Fosthiazate Human Health Ri sk Assessment DP No. 412481

UN I TED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFF I CE OF CHEM I CA L SAF E TY

AND PO L LUTION PREVENT I ON

MEMORANDUM

Date: 01/ 1 4/2014

SUBJECT: Revised Fostbiazate: Human Health Risk Assessment for Registration R ev i ew

PC Code: 129022

Decision No.: 4 7 977 4/ 

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Petition No.: NA DP Barcode: D41 2481

, D412038, D40 5448 Registration No.: NA

Risk Assessment Type: Single

Che mical / Aggregate

TXRNo.:NA Regulatory Action: Registration Re view

Case No.: 7604

MRID No.: 49134001

, 49134002,49134003 CAS N o.: 98886-44-3

40 CFR: 1 80.59 6

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Dona l d Wilbur, Chemist, RAB VI**~** _ 

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, 1 Christophe r Schlosser

, To xicologist

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Health Effec ts Division ( 7509P)



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- \**~** T HRO UG H : Donna Davis, Branch Chief (acting)

, RAB VI**~** and**<:~** Charles S mi t h

, Branch Chief

, RAB I 

# C-- ()**~** Hea l th Effects Division (7509P)

TO: Jame s Parker

, Chemica l Re view Manager

Risk Management and Impl eme ntation Branch I

Pesticide Reevaluation Division (7508P)

P age 1 of23Fosthiazate H uman Health Risk Assessment DP No. 412481

This memorandum is a revision to the Human Health Risk (HED) Office of Pesticide Programs (OPP) preliminary fosthiazate human health ri sk assessment document for regis tration review (DP # D405448, C. Smith, 03/05/13). In response to the preliminar y fosthiazate risk assessment,

HED r eceived comments from ISK Biosciences Corporation regarding the inhalation point of departure. In addition

, in vivo and i n vitro derma l penetration studies, (MRIDs 49134001, and 49134002) and a closed system mixer/loader study, (MRID 49134003) were subm i tted

. The

Pesticide Reevaluation Di vision (PRD) of OPP has requested that HED revie w the comments
and data subm is sions, as well as revise the preliminary fosthiazate risk assessment as appropriate. This revised assessment reflects the change made to the inhalation toxicological endpoint as referenced in ISK's comments on th e preliminary risk assessment. Additionally, this

assessment incorporates a Refined Dermal Equivalent Do se (RDD) which was estimated through

use of the in vivo and in vitro dermal penetration data submitted by ISK Biosciences Corporation

in response to the preliminary risk assessment. The occupational exposure assessment has been updat ed to reflect th ese toxicological endpoint changes. The aggregate exposure assessment

rema i ns unchanged including only dietary exposure (food and water) for lack of registered

re sident ial uses.

Based on thi s revised assessment, HED has determined that there are no potential occupational

risk estimates of concern for the currently registered use of fosthiazate on tomatoes applied v i a drip irrigation using closed mixing/loading systems and a 25 acre per day restriction.

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. The HED team members contributing to this risk assessment inc l ud e Bridgett Bobowiec (occupational assessment and risk assessment), Chris toph er Schlosser (toxicologist), and Donald Wilbur (chemistry assessmen t ).

Keara Moore of the Environmental Fa te and Effects Di v ision (EFED) performed th e drinking

water assessmen t for fosthiazate.

Page 2 of23Fosthiazate Human Health Risk Assessment DP No. 412481

Page 3 of 23 1.0 Excutive Summary

................................ ................................ ................................ ................... 3

2.0 Ingredient Profile

................................ ................................ ................................ ..................... 6

2.1 Structure and Nomenclature

................................ ................................ ................................ ... 6

2.2 Physical/Chemical Characteristics

................................ ................................ ......................... 6

2.3 Sum mary of Existing Uses

................................ ................................ ................................ ..... 6

2.4 Anticipated Exposure Pathways

................................ ................................ ............................. 7

2.5 Consideration of Environmental 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

4.0 Dietary Exposure and Risk Assessment

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

4.1 Degradate Residue Profile

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

4.1.1 Summary of Environmental Degradation

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

4.1.2 Residues of Concern Summary and Rationale

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

4.2 Food Residue Profile

................................ ................................ ................................ .......... 12

