Monsanto Company, member and managing agent of The Acetochlor Registration 

Partnership, authorizes the EPA to publish the following summary of the petition to 

comply with the Food Quality Protection Act of 1996. An electronic copy on computer 

disc is provided with the cover letter for this submission. 

ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-OPP-2012-0302; FRL-XXXX-X]

Acetochlor; Notice of Filing a Pesticide Petition to Amend Tolerances for a 

Certain Pesticide Chemical in or on Food

Pesticide Petition: PP 2F7996

Registration Division Contact: Kable Davis (PM25), Registration Division (7505P), Office of 

pesticide programs, Environmental Protection Agency, 1200 Pennsiylvania Ave., NW, 

Washington, DC 20405-001; telephone number: (703) 306-0415; email address: 

davis.kable@epa.gov.

AGENCY: Environmental Protection Agency (EPA)

ACTION: Notice

SUMMARY: This notice announces the initial filing of a pesticide petition proposing the 

establishment of regulations for residues of a certain pesticide chemicals in or on various food 

commodities.

DATES: Comments, identified by docket identification (ID) number EPA-HQ-OPP-2012-0302, 

must be received on or before XXXX.

ADDRESS: Comments may be submitted electronically, by mail, or by hand delivery/courier. 

Follow the detailed instructions as provided in Unit I, of the SUPPLEMENTARY 

INFORMATION.

* * * * * * * * * * * * * *

Summary of Petition

A summary of the pesticide petition is printed below as required by section 408(d)(3) of 

the FFDCA. The petition summary was prepared by the Petitioner and represents the views of 

the Petitioner. The summary announces the need to amend existing group tolerances for indirect 

or inadvertent residues of acetochlor by removing rice as an exception from grain, of cereal grain 

Group 15 and straw, of forage, fodder and straw of cereal grain Group 16. 

Monsanto Company
Pesticide Petition (PP) 2F7996

EPA has received a pesticide petition (PP 2F7996) from Monsanto Company, 1300 I 

Street NW, Suite 450 East, Washington DC 20005, (a member of the Acetochlor Registration 

Partnership, ARP) proposing pursuant to section 408(d) of the Federal Food, Drug and Cosmetic 

Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR Part 180.470 (d) by removing the exception 

for rice from two existing tolerances for indirect or inadvertent residues of acetochlor (2-chloro2'-methyl-6'-ethyl-N-ethoxymethylacetanilide) and its metabolites containing either the 2-ethyl6-methylaniline (EMA) or the 2-(1-hydroxyethyl)-6- methyl-aniline (HEMA) moiety, to be 

expressed as acetochlor equivalents, in or on the following raw agricultural commodities when 

present therein as a result of the application of acetochlor to soil or growing crops in paragraph 

(a) of 40 CFR Part 180.47, as: Grain, cereal, forage, fodder and straw, group 16, except corn, 

grain sorghum, and wheat, straw at 0.3 ppm, and Grain, cereal, group 15, except corn, grain 

sorghum, and wheat, grain at 0.05 ppm.

EPA has determined that the petition contains data or information regarding the elements 

set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated the 

sufficiency of the submitted data at this time or whether the data supports granting of the 

petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant Metabolism. The metabolism of acetochlor has been studied in cotton, corn, 

soybeans and sorghum. Acetochlor metabolizes extensively to yield a complex array of polar 

metabolites. The major metabolic pathways are: (i) uptake of soil metabolites and subsequent 

metabolism, (ii) uptake of acetochlor followed by oxidative metabolism and conjugation, and 

(iii) uptake of acetochlor, conjugation with glutathione and subsequent catabolism. EPA has 

determined that the tolerance expression contain parent and metabolites hydrolyzed to EMA and 

HEMA. 

2. Analytical method. An adequate enforcement method for residues of acetochlor in 

crops has been approved. Acetochlor and its metabolites are hydrolyzed to either EMA or 

HEMA, which are determined by HPLC-OCED and expressed as acetochlor equivalents. 

3. Magnitude of the residues. Residue trials with application to primary/target cereal 

grain crops, field corn, sweet corn, and sorghum and existing data from trials with cereal grain 

crops (oats, winter wheat, and sorghum) planted in rotation the following season are adequate to 

show that the existing tolerances proposed for amendment will not be exceeded when acetochlor 

is used as directed, and no new residue trials are required. 

