Fosthiazate Human H ealth Risk Assessment D P No. 405448

UN I TED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON

, D.C. 2 0460

MEMORANDUM

Da t e: March 5, 2013 O FFICE OF CHEMICAL S AFETY
A ND POLLU TI ON PRE V ENT I O N

SUBJECT : Fosthiazate

. Preliminary Human H ealth Risk Assessmen t for Registra t ion

Review

PC C o dei 129022

Dec i sion No. : NA

Pet i tion No. : NA
Risk Assess m ent Type: Sing l e Chemica l / Aggregate
TXRNo.:NA

M R IDNo.: NA DP Barco d e : D405448 Reg i stra ti on No. : NA Regu l atory Action: Registration Review

Case No.: 7604

CAS No. : 98886-44

- 3
40 CFR: 180.596

FROM: Charles Smith

, Senior Envirorunental Scientist/Risk Assess

Risk Assessment Branch I
Health Effects Division (7509P)

and

Donald Wilbur

, Chemist

Risk Assessment Branch V I

Hea l th Effects D iv i s i on (7509P)

THROUGH : Felecia Fort

, Branch Chief 

# ..f · ' p-.._ 1 

### ;S} 

# rjJ "3

Risk Assessment Branch VI

## ~U...O. 

# 0 4 vr' 

## l

## ~ Hea l th Effects Division (7509P)

TO: Khue Nguyen

, Chemical Review Manager
Risk Management and Implementation Branch I

Pest i cide Re-evaluation Division (7508P)

Page 1 of 18F osthiazate Human Health Risk Assessment DP No. 4054 48

The Health Effects D iv ision (HED) ofthe Office of Pesticide Programs (OPP) is charged with 

### estimating the risk to human health from exposure to pesticides. As p art of Registration Review,

the Pest icide Re-evaluation Division (PRD) of OPP has requested that HED evaluate the hazard

and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will r es ul t from the registered

uses of fosthiazate.

HED has evaluated the tox ici ty and exposure databases for the active ingredient, fosthiazate, and
has conducted a human health risk assessment in support of Registration Review. Based on this

assessment, HED has determined that there are potential risk estimates of concern to
mixer/loaders for the currently registered use of fosthiazate on tomatoes

.

A summary of the findin gs and an assessment of h uman health risk resulting from the currently registered uses of fosthiazate are provided in this document. The HED team members contributing to this risk assessment include Charles Smith (risk assessment) and Donald Wilbur (chemistry assessment). Keara Moore of th e Environmental Fate and Effects Division (EFED) performed the drinking wate r assessment for fosthiazate.

Page 2 of 18Fosthiazate Human Health Risk Assessment DP No. 405448

Page 3 of 18 1.0 Executive Summary

................................ ................................ ................................ ................... 4
2.0 Ingredient Profile

................................ ................................ ................................ ....................... 6
2.1 Structure and Nomenclature

................................ ................................ ................................ ... 6
2.2 Physical/Chemical Characteristics

................................ ................................ ......................... 6
2.3 Summary of Existing Uses

................................ ................................ ................................ ..... 6
2.4 Anticipated Exposure Pathways

................................ ................................ ............................. 7
2.5 Consideration of Environment al Justice

................................ ................................ ................ 7
3.0 Hazard Characterization and Dose

- Response Assessment

................................ ........................ 7
3.1 Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

.................... 7
3.2 Endocrine Disruption

................................ ................................ ................................ ............. 9
4.0 Dietary Exposure and Risk Assessment

................................ ................................ .................. 10
4.1 Degradate Residue Profile

................................ ................................ ................................ .... 10
4. 1.1 Summary of Environmental Degradation

................................ ................................ ..... 10
4.1.2 Residues of Concern Summary and Rationale

................................ .............................. 10
4.2 Food Residue Profile

................................ ................................ ................................ ............ 11
4.3 Water Residue Profile

................................ ................................ ................................ .......... 11
4.4 Dietary Risk Assessment

................................ ................................ ................................ ...... 12
4.4.1 Description of Residue Data Used in Dietary Assessment

................................ ........... 12
4.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ...................... 12
4.4.3 Acute Dietary Risk Assessment

................................ ................................ .................... 12
4.4.4 Chronic Dietary Risk Assessment