4.3 Water Residue Profile

................................ ................................ ................................ ........ 12

4.4 Dietary Risk Assessment

................................ ................................ ................................ .... 13

4.4.1 D escription of Residue Data Used in Dietary Assessment

................................ ........... 13

4.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ...................... 13

4.4.3 Acute Di etary Risk Assessment

................................ ................................ .................... 13

4.4.4 Chronic Dietary Risk Assessment

................................ ................................ ................ 13

4.4.5 Cancer Dietary Risk Assessment

................................ ................................ .................. 14

4.4.6 Dietary Risk Assessment Summary Table

................................ ................................ .... 14

5.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .......... 14

6.0 Aggregate Exposure/Risk Characterization

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

7.0 Cumulative Exposure/Risk Characterization

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

8 .0 Occupational Exposure/Risk Characterization

................................ ................................ .. 16

8.1 Occupational Handler Exposure and Risk

................................ ................................ ........... 16

8.1.1 Short

- /Intermediate

- Term N on

- Cancer Handler Exposure and Risk

............................ 17

8.2 Occupational Post

- application Exposure and Risk

................................ .............................. 19

8.2.1 Post

- application Inhalation Exposure

................................ ................................ ........... 19

9.0 References

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

................................ ................................ ...................... 21 Appendix B: Toxicology Profile.

................................ ................................ ................................ ...... 22 Appendix C: Refined Dermal Equivalent Dose Calculation

................................ ........................ 22Fosthiazate Human Health Risk Assessment DP No. 412481

Page 4 of 23 1.0 Executive Summary

Fosthiazate (O

- Ethyl S

- (1

- methylpro pyl)(2

- oxo

- 3

- thiazolidinyl) phosphonothioate ) is a n organophosphate (OP) nematicide and insecticide

. The chemical is formulated as a n emulsifiable concentrate (EC) at 75 % active ingredient (ai) and 47.2 % ai. Fosthiazate is registered for drip (trickle) irrigation use on tomatoes. The maximum application rate is 1.5 lb

ai /acre and the label restricts applicators to treating 25 acres per day. Applicator s and other

handler s must wear long sleeved coveralls over long sleeved shirt, long pants, chemical re sistant gloves, shoe plus socks, protective eyewear, and a chemical resistant apron when cleaning equipment, mixing or loading. In addition, closed systems are required for mixing and loading

fosthiazate.

Hazard Assessment : The toxicology database for f osthiazate is c omplete a s described in 40 CFR, Part 158. Overall, the studies available for consideration of fosthiazate toxicity provide a comprehensive database. Like other O P s, fosthiazate causes neurotoxicity through the inhibition of acetylcholinest erase leading to changes in clinical signs and behavior. HED has re

- evaluated the inhalation endpoint using t he methods and dosimetry equations described in EPA’s reference concentration (RfC) guidance (1994) to calculat e a human equivalent concentration ( HEC ) based

on the inhalation toxicity point of departure (BMDL). Additionally, HED has received both in vivo and in vitro dermal penetration studies and has estimated a R efined Dermal Equivalent (RDD) Dose using this data

.

Food Quality Protection Act (FQPA) Safety Factor (SF) Decision: The FQPA Safety Factor for fosthiazate has been reduced to 1X since the endpoints selected for risk assessment are protective of the effects observed in juvenile rats and fetuses.

Dose Response Assessment: T able 3.1

. 1 and Table 3.1.2 are a summary of the points of departure (PODs) selected for assessment of dietary, inhalation, and dermal exposure. R oute

specific toxicity studies were selected for assessment of short

- /intermediate

- term dermal, inhalation, and oral ex posures. Since the PODs and level of concern (LOC) for the different exposure routes are different, combined occupational dermal and inhalation risks should be

calculated u s ing the aggregate risk index (ARI) approach.