B. Toxicological Profile

1. Acute toxicity. The EPA has classified technical acetochlor as toxicity category III for 

acute oral, dermal and inhalation toxicity, and eye irritation. Two dermal irritation studies are 

available. Severe irritation resulting in a classification of Toxicity Category II was observed in a 

study conducted with an obsolete source of technical acetochlor while only minimal irritation 
resulting in a Toxicity Category IV classification was noted with a higher purity test material that 

is more representative of current technical material. Acetochlor is known to be a skin sensitizer.

2. Genotoxicity. Acetochlor has been evaluated in an extensive battery of in vitro and in 

vivo genotoxicity studies. Acetochlor was not mutagenic in the Ames Salmonella assay but 

exhibited a weakly positive response in a mouse lymphoma gene mutation assay. Acetochlor 

also exhibited a weakly positive response in the first of two Chinese hamster ovary 

hypoxanthine-guanine phosphoribosyltransferase (CHO/HGPRT) gene mutation assays but was 

clearly negative in a subsequent CHO/HGPRT assay. Acetochlor was clastogenic at cytotoxic 

dose levels in an in vitro cytogenetics assay in human lymphocytes. However, no evidence of 

clastogenicity or other genotoxic effect was observed in a number of in vivo assays, including a 

rat bone marrow chromosomal aberration assay, two mouse micronucleus assays and dominant 

lethal mutation assays in rats and mice. No evidence of DNA damage was noted in an in vitro

unscheduled DNA synthesis (UDS) assay in rat hepatocytes. A weakly positive response was 

noted in an in vivo rat hepatocyte UDS assay, but only at an excessively high dose level 

associated with marked hepatotoxicity and mortality. Furthermore, no evidence of DNA damage 

was observed in rat nasal olfactory cells (the primary oncogenic target site for acetochlor) using 

gel electrophoresis following 1 or 18 weeks of dietary exposure to acetochlor.

The clastogenic effect observed with acetochlor in vitro has been shown to be a result of 

the reactive chloroacetyl moiety and is most evident under test conditions where glutathione 

concentrations are low. This effect has not been observed under in vivo conditions where higher 

glutathione levels result in the protective binding of acetochlor to glutathione instead of the SHgroups of chromatin and other critical cellular proteins. Thus, the overall weight of evidence 

indicates that the positive responses observed with acetochlor in some in vitro studies are not 

relevant in vivo and that acetochlor would not pose a significant risk of genotoxicity to humans 

under anticipated conditions of exposure. 

3. Subchronic toxicity. Two 90-day rat feeding studies have been conducted, at dietary 

concentrations ranging from 20 to 6000 ppm. The primary effects observed in these studies were 

decreased weight gain and food consumption. Minor changes were noted in several clinical 

pathology parameters and in liver and kidney weights but these were not associated with any 

histopathological changes. The overall No Observable Adverse Effect Level (NOAEL) for both 

studies combined was 200 ppm (approximately 18 mg/kg/day).

Two subchronic dog studies were conducted in which acetochlor was administered via 

capsule at dose levels ranging from 2 to 200 mg/kg/day. In a 119-day study, excessive toxicity, 

including emaciation, decreased body weight and a high rate of mortality, was noted at 200 

mg/kg/day. Changes in several clinical pathology parameters, increased organ weights and 

histopathological lesions of the liver, kidney and bone marrow were observed at 200 and 75 

mg/kg/day. Slightly increased serum ALT activity in males and slightly increased relative liver 

weights in females were also noted at 25 mg/kg/day, the lowest dose tested. However, due to 

lack of corroborative clinical pathology and/or histopathological findings, these were not 

considered to be indicative of a treatment-related adverse effect. In a 90-day study, decreased 

body weight gain, clinical signs of toxicity, clinical pathology changes and increases in relative 

liver weight were noted at 60 mg/kg/day, the highest dose tested (HDT). No effects were 

observed at 10 mg/kg/day, the next lowest dose level. Thus, based on the results of both studies 

combined, 25 mg/kg/day is considered to be the overall NOAEL for subchronic toxicity of 
acetochlor in dogs.

Subchronic (21-day) dermal toxicity studies have been conducted with both rats and 

rabbits. The NOAEL for systemic effects in rabbits was 400 mg/kg/day based on mortality and 

decreased body weight at 1,200 mg/kg/day. No signs of systemic toxicity were noted in rats at 

dose levels up to 100 mg/kg/day (HDT). 

