadcast, Ground (min. 10 gal/A) or air (min. 5 gal/A) 3.8 lb

a.i. /gal

CS Coarse soil

0.71

Medium

0.95

Fine soil

0.95

- 1.2 1 Coarse soil

0.71

Medium

0.95

Fine soil

1.2 NA 85 Apply at planting or up to 2 days after planting. Do not make applications north of Interstate 80, except in IN, MI, and OH.

Do not use in CA.

Kiwi and Other Small Fruit Vines: Amur river grape, gooseberry, fuzzy kiwifruit, hardy kiwifruit, maypop, and Schisandra berry

Surface incorporated

or preemergence, Broadcast or banded, directly to the ground

beneath vines or between rows,Ground (min. 10 gal/A) or chemigation/ irrigation systems 3.8 lb

a.i. /gal

CS 3.0

- 6.0 2 6.0 30 60 Apply after fall harvest, during winter dormancy, and in the spring. Do not feed forage or graze

livestock in treated vines.



### Spray adjuvants were not used in the submitted crop field trials on leaf lettuce, mustard greens, cantaloupe, and kiwifruit. HED has concluded that spray adjuvant use must be prohibited on product labels when the field trials do not include adjuvants ( Note: ChemSAC

, 0 4/ 16/08). The use directions for leaf lettuce, leafy brassica greens, melon, and kiwi and other small fruit vines must be amended to specify that no adjuvants may be added to the spray mixtures for these

crops.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new uses of the CS formulation of pendimethalin on leaf lettuce, leafy brassica greens, melon, vegetable soybean (edamame), and kiwi and other small fruit vi nes. Humans may be exposed to pendimethalin in food and drinking water, since pendimethalin may be applied directly to growing crops and application may result in pendimethalin reaching surface and ground w ater sources of drinking water. There are reside ntial uses of pendimethalin, so exposure to pendimethalin may occur in residential or non

- occupational settings. In an occupational setting, handlers may be exposed while handling the pesticide prior to application, as well as during application. There i s also a potential for post

- application exposure for workers re

entering treated sites.

Risk assessments have been previously prepared for the existing uses of pendimethalin. This risk assessment considers all of the aforementioned exposure pathways ba sed on the proposed new uses of pendimethalin, but also considers the existing uses as well, particularly for the dietary exposure and residential (non

- occupational) risk assessment.

3.5 Consideration of Environmental Justice

Potential areas of environ mental justice concerns, to the extent possible, were considered in this

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 13 of 71 human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established

pr ocedures. 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 residen tial setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are an alyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

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

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database is adequate to support the proposed uses for pendimethalin. The scientific quality of the data base for pendimethalin is relatively high and the toxicity profile can be characterized for a wide range of effects, including potential developmental, reproductive, neurotoxic, and immunotoxic effects.

4.2 Absorption, Distribution, Metabolism, & Elimin ation (ADME)

In a metabolism study (MR I D 00046275), when { 14 

### C } pendimethalin was administered to rats

, about 70% of the radioactivity was excreted in the feces and 20% in the urine within 24 hours.

The exc retion of radioactivity in the ur ine peaked at 6 to 12 ho urs wherein 11.2% of the dose was excreted. The maximum residual radioactivity in the tissues was found in the 6

- hour samples (except for fat at 12 hours). The levels of radioactivity detected in liver, kidney, muscle, fat, and

blood at 6 hours were 29.8, 16.9, 1.3, 12.2, and 5.4 ppm, respectively. Within 96 hours the radioactivity found in the tissues was 0.3 ppm or less, except for fat which was 0.9 ppm. The major portion of the radioactivity that was excreted in the feces was identified as the pare nt compound. Pendimethalin is metabolized in rats mainly through oxidation of the 4

- methyl group attached to the benzene ring as well as oxidation of the alkyl side chain of the N

- substituted dinitroaniline compound.

4.2.1 Dermal Absorption

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 14 of 71 There were no appropriate dermal absorption or toxicity studies available to allow an estimation of the dermal absorption by a route

- to

- route comparison of toxicity. In a previous risk assessment (HIARC doc. 04/18/2000), dermal absorption was estimated to be no great er than 10%. This was based on structurally related chemicals (oryzalin, trifluralin and ethalfluralin) with dermal absorption studies (in monkeys) indicating absorption rates of 2.3%, ~1%, and 2.8%, respectively. The solubility (water) for pendimethalin a nd these related chemicals are also similar at 0.5 ppm, 2.5 ppm, 0.3 ppm and < 1 ppm, respectively. The upper

- bound value of 10% previously estimated for pendimethalin is considered very conservative. Therefore, for risk characterization purposes, a more a ppropriate estimate of 3% was applied. This absorption rate is comparable to those identified for related chemicals.

4.3 Toxicological Effects

P endimethalin has a low acute toxicity via the oral, dermal, or inhalation route. It is not a dermal

or eye irritant ; and is not a d ermal sensitizer. The thyroid is a target organ for pendimethalin. Thyroid toxicity in chronic and subchronic rat and mouse studies was manifested as alterations in thyroid hormones (decreased t otal T4, and T3, increased percent of free T4 and T3), increased thyroid weight, and microscopic thyroid lesions (including increased thyroid follicular cell height, follicular cell hyperplasia, as well as follicular cell adenomas).

Thyroid tumors were observed in both male and female rats in a chron ic/carcinogenicity study

. There were no tumors observed i n the carcinogenicity study in mice. The Health Effects Division (HED) Cancer Peer Review Committee classified pendimethalin ( 0 3/18/92 and re

- affirmed

11/ 0 1/99) as a "Group C", possible human carcinogen based on a statistically significant increased trend and pair

- wise comparison between the high dose group and controls for thyroid

follicular cell adenomas in male and female rats. The Committee also recommended a non

quantitative approach (i.e ., non

- linear, RfD approach) since mode of action studies are available that demonstrate that the thyroid tumors are due to a thyroid

- pituitary imbalance, and also since pendimethalin was shown to be non

- mutagenic in mammalian somatic cells and germ cells. The chronic risk assessment is considered to be protective of any cancer effects; therefore, a separate quantitative cancer aggregate risk assessment is not required.

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

There was no evidenc e of qualitative or quantitative susceptibility in a 2

- generation reproduction study conducted in the rat, and there was no evidence of neurotoxicity in the acute and subchronic neurotoxicity studies. In a developmental thyroid study, there was no increased sensitivity to t he offspring as compared to dams because t hyroid hormones in fetuses and PND 4 pups of exposed dams remained unaltered even when their mothers showed significantly

decreased T 4 levels. Only after exposure via the diet in addition to the milk, serum T 4 levels of PND 21 pups were affected

. Therefore, HED has recommended the 10X FQPA safety factor be removed (reduced to 1X).

4.4 .1 Completeness o f the Toxicology Database

The toxicology database for pendimethalin is complete and adequ ate to support risk assessments.

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 15 of 71 4.4.2 Evidence of N eurotoxicity

There is no evidence of neurotoxicity for pendimethalin exposure. In an acute neurotoxicity study, FOB findings and reduced motor activity were observed on Day 0 only at 300 and 1000 mg/kg

. However, these findings were considered an impairment of the overall condition of the animals following treatment, rather than direct neurotoxic effects of the pendimethalin exposure based on the absence of any neurohistopathological changes in the treated animals and the

transient nature of the observed FOB and neurobehavioral assessments. In a subchronic neurotoxicity study, no neurotoxic effects were observed in rats feeding pendimethalin up to 5400 ppm for 90 days. In addition, th e toxicology database does not reveal any evidence of neurotoxic clinical signs, changes in brain weight, or histopathology of the nervous system in any study with pendimethalin.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Ani mal

There was no indication of pre

- and/ or post

- natal qualitative or quantitative increased susceptibility in the developmental studies in rats and rabbits or the 2

- generation reproduction

studies in rats. In addition, a developmental thyroid toxicity st udy demonstrated that there is no potential thyroid toxicity following pre

- and/or post

- natal exposure to pendimethalin. Thyroid hormones in fetuses and PND 4 pups of exposed dams remained unaltered even when their mothers showed significantly decreased T 4 

### levels. Only after exposure via the diet in addition to the milk, serum T 4 

### levels of PND 21 pups were affected

.

4.4.4 Residual Uncertainty in the Exposure Datab ase

While some refinements were incorporated into the dietary exposure calculations, EPA is confident that the aggregate risk from exposure to pendimethalin in food, drinking water and residential pathways will not be underestimated. The acute dietary exposur e assessment assumed 100% of the proposed and registered crops were treated, and utilized tolerance level residues for all existing and proposed commodities. The chronic dietary exposure assessment

used tolerance level residues for all commodities

, 100 % c rop treated (% CT) and empirical processing estimates when available or DEEM TM defa u lt processing factors. The drinking water assessment utilized water concentration values generated by models and associated modeling parameters which are designed to produce conservative, health protective, high

- end estimates of water concentrations which are not likely to be exceeded. The dietary (food and drinking water) exposure assessment does not underestimate the potential exposure for infants, children, or women of child bearing age.

In addition, the residential exposure assessment incorporates similarly conservati ve assumptions in the assessment of post

- application exposure of children and in the incidental oral exposure assessment for children. These assessments will not underestimate the exposures and risks posed by pendimethalin.

4.5 Toxicity Endpoint and Po int of D eparture Selections

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 16 of 71 4.5.1 Dose

- Response Assessment

The thyroid is the target organ for pendimethalin. Effects of h ormonal changes (alterations in thyroid weights and histopathological lesions) were observed in several studies following oral

admin istration of pendimethalin and it is likely that these changes may cause disruption in the endocrine system. On March 30, 2000, the HIARC re

- affirmed ( 0 9/ 0 7/ 19 99) that the NOAEL of 10 mg/kg/day selected from the 14

- day intra

- thyroidal study reflects a t rue NOAEL for thyroid effects since these effects have been demonstrated to have early onset (before 14 days). On this basis, all studies were considered together for establishing the NOAEL of 10 mg/kg/day. The LOAEL of 31 mg/kg/day, from the 56

- day thyroi d study, is based on several hormonal and histological thyroid changes and thyroid hormonal effects occurred as early as day 3. The

estimated short

- and intermediate

- term dermal and inhalation NOAEL of 10 mg/kg/day for pendimethalin were selected from an o ral study. Therefore, for risk characterization purposes, a dermal absorption factor of 3% and an inhalation absorption factor of 100% were used. Since both dermal and inhalation endpoints were based on the same toxicological effects these route

specific M OEs were combined into a total MOE.

HEDs level of concern (LOC) for pendimethalin dermal and inhalation is 30 (i.e., a margin of exposure (MOE) less than 30 exceeds HED’s level of concern) for occupational scenarios. The

level of concern includes a 10X uncertainty factor (UF) for intra

- species extrapolation. This factor is used to account for human variability in toxicokinetics and toxicodynamics. However, the interspecies UF (used to account for animal to human differences in toxicokinetics and toxicodynamics) may be reduced to 3X with respect to obse rved thyroid effects in the rat because of several important quantitative dynamic differences between rats and humans with

resp ect to thyroid function (Interim Guidance on Thyroid Disrupting Pesticides, dated

11/ 0 1/ 20 05).

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Since the same three studies were used to select endpoints and doses for risk assess ment for chronic dietary, dermal and inhalation routes of exposure (all durations), the risks from these exposure routes need to be aggregated.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Pendimethalin is classified as a “Group C”, p ossible human carcinogen based on a statistically significant increased trend and pair

- wise comparison between the high dose group and controls for thyroid follicular cell adenomas in male and female rats. A non

- quantitative approach (i.e.,

non

- linear, Rf

D approach) was recommended by the Cancer Peer Review Committee since mode of action studies are available to demonstrate that the thyroid tumors are due to a thyroid

pituitary imbalance, and also since pendimethalin was shown to be non

- mutagenic in mammal ian somatic cells and germ cells. The chronic risk assessment is considered to be protective of any cancer effects; such that , a separate quantitative cancer aggregate risk assessment is not required.

4. 5

. 4 Summary of Points of Departure and Toxicity Endp oints Used in Human Risk

Assessment

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 17 of 71 Table 4.5.4.1 Toxicological Doses and Endpoint for Pendimethalin Human Health Risk Assessment Exposure/Scenario Point of Departure Uncertainty/FQPA

Safety Factors RfD, PAD, Level of Concern

for Risk Assessment Study and Toxicological

Effects Acute Dietary (Females 13

- 49) No appropriate endpoint was identified including developmental toxicity studies in rats and rabbits.

Acute Di etary ( General population including infants and

children ) NOAEL=100 mg/kg UF A = 10 X

UF H = 10 X FQPA SF = 1X

Total UF = 10 0X Acute RfD = 1

mg/kg/day

a PAD = Acute RfD FQPA SF

= 1 mg/kg/day Acute neurotoxicity study (MRID 48695601). The LOAEL=300 mg/kg , based on reduced motor activity for

males and females on Day 0.

Chronic Dietary (all populations) NOAEL = 10 mg/kg/day UF A = 3 X

UF H = 10 X FQPA SF = 1X

Total UF = 30X Chronic RfD = 0.3

mg/kg/day

cPAD = Chronic RfD FQPA SF

= 0. 3 mg/kg/day 92

- Day thyroid function study in rats (MRID 42054601); 56

- day thyroid study in rats (MRID 43135001); 14

- day intra thyroid metabolism study in rats (MRID 43135003). LOAEL = 31 mg/kg/day based

on hormonal and histopathological changes in the thyroid. Incidental Oral Exposure

Oral

Short

- Term (1

- 30 days)

Intermediate

– Term (1

- 6 months) NOAEL = 10 mg/kg/day UF A = 3 X

UF H = 10 X FQPA SF = 1X

Total UF = 30X Residential LOC = 30 Occupational LOC = 30 The same as the chronic dietary.

Dermal Exposure

Dermal

Short

- Term (1

- 30 days)

Intermediate

– Term (1

- 6 months)

Long

– Term (>6 months) NOAEL = 10 mg/kg/day UF A = 3 X

UF H = 10 X FQPA SF = 1X

Total UF = 30X

Dermal Absorption =

3% Residential LOC = 30

Occupational LOC = 30 The same as the chronic dietary.

Inhalation Exposure

Inhalation

Short

- Term (1

- 30 days)

Intermediate

– Term (1

- 6 months)

Long

– Term (>6 months) NOAEL = 10 mg/kg/day UF A = 3 X

UF H = 10 X FQPA SF = 1X

Total UF = 30X

Inhalation Absorption = 100% Residential LOC = 30 Occupational LOC = 30 The same as the chronic dietary.

Cancer Cancer (oral, dermal, inhalation) Group C, possible human carcinogen based on a statistically significant increased trend and pair

- wise comparison between the high dose group and controls for thyroid follicular cell adenomas in male and

female rats. A non

- quantitative approach (i.e., non

- linear, RfD approach) was recommended by the

Cancer Peer Review Committee since mode of action studies are available

. UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic)

, RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable. UF A = extrapol ation from animal to human (inter species), UF H = potential variation in sensitivity among membe rs of the human population (intra

- species). UF DB = to account for the absence of key data (i.e., lack of a critical study).

Table 4.5. 4 .2 Summary of Toxicological Doses and Endpoints for Pendimethalin for Use in Occupational

Human Health Risk Assessments

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 18 of 71 Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Dermal Short

Term (1

- 30 days) NOAEL= 10

mg/kg/day UF A =3 x

UF H =10x Occupational

LOC for MOE

= 30 92

- Day thyroid function study in rats (MRID

42054601); 56

- day thyroid study in rats (MRID 43135001); 14

- day intra thyroid metabolism study in rats (MRID 43135003).
LOAEL = 31 mg/kg/day based on hormonal and histopathological changes in the thyroid.

Dermal

Intermediate

Term (1

- 6 months) NOAEL= 10

mg/kg/day UF A =3 x

UF H =10x Occupational

LOC for MOE

= 30 The same as above.

Inhalation

Short

- Term (1

- 30 days) NOAEL=10

mg/kg/day UF A =3 x

UF H =10x Occupational

LOC for MOE

= 30 The same as above.

Inhalation

Intermediate

term (1

- 6 months) NOAEL= 10

mg/kg/day UF A =3 x

UF H =10x Occupational

LOC for MOE

= 30 The same as above.

Cancer (oral, dermal, inhalation) Group C, possible human carcinogen based on a statistically significant increased trend and pair

- wise

comparison between the high dose group and controls for thyroid follicular cell adenomas in male and

female rats. A non

- quantitative approach (i.e., non

- linear, RfD approa ch) was recommended by the Cancer

Peer Review Committee since mode of action studies are available

. 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 extrapola tion 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 (interspeci es). UF H = potential variation in sensitivity among members of the human population (intra

- species). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk

assessment. UF DB = to account for the absence of key da ta (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Plan t Metabolism Studies

HED previously concluded that the nature of the residue in plants is understood, based on adequate studies conducted with [ 14 

### C]

- pendimethalin on potatoes and sweet corn. The results of these studies are supported by additional corn, cotton, dry bean, lima bean, peanut, potato, red table beet, rice, snap bean, soybean, sugarcane, and wheat metabolism data. These data are adequa te to define the nature of the residue in all plants. The residues of concern in plant commodities are pendimethalin and its 3,5

- dinitrobenzyl alcohol metabolite. The current tolerance expression for pendimethalin in 40 CFR §180.361 specifies the combined residues of pendimethalin and its 3,5

- dinitrobenzyl alcohol metabolite. Refer the following document for additional details: 1) Residue Chemistry Memo DP# 329627, W. Drew, 07/12/2006 and 2) Residue Chemistry Chapter, Pendimethalin RED (DP# 221531, B. Cro pp

- Kohlligian,

12/08/1995 )

Livestock Metabolism Studies

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 19 of 71 HED previously concluded that, pending resolution of residue characterization issues for goat kidney, the nature of the residue in animals is adequately understood based on acceptable goat and poult ry metabolism studies. The data indicate that there is no reasonable expectation of finite residues (pendimethalin, Goat Metabolite 6, and the 3,5

- dinitrobenzyl alcohol metabolite) in meat, milk, poultry and eggs (40 CFR §180.6[a][3]). Tolerances for pen dimethalin in/on livestock commodities are not needed for the purpose of these proposals. Refer to the following

referenced documents for the details: 1) Residue Chemistry Memo DP# 329627, W. Drew,

07/12/2006 2) Residue Chemistry Memo DP# s 271502; 310793; 311825; 314085; 314093; 317047; 317053 , W. Drew, 07/12/2006 and 3) Res idue Chemistry Chapter, Pendimethalin RED (DP# 221531, B. Cropp

- Kohlligian, 12/08/1995 )

.