................................ ................................ ................ 12
4.4.5 Cancer Dietary Risk Assessment

................................ ................................ .................. 13
4.4.6 Dietary Risk Assessment Summary Table

................................ ................................ .... 13
5.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .......... 13
6.0 Aggregate Exposure/Risk Characterization

................................ ................................ ............. 14
7.0 Cumulative Exposure/Risk Characterization

................................ ................................ ........... 14
8.0 Occupational Exposure/Risk Characterization

................................ ................................ ........ 14
8.1 Occupational Handler Exposure and Risk

................................ ................................ ........... 14
8.1.1 Short

- /Intermediate

- Term Non

- Cancer Handler Exposure and Risk

............................ 15
8.2 Occupational Postapplication Exposure and Risk

................................ ................................ 16
8.2.1 Postapplication Inhalation Exposure

................................ ................................ ............. 16
9.0 References

................................ ................................ ................................ ................................ 17 Appendix A: Review of Human Research

................................ ................................ .......................... 18Fosthiazate Human Health Risk Assessment DP No. 405448

Page 4 of 18 1.0 Executive Summary

As part of Registration Review, t he Pesticide Re

- evaluation Division ( P RD) of the Office of Pesticide Programs ( OPP ) has requested that the Health Effects Division ( HED ) evaluate the hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the registered
uses of fosthiazate

. A summary of the findings and an assessment of human health risk resulting from the currently registered uses of fosthiazate are provided in this document.

Use Profile : Fosthiazate is a n organophosphate (OP) nematicide and insecticide that is currently registered as a liquid form ulation for drip irrigation use on tomatoes.

Hazard Assessment : The toxicology database for fosthiazate is c omplete a s described in 40 CFR, Part 158. Overall, the studies available for consideration of fosthi a zate toxicity provide a comprehensive database. Like other OPs, fosthiazate causes neurotoxicity through the inhibition of acetylcholinesterase leading to changes in clinical signs and behavior. T he FQPA Safety

Factor for fosthiazate was reduced to 1X si nce available data indicate that fetuses and juvenile
rats are not more sensitive than adult rats.

Dietary Exposure (Food and Drinking Water): The residue chemistry data and environmental fate data are adequate to assess human exposure. E stimated drinking water concentrations (EDWCs) were generated by the Environmental Fate and Effects Division (EFED) using computer modeling methods. The highest surface water EDWCs values are 75.2 ppb (1

- in

- 10 year acute) and 7.8 ppb (1

- in

- 10 year annual average). The groundwater EDWC value was 0.04 ppb.

Acute: A slightly refined acute dietary exposure assessment was performed that directly incorporated potential drinking water residues

. The estimated exposure to the highest population subgroup ( all infants < 1 year old) resulted in an estimated risk of 15 % of the acute population adjusted dose ( aPAD ). The estimated exposure to the general U.S. population resulted in an
estimated risk of 5.6 % of the acute population adjusted dose (aPAD).

Chronic: A n unrefined chronic dietary exposure assessment was performed that directly incorporated potential drinking water residues

. The estimated exposure to the highest population subgroup ( all infants < 1 year old ) resulted in an estimated risk of 45 % of the chronic p opul ation adjusted dose (cPAD). The estimated exposure to the general U.S. population resulted in an
estimated risk of 19 % of the chronic p opulation adjusted dose (cPAD)

.

Residential Exposure : There are currently no registered residential uses associated with
fosthiazate ; therefore, a residential/non

- occupational exposure assessment is not required.

Aggregate Risk: Aggregate risk assessments evaluate the combined risk from dietary exposure (food and water) and any non

- occupational (residential) uses. T here are currently no registered
residential uses associated with fosthiazate ; therefore, a residential/non

- occupational exposure assessment is not required. As a result, the fosthiazate aggregate risk assessment includes onlyFosthiazate Human Health Risk Assessment DP No. 405448

Page 5 of 18 dietary exposure (food and water). The acute and chronic dietary exposure estimates from food and drinking water do not exceed HED’s level of conc ern.

Occupational Exposure/Risk: Occupational handler exposures to the existing uses of
fosthiazate may occur via the dermal and inhalation route. The short

- and intermediate

- term risk
estimates for all occupational handler scenarios exceed HED’s level of concern (M argins of Exposure or M OEs < 100) even with the use of engineering controls.

