UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASH IN GTON, D.C

. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

Date: May 7. 2015

SU BJ EC T: S -Met o l ac hl or

- Ri sk Assessment for Establishment of Tolerances for New Uses

on Let1uce

, Low Growing Ber r y S ub group I 3-07G, except Cranberry ; Vegetable

, Cucurbit, Group 9; Sunflower subgroup 208; Vegetable, Fruiting, Group 

### 8-1 O; except Tabasco Pepper.

FROM: PC Code: I 08800 Deci s i on No.: 488023 P e titi o n No.: 4E8248 Ri s k A ssess m e nt T y pe: Risk Assessment TXR No. : NA MRID No.: NA

Jessica Kidwell, Toxicolog i st!R_jk As Thurst o n Morton
, Ch+!. t 

## /j

. Ivan Nieves

, ORE

_ , "-**·-~** RABIV / HED (7509P) '" H eal th Effects Di visio n (7509 P ) DP Barcodc: 0425168 R eg i s tration No.: I 00-816 Re g ul ato r y Actio n : Sec1ion 3 Registration Ca se No.: 0001 CAS No.: 87392-12

- 9 40 C FR: § 180. 368

# ~

THROUGH : E l issa Rea ves PhD.

, Branch

## Chi**~ ~:.---** 

# 1 RA BI V / H ED (7509P)

TO: Andy Ertman
, RM 05 Minor Use & Em ergency Re sponse Branch Registration Division (7505 P )S-Metolachlor Human H ea lth Ri s k Assessment DP No. D425 I 68

Ta bl e of Co nt e n ts

I Executive Sum1nary

...... . ..... .. ..... .. ............................................................................................ 4 2 I

- l E D Recommendations

.......................................................................................................... 

### 8 2 .1 Data Deficiencies

................................................................ . ...... . . . .... . ..... . .................... . ... 

### 8 2

. 2 Tolerance Considerations

. ................. .. ......... . . . ...... .. ...... . . . ...... . ...... . ..... .................. ........... 

### 8 2.2 .1 Enforcement Analytical Method

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

2.2.2 Recommended Tolerances

. ........... .. ................. .... .... .... . ............ . ............................ .. . 

### 8

2.2 .3 Revision s to P etitio n ed -F o r Tolerances

.................................................................... 

### 9

2.2.4 Intern atio nal Harmonization

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

2.3 Label R ecommen dati o n s

................................................................................................ 1 0 2.3 .1 Recommendation s from Residue Reviews

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

2.3.2 Recommendation s from Occupational Assessment..

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

2.3.3 Reconm1endations from Resident i al Assessment

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

3 I ntroduction

.. . .. .. .. ... . ..... .. . .... .. ..... .. ..... .. ....... . . .. . . ...... . ....... . ...... . ... . .. . . . . . ...... . ..... .. . .... . ................ 10 3.1 C he1nical Identit y

........................................................................................................... 1 0 3

. 2 Physical / C h em ical Characteristics

............................................................................... . . 11 3.3 P est icide Use Pattern

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

..................................................................................... 14 

### 3 .5 Co n siderat ion of Environmental J ustice

............... ..... .. .. . .. ..... .. ..... . ......... .................. .. ... 14 4 H aza rd Characterization and Dose-Response Assessment.

............................. . ..... .. ..... . .... . . . . 15 4

. 1 Toxicology Studies Available for Analysis

.... . .............................................................. 15 4.2 Absorption, Di stribut ion

, Metabolism

, & Eliminati on (ADME)

............ . . .. ..... .... .. .. ..... . 16 4.2.1 Dern1al Absorption

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

4 .3 'fox i co l ogica l Effects

..................................................................................................... 17 4.4 Safe t y Factor for I nfants and Childre n ( FQPA Safety Factor)

....................................... 18 4.4.1 Complete ne ss of the Toxicology Database

...................................... . . ..... . . .... ....... . . . 18

4.4.2 Ev idence of Neurotoxic it y

...................................................................... . .... . ..... . . . .. 18

4.4.3 Ev id e nc e of Sens itivit y/Suscep tibility in the D eve l op in g or Young Animal

.... .. . .. 18

4.4.4 Residual Uncertainty in the Exposure Databas e

.................................................. . . . 19

4.5 Toxicity Endpoint and Point of D epa rture Selections

.. . . .. ..... .. ..... .... .. .. ... . ..... .. ..... ...... .... 19 4.5.1 Dos e- Re s ponse Assessment

. ...... .. ...... . ................ ... .................... . .... . . . ..... . . ..... . . .. . . ... 19

4.5.2 Recommendation for Combining Rout es of Exposures fo r Risk Assessment..

...... 20

4.5.3 Ca ncer C l assification and Risk Assessment Recommendati on

... . .. .. .......... .. ......... . 20

4.5.4 Summary of Points of Departure and Toxicity Endpoi nt s Used in Human Risk Assess m e nt

............................................................................................................................ 21

5 Dietary Exposure a nd Ri sk Assessment

.. ........... .......... .... ..................................................... 23 5.1 Metabolite/Degradate Re s idue Profile

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

............................................... 23

Page 2of70S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 3 of 70 5.1.2 Summary of Environmental Degradation

................................ ............................... 23

5.1.3 Comparison of Metabolic Pathways

................................ ................................ ....... 23

5.1.4 Residues of Concern Summary and Rationale

................................ ........................ 24

5.2 Food Residue Profile

................................ ................................ ................................ ...... 24 5.3 Water Residue Profile

................................ ................................ ................................ .... 25 5. 4 Dietary Risk Assessment

................................ ................................ ................................ 26 5.4.1 Description of Residue Data Used in Dietary Assessment

................................ ..... 26

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ................ 26

5.4.3 Acute Dietary Risk Assessment

................................ ................................ .............. 26

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ .......... 27

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............ 27

5.4.6 Summary Table

................................ ................................ ................................ ....... 27

6 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ ........ 27 6.1 Residential Handler Exposure/Risk Estimates

................................ ............................... 27 6.2 Residential Post

- application Exposure/Risk Estimates

................................ .................. 29 6.3 Residential Risk Estimates for Use in Aggregate Assessment

................................ ...... 31 6.4 Residential Bystander Post

- application Inhalation Exposure

................................ ........ 32 6.5 Spray Drift

................................ ................................ ................................ ...................... 32 7 Aggregate Exposure/Risk Characterization

................................ ................................ ........... 33 7.1 Acute Aggregate Risk

................................ ................................ ................................ .... 33 7.2 Short

- Term Aggregate Risk

................................ ................................ ........................... 33 7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ................ 34 7.4 Chronic Aggregate Risk

................................ ................................ ................................ . 34 7.5 Cancer Aggregate Risk

................................ ................................ ................................ ... 34 8 Cumulative Exposure/Risk Characterization

................................ ................................ ......... 3 4 9 Occupational Exposure/Risk Characterization

................................ ................................ ...... 35 9.1 Short

- and Intermediate

- Term Handler Risk

................................ ................................ .. 35 9.2 Short

- and Intermediate

- Term Post

- Application Risk

................................ ................... 36 9.2.1 Dermal Post

- application Risk

................................ ................................ ................. 37

9.2.2 Inhalation Post

- application Risk

................................ ................................ ............. 37

10 References

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

................................ ....................... 39 Appendix B. Field Trial Summaries

................................ ................................ ............................ 64 Appendix C. Physical/Chemical Properties

................................ ................................ ................. 69 Appendix D. Review of Human Research

................................ ................................ ................... 70S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 4 of 70 1 Executive Summary

Metolachlor (PC Code 108801) is a racemic herbicide that consists of 50% each of the R

enantiomer and the S

- enantiomer which is the herbicidally active isomer. S

- Metolachlor (an isomer enriched form of metolachlor, comprised of 88% S

- isomer and 12% R

- isomer ) is a selective, chloroacetanilide herbicide that is applied to a variety of crops as a preplant, preplant incorporated, preemergence, or postemergence applicat ion, primarily for the control of grass weeds. S

- Metolachlor is registered to Syngenta Crop Protection, Inc. for use on a wide variety of food and feed crops including: corn, cotton, grasses grown for seed, legume vegetables, peanuts, potatoes, safflower, sorghum, sunflower, and tomatoes. In addition, S

- metolachlor is registered for use on residential lawns, commercial turf (including golf courses, sports fields, recreation areas, and sod farms), ornamentals and horticultural nurseries. S

- metolachlor form ulations include emulsifiable and flowable concentrates, granular, and ready

- to

- use products. Application methods for agricultural uses include ground, aerial, irrigation and chemigation. Applications of S

- metolachlor to residential lawns or turf are limit ed to professional applicators using backpack, hose

- end, or handgun sprayers.

Interregional Research Project No. 4 (IR

- 4) submitted petition #4E8248 requesting new uses of S

- Metolachlor on lettuce, Low growing berry subgroup 13

- 07G except cranberry, along with the following crop group expansions: Vegetable, cucurbit group 9, Sunflower subgroup 20B, and Vegetable, Fruiting, group 8

- 10, except tabasco pepper.

The existing toxicological da tabase is primarily comprised of studies conducted with metolachlor. However, bridging studies indicate that the metolachlor toxicology database can be used to assess toxicity for S

- metolachlor. The toxicology database for S

- metolachlor, when combined with the metolachlor database, is complete for risk assessment purposes, with the exception of a required 28

- day inhalation study for metolachlor

. Although t he neurotoxicity battery (870.6200 a and b) is required in accordance with the revised 40 CFR Part 158 Toxicology Data Requirements , t he data requirement for the neurotoxicity studies has been waived at the present time by the Hazard and Science Policy Council (HASPOC) in their meeting of February 14, 2013.

In subchronic (metolachlor and S

- metolachlor) and chronic (metolachlor) toxicity studies in dogs and rats decreased body weight and body weight gain were the most commonly observed effects. No systemic toxicity was observed when metolachlor was administered dermally. No neurotoxicity studies with metolac hlor or S

- metolachlor are available. However, there was no evidence of neurotoxic effects in adult animals in available subchronic and chronic toxicity studies

. There was no evidence of immunotoxicity in mice. Prenatal developmental studies in the rat and rabbit with both metolachlor and S

- metolachlor revealed no evidence of a qualitative or quantitative susceptibility in fetal animals. A two

- generation reproduction study with metolachlor in rats showed no evidence of parental or reproductive toxicity. The FQPA safety factor was reduced to 1X because there are no residual uncertainties with regard to pre

- and/or postnatal toxicity.

There was no evidence of a mutagenic or cytogenetic effect in vivo or in vitro in studies with either metolachlor or S

- metolachlor. Metolachlor has been evaluated for carcinogenic effects inS

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 5 of 70 the mouse and the rat. Metolachlor was classified as a Group C carcinogen with risk quantitated using a non

- linear (Margin of Exposure (MOE)) approach.

S

- Metolachlor exhibits low acute toxicity via the oral (Toxicity Category III), inhalation (Toxicity Category IV), and dermal (Toxicity Category III) routes of exposure. It causes slight eye irritation, and is non

- irritating to the skin, but is a dermal sensitizer.

To xicological endpoints were selected for dietary/drinking water, occupational and residential exposure scenarios. An acute reference dose ( aRfD= 3.0 mg/kg/day) for assessment of food and drinking water exposures was selected from a developmental toxicity stu dy in rats (NOAEL = 300 mg/kg/day). A chronic RfD ( cRfD= 0.097 mg/kg/day) was selected from a chronic toxicity study in dogs (NOAEL = 9.7 mg/kg/day). A short

- term incidental oral POD (NOAEL = 50 mg/kg/day) was selected from a develop mental toxicity study in rats. A point of departure (POD) for dermal exposure was not selected because no dermal or systemic toxicity was seen in rabbits following repeated dermal application at the highest dose tested for 21 days. The short

- and intermediate

- term inhalation expos ure POD (50 mg/kg/day) was selected from a developmental toxicity study in rats

. An uncertainty factor of 100X was applied to endpoints selected for the oral exposure route (10x for interspecies extrapolation, 10x for intraspecies variation) and an
uncerta inty factor of 1000X was applied to endpoints selected for the inhalation exposure route due to a missing route

- specific study (10x for interspecies extrapolation, 10x for intraspecies variation, 10x for database uncertainty factor ).

