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 provi ded with the cover letter for this submission.

ENVIRONMENTAL PROTECTION AGENCY

[OPP

- 2012

- 0829 ; 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 2F8077

Registration Division Contact: Hope Johnson , Registrat ion Division (750 5 P ), Office of
P esticide P rograms, Environmental Protection Agency, 1200 Pennsy lvania Ave., NW, Washington, D C 20460 ; telephone number: (703) 305

- 5410 ; email address: johnso n.hope @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 chemical in or on various food
commodities.

DATES: Comments, identified by docket identification (ID) number OPP

- XXXX

- XXXX, must be received on or before XXXX.

ADDRESS : Comments may be submitted electronically, by mail, or by hand delivery/courier.
Follow the d etailed 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 establish tolerances for residues of
acetochlor in sugar beet and peanut commodities

.

Monsanto Company

P esticide Petition (PP) 2F8077EPA has received a pesticide petition ( PP 2F8077 ) from Monsanto Company, 1300 I Street NW, Suite 450 East, Washington DC 2005, (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 (a ) by establishing
tolerances for residues of acetochlor (2

- chloro

- 2'

- methyl

- 6'

- ethyl

- N

- ethoxymethylacetanilide) and its metabolites containing either the 2

- ethyl

- 6

- methylaniline (EMA) or the 2

- (1

- hydroxyethyl)

- 6

- methyl

- aniline (HEMA) moiety, to be expressed as acetochlor equivalents, resulting from applications to soil or growing crops, in or on the following agricultural
commodities : Beet, sugar, dried pulp at 0.5 ppm, Beet, sugar, molasses at 1.3 ppm, Beet, sugar, roots at 0.3 ppm , Beet, sugar, tops at 0.8 ppm, Peanut at 0.2 ppm, Peanut, hay at 6 .0 ppm , and Peanut, meal at 0.5 ppm; and to delete from 40 CFR Part 180.740 (d) tolerances for indirect or inadvertent residues in Beet, sugar, roots at 0.05 ppm, and Beet, sugar, tops 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 equivalent s.

3. Magnitude of the residues

. Supporting residue trial data with application s to the primary/target crop s of soybeans and peanuts are adequate to show that the proposed tolerances
will not be exceeded when acetochlor is used as directed in proposed labeling

, and no additional residue trials are required.

B. Toxicological Profile

1. Acute toxicity

. Acetochlor has low acute toxicity by the oral, dermal, and inhalation routes of exposure and is mildly irritating to the eyes. The results of two de rmal irritation studies indicate that acetochlor is a mild to strong skin irritant. Acetochlor is known to be a skin
sensitizer.

2. Genotoxicity . Acetochlor has been evaluated in an extensive battery of in vitro and invivo 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 ov ary 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. Howe ver, 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 evide nce 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 hepatotoxic ity 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 ef fect 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 SH

groups of chromatin and other critical cellular proteins. Thus, the overall weight of evidence indicates that the positive response s 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 studie s 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 an d 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 whic h 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 cli nical 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 f emales 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 stud y, 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 f or 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 atdose 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 at rophy 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
admin istered 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 or gans, 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 als o observed at 10 mg/kg/day. No treatment

related 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 cond ucted 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, threshold

mediated mechanisms to which the rat is especially sens itive. The thyroid tumors are caused by induction of a liver enzyme, UD P

- 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 well

known mechanism in rats that is widely believed to have little or no relevance to humans. The
nasal tumors result from the formation of reactive iminoq uinone metabolites by the rat olfactory
ti ssue. 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 con ducted with acetochlor, at dietary concentrations ranging from 10 to 5000 ppm (approximately 1.2 to 973 mg/kg/day). Increasedmortality, 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 1 00 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

tre atment

- 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 m ode 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

ace tochlor 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

- adverse

effect level (NOAEL) of 2.0 mg/kg/day from the chronic dog study, will be protective of both

non

- cancer and cancer effects, including r at 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 of fetuses or offspring to acetochlor exposure in either species. Two rat developmental toxicity studies have been conduct ed, 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 ran ge. 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 mater nal 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 le vel. 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 dietaryconce ntrations 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 la ctation) 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 a nd 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 o bserved 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 bo th 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 d evelopmental 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 immuno toxicity 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 change s 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 acti vity level of these animals was higher than prior to dosing and there was no change in habituation. Therefore, 500 mg/kg/day is c onsid ered by the ARP to be the NOAEL for this study. 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 a ny 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 (DNT) study, citing 1) the lack of increased susceptibility or evidence of neurotoxicity to o ffspring; 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 obse rved 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 studie s 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 t o 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 lo wer 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 consi dered 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 from f oo d and feed uses

