UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: December 11 , 2013 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Acetocblor Human Health Risk Assessment for Proposed New Uses of 

Acetochlor on Sugar Beet and Peanut. 

PC Code: 121601 

Decision No.: 469302 

Petition No.: 2F8077 

Risk Assessment Type: Single Chemical Aggregate 

TXRNo.: NA 

MRIDNo.: NA 

DP Barcode: 413438 

Registration No.: 524-591 

Regulatory Action: Section 3 Registration 

CaseNo.: NA 

CAS No.: 34256-82-1 

40 CFR: 180.470 

FROM: Jessica 

Kelly O'Rourke, 

Kidwell, Risk 

Biologi

Assessor 

st 

~ - ~ • ~ ';l / 

Thurston G. Morton, Chemist 'Z/' _,-(/ 

Susan Hummel, Senior Chemist / /'J /) 

Ayaad Assaad, D.V.M. Ph.D., Toxicologist pLt:;Y5 f'~ / 

Risk Assessment Branch 4 ch 

Health Effects Division (7509P) 

THROUGH: Elissa 

Risk Assessment 

Reaves, Branch 

Branch 

Chief 

4, HED (7509P) 

f ~ =::::-: -

TO: Kable Davis, RM25 

Emily Hartman 

Maggie Ruddick 

Herbicide Branch, Registration Division (7505P) 

The Registration Division (RD) requested that the Health Effects Division (HEO) conduct a 

human health risk assessment for the proposed new use of acetochlor on sugar beets and peanuts 

for the registered product, W ARRAN~ Herbicide (EPA Reg. #524-591). This document 

provides the Health Effect Division's (HED's) human health risk assessment for acetochlor. 
Acetochlor/12160 1 Human Health Risk Assessment DP No. D413438 

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

2.0 HED Recommendations .................................................................................................... 8 

2.1 Data Deficiencies ............................................................................................................ 8 

2.2 Tolerance Considerations .............................................................................................. 9 

2.2.1 Enforcement Analytical Method ................................................................................... 9 

2.2.2 Recommended Tolerances ............................................................................................. 9 

2.2.3 Revisions to Petitioned-For Tolerances ........................................................................ 9 

2.2.4 International Harmonization ........................................................................................ 9 

2.3 Label Recommendations .............................................................................................. 10 

2.3.1 Recommendations from Residue Reviews ................................................................. 10 

2.3.2 Recommendations from Occupational Assessment .................................................. 10 

2.3.3 Recommendations from Residential Assessment ...................................................... 10 

3.0 Introduction ...................... .... ............................................................................................ 10 

3.1 Chemical Identity ......................................................................................................... 10 

3.2 Physical/Chemical Characteristics ............................................................................. 11 

3.3 Pesticide Use Pattern .................................................................................................... 12 

3.4 Anticipated Exposure Path,vays ................................................................................. 13 

3.5 Consideration of Environmental Justice .................................................................... 13 

4.0 Hazard Characterization and Dose-Response Assessment .......................................... 14 

4.1 Toxicology Studies Available for Analysis ................................................................. 14 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ............................. 15 

4.2.1 Dermal Absorption ....................................................................................................... 15 

4.3 Toxicological Effects .................................................................................................... 15 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 16 

4.4.1 Completeness of the Toxicology Database ................................................................. 17 

4.4.2 Evidence of Neurotoxicity ............................................................................................ 17 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ........... 17 

4.4.4 Residual Uncertainty in the Exposure Database ....................................................... 17 

4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 18 

4.5.1 Dose-Response Assessment .......................................................................................... 18 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ........ 19 

4.5.3 Cancer Classification and Risk Assessment Recommendation ................................ 20 

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

Assessment ............................................................................................................................... 20 

5.0 Dietary Exposure and Risk Assessment ............................................................. ..... ....... 23 

5.1 Metabolite/Degradate Residue Profile ....................................................................... 23 

5.1.1 Summary of Plant and Animal Metabolism Studies ................................................. 23 

5.1.2 Summary of Environmental Degradation .................................................................. 23 

5.1.3 Comparison of Metabolic Pathways ........................................................................... 24 

5.1.4 Residues of Concern Summary and Rationale .......................................................... 24 

5.2 Food Residue Profile .................................................................................................... 25 

5.3 Water Residue Profile .................................................................................................. 27 

5.4 Dietary Risk Assessment .............................................................................................. 28 

5.4.1 Description of Residue Data Used in Dietary Assessment ........................................ 28 

5.4.2 Percent Crop Treated Used in Dietary Assessment .................................................. 28 

5.4.3 Acute Dietary Risk Assessment ................................................................................... 28 

Page 2 of79 
Acetochlor/121601 Human Health Risk Assessment DP No. D413438

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5.4.4 Chronic Dietary Risk Assessment............................................................................... 29

5.4.5 Cancer Dietary Risk Assessment ................................................................................ 29

5.4.6 Summary Table ............................................................................................................ 30

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 31

6.1 Spray Drift.................................................................................................................... 31

6.2 Residential Bystander Post-Application Inhalation Exposure ................................ 31

7.0 Aggregate Exposure/Risk Characterization.................................................................. 32

7.1 Acute Aggregate Risk................................................................................................... 32

7.2 Short-Term Aggregate Risk ........................................................................................ 32

7.3 Intermediate-Term Aggregate Risk ........................................................................... 32

7.4 Chronic Aggregate Risk .............................................................................................. 32

7.5 Cancer Aggregate Risk ................................................................................................ 32

8.0 Cumulative Exposure/Risk Characterization ............................................................... 32

9.0 Occupational Exposure/Risk Characterization ............................................................ 33

9.1 Short- and Intermediate-Term Handler Risk ........................................................... 33

9.2 Short-and Intermediate-Term Post-Application Risk.............................................. 37

9.2.1 Dermal Post-application Risk ..................................................................................... 37

9.2.2 Inhalation Post-application Risk................................................................................. 38

10.0 References......................................................................................................................... 39

Appendix A. Toxicology Profile and Executive Summaries .................................................. 40

A.1 Toxicology Data Requirements................................................................................... 40

A.2 Toxicity Profiles............................................................................................................ 41

A.3 Hazard Identification and Endpoint Selection .......................................................... 54

A.4 Executive Summaries................................................................................................... 61

Appendix B. Physical/Chemical Properties............................................................................. 78

Appendix C. Review of Human Research................................................................................ 79
Acetochlor/121601 Human Health Risk Assessment DP No. D413438

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1.0 Executive Summary

Acetochlor, 2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl) acetamide, is an 

encapsulated chloroacetanilide herbicide used for pre- and post- emergence control of weeds 

(annual grasses and broad leaves). 

Monsanto Company has submitted a pesticide petition, 2F8077, proposing tolerances for the 

residues of acetochlor (2-chlor-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl)acetamide) in/on 

sugar beet and peanut commodities. Monsanto is requesting an amendment to the registration of 

MON 63410 Herbicide (EPA Reg. No. 524-591, a microencapsulated formulation, 3 lb a.i./gal) 

to add directions for use in sugar beets and peanuts.

Tolerances for acetochlor are currently established under 40 CFR §180.470(a) and (d) and are 

expressed in terms of acetochlor and its metabolites, to be analyzed as acetochlor, ethyl methyl 

aniline (EMA), and hydroxyethyl methyl aniline (HEMA), and expressed as acetochlor 

equivalents. Tolerances for field corn, pop corn, sweet corn, cotton, sorghum, and soybean 

commodities are established under 180.470(a) and range from 0.05 ppm for field and pop corn

grain, sweet corn kernels plus cob with husk removed, and sorghum grain, to 3.0 ppm for field 

corn forage. Tolerances for rotational crops are established under 180.470(d) and include 

tolerances for non-grass animal feeds, sugar beet root and tops, cereal grain commodities, peas 

and beans, potato, soybean forage and hay, sunflower seed, and wheat commodities. No 

tolerances have been established for livestock commodities. 

There is a potential for acute and chronic dietary exposure, as well as for short- and intermediateterm (dermal and inhalation) occupational exposures to acetochlor during mixing, loading, 

application, and post-application activities; however, chronic exposure is not expected from the 

proposed uses. There are no residential uses of acetochlor.

Residue Chemistry

The qualitative nature of acetochlor residues in plants is adequately understood based on a 

soybean, corn and cotton metabolism study. HED concluded that the residues of concern in corn 

include parent and any metabolites containing the EMA moiety or the HEMA moiety, expressed 

in acetochlor equivalents. The nature of the residue in rotational crops is adequately understood 

based on the results of confined rotational crop studies in lettuce, radishes and wheat. HED 

concluded that acetochlor tolerances for inadvertent residues on rotational crops should be 

expressed as acetochlor and its EMA and HEMA producing metabolites, and residues of 

hydroxymethyl ethyl aniline (HMEA) type metabolites would not be included in the tolerance 

expression, but should be included in the risk assessment.

An adequate HPLC/oxidative coulometric electrochemical detector (OCED) method is available 

for enforcing tolerances of acetochlor and its metabolites in plant commodities. For this method, 

residues are solvent-extracted into aqueous acetonitrile (ACN), and then base-hydrolyzed to 

yield EMA and HEMA. The resulting residues are steam-distilled into dilute acid, adjusted to a 

basic pH, and then partitioned into dichloromethane (DCM). HEMA is methylated, then residues 

of EMA and methylated HEMA (MEMA) are separated, and determined via HPLC/OCED. 
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Residues of EMA and HEMA are expressed in acetochlor equivalents; the validated method 

limits of quantitation (LOQs) are 0.020 ppm for each analyte. 

Hazard Profile

Evidence of neurotoxicity from exposure to acetochlor was observed at relatively high doses in 

several oral studies. The dog appears to be more sensitive than the rat or mouse to effects on the 

nervous system following longer term exposures. In addition to the nervous system, other target 

organs affected in subchronic and chronic studies in rats, dogs and mice exposed to acetochlor 

are the liver, thyroid (secondary to liver), kidney, testes, and erythrocytes. Species specific target 

organs include the nasal olfactory epithelium in rats and the lungs in mice. Effects observed in a 

21-day dermal toxicity study in the rabbit include high mortality and agonal clinical signs of 

toxicity at the highest dose tested (HDT) of 1200 mg/kg/day. The available developmental 

toxicity studies in rats and rabbits do not show evidence of increased susceptibility of the 

offspring and no evidence of increased susceptibility was observed in three two-generation 

reproductive toxicity studies in the rat. Acetochlor is classified as “Suggestive Evidence of 

Carcinogenic Potential” based on weak evidence for benign lung tumors in male and female 

mice and histiocytic sarcomas in female mice. Consequently, linear quantification of 

carcinogenic potential is not required for the mouse tumors. Nasal olfactory epithelial tumors and 

thyroid follicular cell tumors were observed in rats. There are acceptable mode of action data for 

these rat tumors which are adequate to support a non-linear, MOE approach for assessment of 

cancer risk for these tumor types. However, separate quantification of cancer risk is not required 

for the rat tumors since the chronic RfD will be protective of these effects. 

Endpoints and Uncertainty Factors

Endpoints were selected for acute and chronic dietary exposures as well as for short and 

intermediate-term dermal and inhalation occupational exposures. For the acute dietary endpoint 

(all populations), a point of departure (POD) of 150 mg/kg/day was selected from an acute oral 

neurotoxicity study in rats and was based on decreased motor activity in females seen at the 

lowest observed adverse effect level (LOAEL) of 500 mg/kg/day. An uncertainty factor (UF) of 

100X (10X for interspecies extrapolation, 10X for intraspecies variation, 1X FQPA SF) was 

applied to the POD to obtain an acute population adjusted dose (aPAD) of 1.5 mg/kg/day. An 

acute endpoint was not selected specifically for Females 13-49 years old since no developmental 

effects that could be attributed to a single exposure were identified in the acetochlor database.

For the chronic dietary endpoint (all populations), a chronic feeding study in dogs was selected.

A point of departure (POD) of 2.0 mg/kg/day was based on increased salivation and 

histopathology in the testes, kidney and liver seen at the LOAEL of 10 mg/kg/day. An UF of 

100X (10X for interspecies extrapolation, and 10X for intraspecies variation, 1X FQPA SF) was 

applied to the POD to obtain a chronic PAD (cPAD) of 0.02 mg/kg/day.

For short-term dermal exposure, a 21 day dermal toxicity study in rabbits was selected with a

NOAEL of 400 mg/kg/day based on mortality and clinical signs of toxicity seen at the LOAEL 

of 1200 mg/kg/day. For short-term inhalation exposure, a developmental study in rats with a 
Acetochlor/121601 Human Health Risk Assessment DP No. D413438

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NOAEL of 150 mg/kg/day was selected. The LOAEL was based on maternal mortality, clinical 

signs of toxicity and reduced body weight gain observed at 600 mg/kg/day. 

PODs for intermediate-term inhalation and dermal exposure were selected from two co-critical 

oral subchronic toxicity studies in the dog with a POD of 25 mg/kg/day (NOAEL). The LOAEL

is based on clinical signs of toxicity, decreased body weight gain, mild anemia, slightly increased 

relative liver weight, and increased serum alanine aminotransferase observed at 60 mg/kg/day. 

For purposes of estimating intermediate-term dermal exposure, a 20% dermal absorption factor 

was used for route-to-route extrapolation from an oral study. Inhalation exposure was assumed to 

be equivalent to oral exposure in the intermediate-term exposure assessments.

The level of concern (LOC) for short- and intermediate-term dermal exposure assessments is a 

margin of exposure (MOE) of 100. However, based on a review by the Hazard and Science 

Policy Council (HASPOC), an additional 10X uncertainty factor (UF) was applied to the shortand intermediate-term inhalation exposure assessments to account for lack of a subchronic 

inhalation toxicity study, resulting in a level of concern of 1000. Because the dermal and 

inhalation LOCs are different, an aggregate risk index (ARI) was calculated to estimate the 

combined exposure to acetochlor. 

Dietary Exposure and Risk

A screening level acute dietary exposure analysis was performed for the general population and 

all population subgroups. The acute dietary analysis assumed tolerance level residues and 100 %

crop treated for all commodities. Experimentally derived processing factors were used for cereal 

grain commodities. Default processing factors were used for all other commodities. The acute 

analysis incorporated the 1 in 10 year peak surface drinking water estimate from application of 

acetochlor to sorghum. The resulting 95

th percentile acute exposure estimate for infants < 1 year 

old (the most highly exposed subgroup) is not of concern to HED (1.6 % acute population 

adjusted dose (aPAD)). The exposure estimate for the U.S. population was < 1% of the aPAD.

A partially refined chronic dietary exposure analysis was performed for the general U.S. 

population and various population subgroups. Anticipated residues from field trial data and

100% crop treated assumptions were made for all commodities. Experimentally derived 

processing factors were used for cereal grain commodities. Default processing factors were used 

for all other commodities. The chronic analysis incorporated the 1 in 10 year average surface 

drinking water estimate from application of acetochlor to sorghum. Chronic dietary risk 

estimates are not of concern for general population or other population subgroups. The subgroup 

with the highest risk estimate was infants < 1 year old with an exposure estimate of 26 % of the 

cPAD. The general U.S. population estimated exposure was 11 % of the cPAD. 

Quantification of cancer risk is not required since the chronic RfD of 0.02 mg/kg/day, which is 

equivalent to the cPAD, will be protective of both non-cancer and cancer effects. As noted 

above, chronic dietary risks do not exceed HED’s level of concern.

Acetochlor is included in a Cumulative Assessment Group (CAG) of Chloroacetanilide 

pesticides. For purposes of a cumulative risk assessment, it was determined that the common 
Acetochlor/121601 Human Health Risk Assessment DP No. D413438

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mechanism of toxicity group consists of alachlor, acetochlor, and butachlor. An updated 

cumulative risk assessment of the Chloroacetanilide (CAG) pesticides acetochlor and alachlor 

was conducted in April, 2007. Based on the most recent chloroacetanilide CAG cumulative risk 

assessment, cumulative risk is not of concern. A revised quantitative cumulative assessment was 

not conducted because the proposed amended use would not affect the cumulative risk results. 

Not only is acetochlor a very minor contributor to chloroacetanilide cumulative risk when 

compared to alachlor, but adding the use on sugar beets and peanuts will only have a minor 

impact on acetochlor exposure since only low residues occurred on sugar beet and peanut food 

commodities. 

Residential Non-Cancer Risks 

Currently, there are no registered or proposed residential uses for acetochlor.

Aggregate Risk

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. Currently, there 

are no registered or proposed residential uses for acetochlor, therefore, short- and intermediate 

term aggregate risk assessments are not required. In examining acute and chronic aggregate risk, 

HED has assumed that the only pathway of exposure relevant to the acute and chronic time 

frames is dietary exposure. Therefore, the acute and chronic aggregate risk is comprised of 

exposures to acetochlor residues in food and drinking water and is equivalent to the acute and 

chronic dietary risk estimates summarized in Table 5.4.6 in Section 5.4.3. Both the acute and 

chronic dietary risk estimates are well below HED’s level of concern for the general population 

and all population subgroups. HED has concluded that assessments using a non-linear approach 

(e.g. a chronic RfD-based approach) will adequately protect for all chronic toxicity, including 

carcinogenicity that could result from exposure to acetochlor. Chronic aggregate risk estimates 

are below HED’s level of concern, therefore, cancer risk is also below HED’s level of concern. 

Occupational Risks 

The occupational handler exposure and risk estimates indicate that the short- and intermediateterm dermal and inhalation aggregate risk indices (ARIs) are not of concern to HED (i.e., ARI >

1) with the use of chemical-resistant gloves, as directed by the label.

The occupational short- and intermediate-term post-application dermal exposure and risk 

estimates are greater than the LOC of 100 on the day of application, and, therefore, are not of 

concern. Since the post-application assessment is not of concern on Day 0, the restricted entry 

interval (REI) is based on the acute toxicity of acetochlor technical material. Acetochlor is 

classified in Toxicity Category III for acute dermal toxicity, and Categories III and II for primary 

eye and skin irritation, respectively. It is a dermal sensitizer. Therefore, the acute toxicity 

categories for this chemical require a 24-hour REI under 40 CFR 156.208 (c) (2) (ii). The 12-

hour REI, which currently appears on the WARRANT® Herbicide label, is not adequate for the 

proposed and registered uses.
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Based on the Agency's current practices, a quantitative non-cancer occupational post-application 

inhalation exposure assessment was not performed for acetochlor at this time. If new policies or 

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

post-application inhalation exposure assessment for acetochlor. 

2.0 HED Recommendations

HED recommends for the establishment of the requested tolerances for the residues of acetochlor 

in/on sugar beet and peanut commodities, as recommended in Table 2.2.2, pending submittal of 

an analytical reference standard for acetochlor. The field trial data as a result of application of an 

acetochlor micro-encapsulated (ME) formulation on sugar beet and peanut commodities are 

adequate to support the tolerance request. Concurrently with this action, the inadvertent tolerance 

for residues of acetochlor in/on sugar beet, root; and sugar beet, top, published in §180.470(d), 

should be deleted.

HED concludes that there are no risk issues that would preclude recommending for a registration 

and establishing tolerances for the residues of acetochlor on sugar beet and peanuts. Additional 

data are needed as outlined in section 2.1 below. Specific tolerance recommendations are 

discussed in section 2.2. Label recommendations are discussed in section 2.3. 

2.1 Data Deficiencies

Toxicology: A subchronic inhalation toxicity study for acetochlor is required, but not available. 

An alachlor inhalation toxicity study may provide sufficient data on acetochlor, and the registrant 

has recently submitted an alachlor inhalation study (MRID 49031001). This study may be used 

as a surrogate because acetochlor shares a common structure and mechanism of toxicity. The 

HASPOC recommended that a 10X Database Uncertainty Factor (UFDB) should be applied to 

inhalation assessments only until the alachlor inhalation study is reviewed and deemed 

acceptable by the Agency (TXR No. 0056497). Since the study was only recently submitted to 

the Agency by the registrant, it is currently being reviewed and evaluated by HED scientists.

Occupational Assessment: None. [A Dislodgeable Foliar Residue (DFR) study is not required 

for acetochlor at this time since the dermal MOEs are greater than 4 times the LOC based on 

default values for the fraction of application rate available for transfer after a foliar application.]

Residue Chemistry: An analytical reference standard for acetochlor is needed.
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2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate high performance liquid chromatography (HPLC) method with oxidative 

coulometric electrochemical detection (OCED) is available for tolerance enforcement for plant 

commodities. For this method, extracted residues are base hydrolyzed to yield ethyl methyl 

aniline (EMA) and hydroxyethyl methyl aniline (HEMA), HEMA is methylated, and residues of 

EMA and methylated HEMA are separated and determined using HPLC/OCED. Residues of 

EMA and HEMA are expressed in acetochlor equivalents, and the validated method limit of 

quantitation (LOQ) is 0.02 ppm for each analyte. The LC/MS/MS method was adequate for data 

collection based on acceptable concurrent method recoveries in the cotton and soybean field trial 

and processing studies.

2.2.2 Recommended Tolerances

Table 2.2.2. Tolerance Summary for Acetochlor.

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

180.470(a)

Beet, sugar, dried pulp 0.5 0.50

Beet, sugar, molasses 1.3 0.80 Calculated from HAFT of 0.274 x 2.7x

Beet, sugar, roots 0.3 0.30

Beet, sugar, tops 0.8 0.70 Change due to OECD Calculator

Peanut 0.2 0.20

Peanut, hay 6.0 7.0 Change due to OECD Calculator

Peanut, meal 0.5 0.25 Calculated from HAFT of 0.092 x 2.7x

180.470(d) Existing Tolerances

Beet, sugar, root 0.05 Revoke Indirect residues will be covered 

under the sugar beet tolerances from 

direct application to the crop.

Beet, sugar, tops 0.05 Revoke

2.2.3 Revisions to Petitioned-For Tolerances

Tolerance proposals for raw agricultural commodities were changed as a result of the OECD 

Tolerance Calculation Procedures. Tolerance proposals for processed commodities were changed 

as a result of the calculation based on the HAFT multiplied by the average processing factor.

2.2.4 International Harmonization

There are currently no Codex or Canadian MRLs, nor Mexican MRLs on the commodities 

proposed in the current petition. 
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2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

Spray volume must be specified, and must be at least 2 gal/A for aerial application.

2.3.2 Recommendations from Occupational Assessment

Since the post-application assessment is not a concern on Day 0, the REI is based on the acute 

toxicity of acetochlor technical material. Acetochlor is classified in Toxicity Category III for 

acute dermal toxicity, and Categories III and II for primary eye and skin irritation, respectively. 

It is a dermal sensitizer. Therefore, the acute toxicity categories for this chemical require a 24-

hour REI under 40 CFR 156.208 (c) (2) (ii). The 12-hour REI, which currently appears on the 

WARRANT® Herbicide label, is not adequate for the proposed and registered uses.

2.3.3 Recommendations from Residential Assessment

There are no residential uses proposed with this petition.

3.0 Introduction

3.1 Chemical Identity

The chemical structure and nomenclature of acetochlor, the EMA and HEMA moieties, and 

Metabolite 57 are provided in Table 3.1.1. 

Table 3.1.1 Acetochlor Nomenclature.

Chemical structure

Common name Acetochlor

Company experimental name None

IUPAC name 2-chloro-N-ethoxymethyl-6'-ethylacet-o-toluidide

CAS name 2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl)acetamide

CAS registry number 34256-82-1

End-use product (EP) 3 lb/gal Mcap formulation (MON 63410 Herbicide, EPA File Symbol No. 524-

LOR) 3 lb/gal EC formulation (MON 8453, EPA Reg No 524-483)

N

Cl

O O

CH3

H3C

H3C
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Table 3.1.1 Acetochlor Nomenclature.

