Fosthiazate Human Health Risk Assessment DP No. 412481 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

Date: 01/14/2014 

SUBJECT: Revised Fostbiazate: Human Health Risk Assessment for Registration Review 

PC Code: 129022 

Decision No.: 479774/ l/79!1'/, 'liP9'1o? 

Petition No.: NA 

DP Barcode: D412481 , D412038, D405448 

Registration No.: NA 

Risk Assessment Type: Single 

Chemical/ Aggregate 

TXRNo.:NA 

Regulatory Action: Registration Review 

Case No.: 7604 

MRID No.: 49134001 , 49134002,49134003 

CAS No.: 98886-44-3 

40 CFR: 180.596 

FROM: /}'1-....., J .#.-1' /JJ / a I l;c.tj2ol'1 Bridgett Bobowiec, Risk Assessor,~ ~ '/~ ,_,, ~ '/' 

Donald Wilbur, Chemist, RAB VI ~ _ tf-<:v\ , 1 

Christopher Schlosser, Toxicologist, RAB VI~~.....,:#~!~- 1!?/1 ~- /'-~ 1 'I 

Health Effects Division (7509P) 

D t bl/, I • • - \ ~ THROUGH: 

and 

Donna Davis, Branch Chief (acting), RAB VI ~ 

<:~ 

Charles Smith, Branch Chief, RAB I C--() ~ Health Effects Division (7509P) 

TO: James Parker, Chemical Review Manager 

Risk Management and Implementation Branch I 

Pesticide Reevaluation Division (7508P) 

Page 1 of23 
Fosthiazate Human 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 risk assessment document for registration review 

(DP# D405448, C. Smith, 03/05/13). In response to the preliminary fosthiazate risk assessment, 

HED received comments from ISK Biosciences Corporation regarding the inhalation point of 

departure. In addition, in vivo and in vitro dermal penetration studies, (MRIDs 49134001, and 

49134002) and a closed system mixer/loader study, (MRID 49134003) were submitted. The 

Pesticide Reevaluation Division (PRD) of OPP has requested that HED review the comments 

and data submissions, 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 the preliminary risk assessment. Additionally, this 

assessment incorporates a Refined Dermal Equivalent Dose (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 

updated to reflect these toxicological endpoint changes. The aggregate exposure assessment 

remains unchanged including only dietary exposure (food and water) for lack of registered 

residential uses. 

Based on this 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 via 

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 include Bridgett Bobowiec (occupational assessment and risk 

assessment), Christopher Schlosser (toxicologist), and Donald Wilbur (chemistry assessment). 

Keara Moore of the Environmental Fate and Effects Division (EFED) performed the drinking 

water assessment for fosthiazate. 

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Fosthiazate Human Health Risk Assessment DP No. 412481

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1.0 Excutive Summary................................................................................................................... 3

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 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 Description of Residue Data Used in Dietary Assessment........................................... 13

4.4.2 Percent Crop Treated Used in Dietary Assessment ...................................................... 13

4.4.3 Acute Dietary 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 Non-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 ........................................................ 22
Fosthiazate Human Health Risk Assessment DP No. 412481

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1.0 Executive Summary

Fosthiazate (O-Ethyl S-(1-methylpropyl)(2-oxo-3-thiazolidinyl) phosphonothioate) is an 

organophosphate (OP) nematicide and insecticide. The chemical is formulated as an

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. Applicators and other 

handlers must wear long sleeved coveralls over long sleeved shirt, long pants, chemical resistant 

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 fosthiazate is complete as described in 40 

CFR, Part 158. Overall, the studies available for consideration of fosthiazate toxicity provide a 

comprehensive database. Like other OPs, fosthiazate causes neurotoxicity through the inhibition 

of acetylcholinesterase leading to changes in clinical signs and behavior. HED has re-evaluated 

the inhalation endpoint using the methods and dosimetry equations described in EPA’s reference 

concentration (RfC) guidance (1994) to calculate 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 Refined 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: Table 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. Routespecific toxicity studies were selected for assessment of short-/intermediate-term dermal, 

inhalation, and oral exposures. Since the PODs and level of concern (LOC) for the different 

exposure routes are different, combined occupational dermal and inhalation risks should be 

calculated using 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. Estimated 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).
Fosthiazate Human Health Risk Assessment DP No. 412481

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Chronic: An 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 population 

adjusted dose (cPAD). The estimated exposure to the general U.S. population resulted in an 

estimated risk of 19% of the chronic population 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. 

