UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: September 15, 2015 

OFFICE OF 

CHEMICAL SAFETY ANO 

POLLUTION PREVENTION 

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

of Dicrotophos. 

PC Code: 03520 I 

Decision No.: 454409 

Petition No.: NA 

Risk Assessment Type: Human Health Risk Assessment 

TXR No.: NA 

MRID No.: NA 

FROM: Thurston G. Morton, Chemist, RAB IV 

DP Barcode: 428506 

Registration No.: NA 

Regulatory Action: Reg Review 

Case No.: 0145 

CAS No.: 141-66-2 

40 CFR: § 180.299 

Wade Britton, Industrial Hygienist, RAB IV 

Alexandra LaMay, Biologist, RAB VII t{ 

Matthew Lloyd, Industrial Hygienist, RAB VII 

Shalu Shelat, Industrial Hygienist, RAB VI ~ -tJ .

1 1 

. 

Anna Lowit, Ph.D., Senior Scientist, IO '-) {% 

Elizabeth Holman, Physical Scientist, RA 

John Liccione, PhD, Toxicologist, RAB V 

Health Effects Division (7509P) / 

THROUGH: Charles Smith, Branch Chief 

Risk Assessment Branch IV 

Health Effects Division (7509P) 

And 21/~ _:__ 

Christine Olinger, RARC Reviewer (;.~ ,,, -

Elizabeth Mendez, RARC Reviewer _~_._ --....-=::::;i=-~ 

TO: Khue Nguyen and Neil Anderson 

Risk Management and Implementation Branch l 

Pesticide Re-Evaluation Division (PRD) (7508P) 

Page I of97 
1.0 Executive Summary ........................................................................................................... 4 

2.0 HED Recommendations .................................................................................................... 6 

2.1 Data Deficiencies ........................... .............. ................................................................... 7 

2.2 Tolerance Considerations .............................................................................................. 7 

2.2.1 Enforcement Analytical Method ............................................................................... 7 

2.2.2 International Harmonization ..................................................................................... 7 

2.2.3 Recommended Tolerances ......................................................................................... 7 

2.3 Label Recommendations ...................... ............................................................ .............. 8 

2.3.1 Recommendations from Residue Reviews ................................................................ 8 

2.3.2 Recommendations from Occupational Assessment ............ ..................................... 8 

2.3.3 Recommendations from Residential Assessment.. ................................................... 8 

3.0 Introduction ........................................................................................................................ 8 

3.1 Chemical Identity ............................................................................... ............................ 8 

3.2 Physical/Chemical Characteristics ............................................................................... 9 

3.3 Pesticide Use Pattern .................. ....................... .................... .... ........... .......................... 9 

3.4 Anticipated Exposure Pathways ................................................................................. l 0 

3.5 Consideration of Environmental Justice .................................................................... l 0 

4.0 Hazard Characterization and Dose-Response Assessment .......................................... I 0 

4.1 Toxicology Studies Available for Analysis ................................................................. 11 

4.2 Absorption, Distribution, Metabolism, & Excretion (ADME) ................................. I I 

4.2.1 Dermal Absorption ........................... .............. ........ ........................... .............. ......... 12 

4.3 Toxicological Effects .................................................................................................... 12 

4.3.2 Critical Durations of Exposure ............................................................................... 13 

4.4 Literature Review on Neurodevelopment Effects ..................................................... 15 

4.5 Safety Factor for Infants and Children (FQPA SF) .................................................. 20 

4.5.1 Completeness of the Toxicology Database .............................................................. 20 

4.5.2 Evidence of Neurotoxicity ........................................................................................ 21 

4.5.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.. ...... 21 

4.5.4 Residual Uncertainty in the Exposure Database ................................................... 21 

4.6 Toxicity Endpoint and Point of Departure Selections ....................... ........... ............ 2 I 

4.6.1 Dose-Response Assessment ....................................... ............................................... 21 

4.6.2 Recommendation for Combining Routes of Exposures for Risk Assessment.. ... 26 

4.6.3 Cancer Classification and Risk Assessment Recommendation ............................ 26 

4.6.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment ........................................................................................... ........... ......................... 27 

4.7 Endocrine Disruption ............................ ...................... ................................................. 29 

5.0 Dietary Exposure and Risk Assessment ......................................................................... 30 

5.1 Metabolite/Degradate Residue Profile ......... .............................................................. 30 

5.1.1 Summary of Plant and Animal Metabolism Studies ............................................. 30 

5.1.2 Summary of Environmental Degradation .............................................................. 30 

5.1.3 Comparison of Metabolic Pathways ...................................................................... . 30 

5.1.4 Residues of Concern Summary and Rationale ...................................................... 31 

5.2 Food Residue Profile ..... .... ............................................ ........ .... ........... ........................ 31 

5.3 Water Residue Profile .................................................................................................. 31 

5.4 Dietary Risk Assessment .............................................................................................. 32 

5.4.1 Description of Residue Data Used in Dietary Assessment .. .................................. 32 

Page 2 of97 
Page 3 of 97

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 32

5.4.3 Acute Dietary Risk Assessment............................................................................... 32

5.4.4 Steady State Dietary Risk Assessment.................................................................... 38

5.4.5 Cancer Dietary Risk Assessment............................................................................. 42

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 43

6.1 Residential Handler Exposure .................................................................................... 43

6.2 Post-Application Exposure .......................................................................................... 43

6.3 Residential Bystander Postapplication Inhalation Exposure................................... 43

6.4 Spray Drift.................................................................................................................... 43

6.4.1 Combined Risk Estimates from Lawn Deposition Adjacent to Applications .......... 44

7.0 Aggregate Exposure/Risk Characterization.................................................................. 48

7.1 Acute Aggregate Risk................................................................................................... 48

7.2 Short-Term Aggregate Risk ........................................................................................ 48

7.3 Intermediate-Term Aggregate Risk ........................................................................... 48

7.4 Chronic Aggregate Risk .............................................................................................. 48

7.5 Cancer Aggregate Risk ................................................................................................ 48

8.0 Cumulative Exposure/Risk Characterization ............................................................... 48

9.0 Occupational Exposure/Risk Characterization ............................................................ 49

9.1 Short- and Intermediate-term Handler Risk............................................................. 49

9.2 Short-/Intermediate-Term Post-Application Risk .................................................... 54

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates.................. 54

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates....................... 54

10.0 References......................................................................................................................... 58

A.1 Toxicology Data Requirements................................................................................... 66

A.2 Toxicity Profiles............................................................................................................ 67

A.3 Hazard Identification and Endpoint Selection .......................................................... 73

A.4 Executive Summaries................................................................................................... 76

Appendix C. Physical/Chemical Properties............................................................................. 97
Page 4 of 97

1.0 Executive Summary

Dicrotophos is a broad spectrum organophosphate insecticide. The only dicrotophos end-use 

formulation currently registered is a water-miscible formulation which may be foliarly applied to 

established cotton plants or used as a tree injection treatment for ornamental and non-food 

producing trees. It is classified as Restricted Use and may be purchased and used only by 

certified applicators or persons under their direct supervision.

The currently registered use on cotton ranges from an application rate of 0.2 to 0.5 lbs ai/acre 

via ground and aerial application. The applications are specified to be conducted by closed 

system only. The pre-harvest interval (PHI) is 30 days. Additionally, the micro-injection use for 

ornamental trees is applied by closed system (capsule) and is not to be used on trees which will 

produce food within the year following treatment. 

Hazard

Dicrotophos is a member of the organophosphate (OP) class of pesticides. Like other OPs, the 

initiating event in the adverse outcome pathway (AOP)/ mode of action (MOA), for dicrotophos 

involves inhibition of the enzyme acetylcholinesterase (AChE) via phosphorylation of the serine 

residue at the active site of the enzyme. This inhibition leads to accumulation of acetylcholine 

and ultimately to neurotoxicity in the central and/or peripheral nervous system. For dicrotophos, 

AChE inhibition is the most sensitive endpoint in the toxicology database in multiple species, 

durations, lifestages, and routes. OPs also exhibit a phenomenon known as steady state AChE 

inhibition. After repeated dosing at the same dose level, the degree of inhibition comes into 

equilibrium with the production of new, uninhibited enzyme. Therefore, a steady state exposure 

assessments of 21 days and longer was conducted instead of the traditional chronic or long-term 

assessments. 

The toxicology database for dicrotophos is complete for risk assessment. There are acceptable 

studies available for toxicity endpoint selection. Dicrotophos has high quality dose response data 

across multiple lifestages, durations, and routes for both red blood cell (RBC) and brain AChE 

inhibition. High quality dermal and inhalation studies allow for route specific evaluation. 

Clinical signs of neurotoxicity can be found throughout the database of toxicity studies at doses 

much higher than those causing inhibition of AChE. No studies in the database of toxicology 

studies suggest quantitative sensitivity to dicrotophos, including all three components of the 

comparative ChE study (acute dosing in adults and juveniles; repeated dosing in adults and 

juveniles; and gestational exposure). Qualitative susceptibility was observed in the reproduction 

and developmental neurotoxicity (DNT) studies, but the concern is low since clear no-observed 

adverse-effect levels (NOAELs) were established and the benchmark dose (BMD) results using 

AChE inhibition are protective of the effects in these studies. However, the Food Quality 

Protection Act (FQPA) Safety Factor (SF) has been retained for infants, children, youths, and 

women of childbearing age for all exposure scenarios due to uncertainty in the human doseresponse relationship for neurodevelopmental effects (see Section 4.4). As a result, a total 

uncertainty factor of 1000X was applied for all exposure scenarios, except dietary exposures for 

the adult population subgroup 50-99 years old where the FQPA SF does not apply (total 

uncertainty factor = 100X).
Page 5 of 97

Dicrotophos is classified as "Suggestive evidence of carcinogenicity, but not sufficient to assess 

human carcinogenic potential”. This classification is based on the evidence of increased tumor 

incidence for a single tumor type (thyroid) in a single species (mice) which raises a concern for 

carcinogenic effects, but is judged not sufficient for a conclusion as to human carcinogenic 

potential. In acute lethality studies, dicrotophos is acutely toxic (Category I for the oral and 

inhalation route and II for the dermal route). Dicrotophos is Category II for eye irritation and is 

a strong dermal sensitizer but is not irritating to the skin. 

Dietary (Food and Water) Exposure and Risk

Sufficient field trial data have been previously submitted for cotton undelinted seed and cotton 

gin byproducts. The tolerance for dicrotophos and its metabolite monocrotophos in/on 

cottonseed at 0.2 ppm is adequate. The tolerance for dicrotophos and its metabolite 

monocrotophos in/on cotton gin byproducts at 2.0 ppm also is adequate. Residues of 

dicrotophos and monocrotophos do not concentrate in cottonseed hulls, meal or refined oil, 

therefore tolerances are not required for these processed commodities.

The tolerance expression for dicrotophos has been reviewed and should be updated to be 

consistent with current policy.

There are no CODEX, Canadian, or Mexican maximum residue levels (MRLs) established for 

dicrotophos. Therefore, international harmonization is not an issue.

 

Average field trial residue along with 100 % crop treated were used in the dietary exposure 

assessments for cotton commodities. The entire distribution of daily time series drinking water 

outputs for the thirty year simulation was used in the acute and steady state dietary exposure 

assessments. The acute aggregate dietary exposure estimates are below HED’s level of concern

(<100 % the acute population adjusted dose (aPAD)) for the U.S. population and all population 

subgroups for all but one water scenario (NC Cotton Max Rate). Combined dietary exposure 

from food and drinking water at the 95th percentile of exposure ranged from 11-50% of the 

aPAD for the U.S. population and 19-130% of the aPAD for all infants <1 year old), the most 

highly exposed population subgroup. The dietary exposure estimates for food only were ≤11% 

aPAD for all population subgroups. The steady state (2 day average) aggregate dietary (food and 

drinking water) exposure estimates using DEEM-FCID with the 2-day average option are above

HED’s level of concern for all maximum application rate cotton water scenarios. Combined 

dietary exposure from food and drinking water at the 95th percentile of exposure ranged from 10-

52% of the ssPAD for the U.S. population and 50-320% of the ssPAD for all infants <1 year 

old). All typical application rate (as determined by BEAD) cotton scenarios gave aggregate 

dietary (food and drinking water) exposure estimates <100% ssPAD. The dietary exposure 

estimates for food only were ≤23% ssPAD for all population subgroups.

Spray Drift

A quantitative non-occupational spray drift assessment was conducted for dicrotophos. Adult 

dermal risk estimates from indirect exposure to dicrotophos related to spray drift result in buffers 
Page 6 of 97

of 200 feet for aerial applications and 50 feet for groundboom applications (i.e., MOEs < 1,000

at the edge of the field). Children’s (1 to < 2 years old) total (combined dermal and incidental 

oral) risk estimates from indirect exposure to dicrotophos related to spray drift result in buffers 

of 300 feet for both aerial and groundboom applications based on the screening level scenarios

(i.e., MOEs < 1,000 at the edge of the field).

Occupational Exposure and Risk

Based on the label-defined protection for occupational handlers, engineering controls (ECs), all 

exposure scenarios assessed (not including flaggers) result in total (combined dermal and 

inhalation) risk estimates of concern (i.e., MOEs are < 1,000). HED does not have exposure data 

to assess dermal and inhalation exposures for flaggers with engineering controls; therefore, 

flagger risks were assessed in consideration of the maximum level of PPE (i.e., double layer, 

chemical resistant gloves, and PF10 respirator). At this level of PPE, occupational handler 

exposure for flaggers also result in a total risk estimate of concern. 

HED has no exposure data appropriate for assessment of the tree injection use of dicrotophos. 

However, the exposures and risks associated with this use (occupational handler and/or 

postapplication exposure) are not expected to exceed those estimated for the cotton use. 

Occupational post-application risks assessed are not of concern (i.e., MOEs >1000) on the day of 

treatment (i.e., Day 0) for hand weeding activities and three days after application for scouting 

activities in cotton. 

Human Studies Review

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 data, which include Pesticide 

Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task 

Force (AHETF) database; the Agricultural Reentry Task Force (ARTF) database; and the 

Residential SOPs (modified Turf SOP for Spray Drift) are (1) subject to ethics review pursuant 

to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics 

requirements. 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 the Agency website1. 

2.0 HED Recommendations

No additional residue chemistry data are required for registration review. No label changes are 

required based on residue chemistry. Current tolerances need updated as previously discussed. 

 

1 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
Page 7 of 97

2.1 Data Deficiencies

There are no data deficiencies for the registration review eligibility of dicrotophos.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

For the purpose of registration review, adequate methods are available for the enforcement of 

plant commodity tolerances. Analytical methods for determination of dicrotophos residues of 

concern in livestock commodities are not needed because tolerances need not be proposed for 

eggs, milk, and edible livestock tissues. The Pesticide Analytical Manual (PAM) Volume II 

(Section 180.299) lists two gas liquid chromatography (GLC) methods (designated as Methods A 

and B) with KCl thermionic detection. Both of these methods detect residues of dicrotophos and 

monocrotophos, but not other cholinesterase-inhibiting metabolites.

Samples collected from recently evaluated cotton field and processing studies were analyzed for 

dicrotophos and monocrotophos residues using a Gas Chromatography – Flame Photometric 

Detector Phosphorus Mode (GC/FPD-P) method (designated as Method DIC-AM-001) with a 

stated quantitation limit of 0.01 ppm for each analyte. This method has been subjected to a 

successful independent laboratory validation. 

2.2.2 International Harmonization

There are no CODEX, Canadian, or Mexican maximum residue levels (MRL) established for 

dicrotophos. Therefore, international harmonization is not an issue.

2.2.3 Recommended Tolerances

Sufficient field trial data have been submitted and reviewed for cotton undelinted seed and cotton 

gin byproducts. The combined residues of dicrotophos and monocrotophos in/on cottonseed 

samples treated and harvested according to the maximum label use directions ranged from <0.02 

ppm to 0.13 ppm. The tolerance for dicrotophos and its metabolite monocrotophos in/on 

cottonseed at 0.2 ppm is adequate.

These data indicate that the combined residues of dicrotophos and monocrotophos in/on treated 

cotton gin byproducts ranged from 0.12 to 1.8 ppm following treatments according to the 

maximum label use directions. The tolerance for dicrotophos and its metabolite monocrotophos 

in/on cotton gin byproducts at 2.0 ppm is adequate.

Based on the available cottonseed processing study which demonstrated that residues of 

dicrotophos and monocrotophos do not concentrate in cottonseed hulls, meal or refined oil, 

tolerances are not required for these processed commodities.

The tolerance expression for dicrotophos has been reviewed and should be updated as follows 

based on HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09).
Page 8 of 97

Tolerances are established for residues of the insecticide dicrotophos, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels specified below is to be determined by measuring only the sum 

of dicrotophos (dimethyl phosphate of 3-hydroxy-N,N-dimethyl-cis-crotonamide) and its 

metabolite [monocrotophos (dimethyl phosphate of 3-hydroxy-N-methyl-ciscrotonamide)], calculated as the stoichiometric equivalent of dicrotophos, in or on the 

commodity.

Cotton, gin byproducts..................................................................... 2.0 ppm

Cotton, undelinted seed.................................................................... 0.2 ppm

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

No label changes are needed for the residue chemistry.

2.3.2 Recommendations from Occupational Assessment

HED recommends that the directions for use on the “enclosed pamphlet” on the tree injection 

product label (EPA Reg No. 7946-11) be made more explicitly tied to the physical product label. 

The current product label references an enclosed pamphlet for general user directions.

2.3.3 Recommendations from Residential Assessment

Dicrotophos is currently registered as a Restricted Use Pesticide therefore there are currently no 

registered (or proposed) residential uses for dicrotophos. 

3.0 Introduction

3.1 Chemical Identity

Table 3.1 Test Compound Nomenclature

Chemical Structure

O O

N

O

P

O

O

Empirical Formula C8H16NO5P

Common Name Dicrotophos

IUPAC name [(E)-4-dimethylamino-4-oxobut-2-en-2-yl] dimethyl phosphate

CAS Name (1E)-3-(dimethylamino)-1-methyl-3-oxo-1-propenyl dimethyl phosphate

CAS Registry Number 141-66-2

End-use product/EP Bidrin 8, Bidrin XP, Bidrin XP II, Inject-A-Cide B

Chemical Class Organophosphate
Page 9 of 97

3.2 Physical/Chemical Characteristics

Dicrotophos is a mixture of the E- and Z-isomers in which the E-isomer is pesticidally active. 

Technical dicrotophos is a yellow to dark amber liquid at room temperature with a boiling point 

of 111-112 C at 0.022 mm Hg (extrapolated to 398-399 C at 760 mm Hg), density of 1.19-1.22 

g/mL at 20 C, and vapor pressure of 1 x 10-4 mm Hg at 20 C. Dicrotophos is miscible (mixable 

in all proportions) with water, acetone, alcohol, acetonitrile, chloroform, methylene chloride, and 

xylene. Dicrotophos is only slightly soluble in kerosene and diesel fuel.

3.3 Pesticide Use Pattern

The only dicrotophos end-use formulation currently registered is a water-miscible formulation, 

which may be applied foliarly to established cotton plants or used as a tree injection treatment for 

ornamental and non-food producing trees. It is classified as Restricted Use and may be 

purchased and used only by certified applicators or persons under their direct supervision.

Table 3.3. Summary of Directions for Use of Dicrotophos.

Applic. 

Timing, Type, 

and Equip.

Formulation 

[EPA Reg. 

No.]

Applic. 

Rate (lb 

ai/A)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate 

(lb ai/A)

PHI 

(days)

Use Directions and 

Limitations

Cotton

Early Season 

(emergence to 

pre-bloom), 

Apply by air or 

ground

5481-448

0.2 1

0.2 (during 

this growth 

period)

NS

Engineering controls/closed 

system only

Do not graze livestock on 

treated fields

Late Season 

Use (first 

bloom to 30 

days prior to 

harvest), Apply 

by air or ground

0.5 2

1.0 (during 

this growth 

period)

30

Engineering controls/closed 

system only

The minimum application 

interval between 

applications is 14 days; Do 

not graze livestock on 

treated fields

Apply by air or 

ground 5481-552 0.4 NS 1.0 30

Engineering controls/closed 

system only

Do not graze livestock in 

treated areas or cut treated 

crops for feed, do not feed 

gin trash,

Apply by air or 

ground 5481-9024 0.4 NS 1.0 30 Engineering controls/closed system only

Ornamental Trees

Micro-injection 7946-11 NS NS NS NA

Closed system only

This product is not to be 

used on trees which will 

produce food within the

year following treatment
Page 10 of 97

3.4 Anticipated Exposure Pathways

The Pesticide Re-Evaluation Division has requested a registration review assessment of human 

health risk to support the registered uses of dicrotophos. Humans may be exposed to dicrotophos

in food and drinking water, since dicrotophos may be applied directly to growing crops and 

application may result in dicrotophos reaching surface and ground water sources of drinking 

water. There are no residential uses of dicrotophos, so there is not likely to be exposure in 

residential or non-occupational settings. In an occupational setting, applicators may be exposed 

while handling the pesticide prior to application, as well as during application. There is a 

potential for post-application exposure for workers re-entering treated fields. 

3.5 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.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf). 

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled

by the USDA under the National Health and Nutrition 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 

postapplication are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Dicrotophos is a member of the organophosphate (OP) class of pesticides. Like other OPs, the 

initiating event in the adverse outcome pathway (AOP)/ mode of action (MOA), for dicrotophos 

involves inhibition of the enzyme acetylcholinesterase (AChE) via phosphorylation of the serine 

residue at the active site of the enzyme. This inhibition leads to accumulation of acetylcholine 

and ultimately to neurotoxicity in the central and/or peripheral nervous system (see Figure 1). 

For dicrotophos, AChE inhibition is the most sensitive endpoint in the toxicology database in 

multiple species, durations, lifestages, and routes. AChE inhibition is the focus of this hazard 

characterization; the availability of reliable AChE inhibition dose response data is one of the key 

determinants in evaluating the toxicology database. 
Page 11 of 97

Figure 1. Adverse outcome pathway for OPs

4.1 Toxicology Studies Available for Analysis

The toxicology database for dicrotophos is complete for risk assessment. There are acceptable 

studies available for toxicity endpoint selection; they include: 

 subchronic oral toxicity studies in rats, mice and dogs 

 chronic oral toxicity studies in rats and dogs 

 carcinogenicity studies in rats and mice 

 developmental studies in rats and rabbits 

 reproduction study in rats 

 acute and subchronic neurotoxicity studies in rats

 developmental neurotoxicity (DNT) study in rats 

 acute and repeated comparative cholinesterase (ChE) studies in juvenile and adult 

rats

 repeated, gestational ChE study in pregnant rat and fetuses

 delayed neurotoxicity study in hens

 subchronic dermal toxicity in rats 

 in vitro dermal penetration studies in rats and humans

 repeated dosing inhalation studies in rats 

 immunotoxicity study in rats 

 complete mutagenicity study battery 

 metabolism studies in rats

4.2 Absorption, Distribution, Metabolism, & Excretion (ADME)

Some OPs require metabolic activation to the oxon metabolite. However, dicrotophos is not one 

of these OPs (see chemical structure in Table 3.1). Instead, dicrotophos as the parent active 

ingredient is an AChE inhibiting chemical. Generally, absorption and distribution are rapid with 

extensive metabolism and no accumulation in the tissues. Metabolism generally leads to 

detoxification, although a small amount (3%) of administered dicrotophos is converted internally 

to monocrotophos which has comparable biological activity as the parent compound. 

In a rat metabolism study, rats were administered [14C]dicrotophos as a single dose at levels of 

0.5 or 3 mg/kg or a repeat dose of 0.5 mg/kg/day for 14 days and excreta were collected out to 96 

hours post-dose. Following oral dosing, dicrotophos was rapidly absorbed in male and female 

rats and excreted in the urine. Consistent with the results of AChE studies, there was little or no 

influence of sex, dose or route of administration on the rate of absorption. Dicrotophos was 

Target 

Tissue 

Dose

Phosphor

ylation of 

the active 

site of 

Neurotoxi

city

Accumula

tion of 

acetylchol

ine
Page 12 of 97

absorbed and distributed quickly which is consistent with the time to peak effect of 1 hour postdosing for brain and blood AChE inhibition in adult rats. The majority of the radioactivity (58-

75%) was eliminated via urine within the first 12 hours. Total recovery at 96 hours post-dosing 

was 97-99% of the administered dose with urine comprising a total of 82 - 86%, feces 

comprising 2 - 4%, and approximately 5-7% of the radioactivity recovered in expired air. Less 

than 3% of administered radioactivity remained in the tissues/carcass at 96 hours.

In rats, dicrotophos is extensively metabolized via N-demethylation and oxidation of the Nmethyl moiety yielding intact OP (O-desmethyldicrotophos), which may be further dealkylated. 

Metabolism also proceeds via demethylation and dealkylation of the phosphate moiety forming 

various acetoacetamide and acetobutamide products along with dimethyl phosphate. 

Hydroxylation of the N-methyl group followed by N-demethylation is another metabolic 

pathway producing N-methyl-N-hydroxymethyl dicrotophos, monocrotophos and Nhydroxymethyl monocrotophos. Characterized metabolites exceeded 83% of the dose with 

unmetabolized dicrotophos accounting for only 3-7% of the administered dose. 

Hydroxydicrotophos ((E) and (Z)) accounted for as much as 20% of the dose and monocrotophos 

accounting for 3%. 

4.2.1 Dermal Absorption

There is one in vivo dermal penetration rat study (MRID 45099501) and one in vitro human and 

rat epidermis absorption study (MRID 45099502) for dicrotophos. The 28-day dermal rat 

toxicity study (MRID 46484501) includes quality AChE dose response inhibition data and is 

being relied upon for the dermal risk assessment. 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 (4-

72 fold) compared to human skin (calculations are provided in Section 4.5.1) 

4.3 Toxicological Effects

Dicrotophos has high quality dose response data across multiple lifestages, durations, and routes

for both RBC and brain AChE inhibition. Many of these studies have been evaluated using 

benchmark dose modeling techniques. Based on Table 4.3.2.1, brain and RBC AChE inhibition 

are remarkably similar (0.023-0.310 mg/kg/day) for all lifestages evaluated (adults, juveniles, 

pregnant dams, and fetuses) in oral studies. Available studies with adult animals show similar 

findings in gavage and dietary studies. High quality studies in the dermal and inhalation routes 

allow for route specific evaluation. 

Clinical signs of neurotoxicity can be found throughout the database of experimental toxicity 

studies at doses much higher than those causing inhibition of AChE. In the acute neurotoxicity 

study, clinical signs (decreased activity, decreased pupil response, flaccid appearance) were 

observed at a dose of 5 mg/kg, but not at 0.5 mg/kg. In the subchronic neurotoxicity study, 

decreased motor activity was observed at a dose of 2.03 mg/kg/day, but not at 0.45 mg/kg/day. 

In both the rat and rabbit developmental studies, maternal clinical signs (fasciculations in rats; 
Page 13 of 97

diarrhea and mucus on feces in rabbits) of neurotoxicity were observed at 1.0 mg/kg/day, but not

at 0.5 mg/kg/day. 