5.1.2 Summary of Environmental Degradation

Pendimethalin dissipates in the environment by sorbing to soil, metabolizing by microbes, and by volatilizing into air as moisture content increases. Persistence decreased with increased temperature, increased moisture and decreased soil organic carbon. Pendimethalin residues in laboratory and field st udies are tightly sorbed to soil and sediment particles, which is consistent with the laboratory mobility studies.

Pendimethalin is stable to sterile hydrolysis, soil photolysis, and anaerobic soil metabolism, but degrades slowly under aqueous photolysis conditions with a calculated half

- life of 17 days.

Aerobic soil metabolism half

- lives range from 42

- 1322 days with 172 days used for the purpose of exposure assessment. Pendimethalin forms many minor « 1 0% of applied) degradates that consist primarily of an intact benzene ring with rearranged alkyl groups. Anaerobic aquatic

metabolism half

- lives ranged from 6 to 105 days, and aqueous residues bind to sediment under this condition. This association with soil/sediment is consistent with soil mobility studie s which indicated that pendimethalin is essentially immobile in all soils studied.

5.1.3 Comparison of Metabolic Pathways

Residue Chemistry Chapter, Pendimethalin RED (DP# 221531, B

. Cropp

- Kohlligian

, 12/08/1995 )

Pendimethalin IR

- 4 Tolerance Petition (DP# D 329627, W

. Drew, 07/12/2006 )



### The registrant has previously submitted acceptable studies depicting the metabolic fate of pendimethalin in plants , rats and livestock. All studies were conducted in a manner that is applicable and adequate for the proposed new uses. The residues identified in plant and animal metabolism studies include the parent pendimethalin and its 3,5

- dinitrobenzyl alcohol

metabo lite

.

Previously submitted a dequate crop data are available to demonstrate that pendimethalin residues

of concern do not concentrate in plant commodities derived from corn, and potatoes and that

radioactive residues in/on crops will be extensively metabolized. Additionally, t he nature of the

residue of pendimethalin in animals is adequately understood. Previously submitted d ata from the goat metabolism study, along with data from a poultry metabolism study indicate that there is

no rea sonable expectation of finite in meat milk, poultry, nor eggs as a result of the current registered uses and consequently the proposed new uses of pendimethalin

.

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 20 of 71 In a previously submitted rat metabo lism study, radioactive pendimethalin as administered to rats
indicated that about 70% of the radioact ivity is excreted in the feces and 20% in the urine within 24 hours. The major portion of the radioactivity that was excreted in the feces was identified as the parent compound. P endimethalin is metabolized in r ats mainly through oxidation of the 4

- methyl group attached to the benzene ring as well as oxidation of the alkyl side chain of the N

substituted dinitroaniline compound.

5.1.4 Residues of Concern Summary and Rationale

As summarized in Table 5.1 .4. The HED MARC recommends that the parent compound and its

alcohol metabolite as the residues of concern for the tolerance expression and the risk

assessment

, it should be included for all plant commodities

. However, t here is no need for a

residue assessment definition for livestock commodities ( no reasonable expectation of finite

residues )

. The drinking water values consider a total residue methodology analysis.

Table 5.1.4 Summary of Metabolites and Degradates included in the Pendimethalin Risk Assessm ent and Tolerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Pendimethalin and 4

- [(1

- ethylpropyl)amino]

- 2

- methyl

- 3,5

- dinitrobenzyl alcohol (CL 202347) Pendimethalin

and (CL 202347) Rotational Crop

Livestock Ruminant Not applicable

- there is no reasonable expectation of finite residues in

livestock. Poultry

Drinking Water Pendimethalin Not Applicable



### 5 .2 Food Residue Profile

The specific details have been submitted in the following referenced document s : 1) DER

Reference: 47891603.der3 , 2) Residue Chemistry Memo DP# 372876, Y. Barnes, 03/10/2010, 3 ) Residue Chemistry Memo DP# 238469, W. Cutchin, 07/21/1999, and 4 ) Residue Chemistry Chapter, Pendimethalin RED (DP# 221531, B. Cropp

- Kohlligian, 12/08/1995 ) . The food residue profile (Table 5.2) for the new uses is described below.

The available and submitted concurrent storage stability data are adequate to support the submitted crop field trial s. The data indi cate that there are no storage stability issues, and no

corrections for decline after storage are needed.

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 21 of 71 TABLE 5.2 Summaries of Residue Data from Field Trials with Pendimethalin.

Leaf Lettuce Crop Field Trials MRID 48489801

Commodity Analyte Total

Rate (lb a.i. /A) PHI

(days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Leaf lettuce Pendimetha

lin 0.98

- 1.03 18

- 21 9 <0.05 2.251 0.05 2.230 0.062 0.338 0.714

26

- 33 8 <0.05 1.191 0.05 1.010 0.05 0.174 0.338

CL 202347 3 18

- 21 9 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

26

- 33 8 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

Combined 18

- 21 9 <0.10 <2.301 0.10 2.280 0.112 0.388 0.714

26

- 33 8 <0.10 <1.241 0.10 1.060 0.10 0.224 0.338

Mustard Greens Crop Field Trials MRID 48489802

Commodity Analyte Total

Rate (lb a.i. /A) PHI

(days) Residue Levels (ppm) 1

n Sample

Min. Sampl

e Max. LAFT 2 HAFT 2 Media

n Mean Std.

Dev.

Mustard

greens Pendimetha

lin 0.48

- 0.53 21

- 35 8 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

0.97

- 1.04 13

- 35 <0.05 0.107 0.05 0.107 0.05 0.061 0.021

CL 202347 3 0.48

- 0.53 21

- 35 8 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

0.97

- 1.04 13

- 35 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

Combined 0.48

- 0.53 21

- 35 8 <0.10 <0.10 0.10 0.10 0.10 0.10 N/A

0.97

- 1.04 13

- 35 <0.10 0.157 0.10 0.157 0.10 0.107 0.020

Cantaloupe Crop Field Trials MRID 48489803

Commodity Analyte Total App.

Rate (lb

a.i. /A) PHI (days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT

2 HAFT

2 Median Mean Std.

Dev.

3.8 lb a.i. /gal CS formulation

Cantaloupe Pendimethali

n 1.96

-

2.02 35

- 47 8 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

CL 202347 3 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

Combined <0.10 <0.10 0.10 0.10 0.10 0.10 N/A

3.3 lb a.i. /gal EC formulation

Cantaloupe Pendimethali

n 1.96

-

2.00 47

- 49 2 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

CL 202347 3 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

Combined <0.10 <0.10 0.10 0.10 0.10 0.10 N/A

Kiwifruit Field Crop Trials MRID 48489801

Commodity Analyte Total

Rate (lb

a.i. /A) PHI

(days) Residue Levels (ppm) 1

n Sampl

e Min. Sample

Max. LAFT 2 HAFT 2 Media

n Mean Std.

Dev.

Kiwifruit Pendimethalin 6.09

- 6.22 58

- 60 2 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

CL 202347 3 2 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

Combined 2 <0.10 <0.10 0.10 0.10 0.10 0.10 N/A

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. N/A = not applicable.

2 LAFT = lowest average field trial; HAFT = highest average field trial.

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 22 of 71 3 Residues of metabolite CL 202,347 were converted to parent equivalents; the molecular weight conversion factor

is 0.9462.



### No crop field trial data were submitted /or needed in support of the proposed use on vegetable soybean (edamame). The HED’s Chemistry Science Advisory Council ( Note: ChemSAC

, recommendations on 09/15/10 and 10/27/10 ) previously concluded that a tolerance for vegetable soybean (edamame) could be established at the same level as the established tolerances for bean (succulent) and pea (except fiel d pea).

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the

Environmental Fate and Effects Division

, E FED ( Barcode: D390459, 02/23/2012, W. P. Eckel ) and incorporated directly into the dietar y assessment.

This memorandum provided the estimates of human drinking water exposure to the herbicide pendimethalin from the proposed new uses on Kiwi/small fruits (Amur river grape, gooseberry, fuzzy kiwifruit, hardy kiwifruit, maypop, and Schisandra be rry), Leaf lettuce, Leafy brassica greens, Melons (cantaloupe, citron melon, muskmelon, and watermelon) and Edamame (edible soybeans)

. The memorandum specifically referred to the details noted in the last drinking water assessment (DWA) for pendimethalin t hat was completed on February 23, 2009 for the proposed uses on olives and forage grasses (Barcodes D356491 and D355650). The result s of the

aforementioned assessment indicated that the EDWC remained the same as in the 05/08/2007 DWA (Barcode D334061).

The EDWCs for the proposed new uses are 80.5 ppb ( 1

- in

- 10 year annual peak acute

concentration ), 6.2 ppb ( 1

- in

- 10 year annual mean chronic concentration), and 5.0 ppb ( 30

- year annual mean (cancer) chronic concentration ) for surface water (Table 5. 3 ) . These data are slightly higher than the 2007 results due to model changes and new environmental fate data. The ground water EDWC (SCIGROW model) remains unchanged at 0.036 ppb for a 6

- pound/acre application (kiwi and small fruits).

Table 5.3 provides a summa ry of the modeled drinking water concentrations. The model and its description are available at the EPA internet site
: 

### http://www.epa.gov/oppefed1/models/water/

.

Table 5. 3
Summary of Estimated Surface Water and Groundwater Concentrations for Pendimethalin

Scenario Surface Water Conc., ppb a 

### Groundwater Conc., ppb b



### Acute 80.5 0.036

Chronic (non

- cancer) 6.2 0.036

Chronic (cancer) 5.0 NA

a PRZM

- EXAMS

- Index Reservoir model. Input parameters are based on grapes in New York state (See May 8, 2007 DWA, DP Barcode 334061, J. Breithaupt, EFED to D. Rosenblatt, RD).

b From the SCI

- GROW model assuming a maximum seasonal use rate of 6 lbs a.i./A (kiwi and small fruits)

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 23 of 71 5.4 Dietary Risk Assessment
Pendimethalin Dietary Assessment ( D401100.drs

, Y. Barnes

, 05/02/2012 )



### 5.4.1 Description of Residue Data Used in Dietary Assessment

A cute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM

- FCIDTM, Version 2.03 which uses food consumption data from the U.S. Department of Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994

- 1996 and 1998. The

deterministic acute and unrefined chronic analyses are based on tolerance

- level residues

, 100% crop treated assumptions for all of pendimethalin use commodities in this assessment and

DEEMTM d efault processing factor s or empiri cal processing factors where available

. T he drinking water estimates provided by EFED are modeled estimates, and were generated using the most conservative model available for the proposed crops and turf uses

. The deterministic acute
and unrefined chroni c approach to dietary exposure analysis may over estimate risk to the general U.S. population.

5.4.2 Percent Crop Treated Used in Dietary Assessment

T he acute and chronic assessments are based on the assumption tha t 100% for all pendimethalin

use commodit ies, both recommended and registered were treated.

5.4.3 Acute Dietary Risk Assessment

The results for the most highly exposed subgroups for pendimethalin have an estimated exposure (food and water) as follows: 2.0 % of the aPAD for all infants, 1.4 % of the aPAD for children 1

- 2 years old, and 1.2% of the aPAD for children 3

- 5 years old. For the general U.S. population the estimated exposure (food and water) from the use of pendimethalin result in an estimated risk equivalent to <1% of the acute populati on adjusted dose (aPAD) at the 95 th 

### percentile of exposure (Table 5.4.6). The acute dietary risk estimate is below HED’s level of concern at the

95 th 

### percentile of exposure.

5.4.4 Chronic Dietary Risk Assessment

The results of the most highly exposed subgroups for pendimethalin have an estimated exposure (food and water) as follows: 1.0% of the cPAD for all infants, 1.6% of the cPAD for children 1

- 2 years old, and 1.3% of the cPAD for children 3

- 5 years old. For t he general U.S. population the estimated exposure (food and water) from the use of pendimethalin result in an estimated risk equivalent to <1% of the chronic population adjusted dose (cPAD), refer to Table 5.4.6. The chronic dietary risk estimate for food and drinking water are below HED’s level of concern.

5.4.5 Cancer Dietary Risk Assessment

A non

- quantitative approach (i.e., non

- linear, RfD approach) was recommended by the Cancer

Peer Review Committee since mode of action studies are available to dem onstrate that the thyroid tumors are due to a thyroid

- pituitary imbalance, and also since pendimethalin was shown

to be non

- mutagenic in mammalian somatic cells and germ cells. The chronic risk assessment is

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 24 of 71 considered to be protective of any cancer effect s; therefore, a separate quantitative cancer aggregate risk assessment is not required.



## 5.4.6 Summary Table

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

Population Subgroup Acute Dietary 1

(95th Percentile) Chronic Dietary 1

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

General U.S. Population 0. 007460 <1 0.001621 <1

All Infants (< 1 year old) 0. 019305 2 .0 0.003067 1 .0

Children 1

- 2 years old 0. 014344 1. 4 0.004677 1.6

Children 3

- 5 years old 0. 011797 1. 2 0.003840 1.3

Children 6

- 12 years old 0.009042 <1 0.002346 <1

Youth 13

- 19 years old 0.006621 <1 0.001500 <1

Adults 20

- 49 years old 0.006773 <1 0.001250 <1

Adults 50+ years old 0.006115 <1 0.001158 <1

Females 13

- 49 years old 0.006837 <1 0.001265 <1

* Note: HED is concerned when dietary risk estimates exceed 100% of the PAD

. Values for the population with the highest risk are in bold type

.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Pendimethalin: Occupational and Residential Exposure/Risk Assessment for Registration Review and for new Proposed Use on Leaf lettuce; Leafy brassica greens; Melons; Edamame; Kiwi and other small fruit vines. S. Shelat, B. Bobowiec, DP 402406

, 0 5/ 31/ 2012

P endimethalin: REVISED Occupational and Residential Exposure Assessment for Proposed Section 3 Registration for Use on Mint, Citrus Fruits, Tree Nuts, and Carrots. M. Collantes, Z. Figeuroa, DP325175, 0 4/ 0 2/2007.



### The proposed uses for pendimethalin do not include residential (non

- occupational) uses. Although, the proposed uses for Prowl ® 

### H 2 

### O are not anticipated to result in residential exposures, an updated residential handler and post

- application assessment ha s been conducted due to changes in the Standard Operating Procedures for Residential Pesticide Exposure Assessment, body weights, as well as the incorporation of new toxicology data. Updated residential handler and post

- application risk estimates do not e xceed HED’s level of concern (MOEs ≥ 30). Updated residential exposure risk estimates are also provided for consideration in the aggregate risk assessment.

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 25 of 71 The residential scenarios addressed include uses on residential turf and ornamentals. Residentia l

post

- application scenarios include exposure from previously treated golf courses, turf in residential areas, and ornamentals.

6.1 Residential Handler Exposure

The proposed uses of pendimethalin do not involve applications by homeowners or commercial applicators to residential settings. However, pendimethalin is currently registered for use on

several residential/non

- agricultural use sites: i.e., northern and southern grasses ; sod farms ; lawns ; parks; golf courses; in and around ornamentals ; and w eed control in non

- cropland areas, such as landscape ground covers. Pendimethalin is also registered for use on container grown and field grown ornamentals, however, it is not to be used in greenhouses, shade houses, or other

enclosed structures. It is a ssumed that most residential use will result in short

- term (1 to 30 days) handler exposures. Residential handlers are assumed to be wearing short

- sleeved shirts, short pants, shoes and socks during application of pendimethalin

. Although PoDs from an oral study were used to assess residential handler dermal and inhalation risks for pendimethalin, HED

does not believe this assessment is under

- protective of adult handlers.

HED’s level of concern for the MOE is defined by the uncertainty facto rs that are applied to the assessment. HED applies a 3X factor to account for interspecies extrapolation and a 10X factor

to account for intra

- species sensitivity. The total uncertainty factor that has been applied to the

non

- cancer risk assessment for p endimethalin is 30X for residential exposure. Residential exposure and risk estimates resulting in MOEs greater than or equal to 30 will not be of concern

to HED.

The worst case residential handler scenario is summarized in Table 6.1. The MOE was 670 for

residential handlers loading and applying the granular formulation of pendimethalin , and is not of concern to HED (i.e. an MOE > 3 0).