The qualitative natur e of metolachlor residues in plants is adequately understood. Residues of concern in plants, livestock, and rotational crops include metolachlor and its metabolites, determined as the derivatives CGA

- 37913 and CGA

- 49751. The Agency previously concluded tha t the residues of concern for S

- metolachlor are the same as for metolachlor. The residues of concern for S

- metolachlor in drinking water include the parent, C GA

- 354743 (metolachlor ethanesulfonic acid (ESA)) and CGA

- 51202 (metolachlor oxanilic acid (OA)).

Adequate methodology is available for enforcing the established and recommended tolerances. PAM Vol. II, Pesticide Regulation Section 180.368, lists a gas chromatography with nitrogen

phosphorus detector (GC/NPD) method (Method I) for determining residues in/on plant commodities and a gas chromatography with mass selective detector (GC/MSD) method (Method II) for determining residues in livestock commodities. These methods determine residues of metolachlor and its metabolites as either CGA

- 37913 or CGA

- 497 51 following acid hydrolysis. Adequate data are also available on the recovery of metolachlor through FDA’s Multiresidue Method Testing Protocols which indicate that metolachlor is completely recovered through Method 302.

Adequate field trial data have be en submitted with the current petition to sup port the requested tolerances. Geographi c representation was adequate. An adequate analytical met hod was used for the analysis. The data were properly supported by storage stability data.

An adequate confined r otational crop study is available, although additional information pertaining to the study remains outstanding.S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 6 of 70 For acute and non

- cancer chronic exposures, EPA is concerned when estimated dietary risk exceeds 100% of the population adjusted dose (PAD). Since metolachlor is classified as a Group C carcinogen, no separate dietary assessment was performed for cancer, since the chronic dietary exposure is considered protective for cancer effects

. C onservative acute and chronic dietary exposure analys e s was performed for the general U.S. population and various population subgroups. Tolerance

- level residues and 100 percent crop treated assumptions were used. DEEM default processing factors were used to modify the tolerance values. The acute analysis incorporat ed the 1 in 10 year peak groundwater estimate from application of S

- metolachlor on
cotton while the chronic analysis incorporated the 10 year average surface drinking water estimate from applicatio n of S

- metolachlor to lettuce. T he acute dietary exposure e stimates are below HED’s level of concern. The 95 th percentile acute dietary exposure estimates for the general U.S. population and the highest exposed population subgroup, all infants < 1 year old, are 2.1% and 6.1%, respectively, of the acute population adjusted dose (aPAD). The chronic dietary exposure estimate for the general U.S. population and the highest exposed population subgroup, children 1

- 2 years old, is 6.8% and 3.1% of the c hronic population adjusted dose (cPAD), respectively.

Environmental fate data in dicate that parent metolachlor/S

- metolachlor is moderately persistent to persistent. It is mobile to highly mobile in different soils and has been detected extensively in surf ace water and groundwater. Major degradates identified in groundwater include metolachlor ethanesulfonic acid (ESA) and metolachlor oxanilic acid (OA) in bot h groundwater and surface
water. Following the recent recommendation of the Residues of Concern Kno wledgebase Subcommittee (D424250), parent metolachlor, CGA

- 51202 (metolachlor

- OA), CGA

- 40172, and CGA

- 50720 will be assessed together in the drinking water assessment using a total toxic residues (TTR; USEPA 2009a) approach where half

- lives were recalculat ed (PestDF; USEPA, 2009b) to collectively account for the parent and the combined residues of concern. These values will be utilized in surface and ground water modeling to generate aquatic exposure estimates. The EDWC used in the acute assessment is 1.06 0 ppm. The EDWC used in the chronic assessment is 0.0437 ppm.

There are no proposed residential uses at this time; however, there are existing residential uses that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs 1

a long with policy changes for body weight assumptions. The revision of residential exposures will impact the human health aggregate risk assessment for S

- metolachlor.

Pennant MAGNUM TM (EPA Reg. No. 100

- 950) is labeled for use on commercial (sod farm) and

r esidential warm

- season turf grasses and other non

- crop land including golf courses, sports fields, and ornamental gardens. Even though Pennant MAGNUM TM is not intended for homeowner purchase or use (i.e., used by professional/commercial applicators), a ha ndler and post

- application exposure assessment was still quantified since it is not considered a Restricted Use Pesticide (RUP).

All residential handler exposure quantification resulted in MOEs above the Agency’s LOC of 1,000. Therefore, no risk estimates of concern were identified.

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlS

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 7 of 70 Post

- application potential risk was identified for children 1<2 years old with hand

- to

- mouth oral

e xposure playing on treated turf. The r isk estimate was calculated to be 0.038 mg/kg/day resulting in an MOE of 1,300, which is considered not of concern as it does not exceed the Agency’s level of concern (LOC=100).

No turf transferable data were availab le for this chemical. Since the estimated residential turf post

- application exposure using default turf transferable residue ( TTR ) values for S

- metolachlor is minimal in comparison to the level of concern (i.e., the calculated MOE is greater than 10 times higher than the level of concern, MOE = 1,300 compared to the LOC of 100), EPA is waiving the 40CFR TTR data requirement. In this instance, it is unlikely that chemical

- specific TTR data would be needed to further refine exposure assessments or would add a ppreciably to

our general understanding of the availability of turf transferable pesticide residues.

The aggregate acute and chronic risk estimates include exposure to residues of S

- metolachlor in food and drinking water, and does not include dermal, in halation or incidental oral exposure. Since the dietary exposure assessment already includes the highest acute and chronic exposures from the drinking water modeling data, no further calculations are necessary. The acute and chronic risk estimates for al l populations, resulting from aggregate exposure to S

- metolachlor in food and drinking water are below EPA’s level of concern. The food and drinking water exposure estimates for the most highly exposed subgroup are 6.1 % of the aPAD for all infants (< 1 year old) and 6.8 % of the cPAD for children 1

- 2 years old

. There are no residential user exposures associated with the current petition. However, there is potential for residential aggregate exposure to S

- metolachlor from use of registered products wh ich are applied to residential lawns or turf. Potential short

- term residential aggregate risk scenarios anticipated include adult inhalation handler exposure to turf via backpack sprayer and post

- application incidental oral exposure of children playing on treated lawns. The S hort

- term aggregate MOEs were 10,400 for adults and 1100 for children and, therefore, are not of concern. A second potential short

- term risk results from inhalation exposure from spray drift. Although a very high end exposure assessmen t was conducted, based on exposure to flaggers from aerial application, this exposure was less than the potential incidental oral exposure, so the inhalation exposure will not be aggregated with other exposures. No intermediate

- term risk scenarios are anti cipated for the existing and proposed uses of S

- metolachlor.

The occupational handler exposure and risk estimates indicate that the short

- and intermediate

term inhalation Margin of Exposures (MOEs) are not of concern to HED (i.e., MOE > 1000) at the base line level of personal protection (i.e., no gloves and no respirator). Based on the proposed use sites, it is anticipated that there may be occupational post

- application exposure from activities such as scouting or weeding; however, there is no dermal POD for S

- metolachlor, therefore a quantitative assessment was not conducted. However, there is a 24

- hour Restricted Entry Interval (REI) on the registered label for Dual Magnum® (EPA Reg. No. 100

- 816), which is considered adequate under 40 CFR 156.208 (c) (2) (iii) to protect agricultural workers from post

- application exposures to S

- metolachlor. Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed 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

.S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 8 of 70 2 HED Recommendations

HED has examined the database for S

- metolachlor. Pending submission of analyt ical standards and a revised Section F , there are no residue chemistry issues that would preclude setting of the recommended tolerances for S

- metolachlor, as indicated in Section 2.2.2. A subchronic inhalation study in rats for metolachlor is a data gap. In the absence of this study

, a 10X database uncertainty factor is applied to the inhalation risk assessment as outlined in Section 4.1.

2.1 Data Deficiencies

Analytical reference standards are required to be submitted to the pesticide repository now and as requested by the repository staff. A subchronic inhalation toxicity study in rats for metolachlor is a datagap

. For this action, i n the absence of this study, a 10X database uncertainty factor is applied to the inhalation risk assessment

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methodology is available for enforcing the established and recommended tolerances. PAM Vol. II, Pesticide Regulation Section 180.368, lists a gas chromatography with nitrogen

phosphorus detector (GC/N PD) method (Method I) for determining residues in/on plant commodities and a gas chromatography with mass selective detector (GC/MSD) method (Method II) for determining residues in livestock commodities. These methods determine residues of metolachlor and its metabolites as either CGA

- 37913 or CGA

- 49751 following acid hydrolysis. Adequate data are also available on the recovery of metolachlor through FDA’s Multiresidue Method Testing Protocols which indicate that metolachlor is completely recovered through Method 302.

2.2.2 Recommended Tolerances

Tolerances are currently established under 40 CFR §180.368 for residues of S

- metolachlor, including its metabolites and degradates, in or on the commodity(s), as defined. Compliance with the tolerance levels specified i n the following table below is to be determined by measuring only the sum of free and bound S

- metolachlor, S

- 2

- chloro

- N

- (2

- ethyl

- 6

- methylphenyl)

- N

- (2

- methoxy

- 1

- methylethyl)acetamide, its R

- enantiomer, and its metabolites, determined as the derivatives, 2

- ( 2

- ethyl

- 6

- methylphenyl)amino

- 1

- propanol and 4

- (2

- ethyl

- 6

- methylphenyl)

- 2

- hydroxy

- 5

- methyl

- 3

- morpholinone, calculated as the stoichiometric equivalent of S

- metolachlor, in or on the commodity.

The text of the current tolerance expression is in accordance w ith our current guidance (S. Knizner, 5/10/2009)

Recommended tolerances for S

- metolachlor are summarized in Table 2.2.2 below, along with HED’s recommendations on tolerance level, and commodity names.S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 9 of 70 Table 2.2.2. Tolerance Summary for S

- Metolachlor. Commodity Established/ Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments;

Correct Commodity Definition

Proposed tolerances under §180.368(a)(2)
Lettuce 1.5 1.5 Low growing berry subgroup 13

- 07G, except cranberry 0.40 0.40

Sunflower subgroup 20B 0.50 1.0 Based on existing tolerance for sunflower seed of 0.50 ppm. OECD Tolerance Calculation procedures recommend a tolerance of 1.0 ppm. Vegetable, Cucurbit group 9 0.50 0.50 Vegetable, Fruiting, group 8

- 10, except tabasco pepper, and okra 0.40 0.10 Vegetable, Fruiting, group 8

- 10, except tabasco pepper Existing tolerance of 0.1 ppm is appropriate.

Upon establishment of the above tolerances, the following tolerances established under 180.368(a)(2) for S

- metolachlor and its metabolites on the following commodities should be removed, as the proposed tolerances for the above commodities will adequately cover residues of S

- metolachlor on these commodities.

Vegetable, fruiting, group 8, except tabasco pepper

........................... 0.10 ppm Cu cumber

................................ ................................ ............................ 0.13 ppm Melon subgroup 9A

................................ ................................ ............ 0.10 ppm Pumpkin

................................ ................................ .............................. 0.10 ppm Squash, winter

................................ ................................ ..................... 0.10 ppm Sunflower, seed

................................ ................................ ................... 0.50 ppm Okra.............................................................................0.10 ppm

2.2.3 Revisions to Petitioned

- For Tolerances

The tolerance for Sunflower subgroup 20B is based on existing tolerance f or sunflower seed of 0.50 ppm. However, the OECD Tolerance Calculation procedures rec ommend a tolerance of 1.0
ppm. The existing tolerance for Vegetable, Fruiting, group 8

- 10, except tabasco pepper of 0.1 0 ppm is appropriate. The exclusion of ok ra is not necessary.