No studies in the database of toxicology studies suggest quantitative sensitivity to dicrotophos. 

In the acute and repeated comparative ChE studies, juvenile rats, pregnant dams, fetuses and 

non-pregnant adults show similar results in both blood and brain measurements. In the rat and 

rabbit developmental studies, neither study showed effects on the fetus whereas the dams showed 

significant neurotoxicity. Qualitative sensitivity was observed in the reproduction and DNT 

studies. In the reproductive toxicity study, percent of live born pups and whole litter losses were 

observed at the same dose (0.25 mg/kg/day) where reduced body weight was observed in 

parental animals2. In the DNT, morphometric changes in the brain of male and female offspring 

on post-natal day (PND) 12 were observed at lowest-observed adverse effect level (LOAEL) of 

0.4 mg/kg/day (NOAEL is 0.05 mg/kg/day) whereas there were no observed effects on the dams 

at 0.4 mg/kg/day. It is noteworthy that the doses used in the DNT and reproductive studies were 

approximately 10-fold and 8-fold higher, respectively, than the steady state BMDL10s (at or near 

0.03 mg/kg/day) for all lifestages throughout the database suggesting that the parental animals in 

the reproductive toxicity and DNT studies were exhibiting substantial AChE inhibition. 

Moreover, BMD results using AChE inhibition are protective for the effects on the pups 

observed in the DNT and reproductive toxicity studies.

In accordance with the Agency's Draft Cancer Risk Assessment Guidelines (July 2, 1999), 

dicrotophos is classified as showing "Suggestive evidence of carcinogenicity, but not sufficient to 

assess human carcinogenic potential”. This classification is based on the evidence of increased 

tumor incidence for a single tumor type (thyroid) in a single species (mice) which raises a 

concern for carcinogenic effects, but is judged not sufficient for a conclusion as to human 

carcinogenic potential. Dicrotophos was negative in three acceptable genetoxicity assays (MRID 

43603301, 43591401, 43603302) and satisfy the guideline requirements. These assays, however, 

do not exclude the possibility of direct interaction with DNA, based on suggestive evidence of 

clastogenic effects seen in the mouse lymphoma assay. The CARC recommended that an in vivo

comet assay on the target organ be conducted to examine possible interaction with DNA. An 

immunotoxicity study (MRID no. 48404101) is available which shows effects at doses much 

higher than those resulting in AChE inhibition and used for PoD derivation. 

In acute lethality studies, dicrotophos is acutely toxicity (Category I for the oral and inhalation 

route and II for the dermal route). Dicrotophos is Category II for eye irritation and is a strong 

dermal sensitizer but is not irritating to the skin. 

4.3.2 Critical Durations of Exposure

One of the key elements in risk assessment is the appropriate integration of temporality between 

the exposure and hazard assessments. One advantage of an AOP understanding is that human 

health risk assessments can be refined, focused on the most relevant durations of exposure. The 

following text provides an analysis of the temporal pattern of AChE inhibition from acute, single 

dosing and repeated dosing studies in laboratory animals for dicrotophos. This analysis provides 

 

2 AChE inhibition were not measured in the dicrotophos reproductive toxicity or DNT studies.
Page 14 of 97

the basis for determining which exposure durations are appropriate for assessing human health 

risk. Table 4.3.2.1 provides a summary of the selected results from experimental toxicology 

studies with dicrotophos. Dicrotophos has extensive AChE inhibition data; for purposes of trend 

evaluation but to limit the size of the table, data from only a single sex (female) are shown3. 

Table 4.3.2.1 – Dicrotophos BMD10 Results (mg/kg/day) for Brain and RBC ChE Inhibition Over Time in 

Female Adult Rats 

Days of dosing Brain RBC 

1

a 0.120 0.310

15b 0.028 0.036

28c 0.077 0.171

35d 0.048 0.026

37b 0.023 0.038

63d 0.044 0.057

98d 0.045 0.058

371e 0.047 0.040

735e 0.042 0.053

a MRID 46153206 CCA Acute Study – Single Dose

b MRID 46153201 Developmental Neurotoxicity Study (i.e., gestational CCA data); Results for maternal rats.

cMRID 46153208 CCA Repeat Study – 4 weeks

d MRID 43980201 Subchronic Neurotoxicity Study

e MRID 44527802 Chronic Toxicity Study

As show in Table 4.3.2.1, the acute BMD values (0.12 mg/kg in brain and 0.31 mg/kg in RBC) 

are the largest in the table, whereas BMD values from 15 days of dosing up to 2 years are 

remarkably similar. OPs exhibit a phenomenon known as steady state AChE inhibition. After 

repeated dosing at the same dose level, the degree of inhibition comes into equilibrium with the 

production of new, uninhibited enzyme. At this point, the amount of AChE inhibition at a given 

dose remains consistent across duration. In general, OPs reach steady state within 2-3 weeks but 

this can vary among OPs. In the case of dicrotophos the results in Table 4.3.2.1 show a clear 

pattern of steady state reached by 15 days of exposure. In addition to the consistency across 

durations, the data across multiple studies (gestational data from the DNT, subchronic 

neurotoxicity study, and chronic toxicity study) are similar. Given the results in Table 4.3.2.1, 

for dicrotophos, acute (single day) and steady state durations are appropriate for human health 

risk assessment. As such, endpoint selection discussed below focuses on acute, single day 

effects and steady state effects. 

Although there are rat data at a shorter time period (i.e., 15 days) than 21 days, exposure 

assessments of 21 days and longer will be conducted for all routes of exposure (i.e., oral, dermal 

and inhalation) for all single chemical OP assessments. Although the durations of the toxicity 

and exposure assessments may differ, an exact match is not necessary and would suggest a level 

 

3 Note: Only the BMD, not the BMDL, estimates are shown in Table 4.3.2.1. According to the BMD guidance, the 

central estimate (i.e., the BMD) is used for purposes of comparison.
Page 15 of 97

of precision that the toxicity data do not support. Given this, the 21-day and longer exposure 

assessment is scientifically supportable and also provides consistency with the OP cumulative 

risk assessment across the OPs. 

4.4 Literature Review on Neurodevelopment Effects

For the OPs, historically the Agency has used inhibition of AChE as the POD for human health 

risk assessment; at present time, this policy continues. This science policy is based on decades 

of work which shows that AChE inhibition is the initial event in the pathway to acute cholinergic 

neurotoxicity. The use of AChE inhibition data for deriving PODs was supported by the FIFRA 

SAP (2008, 2012) for chlorpyrifos as the most robust source of dose-response data for 

extrapolating risk and is the source of data for PODs for dicrotophos. A detailed review of the 

epidemiological studies used in this review can be found either in the 2014 chlorpyrifos revised 

human health risk assessment (D424485, D. Drew et al, 12/29/2014) or in the 2015 literature 

review for other organophosphates (OPP/USEPA; D331251; 9/15/15). 

Newer lines of research on OPs in the areas of potential AOPs, in vivo animal studies, and 

notably epidemiological studies in mothers and children, have raised some uncertainty about the 

agency’s risk assessment approach with regard to the potential for neurodevelopmental effects in 

fetuses and children. Many of these studies have been the subject of review by the agency over 

the last several years as part of efforts to develop a risk assessment for chlorpyrifos (D424485, 

D. Drew et al, 12/29/2014). Initially, the agency focused on studies from three US cohorts: 1) 

The Mothers and Newborn Study of North Manhattan and South Bronx performed by the 

Columbia Children’s Center for Environmental Health (CCCEH) at Columbia University; 2) the 

Mt. Sinai Inner-City Toxicants, Child Growth and Development Study or the “Mt. Sinai Child 

Growth and Development Study;” and 3) the Center for Health Assessment of Mothers and 

Children of Salinas Valley (CHAMACOS) conducted by researchers at University of California 

Berkeley. The agency has evaluated these studies and sought external peer review (FIFRA SAP 

reviews in 2008 and 2012; federal panel, 20134) and concludes they are of high quality. In the 

three US epidemiology cohort studies, mother-infant pairs were recruited for the purpose of 

studying the potential health effects of environmental exposures during pregnancy on subsequent 

child development. Each of these cohorts evaluated the association between prenatal chlorpyrifos 

and/or OP exposure (with adverse neurodevelopmental outcomes in children through age 7 

years). For the 2014 chlorpyrifos revised human health risk assessment (D424485, D. Drew et 

al, 12/29/ 2014), EPA included epidemiologic research results from these three US prospective 

birth cohort studies but primarily focused on the results of CCCEH since this cohort has 

published studies on the association between cord blood levels of chlorpyrifos and 

neurodevelopmental outcomes. The agency retained the FQPA 10X Safety Factor (SF) in the 

2014 chlorpyrifos revised risk assessment, in large part, based on the findings of these studies.

In the 2015 updated literature review (OPP/USEPA; D331251; 9/15/15), the agency conducted a 

systematic review expanding the scope of the 2012/2014 review focused on US cohort studies 

with particular emphasis on chlorpyrifos. The expanded 2015 review includes consideration of 

the epidemiological data on any OP pesticide, study designs beyond prospective cohort studies, 

 

4 http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2008-0850-0170
Page 16 of 97

and non-U.S. based studies. The updated literature review identified seven studies which were 

relevant (Bouchard et al., 2010; Fortenberry et al., 2014; Furlong et al., 2014; Guodong et al., 

2012; Oulhote and Bouchard, 2013; Zhang et al., 2014; Shelton et al., 2014). These seven

studies have been evaluated in context with studies from the 2012/2014 review (D424485, D. 

Drew et al, 12/29/2014). Only a brief summary is provided below.

The OP exposure being assessed in many of these studies used concentrations of urinary dialkyl 

phosphate metabolites (DAPs) as the urinary biomarker. Total DAPs is a non-specific measure 

of OP exposure and is the sum of six separate molecules - three dimethyl alkylphosphate 

(DMAP) molecules of DMP, DMTP, DMDTP, and three diethyl alkylphosphate (DEAP) 

molecules of DEP, DETP, and DEDTP. Each metabolite is a breakdown product from multiple 

OPs (Table 4.4.1; CDC, 2008)5. Specifically, DMP, DMTP, and DMDTP are associated with 

18, 13, and 5 OPs, whereas DEP, DETP, and DEDTP are associated with 10, 10, and 4 OPs, 

respectively. Thus, using urinary DAPs alone as an exposure measure, it is not possible to 

separate the exposure and associated effects for single, specific OPs. 

Table 4.4.1.CDC Table of organophosphate pesticides and their dialkyl phosphate metabolites (2008). 

Pesticide DMP DMTP DMDTP DEP DETP DEDTP

Azinphos methyl X X X

Chlorethoxyphos X X

Chlorpyrifos X X

Chlorpyrifos methyl X X

Coumaphos X X

Dichlorvos (DDVP) X

Diazinon X X

Dicrotophos X

Dimethoate X X X

Disulfoton X X X

Ethion X X X

Fenitrothion X X

Fenthion X X

Isazaphos-methyl X X

Malathion X X X

Methidathion X X X

Methyl parathion X X

Naled X

Oxydemeton-methyl X X

Parathion X X

Phorate X X X

Phosmet X X X

Pirimiphos-methyl X X

Sulfotepp X X

Temephos X X

Terbufos X X X

 

5 http://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/l26opd_c_met_organophosphorus_pesticides.pdf
Page 17 of 97

Tetrachlorviphos X

Trichlorfon X

DMP = dimethylphosphate; DEP = diethylphosphate; DMTP = dimethylthiophosphate; DMDTP = 

dimethyldithiophosphate; DETP = diethylthiophosphate; DEDTP = diethyldithiophosphate.

For studies which measured urinary 3,5,6-trichloro-2-pyridinol (TCPy) (e.g., Fortenberry et al, 

2014; Eskenazi et al, 2007; Whyatt et al, 2009), this metabolite can be derived from chlorpyrifos, 

chlorpyrifos-methyl, and the herbicide triclopyr. TCPy is also the primary environmental 

degradate of chlorpyrifos, chlorpyrifos-methyl, and triclopyr; thus exposure can be found 

directly on food treated with these pesticides. CCCEH studies have largely used chlorpyrifos 

measured in cord blood as the specific biomarker (e.g., Lovasi et al, 2010; Whyatt et al, 2004; 

Rauh et al, 2011). The CHARGE study (Shelton et al, 2015) did not measure biomarkers but 

instead used geospatial analysis to focus on the residential proximity to OP exposure using data 

from the California Department of Pesticide Regulation, with five OPs accounting for a total of 

73% of the pesticide applied near residential settings (chlorpyrifos, acephate, diazinon,

bensulide, and dimethoate). 

Similarly, DAPs can be found directly on food following OP applications (Zhang et al, 2008; 

Chen et al, 2012). Specifically, studies have shown that DAPs may form as environmental 

degradates from abiotic hydrolysis, photolysis, and plant metabolism (Zhang et al, 2008; Chen et 

al, 2012; Racke et al, 1994). Furthermore, since these DAPs are excreted more rapidly and 

extensively than the parent OPs (Zhang et al, 2008; Forsberg et al, 2008), direct exposure to 

DAPs may lead to an overestimate of OP exposure when using urinary DAPs as a biomarker of 

OP exposure. The agency recognizes that this is a source of uncertainty when using DAPs for 

assessing OP exposure and will continue to monitor this issue in future assessments. 

With respect to neurological effects near birth, the CHAMACOS and Mt. Sinai cohorts measured 

neurological effects at birth, and observed a putative association with total DEAP, total DMAP, 

and total DAP exposure (Engel et al., 2007; Young et al., 2005). Similarly, a Chinese study 

(Zhang et al., 2014) reported statistically significant associations between for total DEAPs, total 

DMAPs, and total DAPs prenatal OP pesticide exposure and neonatal neurodevelopment 

assessed 3 days after birth. However, another cross-sectional Chinese study, Guodong et al 

(2012), observed no association with urinary DAPs and a developmental quotient score for 23-25 

month old children.

The 3 US cohorts (CCCEH, Mt. Sinai, CHAMACOS) each reported evidence of impaired mental 

and psychomotor development, albeit not consistent by age at time of testing (ranging from 6 

month to 36 months across the three cohorts). Attentional problems and ADHD were reported 

by three prospective cohorts [Rauh et al, 2006; Eskenazi et al., 2007; Marks et al, 2010; and 

Fortenberry et al (2014)] investigators with additional support from a case control study, 

Bouchard et al. (2010). The exposure metric varied among these studies. Specifically, 

Fortenberry et al (2014) found suggestive evidence of an association with TCPy and ADHD in 

boys whereas statistically significant associations were observed by Rauh et al (2006) with 

chlorpyrifos exposure and ADHD. Eskenazi et al (2007) reported associations with total 

DMAPs and total DAPs and ADHD; Marks et al (2010) reported associations with total DEAP, 

DMAP, and total DAP exposure and ADHD. In a national cross-sectional study of Canadian 

children, using 2007-2009 data for children age 6-11 years (Oulhote and Bouchard, 2013), there 
Page 18 of 97

were no overall statistically significant associations observed between child urinary DEAP, 

DMAP, or total DAP metabolite levels and parentally reported behavioral problems. In contrast, 

Bouchard et al. (2010), looking at U.S. children age 8-15 years in the 2000-2004 National Health 

and Nutrition Examination Survey (NHANES), observed a positive association between 

attention and behavior problems and total DAPs and DMAPs, but not DEAPs. As part of their 

analysis, Oulhote and Bouchard (2013) noted that their outcome assessment for behavioral 

problems may not have been as sensitive as Bouchard et al (2010), which may in part account for 

the difference in the observed results from these studies. 

In addition, the 3 US cohorts and the CHARGE study have reported suggestive or positive 

associations between OP exposure and autism spectrum disorders (Rauh et al., 2006; Shelton et 

al., 2014; Eskenazi et al, 2007; Furlong et al., 2014). Specifically, Furlong et al (2014) 

documented suggestive evidence of an association between total DEAP exposure and reciprocal 

social responsiveness among blacks and boys. Eskenazi et al (2007) reported a statistically 

significant association between pervasive developmental disorder (PDD) and total DAP 

exposure, whereas Eskenazi et al (2010) reported non-significant, but suggestive, increased odds 

of PDD of 2.0 (0.8 to 5.1; p=0.14). Rauh et al (2006) documented a significant association 

between PDD and specifically chlorpyrifos exposure. Both PDD and reciprocal social 

responsiveness are related to the autism spectrum disorder. Using a different exposure 

assessment method (geospatial analysis and residential proximity to total OP exposure), Shelton 

et al (2014) also showed statistically significant associations between total OP exposure and 

ASD. While these studies vary in the magnitude of the overall strength of association, they have 

consistently observed a positive association between OP exposure and ASD. Finally, CCCEH, 

Mt. Sinai, CHAMACOS have reported an inverse relation between the respective prenatal 

measures of chlorpyrifos and intelligence measures at age 7 years (Rauh et al. ,2011; Engel et al., 

2011; Bouchard et al., 2011). 

Across the epidemiology database of studies, the maternal urine, cord blood, and other 

(meconium) measures provide evidence that exposure did occur to the fetus during gestation but 

the actual level of such exposure during the critical window(s) of susceptibility is not known. 

While significant uncertainties remain about the actual exposure levels experienced by mothers 

and infant participants in the children’s health cohorts, it is unlikely that these exposures resulted 

in AChE inhibition. As part of the CHAMACOS study, Eskenazi et al. (2004) measured AChE 

activity and showed that no differences in AChE activity were observed. The biomarker data 

(chlorpyrifos) from the Columbia University studies are supported by the agency’s dose 

reconstruction analysis using the PBPK-PD model (D424485, D. Drew et al, 12/29/2014). 

Following the recommendation of the FIFRA SAP (2012), the agency conducted a dose 

reconstruction analysis of residential uses available prior to 2000 for pregnant women and young 

children inside the home. The PBPK-PD model results indicate for the highest exposure 

considered (i.e., indoor broadcast use of a 1% chlorpyrifos formulation) <1% RBC AChE 

inhibition was produced in pregnant women. While uncertainty exists as to actual OP exposure 

at (unknown) critical windows of exposure, EPA believes it is unlikely individuals in the 

epidemiology studies experienced RBC AChE inhibition.
Page 19 of 97

A review of the scientific literature on potential modes of action/adverse outcome pathways 

(MOA/AOP)6leading to effects on the developing brain was conducted for the 2012 FIFRA SAP 

meeting (USEPA, 2012) and updated for the December 2014 chlorpyrifos revised risk 

assessment (D424485, D. Drew et al, 12/29/2014). In short, multiple biologically plausible 

hypotheses and pathways are being pursued by researchers that include targets other than AChE 

inhibition, including cholinergic and non-cholinergic systems, signaling pathways, proteins, and 

others. However, no one pathway has sufficient data to be considered more credible than the 

others. The fact that there are, however, sparse AOP data to support the in vitro to in vivo

extrapolation, or the extrapolation from biological perturbation to adverse consequence 

significantly limits their quantitative use in risk assessment. The SAP concurred with the agency 

in 2008 and 2012 about the lack of definable key events in a MOA/AOP leading to 

developmental neurobehavioral effects. However, since the 2014 literature review, there are no 

substantive changes in the ability to define and quantitate steps in an MOA/AOP leading from 

exposure to effects on the developing brain. Published and submitted guideline DNT laboratory 

animal studies have been reviewed for OPs as part of the 2012/2014 review (D424485, D. Drew 

et al, 12/29/2014) and the updated 2015 review (OPP/USEPA; D331251; 9/15/15). 

Neurobehavioral alterations in laboratory animals were often reported, albeit at AChE inhibiting 

doses, but there was generally a lack of consistency in terms of pattern, timing, or dose-response 

for these effects, and a number of studies were of lower quality. However, this information does 

provide evidence of long-lasting neurodevelopmental disorders in rats and mice following 

gestational exposure.

At this time, a MOA(s)/AOP(s) has/have not been established for neurodevelopmental outcomes. 

This growing body of literature does demonstrate, however, that OPs are biologically active on a 

number of processes that affect the developing brain. Moreover, there is a large body of in vivo

laboratory studies which show long-term behavioral effects from early life exposure, albeit at 

doses which cause AChE inhibition. EPA considers the results of the toxicological studies 

relevant to the human population, as qualitatively supported by the results of epidemiology 

studies. The agency acknowledges the lack of established MOA/AOP pathway and uncertainties 

associated lack of ability to make strong causal linkages and unknown window(s) of 

susceptibility. These uncertainties do not undermine or reduce the confidence in the findings of 

the epidemiology studies. The epidemiology studies reviewed in the 2012/2014 and 2015 

literature reviews represent different investigators, locations, points in time, exposure assessment 

procedures, and outcome measurements. Despite all these differences in study design, with the 

exception of two negative studies in the 2015 literature review (Guodong et al, 2012; Oulhote 

and Bouchard, 2013), authors have identified associations with neurodevelopmental outcomes 

associated with OP exposure across four cohorts and twelve study citations. Specifically, there is 

evidence of delays in mental development in infants (24-36 months), attention problems and 

autism spectrum disorder in early childhood, and intelligence decrements in school age children 

who were exposed to OPs during gestation. Investigators reported strong measures of statistical 

association across several of these evaluations (odds ratios 2-4 fold increased in some instances), 

and observed evidence of exposures-response trends in some instances, e.g., intelligence 

measures.

 

6 Mode of action (MOA) and adverse outcome pathways (AOPs) describe a set of measureable key events that make 

up the biological processes leading to an adverse outcome and the causal linkages between such events. 
Page 20 of 97

As section 408(b)(2)(C) of the FFDCA instructs EPA, in making its “reasonable certainty of no 

harm” finding, that in “the case of threshold effects, an additional tenfold margin of safety for the 

pesticide chemical residue and other sources of exposure shall be applied for infants and children 

to take into account potential pre- and postnatal toxicity and completeness of data with respect to 

exposure and toxicity to infants and children.” Section 408 (b)(2)(C) further states that “the 

Administrator may use a different margin of safety for the pesticide chemical residue only if, on 

the basis of reliable data, such margin will be safe for infants and children.” Given the totality of 

the evidence, there is sufficient uncertainty in the human dose-response relationship for 

neurodevelopmental effects which prevents the agency from reducing or removing the statutory 

10X FQPA Safety Factor. For the dicrotophos DRA, a value of 10X has been applied. 

Similarly, a database uncertainty factor of 10X will be retained for occupational risk 

assessments. The agency will continue to evaluate the epidemiology studies and pursue 

approaches for quantitative or semi-quantitative comparisons between doses which elicit AChE 

inhibition and those which are associated with neurodevelopmental outcomes prior to a revised 

human health risk assessment. 

4.5 Safety Factor for Infants and Children (FQPA SF)

The database of toxicology studies for dicrotophos is complete. Neurotoxicity is the most 

sensitive effect in all species, routes, and lifestages and is being used in deriving PoDs. No 

quantitative sensitivity was observed in any experimental laboratory study in the database, 

including all three components of the comparative ChE study (acute dosing in adults and 

juveniles; repeated dosing in adults and juveniles; and gestational exposure). Qualitative 

susceptibility was observed in the reproduction and DNT studies but the concern is low since 

clear NOAELs were established and the BMD results using AChE inhibition are protective of the 

effects in these studies. 

As noted above, the lack of an established MOA/AOP makes quantitative use of the 

epidemiology studies in risk assessment challenging, particularly with respect to determining 

dose-response, critical duration of exposure, and window(s) of susceptibility. However, 

exposure levels in the range measured in the epidemiology studies are likely low enough that 

they are unlikely to result in AChE inhibition. Epidemiology studies consistently identified 

associations with neurodevelopmental outcomes associated with OP exposure such as delays in 

mental development in infants (24-36 months), attention problems and autism spectrum disorder 

in early childhood, and intelligence decrements in school age children. Therefore, there is a need 

to protect children from exposures that may cause these effects; this need prevents the agency 

from reducing or removing the statutory FQPA Safety Factor. Thus, the FQPA 10X Safety 

Factor will be retained for dicrotophos for the population subgroups that include infants, 

children, youths, and women of childbearing age for all exposure scenarios. 

4.5.1 Completeness of the Toxicology Database

The database of toxicology studies for dicrotophos is complete and includes developmental 

studies in rat and rabbit, a reproductive toxicity study, a DNT, and a comparative ChE study with 

three components (acute, repeated, gestational). 
Page 21 of 97

As discussed in Section 4.4, there is uncertainty in the human dose-response relationship for 

neurodevelopmental effects and this warrants retention of the FQPA Safety Factor for the 

population subgroups that include infants, children, youths, and women of childbearing age for 

all exposure scenarios.

4.5.2 Evidence of Neurotoxicity

Dicrotophos is an OP with a neurotoxic AOP; neurotoxicity is the most sensitive effect in all 

species, routes, and lifestages and is being used in deriving PoDs. 

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

Rat and rabbit developmental studies are available and do not show any quantitative 

susceptibility. Similarly, the reproductive toxicity study and developmental neurotoxicity (DNT) 

study do not show any quantitative lifestage susceptibility. Qualitative susceptibility observed in 

the DNT and reproductive toxicity studies were only observed at much higher doses than being 

used for points of departure derivation. The comparative ChE study is available and provides 

AChE quality dose response data from potentially susceptible lifestages (i.e., fetuses, pregnant 

dams, post-natal pups). The CCA study does not show any lifestage sensitivity to AChE 

inhibition with dicrotophos. 

As discussed in Section 4.4, there is uncertainty in the human dose-response relationship for 

neurodevelopmental effects and this warrants retention of the FQPA Safety Factor for the 

population subgroups that include infants, children, youths, and women of childbearing age for 

all exposure scenarios.

4.5.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The refined dietary risk assessment 

uses average field trial residue, estimated drinking water concentrations from maximum

application rate, and 100 % crop treated and will not underestimate dietary exposure to 

dicrotophos.

4.6 Toxicity Endpoint and Point of Departure Selections

4.6.1 Dose-Response Assessment

Table 4.6.4.1 summarizes the dicrotophos toxicity endpoints and PoDs selected from an 

evaluation of the database. This endpoint selection was based on a weight of the evidence 

evaluation using the following considerations:

 Relative sensitivity of the brain and RBC compartments: For dicrotophos, across most 

studies, durations, lifestages, and routes, the brain and RBC compartments tend to be 

similarly sensitive. As such, OPP has emphasized the brain data in PoD derivation as 

these data represent the target tissue and brain data tend to be less variable than RBC 

data.
Page 22 of 97

 Potentially susceptible populations (fetuses, juveniles, pregnancy): The available AChE 

data across multiple lifestages (adults, pregnant adults, fetuses, juveniles) show no 

lifestage sensitivity. 

 Route of exposure: It is preferred to match, to the degree possible, the route of exposure 

in the toxicity study with that of the exposure scenario(s) of interest. In the case of 

dicrotophos, there are oral, dermal, and inhalation studies which contain quality dose 

response AChE data.

 Duration of exposure: It is preferred to match, to the degree possible, the duration of 

toxicity study with that of the exposure duration of interest. In the case of dicrotophos, 

there are single day and steady state oral studies but only steady state dermal and 

inhalation studies. 