Chemical structure of EMA 

moiety

CAS Name: 2-ethyl-6-methylaniline

EMA-type metabolites 1

Chemical structure of HEMA 

moiety

CAS Name: 2-(1-hydroxyethyl)-6-methylaniline

HEMA-type metabolites 1

Metabolite 57

N-(6-ethyl-3-hydroxy-2-methylphenyl) oxamic acid

1

For the EMA- and HEMA-type metabolites, the R1 functional group can consist of –H or –CH2OCH2CH3 and the R2 functional 

group may consist of many different moieties. The R3 functional group for HEMA-type metabolites can consist of –H or a 

variety of components such as sugars.

3.2 Physical/Chemical Characteristics

Acetochlor is a chloroacetanilide herbicide used to control weeds. It is a solid at room 

temperature and decomposes before melting. It is moderately soluble in water, and infinitely 

soluble in common organic solvents used for pesticides. It has a moderate vapor pressure (4.5 ECH3

NH2

H3C

N R2

O

R1

CH3

H3C

CH3

OH NH2

H3C

N R2

O

R1

CH3

H3C

O

R3

HN

O

COOH

H3C

CH3

OH
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5 mm Hg). The octanol-water partition coefficient indicates that acetochlor may accumulate in 

tissues. The physical and chemical properties of acetochlor are detailed in Appendix B.

3.3 Pesticide Use Pattern

Monsanto has submitted supplemental labels to sugar beet and peanut commodities to MON 

63410 (EPA Reg. No. 524-591), a Micro-Encapsulated (ME) formulation (3 lb a.i./gal).

As summarized in Table 3.3, applications of WARRANT® Herbicide (EPA Reg. #524-591) to 

pre-plant, pre-emergent, or early post-emergent sugar beets and peanuts are proposed using 

either groundboom or aerial spray equipment, at a rate of 0.94 to 1.5 pounds ai per acre (lb ai/A). 

A minimum of 7 days between applications is required.

WARRANT® Herbicide (EPA Reg. #524-591) is a micro-encapsulated formulation (suspended 

concentrate) designed for the slow release of pesticide due to the microencapsulation of the 

active ingredient (acetochlor) in tiny beads or capsules. This formulation is designed to use water 

as its mode of dispersion, while remaining in an encapsulated state. Once mixed with water, it is 

then distributed over the crops using a broadcast system. This product contains 33% of its active 

ingredient, acetochlor. Note: concerning post-application, micro-encapsulation is designed to 

dissipate at a slower rate.

Table 3.3. Summary of Directions for Use of Acetochlor.

Applic. Timing; 

Type; and 

Equip.

Formulation

[EPA Reg. 

No.]

Applic. Rate, 

lb ai/A

[soil type]1

Max. 

No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Sugar Beets

Preplant, At 

Plant, 

Preemergence 

surface, and

Postemergence 

surface;

Broadcast 

Ground Boom; 

Aerial

3 lb/gal 

Mcap

[524-591]

<1.5% 

OM

≥1.5% 

OM

3 3.0 NS

No more than 1.5 lb ai/A 

may be applied as a 

preplant or preemergence 

treatment. 

Postemergence 

applications may be made 

up to the 6 leaf stage; no 

more than 1.5 lb ai/A may 

be applied as a postemergence application. 0.94-1.2

[coarse]

0.94-1.3

[medium]

0.94-1.4

[fine]

0.94-1.3

[coarse]

0.98-1.4

[medium]

0.94-1.5

[fine]
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Table 3.3. Summary of Directions for Use of Acetochlor.

Applic. Timing; 

Type; and 

Equip.

Formulation

[EPA Reg. 

No.]

Applic. Rate, 

lb ai/A

[soil type]1

Max. 

No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Peanuts

Preplant, At 

Plant, 

Preemergence 

surface, and

Postemergence 

over-the-top or 

soil directed;

Broadcast 

Ground Boom; 

Aerial

3 lb/gal 

Mcap

[524-591]

<1.5% 

OM

≥1.5% 

OM

3 3.0 NS;90 

day

No more than 1.5 lb ai/A 

may be applied as a 

preplant or preemergence 

treatment. 

Postemergence 

applications may be made 

until flowering; no more 

than 1.5 lb ai/A may be 

applied as a postemergence application. Allow 

7 days between sequential 

applications. Allow 90 

days before grazing or 

feeding hay to livestock.

0.94-1.2

[coarse]

0.94-1.3

[medium]

0.94-1.4

[fine]

0.94-1.3

[coarse]

0.94-1.4

[medium]

0.94-1.5

[fine]

1

 OM = organic matter. NS=not specified. Coarse soils include sand, loamy sand, and sandy loam; medium soils 

include loam, silt loam, silt, and sandy clay loam; and fine soils include silty clay loam, clay loam, sandy clay, silty 

clay, and clay. 

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed new use of acetochlor on peanuts and sugar beets. Humans may be exposed to 

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

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

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

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

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

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

Risk assessments have been previously prepared for the existing uses of acetochlor. This risk 

assessment considers all of the aforementioned exposure pathways based on the proposed new 

uses of acetochlor, but also considers the existing uses as well, particularly for the dietary 

exposure assessment

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 
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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 Continuing 

Survey of Food Intake by Individuals (CSFII) 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 acetochlor is adequate for evaluating and characterizing toxicity and 

selecting endpoints for purposes of this risk assessment, however, an inhalation toxicity study is 

considered a data gap. Studies considered for this assessment include the following: acute 

lethality (oral, dermal and inhalation routes), primary eye and dermal irritation, dermal 

sensitization, chronic and subchronic oral toxicity studies in beagle dogs, 21-day dermal toxicity 

study in rabbits, acute and subchronic neurotoxicity studies in rats, metabolism, immunotoxicity, 

genotoxicity battery, developmental toxicity studies in rats and rabbits, reproduction toxicity 

study in rats, carcinogenicity studies in the rat and mouse, and subchronic toxicity studies in rats.

The Hazard and Science Policy Council (HASPOC) determined that a developmental 

neurotoxicity study (DNT) is not required for acetochlor (TXR No.0056497). This approach 

considered all of the available hazard and exposure information, including: 1) there is no 

evidence of increased susceptibility in the rat and rabbit in the prenatal and postnatal studies; 

2) developmental effects were observed in the presence of maternal effects; and 3) the effects

observed in the neurotoxicity studies were only at high doses. Subsequently, the 10x FQPA 

factor was removed as a data base uncertainty factor (UFDB).

Due to the absence of a subchronic inhalation toxicity study from the database coupled with the 

pattern of use of acetochlor (aerial, chemigation, ground-boom, and tractor-drawn spreader 

equipment), HASPOC concluded that a subchronic inhalation toxicity study is required. The 

HASPOC acknowledged that the alachlor inhalation toxicity study available in the literature may 

provide sufficient data on acetochlor pesticide. The inhalation study with alachlor can be used as 

a surrogate because acetochlor shares a common structure and mechanism of toxicity and was 

included along with alachlor and butachlor in the chloroacetanilide cumulative assessment. Since 

the HASPOC meeting, the registrant has submitted the alachlor inhalation study (Monsanto 

Research Report No. ML-83-158, MRID 49031001) and it is currently undergoing the HED 

review process. The HASPOC recommended that a 10X Database Uncertainty Factor (UFDB) 
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should be applied to inhalation assessments only until the alachlor inhalation study is formally 

reviewed and deemed acceptable by the Agency (TXR No. 0056497). A screen of the study 

indicates the current inhalation risk assessment with the 10X is protective of the effects observed 

in the inhalation study.

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

Following oral administration to rats, acetochlor was well-absorbed and rapidly eliminated (92-

96% of dose by day 5, 1⁄2 life of elimination 20-30 hrs), primarily excreted in urine (about 60% 

by 24 hrs) but significant fecal excretion was observed, especially in males and at the high dose, 

with biliary excretion observed. Elimination was biphasic. Retention in tissue/carcass is 

negligible. Acetochlor was rapidly degraded into many metabolites and the metabolites were

readily excreted in the urine and feces. Acetochlor was completely metabolized, with 

glutathione, mercapturic acid or glucuronide conjugation of n-dealkylated acetochlor a major 

route of metabolism; sulphoxymethyl and cysteine conjugates were also identified in feces. In 

urine, the major metabolite was mercapturic acid conjugate of N-deethylated acetochlor; in bile, 

the major metabolite was the glucuronide conjugate. The major fecal metabolite not 

characterized.

4.2.1 Dermal Absorption

A dermal absorption factor of 20% was estimated from an in vivo rat dermal absorption study 

(MRID # 41778303), based on absorption observed following a 10-hr dermal exposure to 

acetochlor.

4.3 Toxicological Effects

Evidence of neurotoxicity from exposure to acetochlor was observed in several oral studies. 

Salivation and other clinical signs (anogenital staining, diarrhea) were reported in studies in both 

the rat (two developmental toxicity studies) and the dog (subchronic and chronic oral). A 

marginal decrease in brain cholinesterase was observed at the high dose in one subchronic rat 

study. The dog appears to be more sensitive than the rat or mouse to effects on the nervous 

system, in that salivation occurred at lower dose levels and frank neuropathology of the brain 

was observed in one study. In a one-year oral (capsule) toxicity study in the dog, pronounced 

neurological signs (ataxia, abnormal head movements, tremor, depressed righting, hopping and 

flexor reflexes, exaggerated tonic neck reflex and stiffness and rigidity of the hindlimbs) were 

observed at the high dose and were associated with degenerative lesions of the cerebellum. Acute 

and subchronic oral neurotoxicity screening studies in the rat were submitted for acetochlor. In 

the acute study at the time of peak effect, decreased total motor activity at mid and high dose was

observed in females, but not males. At the highest dose, both males and females showed clinical 

signs of toxicity in the functional observational battery (perioral staining, piloerection, hunched 

posture). Single animals showed signs such as chromodacryorrhea, upward curvature of the 

spine and hypothermia. In the subchronic study, decreased body weight/weight gain in both 

sexes at the high dose was observed. A decrease in hindlimb grip strength in males at 2 weeks, 

but not at later times, was observed and considered a possible effect of treatment. The 

neurotoxicity studies did not evaluate cholinesterase levels. 
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In addition to the nervous system, the major target organs affected in subchronic and chronic 

studies in rats, dogs and mice exposed to acetochlor are the liver, thyroid (secondary to liver), 

kidney, testes, and erythrocytes. Species specific target organs include the nasal olfactory 

epithelium in rats and the lungs in mice. Effects observed in a 21-day dermal toxicity study in

the rabbit include high mortality and agonal clinical signs of toxicity at the highest dose tested 

(HDT) of 1200 mg/kg/day. Local dermal irritation was observed at all dose levels. A 21 day 

dermal toxicity study showed excessive dermal irritation at 100 mg/kg/day. 

The available developmental toxicity studies in rats and rabbits do not show evidence of 

increased susceptibility of the offspring and no evidence of increased susceptibility was observed 

in three two-generation reproductive toxicity studies in the rat. Toxicity to offspring was 

observed at or above maternally toxic dose levels. As noted, maternal neurotoxic effects were 

observed in two developmental toxicity studies in rats. One developmental toxicity study in the 

rat also showed increased early resorptions, postimplantation loss and decreased fetal weight at a 

maternally toxic dose of 600 mg/kg/day (HDT). Maternal effects at the HDT, in addition to 

neurotoxicity, included mortality and body weight decrease. In the second developmental study, 

decreased fetal weight was observed at maternally toxic (neurotoxicity, decreased body weight) 

HDT of 400 mg/kg/day.

There was no evidence of reproductive toxicity observed at any dose tested in two of three 

available reproductive toxicity studies in rats. A third reproductive study in rats showed 

decreased number of implantations at the HDT of 1750 ppm. Parental effects at mid- and/or 

high doses included reduced body weight/weight gain and nasal epithelium effects. Offspring 

effects included reduced pup body weights, decreased F2 litter size at birth and decreased 

absolute and relative spleen weights in F2 weanlings at the mid and/or high doses. 

In accordance with the EPA’s Final Guideline for Carcinogen Risk Assessment (March 2005), 

acetochlor is classified as “Suggestive Evidence of Carcinogenic Potential” based on weak 

evidence for benign lung tumors in male and female mice and histiocytic sarcomas in female 

mice. Consequently, linear quantification of carcinogenic potential is not required for the mouse 

tumors. Nasal olfactory epithelial tumors and thyroid follicular cell tumors were observed in 

rats. There are acceptable modes of action data for these rat tumors which are adequate to 

support a non-linear, MOE approach for assessment of cancer risk for these tumor types. 

However, separate quantification of cancer risk is not required for the rat and mouse tumors

since the chronic RfD of 0.02 mg/kg/day will be protective of both cancer and non-cancer

effects. 

A complete toxicity profile for acetochlor is provided in Appendix A.

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

The acetochlor risk assessment team has recommended that the FQPA Safety Factor be reduced 

to 1X for the acute and chronic dietary risk assessments as well as the dermal risk assessments. 

There is an adequate toxicity database for acetochlor and exposure data are complete or are 

estimated based on data that reasonably account for potential exposures. There is no evidence of 
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susceptibility and there are no residual uncertainties concerning pre- or post-natal toxicity. 

Evidence of neurotoxicity was observed mainly at high doses in several studies including the 

acute and subchronic neurotoxicity studies, and all endpoints used in this risk assessment are 

protective of neurotoxic effects. The HASPOC determined that a DNT study is not required. The 

dietary and occupational assessments are based on reliable data and will not underestimate 

exposure.

The FQPA SF was retained at 10X as a database uncertainty factor (UFDB) for inhalation risk 

assessments only due to the data gap of an inhalation study. See section 4.1 for details.

4.4.1 Completeness of the Toxicology Database

The toxicity database for acetochlor is complete for acute and chronic dietary and dermal risk 

assessments. An immunotoxicity study has been reviewed and is acceptable/guideline. 

Immunotoxicity was not observed at the highest dose tested. The acute neurotoxicity (ACN) and 

subchronic neurotoxicity (SCN) studies have also been upgraded to acceptable/guideline based 

on acceptable positive control data and functional observational battery measures.

 

Furthermore, EPA has determined that a developmental neurotoxicity study is not required since: 

1) there is no evidence of increased susceptibility in the rat and rabbit in the prenatal and 2-

generation reproduction postnatal studies; 2) developmental effects were observed in the 

presence of maternal effects; and 3) the effects observed in the neurotoxicity studies were only at 

high doses.

For inhalation risk assessments, an inhalation toxicity study is required. Until the submitted 

alachlor toxicity study is formally reviewed and deemed acceptable, as discussed in section 4.1, 

the FQPA SF of 10X is retained as a UFDB.

4.4.2 Evidence of Neurotoxicity

Evidence of neurotoxicity from exposure to acetochlor was observed in several oral studies. 

However, these effects were typically observed at high doses. The points of departure selected 

for risk assessment are protective of the potential neurotoxicity observed in the database. 

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

No increase in susceptibility was seen in developmental toxicity studies in rats and rabbits or in 

three multi-generation reproductive toxicity studies in rats. Toxicity to offspring was observed at 

dose levels which were the same or greater than those causing maternal or parental toxicity. 

Based on the results of developmental and reproductive toxicity studies, there is no concern for 

increased qualitative and/or quantitative susceptibility following exposure to acetochlor.

4.4.4 Residual Uncertainty in the Exposure Database

Since the dietary and non-dietary exposure estimates were based on several conservative 

assumptions, HED does not believe that the exposure estimates are underestimated. The acute 
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and chronic dietary assessments conducted with DEEM-FCID were screening level or partially 

refined analyses. The assessments utilized tolerance values, average field trial residues, 

experimentally derived and default processing factors, and 100% crop treated was assumed for 

all commodities. The DEEM analysis also assumed that all drinking water will contain 

acetochlor at the highest EDWC levels modeled by EFED for ground water or surface water. 

For these reasons it can be concluded that the DEEM-FCID analysis does not underestimate risk 

from acute or chronic exposure to acetochlor. Similarly, HED does not believe that the nondietary occupational exposures are underestimated because they are also based on conservative 

assumptions, including maximum application rates, and standard values for unit exposures and

acreage treated/amount handled.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The specific toxicity endpoints and points of departure (PODs) are presented in Table 4.5.4.1. 

Toxicity endpoints and PODs for dietary/drinking water and occupational exposure scenarios are 

summarized below. Acute and chronic reference doses (RfDs) were selected for assessment of food 

and drinking water exposures. Occupational endpoints were selected. There are no residential uses 

for acetochlor at this time. A detailed description of the studies used as the bases for the selected 

endpoints are presented in Appendix A.

For the acute dietary endpoint (all populations), a POD of 150 mg/kg/day was selected from an 

acute oral neurotoxicity study in rats. The effects were detected after a single dose based on 

decreased motor activity in females at a LOAEL of 500 mg/kg/day. A UF of 100X (10X for 

interspecies extrapolation, 10X for intraspecies variation, 1X FQPA SF) was applied to the dose 

to obtain an acute reference dose (aRfD) and/or aPAD of 1.5 mg/kg/day. An acute endpoint was 

not selected specifically for Females 13-49 years old since no developmental effects that could 

be attributed to a single exposure were identified in the acetochlor database.

For the chronic dietary endpoint (all populations), a chronic feeding study in dogs was selected

since the duration of the study is one year (long term) and the effects were observed after 

multiple doses. A point of departure (POD) of 2.0 mg/kg/day was based on increased salivation 

and histopathology in the testes, kidney and liver at a LOAEL of 10 mg/kg/day. A UF of 100X 

(10X for interspecies extrapolation, and 10X for intraspecies variation, 1X FQPA SF) was 

applied to the POD to obtain a chronic reference dose (cRfD) and/or cPAD of 0.02 mg/kg/day.

Short and intermediate-term occupational exposures via the dermal and inhalation routes may 

occur based on the use pattern and label directions. The POD for short-term dermal exposure was 

chosen from a 21 day dermal toxicity study in rabbits. The NOAEL was 400 mg/kg/day based on 

mortality and clinical signs of toxicity seen at the LOAEL of 1200 mg/kg/day. This study is 

appropriate for both the route and duration of exposure. Although mortality is an endpoint, it was 

seen at a dose level which is higher than the limit dose. While developmental and neurotoxicity 

effects are not measured in a dermal toxicity study, the endpoint selected from the dermal 

toxicity is considered protective of these effects. The NOAEL of 150 mg/kg/day for both 

developmental and neurotoxicity when coupled with the dermal absorption factor of 20%, results 

in an estimated dermal NOAEL of 750 mg/kg/day. This level of exposure exceeds the dermal 
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toxicity study NOAEL of 400 mg/kg/day. Therefore, use of the dermal toxicity NOAEL as an 

endpoint for risk assessment is protective. Because the endpoint is based on a route-specific 

study, a dermal absorption factor is not applied to the short-term dermal assessment. 

A POD for short-term inhalation was selected from a developmental study in rats with a NOAEL 

of 150 mg/kg/day. The LOAEL was based on maternal mortality, clinical signs of toxicity and 

reduced body weight gain observed at 600 mg/kg/day. An oral study was selected because there 

was no inhalation study of appropriate duration, and inhalation exposure was assumed to be 

equivalent to oral exposure in the short-term inhalation exposure assessments.

PODs for intermediate-term inhalation and dermal exposure were selected from two co-critical 

oral subchronic toxicity studies in the dog with a POD of 25 mg/kg/day (NOAEL). The LOAEL

is based on clinical signs of toxicity, decreased body weight gain, mild anemia, slightly increased 

relative liver weight, and increased serum alanine aminotransferase observed at 60 mg/kg/day. 

The two subchronic dog studies were considered together to provide the highest NOAEL and the 

lowest LOAEL. Oral studies were selected for the intermediate term dermal and inhalation 

exposures since the duration of exposure matched the study duration and route specific studies of 

the appropriate duration are not available at this time. For purposes of estimating intermediateterm dermal exposure, a 20% dermal absorption factor was used for route-to-route extrapolation 

from an oral study. Inhalation exposure was assumed to be equivalent to oral exposure in the 

intermediate-term exposure assessments.

The level of concern (LOC) for short- and intermediate-term dermal exposure assessments is a 

margin of exposure (MOE) of 100. However, based on a review by the Hazard and Science 

Policy Council (HASPOC), an additional 10X uncertainty factor (UF) was applied to the shortand intermediate-term inhalation exposure assessments to account for lack of a subchronic 

inhalation toxicity study. Because the dermal and inhalation LOCs are different, an aggregate 

risk index (ARI) was calculated to estimate the combined exposure to acetochlor. A body weight 

of 80 kg was used in the assessments because fetal effects were only observed at or above 

maternally toxic doses.

Acetochlor is classified as “Suggestive Evidence of Carcinogenic Potential” based on weak 

evidence for benign lung tumors in male and female mice and histiocytic sarcomas in female 

mice. Consequently, linear quantification of carcinogenic potential is not required for the mouse 

tumors. There are acceptable modes of action data for the rat tumors (nasal olfactory epithelial 

tumors and thyroid follicular cell tumors) which are adequate to support a non-linear, MOE, 

approach for assessment of cancer risk (TXR# 0054494).

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential residential exposures to the pesticide, aggregate risk assessment must 

consider exposures from three major sources: oral, dermal and inhalation exposures. A common 

endpoint was not identified for the oral, dermal, and inhalation scenarios. Furthermore, since 

there are no residential uses of acetochlor, only aggregate exposure from food and water 

exposures is required. Dermal and inhalation worker risk estimates were combined in this 

assessment, since the toxicological effects for these exposure routes were similar (mortality and 

clinical signs). 
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4.5.3 Cancer Classification and Risk Assessment Recommendation

In accordance with the EPA’s Final Guideline for Carcinogen Risk Assessment (March 2005), 

the HED Cancer Assessment Review Committee (CARC) classified Acetochlor as “Suggestive 

Evidence of Carcinogenic Potential” based on weak evidence for benign lung tumors in male and 

female mice and histiocytic sarcomas in female mice (TXR No. 0054494). Consequently, linear 

quantification of carcinogenic potential is not required for the mouse tumors. There are 

acceptable mode of action data for the rat tumors (nasal olfactory epithelial tumors and thyroid 

follicular cell tumors) which are adequate to support a non-linear MOE approach for assessment 

of cancer risk. Quantification of cancer risk is not required since the chronic RfD of 0.02 

mg/kg/day (based on chronic oral toxicity in the dog) will be protective of both non-cancer and 

cancer effects, including rat nasal tumors, thyroid tumors, and mouse tumors. 

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

Assessment

Toxicological doses/endpoints selected for the acetochlor risk assessment are provided in Tables 

4.5.4.1 and 4.5.4.2.
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Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Acetochlor for Use in Dietary Human Health 

Risk Assessments

Exposure/S

cenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors RfD, PAD 

Study and Toxicological Effects

Acute 

Dietary

(All 

Populations)

NOAEL = 

150 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF =1x

Acute RfD = 1.5 

mg/kg/day

aPAD = 1.5 

mg/kg/day

Acute oral neurotoxicity in rats 

(MRID # 45357501)

LOAEL = 500 mg/kg/day, based on

decreased motor activity in females.

Chronic 

Dietary

(All 

Populations)

NOAEL = 

2.0 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD = 

0.02

mg/kg/day

cPAD = 0.02 

mg/kg/day

Chronic oral toxicity in beagle dogs

(MRID # 41565118)

LOAEL = 10 mg/kg/day, based on

increased salivation and histopathology

in the testes, kidney and liver.

Incidental 

Oral

Dermal

Inhalation

There are no residential uses for or exposures to acetochlor. Therefore exposure endpoints are not required 

and not selected for residential exposure assessment.