Occupationa l postapplication exposures are not expected based on the currently registered uses
of fosthiazate. Fosthiazate is applied to the soil prior to planting. HED expects that postapplication exposure to fosthiazate soil will be negligible and thus an occupat ional postapplication exposure assessment is not required

.

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 (listed in Appendix A ) have been determined to require a r eview of their ethical conduct and a ll
of the studies utilized in this assessment have received the appropriate review.Fosthiazate Human Health Risk Assessment DP No. 405448

Page 6 of 18 2 .0 Ingredient Profile

Fosthiazate is a n organophosphate nematicide and insecticide that is currently registered for use

on tomatoes

.

2 .1 Structure and Nomenclature

Table 2 .1 : Fosthiazate Nomenclature

Chemical Structure
Fosthiazate: O

- Ethyl S

- (1

- methylpropyl)(2

- oxo

- 3

- thiazolidinyl)phosphonothioate

ASC

- 67131: ( RS )

- S

- sec

- Butyl O

- ethyl N

- [2

- (methylsulfonyl)ethyl] phosphoramidothioate

IUPAC name ( RS )

- [ S

- ( RS )

- sec

- butyl O

- ethyl 2

- oxo

- 1,3

- thiazolidin

- 3

- ylphosphonothioate]

CAS Name O

- ethyl S

- (1

- methylpropyl) P

- (2

- oxo

- 3

- thiazolidinyl)phosphonothioate CAS Registry Number 98886

- 44

- 3

2 .2 Physical/Chemical Characteristics

Fosthiazate ’s vapor pressure ( 2.7 x 10 - 6 mm Hg ) and Henry's Law Constant ( 1.76 X 10 - 05 Pa m 3

mol - 1 ) indicate that the compound is relatively non

- volatile under field conditions. It is generally considered to be moderately persistent in water and soil. In two studies, fosthiazate was found to
h ave low sorption to soil and has been classified as mobile to moderately mobile. Based on the use pattern and environmental fate parameters, there is the potential for fosthiazate to reach

water resources.

2 .3 Summary of Existing Uses

Fosthiazate is for mulated as an emulsifiable concentrate (EC) at 75% active ingredient (ai) and
47.2% ai . The product has the trade names; FOSTHIAZATE 900EC (71512

- 4), NEMATHORIN 500EC (71512

- 5), and FOSTHIAZATE 75%EC (71512

- 17). Tomatoes are the only c urrently registered use site. Applications are made once per season, either prior to or at transplanting for tomatoes. It may only be applied through drip (trickle) irrigation systems.
The maximum application rate is 1.5 lb a.i. /acre and the label restricts applicators t o treating only 25 acres per day.

According to a Biological and Economic Analysis Division (BEAD) memo (R. Prieto, 01/30/2012), there is no reported usage of fosthiazate seen in any of the available usage databases, including the USDA

- NASS (United States Department of Agriculture's National Agricultural Statistics Service); p rivate pesticide market research pesticide usage data from 2001Fosthiazate Human Health Risk Assessment DP No. 405448

Page 7 of 18 to 2008; and the California Department of Pesticide Regulation (DPR) Pesticide Use Reporting (PUR) system

.

2 .4 Anticipated Exposure Pathways

Humans may be exposed to fosthiazate in their diet resulting from residues present in foods
treated with fosthiazate . Further, given the environmental fate parameters of fosthiazate and the registered agricultural uses, the potential exists for fosthiazate to reach water resources resulting in potential residues in drinking water. There are currently no residential uses of fosthiazate , so exposure in residential and non

- occupational settings is not likely. T here is a potential for occupational handler exposures.