 Consistency across studies: In cases where multiple datasets are available for a single 

duration, it is important to evaluate the extent to which data are consistent (or not) across 

studies. The dicrotophos database has striking consistency across studies which allows 

for PoDs to be derived from multiple critical studies thereby increasing the confidence in 

such values. 

Descriptions of the primary toxicity studies used for selecting toxicity endpoints and PoDs for 

various exposure scenarios are presented in Appendix 3 of this document. Summary tables of 

BMD analyses can be found in Appendix 2 and the technical details of the analysis can be found 

in the BMD memo (Liccione & Holman, D414900, 1/28/14)

Consistent with risk assessments for other AChE-inhibiting compounds, OPP has used a 

benchmark response (BMR) level of 10% and has thus calculated BMD10s and BMDL10s (see 

Appendix 1 for summary of OPP’s ChE policy). The BMD10 is the estimated dose where ChE is 

inhibited by 10% compared to background. The BMDL10 is the lower confidence bound on the 

BMD10. As a matter of science policy, the agency uses the BMDL, not the BMD, for use as the 

PoD (USEPA, 2012). All BMD/BMDL modeling for all individual datasets was completed 

using USEPA BMD Software, version 2.2; an exponential model was used to fit the data, with 

the assumption of constant variance across each dataset. BMD results from the OP Cumulative 

Risk Assessment ((CRA (2002, 2006)) were included in the endpoint selection weight of 

evidence evaluation.

Acute Dietary (all populations) 

As shown in Appendix Table 2.1, results of single dosing exposures with dicrotophos are 

consistent across multiple datasets for both RBC and brain data including pups ages post-natal 

day (PND) 8, 15, and 22 in addition to adult male and female rats. 

A PoD for the acute dietary (all populations) exposure scenario was derived from the results of a 

high quality, well-conducted CCA rat study (MRID 46153205). A BMDL10 of 0.07 mg/kg/day

associated with brain ChE inhibition in male and female pups (PND 8 & 15) was selected as a 

suitable PoD for the acute dietary (all populations) exposure scenario. The corresponding 

BMD10 was 0.08 mg/kg/day. 
Page 23 of 97

Brain cholinesterase inhibition was selected for the PoD since the brain is a principal target 

organ for organophosphate pesticides, and the brain ChE data was more robust than RBC ChE 

data. Data from the PND 8 and 15 pups represent highly exposed sub-populations (infants and 

young children) and thus are appropriate for PoD derivation. 

An uncertainty factor of 1000X (10X to account for interspecies extrapolation, 10X for 

intraspecies variation, and 10X for FQPA SF due to uncertainty in the human dose-response 

relationship for neurodevelopmental effects (see Section 4.4)) is applied to the BMDL10 of 0.07 

mg/kg/day. As a result, the acute population adjusted dose (aPAD) is 0.00007 mg/kg/day. The 

only population subgroup that the FQPA safety factor is not retained is adults 50-99; therefore, 

the aPAD for this population subgroup is 0.0007 mg/kg/day.

Steady-State Dietary (all populations)

Table 4.3.2.1 and Appendix Table 2.2 show remarkable similarity in BMD estimates across 

multiple studies, durations, lifestages, and compartments in studies 15 days and longer. Because 

of this consistency, OPP has elected to use BMD/BMDL estimates reported in the OP CRA 

(2002, 2006) for deriving the steady state oral PoD. Results of the OP CRA incorporate multiple 

studies together in a single BMD/BMDL analysis and are thus highly robust. Specifically, in the 

OP CRA, EPA performed a sophisticated statistical analysis using nonlinear mixed effects 

models which allow for combining the results of multiple studies and multiple time points into a 

single BMD estimate. These procedures were reviewed favorably by the FIFRA SAP in 

February 2002. 

In the case of dicrotophos, for the OP CRA, the available AChE data at durations of 21 days and 

longer in adult rats were extracted from the subchronic neurotoxicity study and the chronic study 

rat study (MRIDs 43980201 and 44527802). The plot of the brain AChE data from these studies 

is depicted in Figure 4.6.1 below. A BMDL10 of 0.03 mg/kg/day associated with brain ChE 

inhibition in male and female adult rats was selected as a suitable PoD for the steady-state 

dietary (all populations) exposure scenario. The corresponding BMD10 was 0.04 mg/kg/day. 

An uncertainty factor of 1000X (10X to account for interspecies extrapolation, 10X for 

intraspecies variation, and 10X for FQPA SF due to uncertainty in the human dose-response 

relationship for neurodevelopmental effects (see Section 4.4)) is applied to the BMDL10 of 0.03 

mg/kg/day. As a result, the steady-state population adjusted dose (ssPAD) is 0.00003

mg/kg/day. The only population subgroup that the FQPA SF is not retained is adults 50-99; 

therefore, the ssPAD for this population subgroup is 0.0003 mg/kg/day.
Page 24 of 97

Figure 4.6.1. BMD results from the OP CRA (2002, 2006) for dicrotophos (Extracted from 

USEPA, 2002, Appendix III.B.1) 

Incidental Oral, Steady State

For the purpose of assessing potential risk associated with incidental oral exposure from steady 

state durations resulting from spray drift, OPP selected the dose (PoD) and endpoint from the OP 

CRA (USEPA, 2002 and 2006). Quantitation of incidental oral risks was performed using the 

BMDL10 value of 0.03 mg/kg, based on brain ChE inhibition and the BMD10 of 0.04 mg/kg. 

These values do not represent the sub-populations of interest (infants, toddlers, young children) 

for incidental oral exposure. However, the results of repeated dosing study in juvenile rats (PND 

12-18) are similar to those in adults. Thus data from adults are protective of any effects in the 

young. A total uncertainty factor of 1000X is appropriate for incidental oral exposures (10X for 

interspecies extrapolation, 10X for intraspecies variation, and a 10X FQPA SF due to uncertainty 

in the human dose-response relationship for neurodevelopmental effects (see Section 4.4)).

Dermal, Steady State

A steady state dermal PoD was selected from a 28-day dermal toxicity study (MRID 46484501) 

in rats based on brain ChE inhibition (BMDL10 = 2.1 mg/kg/day; BMD10 = 3.3 mg/kg/day) in 

the female rat. It is noted that although there were no adequate model fits (based on statistical 

goodness of fit results) to the male data , a visual examination of the graphical display of the 
Page 25 of 97

results indicated comparable fits as observed with the female data. There were no significant 

differences between RBC and brain ChE inhibition in the dermal toxicity study. 

A refined dermal equivalent dose (RDD) for human skin may be derived from the in vitro human 

and rat epidermis absorption study (MRID 45099502) to account for the differences in skin 

permeability across species. In the in vitro study, the amount of radiolabel dicrotophos was 4 to 

72 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 9.33 mg/kg/day. The calculations are 

shown in the table below.

Table 4.6.1. 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 4 μg/cm232.9 47.1 10.6 4.44

Dose 40 μg/cm234.9 57.7 12.2 4.73

Refined Dermal Equivalent Dose Calculation

Study/Information 

Type

Rat Dermal 

PoD (BMDL10)

RDD = PoD x Animal In Vitro 

 Human In Vitro

28-day dermal 

toxicity study 2.1 mg/kg/day 2.1 x 4.44 = 9.33 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. 

A total uncertainty factor of 1000X is appropriate for dermal exposures (10X for interspecies 

extrapolation, 10X for intraspecies variation, and a 10X FQPA SF for residential assessments or 

a database uncertainty factor in occupational assessments due to uncertainty in the human doseresponse relationship for neurodevelopmental effects (see Section 4.4)). 
Page 26 of 97

Inhalation, Steady State

A steady state inhalation PoD was selected from a 28-day inhalation toxicity study (MRID 

48146702) in female rats based on brain ChE inhibition (BMDL10 = 0.62 μg/L/day or 0.00062 

mg/L/day; BMD10 = 0.67 μg/L/day or 0.00067 mg/L/day). Although the model fit of the 

female data did not achieve an adequate statistical goodness of fit value (i.e., p values), a visual 

examination of the graphical display of the dose response indicated a comparable fit as 

observed with the male data (BMDL10 = 0.61 μg/L/day ; BMD10 = 0.69 μg/L/day ; acceptable 

p value) , and the fit adequately described the female ChE dose response pattern. Therefore, and 

in order to be consistent with the endpoints derived for oral and dermal exposure, the agency is 

using the female brain ChE data rather than the male data. The particle size distribution from 

this study suggests that most particles were well below the respirable range for an aerosol (1-3 

μm), suggesting that the exposure was mainly via a gas. A human equivalent concentration 

(HEC) was not generated from this study based on the following conditions: 1) exposure was via 

gas and not particles thus resulting in an Regional Gas Dose Ratio (RGDR) instead of Regional 

Deposited Dose Ratio (RDDR); and 2) the effects observed were only systemic (AChE 

inhibition) without portal of entry effects (e.g., irritation). Concentrations were not adjusted for a 

continuous exposure basis as is done for an HEC. 

For steady state inhalation exposures, a total uncertainty factor of 1000X was applied (10X for 

interspecies extrapolation, 10X for intraspecies variation and a 10X for residential assessments 

or a database uncertainty factor in occupational assessments due to uncertainty in the human 

dose-response relationship for neurodevelopmental effects (see Section 4.4)).

4.6.2 Recommendation for Combining Routes of Exposures for Risk Assessment

PoDs for the oral, dermal, and inhalation routes are all derived from brain AChE inhibition. The 

data do not support any differences in response across different lifestages or sexes. Thus, all 

routes can be aggregated. 

4.6.3 Cancer Classification and Risk Assessment Recommendation

In accordance with the Agency's Draft Cancer Risk Assessment Guidelines (July 2, 1999), 

dicrotophos is classified as showing "Suggestive evidence of carcinogenicity, but not sufficient to 

assess human carcinogenic potential”. This classification is based on the evidence of increased 

tumor incidence for a single tumor type (thyroid) in a single species (mice) which raises a 

concern for carcinogenic effects, but is judged not sufficient for a conclusion as to human 

carcinogenic potential. Quantitative risk assessment for dicrotophos using the Reference Dose 

(RfD) approach will adequately account for all chronic toxic effects, including carcinogenicity. 

Quantification of risk using the RfD approach requires comparison of the chronic exposure to 

pesticide residues to the chronic RfD, a quantitative measure of hazard likely to result from long 

term exposure to dicrotophos.
Page 27 of 97

4.6.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.6.4.1 Summary of Toxicological Doses and Endpoints and Points of Departure for 

Dicrotophos

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factorsa

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary (all 

populations, 

except adults 50-

99)

BMDL10 = 

0.07mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 10x

aPAD = 0.00007 

mg/kg/day

BMD10 = 0.08 mg/kg/day

CCA Study (MRID 4615205) in the rat 

– PND 8, 15, & 22 

Inhibition of brain ChE in rat pups.

Acute Dietary 

(Adults 50-99)

BMDL10 = 

0.07mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

aPAD = 0.0007 

mg/kg/day

BMD10 = 0.08 mg/kg/day

CCA Study (MRID 4615205) in the rat 

– PND 8, 15, & 22 

Inhibition of brain ChE in rat pups.

Steady-State 

Dietary (all 

populations except 

adults 50-99)

BMDL10 = 

0.03 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 10x

ssPAD = 0.00003 

mg/kg/day

BMD10 = 0.04 mg/kg/day

Subchronic and chronic toxicity studies 

(OP CRA 2002, 2006; MRID’s 

43980201 and 44527802)

Inhibition of brain ChE in adult rat

Steady-State 

Dietary 

(Adults 50-99)

BMDL10 = 

0.03 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

ssPAD = 0.0003 

mg/kg/day

BMD10 = 0.04 mg/kg/day

Subchronic and chronic toxicity studies 

(OP CRA 2002, 2006; MRID’s 

43980201 and 44527802)

Inhibition of brain ChE in adult rat

Incidental Oral

Steady State 

BMDL10 = 

0.03 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 10x

Residential LOC = 

1,000

BMD10 = 0.04 mg/kg/day

Subchronic and chronic toxicity studies 

(OP CRA 2002, 2006; MRID’s 

43980201 and 44527802)

Inhibition of brain ChE in adult rat

Dermal

Steady State (21 

days and longer)

BMDL10 = 

2.1 mg/kg/day

RDD = 9.33 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 10x 

Residential LOC = 

1,000

BMD10 = 3.3 mg/kg/day

28-day dermal toxicity study (MRID 

46484501) in rats 

Inhibition of brain ChE in adult rat.
Page 28 of 97

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factorsa

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Inhalation

Steady State (21 

days and longer)

BMDL10 = 

0.00062 

mg/L/day

(0.162 

mg/kg/day)*

UFA = 10x

UFH = 10x

FQPA SF = 10x

Residential LOC = 

1,000

BMD10 = 0.00067 mg/L/day

(0.175 mg/kg/day)*

28-day inhalation toxicity study (MRID 

48146702)

Inhibition of brain ChE in adult rat.

Cancer (oral, 

dermal, inhalation)

Classification: "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic 

potential”.

Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. RfC = reference concentration.. RDD = 

refined equivalent dermal dose.MOE = margin of exposure. LOC = level of concern. N/A = not applicable. 

*conversion to oral mg/kg based on 0.00062 g/L x 1 x 6x 43.5 x 1 = 0.162 mg/kg/day. See Appendix 4 for further 

details. 0.00067 g/L x 1 x 6 x 43.5 x 1 = 0.175 

^9.33 mg/kg/day is derived by multiplying the rat PoD of 2.1 by 4.44 (comparison of human to rat absorption); 2.1x 

4.44 = 9.33. See Appendix 4 for further details on this conversion. 

a FQPA SF retained for infants, children, youths, and women of childbearing age for all exposure scenarios due to 

uncertainty in the human dose-response relationship for neurodevelopmental effects (see Section 4.4). This includes 

all exposure scenarios, except the dietary exposure scenarios for the population subgroup adults 50-99 for which the 

FQPA SF has been reduced to 1X.

Table 4.6.4.2 Summary of Toxicological Doses and Endpoints for Dicrotophos for Use in Occupational Human Health 

Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal Single 

Day Steady-State 

BMDL10 = 

2.1 mg/kg/day 

RDD = 9.33 

mg/kg/day

UFA=10x

UFH=10x

UFDB = 10xa

Occupational LOC 

for MOE = 1000

28-day dermal toxicity study (MRID 

46484501) in rats 

BMD10 = 3.3 mg/kg/day

Inhibition of brain ChE in adult rat.

Inhalation Single 

Day Steady-State 

BMDL10 = 

0.00062 

mg/L/day

(0.162

mg/kg/day)*

UFA=10x

UFH=10x

UFDB = 10xa

Occupational LOC 

for MOE = 1000

28-day inhalation toxicity study (MRID 

48146702)

BMD10 = 0.00067 mg/L/day

(0.175 mg/kg/day)*

Inhibition of brain ChE in adult rat

Cancer (oral, 

dermal, 

inhalation)

Classification: "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic 

potential”.

Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 
Page 29 of 97

sensitivity among members of the human population (intraspecies). UFDB = Database uncertainty. MOE = margin of 

exposure. LOC = level of concern. N/A = not applicable.

*conversion to oral mg/kg based on 0.00062 mg/L/day x 1 x 6x 43.5 x 1 = 0.162 mg/kg/day. 0.00067 g/L x 1 x 6 x 

43.5 x 1 = 0.175 

See Appendix A2 for further details on this conversion. 

^9.33 mg/kg/day is derived by multiplying the rat PoD of 2.1 by 4.44 (comparison of human to rat absorption); 2.1x 

4.44 = 9.33. See Appendix 4 for further details on this conversion. 

a UFDB for occupational dermal and inhalation exposures = database uncertainty factor for uncertainty in the human 

dose-response relationship for neurodevelopmental effects (see Section 4.4).

4.7 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 dicrotophos, 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), dicrotophos 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, 20137and includes some

pesticides including dicrotophos 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.

 

7

See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of

chemicals.
Page 30 of 97

Dicrotophos is on List 2. List 2 represents the next set of chemicals for which EPA intends to 

issue test orders/data call-ins in the near future. 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.8

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The requirement for plant metabolism is fulfilled based on an acceptable cotton metabolism 

study. Based on the metabolites identified, the major pathway is the stepwise demethylation and 

hydrolysis of the phosphate group, with subsequent conjugation of acetoacetamide, 

monocrotophos, and N-methylacetoacetamide. The results of the cotton metabolism study were 

presented to the HED Metabolism Committee which concluded both dicrotophos and its 

metabolite monocrotophos should be included in the tolerance expression, and both compounds 

should be included for dietary exposure assessment. 

The requirements for animal metabolism are fulfilled. Acceptable goat and hen metabolism 

studies have been submitted and evaluated. Neither dicrotophos nor monocrotophos were 

detected in eggs and poultry tissues, or milk and ruminant tissues; the metabolites found in 

animals are structurally similar to those found in cotton. Since the HED Metabolism Committee 

previously concluded that dicrotophos and monocrotophos are the residues of concern, HED 

concluded that tolerances are not needed in livestock.

5.1.2 Summary of Environmental Degradation

The most significant degradation pathway for dicrotophos is aerobic soil metabolism (half-life = 

3 days). Dicrotophos is relatively more persistent to hydrolysis with a half-life of 72 days. 

Dicrotophos is stable to hydrolysis. Dicrotophos is mobile with adsorption coefficients (KD) 

ranging from of 0.1 to 3.58 mL/g. A full summary of adsorption/desorption data can be found in 

the Dicrotophos RED. It is not appropriate to use KOC to characterize the mobility of dicrotophos 

because adsorption coefficients do not sufficiently correlate with soil organic carbon content. 

Use of KD rather than KOC is consistent with previous assessments. However, adsorption 

strongly correlates with clay content (r2 = 0.92).

5.1.3 Comparison of Metabolic Pathways

Metabolism in rats generally leads to detoxification, although a small amount of dicrotophos is 

converted internally to monocrotophos. In cotton, the major pathway is the stepwise 

demethylation and hydrolysis of the phosphate group, with subsequent conjugation of 

acetoacetamide, monocrotophos, and N-methylacetoacetamide. The metabolites found in 

animals are structurally similar to those found in cotton. 

 

8 http://www.epa.gov/endo/
Page 31 of 97

5.1.4 Residues of Concern Summary and Rationale

Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants

Primary Crop Dicrotophos and 

Monocrotophos

Dicrotophos and 

Monocrotophos

Rotational Crop Dicrotophos and 

Monocrotophos

Dicrotophos and 

Monocrotophos

Livestock

Ruminant Dicrotophos and 

Monocrotophos

Dicrotophos and 

Monocrotophos

Poultry Dicrotophos and 

Monocrotophos

Dicrotophos and 

Monocrotophos

Drinking Water Dicrotophos Not Applicable

5.2 Food Residue Profile

HED has previously evaluated residue data depicting the magnitude of dicrotophos residues of 

concern in/on cottonseed and cotton gin byproducts. The application rates represent 1x the 

maximum registered rates. The combined residues of dicrotophos and monocrotophos in/on 

treated cottonseed ranged from <0.02 ppm (nondetectable) to 0.13 ppm. The combined residues 

of dicrotophos and monocrotophos in/on treated cotton gin byproducts ranged from 0.12 ppm to 

1.8 ppm.

HED has evaluated residue data pertaining to the potential for concentration of dicrotophos 

residues of concern in the processed commodities of cotton. The cotton processing data indicate 

that dicrotophos and monocrotophos residues did not concentrate in hulls, meal, and refined oil 

processed from cottonseed bearing detectable dicrotophos residues and nondetectable 

monocrotophos residues. Tolerances are, therefore, not required for the processed commodities 

of cotton.

5.3 Water Residue Profile

This revised assessment (A. Shelby, 8/13/15/, D427440) changes the cotton percent cropped area 

(PCA) from 33% to 21% based on updated guidance (EPA, 2014a), incorporates application rate 

and application date recommendations made by the Biological and Economic Analysis Division 

(EPA, 2014b) and addresses comments on the original assessment made by Stone Environmental 

on behalf of the registrant, AMVAC (MRID 49582601). Registrant comments are addressed in 

more detail in the EFED drinking water assessment memo (A. Shelby, 8/13/15/, D427440).

Based on SWCC (Surface Water Concentration Calculator v1.106) modeling runs results from 

the Texas Cotton scenario, the maximum estimated surface water exposure concentrations for 

dicrotophos and assuming maximum application rates for current uses are:
Page 32 of 97

8.75 μg/L for the 1 in 10 year annual peak concentration 

0.507 μg/L for the 1-in-10 year annual average, and 

0.306 μg/L for the 30 year annual average 

Based on ground water modeling results (PRZM-GW), the maximum estimated groundwater 

exposure concentration from six vulnerable scenarios for dicrotophos is 0.0003 μg/L for acute 

and chronic exposure based on post breakthrough average. Since the predicted concentrations in 

ground water are well below those calculated for surface water, surface water exposures are the 

driver for dicrotophos drinking water exposure.

Daily time series outputs for the thirty year simulation were provided to HED for use in dietary 

exposure modeling.

Table 5.3. Summary of Estimated Surface Water and Groundwater Concentrations for 

Dicrotophos.

SWCC 

Scenario

Application rate 

and timing

1-in-10-year 

peak (ppb)

1-in-10-year 21 

day average 

(ppb)

1-in-10-year 

annual average 

(ppb)

Simulation 

average 

(ppb)

Mississippi 

Cotton

Maximum Rate 6.09 4.01 0.381 0.199

Typical Rate -

BEAD dates

3.21 1.67 0.193 0.0860

Typical Rate - 14 

day interval

4.49 2.45 0.204 0.0834

North 

Carolina 

Cotton

Maximum Rate 7.73 4.94 0.507 0.306

Typical Rate 1.62 1.05 0.0901 0.0503

Texas 

Cotton

Maximum Rate 8.75 4.63 0.430 0.222

Typical Rate -

BEAD dates

3.66 2.12 0.238 0.0934

Typical Rate - 14 

day interval

3.69 2.09 0.217 0.0839

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Average field trial residue was used in the dietary exposure assessment for cottonseed oil. The 

entire distribution of daily time series drinking water outputs for the thirty year simulation was

used in the acute and steady state dietary exposure assessments.

5.4.2 Percent Crop Treated Used in Dietary Assessment

A conservative 100 percent crop treated (% CT) was used in the acute and steady state dietary 

exposure assessment.

5.4.3 Acute Dietary Risk Assessment

Dicrotophos acute dietary exposure assessment were conducted using the Dietary Exposure 

Evaluation Model software with the Food Commodity Intake Database DEEM-FCIDTM, Version 
Page 33 of 97

3.16, which incorporates consumption data from USDA’s National Health and Nutrition 

Examination Survey, What We Eat in America, (NHANES/WWEIA). This dietary survey was 

conducted from 2003 to 2008. The analyses was performed to support the registration review of 

dicrotophos. Since average field trial residue and 100 percent crop treated was used, the 

exposure at the 95th percentile of regulation will be used for reporting purposes.

Analyses were conducted using water distributions from three cotton producing areas at the 

maximum label application rate and the typical label application rate. 

The acute aggregate dietary exposure estimates are below HED’s level of concern (<100 % the 

acute population adjusted dose (aPAD)) for the U.S. population and all population subgroups for 

all but one water scenario (NC Cotton Max Rate). Combined dietary exposure from food and 

drinking water at the 95th percentile of exposure ranged from 11-50% of the aPAD for the U.S. 

population and 19-130% of the aPAD for all infants <1 year old), the most highly exposed 

population subgroup. The dietary exposure estimates for food only were ≤11% aPAD for all 

population subgroups.

Table 5.4.3.1 Results of Acute Dietary Exposure Analysis for Dicrotophos (Food Only) 

Population Subgroup aPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00007 0.000004 5.7

All Infants (< 1 year old) 0.00007 0.000002 2.6

Children 1-2 years old 0.00007 0.000008 11

Children 3-5 years old 0.00007 0.000008 11

Children 6-12 years old 0.00007 0.000006 8.2

Youth 13-19 years old 0.00007 0.000004 5.1

Adults 20-49 years old 0.00007 0.000002 3.4

Adults 50-99 years old 0.0007 0.000002 <1

Females 13-49 years old 0.00007 0.000002 3.5

* The values for the highest exposed population is bolded.
Page 34 of 97

Table 5.4.3.2 Results of Acute Dietary Exposure Analysis for Dicrotophos (Food and Drinking Water) MS 

Cotton Typical Rate – BEAD Date of Application

Population Subgroup aPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00007 0.000011 15

All Infants (< 1 year old) 0.00007 0.000024 35

Children 1-2 years old 0.00007 0.000017 25

Children 3-5 years old 0.00007 0.000016 23

Children 6-12 years old 0.00007 0.000012 17

Youth 13-19 years old 0.00007 0.000009 12

Adults 20-49 years old 0.00007 0.000010 15

Adults 50-99 years old 0.0007 0.000010 1.4

Females 13-49 years old 0.00007 0.000010 14

* The values for the highest exposed population is bolded.

Table 5.4.3.3 Results of Acute Dietary Exposure Analysis for Dicrotophos (Food and Drinking Water) MS 

Cotton Typical Rate – 14 Day Retreatment Interval

Population Subgroup aPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00007 0.000010 14

All Infants (< 1 year old) 0.00007 0.000020 29

Children 1-2 years old 0.00007 0.000016 23

Children 3-5 years old 0.00007 0.000015 21

Children 6-12 years old 0.00007 0.000011 16

Youth 13-19 years old 0.00007 0.000008 11

Adults 20-49 years old 0.00007 0.000009 13

Adults 50-99 years old 0.0007 0.000009 1.3

Females 13-49 years old 0.00007 0.000009 13

* The values for the highest exposed population is bolded.
Page 35 of 97

Table 5.4.3.4 Results of Acute Dietary Exposure Analysis for Dicrotophos (Food and Drinking Water) MS 

Cotton Max Rate

Population Subgroup aPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00007 0.000020 29

All Infants (< 1 year old) 0.00007 0.000049 70

Children 1-2 years old 0.00007 0.000030 43

Children 3-5 years old 0.00007 0.000027 38

Children 6-12 years old 0.00007 0.000019 28

Youth 13-19 years old 0.00007 0.000015 22

Adults 20-49 years old 0.00007 0.000020 28

Adults 50-99 years old 0.0007 0.000019 2.8

Females 13-49 years old 0.00007 0.000020 28

* The values for the highest exposed population is bolded.

Table 5.4.3.5 Results of Acute Dietary Exposure Analysis for Dicrotophos (Food and Drinking Water) TX 

Cotton Typical Rate – BEAD Date of Application

Population Subgroup aPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00007 0.000010 15

All Infants (< 1 year old) 0.00007 0.000023 32

Children 1-2 years old 0.00007 0.000017 24

Children 3-5 years old 0.00007 0.000016 23

Children 6-12 years old 0.00007 0.000012 17

Youth 13-19 years old 0.00007 0.000008 12

Adults 20-49 years old 0.00007 0.000010 14

Adults 50-99 years old 0.0007 0.000009 1.3

Females 13-49 years old 0.00007 0.000010 14

* The values for the highest exposed population is bolded.
Page 36 of 97

Table 5.4.3.6 Results of Acute Dietary Exposure Analysis for Dicrotophos (Food and Drinking Water) TX 

Cotton Typical Rate – 14 Day Retreatment Interval

Population Subgroup aPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00007 0.000010 14

All Infants (< 1 year old) 0.00007 0.000021 30

Children 1-2 years old 0.00007 0.000016 23

Children 3-5 years old 0.00007 0.000015 21

Children 6-12 years old 0.00007 0.000011 16

Youth 13-19 years old 0.00007 0.000008 11

Adults 20-49 years old 0.00007 0.000009 13

Adults 50-99 years old 0.0007 0.000009 1.2

Females 13-49 years old 0.00007 0.000009 13

* The values for the highest exposed population is bolded.