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 26 of 71 Table 6.1: Short

- Term Residential Handler Exposure and Risk Estimates for Pendimethalin

Exposure Scenario Target

MOE Dermal Unit

Exposure Inhalation Unit

Exposure Application

Rate a Amount

Treated

or Handled Daily b Dermal Inhalation Total

Dose c MOE d Dose e MOE f MOE g

Mixe r/loader/Applicator

Loading/applying granulars with a belly grinder 30 360 0.039 4 lbs ai/acre 0.028 0.015 670 0.000054 180,000 670

a. Based on a review of the registered labels of pendimethalin for use in or around ornamentals

b. Belly grinder assumption of 12 00 sq ft per day is calculated to b e equivalent to 0.023 acres ((12 00 sq ft/day ) x (43,560 sq ft/1 acre) = 0.023 acres/day)

c. Dermal Dose = Dermal Unit Exposure (mg/kg) x Application Rate ( 4lb ai/acre ) x A mount Treated or Handled ( 0.023 A / day) x DAF ( 3 % )/BW ( 80 kg)

d. Dermal MOE = Dermal NOAEL ( 10 mg/kg/day)/Dermal Dose (mg/kg/day)

e. Inhalation Dose = Dermal Unit Exposure (mg/kg) x Application Rate ( 4 lb ai/acre) x A mount Treated or Handled ( 0.023 A/day) /BW ( 80 kg)

f. Inhalation MOE = Inhalation NOAEL ( 10 mg/kg/da y)/ Inhalation Dose (mg/kg/day)

g. Total MOE = Total MOE = 1/[(1/Dermal MOE) + (1/Inhalation MOE)]

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 27 of 71 6.2 Post

- Application Exposure

Post

- application short

- term dermal and incidental oral exposure and risk estimates have been assessed for pendimethalin exposure from treated turf in residential settings (i.e., lawns and gardens) as well as from exposure to golf courses previously treated by a commercial applicator. When determining the potential for residential exposure, the Agency considers turf transferable residues, transfer coefficients, residue transfer to hands, residue transfer to objects, soil and granular ingestion rates, and e xposure time. Two turf transferable residue studies were utilized in the determination of post

- application exposure from pendimethalin treated turf. Determination of Transferable Turf Residue Dissipation from Turf Treated with Suspension Concentrate and Emulsifiable Concentrate Formulations of Pendimethalin ( MRID No.: 4 66841

- 02). Residues from the Georgia site were selected because they resulted in the highest Day 0 residues.
Pendulum® WDG Herbicide ( MRID No.44969901 ) . The Day 0 residues detected were
generally at or below the LOQ with the exception of 7 days after treatment when residues
averaged 17.5 ng/cm 2 

### at the Pennsylvania site in MRID 44969901. Data from the
Pennsylvania site was used in this assessment as it resulted in the only detectable residue
after application.

Dermal and oral exposures were combined as the same study was used to identify the toxicological effects from the dermal and oral routes of exposure. The scenarios, routes of exposure and lifesta ges assessed include:

Physical activities on turf: adults (dermal) and children 1 < 2 years old (dermal and incidental oral); Mowing: adults (dermal) and children 11 < 16 years old (dermal); and Golfing: adults (dermal), children 11 < 16 years old (derm al), and children 6 < 11 years old (dermal).

Based on the Agency's current practices, a quantitative residential post

- application inhalation exposure assessment was not performed for p endimethalin at this time primarily because pendimethalin’s vapor pressure ( 3 x 10 - 5 

### mm Hg @ 25 °C) and Henry's Law Constant ( 8.6 x 10 -

0 7 

### atm m 3 

### /mol) indicate that the compound is relatively non

- volatile under field conditions. The Agency sought expert advice and input on issues related to volatilization of pes ticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agen cy is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new p olicies or procedures are put into place, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for pendimethalin

The MOEs for worst

- case post

- application dermal exposures are summarized in Tables 6.2

. The

MOE s ranged from 130 to 410 ,000 for both dermal exposure and incidental oral ingestion. All

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 28 of 71 assessed residential exposures and risk estimates resulted in MOEs of > 3 0; and therefore, are not

of concern to HED.

Table 6.2: Short

- Term Residential Post

- application Exposure and Risk Estimates for Pendimethalin

Lifestage Post

- application Exposure Scenario Dose (mg/kg/day) MOEs

Adult

Turf sprays

–

physical activities on turf Dermal 0.032 320

Child 1< 2 Dermal 0.060 170

Hand to Mouth 0.042 240 Object to Mouth 0.0013 7,800 Incidental Soil Ingestion 6.5E

- 05 150,000 Episodic Granular Ingestion 0.71 140

Adult

Turf sprays

- Golfing Dermal 0.0037 2,700
11 to <16 years Dermal 0.0043 2,300
6 to <11 years Dermal 0.0051 2,000

Adult Gardening sprays Dermal 0.078 130 6 to <11 years Dermal 0.053 190



### 6.3 Combined Exposure

HED did not combine exposure resulting from adult handler and post

- application exposure resulting from treated lawns and/or golfing because of the conservative assumptions and inputs within each estimated exposure scenario. HED believes that combin in g exposures resulting from handler and post

- application activities would result in an overestimate of adult exposure. Therefore, HED selected the most conservative adult reside ntial scenario, dermal post

application exposure (MOE = 130 ) as the contributing source of residential exposure to be combined with the dietary exposure for the aggregate assessment

.

The children’s oral exposure is based on post

- application hand

- to

- mouth exposures ( MOE = 240). To include exposure from object

- to

- mouth and soil ingestion in addition to hand

- to

- mouth could result in a very conservative estimation of exposure, as it would overestimate the potential for oral exposure. However , there is the po tential for co

- occurrence of dermal and oral exposure, since the toxicological effects from the dermal and oral routes of exposure are the same. As a result, a combined residential exposure assessment is possible for children. Therefore, one

children’s a ggregate assessments is required (combined post

- application dermal and oral combined with dietary exposure) to ensure no unacceptable risk will result to children when combining residential and dietary exposure for purposes of estimating an aggregate risk.

Table 6.3.1 summarizes the residential exposure scenarios that are to be used for estimating

aggregate exposure.

Table 6.3.1. Short

- Term Residential Exposures for the Pendimethalin Combined Residential Risk Calculations

Population Handler Exposure

(mg/kg/day) 1 Residential

Handler Total Exposure (mg/kg/day) 3 Postapplication Exposure (mg/kg/day) 2 Residential Post

application Total Exposure (mg/kg/day) 3 Dermal Inhalation Dermal Inhalation Oral

Adult 0.015 5.4E

- 05 0.015 0.078 N/A N/A N/A

Child N/A N/A N/A 0.060 N/A 0.042 0.102

1 Handler exposure represents high end dermal exposure resulting from applying granular with a belly grinder

2 Postapplication exposure represents high end dermal and incidental oral exposure for the relevant exposure duration

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 29 of 71 3 F or adults, r esidential total exposure combines the highest dermal and inhalation exposure s (Table 6.1 ) , where applicable. For young children, total residential exposure combines high end post application incidental oral AND dermal exposure
, where applicable (Table 6.2 ). Handler exposures should not routinely be combined with post

- application exposures. NOTE: The highest estimated total residential exposure (for adults and chil d populations ) should be used as the basis of the aggregate

calcu lation in section 7.



### 6.4 Residential Bystander Postapplication Inhalation Exposure

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

- application inhalation exposure assessment was not performed for pendimethalin at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought ex pert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 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 is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalatio n exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment

for pendimethalin.

6. 5 Spray Drift

Spray drift is always a pot ential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground a pplication method employed for pendimethali n

. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more inf ormation at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks

associated with drift.

Although a quantitative residential postapplication inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. Th is exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial postapplication inhalation exposure scenarios

.

7.0 Aggregate Exposure/Risk Characterization

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 30 of 71 In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and com pared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. For pendimethalin, potential exp osures from food , drinking water, and residential scenarios were aggregated. This assessment has considered the changes in the new Residential Standard Operating Procedures (SOPs) implemented in January of 2012.

7.1 Acute Aggregate Risk

The aggregate acute risk estimates include exposure to residues of pendimethalin in food and water, and does not include dermal, inhalation or incidental oral exposure. The acute risk estimate for the U.S. population and all other population subgroups, re sulting from aggregate

exposure to pendimethalin i n food and drinking water

, is below the Agency’s LOC. The food and drinking water exposure estimates are < 1 % of the aPAD for the U.S. general population,

and 2.0 % for the most highly exposed life stage , c hildren < 1 years old.

7.2 Short

- Term Aggregate Risk

There is potential short

- term exposure to pendimethalin via dietary (which is considered background exposure) and residential (which is considered primary) exposure pathways. For adults, these pathways lead to exposure via oral (background) as well as dermal and inhalation (primary) routes. The most conservative scenario was chosen for each population (i.e. combined

hand

- to

- mouth and dermal exposure from treated turf for children 1 < 2 years old). For a description of the residential exposure scenarios considered in the aggregate assessment, see

Section 6.0.

The adult (dermal) aggregate MOE (for males and females) is 12 5 , which indicates that exposure

and risk do not excee d HED’s level of concern (MOE > 30 ). The aggregate MOE for children

1 < 2 years old, including dermal and incidental oral exposures from treated turf is 9 3 , which indicates that exposure and ri sk do not exceed HED’s LOC (MOE > 30 ). Further refinement using additional % CT estimates or more refined EDWCs may need to be incorporated in future

assessments.

Table 7.2 Short

- Term Aggregate Risk Calculations for Pendimethalin

Life stage Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Tota l

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5



### Adult 10 30 0.33 0. 001621 0.078 0. 08 0 12 5

Child 10 30 0.33 0.004677 0.102 0.1 0 7 9 3

1 Intraspecies factor= 10x; Interspecies factor = 3x

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL (10 mg/kg/day) /LOC (30)

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 31 of 71 3 Child Residential Exposure = [Oral exposure (0.042 mg/kg/day) + Dermal exposure (0.060 mg/kg/day) =0.102 mg/kg/day ( Table 6.3.1 )

4 Total Exposure = Avg Food & Water Expo sure + Residential Exposure)

5 Adult (10 mg/kg/day ) / ( Total Exposure (0.08 mg/kg/day )] ; Child Aggregate MOE = (10 mg/kg/day ) / ( Total Exposure (0.107 mg/kg/day)]



### 7.3 Chronic Aggregate Risk

Chronic e xposure is not expected for the residential (dermal and inhalation) exposure pathway. Therefore, the chronic aggregate risk would be equivalent to the chronic dietary exposure

estimate. Refer to Section 5.4. 3 for the chronic dietary (food and drinking wa ter) exposure

assessment.

7. 4 Cancer Aggregate Risk

Pendimethalin is considered a “possible human carcinogen” based on a statistically significant increased trend and pair

- wise comparison between the high dose group and controls for thyroid

follicular cell adenomas in male and female rats. A non

- quantitative approach (i.e., non

- linear, RfD approach) was recommended by the Cancer Peer Review Committee since mode of action studies are available to demonstrate that the thyroid tumors are due to a thyroid

- pituitary imbalance, and also since pendimethalin was shown to be non

- mutagenic in mammalian somatic cells and germ cells. The chronic dietary risk assessment is considered to be protective of any cancer effects; as a result , a separate quantitative cancer aggregate risk assessment is not required

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mecha nism of toxicity finding as to pendimethalin and any other substances and pendimethalin does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore,

EPA has not assumed that pendimethalin has a common mec hanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterizat ion

Pendimethalin: Occupational and Residential Exposure/Risk Assessment for Registration Review and for new Proposed Use on Leaf lettuce; Leafy brassica greens; Melons; Edamame; Kiwi and other small fruit vines, S. Shelat; B. Bobow i ec, DP 402406

, 0 5/ 31 /20 12.



### 9.1 Short

- /Intermediate

- Term Handler Risk

Pendimethalin is a selective herbicide used for controlling an nual grass and broadleaf weeds that

is generally applied early in the growing season as a pre

- emergent and early post

- emergent
herbicide

. Application methods, maximum application rates and use sites are summarized in Table 3.3. Based on the proposed use pattern of pendimethalin there is a potential for short

- and

### Pendimethalin Human Health Risk Assessment DP No. D390457

Page 32 of 71 intermediate

- term occupational exposure during handling (mixing & loading) and limited post

application activities (irrigation, scouting, harvesting). Chronic exposure is not expected for the proposed use patterns. PPE was assessed at baseline ( long pants, a long

- sleeved shirt, shoes, socks, no chemical

- resistant gloves, and no respirator ) as well as varying levels of personal protective equipment. HED evaluated the proposed uses as well as existing uses of pendimethalin.

HED’s level of concern for the MOE is defined by the uncertainty factors that are applied to the

assessm ent. HED applies a 3X factor to account for interspecies extrapolation and a 10X factor

to account for intra

- species sensitivity. The total uncertainty factor that has been applied to the

non

- cancer risk assessment for pendimethalin is 30X for occupation al exposure. Occupational exposure and risk estimates resulting in MOEs greater than or equal to 30 will not be of concern

to HED.

A quantitative dermal and inhalation exposure assessment was performed. Summaries of the

short

- and intermediate

- term risks for occupational handlers applying pendim e thalin to proposed and registered crops are included in Table 9.1.1 and Table 9.1.2 (dry bulk fertilizer uses). The results of the occupational handler exposure and risk assessment indicate that total short

- and

intermediate

- term MOEs are not of concern to HED (i.e. an MOE > 30 ) with baseline attire for most uses, exception of the following exposure scenarios: mixing and loading for chemigation and aerial a pplication of alfalfa and sugarcane (MOE = 24) mixing /loading/application with a handgun sprayer for drench application to turf grasses

and ornamentals (MOE = 20) commercial impregnation for dry bulk fertilizer for grape, kiwi, and other small fruit vines (MOE = 26) These exposure scenarios were assessed wit h additional personal protective equipment. Risk estimates for these uses with gloves and/or respirators do not exceed HED’s level of concern (MOE ≥ 30) for the alfalfa, sugarcane, and the turf and ornamental scenario, however, no

additional PPE can be as sumed for the dry bulk fertilizer use because the commercial impregnation takes into account a closed system . Table 9.1.3 presents the exposure and risk estimates of the aforementioned scenarios with the incorporation of personal protective equipment.

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 33 of 71 Table 9 .1.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin (with baseline protection).

Exposure Scenario Crop or Target Application

Rate 2

lb ai/A Area Treated or

Amount Handled Daily 3 Unit Exposure (mg/lb ai) 1 Dose (mg/kg/day) 4 Short

- and Intermediate

- term
MOEs 5 Combined Short

and

Intermediate

term MOEs 7 Baseline 6

Dermal Baseline 6

Inhalation Baseline

Dermal Baseline

Inhalation Baseline

Dermal Baseline

Inhalation

Mixer/ Loader

Mixing/Loading Liquids for Aerial, and/or Chemigation, Applications (AHETF) Bearing fruit and nut trees,

non bearing fruit and nut

t rees and nonbearing vineyards , olive trees, artichoke, asparagus, clover, Bermuda grass 4 350 acres

0.22 0.000219 0.12 0.0038 87 2600 84

Alfalfa , Sugarcane 4 1200 acres 0.4 0.013 25 760 24

Corn and Cotton 2 1200 acres 0.2 0.0066 51 1500 49

fruiting vegetables, garlic, onion mineral soil, peanuts, potato, strawberry, artichoke, edible beans, fallow, lentil and peas,

tobacco 1.5 350 acres 0.043 0.0014 230 7000 220

Carrots, green onion,

brassica and stem vegetables, leafy brassica

greens 1 350 acres 0.029 0.00096 350 10000 340

Sunflowers 1.75 350 acres 0.51 0 .0017 200 6000 190

Vegetable soybean (edamame) 1.43 350 acres 0.41 0.0014 240 7300 230

Mint 2 350 acres 0.58 0.0019 170 5200 170

Wheat 1.5 1200 acres 0.15 0.0049 67 2000 65

Bearing and non

- bearing grape, kiwi and other small

fruit vines 6 350 acres 0.17 0.0057 58 1700 56

Rice and soybeans 1 1200 acres 0.099 0.0033 100 3000 98

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 34 of 71 Table 9 .1.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin (with baseline protection).

Exposure Scenario Crop or Target Application

Rate 2

lb ai/A Area Treated or

Amount Handled Daily 3 Unit Exposure (mg/lb ai) 1 Dose (mg/kg/day) 4 Short

- and Intermediate

- term
MOEs 5 Combined Short

and

Intermediate

term MOEs 7 Baseline 6

Dermal Baseline 6

Inhalation Baseline

Dermal Baseline

Inhalation Baseline

Dermal Baseline

Inhalation

Mixing/Loading liquids for groundboom applications (AHETF) Carrots for seed production,

mint, onion muck soil 2 80 acres 0.013 0.00044 760 23000 730

Carrots, Green Onion,

brassica head and stem vegetables, leafy brassica greens, and melons 1 80 acres 0.0066 0.00022 1500 46000 1500

Corn and Cotton 2 200 acres 0.033 0.0011 300 9100 290

Rice, soybeans 1 200 acres 0.017 0.00055 610 18000 590

Bearing fruit trees, non bearing fruit trees, and nonbearing vineyards, Olive trees, artichoke, asparagus, clover, bermudagrass 4 80 acres 0.026 0.00088 380 11000 370

Alfalfa, Sugarcane` 4 200 acres 0.066 0.0022 150 4600 150

Bearing and nonbearing

grape , citrus trees, and kiwi

and other small vines 6 80 acres 0.04 0.0013 250 7600 240

Sunflowers 1.75 80 acres 0.012 0.00038 870 26000 840

Wheat 1.5 200 acres 0.025 0.00082 400 12000 390

Fruiting vegetables, garlic, onion mineral soil, peanuts, potato, strawberry, artichoke, edible beans, fallow, grain sorghum, lentils and peas, tobacco 1.5 80 acres 0.0099 0.00033 1000 30000 980

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 35 of 71 Table 9 .1.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin (with baseline protection).

