UNITED STATES ENVIRONMENTAL PROTECT I ON AGENCY

WASHINGTON

, D

. C

. 20 460



### MEMORANDUM

Date: December 11

, 2013 OFFICE OF
CHEMICAL SAFETY AND
POLLUTION P REVEN T ION



### 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 Regi stration

CaseNo.: NA

CAS No.: 34256-82-1

40 CFR: 180.470



### FROM: Jessica Kidwell, Risk Assessor

# ~**~** Kelly O'Rourke, Biologi 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 (7509 P )



### THROUGH: Elissa Reaves, Branch Chief 

# f**~** Risk Assessment Branch 4, HED (7509P) 

## =::::-:

-

TO: Kable Da vis

, 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 acetoch lor on sugar beets and peanuts
for the regis tered product

, W**ARRAN ~**  Herbicide (EPA R eg. # 524-591). This document provides the Health Effect Division's (HED's) human health risk assessment for acetochlor.Acetochlor / 12160 1 Hum an Health Risk Assessment DP No. D413438

1.0 Executive Summary

........................................................................................................... 4

2.0 HED Recommendations

.................................................................................................... 8

2.1 Data Deficiencies

...... . .. ... . . . .... ..... .. ..... ... ..... ... ..... . ... . .................... ...................... . ............. 8

2.2 Tolerance Conside rations

...... ......... . ................................... ... .................. ... ................... 9
2.2 .1 Enforcement Analytical Method

. ....... ..... . .. ....... . ............. .. .. ... . .. ...... .. .... .... . .... ..... .... .. .... 9

2.2.2 Recommended Toleranc es

......................................... .......... ............ ...... .............. ... ....... 9

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

2.2.4 International Ha rmonization ........................................................................................ 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 Int roduc tion

.................. . ... . . .. .. .. .................................... .. .................................................. 10

3.1 Chemical Identity

......................................................................................................... 10

3.2 Physical/Chemical Characteristics

.... .................... ............................... ...................... 11

3.3 Pesticide Use Pattern

...................................................................................... ..... ......... 12

3.4 Anticipated Expos ure Path,vays

................................................................................. 13

3.5 Consideration of Env ironment a l 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 Neurotox icity

............................................................................................ 17

4.4

. 3 Evidence of Sens itivity /S usceptibility 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 Tox icity 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 Environmenta l 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 Us ed in Dietary Assessment

............... ................................... 28

5.4.3 Acute Dietary Risk Assessment

.................................................................................. . 28

Page 2 of79Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 3 of 79 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

................................ ................................ ................ 79Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 4 of 79 1.0 Executive Summary

Acetochlor, 2

- chloro

- N

- (ethoxymet hyl)

- 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 acetoch lor (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, cerea l 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 intermediate

term (dermal and inhalation) occupational exposure s 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 acet ochlor.

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 contain ing 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 a cetochlor tolerance s 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

expre ssion, 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.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 5 of 79 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 do ses in

several oral studies. The dog appears to be more sensitive than the rat or mouse t o 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 r ats, dogs and mice exposed to aceto chlor 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 mortalit y 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 reproductiv e 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 i n rats. There are acceptable mode of action data for

the se 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 exposure s 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 base d on decr eased motor activity in females seen at the lowest observed adverse effect level (LOAEL) of 500 mg/kg/day

. A n uncertainty factor ( UF ) of 100X ( 10X for interspecies extrapolation, 10X for intraspecies variation, 1X FQPA SF) was applied to the POD t o 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 d atabase.

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 o f 10 mg/kg/day

. A n 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 (c PAD ) of 0.02 mg/kg/day.

F or short

- term dermal exposure

, a 21 day dermal toxicity study in rabbits was selected with a

NOAEL of 4 00 mg/kg/day based on mortality and clinical signs of toxicity seen at the LOAEL of 1200 mg/kg/day . F or short

- term inhalation exposure , a developmental study in rats with aAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 6 of 79 NOAEL of 1 50 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 derm al exposure were selected from two co

- critical

oral su bchronic 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 obser ved 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 interme diate

- 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 10 X uncertainty factor (UF) was applied to the short

and 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 diff

erent, an aggregate risk index (ARI) was calculated to estimate the

co mbined exposure to acetochlor.

Dietary Exposure and Risk

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

. 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 ac ute analysis incorporated the 1 in 10 year peak surface drinking water estimate f rom application of

acetochlor to sorghum . The resulting 9 5 th percentile acute exposure estimate for infants < 1 year old (the most highly exposed subgroup) is not of concern t o HED (1.6 % acute population adjust ed 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. A nticipated 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. Th e 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 th e 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 pesti cides. For purposes of a cumulative risk assessment, it was determined that the commonAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 7 of 79 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 n ot 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.

