Sodium AciOuorfen Human Health Risk Assessment DP No. D426393 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: June 17, 20 15 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Sodium Acifluorfen. Draft Human Health Risk Assessment for Registration 

Review 

PC Code: 114402 OP Barcodc: 426393 

Decision No.: 502693 Registr ation No.: NA 

Petition No.: NA Regulatory Act ion: Registration Review Risk 

Assessment 

Risk Assessment Type: Single Chemical/ Aggregate Case No.: 2605 

TXR No.: NA CAS No.: 62476-59-9 

MRIO No.: NA 40 CFR: §180.383 

FROM: 

T HROUGH: 

TO: 

Alexandra Gavelek, M.S., Biologist ' / ..!-',' v-C 4 ·<,_ c-Q J 

Ronnie J. Bever Jr., PhD, DABT, Ifi,' ifo logif- ~ !) r~ fl 

William Donovan, PhD, Chemist e i'- 1l)\ 

Risk Assessment Branch V /VII 

Health Effects Division (7509P) 

Peter Savoia, Chemist a_-a__ ·· '.I'~~ William Irwin, Toxicologist rJl~"N-iri..<...N 

Michael Metzger, Branch Chief 

Risk Assessment Branch V N II 

Health Effects Division (7509P) 

Lata Venkateshwara, Chemical Review Manager 

Pesticide Re-Evaluation Division 

Page 1 of 48 
Sodium Acifluorfen Human Health Risk Assessment DP No. 0426393 

1.0 Executive Summary ........................ ................................................................................... 4 

2.0 HED Recommendations ..... ........... .... ............. .... ................................................... ............ 7 

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

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

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

2.2.2 Recommended Tolerances .......................... ................................................... ....... ..... 8 

2.2.3 Interna tional Harmonization ..................................................................................... 8 

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

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

3.1 Chemical Identity .............................................................................................. .... ......... 9 

3.2 Physical/Chemical Characteristics ............................................................................. l 0 

3.3 Pesticide Use Pattern .................................................................................. .................. I 0 

3.4 Anticipated Exposure Pathways .............. ............ ....................................................... 11 

3.5 Consideration of Environmental Justice .................................................................... 11 

4.0 Hazard Characterization and Dose-Response Assessment .......................................... 12 

4.1 Toxicology Studies Available for Analysis ..................... ............................................ 12 

4.2 Absorption, Distribution, Metabolism, & Elimination {ADME) ............................. 13 

4.2.1 Dermal Absorption ........................................................................ ........................... 13 

4.3 Toxicological Effects ........................................................ .............. .............................. 13 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 15 

4.4.1 Completeness of the Toxicology Database .............................................................. 15 

4.4.2 Evidence of Neurotoxicity ........................................................................................ 15 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal. ....... 16 

4.4.4 Residual Uncertainty in the Exposure Database ......................................... .......... 16 

4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 16 

4.5.1 Dose-Response Assessment ......................... ................ ............................................. 16 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment.. ... 18 

4.5.3 Cancer Classification and Risk Assessment Recommendation ............................ 18 

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

Assessment .. ............................................... .... ................ ................ .............. ............................ 18 

4.6 Endocrine Disruption ........ ............ .... ........................................................................... 20 

5.0 Dietary Exposure and Risk Assessment.. ....................................................................... 21 

5.1 Metabolite/Degradate Residue Profile ....................................................................... 21 

5.1.1 Summa ry of Plant and Animal Metabolism Studies ............................................. 21 

5.1.2 Summary of Environmental Degradation ... ........................................................... 22 

5.1.3 Residues of Concern Summary and Rationale ...................................................... 22 

5.2 Food Residue Profile .................................................... ................................. .... ........... 22 

5.3 Water Residue Profile .. ....... .... .... .... ......................... .... .... ............... ............................. 23 

5.4 Dietary Risk Assessment.. ............................................................................................ 24 

5.4.1 Description of Residue Data Used in Dietary Assessment .................................... 24 

5.4.2 Percent Crop Treated Used in Dietary Assessment .................................. ............ 24 

5.4.3 Acute Dietary Risk Assessment .. .... ......................................................................... 25 

5.4.4 Chronic Dietary Risk Assessment ........................................................................... 25 

5.4.5 Cancer Dietary Risk Assessment ................ ................ ............................................. 25 

5.4.6 Summa ry Table ........... .... ............ .... .... ......... .................... .......... .... .............. ....... ...... 25 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 26 

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Sodium Acifluorfen Human Health Risk Assessment DP No. D426393

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6.1 Residential Bystander Post-application Inhalation Exposure ................................. 26

6.2 Spray Drift.................................................................................................................... 26

7.0 Aggregate Exposure/Risk Characterization.................................................................. 28

7.1 Acute Aggregate Risk................................................................................................... 28

7.2 Short-Term Aggregate Risk ........................................................................................ 29

7.3 Intermediate-Term Aggregate Risk ........................................................................... 29

7.4 Chronic Aggregate Risk .............................................................................................. 29

7.5 Cancer Aggregate Risk ................................................................................................ 29

8.0 Cumulative Exposure/Risk Characterization ............................................................... 29

9.0 Occupational Exposure/Risk Characterization ............................................................ 30

9.1 Short-/Intermediate-Term Handler Risk................................................................... 30

9.2 Short-/Intermediate-Term Post-Application Risk .................................................... 33

9.2.1 Dermal Post-application Risk.................................................................................. 33

9.2.2 Inhalation Post-application Risk............................................................................. 34

10.0 Human Incidents/Epidemiology ..................................................................................... 35

11.0 References......................................................................................................................... 35

Appendix A. Toxicology Profile and Executive Summaries .................................................. 37

A.1 Toxicology Data Requirements................................................................................... 37

A.2 Toxicity Profiles............................................................................................................ 37

Appendix B. Physical/Chemical Properties............................................................................. 46

Appendix C. Review of Human Research................................................................................ 47

Appendix D. International Tolerances and Maximum Residue Limits Sheet ..................... 48
Sodium Acifluorfen Human Health Risk Assessment DP No. D426393

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1.0 Executive Summary

HED has conducted a human health risk assessment to support registrations review for the active 

ingredient, sodium acifluorfen. Sodium acifluorfen is a diphenyl ether used as a contact 

herbicide for selective pre- and post-emergence control of annual broad-leaf weeds and some 

grasses. The registered sodium acifluorfen products are liquid concentrates which are applied 

using ground or aerial equipment. The currently labeled uses include rice, peanuts, strawberries 

and soybeans. All residential products are cancelled or suspended. There are currently no 

registered residential uses. 

The database of toxicology studies for sodium acifluorfen is complete and considered adequate 

for risk assessment. Waivers were recommended by HASPOC for the subchronic inhalation and 

subchronic neurotoxicity studies and the developmental neurotoxicity study (Craig, 2015, TXR# 

0051465).

Sodium acifluorfen results in hematological effects (such as decreases in erythrocyte count, 

hematocrit, and/or mean cell volume), which were noted in dogs, rats, and mice. Additionally, 

the liver (dog, rat, and mouse) and kidney (rat and mouse) are also target organs of oral 

exposure, and effects in these organs were noted following both subchronic and chronic 

exposures. There was no progression of effects from subchronic to chronic dosing durations in 

the rat and mouse (no dog subchronic study). 

There was quantitative fetal susceptibility demonstrated in the Sprague-Dawley rat 

developmental study, but no susceptibility in the Wistar rat or rabbit developmental studies, nor 

in the reproduction study. In the Sprague-Dawley rat developmental study, decreased body 

weights and increased incidences of clinical signs were observed in the maternal animal at the 

highest dose tested, whereas the fetal effects were observed at a lower dose and included 

decreased fetal body weight and increased incidence of slightly dilated lateral ventricles of the 

brain. No adverse effects were noted in the Wistar rat dam or fetus nor in the rabbit dam or fetus. 

In the reproduction study in rats, parental toxicity (dilatation and necrosis of tubules in the outer 

medulla of kidneys in females) was noted at a lower dose than offspring toxicity (decreased body 

weights and increased renal pelvis dilatation). No effects on reproductive parameters were 

observed.

The weight of evidence suggests that acifluorfen is not neurotoxic; effects appearing to be related 

to neurotoxicity are most likely due to systemic toxicity. No immunotoxicity was observed. In 

the dermal toxicity test, skin irritation was observed at all doses, and systemic toxicity was noted 

at the limit dose. An inhalation toxicity study was not submitted nor required. 

Sodium acifluorfen has low acute toxicity by the oral and dermal exposure routes. However, it is 

a severe eye irritant and moderate dermal irritant. It is not considered a skin sensitizer. 

Based on the toxicity, durations of exposure, and uses of sodium acifluorfen, the following 

toxicity endpoints were selected: 
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Acute dietary (General Population, including Infants and Children): acute PAD 

(aPAD) = 2.9 mg/kg/day derived from a NOAEL of 293 mg/kg in an acute neurotoxicity

study. LOAEL = 440 mg/kg based on decreased motor activity in female rats.

Acute dietary (Females 13-49 years of age): acute PAD (aPAD) = 0.20 mg/kg/day 

derived from a NOAEL of 20 mg/kg in a rat developmental study. LOAEL = 90 mg/kg 

based on increased incidence of slightly dilated lateral ventricles of the brain.

Chronic dietary (all populations): chronic PAD (cPAD) = 0.013 mg/kg/day derived 

from a NOAEL of 1.25 mg/kg/day in a rat reproduction study. LOAEL = 25 mg/kg/day 

based on dilatation of tubules in the outer medulla of kidneys were noted in both 

generations in parental females.

Incidental oral exposures (short-term): NOAEL = 25 mg/kg/day in a rat reproduction 

study. LOAEL = 125 mg/kg/day based on decreased pup body weights and renal pelvic 

dilatation.

Dermal (short- and intermediate-term): NOAEL = 25 mg/kg/day in a rat reproduction 

study. LOAEL = 125 mg/kg/day based on decreased pup body weights and renal pelvic 

dilatation. Dermal absorption factor = 18%.

Inhalation (short- and intermediate-term): NOAEL = 1.25 mg/kg/day in a in a rat 

reproduction study. LOAEL = 25 mg/kg/day based on dilatation of tubules in the outer 

medulla of kidneys were noted in both generations in parental females.

Sodium acifluorfen is a peroxisome proliferator and may induce liver tumors in mice. It is likely 

to be carcinogenic to humans at high enough doses to cause the biochemical and 

histopathological changes in livers of rodents associated with peroxisome proliferation, but 

unlikely to be carcinogenic at doses below those causing these changes. EPA determined that 

non-linear extrapolation be used for assessment; therefore, no separate Q1* based cancer 

aggregate assessment is required. The use of the non-linear RfD approach will be protective of 

chronic effects including carcinogenicity.

For the occupational and residential risk assessments, the level of concern (LOC) is for MOEs 

less than 100 (10X intra-species uncertainty factor and 10X interspecies uncertainty factor). The 

FQPA safety factor has been reduced to 1X since the database is complete, points of departure 

are protective for all life stages, there is no clear evidence of neurotoxicity, and exposure 

estimates are not likely to underestimate risk.

The residue chemistry database is complete with the exception of the need for analytical standard 

submissions. The residues of concern for the tolerance expression and dietary risk assessment 

are acifluorfen acid, acifluorfen methyl ester, acifluorfen amine, and acifluorfen amine methyl 

ester. There are adequate analytical methods available for tolerance enforcement. Tolerances 

are based on crop field trial studies that showed residue levels below the limit of quantitation 

(LOQ) in all raw agricultural commodities except rice straw, where residues slightly above the 

LOQ were found. These trials were supported by adequate storage stability studies. Processing 

studies demonstrate that residues do not concentrate in processed commodities. Rotational crop 

studies form the basis for the recommended plant back intervals (PBIs) specified on the sodium 

acifluorfen labels. There are no tolerances for livestock commodities as there is no expectation of 

finite residues in livestock tissue [40 CFR §180.6(a)(3)].
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A risk assessment was conducted for dietary exposure which included all food commodities for 

the registered uses and estimated drinking water concentrations (EDWCs). Acute and chronic 

dietary analyses were performed using conservative assumptions (i.e., 100% crop treated, 

tolerance-level residues, and default processing factors). The resulting acute exposure estimates 

were less than HED’s level of concern (≤100% acute PAD) for all populations. The acute risk 

estimate was < 1% of the aPAD for general U.S. population) and all population subgroups except 

females 13-49 years old. A separate point of departure (PoD) was selected for females 13-49 

years old and the estimated risk was 4.0% aPAD for this population subgroup. The chronic 

exposure estimates were also less than HED’s level of concern (≤100% chronic PAD) for general 

U.S. population (24% cPAD) and all population sub-groups. The most highly exposed 

population subgroup was all infants, at 62% cPAD. Water is the primary contributor to 

aggregate (food + water) dietary exposure to sodium acifluorfen, for both acute and chronic 

exposure scenarios. 