Exposure Scenario Crop or Target Application

Rate 2

lb ai/A Area Treated or

Amount Handled Daily 3 Unit Exposure (mg/lb ai) 1 Dose (mg/kg/day) 4 Short

- and Intermediate

- term
MOEs 5 Combined Short

and

Intermediate

term MOEs 7 Baseline 6

Dermal Baseline 6

Inhalation Baseline

Dermal Baseline

Inhalation Baseline

Dermal Baseline

Inhalation

Mixing/Loading Liquids for open cab airblast (AHETF) Grape and citrus fruit and

nut trees , kiwi and other

small vines 6 40 acres

1.77 0.00471 0.02 0.00066 510 15000 490

Olive trees, asparagus 4 40 acres 0.013 0.00044 760 23000 730

Mixing/Loading Liquids for Aerial Applications (AHETF) Turf 2 350 acres

0.22 0.000219 0.058 0.0019 170 5200 170

Ornamentals 4 350 acres 0. 12 0.0 038 87 2600 84

Loading Granules for

Tractor

- drawn broadcast spreaders Applications (PHED) Turf 2 80 acres

0.0084 0.0017 0.0005 0.0034 20000 2900 2600

Ornamentals 4 80 acres 0.001 0.0068 9900 1500 1300

Mixing/Loading Liquids for

Groundboom Applications (AHETF) Turf 2 80 acres

0.22 0.000219 0.013 0.00044 760 2300 730

Ornamentals 4 80 acres 0.026 0.0009 380 11000 370

Applicator

Applying Sprays via Aerial Equipment (PHED)

(engineered control) A rtichoke, bermudagrass, perennial grass for seed,

asparagus 4 350 acres

0.005 0.000068 0.0026 0.0012 3800 8400 2600

Brassica head and stem vegetables, carrots, green onions, leafy lettuce 1 350 acres 0.00066 0.0003 15000 34000 10000

Mint 2 350 acres 0.0013 0.0006 7600 17000 5200

Sunflowers 1.75 350 acres 0.0011 0.00052 8700 19000 6000

Alfalfa , Sugarcane 4 1200 acres 0.009 0.0041 1100 2500 760

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 36 of 71 Table 9 .1.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin (with baseline protection).

Exposure Scenario Crop or Target Application

Rate 2

lb ai/A Area Treated or

Amount Handled Daily 3 Unit Exposure (mg/lb ai) 1 Dose (mg/kg/day) 4 Short

- and Intermediate

- term
MOEs 5 Combined Short

and

Intermediate

term MOEs 7 Baseline 6

Dermal Baseline 6

Inhalation Baseline

Dermal Baseline

Inhalation Baseline

Dermal Baseline

Inhalation

Wheat 1.5 1200 acres 0.0034 0.0015 3000 6500 2000

Corn, and Cotton 2 1200 acres 0.0045 0.002 2200 4900 1500

Rice and Soybeans 1 1200 acres 0.0023 0.001 4400 9800 3100 fruiting vegetables, garlic, onion mineral soil, peanuts, potato, strawberry, edible beans, fallow, grain sorghum, lentils and peas, onions and shallots, vegetable soybean (edamame) 1.5 350 acres 0.00098 0.00045 10000 22000

7000

Applying Sprays via

Groundboom Equipment (AHETF) Wheat 1.5 200 acres

0.0786 0.00034 0.0088 0.0013 1100 7800 990

Bearing and non bearing grape and citrus and nut

trees and kiwi and other

small vines 6 80 acres 0.014 0.002 710 4900

620

Edible bean, fruiting vegetables, garlic, grain sorghum, lentil and peas, onions mineral soil,

peanuts, potatoes, strawberry, no till sunflowers, tobacco, artichoke, fallow, 1.5 80 acres 0.0035 0.00051 2800 20000

2500

Mint and onions 2 80 acres 0.0047 0.00068 2100 15000 1900

Corn and Cotton 2 200 acres 0.012 0.0017 850 5900 740

Brassica head and stem vegetables, carrots, green onions, leafy lettuce, melon 1 80 acres 0.0024 0.00034 4200 29000 3700

Rice and soybeans 1 200 acres 0.0059 0.00085 1700 12000 1500

Alfalfa , Sugarcane 4 200 acres 0.024 0.0034 420 2900 370

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 37 of 71 Table 9 .1.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin (with baseline protection).

Exposure Scenario Crop or Target Application

Rate 2

lb ai/A Area Treated or

Amount Handled Daily 3 Unit Exposure (mg/lb ai) 1 Dose (mg/kg/day) 4 Short

- and Intermediate

- term
MOEs 5 Combined Short

and

Intermediate

term MOEs 7 Baseline 6

Dermal Baseline 6

Inhalation Baseline

Dermal Baseline

Inhalation Baseline

Dermal Baseline

Inhalation Bearing fruit trees, non bearing fruit trees and nonbearing vineyards, olive trees, artichoke, bermudagrass, clover,

asparagus , olive tress 4 80 acres 0.0094 0.0014 1100 7400 930

Sunflowers 1.75 80 acres 0.0041 0.0006 2400 17000 2100

Applying Sprays via Open Cab Airblast (AHETF) Grape, citrus fruit and nut

trees and kiwi and other

small fruit vines 6

40 acres 1.77 0.00471 0.16 0.014 63 710 58

Bearing fruit trees, Olive

trees, asparagus 4 0.11 0.0094 94 1100 86

Applying Sprays via Aerial Equipment (PHED)

( Engineered Control) Turf 2 350 acres 0.005 0.000068 0.0013 0.0006 7600 17000 5200

Applying Sprays via

Aerial Equipment (PHED)

(Engineered Control) Ornamentals 4 350 acres 0.005 0.000068 0.0026 0.0012 3800 8400 2600

Applying Sprays via

Groundboom Equipment (AHETF) Turf 2

80 acres 0.0786 0.00034 0.0047 0.00068 2100 15000 1900

Applying Sprays via

Groundboom Equipment (AHETF) Ornamentals 4 0.0094 0.0014 1100 7400 930

Applying Granules via open cab solid broadcast spreader (PHED) Turf Landscaping 2

0.0099 0.0012 0.00059 0.0024 17000 4200 3300

Ornamentals 4 80 acres 0.0012 0.0048 8400 2100 1700

Applying Granules via hand (PHED) Turf Landscaping 2 1 acre 104 0.47 0.078 0. 012 130 850 110

### Pendimethalin Human Health Risk Assessment DP No. 390457

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- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin (with baseline protection).

Exposure Scenario Crop or Target Application

Rate 2

lb ai/A Area Treated or

Amount Handled Daily 3 Unit Exposure (mg/lb ai) 1 Dose (mg/kg/day) 4 Short

- and Intermediate

- term
MOEs 5 Combined Short

and

Intermediate

term MOEs 7 Baseline 6

Dermal Baseline 6

Inhalation Baseline

Dermal Baseline

Inhalation Baseline

Dermal Baseline

Inhalation

Ornamentals 4 1 acre 0.16 0.024 64 430 56

Mixer/Loader/Applicator Mixing/Loading/App lying Liquids with Backpack Sprayer

broadcast Landscaping (turf)

outdoor residential areas (AHETF) Turf 2

40 gallons or 1

Acre 8.26 .000258 0.0062 .000065 1600 160000 1600

Mixing/Loading/App lying Liquids with Backpack Sprayer

broadcast Landscaping,

Christmas tree farms Landscaping , Christmas

Tree Farms 4 13.2 0.14 0.02 0.007 510 1400 370

Mixer / Loader / Applicator, Backpack Sprayer Soil directed (drench treatments)(MRID 44339801) Turf 2

8.26 0.00258 0.0062 .000065 1600 160,000 1600

Nurseries, landscaping,

Christmas tree farms 4 0.012 .000013 810 78000 800

Mixing/Loading/App lying Liquids with Manually

- pressurized Handwand (PHED) Turf 2

100 0.03 0.075 0 .00075 130 13000 130

Ornamentals , Orchards 4 0.15 0.0015 67 6700 66

Mixing/Loading/App lying Liquids with Mechanically

pressurized Handgun Sprayer soil directed (drench treatments) (MRID 45773201) Turf 2 5 acres 4.31 3.931 0.016 0.49 620 20 20

Mixer / Loader / Applicator, Olive trees, Orchards,

Ornamentals 4 5 acres 1.3 0.0039 0.0029 (PPE

- G)* 0.00098 3400 (PPE

- G)* 10000 2600

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 39 of 71 Table 9 .1.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin (with baseline protection).

Exposure Scenario Crop or Target Application

Rate 2

lb ai/A Area Treated or

Amount Handled Daily 3 Unit Exposure (mg/lb ai) 1 Dose (mg/kg/day) 4 Short

- and Intermediate

- term
MOEs 5 Combined Short

and

Intermediate

term MOEs 7 Baseline 6

Dermal Baseline 6

Inhalation Baseline

Dermal Baseline

Inhalation Baseline

Dermal Baseline

Inhalation Mechanically

pressurized Handgun Sprayer broadcast orchards, landscaping (non turf) (PHED) Kiwi, grape, citrus trees 6 0.0044 (PPE

- G)* 0.0015 2300 (PPE

- G) * 6800

1700

Mixer / Loader / Applicator, Mechanically

pressurized Handgun Sprayer broadcast Liquids Turf (ORETF) Turf 2 1.14 0.0019 0.0033 (PPE

- G)* 0.0002 3000 (PPE

- G)* 42000 2800

Mixer / Loader / Applicator, Mechanically

pressurized Handgun Sprayer broadcast

water

- dispersible granules Turf (ORETF) Turf 2 1.96 0.042 0.0053 ( PPE

- G)* 0.0053 1900 1900 950

Loader / Applicator Ground "push

- type" rotary spreader Ornamentals 4

5 acres 0.4 0.01 0.003 0.0025 3333 4000 1800

Loader / Applicator Ground "push

- type" rotary spreader Turf 2 0.0015 0.0013 6700 8000 3600

Loader / Applicator

Ground belly grinder Turf 2

1 acres 100 0.0620 0.075 0.0016 130 6500 130

Loader / Applicator Ground belly grinder Ornamentals 4 0.15 0.0031 67 3200 65

Flagger

Flagging for Aerial Sprays Applications (PHED) sugarcane, alfalfa,

artichoke, asparagus, bermudagrass 4

350 acres 0.011 0.00035 0.0058 0.0061 1700 1600 840

Corn, and Cotton, mint, onions, 2 0.0029 0.0031 3500 3300 1700

### Pendimethalin Human Health Risk Assessment DP No. 390457

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- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin (with baseline protection).

Exposure Scenario Crop or Target Application

Rate 2

lb ai/A Area Treated or

Amount Handled Daily 3 Unit Exposure (mg/lb ai) 1 Dose (mg/kg/day) 4 Short

- and Intermediate

- term
MOEs 5 Combined Short

and

Intermediate

term MOEs 7 Baseline 6

Dermal Baseline 6

Inhalation Baseline

Dermal Baseline

Inhalation Baseline

Dermal Baseline

Inhalation Edible bean, fruiting vegetables, garlic, grain sorghum, lentil and peas, onions mineral soil,

peanuts, potatoes, strawberry, no till sunflowers, wheat, vegetable soybean (edamame) 1.5 0.0022 0.0023 4600 4400

2200

Carrots, Green Onion, Rice, soybeans, brassica head and stem vegetables, leafy vegetables, leaf lettuce, leafy brassica

greens 1 0.0014 0.0015 6900 6500

3400

Sunflowers 1.75 0.0025 0.0027 4000 3700 1900

Turf 2 0.0029 0.0031 3500 3300 1700

Ornamentals 4 0.0058 0.0061 1700 1600 840

1. Unit Exposures are taken from “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 26, 2011)

. 2. Applic ation Rate. = Maximum rate liste d from labels 3. Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1. Revised Sep tember 25, 2001 4. Dose (mg/kg/da y) = Unit Exposure (mg/lb ai) * Application Rate * Area treated or Amount handled Body Weight ( 8 0 kg). 5. MOE ( Margin of Exposure ) = NOAEL/ Dose. Dermal NOAEL (ST and IT) = 10 mg/kg bw/day , Inhalation NOAEL (ST and IT) = 1 0 mg/kg bw/day

6. Basel ine = Long

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

7 Combined MOE = 1/ ((1/dermal MOE)+ (1/ inhalation MOE))

Table 9 .1. 2 . Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin Use on Dry Bulk Fertilizer

Exposure

Scenario Crops Dermal

Unit Exposure ( m g/lb ai) 1 Inhalation

Unit Exposure ( m g/lb ai) 1 Applicatio

n Rate 2 Amount

Treated Daily 3 Dose (mg/kg/day) 4 MOE 5 Combined Short

and Intermediate

term MOEs 6 Dermal Inhalati

on Dermal

(LOC =30) Inhalation

(LOC =30)

Mixer/Loader Liquids

### Pendimethalin Human Health Risk Assessment DP No. 390457

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- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin Use on Dry Bulk Fertilizer

Exposure

Scenario Crops Dermal

Unit Exposure ( m g/lb ai) 1 Inhalation

Unit Exposure ( m g/lb ai) 1 Applicatio

n Rate 2 Amount

Treated Daily 3 Dose (mg/kg/day) 4 MOE 5 Combined Short

and Intermediate

term MOEs 6 Dermal Inhalati

on Dermal

(LOC =30) Inhalation

(LOC =30)

Commercial Impregnation of Dry Bulk

Fertilizers Alfalfa, Artichoke,

Asparagus, Bearing Fruit Nut Trees, Non bearing fruit trees,

sugarcane

0.0086

(closed system) 0.000083

(closed system) 40 lb

ai/ton 960 tons 0.13 0.1 79 97 44

500 tons 0.074 0.06 140 170

75

Carrots and Carrots grown for seed production, Corn, Cotton, Mint, and onions, Northern Grasses,

Southern Grasses 20 lb ai/ton 960 tons 0.071 0.058 140 170 78

500 tons 0.037 0.03 270 330

150

Grape, Kiwi and other

small fruit vines 60 lb ai/ton 960 tons 0.21 0.17 47 58 26

500 tons 0.11 0.09 91 110 50

Edible beans, fallow, fruiting vegetables, garlic, grain sorghum, lentil and peas,

peanuts, potatoes, tobacco, wheat 15 lb ai/ton 960 tons 0.053 0.043 190 230 100

500 tons 0.028 0.023 360 440

200

Brassica head and stem vegetables, 9.5 lb

ai /ton 960 tons 0.034 0.027 300 370 160

500 tons 0.017 0.014 570 700 320

Clover 38 lb ai/ton 960 tons 0.13 0.11 75 91 41

500 tons 0.07 0.057 140 180 79

Forage legumes 12 lb ai/ton 960 tons 0.042 0.035 240 290 130

500 tons 0.022 0.018 450 560 250

Green Onions, rice, soybeans, leaf lettuce, melons, 10 lb ai/ton 960 tons 0.035 0.029 280 350 160

500 tons 0.018 0.015 540 670 300

Strawberry, vegetable soybean 14.2 lb

ai/ton lb

ai/ton 960 tons 0.05 0.041 200 240 110

500 tons 0.026 0.021 380 470 210

17 lb ai/ton 960 tons 0.06 0.049 170 200 92

### Pendimethalin Human Health Risk Assessment DP No. 390457

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- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin Use on Dry Bulk Fertilizer

Exposure

Scenario Crops Dermal

Unit Exposure ( m g/lb ai) 1 Inhalation

Unit Exposure ( m g/lb ai) 1 Applicatio

n Rate 2 Amount

Treated Daily 3 Dose (mg/kg/day) 4 MOE 5 Combined Short

and Intermediate

term MOEs 6 Dermal Inhalati

on Dermal

(LOC =30) Inhalation

(LOC =30)

Sunflowers 500 tons 0.031 0.026 320 390 180

Golf Course (commercial) 30 lb ai/ton 960 tons 0.11 0.086 94 120 52

500 tons 0.055 0.045 180 220 100

On

- farm Impregnation of Dry Bulk

Fertilizers Alfalfa, Artichoke,

Asparagus, Bearing Fruit Nut Trees, Non bearing fruit trees,

sugarcane, ornamentals

0.22

Baseline 0.000219

Baseline 4 lb ai/A 160 A 0.053 0.0018 190 5700 180

80 A 0.026 0.00088 380 1100 370

Carrots and Carrots grown for seed production, Corn, Cotton, Mint, onions, Northern Grasses,

Southern Grasses 2.0 lb ai/A 160 A 0.026 0.00088 380 1100 370

80 A 0.013 0.00044 760 23000 730

Grape, Kiwi and other

small fruit vines 6.0 lb ai/A 160 A 0.079 0.0026 130 3800 120

80 A 0.04 0.0013 250 7600 240
Edible beans, fallow, fruiting vegetables, garlic, grain sorghum, lentil and peas,

peanuts, potatoes, tobacco, wheat 1.5 lb ai/A 160 A 0.02 0.00066 510 15000 490

80 A 0.0099 0.00033 1000 30000 980

Brassica head and stem vegetables 0 .95 lb

ai/A 160 A 0.013 0.00042 800 24000 770

80 A 0.0063 0.00021 1600 48000 1500

Clover 3.8 lb ai/A 160 A 0.05 0.0017 200 6000 190

80 A 0.025 0.00083 400 12000 390

Forage legumes 1.2 lb ai/A 160 A 0.016 0.00053 630 19000 610

80 A 0.0079 0.00026 1300 38000 1200
Green Onions, rice, soybeans, leaf lettuce,

melons 1.0 lb ai/A 160 A 0.013 0.00044 760 23000 730

80 A 0.0066 0.00022 1500 46000 1500

Strawberry, vegetable soybean 1.42 lb

ai/A 160 A 0.019 0.00062 530 16000 520

80 A 0.0094 0.00031 1100 3200 1000

Sunflowers 1.7 lb ai/A 160 A 0.022 0.00074 450 13000 430

### Pendimethalin Human Health Risk Assessment DP No. 390457

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- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin Use on Dry Bulk Fertilizer

Exposure

Scenario Crops Dermal

Unit Exposure ( m g/lb ai) 1 Inhalation

Unit Exposure ( m g/lb ai) 1 Applicatio

n Rate 2 Amount

Treated Daily 3 Dose (mg/kg/day) 4 MOE 5 Combined Short

and Intermediate

term MOEs 6 Dermal Inhalati

on Dermal

(LOC =30) Inhalation

(LOC =30)