R esidential 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 aggre gate (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 asses sments 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

exp osures 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 f or 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

a re 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 intermediate

term dermal and inhalation aggregate risk in dices ( 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 i n Toxicity Category III for acute dermal toxicity, and Categories III and I I 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.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 8 of 79 Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation expo sure 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 s ubchronic inhalation toxicity study for acetochlor is required, but not available.

An alachlor inhalation toxicity study may provide sufficien t data on acetochlor , and the re gistrant 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 (UF DB ) should be applied to inhalation assessments only until the alachl or inhalation st udy 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 review ed and evaluated by HED scientists.

O ccupational 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. ]

Re sidue Chemistry: A n analytical reference standard for acetochlor is needed.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 9 of 79 2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

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

coulometric electrochem ical 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 0.5 0 Beet, sugar, molasses 1.3 0.80 Calculated from HAFT of 0.274 x 2.7x
Beet, sugar, roots 0.3 0.3 0 Beet, sugar, tops 0.8 0. 70 Change due to OECD Calculator

Peanut 0.2 0.2 0 Peanut, hay 6.0 7 .0 Change due to OECD Calculator
Peanut, meal 0.5 0. 2 5 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

T here are currently no Codex or Canadian MRLs, nor Mexican MRLs on the commodities proposed in the current petition.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 10 of 79 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 Cat egory 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 cu rrently appears on the

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

2.3.3 Recommendations f rom Residential Assessment

There are no residential uses proposed with this petition.

3.0 In troduction

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)Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 11 of 79 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

– CH 2 OCH 2 CH 3 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 h erbicide 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 E

Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 12 of 79 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 su gar 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

- encapsula ted 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 rem ai ning 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

di ssipate 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 B oom ; 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 stag e; no more than 1.5 lb ai/A may be applied as a postemer

gence application. 0.9 4

- 1.2 [coarse]

0.9 4

- 1.3 [medium]

0.9 4

- 1.4 [fine] 0.9 4

- 1.3

[coarse]

0.98

- 1.4 [medium]

0.94

- 1.5 [fine]Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 13 of 79 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 B oom ; Aerial 3 lb/gal

Mcap [524

- 591 ] <1.5%

OM ≥1.5%

OM

3 3.0 NS ;90 day N o 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 postemer

gence application. Allow 7 days between sequential appl ications. 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 occu pational 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 previous ly 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 a ssessment

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 Addre ss 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 fromAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 14 of 79 pesticide exposures that are based on patterns of that subgroup’s food and water consumpti on, 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, youth s, 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 exposur e 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

T he toxicology database for acetochlo r 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

letha lity (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, me tabolism, 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 susce ptibility 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 (UF DB ).

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

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

HASPOC acknowledge d that the alachlor inhalation toxicity study available in the literature may provide sufficient data on acetochlor pesticide. The inhalation study wi th 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. S ince the HASPOC meeting, the registrant has su bmit ted the alachlor inhalation study (Monsanto Research Report No. ML

- 83

- 158

, MRID 49031001 ) a nd it is currently undergoing the HED review process. The HASPOC recommended that a 10X Database Uncertainty Factor (UF DB )Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 15 of 79 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 10 X is protecti ve of the effects observed in the inhalation study.

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

Following oral administration to rats, a cetochlor was w ell

- absorbed and rapidly eliminated (92

- 96% of dose by day 5, 1⁄2 life of el imination 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

. A cet ochlor was rapidly degraded into many metabolites and t he 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

rou te 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 m ajor 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 stud ies) 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 sa livation 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, ho pping 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 . A t the highest dose, both males and females showed clinical signs of toxici ty 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.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 16 of 79 In addition to the nervous system, the major target organs affected in subchronic and chronic studies in rats, dogs and mice exposed to aceto chlor are the liver, thyroid (secondary to liver), kidney, testes, and erythrocytes. Species specific target o rgans 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 mortalit y 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 sho wed excessive dermal irritation at 100 mg/kg/day.

The available developmental toxicity studies in rats and rabbits do not show evidence of increased susceptibil ity 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 eff ects 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). Mate rnal 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.

Th ere 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),

a cetochlor is classified as “Suggestive Evidence of Carcinogenic Potential” based on weak evidence for benign lung tumors in male and fe male 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 the se 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 F actor 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

. T here is an adequate toxicity database for acetochlor and exposure data are comple te or are estimated based on data that reasonably account for potential exposures. There is no evidence ofAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 17 of 79 susceptibility and there are no residual uncertainties concerning pre

- or post

- natal toxicity. Evidence of neurotoxicity was observed mainly at hig h doses in several studies including the

a cute 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 a ssessments are based on reliable data and will not underestimate

exposure

.