Since there are no uses of sodium acifluorfen existing that would result in residential (nonoccupational) exposure to the pesticide, short- and intermediate-term aggregate risk assessment 

are not required. 

The acute and chronic aggregate risk assessments include only food and drinking water 

exposure, and are equivalent to the acute and chronic dietary (food and water) risk assessments, 

respectively. The acute and chronic dietary risk estimates are not of concern for the general 

population and all population subgroups. 

A spray drift assessment was completed for sodium acifluorfen. The spray drift risk estimates 

are based on an estimated deposited residue concentration as a result of the screening level 

agricultural application scenarios. Children’s (1 to < 2 year old) dermal and incidental oral risk 

estimates from indirect exposure to sodium acifluorfen, related to spray drift, result in no buffers 

for groundboom or aerial applications. Risk estimates from groundboom and aerial applications 

are not of concern at the field edge. 

Sodium acifluorfen is a member of the diphenyl ether group of herbicides, which includes 

lactofen and oxyfluorfen. In addition, acifluorfen is a degradate of lactofen. EPA has some 

evidence that these compounds induce similar toxic effects but has not yet determined whether or 

not these compounds exhibit a common mechanism. 

HED conducted occupational handler and post-application exposure and risk assessments for all 

registered uses. Short- and intermediate-term MOEs for handlers (mixers/loaders and 

applicators) were not of concern to HED as they exceeded the target MOE of 100 with the labelrequired PPE. The occupational post-application exposure and risk estimates indicate that shortand intermediate-term MOEs are not of concern to HED, also significantly exceeding the target 

MOE of 100. 

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.1” 

 

1 http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf.
Sodium Acifluorfen Human Health Risk Assessment DP No. D426393

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This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide to determine their exposure. Appendix C provides additional 

information on the review of human research used to complete the risk assessment. There is no 

regulatory barrier to continued reliance on these studies, and all applicable requirements of 

EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been 

satisfied.

2.0 HED Recommendations

HED has examined the toxicology residue chemistry and exposure databases for sodium acifluorfen. 

Pending resolution of the deficiency identified below, there are no other residue chemistry, 

residential, occupational, or toxicology data deficiencies that would preclude the continuation of the 

current registered uses of sodium acifluorfen and its metabolites as listed in Table 2.2.2. 

2.1 Data Deficiencies

860.1650 Submittal of Analytical Reference Standards

Analytical standards for sodium acifluorfen are currently not available at the EPA National 

Pesticide Standards Repository (personal communication with Theresa Cole, 6/3/15). The 

Repository has requested that the registrant provide analytical standards for sodium acifluorfen 

and acifluorfen amine. They should be sent to the Analytical Chemistry Lab, which is located at 

Fort Meade, to the attention of either Theresa Cole or Thuy Nguyen at the following address:

USEPA

National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

701 Mapes Road

Fort George G. Meade, MD 20755-5350

(Note that the mail will be returned if the extended zip code is not used.)

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods are available for enforcement of tolerances of acifluorfen in plant 

commodities. The Pesticide Analytical Manual (PAM) Volume II lists a gas 

chromatography/electron capture detector (GC/ECD) method, designated as Method I, for the 

enforcement of tolerances in plant commodities. Briefly, residues of sodium acifluorfen and 

acifluorfen amine are extracted with acetonitrile (ACN):1.0 N HCl (7:3, v:v). The extract is 

partitioned into toluene and evaporated to dryness, then dissolved in methanol, washed with

heptane (oily crops only), and concentrated to dryness. The dried residue is dissolved in ethyl 

ether and subjected to methylation with diazomethane to convert acifluorfen and acifluorfen 

amine to the corresponding methyl esters, followed by derivatization with heptafluorobutyramide 

(HFBA) to convert the methyl ester of acifluorfen amine to the HFBA derivative. The resulting 
Sodium Acifluorfen Human Health Risk Assessment DP No. D426393

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residues are purified on a Florisil column prior to GLC analysis. Method I determines residues of 

sodium acifluorfen, acifluorfen, acifluorfen amine, and any other compounds that can be 

converted to acifluorfen methyl ester or the HFBA derivative. Identifications are confirmed by 

GLC/MS (Method A in PAM II). The stated detection limit of Method I is 0.01-0.02 ppm.

2.2.2 Recommended Tolerances

The residue definition needs modification to be consistent with recent guidance on tolerance 

expressions (S. Knizner, 5/27/09). The appropriate language is described below.

(a) General. Tolerances are established for residues of the herbicide sodium acifluorfen (sodium 

5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate), 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 acifluorfen acid (5-[2-chloro4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid), acifluorfen methyl ester(methyl 5-[2-chloro-4-

(trifluoromethyl)phenoxy]-2-nitrobenzoate), acifluorfen amine, (5-[2-chloro-4-

(trifluoromethyl)phenoxy]-2-aminobenzoic acid), and acifluorfen amine methyl ester(methyl 5-

[2-chloro-4-(trifluoromethyl)phenoxy]-2-aminobenzoate), calculated as the stoichiometric 

equivalent of acifluorfen acid, in or on the commodities.

Table 2.2.2. Tolerance Summary for Sodium Acifluorfen.

Commodity Established Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Peanut 0.1 0.10

Rice, grain 0.1 0.10

Rice, straw 0.2 0.20

Soybean, seed 0.1 0.10

Strawberry 0.05 0.05

Tolerance levels for sodium acifluorfen should be expressed using the number of significant 

figures recommended in Table 2.2.2.

2.2.3 International Harmonization

No Codex Maximum Residue Limits (MRLs) have been established for sodium acifluorfen. One 

Canadian MRL for the registered early season use of sodium acifluorfen on soybeans has been 

established at 0.02 ppm (see Appendix D). Although the U.S. and Canada are harmonized with 

respect to residue definition for sodium acifluorfen, the established U.S. tolerance is 0.1 ppm. 

Harmonization at 0.02 ppm is not possible given the 0.1 ppm limit of quantitation (LOQ) of the 

analytical method used to analyze the soybean field trial samples.

2.3 Label Recommendations

None.

3.0 Introduction
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3.1 Chemical Identity

Table 3.1. Chemical Identity 

Common Name Sodium Acifluorfen

IUPAC name Sodium 5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-2-nitrobenzoate

CAS name Sodium 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate

PC Code 114402

CAS registry number 62476-59-9

Case No. 2605

Chemical Structure 

Chemical Identity for Acifluorfen Metabolites

Common Name Acifluorfen; Acifluorfen Acid

IUPAC name 5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-2-nitrobenzoic acid

CAS name 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid

PC Code 114401

CAS registry number 50594-66-6

Chemical Structure

Common Name Acifluorfen amine

CAS name 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-aminobenzoic acid

Chemical Structure

Common Name Acifluorfen methyl ester

CAS name Methyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate

Chemical Structure
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Table 3.1. Chemical Identity 

Common Name Acifluorfen amine methyl ester

CAS name Methyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-aminobenzoate

Chemical Structure

3.2 Physical/Chemical Characteristics

Sodium acifluorfen rapidly dissociates to the acifluorfen anion and is expected to be completely 

dissociated during tank mixture and prior to application. The acifluorfen anion is persistent in 

soil (aerobic soil metabolism half-life 170 days) and in aerobic aquatic environments (estimated 

aerobic half-life 117 days); it is less persistent in anaerobic conditions (aquatic half-life 

estimated to be 2.75 days). Volatilization does not appear to be a significant dissipation pathway 

for acifluorfen (vapor pressure is <1.33 x 10-5 Pa; Henry's Law constant is 7.65 x 10-10 atm 

m3/mol). Acifluorfen is not expected to bioaccumulate because of its low Kow.

Refer to Appendix B for the physical/chemical properties of sodium acifluorfen.

3.3 Pesticide Use Pattern

Refer to Table 3.3 for a summary of use directions for sodium acifluorfen. 

Table 3.3. Summary of Directions for Use of Sodium Acifluorfen.

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

Peanut

Preemergence, at 

cracking,

or postemergence

Broadcast or 

banded foliar

Ground/Aerial

2 lb/gal SC

[7969-76]

[83520-24]

[82534-2]

[70506-60]

0.375 2

(at 0.25 lb/A) 0.50 75

A minimum retreatment 

interval of 15 days is 

specified. PBIs for rotational 

crops: immediate for 

registered crops, 40 days for 

small grains and 100 days for 

other crops. 

Rice

Late tillering to 

early boot

Broadcast

Ground/Aerial

2 lb/gal SC

[7969-76]

[83520-24]

[82534-2]

[70506-60]

0.25 1 0.25 50

A minimum retreatment 

interval of 15 days is 

specified. PBIs for rotational 

crops: immediate for 

registered crops, 40 days for 
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Table 3.3. Summary of Directions for Use of Sodium Acifluorfen.

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

small grains and 100 days for 

other crops. 

Soybean

Postemergence

Broadcast or 

banded foliar

Ground/Aerial

2 lb/gal SC

[7969-76]

[83520-24]

[82534-2]

[70506-60]

0.375 2

(at 0.25 lb/A) 0.50 50

A minimum retreatment 

interval of 15 days is 

specified. For banded 

applications, a minimum

bandwidth of 15 inches and a 

minimum of 15 gal/A are 

specified. PBIs for rotational 

crops: immediate for 

registered crops, 40 days for 

small grains and 100 days for 

other crops. 

Strawberry

Postemergence

Broadcast or 

banded foliar

Ground/Aerial

2 lb/gal SC

[83520-24]

[82534-2]

[70506-60]

0.375 2 0.75 60

A minimum retreatment 

interval of 15 days is 

specified. PBIs for rotational 

crops: immediate for 

registered crops, 40 days for 

small grains and 100 days for 

other crops. 

3.4 Anticipated Exposure Pathways

Humans may be exposed to sodium acifluorfen in food and drinking water, since sodium 

acifluorfen may be applied directly to growing crops and application may result in sodium 

acifluorfen reaching surface and ground water sources of drinking water. There are no 

residential uses of sodium acifluorfen, so there is not likely to be exposure in residential or nonoccupational settings. There is potential for spray drift exposure following agricultural 

applications of sodium acifluorfen. 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. This risk assessment considers 

all of the aforementioned exposure pathways based on the existing uses of sodium acifluorfen. 

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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the National 
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Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and 

are used in pesticide risk assessments for all registered food uses of a pesticide. These data are 

analyzed and categorized by subgroups based on age, season of the year, ethnic group, and 

region of the country. Additionally, OPP is able to assess dietary exposure to smaller, 

specialized subgroups and exposure assessments are performed when conditions or 

circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of 

pesticide products and associated risks for adult applicators and for toddlers, youths, and adults 

entering or playing on treated areas post-application are evaluated. Further considerations are 

currently in development as OPP has committed resources and expertise to the development of 

specialized software and models that consider exposure to bystanders and farm workers as well 

as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database for sodium acifluorfen provides a robust characterization of the hazard 

potential of this pesticide. The toxicology studies for sodium acifluorfen are summarized in 

Appendix A.1. There are studies available for toxicity endpoint selection, which include: 

Subchronic oral toxicity studies in rats and mice

Chronic oral toxicity studies in rats and dogs 

Carcinogenicity studies in rats and mice 

Mutagenicity battery 

Developmental studies in rats and rabbits 

Reproduction study in rats 

Acute neurotoxicity study in rats

Dermal toxicity study in rabbits

Metabolism study in rats

Immunotoxicity studies in rats

A waiver was recommended by Hazard and Science Policy Council (HASPOC) for the 

inhalation toxicity study and subchronic and developmental neurotoxicity studies (Craig, 2015, 

TXR# 0051465). The last risk assessment was performed in 2002 (Farwell, 2002, D279497). 

Since the scoping document (Goodlow, 2010, D370342), a developmental study in rats, an 

immunotoxicity study in female mice, and an acute neurotoxicity study were submitted. The 

studies available for consideration of sodium acifluorfen toxicity provide a comprehensive 

database, with routes of administration that are consistent with potential exposure scenarios. 