Cancer (all 

routes)

Classification: “Suggestive Evidence of Carcinogenic Potential". Quantification of cancer risk is not 

required since the cRfD of 0.02 mg/kg/day will be protective of both non-cancer and cancer effects

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). UFS = use of a short-term study for long-term 

risk assessment. UFDB = to account for the absence of key date (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
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Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Acetochlor 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 Short 

(1-30 days) 

NOAEL= 

400 

mg/kg/day

UFA= 10x

UFH=10x

Occupational LOC 

for MOE = 100

21-day dermal toxicity study in rabbits

(MRID 00116637)

LOAEL = 1200 mg/kg/day, based on

mortality and clinical signs of toxicity.

Dermal 

Intermediate (1-

6 mo) 

NOAEL = 

25 

mg/kg/day

DAF = 

20%

UFA= 10x

UFH=10x

Occupational LOC 

for MOE = 100

Co-critical subchronic oral toxicity studies in 

dogs (MRIDs 00050928 and 41565116)

LOAEL = 60 mg/kg/day, based on

decreased body weight/weight gain,

slight anemia, slight liver effects.

Inhalation 

Short-Term(1-

30 days) Term

NOAEL= 

150 

mg/kg/day

UFA= 10x

UFH=10x

UFDB=10x

Occupational LOC 

for MOE = 1000 Developmental toxicity study in rats (MRIDs 

41592005, 42054903)

Maternal LOAEL=600 mg/kg/day based on 

mortality, clinical signs of toxicity and reduced 

body weight gain during treatment

Inhalation 

IntermediateTerm (1-6 mo) 

NOAEL = 

25 

mg/kg/day

UFA= 10x

UFH=10x

UFDB=10x

Occupational LOC 

for MOE = 1000

Co-critical Subchronic oral toxicity studies in 

dogs (MRIDs 00050928 and 41565116)

LOAEL = 60 mg/kg/day, based on

decreased body weight/weight gain,

slight anemia, slight liver effects.

Cancer (all 

routes)

Classification: “Suggestive Evidence of Carcinogenic Potential". Quantification of cancer risk is not 

required since the cRfD of 0.02 mg/kg/day will be protective of both non-cancer and cancer effects

DAF = Dermal Absorption Factor ; 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). UFS = use of a 

short-term study for long-term risk assessment. UFDB = to account for the absence of key date (i.e., lack of a critical 

study). FQPA SF = FQPA Safety Factor. MOE = margin of exposure. LOC = level of concern. N/A = not 

applicable.
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5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The available cotton, corn and soybean metabolism data are adequate to support the proposed 

uses on peanuts. HED has determined that, for purposes of the subject petitions, the residues of 

concern for risk assessment and tolerance enforcement for existing tolerances are the parent and 

any metabolites containing the EMA or the HEMA moiety, expressed in acetochlor equivalents. 

HED previously concluded that the qualitative nature of acetochlor residues in livestock animals 

is adequately understood based on adequate studies examining the metabolism of various plant 

metabolites (acetochlor EMA type metabolites, HEMA type metabolites, and Metabolite 57) in 

both ruminants and poultry. The residues of concern in ruminants and poultry include 

acetochlor, its EMA- and HEMA-type metabolites, and Metabolite 57 (a ring hydroxylated 

metabolite)). 

5.1.2 Summary of Environmental Degradation

[Excerpted from the 2005 HED Chapter of Tolerance Reassessment Document (TRED) (Protzel A. et al. 7/22/05, 

D306535, D292338)]

The major routes of dissipation for acetochlor appear to be microbially-mediated degradation, 

runoff, and leaching. Although acetochlor generally degrades rapidly when applied to soil, in 

some field situations it can be relatively persistent (e.g. field dissipation half-lives were up to 36 

days) and it has been found in groundwater at numerous locations. There is variable evidence as 

to the persistence of acetochlor in subsoil horizons with a published study by the registrant 

reporting only a modest increase in persistence from surface soils at two sites using in situ

methods (Mills et al. 2001). Lavy et al. (1996) have reported a much more substantial increase 

in persistence at two sites for alachlor, an herbicide that is chemically related to acetochlor and 

tends to have a very similar environmental fate profile. 

Laboratory degradation data indicate that acetochlor does not degrade by abiotic processes 

(hydrolysis and photolysis). While acetochlor has relatively short half-lives in fine-textured 

aerobic soil, it may be moderately persistent in coarser soils (this may be related to the lower rate 

of microbial activity in sandy, low organic matter soils).

The aerobic soil metabolism degradates oxanilicacid (oxamic acid), and sulfonic acid are the 

major environmental degradates of acetochlor. Another metabolite is thioacetic acid sulfoxide.

Environmental fate and monitoring (especially ground and surface water) data demonstrate that 

chronic exposure potential is much greater for the ethanesulfonic acid degradate and to some 

extent the oxanilic acid degradate (they are environmentally more persistent than parent 

acetochlor), however, HED has determined that these are much less toxic than parent. 
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5.1.3 Comparison of Metabolic Pathways

Acetochlor was rapidly eliminated in the rat (92-96% in 5 days). Acetochlor was completely 

metabolized (15 compounds separated in urine, 4 in bile, 5 in feces), with glutathione, 

mercapturic acid or glucuronide conjugation of N-dealkylated acetochlor a major route of 

metabolism; sulphoxymethyl and cysteine conjugates also identified in feces. In urine, the major 

metabolite was mercapturic acid conjugate of N-deethylated acetochlor; in bile, the major 

metabolite was the glucuronide conjugate. The major fecal metabolite was not characterized.

Acetochlor plant metabolism studies are available for soybean, corn and cotton. Livestock 

metabolism studies are available for acetochlor in ruminants (goats) and poultry. Acetochlor is 

metabolized extensively, and distributed throughout the plant and livestock animals. In both 

plants and livestock, acetochlor metabolites primarily contain the EMA or the HEMA moiety. 

5.1.4 Residues of Concern Summary and Rationale

The residues of concern for tolerance purposes in plants (primary crop and rotational crop)

includes parent and any metabolites containing the ethyl methyl aniline (EMA) or hydroxyethyl 

methyl aniline (HEMA) moiety, expressed in acetochlor equivalents. The residues of concern for 

risk assessment purposes in plants (primary crop and rotational crop) includes parent and any 

metabolites containing the ethyl methyl aniline (EMA) or hydroxyethyl methyl aniline (HEMA) 

moiety, as well as its hydroxymethyl ethyl aniline (HMEA) type metabolites, expressed in 

acetochlor equivalents (M. Flood, MARC Memorandum, 9/30/93). Table 5.1.4 provides a 

summary of the Metabolism Assessment Review Committee (MARC) decisions regarding 

residues of concern for acetochlor. There are no livestock tolerances at this time.
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Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants

Primary Crop

Parent and metabolites 

containing the EMA

or HEMA or HMEA moiety

Parent and metabolites 

containing the EMA or 

HEMA moiety

Rotational Crop

Parent and metabolites 

containing the EMA

or HEMA or HMEA moiety

Parent and metabolites 

containing the EMA or 

HEMA moiety

Drinking Water Parent only* Not Applicable

*For drinking water exposure assessments, concentrations of acetochlor degradates are not included 

because of significantly lower toxicological concerns for human health.

5.2 Food Residue Profile

Acetochlor is metabolized extensively in plants and livestock animals. The qualitative nature of 

acetochlor residues in plants is adequately understood based on soybean, corn and cotton 

metabolism studies. HED concluded that the residues of concern in corn and in livestock 

commodities include parent and any metabolites containing the EMA moiety or the HEMA 

moiety, expressed in acetochlor equivalents. The nature of the residue in rotational crops is 

adequately understood based on the results of confined rotational crop studies in lettuce, radishes 

and wheat. HED concluded that acetochlor tolerances for inadvertent residues on rotational crops 

should be expressed as acetochlor and its EMA and HEMA producing metabolites, and residues 

of hydroxymethyl ethyl aniline (HMEA) type metabolites would not be included in the tolerance 

expression, but should be included in the risk assessment.

Acetochlor residues are distributed throughout the plant and on most plants are quantifiable. 

Residues generally do not decline with increasing PHI. Residues of acetochlor will concentrate 

in some processed fractions, but are reduced in some of the more refined fractions. Residues of 

acetochlor will transfer to livestock commodities; however, at the levels of current and proposed 

tolerances for livestock feed stuffs, there is no reasonable expectation of residues in livestock 

tissues, and no tolerances are required for livestock commodities.

Adequate field trial data were submitted for sugar beets and peanuts, following the proposed use 

patterns. A microencapsulated (ME) formulation was used in the field trials. The highest 

residues were seen in the trials from Sugar beets Treatment 4: Postemergence at 6-leaf growth 

stage and Peanuts Treatment 4: Postemergence at BBCH 18-59. These sets of trials were used to 

recommend a tolerance level. All of the field trial data are summarized in the tables below.

Field trial samples were analyzed by an adequate analytical method, and an adequate 

enforcement analytical method is available. The field trials were supported by storage stability 

studies showing that residues of acetochlor and its metabolites were stable for the length of 
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frozen storage prior to analysis. The petitioner should note that the temperature should be 

reported for the frozen storage of analytical samples.

Adequate rotational crop studies are available from an earlier submission. The requirements for 

field accumulation in rotational crops are satisfied. The available extensive rotational crop field 

trials conducted at 3.0 lb ai/A (1x the maximum proposed seasonal application rate for cotton 

and soybean) are adequate and support the PBIs specified on the product labels and the 

tolerances for indirect or inadvertent residues of acetochlor in/on the commodities of nongrass 

animal feeds; sugar beets; cereal grains except corn, sorghum, rice, and wheat; dried shelled peas 

and beans; potatoes; soybeans; sunflower seed; and wheat. 

Adequate processing data were submitted for sugar beets and peanuts. The average processing 

factors from the two studies indicate that total acetochlor residues did not concentrate in refined 

sugar (<0.3x), but appear to concentrate in dried pulp (1.6x) and molasses (2.7x). The calculated 

processing factors for sugar beet dried pulp and molasses did not exceed the maximum 

theoretical concentration factor (experimental) of 20x for sugar beets (OCSPP 860.1520, Table 

1).

The average processing factors from the two studies indicate that total acetochlor residues did 

not concentrate in dry roasted nuts (1.0x), peanut butter (1.0x), or RBD oil (0.4x) but did 

concentrate in peanut meal (2.7x). The calculated processing factor for peanut meal exceeds the 

maximum theoretical concentration factor of 2.2x for peanut meal (OCSPP 860.1520, Table 3).

The samples were analyzed by an adequate analytical method. The studies were adequately 

supported by storage stability data.

TABLE 5.2.1. Summary of Residue Data from Sugar Beet Field Trials with Acetochlor.

Commodity Total 

Applic. Rate

(lb ai/A)

PHI

(days)

Total Acetochlor Residue Levels1

(HEMA- + EMA-Producing Metabolites, ppm)

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. Dev.

Treatment 2: Preemergence plus Postemergence at 6-leaf growth stage

Sugar beet roots 2.94-3.19 63-131 15 <0.006 0.094 <0.007 0.086 0.016 0.024 0.021

Sugar beet tops 2.94-3.19 63-131 15 0.008 0.558 0.009 0.554 0.033 0.074 0.137

Treatment 3: Two Postemergence at 2- and 6-leaf growth stage

Sugar beet roots 2.94-3.06 63-131 15 <0.006 0.089 <0.008 0.079 0.017 0.021 0.017

Sugar beet tops 2.94-3.06 63-131 15 0.009 0.214 0.009 0.209 0.033 0.049 0.050

Treatment 4: Postemergence at 6-leaf growth stage

Sugar beet roots 2.97-3.10 63-131 15 <0.007 0.329 <0.008 0.274 0.021 0.038 0.066

Sugar beet tops 2.97-3.10 63-131 15 0.012 0.981 0.012 0.635 0.034 0.084 0.157

1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and 

standard deviation, the LOQ for HEMA and EMA (0.0015 and 0.0016 ppm in/on roots, and 0.0011 and 0.0037 ppm in/on tops, 

respectively) was used for any results reported as <LOQ in Table C.3. 

2

 LAFT = lowest average field trial; HAFT = highest average field trial.
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TABLE 5.2.2. Summary of Residue Data from Peanut Field Trials with Acetochlor.

Commodity Total 

Applic. Rate

(lb ai/A)

PHI

(days)

Total Acetochlor Residue Levels1

(HEMA- + EMA-Producing Metabolites, ppm)

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. Dev.

Treatment 2: Preplant Incorporated plus Postemergence at BBCH 18-59

Peanut, nutmeat 2.96-3.05 98-128 13 <0.020 0.084 <0.021 0.081 0.041 0.042 0.017

Peanut, hay 2.96-3.05 98-128 13 0.31 3.79 0.32 3.77 1.06 1.47 1.04

Treatment 3: Preemergence plus Postemergence at BBCH 18-59

Peanut, nutmeat 2.94-3.06 98-128 13 <0.023 0.095 <0.029 0.092 0.040 0.046 0.018

Peanut, hay 2.94-3.06 98-128 13 0.44 3.26 0.59 2.96 1.02 1.29 0.70

Treatment 4: Postemergence at BBCH 18-59

Peanut, nutmeat 2.93-3.06 98-128 13 <0.026 0.106 <0.030 0.092 0.046 0.054 0.023

Peanut, hay 2.93-3.06 98-128 13 0.50 4.90 0.57 4.88 1.39 1.65 1.11

1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and 

standard deviation, the LOQ (0.0094 and 0.0090 ppm for HEMA and EMA, respectively, in nutmeat, and 0.0033 and 0.0030 ppm 

for HEMA and EMA, respectively, in hay) was used for any results reported as <LOQ in Table C.3. 

2

 LAFT = lowest average field trial; HAFT = highest average field trial.

5.3 Water Residue Profile

Estimated Surface and Ground Drinking Water Concentrations (EDWCs) for acetochlor, an 

acetanilide herbicide, were evaluated for the proposed new uses. This drinking water exposure 

assessment incorporates proposed use patterns for peanuts and sugar beets. Acute and chronic 

exposure estimates for surface supply scenarios representing these new uses remain below the 

maximum EDWCs previously estimated (see DP Barcode D359995, review dated 6/24/2009), 

however, well water exposure models have been updated, and the acute and chronic exposure 

estimates from groundwater sources have increased from previous estimates. The current 

(partially revised) acute and chronic drinking water exposure estimates are summarized in Table 

5.3.1. Although EFED at this time recommends that the Agency rely on these estimates in human 

health risk assessments, a basis for a refined assessment which would likely lower the EDWCs is 

presented in the following paragraphs. Specifically, the Table 5.3.1 estimates are based on Tier 1 

modeling; analysis of extensive targeted monitoring data for acetochlor indicates that actual 

exposure at drinking water wells may be significantly lower.
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Table 5.3.1. Tier I Estimated Drinking Water Concentrations (EDWCs) for human health 

drinking water risk assessment.

DRINKING WATER 

SOURCE

(MODEL USED) 

HIGH EXPOSURE SCENARIO

(rate modeled)

MAXIMUM ESTIMATED DRINKING 

WATER CONCENTRATION 

(EDWC)c ( ppb); selected values in bold 

italics.

Conservative Values for Updated Drinking Water Exposure Estimate 

Groundwater

(PRZM-GW) FL Astatula sand Scenario – citrus1

Acute 129.0

Lifetime 82.6

Surface Water

PRZM-EXAMS

Ks sorghum

CA sugarbeet “OP” scenario2

Acute 74.9

Lifetime 4.84

Recommended values are based upon the most conservative Tier 1 modeling results; targeted surface and groundwater monitoring studies provide more insights into exposure levels under actual usage conditions and are 

discussed later in this review. 

1 Citrus is the nominal crop upon which the scenario estimated the highest EDWC is based, but results are used for 

all national assessments in a Tier 1 screen. 

2 OP = Scenario parameters originally designed to evaluate exposure to organophosphate use areas; this scenario 

may or may not be appropriately conservative for a national evaluation of impacts from uses of non-OP pesticides 

such as acetochlor. 

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Tolerance level residues were used in the acute dietary exposure assessment while average field 

trial residues were used in the chronic dietary exposure assessment.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated was not refined in the dietary exposure assessment. It was assumed that 100 

% of the crop was treated.

5.4.3 Acute Dietary Risk Assessment

The acute dietary analysis is an unrefined screening level analysis. In addition, the 100% crop 

treated estimate used for all crops in the assessment will considerably overestimate the actual 

percent crop treated. 
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Table 5.4.3: Summary of Acute Dietary Exposure and Risk for Acetochlor

Population Subgroup aPAD (mg/kg/day) Acute (95th Percentile)

Exposure (mg/kg/day) % aPAD

General U.S. Population

1.5

0.008053 <1

All Infants (< 1 year old) 0.023419 1.6

Children 1-2 years old 0.013567 <1

Children 3-5 years old 0.010845 <1

Children 6-12 years old 0.007987 <1

Youth 13-19 years old 0.006423 <1

Adults 20-49 years old 0.007742 <1

Adults 50-99 years old 0.006824 <1

Females 13-49 years old 0.007783 <1

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary analysis is somewhat refined. Average field trial residues used in the 

analysis are expected to exceed the residues actually consumed. In addition, the 100% crop 

treated estimate used for all crops in the assessment will considerably overestimate the actual 

percent crop treated. 

Table 5.4.4: Summary of Chronic Dietary Exposure and Risk for Acetochlor

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) % cPAD

General U.S. Population

0.02

0.002155 11

All Infants (< 1 year old) 0.005179 26

Children 1-2 years old 0.003868 19

Children 3-5 years old 0.003194 16

Children 6-12 years old 0.002175 11

Youth 13-19 years old 0.001606 8.0

Adults 20-49 years old 0.002065 10

Adults 50-99 years old 0.002011 10

Females 13-49 years old 0.002044 10

5.4.5 Cancer Dietary Risk Assessment

Quantification of cancer risk is not required since the cRfD of 0.02 mg/kg/day will be protective 

of both non-cancer and cancer effects.
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5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and 

Risk for Acetochlor

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

General U.S. Population 0.008053 <1 0.002155 11

All Infants (< 1 year old) 0.023419 1.6 0.005179 26

Children 1-2 years old 0.013567 <1 0.003868 19

Children 3-5 years old 0.010845 <1 0.003194 16

Children 6-12 years old 0.007987 <1 0.002175 11

Youth 13-19 years old 0.006423 <1 0.001606 8.0

Adults 20-49 years old 0.007742 <1 0.002065 10

Adults 50-99 years old 0.006824 <1 0.002011 10

Females 13-49 years old 0.007783 <1 0.002044 10
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Currently, there are no registered or proposed residential uses for acetochlor.

6.1 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for acetochlor. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information1. The 

Agency has completed its evaluation of the new database submitted by the Spray Drift Task 

Force, a membership of U.S. pesticide registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 

off-target drift with specific products with significant risk estimates associated with drift.

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

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios. 

6.2 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for acetochlor at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and low vapor pressure (3.4x10-8 mm Hg). However, 

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, 20102. The Agency is in the process of evaluating the SAP report and may, as 

appropriate, develop policies and procedures to identify the need for and, subsequently, the way 

to incorporate post-application inhalation exposure into the Agency's risk assessments. If new 

policies or procedures are developed, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for acetochlor.

 

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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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

In examining acute aggregate risk, HED has assumed that the only pathway of exposure relevant 

to the acute time frame is dietary exposure. Therefore, the acute aggregate risk is comprised of 

exposures to acetochlor residues in food and drinking water and is equivalent to the acute dietary 

risk estimates summarized in Table 5.4.6 in Section 5.4.3. The acute dietary risk estimates are 

well below HED’s level of concern for the general population and all population subgroups.

7.2 Short-Term Aggregate Risk

Currently, there are no registered or proposed residential uses for acetochlor, therefore, a shortterm aggregate risk assessment is not required.

7.3 Intermediate-Term Aggregate Risk

Currently, there are no registered or proposed residential uses for acetochlor, therefore, an 

intermediate-term aggregate risk assessment is not required.

7.4 Chronic Aggregate Risk

In examining chronic aggregate risk, HED has assumed that the only pathway of exposure 

relevant to the chronic time frame is dietary exposure. Therefore, the chronic aggregate risk is 

comprised of exposures to acetochlor residues in food and drinking water and is equivalent to the 

chronic dietary risk estimates summarized in Table 5.4.6 in Section 5.4.4. The chronic risk 

estimates are below HED’s level of concern for all population subgroups. 

7.5 Cancer Aggregate Risk

HED has concluded that assessments using a non-linear approach (e.g. a chronic RfD-based 

approach) will adequately protect for all chronic toxicity, including carcinogenicity that could 

result from exposure to acetochlor. Chronic aggregate risk estimates are below HED’s level of 

concern, therefore, cancer risk is also below HED’s level of concern. 

8.0 Cumulative Exposure/Risk Characterization

As part of the provisions of the Food Quality Protection Act (FQPA, 1996), EPA must consider 

the cumulative effects on human health that may result from exposure to different chemicals that 
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cause toxic effects by the same mode of action. The chloroacetanilides have been evaluated by 

the Agency and the FIFRA Scientific Advisory Panel (SAP) as a related group of chemicals for 

this purpose. Acetoclor is included in a Cumulative Assessment Group (CAG) of 

Chloroacetanilide pesticides. Structurally related chloroacetanilides include acetochlor, alachlor, 

butachlor, propachlor and metolachlor. For purposes of a cumulative risk assessment, it was 

determined that the common mechanism of toxicity group consists of alachlor, acetochlor and 

butachlor. Butachlor is excluded from the group for risk assessment purposes at present there are 

no registered uses or tolerances for this chemical in the US. The group was selected based on 

common endpoints of (1) nasal turbinate tumors in rats, and a known mechanism of toxicity for 

development of these tumors and (2) induction of hepatic UDP-Glucuronosyl Transferase 

(UDPGT), which results in increased incidence of thyroid follicular cell tumors secondary to 

disruption of pituitary-thyroid homeostasis. Thyroid effects were not included in the final 

cumulative assessment of the chloroacetanilide herbicides because they were determined to 

occur at excessively toxic dose levels, and therefore were not considered relevant to human risk 

assessment. Nasal tumors represent the most sensitive endpoint for both compounds.

An updated cumulative risk assessment of the Chloroacetanilide (CAG) pesticides acetochlor 

and alachlor conducted in April, 2007 provides an assessment of existing and new uses of those 

chemicals to date. Based on the most recent chloroacetanilide CAG cumulative risk assessment, 

cumulative risk is not of concern. A revised quantitative cumulative assessment was not 

conducted because the proposed amended use would not affect the cumulative risk results. Not 

only is acetochlor a very minor contributor to chloroacetanilide cumulative risk when compared 

to alachlor, but adding the use on sugar beets and peanuts will only have a minor impact on 

acetochlor exposure since only low residues occurred on sugar beet and peanut food 

commodities. 

9.0 Occupational Exposure/Risk Characterization

WARRANT® Herbicide is proposed to be applied pre-plant, pre-emergent, or early postemergent to sugar beets and peanuts using either groundboom or aerial spray equipment at a rate 

of 0.94 to 1.5 pounds ai per acre (lb ai/A). A minimum of 7 days is allowed between sequential 

applications.

There is a potential for short- and intermediate-term occupational exposure to acetochlor during 

mixing, loading, application, and post-application activities; however, chronic exposure is not 

expected from the proposed uses.

9.1 Short- and Intermediate-Term Handler Risk

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 proposed uses

on peanuts and sugar beet. The quantitative exposure/risk assessment developed for 

occupational handlers is based on the following scenarios: 

1) Mixing/loading liquids for aerial and groundboom applications;

2) Applying sprays via aerial and groundboom equipment; and
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3) Flagging for aerial applications.

It is the policy of HED to use the best available data to assess handler exposure. Sources of 

generic handler data, used as surrogate data in the absence of chemical-specific data, include 

PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) 

database, or other registrant-submitted occupational exposure studies. Some of these data are 

proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. 