4. Chronic toxicity and oncogenicity. Two one-year dog studies have been conducted 

with acetochlor. In the first study, dogs were administered acetochlor via capsule at dose levels 

of 0, 4, 12, and 40 mg/kg/day. Slightly decreased food consumption, markedly decreased body 

weight gain, testicular atrophy and some indications of liver toxicity were observed at 40 

mg/kg/day. A possible indication of liver toxicity was also noted in one animal at 12 mg/kg/day 

but no effects on any parameter were noted at 4 mg/kg/day. In a second study, dogs were 

administered acetochlor via capsule at dose levels of 0, 2, 10, and 50 mg/kg/day. Excessive 

toxicity (including weight loss, emaciation, clinical signs of toxicity, alterations in a number of 

clinical pathology parameters, macroscopic lesions in a number of organs, and histopathological 

changes in the brain, kidneys and testes) was evident at 50 mg/kg/day and resulted in the 

premature sacrifice (post week 39) of a number of high-dose animals for humane reasons. 

Histopathological changes in the kidneys were also observed at 10 mg/kg/day. No treatmentrelated effects were noted at 2 mg/kg/day. Thus, based on both studies, the overall NOAEL for 

chronic toxicity of acetochlor in dogs is considered to be 4 mg/kg/day.

Three chronic rat feeding studies have been conducted with acetochlor, at dietary 

concentrations ranging from 18 to 5000 ppm (approximately 0.8 to 297 mg/kg/day for both sexes 

combined). The overall results from the three studies indicate that the Maximum Tolerated Dose 

(MTD) for acetochlor in rats is approximately 1000 ppm (54 mg/kg/day). The primary 

indications of toxicity at this level were decreased body weights, mild liver effects (as evidenced 

by increased liver weights and clinical pathology changes) and kidney lesions. Increased 

incidences of nasal olfactory and thyroid follicular tumors were observed at dose levels greater 

than or equal to 1000 ppm. The EPA also considered a single nasal tumor at 500 ppm in one 

study to be treatment related, although a single nasal tumor was also observed in a control animal 

from a subsequent acetochlor study. An increased incidence of liver tumors occurred only at 

5000 ppm, a dose level which greatly exceeded the MTD, and is thus not considered relevant for 

human risk assessment. Based on all 3 studies, the overall NOAEL for chronic toxicity in the rat 

was considered to be 200 ppm (approximately 10 mg/kg/day). This dose level was also 

considered to be the unequivocal NOEL for oncogenicity.

A number of mechanistic studies have been conducted to determine the mode of action 

for the thyroid and nasal tumors observed in the chronic rat feeding studies with acetochlor. 

These studies have demonstrated that both tumors are produced by non-genotoxic, thresholdmediated mechanisms to which the rat is especially sensitive. The thyroid tumors are caused by 

induction of a liver enzyme, UDP-glucuronyltransferase (UDPGT), that results in decreased 

levels of thyroid hormone and a compensatory increase in thyroid stimulating hormone (TSH), 

which acts upon the rat thyroid to induce hyperplasia and ultimately neoplasia. This is a wellknown mechanism in rats that is widely believed to have little or no relevance to humans. The 

nasal tumors result from the formation of reactive iminoquinone metabolites by the rat olfactory 

tissue. These metabolites bind to the cysteine residues in nasal proteins and cause oxidative 

stress. The resulting cytotoxicity and regenerative cell proliferation, if sustained, eventually 

results in formation of olfactory tumors. However, large species differences at several steps in 
the production of the reactive quinoneimine metabolites indicate that this mode of action would 

be unlikely to occur in humans, particularly at anticipated levels of exposure. 

Two mouse oncogenicity studies have been conducted with acetochlor, at dietary 

concentrations ranging from 10 to 5000 ppm (approximately 1.2 to 973 mg/kg/day). Increased 

mortality, decreased weight gain, anemia and signs of kidney and liver toxicity were noted at 

1500 and 5000 ppm. Renal toxicity and anemia were also noted at 1000 ppm (approximately 

126 mg/kg/day), which was considered to be the MTD. Some minor differences from controls 

were noted at 100 ppm but were not considered to be toxicologically significant. Thus, the ARP 

concluded that 100 ppm (approximately 12 mg/kg/day) was the NOAEL for mice. The EPA, 

however, considered the slight differences at 100 ppm to be indicative of a treatment-related 

adverse effect and concluded that 10 ppm (approximately 1.1 mg/kg/day) was the NOAEL. A 

treatment-related increased incidence of liver tumors was noted in male mice at 5000 ppm. 

However, these tumors were not considered relevant for human risk assessment since they 

occurred only at a dose level that greatly exceeded the MTD. Slightly increased incidences of 

lung tumors and histiocytic sarcomas were also noted. However, these tumors were considered 

unrelated to treatment by panels of independent expert pathologists and of only equivocal 

relationship to treatment by the EPA. 