2 .5 Consideration of Environmental Justice

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

- Income Populations,” ( http://www.eh.doe.gov/oepa/guidanc e/justice/eo12898.pdf . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposur es that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agri culture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categor ized by subgroups based on age an d ethnic group

. 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 pesti cide 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 expert ise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

3.0 Hazard Characterization and Dose

- Response Assessment

3.1 Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

HED updated the hazard characterization and endpoint selection for fosthiazate in 2008 (J. Facey; TXR0054845; 06/02/2008 ). The 2008 document incorporated new fosthiazate toxicologic al studies in adults and juvenile rats descri bing the time

- course and dose

- response for brain and red blood cell (RBC) cholinesterase (ChE) inhibition. These studies included the following: 1) a comparative cholinesterase assessment (CCA) study in which ChE activity was
measured following gestational exposure, describing time of peak effect, and following acuteFosthiazate Human Health Risk Assessment DP No. 405448

Page 8 of 18 exposures (postnatal day, PND 11, 42) and repeated exposures (PND 11

- 21 and 42

- 52) and 2) a 28 day inhalation toxicity study with blood and brain ChE measurements.

Overall, the studies available for consideration of fosthi a zate toxicity provide a comprehensive
database. Like other OPs, fosthiazate causes neurotoxicity through the inhibition of acetylcholinesterase leading to changes in clinical si gns and behavior. T he FQPA Safety Factor
for fosthiazate was reduced to 1X since available data indicate that fetuses and juvenile rats are
not more sensitive than adult rats.

No new toxicological data have been submitted to the Agency since the 2008 doc ument. As a
result no changes to the fosthiazate endpoints or hazard characterization were required for Registration Review

. Tables 3.1 .1 and 3. 1.2 provide the t oxicological doses and endpoints for use in fosthiazate dietary and occupational assessments, respectively.

Table 3. 1 .1 : Toxicological Doses and Endpoint for Use in Fosthiazate Dietary Human Health Risk
Assessments
Exposure Scenario Point of Departure Uncertainty/FQPA

Safety Factors RfD, PAD, Level of
Concern for Risk
Assessment Study and Toxicological Effects

Acute Dietary (Children) 0.6 5 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD= 0.0065
aPAD= 0.0065 Comparative Cholinesterase Rat

Study (MRID 46744902)

BMD 10 =1.26 mg/kg/day and

BMDL 10 = 0.65 mg/kg/day,
based on RBC ChE inhibition in postnatal day 11 ( PND 11 ) pups Acute Dietary (Adults) 0.87 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD= 0.0087
aPAD= 0.0087 Comparative Cholinesterase Rat

Study (MRID 46744902)

BMD 10 =1.29 mg/kg/day and

BMDL 10 = 0.87 mg/kg/day,
based on RBC ChE inhibition in young adult rats following acute

exposure Chronic Dietary (all populations) 0. 096 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Chronic RfD=
0.00096
aPAD= 0.00096 Comparative Cholinesterase Rat

Study (MRID 46744902)

BMD 10 = 0.10 mg/kg/day and

BMDL 10 = 0. 096 mg/kg/day,
based on RBC ChE inhibition in young adult rats expos ed for 11 days
Cancer (oral, dermal, inhalation) Classification: “Not likely to be carcinogenic to humans.”

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, 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).Fosthiazate Human Health Risk Assessment DP No. 405448

Page 9 of 18 Table 3. 1

. 2 : Toxicological Doses and Endpoint for Use in Fosthiazate Occupational Human Health
Risk Assessments
Exposure Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD, Level of
Concern for Risk
Assessment Study and Toxicological Effects

Dermal (short and intermediate term) 0.44 mg/kg/day UF A = 10x

UF H = 10x MOE = 100 21 Day Dermal Rat study (MRID 43916806) BMD 10 = 1.00 mg/kg/day and BMDL 10 = 0.44 mg/kg/day, based on RBC ChE inhibition in rats (females) Inhalation (short and intermediate term) 0.0025 mg/kg/day UF A = 10x

UF H = 10x MOE = 100 28 Day Inhalation study (MRID 46744901) BMD 10 = 0.0047 mg/kg/day and BMDL 10 = 0.0025 mg/kg/day, based on
RBC ChE inhibition in rats
Cancer (oral, dermal, inhalation) Classification: “Not likely to be carcinogenic to humans.”

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, 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).