The FQPA SF was retained at 10X as a database uncertainty factor (UF DB ) for inhalation risk assessments only due to the data gap of an inhalation study. See section 4.1 for detail s.

4.4 .1 Completeness o f 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 prenata l 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 UF DB

.

4.4.2 Evidence of N eurotoxicity

Evidence of neurotoxicity from exp osure 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 Evi dence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

No increase in susceptibility was seen in developmental toxicity studies in rat s and rabbit s or in

three multi

- generation reproductive toxicity studies in rat s . 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 Datab ase

Since the dietary and non

- dietary exposure estimates were based on several conservative assumptions, HED does not believe that the exposu re estimates are underestimated. The acuteAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 18 of 79 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 def ault processing factors, and 100% crop treated was assumed for all commodities. The DEEM analysis also assumed that all drinkin g 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 non

dietary occupational exposures are underestimated because they are also based on conserv ative assumptions, including maximum application rates, and standard values for unit exposures and acreage treated/amount handled.

4.5 Toxicity Endpoint and Point of D eparture 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 se lected 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 . T he 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 dur ation 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 neur otoxicity when coupled with the dermal absorption factor of 20%, results

in a n estimated dermal NOAEL of 750 mg/kg/day. This level of exposure exceeds the dermalAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 19 of 79 toxicity study NOAEL of 400 mg/kg/day . Therefore, use of the dermal toxicity NOAEL as an endpo int 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 derm al exposure were selected from two co

- critical

oral subchronic toxicity studies in the dog w ith 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 subchroni c 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

exposure s since the duration of exposure matched the study duration and route specific stud ies of the appropriate duration are not available at this time

. 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 b e 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 Scien ce Policy Council (HASPOC), an additional 10 X uncertainty factor (UF) was applied to the short

and 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 assessment s because fetal effects were only observed at or above maternally toxic doses.

Acetochlor is classi fied 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 mo use 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 com mon endpoint was not identified for the oral, dermal, and inhalation scenarios. Furthermore, s ince

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)

.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 20 of 79 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 tumo rs 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 o lfactory 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 o ral 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

.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 21 of 79 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 UF A = 10x

UF H =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 UF A = 10x

UF H =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 c RfD 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 ris k associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF S = use of a short

- term study for long

- term
risk assessment. UF DB = 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

exposureAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 22 of 79 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 UF A = 10x

UF H =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% UF A = 10x

UF H =10x Occupational LOC

for MOE = 100 Co

- critical s ubchronic 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 UF A = 10x

UF H =10x

UF DB = 10x Occupational LOC

for MOE = 100 0 Developmental toxicity study in rats (MRID s

41592005, 42054903 ) Maternal LOAEL=600 mg/kg/day based on mortality, clinical signs of toxicity and reduced body weight gain during treatment

Inhalation

Intermediate

Term (1

- 6 mo) NOAEL =

25 mg/kg/day UF A = 10x

UF H =10x

UF DB = 10x Occupational LOC

for MOE = 100 0 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 ad verse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies).

UF H = potential variation in sensitivity among members of the human population (intraspecies). UF S = us e of a

short

- term study for long

- term risk assessment. UF DB = 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.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 23 of 79 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 dete rmined 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 a dequate studies examining the metabolism of various plant metabolites (acetochlor EMA type metabolites, HEMA type metabo lites, 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 Degrad ation
[Excerpted from the 2005 HED Chapter of Tolerance Reassessm e nt 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 grou ndwater at numerous locations. There is variable evidence as to the persis tence 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

method s (Mills et al. 2001). Lavy et al. (1996) have reported a much more substantial increase in persist ence at two sites for alachlor, a n herbicide that is chemically related to acetochlor and tends to have a very similar environmental fate profile.

Labora tory degradation data indicate that acetochlor does not degrade by abiotic processe s (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 oxanilic acid (oxamic acid), and sulfonic acid are the major environmental degradates of acetochlor. Another metabolite is thioaceti c 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 envir onmentally more per sistent than parent acetochlor), however, HED has determined that these are much less toxic than parent.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 24 of 79 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 ma jor 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 m ajor fec al 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 live stock 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 cr op) 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 , expre ssed in acetochlor equivalents (M. Flood, MARC Memorand um, 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.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 25 of 79 Table 5.1.4 Summary of Metabolites and Degradates to be included in th e 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 adequ ately 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 contai ning the EMA moiety or the HEMA moiety, expre ssed in acetochlor equivalents. The nature of the residue in rotational crops is adequately understood based on the results of confined rotational crop studies i n lettuce, radishes

and wheat. HED concluded that acetochlor tolerance s 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

expr ession, 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 pr ocessed 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, an d 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 f ield 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 f ield 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 ofAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 26 of 79 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 se asonal 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 grai ns 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 co ncentration 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 oi l (0.4x) but did

conc entrate 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 Levels 1
(HEMA

- + EMA

- Producing Metabolites, ppm)

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std. Dev.