Table 5.4.3.7 Results of Acute Dietary Exposure Analysis for Dicrotophos (Food and Drinking Water) TX 

Cotton Max Rate

Population Subgroup aPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00007 0.000022 31

All Infants (< 1 year old) 0.00007 0.000053 76

Children 1-2 years old 0.00007 0.000033 47

Children 3-5 years old 0.00007 0.000029 41

Children 6-12 years old 0.00007 0.000021 30

Youth 13-19 years old 0.00007 0.000016 24

Adults 20-49 years old 0.00007 0.000021 30

Adults 50-99 years old 0.0007 0.000021 3.0

Females 13-49 years old 0.00007 0.000021 30

* The values for the highest exposed population is bolded.
Page 37 of 97

Table 5.4.3.8 Results of Acute Dietary Exposure Analysis for Dicrotophos (Food and Drinking Water) NC 

Cotton Typical Rate

Population Subgroup aPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00007 0.000008 11

All Infants (< 1 year old) 0.00007 0.000013 19

Children 1-2 years old 0.00007 0.000013 18

Children 3-5 years old 0.00007 0.000012 18

Children 6-12 years old 0.00007 0.000009 13

Youth 13-19 years old 0.00007 0.000006 9.2

Adults 20-49 years old 0.00007 0.000007 9.9

Adults 50-99 years old 0.0007 0.000006 <1

Females 13-49 years old 0.00007 0.000007 9.7

* The values for the highest exposed population is bolded.

Table 5.4.3.9 Results of Acute Dietary Exposure Analysis for Dicrotophos (Food and Drinking Water) NC 

Cotton Max Rate

Population Subgroup aPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00007 0.000035 50

All Infants (< 1 year old) 0.00007 0.000092 130

Children 1-2 years old 0.00007 0.000052 75

Children 3-5 years old 0.00007 0.000046 66

Children 6-12 years old 0.00007 0.000033 48

Youth 13-19 years old 0.00007 0.000026 38

Adults 20-49 years old 0.00007 0.000035 50

Adults 50-99 years old 0.0007 0.000035 5.0

Females 13-49 years old 0.00007 0.000035 50

* The values for the highest exposed population is bolded.
Page 38 of 97

5.4.4 Steady State Dietary Risk Assessment

The DEEM acute module was used to conduct steady-state assessments using the steady-state 

endpoint, two-day average dietary exposure, and 21-day rolling water averages. The steady-state 

assessments are refined using average field trial residue, 100% crop treated, and default 

processing factors. EFED provided daily time-series outputs that simulate 29 years of residues of 

ethoprop in water for multiple scenarios as mentioned previously. These distributions were 

converted into 21-day rolling averages and incorporated into Residue Distribution Files (RDFs) 

that were used in DEEM for water, direct all sources and water, indirect all sources.

The steady state (2 day average) aggregate dietary (food and drinking water) exposure estimates 

using DEEM-FCID with the 2-day average option are above HED’s level of concern for all 

maximum application rate cotton water scenarios. Combined dietary exposure from food and 

drinking water at the 95th percentile of exposure ranged from 10-52% of the ssPAD for the U.S. 

population and 50-320% of the ssPAD for all infants <1 year old). All typical application rate 

(as determined by BEAD) cotton scenarios gave aggregate dietary (food and drinking water) 

exposure estimates <100% ssPAD. The dietary exposure estimates for food only were ≤23% 

ssPAD for all population subgroups.

Table 5.4.4.1 Results of Steady State Dietary Exposure Analysis for Dicrotophos (Food Only)

Population Subgroup ssPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00003 0.000003 10

All Infants (< 1 year old) 0.00003 0.000002 5.9

Children 1-2 years old 0.00003 0.000007 22

Children 3-5 years old 0.00003 0.000007 23

Children 6-12 years old 0.00003 0.000005 17

Youth 13-19 years old 0.00003 0.000003 11

Adults 20-49 years old 0.00003 0.000002 7.3

Adults 50-99 years old 0.0003 0.000002 <1

Females 13-49 years old 0.00003 0.000002 7.5

* The values for the highest exposed population is bolded.
Page 39 of 97

Table 5.4.4.2 Results of Steady State Dietary Exposure Analysis for Dicrotophos (Food and Drinking 

Water) MS Cotton Typical Rate – BEAD Date of Application

Population Subgroup ssPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00003 0.000011 16

All Infants (< 1 year old) 0.00003 0.000025 83

Children 1-2 years old 0.00003 0.000017 58

Children 3-5 years old 0.00003 0.000016 52

Children 6-12 years old 0.00003 0.000012 39

Youth 13-19 years old 0.00003 0.000009 29

Adults 20-49 years old 0.00003 0.000010 35

Adults 50-99 years old 0.0003 0.000010 3.3

Females 13-49 years old 0.00003 0.000010 34

* The values for the highest exposed population is bolded.

Table 5.4.4.3 Results of Steady State Dietary Exposure Analysis for Dicrotophos (Food and Drinking 

Water) MS Cotton Typical Rate–14 Day Retreatment Interval

Population Subgroup ssPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00003 0.000010 14

All Infants (< 1 year old) 0.00003 0.000022 72

Children 1-2 years old 0.00003 0.000016 53

Children 3-5 years old 0.00003 0.000015 48

Children 6-12 years old 0.00003 0.000011 36

Youth 13-19 years old 0.00003 0.000008 27

Adults 20-49 years old 0.00003 0.000010 32

Adults 50-99 years old 0.0003 0.000009 3.0

Females 13-49 years old 0.00003 0.000009 31

* The values for the highest exposed population is bolded.
Page 40 of 97

Table 5.4.4.4 Results of Steady State Dietary Exposure Analysis for Dicrotophos (Food and Drinking 

Water) MS Cotton Max Rate

Population Subgroup ssPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00003 0.000021 30

All Infants (< 1 year old) 0.00003 0.000053 180

Children 1-2 years old 0.00003 0.000032 110

Children 3-5 years old 0.00003 0.000028 94

Children 6-12 years old 0.00003 0.000020 68

Youth 13-19 years old 0.00003 0.000016 53

Adults 20-49 years old 0.00003 0.000021 68

Adults 50-99 years old 0.0003 0.000020 6.6

Females 13-49 years old 0.00003 0.000020 68

* The values for the highest exposed population is bolded.

Table 5.4.4.5 Results of Steady State Dietary Exposure Analysis for Dicrotophos (Food and Drinking 

Water) TX Cotton Typical Rate – BEAD Date of Application

Population Subgroup ssPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00003 0.000011 15

All Infants (< 1 year old) 0.00003 0.000023 78

Children 1-2 years old 0.00003 0.000017 56

Children 3-5 years old 0.00003 0.000015 51

Children 6-12 years old 0.00003 0.000011 38

Youth 13-19 years old 0.00003 0.000008 28

Adults 20-49 years old 0.00003 0.000010 33

Adults 50-99 years old 0.0003 0.000009 3.2

Females 13-49 years old 0.00003 0.000010 33

* The values for the highest exposed population is bolded.
Page 41 of 97

Table 5.4.4.6 Results of Steady State Dietary Exposure Analysis for Dicrotophos (Food and Drinking 

Water) TX Cotton Typical Rate–14 Day Retreatment Interval

Population Subgroup ssPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00003 0.000010 14

All Infants (< 1 year old) 0.00003 0.000022 74

Children 1-2 years old 0.00003 0.000016 53

Children 3-5 years old 0.00003 0.000015 49

Children 6-12 years old 0.00003 0.000011 36

Youth 13-19 years old 0.00003 0.000008 27

Adults 20-49 years old 0.00003 0.000010 32

Adults 50-99 years old 0.0003 0.000009 3.0

Females 13-49 years old 0.00003 0.000009 31

* The values for the highest exposed population is bolded.

Table 5.4.4.7 Results of Steady State Dietary Exposure Analysis for Dicrotophos (Food and Drinking 

Water) TX Cotton Max Rate

Population Subgroup ssPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00003 0.000022 32

All Infants (< 1 year old) 0.00003 0.000057 190

Children 1-2 years old 0.00003 0.000034 110

Children 3-5 years old 0.00003 0.000030 100

Children 6-12 years old 0.00003 0.000022 73

Youth 13-19 years old 0.00003 0.000017 57

Adults 20-49 years old 0.00003 0.000022 73

Adults 50-99 years old 0.0003 0.000021 7.1

Females 13-49 years old 0.00003 0.000022 73

* The values for the highest exposed population is bolded.
Page 42 of 97

Table 5.4.4.8 Results of Steady State Dietary Exposure Analysis for Dicrotophos (Food and Drinking 

Water) NC Cotton Typical Rate

Population Subgroup ssPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00003 0.000008 11

All Infants (< 1 year old) 0.00003 0.000015 50

Children 1-2 years old 0.00003 0.000013 43

Children 3-5 years old 0.00003 0.000012 40

Children 6-12 years old 0.00003 0.000009 30

Youth 13-19 years old 0.00003 0.000006 21

Adults 20-49 years old 0.00003 0.000007 24

Adults 50-99 years old 0.0003 0.000007 2.2

Females 13-49 years old 0.00003 0.000007 23

* The values for the highest exposed population is bolded.

Table 5.4.4.9 Results of Steady State Dietary Exposure Analysis for Dicrotophos (Food and Drinking 

Water) NC Cotton Max Rate

Population Subgroup ssPAD (mkd)

95th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.00003 0.000036 52

All Infants (< 1 year old) 0.00003 0.000097 320

Children 1-2 years old 0.00003 0.000053 180

Children 3-5 years old 0.00003 0.000046 150

Children 6-12 years old 0.00003 0.000033 110

Youth 13-19 years old 0.00003 0.000027 90

Adults 20-49 years old 0.00003 0.000036 120

Adults 50-99 years old 0.0003 0.000036 12

Females 13-49 years old 0.00003 0.000036 120

* The values for the highest exposed population is bolded.

5.4.5 Cancer Dietary Risk Assessment

Dicrotophos is classified as showing "Suggestive evidence of carcinogenicity, but not sufficient 

to assess human carcinogenic potential”. Quantitative risk assessment for dicrotophos using the 

Reference Dose (RfD) approach will adequately account for all chronic toxic effects, including 

carcinogenicity. 
Page 43 of 97

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no registered (or proposed) residential uses for dicrotophos at this time. However, that 

does not preclude non-occupational exposure to dicrotophos.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. There are currently no registered or proposed residential uses for 

dicrotophos; therefore a residential handler assessment was not performed. 

6.2 Post-Application Exposure

There are currently no registered or proposed residential uses for dicrotophos. The potential for 

non-occupational exposure from agricultural applications of dicrotophos has been assessed 

below in Section 6.4. 

6.3 Residential Bystander Postapplication Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and 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 has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for 

dicrotophos.

6.4 Spray Drift

Off-target movement of pesticides can occur via many types of pathways and it is governed by a 

variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those it may directly contact. They can also deposit on 

surfaces where contact with residues can eventually lead to exposures (e.g., children playing on 

lawns where residues have deposited next to treated fields). The potential risk estimates from 

these residues can be calculated using drift modeling coupled with methods employed for 

residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment includes 

assessing exposures for children (1 to 2 years old) and adults who have contact with turf where 

residues are assumed to have deposited via spray drift thus resulting in an exposure scenario. 

Aside from the predicted residues available for transfer, the routes of exposure and assessment 

methodology is analogous to how exposures to turf products are considered in risk assessment. 
Page 44 of 97

In order to evaluate the drift potential and associated risks, an approach based on drift modeling 

coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, 

a residential turf assessment based on exposure to deposited residues has been completed to 

address drift from the agricultural applications of dicrotophos. In the spray drift scenario, the 

deposited residue value was determined based on the amount of spray drift that may occur at 

varying distances from the edge of the treated field using the AgDrift (v2.1.1) model. Exposures 

were considered for 50 feet wide lawns where the nearest side of the property was directly 

adjoining the treated field (at field edge) and at varied distances up to 300 feet downwind of a 

treated field. Once the deposited residue values were determined, the remainder of the spray 

drift assessment was based on the algorithms and input values specified in the recently revised 

(2012) Standard Operating Procedures for Residential Risk Assessment (SOPs).

A screening approach was developed for situations where specific label guidance for application 

parameters is not available.9 AgDrift is appropriate for use only when applications are made by 

aircraft, airblast sprayers, and groundboom sprayers. When AgDrift was developed, a series of 

screening values (i.e., the Tier 1 option) were incorporated into the model and represent each 

equipment type and use under varied conditions. The screening options specifically 

recommended in this methodology were selected because they are plausible and represent a 

reasonable upper bound level of drift for common application methods in agriculture. In all 

cases, each scenario is to be evaluated unless it is not plausible based on the anticipated use 

pattern (e.g., herbicides are not typically applied to tree canopies) or specific label prohibitions 

(e.g., aerial applications are not allowed). Section 6.4.1 provides the screening level drift related 

risk estimates along with additional risk management options if necessary. These drift estimates 

represent plausible options for pesticide labels. 

6.4.1 Combined Risk Estimates from Lawn Deposition Adjacent to Applications

The spray drift risk estimates are based on an estimated deposited residue concentration as a 

result of the screening level agricultural application scenarios. Dicrotophos is used on cotton and 

can be applied via groundboom and aerial equipment at a maximum application rate of 0.5 lbs 

ai/acre. The recommended drift scenario screening level options are listed below: 

 Groundboom applications are based on the AgDrift option for high boom height and 

using very fine to fine spray type using the 90th percentile results. 

 Aerial applications are based on the use of AgDrift Tier 1 aerial option for a fine to 

medium spray type and a series of other parameters which will be described in more 

detail below (e.g., wind vector assumed to be 10 mph in a downwind direction for entire 

application/drift event).

In addition to the screening level spray drift scenarios described above, additional results are 

provided which represent viable drift reduction technologies (DRTs) that represent potential risk 

management options. In particular, different spray qualities have been considered as well as the 

 

9http://www.agdrift.com/ 
Page 45 of 97

impact of other application conditions (e.g., boom height, use of a helicopter instead of fixed 

wing aircraft, crop canopy conditions).

Dermal risk estimates were estimated for adults. For adults, when an endpoint is not sex-specific 

(i.e., the endpoints are based on developmental or fetal effects) a body weight of 80 kg is 

typically used in risk assessment; however, in this case, a female-specific body weight of 69 kg 

was used. While the endpoint of concern, brain AChE inhibition, is not sex-specific, the femalespecific body weight was used to protect for pregnant women due to uncertainty in the human 

dose-response relationship for neurodevelopmental effects (see Section 4.4). Dermal and 

incidental oral risk estimates for children 1<2 years old were combined because the toxicity 

endpoint for each route of exposure is the inhibition of brain cholinesterase (ChE). The total 

applicable LOC is 1000, so MOEs < 1000 represent risk estimates of concern. Adult dermal risk

estimates from indirect exposure to dicrotophos related to spray drift result in buffers of 200 feet 

for aerial applications (i.e., MOEs ≥ 1000 at the edge of the field) and 50 feet for groundboom 

applications. Children’s (1 to < 2 years old) dermal and incidental oral risk estimates from 

indirect exposure to dicrotophos related to spray drift result in buffers of 300 feet for both aerial 

and groundboom applications based on the screening level scenarios.

Results are presented in Tables 6.4.1 and 6.4.2 and indicate that there are risks of concern for 

both aerial and groundboom applications. Appropriate drift reduction technologies such as 

changing the spray type/nozzle configuration to coarser spray applications may result in less drift 

and reduced risk concerns (i.e., higher MOEs) from aerial applications. Similarly, using coarser 

sprays and lowering boom height for groundboom sprayers reduces risk concerns.
Dicrotophos Human Health Risk Assessment DP No. D428506

Page 46 of 97

Table 6.4.1. Adult Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Dicrotophos for the Dermal Route of Exposure

Crop/Rate 

Group

Spray Type/ 

Nozzle 

Configuration

Appl.

Rate (lb 

ai/A)

TTR 

(ug/cm2)

At 

Edge

10 

Feet

25 

Feet

50 

Feet

75 

Feet

100 

Feet

125 

Feet

150 

Feet

200 

Feet

250 

Feet

300 

Feet

Cotton

Aerial

Fine to Medium

0.5 0.056

 

170 

 

210 

 

250 

 

330 

 

440 

 

560 

 

680 

 

790 

 

1,000 

 

1,300 

 

1,500 

Medium to 

Coarse

 

200 

 

280 

 

370 

 

520 

 

740 

 

980 

 

1,200 

 

1,500 

 

2,000 

 

2,700 

 

3,300 

Coarse to Very 

Coarse

 

230 

 

350 

 

520 

 

810 

 

1,200 

 

1,500 

 

2,000 

 

2,400 

 

3,300 

 

4,300 

 

5,400 

Very Fine to 

Fine

 

120 

 

130 

 

140 

 

160 

 

190 

 

220 

 

250 

 

280 

 

340 

 

400 

 

450 

AT401, M, 10 

mph, 37% SD

 

180 

 

230 

 

300 

 

410 

 

550 

 

720 

 

880 

 

1,000 

 

1,300 

 

1,700 

 

2,000 

WASP, M, 10 

mph, 37% SD

 

200 

 

250 

 

330 

 

500 

 

680 

 

880 

 

1,100 

 

1,300 

 

1,700 

 

2,000 

 

2,400 

AT401, C, 10 

mph, 25% SD

 

220 

 

300 

 

430 

 

640 

 

910 

 

1,200 

 

1,500 

 

1,800 

 

2,500 

 

3,300 

 

3,900 

WASP, C, 10 

mph, 25% SD

 

250 

 

350 

 

510 

 

810 

 

1,100 

 

1,500 

 

1,900 

 

2,400 

 

3,300 

 

4,300 

 

4,800 

AT401, VC, 10 

mph, 20% SD

 

250 

 

370 

 

600 

 

980 

 

1,400 

 

1,900 

 

2,400 

 

3,100 

 

4,300 

 

5,400 

 

7,200 

WASP, VC, 10 

mph, 20% SD

 

310 

 

490 

 

750 

 

1,200 

 

1,700 

 

2,300 

 

3,100 

 

3,600 

 

5,400 

 

6,100 

 

7,200 

Groundboom

High Boom 

Very fine to 

Fine

 

230 

 

460 

 

770 

 

1,200 

 

1,700 

 

2,100 

 

2,500 

 

3,100 

 

3,900 

 

5,400 

 

6,100 

Low Boom Very 

fine to Fine

 

500 

 

1,300 

 

2,100 

 

3,300 

 

4,300 

 

5,400 

 

6,100 

 

7,200 

 

8,600 

 

11,000 

 

14,000 

High Boom Fine 

to 

Medium/Coarse

 

880 

 

2,300 

 

3,300 

 

4,800 

 

6,100 

 

7,200 

 

8,600 

 

8,600 

 

11,000 

 

14,000 

 

14,000 

Low Boom Fine 

to 

Medium/Coarse

 

1,300 

 

3,600 

 

5,400 

 

7,200 

 

8,600 

 

11,000 

 

14,000 

 

14,000 

 

21,000 

 

21,000 

 

21,000 
Dicrotophos Human Health Risk Assessment DP No. D428506

Page 47 of 97

Table 6.4.2. Children (1<2 years old) Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Dicrotophos for the Combined Dermal and Oral Routes 

of Exposure

Crop/Rate 

Group

Spray Type/ 

Nozzle 

Configuration

Appl. Rate 

(lb ai/A)

TTR 

(ug/cm2)

At 

Edge

10 

Feet

25 

Feet

50 

Feet

75 

Feet

100 

Feet

125 

Feet

150 

Feet

200 

Feet

250 

Feet

300 

Feet

Cotton

Aerial

Fine to 

Medium

0.5 0.056

13 16 20 26 35 45 54 63 83 100 120

Medium to 

Coarse 16 22 30 42 59 77 97 120 160 210 260

Coarse to Very 

Coarse 19 27 42 64 92 120 150 190 260 340 430

Very Fine to 

Fine 9 10 11 13 15 17 19 22 27 32 36

AT401, M, 10 

mph, 37% SD 15 19 24 32 44 57 70 81 110 130 160

WASP, M, 10 

mph, 37% SD 16 20 26 40 54 70 85 100 130 160 190

AT401, C, 10 

mph, 25% SD 17 24 34 51 72 95 120 140 200 260 310

WASP, C, 10 

mph, 25% SD 20 28 41 64 90 120 150 190 260 340 380

AT401, VC, 10 

mph, 20% SD 19 30 47 77 110 150 190 240 340 430 570

WASP, VC, 10 

mph, 20% SD 25 39 60 95 140 180 240 280 430 490 570

Groundboom

High Boom 

Very fine to

Fine

18 37 61 97 140 170 200 240 310 430 490

Low Boom 

Very fine to 

Fine

40 110 170 260 340 430 490 570 680 850 1,100

High Boom 

Fine to 

Medium/Coarse

70 180 260 380 490 570 680 680 850 1,100 1,100

Low Boom 

Fine to 

Medium/Coarse

100 280 430 570 680 850 1,100 1,100 1,700 1,700 1,700
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7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, when there are potential residential exposures to a pesticide, 

aggregate risk assessment must consider exposures from three major routes: oral, dermal, and 

inhalation. There are three sources for these types of exposures: food, drinking water, and 

residential uses. In an aggregate assessment, exposures from relevant sources are added together 

and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks 

themselves can be aggregated. When aggregating exposures and risks from various sources, 

HED considers both the route and duration of exposure. The registered dicrotophos uses are not 

anticipated to result in residential exposure. 

7.1 Acute Aggregate Risk

The acute exposure estimates provided in the Dietary Exposure Section represent acute aggregate 

exposure.

7.2 Short-Term Aggregate Risk

The acute and steady state exposure estimates provided in the Dietary Exposure Section 

represent aggregate exposure.

7.3 Intermediate-Term Aggregate Risk

No intermediate-term exposure scenarios were identified for dicrotophos, therefore, no 

intermediate-term aggregate risk was calculated.

7.4 Chronic Aggregate Risk

No chronic exposure scenarios were identified for dicrotophos, therefore, no chronic aggregate 

risk was calculated.

7.5 Cancer Aggregate Risk

Dicrotophos is classified as showing "Suggestive evidence of carcinogenicity, but not sufficient 

to assess human carcinogenic potential”. Quantitative risk assessment for dicrotophos using the 

Reference Dose (RfD) approach will adequately account for all chronic toxic effects, including 

carcinogenicity. 

8.0 Cumulative Exposure/Risk Characterization

OPs, like dicrotophos, share the ability to inhibit AChE through phosphorylation of the serine 

residue on the enzyme leading to accumulation of acetylcholine and ultimately cholinergic 

neurotoxicity. This shared MOA/AOP is the basis for the OP common mechanism grouping per 

OPP’s Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common 

Mechanism of Toxicity (USEPA, 1999). The 2002 and 2006 CRAs used brain AChE inhibition 

in female rats as the source of dose response data for the relative potency factors and PODs for
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each OP, including dicrotophos. Prior to the completion of Registration Review, OPP will 

update the OP CRA on AChE inhibition to incorporate new toxicity and exposure information 

available since 2006. 

As described in Section 4.4, OPP has retained the FQPA Safety Factor for OPs, including 

dicrotophos, due to uncertainties associated with neurodevelopmental effects in children and 

exposure to OPs. There is a lack of an established MOA/AOP for the neurodevelopment 

outcomes which precludes the agency from formally establishing a common mechanism group 

per the Guidance For Identifying Pesticide Chemicals and Other Substances that have a 

Common Mechanism of Toxicity (USEPA, 1999) based on that outcome. Moreover, the lack of a 

recognized MOA/AOP and other uncertainties with exposure assessment in the epidemiology 

studies prevent the agency from establishing a causal relationship between OP exposure and 

neurodevelopmental outcomes. The agency will continue to evaluate the epidemiology studies 

associated with neurodevelopmental outcomes and OP exposure prior to the release of the 

revised DRA. During this period, the agency will determine whether or not it is appropriate to 

apply the draft guidance document entitled, Pesticide Cumulative Risk Assessment: Framework 

for Screening Analysis for the neurodevelopment outcomes. 

9.0 Occupational Exposure/Risk Characterization

9.1 Short- and Intermediate-term Handler 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 anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the registered uses 

of dicrotophos. The quantitative exposure/risk assessment developed for occupational handlers 

is based on the following scenarios: 

 Mixer/Loader (aerial and groundboom equipment)

 Applicators (aerial and groundboom equipment)

 Flagger (from aerial spray applications)

The above exposure scenarios best represent the registered use pattern (i.e., cotton applications) 

for dicrotophos. Chemigation applications are prohibited on the product labels. 

Dicrotophos is available as a Restricted Use product (EPA7946-11) for micro-injection for 

systemic suppression of certain insects on ornamental trees. HED has no exposure data 

appropriate for assessment of the tree injection use of dicrotophos. However, the exposures and 

risks associated with this use (occupational handler and/or postapplication exposure) are not 

expected to exceed those estimated for the cotton use.
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Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate: Product labels indicate that dicrotophos can be used at a maximum single 

application rate of 0.5 lbs ai/A. See Section 4 for additional information. The occupational 

handler assessment was completed assuming the single maximum application rate.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. 

Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, 

include PHED 1.1, the 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 handler exposure that are used in this 

assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit 

Exposure Surrogate Reference Table10”, which, along with additional information on HED 

policy on use of surrogate data, including descriptions of the various sources, can be found at the 

Agency website11. 

Area Treated or Amount Handled: Based on HED ExpoSAC Policy 9.1, the amount treated or 

handled per day was assumed to be: 

 200 acres for mixing/loading groundboom applications and applying via ground 

equipment on cotton,

 1200 acres for mixing/loading for aerial applications and applying via aircraft on cotton, 

and

 350 acres for flagging for aerial application on cotton crops.

 

Body Weight: For adults, when an endpoint is not sex-specific (i.e., the endpoints are based on 

developmental or fetal effects) a body weight of 80 kg is typically used in risk assessment; 

however, in this case, a female-specific body weight of 69 kg was used. While the endpoint of 

concern, brain ChE inhibition, is not sex-specific, the female-specific body weight was used to 

protect for pregnant women due to uncertainty in the human dose-response relationship for 

neurodevelopmental effects (see Section 4.4). 

 

Absorption Factors: 

Since the steady-state dermal point of departure POD was based on a route-specific toxicity 

study, no absorption factor was necessary to estimate exposure. In addition, the POD was 

adjusted to account for the higher rat skin permeability compared to human skin. 