3. 2 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmen tal, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility , pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of regis tration review

, EPA will review these data and select the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), fosthiazate is subject to the endocrine screening

pa rt of the Endocrine Disr uptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “natu rally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required
determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the p otential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endo crine

- related effects caused by the substance, and
establish a dose

- response relationship between the do se and the E, A, or T effect.Fosthiazate Human Health Risk Assessment DP No. 405448

Page 10 of 18 Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. In November of 2010, issued test orders/data call

- ins for the second group of 134 chemicals, which contains 5 1

p esticide active ingredients

. Fosthiazate is not among the 109 pesti cide active ingredients on the
first and second list s to be screened under the EDSP. For further information on the status of the EDSP, the policies and procedures, the list of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

4 .0 Dietary Exposure and Risk Assessment

4 .1 Degradate Residue Profile

4.1.1 Summary of Environmental Degradation

Based on laboratory studies, fosthiazate is expected to degrade slowly in the environment, with the major routes of dissipation being aerobic soil and anaerobic aquatic soil metabolisms with
half

- lives of approximately 45 and 37 days, respectively. Under alkaline conditions, fosthiazate may also dissipate quite rapidly via hydrolysis with a half

- life of less than 1 week. Photo

degradation in water is not significant.

Although mobile in all soils tested under laboratory conditio ns, in the field fosthiazate residues were seen to remain mostly on the surface soils. Insignificant amounts of residues (< 10% of total applied) were found in the deeper 15

- 30 cm. soil layers, and no residues were found in soil below the 30 cm. layer. F osthiazate’s half

- life ranged from 10

- 17 days in the avaialbel terrestrial field dissipation studies.

4.1 .2 Residues of Concern Summary and Rationale

The HED Metabolism Assessment Review Committee (MARC) considered the available data on the nature and magnitude of residues in fosthiazate and has concluded that for plants, the parent compound and its ASC

- 67131 metabolite should be included for tolerance enforcement and dietary risk assessment (S. Kinard ; D 285024 ; 08 /27/2002). T here are no significant animal feedstuffs associated with the current use pattern, so the committee had no recommendation on residues of concern in livestock. For drinking water, the MARC recommended including the
parent compound on ly for risk assessment

. The residues of concern for fosthiazate are summarized in Table 4.1.2

.

Table 4.1.2: Summary of Metabolites and Degradates to be included in th e Risk

Assessment and Tolerance Expression for Fosthiazate

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop Parent, ASC

- 67131 Parent, ASC

- 67131

Rotational Crop Parent, ASC

- 67131 Parent, ASC

- 67131

Livestock Ruminant NA NA

Poultry NA NA Drinking Water Parent only NAFosthiazate Human Health Risk Assessment DP No. 405448

Page 11 of 18 4

. 2 Food Residue Profile

The submitted data on the metabolism of fosthiazate in potato, peach, and tomato demonstrate that residues are generally low, but do translocate throughout the plants. The highest residues are generally found in the foliage (leaves and st ems) , and not in the fruit (edible portion) of the commodity. Field trial data submitted for tomato show ed no quantifiable residues of fosthiazate in any tomato sample.

Adequat e residue chemistry data have been provided for fosthiazate . Field trials are of adequate number and geographic representation, were generated using adequate analytical methods and are supported by adequate storage stability data. Adequate studies were submitted for tomato to elucidate the fate of fosthiazate in processed commodit ies. The Agency has determined that the
current use of fosthiazate on tomato does not have any associated animal feedstuffs and therefore no exposure from animal commodities is expected . Confined rotational crops studies show that
the metabolism of fosth iazate in rotated crops is similar to that in primary crops. The available
field trial data for fosthiazate in/on tomato indicate that following application via drip irrigation
at 4 and 6 lb a

. i

. /A, residues of fosthiazate and its metabolite ASC

- 67131 were below the LOQ (<0.01 ppm each) in/on all tomato samples.

4

. 3 Water Residue Profile

Estimated drinking water concentrations (EDWCs) for fosthiazate (K. Moore; D 340347 and D340348; 0 2/26/2008) were previously generated by the Environmental Fate and Effects Division (EFED). The fosthiazate concentrations in surface water were simulated in an Index Reservoir, with 30 years of scenario specific weather data, using the linked PRZM (v3.12.2, May 12, 2005) and EXAMS (v2.98.04.06, April 25, 2005) models with a national default PCA of
0.87. Estimated groundwater EDWCs were calculated using the screening model SCI

- GROW (Screening Concentrations in Ground Water, version 2.3, 07/29/03). A dditional information about model assumptions and uncertainties , input guidance, and scenario metadata are available
at the Agency’s water modeling website, http://www.epa.gov/oppefed1/models/water/

.