Treatment 2: P reemergence 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.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 27 of 79 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 Levels 1

(HEMA

- + EMA

- Producing Metabolites, ppm)

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std. Dev.

Treatment 2: P replant 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: P reemergence plus Postemergence at BBCH 18

- 59

Peanut, nutmeat 2.9 4

- 3.0 6 98

- 128 13 <0.023 0.095 <0.029 0.092 0.040 0.046 0.018

Peanut, hay 2.9 4

- 3.0 6 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 b een 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 lowe r 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 d ata for acetochlor indicates that actual exposure at drinking water wells may be significantly lower

.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 28 of 79 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

– citrus 1 Acute 129.0

Lifetime 82.6

Surface Water

PRZM

- EXAMS Ks sorghum

CA sugarbeet “OP” scenario 2 Acute 74

. 9

Lifetime 4.84

Recommended values are based upon the most conservative Tier 1 modeling results; targeted surface and ground

water 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 organophosp h ate use areas; this scenario may or may not be appr opriately 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 overe stimate the actual percent crop treated.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 29 of 79 Table 5 .4.3 : Summary of Acute Dietary Exposure and Risk for Acetochlor

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

.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 30 of 79 5.4.6 Summary Table

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

Risk for Ace tochlor

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 10Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 31 of 79 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 metho d 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 Dr ift website for more information 1 . 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 A gDRIFT 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 dr ift 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 fie lds, 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 inhalatio n 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 A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 2 . Th e 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 post

application 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.htmlAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 32 of 79 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, H ED 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 ge neral population and all population subgroups.

7.2 Short

- Term Aggregate Risk

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

term 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 u sing 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, the refore, 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 thatAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 33 of 79 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 incl uded 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. B utachlor 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 f ollicular 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 post

emerge nt 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 pattern s 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 handle rs is based on the following scenarios:

1) Mixing/loading liquids for aerial and groundboom applications; 2) Applying sprays via aerial and groundboom equipment; andAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 34 of 79 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 Tas k 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 an d Risk Estimates

As summarized in Tables 9.1.1 and 9.1.2, t he 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 wh ere 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 eng ineering 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.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 35 of 79 Table 9 .1 .1. Short

- Term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Acetochlor

.

Exposure Scenario Crop or Target Dermal Unit

Exposure ( μ g/lb ai) 1 Inhalation Unit

Exposure ( μ g/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Dermal

(LOC = 100) Inhalation
(LOC = 1000) Total

(LOC = 1)

Mitigation Level Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 ARI 8

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 ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/ day) × DAF (100%) ÷ BW ( 80 k g).

5 Dermal MOE = Dermal NOAEL ( 400 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × 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 I ndex (ARI) = 1÷ (1 ÷ RI dermal ) + (1 ÷ RI inhalation ) ; Where: Risk Index (RI) = MOE ÷ LOC (100 for dermal and 1000 for inhalation).Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 36 of 79 Table 9 .1. 2

. Intermediate

- Term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Acetochlor

.

Exposure Scenario Crop or Target Dermal Unit

Exposure ( μ g/lb ai) 1 Inhalation Unit

Exposure ( μ g/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Dermal

(LOC = 100) Inhalation
(LOC = 1000) Total

(LOC = 1)

Mitigation Level Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 ARI 8

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

Applica tor

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 = Der mal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/ day) × DAF (20%) ÷ BW ( 80

k g).

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

6 Inhalati on Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × 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 ÷ RI dermal ) + (1 ÷ RI inhalation ) ; Where: Risk Index (RI) = MOE ÷ LOC (100 for dermal and 1000 for inhalation).Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 37 of 79 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 re

entry exposure). Such exposures may occur w hen 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 activi ty, 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 po st

- application exposure.