Aggregate 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 assessment 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 

concern. 

Occupational 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 scenarios 

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. Post-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 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 review of their ethical conduct and all 

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 their 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.html
Fosthiazate Human Health Risk Assessment DP No. 412481

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2.0 Ingredient Profile

Fosthiazate is an organophosphate nematicide and insecticide that is currently registered for use 

on tomatoes.

2.1 Structure and Nomenclature

The chemical structure and nomenclature of fosthiazate and ASC-67131are presented in Table 

2.1.

Table 2.1: Fosthiazate Nomenclature

Chemical Structure

N

P

S

O

CH3

CH3

OC2H5

S

O

Fosthiazate: O-Ethyl S-(1-methylpropyl)(2-oxo-3-thiazolidinyl)phosphonothioate

H3C

S

N

H

P

S

O

OC2H5

CH3

CH3

O

O

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 m3

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 

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 reach 

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 FOSTHIAZATE 75%EC (71512-17). Tomatoes are 

the only currently 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 to treating 25 

acres per day.
Fosthiazate Human Health Risk Assessment DP No. 412481

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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); private pesticide market research pesticide usage data from 2001 

to 2008; and the California Department of Pesticide Regulation (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 no residential uses of 

fosthiazate, so exposure in residential and non-occupational settings is not likely. There is a 

potential for dermal and inhalation 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/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 residential 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 registered food uses of a 

pesticide. These data are analyzed and categorized 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 conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

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 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

Like other OPs, fosthiazate causes neurotoxicity through the inhibition of acetylcholinesterase 

leading to changes in clinical signs and behavior. Overall, the studies available for consideration 

of fosthiazate toxicity provide a comprehensive database. See Appendix 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

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Tables 3.1.1 and 3.1.2 provide the toxicological doses and endpoints for use in fosthiazate 

dietary and occupational assessments, respectively.

The inhalation exposure endpoint has been updated to include the methods and dosimetry 

equations described in EPA’s reference concentration (RfC) guidance (1994) to calculate a 

human equivalent concentration (HEC) based on the 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 interspecies 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 the 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 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.

The acute and chronic dietary PoDs remain the same as the 2008 memorandum based on a BMD 

modeling approach of an acute cholinesterase study consistent 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

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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) 0.65 mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF = 1x

Acute RfD= 0.0065

aPAD= 0.0065

Comparative Cholinesterase Rat 

Study (MRID 46744902)

BMD10=1.26 mg/kg/day and 

BMDL10 = 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

UFA= 10x

UFH= 10x

FQPA SF = 1x

Acute RfD= 0.0087

aPAD= 0.0087

Comparative Cholinesterase Rat 

Study (MRID 46744902)

BMD10=1.29 mg/kg/day and 

BMDL10 = 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

UFA= 10x

UFH= 10x

FQPA SF = 1x

Chronic RfD= 0.00096

aPAD= 0.00096

Comparative Cholinesterase Rat 

Study (MRID 46744902)

BMD10= 0.10 mg/kg/day and 

BMDL10 = 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 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. UFA= 

extrapolation from animal to human (interspecies), UFH = potential variation in sensitivity among members of the human population 

(intraspecies).

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

Refined Dermal 

Equivalent Dose = 

1.5 mg/kg/day

UFA= 10x

UFH= 10x MOE = 100

21 Day Dermal Rat study (MRID 

43916806) BMD10= 1.00 mg/kg/day 

and BMDL10 = 0.44 mg/kg/day, 

based on RBC ChE inhibition in rats 

(females)

Inhalation (short and 

intermediate term)

0.0025 mg/L

UFA= 3x

UFH= 10x MOE = 30

28 Day Inhalation study (MRID 

46744901) BMD10= 0.0047 mg/L 

and BMDL10 = 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 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. UFA= 

extrapolation from animal to human (interspecies), UFH = 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 factor (AF) x exposure duration

 = 0.0562 mg/L x 11.8 L/hr/kg BW x 1.2 x 8 hrs = 0.643 mg/kg/day
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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, developmental, 

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 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 thyroid (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 tests 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 

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. A second list of chemicals 

identified for EDSP screening was published on June 14, 20131and 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/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of chemicals.

2

2 http://www.epa.gov/endo/
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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. Photodegradation in water is not significant.

Although mobile 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 residues 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) 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; D285024; 08/27/2002). There 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 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 the 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 NA
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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 stems), and not in the fruit (edible portion) of the 

commodity. Field trial data submitted for tomato showed no quantifiable residues of fosthiazate

in any tomato sample.