To support Registration Review, a search of the open literature was conducted for toxicity

studies involving sodium acifluorfen using a database of the National Library of Medicine’s 

TOXNET System and the Google scholar search. No additional studies relevant to HED’s 

human health risk assessments were found.
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4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

The ADME was evaluated in male and female Fischer 344 rats following three oral dosages 

(single low at 16-17 mg/kg, single high at 116 mg/kg, and multiple low at 10-12 mg/kg daily for 

14 days) and an intravenous dosage (11-15 mg/kg). Sodium acifluorfen is rapidly (peak blood 

concentration [tmax] = 0.5-5.4 h) and almost completely absorbed (bioavailability ~ 80-97%) into 

the systemic circulation. The terminal excretion half-life (t1/2 β) = 3.7-8.9 h. Very little 

radioactivity was detectable in tissues of rats 96 hours after administration of each of four dosage 

regimens. Excluding the gastrointestinal system, the highest percentage of residues were isolated 

in the liver and kidneys of males and livers of females at 96 hours. The radioactivity recovered in 

urine and feces in female animals, 96 hours after administration, was 60-82% and 5-23% of the 

dose, respectively. In contrast, the radioactivity recovered in urine and feces in male rats was 

46-58% and 21-41% of the dose, respectively. The major radioactive component present in blood 

(95-98%), urine (95%), and bile (93%) was unchanged acifluorfen. The major component in 

feces was the amine metabolite, which accounted for 60-80% of the radioactivity.

4.2.1 Dermal Absorption

No acceptable dermal absorption studies are available for acifluorfen. However, a dermal 

absorption study conducted in rats for structurally-related oxyfluorfen (shown below) is 

available, and reported a dermal absorption factor (DAF) of 18%. 

 

Oxyfluorfen Sodium Acifluorfen

Based on chemical structure, and physical properties, sodium acifluorfen is expected to have a 

lower potential for dermal penetration as it is in its more polar, ionized form, and has a lower log 

Kow (1.55 and 4.75 for sodium acifluorfen and oxyfluorfen, respectively). Additionally, in vitro

modeling was conducted on both sodium acifluorfen and the un-ionized acifluorfen molecule 

using the CDC/NIOSH Finite Dose Skin Permeation Calculator2. Based on the available 

physical/chemical properties, the dermal absorption following a 10-hour exposure to either 

molecule did not exceed 18%, with the ionized molecule having a dermal absorption of < 5%. 

Therefore, the DAF factor of 18% from structurally-related oxyfluorfen is considered a 

conservative estimate and acceptable for use in risk assessment. 

4.3 Toxicological Effects

The herbicidal mode of action for sodium acifluorfen is the inhibition of protoporphyrinogen IX 

oxidase (protox), leading to an accumulation of protoporphyrinogen IX. This inhibition leads to 

cell membrane disruption through reactive oxygen species in the presence of light. Blockage of 

the porphyrin pathway at this site inhibits synthesis of both chlorophylls and heme. Heme is a 

 

2 http://www.cdc.gov/niosh/topics/skin/finiteskinpermcalc.html
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feedback regulator of the porphyrin pathway. Hematological effects (such as decreases in 

erythrocyte count, hematocrit, and/or mean cell volume) were noted in dog, rat, and mice. 

The liver (dog, rat, and mouse) and kidney (rat and mouse) are also target organs of oral 

exposure, and effects in these organs were noted following both subchronic and chronic 

exposures. Indications of liver toxicity included findings such as increased liver weight, 

hypertrophy, clinical chemistry findings, urinary urobilinogen, focal necrosis; proliferation of 

oval or bile duct cells, and fatty infiltration. Indications of kidney toxicity include increases in 

the following parameters: kidney weight; serum electrolytes, BUN, and creatinine; and urinary 

nitrate.

There was no progression of effects in the rat and mouse from subchronic to chronic dosing 

durations (no dog subchronic study). This observation may be in part attributed to short half-life 

of this chemical (t1/2 β = 3.7-8.9 h), and because the tmax is reached quickly, within 0.5-5.4 h.

There was quantitative fetal susceptibility demonstrated in the Sprague-Dawley rat 

developmental study, but no susceptibility in the Wistar rat or rabbit developmental studies, nor 

in the reproduction study. In the Sprague-Dawley rat developmental study, decreased body 

weights and increased incidences of clinical signs were observed in the maternal animal at the 

highest dose tested, whereas the fetal effects were observed at a lower dose and included 

decreased fetal body weight and increased incidence of slightly dilated lateral ventricles of the 

brain. In the developmental studies, no adverse effects were noted in the Wistar rat dam or fetus 

nor in the rabbit dam or fetus. In the reproduction study in rats, parental toxicity (dilatation and 

necrosis of tubules in the outer medulla of kidneys in females) was noted at a lower dose than 

offspring toxicity (decreased body weights and increased renal pelvis dilatation). No effects on 

reproductive parameters were observed.

Acifluorfen was negative in several genetic toxicology studies but was weakly mutagenic in a 

bacterial reverse mutation assay with metabolic activation and was weakly recombinogenic in 

Saccharomyces cerevisiae without metabolic activation. The Mechanism of Toxicity 

Assessment Review Committee concluded that the currently available data are considered to be 

sufficient to support peroxisome proliferation as one of the key events in the mode of action of 

acifluorfen-induced liver tumors in mice according to the criteria recommended by International 

Life Sciences Institute (Kidwell, 2003, TXR No. 0052014). Sodium acifluorfen is likely to be 

carcinogenic to humans at high enough doses to cause the biochemical and histopathological

changes in livers of rodents, but unlikely to be carcinogenic at doses below those causing these 

changes. 

Evidence possibly related to neurotoxicity was noted in the 180 mg/kg/day dams in a rat 

developmental study based on increased incidence of clinical signs (25 rats observed/dose with a 

total of 375 animal days; incidence reported as # rats affected/total animal days): excessive salivation 

(19/39), urine-stained fur (14/30), and decreased motor activity (4/4). Increased incidences of slightly 

dilated lateral ventricles of the brain were noted in the fetuses at 90 mg/kg/day (litters: 42.1% treated 

vs 9.5% controls; fetuses: 13.9% treated vs 2.4% controls). A similar incidence was noted at 180 

mg/kg/day (litters: 31.6%; fetuses: 14.7%). In the acute neurotoxicity study in females during the 

0-10 minute interval of Days 0 (treated) and 1, ambulatory and total (fine + ambulatory) motor 
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activities were decreased (p≤0.05) by 27-44% at 440 and 660 mg/kg. No other evidence in the 

database indicated neurotoxicity. Weight of evidence indicates that acifluorfen is unlikely to be 

neurotoxic. This conclusion is based on the following: 1) indications of treatment-related toxicity 

in the ACN are well-characterized, and effects on motor activity could be an indication of 

systemic toxicity from the bolus dose; 2) the slight effect observed in fetuses in a developmental 

toxicity study with Sprague-Dawley rats (dilated brain ventricles) were not reproduced in another 

developmental toxicity study with Wistar rats nor in developmental toxicity studies with rabbits; 

3) decreased motor activity was observed at relatively high doses and may be a result of a 

systemic effect rather than a neurotoxic effect; and 4) there was no indication of treatmentrelated neurotoxicity observed in any studies for structurally-related chemicals (fomesafen, 

lactofen, and oxyfluorfen), except for decreased motor activity in an acute neurotoxicity study 

with fomesafen at the same dose where general systemic toxicity (body weight loss) was

observed. 

No immunotoxicity was observed. In the dermal toxicity test, skin irritation was observed at all 

doses, and systemic toxicity was noted at the limit dose. An inhalation toxicity study was not 

submitted, and the HASPOC recommended that this study be waived. 

Sodium acifluorfen has low acute toxicity by the oral and dermal exposure routes (toxicity 

category III, LD50 ≥ 1370 mg/kg). However, it is a severe eye irritant (toxicity category I) and 

moderate dermal irritant (toxicity category II). It is not considered a skin sensitizer. 

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

HED recommends that the 10x FQPA Safety Factor (for the protection of infants and children) 

be reduced to 1x for reasons detailed in the subsections below. The toxicological database for 

sodium acifluorfen is complete with regard to pre- and postnatal toxicity, neurotoxicity, and 

immunotoxicity; there are no residual uncertainties. Additionally, the dietary exposure 

assessment is based on conservative, health-protective assumptions that ensure that exposures to 

sodium acifluorfen are not underestimated. 

4.4.1 Completeness of the Toxicology Database

The toxicology database is complete, and the toxicology studies are adequate for assessing 

increased susceptibility under FQPA (see Appendix A.1). Developmental toxicity studies in rats 

and rabbits and a reproductive toxicity study in rats are available. An acute neurotoxicity study 

in rats and immunotoxicity study in rats are available. Waivers were recommended by HASPOC 

for the subchronic inhalation and neurotoxicity studies and the developmental neurotoxicity 

study (Craig, 2015, TXR# 0051465).

4.4.2 Evidence of Neurotoxicity

Weight of evidence indicates that sodium acifluorfen is unlikely to be neurotoxic. This conclusion is 

based on the following: 1) indications of treatment-related toxicity in the ACN are wellcharacterized, and effects on motor activity could be an indication of systemic toxicity from the 

bolus dose; 2) the slight effect observed in fetuses in a developmental toxicity study with 
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Sprague-Dawley rats (dilated brain ventricles) were not reproduced in another developmental 

toxicity study with Wistar rats nor in developmental toxicity studies with rabbits; 3) decreased 

motor activity was observed at relatively high doses and may be a result of a systemic effect 

rather than a neurotoxic effect; and 4) there was no indication of treatment-related neurotoxicity 

observed in any studies for structurally-related chemicals (fomesafen, lactofen, and oxyfluorfen), 

except for decreased motor activity in an acute neurotoxicity study with fomesafen at the same 

dose where general systemic toxicity (body weight loss) was observed.

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

There is evidence of increased susceptibility following in utero exposure to sodium acifluorfen

in the Sprague Dawley rat developmental toxicity study. However, there is low concern because 

effects are well-characterized with clear NOAEL/LOAEL values and the chosen points of 

departure for risk assessment for each exposure scenario are protective for these effects.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary exposure estimates 

assumed 100% of percent of crop treated, tolerance-level residue in food and upper-bound 

drinking water estimates based on modeling, which are considered conservative assumptions (see 

Section 5.4.1). HED is confident that the dietary risk is not underestimated. Additionally, since 

the non-dietary exposure and risk estimates are based on several conservative assumptions, HED 

is confident that the exposure estimates are not underestimated. The assumptions are detailed in 

Sections 6.0 and 9.0.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Since the last risk assessment, an acute neurotoxicity study has been received which allows the 

determination of the acute dietary point of departure for the general population. Furthermore, 

short- and intermediate-term oral endpoints must now be considered due to the possibility of 

spray drift. The detailed description of the toxicity studies used for selecting toxicity endpoints 

and points of departure for various exposure scenarios are presented in Appendix A.4.

Acute Dietary Endpoint (General Population, including Infants and Children): The acute 

dietary endpoint for the general population was from an acute neurotoxicity study in rats. 

Decreased motor activity was observed in female rats at a LOAEL of 440 mg/kg. The acute 

Population Adjusted Dose (aPAD) of 2.9 mg/kg/day is based on a NOAEL of 293 mg/kg with a 

100-fold uncertainty factor (10X interspecies and 10X intraspecies) applied and an FQPA SF of 

1. 

Acute Dietary Endpoint (Females 13-49 years of age): The acute dietary endpoint for women of 

child-bearing age was from a rat developmental study. The developmental LOAEL was 90

mg/kg/day based on increased incidence of slightly dilated lateral ventricles of the brain. These 

anatomical variations are considered to be possibly due to a single exposure; therefore, this 
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finding is suitable for an acute endpoint. The aPAD of 0.20 mg/kg is based on a NOAEL of 20 

mg/kg/day with a 100-fold uncertainty factor (10X interspecies and 10X intraspecies) applied

and an FQPA SF of 1. 

Chronic Dietary Endpoint: The chronic dietary endpoint was from a dilatation of tubules in the 

outer medulla of kidneys were noted in both generations in parental females. This study is 

appropriate for the duration of concern and protective of effects seen in all species following 

long-term exposure. The chronic PAD (cPAD) of 0.013 mg/kg/day is based on a NOAEL of 1.25 

mg/kg/day with a 100-fold uncertainty factor (10X interspecies and 10X intraspecies) applied 

and an FQPA SF of 1. 