9.2.1 Dermal Post

- application Risk

For acetochlor, based on the proposed use s , short

- and intermediate

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

b oth 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 chemical

specific data, are derived from ARTF exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting post

- application exposure that are used in this assessment, known as “transfer coefficients”, are presented in the ExpoSAC Policy 3 3 ” which, along with additional information about the ARTF data, can be found at the Agency website 4

. 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 (cm 2 /hr ) Activities

Sugar beets
Field / row

crop, low /

medium L ow Min/ F ull 210 Scouting

Peanuts Low F ull 1

, 900 Irrigation (hand set)

Low Min/ F ull 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. C hemical

- 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.htmlAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 38 of 79 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 folia r application.

Occupational Post

- application Non

- Cancer Dermal Risk Estimates

As show n in Table 9 .2.2.2., t he 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 (cm 2 /hr) DFR 1

(Day 0) Dermal Dose

(mg/kg/day) 2 MOE 3

(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/cm 2 ; where F = 0.25 and D = 0.10 per day

2 Daily Dermal Dose = [DFR (μg/cm 2 ) × 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 (RE I) 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. Ther efore, 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 post

application 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 Fede ral Insecticide, Fungicide, and Rodenticide Act Scientific Advisory PanelAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 39 of 79 (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 5 . The Agency is in the process of evaluating the SAP report as well as available post

- application inhalat ion 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 n ew 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 assessm ent 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. Therefo re, 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. 0 8 /2 1 /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 Rep ort of the Cancer Assessment

Review Committee.

Morton, T. 06/ 2 6/2013. 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 Expo sure Assess ment 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 Subchron ic Inhalation, Positive Control Data for the Acute and Subchronic Neurotoxicity, and a Developmental Neurotoxicity Study.

5 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meet ing.htmlAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 40 of 79 A ppendix 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

................................ .................. yes a

yes

yes a

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

-
y es 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)Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 41 of 79 A.2 Toxicity Profile s

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 LD 50 = 4238 mg/kg (males);

4025 mg/kg (females); 4124 mg/kg (combined) III

870.1200 Acute dermal, rabbit 41565105 (1986) Acceptable/guideline LD 50 > 2000 mg/kg (combined

males and females) III

870.1300 Acute inhalation, rat 41565106 (1989) Acceptable/guideline LC 50 >4.46 mg/L (males)

LC 50 = 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/AAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 42 of 79 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 (198 6) 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 sex es, 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 toxic ity (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 irritatio n 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 s cientists.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 43 of 79 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) Materna l NOAEL = 200 mg/kg/day LOAEL = 400 mg/kg/day based on clinical signs of toxicity and decreased maternal body weight/weight gain. Developmenta l 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) Materna l NOAEL = 300 mg/kg/day LOAEL >300 mg/kg/day (HDT; study acceptable based on results of a range

- finding study). Developmenta l 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) Materna l NOAEL = 50 mg/kg/day LOAEL = 190 mg/kg/day based on body weight loss. Developmenta l 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 lactatio n 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 = 123.8/15 7.4 mg/kg/day (HDT). LOAEL > 123.8/157.4 mg/kg/day males/females.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 44 of 79 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 neph ritis, 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 a ccording to Agency pathology working group/peer review policy and the findings do not change the original dog study (MRID 41565118) conclusions.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 45 of 79 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 incre ased 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 higher

increased incidence of n asal 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 (mal es) 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, h epatocellular 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 n ot 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 infilt ration 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

rec lassified by the PWG and are not considered treatment

related 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 (male s).

E vidence 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 H uman Health Risk Assessment DP No. D413438

Page 46 of 79 Table A.2

. 2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.4300 Carcinogeni city (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 (male s) at 116/135 mg/kg/day.

Gene Mutation

870.5100 Bacterial

reverse mutation Salmonella typhimurium 00050930 (1978) Acceptable/guideline

0.001

- 1 μ l/plate

- /+ S9 Negative up to the highest dose tested (1 μ l/plate

- /+ S9); higher concentrations ( ≤ 10 μ l/plate

- /+ S9) were cytotoxic

Gene Mutation

870.5100 Bacterial

reverse mutation Salmonella typhimurium 41565121 (1989) Acceptable/guideline

1.6

- 5000 μ g/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 μ g/plate

- /+ S9 (Arochlor 1254 or Pheno

barbital / 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

2 5

- 150 μ g/mL

- S9

25

- 125 μ g/mL + 10% S9 Positive ≤ 2

- fold in mutation frequency (MF) at 125 or 150

μ g/mL

- S9 & 125 μ g/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 μ g/mL

- S9

50

- 300 μ g/mL + 1, 2, 5 or

10% S9 Negative up to cytotoxic levels ( ≤ 200 μ g/mL

- /+ 10% S9)