Adequate 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 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 fosthiazate 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; D340347 and 

D340348; 02/26/2008) 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). Additional 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 currently 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

Tomatoc

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 bolded
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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 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) were 

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 the 

1 in 10 year point 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 tolerance 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 II 

PRIZM-EXAMS model. This conservative exposure assessment showed no risks of concern 

(<100% of the acute population adjusted dose (aPAD)) for the U.S. General Population or any 

subpopulation at the 95th percentile of exposure. The estimated exposure to the U.S. General 

Population resulted in a risk estimate equivalent to 5.5% of the aPAD. The estimated exposure 

to all infants, the most highly exposed subpopulation, resulted in a risk estimate equivalent to 

15% of the aPAD. 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 tolerance 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, resulted in 

a risk estimate equivalent to 45% of the cPAD. Results for all subpopulations are summarized in 

Table 4.4.6 below.
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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 

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

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

fosthiazate application method allowable on the current labels.
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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 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 m3 mol-1) indicate that the compound is relatively non-volatile under field conditions. 

However, volatilization of pesticides may be a potential 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 Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s 

final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application 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 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 combined 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 chronic dietary 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 was 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 fosthiazate 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.
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8.0 Occupational Exposure/Risk Characterization

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

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 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 quantitative 

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 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 occupational exposure 

studies. Some of these data are proprietary (e.g., AHETF data) and subject to the data protection 

provisions of FIFRA. The standard values recommended for use in predicting 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 surrogate data, including descriptions of the 

various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html.

HED acknowledges that ISK submitted a closed 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. It 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 is 
Fosthiazate Human Health Risk Assessment DP No. 412481

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consistent with HED’s approach for other handler scenarios for which AHETF has plans to 

produce new exposure data. In addition, it 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

Handler exposure is expected to be short- or intermediate-term in duration based on information 

provided on the proposed labels. The 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 durations. Long-term exposures 

are not expected; therefore, a long-term assessment was not conducted. 

Short- and intermediate-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 

taken 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 the use of closed 

systems for mixing and loading. 

Table 8.1.1 presents the estimated dermal, inhalation, and combined ARI occupational handler 

risk estimates for the currently registered uses of fosthiazate. The short- and intermediate-term 

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

concern (ARIs ≥ 1) using closed systems and crop acreage restrictions.
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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 

Daily2

Inhalation 

Unit of 

Exposure

(μg/lbs ai)

Dermal Unit

of Exposure

(μg/lbs ai)

Inhalation 

MOE3 Dermal MOE4 Total ARI5

Baseline

No 

Respirator

(NR)

Base

line G G,DL EC 6 Baseline

Base

line G GDL EC 6

Base

Line

+NR

G

+NR

GDL + 

NR

EC 6

Mixer/Loader

Mixing/Load

ing 

Emulsifiable 

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, 5th 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 controls, 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.
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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 postapplication exposure to fosthiazate soil will be negligible and thus an occupational postapplication 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 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 m3 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 pesticides. The Agency sought expert advice and input on issues related to volatilization 

of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory 

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for fosthiazate.
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9.0 References

Metabolism Assessment Review Committee (MARC) Memo for Fosthiazate, D285024, S. 

Kinard, 08/27/2002

Fosthiazate EFED Drinking Water Memo, D340347 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, Unpublished 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 of inhalation reference concentrations and applications 

of inhalation dosimetry.
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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) have been determined to require a review of their 

ethical conduct, have received that review, and have been determined to be ethically conducted.
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Appendix B: Toxicology Profile.

Acute Toxicity of Fosthiazate 

Guideline No./Study Type MRID Results Toxicity Category

8700.1100

Acute Oral Rat; 1989

41347622 LD50 = 73 mg/kg- M;

= 51-64- F

II

8700.1200

Acute Dermal Rat; 1989 41347625

LD50 = 2396 mg/kg- M;

=861 mg/kg- F

II

8700.1300

Acute Inhalation Rat1; 1989

41347626 LC50 = 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 Rabbit; 1989

41347629 Non-irritating IV

8700.2600

Dermal Sensitization Guinea pig; 1989

41347630 Sensitizer NA
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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 epidermis. 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/cm249 51 15 3.4

Dose 200 μg/cm234 20 9 2.2

Dose 1000 μg/cm224 22 5

Refined Dermal Equivalent Dose Calculation

Study/Information Type Rat Dermal PoD 

(BMDL10)

RDD = PoD x Animal 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 human 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 dermal 

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 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 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.