 Because a clear mode of action was demonstrated for the rat tumors, EPA based the 

cancer classification on the data from the mouse. Given the weakness of these data (benign lung 

tumors in male and female mice and histiocytic sarcomas in female mice), EPA has classified 

acetochlor as having "Suggestive Evidence of Carcinogenic Potential" and determined that linear 

quantification of carcinogenic potential would not be appropriate for the mouse tumors. The rat 

nasal tumors, with a point of departure (POD) of 10 mg/kg/day, are the most sensitive effect for 

cancer risk. The chronic population adjusted dose (cPAD), based on the no-observed-adverseeffect level (NOAEL) of 2.0 mg/kg/day from the chronic dog study, will be protective of both 

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

5. Reproductive and developmental toxicity. Studies in rats and rabbits indicate that 

acetochlor has only minimal potential to induce reproductive or developmental toxicity, and that 

such effects, occur only in the presence of significant maternal toxicity. There is no evidence of 

increased qualitative or quantitative susceptibility to fetuses or offspring in either species.

Two rat developmental toxicity studies have been conducted, at dose levels ranging from 

40 to 600 mg/kg/day. In the first study, rats were administered acetochlor by gavage at dose 

levels of 0, 50, 200, and 400 mg/kg/day. Decreased maternal weight gain and clinical signs of 

toxicity were observed at 400 mg/kg/day. A slight decrease in mean fetal weights was also noted 

at 400 mg/kg/day. However, this was not considered to be treatment-related because the 

difference was not statistically significant and the mean value was well within the historical 

control range. In a second study, rats were administered acetochlor at dose levels of 0, 40, 150, 

and 600 mg/kg/day. Both maternal and fetal toxicity were observed at 600 mg/kg/day, as 

evidenced by animals sacrificed moribund, clinical observations, decreased maternal weight 

gain, increased post-implantation loss and decreased fetal weight. No maternal or developmental 

effects were noted at 150 mg/kg/day. Thus, based on the results from both studies combined, the 

ARP considers 200 mg/kg/day to be the overall NOAEL for maternal toxicity and 400 

mg/kg/day to be the overall NOAEL for developmental toxicity.

Two rabbit developmental toxicity studies have been conducted, at dose levels ranging 

from 15 to 300 mg/kg/day. No developmental toxicity was noted at any dose level. The overall 
NOAEL for maternal toxicity was 100 mg/kg/day based on decreased weight gain at 190 

mg/kg/day, and decreased weight gain and mortality at 300 mg/kg/day. 

Three multigeneration rat reproduction studies have been completed, at dietary 

concentrations ranging from 18 to 5000 ppm. In the first study, acetochlor was administered at 

dietary concentrations of 0, 500, 1500 and 5000 ppm. Decreased numbers of live pups at birth 

and decreased pup weights (particularly during the latter portion of lactation) were observed at 

5000 ppm. However, this level also induced excessive parental toxicity as indicated by 

substantially decreased body weights (up to 33% in females) and kidney lesions. Decreased 

parental body weights and a slight decrease in pup weights were also noted at 1500 ppm. Based 

on these results, 500 ppm (approximately 30 to 46 mg/kg/day) was considered to be the NOAEL 

for both parental and offspring toxicity. In a second study, acetochlor was administered at dose 

levels of 0, 18, 175 and 1750 ppm. No effect on reproductive performance was noted at any 

dose level. Decreased body weights, slightly reduced food consumption and increased relative 

organ weights in parents, and decreased pup weight gain during lactation, were noted at 1750 

ppm. Thus, 175 ppm (approximately 13 to 18 mg/kg/day) was considered to be the NOAEL for 

both parental and offspring toxicity. In the most recent study, acetochlor was administered to 

rats at dietary concentrations of 0, 200, 600 and 1750 ppm. Effects observed in adult animals at 

1750 and 600 ppm included decreased body weights; increased liver, kidney and/or thyroid 

weights; and histopathological changes (including benign tumors) of the nasal olfactory 

epithelium. Decreased pup weights were noted at both 600 and 1750 ppm. Decreased numbers 

of uterine implantations and a delay in vaginal opening in F1 pups were also noted at 1750 ppm. 

However, the delayed vaginal opening was attributed to the delay in reaching critical body 

weight, and not a specific developmental effect, since the body weight of the 1750 ppm pups at 

time of vaginal opening was comparable to that of controls. Based on these results, 600 ppm 

(approximately 57 to 71 mg/kg/day) was considered to be the NOAEL for reproductive effects 

while 200 ppm (approximately 19 to 22 mg/kg/day) was the NOAEL for overall toxicity. 