80 A 0.011 0.00037 890 27000 860

Golf Course ( commercial) 0.22

Baseline 0.000219

Baseline 3.0 lb ai/A 160 A 0.04 0.0013 250 7600 240

80 A 0.02 0.00066 510 15000 490
Applicator

Commercial Impregnation of Dry Bulk

Fertilizers

320

- 160 Acres

And

On

- Farm Impregnation of Dry Bulk

Fertilizer at

160 and 80

Acres Alfalfa, Artichoke,

Asparagus, Bearing Fruit Nut Trees, Non bearing fruit trees,

sugarcane, ornamentals

0.0099

Baseline 0.0012

Baseline 4.0 lb ai/A 320 A 0.0048 0.019 2100 520 420

160 A 0.0024 0.0096 4200 1000 840

80 A 0.0012 0.0048 8400 2100 1700

Carrots and Carrots grown for seed production, Corn, Cotton, Mint, onions, Northern Grasses,

Southern Grasses 2.0 lb ai/A 320 A 0.0024 0.0096 4200 1000 840

160 A 0.0012 0.0048 8400 2100 1700

80 A 0.00059 0.0024 17000 4200 3300

Grape, Kiwi and other

small fruit vines 6.0 lb ai/A 320 A 0.0071 0.029 1400 350 280

160 A 0.0036 0.014 2800 690 560

80 A 0.0018 0.0072 5600 1400 1100

Edible beans, fallow, fruiting vegetables, garlic, grain sorghum, lentil and peas,

peanuts, potatoes, tobacco, wheat 1.5 lb ai/A 320 A 0.0018 0.0072 5600 1400 1100

160 A 0.00089 0.0036 1100 2800 2200

80 A 0.00045 0.0018 22000 5600 4500

Brassica head and stem vegetables .95 lb ai/A 320 A 0.0011 0.0046 8900 2200 1800

160 A 0.00056 0.0028 18000 4400 3500

80 A 0.00028 0.0011 35000 8800 7000

Clover 3.8 lb ai/A 320 A 0.0045 0.018 2200 550 440

160 A 0.0023 0.0091 4400 1100 880

80 A 0.0011 0.0046 8900 2200 1800

Forage legumes 1.2 lb ai/A 320 A 0.0014 0.0058 7000 1700 1400

160 A 0.00071 0.0029 14000 3500 2800

80 A 0.00036 0.0014 28000 6900 5600
Green Onions, rice, 1.0 lb ai/A 320 A 0.0012 0.0048 8400 2100 1700

### Pendimethalin Human Health Risk Assessment DP No. 390457

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- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin Use on Dry Bulk Fertilizer

Exposure

Scenario Crops Dermal

Unit Exposure ( m g/lb ai) 1 Inhalation

Unit Exposure ( m g/lb ai) 1 Applicatio

n Rate 2 Amount

Treated Daily 3 Dose (mg/kg/day) 4 MOE 5 Combined Short

and Intermediate

term MOEs 6 Dermal Inhalati

on Dermal

(LOC =30) Inhalation

(LOC =30)

soybeans, leaf lettuce,

melons 160 A 0.00059 0.0024 17000 4200 3300

80 A 0.0003 0.0012 34000 8300 6700

Strawberry, vegetable soybean 1.42 lb

ai/A 320 A 0.0017 0.0068 5900 1500 1200

160 A 0.00084 0.0034 12000 2900 2400

80 A 0.00042 0.0017 24000 5900 4700

Sunflowers 1.7 lb ai/A 320 A 0.002 0.0082 5000 1200 980

160 A 0.0012 0.0041 9900 2500 2000

80 A 0.0005 0.002 20000 4900 3900

Commercial Impregnation of Dry Bulk

Fertilizers

320

- 160 Acres

And

On

- Farm Impregnation of Dry Bulk

Fertilizer at

160 and 80

Acres Golf Course

(commercial) 3.0 lb

ai/A3.0 lb

ai/A 320 A 0.0036 0.014 2800 690 560

160 A 0.0018 0.0072 5600 1400 1100

80 A 0.00089 0.0036 1100 2800 2200

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 26, 2011); includes data from PHED/ORE TF/AHETF

2 Based on proposed labels for Pendimethalin (see Tab le 3.1 and 3.2 in Section 3.0)

3 Exposure Science Advisory Council Policy #9.1 and industry information.

4 Dose = Unit Exposure (ug/lb ai) x CF (0.001 mg/ug) x Application Rate (lb ai/acre or lb ai/ton) x Area Treated or Amount Handled (A/ day or tons/day) / BW (80 kg).

5 MOE ( Margin of Exposure ) = NOAEL/ Dose. Dermal NOA EL (ST and IT) = 10 mg/kg bw/day , Inhalation NOAEL (ST and IT) = 1 0 mg/kg bw/day

6 Combined MOEs = 1/ (1/dermal MOE) + (1/inhalation MOE)

Table 9 .1. 3 . Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin with Additional Personal Protective Equipment

Exposure Scenario Crop or Target Applicatio

n Rate 2 Area

Treated or

Amount

Handled Daily 3 Unit Exposure (mg/lb

ai) 1 Dose (mg/kg/day) 4 Short

- and

Intermediate

- term
MOEs 5 Combined Short and

Intermediate

- term
MOEs 6 PPE

- G

Dermal Inhalation PPE

- G

Dermal Inhalation PPE

- G

Dermal Inhalation

Mixer/Loader/Applicator

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 45 of 71 Table 9 .1. 3 . Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Pendimethalin with Additional Personal Protective Equipment

Exposure Scenario Crop or Target Applicatio

n Rate 2 Area

Treated or

Amount

Handled Daily 3 Unit Exposure (mg/lb

ai) 1 Dose (mg/kg/day) 4 Short

- and

Intermediate

- term
MOEs 5 Combined Short and

Intermediate

- term
MOEs 6 PPE

- G

Dermal Inhalation PPE

- G

Dermal Inhalation PPE

- G

Dermal Inhalation

Mixing/Loading Liquids for Aerial, and/or Chemigation, Applications (AHETF) Alfalfa

, Sugarcane (high yield crops) 4 lb ai/A 1200

Acres 0.0376 0.000219

(Baseline) 0.068 0.013 (Baseline) 150 760

(Baseline) 120

Mixing/Loading/Applying Liquids with Mechanically

- pressurized Handgun Sprayer soil directed (drench treatments) (MRID

45773201) Turf 2 lb ai/A 5 A cres 4.31 0.789 (PPE

- R 80%) 0.0062 0.098

(PPE

- R 80%) 620 100

(PPE

- R 80%) 87

1. Unit Exposures are taken from “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 26, 2011)

. 2. Applic. Rate. = Maximum rate liste d from labels. 3. Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1. Revised Sep tember 25, 2001. 4. Dose (mg/kg/day) = Unit Exposure (mg/lb ai) * Application Rate * Area treated or Amount handled Body Weight ( 8 0 kg). 5. MOE = Margin of Exposure = NOAEL/ Dose. Dermal NOAEL (ST and IT) = 10 mg/kg bw/day , Inhalation NOAEL (ST and IT) = 1 0 mg/kg bw/day 6. Combined MOE = 1/ (1/dermal MOE) + (1/inhalation MOE)

### Pendimethalin Human Health Risk Assessment DP No. 390457

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- /Intermediate

- Term Post

- Application Risk

9.2.1 Dermal Post

- application Risk

Pendimethalin is mainly used a s a pre

- emergent or early post

- emergent herbicide . Pendimethalin is registered for post

- emergent applications to the following crops; alfalfa, bearing fruit trees, bermudagrass, brassica head and stem vegetables, carrots, clover, corn, cotton, garlic, grain sorghum, grape vines, green onion, lentils, mint, olive trees, potatoes, rice, an d strawberries, sugarcane, tobacco, wheat. The following proposed new uses also include post

- emergent applications; leaf lettuce, leafy brassica greens, melons, and kiwi and other small fruit vines.

Most of the applications made to post

- emergent crops ar e not of concern because the application method is ground directed layby or between rows of production. The labels direct users to avoid contact with buds, vines, and crop foliage to limit crop damage. Additionally applications, such

as on corn are restri cted to certain growth stages of the crop and therefore most post

- application activity would unlikely result in post

- application exposure with the exception of scouting. These restrictions suggest that only few post

- emergent crop applications would result in post

application exposure, these include alfalfa, clover, cotton, green onions, grain sorghum, onions, potatoes, rice, and wheat. Pendimethalin application to golf course use sites will also result in exposure to occupational post

- application workers. Of the proposed uses, Prowl ® 

### H 2 

### O use on leaf lettuce and brassica greens may occur in the early growth stages of the crops.

Chemical

- specific DFR data were available for p endimethalin on sugarcane and tobacco. Since DFR data are not available for the proposed uses, the available data were used as surrogates. Based on a review of the available data, it was decided that the DFR data for sugarcane treated

with PROWL 3.3 EC Herbicide in North Carolina would be used to represent non

- foliar pendimethalin applications. I t is believed that the sugarcane and tobacco data are representative

of the non

- foliar applications because the layby application (ground

- directed spray) of an aqueous solu tion of PROWL 3.3EC herbicide was made to established (10

- leaf, vegetative stage)

sugarcane plants and a tractor

- mounted cone tank application to established tobacco (10

- 12 leaf stage) was made to the tobacco plants.

The data shows that the residues wer e determined to be less than the LOQ in all cases except for one detected at the DAT 0.5 time point on one of the triplicate samples from the tobacco plant. This information verifies that negligible post

- application exposure is expected from non

- foliar

ap plications of pendimethalin.

The post

- application exposure scenarios that resulted from the application of pendimethalin to

post

- emergent crops were performed by using the default DFR value. The fraction of a.i. retained on foliage is assumed to be 2 5 % (0.2 5 ) on the day of application (= % DFR, after initial treatment) for agricultural crops. This fraction is assumed to further dissipate at the rate of 10% (0.1) per day on following days. These are default values established by HED’s Science Advisory Council (SAC) for Exposure.

Table 9.2.1 presents the risk estimates for each of the foliar application scenarios and the corresponding highest transfer coefficient activity.

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 47 of 71 Table 9. 2 .1 Summary of Occupational Postapplication Risk Estimates for Pendimethalin

Crop/Site Highest Transfer Coefficient for Crop (cm 2 /hr)
and Associated Activity DFR Day 0 MOE Day at which MOE

≥ LOC

Leafy lettuce, leafy brassica greens 4,200 (hand weeding) 2.244 350 0

Alfalfa, Cotton, Clover, Rice, Wheat 1,900 (alfalfa ) (Irrigation) 35.901 49 0

Grain, Sorghum, 1,900 (Irrigation) 8.98 200 0

Green onions, Onions mineral and muck soil,

Potatoes 4,200 (Hand Weeding) 8.975 88 0

Brassica head and stem vegetables 4200

(scouting, hand harvesting, hand

weeding) 2.244 350 0

Ornamentals 1900 (Irrigation) 35.901 49 0

a. Default DFR = 2 5 % (0.2 5 ) x Application Rate on the day of application (DAT 0) for agricultural crops. These are default values established by HED’s Science Advisory Council (SAC) for Exposure. b. Dermal Dose = [DFR (ug/cm 2 ) x TC (cm 2 /hr) x 0.001 mg/ug x 8 hrs/day] body weight (80 kg). c. MOE = NOAEL ( 10 mg/kg/day)/ Dermal Dose (mg/kg/day).



### TTR studies were used to assess the liquid and granular formulation scenarios. For the liqu id

formulation Determination of Transferable Turf Residue Dissipation from Turf Treated with Suspension Concentrate and Emulsifiable Concentrate Formulations of Pendimethalin (MRID

466841

- 02) was utilized. Data were collected at three sites in the TTR st udy including Pennsylvania, Georgia, and California. Data from the Georgia site was used in this assessment as it resulted in the highest predicted Day 0 residues. For the granular formulation scenarios, two

TTR studies were available for use: Determinat ion of Transferable Residues of Dimethenamid

- P

and Pendimethalin on Turf Treated with Tower Herbicide and Freehand Herbicide ( MRID 47901302) and Determination of Transferable Residues in Turf Treated with Pendulum® 2G or

Pendulum® WDG Herbicide (MRID No.44 969901 ) . In both studies, the Day 0 residues detected were generally at or below the LOQ (4.31 ng/cm 2 

### ) with the exception of 7 days after treatment when residues averaged 17.5 ng/cm 2 

### at the Pennsylvania site in MRID 44969901.

Data from the Pennsylvania site was used in this assessment as it resulted in the only detectable residue after application.

Table 9.2.2 presents the risk estimates for turf application scenarios.

Table 9 .2. 2 . Dermal Post

- application Exposure and Risk Estimate for Turf Applications Using TTR Data

Crop Group Proposed Crop Transfer

Coefficients (cm 2 /hr) DAT Study Test

Site TTR a

(ug/cm 2 ) Dermal Dose b

(mg/kg/day) MOE c

Liquid

Tur f/Sod Turf, golf course 3700 (maintenance) 0 Georgia 0.47 0.005 1900

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 48 of 71 Table 9 .2. 2 . Dermal Post

- application Exposure and Risk Estimate for Turf Applications Using TTR Data

Crop Group Proposed Crop Transfer

Coefficients (cm 2 /hr) DAT Study Test

Site TTR a

(ug/cm 2 ) Dermal Dose b

(mg/kg/day) MOE c

Turf Turf, sod farms 6700 (Harvesting, maintenance, transplanting) 0 Georgia 0.31 0.006 1600

Granular

Turf/Sod Turf, golf course 3700 (maintenance) 0 Pennsylvania 0.018 0.0002 50,000

Turf Turf, sod farms 6700 (Harvesting, maintenance, transplanting) 0 Pennsylvania 0.012 0.00024 41,000

a. For the liquid formulation, TTR values resulting from golf course applications (3 lbs ai/acre) are 0.47 ug/cm 2 and sod farm or turf applications (2 lbs ai/acre) are 0.31 ug/cm 2 . For the granular formulation, TTR values resulting from golf course applications (3 lbs ai/acre) are 0.018 ug/cm 2 and sod farm or turf applications (2 lbs ai/acre) are 0.012 ug/cm 2

. b. D ermal Dose = [DFR (ug/cm 2 ) x TC (cm 2 /hr) x 0.001 mg/ug x 8 hrs/day] body weight (80 kg). c. MOE = NOAEL (10 mg/kg/day)/ Dermal Dose (mg/kg/day).



### 9.2.2 Inhalation Postapplication Risk

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

- application inhalation exposure assessment was not performed for pendimethalin at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV). However, there are mult iple 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 th at contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 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 is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational

post

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

post

- application inha lation exposure assessment for pendimethalin.

Although a quantitative occupational postapplication inhalation exposure assessment was not performed, an inhala tion exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than postapplication exposure. Therefore, it is expected that these han dler inhalation exposure estimates would be protective of most occupational postapplication inhalation exposure scenarios.

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 49 of 71 10.0 References

Residue Chemistry References Pendimethalin. Human Health Assessment for the Proposed Food Uses of the Herbicide on Artichoke, Globe; Asparagus; Brassica Head and Stem Vegetables, Subgroup 5A; and Grape (PP#6E7129). PC Code 108501; DP Barcode D334062; D. Rate; 08/22/07.

Pendimethalin. Human Health Risk Assessment for the Proposed Food/Feed Use of the Herbicide (Associated with Section 18 Registration) on Bermuda Grass and Hay Fields in Texas. PC Code 108501; DP Barcode D349723; W. Drew; 05/20/08.

Pendimethalin. Human Health Risk Asse ssment for the Proposed Tolerance in/on Crayfish. PC Code 108501; DP Barcode D350493; C. Olinger; 03/31/08.

Pendimethalin. Discussion of Impurities . PC Code 108501; DP Barcode D386760; F. Fort.;

06/01/11

. Pendimethalin: Petition for the Establishment of Permanent Tolerances and Registration for Use on Lettuce, Leaf; Brassica, Leafy Greens, Subgroup 5B, and Turnip Greens; Melon Subgroup 9A; Vegetable, Soybean; and Small Fruit Vine Climbing Subgroup 13

- 07E, Except Grape. Submission of Crop Field Trial Dat a on Green Onion and Wheat Processing Data in Response to DP#s 271502; 310793; 311825; 314085; 314093; 317047; 317053, Submission of Citrus Fruit Crop Field Trial and Processing Data in Response to DP# 238469, and Submission

of Limited Field Accumulation i n Rotational Crop Data in Response to DP# 319412. Summary of Analytical Chemistry and Residue Data. DP Barcode 372189; Y. Barnes; 6/5 /12

. Drinking Water Assessment Drinking Water Assessment for Proposed New Uses of Pendimeth alin on Kiwi/small fruits, Leaf lettuce, Leafy brassica, Melon, and Edamame (edible soybeans); IR

- 4 Tolerance Petition E7878

. DP Barcode D390459 ; W. P. Eckel ; 02/23/2012 Dietary Exposure Assessment

Pendimethalin : Acute and Chronic Dietary (Food and Drin king Water) Analysis and Risk Assessment to Support N ew U se on Lettuce, Leaf; Brassica, Leafy Greens, Subgroup 5B, and Turnip Greens; Melon Subgroup 9A; Vegetable, Soybean; and Small Fruit Vine Climbing Subgroup 13

- 07E, e xcept Grape. DP Barcode 401100.drs ; Y. Barnes ; 05/02/2012

. Occupational/Residential Assessment

Pendimethalin: Occupational and Residential Exposure/Risk Assessment for Registration Review and for new Proposed Use on Leaf lettuce; Leafy brassica greens; Melons; Edamame;

Kiwi and other s mall fruit vines. S. Shelat, B. Bobowiec; DP 402406 , 05/31/2012

.

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 50 of 71 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for pendimethalin are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

TABLE A.1 Toxicology Data Requirements for Pendimethalin.