2.2.4 International Harmonization

No maximum residue limits (MRLs) for S

- metolachlor have been established or proposed by Codex, so no International Residue Status Sheet is attached. MRLs for S

- metolachlor have been established in Canada and MRLs for metolachlor have been established in Mexico; however, no MRLs have been established in either country for the requested crops.S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 10 of 70 2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

No label changes ar e needed for the proposed uses

. The rotational crop restrictions on the label for EPA Reg. No. 100

- 816 have been evaluated previously (DP#s 332846, etc., 10/21/08, D. McNeilly). It was concluded that the proposed restrictions are supported by the available data, provided that that rotational crop directions for crops with a 60

- day plant back interval ( PBI ) be amended to prohibit a second application of S

- metolachlor to any of these crops replanted within 60 days of the original application. This label amend ment has not been made.

2.3.2 Recommendations from Occupational Assessment

There are no label recommendations based on the proposed uses.

2.3.3 Recommendations f rom Residential Assessment

There are no label recommendations based on the proposed uses.

3 In troduction

3.1 Chemical Identity

The chemical structure and nomenclature of S

- metolachlor and its regulated hydrolytic derivatives are presented in Table 3.1

Table 3.1. Nomenclature of S

- Metolachlor and its Regulated Hydrolytic Derivatives. Parent compound

Common name S

- Metolachlor Company experimental name CGA

- 77102 (R

- Metolachlor is CGA

- 77101)
IUPAC name (S)

- 2

- chloro

- N

- (2

- ethyl

- 6

- methyl

- phenyl)

- N

- (2

- metonym

- 1

- methyl

- ethyl)

- acetamide
CAS name 2

- chloro

- N

- (2

- ethyl

- 6

- methylphenyl)

- N

- [(1S)2

- methoxy

- 1

- methylethyl]

- acetamide CAS registry number 87392

- 12

- 9
End

- use product (EP) Dual Magnum® Herbicide (7.62 lb/gal EC; EPA Reg. No. 100

- 816) and Dual II Magnum® Herbicide (7.64 lb/gal EC; EPA Reg. No. 100

- 818)S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 11 of 70 Table 3.1. Nomenclature of S

- Metolachlor and its Regulated Hydrolytic Derivatives. Regulated residue

Common name None Company experimental names CGA

- 37913 SYN506357 (S

- enantiomer of CGA 37913)
Chemical name 2

- [(2

- ethyl

- 6

- methylphenyl) amino]

- 1

- propanol CAS registry number 61520

- 53

- 4 82508

- 08

- 5 (S

- enantiomer) Regulated residue

Common name None Company experimental names CGA

- 49751 SYN508500 (S

- enantiomer of CGA 49751)
Chemical name 4

- (2

- ethyl

- 6

- methylphenyl)

- 2

- hydroxy

- 5

- methyl

- 3

- morpholinone CAS registry number 61520

- 54

- 5

3.2 Physical/Chemi cal Characteristics

S

- metolachlor is fairly soluble in water (0.48 g/L), and completely miscible with typical pesticide solvents. It has a moderately low vapor pressure ( 2.8 x 10

- 5 mm Hg) . It does not dissociate. It has a high octanol

- water partition coefficient ( Log(K OW ) = 3.0 at 25 C), indicating a potential for bioaccumulation or partitioning in to human milk

. Environmental fate data in dicate that parent metolachlor/S

- metolachlor is modera tely persistent to persistent. It is mobile to highly mobile in different soils and has been detected extensively in surface water and groundwater. Metolachlor/S

- metolachlor degradation appears to be dependent on microbially m ediated and abiotic processes. The physical

- chemical properties are tabulated in Appendix C, Table C1.

3.3 Pesticid e Use P attern

The petitioner provided a text listing of proposed uses in Section B of the petition; these included proposed uses for Dual Magnum® (EPA Reg. No. 100

- 816), a 7.62 lb/gal EC formulation, and Dual II Magnum® (EPA Reg. No. 100

- 818), a 7.64 lb/g al EC formulation.

The proposed uses are presented below in Table 3.S

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Page 12 of 70 Table 3. Summary of Proposed Directions for Use of S

- Metolachlor. 1 Applic. Timing; Type; and Equip. (minimum volume) Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic . per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations
Cucurbits, Group 9
Pre

- plant, Preemergence; Broadcast; Ground or aerial (2 GPA) 7.62 lb/gal EC [100

- 816] 0.64

-

1.27 2 1 1.27 30 Preplant is no more than 14 days before planting. Preemergence application is to be made after planting. Postemergence; Broadcast or to Row Middles; Ground or aerial Postemergence application is to be made to plants with at least 1 true leaf. Low Growing Berry Subgroup 13

- 07G, except Cranberry ( bearberry; bilberry; blueberry (lowbush); cloudberry; lingonberry; muntries; partridgeberry; strawberry (annual and perennial); cultivars, varieties, and/or hybrids of
t hese.

Pre

- plant, Pre

transplant, Postemergence; Broadcast or to row middles; Ground or aerial 7.62 lb/gal EC [100

- 816] 0.64

-

1.27 2 2 2.4 30 Application to be made before transplanting. Pre

- plant Soil incorporation is not recommended, Postmergence treatments can be made post transplant.
Leaf Lettuce

Pre

- plant, Preemergence; Broadcast; Ground or aerial 7.62 lb/gal

[100

- 816] 0.64

- 0.95 2 1.27 25 Preemergence application is to be made after planting.

Postemergence; Broadcast; Ground 7.64 lb/gal EC [100

- 818] 0.64 2 2 1.27 25 The postemergence application may be made to row middles

Lettuce, Head
Pre

- plant, Preemergence; Broadcast; Ground or aerial 7.62 lb/gal

[100

- 816] 0.64

- 0.95 2 1.9 20 Preemergence application is to be made after planting.

Postemergence; Broadcast; Ground 7.64 lb/gal EC [100

- 818] 0. 64

-

0.95 2 2 1.9 20 The postemergence application may be made to row middlesS

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Page 13 of 70 Table 3. Summary of Proposed Directions for Use of S

- Metolachlor. 1 Applic. Timing; Type; and Equip. (minimum volume) Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic . per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations
Fruiting Vegetables

Pre

- plant, Preemergence, Pre

- transplant, Postemergence; Directed spray; Ground (10 GPA) 7.62 lb/gal EC [100

- 816] 0.67

- 1.6 2 1 1.6 60 Pre

- plant and Pre

transplant application should not be incorporated; application may be directed to the soil (or row middle). Crop must be more than 4” tall. Sunflower Group 20B Preplant incorporated, Preemergence; Ground broadcast, or aerial 7.62 lb/gal EC [100

- 816] 1.0

- 1.9 2 1 1.9 100 Do not allow livestock to graze or feed treated

area.

1 NS = Not specified. GPA = Gallons per acre.

2 The lower rates are to be used on soils that are relatively coarse textured and the higher rates are to be used on fine

- textured soils.

3 Muck soils defined as soils with >20% organic matter.

All proposed uses specify that lower rates should be used on relatively coarse textured soils and higher rates should be used on fine textured soils. If crops are grown on plastic mulch, the Dual Magnum pre

- emergence application should be m ade before laying the plastic. Dual Magnum may also be applied as a row mi ddle application after th e laying of the plastic mulch. For all crops with postemergence uses, it is stated that use of an adjuvant may increase risk to the crop.

Minimum gallons/A and Plantback restrictions for the proposed uses were not included in Sect ion B.

The following crop rotation restrictions are specified on accepted labels for EPA Reg. No. 100

- 816:

 a 0

- day plantback interval (PBI) for any crop on the Dual Magnum label, or on a supplemental Dual Magnum label, provided that the rate of Dual Magnum applied to the previous crop was not greater than the labeled rate for the crop to be replanted;

 a 4

- month PBI for alfalfa (provided no more than 1.9 lb ai/A was applied to the previous crop);

 a 41⁄2

- month PBI for barley, oats, rye, and wheat;

 a 9

- mon th PBI for clover (provided no more than 1.9 lb ai/A was applied to the previous crop);

 a 60

- day PBI for the crops and/or crop groups listed in the table below, depending on the amount of S

- metolachlor applied to the previous crop;

 tobacco, buckwheat, and rice may be planted the next spring;

 a 12

- month PBI for all other food or feed crops.S

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Page 14 of 70 Crops/crop groups allowed for rotation 60 days after application of S

- metolachlor. Crop group/subgroup/crop Amount of S

- metolachlor previously applied to field 1
≤1.3 lb ai/A ≤1.6 lb ai/A ≤1.9 lb ai/A Root vegetables (subgroup 1B) yes no no Bulb vegetables (group 3), green plants yes no no Winter squash, including pumpkins yes no no Fruiting vegetables, except cucurbits (group 8) yes yes no Tuberous and corm vegetables (subgroup 1C) yes yes yes Bulb vegetables (group 3), dry bulbs yes yes yes Leaf petiole vegetables (subgroup 4B) yes yes yes Head and stem Brassica vegetables (subgroup 5A) yes yes yes
1 If the rate of S

- metolachlor applied to the previous crop was greater than the rate listed here, crops from the various groups cannot be planted until the following spring.

Conclusions . The proposed use directions are adequate to allow for evaluation of the submitted residue data relative to the proposed uses.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the
pro posed new uses and crop group expansions

. Humans may be exposed to S

- metolachlor in food and drinking water since S

- metolachlor may be applied directly to growing crops and S

metolachlor may reach surface and ground wa ter sources of drinking water. The d ie tary exposure analyses have been updated . Although no residential application scenarios exist, children may be exposed to S

- metolachlor after professional application on residential turf. In an occupational setting, applicators may be exposed while handli ng the pesticide prior to application, as well as during application. There is a potential for post

- application exposure for worke rs re

- entering treated fields. Risk assessments have been previously prepared for the existing uses of S

metolachlor. This ris k assessment considers the new uses and all of the aforementioned exposure pathways based on the existing uses of S

- metolachlor.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates ri sks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption pa tterns are compiled by the U.S. Department ofS

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Page 15 of 70 Agriculture’s (USDA’s) National Health and Nutrition Examination Survey / What We Eat in America, (NHANES/WWEIA)

, 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 gro up, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when condit ions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluate d. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary pat terns among specific subgroups.

4 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studi es Availa ble for Analysis

The existing toxicological database is comprised primarily of studies conducted with metolachlor. The toxicology database for S

- metolachlor consists of bridging data, which include an acute toxicity battery, subchronic toxicity studies in rats and dogs, developmental toxicity studies in rats and rabbits, a mutagenicity battery, metabolism studies and an immunotoxicity study. Base d on a comparison of findings in the two databases by HED’s Hazard Identification Assessment Review Committee (HIARC) as well as the Metabolism Assessment Review Committee (MARC) (Dobozy, 2001), both in 2001, it was concluded that S

- metolachlor is of
compa rable toxicity to the racemic mixture, metolachlor, and that studies with both chemicals can be used interchangeably for toxicology endpoint selection. The combined metolachlor and S

metolachlor toxicity data bases are adequate to characterize the toxicity of S

- metolachlor for risk assessment purposes , with the exception of a required subchronic inhalation study for metolachlor

.