6. Immunotoxicity. No evidence of a direct or specific effect on the immune system was 

observed in an immunotoxicity study conducted in mice. In the study, acetochlor was 

administered to female mice for 28 days at dietary concentrations of 0, 500, 1500, and 5000 ppm. 

Over the entire 28-day study period, there were no treatment related effects at any of the dose 

levels tested. The NOAEL for neurotoxicity in this study was 5000 ppm (1535.5 mg/kg body 

weight/day), the highest dietary concentration tested.

7. Neurotoxicity. No evidence of a direct or specific effect on the nervous system was 

observed in acute and subchronic neurotoxicity studies conducted in the rat. In the acute study, 

acetochlor produced general signs of toxicity, including mortality and transient changes in motor 

activity, following a single oral dose of 1500 mg/kg. A statistically significant decrease in motor 

activity was also noted one day after dosing in females at 500 mg/kg. However, this was not 

considered to be treatment related because the activity level of these animals was higher than 

prior to dosing and there was no change in habituation. Therefore, 500 mg/kg/day was 

considered by the ARP to be the NOAEL. EPA, however, has concluded that the NOAEL for 

this study was 150 mg/kg/day.

In the sub-chronic study, acetochlor was administered to rats for 13 weeks at dietary 

concentrations of 0, 200, 600 and 1750 ppm. Decreased weight gain and food consumption were 

observed at 1750 ppm but no evidence of neurotoxicity was observed at any dose level. The 
NOAEL for this study was 600 ppm (approximately 52 mg/kg/day). 

The EPA has accepted a waiver from the ARP for a developmental neurotoxicity study, 

citing 1) the lack of increased susceptibility or evidence of neurotoxicity to offspring; 2) the 

neuropathology and behavioral effects observed in the chronic dog study at 50 mg/kg/day (study 

NOAEL of 2 mg/kg/day) were associated with significant toxicity, including renal toxicity, 

indicating possible uremic encephalopathy following a sustained chronic high exposure level, 

rather than direct neurotoxicity; 3) effects observed in the rat acute and sub-chronic neurotoxicity 

studies were transient, seen at higher doses and not consistent among studies or sexes; and 4) 

lack of neurotoxicity in the chloroacetanilides as a group. 

8. Animal metabolism. Numerous in vivo studies have been conducted to evaluate the 

absorption, distribution, metabolism and/or excretion of acetochlor in rats, mice, monkeys, goats 

and hens. In addition, the metabolism of acetochlor has also been evaluated in vitro using liver 

and nasal tissues from rats, mice and monkeys, and nasal tissues in humans. These studies have 

shown that acetochlor is well absorbed following oral administration and is extensively 

metabolized and rapidly excreted. No major sex differences were noted. However, significant 

species differences were observed, particularly with respect to the formation and distribution of 

the metabolite(s) believed responsible for the occurrence of nasal tumors in the rat. 

9. Metabolite toxicology. A number of studies have been conducted to evaluate the 

potential effects that may be associated with the t-ethane sulfonic (ESA) and t-oxanilic (OXA) 

acid metabolites of acetochlor. These are environmental degradates that are formed by soil 

microbes and have been detected in ground and surface water. These metabolites are highly polar 

and water soluble, and lack the reactive chlorine of parent acetochlor. The results from the 

toxicology studies indicate that acetochlor ESA and OXA are more poorly absorbed, more 

rapidly excreted and exhibit a lower degree of toxicity than parent acetochlor. Furthermore, they 

do not produce the preneoplastic changes responsible for the rat nasal and thyroid tumors that 

occur with parent acetochlor, and thus are unlikely to be carcinogenic. Consequently, the EPA 

has concluded that the ESA and OXA metabolites should not be included in the acute, chronic or 

cancer risk assessments for acetochlor.

10. Endocrine disruption. No evidence of a direct effect of acetochlor on the endocrine 

system has been observed. As previously noted, acetochlor did produce a secondary effect on 

thyroid hormone homeostasis at high dose levels in rats as a result of induction of the hepatic 

enzyme UDPGT. However, this is a relatively common finding in rats that is generally thought 

to have little to no relevance to human risk assessment, particularly at the low doses to which 

humans are likely to be exposed. Similarly, the observation of delayed vaginal opening at the 

high-dose level in the most recent reproduction study is also considered to be a secondary effect 

resulting from decreased body weight gain in the pups. Neither of these findings is considered to 

pose a significant concern for human risk assessment.