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. T he 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 incorporat ed 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. popul ation resulted in an

estimated risk of 5.6 % of the acute population adjusted dose (aPAD).Fosthiazate Human Health Risk Assessment DP No. 412481

Page 5 of 23 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 opulation adjusted dose (cPAD). The estimated exposure to the general U.S. population resulted in an

estimated risk of 19 % of the chronic p opulatio n adjusted dose (cPAD)

.

Residential (

Non

- Occupational) Exposure and Risk Assessment : There are currently no registered residential uses associated with fosthiazate ; therefore, a residential/non

- occupational exposure assessment is not required.

Aggre gate Risk Estimates: In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from dietary (food and water) and residential (dermal, inhalation, and/or incidental oral) sources. When aggregating exposures and risks from these sources, HED considers the route and duration of exposure as well as the toxicological effects for each route. There are currently no registered residential uses associated with fosthiazate ; therefore, a

residential/non

- occupational exposure assessm ent is not required. As a result, the fosthiazate aggregate risk assessment includes only 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.

Occupatio nal Exposure and Risk Assessment: The expected dermal and inhalation occupational exposure assessment has been revised to incorporate changes to the toxicological endpoints

. The short

- and intermediate

- term risk estimates for all occupational handler sce narios
do not exceed HED’s level of concern (ARI ≥ 1) with the label mandated use of closed systems for mixing/loading and acreage restrictions.

Occupational post

- application exposures are not expected based on the currently registered uses

of fosthiazate

. Fosthiazate is applied to the soil prior to planting. P ost

- application exposure to

fosthiazate treated soil will be negligible and thus an occupational post

- application exposure

assessment is not required for the currently registered uses

.

Review of H

uman 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 ethi cal conduct and a ll

of the studies utilized in this assessment have received the appropriate review. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on t heir use, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

. http:/ /www.epa.gov/pesticides/science/post

- app

- exposure

- data.htmlFosthiazate Human Health Risk Assessment DP No. 412481

Page 6 of 23 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

The chemical structure an d nomenclature of fosthiazate and ASC

- 67131are presented in Table

2.1.

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 Physica l/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 persi stent in water and soil. In two studies, fosthiazate was found to have 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 reac h

water resources.

2 .3 Summary of Existing Uses

Fosthiazate is formulated 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 FOSTH IAZATE 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 applica tion rate is 1.5 lb a.i. /acre and the label restricts applicators to treating 25 acres per day.Fosthiazate Human Health Risk Assessment DP No. 412481

Page 7 of 23 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 ava ilable 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 2001 to 2008; and the California Department of Pesticide Regul ation (DPR) Pesticide Use Reporting (PUR) system.

2 .4 Anticipated Exposure Pathways

Based on the registered fosthiazate application scenarios, dietary exposure is anticipated as residues may be found in/on crops and drinking water. There are currently n o residential uses of

fosthiazate , so exposure in residential and non

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

2 .5 Consideration of Environmental Justice

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

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

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

. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when cond itions 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
post

- application 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 di etary 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

Like other OPs, fosthiazate causes neurotoxicity through the inhibition of acet ylcholinesterase leading to changes in clinical signs and behavior. Overall, the studies available for consideration of fosthiazate toxicity provide a comprehensive database. See A ppendix B for acute toxicity

table. Since endpoint selection in 2008 (J. Facey; TXR0054845; 06/02/2008 ) , HED has revised the endpoint selections used for inhalation and dermal occupational exposure risk assessment.Fosthiazate Human Health Risk Assessment DP No. 412481

Page 8 of 23 Tables 3.1 .1 and 3. 1.2 provide the t oxicological doses and endpoints for use in fosthiazate dietary and occupatio nal assessments, respectively.

The inhalation exposure endpoint has been updated to include t he methods and dosimetry equations described in EPA’s reference concentration (RfC) guidance (1994) to calculat e a human equivalent concentration ( HEC ) based on t he inhalation toxicity point of departure ( BMDL). See Appendix C for refined dermal equivalent dose calculations. The inhalation PoD

is based on RBC ChE inhibition seen in the 28 day rat inhalation study

. For inhalation exposure, the standard interspeci es extrapolation uncertainty factor can be reduced from 10X to 3X due to the HEC calculation accounting for pharmacokinetic (not pharmacodynamic) interspecies

differences. The intraspecies uncertainty factor remains at 10X.