The Hazard and Science Policy Council ( HASPOC ) recently reviewed metolachlor and S

metolachlor (VanAlstine, Julie, 2013). The HASPOC, based on a WOE approach, concluded that a neurotoxicity battery is not required for metolachlor at this time. This approach considered all of the available hazard and exposure information including: 1) the lack of evidence for clinical signs of neurotoxicity or neuropathology in adult animals in subchronic and chronic studies; 2) clinical signs of neurotoxicity were seen only at very high doses (Limit Dose) in pregnant rats and is used as the endpoint of concern for assessing acute dietary risk; 3) evidence for neurotoxicity (functional/behavioral effects) was seen only at high doses in acute neurotoxicity studies with structurally

- related compounds (acetochlor and propachlor) and in a subchronic neurotoxicity study with acetochlor; 4) the POD an d endpoint for chronic dietary risk assessment is based on effects seen in dogs which appear to be the more sensitive species; and 5) since the neurotoxicity studies will be tested at very high doses to elicit effects, they will not provide PODs lower than those currently used for overall risk assessment (TXR No. 0056586). The HASPOC also concluded that a subchronic inhalation study with metolachlor is required at this time. A 10X data base uncertainty factor will be applied only for assessing risk for inh alation scenarios.S

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Page 16 of 70 T he following studies are available for metolachlor :

 Acute Toxicity Battery

 90

- Day Oral Toxicity in the Rat

 90

- Day Oral Toxicity in the Dog

 21

- Day Dermal Toxicity in the Rabbit

 Prenatal Developmental Toxicity in the Rat

 Prenatal Developmental Toxicity in the Rabbit

 Reproduction and Fertility Effects in the Rat

 Chronic Toxicity in the Dog

 Chronic Toxicity

/Carcinogen i city in the Rat

 Carcinogenicity in the Mouse

 Genetic Toxicology Battery

 Metabolism and Pharmacokinetics in the Rat

T he following bridging studies are available for S

- Metolachlor:

 Acute Toxicity Battery

 90

- Day Oral Toxicity in the Rat

 90

- Day Oral Toxicity in the Dog

 Prenatal Developmental Toxicity in the Rat

 Prenatal Developmental Toxicity in the Rabbit

 Genetic Toxicolo gy Battery

 Metabolism and Pharmacokinetics in the Rat

 Immunotoxicity in Mice

4.2 Absorption, Distribution, Meta bolism, & El imination (ADME)

Metolachlor is extensively absorbed and metabolized following oral administration in the rat. After oral or intravenous administration of metolachlor, between 69.6% and 93.2% of the administered dose was absorbed. A biphasic plasma profile showed two concentration maxima (C max ); a fast rising first C max , which was reached at 0.25

- 1 hour post dosing

, which wa s succeeded by a second C max at 8 and at 12

- 24 hours following administ ration of the low and high dose. Eliminati on is via the urine and feces. R esidual radioactivity at 7 days post dose were found in carcass (0.9

- 2.2% of the administered dose) and red blood cells (0.95

- 1.53 μg equivalents/gram in blood cells for all low dose male and female rats). There was no apparent accumulation of residual radioactivity.

Excretion data showed that urine and feces were both significant routes for elimination of metolachlor derived radioactivity. In the low dose groups, the urine appeared more of a predominant route for excretion in female rats than in males, whereas fecal excretion was slightly higher in males. However, at the high oral dose, there were no appar ent sex related differences in the pattern of urinary excretion. Examination of urinary excretion data indicated that at the 1 00 mg/kg dose, excretion was delayed vs the low oral dose, suggesting saturation of elimination.S

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Page 17 of 70 The major metabolic pathway pro posed from analysis of urinary as well as fecal metabolites is one of cleavage of the ether bond and subsequent oxidation to the carboxylic acid, as well as hydrolytic removal of the chlorine atom. Conjugation of metolachlor or metabolites with gluronic ac id or sulfate does not appear to occur.

4.2.1 Derm al Absorption

There was no evidence of systemic tox icity at the limit dose in a 21

- day dermal toxicity metolachlor study in rabbits, however

, dermal irritation was observed at lower doses. A dermal absorption study is not needed.

4.3 Toxicolo gical Effects

In subchronic (metolachlor and S

- metolachlor) and chronic (metolachlor) toxicity studies in dogs , rats and mice decreased body weight and body weight gain were the most commonly observed effects. There was no evidence of immunotoxicity in mice with S

- Metolachlor. There was no evidence of systemic toxicity at the limit dose in a 21

- day dermal toxicity metolachlor study in rabbits, however, dermal irritation was observed at lower doses. No neurotoxic ity studies with metolachlor or S

- metolachlor are available , nor are they required

. There was no evidence of a mutagenic or cytogenetic effect in vivo or in vitro in studies with either metolachlor or S

- metolachlor. Metolachlor has been classified as a G roup C carcinogen based on liver tumors in female rats w ith risk quantitated using a non

- linear (Margin of Exposure (MOE)) approach (TXR No. 0011347, 1994)

. There was no evidence of increased quantitative or qualitative fetal susceptibility in the prena tal developmental studies in rats and rabbits with either metolachlor or S

- metolachlor. In general, significant developmental toxicity was not seen in rats or rabbits with either compound. In the metolachlor rabbit prenatal developmental toxicity study, ma ternal animals had persistent anorexia a nd decreased body weight gain. There were no developmental effects. In the rat prenatal developmental toxicity study on metolachlor, death, clinical signs (clonic and/or tonic convulsions, excessive salivation, urine

- stained abdominal fur and/or excessive salivation) and decreased body weight gain was observed at the limit dose in maternal animals. Developmental effects at the limit dose included slightly decreased number of implantations per dam, decreased number of live fetuses/dam, increased number of resorptions/dam and significant decre ase in mean fetal body weight. In the S

- metolachlor rat developmental toxicity study, maternal toxicity, including increased clinical signs (pushing head through bedding), and decre ased body weight/weight gain, food consumption and food efficiency, was observed at the mid

- dose of 500 mg/kg/day

. There were no developmental effects at the highest dose tested. In the rabbit, clinical signs of toxicity (little/non/soft stool) were observ ed at the mid

- dose in maternal anim als tested with S

- metolachlor. No developmental effects were observed at the highest dose tested.

In the two

- generation reproduction study in rats conducted with metolachlor, there was no evidence of parental or reprod uctive toxicity at the highe st dose tested (~80 mg/kg/day). At this dose, there was a minor decrease in fetal body weight beginning at lactation day 4. Since aS

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Page 18 of 70 similar body weight decrease was not seen on lactation day 0, the cause of the effect on later l actation days is most likely due to exposure of the pups to metolachlor in the diet and/or milk and

, therefore

, is not evidence of an increased quantitative susceptibility in post

- natal animals. S

- Metolachlor exhibits low acute toxicity via the oral (Tox icity Category III), inhalation (Toxicity Category IV), and dermal (Toxicity Category III) routes of exposure. It causes slight eye irritation, and is non

- irritating to the skin, but is a dermal sensitizer.

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

The FQPA Safety Factor (SF) is 1X. The toxicity database for S

- metolachlor/metolachlor is sufficient for a full hazard evaluation and is considered adequate to evaluate risks to infants and children. Acceptable developmental toxicity studies in the rat and rabbit and an acceptable

re production study in the rat are available with clearly defined LOAELs and NOAELs. Based on the results of the available toxicity studies, there i s no evidence for neurotoxicity.

4.4.1 Completen ess of the Toxicology Database

The toxicology database for metolac hlor and S

- metolachlor is complete

, with the exception of a required subchronic inhalation study for metolachlor

.

The Hazard and Science Policy Council ( HASPOC ) recently reviewed metolachlor and S

metolachlor ( TXR No. 0056586 ). HASPOC , based on a WOE ap proach considering all available hazard and exposure information conclude d that the acute, subchronic, and developmental neurotoxicity studies are not required at this time. The HASPOC concluded that a subchronic inhalation study with metolac hlor is requir ed at this time. A 10X data base uncertainty factor (UF DB ) will be applied only for assessing risk for inhalation exposure scenarios.

4.4.2 Evi dence of Neurotoxicity

There are no acute or subchronic neurotoxicity studies available for S

- metolachlor or metolach lor. In the developmental rat study, c linical signs of neurotoxicity, including clonic and/or tonic convulsions, excessive salivation, urine

- stained abdominal fur and/or excessive l acrimation were observed in pregnant dams but only at the limit dose of 1000 mg/kg/day. There was no evidence of neurotoxic effects in adult animals in available subchronic or chronic toxicity studies. The HASPOC, based on a WOE approach, concluded that a neurotoxicity battery is not required for metolachlor at this time ( TXR No. 0056586)

.

4.4.3 Evidence of Sensitivity/Suscep tibility in the Developing o r Young Animal

There was no evidence of increased quantitative or qualitative fetal susceptibility in the prenatal developmental studies in rats and rabbits or in the reproductive toxicity study in rats, with either metolachlor or S

- metolachlor. In general, significant developmental toxicity was not seen in rats or rabbits with either compound. The only effects observed in fetal animals were in the rat prenatal developmental study a nd included slightly decreased number of implantations per dam,S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 19 of 70 decreased number of live fetuses/dam, increased number of resorptions/dam and significant decrease in mean fetal body weight. T hese effects occurred at maternally toxic doses (1000 mg/kg/day).

4.4.4 Residual Uncertainty in the Expos ure Datab ase

There is no residual uncerta inty in the exposure database. The dietary exposure assessment is conservative, based on tolerance level residues and 100% crop treated. The residential exposure assessment is based on the Residential SOPs, which are designed to produce conservative exposure estimates.

4.5 Toxicity Endpoint an d Point of Departure Selections

4.5.1 Dose

- Response Assessment

The detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in the appendix. The specific toxicity endpoints and PODs are presented in Tables 4.5.4.1 and 4.5.4. 2. Toxicological endpoints were selected for dietary/drinking water, occupational and residential exposure scenarios. An acute reference dose (RfD; 3.0 mg/kg/day) for assessment of food and drinking water exposures was selected from a developmental toxicit y study in rats with metolachlor (NOAEL = 300 mg/kg/day). The endpoint of mortality and clinical signs identified in the developmental toxicity study in rats (MRID 00151941) was chosen for the acute dietary (general population) endpoint because it was cons idered adverse and results from a single exposure. An endpoint was not selected for Females 13

– 49 years old because no developmental effects were identified in the metolachlor/S

- metolachlor database that could be attributed to a single exposure. A chronic RfD (0.097 mg/kg/day) was selected from a chronic toxicity study in dogs with metolachlor (NOAEL = 9.7 mg/kg/day). The endpoint of decreased body weight gain identified in the chronic feeding study in dogs was chosen for the chronic dietary (all populations) endpoint because the duration of the exposure in this study is appropriate for a chronic dietary endpoint, and t he dog study provides the lowest NOAEL in the database. T he database shows dogs were the more sensitive species and decreased body weight gain the most sensitive endpoint.

The registered uses of S

- metolachlor/metolachlor are expected to result in residen tial exposure via incidental oral exposure for toddlers. A short

- term incidental oral POD (NOAEL = 50 mg/kg/day) was selected from a developmental toxicity study with S

- metolachlor in rats (MRID 43928925)

. This endpoint was based on increased incidence of clinical signs and decreased body weight/body weight gain

. This study was selected because the effects were judged to be signs o f frank toxicity and were approp riate to use for risk assessment. The NOAEL of 20 mg/kg/day for the prenatal developmental toxi city study in rabbits with S

- metolachlor (MRID 43928924) was lower than the 50 mg/kg/day from the rat developmental study, however, the endpoint was based on weak clinical signs of toxicity (increase in little/none/soft stool observations) at 100 mg/kg/day . Although there was a dose

- related increase in this effect, it was not considered to be evidence of frank toxicity and was judged not to be appropriate for risk assessment.S

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Page 20 of 70 A point of departure (POD) for dermal exposure for both occupational and residen tial scenarios was not selected because no systemic toxicity was seen in rabbits following repeated dermal application of metolachlor at the highest dose tested for 21 days. No inhalation studies were available for the short

- term and intermediate

- term occu pational inhalation scenarios. The HASPOC met on February 14, 2013 to discuss the need for a subchronic inhalation study for metolachlor (TXR #0056586). The decision was made that this study is required. In the absence of a route

- specific study and based on the current updated HED policies , a short

- and intermediate

- term inhalation exposure POD of 50 mg/kg/day was selected from an oral developmental toxicity study in rats with S

- metolachlor . The endpoint of increased incidence of clinical signs and decreased body weight/body weight gain from the developmental toxicity study in rats (MRID 43928925) was identified for the short

- and intermediate ter m inhalation exposure endpoint s

. This study was selected because the effects were judged to be signs o f frank toxicity and the duration s of exposure w ere a ppropriate. (The previous intermediate

- term inhalation POD of 9.7 mg/kg/day from a subchronic dog study was considered overly conservative and the current endpoint is protective of both short

- and interm ediate term
exposures .) An uncertainty factor of 100X was applied to endpoints selected for the oral exposure route (10x for interspecies extrapolation, 10x for intraspecies variat ion) and an uncertainty factor of 1000X was applied to endpoints selected fo r the inhalation exposure route due to a missing route

- specific study (10x for interspecies extrapolation, 10x for intraspecies variation, 10x for database uncertainty factor for the missing study ).