Cytogenetics

870.5300 Mammalian cell gene mutation Mouse lymphoma L5178Y cells 00131394 (1982) Acceptable/guideline

20

- 400 μ L/mL

- S9

5

- 250 μ L/mL +S9 Positive 30

- 50 μ L/mL +S9

2.2

- 5.2 fold increase accompanied by cytotoxicity (<10%

survival at ≤ 50 μ L/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 μ g/mL

- /+ S9

(2) 0, 100 μ g/mL

- S9 (whole blood) 0, 75 μ g/mL

- S9 (separated blood) Positive at 50 and 100 μ g/mL +S9 accompanied by marked

reduction in mitotic indices at 100 μ g/mL ( ≤ 59% decrease). Types of aberrations: breaks, fragment and minutes.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 47 of 79 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, 100 μ g/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 μ M (2.7 μ g/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 μ g/well Negative up to cytotoxic concentrations ( ≤ 10.6 μ g/well )Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 48 of 79 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)

A cceptable (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)

A cceptable (guideline)

- 0, 200, 600, 175 0 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 we ek 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 ( 14 C

- 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 termin ation. 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 ( 14 C

- 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 well

perfused organs (heart, spleen, kidney, lungs, liver). Acetochlor was completely metabolized (15 compounds separated in urine, 4 in bile, 5 in fe ces), 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

- de ethylated acetochlor; in bile, major metabolite was the glucuronide conjugate. Major fecal metabolite not characterized.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 49 of 79 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 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/10 6 spleen 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 time

related 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 t o 11.772 or 0.763 mg/g, respectively). The average DAF was calculated as 20%Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 50 of 79 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 ( 14 C

- acetochlor) Differe nces 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

h epatic 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 chloramide

enterohepatic 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 pp m 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 m ice 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 14 C

acetochlor 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.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 51 of 79 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 14 C

acetochlor) 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) 444962 12 (1998) Unacceptable/non

- guideline (upgradable) 7 mg/kg/day 14 C

- 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

- g uideline 126 mg/kg 14 C

- 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 g iven 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

14 C

- acetochlor sulfoxide (0.025 mM, 15.5 k Bq)

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 d etected in the sample of human nasal tissue.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 52 of 79 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)

14 C

- acetochlor (30 mM, 0.05 mBq) Study evaluated rates of steps in metabolism of aceto chlor to p

hydroxy

- 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 epi thelia. 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 olfactor y 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 fo rm 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 14 C

- acetochlor sulfoxide; in vitro binding,

0.4 mM 14 C

- acetochlor sulfoxide, 407

- 458 Kbq to

cellular fractions of nasal and

liver tissue Unacceptable/non

- guideline (upgradable) (1) HPLC analysis comparing radioactivity of acid hy drolysates 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 an d 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 hig hest 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

- OH

acetochlor 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.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 53 of 79 Table A.2

. 3 Special (Non

- guideline) Mechanistic Study Toxicity Profile

Study Type MRID No. (year)/

Classification /Doses Results

Studies on thyroi d 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. Incr eased 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).Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 54 of 79 A.3 Hazard Identifi cation 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. N o 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:AP f S D (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 stu dy 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 fe males 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, piloer ection 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 fem ale, 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 eff ects 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 re ductions 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 gr oss 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 b ody weight gainAcetochlor /121601 H uman 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 A cceptable/Guideline and satisfies the guideline requirement for an acute neurotoxicity study in rats (870.6200; OECD 424).

Dose and Endpoint for Establishing an a RfD : 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 adminis tered 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 cho linesterase 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 pe rformed 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 c linical chemistry values included increased ALT, GGT, OCT , cholesterol and triglycerides, along with increased urea, creatinine and Acute RfD ( General Population ) = 1 50 mg/kg (NOAEL) = 1

. 5 mg/kg

100 (UF)Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 56 of 79 decreased glucose. In females, statistically significant increases in plasma AChE at week 24 and

BChE at week 24 and 50 we re 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 (ab s 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, collecti ng 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 ophthal mologic 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 a cetochlor; 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%; [ 14 C]

- 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 a queous dilution), and 707.31 mg/ g ( formulation conc entrate) to the backs of rats (24 rats/dose/ group). Four rats within each dose

group were sacr ificed at 0.5, 1.0, 2.0, 4.0, 10.0, and 24.0 hours following d ermal application toAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 57 of 79 assess derm al absorption of acetoc hlor. The percent absorption in 24 hours of a radio

- lab e led

dose of acetochlor was found to be as fol lows: 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 level s of acetochlor were also propor tional 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 fr om 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:

I n 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 conges tion; 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 de aths 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

rev ealed 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 hig her 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 l esions. 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

– 10 x for interspecies extrapolation and 10x for intraspecies

variation

Comments about Study/Endpoint : The route and duration of exposure is appropria te 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 prot ective ofAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 58 of 79 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 s tudy 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 d ied 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 weigh t. 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

de creased 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 s tudy 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 throu gh 10. A statistically significantly decrease in mean body weight gain was observed in both sexes. InAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 59 of 79 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 i n 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, mil d 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 pro vide 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. A t 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 bo dy 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 c ontrols andAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 60 of 79 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 dev elopmental 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 o n mortality, clinical signs of toxicity and reduced body weight gain during treatment at a LOA E L = 600 mg/kg/day.