Short-Term Incidental Oral Endpoints (residential due to spray drift): The endpoint selected for 

short- term incidental oral exposure scenarios was from a reproduction toxicity study in SpragueDawley rat. The offspring NOAEL was 25 mg/kg/day. The LOAEL was 125 mg/kg/day based 

on decreased pup body weights and renal pelvic dilatation. As it is unknown exactly how long 

treatment must continue to result in the nephrotoxicity observed in the reproduction study, it was 

assumed that the toxicity may result from short-term exposure in order to be protective of this 

possibility. The study is protective of effects seen in all species following sub-chronic exposure. 

The standard 100X UF was applied to account for interspecies extrapolation and intra-species 

variation. A margin of exposure (MOE) of 100 is considered adequate for the level of concern.

The FQPA SF is 1 for residential exposures. This study is appropriate for the sentinel population 

of ages 1-2, which is subject to the greatest exposure due to hand-to-mouth feeding. 

Short-Term Dermal Endpoints (residential due to spray drift): The endpoint selected for shortterm dermal exposure scenarios was from a reproduction toxicity study in rat. The offspring 

NOAEL was 25 mg/kg/day. The LOAEL was 125 mg/kg/day based on decreased pup body 

weights and renal pelvic dilatation. The dermal toxicity study in rabbits was considered; 

however, quantitative susceptibility was observed in the rat developmental study. The dermal 

toxicity study did not evaluate findings in the fetus or offspring. The developmental NOAEL in 

the rat study (20 mg/kg/day) is similar to the offspring point of departure, and effects were seen 

as similar doses (90-125 mg/kg/day); therefore, the selected endpoint is also protective of the 

developmental effects seen in rats. Using the reproduction study allows a common endpoint 

with incidental oral exposure and inhalation exposures (nephrotoxicity). A common endpoint 

allows aggregate assessment to be performed, resulting in a more protective risk assessment than 

using the developmental study for a point of departure. Consequently, the developmental study 

was considered to be supportive of the reproduction study. The chosen endpoint is thus 

protective of offspring and fetal effects, as well as all effects observed in the dermal toxicity 

study. The parental kidney effect seen in the reproduction study is not of concern, since kidney 

was evaluated in the route specific dermal study. The reproduction study is protective of the 

sentinel population for residential exposure (children exposed due to spray drift). The standard 

100X UF was applied to account for interspecies extrapolation and intra-species variation. A 

margin of exposure (MOE) of 100 is considered adequate for the level of concern. The FQPA SF 

is 1 for residential exposures. The dermal absorption factor is estimated to be 18% (see Section 

4.2.1).
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Short- and Intermediate-Term Dermal Endpoints (occupational): The endpoint selected for 

short- term dermal exposure scenarios was from a reproduction toxicity study in rat. The 

offspring NOAEL was 25 mg/kg/day. The LOAEL was 125 mg/kg/day based on decreased pup

body weights and renal pelvic dilatation. The standard 100X UF was applied to account for 

interspecies extrapolation and intra-species variation. A margin of exposure (MOE) of 100 is 

considered adequate for risk assessment level of concern. The dermal absorption factor is 

estimated to be 18%. This study was chosen for the reasons provided above for dermal 

residential endpoints. Considering the similar NOAEL/LOAEL values in the rat developmental 

study, the reproduction study is also protective of pregnant workers. 

Short- and Intermediate-Term Inhalation Endpoints (occupational): The endpoint selected for 

short- and intermediate-term inhalation exposure scenarios was from a reproduction study in rats. 

The parental NOAEL was 1.25 mg/kg/day. At the study LOAEL of 25 mg/kg/day, dilatation of 

tubules in the outer medulla of kidneys were noted in both generations in parental females. No 

route specific study was available. As it is unknown exactly how long treatment must continue to 

result in the nephrotoxicity observed in the reproduction study, it was assumed that the toxicity 

may result from short-term exposure in order to be protective of this possibility. This endpoint is 

the most protective endpoint for these exposure scenarios. The standard 100X UF was applied to 

account for interspecies extrapolation and intraspecies variation. A margin of exposure (MOE) 

of 100 is considered adequate for the level of concern. Toxicity by the inhalation route is 

considered to be similar to the oral route.

Carcinogenicity: Sodium acifluorfen is considered likely to be carcinogenic to humans at high 

enough doses to cause the biochemical and histopathological changes in livers of rodents, but 

unlikely to be carcinogenic at doses below those causing these changes. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For short-term exposures, a specific toxic effect (nephrotoxicity) is common to oral, dermal, and 

inhalation routes; therefore, these routes can be combined for risk assessment. For intermediateterm exposures, a specific toxic effect (nephrotoxicity) is common to dermal and inhalation 

routes; therefore, these routes can be combined. Long-term occupational exposures are not 

expected. The endpoint selections for sodium acifluorfen are listed in Table 4.5.4. 

4.5.3 Cancer Classification and Risk Assessment Recommendation

The Cancer Assessment Review Committee (CARC) considered sodium acifluorfen as “likely to be 

carcinogenic to humans at high enough doses to cause the biochemical and histopathological 

changes in livers of rodents, but unlikely to be carcinogenic at doses below those causing these 

changes” (Kidwell, 2003, TXR# 0052014). EPA determined that non-linear extrapolation be 

used for assessment. The non-linear RfD approach will be protective for chronic effects,

including carcinogenicity.

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

Assessment
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Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Sodium Acifluorfen for Use in Dietary 

and Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

NOAEL= 

293 mg/kg

UFA=10x

UFH=10x

FQPA SF=1x

Acute RfD = 

2.9 mg/kg

aPAD = 2.9

mg/kg 

49318001, Acute neurotoxicity

LOAEL = 440 mg/kg based on decreased 

motor activity in females

Acute Dietary 

(Females 13-

49 years of 

age)

NOAEL= 

20 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF=1x

Acute RfD = 

aPAD = 0.20

mg/kg 

00122743, Rat developmental

Developmental LOAEL = 90 mg/kg/day 

based on increased incidence of slightly 

dilated lateral ventricles of the brain

Chronic 

Dietary (All 

Populations)

NOAEL= 

1.25 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF=1x

Chronic RfD 

= cPAD = 

0.013

mg/kg/day 

00155548, Rat reproduction

Parental LOAEL = 25 mg/kg/day based 

on dilatation of tubules in the outer 

medulla of kidneys in parental females of 

both generations (33/35 (P1) and 28/40 

(F1) treated parents vs 0/35-41 controls); 

one occurrence of tubular epithelial 

necrosis was noted in the P1 females 

(compared to 0 controls)

Incidental 

Oral ShortTerm (1-30 

days)

NOAEL= 

25 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF=1x

Residential 

LOC for 

MOE = 100

No residential 

uses. 

Accounts for 

spray drift.

00155548, Rat reproduction

Offspring LOAEL = 125 mg/kg/day 

decreased body weight (both generations; 

↓6-26%) and increased incidence of 

dilatation of the renal pelvis in the F2 

generation

Dermal ShortTerm (1-30 

days)

NOAEL= 

25 

mg/kg/day

DAF=18%

UFA=10x

UFH=10x

FQPA SF=1x

Residential

LOC for 

MOE = 100

No residential 

uses. 

Accounts for 

spray drift.

00155548, Rat reproduction

Offspring LOAEL = 125 mg/kg/day 

decreased body weight (both generations; 

↓6-26%) and increased incidence of 

dilatation of the renal pelvis in the F2 

generation

00122743, Rat developmental is 

supportive

Cancer (oral, 

dermal, 

inhalation)

Classification: likely to be carcinogenic to humans at high enough doses to cause the 

biochemical and histopathological changes in livers of rodents, but unlikely to be carcinogenic 

at doses below those causing these changes. The non-linear RfD approach will be protective for 

chronic effects, including carcinogenicity.

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 
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sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. 

DAF = dermal absorption factor.

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Sodium Acifluorfen 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 Shortand 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL= 

25 

mg/kg/day

DAF=18%

UFA=10x

UFH=10x

Occupational 

LOC for MOE = 

100

00155548, Rat reproduction

Offspring LOAEL = 125 mg/kg/day 

decreased body weight (both generations; 

↓6-26%) and increased incidence of

dilatation of the renal pelvis in the F2 

generation

00122743, Rat developmental is 

supportive

Inhalation 

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL= 

1.25 

mg/kg/day

UFA=10x

UFH=10x

Occupational 

LOC for MOE = 

100

00155548, Rat reproduction

Parental LOAEL = 25 mg/kg/day based 

on dilatation of tubules in the outer 

medulla of kidneys in parental females of 

both generations (33/35 (P1) and 28/40 

(F1) treated parents vs 0/35-41 controls); 

one occurrence of tubular epithelial 

necrosis was noted in the P1 females 

(compared to 0 controls)

Cancer (oral, 

dermal, 

inhalation)

Classification: likely to be carcinogenic to humans at high enough doses to cause the 

biochemical and histopathological changes in livers of rodents, but unlikely to be carcinogenic 

at doses below those causing these changes. The non-linear RfD approach will be protective for 

chronic effects, including carcinogenicity.

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

4.6 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
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taxonomic groups. As part of its preliminary re-registration decision for sodium acifluorfen, 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), 

sodium acifluorfen 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, 20133and includes some

pesticides scheduled for registration review and chemicals found in water. Neither of these lists 

should be construed as a list of known or likely endocrine disruptors. 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 website4.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The requirements for plant metabolism are fulfilled. Adequate studies are available for depicting 

the metabolism in rice, peanuts, and soybeans. Major metabolites in crops included acifluorfen, 

acifluorfen amine and several conjugated metabolites. Tolerances for plant commodities are 

currently expressed in terms of the combined residues of sodium acifluorfen and its metabolites, 

including the corresponding acid, methyl ester, and amino analogues. These data are adequate to 

cover all registered crop uses. 

 

3

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

4

http://www.epa.gov/endo/
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Adequate studies are available for depicting the metabolism in ruminants and poultry, although 

tolerances are not required in livestock commodities as there is no expectation of finite residues 

in livestock tissue [40 CFR §180.6(a)(3)]. 

5.1.2 Summary of Environmental Degradation

D426465. A. Shelby. Acifluorfen: Drinking Water Assessment for Registration Review

Sodium acifluorfen rapidly dissociates to the acifluorfen anion and is expected to be completely 

dissociated during tank mixture and prior to application. The acifluorfen anion is persistent in 

soil (aerobic soil metabolism half-life 170 days) and in aerobic aquatic environments (estimated 

aerobic half-life 117 days); it is less persistent in anaerobic conditions (aquatic half-life 

estimated to be 2.75 days). The acifluorfen ion is mobile to moderately mobile; Koc’s range from 

50 to 199 mL/g. Adsorption and desorption were strongly correlated with soil clay content. 

Acifluorfen undergoes photolytic degradation in water with a half-lives ranging from 21.7 hours 

to 352 hours depending on the pH and buffer systems used. With metabolic persistence and 

mobility in soil, acifluorfen is expected to dissipate and accumulate in groundwater. Acifluorfen 

in surface water is expected to dissipate through photolysis and anaerobic aquatic metabolism. 

Acifluorfen may degrade rapidly in surface water bodies with clear and/or shallow water that is 

able to transmit adequate light. It is stable to hydrolysis, and photodegradation on soil is not a 

major degradation route in the environment. Volatilization does not appear to be a significant 

dissipation pathway for acifluorfen (vapor pressure is <1.33 x 10-5 Pa; Henry's Law constant is 

7.65 x 10-10 atm m3/mol). Acifluorfen is not expected to bioaccumulate in aquatic organisms 

because of its low Kow.

5.1.3 Residues of Concern Summary and Rationale

The residues to be regulated and of toxicological concern in plants are those in the current 

tolerance expression, i.e., the parent compound (sodium salt is not expected to be present), 

acifluorfen acid, acifluorfen amine, and the methyl esters of the acid and the amine. As 40 CFR 

§180.6(a)(3) is applicable for livestock, there is no need to define residues of concern in 

livestock commodities. The residue of concern to be used for the assessment of drinking water 

exposure is acifluorfen acid (D426465, A. Shelby, 4/29/2015). This information is summarized 

in Table 5.1.3.

Table 5.1.3 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

Acifluorfen acid, acifluorfen methyl ester, 

acifluorfen amine, and acifluorfen amine 

methyl ester

Acifluorfen acid, acifluorfen methyl ester, 

acifluorfen amine, and acifluorfen amine methyl 

ester

Livestock Not Applicable Not Applicable

Drinking Water Acifluorfen acid Not Applicable

5.2 Food Residue Profile
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The residue chemistry database is adequate for supporting regulatory conclusions, tolerance 

reassessment, and for the purposes of this risk assessment. The crop field trial results 

demonstrate that residues of sodium acifluorfen are not expected in the raw agricultural 

commodities (RACs) of the registered crops, as all trial samples had <LOQ residues, except for 

rice straw, a livestock feedstuff. Further, exaggerated rate processing studies showed that 

residue concentration does not occur in processed commodities. These residue studies were 

supported by storage stability data for plant commodities (peanut, rice, soybean, and strawberry). 