4.5.2 Recommendation for Combining Routes of Exposures for Ris k Assessment

Dietary and drinking water exposure are combined in the dietary exposure assessment. Children’s incidental oral hand

- to

- mouth exposure and adult handler exposure via inhalation will be combined with dietar y and drinking water exposure. The dermal route of exposure will not be combined with other routes of exposure for S

- metolachlor, since there was no systemic toxicity seen at the limit dose in dermal toxicity studies.

4.5.3 Cancer Classification and Risk Assessment Recommendation

There was no evidence of carcinogenicity in mice; however, there were statistically significant increases in liver adenomas and combined adenomas/carcinomas in female rats. In male rats, there was a statistically significant trend but no pair

- wise signific ance for liver tumors. There was no evidence of a mutagenic or cytogenetic effect in vivo or in vitro in studies with either metolachlor or S

- metolachlor. Metolachlor has been classified as a Group C, possible human carcinogen, based on liver tumors in ra ts at the highest dose tested. Q uantification of risk using a

non

- linear approach (i.e., reference dose (RfD)) will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to metolachlor.S

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Page 21 of 70 4.5.4 Summary of Poin ts of Departure and Toxicity Endpoints Used in Human Risk Assessment

The points of departure, uncertainty factors, and toxicity endpoints are presented in the following tables. No endpoint is selected for dermal exposure scenarios. No hazard was identif ied at the maximum dermal dose tested.

Table 4.5.4.1. Summary of Toxicological Endpoints for S

- M etolachlor for Use in Dietary Human Health Risk Assessments

Exposure/Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD,

LOC for Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population) NOAEL =

300 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Acute RfD = 3.0

mg/kg/day aPAD = 3.0 mg/kg/day Developmental Toxicity Study

- Rat

Metolachlor (MRID 00151941) LOAEL = 1000 mg/kg/day based increased incidence of death, clinical signs (clonic and/or tonic convulsions, excessive salivation, urine

- stained abdominal fur and/or excessive lacrimation) and decreased body weight gain.

Chronic Dietary (All Populations) NOAEL =

9.7 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Chronic RfD =

0.097 mg/kg/day cPAD = 0.097mg/kg/day One Year Chronic Toxicity

– Dog;

Metolachlor (MRIDs 40980701, 41164501, 42218601 and 42218602) LOAEL = 33 mg/kg/day based decreased body wei ght gain in females
Cancer (all routes) Metolachlor has been classified as a Group C carcinogen with risk quantitated using a non

linear (Margin of Exposure) approach. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (i ntraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.S

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Page 22 of 70 Table 4.5.4.2 . Summary of Toxicological Doses and Endpoints for S

- MET OLACHLOR for Use in Residential and Occupational Human Health Risk Assessments
Exposure/ Scenario Point of

Departure Uncertainty

Factors Level of

Concern for Risk Assessment Study and Toxicological Effects

Incidental Oral Short

term (1

- 30 days) NOAEL=

50 mg/kg/day UF A = 10x

UF H =10x Residential LOC

for MOE = 100 Developmental Toxicity Study

- Rat

S

- Metolachlor (MRID 43928925) LOAEL = 500 mg/kg/day based on increased incidence of clinical signs, decreased body weight/body weight gain, food consumption and food efficiency seen in maternal animals.

Dermal Short

- and Intermediate

- Term No hazard identified

. 21

- day dermal toxicity study

– Rabbits Metolachlor (MRID 41833101) Systemic LOAEL = Not observed
S ystemic NOAEL = 1000 mg/kg/day.

Inhalation Short

- Term (1

- 30 days) and Intermediate

- Term (1

- 6 months) NOAEL=

50 mg/kg/day UF A = 10x

UF H =10x UF D =10x Occupational

LOC for MOE = 1000 Developmental Toxicity Study

- Rat

S

- Metolachlor (MRID 43928925) LOAEL = 500 mg/kg/day based on increased incidence of clinic al signs, decreased body weight/body weight gain, food consumption and food efficiency seen at the LOAEL in maternal animals. Cancer (all routes) Metolachlor has been classified as a Group C carcinogen with risk quantitated using a non

linear (Margin of Exposure) approach. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to m ark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation fr om animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to acco unt for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 23 of 70 5 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The qualitative nature of metolachlor residues in plants and livestock is adequately understood, based on adequate corn, potato, an d soybean metabolism studies, ruminants, poultry, and rotational crops

. Residues of concern in plants, livestock, and rotational crops include metolachlor and its metabolites, determined as the derivatives CGA

- 37913 and CGA

- 49751. The Agency previously co ncluded that the residues of concern for S

- metolachlor are the same as for metolachlor. Metolachlor is metabolized extensively in both plants and livestock. The residues of concern for S

- metolachlor in drinking water include the parent, CGA

- 354743 ( metolac hlor ethanesulfonic acid (ESA)) and CGA

- 51202 ( metolachlor oxanilic acid (OA))

.

5.1.2 Summary of Environmental Degradation

Environmental fate data in dicate that parent metolachlor/S

- metolachlor is moderately persistent to persistent. It is mobile to highly mo bile in different soils and has been detected extensively in surface water and groundwater. Metolachlor/S

- metolachlor degradation appears to be dependent

on microb i al mediated and abiotic processes. Major degradates identified in groundwater include metola chlor ESA and metolachlor OA in bot h groundwater and surface water. D epending on the soil (i.e. organi c matter content), metolachlor/S

- metolachlor has the potential to range from a moderately mobil e to a highly mobile material. The Environmental Fate and E ffects Division (EFED) concluded there is no difference in soil sorption affinity between metolachlor and S

metolachlor. Available data suggest that metolachlor and S

- metolachlor are expected to be highly mobile to mobile in soil and water environments.

5.1.3 Comparison of Metabolic Pathways

Metolachlor and S

- metolachlor are extensively metabolized in plants, livestock animals and rats. Side by side metabolism was studied only with a single oral dose in rats; no comparative studies were conducted with a high dose or repeated doses. The metabolism of metolachlor in plants involves conjugation with glutathione, breakage of this bond to form the mercaptan, conjugation of the mercaptan with glucuronic acid, O

- demethylation of the methyl ether, and conjugation of the resultant alcohol with a neutral sugar. A minor pathway may involve sugar conjugation of metolachlor directly to the corresponding oxo

- compounds. Most of the metabolites of metolachlor and S

- metolachlor have not been identified.

Metolachlor is rapid ly metabolized and almost totally eliminated in the urine and feces of ruminants (goats), non

- ruminants (rats), and poultry. There were some minor sex differences in the elimination pattern in rats. Metolachlor per se was not detected in any of the excreta or tissues. Metolachlor and S

- metolachlor were readily absorbed and extensively metabolized by goats via glutathione conjugation and/or oxidation reactions. Oxidized metabolites were also conjugated with glucuronic a cid. Metolachlor and S

- metolachlor were extensively metabolizedS

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 24 of 70 in poultry via O

- demethylation and subsequent glucuronic acid conjugation or oxidation to dihydroxy or carboxylic acid metabolites that may also be conjugated with glucuronic acid. As in plant s, metolachlor residues of concern in livestock commodities include metolachlor and its metabolites, determined as the derivatives CGA

- 37913 and CGA

- 49751.

5.1.4 Residues of Concern Summary and Rationale

The metabolism of metolachlor and S

- metolachlor has been reviewed by the Metabolism Assessment Review Committee (MARC) on August 14, 2001 (Dobozy, V, 2001). The MARC determined that, although both metolachlor ethanesulfonic acid (ESA) (CGA

- 354743) and metolachlor oxanilic acid (OA) (CGA

- 51202) appear to be less toxic than the parent metolachlor and S

- metolachlor, both should be determined in the drinking water risk assessment since these metabolites were found in greater abundance than the parent in water monitoring studies. The summary of metabolites and degrad ates is provided below.

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 Metolachlor and metabolites determined as the derivatives CGA

- 37913 and CGA

- 49751. Metolachlor and metabolites determined as the derivatives CGA

- 37913 and CGA

- 49751.

Rotational Crop Metolachlor and metabolites determined as the derivatives CGA

- 37913 and CGA

- 49751. Metolachlor and metabolites determined as the derivatives CGA

- 37913 and CGA

- 49751.

Livestock Ruminant Metolachlor and metabolites determined as the derivatives CGA

- 37913 and CGA

- 49751. Metolachlor and metabolites determined as the derivatives CGA

- 37913 and CGA

- 49751.

Poultry Metolachlor and metabolites determined as the derivatives CGA

- 37913 and CGA

- 49751. Metolachlor and metabolites determined as the derivatives CGA

- 37913 and CGA

- 49751.

Drinking Water parent metolachlor, metolachlor

- OA, CGA40172, and CGA

- 50720 Not Applicable

5.2 Food Residue Profile

The qualitative nature of metolachlor residues in plants and livestock is adequately understood, based on adequate corn, potato, and soybean metabolism studies, ruminants, poultry, and rotational crops . Residues of concern in plants, livestock, and rotational crops include metolachlor and its metabolites, determined as the derivatives CGA

- 37913 and CGA

- 49751.

The petitioner submitted field trial data in suppor t of the proposed uses on lettuce, low growing berry subgroup 13

- 07G, except cranberry (strawberry); vegetable, cucurbit, group 9 (cantaloupe,S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 25 of 70 summer squash and previously submitted data on cucumber); vegetable, fruiting, group 8

- 10; except tabasco pepper (updating crop group, based on previously submitted data on tomato and pepper); and sunflower subgroup 20B (previously submitted data on sunflower) . The petitioner is relying on existing data on cucumber to partially support the proposed use on cucurbits, and existing data on sunflower to support the use on the sunflower subgroup 20B. The proposed use on fruiting vegetables is to update the crop group. The bell pepper, hot pepper, and tomato field trial data are adequate and support the use of S

- metolachl or (EC) as either a single preplant incorporated or post

- emergent foliar application prior to fruit set to fruiting vegetables at ~1.70 lb ai/A. The data support a 60

- day PHI. The residue data are adequate to support a tolerance of 0.1 ppm S

- metolachlor on fruiting vegetables, group 8

- 10, excl uding tabasco pepper. The exclusion of tabasco is acceptable because these crops have different use patterns and have separate tolerances. The number and geographic representation of the pepper and tomato field trials are in accordance with those specified in OPPTS Series 860 Guidelines, Section 1500. The submitted data support a single postemergence foliar application of S

- metolachlor to cucumber at up to 1.3 lb ai/A, provided that application is only made to cucumber up to the 2

- leaf growth stage. The submitted data will support a tolerance for S

- metolachlor residues in/on cucumber of 0.13 ppm, expressed as metolachlor equivalents. Samples were stored frozen from collection to analysis for up to 10 months, an interv al supporte d by available stability data. The submitted field trial data are tentatively adequate to support the proposed uses on low growing berry subgroup 13

- 07G, except cranberry, based on field trial data for the representative commodity, strawberry.