Test Technical

Required Conducted

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 (non

- rodent)

870.3200 21/28

- Day Dermal

870.3250 90

- Day Dermal

870.3465 90

- Day Inhalation yes

yes

yes

no

no yes

yes

yes

no

no

870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (non

- rodent) 870.3800 Reproduction yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (non

- rodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation (bacterial) 870.5300 Mutagenicity

— Gene Mutation (mammalian) 870.5375 Mutagenicity

— Structural Chromosomal Aberrations 870.5395 Mutagenicity

— Other Genotoxic Effects 870.5500 Mutagenicity

— Other Genotoxic Effects yes

yes

yes

yes

ye s 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 Developmental Neurotoxicity no

no

yes

yes

no no

no

yes

yes

no

870.7485 General Metabolism

870.7600 Dermal Penetration 870.7800 Immunotoxicity yes

no

yes yes

yes

yes

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 51 of 71 A.2 Toxicity Profile s

Table A. 2. 1 Acute Toxicity Profile

- Pendimethalin

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [Rat] 00026657 LD 50 =1250 mg/kg (m) =1050 mg/kg (f) III

870.1200 Acute dermal [Rabbit] 00026657 LD 50 = >1250 mg/kg IV

870.1300 Acute inhalation [Rat] 00073342 LC 50 = 32 mg/L IV

870.2400 Acute eye irritation [Rabbit] 00026657 Slight conjunctival

irritation III

870.2500 Acute dermal irritation [Rabbit] 00026657 No dermal irritation IV

870.2600 Skin sensitization [Guinea pig] 00153767 Non

- sensitizer

-

TABLE A. 2. 2 Subchronic, Chronic and Other Toxicity Profile for Pendimethalin.

Guideline

Number Study Type MRID Number

& Classification Dose Levels Results

870.3100 Subchronic oral

[Rat] (30

- day) 000106754

Supplementary 0, 800, 1600, 3200 ppm

0, 80, 160, 320 mg/kg/day NOAEL = 160 mg/kg/day. LOAEL = 320 mg/kg/day,

based on increased liver weight.

870.3100 Subchronic oral

[Rat] (13

- week) 00156081 0, 100, 500, 5000 ppm

0, 10, 50, 500 m g/kg/day NOAEL = 50 mg/kg/day. LOAEL = 500 mg/kg/day, based on decreased body weight gain and food consumption, decreased hematocrit and hemoglobin with increases in platelets in males, increased liver weight, red thyroids, and hypertrophy

of the liver.

870.3100 Subchronic oral

[Rat] (13

- week) 00059468

Supplementary 0, 25, 50, 100, 500, 2500

ppm

0, 2.5, 5, 10, 50, 250 mg/kg/day NOAEL = 250 mg/kg/day.

LOAEL was not determined.

870.3100 Subchronic oral

[Rat] (13 week) 00059469

Supplementary 0, 2500 ppm

0, 250 mg/kg/day NOAEL = 250 mg/kg/day.

LOAEL was not determined.

870.3100 Subchronic oral

[Rat] (92

- day) 42054601 0, 100, 5000 ppm

0, 4.98, 245.4 mg/kg/day NOAEL = 4.98 mg/kg/day. LOAEL = 245.4 mg/kg/day, based on thyroid effects.

870.3100 Subchronic oral

[Rat] (56

- day) 43135001 0, 500, 5000 ppm

0, 31, 292 mg/kg/day NOAEL was not determined.

LOAEL = 31 mg/kg/day, based on thyroid effects.

870.3100 Subchronic oral

[Rat] (14

- day) 43135003 0, 100, 500 ppm

0, 10, 500 mg/kg/day NOAEL = 10 mg/kg/day. LOAEL = 500 mg/kg/day, based on thyroid effects.

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 52 of 71 TABLE A. 2. 2 Subchronic, Chronic and Other Toxicity Profile for Pendimethalin.

Guideline

Number Study Type MRID Number

& Classification Dose Levels Results

870.3100 Subchronic oral

[Dog] (90

- day) 00026672

Supplementary 0, 62.5, 250, 1000

mg/kg/day NOAEL = 62.5 mg/kg/day. LOAEL = 250 mg/kg/day, based on body weight loss.

870.3150 Subchronic oral

[Mouse] (30

- day) 000106754

Supplementary 0, 500, 1000, 2000 ppm

0, 75, 150, 300 mg/kg/day NOAEL = 300 mg/kg/day.

LOAEL was not determined.

870.3200 21

- Day dermal

toxicity [Rat] 00026663 0, 250, 500, 1000 mg/kg/day NOAEL = 1000 mg/kg/day.

LOAEL was not determined.

870.3700a Prenatal

developmental toxicity [Rat] 00025752

Supplementary, but satisfactory

when considered

with the rabbit developmental. 0, 125, 250, 500

mg/kg/day Maternal NOAEL = 500 mg/kg/day (highest dose tested).

Developmental NOAEL = 500 mg/kg/day (highest dose tested).

870.3700b Prenatal

developmental toxicity [Rabbit)] 00117444

Supplementary, upgradeable. 0, 15, 30, 60 mg/kg/day Maternal NOAEL = 60 mg/kg/day (highest dose tested).

Developmental NOAEL = 60 mg/kg/day (highest dose tested).

Note: a range finding study
indicated doses ≥125 mg/kg/day associated with

increased mortality.

870.3800 Reproduction and

fertility effects [Rat]

(2

- generation reproduction) 41725203 Acceptable 0, 500, 2500, 5000 ppm

0, 34/43, 172/216, 346/436 mg/kg/day (M/F)

HED RED

0, 25, 125, 250 mg/kg/day

HIARC Document

Note: Doses were obtained

from an HED pendimethalin RED, and a

HIARC document (4/18/2000) which resulted

in different dose calculations for mg/kg/day. Consequently, doses are given as a range, based

on calculations from actual chemical intake, and a generic r atio (1:20) of Parental/Systemic

NOAEL = 25

- 34/43 (M/F) mg/kg/day (500 ppm).

LOAEL = 125

- 172/216 (M/F) mg/kg/day (2500 ppm), based on decreased body weight gain and food consumption.

Reproductive/Offspring

NOAEL = 25

- 34/43 (M/F) mg/kg/day (500 ppm).

Reproductive/Offspring

LOAEL = 125

- 172/216 (M/F) mg/kg/day (2500 ppm), based on decreases in the number of pups born, and pup weights.

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 53 of 71 TABLE A. 2. 2 Subchronic, Chronic and Other Toxicity Profile for Pendimethalin.

Guideline

Number Study Type MRID Number

& Classification Dose Levels Results

dietary intake.

870.3800 Reproduction and

fertility effects [Rat]

(3

- generation reproduction) 00026671, 0040304,

00059470

Acceptable 0, 500, 5000 ppm

0, 25, 250 mg/kg/day Parental/Systemic

NOAEL = 25 mg/kg/day.

LOAEL = 250 mg/kg/day, based on decreased body weight.

Reproductive/Offspring

NOAEL = 25 mg/kg/day.

Reproductive/Offspring

LOAEL = 250 mg/kg/day, based on decreased pup body weight gain, and possible decreased pups born alive and pup survival.

870.4100b Chronic toxicity [Dog]

(2

- year oral) 00058657 0, 12.5, 50, 200 mg/kg/day NOAEL = 200 mg/kg/day.

LOAEL was not established.

870.4200 Chronic toxicity/

carcinogenicity [Rat]

(2

- year oral) 40174401

Acceptable 0, 100, 500, 5000 ppm

0, 5, 25, 250 mg/kg/day NOAEL = 25 mg/kg/day.

LOAEL = 250 mg/kg/day, based on decreased survival and body weight gain, decreased food consumption, increased gamma glutamyl transferase, cholesterol and liver weights, and thyroid

effects.

870.4200 Chronic toxicity [Rat]

(2

- year oral) 42027802

Acceptable 0, 1250, 2500, 3750, 5000

ppm

0, 51, 103, 154, 213 mg/kg/day NOAEL was not determined.

LOAEL = 51 mg/kg/day, based on

non

- neoplastic thyroid follicular cell changes.

870.4300 Carcinogenicity

[Mouse] (18

- month oral) 40909901

Acceptable 0, 100, 500, 5000 ppm

0, 12.3/15.6, 62.3/78.3, 622.1/806.9 mg/kg/day (M/F) NOAEL = 62.3/78.3 mg/kg/day.

LOAEL = 622./806.9 mg/kg/day, based on mortality, body weight decrease, organ weight changes, and amyloidosis.

870.5100 Reverse gene mutation

assay [Bacterial

strains of S. typhimurium] 00153768 50, 158, 500, 1581, 5000 μg/plate Positive

Evidence of a 2

- fold increase in

the number of induced mutant colonies over background (at all doses from 50 to 5000 μg/plate).

870.5100 Reverse gene mutation

assay [Escherichia coli WP2] 43177801 25, 50, 100, 250, 500, 750 μg/plate Negative

870.5100 Reverse gene mutation

assay [Escherichia coli WP2] 43135005 50, 158, 500, 1581, 5000 μg/plate or 1000 μg/paper disk/plate Negative

870.5100 Reverse gene mutation

assay [Escherichia coli WP2] 43135006 50, 100, 250, 500, 750 μg/plate Negative

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 54 of 71 TABLE A. 2. 2 Subchronic, Chronic and Other Toxicity Profile for Pendimethalin.

Guideline

Number Study Type MRID Number

& Classification Dose Levels Results

870.5300 Mammalian cell gene

mutation [Chinese hamster ovary] 43177802 1, 5, 7.5, 10, 20, 30, 40, 50 μg/plate (

- S9) 10, 25, 50, 75, 100, 125, 150, 175 μg/plate (+S9) Negative

870.5375 Chromosomal

aberration [Chinese hamster ovary] 00153770 Doses ranging from 5

- 50 μg/ml Negative

870.5395 Micronucleus study

[Mouse] 42027801 313, 625, 1250 mg/kg Negative

870.5550 Alkaline elution assay

[Rat] 43135007 1250, 2500, 5000 mg/kg Negative

870.6200 Acute neurotoxicity 48695601

Acceptable 0, 100, 300, or 1000 mg/kg NOAEL=100 mg/kg,

LOAEL= 300 mg/kg, based on reduced motor activity for males and females (↓19 and ↓51%, respectively, on Day 0.

870.6200 Subchronic

neurotoxicity 42054601

Acceptable 0, 42.0/50.1, 126.5 / 151.9,

386.8/423.1 mg/kg bw/day [M/F] NOAEL= 386.8/423.1 mg/kg/day (HDT).

LOAEL not established.

870.7800 Immuotoxicity 48608901

Acceptable 0, 38, 72, 276 mg/kg/day NOAEL=276 mg/kg/day (HDT)

LOAEL not established.

870.7485 Metabolism and

pharmacokinetics
[Rat] 00046275

Acceptable NA* Pendimethalin is eliminated from the body within 24 hours, with 70% being excreted in feces (primarily the parent compound),

and 20% in urine.

Non

guideline Developmental

Thyroid Study 48695603

Acceptable 0, 31, 62 or 186 mg/kg /day

(GD 6

- PND 21) Developmental thyroid function, The thyroid function in fetuses or post partum day (PND 4) was not affected by the treatment of pendimethalin.

Parental thyroid function,

Decreased thyroxine (T4) levels were observed in pregnant dams

and PND 21 male and female pups at 31 mg/kg/day (LOAEL)

. * NA = Not Applicable.

Note: Some of the LOAELs/NOAELS were previously denoted as LOELs/NOELS in Data Evaluation Records (DERs). The language was updated to comply with current standards wit hout re

- examining effects.



### A.3 Hazard Identification and Endpoint Selection

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 55 of 71 A.3.1 Acute Reference Dose (aRfD)

- Females age 13

- 49

Study Selected : None

MRID No .: N/A Executive Summary : None Comments about Study/Endpoint/Uncertainty Factor(s) : No appropriate endpoint attributable to a single exposure (dose) was identified from the oral toxicity studies including developmental toxicity studies in rats and rabbits. Therefore, an acute RfD was not established.

A.3.2 Acute Reference Dose (aRfD )

- General Population

Study Selected : Acute neurotoxicity study in rats

MRID No .: 48695601 Executive Summary : See appendix, Guideline 870.6200. Dose and Endpoint for Risk Assessment : NOAEL= 100 mg/kg based on reduced motor activity on day 0 at LOAEL = 300 mg/kg/day Comments about Study/Endpoint/Uncertainty Factor(s): The effects were seen after a single oral dose which is appropriate for this exposure period of concern. The uncertainty factor (UF)

includes a 10X for intraspecies extrapolation and a 10 X for interspecies extrapolation (used to account for animal to human differences in toxicokinetics and toxicodynamics).

A.3.3 Chronic Reference Dose (cRfD )

Study Selected : 92

- day thyroid function in rats



### 56

- day thyroid function in rats

14

- day intra

- thyroid metabolism study in rats

MRID No .: 420554601, 43135001, 43135003 Executive Summary : See appendix, Dose and Endpoint for Risk Assessment : NOAEL= 10 mg/kg based on thyroid effects at LOAEL= 31 mg/kg/day Comments about Study/Endpoint/Uncertainty Factor(s): These three studies were considered together to select the dose and endpoint for establishing the chronic reference dose (cRfD). The cRfD is derived from the NOAEL of 10 mg /kg/day for thyroid effects based on hormonal and histological changes in the thyroid observed at the LOAEL of 31 mg/kg/day. The HIARC re

affirmed (9/7/99) that the 14

- day NOAEL of 10 mg/kg/day reflects a true NOAEL for thyroid

effects since these effect s have been demonstrated to have early onset (before 14 days). On this basis, all studies were considered together for establishing the LOAEL at 31 mg/kg/day and the NOAEL at 10 mg/kg/day. The uncertainty factor (UF) includes a 10X for intraspecies

extra polation and a 3X for interspecies extrapolation (used to account for animal to human differences in toxicokinetics and toxicodynamics). The intersp ecies UF can be rduc ed because of several important quantitative dynamic differences between rats and humans with respect to thyroid function (Interim Guidance on Thyroid Disrupting Pesticides, dated 11/1/05).

A.3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

Study Selected : 92

- day thyroid function in rats

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 56 of 71 56

- day thyroid function in rats

14

- day intra

- thyroid metabolism study in rats

MRID No .: 420554601, 43135001, 43135003 Executive Summary : See appendix. Dose and Endpoint for Risk Assessment : NOAEL= 10 mg/kg based on thyroid e ffects at LOAEL= 31 mg/kg/day. Comments about Study/Endpoint/Uncertainty Factor(s): The 14

- day NOAEL of 10 mg/kg/day reflects a true NOAEL for thyroid effects since these effects have been demonstrated to have early onset (before 14 days). On this basis, all studies were considered together for establishing the LOAEL at 31 mg/kg/day and the NOAEL at 10 mg/kg/day. HEDs level of concern (LOC) for pendimethalin incidental oral exposure is 30 (i.e., a margin of exposure (MOE) less than 30 exceeds HED’s level o f concern) for occupational scenarios. The level of concern includes a 10X uncertainty factor (UF) for intraspecies extrapolation and a 3X UF for interspecies (used to account for animal to human differences in toxicokinetics and

toxico dynamics)

.

A.3. 5 Dermal Exposure (Short

- , Intermediate

- and Long

- Term )

Study Selected : 92

- day thyroid function in rats



### 56

- day thyroid function in rats

14

- day intra

- thyroid metabolism study in rats

MRID No .: 420554601, 43135001, 43135003 Executive Summary : See appendix. Dose and Endpoint for Risk Assessment : NOAEL= 10 mg/kg based on thyroid effects at LOAEL= 31 mg/kg/day. Comments about Study/Endpoint/Uncertainty Factor(s): B ased on the results of the thyroid

studies in rats discussed a bove under chronic RfD, short

- term (1

- 7 days), intermediate

- term (one week to several months), and long

- term/chronic (90 days or more) occupational and residential exposure estimates should be compared to the NOAEL of 10 mg/kg/day established in the 14

- day intra

- thyroidal study. The LOAEL of 31 mg/kg/day (LDT), from the 56

- day thyroid study, is based on several hormonal and histological thyroid changes 

### and thyroid hormonal effects occurred as early as day 3). Since an oral NOAEL was selected, 3% dermal abs orption factor should be used for route

- to

- route extrapolation. HEDs level of concern (LOC) for pendimethalin dermal exposure is 30 (i.e., a margin of exposure (MOE) less than 30 exceeds HED’s level of concern) for occupational

scenarios. The level of con cern includes a 10X uncertainty factor (UF) for intraspecies extrapolation and a 3X for interspecies extrapolation (used to account for animal to human differences in toxicokinetics and toxicodynamics).

A.3.6 Inhalation Exposure (Short

- , Intermediate

- and Long

- Term)

Study Selected : 92

- day thyroid function in rats



### 56

- day thyroid function in rats

14

- day intra

- thyroid metabolism study in rats

MRID No .: 420554601, 43135001, 4313500 3 Executive Summary : See appendix. Dose and Endpoint for Risk Assessment : NOAEL= 10 mg/kg based on thyroid effects at LOAEL= 31 mg/kg/day

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 57 of 71 Comments about Study/Endpoint/Uncertainty Factor(s): Except for an acute inhalation toxicity study (MRID# 00073342) for which pendimethalin was placed in toxicity Category IV (LC 50 

### > 32 mg/L); no other studies are available via this route. HEDs level of concer n (LOC) for pendimethalin inhalation exposure is 30 (i.e., a margin of exposure (MOE) less than 30 exceeds

HED’ s level of concern) for occupational scenarios. The level of concern includes a 10X uncertainty factor (UF) for intraspecies extrapolation and a 3X for interspecies extrapolation (used to account for animal to human differences in toxicokinetics and toxic odynamics). Since the dose identified is from an oral study, route

- to

- route extrapolation is required as follows.