Additionally, HED has received both in vivo and in vitro dermal penetration studies , (MRIDs 49134401, and 49134002)

. The dermal exposure endpoint now includes a RDD equal to 1.5 mg/kg/day

. The dermal PoD was adjusted using the “triple pack” approach, if in vitro data

obtained using animal skin is shown to be a good predictor of animal in vivo dermal absorption for a chemical, then the identical technique performed in vitro with human skin may be useful in extrapolating human dermal absorption

. Mathematically, the PoD derived from th e 28

- day dermal rat toxicity study has been adjusted to account for greater rat skin permeability (1.6

- 4.4 fold) compared to human skin (e.g., Calculations are provided in Appendix C ). A total uncertainty factor of 100X is appropriate for dermal exposures [ 10X for interspecies extrapolation, 10X for intraspecies variation and a 1X FQPA safety factor]. Note: Although human information has been used to derive a human adjusted PoD, the full 10X interspecies factor is retained. The adjustments made here rel ate only to dermal adsorption, not to systemic pharmacokinetics which impact species differences in internal dosimetry and not to pharmacodynamics which relate to species differences in AChE inhibition.

The acute and chronic dietary PoDs remain the same a s the 2008 memorandum based on a BMD modeling approach of an acute cholinesterase study c onsistent with EPA policy. The 10x intraspecies and 10x interspecies factors are applicable, however, the 10x FQPA database uncertainty factor is reduced to 1x since data was based on the most sensitive endpoint.Fosthiazate Human Health Risk Assessment DP No. 412481

Page 9 of 23 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)

B MD 10 = 0.10 mg/kg/day and

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

UF = uncertainty factor, FQPA SF = FQPA sa fety 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).

Table 3. 1

. 2 : Toxicological Doses and Endpoint for Use in Fosthiazate Occupational Human Health Risk Assessments

Exposure Scenario Poi nt 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

Refined Dermal Equivalent Dose = 1.5 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/L

UF A = 3 x UF H = 10x MOE = 30 28 Day Inhalation study (MRID

46744901 ) BMD 10 = 0.0047 mg/L

and BMDL 10 = 0.0025 mg/L, based

on RBC ChE inhibition in rats HEC = 0.00562 mg/L

HED = 0.643 mg/kg/day Cancer (oral, dermal, inhalation) Classification: “Not likely to be carcinogenic to humans.”

UF = uncertainty factor, FQPA S F = 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 Applic able. UF A = extrapolation f

rom animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies).

* HEC = LOAEL x RDDR = 0.0025 x 2. 997 = 0.00562 ** HED = HEC x human specific conversion factor (CF) x relative activity fa ctor (AF) x exposure duration

= 0.0 562 mg/L x 11.8 L/hr/kg BW x 1.2 x 8 hrs = 0.643 mg/kg/dayFosthiazate Human Health Risk Assessment DP No. 412481

Page 10 of 23 3. 2 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemic als. Collectively, these studies include acute, subchronic

, and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be
suscept ible 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 its reregistration decision for fosthiazate, EPA reviewed these data and selected 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 part of the Endocrine Disruptor 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 “naturally 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 thyroi d (E, A, or T) hormonal
systems. Chemicals that go through Tier 1 screening and are found to have the potential 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 t ests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T effect. Under FFDCA

secti on 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. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our

website. 2

1 See http://www.regulations.gov/#!do cumentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of chemicals.
2 2 http://www.epa.gov/endo/Fosthiazate Human Health Risk Assessment DP No. 412481

Page 11 of 23 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 metaboli sms 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 mobil e in all soils tested under laboratory conditions, 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 residue s were found in soil below the 30 cm. layer. Fosthiazate’s half

- life ranged from 10

- 17 days in the available terrestrial field dissipation studies.