A route-specific inhalation study is available and was used in the assessment; no absorption 

factor is necessary to the inhalation assessment.

 

10 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

11 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
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Exposure Duration: 

HED typically classifies exposures from 1 to 30 days as short-term and exposures 30 days to six 

months as intermediate-term. Exposure duration is determined by many things, including the 

exposed population, the use site, the pest pressure triggering the use of the pesticide, and the 

cultural practices surrounding that use site. For the organophosphate pesticides, the match 

between the toxicological endpoint selection and the exposure duration is different than HED’s 

approach for conventional chemicals. The endpoint selection for organophosphate pesticides 

involves a “single day” and “steady state” approach based on an individual chemical’s 

cholinesterase inhibition. The steady state approach is appropriate for dicrotophos given the 

toxicological and exposure profile. The “steady state” endpoint selection for dicrotophos 

overlaps HED’s traditional short-term exposure duration endpoint selection and is considered 

health protective for occupational handlers that apply commercially over longer periods of time 

(i.e., intermediate-term exposures).

For most agricultural uses, it is reasonable to believe that occupational handlers will not apply 

the same chemical every day for more than a one-month time frame; however, there may be a 

large agribusiness and/or commercial applicators who may apply a product over a period of 

weeks (e.g. completing multiple applications for multiple clients within a region).

Dicrotophos is a RUP intended for broad spectrum application to cotton fields via aerial and 

ground equipment. The available product labels indicate that the product can be used in multiple 

applications per season (early and mid-season use) with a minimum 14 day retreatment interval. 

The intended pests are similar in the early and mid-season uses (boll weevils, spider mites, 

aphids, etc.). 

Mitigation/Personal Protective Equipment: Estimates of dermal and inhalation exposure were 

calculated based on the mitigation of agricultural uses from the 2006 dicrotophos Reregistration 

Eligibility Decision (RED). Specifically, the RED required ECs such as closed cabs and closed 

mixing/loading systems for occupational handlers. All current dicrotophos labels indicate this 

level of personal protection for occupational handlers.

Combining Exposures/Risk Estimates:

Dermal and inhalation risk estimates were combined in this assessment, since the toxicological 

effects for these exposure routes were similar. Dermal and inhalation risk estimates were 

combined using the following formula:

Total MOE = Point of Departure (mg/kg/day) ÷ Combined dermal + inhalation dose (mg/kg/day)

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

Based on the label-defined protection for occupational handlers (engineering controls), all 

exposure scenarios assessed (not including flaggers) result in combined (dermal and inhalation) 

risk estimates of concern (i.e., MOEs are < 1,000). MOEs for these occupational handler 

exposure scenarios range from 78 to 870.
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HED does not have unit exposure data for assessing dermal and inhalation exposure for flaggers 

with engineering controls. HED has presented flagger risk estimates in consideration of the 

maximum level of PPE feasible (i.e., double layer, chemical resistant gloves, and PF10 

respirator) even though engineering controls for flaggers are required on the registered product 

labels. Occupational handler exposures for flaggers also result in a combined risk estimate 

(dermal and inhalation) of concern with an MOE = 290. 

HED has no data to assess exposures to pilots using open cockpits. The only data available is for 

exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, 

and socks); pilots are not required to wear protective gloves. With this level of protection, no 

risk estimates of concern for applicators were identified.

The Agency matches quantitative occupational exposure assessment with appropriate 

characterization of exposure potential. While HED presents quantitative risk estimates for 

human flaggers where appropriate, agricultural aviation has changed dramatically over the past 

two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of 

their membership, the use of GPS for swath guidance in agricultural aviation has grown steadily 

from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide 

applications has decreased steadily from ~15% in the late 1990’s to only 1% in the most recent 

(2012) NAAA survey. The Agency will continue to monitor all available information sources to 

best assess and characterize the exposure potential for human flaggers in agricultural aerial 

applications.

Table 9.1 presents a summary of the occupational handler exposure and risk estimates for 

dicrotophos.
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Table 9.1. Steady-State Occupational Handler Exposure and Risk Estimates for Dicrotophos. 

Exposure Scenario Crop or 

Target

Dermal Unit 

Exposure

(ug/lb ai)1

Inhalation Unit 

Exposure 

(ug/lb ai)1

Maximum 

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Total

Level of PPE 

or EC

Mitigation Level Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

Mixer/Loader

Aerial Application Cotton EC – 8.6 EC – 0.083 0.5 1200 A/day 0.0748 120 0.000722 220 78

Groundboom Application Cotton EC – 8.6 EC – 0.083 0.5 200 A/day 0.0125 750 0.00012 1,400 490

Applicator

Aerial Application Cotton EC – 2.1 EC – 0.0049 0.5 1200 A/day 0.0181 520 0.0000426 3,800 460

Groundboom Application Cotton EC – 5.1 EC – 0.043 0.5 1200 A/day 0.00739 1,300 0.0000623 2,600 870

Flagger

Flagger- from Aerial 

Application Cotton

Double Layer/ 

Gloves/ PF10 

Respirator - 10.6

Baseline – 0.035 0.5 350 A/day 0.027 350 0.0000888 1,800 290

1 PHED/ORETF (PPE= Personal Protective Equipment; EC= Engineering. Controls; PF10= Protection Factor 10).

2 Based on registered label (e.g. Reg. No. #5481-00448).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A) / BW (69 kg).

5 Dermal MOE = Dermal PoD (9.33 mg/kg/day)/Dermal Dose (mg/kg/day).

6

Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A) / BW (69 kg).

7

Inhalation MOE = Inhalation BMDL10 (0.162 mg/kg/day)/ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL (mg/kg/day) ÷ Dermal Dose + Inhalation Dose OR Total MOE = 1 ÷ (1/Dermal MOE + 1/Inhalation MOE).
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9.2 Short-/Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

Occupational post-application dermal exposures are expected from the dicrotophos cotton use. 

Post-application exposures are not anticipated from the tree injection use. 

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates

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 has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for dicrotophos.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

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

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates

Occupational Post-application Dermal Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

post-application risk assessments. Each assumption and factor is detailed below on an individual 

basis.

Exposure Duration: 

The endpoint selection for organophosphate pesticides involves a “single day” and “steady state” 

approach based on an individual chemical’s cholinesterase inhibition. The steady state approach 

is appropriate for dicrotophos given the toxicological and exposure profile. The “steady state” 
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endpoint selection for dicrotophos overlaps HED’s traditional short-term exposure duration 

endpoint selection as well as being appropriately health protective for workers that are exposed 

over longer periods of time (i.e., intermediate-term exposures).

Transfer Coefficients: It is the policy of HED to use the best available data to assess postapplication exposure. Sources of generic post-application data, used as surrogate data in the 

absence of chemical-specific data, are derived from ARTF exposure monitoring studies, and, as 

proprietary data, are subject to the data protection provisions of FIFRA. The standard values 

recommended for use in predicting post-application exposure that are used in this assessment, 

known as “transfer coefficients”, are presented in the ExpoSAC Policy 312” which, along with 

additional information about the ARTF data, can be found at the Agency website13.

Table 9.2.2.1: Anticipated Post-Application Activities and Dermal Transfer Coefficients.

Crops Policy Crop Group Category Transfer 

Coefficients Activities

cm2/hr

Cotton Field/ Row Crop, Low/Medium

0 Irrigation, Mechanical Weeding

70 Hand Weeding

210 Scouting

Application Rate: 

The application rates for dicrotophos on the available product labels range from 0.2 to 0.5 lbs 

ai/A, depending on the target pest. The occupational post-application assessment was conducted 

at the maximum single application rate (0.5 lbs ai/A).

Body Weight: 

For adults, when an endpoint is not sex-specific (i.e., the endpoints are based on developmental 

or fetal effects) a body weight of 80 kg is typically used in risk assessment; however, in this case, 

a female-specific body weight of 69 kg was used. While the endpoint of concern, brain ChE 

inhibition, is not sex-specific, the female-specific body weight was used to protect for pregnant 

women due to uncertainty in the human dose-response relationship for neurodevelopmental 

effects (see Section 4.4).

Absorption Factor: 

Since the steady-state dermal POD was based on a route-specific toxicity study, no absorption 

factor was necessary to estimate exposure. The POD was adjusted to account for the higher rat 

skin permeability compared to human skin, however.

Exposure Time:

The average occupational workday is assumed to be 8 hours. 

Dislodgeable Foliar Residues: 

Chemical specific dislodgeable foliar residue (DFR) data have been submitted for dicrotophos 

use on cotton (see MRID 44731001). At two test sites (Mississippi and Texas), two applications 

 

12 Available: http://www.epa.gov/pesticides/science/exposac_policy3.pdf

13 Available: http://www.epa.gov/pesticides/science/post-app-exposure-data.html
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of Bidrin® 8, an emulsifiable concentrate formulation containing 84.2% active ingredient (E 

isomer), dicrotophos (8 lb ai/gal), were made to cotton foliage at the target rate of 0.5 lb 

ai/A/application for a total seasonal rate of 1.0 lb ai/A. At all sites, the highest average 

dicrotophos DFR value occurred immediately after the first application and dropped to below the 

LOQ by 14 days after application. The highest average DFR values (and percent of application 

rate) were 0.422 μg/cm2 (7.84%) at the Mississippi site and 1.001 μg/cm2 (18.23%) at the Texas 

site. Following the second application, the highest average dicrotophos DFR value occurred 

immediately after application and dropped to below the LOQ by 7 days after application at the 

Mississippi site and by 14 days after application at the Texas site. The highest average DFR 

values (and percent of application rate) following application 2 were 0.180 μg/cm2 (3.22%) at the 

Mississippi site and 0.343 μg/cm2(6.13%) at the Texas site. 14 days is the minimal retreatment 

interval. HED determined that the Texas site data is more appropriate for use in human health 

risk assessment, as precipitation concerns make the Mississippi data significantly less reliable. 

Typically the DFR after multiple applications would be used for the regression analysis; 

however, residue data after the first application at the Texas site was used in this assessment as it 

provided higher dislodgeable residues values and is thus more conservative. See the summary of 

this data in the table below.

Table 9.2.2.2. Summary of Dicrotophos DFR Residues and Versar Regression Analysis 

Results for Cotton Leaves Treated with Dicrotophos 

Statistic Texas

Application Rate (lb ai/A)

Target Application Rate = 0.50 lb ai/A

0.49 (first application)

0.50 (second application)

Measured Average Day 0 Residue

(μg/cm2)

1.001 (first application)

0.343 (second application)

Predicted Day 0 Residue

(μg/cm2)

0.936

Slope -0.402

Half-life (days) 1.7

R

2 0.945

Registrant’s predicted half-life (days) 2.33

Registrant’s R2 0.971

Occupational Post-application Non-Cancer Dermal Exposure and Risk Estimate Equations

The algorithms used to estimate non-cancer exposure and dose for occupational post-application 

workers can be found in the supporting occupational and residential exposure assessment14.

 

14 Dicrotophos. Occupational and Residential Exposure Assessment for the Registration Review Risk Assessment. 

D428507, 9/15/15, W. Britton, M. Lloyd, A. Lamay, S. Shelat. 
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Occupational Post-application Non-Cancer Dermal Risk Estimates

Table 9.2.2.3: Summary of Occupational/Commercial Post-application Risk Estimates for Dicrotophos.

Crop/Site Activities DFR/TTR1 DAT MOE2

Steady State

Cotton

Hand Weeding 0.94 0 1,200

0.084 6 14,000

Scouting

0.94 0 410

0.63 1 610

0.42 2 920

0.28 3 1,400

0.19 4 2,000

0.13 5 3,100

0.084 6 4,600

1. DFR derivedfrom chemical-specific study data (MRID 44731001).

2. MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm2) x TC x 0.001 mg/μg x 8 hrs/day ]  BW (69 kg)

Cotton harvesting: Although dicrotophos can be applied to cotton after bloom, exposure to 

dicrotophos residues during harvesting or post-harvest activities is expected to be negligible as 

residues are expected to be minimal after the label-required 30-day pre-harvest interval and 

considering that dicrotophos dissipated with a half-life of approximately 2 days from the 

terrestrial field studies (D276599). The assessment of pre-harvest activities is expected to cover 

any harvest-related exposure to dicrotophos, which would not occur until 30-days after 

application.

Restricted Entry Interval

The REI specified on the label of 6 days is based on the acute toxicity of dicrotophos and the 

mitigation specified in the dicrotophos RED. Dicrotophos is classified as Toxicity Category I 

via the oral and inhalation route, Toxicity Category II via the dermal route and for eye irritation, 

and Toxicity Category IV for skin irritation potential. It is a strong skin sensitizer. Steady-state 

risk occupational post-application risk estimates are not of concern (i.e., MOEs >1000) on the 

day of treatment (i.e., Day 0) for hand weeding activities and three days after application for 

scouting activities. Under 40 CFR 156.208 (c) (2), if the product contains only one active 

ingredient and it is in toxicity category I, the restricted entry interval shall be 48 hours. If the 

active ingredient is an organophosphorus ester that inhibits cholinesterase and that may be 

applied outdoors in an area where the average rainfall is less than 25 inches per year, the 

restricted interval should be listed as 72 hours. Thus, the REI on the labels (6 days) meets the 

minimum requirements. 
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Appendix 1. Summary of OPP’s ChE Policy & Use of BMD Modeling

OPP’s ChE policy (USEPA, 200015) describes the manner in which ChE data are used in human 

health risk assessment. The following text provides a brief summary of that document to provide 

context to points of departure selected. 

AChE inhibition can be inhibited in the central or peripheral nervous tissue. Measurements of 

AChE or cholinesterase (ChE) inhibition in peripheral tissues (e.g., liver, diaphragm, heart, lung 

etc) are rare. As such, experimental laboratory studies generally measure brain (central) and 

blood (plasma and red blood cell, RBC) ChE. Blood measures do not represent the target tissue, 

per se, but are instead used as surrogate measures for peripheral toxicity in studies with 

laboratory animals or for peripheral and/or central toxicity in humans. In addition, RBC 

measures represent AChE, whereas plasma measures are predominately butyryl-ChE (BuChE). 

Thus, RBC AChE data may provide a better representation of the inhibition in target tissues. As 

part of the dose response assessment, evaluations of neurobehavior and clinical signs are 

performed to consider the dose response linkage between AChE inhibition and apical outcomes.

Refinements to OPP’s use of ChE data have come in the implementation of BMD approaches in 

dose response assessment. Beginning with the OP CRA, OPP has increased its use of BMD 

modeling to derive PoDs for AChE inhibiting compounds. Most often the decreasing 

exponential empirical model has been used. 

OPP does have not a defined benchmark response (BMR) for OPs. However, the 10% level has 

been used in the majority of dose response analyses conducted to date. This 10% level 

represents a 10% reduction in AChE activity (i.e., inhibition) compared to background (i.e., 

controls). Specifically, the BMD10 is the estimated dose where ChE is inhibited by 10% 

compared to background. The BMDL10 is the lower confidence bound on the BMD10. 

The use of the 10% BMR is derived from a combination of statistical and biological 

considerations. A power analysis was conducted by the Office of Research and Development 

(ORD) on over 100 brain AChE datasets across more than 25 OPs as part of the OP CRA 

(USEPA, 2002). This analysis demonstrated that 10% is a level that can be reliably measured in 

the majority of rat toxicity studies. In addition, the 10% level is generally at or near the limit of 

sensitivity for discerning a statistically significant decrease in ChE activity in the brain 

compartment and is a response level close to the background brain ChE level. With respect to 

biological considerations, a change in 10% brain AChE inhibition is protective for downstream 

clinical signs and apical neurotoxic outcomes. With respect to RBC AChE inhibition, these data 

tend to be more variable than brain AChE data. OPP begins its BMD analyses using the 10% 

BMR for RBC AChE inhibition but BMRs up to 20% could be considered on a case by case 

basis as long as such PoDs are protective for brain AChE inhibition, potential peripheral 

inhibition, and clinical signs of neurotoxicity.

 

15 USEPA (2000) Office of Pesticide Programs, US Environmental Protection Agency, Washington DC 20460. 

August 18, 2000 Office of Pesticide Programs Science Policy of The Use of Data on Cholinesterase Inhibition

for Risk Assessments of Organophosphorous and Carbamate Pesticides.
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Appendix 2 – Results for BMD/BMDL modeling for Dicrotophos 

Appendix Table 2.1 BMD results of single dose studies.

Dicrotophos/Study Sex/age Compartment

BMD Results

BMD10 (mg/kg) BMDL10 (mg/kg)

MRID 46153205

CCA Acute Study –

Single Dose 

Male 

PND8 

Brain No reliable fit No reliable fit

Female

PND8

Brain 0.082 0.071

MRID 46153205

CCA Acute Study –

Single Dose 

Male 

PND8 

RBC 0.10 0.051

Female

PND8

RBC 0.11 0.059

MRID 46153205

CCA Acute Study –

Single Dose 

Male 

PND15 

Brain 0.079 0.070

Female

PND15

Brain No reliable fit No reliable fit

MRID 46153205

CCA Acute Study –

Single Dose 

Male 

PND15 

RBC No reliable fit No reliable fit

Female

PND15

RBC 0.10 0.067

MRID 46153205

CCA Acute Study –

Single Dose 

Male 

PND22 

Brain 0.23 0.13

Female

PND22

Brain No reliable fit No reliable fit

MRID 46153205

CCA Acute Study –

Single Dose 

Male 

PND22 

RBC 0.12 0.088

Female

PND22

RBC 0.14 0.099

MRID 46153206

CCA Acute Study –

Single Dose 

Adult Male 

PND42

Brain 0.38 0.22

Adult Female

PND42

Brain 0.12 0.092

MRID 46153206

CCA Acute Study –

Single Dose 

Adult Male 

PND42

RBC No reliable fit No reliable fit

Adult Female

PND42

RBC 0.31 0.20
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Appendix Table 2.2 BMD results of repeated dosing studies ranging in duration from 7 days to 2 years.

Dicrotophos/Study Sex/age Compartment

BMD Results

BMD10 (mg/kg/day) BMDL10 (mg/kg/day)

MRID 46153204

CCA Repeat Study – 7 

days

Adult Male 

PND42

Brain 0.11 0.054

Adult Female

PND42

Brain No reliable fit No reliable fit

MRID 46153204

CCA Repeat Study – 7 

days

Adult Male 

PND42

RBC 0.072 0.051

Adult Female

PND42

RBC 0.095 0.069

MRID 46153204

CCA Repeat Study – 7 

days 

Pup Male 

PND12

Brain 0.064 0.032

Pup Female

PND12

Brain 0.049 0.028

MRID 46153204

CCA Repeat Study – 7 

days 

Pup Male 

PND12

RBC 0.045 0.042

Pup Female

PND12

RBC 0.024 0.017

MRID 46153208

CCA Repeat Study – 

4-Weeks 

Adult Male Brain 0.060 0.015

Adult Female Brain 0.077 0.059

MRID 46153208

CCA Repeat Study – 

4-Weeks 

Adult Male RBC 0.12 0.097

Adult Female RBC 0.17 0.042

MRID 46153201

Developmental 

Neurotoxicity in Rats

Maternal

Gestation Day 22

(~15D of dosing)

Brain 0.028 0.021

Maternal 

Lactation Day 22

(~37D of dosing)

Brain 0.023 0.017

MRID 46153201

Developmental 

Neurotoxicity in Rats

Maternal

Gestation Day 22

(~15D of dosing)

RBC 0.036 0.028
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Dicrotophos/Study Sex/age Compartment

BMD Results

BMD10 (mg/kg/day) BMDL10 (mg/kg/day)

Maternal 

Lactation Day 22

(~37D of dosing)

RBC 0.038 0.029

MRID 46153201

Developmental 

Neurotoxicity in Rats

Male Fetus 

Gestation Day 22

Brain 0.064 0.036

Female Fetus 

Gestation Day 22

Brain 0.094 0.064

MRID 46153201

Developmental 

Neurotoxicity in Rats

Male Fetus 

Gestation Day 22

RBC 0.066 0.045

Female Fetus 

Gestation Day 22

RBC 0.049 0.033

Dicrotophos/Study Sex/age Compartment

BMD Results

BMD10 (mg/kg/day) BMDL10 (mg/kg/day)

MRID 43980201 

Subchronic 

Neurotoxicity in Rats 

Male Adult

35D of dosing

Brain 0.039 0.036

Female Adult

35D of dosing

Brain 0.048 0.042

MRID 43980201 

Subchronic 

Neurotoxicity in Rats 

Male Adult

63D of dosing

Brain 0.041a 0.035a

Female Adult

63D of dosing

Brain 0.044 0.041

MRID 43980201 

Subchronic 

Neurotoxicity in Rats 

Male Adult

98D of dosing

Brain 0.048 0.044

Female Adult

98D of dosing

Brain 0.045 0.042

MRID 43980201 

Subchronic 

Neurotoxicity in Rats 

Male

35D of dosing

RBC 0.045 0.027

Female Adult

35D of dosing

RBC 0.026 0.015

MRID 43980201 

Subchronic 

Neurotoxicity in Rats 

Male Adult

63D of dosing

RBC 0.048 0.022

Female Adult

63D of dosing

RBC 0.057 0.033
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Dicrotophos/Study Sex/age Compartment

BMD Results

BMD10 (mg/kg/day) BMDL10 (mg/kg/day)

MRID 43980201 

Subchronic 

Neurotoxicity in Rats 

Male Adult

98D of dosing

RBC 0.023 0.013

Female Adult

98D of dosing

RBC 0.058 0.030

MRID 44527802

Chronic Toxicity in Rats 

(2 year) 

Male Adult

371D of dosing

Brain 0.028a 0.025a

Female Adult

371D of dosing

Brain 0.047b 0.037b

MRID 44527802

Chronic Toxicity in Rats 

(2 year) 

Male Adult

700D of dosing

Brain 0.027 0.022

Female Adult

735D of dosing

Brain 0.042c 0.035c

MRID 44527802

Chronic Toxicity in Rats 

(2 year)

Male

371D of dosing

RBC 0.039d 0.034d

Female

371D of dosing

RBC 0.040 0.016

MRID 44527802

Chronic Toxicity in Rats 

(2 year)

Male Adult

700D of dosing

RBC No reliable fit No reliable fit

Female Adult

735D of dosing

RBC 0.053d 0.042d

a Due to dose spacing issues, adequate statistical model fit (p>0.1) were not obtained for these specific analyses for Brain ChE. However, they are listed here for 

characterization purposes, as these results are similar in magnitude to those obtained using the more robust techniques used in the 2006 CRA (which included the 

results of both the subchronic neurotoxicity and chronic toxicity brain ChE data). 

b p=0.077 for model fit; based on visual inspection and taking into account the observed dose spacing issues, this model fit is adequate. 

c p=0.0896 for model fit; based on visual inspection and taking into account the observed dose spacing issues, this model fit is adequate. 

d Dropped high dose in order to improve model fit. 
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BMD results of repeated exposure studies via the dermal and inhalation routes.

Dicrotophos/Study Sex/age Compartment

BMD Results

BMD10 BMDL10

MRID 46484501

28-Day Dermal 

Toxicity Study 

Male Brain No reliable fit

(p=0.062; 3.67 mg/kg/day)

No reliable fit

(p=0.062; 2.41 mg/kg/day)

Female Brain 3.35 mg/kg/day 2.14 mg/kg/day

MRID 46484501

28-Day Dermal 

Toxicity Study 

Male RBC 3.15 mg/kg/day 2.12 mg/kg/day

Female RBC 3.65 mg/kg/day 2.54 mg/kg/day

MRID 48146702

28-Day Inhalation 

Toxicity Study 

Male RBC 0.42 ug/L/day 0.34 ug/L/day

Female RBC 0.71 ug/L/day 0.49 ug/L/day

MRID 48146702

28-Day Inhalation 

Toxicity Study 

Male Brain 0.68 ug/L/day 0.61 ug/L/day

Female Brain No reliable fit

(p=0.01; 0.67 ug/L/day)

No reliable fit

(p=0.01; 0.62 ug/L/day)
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Appendix 3. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for the food use for Dicrotophos are in Table A.1. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

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

870.3200 21/28-Day Dermal.........................................................

870.3250 90-Day Dermal..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

yes

yes

yes

yes

870.3700a Developmental Toxicity (rodent) ..................................

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

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

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

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

870.4300 Chronic/Oncogenicity ...................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

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

870.6100b 90-Day Neurotoxicity (hen) ..........................................

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

870.6200b 90-Day Neurotoxicity Screening Battery (rat) ..............

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

CR

no

yes

yes

CR

yes

yes

yes

870.7485 General Metabolism ......................................................

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

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

yes

CR

yes

yes

yes

yes

Special Studies 

Comparative Cholinesterase (rat) ...............................

In vitro dermal penetration (human)...........................

-

-

yes

yes
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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Dicrotophos

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

870.1100 Acute oral - Rat 00156063/

43893901

M/F LD50 = 11/8 

mg/kg

I

870.1200 Acute dermal - Rabbit 00156063 M/F LD50

876/476 = mg/kg

II

870.1300 Acute inhalation -Rat 46411001 LC50 > 0.059 mg/L I

870.2400 Acute eye irritation - Rabbit 00156063 Lesions reversed

by 14 days

II

870.2500 Acute dermal irritation - Rabbit 00156063 Non-irritating IV

870.2600 Skin sensitization – guinea pig 00156063 Strong sensitizer —

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Dicrotophos

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral toxicity 

rodents

See Subchronic 

Neurotoxicity study 

870.6200b

870.3150 180-Day oral 

toxicity in

nonrodents

00013441 

870.3200 21-Day dermal 

toxicity rats

45378201 (2001)

0, 2, 5, 10, or 80 mg/kg/day

Dermal and systemic NOAEL > 80 mg/kg/day

Dermal and systemic LOAEL was not established

Cholinesterase Inhibition NOAEL = Not established

Cholinesterase Inhibition LOAEL = 2 mg/kg/day 

based on decreased erythrocyte cholinesterase 

activity in male rats and decreased plasma 

cholinesterase activity in female rats.

Acceptable/Guideline

870.3700a Prenatal 

developmental in 

rodents

00161578 (1986)

0, 0.1, 0.5, 1.0, or 2.0 

mg/kg/day

Maternal toxicity NOAEL = 0.5 mg/kg/day.

Maternal toxicity LOAEL = 1.0 mg/kg/day based on 

decreased body weight gain and fasciculations

Developmental toxicity NOAEL = 2.0 mg/kg/day 

(highest dose tested)

Developmental toxicity LOAEL = Not established

Acceptable/Guideline

870.3700b Prenatal 

developmental in 

(New Zealand 

White) rabbits

45390701 (2001) 

0, 0.5, 1.0, or 2.0 mg/kg/day

Maternal toxicity NOAEL = 0.5 mg/kg/day.

Maternal toxicity LOAEL = 1.0 mg/kg/day based on 

clinical signs of toxicity 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Dicrotophos

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Developmental toxicity NOAEL = Not established

Developmental toxicity LOAEL = 0.5 mg/kg/day 

based on decreased male and female fetal body 

weights.