The modeling was conducted using application of fosthiazate to tomatoes by ground spray, banded application, or through drip irrigation at a maximum application rate of 4.5 lb a.i./A, with all methods requiring either incorporation to 4 inches or cover with plastic mulch. It is important
to note that the current ly labeled use rate is only 1.5 lbs a.i./A and thus the EDWCs calculated by

EFED should be considered highly conservative. The recommended fosthiazate EDWCs for the
human health risk assessment are summarized in Table 4.3.

Table 4.3: Maximum EDWCs (μg/L) from proposed uses of fosthiazate applied as

ground spray, corrected for Percent Cropped Area

Surface Water a Groundwater b

Use Acute

[1

- in

- 10 year peak] Chronic

[1

- in

- 10 year average] Cancer Chronic [30

- year average] Acute and Chronic

Tomato 75.2 7.8 3.4 1.8

a Generated using Tier II linked simulation models PRZM (3.12.2) /EXAMS (2.98.04.06).

b Generated using Tier I model SCIGROW (2.3). EDWCs used for acute and chronic dietary exposure assessments are boldedFosthiazate Human Health Risk Assessment DP No. 405448

Page 12 of 18 4

. 4 Dietary Risk Assessment

Fosthiazate acute and chronic dietary risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM

- FCIDTM, Version 3.16 which uses food consumption data from the U.S. Department of Agriculture’s National Health and Nutri tion Examination Survey, What We Eat in America, (NHANES/WWEIA)

4 .4.1 Description of Residue Data Used in Dietary Assessment

Fosthiazate tolerance level residue inputs (combined parent and metabolite ASC

- 67131) wer e used to estimate the acute and chronic dietary risk for all commodities included in the

assessment . DEEM default processing factors were used for all processed tomato commodities with the exception of tomato juice and puree. A 30

- year water distribution of daily values was used as the input for indirect and direct drinking water exposure in the acute assessment, and t he 1 in 10 year point estimate average drinking water value was used as the input for indirect and direct drinking water exposu re for the chronic assessment (D340347 and D340348, Moore, 02/26/2008)

.

4 .4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary risk assessment assumed 100% crop treated for all commodities
included in the assessment.

4

. 4

. 3 A cute Dietary Risk Assessment

A slightly refined acute dietary risk assessment was conducted which used to lerance level residues, 100 % crop treated (% CT) for all commodities, DEEM default and empirical processing factors, and a distribution of modeled dri nking water estimates from the Tier I I

PRIZM

- EXAMS model

. This conservative exposure assessment showed no risks of concern (<100% of the acute population adjusted dose (a PAD)) for the U.S. General Population or any subpopulation at the 95 th percentile of exposure . The estimated exposure to the U.S. General Population resulted in a risk estimate equivalent to 5.5 % of the a PAD. The estimated exposure

to all infants , the most highly exposed subpopulation, resulted in a risk estimate equivalent to
15% of the a PAD. Results for all subpopulations are summarized in Table 4.4.6 below.

4

. 4

. 4 Chronic Dietary Risk Assessment

An unrefined chronic dietary risk assessment was conducted which used to lerance level residues,
100 % crop treated (% CT) for all commodities, DEEM default and empirical processing factors, and an average drinking water estimate from the Tier II PRIZM

- EXAMS model . This highly conservative risk assessment showed no risks of concern (<100% of the chronic population adjusted dose (cPAD)) for the U.S. General Population or any subpopulation. The estimated exposure to the U.S. General Population resulted in a risk estimate equivalent to 19 % of the cPAD. The estimated exposure to all infants , the most highly exposed subpopulation, r esulted in
a risk estimate equivalent to 45 % of the cPAD. Results for all subpopulations are summarized
in Table 4.4.6 below.Fosthiazate Human Health Risk Assessment DP No. 405448

Page 13 of 18 4.4

. 5 Cancer Dietary Risk Assessment

The Agency has classified fosthiazate as “ Not likely to be carcinogenic to humans”; theref ore, a cancer assessment was not performed.