4.1 .2 Residues of Concern Summary and Rationale

The HED Metabolism Assessment Review Committee (MARC) con sidered 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 2850 24 ; 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 only f

or 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 the Risk Assessment and Tolerance Expression for Fosthiazate

Matrix Residues included in Ris k

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. 412481

Page 12 of 23 4

. 2 Food Resid ue 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 stems)

, 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 a dequate 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 commodities. 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 fosthiazat e 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 bel ow 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

D ivision (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 nati onal 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

EF ED 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 per cent cropped a rea 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 c 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).

c ) EDWCs used for acute and chronic dietary exposure assessments are boldedFosthiazate Human Health Risk Assessment DP No. 412481

Page 13 of 23 4

. 4 Dietary Risk Assessment

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

- FCIDTM, Version 3.16 which uses food consumption data from the U.S. Department of Agriculture’s National Health and Nutrition 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 wer e 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 poin t estimate average drinking water value was used as the input for indirect and direct drinking water exposure 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 Acute 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 drinking water estimates from the Tier I I

PRIZM

- EXAMS model

. This conservative exposure assessment showed no risks of concern (<100% of the acute popul ation 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 ris k 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

conservativ e 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 % o f the cPAD. The estimated exposure to all infants , the most highly exposed subpopulation, resulted 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. 412481

Page 14 of 23 4.4

. 5 Cancer Dietary Risk Assessment

The Agency has classified fosthiazate as “ Not likely to be carcinogenic to humans”; therefore, 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

Ri sk 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 0.00 0435 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

Ad ults 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

A sp ray drift assessment is not included in this memo because drip irrigation is the only

fosthiazate applicat ion method allowable on the current labels.Fosthiazate Human Health Risk Assessment DP No. 412481

Page 15 of 23 5 .2 Inhalation Post

- application Exposure

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

- application inhalation exposure assessment was not performed for fosthiazate at this time primar ily 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 potent ial source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and

Rodenticide Act Scien tific 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 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 qu antitative post

- application inhalation exposure assessment

for fosthiazate

.

6.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from dietary (food and water) and residential (dermal, inhalation, and/or incidental oral) sources. When aggregating exposures and risks from these sources, HED considers the route and duration of exposure as well as the toxicological effects for each route. Aggregate risk assessments

evaluate the c ombined risk from dietary exposure (food and water) and any non

- occupational (residential) uses. There are currently no registered residential uses associated with fosthiazate

. 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 (FQP A) 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 was pub lished 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. Pr ieto, 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 fosthi azate 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 any significant exposure to the organophosphate cumulative

risk assessment.Fosthiazate Human Health Risk Assessment DP No. 412481

Page 16 of 23 8.0 Occupational Exposure/Risk Characterization

Fosthiazate is cu rrently registered for use on tomatoes applied through drip irrigation equipment.

Based on the existing use pattern for fosthiazate , there is potential for occupational handle r 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 applic ations and exposures can vary depending on the specifics of each task. 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 quantitat ive exposure/risk assessment developed for occupational handlers is 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 o ccupational 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 Expos ure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data) and subject to the data protection provisions of FIFRA. The standard values recommended for use in predict ing 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), wh ich, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/scienc e/handler

- exposure

data.html

.

HED acknowledges that ISK submitted a c losed system mixer/loader risk assessment (MRID 49134003) in response to the preliminary risk assessment. Part of this assessment included a

discussion of the PHED data used to assess closed system mixing and loading. The data was

described in the submission as less than credible

, however HED does not agree with this statement. This data has been used for over 15 years in various risk assessments across multiple regulatory Agencies. I t is currently the best available data to assess the closed system mixing and loading scenario. HED is aware that AHETF is currently working on producing new closed system mixing/loading exposure data . This data, once completed and reviewed by HED, may replace the PHED data in HED risk assessments but until then HED will continue to use the PHED data for assessing the closed system mixing and loading scenario. This approach isFosthiazate Human Health Risk Assessment DP No. 412481

Page 17 of 23 consistent with HED’s approach for other handler scenarios for which AHETF ha s plans to produce new exposure data. In addition, i t is not appropriate to attempt to manipulate the PHED data by removing certain monitoring units from a scenario as suggested in the ISK submission. As a result, this revised assessment continues to be based on the standard PHED closed system mixing and loading unit exposures.