The field trial data were properly supported by analytical validation data and storage stability data. No processing data are needed to support the current tolerance request s

. Although the new tolerance represents a large increase in the dietary burden of S

- metolachlor and metolachlor to beef cattle, the current tolerance for beef commodities is based on a higher dietary burden for S

- metolachlor an d metolachlor to dairy cattle. The dietary burden for metolachlor and S

- metolachlor for dairy cattle did not c hange as a result of the current petition, and no increase is needed in the tolerances in livestock commodities.

5.3 Water Residue Profile

D 420047 , C. Koper, 12/16/14

Following the recent recommendation of the Residues of Concern Knowledgebase Subcommittee (D424250), parent metolachlor, CGA

- 51202 (metolachlor

- OA), CGA

- 40172, and CGA

- 50720 will be assessed together in the drinking water assessment using a total toxic

res idues (TTR; USEPA 2009a) approach where half

- lives were recalculated (PestDF; USEPA, 2009b) to collectively account for the parent and the combined residues of concern. These values will be utilized in surface and ground water modeling to generate aquatic exposure estimates.

The highest annual application rate for the proposed IR

- 4 label (3.7 lbs a.i./A; note that sunflower maximum annual application rate is unspecified) is less than what EFED believes is the highest previously registered application ra tes (4 lbs a.i./A to corn or cotton). Therefore,S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 26 of 70 EFED is providing new EDWCs based on the scenario/annual application rate combination that will produce the highest EDWCs because degradates of concern and the calculation method have changed. Recommended E DWCs of S

- metolachlor in surface water and ground water are reported in Table 5.3.

Table 5.3

. Recommended EDWCs for S

- Metolachlor Use on Various Crops

Drinking Water Source Crop Scenario 1

- in

- 10 year acute ( μg/L ) 1

- in

- 10 year

chronic ( μg/L ) 30

- year average

cancer chronic ( μg/L ) Surface Water MS Corn 1 (aerial) 371

-- --

CA Lettuce 2 (aerial)

-- 43.70 * 21.80
Ground Water NC Cotton 3 (aerial) 1060 * NA

--

WI Corn 3 (aerial)

-- NA 978

1 EDWC calculated from the maximum rate (2 apps x 2.0 lbs a.i./A) registered on corn and cotton generated using SWCC model (aerial application; TTR approach) with a PCA factor of 0.91.

2 Current proposed use on lettuce (2 apps x 0.95 lbs a.i./A x 2 season s).
3 Highest EDWCs generated using PRZM

- GW model based on a 30 year simulation of 2 foliar applications of 2.0 lbs a.i./A for a maximum annual rate of 4.0 lbs a.i/A for corn/cotton (Metolachlor RED; D185152, 172022 )

. *Bolded EDWCs were used in the dietary exposure analyses.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute and chronic dietary exposure analyses assumed tolerance level residues.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary exposure analyses assumed 100% crop treated (CT).

5.4.3 Acute Dietary Risk Assessment

A conservative acute dietary exposure analysis was performed for the general U.S. population and various population subgroups. Tolerance

- level residues and 1 00 percent crop treated assumptions were used. DEEM default processing factors were used to modify the tolerance values. The acute analysis incorporated the 1 in 10 year peak ground water estimate f rom application of S

- metolachlor on cotton

. This assessme nt concludes that, for all supported commodities, the acute dietary exposure estimates are below HED’s level of concern. The 95 th percentile acute dietary exposure estimate s for the general U.S. population and the highest exposed population subgroup, all infants < 1 year old, are 2.1% and 6.1 % , respectively, of the acute population adjusted dose (aPAD).S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 27 of 70 5.4.4 Chronic Dietary Risk Assessment

A conservative chronic dietary exposure analysis was performed for the general U.S. population and various population subgroups. Tolerance

- level residues and 100 percent crop treated assumptions were used. DEEM default processing factors were used to modify the tolerance values. The chronic analysis incorporated the 10 yea r average surface drinking water estimate from application of S

- metolachlor to lettuce

. The chronic dietary exposure estimate for the general U.S. population and the highest exposed population subgroup, children 1

- 2 year s old, is 6.8 % and 3.1% of the chron ic population adjusted dose (cPAD) , respectively

.

5.4.5 Cancer Dietary Risk Assessment

Metolachlor has been classified as a Group C, possible human carcinogen, based on liver tumors in rats at the highest dose tested. A linear risk assessment is not required. The chronic RfD is protective of any potential cancer effect.

5.4.6 Summary Table

Table 5.4.6 Summary of Dietary Food and Drinking Water Exposure and Risk for S

- metolachlor and Metolachlor

.

Population Subgroup Acute Dietary ( 95th Percentile) Chronic Dietary
Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD*

General U.S. Population 0.061369 2.1 0.003008 3.1 All Infants (<1 year old) 0.184 165 6.1 0.005652 5.8
Children 1

- 2 years old 0.096061 3.2 0.006 557 6. 8
Children 3

- 5 years old 0.077899 2.6 0.005513 5.7
Children 6

- 12 years old 0.059378 2.0 0.003690 3.8
Youth 13

- 19 years old 0.049953 1.7 0.002407 2.5
Adults 20

- 49 years old 0.059238 2.0 0.002687 2.8
Adults 50

- 99 years old 0.053503 1.8 0.00 2644 2.7
Females 13

- 49 years old 0.059990 2.0 0.00 2687 2.8 *The subpopulation(s) with the highest risk estimates are bolded.

6 Residential (Non

- Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure/Risk Estimates

Pennant MAGNUM TM (EPA Reg. No. 100

- 950) is labeled for use on commercial (sod farm) and residential warm

- season turf grasses and other non

- crop land including golf courses, sports fields, and ornamental gardens. Even though Pennant MAGNUM TM is not intended forS

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 28 of 70 homeowner purchase or use (i.e., used by professional/commercial applicators), a handler exposure assessment was still quantified since it is not considered a Restricted Use Pesticide (RUP).

HED uses the term “handlers” to describe those individuals who are involve d in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handlers are addressed somewhat differently by HED as homeowners a re assumed to complete all elements of an application without use of any protective equipment.

The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:

 Mixing/loading/applying gardens/trees with manually

- pressurized handwand, hose

- end sprayer, backpack, and sprinkler can equipment; and

 Mixing/loading/applying lawns/turf with manually

- pressurized handwand, hose

- end sprayer, backpack, and sprinkler can equipment.

Residential Handler Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. Each assumption and factor is detailed below.

Application Rate: Based on registered residential uses the maximum application rate for handlers is of 2.6 pts/A. With 7.62 lb S

- metolachlor/gallon of product the maximum application rate can be calculated to be 0.000056 lb ai/sq. ft. or 2.47 lb ai/A. Additionally, the l abel states to use a minimum of 10 gallons of spray mixture per acre or 0.24 lb ai/gallon.

Unit Exposures and Area Treated or Amount Handled: Unit exposure values and estimates for area treated or amount handled were taken from HED’s 2012 Residential S OPs 2

.
Exposure Duration: Residential handler exposure is expected to be short

- term in duration. Intermediate

- term exposures are not likely because of the intermittent nature of applications by homeowners.

Residential Handler Non

- Cancer Exposure and Ri sk Estimate Equations The algorithms used to estimate exposure and dose for residential handlers can be found in Appendix A and/or the 2012 Residential SOPs 3

. Summary of Residential Handler Non

- Cancer Exposure and Risk Estimates All residential handler ex posure quantification resulted in MOEs above the Agency’s LOC of 1,000. Therefore, no risk estimates of concern were identified. Results from this assessment have been used to assess aggregate risk from exposure to food, drinking water, and residential l awns.

2 Available: http://ww w.epa.gov/pesticides/science/residential

- exposure

- sop.html

3 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlS

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Page 29 of 70 Table 6.1.1. Residential Handler Non

- cancer Exposure and Risk Estimates for S

- metolachlor.

Exposure Scenario Application

Equipment/ Method Maximum

Application Rate 1 Area

Treated or Amount Handled Daily 2 Inhalation

Unit Exposure (mg/lb ai) Inhalation

Absorbed Dose 3 (mg/kg/day) Inhalation

MOE 4 LOC=1,000

Mixer/Loader/Applicator

Gardens / Trees Manually

pressurized handwand 0.000056

lb ai/ft2 1200 ft2 0.018 0.000015 3,300,000

Hose

- end Sprayer/ Sprinkler can 0.0014 0.0000012 43,000,000

Backpack 0.14 0.00012 430,000

Lawns / Turf Hose

- end Sprayer 2.47 lb ai/acre 0.5 acres 0.022 0.00034 150,000
Manually

pressurized handwand 0.24

lb ai/gallon 5 gallons 0.018 0.00027 190,000

Backpack 0.14 0.0021 24,000

Sprinkler can 0.000056

lb ai/ft2 1000 ft2 0.022 0.000015 3,200,000

1. Based on registered label (EPA Reg. No. 100

- 950). 2. Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ). 3. Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day; ft 2 /day or gallons/day) ÷ BW (80 kg). 4. Inhalation MOE = Inhalation NOAEL (50 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

6.2 Residential Post

- application Exposure/Risk Estimates

There is the potential for post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with S

- metolachlor. The quantitative exposure/risk assessment for residential post

- application exposures is based on the following scenarios:

 Hand

- to

- mouth incidental oral exposure of children 1

- 2 years old playing on turf treated wi th S

- metolachlor.

The lifestages selected for each post

- application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs 4 . While not the only lifestage potentially exposed for these post

- application scenarios, the lifestage that is included in the quantitative assessment is health protective for the exposures and risk estimates for any other potentially exposed lifestage.

Residential Post

- application Exposure Data and Assumptions

4 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlS

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 30 of 70 A series of assumptions and exposur e factors served as the basis for completing the residential post

- application risk assessment. Each assumption and factor is detailed in the 2012 Residential SOPs 5

. Application Rate: The maximum application rate used was 2.4 lb S

- metolachlor/acre, based on registered product Pennant MAGNUM TM (EPA Reg. No. 100

- 950).

Residential Post

- application Non

- Cancer Exposure and Risk Equations The algorithms used to estimate residential post

- application exposure and dose can be found in Appendix A and/or the 2012 Re sidential SOPs

. Combining Exposure and Risk Estimates The incidental oral scenarios (i.e., hand

- to

- mouth, object

- to

- mouth, and soil ingestion) should be considered inter

- related and it is likely that they occur interspersed amongst each other across time. However, combining these scenarios is considered overly

- conservative because of the conservative nature of each individual assessment. Therefore, the post

- application exposure scenario assessed for children 1 < 2 years was the hand

- to

- mouth scenario sin ce no dermal endpoint was selected. No turf transferable residue data were used.

Summary of Residential Post

- application Non

- Cancer Exposure and Risk Estimates The residential exposure (absorbed dose) to children 1< 2 for hand

- to

- mouth oral exposure was calculated to be 0.038 mg/kg/day resulting in an MOE of 1,300. The MOE from the residential risk scenario for exposure to S

- metolachlor does not exceed the Agency’s level of concern. Results from this assessment have been used to assess aggregate risk from exposure to food, drinking water, and residential lawns. A summary is provided below in Table 6 .2.1

5 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlS

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 31 of 70 Table 6.2.1. Residential Post

- application Non

- cancer Exposure and Risk Estimates for S

- metolachlor. Maximum S ingle Application Rate: 2.47 lb ai/A

Lifestage HR t F M

SA H (cm 2 ) Exposure Time (hours/ day) N_Replen SE Freq_H tM

Absorbed

Dose (mg/kg/day) MOE

LOC= 1000 Hand Residue (mg/cm 2 ) Fracti

on of Hand Surfa

ce Area Mout hed / Event Number of replenishmen
t intervals per hr (intervals/hr) Extractio

n by Saliva HtM

events per hour

1 to <2
years 0.00404 0.127 150 1.5 4 0.48 13.9 0.038 1,300

1 Based on registered or proposed label (Reg. No. 100

- 950). 2 Dose (mg/kg/day) equations provided in Appendix [ A ]. 3 MOE = POD (50 mg/kg/day) ÷ Dose (mg/kg/day).