Step I: Convert the inhalation exposure (μg/lb ai) using 100% inhalation

absorption rate, application rate and acres treated and to an oral equivalent dose (mg/kg/day).

Step II: Convert the dermal exposure (mg/kg/day) using 3% dermal

absorption rate, application rate and acres treated to an oral equivalent dose (mg/kg/day). This dose should be combined with the converted oral dose in Step I.

Step III: To calculate the MOE’s, the combined dose from Step II should

then be compared to the oral NOAEL of 10 mg/kg/day for any time period.

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

In a special 92

- day thyroid function feeding study (MRID 42054601), AC 92,553 (pendimethalin, 92.6%, Lot #AC5213

- 72A) was administered to groups of 80 male CD[Crl:CD(SD)] rats at dose levels of 0, 100, or 5,000 ppm (corresponding to 0, 4.98, or 245.4 mg/kg/day) for 92 days. Groups of 20 male rats were sacrificed at 15, 29, 57 and 92 days. At 100 ppm there was decreased total T 4

, T3, total free T4 and increased percent T 3 , increased follicular cell height and decreased area occupie d by colloid. At 5,00 0 ppm there were decreased body weight and food consumption compared to controls, increased thyroid weight, decreased total

T 4 , total T 3 , rT 3 , total free T4 and [ 125 

### I]

- T4 to transthyretin bonding, increased percent free T4 , percent fr ee T3 and [ 125 

### I]

- T4 to albumin binding, increased follicular cell height and decreased area occupied by colloid and ultrastructural thyroid changes. Most parameters were reversible after treatment subsided except for decreased body weight. The NOAEL was es tablished at 100 ppm (4.98 mg/kg/day). The LOAEL was determined to be 5000 ppm.

In a special 56

- day feeding study (28

- day treatment, 28

- day recovery) to determine thyroid function (MRID 43135001), groups of 65

- 70 (5

- 15 per sacrifice time) male Crl:CD(SD) rats were treated at dose levels of 0, 500 or 5000 ppm (0, 31 or 292 mg/kg/day) of AC 92,553 (pendimethalin, 92.6%, Lot #AC5213

- 72A) in the diet for 28 days. A recovery period of up to 28 days was employed. Animals were sacrificed at many time points duri ng the study beginning as early as day 3.There were no deaths or clinical signs of toxicity during or after the treatment period at either dose. At 500 ppm there was decreased total T4 (38%), rT3 (25%) and total free

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 58 of 71 T4 (28%) and increased percent free T3 (13%), increased follicular cell height (40%) and decreased area occupied by colloid (51%) during treatment. At 5000 ppm, body weight (8%), body weight gain (29%) and food consumption (15%) were decreased compared to controls during the treatment period. T hyroid changes during treatment with 5000 ppm included: increased absolute (15%) and relative (23%) thyroid weight; decreased total T4 (74%), total T3 (25%), rT3 (36%), total free T4 (40%), and [ 125 I]

- T4 to transthyretrin binding; increased percent free T4 (117%), percent free T3 (26%) and [ 125 I]

- T4 to albumin binding; increased follicular cell height (75%) and decreased area occupied by colloid (45%); ultrastructural thyroid changes were consistent with mild to moderate TSH stimulation except for the a ccumulation of

dense

- bodies in the cytoplasm which may be reaction products of AC 92,553. Many of these effects were observed as early as day 3. Most parameters were reversible post treatment except for a slight decreased body weight compared to controls ( 7%) at 5000 ppm. There were no changes in TSH, total free T3 or diameter of follicular cells. The LOAEL was 500 ppm (31 mg/kg/day) based on thyroid effects. The NOAEL could not be determined.

In a special 14

- day feeding study to determine thyroid function (MRID 43135003), AC 92,553 (pendimethalin, 92.6%, Lot #AC5213

- 72A) was administered in the diet to groups of 10 male Crl:CD(SD) rats at dose levels of 0, 100 or 5,000 ppm (corresponding to 0, 10 or 500 mg/kg/day). At 5000 ppm AC 92, 533 for 14 days, TSH w as increased and T4 and T3 were decreased. No treatment related effects were observed for rT3 levels, thyroid weight, 131 

### I uptake in MIT, DIT or T 4 . There was a significant increase of 131 

### I uptake by the thyroid of rats in the 5000 ppm group and an increase in incorporation of 131 

### I in T 3 . Total T3 and T4 levels in the thyroid were not affected by treatment at 5,000 ppm. The LOAEL is 5,000 ppm (500 mg/kg/day) based on thyroid effects. The NO AEL is 100 ppm (10 mg/kg/day)

.

In a second special 14

- day feeding study (MRID 43135004) to determine biliary excretion and hepatic metabolism, AC 92,553 (pendimethalin, 92.98%, Lot #AC6539

- 77A) was administered to groups of 10 male Crl:CD(SD) rats at dose levels of 0, 100, or 5,000 ppm (corresponding to 0, 10, or 500 mg/kg/day). Ingestion of 5,000 ppm produced decreases in serum T3 and T4 with a compensatory increase in TSH. Also increased were liver weight, bile flow and cumulative biliary excretion of 12 5 

### I

- T4 with a slight increase in T4

- glucuronytransferase activity detected by generation of 125 

### I

- T4 glucuronide from 125 

### I

- T4 in vitro by hepatic microsomes. The increase in enzyme activity was also demonstrated in vivo by a significant increase in bil iary excretion of

125 

### I

- T4

- glucuronide. The LOAEL is 5,000 ppm (500 mg/kg/day) based on thyroid effects. The NOAEL is 100 ppm (10 mg/kg/day).

These studies are Acceptable when used in combination and satisfy the requirements for a chronic feeding study in rats

.

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

- Rat

In a developmental toxicity (MRID 00025752), pendimethalin (94.2% a.i .) was administered in corn oil to groups of 30 mated Sprague

- Dawley CD strain rats by gavage at daily dose levels of 0, 125, 250, or 500 mg/kg/day from gestation day 6 through 15. Females were observed for

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 59 of 71 signs of toxicity, and body weights were measure d during gestation. Animals were sacrificed on gestation day 21 and examined grossly and microscopically. The uteri were examined for live

fetuses and intra

- uterine deaths. Fetuses were weighed, sexed, and examined for external, visceral, and skeletal al terations. There were no maternal or developmental effects noted at any dose level tested. Based on these results, the NOAELs for developmental and maternal toxicity are 500 mg/kg/day (highest dose tested).

This study is classified as acceptable and sa tisfies the Subdivision F guideline requirement for a prenatal developmental toxicity study in rats.

870.3700b Prenatal Developmental Toxicity Study

- Rabbit

In a developme ntal toxicity (MRID 00117444), p endimethalin was administered in corn oil to groups of 20 artificially inseminated New Zealand White strain rabbits by gavage at dose levels of 0, 15, 30, or 60 mg/kg/day from gestation day 6 through 18. Females were observed for signs of toxicity, and bod y weights were measured during gestation. Animals were sacrificed on gestation day 29. The rabbits were examined grossly and microscopically. The uteri were

examined for live fetuses and intra

- uterine deaths. Fetuses were weighed, sexed, and examined
for external, visceral, and skeletal alterations. No maternal toxicity was reported at doses 60 mg/kg/day (highest dose tested).

There was a slight increase in the mean incidence of skeletal anomalies in the mid

- and high

dose groups. These findings i ncluded less than twelve pairs of ribs (0/111, 1/118 and 4/107 fetuses in the control, mid

- , and high

- dose groups, respectively, not statistically significant) and/or missing or incompletely ossified vertebrae (0/111, 1/118 and 7/107 fetuses in the control

, mid and high dose groups, respectively). When compared to historical control data of the testing lab, skeletal anomalies observed in the mid

- and high

- dose groups were within the range and the

mean of the historical incidence. Therefore, it was determi ned that these effects are not

treatment

- related. Consequently, the NOAEL for developmental toxicity was > 60 mg/kg/day (HDT).

In the range

- finding study (Accession No. 00248659), New Zealand White rabbits received pendimethalin in corn oil at doses of 0, 31.25, 62.5, 125, 250 or 500 mg/kg/day during gestation days 6 thru 18. Maternal toxicity was manifested as mortality and decreases in body weight gain at doses 62.5 mg/kg/day and above. Mortality occurred in 1/5 (20%) , 3/5 (60%) , 5/5 (100%) and 4/5 ( 80%) in the 62.5, 125, 250, and 500 mg/kg/day, respectively compared with 0/5 in the control group. In addition, the two remaining females at the 125 mg/kg/day group aborted prior to gestation day 29 and were sacrificed. Mean body weight losses for the c ontrol, 31.25, 62.5, 125, 250, or 500 mg/kg/day groups were 56, 289, 242, 720, 918 and 492 grams, respectively. Thus, based on the mortality and the severe body weight losses, it is apparent that at dose levels of 125 mg/kg/day and above, pendimethalin is toxic to pregnant rabbits. Consequently, it was determined that the 60 mg/kg/day dose tested in the main study approached a maximum tolerated dose and the dams could not have tolerated higher doses.

A.4.3 Reproductive Toxicity

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 60 of 71 In a 2

- generation reproduction study (MRID 417252203), AC 92,533 (pendimethalin, 92.6%,

Lot #AC5213

- 72A) was administered to groups of 25 male and 25 female Sprague

- Dawley

derived OFA

- SD (IOPS

- CAW) rats at dose levels of 0, 500, 2500 or 5000 ppm (correspon ding to 0, 25, 125 and 250 mg/kg/day).

There were no clinical signs or changes in organ weight data. There was a minimal (5%) decrease in body weight gain and food consumption (possibly due to palatability) at 2500 ppm. At 5000 ppm, the decrease in bo dy weight gain (13%) and food consumption (approximate 8%/14% males/females, respectively). At 2500 mg/kg/day, body weight gain decreases (7%) were observed. There were decreases in food consumption of 10/15% in males/females, respectively).

At 5000 and 2500 ppm, the mean numbers of pups born were significantly decreased compared to controls at 21% and 15%, respectively. Mean pup weights were decreased during lactation at 5000 ppm (10

- 21%) and 2500 ppm (7

- 11%).

The parental NOAEL is 500 ppm (25 mg/ kg/day), based on decreased body weight gain and food consumption at the LOAEL of 2500 ppm. The reproductive NOAEL is 500 ppm (25 mg/kg/day), based on decreases in the number of pups born and pup body weights at the LOAEL of 2500 ppm (125 mg/kg/day)

.

Thi s study is acceptable according to guidelines for a reproductive toxicity study in rats

.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Combined Chronic/Carcinogenicity

– Rat

In a 2

- year study in rats (MRID 40174401), AC 92,533 (pendimethalin, 91.9%, Lot #AC3528

- 129

- 1), was administered to groups of 55 male and 55 female Crl:CD(SD)BR rats in the diet at levels of 0, 100, 500 or 5,000 ppm (corresponding to 0, 5, 25, or 250 mg/kg /day). Ten rats/sex/group were interim sacrificed as 12 months. At 5,000 ppm, survival in males was slightly decreased and body weight gain was decreased. There was decreased food consumption, increased gamma glutamyl transferase and cholesterol, increa ses in liver weight, as well as liver to body and/or brain weight ratios, generalized uterus, dark adipose tissue in females, diffusely dark thyroids, and follicular cell hyperplasia of the thyroid. At 500 ppm there was pigmentation of the thyroid folli cular cells in males and females and follicular cell adenomas. The NOAEL is 500 ppm (25 mg/kg/day). The LOAEL of 5000 ppm (250 mg/kg/day) is based on decreased survival, body weight gain and food consumption, increased gamma glutamyl transferase

and chole sterol, increase in absolute and/or relative liver weight, generalized uterus, dark adipose tissue in females, diffusely dark thyroids and follicular cell hyperplasia of the thyroid.

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study

– rat

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 61 of 71 See A.4.4

870.4200b Carcinogenicity (feeding)

– Mouse

In an 18

- month feeding study in mice (MRID 40909901),AC 92,533 (pendimethalin, 92.6%, Lot

#AC5218

- 72A) was administered to groups of 65 male and 65 female Charles River CD

- 1 mice at dose levels of 100, 500, or 5,000 ppm (corresponding to 12.3, 62.3 and 622 .1 mg/kg/day in males and 15.6, 78.3 and 806.9 mg/kg/day in females). There were 2 control groups consisting of 65 mice/sex. Ten mice/sex were sacrificed at 12 months in 1 control and all treated groups. (One control group only consisted of 55 mice/sex.) At 5,000 ppm there was increased mortality in females, decreased body weight in females, increased absolute thyroid, liver and gall bladder weights and/or relative body and brain weight ratios in males and females as well as amyloidosis

in males. There were no tumors observed in mice. The LOAEL is 5,000 ppm (622.1 mg/kg/day [M]; 806.99 mg/kg/day [F]) based on mortality, body weight decrease, organ weight changes and amyloidosis. The NOAEL is 500 ppm (62.3 mg/kg/day [M]; 78.3 mg/kg/day [F]).

A.4.6 Muta genicity

Mutagenicity tests were performed on pendimethalin and included acceptable studies for all three categories (gene mutations, structural chromosome aberrations and other ge notoxic effects) which satisfied the 1991 mutagenicity guidelines. The C an cer P eer R eview C ommittee

had reviewed these studies and concluded that it was not mutagenic in mammalian somatic cells and germ cells. The studies included 3 reverse gene mutation tests using Salmonella, 2 forward

mutation studies using Chinese hamster ov ary cells, 1 micronucleus test in mice, one dominant lethal assay, and one DNA repair test. All mutagenicity tests were negative for mutagenic

effects.

Gene Mutation

870.5100, Reverse gene mutation assay [Bacterial strains of S. typhimurium]

MRID 00153768 μg/plate = 50, 158, 500, 1581, 5000 Positive

Evidence of a 2

- fold increase in the number of induced mutant colonies over background (at all doses from 50 to 5000 μg/plate).

870.5100. Reverse gene mutation assay [Escherichia coli WP2]

MRID 43177801

μg/plate = 25, 50, 100, 250, 500, 750 Negative

870.5100, Reverse gene mutation assay [Escherichia coli ]

MRID 43135005

50, 158, 500, 1581, 5000 μg/plate or 1000 μg/paper disk/plate Negative

870.5100, Reverse gene mutation assay [Escherichia coli WP2]

MRID 43135006

μg/plate = 50, 100, 250, 500, 750 Negative

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 62 of 71 870.5300, Mammalian cell gene mutation [Chinese hamster ovary]

MRID 43177802

μg/plate = 1, 5, 7.5, 10, 20, 30, 40, 50 (

- S9)

μg/plate = 10, 25, 50, 75, 100, 125, 150, 175 (+S9) Negative



### Cytogenetics

870.5395, Micronucleus study
[Mouse]

MRID 42027801
313, 625, 1250 mg/kg Negative



### Chromsomal Aberration

870.5375, Chromosomal aberration [Chinese hamster ovary]

MRID 00153770
Dose ranging from 5

- 50 μg /mL Negative



### Other Genotoxicity

870.5550,Alkaline elution assay (Rat)

MRID 43135007

1250, 2500, 5000 m g /kg Negative



### A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID 4 8695601)

, pendimethalin (BAS 455 H, 93.3±1.0 % a.i.,

batch # COD

- 001337 ) was administered by a single oral gavage (5 ml/kg) dose in corn oil to groups of male and female, non

- fasted Wistar (Crl:WI, Han) rats ( 10/sex/dose ) at doses of 0

, 100

, 300, or 1000 mg/kg bw and observed for 14 days. Neurobehavioral assessment (functional observational battery and motor activity testing) was performed o n all animals prior to test substance administration (Day

- 7), on the day of treatment (Day 0), and on Days 7 and 14. At study termination (Day 15), 5 animals/sex/gro up were fixe d by in situ perfusion under deep

anesthesia with isoflurane and subjected to neuropathological examinations. The remaining animals were sacrificed using CO2 without further examination. The brain and peripheral nervous system tissues collected from the p erfused animals in the control and 1,000 mg/kg groups were subjected to histopathological evaluation.

All animals survived to the scheduled necropsy, except for one female in the 1,000 mg/kg group which was sacrificed due to moribund condition on Day 1.

No adverse, treatment

- related effects were observed on general clinical observations or mean body weights at any dose level in males and females, throughout the study, however mean body weight gain between Days 0

- 7 in the male 1,000 mg/kg group was signi ficantly lower ( ↓ 19%)

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 63 of 71 than the control group. C linical signs were observed in only two females of the 1,000 mg/kg group and included abdominal position, red encrusted eye, labored respiration, semi

- closed eyelids and poor general state. One of these two fe males was moribund and was sacrificed on Day 1 after treatment while the other female still showed slight poor general state but survived to scheduled sacrifice on Day 14.

Treatment

- related FOB findings were observed in the 1,000 mg/kg group on Day 0 (pos t

- dosing) in males and females, but not on Days 7 and 14; thus, observed effects were transient. The following test substance

- related findings were obtained in the 1,000 mg/kg group males: chromodacryorrhea, slight impairment of coordination, piloerection and urine discoloration. At 300 mg/kg, urine discoloration occurred in one male rat on Day 0 and hypothermia was observed in another male on Day 7. At 100 mg/kg, accelerated respiration was observed in one male animal on Day 0 only, and vocalization was a lso noted in one male on Days 0 and 14, but not Day 7. These findings in the 100 mg/kg male group were considered to be incidental. In female animals, FOB findings were only observed on Day 0 at dose levels of 300 and 1,000 mg/kg and included squatting po sture, slight eyelid closure, and slight impairment of coordination, severe reduced exploration of the area (apathetic animal) and urine discoloration. The eyelid closure and the discoloration of urine were observed in more animals in the 1,000 mg/kg group than the 300 mg/kg group. All of these effects in females were reversible , as they were not present on Days 7

and 14

.