4.4

. 6 Dietary Risk Assessment Summary Table

Table 4.4.6: Summary of Dietary (Food and Drinking Water) Exposure and Risk for Fosthiazate

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary

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

General U.S. Population 0.000361 5.6 0.000184 19 All Infants (< 1 year old) 0.000948 15 0.000435 45

Children 1

- 2 years old 0.000534 8.2 0.000278 29

Children 3

- 5 years old 0.000498 7.7 0.000244 25

Children 6

- 12 years old 0.000348 5.4 0.000173 18

Youth 13

- 19 years old 0.000273 4.2 0.000139 14

Adults 20

- 49 years old 0.000357 5.5 0.000182 19 Adults 50+ years old 0.000342 5.3 0.000177 18

Females 13

- 49 years old 0.000356 5.5 0.000180 19 * Most highly exposed subpopulation is highlighted in bold.

5.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are currently no registered residential uses associated with fosthiazate ; therefore, a
residential/non

- occupational exposure assessment is not required.

5

. 1 Spray Drift

Spray drift is not likely for fosthiazate as drip irrigation is the only application method allowable
on the current fosthiazate labels.

5 .2 Inhalation Postapplication Exposure

Based on the Agency's current practices, a quantitative residential postapplication inhalation exposure assessment was not performed for fosthiazate at this time primarily because
fosthiazate ’s vapor pressure ( 4.20X10

- 6 mm Hg at 25 deg C ) and Henry's Law Constant ( 1.76 X
10 - 05

, Pa m 3 mol - 1 ) indicate that the compound is relatively non

- volatile under field conditions. However, volatilization of pesticides may be a potential source of postapplication inhalation exposure to individu als nearby pesticide applications. 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 and may, as appropriate, develop policies and procedures toFosthiazate Human Health Risk Assessment DP No. 405448

Page 14 of 18 identify the need for and, subsequ ently, the way to incorporate postapplication 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 postapplication inhalation exposure assessment
for f osthiazate

.

6.0 Aggregate Exposure/Risk Characterization

Aggregate risk assessments evaluate the combined risk from dietary exposure (food and water) and any non

- occupational (residential) uses. There are currently no registered residential uses
associated with fosthiazate ; therefore, a residential/non

- occupational exposure assessment is not required. As a result, the fosthiazate aggregate risk assessment includes only dietary exposure (food and water). The acute and c hronic d ietary exposure estimates from food and drinking
water do not exceed HED’s level of concern (see Sections 4 .4. 3 and 4 .4. 4)

.

7.0 Cumulative Exposure/Risk Characterization

The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. Fosthiazate is a member of the organophosphate common mechanism group. The most recent cumulative risk assessment for the organophosphates wa s published on July 31, 2006 and is available at http://www.epa.gov/pesticides/cumulative/2006

- op/op_cra_main.pdf

.

As discussed above in Section 2.3, according to a BEAD memo ( R. Prieto, 01/30/2012), there is no reported usage of fosthiazate seen in any of the available usage databases. In addition, the available field trial data for fosthiazate in/on tomato indicate that following application via drip irrigation, residues of f

osthiazate and its metabolite ASC

- 67131 were below the LOQ (<0.01 ppm each) in/on all tomato samples. Thus, based on the current use pattern and available residue data, fosthiazate will not contribute exposure to the organophosphate cumulative risk assess ment.

8.0 Occupational Exposure/Risk Characterization

Fosthiazate is cu rrently registered for use as in drip irrigation equipment on tomatoes. Based on
the existing use pattern for fosthiazate , there is potential for occupational handler exposure to

occur.

8 .1 Occupational Handler Exposure and Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the currently registered use patterns and types of equipment and techniques that can potentially be used, occupational handler exposure is expected for fosthiazate . The quantitativeFosthiazate Human Health Risk Assessment DP No. 405448

Page 15 of 18 exposure/risk assessment developed for occupational handlers i s based on the following
scenarios:

1) Mixing/loading liquids for drip irrigation.

It is the policy of HED to use the best available data to assess handler exposure. Sources of generic occupational handler data, used as surrogate data in the absence of chemical

- specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occ upational exposure studies. Some of these data are proprietary (e.g., AHETF data) and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting occupational handler exposure that are used in this assessment , known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler

- exposure

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

- exposure

data.html

.