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

As summarized in Tables 9.1.1 and 9.1.2, the occupational handler exposure and risk estimates 

indicate that the short-and intermediate-term dermal and inhalation aggregate risk indexes 

(ARIs) are not of concern to HED (i.e., ARI > 1) with the use of chemical-resistant gloves, as 

directed by the label.

The Agency matches quantitative occupational exposure assessment with appropriate 

characterization of exposure potential. While HED presents quantitative risk estimates for human 

flaggers where appropriate, agricultural aviation has changed dramatically over the past two 

decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of 

their membership, the use of GPS for swath guidance in agricultural aviation has grown steadily 

from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide 

applications has decreased steadily from ~15% in the late 1990’s to only 1% in the most recent 

(2012) NAAA survey. The Agency will continue to monitor all available information sources to 

best assess and characterize the exposure potential for human flaggers in agricultural aerial 

applications.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for 

exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, 

and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, 

pilots are not required to wear protective gloves for the duration of the application. With this 

level of protection, there are no risk estimates of concern for applicators.
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Table 9.1.1. Short-Term Occupational Handler Non-Cancer Exposure and Risk Estimates for Acetochlor. 

Exposure Scenario Crop or 

Target

Dermal Unit 

Exposure (μg/lb 

ai)1

Inhalation Unit 

Exposure (μg/lb 

ai)1

Maximum 

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal

(LOC = 100)

Inhalation

(LOC = 1000)

Total

(LOC = 1)

Mitigation Level Baseline Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 ARI8

Mixer/Loader

Aerial application of liquid 

formulation Sugar Beets 

and

Peanuts

220

(baseline)

37.6

(gloves)

0.219

1.5

lb ai/A

1,200

4.95

(baseline)

0.846

(gloves)

81

(baseline)

470

(gloves)

0.00493 30,000

0.79

(baseline)

4.1

(gloves)

Groundboom application of 

liquid formulation

220

(baseline) 0.219 200 0.825(baseline) 480 0.000821 180,000 4.7(baseline)

Applicator

Aerial spray application Sugar Beets 

and

Peanuts

2.08

(engineering 

control)

0.0049

1.5

lb ai/A

1,200

0.0468

(engineering 

control)

8,500 0.00011 1,400,000

80

(engineering 

control)

Groundboom spray 

application

78.6

(baseline) 0.34 200 0.295(baseline) 1,400 0.00128 120,000 13

(baseline)

Flagger

Flagging for aerial spray 

application

Sugar Beets 

and

Peanuts

11

(baseline)

0.35

1.5

lb ai/A

350 0.0723

(baseline) 5,500 0.0023 65,000 30

(baseline)

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ; Level of mitigation: Baseline dermal attire (or addition of gloves when indicated); no respirator.

2 Based on registered or proposed label (Reg. No. 524-591).

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 (100%) ÷ BW 

(80 kg).

5 Dermal MOE = Dermal NOAEL (400 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 (80 kg).

7 Inhalation MOE = Inhalation NOAEL (150 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Aggregate Risk Index (ARI) = 1÷ (1 ÷ RIdermal) + (1 ÷ RIinhalation); Where: Risk Index (RI) = MOE ÷ LOC (100 for dermal and 1000 for inhalation).
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Table 9.1.2. Intermediate-Term Occupational Handler Non-Cancer Exposure and Risk Estimates for Acetochlor. 

Exposure Scenario Crop or 

Target

Dermal Unit 

Exposure (μg/lb 

ai)1

Inhalation Unit 

Exposure (μg/lb 

ai)1

Maximum 

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal

(LOC = 100)

Inhalation

(LOC = 1000)

Total

(LOC = 1)

Mitigation Level Baseline Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 ARI8

Mixer/Loader

Aerial application of liquid 

formulation Sugar Beets 

and

Peanuts

220

(baseline)

37.6

(gloves)

0.219

1.5

lb ai/A

1,200

0.99

(baseline)

0.169

(gloves)

25

(baseline)

150

(gloves)

0.00493 5,100

0.24

(baseline)

1.2

(gloves)

Groundboom application of 

liquid formulation

220

(baseline) 0.219 200 0.165(baseline) 150 0.000821 30,000 1.4

Applicator

Aerial spray application Sugar Beets 

and

Peanuts

2.08

(engineering 

control)

0.0049

1.5

lb ai/A

1,200

0.00935

(engineering 

control)

2,700 0.00011 230,000

24

(engineerin

g control)

Groundboom spray 

application

78.6

(baseline) 0.34 200 0.059(baseline) 420 0.00128 20,000 3.5

(baseline)

Flagger

Flagging for aerial spray 

application

Sugar Beets 

and

Peanuts

11

(baseline) 0.35

1.5

lb ai/A 350 0.0145

(baseline) 1,700 0.0023 11,000 6.7

(baseline)

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ; Level of mitigation: Baseline dermal attire (or addition of gloves when indicated); no respirator.

2 Based on registered or proposed label (Reg. No. 524-591).

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 (20%) ÷ BW (80 

kg).

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 (80 kg).

7 Inhalation MOE = Inhalation NOAEL (25 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Aggregate Risk Index (ARI) = 1÷ (1 ÷ RIdermal) + (1 ÷ RIinhalation); Where: Risk Index (RI) = MOE ÷ LOC (100 for dermal and 1000 for inhalation).
Acetochlor/121601 Human Health Risk Assessment DP No. D413438

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9.2 Short-and 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

For acetochlor, based on the proposed uses, short- and intermediate-term exposures are expected 

for the following reasons: (1) acetochlor is an herbicide used to control a broad range of weeds 

both pre-emergence and post-emergence; and (2) up to three applications can be made 7 days 

apart. 

It is the policy of HED to use the best available data to assess post-application exposure. 

Sources of generic post-application data, used as surrogate data in the absence of chemicalspecific data, are derived from ARTF exposure monitoring studies, and, as proprietary data, are 

subject to the data protection provisions of FIFRA. The standard values recommended for use in 

predicting post-application exposure that are used in this assessment, known as “transfer 

coefficients”, are presented in the ExpoSAC Policy 33” which, along with additional information 

about the ARTF data, can be found at the Agency website4. Table 9.2.2.1 presents the transfer 

coefficients applicable to the proposed crops.

Table 9.2.1.1 Anticipated Post-Application Activities and Dermal Transfer Coefficients.

Proposed Crops

Policy Crop 

Group 

Category

Crop 

Height

Foliage 

Density

Transfer 

Coefficients 

(cm2/hr)

Activities

Sugar beets

Field / row 

crop, low / 

medium

Low Min/Full 210 Scouting

Peanuts

Low Full 1,900 Irrigation (hand set)

Low Min/Full 210 Scouting

Applications of WARRANT® Herbicide (EPA Reg. #524-591) to sugar beets and peanuts are 

proposed at a maximum rate of 1.5 lb ai/A. The average occupational workday is assumed to be 

8 hours. Chemical-specific dislodgeable foliar residue data have not been submitted for 

acetochlor. Therefore, this assessment uses HED’s default assumption that 25% of the 

application is available for transfer on day 0 following the application and the residues dissipate 

at a rate of 10% each following day. A DFR study is not required for acetochlor at this time 

 

3 Available: http://www.epa.gov/pesticides/science/exposac_policy3.pdf

4 Available: http://www.epa.gov/pesticides/science/post-app-exposure-data.html
Acetochlor/121601 Human Health Risk Assessment DP No. D413438

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since the dermal MOEs are greater than 4 times the LOC based on default values for the fraction 

of application rate available for transfer after a foliar application.

Occupational Post-application Non-Cancer Dermal Risk Estimates

As shown in Table 9.2.2.2., the occupational short- and intermediate-term post-application 

dermal exposure and risk estimates are greater than the LOC of 100 on the day of application, 

and therefore, are not of concern. 

Table 9.2.2.2. Occupational Post-application Non-Cancer Exposure and Risk Estimates for acetochlor.

Crop/Site Activities Transfer Coefficient 

(cm2/hr)

DFR1

(Day 0)

Dermal Dose 

(mg/kg/day)2

MOE3

(LOC = 100)

Short-term

Sugar beets Scouting 210

4.21

0.088 4,500

Peanuts

Irrigation (hand set) 1,900 0.799 500

Scouting 210 0.088 4,500

Intermediate-term

Sugar beets Scouting 210

4.21

0.018 1,400

Peanuts Scouting 210 0.018 1,400

1 DFR = Application Rate × F × (1-D)t × 4.54E+8 μg/lb × 2.47E-8 acre/cm2; where F = 0.25 and D = 0.10 per day 

2 Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (100% for short-term; 20% for 

intermediate-term)] BW (80 kg).

3 MOE = POD (400 mg/kg/day for short-term; 25 mg/kg/day for intermediate-term) / Daily Dermal Dose. 

Restricted Entry Interval

The occupational short- and intermediate-term post-application dermal exposure and risk 

estimates are greater than the LOC of 100 on the day of application. Since the post-application 

assessment is not a concern on Day 0, the restricted entry interval (REI) is based on the acute 

toxicity of acetochlor technical material. Acetochlor is classified in Toxicity Category III for 

acute dermal toxicity, and Categories III and II for primary eye and skin irritation, respectively. 

It is a dermal sensitizer. Therefore, the acute toxicity categories for this chemical require a 24-

hour REI under 40 CFR 156.208 (c) (2) (ii). The 12-hour REI, which currently appears on the 

WARRANT® Herbicide label, is not adequate to protect agricultural workers from postapplication exposures for the proposed uses of acetochlor.

9.2.2 Inhalation Post-application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for acetochlor at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and low vapor pressure (3.4x10-8 mm Hg). However, 

there are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 
Acetochlor/121601 Human Health Risk Assessment DP No. D413438

Page 39 of 79

(SAP) in December 2009, and received the SAP’s final report on March 2, 20105. The Agency is 

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

exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, 

to identify the need for and, subsequently, the way to incorporate occupational post-application 

inhalation exposure into the Agency's risk assessments. If new policies or procedures are put 

into place, the Agency may revisit the need for a quantitative occupational post-application 

inhalation exposure assessment for acetochlor.

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 

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

inhalation exposure scenarios.

10.0 References

Barrett, M. 06/25/2013. D411002. Acetochlor Drinking Water Assessment for Additional Food 

Uses on Peanuts and Sugar Beets.

Hummel, S. 08/21/2013. D406522. Acetochlor. PP#2F8077. Request to Establish a Tolerance for 

Acetochlor Residues In/On Sugar Beets and Peanuts.

Kidwell, J. 01/03/2007, TXR No. 0054494. Acetochlor: Fifth Report of the Cancer Assessment 

Review Committee. 

Morton, T. 06/26/2013. D412053. Acetochlor-Revised Acute and Chronic Dietary and Drinking 

Water Exposure and Risk Assessments.

O’Rourke, K. 07/18/2013. D413437. Acetochlor. Occupational and Residential Exposure 

Assessment for a Proposed Use on Sugar Beets and Peanuts.

Van Alstine, J. 01/17/2013. TXR No. 0056497. Acetochlor: Summary of Hazard and Science 

Policy Council (HASPOC) Meeting of October 25, 2012: Recommendations on Data 

Requirements for a Subchronic Inhalation, Positive Control Data for the Acute and Subchronic 

Neurotoxicity, and a Developmental Neurotoxicity Study.

 

5 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Acetochlor/121601 Human Health Risk Assessment DP No. D413438

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for Food Use for Acetochlor are in Table A.1. Use of the 

new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1. Guideline Data Requirements

Test

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent) .........................................

870.3200 21-Day Dermal ..............................................................

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

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

yes

yes

yes

no

yes

yes

yes

yes

no

recently received 

and in review

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent) ..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300* Chronic/Oncogenicity ..................................................

yesa

yes

yesa

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5375 Mutagenicity—Structural Chromosomal Aberrations...

870.5900 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

870.6300 Develop. Neuro..............................................................

no

no

yes

yes

yes**

-

-

yes

yes

-

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

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

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

yes

-

yes

yes

-

yes

* Guideline 870.4300 satisfies guideline 870.4100a and 870.4200a.

**Developmental Neurotoxicity study in rats was waived by HASPOC (1/17/13, TXR No.0056497)
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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Acetochlor Technical

Guideline 

No.

Study Type MRID # Results Toxicity

Category

870.1100 Acute oral, rat 41565104 (1986)

Acceptable/guideline

LD50 = 4238 mg/kg (males);

4025 mg/kg (females);

4124 mg/kg (combined)

III

870.1200 Acute dermal, rabbit 41565105 (1986)

Acceptable/guideline

LD50 > 2000 mg/kg (combined 

males and females)

III

870.1300 Acute inhalation, rat 41565106 (1989)

Acceptable/guideline

LC50 >4.46 mg/L (males)

LC50 = 3.99 mg/L (females)

III

870.2400 Primary eye 

irritation, rabbit

(1) 41592003 (1989)

Acceptable/guideline

(2) 00118947 (1982)

Acceptable/guideline

minimally irritating (both 

studies)

III

870.2500 Primary dermal 

irritation, rabbit

(1) 41565107 (1989)

Acceptable/guideline

severe (including microscopic 

changes)

II

870.2600 Skin sensitization, 

guinea pig

41565108 (1989)

Acceptable/guideline Both studies-very strong dermal 

sensitizer

N/A
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.3100

90-Day oral toxicity (rat)

00050933 (1980)

Acceptable/guideline

0, 800, 2000, 6000 ppm 

(diet)

0, 40, 100, 300 mg/kg/day

NOAEL = 40 mg/kg/day

LOAEL = 100 mg/kg/day based on decreased mean body 

weight/weight gain in males and females.

870.3100

90-Day oral toxicity (rat)

41565115 (1986)

Acceptable/guideline

0, 20, 200, 2000 ppm (diet)

males 0, 1.6, 16.1, 161.1 

mg/kg/day;

females 0, 1.9, 18.7, 191.9 

mg/kg/day

NOAEL = 16.1 mg/kg/day males (18.7 mg/kg/day females)

LOAEL = 161.1 mg/kg/day males (18.7 mg/kg/day females) 

based on decreased body weight/weight gain in males and 

females.

870.3150

119-Day oral toxicity 

(dog)

00050928 (1980)

Acceptable/guideline

0, 25, 75, 200 (capsule)

NOAEL = 25 mg/kg/day

LOAEL = 75 mg/kg/day based on death of 1 male (diarrhea, 

emaciation also in this animal) and in both sexes, decr. body 

weights and decrease food consumption, liver effects. (It is 

noted that in this study, mid and high dose animals were 

acclimated by increasing dose weekly: mid dose started at 25 

mg/kg/day week 1, 50 mg/kg/day week 2, then 75 mg/kg/day. 

High dose started at 50 mg/kg/day, incr. weekly by 50 

mg/kg/day then 200 mg/kg/day)

870.3150

90-Day oral toxicity (dog)

41565116 (1986)

Acceptable/guideline

0, 2, 10, 60 mg/kg/day 

(capsule)

NOAEL = 10 mg/kg/day

LOAEL = 60 mg/kg/day based on mucous diarrhea, decr. body 

wt, slight anemia, incr. alanine aminotransferase, incr. relative 

liver weight, decr. blood glucose.

870.3200

21-Day dermal toxicity 

(rabbit)

00116637 (1981)

Acceptable/guideline

0, 100, 400, 1200 

mg/kg/day (applied 5 

days/week for 3 weeks)

systemic NOAEL = 400 mg/kg/day

systemic LOAEL = 1200 mg/kg/day based on high mortality 

and agonal clinical signs of toxicity.

Local dermal irritation was observed at all dose levels.

870.3200

21-Day dermal toxicity 

(rat)

41565117 (1989)

Acceptable/guideline

0, 0.1 1.0, 10, 100 

mg/kg/day (applied 5 

days/week for 3 weeks)

systemic NOAEL = 100 mg/kg/day (HDT)

systemic LOAEL = >100 mg/kg/day (not tested at higher dose 

levels due to reported excessive dermal irritation in 

preliminary testing).

Local dermal irritation reported in this study in all groups 

including controls but epithelial hyperplasia was observed at 

100 mg/kg/day.

870.3465

90-Day inhalation toxicity

HASPOC concluded that a subchronic inhalation toxicity study is required, but 

acknowledges the alachlor inhalation toxicity study available in the literature, may provide 

sufficient data on acetochlor pesticide. The alachlor study was recently submitted by the 

registrant and is currently under review by HED scientists.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.3700a

Prenatal developmental in 

rats

00050929 (1980)

Acceptable/guideline

0, 50, 200, 400 mg/kg/day 

(gavage)

Maternal NOAEL = 200 mg/kg/day

LOAEL = 400 mg/kg/day based on clinical signs of toxicity 

and decreased maternal body weight/weight gain.

Developmental NOAEL = 200 mg/kg/day

LOAEL = 400 mg/kg/day based on slightly decreased mean 

fetal weight. 

870.3700b

Prenatal developmental in 

rats

41592005 (1989), 

42054903

Acceptable/guideline

0, 40, 150, 600 mg/kg/day 

(gavage)

Maternal NOAEL = 150 mg/kg/day

LOAEL = 600 mg/kg/day based on mortality, clinical signs of 

toxicity and decreased maternal body weight gain.

Developmental NOAEL = 150 mg/kg/day

LOAEL = 600 mg/kg/day based on increased early resorptions, 

post-implantation loss and decreased fetal weight.

870.3700b

Prenatal developmental in 

rabbits

40134101(1986)

Acceptable/guideline

0, 30, 100, 300 mg/kg/day 

(gavage)

Maternal NOAEL = 300 mg/kg/day

LOAEL >300 mg/kg/day (HDT; study acceptable based on 

results of a range-finding study).

Developmental NOAEL = 300 mg/kg/day

LOAEL >300 mg/kg/day .

870.3700b

Prenatal developmental in 

rabbits

41592006 (1989)

Acceptable/guideline

0, 15, 50, 190 mg/kg/day 

(gavage)

Maternal NOAEL = 50 mg/kg/day

LOAEL = 190 mg/kg/day based on body weight loss.

Developmental NOAEL = 190 mg/kg/day

LOAEL >190 mg/kg/day (HDT).

870.3800

Reproduction and fertility 

effects

rats

00131391(1982)

Acceptable/guideline

0, 500, 1500, 5000 ppm 

(diet)

F0 premating 0, 30.8, 60.4 

or 316 mg/kg/day, males; 

0, 46.2, 130.4 or 442 

mg/kg/day, females;

F1 premating 0, 29.9, 87.8 

or 333 mg/kg/day, males; 

0, 43.6, 129.8 or 441 

mg/kg/day, females.

Parental/Systemic NOAEL = 30.8/46.2 mg/kg/day 

males/females

LOAEL = 60.4/130.4 mg/kg/day males/females, based on 

decreased maternal gestation body weight gain and slightly 

reduced male and female premating body weight gain.

Offspring NOAEL = 30.8/46.2 mg/kg/day males/females

LOAEL = 60.4/130.4 mg/kg/day males/females, based on 

slightly decreased mean pup weights in F2b pups at lactation 

day 21.

Reproductive NOAEL = 316/442 mg/kg/day males/females.

LOAEL = mg/kg/day (HDT).

870.3800

Reproduction and fertility 

effects

rats

41565120 (1989)

Acceptable/guideline

0, 18, 175, 1750 ppm (diet)

Premating F0 males 0, 

1.27, 12.6 or 123.8 

mg/kg/day; F0 females 0, 

1.63, 15.5 or 157.4 

mg/kg/day

Premating F1 males 0, 

1.53, 15.2 or 152.1 

mg/kg/day; F1 females 0, 

1.83, 18.3 or 192.4 

mg/kg/day

Parental/Systemic NOAEL = 12.6 mg/kg/day males/15.2 

mg/kg/day females

LOAEL = 123.8 mg/kg/day males/157.4 mg/kg/day females, 

based on decreased body weight gain during premating.

Offspring NOAEL = 12.6 mg/kg/day males/15.2 mg/kg/day 

females.

LOAEL = 123.8/157.4 mg/kg/day males/females, based on 

reduced pup weight during lactation.

Reproductive NOAEL = 123.8/157.4 mg/kg/day (HDT). 

LOAEL > 123.8/157.4 mg/kg/day males/females.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.3800

Reproduction and fertility 

effects

rats

45357503 (2001)

Acceptable/guideline

0, 200, 600, 1750 ppm 

(diet)

Premating F1 males 0, 

21.2, 65.6, 196.4 

mg/kg/day;

Premating F1 females 0, 

22.4, 70.9, 215.9 

mg/kg/day 

Parental/Systemic NOAEL = males 21.2 mg/kg/day; females 

22.4 mg/kg/day

LOAEL = males 65.6 mg/kg/day; females 70.9 mg/kg/day, 

based on focal hyperplasia and polypoid adenomata in nasal 

epithelium of adult F1 offspring at study termination.

Offspring NOAEL = males 65.6 mg/kg/day; females 70.9 

mg/kg/day

LOAEL = males 196.4 mg/kg/day; females 215.9 mg/kg/day 

based on decreased pup weights during lactation (F1 and F2), 

decreased F2 litter size at birth, focal hyperplasia and polypoid 

adenomata in nasal epithelium of adult F1 offspring at study 

termination.

Reproductive NOAEL = males 65.6 mg/kg/day; females 70.9 

mg/kg/day

LOAEL = males 196.4 mg/kg/day; females 215.9 mg/kg/day 

based on decreased implantations.

870.4100a

Chronic toxicity

(rat)

See 870.4200, below

870.4100b

Chronic toxicity (dog)

00116631, 00164944 

(1981)

Acceptable/guideline

0, 4, 12, 40 mg/kg/day 

(capsule)

NOAEL = 12 mg/kg/day

LOAEL = 40 mg/kg/day based on decr. body wt. (females) and 

decr. wt. gain (males), incr. adrenal wt. (females), incr. liver 

weight (males and females), decr. testes wt., testicular atrophy.

870.4100b

Chronic toxicity (dog)

41565118 (1988), 

Acceptable/guideline

0, 2, 10, 50 mg/kg/day 

(capsule)

46100901 (2003)

Unacceptable/nonguideline 

(reexamination of 

testicular / epididymal 

tissue)

NOAEL = 2 mg/kg/day

LOAEL = 10 mg/kg/day based on incr. salivation, incr. 

ornithine carbamyltransferase and triglycerides, decr. blood 

glucose; incr. incidence of interstitial nephritis, testicular 

degeneration/hypospermia and liver glycogen depletion.

[Neurotoxic effects seen at 50 mg/kg/d - salivation, ataxia, 

histopathological changes in the brain]

Reexamination of testicular/epididymal tissue (MRID 

46100901) was not performed according to Agency pathology 

working group/peer review policy and the findings do not 

change the original dog study (MRID 41565118) conclusions.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.4200

Carcinogenicity

(rat)

00131088, 40484801 

(1983)

0, 500, 1500 or 5000 ppm 

in diet

males: 0, 22, 69 or 250 

mg/kg/day, 115 weeks 

females: 0, 30, 93 or 343 

mg/kg/day for 103 weeks 

(females; discontinued 

earlier due to high 

mortality).

NOAEL <22 mg/kg/day

LOAEL = 22 mg/kg/day based on decreased body 

weight/weight gain (males) and increased abs/rel thyroid 

weight in females. HDT (250 males, 343 females) considered 

excessive based on high mortality and markedly reduced body 

weight/weight gain, both sexes.

Evidence of carcinogenicity)-at 69/93 mg/kg/day and higherincreased incidence of nasal epithelial adenomas (males). At 

250/343 mg/kg/day (excessively toxic dose based on high 

mortality and markedly decreased body weight/weight gain 

(both sexes)-increased incidence of nasal epithelial carcinomas 

and thyroid follicular cell adenomas (males) and hepatocellular 

tumors (both sexes).