Forelimb grip strength was significantly ( p≤0.0 1) reduced by ↓22% in males at the dose level of 1,000 mg/kg on Day 0, but not in females at any dose level. In addition, hind limb grip strength, rearing and landing foot splay were unaffected by test substance in either sex throughout the exposure period . Only on Day 0, overall mean motor activity was significantly ( p≤0.0 1) reduced by ↓59% in males at the dose level of 1,000 mg/kg and by ↓51% and ↓75% in females at dose levels of 300 and 1,000 mg/kg, respectively. These effects were also transient, as th ey had resolved by Day 7.

No test substance

- related alterations were observed in gross histopathology observations or microscopic neurohistopathology in the 1,000 mg/kg male and female groups.

It is concluded that the reversible effects observed in males and females can be explained by impairment of the overall condition of the animals following treatment, rather than direct neurotoxic effects of the Pendimethalin exposure. This conclusion is based on the absence of any neurohistopathological changes in the treated animals and the transient nature of the

observed FOB and neurobehavioral assessments.

Based on the results of this study, the N OAEL for acute neurotoxicity of Pendimethalin is 100 mg/kg body weight for males and females

. The LOAEL for acute neurotoxicity is 300 mg/kg body weight, based on reduced motor activity for males and females (↓19 and ↓51%, respectively, on Day 0.

The study is classified as acceptable/guideline and satisfies the guideline requirement ( OPPTS

870.6200 a; OECD 424 ) for a n acute neurotoxicity study in rats.

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 64 of 71 870.6200 Subchronic Neurotoxicity Screening Battery

In a subchronic neurotoxicity oral (dietary) study (MRID 48695602), pendimethalin ( 99.9 % a.i.,

batch/lot # FH20726 ) was administered to Wistar (CrlGlxBrlHan:WI) ra ts ( 10/sex/ group ) at dose levels of 0, 600

, 1800 , or 54 00 ppm (equivalent to 0, 42.0/50.1

, 126.5 / 151.9

, 386.8/423.1 mg/kg bw/day [M/F], respectively ) for 3 months . Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in all animals at pre

- dosing (Day

- 7) and Days 1, 22, 50 and 85. Ophthalmology exams were conducted on all animals prior to dosing and on the control and 5000 group at the end of the study. Hematology and clinical chemistry parameters along w ith select organ weights and gross histopathology observations were also determined on 5/sex/group. At study termination, 5 animals/sex/group were euthanized and perfused in situ for neuropathological examination. The brain and peripheral

nervous system t issues collected from the perfused animals in the control and 5400 ppm groups were subjected to microscopic histopathological evaluation.

All animals survived to the scheduled necropsy. No adverse, permanent treatment

- related effects were observed on gen eral clinical observations, ophthalmology, FOB findings, or motor activity at any dietary concentration level in males and females. Only transient decreases ( ↓31%) in motor activity were observed only on Day 1 in males and females in the 5400 ppm groups. I n addition, there were no test substance

- associated alterations observed in brain weights, gross histopathology observations or microscopic neurohistopathology findings in the 5400 ppm (high dose) male and female groups.

Treatment

- related effects on body weights and body weight gains were evident at the dietary concentration level of 5400 ppm in males and females throughout the study. Body weights were significantly (p≤0.05 or p≤0.01) reduced by 6%

- 12% and 7%

- 13% in males and females, respectively, throughout the treatment period. Body weight gains were also decreased (p≤0.01) in males (↓19%

- 25%) and females (↓29%

- 51%) throughout the treatment period. No significant differences in body weights were noted in males at di etary concentration level of 600 or 1800 ppm. Body weight and body weight gains were also decreased in females in the 1800 ppm group, but no differences were noted in the 600 ppm female group.

Treatment related

- effects on food consumption were noted at 5400 ppm in males (Days 7, 21

- 35, 56 and 70) and females (Days 7 though 91). At 5400 ppm, lower (p≤0.05 or p≤0.01) food consumption ranged from ↓8% to ↓ 10% on Days 7, 21

- 35, 56 and 70 in males and from ↓16% to ↓ 22% in females on Day 7 though the end of the treatment period (Day 91), when compared to

the controls. No treatment

- related effects on food consumption were observed at 600 and 1800 ppm in males or at 600 ppm in females.

Treatment

- related effects on hemoglobin, hematocrit and red blood cell count were noted in the

1800 and 5400 ppm group females, but not in males. Higher (p≤0.01) cholesterol was noted in males (↑72 %) and females (↑62 %) at 5400 ppm. As well, significantly higher concentra tions of albumin (↑9%), creatinine (↑16%) and total protein (↑9%) were noted in the 5400 ppm group males. Serum γ

– glutamyltransferase activity and cholesterol were significantly higher in males and females at the dietary concentration level of 5400 ppm. No treatment

- related changes were

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 65 of 71 observed in the other clinical chemistry parameters at any dietary concentration level in either

males or females.

Treatment related effects on absolute and relative (to body) liver weights were noted at 1800 ppm and 5400 p pm in males and females. However, there were no test substance

- associated alterations observed in liver gross histopathology observations or microscopic histopathology findings in the 5400 ppm group males and females. These results, together with the incr eased

serum γ

– glutamyltransferase activity levels observed in the 5400 ppm males and females, suggest that the increase in liver weight observed in the high dose groups is due to an adaptive effect rather than a toxic response in this organ.

It is concl uded that pendimethain did not exhibit neurotoxic potential in this 3

- month subchronic feeding study involving male and female Wistar rats at dietary concentration levels of 300, 1800 and 5400 ppm, based on the lack of altered behavior in the FOB, only tra nsient decreases in motor activity, and no effects on the macroscopic and microscopic pathology of nervous system

tissues. However, systemic toxicity of Pendimethalin was apparent in males and females. This was characterized by decreased body weights, sig nificant reductions in body weight gains and decreased food consumption, as well as altered hematologic and clinical chemistry parameters in

both males and females.

Based on the results of this study, the NOAEL for subchronic neurotoxicity of

Pendimethali n is 5400 ppm (equivalent to 386.8/423.1 mg/kg body weight/day for males and females, respectively ).

The NOAELs for systemic toxicity are 1800 ppm in males (equivalent to 126.5 mg/kg body weight/day) and 600 ppm in females (equivalent to 50.1 mg/kg bod y weight/day), based on significant reduction in body weights, body weight gains and food consumption, as well as altered hematologic and clinical chemistry parameters.

The study is classified as acceptable/guideline and satisfies the guideline requirement ( OPPTS

870.6200 b ) for a subchronic neurotoxicity study in rats.

A.4.8 Metabolism

870.7485 Metabolism

- Rat

In a metabo lism study (MRJD 00046275), { 14 

### C } pendimethalin was administered to rats , about 70% of the radioactivity was excreted in the feces and 20% in the urine within 24 hours. The excretion of radioactivity in the mine peaked at 6 to 12 horns wherein 11.2% of the dose was excreted. The maximum residual radioactivity in the tissues wa s found in the 6

- hour samples (except for fat at 12 hours). The levels of radioactivity detected in liver, kidney, muscle, fat, and blood at 6 hours were 29.8, 16.9, 1.3, 12.2, and 5.4 ppm, respectively. Within 96 horns, the radioactivity found in the tiss ues was 0.3 ppm or less, except for fat which was 0.9 ppm. The major portion of the radioactivity that was excreted in the feces was identified as the parent compound. Pendimethalin is metabolized in rats mainly through oxidation of the 4

- methyl group

atta ched to the benzene ring as well as oxidation of the alkyl side chain of the N

- substituted

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 66 of 71 dinitroaniline compound. Pendimethalin is rapidly eliminated from the body with 70% being excreted in the feces primarily unchanged as parent compound and 20% in the urine within 24 horns. It is mainly metabolized through oxidation of the 4

- methyl group on the benzene ring and the alkyl side chain.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In a 28

- day dietary immunotoxicity study (MRID 48608901 ), p endimethalin

, (93.3% a.i., Batch

No. COD

- 001337 ) was administered in the diet to female Crl:WI(Han) rats (8/group) at dietary

concentr ations of 0, 500, 1000, or 3000 ppm (equivalent to 0, 38, 72 or 276 mg/kg/day, respectively) for 28 days. Animals in the positive con trol group (8/group) received cyclophosphamide (4.5 mg/kg /day ) by gavage for 28 days. Animals in all study groups were immunized with sheep red blood cells (SRBC) by intraperitoneal injection (0.5 mL/animal, 4 x

10 8 

### SRBC/mL) six days prior to the schedule d sacrifice. At termination, blood was taken from the retroorbital venous plexus from fasted animals. The animals were anaesthetized using isoflurane. Measurement of the SRBC IgM antibody titers were performed at the end of the study

with an Enzyme Linked Immunobsorbent Assay ( ELISA ) . Additionally, all animals were assessed by gross pathology ; the weights of liver, spleen and thymus were measured.

There were no test substance

- related effects on mortality, clinical observations, hematology or

mean absolute and relative (to terminal body weight) thymus weights in any group. D ecrease d mean body weight and body weight gains were observed at 3000 ppm. I ncreased liver weights were observed at 3000 ppm and were regarded as treatment

- related, as previously observed in

the overall mammalian toxic ological profile of BAS 455 H (p endimethalin).

Animals in the po sitive (cyclophosphamide ) control group had decreases in mean absolute and relative (to terminal body weight) spleen and thymus weights when compared to vehi cle control

group.

For systemic toxicity, the LOAEL is 3000 ppm ( 276 mg/kg/day) based on decreased mean body weights, body weight gains, and increased liver weights. The NOAEL for systemic toxicity in rats is 1000 ppm (72 mg/kg/day).

There were no significant differences in anti

- SRBC IgM titers compared to the untreated control group at all dose levels tested. A high inter

- individual variability was noted in all the treatment groups as well as in the control group. Evaluation of indivi dual animal data of this study did not show any trend or distribution that would demonstrate significant suppression of anti

- SRBC IgM

response. Animals in the positive control group showed marked decreases in anti

- SRBC IgM

concentration. The positive contr ol group confirmed the ability of the test system to detect

immuno

- suppressive effects and confirmed the validity of the study design.

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database for pendimethalin does n ot reveal any evidence of treatment

- related effects on the immune

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 67 of 71 system. The overall weight of evidence suggests that this chemical does not directly target the immune system. Under HED guidance, a NK cells activity assay is not required at this time.

Fo r immunotoxicity, the NOAEL is 3000 ppm (276 mg/kg/day). The LOAEL could not be

determined.

This 28

- day dietary immunotoxicity study in the rat is acceptable/ guideline and satisfies guideline requirement for an immunotoxicity study (OPPTS 870.7800)

.

A.4.9 Special/Other Studies

Developmental Thyroid Study (non

- guideline)

In a developmental thyroid study (MRID 48695603 ), pendimethalin ( BAS 455 H , 99.9%; Batch

# FH20726 ) was administered in the diet to naturally

- mated presumed pregnant Sprague

- Dawley (Crl:CD(SD)) rats (35/dose) at doses of 0, 31, 62 or 186 mg/kg bw/day from gestation days (GD) 6

- 21

. On GD 20

, 10 dams/group were sacrificed and blood samples were withdrawn from

dams and their fetuses for the determination of thyroid hormones . The fet uses were examined for external malformations and variations. The remaining dams were allowed to litter and rear their pups until PND 4 or PND 21.

No mortality or clinical signs of toxicity were observed in this study. During the gestation period, m ean b ody weights of dams administered 186 mg/kg bw/day were statistically significantly decreased 5

- 6% when compared to controls on GD 15 and 20. Body weight gain of the dams administered 186 mg/kg bw/day was statistically significantly decreased on GD 6

- 8

and 17

- 20 by up to 16% when compared to controls. During the lactation period, Mean body weights of dams administered 186 mg/kg bw/day were statistically significantly decreased 6% when compared to controls on (post natal day) PND 7. They were still lower than controls at the end of the lactation period. During the gestation period m ean food consumption was statistically significantly decreased in females administered 186 mg/kg bw/day by 16

- 29% when compare d

to controls on GD 6

- 15 and GD 17

- 20. During the lactation period m ean food consumption was statistically significantly decreased in females administered 62 mg/kg bw/day on GD 6

- 13 by 6

- 10% when compared to controls Mean food consumption was also statistically significantly

decreased in females administe red 62 mg/kg bw/day on GD 6

- 13 by 6

- 10% when compared to

controls.

T 4 (thyroxine) levels were significantly decreased in all dose groups compared to the controls on

Post Coital (PC) Day 20 and on PND 21

. T 4 levels were decreased 42, 58 , and 61 % when

comp ared to controls on G D 20 at 31, 62, and 186 mg/kg /day, respectively. On PND 21, T 4

levels were statistica lly significantly decreased 33, 49, and 68 % when compared to controls at 31, 62, and 186 m g/kg/day, respectively. Additionally, dams on PND 21 had sta tistically significantly decreased triiodothyronine (T 3 ) levels by 9.5 and 16. 2% when compared t o controls at 62 and 186 mg/kg /d ay, respectively

.

The maternal toxicity LOAEL is 31 mg/kg bw/day based on decreased thyroxine (T 4 )

levels. The maternal toxic ity NOAEL is less than 31 mg/kg bw/day.

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 68 of 71 Thyroid hormone levels were not affected in fetuses (GD 20) or pups on post

- natal day (PND 4 ) by administration of the test substance. On PND 21, male pups had statistically significantly

decreased T 4 levels of 21, 22, and 37% when compared to cont rols at 31, 62, and 186 mg/kg /day

, respectively. On PND 21, female pups had statistically significantly decreased T 4 levels of 14, 24, and 36% when compared to cont rols at 31, 62, and 186 mg/kg /day , respectiv ely

. The offspring demonstrated there was no increased sensitivity as compared to dams because

t hyroid hormones in fetuses and PND 4 pups of exposed dams remained unaltered even when their mothers showed significantly decreased T 4 levels. Only after exposu re via the diet in addition to the milk, serum T 4 levels of PND 21 pups were affected

.

For thyroid function , the LOAEL was 31 mg/kg/day based on decreases in thyroxine (T 4 ) levels in pregnant dams and 21 days old male and female pups. The NOAEL was not

es tablished. The thyroid function in fetuses or post partum day (PND 4) was not affected by the treatment of pendimethalin.

No treatment related effects were observed in altered growth, external developmental variations

or external malformations.

The devel opmental LOAEL was not observed. The developmental NOAEL is 186 mg/kg bw/day.

This study is classified acceptable/non

- guideline and can serve as a special study on thyroid function within the context of a developmental toxicity study

.

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 69 of 71 Appendix B

. International Residue Limits



## Pendimethalin (108501)

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 

### Codex 3



### 40 CFR 180.361:

Plant: N

- (1

- ethylpropyl)

- 3,4

- dimethyl

- 2,6

- dinitrobenzenamine and its metabolite, 4

- [(1

- ethylpropyl)amino]

- 2

- methyl

- 3,5

- dinitrobenzyl alcohol

Livestock: N

- (1

- ethylpropyl)

- 3,4

- dimethyl

- 2,6

- dinitrobenzenamine and its metabolite, 4

- [(1

- ethylpropyl)amino]

- 2

- methyl

- 3,5

- dinitrobenzyl alcohol benzenamine, N

- (1

- ethylpropyl)

- 3, 4

- dimethyl

2,6

- dinitro

- , including the

metabolite benzenemethanol, 4

- [(1

- ethylpropyl)amino]

- 2

- methyl

- 3,5

- dinitro

None

Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 

### Codex 3



### Lettuce, Leaf 4.0 Brassica, leafy greens, subgroup 5B 0.2 Turnip greens 0.2 Melon, subgroup 9A 0.1 Vegetable, soybean, succulent 0.1 Fruit, Citrus, Group 10

- 10 0.1
Citrus, Oil 0.5
Onion, bulb 0.1 0.1 Fruit, pome group 11 0.1 0.1 Fruit, stone group 12 0.1 0.1

Completed: M. Negussie and Y. Barnes ; 12/05/2011 and 04/25/2012

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 70 of 71 Appendix C

. Physical/Chemical Properties

Appendix Table C.1. Physicochemical Properties of Pendimethalin.

Parameter Value Reference

Melting point/range 54

- 58 °C (TGAI) Product Chemistry Chapter of Pendimethalin RED, DP# 221531, 12/8/1995, B. Cropp

- Kohlligian

pH 4.7 (TGAI) CB# 789, 06/13/1986, G. Makhijani

Density 1.461 g/cm 3 (at room temperature) DP#s 271502 and 317053, 07/12/2006, W. Drew

Water solubility of PAI 0.275 ppm at 25 °C CB# 789, 06/13/1986, G. Makhijani

Solvent solubility of TGAI Solvent g/100 mL at 25 oC

n

- Heptane 11.2

2

- Propanol 6.1

Acetone 161.0

Toluene 128.4 Methyl alcohol 5.5 Dimethyl sulfoxide 21.4 Methylene chloride 232.0 CB# 789, 06/13/1986, G. Makhijani

Vapor pressure 1.24 x 10 - 8 Pa at 20 °C DP#s 271502 and 317053,
07/12/2006, W. Drew

Dissociation constant, pK

a Too small to measure CB# 789, 06/13/1986, G. Makhijani

Octanol/water partition coefficient, Log(K OW ) 5.18 DP#s 271502 and 317053,
07/12/2006, W. Drew

UV/visible absorption

spectrum UV molecular extinction =

3.81 x 10 4 at 234 nm,

1.93 x 10 4 at 280 nm. DP#s 271502 and 317053,
07/12/2006, W. Drew

### Pendimethalin Human Health Risk Assessment DP No. 390457

Page 71 of 71 Appendix D

. Review of Human Research

Studies reviewed for ethical conduct:

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database , Version 1.1. Electronic Database. Task Force members Health Canada, U. S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table. U.S. Environmental Protection Agency. Released June 21, 2011.

Data from the Outdoor Residential Exposure Tas k Force (ORETF).