Storage stability data for animal commodities are not needed as magnitude of the residue data for 

meat, milk, poultry, and eggs are not required (40 CFR §180.6(a)(3)). Sufficient rotational crop 

studies were conducted to support the following plant-back intervals (PBIs) for rotational crops: 

40 days for small grains and 100 days for other crops. Registered crops may be replanted 

immediately.

5.3 Water Residue Profile

D426465. A. Shelby. Acifluorfen: Drinking Water Assessment for Registration Review

Revised estimated drinking water concentrations (EDWCs) were determined by the 

Environmental Fate and Effects Division (EFED) for dietary assessment. Based on groundwater 

modeling results from Pesticide Root Zone Model – Ground Water (PRZM-GW), the maximum 

EDWC for sodium acifluorfen for acute, chronic and 30 year exposure assuming maximum 

application rates for current uses is 146 ppb for the 1 in 10 year peak, annual average, and 30 

year annual average concentrations.

The acute EDWC for use on rice is 218 ppb and the chronic EDWC for use on rice is 88 ppb. 

The level of 218 ppb is higher than the acute EDWC recommended for use by HED in this 

assessment but significant dilution and degradation can be expected to occur with acifluorfen 

concentrations expected to be lower than the acute groundwater EDWC for strawberries (146 

ppb) before reaching a drinking water intake. Therefore, the acute EDWC recommended for use 

by HED is 146 ppb.

This maximum EDWC is derived from the strawberry use on the Wisconsin Sands PRZM-GW 

scenario. Surface water modeling resulted in lower EDWCs. The maximum estimated surface 

exposure concentration for acifluorfen is 66.8 ppb for acute exposure. 

Table 5.3 Summary of Estimated Surface Water and Groundwater Concentrations 

for Acifluorfen

Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute 66.8 146

Chronic (non-cancer) 9.67 146

a From the Tier II PRZM-EXAMS - Index Reservoir model. 

b From the PRZM-GW model.

Acifluorfen is a rapidly forming degradate of the registered pesticide active ingredient lactofen 

(PC Code 128888). Acifluorfen and lactofen have similar soybean, peanut, and strawberry use 

patterns in common. Given the overlap in residues and use pattern, acifluorfen has the potential 
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to be in surface water or groundwater as a result of an application of either active ingredient. 

However, maximum label use rates for each lactofen use are half or less than the respective 

acifluorfen application rate for the same use site. Therefore, groundwater EDWCs derived from 

the acifluorfen use pattern are conservative with respect to expected groundwater EDWCs for 

lactofen. 

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Established tolerances for sodium acifluorfen are listed under 40 CFR §180.383. These values 

form the basis for the residue levels used in the acute and chronic analyses, together with default 

processing factors. The residue chemistry database for sodium acifluorfen indicates no residue 

concentration in processed commodities from rice, soybean, or peanut (D252560, W. Hazel, 05-

MAY-2000). Thus, all processing factors were set to a default of one (1). 

Acifluorfen is a degradate of two registered herbicides, lactofen and sodium acifluorfen. 

Acifluorfen and lactofen have similar soybean, peanut, and strawberry use patterns in common. 

Because the maximum use rates for lactofen are no more than half the corresponding acifluorfen 

rates, and no acifluorfen residues were found in foods from the field trial studies, HED considers 

the use of acifluorfen tolerance level residues to include any potential food contributions to total 

acifluorofen exposure from lactofen. 

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

Environmental Fate and Effects Division (EFED) in the following memorandum: “Acifluorfen: 

Drinking Water Assessment for Registration Review” (D426465, A. Shelby, 04/29/2015) and 

incorporated directly into this dietary assessment. Water residues were incorporated in the 

DEEM-FCID into the food categories “water, direct, all sources” and “water, indirect, all 

sources.” 

EFED provided surface and ground water modeling results for registered acifluorfen crop uses. 

As the ground water models gave higher water concentrations than the surface water models, 

ground water results form the basis for the EDWCs recommended for use in the current dietary 

assessment. The rice use was modeled using the Pesticides in Flooded Application Model 

(PFAM); however, water concentrations from the rice use are expected to be lower than the 

ground water EDWCs from the strawberry use, due to dilution and degradation effects involved 

with acifluorfen treated rice paddy water.

Groundwater EDWCs were calculated from PRZM-GW for uses on soybean, peanut, and 

strawberry with six groundwater scenarios, which are intended to broadly represent vulnerable, 

shallow unconsolidated aquifers across the United States. The highest ground water estimate for 

acifluorfen came from the strawberry use pattern in WI sands (146 ppb) and was used in both the 

acute and chronic dietary analyses. 

5.4.2 Percent Crop Treated Used in Dietary Assessment
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For the acute and chronic dietary analyses, 100% crop treated was assumed for all crops.

5.4.3 Acute Dietary Risk Assessment

An unrefined acute dietary (food and drinking water) exposure assessment was conducted for all 

established uses of sodium acifluorfen. Maximum estimated drinking water concentrations 

(EDWCs) from the Environmental Fate and Effects Division (EFED) were also included. No 

percent crop treated (%CT) refinements were utilized (i.e., 100% CT was assumed for all crops). 

Tolerance level residues along with default processing factors were used where appropriate. At 

the 95th percentile of exposure, the estimated risk was < 1% of the acute population adjusted dose 

(aPAD) for the U.S. population and all population subgroups except females 13-49 years old . . 

A separate point of departure (PoD) was selected for females 13-49 years old and the estimated 

risk was 4.0% of the aPAD for this population subgroup. A food only analysis demonstrated that 

water is the primary contributor to aggregate (food + water) dietary exposure to sodium 

acifluorfen. 

5.4.4 Chronic Dietary Risk Assessment

An unrefined chronic dietary exposure analysis was performed for all established uses of sodium 

acifluorfen. Tolerance level residues, 100% CT assumptions, and default processing factors 

were used. The estimated risk was 24% of the chronic population adjusted dose (cPAD) for the 

U.S. population. The most highly exposed population subgroup was all infants at 62% of the 

cPAD. A food only analysis demonstrated that water is the primary contributor to aggregate 

(food + water) dietary exposure to sodium acifluorfen. 

5.4.5 Cancer Dietary Risk Assessment

Sodium acifluorfen was classified as “likely to be carcinogenic to humans at high enough doses 

to cause the biochemical and histopathological changes in livers of rodents, but unlikely to be 

carcinogenic at doses below those causing these changes. EPA determined that non-linear 

extrapolation be used for assessment; therefore, no separate Q1* based cancer dietary exposure 

assessment was required.

The chronic RfD of 0.013 mg/kg/day is protective of both cancer and non-cancer effects. A noncancer chronic dietary risk assessment was completed as described in Section 5.4.4.; risk levels 

were below the LOC of 100% cPAD and are considered protective for both non-cancer and 

cancer risk. 

5.4.6 Summary Table

Table 5.4.6 summarizes the results of the acute and chronic dietary analyses conducted for 

sodium acifluorfen. Although highly conservative assumptions were used in these dietary 

assessments, risk levels do not exceed HED’s level of concern of 100% aPAD or 100% cPAD.
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Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Sodium 

Acifluorfen.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.008117 < 1 0.003153 24

All Infants (<1 year old)* 0.025328 < 1 0.008113 62

N/A N/A

Children 1-2 years old 0.012729 < 1 0.004678 36

Children 3-5 years old 0.010161 < 1 0.003939 30

Children 6-12 years old 0.007742 < 1 0.002818 22

Youth 13-19 years old 0.006794 < 1 0.002307 18

Adults 20-49 years old 0.007963 < 1 0.003132 24

Adults 50-99 years old 0.007107 < 1 0.003084 24

Females 13-49 years old* 0.008066 4.0 0.003112 24

*The subpopulation(s) with the highest risk estimates.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no registered residential uses at this time. The previously registered products with 

residential uses have been cancelled or suspended. 

6.1 Residential Bystander Post-application 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 sodium 

acifluorfen.

6.2 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 indirect 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 onto 50-feet wide lawns 

coupled with methods employed for residential risk assessments for turf products.
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The approach to be used for quantitatively incorporating spray drift into risk assessment is based 

on a premise of compliant applications which, by definition, should not result in direct exposures 

to individuals because of existing label language and other regulatory requirements intended to 

prevent them.5 Direct exposures would include inhalation of the spray plume or being sprayed 

directly. Rather, the exposures addressed here are thought to occur indirectly through contact 

with impacted areas, such as residential lawns, when compliant applications are conducted. 

Given this premise, 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 indirect 

exposure, are the focus of this analysis analogous to how exposures to turf products are 

considered in risk assessment. 

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 sodium acifluorfen. 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 and the 

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift Policy. 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 based on the use of the AgDrift model in situations where 

specific label guidance that defines application parameters is not available.6,7 AgDrift is 

appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and 

ground boom 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. These screening options are consistent with how 

spray drift is considered in a number of ecological risk assessments and in the process used to 

develop drinking water concentrations used for risk assessment. 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). Tables 6.2.1 and 6.2.2 provide the screening level drift-related risk estimates. 

The spray drift risk estimates are based on an estimated deposited residue concentration, as a 

result of the screening level agricultural application scenarios. Sodium acifluorfen can be 

applied via ground boom and aerial equipment. The spray drift assessment was completed 

assuming the maximum single application rate of 0.375 lb ai/acre; this is protective of all 

applications at a lower rate. Chemical-specific TTR data were not available; therefore, default 

assumptions were used to estimate transferable residue. 

 

5 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.

6http://www.agdrift.com/ 

7 Note that for many cases the scenarios outlined in the screening approach represent actual use practice so risk assessors should 

be aware and characterize these appropriately.
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The recommended drift scenario screening level options are listed below: 

 Ground boom 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).8

Spray drift exposure is possible for adults and children. Adults may have short-term dermal 

exposure and children may have short-term dermal and incidental oral exposure from spray drift. 

The applicable Level of Concern is 100, so MOEs < 100 would be of concern. Exposures were 

considered for 50 feet wide lawns where the nearest side of the property was directly adjoining 

the treated field (at field edge). Results are presented in Tables 6.6.1 and 6.6.2; no risk estimates 

of concern were identified at field edge for adults or children.

Table 6.2.1 Adult Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Sodium 

Acifluorfen for the Dermal Route of Exposure

Crop/Rate Group Spray Type/ Nozzle 

Configuration

Appl. Rate 

(lb ai/A) TTR (μg/cm2

) MOE At Field Edge

Groundboom High Boom Very fine to 

Fine 0.375 0.0417

5,300

Aerial Fine to Medium 3,800

Table 6.2.2 Children (1<2 years old) Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for 

Sodium Acifluorfen for the Combined Dermal and Oral Route of Exposure

Crop/Rate Group Spray Type/ Nozzle 

Configuration

Appl. Rate 

(lb ai/A) TTR (μg/cm2

) MOE At Field Edge

Groundboom High Boom Very fine to 

Fine 0.375 0.0417

2,400

Aerial Fine to Medium 1,700

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and 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.

7.1 Acute Aggregate Risk

 

8 AgDrift allows for consideration of even finer spray patterns characterized as very fine to fine. However, this 

spray pattern was not selected as the common screening basis since it is used less commonly for most agriculture.
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The acute aggregate risk assessment includes food and water exposure only. The acute food plus 

drinking water risk estimates are not of concern to HED for the general population and all 

population subgroups. Refer to section 5.4.3 for a detailed discussion of the chronic dietary risk 

assessment.

7.2 Short-Term Aggregate Risk

Since there are no uses for sodium acifluorfen that would result in residential (non-occupational) 

exposure, a short-term aggregate risk assessment is not required. 

7.3 Intermediate-Term Aggregate Risk

Since there are no uses for sodium acifluorfen that would result in residential (non-occupational) 

exposure, an intermediate-term aggregate risk assessment is not required. 

7.4 Chronic Aggregate Risk

The chronic aggregate risk assessment includes food and water exposure only. The chronic food 

plus drinking water risk estimates are not of concern to HED for the general population and all 

population sub-groups. Refer to section 5.4.4 for a detailed discussion of the chronic dietary risk 

assessment.