870.4200

Carcinogenicity

(rat)

40077601 (1986)

Acceptable/guideline

0, 40, 200 or 1000 ppm in 

diet

0, 2, 10 or 50 mg/kg/day in 

diet (estimated for both 

sexes using standard 

conversion factor of 0.05)

NOAEL = 10 mg/kg/day

LOAEL = 50 mg/kg/day based on decreased body 

weight/weight gain (both sexes, slight in females), increased 

bilirubin in females and in males, increased GGT, cholesterol, 

thyroid c-cell hyperplasia, papillary hyperplasia of the nasal 

epithelium, hepatocellular alterations and necrosis.

evidence of carcinogenicity-at 50 mg/kg/day, increased 

incidence of nasal epithelial papillary adenoma in males and 

females and thyroid follicular cell adenoma/cystadenoma in 

females. PWG reevaluation of liver did not show increase 

with treatment.

870.4200

Carcinogenicity

(rat)

41592004 (1988)

Acceptable/guideline

0, 18, 175 or 1750 ppm in 

diet

males 0, 0.67, 6.37 or 66.9 

mg/kg/day;

females 0, 0.88, 8.53 or 

92.1 mg/kg/day

NOAEL = 6.37 mg/kg/day 

LOAEL = 66.9 mg/kg/day based on decreased body 

weight/weight gain, increased GGT and cholesterol (both 

sexes; marginal in females), nasal epithelial hyperplasia, 

degeneration of retinal outer layer, renal pelvic epithelial 

hyperplasia, stromal fatty infiltration of the pancreas.

evidence of carcinogenicity-increased incidence of nasal 

epithelial adenoma/carcinoma and thyroid follicular cell 

adenomas in males and females. Benign chondroma of femur 

and basal cell tumor of the stomach were reevaluated and 

reclassified by the PWG and are not considered treatmentrelated tumors.

870.4300

Carcinogenicity

(mouse)

00131089 (1983)

Acceptable/guideline

0, 500, 1500 or 5000 ppm 

in diet

0, 75, 225, 750 mg/kg/day 

(estimated for both sexes 

using standard conversion 

factor of 0.15)

NOAEL = 75 mg/kg/day

LOAEL = 225 mg/kg/day based on reduced survival (females), 

slightly decreased body weight during part of study (males), 

anemia (females), increased abs/re/thyroid weight (females) 

and renal interstitial nephritis (males).

Evidence of carcinogenicity-incidence of lung tumors showed 

a dose-related increase. A PWG reevaluation of liver showed 

increases only at the HDT (excessive dose); ovarian and

kidney tumors were not considered treatment-related.
Acetochlor/121601 Human Health Risk Assessment DP No. D413438

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.4300

Carcinogenicity

(mouse)

41565119 (1989)

Acceptable/guideline

0, 10, 100 or 1000 ppm in 

diet

Males 0, 1.1, 11, 116 

mg/kg/day; females 0, 1.4, 

13, 135 mg/kg/day

NOAEL = 1.1 mg/kg/day males; 135 mg/kg/day females

LOAEL = 11 mg/kg/day in males, based on increased 

incidence of brochiolar hyperplasia and possibly renal tubular 

hyperplasia; > 135 mg/kg/day in females.

Evidence of carcinogenicity-increased incidence of lung 

adenomas (females) and adenoma/carcinoma (males) at 

116/135 mg/kg/day. 

Gene Mutation

870.5100 Bacterial 

reverse mutation 

Salmonella typhimurium

00050930 (1978)

Acceptable/guideline

0.001-1 μl/plate - /+ S9

Negative up to the highest dose tested (1 μl/plate - /+ S9); 

higher concentrations (≤10 μl/plate - /+ S9) were cytotoxic 

Gene Mutation

870.5100 Bacterial 

reverse mutation 

Salmonella typhimurium

41565121 (1989)

Acceptable/guideline

1.6-5000 μg/plate - /+ S9

Equivocal positive in TA 1538 at 2500 and 1000 g/plate + 

S9; reproducible at 1000 μg/plate but ≤ 2-fold, not dose-related 

and not seen in TA98 

Gene Mutation

870.5100 Bacterial 

reverse mutation 

Salmonella typhimurium

(strain T1538 only)

44863202 (1989)

Acceptable/non-guideline

100-5000 μg/plate - /+ S9 

(Arochlor 1254 or Phenobarbital /β-naphthoflavone 

induced rat livers)

Negative in TA1538 using 3 different batches of acetochlor 

(89.8-99.6%) in two separate tests 

Gene Mutation

870.5300 Mammalian cell 

gene mutation Chinese 

hamster ovary (CHO) 

cells

00131395 (1983)

Acceptable/guideline

25-150 μg/mL - S9

25-125 μg/mL + 10% S9

Positive ≤ 2-fold in mutation frequency (MF) at 125 or 150 

μg/mL - S9 & 125 μg/mL + S9 accompanied by cytotoxicity 

(61% or 93% decrease in cell survival -/+S9)

Gene Mutation

870.5300 Mammalian cell 

gene mutation

CHO cells

42713106 (1989) 

Acceptable/guideline

50-200 μg/mL -S9

50-300 μg/mL + 1, 2, 5 or 

10% S9

Negative up to cytotoxic levels

(≤ 200 μg/mL -/+ 10% S9) 

Cytogenetics 

870.5300 Mammalian cell 

gene mutation Mouse 

lymphoma L5178Y cells 

00131394 (1982) 

Acceptable/guideline

20-400 μL/mL -S9

5-250 μL/mL +S9

Positive 30-50 μL/mL +S9

2.2-5.2 fold increase accompanied by cytotoxicity (<10% 

survival at ≤ 50 μL/mL +S9)

870.5375

Cytogenetics 

In vitro mammalian cell 

chromosomal aberration 

assay

human lymphocytes 

(whole blood vs separated 

blood)

44863204 (1998)

Acceptable/guideline

(1) 0, 10, 75 150 μg/mL -

/+ S9

(2) 0, 100 μg/mL - S9 

(whole blood)

0, 75 μg/mL - S9 

(separated blood)

Positive at 50 and 100 μg/mL +S9 accompanied by marked 

reduction in mitotic indices at 100 μg/mL (≤ 59% decrease). 

Types of aberrations: breaks, fragment and minutes.
Acetochlor/121601 Human Health Risk Assessment DP No. D413438

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.5375

Cytogenetics 

In vitro mammalian cell 

chromosomal aberration 

assay

human lymphocytes

41565122 (1989)

Acceptable/guideline

0, 10, 50, 100μg/mL +/- S9

Negative up to overt toxicity

(significant decrease in body weight gain)

870.5385

Mammalian Bone Marrow 

Chromosomal Aberration 

Test Rat

00131392 (1983)

Acceptable/guideline

0, 40, 150, 500 mg/kg IP 

injection

Negative up to overt toxicity

(mortality) & cytotoxicity (significant decrease in PCE:NCE 

ratio at 2000 mg/kg, both sexes combined)

870.5395

Mammalian Erythrocyte 

Micronucleus Test CD-1 

Mice

00164941 (1986)

Acceptable/guideline

0, 200, 660, 2000 mg/kg 

oral gavage

870.5395

Mammalian Erythrocyte 

Micronucleus Test CD-1 

Mice

41565123 (1989)

Acceptable/guideline

0, 898 or 1436 mg/kg 

0, 1075 or 1719 mg/kg

Negative up to a cytotoxic dose (significant decrease in 

PCE:NCE ratio) seen at both doses in 

870.5450

Cytogenetics

Dominant Lethal Rat

44069502 (1996)

Unacceptable/guideline

0, 200, 1000, 1500 ppm for 

10 weeks

Negative for dominant lethal mutations but dosage was 

insufficient

870.5450

Cytogenetics

Dominant Lethal Rat

41963309/44093703 

(1991/1996)

Acceptable/guideline

0, 200, 1000, 2000 mg/kg 

oral gavage

Negative; earlier report of positive results now considered to 

be due to reproductive (infertility) toxicity 

870.5450

Cytogenetics

Dominant Lethal Mouse

44093701(1996)

Unacceptable/guideline

0, 200, 1000, 3500 ppm for 

8 weeks

Negative for dominant lethal mutations but dosage was 

insufficient

870.5900

Other Genotoxicity 

In vitro sister chromatid 

exchange assay Human 

Lymphocytes 

Hill et al. (1997) 

Acceptable/guideline

10 μM (2.7 μg/mL)

Weak evidence of positive response (1.5-fold increase) in one 

of two donor cells

870.5550

Other Genotoxicity 

In vitro UDS in Primary 

Rat Hepatocytes

00131393 (1983)

Acceptable/guideline

0.032-320 μg/well

Negative up to cytotoxic concentrations (≤ 10.6 μg/well)
Acetochlor/121601 Human Health Risk Assessment DP No. D413438

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.5550

Other Genotoxicity 

In vitro UDS in Primary 

Rat Hepatocytes

41565124 (1989) 

Acceptable/guideline

0, 500, 1000, 2000 mg/kg 

oral gavage

Weak positive response accompanied by major hepatic 

pathology (necrosis, 70% decreased GSH, 60-fold increase in 

aspartate transaminase )

870.6200

Other Genotoxicity 

In vivo Comet Assay in 

Rat Olfactory and 

respiratory cells

44863208 (1999)

Acceptable/non-guideline

1750 ppm (175 mg/kg/day) 

7 days 

Negative at a tumorigenic dose in vivo

870.6200a

Acute neurotoxicity 

screening battery

MRID 45357501 (2001) 

Acceptable (guideline)-

0, 150, 500, 1500 mg/kg

NOAEL = 150 mg/kg (females); 500 mg/kg (males)

LOAEL = 500 mg/kg based on decreased motor activity in 

females (1500 mg/kg in males based on clinical signs in the 

FOB and decreased body weight/weight gain).

870.6200b

Subchronic neurotoxicity 

screening battery

MRID 45357502 (2001) 

Acceptable (guideline)-

0, 200, 600, 1750 ppm 

( 0, 15.4, 47.6, 139.0 

mg/kg/day; 0, 18.3, 

55.9, 166.5 mg/kg/day)

NOAEL = 47.6 mg/kg/day

LOAEL = 139.0 mg/kg/day based on decreased body 

weight/weight gain in males and females, possible transiently 

decreased hindlimb grip strength in males at week 2.

870.6300

Developmental 

neurotoxicity

Not available Waived by HASPOC (1/17/13, TXR No. 0056497)

870.7485

Metabolism and 

pharmacokinetics (rat)

00130839 (1983)

Acceptable/guideline

Oral 10 mg/kg, 400 mg/kg 

(

14C-acetochlor)

Rapidly eliminated (>70% of administered dose by day 2), 

elimination biphasic (rapid phase 1⁄2-life 5.4-10.4 hrs, slow 

phase 128.6-286.4 hrs for 10 mg/kg dose). Tissues did not 

retain high levels of radioactivity except for RBC, which 

retained about 2.5% of dose at study termination. Acetochlor 

was completely metabolized, via N-dealkylation and 

glucuronide conjugation, primarily to mercapturic acid 

derivatives, with other sulfur-containing derivatives identified.

870.7485

Metabolism and 

pharmacokinetics

(rat)

41565125, -26, -27, 

41592007, -08 

(1987, 1989, 1990)

Acceptable/guideline

Oral 10 mg/kg, 200 mg/kg 

and 10 mg/kg/day x 14 

days (14C-acetochlor)

Well-absorbed and rapidly eliminated (92-96% of dose by day 

5, 1⁄2 life of elimination 20-30 hrs), primarily excreted in urine 

(about 60% by 24 hrs) but significant fecal excretion observed, 

especially males and at high dose, with biliary excretion 

observed. Elimination biphasic. Retention in tissue/carcass 

negligible, primarily in blood (binding to RBC) and wellperfused organs (heart, spleen, kidney, lungs, liver). 

Acetochlor was completely metabolized (15 compounds 

separated in urine, 4 in bile, 5 in feces), with glutathione, 

mercapturic acid or glucuronide conjugation of n-dealkylated 

acetochlor a major route of metabolism; sulphoxymethyl and 

cysteine conjugates also identified in feces. In urine, major 

metabolite was mercapturic acid conjugate of N-deethylated 

acetochlor; in bile, major metabolite was the glucuronide 

conjugate. Major fecal metabolite not characterized.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.7800

Immunotoxicity (mouse) 48358201 (2013)

Acceptable/guideline

0, 118.9, 333.6, and 1535.5 

mg/kg bw/day (feeding)

There were no test substance-related effects on survival, body 

weight, food consumption, or parameters evaluated during 

histopathological examinations. There were no test substancerelated effects on absolute or relative (to final body weight) 

spleen or thymus weights, spleen cellularity, or the TDAR (Tcell dependent antibody response), as measured by the AFC 

IgM Specific Activity (AFC/106spleen cells) or Total Spleen 

Activity (AFC/spleen), at any dosage level tested.

The LOAEL for immunotoxicity is not detected. The NOAEL 

for immunotoxicity is 5000 ppm (1535.5 mg/kg body 

weight/day).

870.7600

Dermal in vivo penetration 

(rat)

41778303 (1990)

Acceptable/guideline

Acetochlor was dermally absorbed in rats in a dose and timerelated manner. Maximum % of dose absorbed during a 10 hr 

exposure duration (used for unintentional occupational 

exposure) was 19-23% using an application of 1/70 or 1/1000 

dilution of formula concentrate (equivalent to 11.772 or 0.763 

mg/g, respectively). The average DAF was calculated as 20%
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Table A.2.3 Special (Non-guideline) Mechanistic Study Toxicity Profile

Study Type

MRID No. (year)/ 

Classification /Doses Results

Studies on Nasal Tumorigenesis

Comparative 

metabolism

(rat/mouse)

44496203 (1998)

Acceptable/non-guideline

(1) 200 mg/kg single gavage 

dose or (2) 1750 ppm in diet 

for 6 months, then 200 mg/kg 

single dose or (30 0, 10, 200, 

1000 or 2000 mg/kg single 

gavage dose

(

14C-acetochlor)

Differences in metabolism between rats and mice were seen. 

Initial reactions both species were oxidative O-deethylation of 

the N-ethoxymethyl sidechain and glucuronidation of the 

methylol group. 

In rats-glucuronide conjugate excreted in the bile, followed by 

hepatic removal of methylol group and glutathione conjugation, 

yielding mercapturic acid derivative of the glutathione 

conjugate (major urinary metabolite in rats). Sulfoxides and 

sulfone derivatives also identified. 

In mice-major urinary metabolite was a chloramideenterohepatic circulation not observed and glutathione 

conjugation not a major route of metabolism.

Nasal cell proliferation

(rat)

44496207 (1996)

Acceptable/non-guideline

0, 200, 1750 or 5000 ppm in 

diet for 160 days

Cell proliferation in nasal turbinate olfactory respiratory 

epithelium, but not respiratory epithelium, was significantly 

increased at 1750 and 5000 ppm as measured by tritiated 

thymidine incorporation into DNA at each dose level at 60 days 

(5000 ppm only), 90 or 160 days of treatment. 

Bromodeoxyuridine incorporation also showed significant 

increases after 160 days at 1750 and 5000 ppm, but not at 200 

ppm. No increase was seen in respiratory epithelium. Cell 

proliferation increased 1.5-2.0-fold at 5000 ppm and 1.3-1.5-

fold at 1750 ppm.

Nasal cell proliferation 

(mouse)

44496209 (1996)

Acceptable/non-guideline

0, 1000 or 5000 ppm in diet 

for 60 and 90 days.

Acetochlor did not cause increased nasal olfactory or 

respiratory epithelial cell proliferation in mice as evaluated by 

bromodeoxyuridine nuclear incorporation.

Quinoneimine-protein 

binding, 

autoradiography

(rat)

44496210 (1998)

Unacceptable/non-guideline 

(upgradable)

1710 or 5170 ppm acetochlor 

in diet containing 14Cacetochlor for 14 days.

In rat nasal turbinate tissue, a dose-dependent formation of 3-

ethyl, 5-methyl-benzoquinoneimine-cysteine (EMIQ-cysteine) 

adducts was observed (119 and 206 pmole/mg protein at 1710 

and 5170 ppm, respectively) (determined by acid hydrolysis 

and HPLC).

Whole body autoradiography showed localization of 

radioactivity in gut, stomach contents, urinary bladder, highly 

perfused organs and in the nasal turbinates, adrenal and 

preputial glands. Microautoradiography of decalcified noses 

showed localization in Bowman’s glands at 1720 and 5170 

ppm and RBC at 5170 ppm, with equivocal localization in the 

neuron layer of the olfactory surface epithelium.
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Table A.2.3 Special (Non-guideline) Mechanistic Study Toxicity Profile

Study Type

MRID No. (year)/ 

Classification /Doses Results

Quinoneimine-protein 

binding 

autoradiography 

(mouse)

44496211 (1998)

Unacceptable/non-guideline 

(upgradable)

1800 or 4750 ppm acetochlor 

in diet containing 14Cacetochlor) for 14 days.

EMIQ-cysteine adduct formation not observed in mice as 

assessed by acid hydrolysis and HPLC.

Quinoneimine-protein 

binding

autoradiography

acetochlor secondary 

sulfide (rat)

44496212 (1998)

Unacceptable/non-guideline 

(upgradable)

7 mg/kg/day 14C-acetochlor 

for either 5 consecutive days 

or single dose, sacrificed 

either one or 5 days after 

final dose.

EMIQ-cysteine adducts were observed in nasal turbinate tissue 

as assessed by acid hydrolysis and HPLC.

Autoradiography showed localization in nasal turbinates and 

microautoradiography of decalcified noses showed binding in 

the Bowman’s glands.

Quinoneimine-protein 

binding 

autoradiography 

(Rhesus monkey)

44496213 (1998)

Acceptable/non-guideline

126 mg/kg 14C-acetochlor for 

14 days

EMIQ-cysteine adducts were not detected in nasal turbinate 

tissues as assessed by acid hydrolysis and HPLC.

Nasal tumor mapping 

(rat)

44496214 (1997)

Acceptable/nonguideline

nasal passages examined 

from rats in 

chronic/carcinogenicity 

dietary studies on acetochlor 

(1750 ppm) and butachlor 

(3000 ppm) and a one-year 

gastric initiation-promotion 

study on alachlor (126 

mg/kg).

Hyperplastic and preneoplastic/neoplastic lesions for all 

compounds were located primarily in the ethmoid turbinates, 

regions normally lined by olfactory mucosa, with many near 

the olfactory-respiratory junctions. Olfactory to respiratory 

metaplasia was a significant feature of neoplastic progression. 

Females given acetochlor also showed basal cell hyperplasia in 

the region underlying Bowman’s glands in dorsal and medial 

airways. 

In vitro metabolism 

(rat/mouse/one human 

sample)

44530001 (1998)

Acceptable/non-guideline

14C-acetochlor sulfoxide 

(0.025 mM, 15.5 kBq) 

incubated w/microsomes 

from rat liver, nasal olfactory 

and nasal respiratory 

epithelia; mouse nasal 

olfactory and liver cells; and 

human nasal epithelia (mixed 

olfactory/respiratory)

Acetochlor sulfoxide was rapidly hydroxylated in rat and 

mouse olfactory microsomal fractions, but not respiratory or 

liver fractions. Major metabolites were (1) side chain oxidation 

product of acetochlor sulphone and (2) para-hydroxy 

metabolite of acetochlor sulfoxide. Hydroxylation of acetochlor 

sulfoxide was not detected in the sample of human nasal tissue.
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Table A.2.3 Special (Non-guideline) Mechanistic Study Toxicity Profile

Study Type

MRID No. (year)/ 

Classification /Doses Results

In vitro metabolism 

(rat/mouse/squirrel 

monkey)

44530002 (1998)

46081803 (2003)

Unacceptable/non-guideline 

(upgradable)

14C-acetochlor (30 mM, 0.05 

mBq) 

Study evaluated rates of steps in metabolism of acetochlor to phydroxy-2-ethyl-6-methylaniline (pOH-EMA), a precursor to 

quinoneimine formation, in cellular fractions from rat and 

mouse liver, nasal olfactory epithelia and nasal respiratory 

epithelia; and from monkey combined nasal 

olfactory/respiratory epithelia. In mice and rat tissues, the rate 

of acetochlor-GSH conjugation of acetochlor was comparable, 

but slightly higher in rat olfactory tissue than mouse olfactory 

tissue. Rate of secondary sulfide hydrolysis to EMA was 

significantly lower in olfactory and respiratory tissues of mice 

vs. rats; p-hydroxylation of EMA was comparable in nasal 

tissues of rats and mice but lower in rat liver than mouse liver. 

Overall conversion of acetochlor to pOH-EMA was slower in 

mice than rats, lowering potential to form reactive 

intermediates. Rates of all reactions were much lower in 

monkey nasal tissue than rat nasal or liver tissue, suggesting 

lower potential to form reactive intermediates.

Protein adduct 

formation

(rat)

46009402 (2001)

in vivo protein binding, 10 

mg/kg 14C-acetochlor 

sulfoxide; in vitro binding, 

0.4 mM 14C-acetochlor 

sulfoxide, 407-458 Kbq to 

cellular fractions of nasal and 

liver tissue 

Unacceptable/non-guideline 

(upgradable)

(1) HPLC analysis comparing radioactivity of acid 

hydrolysates from olfactory vs respiratory mucosa showed 

significantly higher levels of radioactivity in the olfactory 

mucosa; (2) SDS-PAGE of bound proteins from incubation of 

olfactory epithelial microsomal fractions showed similar 

patterns for carbonyl and phenyl-labeled acetochlor sulfoxide, 

indicating that the sulfoxide moiety was retained in much of the 

bound radioactivity; (3) Histoautoradiography of the olfactory 

and respiratory regions of the rat nasal cavity at 8 and 24 hrs 

postdosing showed the highest levels of bound radioactivity 

over Bowman’s glands in the olfactory mucosa, with none in 

the respiratory region. The areas of binding coincide with the 

cellular location of xenobiotic metabolizing enzymes in the 

nasal passages.

In vitro metabolism

(rat/mouse/squirrel 

monkey/human)

46009401 (2000)

46081802 (2003)

Unacceptable/non-guideline 

(upgradable)

Rate of hydroxylation of acetochlor sulfoxide to p-OHacetochlor sulfoxide evaluated. Highest levels of activity 

observed in the rat and mouse nasal olfactory tissues, no 

detectable activity seen in monkey or human samples. Enzyme 

characterization studies indicated that the reaction is catalyzed 

by a cytochrome similar to the CYP2A family, but not 

coumarin hydroxylase itself.
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Table A.2.3 Special (Non-guideline) Mechanistic Study Toxicity Profile

Study Type

MRID No. (year)/ 

Classification /Doses Results

Studies on thyroid tumorigenesis

Characterization of 

thyroid toxicity and 

liver effects-time 

course (rats)

44496208 (1996)

Acceptable/non-guideline

0, 1750 or 5000 ppm (0, 

100.6 or 280.9 mg/kg/day) in 

diet for 14, 28 or 56 days; 

0, 200, 1750 or 5000 ppm (0, 

10.4, 91.9 or 270.3 

mg/kg/day) in diet for 160 

days.

Effects on liver and thyroid weights, thyroid hormones and 

liver UDPGT activity were observed at 1750 and 5000 ppm, 

consistent w/perturbation of thyroid-pituitary homeostasis via 

UDPGT-mediated clearance of T4. Increased hepatic UDPGT 

activity (by day 14), increased TSH (by day 14 at 5000 ppm 

and day 56 at 1750 ppm) and T4 (day 14 only) and decreased 

T3 (day 14 only) were observed. Liver and thyroid weights 

were increased (days 14-90; liver also at day 160).