C. Aggregate Exposure

1. Dietary exposure – food and feed uses. Acetochlor is currently registered for use on 

field corn, sweet corn, pop corn, cotton, sorghum, and soybeans. Tolerances for acetochlor 

and/or its metabolites containing the EMA or HEMA moieties have been established for field 
corn, sweet corn, pop corn, cotton, sorghum, and soybean commodities as well as tolerances for 

indirect or inadvertent residues in soybean; wheat; grain; cereal grain, group 15, except corn, 

grain sorghum, rice and wheat; individual tolerances for forage, hay, stover and straw of cereal 

grains, group 16, except corn, grain sorghum, rice and wheat; sugar beet, root; sugar beet, tops; 

pea and bean, dried shelled, subgroup 6C (except soybean); potato; sunflower seed; animal feed, 

nongrass, group 18, forage; and animal feed, nongrass, group 18, hay. No tolerances have been 

established for livestock commodities because there is no reasonable expectation of finite 

residues based on the results of exaggerated rate feeding studies.

Potential acute and chronic dietary exposures were estimated by EPA in the Human 

Health Risk Assessment associated with the establishment of acetochlor tolerances for cotton and 

soybean commodities ((PC Code: 121601, DP Barcode: D400597, and D400596) at 

http://www.regulations.gov in docket ID number EPA-HQ-OPP-2009-0002) using the Dietary 

Exposure Evaluation Model-Food Consumption Intake Database (DEEM-FCIDTM). The acute 

dietary analysis was based on tolerance level residues and 100% crop treated assumptions for all 

commodities. Experimentally derived processing factors were used for cereal grain 

commodities. Default values were used for all other processed commodities. The chronic 

dietary analysis included anticipated residues from field trial data and 100% crop treated 

assumptions for all commodities. Experimentally derived processing factors were used for 

cereal grain commodities. Default values were used for all other processed commodities. The 

present assessment incorporated these same assumptions plus included residues in rice grain, and 

rice straw, at the tolerance levels established for grain of cereal grain Group 15, and for straw, of 

the forage, fodder and straw of cereal grain Group 16, respectively.

Based on the results of carcinogenicity studies in rats and mice, EPA classified acetochlor 

as having "Suggestive Evidence of Carcinogenic Potential" but determined that the chronic risk 

assessment will be protective of both non-cancer and cancer effects. Therefore, a separate 

exposure assessment to evaluate cancer risk is unnecessary.

2. Dietary exposure from drinking water. The ARP has conducted extensive monitoring 

of surface and ground water for residues of acetochlor. These monitoring data were collected in 

corn-growing areas during a period of high use of acetochlor. The ARP considers these

monitoring data to be most appropriate for characterizing potential ground and surface water 

residues from the proposed use of acetochlor as described in this petition. Given that exposure to 

acetochlor parent was significantly higher in the surface water monitoring sites than in the 

ground water monitoring sites, the appropriate value to use in the acute dietary assessment would 

be that from a surface water monitoring site that produced the highest concentration of 0.01821 

ppm. The most appropriate concentration to use in the chronic dietary assessment would be that

from a surface water monitoring site that produced the highest time-weighted annualized mean 

(TWAM) concentration for a single year of 0.00143 ppm. 

However, a more conservative approach is to use the estimates based on the Pesticide Root 

Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS). Based on PRZM/EXAMS, 

the estimated drinking water concentration (EDWC) of acetochlor for acute exposures is 

estimated to be 75 parts per billion (ppb) for surface water. The EDWC for chronic exposures for 

non-cancer assessments is estimated to be 4.8 ppb for surface water. Residues of parent 

acetochlor in ground water are expected to be insignificant compared to residues in surface 

water. These modeled estimates of drinking water concentrations were incorporated in the 

DEEM-FCIDTM analysis into the food categories “water, direct, all sources” and “water, indirect, 
all sources”. For acute dietary risk assessment, the water concentration value of 75 ppb was used 

to assess the contribution to drinking water. For chronic dietary risk assessment, the water 

concentration of value 9.5 ppb was used to assess the contribution to drinking water. This value 

is higher than the modeled EDWC for chronic exposures (4.8 ppm) and was derived from 

preliminary modeling that was subsequently refined. Since chronic exposure estimates using the 

higher value are below EPA's LOC, the dietary exposure assessment was not revised to reflect 

the final modeled EDWC.

3. Non-Dietary Exposure. There are no residential or non-agricultural uses of 

acetochlor. Therefore, non-dietary, non-occupational exposure to acetochlor is expected to be 

negligible. In addition, 21-day dermal toxicity studies with acetochlor indicate a very low 

potential for systemic toxicity, even after repeated dermal exposures. 