No turf transferable data were available for this chemical. Since the estimated residential turf post

- application exposure for residential turf using default TTR values for S

- metolachlor is minimal in comparison to t he level of concern (i.e., the calculated MOE is greater than 10 times higher than the level of concern, MOE = 1,300 compared to the LOC of 100); EPA is waiving the 40CFR TTR data requirement. In this instance, it is unlikely that chemical

- specific TTR da ta would be needed to further refine exposure assessments or would add appreciably to our general understanding of the availability of turf transferable pesticide residues.

6.3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6 .3.1 reflects the residential risk estimates that are recommended for use in the aggregate assessment for S

- metolachlor.

 The recommended residential exposure for use in the adult aggregate assessment reflects inhalation exposure from applications to turf via backpack sp rayer.

 The recommended residential exposure for use in the children 1<2 years old aggregate assessment reflects hand

- to

- mouth exposure from post

- application exposure to lawns/turf applications.S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 32 of 70 Table 6.3.1. Recommendations for the Residential Exposure s for the S

- metolachlor Aggregate Assessment.
Lifestage Exposure

Scenario Dose (mg/kg/day) 1 MOE 2

Inhalation Oral Total Inhalation Oral Total

Adult Backpack 0.0021 N/A 0.0021 24,000 N/A 24,000

Child Hand

- to

Mouth Oral Ingestion N/A 0.038 0.038 N/A 1,300 1,300

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + i ncidental oral (where applicable). 2 MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental Oral MOE), where applicable.

6.4 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not pe rformed for S

- metolachlor at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), and low vapor pressure (2.8 x 10

- 5 mm Hg). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and re ceived the SAP’s final report on March 2, 2010 1 . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalat ion 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 S

- metolachlor.

6.5 Spray Drift

Spray drift is a potential so urce of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom) employed for S

- metolachlor. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regu lation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information). The Agency is also taking means to qualitatively and qualitatively address spray drift as a potential source of expo sure in risk assessments for pesticides through existing programs such as Ag Drift and chemical specific properties of pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process whi ch ensures that all uses for that pesticide will be considered concurrently.S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 33 of 70 7 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

7.1 Acute Aggregate Risk

The aggregate acute risk estimates include s exposure to residues of S

- metolachlor in food and drinking water, and does not include der mal, inhalation or incidental oral exposure. Since the dietary exposure assessment already includes the highest acute exposure from the drinking water modeling data, no further calculations are necessary. The acute risk es timates for all populations

resu lting from aggregate exposure to S

- metolachl or in food and drinking water are below EPA’s level of concern. The food and d rinking water exposure estimate for the most highly exposed subgroup was 6.1% of the aPAD for all infants (< 1 year old ). See Section 5.4.3 for a detailed discussion of the acute dietary assessment.

7.2 Short

- Term Aggregate Risk

Short

- term aggregate assessments include exposures that will occur from one to thirty days. For food and water, the exposure input is taken from the chronic dietary exposure assessment.

There are no residential user exposures associated with the curren t petition. However, there is potential for residential exposure to S

- metolachlor from use of registered products which are applied to residential lawns or turf. P otential short

- term residential risk scenario s anticipated include adult inhalation handler exposure to turf via backpack sprayer and post

- application incidental oral exposure of children playing on treated lawns. Refer to Section 6.2. for the residential exposures that are likely to be combined. Results from that assessment have been used to ass ess aggregate risk from exposure to food, drinking water, and residential lawns for this analysis. Based on this analysis, short

- term aggregate MOEs are not of concern.

A second potential short

- term risk results from inhalat ion exposure from spray drift. Although a very high end exposure assessment was conducted, based on exposure to flaggers from aerial application, this exposure was less than the potential incidental oral exposure, so the inhalation exposure will not be aggregated with other exposures.S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 34 of 70 Table 7.2 Short

- Term Aggregate Risk Calculations for S

- Metolachlor

Population NOAEL 1

mg/kg/day LOC 2 Average

Food & Water Exposure mg/kg/day Residential

Exposure 3 mg/kg/day Aggregate MOE

(food/water and residential) 5

Adult 50 1000 0.0027 0.0021 3 10,400 Children 1

- 2 50 100 0.007 0.0 38 4 1100

1 NOAEL for incidental oral exposure. 2 The level of concern (LOC) for MOE is 1000 for the adult inhalation scenario and 100 for the children’s scenario. 3 Residential exposure for adults = [Inhalation exposure from applications to turf via backpack sprayer] 4 R esidential Exposure for children 1

- 2 = [Incidental Oral exposure ( from hand

- to

- mouth oral exposure ) ]. 5 Aggregate MOE = [NOAEL ÷ (Avg Food & Water Exposure + Residential Exposure)]

7.3 Intermediate

- Term Aggregate Risk

Intermediate

- term aggregate assessments include exposures that will occur from thirty days to six months. There are no residential scenarios which are expected to be intermediate

- term exposure.

7.4 Chronic Aggregate Risk

Chronic or long

- ter m aggregate assessments include exposures that will exceed six months. The chronic risk estimates include exposure to residues of S

- metolachlor in food and drinking water, and do not include dermal, inhalation or incidental oral exposure s . Since the dieta ry exposure assessment already includes the highest chronic exposures from the drinking water modeling data, no further calculations are necessary. The chronic risk estimates for all populations, resulting from aggregate exposure to S

- metolachl or in food a nd drinking water are below EPA’s level of concern. The food and dr inking water exposure estimate for the most highly exposed subgroup is 6.8% of the cPAD for children 1

- 2 years old. See S ection 5.4.4 for a detailed discussion of the chronic dietary assess ment.

7.5 Cancer Aggregate Risk

As risks are estimated based on the chronic reference dose are protective of cancer effects, no separate cancer risk assessment is necessary. The chronic dietary aggregate risk assessment is below the Agency’s level of concer n

.

8 Cumulative Exposure/Risk Characterization

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding asS

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 35 of 70 to S

- metolachlor and any other substances and S

- metolachlor does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that S

- metolachlor has a c ommon mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’ s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9 Occupational Exposure/Risk Char acterization

9.1 Short

- and Intermediate

- Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications an d exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The qu antitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:

 Mixer/Loader (aerial, chemigation and groundboom equipment);

 Applicators (aerial and groundboom equipment);

 Mixer/Loader/Applicator (mechanically

- pressurized handgun); and

 Flagger (from aerial spray applications).

The occupational handler exposure and risk estimates indicate that the short

- and intermediate

term inhalation Margin of Exposures (MOEs) are not of concern to HED (i.e., MOE > 1000) at the baseline level of personal protection (i.e., no gloves and no respirator )

. The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. While HED presents quantitative risk estima tes for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of GPS for swath guidance in agricu ltural 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.S

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Page 36 of 70 HED has no data to assess exposures to pilots using open cockpits. The only data ava ilable is for exposure t o 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 Stand ard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application. With this level of protection, there are no risk estimates of concern for applicators.

Table 9 .1.1. Occupational Handler Non

- Cancer Inhalation Exposure and Risk Estimates for S

- metolachlor.

Exposure Scenario Crop or

Target Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate 2 Area Treated or

Amount Handled Daily 3 Short

- & Intermediate

term
Dose (mg/kg/day) 4 MOE 5

LOC=1,000
Mixer/Loader
Aerial Field crop,

high acreage Baseline: 0.219 1.9 lb ai/A 1200 A 0.0062 8,000 Chemigation 350 A 0.0018 27,000

Groundboom 200 A 0.0010 48,000 Applicator

Aerial Field crop,

high acreage Engineering

Controls: 0.0049 1.9 lb ai/A 1200 A 0.00014 360,000

Groundboom Baseline: 0.34 200 A 0.0016 31,000 Flagger
Aerial Equipment Field crop,

high acreage Baseline: 0.35 1.9 lb ai/A 350 A 0.0029 17,000

Mixer/Loader/Applicator Mechanically

pressurized Handgun Field crop, typical Baseline: 3.9 0.32 lb ai/gallon 1,000 gallons 0.016 3,200

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Base line, PF5 Respirator, Eng. Controls. 2 Based on supplemental label to registered product (Reg. No. 100

- 816). 3 Exposure Science Advisory Council Policy #9.1. 4 Short

- &Intermediate

- term Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treate d or Amount Handled Daily (A or gal/day) ÷ BW (80 kg). 5 Short

- & Intermediate

- term Inhalation MOE = Inhalation NOAEL (50 mg/kg/day) ÷ Short

- term Inhalation Dose (mg/kg/day).

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 when workers enter previously treated area s to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.S

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Page 37 of 70 9.2.1 Dermal Post

- ap plication Risk

Based on the proposed use sites, it is anticipated that there may be occupational post

- application
exposure from activities related to crop production, such as scouting for pests or harvesting ; however , there is no dermal POD for S

- metolachlor, therefore, a quantitative assessment was not conducted. However, there’s a 24

- hour Restricted Entry Interval (REI) on the registered label for Dual Magnum® (EPA Reg. No. 100

- 816). S

- metolachlor is classified as Toxicity Category II I for acute oral and dermal and as category IV for inhalation toxicity. It is classified as category III for eye irritation potential and IV for skin irritation potential. It is a skin sensitizer. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as A cute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI. Therefore the REI specified in the label is considered adequate to protect agricultural workers from post

- application exposures to S

- metolachlor.

9.2.2 Inhalation Post

- application Risk

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and re

- suspension of dusts and/or particulates that contain pesticides. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP ) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatili zation Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determ ine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for S

- metolachlor

. In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Re

- entry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the agency's risk assessments.

Although a quant itative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to re sult in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.S

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Page 38 of 70 10 References

Dapson, S and Rinde, E. 11/16/1994. TXR No. 0011347. Carcinogenicity Peer Review of Metolachlor (4 th ).

Hummel, S. 10/27/14. D420046. S

- Metolachlor. Petition for the Establishment of Permanent Tolerances for New Uses on Lettuce, Low Growing Berry Subgroup 13

- 07G, except Cra nberry; Vegetable, Cucurbit, Group 9; Vegetable, Fruiting, Group 8

- 10; except Tabasco Pepper and Okra and Sunflower subgroup 20B. Summary of Analyti cal Chemistry and Residue Data.

Hummel, S/ 12/3/14. D424250. Metolachlor and S

- Metolachlor. Recommended E nvironmental Degradates to Includ e in Drinking Water Assessment.

Koper, C. 12/16/14. D 420047. Tier II Drinking Water Assessment for the Proposed S

Metolachlor Use on Lettuce (Head and Leaf), Low

- Growing Berry Subgroup 13

- 07G (excluding Cranberry), Cucurbi t Vegetable Group 9, Sunflower Subgroup 20B and Fruiting Vegetable Group 8

- 10.

Morton, T. 5 / 7 /15. D425169. S

- Metolachlor

- Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for Establishment of Tolerances for New Uses on Lettuce, Low Growing Berry Subgroup 13

- 07G, except Cranberry; Vegetable, Cucurbit, Group 9; Sunflower subgroup 20B; Vegetable, Fruiting, Group 8

- 10; except Tabasco Pepper.

Nieves, I. 3/4/2 015. D420046

. S

- M etolachlor: Occupational and Residential Exposure Assessment for Proposed Uses on Lettuce, Cucurbit Group 9, Low Growing Berry Subgroup 13

- 07G (except cranberry), Sunflower Subgroup 20B, and Crop Group conversion for Fruiting Vegetable Group 8

- 10.

VanAlstin e , J. 3/20/13 . TXR No. 0056586

. Metolachlor: Summary of Hazard and Science Policy Council (HASPOC) Meeting of February 14, 2013. Recommendations on the Need for a Neurotoxicity Battery, a Developmental Neurotoxicity Study, an d a Subchronic Inhalation Study.S

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Page 39 of 70 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for Metolachlor are listed in the Table below . Use of the new guideline numbers does not imply that the new (1998) guideline proto cols were used. Bridging studies for S

Metolachlor include an Acute Toxicity Battery, subchronic toxicity studies in rats and dogs, developmental toxicity studies in rats and rabbits, mutagenicity battery, metabolism studies and an immunotoxicity study.