Studies on acute liver toxicity (supplemental data for UDS studies) and liver cell proliferation

Acute liver toxicity 

(rats)

(1993)

Unacceptable/non-guideline 

(upgradable with test material 

purity information)

(1) 2000 mg/kg via gavage in 

corn oil (evaluation of UDS);

(2) 0, 500, 1000 or 2000 

mg/kg via gavage in corn oil 

(evaluation of liver tissue 

non-protein sulphydryl 

groups)

Dose-dependent depletion of hepatocellular glutathione leading 

to mild to marked necrosis at 500 mg/kg was observed, with 

slight stimulation of UDS at 2000 mg/kg. Increased serum 

AST and ALT were observed at 2000 mg/kg. UDS therefore 

observed at conditions of excessive hepatocellular toxicity and 

reduced hepatocellular glutathione levels.

Acute liver toxicity 

(rats)

44863207 (1994)

Unacceptable/non-guideline 

(upgradable with submission 

of test material purity)

0, 500, 1000 or 2000 mg/kg 

via gavage in corn oil

Dose-dependent depletion of hepatocellular glutathione 

observed at 500 mg/kg, peaking 6-12 hrs post-dosing (17 to 

63% of control levels between 3-12 hrs). Necrosis and serum 

liver enzymes returned to normal levels thereafter and normal 

levels of glutathione were observed by 48 hr. 

Hepatocellular 

proliferation

(mice)

44863601 (1999)

Acceptable/non-guideline

0, 1000 or 5000 ppm in diet 

for 90 days (males only). 

Equivalent to 0, 166.6 or 

887.9 mg/kg/day).

Incorporation of BrdU in mice treated with acetochlor was 

approximately doubled (0.15, 0.35, 0.38 at 0, 1000 and 5000 

ppm, respectively).
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A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

A separate aRfD for the population subgroup Females age 13-49 was not chosen. No 

developmental effects that could be attributed to a single exposure were identified in the 

acetochlor database.

A.3.2 Acute Reference Dose (aRfD) - General Population

Selected Study: Acute oral neurotoxicity screening in the rat 

MRID No. 45357501

Executive Summary:

In an acute neurotoxicity study, groups of fasted, 42 day old Alpk:APfSD (Wistar-derived) rats 

(10/sex/dose) were given a single oral dose of acetochlor (94.7% a.i.) at doses of 0, 150, 500 or 

1500 mg/kg bw and observed for 14 days. Neurobehavioral assessment (FOB and motor activity 

testing) was performed at pre-test and study Days 1 (time of peak effect), 8 and 15. 

Cholinesterase activity was not determined. At study termination, 5 animals/sex/group were 

euthanized and perfused in situ for neuropathological examination. Of the perfused animals, 5 

rats/sex from the control and high dose groups were subjected to histopathological evaluation of 

brain and peripheral nervous system tissues.

At 1500 mg/kg bw, body weights adjusted for initial weight were significantly lower than the 

control group on Day 8 for males and on Days 1 (peak effect), 8 and 15 for females. Body 

weight gains were significantly lower for the Day –7 to 8 time period for males (77% of 

controls) and during throughout the study for females (65-76% of controls). Food consumption 

by the high-dose males and females was significantly reduced during the first week of the study 

compared with the controls. During the FOB, findings were limited to the time of peak effect at 

the high-dose level. These consisted of hunched posture observed in 5-6 animals/sex, 

piloerection on 7-10/sex, and staining around the mouth seen in 3-4/sex. The severity was 

considered slight in the males and from slight to moderate in females. Other findings at 1500 

mg/kg bw were decreased activity in one female, chromodacryorrhea in one female, hypothermia 

in one female, labored breathing in one male, sides pinched in one male, and upward curvature 

of the spine in one female. No effects of treatment were noted on landing foot splay 

measurement, time to tail-flick, or grip strengths. No effects of treatment were noted for motor 

activity in males. Total activity counts for high-dose females on Day 1 were significantly 

decreased compared to controls at 500 and 1500 mg/kg (401.7 and 251.7, respectively, vs. 571.4 

for controls; equivalent to reductions of 30% and 56%) and also were decreased by 43.8% of the 

pre-test value. A statistically significant increase in motor activity of 28% was also observed in 

high dose females on Day 8. There were no treatment-related effects on brain weights or gross 

and histologic pathology or neuropathology. The LOAEL in females was 500 mg/kg bw, based 

on dose-related decreases in motor activity on Day 1 and the NOAEL was 150 mg/kg bw. In 

males, the LOAEL was 1500 mg/kg bw, based on decreased body weights and body weight gain 
Acetochlor/121601 Human Health Risk Assessment DP No. D413438

Page 55 of 79

(males and females), reduced food consumption (males and females), increased incidence of 

clinical signs during the FOB (males and females) at the time of peak effect, with a NOAEL of 

500 mg/kg bw. 

This neurotoxicity study is classified as Acceptable/Guideline and satisfies the guideline

requirement for an acute neurotoxicity study in rats (870.6200; OECD 424). 

Dose and Endpoint for Establishing an aRfD: NOAEL =150 mg/kg/day based on 

decreased motor activity in females at LOAEL of 500 mg/kg on the day of dosing.

Uncertainty Factor (UF): 100x (10x for interspecies variations, 10x for intraspecies 

variations and 10x, FQPA SF= 1x)

Comments about Study/Endpoint: The effect observed at the selected endpoint 

(decreased motor activity in females on the day of dosing) occurred following a single dose. 

A.3.3 Chronic Reference Dose (cRfD) `

Selected Study: Chronic (1-year) oral toxicity in the dog.

MRID No. 41565118

Executive Summary:

In a chronic toxicity study, acetochlor (90.5% a.i.) was administered to 5 beagle 

dogs/sex/dose in gelatin capsules at dose levels of 0 (empty capsules only), 2, 10 or 50 mg/kg 

bw/day) for 52 weeks. In addition to the standard parameters evaluated in a chronic oral toxicity 

study in the dog, plasma and erythrocyte cholinesterase activities (at 12, 24 and 50 weeks) and 

brain cholinesterase activity (termination) were evaluated. A neurological evaluation (tests 

examining cranial nerve function, segmental reflexes, postural reactions and general 

observations) was also performed at Week 47 to assess treatment-related signs of toxicity.

At 10 mg/kg/day, male dogs showed an increased incidence of salivation following 

dosing throughout the study. Males also showed increased incidence of renal interstitial 

nephritis and renal chronic vasiculitis, tubular degeneration of the testes, hypospermia of the 

epididymides and reduced glycogen in the liver. At 50 mg/kg/day, the incidence of salivation 

was markedly increased in both sexes and neurologic symptoms including head shaking/nodding 

and ataxia (also hunched posture, abnormal gait, tremor) were reported in both sexes towards the 

later weeks of the study. Mean body weight gain was reduced significantly during weeks 13-26. 

Water consumption was increased. Changes in clinical chemistry values included increased 

ALT, GGT, OCT , cholesterol and triglycerides, along with increased urea, creatinine and 

Acute RfD (General Population) = 150 mg/kg (NOAEL) = 1.5 mg/kg

 100 (UF)
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decreased glucose. In females, statistically significant increases in plasma AChE at week 24 and 

BChE at week 24 and 50 were observed. At weeks 23 and 49, significantly increased urinary 

volume in males and reduced specific gravity in both sexes were observed. Organ weight 

changes included increased relative brain weight in females, decreased testicular weights in 

males (abs and rel) and possibly increased absolute adrenal weights in females, increased relative 

liver weights in both sexes and thyroid weights in males. Kidneys showed grossly visible 

abnormal shape, pale areas, cortical fibrosis and/or scarred areas, collecting duct hyperplasia, 

dilatation of Bowman’s space, cortical atrophy, transitional cell hyperplasia and lipofuchsin 

pigment in cortical tubules were reported in the microscopic evaluation. Brain histopathology 

(degeneration of the granular layer, depletion of Purkinje cells, demyelination and degeneration 

of granule cell axons) was observed, along with maturation arrest within the testes, pigment in 

hepatocytes. There were no treatment-related effects observed on brain cholinesterase activity or 

on ophthalmologic or hematological parameters. The LOAEL is 10 mg/kg/day, based on 

testicular, hepatic and renal histopathology and increased salivation in males. The NOAEL is 2 

mg/kg/day.

Dose and Endpoint for Establishing a cRfD: NOAEL =2.0 mg/kg/day, based on 

excessive salivation and histopathology of the testes, kidney and liver at a LOAEL of 10 

mg/kg/day.

Uncertainty Factor (UF): 100x (10x for interspecies variation and 10x for intraspecies 

variation, FQPA SF=1x)

Comments about Study/Endpoint/Uncertainty Factor: The chronic dog study is 

appropriate for both the route and duration of exposure.

Chronic RfD = 2.0 mg/kg (NOAEL) = 0.02 mg/kg

 100 (UF)

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

There are no residential uses for acetochlor; therefore, selection of a toxicity endpoint is 

not necessary for this exposure scenario at this time.

A.3.5 Dermal Exposure 

A dermal absorption factor of 20% was estimated from an in vivo rat dermal absorption 

study (MRID 41778303), based on absorption observed following a 10-hr dermal exposure to 

acetochlor (see HIARC Document, TXR #00135858).

Material: unlabeled acetochlor, purity 99.5%; [14C]-phenyl- Acetochlor, purity> 98%.

The technical grade of Acetochlor was applied in doses of 0.763 mg/g (1/1000 aqueous dilution), 

11.772 mg/g (1/70 aqueous dilution), 76.926 mg/g (1/10 aqueous dilution), and 707.31 mg/g 

(formulation concentrate) to the backs of rats (24 rats/dose/group). Four rats within each dose 

group were sacrificed at 0.5, 1.0, 2.0, 4.0, 10.0, and 24.0 hours following dermal application to 
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assess dermal absorption of acetochlor. The percent absorption in 24 hours of a radio-labeled

dose of acetochlor was found to be as follows: 0.763 mg/g, 31.4%; 11.772 mg/g, 29.6%; 76.926 

mg/g, 17.5%; 070.32 mg/g, 12.6%. Acetochlor was thus absorbed in a dose-dependent manner.

Blood levels of acetochlor were also proportional to the applied dose, but were much greater than 

the corresponding plasma concentrations, indicating binding of acetochlor to red blood cells. 

Evidence of bioaccumulation was also observed in the carcass. Residual acetochlor was easily 

washed from the skin with little residue remaining. Volatilization was significant from the 

application site, especially at the lowest dose.

A.3.5.1 Dermal Exposure – Short Term

Selected Study: 21-day dermal toxicity in the rabbit; 

MRID No. 00116637

Executive Summary:

In a 21 day dermal toxicity study, acetochlor as MON -097 (94.5%;) was applied to the 

abraded and intact shaved skin of groups of 10 New Zealand white rabbits/sex/dose at dose 

levels of 0,100, 400 or 1200 mg/kg bw/day, 6 hours/day for 5 days/week during a 21-day period. 

At 1200 mg/kg/day, excessive mortality (8/10 males and 7/10 females) was observed (first death 

occurred on Day 7, last on Day 19). Clinical signs of toxicity were first observed on Day 5 and 

included nasal and ocular discharge, nasal congestion; this group also exhibited possible 

treatment-related signs of anorexia, respiratory congestion, labored breathing, ataxia, 

hypoactivity, rigid body, tonic convulsions, decreased limb tone, impaired righting reflex, 

emaciation and hypothermia. No deaths were seen at lower levels and there were no adverse 

effects on body weight, hematology, clinical chemistry or organ weight but it is noted that there 

were insufficient surviving high dose animals to evaluate effects at termination. Histopathology 

revealed skin lesions at the application sites in all treatment groups. Irritation consisted of 

erythema and edema; desquamation was observed both macroscopically and microscopically in 

all dosed groups. At day 21, the intensity of dermal irritation was higher in the mid-dose group 

than in the low dose group. The LOAEL (for systemic effects) is 1200 mg/kg/day, based on 

mortality and clinical signs of toxicity. The NOAEL is 400 mg/kg/day. The LOAEL for local 

dermal effects is 100 mg/kg/day, based on skin lesions. The NOAEL for local effects is not 

established.

Dose and Endpoint for Risk Assessment: NOAEL = 400 mg/kg/day, based on mortality 

and clinical signs at the LOAEL of 1200 mg/kg/day.

Uncertainty Factor (UF): 100 – 10x for interspecies extrapolation and 10x for intraspecies 

variation

Comments about Study/Endpoint: The route and duration of exposure is appropriate for 

this exposure scenario. Although mortality is an endpoint, it was seen at a dose level which is 

higher than the limit dose. While developmental and neurotoxicity effects are not measured in a 

dermal toxicity study, the endpoint selected from the dermal toxicity is considered protective of 
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these effects. The NOAEL of 150 mg/kg/day for both developmental and neurotoxicity when 

coupled with the dermal absorption factor of 20%, results in a dermal NOAEL estimate of 750 

mg/kg/day. This level of exposure exceeds the dermal toxicity study NOAEL of 400 mg/kg/day. 

Therefore, use of the dermal toxicity NOAEL as an endpoint for risk assessment is protective. 

A.3.5.2 Dermal Exposure – Intermediate Term

Selected Study: Co-critical subchronic oral toxicity studies in the dog:

MRID No. 00050928 

Executive Summary:

In a 119-day oral toxicity study acetochlor (91.3% a.i.) was administered to 6 beagle 

dogs/sex/dose in gelatin capsules at dose levels of 0 (capsule only), 25, 75 or 200 mg/kg bw/day. 

There were no treatment-related effects observed at 25 mg/kg/day. At 75 mg/kg/day, one male 

died at week 11, with diarrhea and inactivity occurring in the last weeks prior to death. Mean 

body weights were lower for much of the study and at termination; weight gain at termination 

was reduced. Increased liver enzyme SGPT was observed in males and females at some time 

points. Relative liver weights were increased. Atrophy of the liver in one male and infiltration of 

the kidney in one male were observed. At 200 mg/kg/day, 5 males and 6 females died or were 

sacrificed in extremis, beginning at week 5, with no females surviving by Week 12 and only one 

male surviving from week 8 through 17. There was severity of clinical signs (bloody diarrhea, 

vomiting) increased and increased relative liver weight. Food consumption was significantly 

reduced. Mean body weights showed statistically significant reductions in surviving males and 

surviving females showed statistically significantly reduced mean body weights. Some dogs 

showed protein-urea and hemato-urea, primarily at Month 2 (evaluations not performed later due 

to mortality). Microscopic findings included hypercellularity of the bone marrow, atrophy of the 

liver, infiltration of the kidneys and thymic atrophy. The LOAEL is 75 mg/kg/day, based on 

decreased body weight/weight gain, mortality and slight effects on the liver and kidney. The 

NOAEL is 25 mg/kg/day. 

Selected Study: Co-critical subchronic oral toxicity studies in the dog:

MRID No. 41565116

Executive Summary:

In a 90-day oral toxicity study acetochlor (91% a.i.) was administered to 4 beagle 

dogs/sex/dose in gelatin capsules at dose levels of 0, 2.0, 10 or 60 mg/kg bw/day. Erythrocyte 

and brain cholinesterase were evaluated in addition to guideline parameters. At 60 mg/kg/day, 

increased incidence of mucous diarrhea was reported for both sexes, beginning during week 1. 

Females had an increased incidence of salivation during the last 5 weeks of the study. 

Occasional emesis and vocalization during defecation was reported from weeks 8 through 10. A 

statistically significantly decrease in mean body weight gain was observed in both sexes. In 
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females food consumption was reduced at weeks 12 and 13. Other effects included mild anemia 

in females, increased alanine aminotransferase and slightly reduced blood glucose in both sexes 

and slightly increased relative liver weight in both sexes. There were no treatment-related 

effects observed at 10 mg/kg/day. No mortality, abnormalities of the urinalysis or 

ophthalmologic parameters, nor alterations in the gross or microscopic pathological evaluation 

were observed at any dose level. Plasma, erythrocyte and brain cholinesterase were not affected 

by treatment. The LOAEL is 60 mg/kg/day, based on clinical signs of toxicity, decreased body 

weight gain, mild anemia, slightly increased relative liver weight and increased serum alanine

aminotransferase. The NOAEL is 10 mg/kg/day.

Dose and Endpoint: NOAEL =25 mg/kg/day, based on clinical signs of toxicity, 

decreased body weight gain, mild anemia, slightly increased relative liver weight and increased 

serum alanine aminotransferase at the LOAEL of 60 mg/kg/day. 

Uncertainty Factor (UF): 100 – 10x for interspecies extrapolation and 10x for 

intraspecies variation.

Comments about Study/Endpoint: Oral studies were selected because a dermal study of 

the appropriate duration was not available. The two subchronic dog studies were considered 

together to provide the highest NOAEL and the lowest LOAEL. The selection of this endpoint is 

further supported by the NOAELs and LOAELs for multi-generation reproductive toxicity 

studies in rats. Since an oral NOAEL was selected, the 20% dermal absorption factor should be 

used in risk assessment.

A.3.6 Inhalation Exposure

A.3.6.1 Inhalation Exposure – Short Term

Selected Study: Developmental toxicity in the rat (oral):

MRID No. 41592005, 42054902, and 42054903

Executive Summary:

In a developmental toxicity study (MRIDs 41592005, 42054902 and 42054903), 25 

mated female Crl:CD (SD)BR VAF/Plus rats were administered acetochlor (90.5% a.i.) by 

gavage in corn oil vehicle as single daily doses of 0, 40, 150 or 600 mg/kg/day from Gestation 

Days 6 through 15, inclusive. At 600 mg/kg/day, two females died (on GD 13 and 15), 

apparently due to treatment. Clinical signs of increased salivation post-dosing and urogenital 

staining were reported. Mean body weight gain was reduced during the dosing period by 47% 

(mean corrected body weight gain from Days 6 to 20 was -38% below controls). A significant 

reduction in food consumption on Days 6-7 and 8-9 (20% and 16% respectively) was observed 

only between Days 6-9 of dosing; thereafter, consumption was comparable among all groups. 

The maternal toxicity LOAEL is 600 mg/kg/day, based on mortality, clinical signs of toxicity 

and reduced body weight gain during treatment. The NOAEL is 150 mg/kg/day. At 600 

mg/kg/day, the following effects showed statistically significant differences from controls and 
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were considered treatment-related: increased early resorptions/dam and total resorptions/dam; 

increased postimplantation loss and reduced mean fetal weight. There were no treatment-related 

increases in fetal variations or malformations. The developmental toxicity LOAEL is 600 

mg/kg/day, based on increased fetal early resorptions and post-implantation loss and reduced 

mean fetal weight. The developmental toxicity NOAEL is 150 mg/kg/day.

Dose and Endpoint: Maternal NOAEL = 150 mg/kg/day based on mortality, clinical 

signs of toxicity and reduced body weight gain during treatment at a LOAEL = 600 mg/kg/day.

Uncertainty Factor (UF): 1000 (10x for interspecies extrapolation, 10x for intraspecies 

variation, and 10x Database Uncertainty Factor (UFDB) for lack of route specific inhalation 

study.

Comments about Study/Endpoint: Since an oral NOAEL was selected for inhalation risk 

assessment, an inhalation absorption factor of 100% (default value) is assumed due to lack of 

route-specific study and use of an oral study instead of an inhalation study. 

A.3.6.2 Inhalation Exposure – Intermediate Term

Selected Study: Co-critical subchronic oral toxicity studies in the dog:

MRID No. 00050928 

Executive Summary:

In a 119-day oral toxicity study acetochlor (91.3% a.i.) was administered to 6 beagle 

dogs/sex/dose in gelatin capsules at dose levels of 0 (capsule only), 25, 75 or 200 mg/kg bw/day. 

There were no treatment-related effects observed at 25 mg/kg/day. At 75 mg/kg/day, one male 

died at week 11, with diarrhea and inactivity occurring in the last weeks prior to death. Mean 

body weights were lower for much of the study and at termination; weight gain at termination 

was reduced. Increased liver enzyme SGPT was observed in males and females at some time 

points. Relative liver weights were increased. Atrophy of the liver in one male and infiltration of 

the kidney in one male were observed. At 200 mg/kg/day, 5 males and 6 females died or were 

sacrificed in extremis, beginning at week 5, with no females surviving by Week 12 and only one 

male surviving from week 8 through 17. There was severity of clinical signs (bloody diarrhea, 

vomiting) increased and increased relative liver weight. Food consumption was significantly 

reduced. Mean body weights showed statistically significant reductions in surviving males and 

surviving females showed statistically significantly reduced mean body weights. Some dogs 

showed proteinuria and hematuria, primarily at Month 2 (evaluations not performed later due to 

mortality). Microscopic findings included hypercellularity of the bone marrow, atrophy of the 

liver, infiltration of the kidneys and thymic atrophy. The LOAEL is 75 mg/kg/day, based on 

decreased body weight/weight gain, mortality and slight effects on the liver and kidney. The 

NOAEL is 25 mg/kg/day. 

Selected Study: Co-critical subchronic oral toxicity studies in the dog:
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MRID No. 41565116

Executive Summary:

In a 90-day oral toxicity study acetochlor (91% a.i.) was administered to 4 beagle 

dogs/sex/dose in gelatin capsules at dose levels of 0, 2.0, 10 or 60 mg/kg bw/day. Erythrocyte 

and brain cholinesterase were evaluated in addition to guideline parameters. At 60 mg/kg/day, 

increased incidence of mucous diarrhea was reported for both sexes, beginning during week 1. 

Females had an increased incidence of salivation during the last 5 weeks of the study. 

Occasional emesis and vocalization during defecation was reported from weeks 8 through 10. A 

statistically significantly decrease in mean body weight gain was observed in both sexes. In 

females food consumption was reduced at weeks 12 and 13. Other effects included mild anemia 

in females, increased alanine aminotransferase and slightly reduced blood glucose in both sexes 

and slightly increased relative liver weight in both sexes. There were no treatment-related 

effects observed at 10 mg/kg/day. No mortality, abnormalities of the urinalysis or 

ophthalmologic parameters, nor alterations in the gross or microscopic pathological evaluation 

were observed at any dose level. Plasma, erythrocyte and brain cholinesterase were not affected 

by treatment. The LOAEL is 60 mg/kg/day, based on clinical signs of toxicity, decreased body 

weight gain, mild anemia, slightly increased relative liver weight and increased serum alanine

aminotransferase. The NOAEL is 10 mg/kg/day.

Dose and Endpoint: NOAEL =25 mg/kg/day, based on clinical signs of toxicity, 

decreased body weight gain, mild anemia, slightly increased relative liver weight and increased 

serum alanine aminotransferase at a LOAEL of 60 mg/kg/day. 

Uncertainty Factor (UF): 1000 (10x for interspecies extrapolation, 10x for intraspecies 

variation, and 10X Database Uncertainty Factor (UFDB) for lack of route specific inhalation 

study.

Comments about Study/Endpoint: Oral studies were selected because a route specific study of 

the appropriate duration was not available. The two subchronic dog studies were considered 

together to provide the highest NOAEL and the lowest LOAEL. The selection of this endpoint is 

further supported by the NOAELs and LOAELs for multi-generation reproductive toxicity 

studies in rats. Since an oral NOAEL was selected for inhalation risk assessment, an inhalation 

absorption factor of 100% (default value) is assumed due to lack of route-specific study and 

using an oral study instead of an inhalation study. 