4. Cumulative Effects. The chloroacetanilides have been evaluated by the Agency and the 

FIFRA Scientific Advisory Panel (SAP) as a related group of chemicals for this purpose. 

Acetochlor 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 since there are no 

registered uses or tolerances for this chemical in the United States. 

Mechanistic studies indicate that acetochlor and its close structural analog, alachlor, share 

common modes of action for both the nasal turbinate tumors in rats and the thyroid follicular cell

tumors secondary to disruption of pituitary thyroid homeostasis. However, the EPA and FIFRA 

Scientific Advisory Panel have concluded that the thyroid tumors are not an appropriate endpoint 

for cumulative risk assessment for acetanilides because increased incidences of these tumors 

were marginal and/or occurred only at high dose levels, and were produced via a well-known, 

non-genotoxic mechanism to which the rat is especially sensitive.

An updated cumulative risk assessment of the Chloroacetanilide CAG pesticides, 

acetochlor and alachlor, was conducted in April 2007: "ACETOCHLOR/ALACHLOR: Revised 

Cumulative Risk Assessment for the Chloroacetanilides to Support the Proposed New Uses on 

Alachlor and Acetochlor". PP 8F05000 and 8F5025 (Alachlor), PP 6F4791, 1F6263 and 5F6918 

(Acetochlor) is available in the docket established for previous action (EPA-HQ-OPP-2009-

0002) establishing tolerances in cotton and soybean. Based on this most recent Chloroacetanilide 

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

cumulative assessment was not conducted for the current assessment of proposed amended 

tolerances for acetochlor, because the use of rice as a rotational crop would not affect the 

cumulative risk results. Acetochlor is a very minor contributor to cumulative risk when 

compared to alachlor, and the proposed new use (rice as a rotational crop) is a negligible 

contributor to acetochlor dietary risk.

D. Safety Factor for Infants and Children

1. In general. Section 408(b)(2)(C) of FFDCA provides that EPA shall apply an additional 

tenfold (10X) margin of safety for infants and children in the case of threshold effects to account 

for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure 
unless EPA determines based on reliable data that a different margin of safety will be safe for 

infants and children. This additional margin of safety is commonly referred to as the FQPA 

safety factor (SF). In applying this provision, EPA either retains the default value of 10X, or uses 

a different additional SF when reliable data available to EPA support the choice of a different 

factor.

2. Prenatal and postnatal sensitivity. The prenatal and postnatal toxicity database for 

acetochlor includes two rat and two rabbit developmental toxicity studies and three reproduction 

toxicity studies in rats. No evidence of qualitative or quantitative susceptibility of fetuses or 

offspring to acetochlor exposure in any of these studies.

3. Conclusion. Retaining the FQPA safety factor of 10X as a database UF for acetochlor in 

the acute risk assessment is expected to be adequately protective based on the following:

i. The toxicity database for acetochlor is complete. The EPA has granted a waiver for 

additional data pertaining to acetochlor's potential to cause developmental neurotoxicity (DNT).

ii. There is a lack of increased susceptibility or evidence of neurotoxicity to offspring. There 

is no evidence that acetochlor results in increased susceptibility in in utero rats or rabbits in the 

prenatal developmental studies or in offspring in the 2-generation reproduction studies.

iii. The neuropathology and behavioral effects observed in the chronic dog study at 50 

mg/kg/day (study NOAEL of 2 mg/kg/day) were associated with significant toxicity, including 

renal toxicity, indicating possible uremic encephalopathy following a sustained chronic high 

exposure level, rather than direct neurotoxicity.

iv. The effects observed in the rat acute and sub-chronic neurotoxicity studies were transient, 

seen at higher doses, and not consistent among studies or sexes.

v. Based on the results of the immunotoxicity study there is no evidence that acetochlor is 

immunotoxic.

vi. There are no residual uncertainties identified in the exposure databases. The acute and 

chronic dietary, including food and water, exposure assessments will not underestimate the 

exposure and risks posed by acetochlor.

Retaining the FQPA 10X safety factor for acute exposures will be adequately protective of 

infants and children. For chronic exposures, reliable data show that removal of the FQPA 10X 

factor will be safe for infants and children. 