Acceptable/Guideline

870.3800 Reproduction and 

fertility effects

(Alpk:APfSD) rats

44296101 (1997)

0, 0.5, 5.0 or 10/15/25 ppm 

for two generations

F0 males: 0, 0.5, 0.49, and 

2.53 mg/kg/day; F0 females: 

0, 0.5, 0.53, and 2.79

mg/kg/day; F1 males: 0, 0.5, 

0.56, and 1.15 mg/kg/day; F1

females: 0, 0.6, 0.59, and 

1.25 mg/kg/day dicrotophos

(87.65% ai) (dietary) 

Parental/Systemic NOAEL = 0.5 ppm (F0

males/females: 0.5/0.5 mg/kg/day; F1 males/females: 

0.5/0.6 mg/kg/day).

Parental/Systemic LOAEL = 5.0 ppm

Reproductive NOAEL = 0.5 ppm (F0 males/females: 

0.5/0.5 mg/kg/day; F1 males/females: 0.5/0.6

mg/kg/day).

Reproductive LOAEL = 5.0 ppm

Acceptable/Guideline

870.4100b Chronic toxicity 

dogs

44328401 (1997) 

0, 0.025, 0.1 or 1.0/0.5 

mg/kg/day for one year. 

High-dose dogs received 1.0 

mg dicrotophos/kg/day for 

13 weeks, after which they 

were not dosed for 7 days, 

and were then given 0.5 

mg/kg/day from week 15-52. 

NOAEL = 0.025 mg/kg/day

LOAEL = 0.1 mg/kg/day based on decreased body 

weight gain (26%; weeks 1-52) and food efficiency 

in females.

Cholinesterase Inhibition NOAEL = 0.025 

mg/kg/day

Cholinesterase Inhibition LOAEL = 0.1 mg/kg/day 

based on statistically significantly decreased brain 

and plasma ChE.

Acceptable/Guideline

870.4200a Chronic toxicity/

Carcinogenicity

rat

44527802 (1998)

0, 0.5, 5 or 25 ppm (0, 0.02, 

0.25 or 1.42 mg/kg/day for 

male rats and 0, 0.03, 0.32, 

or 1.72 mg/kg/day for female 

rats. 

NOAEL = 0.5 ppm (0.02 mg/kg/day for males and 

0.03 mg/kg/day for females).

LOAEL = 5 ppm (0.25 mg/kg/day for males and 

0.32 mg/kg/day for females) based on decreased 

survival in male rats, and aspiration pneumonia and 

esophageal luminal dilatation in female rats.

Cholinesterase Inhibition NOAEL = Not established

Cholinesterase Inhibition LOAEL = 0.5 ppm (0.02 

mg/kg/day for males and 0.03 mg/kg/day for 

females) based on statistically significantly 

decreased brain, erythrocyte and plasma ChE.

No evidence of carcinogenicity was observed in rats 

fed dicrotophos at dietary concentrations of 0.5, 5, or 

25 ppm for 97-100 weeks for males and 105 weeks 

for females. 

Acceptable/Guideline

870.4200b Carcinogenicity

mice

44527801 (1) NOAEL = 10/2 ppm (1.12/0.31 mg/kg/day) for 

males/females, respectively.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Dicrotophos

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

0, 2, 10, or 50 ppm (0, 0.22, 

1.12, or 6.42 mg/kg/day for 

males and 0, 0.31, 1.58, or 

9.06 mg/kg/day for females)

for up to 2 years.

LOAEL = 50 ppm (6.42 mg/kg/day) for males based 

on neurological signs, kidney toxicity and thyroid 

follicular cell adenomas. 

LOAEL = 10 ppm (1.58 mg/kg/day) for females 

based on decreased survival rate. 

Treatment for up to 105 weeks with dicrotophos 

resulted in a significant increase in 

Acceptable/Guideline

870.6100b Delayed 

Neurotoxicity Study 

Hen

44943901, 45170201 (1999) 

Single oral gavage dose of 11 

mg/kg

Oral administration of dicrotophos at 11 mg/kg does 

not produce delayed neuropathy in the hen.

870.6200a Acute 

Neurotoxicity 

Rat (Oral gavage)

43759801 (1995)

0, 0.5, 5, or 10 mg/kg

NOAEL = 0.5 mg/kg

LOAEL = 5 mg/kg based on clinical signs 

(principally decreased activity, upward curvature of 

spine, pinched in sides, flaccid appearance and 

decreased pupil response).

Acceptable/Guideline

870.6200b Subchronic 

Neurotoxicity

Rat (Oral dietary)

43980201 (1995)

0, 0.5, 5, or 25 ppm (0, 0.04, 

0.39, and 2.03 mg/kg/day in 

males and 0, 0.04, 0.45, and 

2.38 mg/kg/day in females)

Systemic NOAEL = 25 ppm (2.03 and 2.38 

mg/kg/day in males and females, respectively)

Systemic LOAEL = 5 ppm (0.39 and 0.45 mg/kg/day 

in males and females, respectively), based on 

changes in motor activity and body weight decreases 

in both sexes.

Cholinesterase Inhibition NOAEL = Not determined

Cholinesterase Inhibition LOAEL = 0.5 ppm (0.04 

mg/kg/day) based on cholinesterase inhibition in 

brain, plasma, and erythrocytes.

Acceptable/Guideline

870.6300 Developmental 

Neurotoxicity 

Rat (Oral gavage)

46153202 (2003)

0, 0.01, 0.05, or 0.4 

mg/kg/day from GD7 

through parturition to 

lactation day 7.

Pups 0, 0.01, 0.05, or 0.4 

mg/kg/day from PND 8 to 22

Maternal systemic NOAEL ≥0.4 mg/kg/day (highest 

dose tested).

Maternal systemic LOAEL = Not identified

Offspring systemic NOAEL = Not established

Offspring systemic LOAEL = 0.4 mg/kg/day based 

on morphometric changes in the brain of male and 

female offspring on PND 12.

Acceptable/Nonguideline

870.7485 Metabolism and 

pharmacokinetics

43942001 (1996)

Labeled dicrotophos 

administered to CD rats via 

In a 96-hour rat metabolism study (MRID 

43942001), [3-

14C]dicrotophos (98.9% ai) was 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Dicrotophos

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

gavage as a single dose at 0.5 

or 3 mg/kg or as a single 

dose at 0.5 mg/kg following 

a 14-day pretreatment with 

unlabeled dicrotophos at 0.5 

mg/kg/day. 

administered to male and female CD rats (5 or 7 

animals/sex/dose) by gavage as a single dose at 

levels of 0.5 or 3 mg/kg, or as a single dose at 0.5 

mg/kg following a 14-day pretreatment with 

unlabeled dicrotophos at 0.5 mg/kg/day. Five 

additional rats/sex received a single 0.5 mg/kg 

intravenous dose in a 96-hour study.

[

14C]Dicrotophos was rapidly absorbed by male and 

female rats following oral and intravenous dosing. 

The orally and intravenously administered 

radioactivity was quantitatively recovered from each 

dosing regimen; total recovery was 97-99% of the 

dose. There was no difference in the relative pattern 

of excretion between male and female rats and no 

appreciable difference among dose levels or routes. 

Greater than 80% of the radioactivity was recovered 

in urine during the first 24 hours from all dose 

groups, and after 96 hours 83-88% was excreted in 

urine and feces. Volatile radioactive products 

accounted for 5-7% of the radioactivity. Only 1.1-

2.6% of the dose was in the tissues/carcass. Liver 

had the highest percentage of the dose at 0.07-

0.09%. The concentration of radioactivity was 

highest in fat: 0.014-0.018 ppm for single oral and 

intravenous low doses, 0.023-0.033 ppm for the oral 

repeated low dose, and 0.106-0.124 ppm for the 

single oral high dose. 

Dicrotophos metabolites were investigated in Day-1 

urine. The results indicated that dicrotophos is 

extensively metabolized via N-demethylation and 

oxidation of the N-methyl moiety yielding intact 

organophosphate products, which may be 

dealkylated. Metabolism may also proceed via 

demethylation and dealkylation of the phosphate 

moiety forming various acetoacetamide and 

acetobutamide products. Twenty-one metabolic 

components were identified, including parent, 19 

Phase 1 metabolites, and one conjugate. 

Characterized metabolites exceeded 83% of the dose. 

Un-metabolized dicrotophos accounted for 3-7% of 

the doses. Hydroxydicrotophos accounted for up to 

20% of the dose and monocrotophos accounted for 

up to 3%. Other intact organophosphates, numerous 

acetoacetamide and acetobutamide products, and one 

conjugate, N-acetylmonocrotophos were identified, 

but were not separately quantified.

Acceptable/Guideline

870.7800 Immunotoxicity 48404101 (2011) Immunotoxicity NOAEL = 25 ppm (1.91 mg/kg/day)
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Dicrotophos

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Oral diet 0, 5, 15, or 25 ppm 

(0, 0.37, 1.14, or 1.91 mg/kg 

bw/day). 

Immunotoxicity LOAEL = Not established (> 25 

ppm)

Systemic NOAEL = 25 ppm (1.91 mg/kg/day)

Systemic LOAEL = 5 ppm (0.37 mg/kg/day) based 

on statistically significant depression in both 

erytrhocytes and brain cholinesterase activity. 

Acceptable/Guideline

Comparative 

Cholinesterase

Rat

46153205- single oral gavage 

dose of 0 or 5 mg 

dicrotophos

46153204- single oral gavage 

dose of 0, 0.008, 0.02, 0.08, 

0.4, or 1.0 mg/kg/day, 

46153207-repeated dose 

exposure via oral gavage of 

0, 0.008, 0.02, or 0.4 

mg/kg/day for 4 weeks

46153208 – repeated dose 

exposure via oral gavage of 0 

or 0.4 mg dicrotophos for 4 

or 8 weeks.

For repeated oral exposure to dicrotophos, the 

overall adult LOAEL for cholinesterase inhibition is 

0.4 mg/kg/day based on brain and red blood cell; the 

NOAEL is 0.08 mg/kg/day. 

For repeat oral exposure to dicrotophos, the overall 

offspring LOAEL is 0.08 mg/kg/day based on brain 

and RBC; the NOAEL is 0.02 mg/kg/day. 

Acceptable/Nonguideline

In Vitro Dermal 

Penetration

Rat and Human skin

45099502 (1999) The invitro study results show that rat epidermis is 

more permeable than human epidermis.

Acceptable/Nonguideline

PoD Conversion Calculations

As summarized in Section 4.5.4, inhalation and dermal PoDs were derived using the following conversion 

calculations: 

Inhalation BMDL10

0.00062 mg/L/day (Female Brain AChE result from BMD modeling summarized in Appendix 1). 

This value is converted to mg/kg/day using the equation: 

mg/L x absorption x duration x conversion factor x activity factor 

Absorption - ratio of deposition and absorption in the respiratory tract compared to absorption by the oral route = 1

Duration – duration of daily animal or human exposure (hr) = 6 hrs

Conversion factor – a L/hr/kg factor which accounts for respiratory volume and BW for a given species and strain = 

43.5 L/hr/kg
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Activity factor – accounts for increased exposure resulting from increased respiration (default is 1). 

Therefore, the mg/kg/day value is: (0.00062 mg/L/day x 1 x 6 hrs x 43.5 L/hr/kg x 1 = 0.162 mg/kg/day

Inhalation BMD10

Similarly, the Inhalation BMD10 is derived using the 0.0007 mg/L/day result (Female Brain AChE result from 

BMD modeling summarized in Appendix 1). This value is converted to mg/kg/day using the same equation above:

(0.00067 mg/L/day x 1 x 6 hrs x 43.5 L/hr/kg x 1 = 0.175 mg/kg/day. 

Dermal Human Adjusted Point of Departure

9.33 mg/kg/day POD is derived by multiplying the rat PoD of 2.1 by 4.44 (comparison of human to rat absorption): 

(2.1mg/kg/day) (4.44) = 9.33 mg/kg/day. 
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A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Dietary Reference Dose (aRfD) – All Populations

Study Selected: Comparative Cholinesterase (CCA) Acute Studies in Rats– Single Dose

MRID No.: 46153205; 46153206

Dose and Endpoint for Risk Assessment: A BMDL10 of 0.07 mg/kg/day associated with brain 

ChE inhibition in male and female pups was selected as a suitable PoD for the acute dietary (all 

populations) exposure scenario. The corresponding BMD10 was 0.08 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: Brain cholinesterase inhibition was 

selected for the PoD since the brain is a principal target organ for organophosphate pesticides, 

and the brain ChE data was more robust than RBC ChE data. Data from the PND 8 and 15 pups 

represent highly exposed sub-populations (infants and young children) and thus are appropriate 

for PoD derivation. An uncertainty factor of 100X (10X to account for interspecies extrapolation 

and 10X for intraspecies variation) is applied to the BMDL10 to obtain an aRfD of 0.0007

mg/kg/day. Based on the FQPA safety factor of 1X, the acute population adjusted dose (aPAD) 

is 0.0007 mg/kg/day.

Acute RfD (All Populations) = aPAD= (BMDL10) 0.07 mg/kg = 0.0007 mg/kg

 (UF) 100

A.3.2 Steady State Reference Dose (ssRfD) –All Populations 

Study Selected: Comparative Cholinesterase (CCA) Repeat Dose Studies in Rats

MRID No.: 43980201; 44527802

Dose and Endpoint for Risk Assessment: A BMDL10 of 0.03 mg/kg/day associated with brain 

ChE inhibition in male and female adult rats was selected as a suitable PoD for the steady-state 

dietary (all populations) exposure scenario. The corresponding BMD10 was 0.04 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: The available AChE data at 

durations of 21 days and longer in adult rats (from the OP CRA) were extracted from the 

subchronic neurotoxicity study and the chronic study in rats. An uncertainty factor of 100X 

(10X to account for interspecies extrapolation and 10X for intraspecies variation) is applied to 

the BMDL10 to obtain a ssRfD16 of 0.0003 mg/kg/day. Based on the FQPA safety factor of 1X, 

the steady-state population adjusted dose (ssPAD) is 0.0003 mg/kg/day.

ssRfD (All Populations)= ssPAD = (BMDL10) 0.03 mg/kg/day= 0.0003 mg/kg/day

 (UF) 100

A.3.4 Incidental Oral Exposure (Single Day)

Study Selected: Comparative Cholinesterase (CCA) Acute Study in Rats– Single Dose

 

16 ssRfD: Reference dose derived from steady state duration
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MRID No.: 46153205

Dose and Endpoint for Risk Assessment: A BMDL10 of 0.07 mg/kg/day associated with brain 

ChE inhibition in male and female pups was selected as a suitable PoD for assessing the potential 

risk associated with incidental oral exposure from a single day exposure scenario. The 

corresponding BMD10 was 0.08 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: Brain cholinesterase inhibition was 

selected for the PoD since the brain is a principal target organ for organophosphate pesticides, 

and the brain ChE data was more robust than RBC ChE data. Data from the PND 8 and 15 pups 

represent highly exposed sub-populations (infants and young children) and thus are appropriate 

for PoD derivation. The total UF is 100X (10X to account for interspecies extrapolation and 

10X for intraspecies variation). 

A.3.5 Incidental Oral Exposure (Steady State)

Study Selected: Comparative Cholinesterase (CCA) Acute Study in Rats– Single Dose

MRID No.: 

Dose and Endpoint for Risk Assessment: For the purpose of assessing potential risk associated 

with incidental oral exposure from steady state durations, OPP selected the dose (PoD) and 

endpoint from the OP CRA (USEPA, 2002 and 2006). A BMDL10 of 0.03 mg/kg/day associated 

with brain ChE inhibition in adults was selected as a suitable PoD for assessing the potential risk 

associated with incidental oral exposure at steady-state. The corresponding BMD10 was 0.04 

mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: These values do not represent the 

sub-populations of interest (infants, toddlers, young children) for incidental oral exposure. 

However, the results of repeated dosing studies in juvenile rats (PND 12-18) are similar to those 

in adults. Thus data from adults are protective of any effects in the young. 

The total UF is 100X (10X to account for interspecies extrapolation and 10X for intraspecies 

variation). 

A.3.6 Dermal Exposure (Single Day and Steady State)

Study Selected: 28-day Dermal Toxicity Study

MRID No.: 46484501; 45099502

Dose and Endpoint for Risk Assessment: A BMDL10 of 2.1 mg/kg/day associated with brain 

ChE inhibition in adult rats, following dermal exposure, was selected as a suitable PoD for 

assessing the potential risk associated with dermal exposure (single day and steady-state). The 

corresponding BMD10 was 3.3 mg/kg/day. A refined dermal equivalent dose (RDD) for human 

skin was derived using data from an in vitro human and rat epidermis absorption study (MRID 

45099502) to account for differences in skin permeability across species. 

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 (%)
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Using the equation above, the PoD derived from the 28-day dermal rat toxicity study can be 

adjusted to account for higher skin permeability compared to human skin. Therefore, the human 

adjusted dermal dose for use as the PoD is 9.33 mg/kg/day17. The calculations are shown in 

Table 4.5.1.

Comments about Study/Endpoint/Uncertainty Factors: A dermal study that measures AChE

inhibition after a single exposure is not available for dicrotophos. Therefore, the 28-day dermal

study is the only study available and was used for both the single day and the steady-state dermal 

assessment. The total UF is 100X (10X to account for interspecies extrapolation and 10X for 

intraspecies variation). 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.

A.3.7 Inhalation Exposure (Single Day and Steady State) 

Study Selected: 28-day Inhalation Toxicity Study

MRID No.: 48146702

Dose and Endpoint for Risk Assessment: A BMDL10 of 0.62 μg/L/day or 0.00062 mg/L/day 

associated with brain ChE inhibition in female rats, following inhalation exposure, was selected 

as a suitable PoD for assessing the potential risk associated with inhalation exposure (single day 

and steady-state). The corresponding BMD10 was 0.67 μg/L/day or 0.00067 mg/L/day.

Comments about Study/Endpoint/Uncertainty Factors: An inhalation study that measures

AChE inhibition after a single exposure is not available for dicrotophos. Therefore, the 28-day 

inhalation study is the only study available and was used for both the single day and the steadystate inhalation assessment. The particle size distribution from this study suggests that most 

particles were well below the respirable range for an aerosol (1-3 μm), suggesting that the 

exposure was mainly via a gas. A human equivalent concentration (HEC) was not generated 

from this study based on the following conditions: 1) exposure was via gas and not particles thus 

resulting in an RGDR instead of RDDR; and 2) the effects observed were only systemic (AChE 

inhibition) without portal of entry effects (e.g., irritation). Concentrations were not adjusted for a 

continuous exposure basis as is done for an HEC. 

 For steady state inhalation exposures, a total uncertainty factor of 100X was applied (10X for 

interspecies uncertainty factor and 10X for intraspecies variability and a 1X FQPA SF).

 

17 9.33 mg/kg/day is derived by multiplying the rat PoD of 2.1 by 4.44 (2.1x4.44 =9.33)
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A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity – Rat 

See Subchronic Neurotoxicity study 870.6200b [MRID 43980201]

870.3150 90-Day Oral Toxicity – Non-Rodent [00013441]

[TBA]

870.3200 21/28-Day Dermal Toxicity – Rat

In a repeated dose dermal toxicity study (MRID 45378201), groups of 10 male and 10 female 

Crl:CD(SD)BR rats received applications of 0, 2, 5, 10, or 80 mg/kg/day Dicrotophos (87.6%, 

Batch No. 403001B) in deionized water, 6 hours/day for 21 days in a 28-day period. Additional 

groups of 5 male and 5 female rats were assigned to each dose level and designated as satellite 

animals for assessment of brain, erythrocyte, and plasma cholinesterase activity.

There were no deaths, clinical signs, dermal, hematology or clinical chemistry, opthalmological 

or gross or histopathological effects attributable to treatment. No treatment-related body weight 

or food consumption effects were observed and there were no treatment-related effects on organ

weight. No treatment-related Functional Observational Battery (FOB) or motor activity effects 

were noted. 

There was a decrease in brain cholinesterase activities in males and females in hte 10 mg/kg/day 

(males: p<0.01, 27% decrease; females p<0.05, 26% decrease) and 80 mg/kg/day (males : 

p<0.01, 57% decrease; females p<0.01, 65% decrease) treatment groups compared to controls. 

Erythrocyte cholinesterase activities were decreased for males in all treatment groups (p<0.01, 

11-46% decrease) and for females at 5 (p<0.05, 16% decrease, 10 (p<0.01, 23% decrease, or 80 

(p<0.01, 57% decrease) mg/kg/day compared to controls. Plasma cholinesterase activities were 

decreased for females in all treatment groups (p<0.01, 38-70% decrease) and for males at 10 

(p<0.05, 16% decrease) or 80 mg/kg/day (p<0.01, 35% decrease). 

The dermal and systemic NOAEL for Dicrotophos in rats are >80 mg/kg/day. The dermal 

and systemic LOAELs were not identified. The NOAEL for cholinesterase inhibition is not 

identified and the LOAEL for cholinesterase inhibition is 2 mg/kg/day based on decreased 

erythrocyte cholinesterase activity in male rats and decreased plasma cholinesterase 

activity in female rats. 

This study is classified as Acceptable/Guideline and does satisfy the guideline requirements for 

a repeated-dose dermal study [OPPTS 870.3200 (§82-2)] in rats.

870.3465 Subchronic Inhalation – Rat
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In a subchronic inhalation toxicity study (MRIDs # 48146702 & 48146701), dicrotophos (88.9% 

purity; batch/lot # GB101309-01) was administered to 4 groups of Cr1:CD® (SD) rats 

10/sex/concentration by dynamic nose only exposure at concentrations of 0, 0.1, 0.75, or 3.0 

μg/L for 6 hours per day, 5 days/week for a total of 20 days. 

There were no compound related effects in mortality, clinical signs, body weight, food 

consumption, hematology, clinical chemistry, organ weights, or gross and histologic pathology. 

Biologically significant, dose-related reductions in erythrocyte (M: ↓ 79%, F: ↓ 81% for the 0.75 

μg/L and M: ↓ 48%, F: ↓ 64% for the 3.0 μg/L dose) and brain cholinesterase activity (M: ↓ 

89%, F: ↓ 85% for the 0.75 μg/L and M: ↓ 65%, F: ↓ 62% for the 3.0 μg/L dose), were observed 

in both sexes exposed to 0.75 and 3.0 μg/L, respectively.

The LOAEL is 0.75 μg/L /day, based on biologically significant reductions in erythrocyte and 

brain cholinesterase activity in both sexes. The NOAEL is 0.1 μg/L /day.

This subchronic inhalation toxicity study in the rat is Acceptable, Non-guideline and dose not 

satisfy the guideline requirement for a subchronic inhalation study OPPTS 870.3465; OECD 413 

in the rat. The study animals were exposed to the test material over 20 days only, while OPPTS 

870.3465; OECD 413 requires 90 days of exposure.

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRID 00161578), 25 presumed pregnant Charles River Crl: 

CD(SD)BR rats per group were administered 5 mL/kg/day dicrotophos (89.7% a.i.) in water 

once daily, orally by gavage, at dosage levels of 0 (sterile water vehicle), 0.1, 0.5, 1.0, or 2.0 

mg/kg/day, on gestation days 6 through 15 inclusive. Animals were observed daily (30 minutes 

and 2 hours following dose administration) and body weights and food consumption recoreded 

on pre-treatment day 0, on treatment days 6, 9, 12, and 15, and on post-treatment days 18 and 20. 

On GD 20, dams were sacrificed, subjected to gross necropsy, and all fetuses examined

externally. Approximately one-half of each litter was processed for visceral examination and the 

remaining one-half was processed for skeletal examination.

All animals survived to terminal sacrifice. Significant levels of fasciculations were recorded in

the 1.0 and 2.0 mg/kg groups, in 20 and 25 animals, respectively. Additionally, dams in the 2.0 

mg/kg group exhibited tremors (20 animals), decreased limb tone (18 animals), gritting of teeth 

(15 animals), tachypnea (excessive, shallow breathing, 5 animals), and salivation (12 animals). 

Peak toxicological effects were observed generally 2 hours after dosing. Animals in the 2.0 

mg/kg group also had increased levels of yellow urogenital staining, soft stool and dried red 

matter around the eyes and nose (respectively, in 14, 10, and 9 animals). 

Significant mean body weight losses occurred in the two highest groups, 1.0 and 2.0 mg/kg, 

especially during the first three days of compound administration. 
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No clinical signs of toxicity were observed in any animal. Maternal body weights, body weight 

gains, and food consumption were similar between the treated and control groups throughout the 

study. Maternal necropsy was unremarkable.

Therefore, the maternal toxicity NOAEL is 0.5 mg/kg/day and the maternal toxicity 

LOAEL is 1.0 mg/kg/day, based on decreased body weight gain and fasciculations.

No differences were observed between the treated and control groups for number of corpora 

lutea, number of implantation sites, live fetuses/dam, pre- and post-implantation losses, fetal 

body weights, or fetal sex ratios.

No treatment-related external, visceral, or skeletal malformations/variations were observed in 

any fetus from any group.

Therefore, the developmental toxicity NOAEL is 2.0 mg/kg/day and the developmental 

toxicity LOAEL was not identified.

This study is classified as Acceptable/Guideline and satisfies the requirements for a 

developmental toxicity study [OECD 870.3700 (§83-3a)] in rats.

870.3700a Prenatal Developmental Toxicity Study - Rat

In a developmental toxicity study (MRID 00263684), five groups of Sprague-Dawley (Charles 

River Crl: CD [SD] Br) mated female rats (25/group) were administered single doses of 5 

mL/kg/day test article (Bidrin technical, 89.7% a.i.) orally by gavage at levels of 0 (sterile water 

vehicle), 0.1, 0.5, 1.0, or 2.0 mg/kg/day from (presumed) gestation day 6 through 15 inclusive, 

and survivors sacrificed on gestation day 20. 

Prior to conducting the main developmental toxicity study, a preliminary dose-selection

investigation was performed, using 6 oral dosage levels (0, 0.5, 1.0, 5.0, 10.0 and 15.0 

mg/kg/day) administered by gavage to groups of 8 mated Crl: CD[SD]Br females each from 

gestation days 6 through 15. Twenty-three animals died, one to seven days after beginning 

treatment: 7/8 of the 5.0 mg/kg/day group, and all 8 of both 10.0 and 15.0 mg/kg/day groups. 

Numerous clinical signs of compound (OP) toxicity were evident in these animals. The single 

survivor on 5.0 mg/kg/day lost weight and ate less during the study, and at scheduled necropsy 

(day 20) was found to have viable fetuses, apparently normal according to gross fetal 

examination. Animals of the second lowest dose group (1.0 mg/kg/day) manifested 

fasciculations (muscle twitching) 30 minutes following dosing, beginning on gestation day 14. 

No changes from control were noted at the LDT, 0.5 mg/kg/day group on fetal intrauterine 

survival, sex ratio, mean fetal weights, or gross examination. Based on these results, dose levels, 

as indicated above, for the definitive study were selected.

During the definitive study, animals were observed daily, and body weights and food 

consumption recorded periodically . Gross clinical, reproductive and fetal parameters were 

recorded at termination. One-half of each fetal litter was examined for soft tissue anomalies and 
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fetal kidneys graded for renal papillar development, while the remainder of each litter was 

prepared for skeletal examination; fetal values were reported both individually as well as by 

litter. Statistical analyses were conducted on all relevant data sets.