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 th e proposed labels. T he short

- and intermediate

- term toxicological endpoints are

the same for the respective routes of exposure ; therefore, the estimates of risk for short

- term duration exposures are protective of those for intermediate

- term duration s . Lo ng

- term exposures are not expected ; therefore, a long

- term assessment was not conducted.

Short

- and i ntermediate

- term occupational handler exposure and risks were estimated using 1) unit exposures taken from the “Occupational Pesticide Handler Unit Expo sure 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 curr ent fosthiazate labels require the use of closed systems for mixing and loading.

Table 8 .1.1 presents the estimated dermal

, inhalation , and combined ARI occupational handler

risk estimate s for the currently registered uses of fosthiazate

. The short

- an d intermediate

- term
combined risk estimates for all occupational handler scenarios do not exceed HED’s level of

concern ( ARI s ≥ 1 ) using closed systems and crop acreage restrictio ns.Fosthiazate Human Health Risk Assessment DP No. 412481

Page 18 of 23

Table 8.1.1: Summary of Occupational Handler Short

- and Intermediate

- term Dermal and Inhalation Risk Estimates. 1

Exposure

Scenario Crop Application

Rate 2 Area

Treate

d Daily 2 Inhalation

Unit of

Ex posure (μg/lbs ai) Dermal Unit

of Exposure (μg/lbs ai) Inhalation

MOE 3 Dermal MOE 4 Total ARI 5

Baseline

No Respirator (NR) Base

line G G,DL EC 6 Base

line Base

line G GDL EC 6 Base

Line

+NR G

+NR GDL +
NR EC 6

Mixer/Loader Mixing/Load ing

Emulsifiabl e Concentrates for Drip Irrigation Applications (PHED) Tomato 1.5 lb ai/A 25 A 0.219 220 37.6 29.1 8.6 6,200 15 85 110 370 0.15 0.85 1.1 3.7

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table July, 5 th 2000. Dermal PPE represented includes ; Baseline = long sleeve shirt, long pants, and chemical

resistant footwear G + NR = baseline PPE plus gloves, G, DL + NR = baseline PPE plus gloves and long sleeved coveralls, and EC = engineering control s , closed loading and mixing system

2 Based on registered label fosthiazate labels. Reg Nos. 71512

- 17, 71512

- 4,71512

- 5, 71512

- 6. Acreage restriction to 25 acres a day.

3 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

4 Dermal MOE = Dermal NOAEL (mg/kg/day ) ÷ Dermal Dose (mg/kg/day).

5 ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)].

6 Current labels require closed systems for mixing and loading fosthiazate.Fosthiazate Human Health Risk Assessment DP No. 412481

Page 19 of 23 8.2 Occupational Post

- application Exposure and Risk

Occupational post

- application exposures are not expected based on the currently registered uses of fosthiazate. Fosthiazate is applied to the soil prior to planting. HED expects that post

application exposure to fosthiazate soil will be negligible and thus an occupational post

application exposure assessment is not required

.

8 .2.1 Post

- application Inhalation Exposure

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

- application inhalation exposure assessment was not perform ed 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, 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 partic ulates that 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 Reen try 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. 412481

Page 20 of 23 9.0 References

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

, S.

Kinard

, 08 /2 7/2002

Fosthiazate EFED Drinking Water Memo, D 340347 and D340348

, K. Moore, 02/26 /2008

Reifenrath, W. (2010) Skin Penetration of Fosthiazate after Topical Application to Excised Rat and Human Skin: Final Report. Project Number: 95077. MRID 49134001, Unpu blished study prepared by Stratacor, Inc. 122p.

Reifenrath, W. (2010) Skin Penetration of Fosthiazate after Topical Application to Live Rats: Final Report. Project Number: 95083. MRID 49134002, Unpublished study prepared by

Pacific Bio Labs and Stratacor , Inc. 104p.

Ross, J.; Driver, J.; Cochran, R. (2013) Closed System Mixer/Loader Risk Assessment for Fosthiazate. Project Number: ISK/001/13. MRID 49134003. Unpublished study prepared by Risksciences.net, LLC. 21p.