Uncertainty Factor (UF ): 100 0 (10 x for interspecies extrapo lation, 10x for intraspecies variation, and 10x Database Uncertainty Factor (UF DB ) 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 us e 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 aceto chlor (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 female s 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 show ed 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

mortali ty). 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:Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 61 of 79 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 diar rhea 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 s ignificantly 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 microscop ic 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 incre ased 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 (UF DB ) for lack of route specific inha lation 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 LOAE L. 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 v alue) 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) :Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 62 of 79 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 wa s 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 activ ity; 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 high

dose, the LOAE L 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 requi rements (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 clin ical 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, infiltr ation 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.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 63 of 79 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 ami notransferase 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 pa rameters, 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, decr eased 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 po ssible

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 applicat ion 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

.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 64 of 79 870.3465 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 r egistrant 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 shar es 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 accept able for use in risk assessment. The HASPOC recommended that a 10X Database Uncertainty Factor (UF DB ) should be applied to inhalation assessments only until the alachlor inhalation study is submitted and deemed acceptable by the Agency. The alachlor inhala tion 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 LOAE L 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, inc lusive, with sacrifice and cesarean evaluations on Day 20. At 400 mg/kg/day, excessive salivation (post

dosing in 3 females on one occasion) and increased frequency of urogenital staining were observed. Mean body weight gain during treatment (Days 6

- 20) w as 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. AAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 65 of 79 slight but not statistically significant reduction in mean fetal weight was observed At 400 mg/kg/day. No other cesarean para meters 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 toxic ity 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 f ollowing 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 treat ment

- 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/k g/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 effect s 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 cesa rean 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 t reatment observed onAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 66 of 79 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 range

finding 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 o r 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 rang e

- 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 pr emating 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 pr emating in both generations. The parental systemic NOAEL is 500

ppm.

At 1500 ppm, mean pup body weights on La ctation 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 pu p groups were reduced and mean li tter size tended to be smaller (statistical significance only achieved for the F1b gener ation). Although statistically significantly increased absolute/relative thyroid weights were reported at low and mid dose, they were n ot considered to

be a clear treatment

- related finding based on lack of a dose

- response and lack of a correspondingAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 67 of 79 increase in liver weights. No effects on pup survival, birth weight, gross abnormalities or other cesarean offspring parameter were ob served. 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 i s 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, 17 5 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/k g 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

cont rols, 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, clin ical 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 sy stemic 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.

M RID # 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 selecte d 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

obs ervations 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 termi nation. The parental NOAEL is 200 ppm.Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 68 of 79 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 wi th 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 i n 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 coul d 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

bra in cholinesterase activity (termination) were evaluated. A neurological evaluation (testsAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 69 of 79 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 (a lso 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 inclu ded 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 increa sed 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,

dilatatio n 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, demyelinat ion 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 param eters. 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

abs olute /rel ative 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 ofAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 70 of 79 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). Th e 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 m g/kg/day, decreased body weight/weight gain (both sexes, slight in females), increased bilirubin in females and in males, increased G GT, cholesterol, thyroid c

- cell hyperplasia, papillary hyperplasia of the nasal epithelium, hepatocellular alterations and necrosis , were observed

. E vidence of carcinogenicity at

50 mg/kg/day

, marked by increased incidenc e 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 NOA EL = 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 con secutive 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) wer e 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 epithe lial 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 cel l 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

- bre d 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 sexe s (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), sli ghtly decreased body weight during part of study (males), anemia (females), increased abs olute /re lative thyroid weight (females) and renalAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 71 of 79 interstitial nephritis (males) , were observed

. E vidence of carcinogenicity

- incidence was marked by lung tumors that s howed 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. I ncreased incidence of bro n chiolar hyperplasia and pos sibly renal tubular hyperplasia at ≥ 135 mg/kg/day in females. Evidence of carcinogenicity characterized by increased incidence of lung adenomas (females) and

adenoma/car cinoma (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 μ l/plate