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 91-Day Oral Toxicity Study – Rat

MRID #: 41565115 (1986):
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Groups of Sprague-Dawley CD rats (10/sex/dose) were administered acetochlor in the 

diet for 13 weeks. Dietary levels tested: 0, 20, 200, and 2000 ppm (Male: 0, 1.6, 16.1, and 161.1 

mg/kg-day; Female: 0, 1.9, 18.7, and 191.9 mg/kg-day); Systemic toxicity was observed at 2000 

ppm. These effects, although somewhat marginal, included hematological effects in both male 

and female rats; increased organ-to-body weight ratios for the liver, kidney, and brain; decreased 

plasma acetyl- and butyrylcholinesterase activity; decreased brain acetylcholinesterase activity 

(males only); and increased plasma urea and cholesterol. No significant effects related to test 

article administration were observed at other doses. Based on the effects observed at the highdose, the LOAEL for systemic toxicity is 2000 ppm (Male: 161.1 mg/kg-day; Female: 191.9 

mg/kg-day). The NOAEL for systemic toxicity is 200 ppm (Male: 16.1 mg/kg-day; Female: 18.7 

mg/kg-day). These effects were marginal, and the study does not satisfy the guideline 

requirements (82-1) for a subchronic oral toxicity study in rats. Information on the purity of the 

test material, as well as an explanation of the impact of the color change of test material during 

storage on test article stability and purity are requested.

870.3100 90-Day Oral Toxicity – Mouse (Not available)

870.3150 90-Day Oral Toxicity – Dog:

MRID No. 00050928 

In a 119-day oral toxicity study, acetochlor (91.3% a.i.) was administered to 6 beagle 

dogs/sex/dose in gelatin capsules at dose levels of 0 (capsule only), 25, 75 or 200 mg/kg bw/day. 

There were no treatment-related effects observed at 25 mg/kg/day. At 75 mg/kg/day, one male 

died at week 11, with diarrhea and inactivity occurring in the last weeks prior to death. Mean 

body weights were lower for much of the study and at termination; weight gain at termination 

was reduced. Increased liver enzyme SGPT was observed in males and females at some time 

points. Relative liver weights were increased. Atrophy of the liver in one male and infiltration of 

the kidney in one male were observed. At 200 mg/kg/day, 5 males and 6 females died or were 

sacrificed in extremis, beginning at week 5, with no females surviving by Week 12 and only one 

male surviving from week 8 through 17. There was severity of clinical signs (bloody diarrhea, 

vomiting) increased and increased relative liver weight. Food consumption was significantly 

reduced. Mean body weights showed statistically significant reductions in surviving males and 

surviving females showed statistically significantly reduced mean body weights. Some dogs 

showed proteinuria and hematuria, primarily at Month 2 (evaluations not performed later due to 

mortality). Microscopic findings included hypercellularity of the bone marrow, atrophy of the 

liver, infiltration of the kidneys and thymic atrophy. The LOAEL is 75 mg/kg/day, based on 

decreased body weight/weight gain, mortality and slight effects on the liver and kidney. The 

NOAEL is 25 mg/kg/day. 
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MRID No. 41565116

In a 90-day oral toxicity study acetochlor (91% a.i.) was administered to 4 beagle 

dogs/sex/dose in gelatin capsules at dose levels of 0, 2.0, 10 or 60 mg/kg bw/day. Erythrocyte 

and brain cholinesterase were evaluated in addition to guideline parameters. At 60 mg/kg/day, 

increased incidence of mucous diarrhea was reported for both sexes, beginning during week 1. 

Females had an increased incidence of salivation during the last 5 weeks of the study. 

Occasional emesis and vocalization during defecation was reported from weeks 8 through 10. A 

statistically significantly decrease in mean body weight gain was observed in both sexes. In 

females food consumption was reduced at weeks 12 and 13. Other effects included mild anemia 

in females, increased alanine aminotransferase and slightly reduced blood glucose in both sexes 

and slightly increased relative liver weight in both sexes. There were no treatment-related 

effects observed at 10 mg/kg/day. No mortality, abnormalities of the urinalysis or 

ophthalmologic parameters, nor alterations in the gross or microscopic pathological evaluation 

were observed at any dose level. Plasma, erythrocyte and brain cholinesterase were not affected 

by treatment. The LOAEL is 60 mg/kg/day, based on clinical signs of toxicity, decreased body 

weight gain, mild anemia, slightly increased relative liver weight and increased serum alanine 

aminotransferase. The NOAEL is 10 mg/kg/day.

870.3200 21/28-Day Dermal Toxicity – Rabbit:

MRID No. 00116637

In a 21 day dermal toxicity study, acetochlor as MON -097 (94.5%;) was applied to the 

abraded and intact shaved skin of groups of 10 New Zealand white rabbits/sex/dose at dose 

levels of 0,100, 400 or 1200 mg/kg bw/day, 6 hours/day for 5 days/week during a 21-day period. 

At 1200 mg/kg/day, excessive mortality (8/10 males and 7/10 females) was observed (first death 

occurred on Day 7, last on Day 19). Clinical signs of toxicity were first observed on Day 5 and 

included nasal and ocular discharge, nasal congestion; this group also exhibited possible 

treatment-related signs of anorexia, respiratory congestion, labored breathing, ataxia, 

hypoactivity, rigid body, tonic convulsions, decreased limb tone, impaired righting reflex, 

emaciation and hypothermia. No deaths were seen at lower levels and there were no adverse 

effects on body weight, hematology, clinical chemistry or organ weight but it is noted that there 

were insufficient surviving high dose animals to evaluate effects at termination. Histopathology 

revealed skin lesions at the application sites in all treatment groups. Irritation consisted of 

erythema and edema; desquamation was observed both macroscopically and microscopically in 

all dosed groups. At day 21, the intensity of dermal irritation was higher in the mid-dose group 

than in the low dose group. The LOAEL (for systemic effects) is 1200 mg/kg/day, based on 

mortality and clinical signs of toxicity. The NOAEL is 400 mg/kg/day. The LOAEL for local 

dermal effects is 100 mg/kg/day, based on skin lesions. The NOAEL for local effects is not 

established.
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870.3465 90-Day Inhalation – Rat:

Due to the absence of a subchronic inhalation toxicity study from the database coupled 

with the pattern of use of acetochlor (aerial, chemigation, ground-boom, and tractor-drawn 

spreader equipment), HASPOC concluded that a subchronic inhalation toxicity study is required, 

but acknowledges the alachlor inhalation toxicity study available in the literature, may provide 

sufficient data on acetochlor pesticide. Since the HASPOC meeting, the registrant has agreed to 

submit an alachlor inhalation study that is available in the literature (Monsanto Research Report 

No. ML-83-158 –Appendix A). The study was submitted recently to HED, and is currently in the 

reviewing process by HED scientists.

Pending submission and Agency review of the literature study, the HASPOC concludes 

that a subchronic inhalation toxicity study is not required for acetochlor at this time. An 

inhalation study with alachlor can be used as a surrogate because acetochlor shares a common 

structure and mechanism of toxicity and was included along with alachlor and butachlor in the 

chloroacetanilide cumulative assessment. This waiver may be reconsidered if the Agency review 

of the literature study determines that it is not acceptable for use in risk assessment. The 

HASPOC recommended that a 10X Database Uncertainty Factor (UFDB) should be applied to 

inhalation assessments only until the alachlor inhalation study is submitted and deemed 

acceptable by the Agency. The alachlor inhalation toxicity study is summarized below: 

“Sprague-Dawley rats were exposed by nose only inhalation to alachlor (94.3%), a structurally 

and functionally pesticide similar to acetochlor, for 6 hours/day/5 days a week for one month at 

dose levels of 0, 0.06, 0.2, 0.6 mg/L. Signs of sensory irritation were detected at 0.06, 0.2 and 0.6 

mg/L. The authors reported that for inhalation exposures a NOAEL was not established since 

effects were observed at the lowest concentration tested (0.06 mg/L). A systemic LOAEL of 0.2 

was based on decrease body weights and serum glucose, and an increase in liver weight. The 

NOAEL was 0.06 mg/L.”

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat:

MRID # 00050929:

In a developmental toxicity study 25 mated female Crl:CD (SD)BR VAF/Plus rats were 

administered acetochlor (91.4% a.i.) by gavage in corn oil vehicle as single daily doses of 0 

(corn oil only), 50, 200 or 400 mg/kg/day from Gestation Days 6 through 19, inclusive, with 

sacrifice and cesarean evaluations on Day 20. At 400 mg/kg/day, excessive salivation (postdosing in 3 females on one occasion) and increased frequency of urogenital staining were 

observed. Mean body weight gain during treatment (Days 6- 20) was decreased by 30% and 

gestational weight gain (Days 0-20) was approximately 50% less than controls. There were no 

treatment-related effects on survival or cesarean parameters. Food consumption was not 

evaluated in this study. The maternal toxicity LOAEL is 400 mg/kg/day, based on clinical signs 

of toxicity and reduced body weight gain during treatment. The NOAEL is 200 mg/kg/day. A 
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slight but not statistically significant reduction in mean fetal weight was observed At 400 

mg/kg/day. No other cesarean parameters were affected and there were no treatment-related 

increases in fetal variations or malformations. The developmental toxicity LOAEL is 400 

mg/kg/day, based on slightly (not statistically significant) reduced mean fetal weight. The 

developmental toxicity NOAEL is 200 mg/kg/day. 

MRIDs # 41592005, 42054902 and 42054903:

In a developmental toxicity study, 25 mated female Crl:CD (SD)BR VAF/Plus rats were 

administered acetochlor (90.5% a.i.) by gavage in corn oil vehicle as single daily doses of 0, 40,

150 or 600 mg/kg/day from Gestation Days 6 through 15, inclusive. At 600 mg/kg/day, two 

females died (on GD 13 and 15), apparently due to treatment. Clinical signs of increased 

salivation post-dosing and urogenital staining were reported. Mean body weight gain was 

reduced during the dosing period by 47% (mean corrected body weight gain from Days 6 to 20 

was -38% below controls). A significant reduction in food consumption on Days 6-7 and 8-9 

(20% and 16% respectively) was observed only between Days 6-9 of dosing; thereafter, 

consumption was comparable among all groups. The maternal toxicity LOAEL is 600 

mg/kg/day, based on mortality, clinical signs of toxicity and reduced body weight gain during 

treatment. The NOAEL is 150 mg/kg/day. At 600 mg/kg/day, the following effects showed 

statistically significant differences from controls and were considered treatment-related: 

increased early resorptions/dam and total resorptions/dam; increased postimplantation loss and 

reduced mean fetal weight. There were no treatment-related increases in fetal variations or 

malformations. The developmental toxicity LOAEL is 600 mg/kg/day, based on increased fetal 

early resorptions and postimplantation loss and reduced mean fetal weight. The developmental 

toxicity NOAEL is 150 mg/kg/day. 

870.3700b Prenatal Developmental Toxicity Study – Rabbit:

MRID # 40134101:

In a developmental toxicity study, acetochlor (94.2% a.i.) was administered to 20 

artificially inseminated female New Zealand White rabbits/dose by gavage in corn oil at dose 

levels of 0, 15, 50 or 190 mg/kg bw/day from days 7 through 19 of gestation, inclusive. Loss of 

weight during treatment was reported in high dose females. A rebound in body weight gain was 

observed postdosing. There were no treatment-related effects on survival, clinical signs of 

toxicity or cesarean parameters. The maternal toxicity LOAEL is 190 mg/kg bw/day, based on 

weight loss during treatment. The maternal toxicity NOAEL is 50 mg/kg bw/day. There were no 

treatment-related effects on litter cesarean parameters, or on the incidence of fetal variations or 

malformations. The developmental toxicity NOAEL is 190 mg/kg bw/day. A developmental 

toxicity LOAEL was not established in this study (>190 mg/kg bw/day). 

MRIDs 41592006, 42054901 and 42077101:

In a developmental toxicity study, acetochlor (90.5% a.i.) was administered to 16 female New 

Zealand White rabbits/dose by gavage in corn oil at dose levels of 0, 30, 100 or 300 mg/kg 

bw/day from days 6 through 18 of gestation. There were no effects of treatment observed on 
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maternal survival, clinical signs of toxicity, body weight or weight gain, food consumption or 

cesarean parameters. Although no toxicity was observed in this study, the results of the rangefinding study (MRID 42077101) indicated that toxicity (body weight decrement) was observed 

between 200-400 mg/kg bw/day and therefore that a LOAEL was approached in the main study; 

dose selection was therefore determined to be appropriate. The maternal toxicity NOAEL is 300 

mg/kg bw/day (highest dose tested). A maternal LOAEL was not established in this study but 

was likely approached, based on the results of the range-finding study. There were no effects of 

treatment observed on cesarean parameters and no effect on the incidence of fetal variations or 

malformations. The developmental NOAEL is 300 mg/kg bw/day (highest dose tested). A 

developmental LOAEL was not established in this study. Although a maternal toxicity LOAEL 

was not achieved, dosing is considered adequate based on the results of the range-finding study. 

In addition, a second acceptable developmental toxicity study in the rabbit showed weight loss 

during treatment at 190 mg/kg bw/day.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat:

MRID # 00131391:

In a two-generation reproduction study, acetochlor (94.2%) was continuously 

administered to 24 female and 12 male Charles River albino rats/dose in the diet at dose levels of 

0, 500, 1500 or 5000 ppm (equivalent to average daily intakes during premating in F0 animals of 

0, 30.8, 60.4 or 316 mg/kg bw/day, males and 0, 46.2, 130.4 or 442 mg/kg bw/day, females and 

in F1 animals of 0, 29.9, 87.8 or 333 mg/kg/day, males and 43.6, 129.8 or 441 mg/kg/day, 

females). Mating was initiated after at least 100 days of treatment for the F0 parental animals and 

at least 120 days of treatment for the F1 parental animals. Matings were performed twice for 

each generation. Five F1b and F2b pups/sex/dose and ten F1 parents/sex/dose were also selected 

for evaluation of testes, ovary, pituitary, thyroid, spleen and liver weights and histopathology. 

Mean parental premating body weights were slightly reduced compared to controls at 1500 ppm. 

At 5000 ppm, mean parental body weights were reduced compared to controls for all groups. 

Slight reductions in food consumption were also reported. Some increases in absolute/relative 

organ weights were observed in F1 parents (e.g., thyroid, liver, kidney). The incidence of chronic 

nephritis was increased in F1 females. F0 animals were not evaluated for organ weights except 

testes in males, which showed no effects. There were no treatment-related effects on survival or 

clinical signs of toxicity. The parental systemic LOAEL is 1500 ppm, based on reduced body 

weight/weight gain during premating in both generations. The parental systemic NOAEL is 500 

ppm. 

At 1500 ppm, mean pup body weights on Lactation Day 21 showed a slight decrease in 

the F2a and F2b offspring. At 5000 ppm, mean pup body weights on Lactation Day 21 in all F1 

and F2 pup groups were reduced and mean litter size tended to be smaller (statistical significance 

only achieved for the F1b generation). Although statistically significantly increased 

absolute/relative thyroid weights were reported at low and mid dose, they were not considered to 

be a clear treatment-related finding based on lack of a dose-response and lack of a corresponding 
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increase in liver weights. No effects on pup survival, birth weight, gross abnormalities or other 

cesarean offspring parameter were observed. The offspring LOAEL is 1500 ppm, based on 

slightly reduced pup body weight during lactation in F2 offspring. The offspring NOAEL is 500 

ppm. There was no evidence of reproductive toxicity observed at any dose tested in this study. 

The reproductive NOAEL is 5000 ppm. A reproductive toxicity LOAEL was not determined in 

this study. 

MRID # 41565120:

In a two-generation reproduction study, acetochlor (90.8% a.i.) was administered to 25 

Sprague-Dawley CD rats/sex/dose in the diet at dose levels of 0, 18, 175 or 1750 ppm 

(equivalent to average daily premating intakes for the F0 generation of 0, 1.27, 12.6 or 123.8 

mg/kg/day, F0 males and 0, 1.63, 15.5 or 157.4 mg/kg/day, F0 females; 0, 0, 1.53, 15.2 or 152.1 

mg/kg bw/day, F1 males and 1.83, 18.3 or 192.4 mg/kg bw/day, F1 females). Matings were 

performed twice for each generation. 

At 1750 ppm, mean body weights were significantly lower by the end of premating in all 

parental animals. Premating mean body weight gain of parental animals was also lower than 

controls, and slight reductions in food consumption were reported. Some increases in 

absolute/relative organ weights were observed (e.g., liver, kidney) but were not accompanied by 

microscopic findings. There were no treatment-related effects on survival, clinical signs of 

toxicity or gross/microscopic pathology (microscopic examination included evaluation of nasal 

turbinates). The parental systemic LOAEL is 1750 ppm, based on reduced body weight/weight 

gain during premating in both generations. The parental systemic NOAEL is 175 ppm. 

Mean pup body weights were reduced at 1750 ppm, on lactation Day 21. No effects on pup 

survival, birth weight, gross abnormalities or other offspring parameters were observed. The 

offspring LOAEL is 1750 ppm, based on reduced pup body weight during lactation. The 

offspring NOAEL is 175 ppm. There was no evidence of reproductive toxicity observed at any 

dose tested in this study. The reproductive NOAEL is 1750 ppm. A reproductive toxicity 

LOAEL was not determined in this study. 

MRID # 45357503:

In a 2-generation reproduction toxicity study, acetochlor was administered continuously in the 

diet to CD (SD) IGS BR (Sprague-Dawley) rats (26/sex/dose) at nominal dose levels of 0, 200, 

600, or 1750 ppm (equivalent to 0, 21.2, 65.6, and 196.4 mg/kg/day in F1 males and 0, 22.4, 

70.9, and 215.9 mg/kg/day in F1 females). F0 animals were given test article diet formulations 

for 10 weeks prior to mating to produce the F1 litters. On postnatal day (PND) 29, F1 animals 

(26/sex/dose) were selected to become the F1 parents of the F2 generation and were given the 

same concentration test formulation as their dams. F1 animals were given test formulations for 

10 weeks prior to mating to produce the F2 litters. No parental treatment-related clinical 

observations were observed in this study. Survival of parental animals was unaffected by 

treatment at any dose level. The parental LOAEL is 600 ppm, based on focal hyperplasia and 

polypoid adenomata in the nasal epithelium of adult F1 offspring at study termination. The 

parental NOAEL is 200 ppm. 
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A significant treatment-related decrease in the number of implantations was observed at 

1750 ppm in both the F0 and F1 generations. In addition, the mean number of live pups on 

postnatal day 1 decreased in a dose related manner in both the F1 and F2 litters. Mean live F1 

pups per litter was significantly decreased at 1750 ppm, and the mean number of live-plus-dead 

pups per litter was statistically significantly lower in F1 and F2 litters at 1750 ppm and also in F2 

litters at 600 ppm. These findings are considered possible evidence of fetal loss. Postnatal 

survival was not affected by treatment. Initial mean body weights of F1 pups of both sexes were 

significantly decreased in both the 600 and 1750 ppm groups. At the 1750 ppm level, 

significantly decreased mean F1 pup body weights were also observed in late lactation and 

overall body weight gain was significantly reduced as compared to controls. In F2 litters, male 

and female pup body weights were reduced in both 1750 and 600 ppm dose levels and overall F2 

pup weight gain was reduced. A decrease in anogenital distance in F2 males on PND 1, and a 3-

day treatment-related delay in the day of vaginal opening in F1 females at the high dose level 

appeared to be associated with delayed growth. Decreases in absolute mean brain weights of F1 

males and F2 males and females were noted at 1750 ppm. Relative brain weight ratios were 

statistically increased in F2 pups at the 600 ppm dose. Mean absolute spleen weights were 

decreased in F1 males and both sexes of F2 pups at mid and high doses. Mean relative spleen 

weights were reduced in 600 ppm F2 females. Mean absolute thymus weights were decreased in 

F2 pups at the high dose level. No macroscopic changes were reported. The offspring LOAEL is 

600 ppm, based on decreased F2 litter size at birth, decreased F1 and F2 pup body weights 

during lactation, and decreased absolute and relative spleen weights in F2 weanlings; and on the 

presence of focal hyperplasia and polypoid adenomata in the nasal epithelium of adult F1 

offspring at study termination. The offspring NOAEL is 200 ppm. 

The number of implantations decreased in a dose related manner in both the F0 and F1 

generations, the differences reaching statistical significance at the high dose level in both 

generations. In addition, the mean number of live pups on postnatal day 1 decreased in a dose 

related manner in both the F0 and F1 litters. Due to the lack of corpora lutea count data, the 

origin of the decreased implantation counts could not be determined; therefore, this was 

conservatively interpreted as a possible effect on reproduction. The LOAEL for reproductive 

toxicity is 1750 ppm, based on decreased number of implantations. The reproductive toxicity 

NOAEL is 600 ppm.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat (see 870.4100a)

870.4100b Chronic Toxicity – Dog:

MRID No. 41565118:

In a chronic toxicity study, acetochlor (90.5% a.i.) was administered to 5 beagle 

dogs/sex/dose in gelatin capsules at dose levels of 0 (empty capsules only), 2, 10 or 50 mg/kg 

bw/day) for 52 weeks. In addition to the standard parameters evaluated in a chronic oral toxicity 

study in the dog, plasma and erythrocyte cholinesterase activities (at 12, 24 and 50 weeks) and 

brain cholinesterase activity (termination) were evaluated. A neurological evaluation (tests 
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examining cranial nerve function, segmental reflexes, postural reactions and general 

observations) was also performed at Week 47 to assess treatment-related signs of toxicity.

At 10 mg/kg/day, male dogs showed an increased incidence of salivation following 

dosing throughout the study. Males also showed increased incidence of renal interstitial 

nephritis and renal chronic vasculitis, tubular degeneration of the testes, hypospermia of the 

epididymides and reduced glycogen in the liver. At 50 mg/kg/day, the incidence of salivation 

was markedly increased in both sexes and neurologic symptoms including head shaking/nodding 

and ataxia (also hunched posture, abnormal gait, tremor) were reported in both sexes towards the 

later weeks of the study. Mean body weight gain was reduced significantly during weeks 13-26. 

Water consumption was increased. Changes in clinical chemistry values included increased 

ALT, GGT, OCT , cholesterol and triglycerides, along with increased urea, creatinine and 

decreased glucose. In females, statistically significant increases in plasma AChE at week 24 and 

BChE at week 24 and 50 were observed. At weeks 23 and 49, significantly increased urinary 

volume in males and reduced specific gravity in both sexes were observed. Organ weight 

changes included increased relative brain weight in females, decreased testicular weights in 

males (abs and rel) and possibly increased absolute adrenal weights in females, increased relative 

liver weights in both sexes and thyroid weights in males. Kidneys showed grossly visible 

abnormal shape, pale areas, cortical fibrosis and/or scarred areas, collecting duct hyperplasia, 

dilatation of Bowman’s space, cortical atrophy, transitional cell hyperplasia and lipofuchsin 

pigment in cortical tubules were reported in the microscopic evaluation. Brain histopathology 

(degeneration of the granular layer, depletion of Purkinje cells, demyelination and degeneration 

of granule cell axons) was observed, along with maturation arrest within the testes, pigment in 

hepatocytes. There were no treatment-related effects observed on brain cholinesterase activity or 

on ophthalmologic or hematological parameters. The LOAEL is 10 mg/kg/day, based on 

testicular, hepatic and renal histopathology and increased salivation in males. The NOAEL is 2 

mg/kg/day.

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study – rat

Combined Chronic Toxicity/Carcinogenicity Study (27 month, male/24 month, female):

MRIDs # 00131088, 40484801 (1983, 1987):

In a chronic toxicity/carcinogenicity in rats, acetochlor technical (94.5% a.i.) was 

administered in the diet to Sprague-Dawley CD rats (60/sex/dose) at dose levels of 0, 500, 1500 

or 5000 ppm for 115 consecutive weeks (males) or 103 consecutive weeks (females; 

discontinued earlier due to high mortality). Doses were equivalent to an average daily intake of 

0, 22, 69 or 250 mg/kg/day, males and 0, 30, 93 or 343 mg/kg/day, females). Groups of 

10/sex/dose additional animals were also treated for 52 weeks for an interim pathological 

evaluation. At 5000 pm, a decreased body weight/weight gain (males) and increased 

absolute/relative thyroid weight in females were observed. HDT (250 males, 343 females) 

considered excessive based on high mortality and markedly reduced body weight/weight gain, 

both sexes. Evidence of carcinogenicity): at 69/93 mg/kg/day and higher-increased incidence of 
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nasal epithelial adenomas (males). At 250/343 mg/kg/day (excessively toxic dose based on high 

mortality and markedly decreased body weight/weight gain (both sexes)-increased incidence of 

nasal epithelial carcinomas and thyroid follicular cell adenomas (males) and hepatocellular 

tumors (both sexes). The LOAEL = 22 mg/kg/day, and the NOAEL <22 mg/kg/day.