E. Aggregate Risks and Determination of Safety

EPA determines whether acute and chronic pesticide exposures are safe by comparing 

aggregate exposure estimates to the acute population adjusted dose (aPAD) and chronic 

population adjusted dose (cPAD). The aPAD and cPAD represent the highest safe exposures, 

taking into account all appropriate Safety Factors (SFs). EPA calculates the aPAD and cPAD by 

dividing the Point of Departure (POD) by all applicable Uncertainty Factors (UFs). For linear 

cancer risks, EPA calculates the probability of additional cancer cases given the estimated 

aggregate exposure. Short-term, intermediate-term, and chronic-term risks are evaluated by 

comparing the estimated aggregate food, water, and residential exposure to the POD to ensure 

that the MOE called for by the product of all applicable UFs is not exceeded. Potential acute and 

chronic risks from exposure to acetochlor were determined using the toxicology endpoints 
utilized by EPA in the March 2006 Tolerance Reassessment Eligibility Decision (TRED) 

document and in the previous Human Health Risk Assessment associated with the establishment 

of acetochlor tolerances for cotton and soybean commodities (PC Code: 121601, DP Barcode: 

D400597, and D400596) at http://www.regulations.gov in docket ID number EPA-HQ-OPP2009-0002. 

1. Acute risk. Acute risks for all population subgroups were assessed using an acute RfD 

of 0.15 mg/kg. This was based on a NOAEL of 150 mg/kg from the acute rat neurotoxicity 

study and a 1000-fold uncertainty factor. Although no evidence of increased sensitivity to 

offspring was noted in rats or rabbits following in utero and/or postnatal exposure, the EPA has 

accepted a proposal to retain the FQPA 10X uncertainty factor in lieu of conducting a rat 

developmental neurotoxicity (DNT) study, for acute exposure. The EPA has determined that 

retaining the FQPA 10X uncertainty factor is expected to be adequately protective of 

neurodevelopmental toxicity, based on the following: 1) lack of increased susceptibility or 

evidence of neurotoxicity to offspring; 2) the neuropathology and behavioral effects observed in 

the chronic dog study at 50 mg/kg/day (study NOAEL of 2 mg/kg/day) were associated with 

significant toxicity, including renal toxicity, indicating possible uremic encephalopathy 

following a sustained chronic high exposure level, rather than direct neurotoxicity; 3) effects 

observed in the rat acute and sub-chronic neurotoxicity studies were transient, seen at higher 

doses and not consistent among studies or sexes; and 4) lack of neurotoxicity in the 

chloroacetanilides as a group. Based on the above discussed assumptions, the current and 

proposed use of acetochlor would result in an estimated 95th percentile acute dietary (food and 

water) exposures of 0.0045 mg/kg/day for the overall US population and 0.0159 mg/kg/day for 

all infants less than 1 year old, the most highly exposed population subgroup. These exposures 

utilize 3% and 11% of the aPAD, respectively. 

2. Chronic risk. Chronic (non-cancer) risks were assessed using a chronic RfD of 0.02 

mg/kg/day which was derived from a NOAEL of 2.0 mg/kg/day from the second one-year dog 

study and a 100-fold uncertainty factor. No additional database or FQPA uncertainty factor was 

utilized for the chronic risk assessment. Based on the above assumptions, chronic dietary (food 

and water) exposure of the overall US population to acetochlor is estimated to be 0.0004

mg/kg/day. This represents 2% of the chronic population adjusted dose (cPAD). Chronic 

exposure from food and water for infants less than 1 year old, the population subgroup receiving 

the greatest exposure, is estimated to be 0.0012 mg/kg/day, which represents 6% of the cPAD. 

Both of these values are well below 100% of the cPAD. Therefore, there is a reasonable 

certainty that dietary (food and water) exposure to acetochlor will not pose a significant risk to 

the US population, including infants and children.

3. Short-term/intermediate-term risk. Short-term and intermediate-term aggregate 

exposure take into account short-term or intermediate-term residential exposure plus chronic 

exposure from food and water (considered to be a background exposure level). Acetochlor is not 

registered for any use patterns that would result in residential exposure. Therefore, the short-term 

or intermediate-term aggregate risk is the sum of the risk from exposure to acetochlor through 

food and water and will not be greater than the chronic aggregate risk.

4. Cancer Risk. The risk assessments based on the endpoint selected for chronic risk 

assessment are considered to be protective of any potential carcinogenic risk from exposure to 

acetochlor. Based on the results of the chronic risk assessment EPA concludes that acetochlor is 

not expected to pose a cancer risk.
5. Determination of Safety. Based on the data summarized herein, there is a reasonable 

certainty that no harm will result to the general population, or to infants and children, from 

aggregate exposure to acetochlor residues from the current and proposed uses of acetochlor. 

F. International Tolerance

There are no Codex Maximum Residue Levels established for residues of acetochlor on 

agricultural commodities.