No dams died, aborted or delivered spontaneously during the course of the study, but significant 

levels of fasciculation were recorded at 1.0 and 2.0 mg/kg/day (respectively, in 20 and 25 

animals), as well as significant mean body weight losses and decreased food consumption (the 

latter recovered to control levels during the post-treatment period, days 16 through 20, 

Additionally at the HDT, 20/25 dams had tremors, 18/25 decreased limb tone, 15/25 gritting of 

the teeth, while shallow breathing was observed in 5/25, and salivation in 12. Finally, urogenital 

staining, soft stool and dried red ocular/nasal matter were common in HDT animals. No gross 

pathological changes attributable to test article were revealed; incidental findings unrelated to 

treatment were described in a small number of animals at all doses.

No compound-related adverse embryotoxic/fetotoxic effects in test animals compared to water 

controls were recorded for any fetal parameter. Gross external and/or visceral malformations 

were recorded in a few fetuses from different litters, equally distributed over the five dosage 

groups, while skeletal examinations revealed minor changes unremarkably similar in all groups 

(including controls).

Thus the maternal NOAEL in this rat study appears to be 0.5 mg/kg/day, and the maternal 

LOAEL for clinical toxicity 1.0 mg/kg/kg, while the developmental (fetal) NOAEL is 2.0 

mg/kg/day, with the LOAEL greater than the HDT.

This study is classified as Acceptable/Guideline and satisfies the requirements for a developmental toxicity study [OECD 870.3700 (§83-3a)] in rats.

870.3700b Prenatal Developmental Toxicity Study – Rabbit

In a developmental toxicity study (MRID 45390701), 28 presumed pregnant New Zealand white 

rabbits per group were administered dicrotophos (86.7% a.i.; Batch No.: 403001B, KB-80-9) 

aqueous solution by gavage at doses of 0, 0.5, 1.0, or 2.0 mg/kg/day on gestation days (GD) 5-

29, inclusive. On GD 30, all surviving does were sacrificed and the uteri were weighed and 

examined. All fetuses were examined for visceral anomalies by fresh dissection, sexed and 

eviscerated. One-half of the fetuses in each litter were fixed in 70% methylated spirits; after 

24 hours, the heads were sectioned along the fronto-parietal suture line for examination of the 

brain. The remaining fetuses were decapitated and the bodies fixed in 70% methylated spirits 

and the heads fixed in Bouin’s solution for serial sectioning. All carcasses were then stained for 

skeletal examination. Fetal defects were classified as major, minor, or variant. The degree of 

ossification of the manus and pes were scored on a scale of 1 (good) to 6 (poor). 

Two high-dose animals were sacrificed in extremis on GD 29 due to severity of clinical signs of 

toxicity. One mid-dose doe was sacrificed on GD 30 following signs of abortion. All remaining 

animals survived to terminal sacrifice. Clinical signs of toxicity in the high-dose animals 

included shaking, increased breathing rate, wetness around the nose, mucus in the feces, and 
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diarrhea observed in 23-27 animals, and hunched posture, abnormal respiratory noise, salivation, 

subdued behavior, and staining in the genital area observed in 7-15 animals. In the mid-dose 

group diarrhea and mucus in the feces were observed in 22 and 9 animals, respectively. No 

treatment-related clinical signs of toxicity were observed in the low-dose group.

Covariant analyses based on GD 5 body weight, showed significantly (p  0.05) lower adjusted 

mean weights for the high-dose group on GD 6, 29, and 30 as compared with the controls. The 

body weight gain in the high dose group was decreased (-27%) compared to the controls over the 

entire treatment period (GD 5-29). Contrary to this finding, the adjusted body weight was only 

slightly lower (4%) compared to controls. Therefore, the decreased maternal body weight gain 

in the high dose group possibly resulted from reduced fetal body weights. During the latter part 

of gestation, the high-dose group gained less weight than the controls with weight gain 48% of 

the control level for GD 20-30. Food consumption by the high-dose group was significantly 

(68% of control; p  0.01) less than that of the controls for GD 26-30. Body weights, body 

weight changes, and food consumption in the low- and mid-dose groups were not affected by 

treatment.

No treatment-related lesions were observed in animals that were killed intercurrently. At 

scheduled necropsy, red or black spots on the glandular stomach were seen in 4, 4, 10, and 

7 animals in the control, low-, mid-, and high-dose groups, respectively. Other gross findings 

occurred at a low incidence and were considered incidental to treatment.

Therefore, the maternal toxicity LOAEL for dicrotophos in rabbits is 1.0 mg/kg/day based 

on clinical signs of toxicity and the maternal toxicity NOAEL is 0.5 mg/kg/day.

All treated groups had slightly or significantly (p 0.05 or 0.01) greater numbers of implantations/doe and live fetuses/doe, increased gravid uterine weights, and decreased post-implantation 

losses as compared with the control group. Mean fetal body weights were significantly (p 0.01) 

decreased in the mid- and high-dose groups (8 and 10%, respectively) and were slightly less 

(4%) in the low-dose group than that of the control group. When male and female fetuses were 

analyzed separately, significantly reduced body weights were found for the high-dose males and 

females (p0.01), the mid-dose males (p  0.01), and the low-dose males (p  0.05). The effects 

on fetal body weights in the low-, mid- and high-dose groups are considered to be treatment 

related. 

The total number of fetuses (litters) examined in the control, low-, mid-, and high-dose groups 

was 171(24), 224(25), 239(26), and 196(23), respectively. No treatment-related external, 

visceral, or skeletal malformations/variations were observed in this study.

Therefore, the developmental toxicity LOAEL for dicrotophos in rabbits is 0.5 mg/kg/day 

based on decreased male and female fetal body weights. The developmental toxicity 

NOAEL is not established.

This study is classified as Acceptable/Guideline and does satisfy the guideline requirements for 

a developmental toxicity study [OECD 870.3700 (§83-3b)] in rabbits.
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A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects - Rat

In a multi-generation reproduction study (MRID 44296101), Dicrotophos (87.65% a.i.; Batch 

No. 403001 B) was administered to groups of 26 male and 26 female Alpk:APfSD rats (from the 

Rodent Breeding Unit, Alderley Park) in the diet at concentrations of 0 0.5, 5.0, or 10/15/25 ppm 

for two generations. Two litters were produced in the first generation and one litter was 

produced in the second generation. Premating doses for the adult F0 males were 0.5, 0.49, and 

2.53 mg/kg/day and for the F0 females were 0.5, 0.53, and 2.79 mg/kg/day, respectively. 

Premating doses for the adult F1 males were 0.5, 0.56, and 1.15 mg/kg/dy and for the F1 females 

were 0.6, 0.59, and 1.25 mg/kg/day, respectively. Due to a high mortality in the F1a pups in the 

25 ppm group, the dietary concentration of dicrotophos was lowered to 10 ppm for four dams 

from lactation day 8 through termination of the litter. During mating, gestation, and lactation of 

the F1b litters, high-dose animals were given diets containing 15 ppm. The control, low-, and 

mid-dose F1 pups were weaned onto the same diets as their parents. The F1 pups in the high 

dose group were weaned onto diets containing 10 ppm dicrotophos. Animals were given test or 

control diet for 10 weeks then mated within the same dose group. All animals were exposed to 

test material either in the diet or during lactation until sacrifice.

Clinical signs of toxicity were observed during premating weeks 2-5 as involuntary shaking of 

the limbs in 5/26 F0 males (p<0.05) and 11/16 F0 females (p<0.01) given 25 ppm. No dose- or 

treatment-related clincal signs of toxicity were observed inthe parental F0 or F1 animals given 

diets containing less than 25 ppm. No dose- or treatment-related gross abnormalities were 

observed in the F0 or F1 adults at necropsy; histopathological evaluations were not performed. 

Mid and high-dose F0 males had significantly lower mean body weights as compared to controls 

(p<0.05 or 0.01). Food consumption was significantly (p<0.01) reduced in the high-dose F0

males as compared with controls during premating. Food utilization was significantly (p<0.05 or 

0.01) lower in the mid- and high-dose F0 males as compared with the controls. 

Mid and high-dose F0 females had significantly lower mean body weights than the controls 

during premating (p<0.05 or 0.01). Food consumption by the high-dose F0 females was 

significantly (p<0.01) less at the beginning of premating, but was significantly (p<0.05 or 0.01) 

greater than the controls during latter premating. High-dose F0 females also had significantly 

(p<0.01) lower food utilization at the beginning of premating and then significantly (p<0.05) 

higher food utilization during latter premating weeks as compared with the controls. 

Mean body weights of the mid- and high-dose F1 males were significantly (p<0.01) lower than 

the controls during week 1 of the premating period. Food consumption by the F1 males was 

similar between the treated and control groups throughout the premating period. Food utilization 

was significantly (p<0.05) reduced in the mid- and high-dose groups during early premating. 

Mean body weights of all treated F1 female groups were significantly (p<0.05 or 0.01) lower 

than the controls during week 1 of hte premating period. No statistically significant differences 

in body weights occurred during the remainder of the premating period. In the high-dose F1

females, food consumption was significantly (p<0.05 or 0.01) greater than the controls during 
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most of the premating period and food utilization was significantly (p<0.05) greater during 

weeks 8-10. 

The Systemic Toxicity NOEL is 0.5 ppm and the Systemic Toxicity LOEL is 5.0 ppm based 

on lower body weights in the F0 and F1 males and females and reduced food utilization in 

F0 males and females and F1 males.

High-dose F0 females had significantly (p<0.05 or 0.01) lower body weights than the controls 

during gestation of litter A. No differences in body weights occurred between treated and 

control groups during gestation of litter B. During lactation of litter A, maternal body weights of 

the mid- and high-dose animals were significantly (p<0.05 or 0.01) lower than the controls. 

During lactation of litter B, maternal body weights of the mid- and high-dose animals were 

significantly (p<0.05 or 0.01) lower than the controls. Food consumption by the treated F0 

groups was greater than the controls during gestation of both the A and B litters with occasional 

statistical significance in the mid- and high-dose groups. In contrast, food consumption by the 

high-dose F0 females was significantly (p<0.05 or 0.01) less than the controls thoughout 

lactation of both litters (68-80%).

No treatment-related differences in body weights were observed in the F1 females during 

gestation. However, all treated F1 groups had significantly (p<0.05 or 0.01) lower maternal 

body weights as compared with the controls during lactation. Food consumption was 

significantly (p<0.01) greater than the controls by the high-dose F1 females throughout gestation 

and once by the mid-dose F1 females. In contrast, food consumption during lactation was 

occasionally significantly (p<0.05 or 0.01) less than the controls in all treated dams.

For the control, low-, mid-, and high-dose F0 adults in production of litter A, the proportion of 

successful matings was 70%, 67.9%, 85.7%, and 33.3% (p<0.01), respectively; the percent of 

live born pups was 97%, 99.2%, 98%, and 90.4% (p<0.05), respectively; and whole litter losses 

were 4/21, 0/19, 5/24, and 8/12 (p<0.05), respectively. Whole litter losses during production of 

litter B were 4/22, 2/18, 6/23, and 10/19 (p<0.05), respectively. Whole litter losses by the F1 

generation were 0/20, 1/23, 2/21, and 6/23 (p<0.05), for the control, low-, mid-, and high-dose 

groups, respectively.

During lactation, no dose- or treatment-related clinical signs of toxicity or differences in pup 

body weights were observed in the offspring of either generation. For both litters produced by 

the F0 animals, there was a significant (p<0.05 or 0.01) decrease in the number of F1 pups/litter 

inthe high-dose group after day 1 of lactation. Pup deaths in the high-dose group resulted in 

significantly lower lactation indices of 56.6% (p<0.01) vs. 88.0% for the controls for litter A and 

75.4% (p<0.05) vs 92.7% for the controls for litter B. The number of F2 pups/litter was 

significantly (p<0.01) decreased due to treatment in the mid- and high-dose groups as compared 

to controls after lactation day 1. Lactation indices for the control, low-, mid-, and high-dose F2 

litters were 96.8%, 94.1%, 83.8% (p<0.05), and 75.6% (p<0.01), respectively.

The Reproductive Toxicity NOEL is 0.5 ppm and the Reproductive Toxicity LOEL is 5.0 

ppm based on a reduced number of F2 pups/litter during lactation. 
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This study is classified as Acceptable/Guideline and satisfies the guideline requirement for 

a reproduction study (OPPTS 870.3800 §83-4) in rats.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

See Carcinogenicity section below.

870.4100b Chronic Toxicity - Dog

In a chronic toxicity study (MRID 44328401), dicrotophos (87.65% w/w, Batch No. 403001 B) 

in corn oil was administered to 4 beagle dogs/sex/dose by capsule at doses of 0 (corn oil only), 

0.025, 0.1, or 1.0/0.5 mg/kg/day for 1 year (high-dose dogs received 1.0 mg dicrotophos/kg/day 

for 13 weeks, after which they were not dosed for 7 days, and were then given 0.5 mg/kg/day 

from week 15-52.

No animals died during the study. Treatment-related clinical signs were seen primarily at the 

high dose before it was lowered to 0.5 mg/kg/day, and were correlated with the inhibition of 

plasma and erythrocyte cholinesterase (ChE) activity. Signs included shaking and subdued 

behavior (2/4 or more dogs/sex during weeks 13-14 and in one female duing week 24); unsteady 

gait (one female at week 13) and a slight increase in the incidence/frequency of fluid feces, 

regurgitation, and vomiting (both sexes). High-dose dogs also resisted dosing and males had 

reddening and peeling of the scrotal skin with sores primarily during the first 14 study weeks. 

Weekly body weights of high-dose males were lower than those of controls (≤ 8.4%; p<0/05) 

several times between weeks 5 and 14, and their week 1-14 body weight gain was 48% of 

controls. After the high dose was lowered, the body weights improved and their overall weight 

gain was greater than of the controls. Weekly body weights of mid- and high-dose females were 

up to 10.3% lower than controls throughout the study (p<0.05 for weeks 6, 7 9, 14, 47, and 49-53 

at one or both doses), and their overall weight gain and food efficiency were 74-78% of controls. 

There were no toxicologically significant differences from the controls for hematology, clinical 

chemistry, urinalysis, or ophthalmoscopic parameters, organ weights, or gross and microscopic 

pathology. No neoplastic lesions attributable to test article administration were reported. 

Based on the 26% lower overall (week 1-52) body weight gain (and food efficiency) in middose females, 0.1 mg/kg/day is concluded to be the LOEL under the conditions of this 

study; the corresponding NOEL is 0.025 mg/kg/day. The reviewer disagrees with the study 

author that the body weight changes at the mid-dose were not toxicologically significant and that 

only the high dose represents a LOEL for body weight changes. 

Plasma, RBC, and brain ChE activities were inhibited by dicrotophos treatment thoughout most 

of the study in both sexes. The degree of inhibition was clearly dependent on the dose but not on 

the exposure duration. At the high-dose, the plasma, RBC, and brain ChE values were 36-64% 

of controls (p≤0.01) and neurologic impairment was clinically evident. At the mid-dose, plasma 

ChE activity ws 55-61% of controls (p≤0.01) in both sexes, RBC ChE activity was 83-91% of 
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controls (p≤0.05 or 0.01 for males only), and brain ChE was 81-88% of controls (p≤0.05 for 

females only). Although there were no visible neurological effects a the mid-dose, because the 

parameter most germane to neurotoxicity, i.e. brain ChE, was statistically significantly 

inhibited in females (19%, p≤0.05), and plasma ChE was substantially inhibited in both 

sexes, the LOEL for ChE inhibition is considered to be 0.1 mg/kg/day, and the NOEL is 

0.025 mg/kg/day. The reviewer disagrees with the study author that the high dose is the LOEL 

for ChE inhibition. 

This chronic oral toxicity study in dogs is classified as Acceptable/Guideline and satisfies the 

guideline requirement for a chronic oral toxicity study [OPPTS: 870.4100b (§83-1b)] in dogs. 

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study - Rat

In a chronic toxicity/carcinogenicity study (MRID 44527802), Dicrotophos (Lot No. 403004B, 

878.65% (E isomer)) was administered to groups of 88 male and 88 female Alpk:ApfSD rats in 

the diet at concentrations of 0, 0.5, 5, or 25 ppm (0, 0.02, 0.25, and 1.42 mg/kg/day for male rats 

and 0, 0.03, 0.32, and 1.74 mg/kg/day for females). Groups of 52 males and 52 females were 

designated for the main study and maintained on the treated food for up to 105 weeks. Groups of 

12 males and 12 females were sacrificed at 52 weeks for interim evaluation at 52 weeks and 

study termination, respectively.

Survival was decreased to 26% in 25 ppm group males at week 97 (compared with 54% for 

controls) prompting termination of this group at this time; survival in the 5 ppm group males was 

only 19% at week 100 (compared with 49% for controls) prompting termination of the remaining 

groups at this time. Survival in females showed a dose-related decrease at study termination (66, 

46, 39, and 29% at 0, 0.5, 5, and 25 ppm, respectively). Numerous treatment-related clinical 

signs related to respiration, gastrointestinal effects, urinary effects, and scabs and sores were 

observed in treated animals, particularly at 25 ppm in one or both sexes. Clinical signs indicative 

of cholinesterase inhibition were observed at 25 ppm in both sexes. 

In 25 ppm group male rats, body weights were less than control weight up to week 90 of 

treatment. Females fed the 5 and 25 ppm diet gained 6-11% more weight than controls during 

the first year and 52-59% less weight than controls during the second year; overall weight gain 

was similar to that of control. Food consumption for both sexes fed the 25 ppm diet exceeded 

that of controls by as much as 17-19% after 4 weeks of treatment. Food utilization (efficiency) 

calculated for the first 12 weeks of the study was decreased by 7% for 25 pm group males and 

was similar to that of controls for 25 ppm group females.

Treatment with 25 ppm caused a mild leukocytosis in both sexes characterized by significantly 

(p<0.01 or <0.05) elevated white blood cell counts (up to 142% of the control value in males and 

179% in females). Statistically significant increases were noted for aspartate and alanine 

aminotransferase activities (up to 153 and 167%, respectively) in 25 pm group male and female 
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rats, but the increases could not be associated with microscopic lesions. Decreases in urine 

volumes for males during the first year (65-72% of control values) and for females throughout 

the study (56-76% of control values) were considered treatment related.

The only gross change considered treatment related were distended esophagus in male and 

female rats at 25 ppm and in female rats at 5 ppm. This lesion was associated microscopically 

with luminal dilatation of the esophagus and aspiration pneumonia. The esophageal lesion 

occurred in 0/51, 1/51, 7/51 (p<0.01) and 12/52 (p<0.01) females and none of the males fed 0, 

0.5, , or 25 ppm. Aspiration pneumonia occurred in 2/52, 4/52, 9/252 (p<0.01), and 21/52 

(p<0.01) females, respectively, and 0/52, 0/52, 1/52, and 5/53 (p<0.05) males, respectively. In 

addition, alveolar macrophage infiltration (probably associated with aspiration of the treated 

food) occurred in 2/52, 3/52, 1/52, and 12/53 (p<0.01) male rats, respectively; and 

atrophy/degeneration of the acinal epithelium in the Harderian gland occurred in 35/52, 30/52, 

36/51, and 49/51 (p<0.01) female rats, respectively. Hepatitis occurred with statistically 

significant increased incidence in males at 25 ppm (12/52 vs 2/52 in controls, p p<0.01).

For chronic toxicity, the LOAEL is 5 ppm (0.25 mg/kg/day for males and 0.32 mg/kg/day 

for females), based on decreased survival in male rats, aspiration pneumonia and 

esophageal luminal dilatation in female rats. The NOAEL is 0.5 ppm (0.02 mg/kg/day for 

males and 0.03 mg/kg/day for females).

Cholinesterase activity was statistically significantly decreased at all dietary levels compared 

with the controls. At week 52 and study termination, respectively, brain cholinesterase activity 

in the 0.5 ppm group animals was inhibited by 19 and 12% for males and 23 and 18% for 

females, erythrocyte cholinesterase activity by 27 and 25% for males and 19 and 39% for 

females and plasma cholinesterase activity by 27 and 25% for males and 19 and 39% for 

females. Only the plasma activity determined at study termination in 0.5 ppm group males was 

not statistically significant.

The LOAEL for cholinesterase inhibition was 0.5 ppm (0.02 mg/kg/day for males and 0.03 

mg/kg/day for females); a NOAEL was not established.

No evidence of carcinogenicity was observed in rats fed dicrotophos at dietary 

concentrations of 0.5, 5, or 25 ppm for 97-100 weeks for males and 105 weeks for females.

The chronic toxicity/carcinogenicity study in the rat is Acceptable/Guideline and satisfies the 

guideline requirements for a chronic toxicity/carcinogenicity oral study (OPPTS 870.4200a; §

83-1;) in rats. A deficiency in male rats was the low survival at study termination; however, 

adequate numbers of animals were alive at 18 months to evaluate late-developing lesions.

870.4200b Carcinogenicity (feeding) - Mouse

In an oncogenicity study (MRID 44527801), Dicrotophos (87.65% a.i., Batch No. 403001 B) 

was administered to groups of 55 male and 55 female C57BL/10JfCD-1® Alpk mice in the diet 

at concentration of 0, 2, 10, or 50 ppm for up to 2 years. These concentrations resulted in a 
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nominal compound intake for each concentration level of 0.22, 1.12, and 6.42 mg/kg/day for 

males; 0.31, 1.58, and 9.06 mg/kg/day for females for low-, mid-, and high-dose, respectively.

Treatment with 50 ppm Dicrotophos resulted in a rapid decrease in survival in females after 

treatment week 86. High-dose females were terminated at week 101 when their survival reached 

25%. Survival of females at 10 ppm also rapidly decreased after about week 100 and was 38% at 

scheduled termination during week 104; 55% of control females survived. There was no 

treatment-related effect on survival in males. Clinical signs observed during treatment only at 50 

ppm included involuntary shaking of the limbs (males, 25%; females, 40%) seen from weeks 2 

to 4, and rigidity and convulsions during handling (males, 13%; females, 29%) seen from week 

39 to 40. Increased numbers of observations of opaque eyes were noted at the high dose in both 

sexes compared to the control groups. Ophthalmoscopic examinations during week 92 showed 

corneal opacities in all groups with a slight increase at the high dose in both sexes (males: 

control, 7%; 50 ppm, 14%, NS; females: control, 26%; 50 ppm, 40%, NS). The incidence of 

opaque eyes was also slightly increased in high-dose mice during gross necropsy (males: control, 

4%; 50 ppm 9%, NS; females: control, 18%; 50 ppm, 33%, p<0.05). Body weights of both sexes 

of mice at 50 ppm were generally up to about 12% lower than that of the controls for the first 12 

weeks of the study but were the same or slightly greater than the controls during the second year

of the study. Overall weight gains were comparable to the controls. The overall food efficiency 

values for the first 12 weeks in males at 50 ppm were about 20% (p<0.01) lower than the control 

values. Decreased food efficiency was not seen in treated females. 

Increases in the incidence and severity of kidney tubular vacuolation were seen upon 

microscopic examination in males at 50 ppm compared to the controls (total incidence: control, 

42%; 50 ppm 71%, p<0.01; lesions graded slight or moderate: control, 4%; 50 ppm, 22%, 

p<0.01). Kidney tubular vacuolation was seen in only 1 female.

The LOAEL is 50 ppm (6.42 mg/kg/day) for males based on neurological signs, kidney 

toxicity and thyroid follicular cell adenomas. For females, the LOAEL is 10 mg/kg/day 

(1.58 mg/kg/day) based on decreased survival rate. The NOAEL was 10 ppm (1.12 

mg/kg/day) for males; and 2 ppm (0.31 mg/kg/day) for females.

Treatment for up to 105 weeks with Dicrotophos resulted in a significant increase in the 

incidence of thyroid follicular cell adenomas in male mice at 50 ppm (control, 0%, 50 ppm 10%, 

p<0.01, Cochran-Armitage, p<0.05, Fishers exact test). Male mice had significant increasing 

trend at p<0.01, and a significant difference in the pair-wise comparison of the 50 ppm dose 

groups with the controls at p<0.05, for thyroid follicular cell adenomas. The incidence of thyroid 

adenomas was not increased in females. 

The CARC concluded that under the Draft Cancer Risk Assessment Guidelines (July 2, 1999), 

there is "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic 

potential". The evidence from animal data is suggestive of carcinogenicity, which raises a 

concern for carcinogenic effects, but is judged not sufficient for a conclusion as to human 

carcinogenic potential.
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The study is classified as Acceptable/Guideline and satisfies the guideline requirements for a 

carcinogenicity toxicity study in mice (OPPTS 870.4200; §83-5).

A.4.6 Mutagenicity

Mutagenicity Studies with Dicrotophos

Gene Mutation

870.5100

Salmonella/Escherichia

bacterial reverse 

mutation assay

43603301(1994)

and 5000.0 μg/plate in the 

presence and absence of 

mammalian metabolic 

activation (S9-mix)

Strains TA98, TA100, TA1535, TA1537, and TA 1538 of S. 

typhimurium were exposed to dicrotophos in vehicle from 

concentrations of 6.7 to 5000.0 μg/plate in the presence and 

absence of mammalian metabolic activation (S9-mix). There 

was no evidence of induced mutant colonies over 

background.

Acceptable/Guideline

Gene Mutation

870.5300

mammalian cell gene 

mutation assay in 

cultures of mouse 

lymphoma (L5178Y) 

cells

43591401 (1995)

concentrations of 0, 100, 

500, 750, 1000, 2000, or 

3000 μg/mL in the 

presence and absence of 

mammalian metabolic 

activation (S9-mix).

Dose-dependent and reproducible gene mutation was 

recorded in both the presence and absence of S9 activation at 

non-toxic doses of 750 μg/ml up to the cytotoxic HDTs, 

2000-3000 μg/ml. 

Acceptable/Guideline

Cytogenetics 870.5395 

Micronucleus assay in 

mouse bone marrow 

cells

43603302 (1994)

Doses of 1.7, 3.3, and

6.6 mg/kg body weight

Mice were administered single doses of Dicrotophos by i.p. 

injection, and bone marrow sampled for the presence of 

micronuclei in polychromatic erythrocyte. No increased 

incidences of micronuclei were found at doses up to a 

severely toxic level (6.6 mg/kg).

Acceptable/Guideline

A.4.7 Neurotoxicity

870.6100b Delayed Neurotoxicity Study – Hen

In a delayed neurotoxicity range-finding study (MRID 44943901), groups of 5 domestic hens 

were administered 0, 3, 5, 7, 9, 11, 15, or 20 mg/kg of dicrotophos (87.2% purity; Lot no. 