7.5 Cancer Aggregate Risk

Sodium acifluorfen was classified as “likely to be carcinogenic to humans at high enough doses 

to cause the biochemical and histopathological changes in livers of rodents, but unlikely to be 

carcinogenic at doses below those causing these changes. EPA determined that non-linear 

extrapolation be used for assessment; therefore, no separate Q1* based cancer aggregate 

assessment is required.

A non-cancer chronic dietary risk assessment was completed as described in Section 5.4.4; risk 

levels were below the LOC of 100% cPAD and are considered protective for both non-cancer 

and cancer risk. 

8.0 Cumulative Exposure/Risk Characterization

Sodium acifluorfen is a member of the diphenyl ether group of herbicides, which includes 

lactofen and oxyfluorfen. In addition, acifluorfen is a degradate of lactofen (acifluorofen 

exposure from lactofen is addressed in Section 5.3 and 5.4.1). EPA has some evidence that these 

compounds induce similar toxic effects but has not yet determined whether or not these 

compounds exhibit a common mechanism. For this assessment of acifluorfen, therefore, EPA 

will not conduct a cumulative risk assessment. 
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9.0 Occupational Exposure/Risk Characterization

An occupational exposure and risk assessment was completed to include all registered uses of 

sodium acifluorfen.

9.1 Short-/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. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: 

 Mixing/loading L/SC/EC in support of aerial application to typical and high-acreage field 

crops

 Mixing/loading L/SC/EC in support of ground boom application to typical and highacreage field crops

 Applying spray via aerial application to typical and high-acreage field crops

 Applying spray via ground boom application to typical and high-acreage field crops

 Flagging in support of aerial application

 Mixing/loading/applying L/SC/EC via mechanically-pressurized handgun

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. Maximum application rates were assumed. 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 Table9”. Area treated assumptions are from Exposure Science Advisory Council 

Policy #9.1.

Occupational handler combined dermal and inhalation MOEs range from 99 to 33,000 with 

baseline PPE (single layer clothing, no gloves, and no respirator for all scenarios, except aerial 

applicator where engineering controls were used). The one scenario with an MOE < 100 

(mixing/loading in support of aerial application to high acreage field crop) was not of concern 

with the addition of gloves. Since gloves are currently required on the registered labels, there are 

no occupational handler risk estimates of concern for registered uses.

 

9 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf
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Table 9.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Sodium Acifluorfen. 

Exposure Scenario Crop or 

Target

Level of 

Concern

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Total

Mitigation 

Level

Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

Mixer/Loader

Mixing/loading, L/SC/EC, 

Aerial, Broadcast

Typical 

Field Crop

100

SL/No G: 220 No R: 0.219 0.375 350 acres 0.065 380 0.000359 3,500 340

High 

Acreage 

Field Crop

SL/No G: 220

No R: 0.219 0.375

1200 acres

0.223 110

0.00123 1,000

99

SL/G: 37.6 0.038 660 400

SL/No G: 220 No R: 0.219 0.25 0.149 170 0.000821 1,500 150

Mixing/loading, L/SC/EC, 

Groundboom

Typical 

Field Crop SL/No G: 220 No R: 0.219 0.375 80 acres 0.0149 1,700 0.0000821 15,000 1,500

High 

Acreage 

Field Crop

SL/No G: 220 No R: 0.219 0.375

200 acres

0.0371 670 0.000205 6,100 600

SL/No G: 220 No R: 0.219 0.25 0.0248 1,000 0.000138 9,100 900

Applicator

Applicator, Spray, Aerial

Typical 

Field Crop

100

Eng. Control: 

2.08

Eng. Control: 

0.0049 0.375 350 acres 0.000614 41,000 0.00000804 160,000 33,000

High 

Acreage 

Field Crop

Eng. Control: 

2.08

Eng. Control: 

0.0049 0.375

1200 acres

0.00211 12,000 0.0000276 45,000 9,500

Eng. Control: 

2.08

Eng. Control: 

0.0049 0.25 0.0014 18,000 0.0000184 68,000 14,000

Applicator, Spray, 

Groundboom

Typical 

Field Crop SL/ No G: 78.6 No R: 0.34 0.375 80 acres 0.00531 4,700 0.000128 9,800 3,200

High 

Acreage 

Field Crop

SL/ No G: 78.6 No R: 0.34 0.375

200 acres

0.0133 1,900 0.000319 3,900 1,300

SL/ No G: 78.6 No R: 0.34 0.25 0.00884 2,800 0.000213 5,900 1,900

Mixer/Loader/Applicator

Mixer/Loader/Applicator, 

L/SC/EC, Mechanicallypressurized handgun

Typical 

Field Crop 100 SL/ No G: 1300 No R: 3.9

0.01875 lb 

ai/gallon 

(20 gal 

H2O/A)

1000 

gallons 0.0549 460 0.000914 1,400 350

Flagger

Flagging in support of Typical/ 100 SL/ No G: 11 No R: 0.35 0.375 350 acres 0.00324 7,700 0.000574 2,200 1,700
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Table 9.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Sodium Acifluorfen. 

Exposure Scenario Crop or 

Target

Level of 

Concern

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Total

Mitigation 

Level

Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

aerial application High 

Acreage 

Field Crop

SL/ No G: 11 No R: 0.35 0.25 0.00217 12,000 0.000383 3,300 2,600

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline, PPE, Eng. Controls.

2 Based on registered labels (See Section 4.0).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF (18%) ÷ BW 

(80kg).

5 Dermal MOE = Dermal NOAEL (25 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (80kg).

7 Inhalation MOE = Inhalation NOAEL (1.25 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 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.

9.2.1 Dermal Post-application Risk

HED has determined that there are potential exposures to persons entering treated sites (e.g., 

harvesters) after application of sodium acifluorfen is complete. A series of assumptions and 

exposure factors served as the basis for completing the occupational post-application risk 

assessments. Maximum application rates were assumed. 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 310”. There are DFR data available on 

soybean plants treated with sodium acifluorfen (D270366, T. Dole, 2/13/01). The results of the 

post-application occupational exposure and risk assessment indicate that risk estimates are not a 

concern on the day of application (12 hours following the end of the application). HED concurs 

with the default 48-hr REI.

The table below summarizes the occupational post-application risk estimates for the registered

applications of sodium acifluorfen. The occupational post-application exposure and risk 

estimates indicate that short- and intermediate-term MOEs are not of concern to HED (i.e., 

MOEs > 100). Occupational post-application dermal MOEs range from 1,000 to 41,000 and are 

not of concern (LOC = 100).

Table 9.2. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Sodium 

Acifluorfen.

Crop/Site Activities Transfer Coefficient 

(cm2/hr)

DFR/TTR1 

(Day 0)

Dermal Dose 

(mg/kg/day)2 MOE3

Short- and Intermediate-term

Peanuts 

Hand weeding 70

0.72

0.0009 28,000

Scouting 210 0.0027 9,200

Irrigation 1900 0.0246 1,000

Rice

Hand weeding 70

0.48

0.0006 41,000

Scouting 1100 0.0095 2,600

Soybeans 

Hand weeding 70

0.72

0.0009 28,000

Scouting 1100 0.0142 1,800

 

10 Available: http://www.epa.gov/pesticides/science/exposac_policy3.pdf
Sodium Acifluorfen Human Health Risk Assessment DP No. D426393

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Table 9.2. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Sodium 

Acifluorfen.

Crop/Site Activities Transfer Coefficient 

(cm2/hr)

DFR/TTR1 

(Day 0)

Dermal Dose 

(mg/kg/day)2 MOE3

Short- and Intermediate-term

Strawberries 

Hand weeding 70

0.72

0.0009 28,000

Scouting 210 0.0027 9,200

1 DFR from chemical-specific study. The DFR was adjusted for the different application rate for rice.

2 Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)] ÷ BW (kg).

3 MOE = POD (25 mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm2) × TC × 0.001 mg/μg × 8 hrs/day ×

dermal absorption factor (%)]  BW (kg).

Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of sodium acifluorfen. 

Sodium acifluorfen is classified as Toxicity Category III via the dermal route, Toxicity Category 

II for skin irritation potential, and Toxicity Category I for acute eye irritation. It is not a skin 

sensitizer. Short- and intermediate-term post-application risk estimates were not a concern on 

day 0 (12 hours following application) for all post-application activities. Under 40 CFR 

§156.208 (c) (2) (iii), ai’s classified as Acute Category I for acute dermal, eye irritation or 

primary skin irritation are assigned a 48-hour REI. Therefore, the [156 subpart K] Worker 

Protection Statement interim REI of 48 hours is adequate to protect agricultural workers from 

post-application exposures to sodium acifluorfen. 

9.2.2 Inhalation Post-application Risk

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 sodium acifluorfen.

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.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 
Sodium Acifluorfen Human Health Risk Assessment DP No. D426393

Page 35 of 48

inhalation exposure estimates would be protective of occupational post-application inhalation 

exposure scenarios.

10.0 Human Incidents/Epidemiology 

D426519. Sodium Acifluorfen: Tier I Update Review of Human Incidents/Epidemiology for Draft Risk Assessment. 

S. Recore. 4/2/15.

Sodium acifluorfen was previously reviewed in 2009 (S. Recore, 11/24/2009, D370339). At the 

time, no sodium acifluorfen incidents were found in Main IDS for the single chemical sodium 

acifluorfen reviewing data from 2002 to 2009. It was concluded that “Because there are no 

incident cases identified, there does not appear to be a risk concern at this time that would 

warrant further investigation.” 

The current IDS analysis from January 1, 2010 through March 26, 2015, shows no incidents 

reported involving sodium acifluorfen in Main IDS and one incident, classified as minor 

severity, reported to Aggregate IDS. Further, a query of SENSOR-Pesticides 1998-2011 

identifies no incidents involving sodium acifluorfen.

The Agricultural Health Study (AHS) is also a potential source of information associated with 

human health effects associated with certain pesticides. Sodium acifluorfen is included in the 

AHS, but is only in phase III and the data is not currently available. Therefore this study does not 

provide information for this report.

Based on the low frequency and mostly low severity of incident cases reported for sodium 

acifluorfen in both IDS and NIOSH SENSOR-Pesticides, there does not appear to be a concern 

at this time that would warrant further investigation. The Agency will continue to monitor the 

incident and epidemiology information and if a concern is triggered, additional analysis will be 

conducted.

11.0 References 

Author Barcode Date Title

W. Donovan D427185 5/18/15

Sodium Acifluorfen. Acute and Chronic Aggregate Dietary (Food 

and Drinking Water) Exposure and Risk Assessments for 

Registration Review. 

A.Gavelek D427186 6/17/15 Sodium Acifluorfen. Occupational and Residential Exposure 

Assessment for Registration Review

A. Shelby D426465 4/29/15 Acifluorfen: Drinking Water Assessment for Registration Review. 

S. Recore D426319 4/2/15 Sodium Acifluorfen: Tier I Update Review of Human 

Incidents/Epidemiology for Draft Risk Assessment. 

T. Goolow et 

al. D370342 3/23/10 Sodium Acifluorfen. Human Health Assessment Scoping Document in Support of Registration Review. 

F. Fort D279845 12/18/01 Sodium Acifluorfen. Revised Product and Residue Chemistry 

Chapters of the Reregistration Eligibility Decision

F. Fort D279844 12/18/01

Sodium Acifluorfen. Response to Registrant Comments Regarding 

the Product and Residue Chemistry Chapters of the Reregistration 

Eligibility Decision

F. Fort D279173 12/6/01 Sodium Acifluorfen. Dietary Exposure Analyses for the HED 

Preliminary Human Health Risk Assessment. 
Sodium Acifluorfen Human Health Risk Assessment DP No. D426393

Page 36 of 48

Author Barcode Date Title

T. Dole D279482 11/13/01

Sodium Acifluorfen: Second Revised Occupational and 

Residential Exposure and Risk Assessment for the Reregistration 

Eligibility Decision (RED) Document

K. Farwell D291742 7/14/03 Sodium Acifluorfen. Revision to the HED Chapter of the 

Reregistration Eligibility Decision Document

T. Dole D270365 2/14/01

Review of Acifluorfen (Blazer) Groundboom 

Mixer/Loader/Applicator Exposure and Biomonitoring Study

(MRID 423615-01) for use in Acifluorfen exposure and 

assessment

T. Dole D270366 2/13/01

Review of Acifluorfen (Blazer) Foliar Dislodgeable Residues on 

Soybeans (MRID 440911-01) and Storage Stability of 

Acifluorfen-Amine in Foliar Dislodging Solution (MRID 440911-

02) for use in Acifluorfen exposure and assessment

K. Farwell D279497 1/15/02 Sodium Acifluorfen. HED Chapter for the Reregistration 

Eligibility Decision Document.