MRID #: 40077601 (1986):

In a chronic toxicity/carcinogenicity study in rats, acetochlor technical (94.5% a.i.) was 

administered in the diet to Sprague-Dawley CD rats (60/sex/dose) at dose levels of 0, 40, 200 or 

1000 ppm for 24 months (average daily intakes of 0, 2.0, 10.0 or 50.0 mg/kg/day, estimated by 

conversion factor of 0.05). Groups of 10/sex/dose additional animals were also treated for 52 

weeks for an interim pathological evaluation. At 50 mg/kg/day, decreased body weight/weight 

gain (both sexes, slight in females), increased bilirubin in females and in males, increased GGT, 

cholesterol, thyroid c-cell hyperplasia, papillary hyperplasia of the nasal epithelium, 

hepatocellular alterations and necrosis, were observed. Evidence of carcinogenicity at 

50 mg/kg/day, marked by increased incidence of nasal epithelial papillary adenoma in males and 

females and thyroid follicular cell adenoma/cystadenoma in females. The LOAEL = 50 

mg/kg/day and the NOAEL = 10 mg/kg/day.

MRID #: 41592004 (1988):

In a chronic toxicity/carcinogenicity study in rats, acetochlor technical (91.0% a.i.) was 

administered in the diet to Sprague-Dawley CD rats (50/sex/dose) at dose levels of 0, 18, 175 or 

1750 ppm for 104 consecutive weeks. Dose levels were equivalent to average daily intakes of 0, 

0.67, 6.37 or 66.9 mg/kg/day (males), and 0, 0.88, 8.53 or 92.1 mg/kg/day (females). Additional 

interim sacrifice animals (20/sex at 0 and 1750 ppm and 10/sex at 18 and 175 ppm) were also 

administered these diets for 52 weeks. At 66.9/92.1 mg/kg/day, decreased body weight/weight 

gain, increased GGT and cholesterol (both sexes; marginal in females), nasal epithelial 

hyperplasia, degeneration of retinal outer layer, renal pelvic epithelial hyperplasia, stromal fatty 

infiltration of the pancreas. Evidence of carcinogenicity marked by increased incidence of nasal 

epithelial adenoma/carcinoma and thyroid follicular cell adenomas in males and females. Benign 

chondroma of femur and basal cell tumor of the stomach were not considered treatment-related 

tumors. The NOAEL = 6.37/8.53 mg/kg/day, and the LOAEL = 66.9/92.1 mg/kg/day

(male/female).

870.4200b Carcinogenicity (feeding) – Mouse

MRID #: 00131089 (1983):

Acetochlor was administered in the diet to 50 Swiss-bred CD-1 albino mice/sex/dose for 

up to 23 months at dose levels of 0, 500, 1500 or 5000 ppm. Dose levels were equivalent to an 

estimated average daily intake of 0, 75, 225 or 750 mg/kg/day for both sexes (calculated using a 

dietary ppm-to-mg/kg/day conversion factor of 0.15). Additional groups of 10 mice/sex/dose 

were administered these diets for 12 months and sacrificed for a one-year interim evaluation. At 

225 mg/kg/day, reduced survival (females), slightly decreased body weight during part of study 

(males), anemia (females), increased absolute/relative thyroid weight (females) and renal 
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interstitial nephritis (males), were observed. Evidence of carcinogenicity-incidence was marked 

by lung tumors that showed a dose-related increase. The NOAEL = 75 mg/kg/day, and the 

LOAEL = 225 mg/kg/day.

MRID #: 41565119 (1989):

Acetochlor (tech., 90.5% a.i.) was administered in the diet to 50 CD-1 mice/sex/dose for

78 weeks at dose levels of 0, 10, 100 or 1000 ppm. Dosing was equivalent to an average daily 

intake of 0, 1.1, 11 or 116 mg/kg/day (males) and 0, 1.4, 13 or 135 mg/kg/day (females). 

Additional groups of 10 CD-1 mice/sex/dose were administered the test material at the same 

dose levels for 52 weeks for interim evaluation at one year. Increased incidence of bronchiolar 

hyperplasia and possibly renal tubular hyperplasia at ≥ 135 mg/kg/day in females. Evidence of 

carcinogenicity characterized by increased incidence of lung adenomas (females) and 

adenoma/carcinoma (males) at 116/135 mg/kg/day. The NOAEL = 1.1 mg/kg/day males; 135 

mg/kg/day females, and the LOAEL = 11 mg/kg/day in males.

A.4.6 Mutagenicity

Gene Mutation:

Study Type

MRID No. (year)/ 

Classification /Doses Results

Gene Mutation

870.5100 Bacterial 

reverse mutation 

Salmonella typhimurium

00050930 (1978)

Acceptable/guideline

0.001-1 μl/plate - /+ S9

Negative up to the highest dose tested (1 μl/plate - /+ S9); 

higher concentrations (≤10 μl/plate - /+ S9) were cytotoxic 

Gene Mutation

870.5100 Bacterial 

reverse mutation 

Salmonella typhimurium

41565121 (1989)

Acceptable/guideline

1.6-5000 μg/plate - /+ S9

Equivocal positive in TA 1538 at 2500 and 1000 g/plate + 

S9; reproducible at 1000 μg/plate but ≤ 2-fold, not dose-related 

and not seen in TA98 

Gene Mutation

870.5100 Bacterial 

reverse mutation 

Salmonella typhimurium

(strain T1538 only)

44863202 (1989)

Acceptable/non-guideline

100-5000 μg/plate - /+ S9 

(Arochlor 1254 or Phenobarbital /β-naphthoflavone 

induced rat livers)

Negative in TA1538 using 3 different batches of acetochlor 

(89.8-99.6%) in two separate tests 

Gene Mutation

870.5300 Mammalian cell 

gene mutation Chinese 

hamster ovary (CHO) 

cells

00131395 (1983)

Acceptable/guideline

25-150 μg/mL - S9

25-125 μg/mL + 10% S9

Positive ≤ 2-fold in mutation frequency (MF) at 125 or 150 

μg/mL - S9 & 125 μg/mL + S9 accompanied by cytotoxicity 

(61% or 93% decrease in cell survival -/+S9)

Gene Mutation

870.5300 Mammalian cell 

gene mutation

CHO cells

42713106 (1989) 

Acceptable/guideline

50-200 μg/mL -S9

50-300 μg/mL + 1, 2, 5 or 

10% S9

Negative up to cytotoxic levels

(≤ 200 μg/mL -/+ 10% S9) 
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Cytogenetics:

Study Type

MRID No. (year)/ 

Classification /Doses Results

Cytogenetics 

870.5300 Mammalian cell 

gene mutation Mouse 

lymphoma L5178Y cells 

00131394 (1982) 

Acceptable/guideline

20-400 μL/mL -S9

5-250 μL/mL +S9

Positive 30-50 μL/mL +S9

2.2-5.2 fold increase accompanied by cytotoxicity (<10% 

survival at ≤ 50 μL/mL +S9)

870.5375

Cytogenetics 

In vitro mammalian cell 

chromosomal aberration 

assay

human lymphocytes 

(whole blood vs separated 

blood)

44863204 (1998)

Acceptable/guideline

(1) 0, 10, 75 150 μg/mL -

/+ S9

(2) 0, 100 μg/mL - S9 

(whole blood)

0, 75 μg/mL - S9 

(separated blood)

Positive at 50 and 100 μg/mL +S9 accompanied by marked 

reduction in mitotic indices at 100 μg/mL (≤ 59% decrease). 

Types of aberrations: breaks, fragment and minutes.

870.5375

Cytogenetics 

In vitro mammalian cell 

chromosomal aberration 

assay

human lymphocytes

41565122 (1989)

Acceptable/guideline

0, 10, 50, 100μg/mL +/- S9

Negative up to overt toxicity

(significant decrease in body weight gain)

870.5385

Mammalian Bone Marrow 

Chromosomal Aberration 

Test Rat

00131392 (1983)

Acceptable/guideline

0, 40, 150, 500 mg/kg IP 

injection

Negative up to overt toxicity

(mortality) & cytotoxicity (significant decrease in PCE:NCE 

ratio at 2000 mg/kg, both sexes combined)

870.5395

Mammalian Erythrocyte 

Micronucleus Test CD-1 

Mice

00164941 (1986)

Acceptable/guideline

0, 200, 660, 2000 mg/kg 

oral gavage

870.5395

Mammalian Erythrocyte 

Micronucleus Test CD-1 

Mice

41565123 (1989)

Acceptable/guideline

0, 898 or 1436 mg/kg 

0, 1075 or 1719 mg/kg

Negative up to a cytotoxic dose (significant decrease in 

PCE:NCE ratio) seen at both doses in 

870.5450

Cytogenetics

Dominant Lethal Rat

44069502 (1996)

Unacceptable/guideline

0, 200, 1000, 1500 ppm for 

10 weeks

Negative for dominant lethal mutations but dosage was 

insufficient

870.5450

Cytogenetics

Dominant Lethal Rat

41963309/44093703 

(1991/1996)

Acceptable/guideline

0, 200, 1000, 2000 mg/kg 

oral gavage

Negative; earlier report of positive results now considered to 

be due to reproductive (infertility) toxicity 
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870.5450

Cytogenetics

Dominant Lethal Mouse

44093701(1996)

Unacceptable/guideline

0, 200, 1000, 3500 ppm for 

8 weeks

Negative for dominant lethal mutations but dosage was 

insufficient

Other Genotoxicity:

Study Type

MRID No. (year)/ 

Classification /Doses Results

870.5900

Other Genotoxicity 

In vitro sister chromatid 

exchange assay Human 

Lymphocytes 

Hill et al. (1997) 

Acceptable/guideline

10 μM (2.7 μg/mL)

Weak evidence of positive response (1.5-fold increase) in one 

of two donor cells

870.5550

Other Genotoxicity 

In vitro UDS in Primary 

Rat Hepatocytes

00131393 (1983)

Acceptable/guideline

0.032-320 μg/well

Negative up to cytotoxic concentrations (≤ 10.6 μg/well)

870.5550

Other Genotoxicity 

In vitro UDS in Primary 

Rat Hepatocytes

41565124 (1989) 

Acceptable/guideline

0, 500, 1000, 2000 mg/kg 

oral gavage

Weak positive response accompanied by major hepatic 

pathology (necrosis, 70% decreased GSH, 60-fold increase in 

aspartate transaminase )

870.6200

Other Genotoxicity 

In vivo Comet Assay in 

Rat Olfactory and 

respiratory cells

44863208 (1999)

Acceptable/non-guideline

1750 ppm (175 mg/kg/day) 

7 days 

Negative at a tumorigenic dose in vivo

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study – Hen

Not required-not available.

870.6200 Acute Neurotoxicity Screening Battery:

MRID # 45357501:

 In an acute neurotoxicity study, groups of fasted, 42 day old Alpk:APfSD (Wistarderived) rats (10/sex/dose) were given a single oral dose of acetochlor (94.7% a.i.) at doses of 0, 

150, 500 or 1500 mg/kg bw and observed for 14 days. Neurobehavioral assessment (FOB and 

motor activity testing) was performed at pre-test and study Days 1 (time of peak effect), 8 and 

15. Cholinesterase activity was not determined. At study termination, 5 animals/sex/group were 

euthanized and perfused in situ for neuropathological examination. Of the perfused animals, 5 

rats/sex from the control and high dose groups were subjected to histopathological evaluation of 

brain and peripheral nervous system tissues.

At 1500 mg/kg bw, body weights adjusted for initial weight were significantly lower 
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than the control group on Day 8 for males and on Days 1 (peak effect), 8 and 15 for females. 

Body weight gains were significantly lower for the Day –7 to 8 time period for males (77% of 

controls) and during throughout the study for females (65-76% of controls). Food consumption 

by the high-dose males and females was significantly reduced during the first week of the study 

compared with the controls. During the FOB, findings were limited to the time of peak effect at 

the high-dose level. These consisted of hunched posture observed in 5-6 animals/sex, 

piloerection on 7-10/sex, and staining around the mouth seen in 3-4/sex. The severity was 

considered slight in the males and from slight to moderate in females. Other findings at 1500 

mg/kg bw were decreased activity in one female, chromodacryorrhea in one female, hypothermia 

in one female, labored breathing in one male, sides pinched in one male, and upward curvature 

of the spine in one female. No effects of treatment were noted on landing foot splay 

measurement, time to tail-flick, or grip strengths. No effects of treatment were noted for motor 

activity in males. Total activity counts for high-dose females on Day 1 were significantly 

decreased compared to controls at 500 and 1500 mg/kg (401.7 and 251.7, respectively, vs. 571.4 

for controls; equivalent to reductions of 30% and 56%) and also were decreased by 43.8% of the 

pre-test value. A statistically significant increase in motor activity of 28% was also observed in 

high dose females on Day 8. There were no treatment-related effects on brain weights or gross 

and histologic pathology or neuropathology. The LOAEL in females was 500 mg/kg bw, based 

on dose-related decreases in motor activity on Day 1 and the NOAEL was 150 mg/kg bw. In 

males, the LOAEL was 1500 mg/kg bw, based on decreased body weights and body weight gain 

(males and females), reduced food consumption (males and females), increased incidence of 

clinical signs during the FOB (males and females) at the time of peak effect, with a NOAEL of 

500 mg/kg bw.

870.6200 Subchronic Neurotoxicity Screening Battery

MRID # 45357502:

 In an oral subchronic neurotoxicity study (MRID 45357502) acetochlor (94.7% ai) was 

administered to the diet to 12 Alpk:APfSD rats/sex/group at dose levels of 0, 200, 600 or 1750 

ppm (equivalent to 0, 15.4, 47.6 or 139.9 mg/kg/ bw/day, males and 0, 18.3, 55.9 or 166.5 mg/kg 

bw/day, females) for 93 days. A neurobehavioral assessment (functional observational battery 

and motor activity testing) was performed in all animals/sex/group at -1 week pretest and at 

weeks 2,5, 9 and 14. At study termination, 5 animals/sex/group were euthanized and perfused in 

situ for neuropathological examination (brain, spinal cord and peripheral nervous system of the 

control and high dose animals were examined microscopically; brain weights were also 

measured).

At 1750 ppm, slight but statistically significant decreases in mean body weight and 

weight gain were reduced in both sexes in the early weeks of the study. During the FOB 

evaluations at week 2, a statistically significant decrease in hindlimb grip strength in males was 

observed, which was of unclear significance but considered a possible treatment-related effect 

based on neuromuscular effects to hindlimbs observed in dog studies. There were no treatmentrelated increases in clinical signs of toxicity or effects on other neurobehavioral parameters in the 

FOB, motor activity, brain weight or gross/microscopic neuropathology. The LOAEL is 1750 
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ppm based on marginal decreases in mean body weight/weight gain in both sexes and a possible 

transient decrease in hindlimb grip strength in males at week 2. The NOAEL is 600 ppm. 

870.6300 Developmental Neurotoxicity Study:

The Hazard and Science Policy Council (HASPOC) in its Meeting of October 25, 2012 

(TXR # 0056497) concluded, based on a Weight of Evidence Approach (WOE), that a 

developmental neurotoxicity study (DNT) is not required for acetochlor at this time.

A.4.8 Metabolism

870.7485 Metabolism – Rat:

Two acceptable/guideline metabolism studies in the rat were submitted for 

acetochlor:

MRID # 00130839: Rats were dosed orally with either 10 mg/kg or 400 mg/kg of an isotopically 

labeled mixture of (

12C,13C,14C-acetochlor). Acetochlor was rapidly degraded into many

metabolites and that the metabolites were readily excreted in the urine and feces. Urinary 

metabolites accounted for 32 to 68% of the dose administered, and fecal metabolites accounted 

for 19 to 50%. Total recoveries of 14C radioactivity ranged between 80 and 90% of the dose, with

> 95% of the recovered dose eliminated in the urine and feces within the first 72 hours after 

dosing. Animals were sacrificed 7 days after dosing and the tissues and organs were analyzed for

14C-content. It was found that the blood contained low levels of 14C-radioactivity (2-3% of the 

dose) and that no accumulation of the metabolites were evident in any other tissue or organ (less 

than 1 percent of the dose combined retention). Metabolites from urine and feces were 

chromatographed and it was observed that acetochlor was extensively metabolized by the rat. A 

small percentage of acetochlor (approximately 1 percent of the dose or less) was excreted in the 

feces-while no acetochlor was detected in the urine. 

Chemical derivatization and spectral methods were used to elucidate the structures of 14 urinary 

and 7 fecal metabolites 'Which include mercapturic and conjugates, methyl sulfoxides, and 

methyl sulfones. Other metabolites were characterized and the urinary metabolites were 

quantified. The nature of the 14C radioactivity associated with the blood was characterized.

The metabolism of acetochlor in the rat appears to follow well-established mechanisms of 

xenobiotic metabolism based upon the rates and routes of elimination, and the identity and 

amount of metabolites formed.

MRIDs # 41565125, -26, -27, 41592007, -08: Rats were dosed orally by at dose levels of 

10 mg/kg, 200 mg/kg or 10 mg/kg/day x 14 days with (

14C-acetochlor). Acetochlor was wellabsorbed and rapidly eliminated (92-96% of dose by day 5, 1⁄2 life of elimination 20-30 hrs), 

primarily excreted in urine (about 60% by 24 hrs) but significant fecal excretion observed, 

especially males and at high dose, with biliary excretion observed. Elimination biphasic. 

Retention in tissue/carcass negligible, primarily in blood (binding to RBC) and well-perfused 

organs (heart, spleen, kidney, lungs, liver). Acetochlor was completely metabolized (15 

compounds separated in urine, 4 in bile, 5 in feces), with glutathione, mercapturic acid or 

glucuronide conjugation of n-dealkylated acetochlor a major route of metabolism; 
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sulphoxymethyl and cysteine conjugates also identified in feces. In urine, major metabolite was 

mercapturic acid conjugate of N-deethylated acetochlor; in bile, major metabolite was the 

glucuronide conjugate. Major fecal metabolite not characterized.

870.7600 Dermal Absorption – Rabbit:

A dermal absorption factor of 20% was estimated from an in vivo rat dermal absorption study 

(MRID # 41778303), based on absorption observed following a 10-hr dermal exposure to 

acetochlor.

Material: unlabeled acetochlor, purity 99.5%; [14C]-phenyl- Acetochlor, purity> 98%.

The technical grade of Acetochlor was applied in doses of 0.763 mg/g (1/1000 aqueous dilution), 

11.772 mg/g (1/70 aqueous dilution), 76.926 mg/g (1/10 aqueous dilution), and 707.31 mg/g 

(formulation concentrate) to the backs of rats (24 rats/dose/group). Four rats within each dose 

group were sacrificed at 0.5, 1.0, 2.0, 4.0, 10.0, and 24.0 hours following dermal application to 

assess dermal absorption of acetochlor. The percent absorption in 24 hours of a radio-labled dose 

of acetochlor was found to be as follows: 0.763 mg/g, 31.4%; 11.772 mg/g, 29.6%; 76.926 mg/g, 

17.5%; 070.32 mg/g, 12.6%. Acetochlor was thus absorbed in a dose-dependent manner.

Blood levels of acetochlor were also proportional to the applied dose, but were much greater than 

the corresponding plasma concentrations, indicating binding of acetochlor to red blood cells. 

Evidence of bioaccumulation was also observed in the carcass. Residual acetochlor was easily 

washed from the skin with little residue remaining. Volatilization was significant from the 

application site, especially at the lowest dose.

A.4.9 870.7800 Immunotoxicity

MRID # 48358201:

In an Immunotoxicity study, acetochlor (95.4% a.i, lot # 069K8213) was administered to 

10 female Crl:CD1(ICR) mice/dose in diet at dose levels of 0, 500, 1500, or 5000 ppm (0, 118.9, 

333.6, and 1535.5 mg/kg bw/day, respectively) for 28 days. A concurrent positive control group 

received 50 mg/kg/day cyclophosphamide monohydrate [CPS] once daily during study days 24-

27 via IP injection. The CD-1 mouse was utilized in this study because it is a widely used strain 

for which significant historical control data are available. This species and strain of animal is 

recognized to be appropriate for immunotoxicity studies. Only female animals were used for 

immunotoxicity evaluation because females are considered to be more consistent responders than 

males for the evaluation of the humoral immuno response using the AFC (antibody forming cell) 

assay. All animals were observed twice daily for mortality and moribundity. Clinical 

examinations were performed daily, and detailed physical examinations were performed weekly. 

Individual body weights were collected twice weekly, and food consumption was recorded 

approximately weekly. All animals were immunized with an intravenous injection of 108 SRBC 

(Sheep Red Blood Cell) antigen in the tail vein on study day 24.

Blood samples for serum IgM antibody analysis were collected from all animals at the scheduled 

necropsy (study day 28) from the caudal vena cava. The mesenteric lymph node, Peyer’s patch, 
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spleen, and thymus were collected. In addition, organ weights for the spleen and thymus were 

recorded at the scheduled necropsy, and the spleens for the AFC assay.

Over the entire 4-week study period, there were no test substance-related effects on survival, 

body weight, food consumption, or parameters evaluated during histopathological examinations.

There were no test substance-related effects on absolute or relative (to final body weight) spleen 

or thymus weights, spleen cellularity, or the TDAR(T-cell dependent antibody response), as 

measured by the AFC IgM Specific Activity (AFC/106spleen cells) or Total Spleen Activity 

(AFC/spleen), at any dosage level tested. The LOAEL for immunotoxicity is not detected. The 

NOAEL for immunotoxicity is 5000 ppm (1535.5 mg/kg body weight/day).
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Appendix B. Physical/Chemical Properties

Table C1. Physical/Chemical Properties of Acetochlor.

Parameter Value Reference

Melting point/range 163 oC at 10 mm Hg; decomposition 

occurs before the boiling point at 

atmospheric pressure (calculated by 

extrapolation of vapor pressure at lower 

temperature)

Residue Chemistry Chapter 

of the Acetochlor TRED 

(DP# 297062, 5/31/05, S. 

Ary)

pH 4.41, 1% solution in acetone:water (1:1, 

v:v)

Density 1.123 g/mL at 20 oC

Water solubility 223 mg/L at 25 oC

Solvent solubility Infinitely soluble in acetone, benzene, 

carbon tetrachloride, ethanol, chloroform, 

and toluene at 25 oC

Vapor pressure 0.045 μm Hg (4.5 x 10-5 mm Hg) at 25 oC

Dissociation constant, pKa Not applicable because acetochlor is 

neither an acid nor a base. 

Octanol/water partition coefficient, 

Log(KOW)

970 (Dow study) or 1082 (Monsanto 

study); differences are likely due to 

experimental error

UV/visible absorption spectrum Not available
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Appendix C. Review of Human Research

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

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

PHED 1.1; the AHETF database; and the 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 website6. 

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task 

Force members Health Canada, U.S. Environmental Protection Agency, and the National 

Agricultural Chemicals Association, released February, 1995.

Agricultural Re-entry Task Force (ARTF) data base (SOP #3.1)

 

6

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

http://www.epa.gov/pesticides/science/post-app-exposure-data.html