USEPA. (1994). Methods for derivation o f inhalation reference concentrations and appli cations of inhalation dosimetry.Fosthiazate Human Health Risk Assessment DP No. 412481

Page 21 of 23 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 oth er chemical. These studies, which comprise the Pesticide Handlers Exposure Database (PHED) have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethically conducted.Fosthiazate Human Health Risk Assessment DP No. 412481

Page 22 of 23 Appendix B: Toxic ology Profile.

Acute Toxicity of Fosthiazate

Guideline No./Study Type MRID Results Toxicity Category

8700.1100

Acute Oral Rat; 1989 41347622 LD 50 = 73 mg/kg

- M;

= 51

- 64

- F II

8700.1200

Acute Dermal Rat; 1989 41347625 LD 50 = 2396 mg/kg

- M; =861 mg/kg

- F II

8700.1300

Acute Inhalation Rat 1 ; 1989 41347626 LC 50 = 0.83 mg/L

- M = 0.56 mg/L

- F III

8700.2400

Primary Eye Irritation Rabbit; 1989 41347627

41347628 Mildly irritating; corneal

opacity reversible within 7

days II

8700.2500

Primary Skin Irritation R abbit; 1989 41347629 Non

- irritating IV

8700.2600

Dermal Sensitization Guinea pig; 1989 41347630 Sensitizer NAFosthiazate Human Health Risk Assessment DP No. 412481

Page 23 of 23 Appendix C : Refined Dermal Equivalent Dose Calculation

A refined dermal equivalent dose (RDD) for human skin may be derived from the in vitro human and rat epidermis absorption study (MRID 49134001) to account for the differences in skin permeability across species. In the in vitro study, the amount of radiolabel dicrotophos was 1.1 to 4.4 fold higher in rat epidermis compared to human epidermi s. The RDD was calculated by the following formula:

Refined Dermal Equivalent Dose (RDD) (mg/kg/day) =

Dermal PoD (mg/kg/day) x Animal In Vitro Absorption (%)

Human In Vitro Absorption (%)

Using the equation above, the PoD derived from the 28

- day dermal rat toxicity study can be refined to account for higher skin permeability in rat compared to human skin. Therefore, the refined dermal dose for human skin to use as the PoD is 1.5 mg/kg/day. The calculations are

shown in the table below.

Table B.1 : Calculations Used to Derive a Refined Dermal Equivalent Dose “Triple Pack” Data

Study/Information Type In vivo Rat (24 hr) In vitro Rat

(24 hr) In vitro Human

(24 hr) Animal in vitro

Human in vitro

Dose 20 μg/cm 2 49 51 15 3.4

Dose 200 μg/cm 2 34 20 9 2.2

Dose 1000 μg/cm 2 24 22 5 Refined Dermal Equivalent Dose Calculation

Study/Information Type Rat Dermal PoD (BMDL 10 ) RDD = PoD x Animal In Vitro Human In Vitro

28

- day dermal toxicity study 0.44 mg/kg/day 0.44 x 3.4 = 1.5 mg/kg/day

Please note that the dermal absorption value from in vivo and in vitro studies at 24 hours were

used in estimation of h uman adjusted dermal absorption value because there was continued absorption after skin washing. The 24 hour animal in vitro absorption value was also considered to be a good predictor animal in vivo absorption ( in vitro / in vivo ≈ 1) . Additionally, the der mal absorption values at the low dose were used for refinement as they represented the most

conservative estimate and were consistent with dermal absorption values from the formulated

concentration

.

A total uncertainty factor of 100X is appropriate for d ermal exposures [ 10X for interspecies extrapolation, 10X for intraspecies variation and a 1X FQPA safety factor]. Note: Although human information has been used to derive a human adjusted PoD, the full 10X interspecies factor is retained. The adjustment s made here relate only to dermal adsorption, not to systemic pharmacokinetics which impact species differences in internal dosimetry and not to pharmacodynamics which relate to species differences in AChE inhibition.