K. Farwell D274255 4/27/01 Sodium Acifluorfen. HED Chapter for the Reregistration 

Eligibility Decision Document

K. Farwell D252555 5/31/00 Sodium Acifluorfen. HED Chapter for the Reregistration 

Eligibility Decision Document.

B. Tarplee None 9/29/99 Acifluorfen: Report of the FQPA Safety Factor Committee. TXR 

No. 013764

P. Chin None 4/7/99 Acifluorfen: Report of the Hazard Identification Assessment 

Review Committee. TXR No. 013308

NA None 9/2003 Reregistration Eligibility Decision for Sodium Acifluorfen

E. Craig None 5/7/15

Sodium Acifluorfen: Summary of Hazard and Science Policy 

Council (HASPOC) Meeting of February 19, 2015: 

Recommendations on the Need for a Subchronic and 

Developmental Neurotoxicity Studies and a Subchronic Inhalation 

Toxicity Study.
Sodium Acifluorfen Human Health Risk Assessment DP No. D426393

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for food-use for sodium acifluorfen are in Table 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 28-Day Dermal..............................................................

870.3250 90-Day Dermal..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

yes

yes

yes a

yes

-

yes b

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) ...................................................

yes

no

yes

yes

yes

-

yes

yes

870.5100 Mutagenicity—Bacterial reverse mutation assay ....................

870.5300 Mutagenicity—In vitro mammalian cell gene mutation test.......

870.5375 Mutagenicity—In vitro mammalian chromosome aberration test

870.5395 Mutagenicity—Mammalian erythrocyte micronucleus test........

yes

yes

yes

yes

yes c

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen) ..........................................

870.6200a Acute Neurotoxicity Screening Battery (rat).................

870.6200b 90-Day Neurotoxicity Screening Battery (rat) ..............

870.6300 Developmental Neurotoxicity .......................................

no

no

yes

yes

yes

-

-

yes

yes b

yes b

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

yes

yes

yes

yes

yes

a Test was not submitted but is not required at this time because the toxicological data requirements for the 90-day feeding 

study in non-rodents are satisfied by the 1-year feeding study in dogs.

b A waiver for this study was obtained from HASPOC (Craig, 2015, TXR# 0051465).

c Over 20 mutagenicity studies were submitted. A select number are presented in the Toxicity Profile table. Requirements 

for the mutagenicity battery were satisfied.

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile – Acifluorfen 2S a
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Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral - Rat 00122724 LD50 = 2025 

mg/kg ♂

LD50 = 1370 

mg/kg ♀

III

870.1200 Acute dermal - Rat 00061626 LD50 > 2000 

mg/kg

III

870.1300 Acute inhalation - Rat 00061627 LC50 > 6.9 mg/L IV

870.2400 Acute eye irritation - Rabbit 00061628 Severe eye irritant I

870.2500 Acute dermal irritation - Rabbit 00061629 Moderate to 

severe erythema

II

870.2600 Skin sensitization - Guinea Pig 46683402 Not a sensitizer NA

a Purity of 20.2-23.25% a.i.

Table A.2.2 Sub-chronic, Chronic and Other Toxicity Profile - Sodium Acifluorfen

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.3050 28-Day oral 

toxicity (mouse)

45323503 (1983) 

Acceptable, guideline

♂♀: 0, 59, 181, 522, 

1286, 2471, 4983 ppm

♂♀: 0, 8.8, 27, 78, 193, 

371, 747 mg/kg/day based 

on 1 ppm = 0.15 

mg/kg/day

83.9% a.i.

NOAEL = 27 mg/kg/day

LOAEL = 78 mg/kg/day based on increased 

absolute and relative liver weight and 

histological changes in liver (# treated/10 vs 

0/10 controls): slight to moderate multifocal 

acidophilia (2-3), multifocal cell disassociation 

(1 each sex), multifocal hepatocellular 

hypertrophy (7-10), and diffuse hepatocellular 

hypertrophy (1 female)

At 193 mg/kg/day, increased absolute and 

relative liver weight and histological changes in 

liver (# treated/10 vs 0/10 controls): slight to 

moderate multifocal acidophilia (10 each sex), 

multifocal cell disassociation (8-9), diffuse cell 

disassociation (2 males), multifocal 

hepatocellular hypertrophy (7-10), diffuse 

hepatocellular hypertrophy (2 each sex), and 

coagulative necrosis (1 each sex)

At 371 and/or 747 mg/kg/day, histological 

findings in the liver were more pronounced. 

Serum ALT, AST, and cholesterol were 

increased, and serum glucose was decreased. 

Body weights were decreased. In the kidney, 

increased organ weight, mitotic increase, and 

nuclear enlargement was noted.
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Table A.2.2 Sub-chronic, Chronic and Other Toxicity Profile - Sodium Acifluorfen

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.3100 90-Day oral 

toxicity (Fischer 

344 rat)

00122730 (1982)

Acceptable, guideline

♂♀: 0, 20, 80, 320, 1250, 

2500, 5000 ppm

♂♀: 0, 2, 8, 32, 125, 250, 

500 mg/kg/day based on 1 

ppm = 0.1 mg/kg/day

Tackle 2S, 20.4-23.6% a.i.

NOAEL = 32 mg/kg/day

LOAEL = 125 mg/kg/day based on decreases

in hematology parameters (erythrocyte count 

[↓11%] and hematocrit concentration [↓11%) in 

males), increases in liver and kidney weights, 

and increased incidence of hypertrophy of liver 

cells 

At 2500 and 5000 ppm, changes in body 

weights, hematology (erythrocyte count and 

hemoglobin concentration), clinical chemistry 

(serum electrolytes, calcium and phosphorous; 

SGPT and alkaline phosphatase activities; 

BUN, creatinine, total serum protein, albumin, 

and globulin concentrations), urine (nitrate and 

urobilinogen content), liver and kidney weights 

(absolute and relative), and histopathologic

changes in the liver (increased cellular 

hypertrophy, cell death, mitotic activity, and 

proliferation of oval or bile duct cells) were 

noted.

Note: Although the effects observed at 125 

mg/kg/day are probably not adverse, this study 

was not updated as it is not essential to risk 

assessment.

870.3100 90-Day oral 

toxicity (mouse)

00252826 (1982)

Unacceptable, guideline

♂♀: 0, 20, 80, 320, 1250, 

2500, 5000 ppm

♂♀: 0, 3, 12, 48, 187.5, 

375, 750 mg/kg/day based 

on 1 ppm = 0.15

mg/kg/day

Tackle 2S, 20.4-23.2% a.i.

NOAEL = 48 mg/kg/day

LOAEL = 187.5 mg/kg/day based on fatty 

infiltration of the liver in males (17/20 treated 

vs 5/20 controls) and females (17/20 treated vs 

8/18 controls) 

Changes in mean body weights, hematology 

(total white blood cell numbers, MCV,

reticulocyte counts), clinical chemistry (SGPT, 

SAP, serum glucose), liver weights (absolute 

and relative), and histopathologial changes in 

the liver (hypertrophy, increased mitotic

activity, individual cell death, focal necrosis) 

were noted in males and females at the 2500 

and 5000 ppm dose at 30 and 90 days.

Upgradable if the registrant submitted the 

following: a) individual animal histopathology 

and b) explain "water mechanical problems" 

and "cage flooding by equipment malfunction."

TXR0003963 says that (b) was explained but 

individual histology was not received as of 

1989. This study is not essential to risk 

assessment.

870.3150 90-Day oral 

toxicity (dog)

Not submitted and not 

required

-
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Table A.2.2 Sub-chronic, Chronic and Other Toxicity Profile - Sodium Acifluorfen

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.3200 21-Day dermal 

toxicity (rabbit)

00122731 (1981)

Acceptable, non-guideline

♂♀: 0, 100, 300, 1000 

mg/kg/day; high dose 

reduced to 500 mg/kg/day 

on Day 4 by which time 4 

rabbits/sex were dead

Tackle 2S, 21.1% a.i

NOAEL = 300 mg/kg/day

LOAEL = 1000 mg/kg/day based on mortality

Skin irritation (based on erythema and edema 

scores) was noted at the lowest dose tested.

19/20 animals at the high dose died by Day 8, 

resulting in the study effectively having only 2 

dose groups for evaluation. In addition,

histopathological examinations were limited to 

the liver and kidneys in all animals and to

organs with gross lesions.

870.3250 90-Day dermal 

toxicity (species)

Not submitted and not 

required

-

870.3465 90-Day inhalation 

toxicity (species)

Not submitted and not 

required

-

870.3700a Prenatal 

developmental 

(SD rat)

00122743 (1981)

Acceptable, guideline

0, 20, 90, 180 mg/kg/day

GD 6-19

Tackle “2S” (22.4% a.i.)

Maternal NOAEL = 90 mg/kg/day

LOAEL = 180 mg/kg/day based on decreased 

body weights and increased incidence of 

clinical signs, such as excessive salivation, 

urine-stained fur of the abdomen, rales, 

decreased motor activity and

chromodacryorrhea

Developmental NOAEL = 20 mg/kg/day

Developmental LOAEL = 90 mg/kg/day based 

on decreased fetal body weight and increased 

incidence of slightly dilated lateral ventricles of 

the brain

At 180 mg/kg/day, the effect on body weight 

was magnified while the incidence of brain 

effect remained similar.

870.3700a Prenatal 

developmental 

(Wistar rat)

49297001 (2015)

Acceptable, non-guideline

0, 30, 60, 90 mg/kg/day

GD 5-19

Acifluorfen Sodium TC 

(43.4% a.i.)

Maternal NOAEL = 90 mg/kg/day

LOAEL was not observed

Developmental NOAEL = 90 mg/kg/day

LOAEL was not observed

The animals could have tolerated a higher dose.

870.3700b Prenatal 

developmental 

(rabbit)

00122744 (1980)

Acceptable, non-guideline

0, 3, 12, 36 mg/kg/day

GD 6-29

Tackle “2S” (22.4% a.i.)

Maternal NOAEL = 36 mg/kg/day

LOAEL was not observed

Developmental NOAEL = 36 mg/kg/day

LOAEL was not observed

The animals could have tolerated a higher dose.
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Table A.2.2 Sub-chronic, Chronic and Other Toxicity Profile - Sodium Acifluorfen

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.3700b Prenatal 

developmental 

(rabbit)

00107485 (1979)

Unacceptable, guideline

0, 20, 60, 180 mg/kg/day

GD 7-19

(39.8% a.i.)

Maternal NOAEL = 20 mg/kg/day

LOAEL = 60 mg/kg/day based on clinical signs 

observed during GD 7-19: anorexia (9/15 

treated vs 5/15 controls), depression (5/15 vs 

1/15 control), and dyspnea (1/15 vs 0/15 

controls).

At 180 mg/kg/day, excessive mortality was 

observed (11/15 treated vs 1/15 controls).

Developmental NOAEL = 60 mg/kg/day

LOAEL = 180 mg/kg/day based on fetal 

resorptions

Considered unacceptable, because it was not 

stated how often the dose formulations were 

prepared. Furthermore, no concentration or 

stability data were submitted. Consequently, 

there is no way to verify the actual

concentration of the test material given to the 

does.

870.3800 Reproduction and 

fertility effects

(SD rat)

00155548 (1986)

Acceptable, guideline

♂♀: 0, 25, 500, 2500 ppm 

♂♀: 0, 1.25, 25, 125

mg/kg/day based on 1 

ppm = 0.05 mg/kg/day

Tackle

Parental/Systemic NOAEL = 1.25 mg/kg/day

LOAEL = 25 mg/kg/day based on dilatation of 

tubules in the outer medulla of kidneys in

females of both generations (33/35 (P1) and 

28/40 (F1) treated vs 0/35-41 controls)

At 125 mg/kg/day, increased mortality was 

noted in both generations, as well as decreased 

body weight. Renal tubular necrosis was also 

observed.

Reproductive NOAEL = 125 mg/kg/day

LOAEL was not observed

Offspring NOAEL = 25 mg/kg/day

LOAEL = 125 mg/kg/day decreased body 

weight (both generations; ↓6-26%) and 

increased incidence of dilatation of the renal 

pelvis in the F2 generation (litters: 38% treated 

vs 7% controls; pups: 7% treated vs 1% 

controls).