. A cetochlor is currently registered for
direct use i n field corn, sweet corn, pop corn, cotton, sorghum, and soybeans , and for rotation to a variety of crops

, with rotation to rice pending approval . Tolerances for acetochlor and/or its
metabolites containin g 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 potato; soybean , forage; soybean, hay ; wheat

, forage; wheat, grain ;wheat, hay ; and wheat, straw ; 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. A petition to remove rice as an exception from the tolerance for cereal grain, gr oup 15, and straw of cereal grain, group 16, is pending approval. 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.
Potenti al acute and chronic dietary exposures were estimated using the Di etary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID TM /Calendex, ver. 3.14)

. The acute dietary analysi s was based on tolerance level residues and 100% crop treated assumptions for all commodities. Experimentally derived processing factors were used for cereal grain commodities and for proposed sugar beet and peanut commodities. Default values were used for all other p rocessed commodities. The chronic dietary analysis included average residues from field trial data for all commodities except cotton and soybean where tol erance level residues were used, and proposed tolerance levels were applied to sugar beet and peanut commodities. The chronic analysis included 100% crop treated assumptions for all commodities. Experimentally derived processing factors were used for processed cereal grain commodities and sugar beet and peanut commodities. Default values were used for a ll other processed
commodities. 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 bo th non

- cancer and cancer effects. Therefore, a separate exposure assessment to evaluate cancer risk is unnecessary.

2. Dietary exposure from drinking w ater. The ARP has conducted extensive monitoring of surface and ground water for residues of acetochlo r

. 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 s of acetochlor as described in this petition. Given that e xposure 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 wo uld
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 w ould be that from a surface water monitoring site that produced the highe st 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/EX AMS, 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 waterconcentration of valu e 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 fo r 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 inc luded 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.
Me chanistic studies indicate that a cetochlor and i t s 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 h igh 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: " ACE TOCHLOR/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 c onducted for the current assessment of proposed tolerances for acetochlor, because uses in sugar beets and peanuts would not affect the cumulative risk results. Acetochlor is a very minor contributor to cumulative risk when compared to ala chlor, and the

pr oposed new uses do not contribute significantly 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 a nd 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 usesa 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 adequa tely 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.

i ii. T he 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 sustaine d 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 th e 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 infant s 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 H uman Health Risk Assessment associated with the establishmentof acetochlor tolerances for cotton and soybean commodities (PC Code: 121601, DP Barcode:
D 400597

, and D400596 ) at http://www.regulations.gov in docket ID number EPA

- HQ

- OPP

2009

- 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 developmen tal 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 ur emic 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 sex es; and 4) lack of neurotoxicity in the chloroacetanilides as a group. Based on the above discussed assumptions, the current and proposed use s of acetochlor would result in an estimated 95 th percentile acute dietary (food and water) exposures of 0.00 504 mg /kg/day for the general US population and 0.01 5174 mg/kg/day
for non

- nursing infants, the most highly exposed population subgroup. These exposures utilize 3% and 10 % of the aPAD, respectively.

2. Chronic risk

. Chronic (non

- cancer) risks were assessed us ing 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. Base d on the above assumptions, chronic dietary (food and water) exposure of the overall US population to acetochlor is estimated to be 0.000 597 mg/kg/day. This represents 3 % of the chronic population adjusted dose ( cPAD ) . Chronic

exposure from food and water is estimated to be 0.001587 mg/kg/day for children 1

- 2 years old

, the population subgroup receiving the highest estimated exposure which represents 8 % 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. T herefore, 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 sel ected 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. D etermination of Safety

. Based on the data summarized herein, there is a reasonablecertainty 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.