- /+ S9 Negative up to the highest dose tested (1 μ l/plate

- /+ S9); higher concentrations ( ≤ 10 μ l/plate

- /+ S9) were cytotoxic

Gene Mutation

870.5100 Bacterial

reverse mutation Salmonella typhimurium 41565121 (1989) Acceptable/guideline

1.6

- 5000 μ g/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

an d not seen in TA98

Gene Mutation

870.5100 Bacterial

reverse mutation Salmonella typhimurium (strain T1538 only) 44863202 (1989) Acceptable/non

- guideline

100

- 5000 μ g/plate

- /+ S9 (Arochlor 1254 or Pheno

barbital / 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 μ g/mL

- S9

25

- 125 μ g/mL + 10% S9 Positive ≤ 2

- fold in mutation frequency (MF) at 125 or 150

μ g/mL

- S9 & 125 μ g/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 μ g/mL

- S9

50

- 300 μ g/mL + 1, 2, 5 or

10% S9 Negative up to cytotoxic levels
( ≤ 200 μ g/mL

- /+ 10% S9)Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 72 of 79 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 μ L/mL

- S9

5

- 250 μ L/mL +S9 Positive 30

- 50 μ L/mL +S9

2.2

- 5.2 fold increase accompanied by cytotoxicity (<10%

survival at ≤ 50 μ L/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 μ g/mL

- /+ S9

(2) 0, 100 μ g/mL

- S9 (whole blood) 0, 75 μ g/mL

- S9 (separated blood ) Positive at 50 and 100 μ g/mL +S9 accompanied by marked

reduction in mitotic indices at 100 μ g/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, 100 μ g/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/guidelin e 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) toxicityAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 73 of 79 870.5450 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 μ M (2.7 μ g/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 μ g/well Negative up to cytotoxic concentrations ( ≤ 10.6 μ g/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:AP f SD (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 as sessment (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 neuropatho logical 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 lowerAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 74 of 79 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 f emales (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 le vel. 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 la nding 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 femal es 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 effe ct, 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:AP f SD 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 ac tivity 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 nervo us 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 treatment

related 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 1750Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 75 of 79 p pm 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 Pol icy 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 a cceptable/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 a n isotopically

labeled mixture of ( 12 C

, 13 C

, 14 C

- acetochlor). A cetochl or 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 14 C 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. A nimals were sacrificed 7 days after dosing and the tissues and organs were analyzed for

14 C

- c ontent. It was found that the blood contained low levels of 14 C

- radioactivity (2

- 3% of the dose) and that no accumulation of the metabolites were evident in any othe r 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

f eces

- 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 14 C radioactivity associated with the blood was characterized. The metabolism of acetochlor in the rat appears to follow well

- established mechanisms of

xen obiotic 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 wit h ( 14 C

- acetochlor) . Acetochlor was w ell

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 dos e, 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 separa ted in urine, 4 in bile, 5 in feces), with glutathione, mercapturic acid or glucuronide conjugation of n

- dealkylated acetochlor a major route of metabolism;Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 76 of 79 sulphoxymethyl and cysteine conjugates also identified in feces. In urine, major metabolite was

mer capturic 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%; [ 14 C]

- 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 a queous dilution), and 707.31 mg/ g ( formulation concentrate) to the backs of rats (24 rats/dose/ group). Four rats within each dose

group were sacr ificed at 0.5, 1.0, 2.0, 4.0, 10.0, and 24.0 hours following d ermal application to

assess derm al absorption of acetoc hlor. The percent absorption in 24 hours of a radio

- labled dose

of acetochlor was found to be as fol lows: 0.763 mg/g, 31.4%; 11.772 mg/g, 2 9.6% ; 76.926 mg/g, 17.5%; 070.32 mg/ g, 12.6%. Acetochlor was thus absorbed in a dose

- dependent manner.

Blood level s of acetochlor were also propor tional to the applied dose, but were much greater than

the corresponding plasma concentrations, indicating bin ding 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 fr om 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 injecti on. 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 mort ality 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 imm unized with an intravenous injection of 10 8 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 c ava. The mesenteric lymph node, Peyer’s patch,Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 77 of 79 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 w eights, spleen cellularity, or the TDAR(T

- cell dependent antibody response), as measured by the AFC IgM Specific Activity (AFC/10 6 spleen 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).Acetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 78 of 79 Appendix B

. Physical/Chemical Properties

Table C1. Physical/ C hemical 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 availableAcetochlor /121601 H uman Health Risk Assessment DP No. D413438

Page 79 of 79 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 website 6

.

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.go v/pesticides/science/post

- app

- exposure

- data.html