8070030051) by gavage and observed for 7 days. The LD50 was 11 mg/kg with confidence 

limits of 9 and 15 mg/kg. As part of this study, the efficacy of atropine and 2-pyridine aldoxime 

methiodide (2-PAM) in preventing mortality was tested. In a 21-day delayed neurotoxicity study 

(MRID 45170201), a group of 20 domestic hens was administered a single oral dose of 11 mg/kg 

of dicrotophos on day 0. Atropine and 2-PAM were administered to prevent mortalities. An 

additional group of 12 birds was given 600 mg TOCP/kg as the positive control and a group of 

12 hens served as the negative control. Toxicity assessments included clinical observations, 

assessment of ataxia, body weight and food consumption measurements, acetylcholinesterase 
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and neurotoxic esterase activities, and microscopic evaluation of the brain, spinal cord, and 

peripheral nerves.

In the 21-day study, there were no mortalities, but dicrotophos-treated hens showed clinical signs 

of toxicity beginning on day 1 and continuing in one hen through day 7. These signs included 

reduced reaction to external stimuli, wing droop, loss of coordination, lower limb weakness, and 

gaping. All hens in the negative and positive control groups appeared normal. Body weights 

and food consumption were reduced compared with the negative control group; body weights 

bur not food consumption were reduced in the positive control group. Differences were not 

significant in either group by day 21. Hens in the dicrotophos-treated group showed slight ataxia 

up to day 13, whereas positive control birds showed slight ataxia on days 9-20. The early 

clinical signs and slight ataxia which abated with time in the dicrotophos group are not 

considered a sign of delayed neurotoxicity. AChE was depressed by 84% (p<0.01) in the brain 

of the dicrotophos-treated group, but NTE was non-significantly reduced in the brain and spinal 

cord (8 and 25%, respectively). AChE activity in the brain and NTE activities in the brain and 

spinal cord were significantly reduced in the TOCP-treated group (AChE by 21% and NTE in 

brain and spinal cord by 91% and 86%, respectively). Neurohistopathological lesions indicative 

of delayed neuropathy were not observed in hens in any group. The single dose of 11 mg/kg was 

sufficiently high as mortalities occur at this dose without treatment with anticholinergics.

Therefore, under the conditions of this study, oral administration of Dicrotophos at 11 

mg/kg does not produce delayed neuropathy in the hen.

870.6200a Acute Neurotoxicity Screening Battery – Rat

In an acute neurotoxicity study (MRID 43759801) dicrotophos (87.65% ai) was administered by 

gavage to 10/sex/group to Sprague-Dawley CD rats (20/sex/group) at dose levels of 0, 0.5, 5 or 

10 mg/kg (in water, 10 ml/kg). The rats were evaluated for reactions in functional observations 

and motor activity measurements (3 hours, and 8 and 15 days postdosing). Two satellite groups 

(5/sex/group) were also included for the purpose of measuring plasma ChE and erythrocyte and 

brain AChE on days 1 and 8. 

At 0.5 mg/kg, dicrotophos inhibited brain (21% in females and 22% in males) and erythrocyte 

AChE (16% in females and 19% in males) and plasma ChE (46% in females and 38% in males) 

on day 1 (all depressions were statistically significant). Brain AChE and plasma ChE reached 

about 90% inhibition at 10 mg/kg. RBC AchE never exceeded 50% inhibition. Brain AChE 

remained inhibited (7%-14%) for males at all doses by day 15. The NOEL and LOEL for 

ChE/AChE inhibition is < 0.5 mg/kg. At 5 mg/kg and above, dicrotophos produced clinical 

signs (prinicipally decreased activity, upward curvature of spine, pinched in sides, flaccid 

appearance and decreased pupil response in most or all animals and several other signs in some 

animals. Overall some 25 in males and 24 in females FOB parameters were reported affected by 

treatment in the 5 and/or 10 mg/kg dose levels of dicrotophos. Motor activity was decreased. At 

10 mg dicrotophos/kg produced deaths (7 females and 1 male) within 3 hours after dosing. Most 
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signs regressed after one day but some persisted for 3 or 4 days. The LOEL for neurotoxicity is 

5 mg/kg based on clinical signs. The NOEL is 0.5 mg/kg.

This acute neurotoxicity study is classified Acceptable/Guideline and satisfies the guideline 

requirement for an acute neurotoxicity study [OPPTS 870.6200a (§81-8)] in rats. 

870.6200b Subchronic Neurotoxicity Screening Battery – Rat

In a subchronic oral neurotoxicity feeding study (MRID 43980201), 12 Alpk:APfSD 

rats/sex/group were fed diets containing 0, 0.5, 5, or 25 ppm dicrotophos (87.65% w/w, Batch 

No. 403001B) for 13 weeks. Two satellite groups, each with 6 Alpk:APfSD rats/sex/dose, were 

similarly treated and included for the purpose of measuring cholinesterase activity (ChE) at week 

5 (Group A) and week 9 (Group B). The average consumption of test material in the 0, 0.5, 5, 

and 25 ppm dose groups for males was 0, 0.04, 0.39, and 2.03 mg/kg/day and for females was 0, 

0.04, 0.45, and 2.38 mg/kg/day. 

There was no treatment-related effect on mortality. Effects on body weights were minimal: 

weights were statistically significantly lower than controls at the high dose (≤ 10.4%, p ≤ 0.05 or 

0.01) during weeks 2-6 in males and 2-4 in females, and were correlated with decreased food 

consumption during weeks 1 and 2 (and decreased food efficiency in males). No notable 

changes were seen in behavior or appearance upon clinical examination. Treatment-related 

effects on motor activity were seen only at 25 ppm in both sexes: forelimb grip strength was 

decreased at weeks 9 and 14 in females (13-14%, p ≤ 0.05 or 0.01) and at week 5 in mals (14%, 

p≤ 0.05). Hindlimb grip strength was decreased only in females at week 9 (16%, p ≤ 0.05). The 

mean overall motor activity was decreased at week 9 in males (34%, respectively; p ≤ 0.01) and 

at weeks 9 and 14 in females (23 and 33%, respectively; p ≤ 0.05; p ≤ 0.01). The neurotoxic 

effects, as well as the statistically significant increase in brain weight in 25 ppm males (≤ 5.2%), 

had no histopathological correlates. 

Based on the motor activity alterations and marginal body weight decreases in both sexes 

of rats, 25 ppm is identified as the LOEL and 5 ppm is the NOEL for systemic 

toxicity/neurotoxicity.

Brain, plasma, and erythrocyte ChE activities were inhibited by dicrotophos treatment in all 

groups of rats, most markedly in the brain: 11-20% at 0.5ppm, 56-63% at 500m, and 87-90% at 

25 ppm (p ≤ 0.01). ChE was inhibited slightly more in females. Based on the dose-related 

inhibition in brain, plasma, and erythrocyte ChE activity, 0.5 ppm is the LOEL for ChE 

inhibition; a NOEL cannot be assigned because 0.5 ppm was the lowest dose tested. 

This study is classified as Acceptable/Guideline, satisfying the guideline requirement for a 

subchronic oral neurotoxicity feeding study [OPPTS 870.6200b (§82-7)] in the rat. 

870.6300 Developmental Neurotoxicity – Rat

In a developmental neurotoxicity study (MRID 46153202), dicrotophos (87.6% a.i., batch # 

403001B) was administered by gavage to 30 parent female Alpk:APfSD Wistar-derived rats/dose 

by gavage at dose levels of 0, 0.01, 0.05 or 0.4 mg/kg/day from gestation day (GD) 7 through 

parturition to lactation day 7. Selected pups were dosed by gavage with 0, 0.01, 0.05 or 0.4 
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mg/kg/day from post natal days (PNDs) 8 to 22; pups were weaned on day 29 and the study was 

terminated on PND 63. Doses were selected on the basis of a range-finding study (MRID 

46153201). A Functional Operational Battery (FOB) was performed on 30 dams/dose on GDs 

10 and 17, and lactation days 2 and 9. On PND 5, litters were culled to yield four males and four 

females (as closely as possible). Offspring selected for F1 generation were allocated 

(one/sex/litter) FOB, assessment of motor activity, assessment of auditory startle response 

habituation, assessment of learning and memory, and neuropathology at study termination (day 

63 of age). On days 12 and 63, the whole brain was collected from 10 pups/sex from control and 

high dose groups for micropathologic examination and morphometric analysis. Pup physical 

development was assessed by body weight, and sexual maturation of females was assessed by 

age at vaginal opening. Maturation of males was assessed by age at completion of preputial 

separation. Cholinesterase activity, either in the dams or the offspring, was not measured in this 

study. 

In dams during gestation and lactation, no treatment-related effects on mortality, clinical signs, 

body weight, body weight gain, food consumption, FOB, or reproductive parameters were noted. 

The maternal systemic NOAEL is 0.4 mg/kg/day, the highest dose tested. The maternal 

LOAEL is not identified.

In offspring, there were no treatment-related deaths or clinical signs or effects on birth weight, 

body weight or body weight gain pre- or post-weaning, clinical observations, developmental 

landmarks, FOB parameters, motor or locomotor activity, auditory startle response, or learning 

and memory tests. At necropsy, no treatment-related gross lesions or changes in absolute 

weight were seen. 

The brain morphometric analyses revealed statistically significant decreases (9-14%) in cortex 

measurements in males at PND 12 and the overall width of the thalamus/cortex (5%) in males 

at PND 63. In females, measurements of the hippocampus at various levels are significantly 

increased (7-10% ) at PND 12 and the hippocampus length and thalamus width are decreased 

(4-11%) at PND 63. These changes are considered related to treatment. Because of the 

changes seen at the high dose, morphometric data for all tissues (cortex, hippocampus, and 

thalamus) for the low and mid dose groups should be evaluated.

The offspring systemic LOAEL is 0.4 mg/kg/day based on morphometric changes in the 

brain of male and female offspring on PND 12. The NOAEL is not established.

This study is classified Acceptable/Nonguideline and may be used for regulatory purposes. It 

does not, however, satisfy the guideline requirement for a developmental neurotoxicity study in 

rats (OPPTS 870.6300, §83-6); OECD 426 (draft) due to the lack of brain morphometric data at 

the low and mid dose groups and pending review of the positive control data.

A.4.8 Metabolism

870.7485 Metabolism – Rat
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In a 96-hour rat metabolism study (MRID 43942001), [3-

14C]dicrotophos (98.9% ai) was 

administered to male and female CD rats (5 or 7 animals/sex/dose) by gavage as a single dose at 

levels of 0.5 or 3 mg/kg, or as a single dose at 0.5 mg/kg following a 14-day pretreatment with 

unlabeled dicrotophos at 0.5 mg/kg/day. Five additional rats/sex received a single 0.5 mg/kg 

intravenous dose in a 96-hour study.

[

14C]Dicrotophos was rapidly absorbed by male and female rats following oral and intravenous 

dosing. The orally and intravenously administered radioactivity was quantitatively recovered 

from each dosing regimen; total recovery was 97-99% of the dose. There was no difference in 

the relative pattern of excretion between male and female rats and no appreciable difference 

among dose levels or routes. Greater than 80% of the radioactivity was recovered in urine 

during the first 24 hours from all dose groups, and after 96 hours 83-88% was excreted in urine 

and feces. Volatile radioactive products accounted for 5-7% of the radioactivity. Only 1.1-2.6% 

of the dose was in the tissues/carcass. Liver had the highest percentage of the dose at 0.07-

0.09%. The concentration of radioactivity was highest in fat: 0.014-0.018 ppm for single oral 

and intravenous low doses, 0.023-0.033 ppm for the oral repeated low dose, and 0.106-0.124 

ppm for the single oral high dose. 

Dicrotophos metabolites were investigated in Day-1 urine. The results indicated that dicrotophos 

is extensively metabolized via N-demethylation and oxidation of the N-methyl moiety yielding 

intact organophosphate products, which may be dealkylated. Metabolism may also proceed via 

demethylation and dealkylation of the phosphate moiety forming various acetoacetamide and 

acetobutamide products. Twenty-one metabolic components were identified, including parent, 

19 Phase 1 metabolites, and one conjugate. Characterized metabolites exceeded 83% of the 

dose. Un-metabolized dicrotophos accounted for 3-7% of the doses. Hydroxydicrotophos 

accounted for up to 20% of the dose and monocrotophos accounted for up to 3%. Other intact 

organophosphates, numerous acetoacetamide and acetobutamide products, and one conjugate, Nacetylmonocrotophos were identified, but were not separately quantified.

This metabolism study in the rat is classified Acceptable/Guideline and satisfies the guideline 

requirement for a metabolism study [OPPTS 870.7485 (§85-1)] in the rat. The nature of the 

metabolic products of dicrotophos in rats has been well characterized. However, numerous 

metabolites were identified in urine but not separately quantified, including several intact 

organophosphates. In the event that a particular class of components is deemed toxicologically 

significant, e.g., organophosphates, additional data to quantify these components may be 

required.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID # 48404101), Dicrotophos Technical (88.9%, batch # 

GB1013 09-01) was administered to male HsdHanTM:WIST rats (10/dose) in diet at dose levels 

of 0, 5, 15, or 25 ppm (0, 0.37, 1.14, or 1.91 mg/kg bw/day, respectively) for 28 days. 

Additionally, eight male rats received cyclophosphamide (positive control) at 50 mg/kg
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administered by i.p injection on Day 27. All animals (Group 1 to 5) were immunized by 

intravenous injection of sheep red blood cells (SRBC 2 x 108/mL, 1.0 mL/animal) on Day 25. All 

animals were sacrificed by carbon dioxide asphyxiation on Day 29. The following parameters 

were measured and recorded: clinical observations, body weight and bodyweight gain, food, 

water and compound consumptions, blood and brain cholinesterase activity, macroscopic 

pathology, organ weights, and T-cell dependent antibody response (TDAR) by plaque forming 

cell (PFC) assay.

All animals survived the treatment period. There were no treatment-related clinical signs or 

compound toxicity. Body weights of males receiving 5 or 15 ppm were unaffected by treatment. 

A lower than control bodyweight gain (p<0.05) was observed in males receiving 25 ppm. Food 

and water consumptions, gross pathological examination, thymus and brain weights, were not 

affected by treatment.

Erythrocyte and brain acetylcholinesterase activity were reduced markedly, compared with the 

controls, at all dietary concentrations (p<0.01). The percentage reduction for brain 

acetylcholinesterase activity was 58, 81 and 86% at 5, 15 and 25 ppm, respectively. For 

erythrocytic acetylcholinesterase activity the percentage reduction was 66, 83 and 86% at 5, 15 

and 25 ppm, respectively. 

The cholinesterase inhibition LOAEL was 5 ppm (0.37 mg/kg/day) based on statistically 

significant depression in both erythrocytes and brain cholinesterase activity; the NOAEL is 

not established. The systemic toxicity LOAEL was 25 ppm (1.91 mg/kg/day) based on 

statistically significant decrease in body weight gains; the NOAEL is 15 ppm (1.14 

mg/kg/day).

There were statistically significant increases of spleen cellularity and total activity (PFC/spleen)

at 25 ppm when compared to the vehicle control. There was also a slight increase in specific 

activity (PFC/106viable cells) but did not attained statistical significance. There were no 

statistically significant changes at 5 or 15 ppm. There was a high inter-individual variability 

noted in all the treatment groups as well as in the control group. Evaluation of individual animal 

data of this study did not show any trend or distribution that would demonstrate significant 

suppression of anti-SRBC PFC response to sheep red blood cells (SRBC). Animals in positive 

control group, showed a significant decrease of PFC response to a challenge with SRBCs. This 

confirmed the ability of the test system to detect immunosuppressive effects and confirmed the 

validity of the study design.

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database 

for dicrotophos does not reveal any evidence of treatment-related effects on the immune system.

The overall weight of evidence suggests that this chemical does not directly target the immune 

system. Under HED guidance, a NK cells activity assay is not required at this time. 

Under conditions of this study, the NOAEL for immunotoxicity is 25 ppm (1.91 

mg/kg/day); the LOAEL was not established (>25 ppm).
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This study is classified Acceptable/Guideline, and satisfies the guideline requirement for an 

immunotoxicity study (OPPTS 870.7800) in rats. 

Special Studies

Comparative Cholinesterase Studies

A series of studies was performed to investigate the effect of dicrotophos on blood and brain 

cholinesterse (ChE) activity and to determine the peak time of ChE inhibition (ChEI) following 

both acute and repeated dosing in pre-weaning, young, and older adult Alpk:APfSD rats. No 

plasma ChE activity was measured. The studies were conducted as follows:

 In a time-course study (MRID 46153205), a single oral dose of 0 or 5 mg dicrotophos (86.9% 

a.i., Lot #403001B)/kg was administered by gavage to 15-day- or 42-day-old female rats 

(25/group). 

 In acute exposure studies, single oral doses of dicrotophos (90.4% a.i., Lot # 403001B) were 

administered by gavage at doses of 0.0, 0.1, 0.3, 1.0 or 5.0 mg/kg to 5 male and 5 female 

pre-weaning rats of 8, 15 and 22 days of age (MRID 46153205), and single oral doses of 

dicrotophos (87.6% a.i., Lot # 403001B) of 0.0, 0.1, 0.3, or 5.0 mg/kg were administered by 

gavage to groups of 15 young adult male and female rats (MRID 46153206). 

 In repeat exposure studies, dicrotophos (90.4% a.i., Lot # 403001B) was administered by 

gavage at 0, 0.008, 0.02, 0.08, 0.4 or 1.0 mg/kg/day to pre-weaning and young adult rats 

(5/sex) at 12 or 42 days age, respectively, for 7 days (MRID 46153204). In another study, 5 

male and 5 female adult rats received test compound (87.6% a.i., Lot # 403001B) by gavage 

at 0, 0.008, 0.02, or 0.4 mg/kg/day for 4 weeks (MRID 46153208). For a bridging study 

(MRID 46153207), adult rats (10/sex) received daily gavage doses of 0.0 or 0.4 mg 

dicrotophos (87.6% a.i, Lot # 403001B)/kg/day for 4 or 8 weeks. 

Treatment-related mortality was observed among pups receiving a single oral dose of 5 mg/kg 

(one of five males in the definitive study and three of 25 females in the time-course study). At a 

dose of 5 mg/kg, there was inhibition of RBC and brain ChE activity in pups and adults which 

correlated with clinical observations of tremors (all PND 8, 15, and 22 pups and 14/15 adult 

males and 15/15 adult females), splayed gait, shaking, and fast/irregular breathing. Clinical 

signs of ChE activity inhibition were first seen in pups and young adult rats within 

approximately 30 minutes after dosing. In the pups the clinical effects were seen over a longer 

period than those in adults. No sex-related differences were evident. The peak time of effect 

was reached by three hours in pups and one hour in adults. At the dose of 5 mg/kg, pups had 

greater ChE activity inhibition than adults in both compartments. In pups, dose-dependent RBC 

and brain ChE activity inhibition was observed at single oral doses of 0.1 mg/kg (lowest dose 

tested), while in adult rats dose-dependent ChE activity inhibition was observed at doses of 0.3 

mg/kg. Single doses of 0.1 mg/kg caused no significant effects in adult rats. 

No mortality or clinical signs were observed in repeat-dose studies. There were no treatmentrelated effects on body or brain weight. Repeat oral administration for 7 days at 0.08 to PND 18 
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pups inhibited brain ChE activity by 15% (both sexes; NS) and RBC activity by 19 and 25% in 

male and female pups, respectively (both p<0.01). Young adults were affected at 0.4 mg/kg/day 

(brain: 23 and 36% ChEI in males and females, respectively; RBC: 47 and 38% ChEI in males 

and females, respectively). Inhibition was dose-related. Repeated 7-day exposure to 0.02 

mg/kg/day or 0.08 mg/kg/day caused no significant ChE activity inhibition in pre-weaning and 

adult rats, respectively. A daily dose of 0.4 mg/kg/day for 4 weeks to adult rats caused inhibition 

of ChE activity in both compartments which returned to almost normal after a 4-week recovery 

period. No sex related differences were seen. Following repeat dosing at 0.4 mg/kg/day for 4 or 

8 weeks, maximum inhibition was achieved within four weeks in adults (brain, 33-35%; RBC, 

48-49%). Pre-weaning rats were not tested in this study. 

Overall, the results of all six studies together provide consistent evidence of greater sensitivity in 

young animals with respect to ChEI following acute and repeated dicrotophos exposure. This 

finding is further supported by the results of an earlier developmental neurotoxicity study in rats 

(MRID 46153202) in which clinical signs and neuropathology were observed in pups at 0.4 mg 

dicrotophos/kg/day while no toxicity was evident in maternal animals indicating greater 

sensitivity of pups to dicrotophos treatment. 

For acute exposure:

the adult LOAEL for brain ChEI is 5 mg/kg (males), 0.3 mg/kg (females)

the adult NOAEL for brain ChEI is 0.3 mg/kg (males), 0.1 mg/kg (females);

the PND 8, 15, and 22 LOAEL for brain ChEI is 0.1 mg/kg (both sexes)

the PND 8, 15, and 22 NOAEL for brain ChEI is not determined (<0.1 mg/kg; both sexes);

the adult LOAEL for RBC ChEI is 0.3 mg/kg (both sexes)

the adult NOAEL for RBC ChEI is 0.1 mg/kg (both sexes);

the PND 8, 15, and 22 LOAEL for RBC ChEI is 0.1 mg/kg (both sexes)

the PND 8, 15, and 22 NOAEL for RBC ChEI is not determined (<0.1 mg/kg; both sexes).

For acute oral exposure to dicrotophos, the overall adult LOAEL for cholinesterase 

inhibition in rats is 0.3 mg/kg based on enzyme inhibition in brain and RBC; the adult

NOAEL is 0.1 mg/kg.

For acute oral exposure to dicrotophos, the overall offspring LOAEL for cholinesterase 

inhibition in rats is 0.1 mg/kg based on enzyme inhibition in brain and RBC; the offspring 

NOAEL is not determined (<0.1 mg/kg).

For repeated exposure:

the adult LOAEL for brain ChEI is 0.4 mg/kg/day (both sexes)

the adult NOAEL for brain ChEI is 0.08 mg/kg (both sexes);

the offspring LOAEL for brain ChEI is 0.08 mg/kg/day (both sexes)
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the offspring NOAEL for brain ChEI is 0.02 mg/kg/day (both sexes);

the adult LOAEL for RBC ChEI is 0.4 mg/kg/day (both sexes)

the adult NOAEL for RBC ChEI is 0.08 mg/kg (both sexes);

the offspring LOAEL for RBC ChEI is 0.08 mg/kg/day (both sexes)

the offspring NOAEL for RBC ChEI is 0.02 mg/kg/day (both sexes).

For repeated oral exposure to dicrotophos, the overall adult LOAEL for cholinesterase 

inhibition is 0.4 mg/kg/day based on brain and red blood cell; the NOAEL is 

0.08 mg/kg/day. 

For repeat oral exposure to dicrotophos, the overall offspring LOAEL is 0.08 mg/kg/day 

based on brain and RBC; the NOAEL is 0.02 mg/kg/day. 

The cholinesterase activity measurements following acute and repeat oral doses of dicrotophos 

demonstrate greater susceptibility in juveniles than in adult rats. This susceptibility was 

observed in terms of the dose level at which an effect was observed (i.e., the LOAEL for 

cholinesterase inhibition was lower for juveniles than for adults in both the acute and repeat-dose 

studies). Although LOAELs were based on both RBC and brain ChEI, brain ChEI was generally 

greater than RBC ChEI for both age groups in the acute study. This difference in RBC and brain 

ChEI inhibition was not demonstrated in the 7-day repeat dose study. The relative susceptibility 

of dams and GD 20 fetuses was not addressed in this series of studies.

Taken together, these studies are classified as Acceptable/Nonguideline for the determination of 

RBC brain cholinesterase activities following treatment with dicrotophos in young adult and 

juvenile (pre-weaning) rats. Main deficiencies are omission of plasma ChE measurements and 

lack of assessment in dams and fetuses.

In Vitro Dermal Penetration 

In an in vitro dermal absorption study (MRID 45099502), groups of six rat and six human 

epidermal samples were exposed to 1258, 417, 42.6, or 9.66 μg/cm2of aqueous 14C-dicrotophos 

per concentration and the amount of absorption determined at 0.5, 1, 2, 4, 10, and 24 hours after 

application. At each time point, the amount of radioactivity present within six human and six rat 

epidermal chambers, collection fluid, carbon filters, epidermal samples, and receptor fluids was 

determined.

The study results show that the rat epidermis was more permeable to dicrotophos than human 

epidermis, the absorption rate ranging from 4.8 times at the low dose to ~68 times faster at the 

high dose over a 24-hour period. Likewise, the amount of radiolabeled dicrotophos crossing the 

rat epidermal layer into the receptor fluid was 4-72 times greater than the human epidermis. The 

amount of dicrotophos absorbed by rat or human epidermis was related to the concentration 

applied, however absorption appeared to be saturated at the higher doses by both human and rat 

epidermal preparations. Rat epidermis absorbed an average of 272 μg/cm2and 230 μg/cm2of 

the concentrate and 1:10 dilution, respectively, suggesting saturated absorption. However, at a 
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1:1000 dilution, the amount absorbed by rat epidermis was 24.6 μg/cm2, indicating absorption 

was proceeding at a submaximal rate. The maximal absorption rate of human epidermis was 

considerably less than rat epidermis and the data suggests that absorption was saturated at the 

three highest concentrations. At the concentrate, 1:10, and 1:100 dilutions, the absorption rate of 

human epidermis ranged from 3.8-5.9 μg/cm2of the amount applied over a 24-hour period. The 

absorption rate of the 1:1000 dilution of dicrotophos was 1.0 μg/cm2, indicating that absorption 

was not saturated.

Although there are differences in the in vitro absorption behavior of dicrotrophos from rat and 

human epidermis, no conclusions can be made from these results to the in vivo absorption of this 

chemical. The in vitro results in the rat show higher absorption rates than those obtained from a 

companion in vivo study at similar applications (MRID 45099501, reviewed in a separate DER) 

where the maximum absorption was 35% of the applied dose at a 1/100 dilution application of 

dicrotophos (contrast to 58% in vitro absorption at the same application rate) over 24 hour 

exposure and 26% of the applied dose absorption in vivo compared to 47% in vitro absorption 

over 10 hour exposure. The process of skin absorption in vitro is likely a passive process where 

as in vivo absorption, it is an active process involving absorption, distribution (blood), 

metabolism and excretion. Thus based on results of this in vitro study, no determination of the in 

vivo dermal absorption of dicrotrophos in humans can be made.

In summary, the in vitro study results show that rat epidermis is more permeable than human 

epidermis. This in vitro dermal absorption study is Acceptable/Nonguideline for the determination of absorption by rat and human epidermal skin. 
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Appendix C. Physical/Chemical Properties

Table C1. Physico-Chemical Properties

Parameter Value Reference

Molecular Weight 237.19

pH

Water solubility (20°C) 11,990 43603202, 43603201

Solvent solubility (20°C to 25°C)

miscible (mixable in all 

proportions) with water, 

acetone, alcohol, 

acetonitrile, chloroform, 

methylene chloride, and 

xylene

Vapor pressure (25°C) 7 x 10-5 43500401

Dissociation constant, pKa

Octanol/water partition coefficient, log KOW

(25°C)

2.445 (E-isomer) and 

0.000481 (Z-isomer)

Soil Half-life (days) 8.1 (parent) 160826