8 .1.1 Short

- /Intermediate

- Term Non

- Cancer Handler Exposure and Risk

H andler exposure is expected to be short

- or intermediate

- term in duration based on information provided on the proposed labels. T he short

- and intermediate

- term toxicological endpoints are
the same for the respective ro utes of exposure ; therefore, the estimates of risk for short

- term duration exposures are protective of those for intermediate

- term duration s . Long

- term exposures are not expected ; therefore, a long

- term assessment was not conducted.

Short

- and i ntermed iate

- term occupational handler exposure and risks were estimated using 1) unit exposures taken from the “Occupational Pesticide Handler Unit Exposure Surrogate
Reference Table” ; 2) the maximum fosthiazate label application rates ; and 3) acres treated value
take n from the current fosthiazate labels as the label restricts applicators to treating a maximum
of 25 acres per day. HED notes that the current fosthiazate labels require long sleeves, long pants, chemical resistant gloves, chemical resi stant footwear, and protective eyewear to be worn when handling this chemical. In addition, a chemical resistant apron is required to be worn during mixing/loading or equipment cleaning activities.Fosthiazate Human Health Risk Assessment DP No. 405448

Page 16 of 18 Table 8 .1.1 presents the estimated dermal

, inhalation

, and combined non

- cancer occupational
handler risk estimate s for the currently registered uses of fosthiazate

. The short

- and
intermediate

- term combined risk estimates for all occupational handler scenarios exceed HED’s
level of concern (MOEs < 100 ) even with the use of engineering controls

.

Table 8.1.1 : Summary of Occupational Handler Short

- and Intermediate

- term Total M OEs

Exposure Scenario Crop or Target Application

Rate a Area

Treated Daily Total Dermal + Inhalation MOEs b

Baseline G +

NR G,DL

+ NR G + 80%

- R G + 90%

- R G,DL +

80%

- R G,DL + 90%

- R EC

Mixer/Loader Mixing/Loading Emulsifiable Concentrates for Drip Irrigation Applications (PHED) Tomatoes 1 .5 lb ai/A 25 A 3.6 12 14 21 25 23 28 40

a Application Rates are based on the maximum application rates listed on the current fosthiazate labels.

b Total MOE (combined dermal and inhalation) = 1 / ((1/dermal MOE) + (1/inhalation MOE)) Baseline = long sleeve shirt, long pants, and chemical resistan t footwear G + NR = baseline PPE plus gloves, no respirator G, DL + NR = baseline PPE plus gloves and coveralls, no respirator
G + 80%

- R = baseline PPE plus gloves, dust

- mist respirator G, DL + 80%

- R = baseline PPE plus gloves and coveralls, dust

- mist respirator
G + 90%

- R = baseline PPE plus gloves, organic vapor respirator G, DL + 90%

- R = baseline PPE plus gloves and coveralls, organic vapor respirator EC = engineering controls

8.2 Occupational Postapplication Exposure and Risk

Occupational postapplication exposures are not expected based on the currently registered uses of fosthiazate. Fosthiazate is applied to the soil prior to planting. HED expects that postapplication exposure to fosthiazate soil will be negligible and thus an occupatio nal postapplication exposure assessment is not required

.

8 .2.1 Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative residential postapplication inhalation exposure assessment was not performed for fosthiazate at thi s time primarily because
fosthiazate ’s vapor pressure ( 4.20X10

- 6 mm Hg at 25 deg C ) and Henry's Law Constant (1.76 X
10 - 05 , Pa m 3 mol - 1 ) indicate that the compound is relatively non

- volatile under field conditions. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pest icides. 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 inhalation exposure assessment for fosthiazate

.Fosthiazate Human Health Risk Assessment DP No. 405448

Page 17 of 18 9.0 References

Metabolism Assessment Review Committee (MARC) Memo for Fosthiazate , D 285024

, S.
Kinard

, 08 /27/2002

Fosthiazate EFED D rinking Water Memo, D 340347 and D340348

, K. Moore

, 0 2/26/2008Fosthiazate Human Health Risk Assessment DP No. 405448

Page 18 of 18 Appendix A : 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, which comprise the Pesticide Handlers Exposure Database (PHED), the Outdoor Residential Expo sure Task Force (ORETF) Database, the Agricultural Handler Exposure Task Force (AHETF), and the Agricultural Reentry Task Force (ARTF) have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethically conducted.