870.4100a Chronic toxicity

(rat)

Not submitted. See 

870.4300.

-
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Table A.2.2 Sub-chronic, Chronic and Other Toxicity Profile - Sodium Acifluorfen

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.4100b Chronic toxicity 

(dog)

00131162 (1983)

Unacceptable, guideline

Upgradable

♂♀: 0, 20, 300, 4500 ppm 

♂♀: 0, 0.5, 7.5, 112.5

mg/kg/day based on 1 

ppm = 0.025 mg/kg/day

Tackle 2S

NOAEL = 7.5 mg/kg/day

LOAEL = 112.5 mg/kg/day based on decreased

body weight gain, increased absolute and

relative liver and kidney weights, changes in

hematology, biochemistry, and urinalysis

parameters and increased incidence of 

microscopic changes in the liver 

Reasons for this classification are the purity of 

the test substance was not adequately identified 

in the text of the report and stability of the test

substance in dog chow was not reported. 

However, a new study is not required because

when this study and the data of another chronic

feeding study in dog (MRID 00107484) with 

Blazer are analyzed together, they provide a 

reasonable understanding of the chronic

toxicity of acifluorfen in dogs. The previous 

chronic feeding study in dog (MRID 00107484; 

1978) was classified as core guideline data. 

870.4100b Chronic toxicity 

(dog)

00107484 (1978)

Acceptable, guideline

♂♀: 0, 50, 300, 1800, 

5400 ppm 

♂♀: 0, 1.25, 7.5, 45, 135

mg/kg/day based on 1 

ppm = 0.025 mg/kg/day

Blazer

NOAEL = 1.25 mg/kg/day

LOAEL = 7.5 mg/kg/day based on coagulation 

effects 

There were changes in hematological and 

biochemical parameters related to effects in the 

liver in dogs at 45 and 135 mg/kg/day when 

compared to the controls. Histopathologically, 

treatment-related alterations were observed in 

the liver, kidney, gall bladder, and eyes. The 

DER was not available, this information was 

extracted from the review of A. Arce dated 

May 2, 1979 in HED Doc. No. 001099.

870.4200a Carcinogenicity

(rat)

Not submitted. See 

870.4300.

-

870.4200b Carcinogenicity

(mouse)

00122732 (1982)

Acceptable, guideline

♂♀: 0, 625, 1250, 2500

ppm 

♂: 0, 119, 259, 655

mg/kg/day

♀: 0, 143, 313, 711

mg/kg/day

Tackle 2S, 24% a.i.

NOAEL not determined

LOAEL = 119 mg/kg/day based on reduced 

body weight, increased absolute and relative 

liver weights, and changes in hematologic

parameters (decreased MCV, decreased 

segmented neutrophil counts, increased RBC 

counts, and increased lymphocyte counts)

increase in the incidence of liver tumors 

(adenomas, carcinomas, and 

adenomas/carcinomas combined) and 

stomach tumors (papillomas) in both sexes
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Table A.2.2 Sub-chronic, Chronic and Other Toxicity Profile - Sodium Acifluorfen

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.4200b Carcinogenicity

(mouse)

00082897 (1979)

Acceptable, guideline

when considered in 

conjunction with MRID 

00122732

♂♀: 0, 7.5, 45, 270 ppm 

♂♀: 0, 1.125, 6.75, 40.5

mg/kg/day based on 1 

ppm = 0.15 mg/kg/day

Blazer (39.4-40.5% a.i.)

NOAEL = 6.75

LOAEL = 40.5 mg/kg/day based on increased 

absolute and relative liver weights, increased 

relative kidney weights, and increased levels of

alkaline phosphatase and glutamic pyruvic

transaminase activities

increase in the incidence of liver tumors 

(primary adenomas) in 40.5 mg/kg/day 

females

870.4300 Combined 

Chronic Toxicity/ 

Carcinogenicity

(Fischer 344 rat)

00128253 (1983)

Acceptable, guideline

♂♀: 0, 25, 150, 500, 

2500, 5000 ppm 

♂♀: 0, 1.25, 7.5, 25, 125, 

250 mg/kg/day based on 1 

ppm = 0.05 mg/kg/day

Tackle (19.1-25.6% a.i.)

NOAEL = 25 mg/kg/day

LOAEL = 125 mg/kg/day based on reduced 

body weight, increased absolute and relative 

liver weights and increased kidney weights,

increased incidence of nephritis/pyelonephritis, 

increased incidence of acidophilic cells in the

liver, and related changes in clinical chemistry 

parameters

no evidence of carcinogenicity

870.5275 Genotoxicity

Sex-linked 

recessive lethal 

test in Drosophila 

melanogaster

00122737 (1981)

Acceptable, guideline

1.5% Tackle 2S solutions 

for 2 or 24 hours

Tackle 2S is positive in Y chromosome loss 

and dominant lethal mutations assays and 

negative in somatic reversion of white-ivory, 

bithorax test of Lewis, and sex-linked lethals 

assays.

870.5300 Genotoxicity

In vitro 

mammalian cell 

gene mutation in 

the thymidine 

kinase locus in 

mouse lymphoma 

cells

00122739 (1980)

Unacceptable, guideline

+S9: 25-387.3 μg/ml

-S9: 18-127.6 μg/ml

Not mutagenic. Test chemical did not cause 

forward mutations.

Upgradable pending submission of positive 

control data.

870.5385 Genotoxicity

In vivo 

mammalian 

chromosome 

aberration assay 

00122741 (1981)

Acceptable, guideline

0, 0.37, 1.11, or 1.37 

mg/kg/day Tackle 2s 

(23.6% a.i.) for 5 

consecutive days

Not mutagenic. No increase in clastogenic 

activity.

870.5450 Genotoxicity

Rodent dominant 

lethal assay

00122738 (1981)

Acceptable, guideline

80, 360, 800 mg/kg/day 

Tackle 2S

Not mutagenic. No clear indication of an 

adverse effect in the nine calculated indices.
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Table A.2.2 Sub-chronic, Chronic and Other Toxicity Profile - Sodium Acifluorfen

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.5550 Genotoxicity

Unscheduled 

DNA synthesis 

assay in primary 

rat hepatocytes

00122742 (1981)

Acceptable, guideline

0.10-50.00 μg/mL Tackle

Not mutagenic. There were no indications of 

UDS activity.

870.5550 Genotoxicity

Unscheduled 

DNA synthesis 

assay in primary 

rat hepatocytes

41761103 (1990)

Acceptable, guideline

0.25, 0.75, 2.5, 7.5, 25 

μg/mL

Not mutagenic. There were no indications of 

UDS activity.

870.5575 Genotoxicity

Mitotic gene 

conversion in 

S. cerevisiae

00148272 (1981)

Acceptable, guideline

±S9: 0.03-15 mg/plate 

Tackle 

Mutagenic. An increase in recombination 

frequency was obtained in an initial test at 1.5 

mg/plate without the activation system and at a 

3 mg/plate with activation; toxicity was 

observed at 7.5 mg/plate. A repeat assay found 

a dose-related increase in recombination

frequency without activation and a positive

result (not dose-related) with activation.

870.6200a Acute 

neurotoxicity 

screening battery

(Wistar rat)

49318001 (2014)

Acceptable, non-guideline

♂♀: 0, 293, 440, 660 

mg/kg

Acifluorfen Sodium TC 

(43.40% a.i.)

NOAEL = 293 mg/kg

LOAEL = 440 mg/kg based on decreased (27-

44%) ambulatory motor and total motor 

activities in females 

The study is upgradable to guideline pending 

the submission of satisfactory positive control 

data for the FOB and motor activity assays.

870.6200b Subchronic 

neurotoxicity 

screening battery

Not submitted and not 

required

-

870.6300 Developmental 

neurotoxicity

Not submitted and not 

required

-
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Table A.2.2 Sub-chronic, Chronic and Other Toxicity Profile - Sodium Acifluorfen

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.7485 Metabolism and 

pharmacokinetics

(rat)

00122746 (1982)

Acceptable, non-guideline

single 16-17 mg/kg

single 116 mg/kg

10-12 mg/kg/day for 14 

days

Single intravenous 11-15 

mg/kg

Compound is rapidly (tmax = 0.5-5.4 h) and 

almost completely absorbed (bioavailability ~ 

80-97%) into the systemic circulation. Very 

little radioactivity was detectable in tissues of 

rats 96 hours after administration of each of the 

four dosage regimens. The radioactivity 

recovered in urine and feces in female animals, 

96 hours after administration, was 60-82% and 

5-23% of the dose, respectively. In contrast, the 

radioactivity recovered in urine and feces in 

male rats was 46-58% and 21-41% of the dose,

respectively. The major radioactive component 

present in blood (95-98%), urine (95%), and 

bile (93%) was unchanged acifluorfen. The 

major component in feces was the amine 

metabolite which accounted for 60-80% of the

radioactivity.

Classified as non-guideline due to low overall 

recovery of radioactivity (70.9-92.5%).

870.7600 Dermal 

penetration (rat)

00156020 (1986)

Unacceptable, guideline

♂♀: 2.1-3.3, 0.21-0.33, 

0.021-0.034 mg/cm2

Tackle (20.3% a.i.)

Total dermal penetration of Tackle following 

10 hours exposure was 0.02% for each dose as

calculated by addition of the quantities in urine, 

feces, carcass and blood. However,

significantly large amounts of dose remained 

on the skin (2.3, 20 and 43.5% of the respective

doses) after washing with deionized water and 

may be available for absorption.

The guidelines were not followed: the chemical 

should have been placed on no less than 10 cm2

of the rat’s skin instead of 4.9 cm2. This 

minimal area is necessary for even spreading of 

the dose formulation. From this study, a 

dermal penetration of 0.02% does not correctly 

approximate what was observed in the dermal 

toxicity study.

870.7800 Immunotoxicity 

(rat)

49321301 (2014)

Acceptable, guideline 0, 

500, 1500, 2500, 3750 

ppm 

adjusted 43.4% a.i. to 0, 

81, 244, 408, 681 

mg/kg/day 

Systemic NOAEL = 408 mg/kg/day

Systemic LOAEL = 681 mg/kg/day based on 

reduced body weights and body weight gains.

Immunotoxicity NOAEL = 681 mg/kg/day

Immunotoxicity LOAEL was not determined.
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Appendix B. Physical/Chemical Properties

Table B1. Physico-Chemical Properties of Sodium Acifluorfen

Parameter Value Reference

Molecular Weight (g/mol) 361.66 D426465, A. Shelby, 

4/29/2015

Physical State Light yellow powder (solid)

D165551, F. Toghrol, 

5/5/1992

Melting Point (°C) 274-278

Water solubility (25°C, pH 7) 61 g/100 g 

Solvent solubility (25°C)

Octanol 5.37 g/100 mL

Methanol 64.15 g/100 mL

Hexane <5 x 10-5 g/100 mL

Vapor pressure (25°C) <1.33 x 10-5 Pascal

Dissociation constant, pKa 3.86

pH 5.45

Octanol/water partition coefficient, log

KOW (25°C, pH 7)

1.55

Organic Carbon Soil Partition 

Coefficient (mL/g o.c.) Koc = 109

D426465, A. Shelby, 

Aerobic Soil Half-life (Days) 173 4/29/2015

Aerobic Aquatic Half-life (Days) 114

UV/visible absorption spectrum (pH 7.9)

204 nm - 2.75 x 104 Ɛ (L/(mol x cm))

259 nm - 6.06 x 103 ”

282 nm - 8.05 x 103 ”

300 nm - 6.76 x 103 ”

D323251, T. Goodlow, 

2/8/2006
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Appendix C. Review of Human Research

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 studies from 

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

Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force 

(ORETF) database; and/or the Agricultural Reentry Task Force (ARTF) database; 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 website11. 

 

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

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
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Appendix D. International Tolerances and Maximum Residue Limits Sheet

Sodium Acifluorfen (PC Code 114402)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

40 CFR 180.383:

Sodium acifluorfen, sodium 5-[2-

chloro-4-(trifluoromethyl)phenoxy]-

2-nitrobenzoate, and its metabolites 

(the corresponding acid, methyl 

ester, and amino analogues)

sodium 5-[2-chloro-4-

(trifluoromethyl)phenoxy

]-2- nitrobenzoate, 

including the metabolites 

consisting of the 

corresponding acid, 

methyl ester and amino 

analogues

None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex

Peanut 0.1

Rice, grain 0.1

Rice, straw 0.2

Soybean, seed 0.1 0.02

Strawberry 0.05

Completed: M. Negussie; 06/09/15

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.