S tudy 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 a 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 yes yes yes yes y es b

yes yes yes yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial 870.5300 Mutagenicity

— Gene Mutation

- mammalian 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations 870.5xxx Mutagenicity

— Other Genotoxic Effects yes yes yes yes yes

yes yes yes

870.6100a Acute Delayed Neurotoxicity (hen) 870.6100b 90

- Day Neurotoxicity (hen) 870.6200a Acute Neurotoxicity Screening Battery (rat) 870.6200b 90

- Day Neurotoxicity Screening Battery (rat) 870.6300 Develop. Neurotoxicity no

no yes c yes c conditional c -

-

-

-

- 870.7485 General Metabolism 870.7600 Dermal Penetration 870.7800 Immunotoxicity yes yes yes yes

yes yes Special Studies for Ocular Effects Acute Oral (rat) Subchronic Oral (rat) Six

- month Oral (dog) no

a Required by HASPOC (TXR No. 0056586)

b Satisfied with combined chronic toxicity/carcinogenicity study

c Waived by HASPOC (TXR No. 0056586)S

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Page 40 of 70 A.2 Toxicity Profile s

Table A.2.1 a Acute Toxicity Profile

- Metolachlor Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute oral

- Rat 00015523 LD 50 = 2780 mg/kg III 870.1200 Acute dermal

- Rabbit 00015526 LD 50 = > 10 g/kg III 870.1300 Acute inhalation

- Rat 00015535 LC 50 = > 1.75 mg/L III 870.2400 Acute eye irritation

- Rabbit 00015528 Non

- irritating IV 870.2500 Acute dermal irritation

- Rabbit 00015530 Non

- irritating IV 870.2600 Skin sensitization

– guinea pig 00015631 positive

Table A.2.1 b Acute Toxicity Profile

– S

- Metolachlor Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute oral

- Rat 43928915 LD 50 = 3267 mg/kg (♂); 2577 mg/kg/day (♀); 2672 mg/kg/day (combined) III

870.1200 Acute dermal

- Rabbit 43928916 LD 50 = > 2000 mg/kg III 870.1300 Acute inhalation

- Rat 43928917 LC 50 = > 2.91 mg/L IV 870.2400 Acute eye irritation

- Rabbit 43928918 Slight to moderate conjunctival irritation that cleared in 48 hours III

870.2500 Acute dermal irritation

- Rabbit 43928919 non

- irritating IV 870.2600 Skin sensitization

– guinea pig 43928920 positive

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Metolachlor Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90

- Day oral

toxicity (rat) 44775401 (1999)

0, 30, 300, 3000 ppm (M/F: 0, 2.00/2.32, 20.2/23.4, 210/259 mg/kg/day) NOAEL for males = 3000 ppm LOAEL for males not established NOAEL for females = 300 ppm LOAEL for females = 3000 ppm based on decreased body weight/body weight gain Acceptable/Guideline 870.3150 6

- Month oral

toxicity (dog) 00032174 (1980),

43244001 0, 100, 300, 1000 ppm (M/F: 0, 2.92/2.97, 9.71/8.77, 29.61/29.42) NOAEL = 300 ppm LOAEL = 10 00 ppm based on decreased body weight gain A cceptable/Guideline

870.3200 21

- Day dermal

toxicity rabbits 41833101 (1987)

0, 10, 100 or 1000 mg/kg/day Systemic NOAEL = 1000 mg/kg/day. Systemic LOAEL was not established Dermal irritation NOAEL was not established Dermal irritation LOAEL = 10 mg/kg/day based on very slight erythema, dry skin and fissuring (one animal) Acceptable/Guideline 870.3700a Prenatal

developmental toxicity in rodents 00151941 (1985)

0, 30, 100, 300 or 1000 mg/kg/day Maternal toxicity NOAEL = 300 mg/kg/day. Maternal toxicity LOAEL = 1000 mg/kg/day based on an increased incidence of death,S

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Page 41 of 70 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Metolachlor Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

(rat) clinical signs of toxicity (clonic and/or toxic convulsions, excessive salivation, urine

- stained abdomina l fur and/or excessive lacrimation) and decreased body weight gain. Developmental toxicity NOAEL = 300 mg/kg/day Developmental toxicity LOAEL = 1000 mg/kg/day based on slightly decreased number of implantations per dam, decreased number of live fetuses/da m, increased number of resorptions/dam and significant decrease in mean fetal body weight Acceptable/Guideline

870.3700b Prenatal

developmental in (New Zealand White) rabbits 00041283 (1980)

0, 36, 120 or 360 mg/kg/day Maternal toxicity NOAEL = 120 mg/kg/day. Maternal toxicity LOAEL = 360 mg/kg/day based on an increased incidence of clinical observations (persistent anorexia) and decreased body weight gain Developmental toxicity NOAEL = 360 mg/kg/day Developmental toxicity LOAEL was not established. Acceptable/Guideline 870.3800 Reproduction and

fertility effects (CD albino) rats 00080897 (1981)

0, 30, 300 or 1000 ppm F 0 males: 0, 2.4, 23.5, and 75.8 mg/kg/day; F 0 females: 0, 2.5, 26.0, and 85.7 mg/kg/day; F 1 males: 0, 2.3, 23.7, and 76.6 mg/kg/day; F 1 females: 0, 2.6, 25.7, and 84.5 mg/kg/day metolachlor (95.4% ai) (dietary) Parental/Systemic NOAEL = 1000 ppm (F 0 males/females: 75.8/85.7 mg/kg/day; F 1 males/females: 76.6/84.5 mg/kg/day) highest dose tested. LOAEL = Not established Reproductive NOAEL = 1000 ppm (F 0 males/females: 75.8/85.7 mg/kg/day; F 1 males/females: 76.6/84.5 mg/kg/day) highest dose tested. LOAEL = Not established Offspring NOAEL = 300 ppm (F 0 males/females: 23.5/26.0 mg/kg/day; F 1 males/fem ales: 23.7/25.7 mg/kg/day LOAEL = 1000 ppm (F 0 males/females: 75.8/85.7 mg/kg/day; F 1 males/females: 76.6/84.5 mg/kg/day based on decreased body weight in F 1 and F 2 litters. Acceptable/Guideline 870.4100b Chronic toxicity

dogs 40980701, 41164501,

42218601 and 42218602. (1989) 0, 100, 300 or 1000 ppm (males: 0, 3.5, 9.7 and 32.7 mg/kg/day, respectively; females: 0, 3.6, 9.7 and 33.0 mg/kg/day, respectively) for one year. NOAEL = 300 ppm (9.7 mg/kg/day) for females LOAEL = 1000 ppm for females (33.0 mg/kg/day) based on decreased body weight gain NOAEL = 1000 ppm (32.7 mg/kg/day). LOAEL for males was not established; Acceptable/GuidelineS

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Page 42 of 70 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Metolachlor Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.4200 Chronic toxicity/

Carcinogenicity
rat 00129377 (1983)

0, 30, 300 or 3000 ppm (0, 1.5, 15 or 150 mg/kg/day based on 1 ppm in food equals 0.05 mg/kg/day) NOAEL = 300 ppm (15 mg/kg/day) for females LOAEL = 3000 ppm (150 mg/kg/day) for females based on slightly decreased body weight gain and food consumption. The LOAEL was not established for males. The NOAEL was 3000 ppm (150 mg/kg/day). Administration of doses up to 3000 ppm was associated with statistically significant increases in liver adenomas and combined adenoma/carcinoma in female rats. In male rats, there was a statistically significant trend but not pair

- wise significance for liver tumors. Acceptable/Guideline 870.4300 Carcinogenicity

mice 00117597 (1982)

0, 300, 1000 or 3000 ppm (0, 45, 150 or 450 mg/kg/day) NOAEL = 100 ppm (150 mg/kg/day) LOAEL = 3000 ppm (450 mg/kg/day) based on possible treatment

- related deaths in females and decreased body weight/body weight gain in males and females no evidence of carcinogenicity Acceptable/Guideline 870.5100 Gene Mutation

bacterial reverse mutation 00015397 (1976)

10, 100, 1000 and 10,000 ug/plate Negative up to cytotoxic doses (1000 ug/plate) Acceptable/Guideline

870.5300 Gene Mutation

mouse lymphoma 00158929 (1984)

9.5

- 190 nL/mL without activation; 10.5

- 280 nL/mL with activation No effect on the incidence of mutations in the presence or absence of metabolic activation Acceptable/Guideline

870.5395 Cytogenetics

micronucleus assay in Chinese hamsters 00158925 (1984)

0, 1250, 2500 or 5000 mg/kg No effect of treatment on incidence of micronuclei induction Acceptable/Guideline

870.5450 Cytogenetics

dominant lethal assay in mice 00015630 (1978)

100 or 300 mg/kg No effect on embryonic death, pre

- and post

implantation or fertility rates in mated females Acceptable/Guideline

870.5550 Other Effects

DNA Damage/Repair in
rat hepatocytes 00142828 (1984)

0.125, 0.625, 3.125 or 15.625 nL/mL Negative Acceptable/Guideline

870.5550 Other Effects

DNA Damage/Repair in human fibroblasts 00142827

0.125, 0.625, 3.125 or 15.625 nL/mL Negative Acceptable/Guideline

870.5550 Other Effects

Unscheduled DNA synthesis in rat hepatocytes 43244003 (1994)

1250, 2500 or 4000 mg/kg to males; 500, 1000 or 1500 mg/kg to females Negative for induction of UDS; however, significant increases in percentage of cells in S

phase were observed in females dosed at 500 mg/kg (but not at 1000 or 1500 mg/kg) and sacrificed at 15 hours Acceptable/Guideline 870.7485 Metabolism and

pharmacokinetics rodents MRID 00015425 (1974)

52, 28 or 33 mg/kg to male rats Urinary metabolites of CGA 24705 (N

- (2

- methoxy

- 1

- methylethyl)

- 2

- ethyl

- 6

- methyl

chloroacetanilide) were identified followingS

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Page 43 of 70 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Metolachlor Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

oral administration of 52 mg/kg, 28 mg/kg, and 33 mg/kg to male rats. Two metabolites, each comprising approximately 5% of chlorofor m extractable urinary radioactivity, were identified from oral administration of CGA 24705. The major metabolic pathway proposed from analysis of urinary as well as fecal metabolites is one of cleavage of the ether bond and subsequent oxidation to the car boxylic acid, as well as hydrolytic removal of the chlorine atom. Conjugation of CGA 24705 or metabolites with glucuronic acid or sulfate does not appear to occur. Current guideline recommendations as to dose levels and use of both sexes in metabolism stud ies were not followed. Thus, whether the metabolic pattern is altered with dose or repeated exposure cannot be evaluated from these data. Unacceptable/Non

- guideline 870.7485 Metabolism and

pharmacokinetics 40114401 (1987)

Single low (1.5 mg/kg), single high (300 mg/kg) and repeated low (1.5 mg/kg/day for 15 days) Single low (1.5 mg/kg), single high (300 mg/kg) and repeated low (1.5 mg/kg/day for 15 days) oral doses of metolachlor were readily absorbed and eliminated by male and female rats. Urinary and f

ecal elimination of radioactivity associated with orally administered [ 14 C] metolachlor was essentially complete within 48 to 72 hours after dosing. Relatively low levels of radioactivity were present in the tissues of all animals at 7 days postdosing. U nacceptable/Non

- guideline 870.7485 Metabolism and

pharmacokinetics 43164201 (1992)

low oral dose (1.5 mg/kg x 14 days), and a single high dose (300 mg/kg) Comparison of oral and intravenous data showed that of the administered dose, between 69.6% and 93.2% was absorbed. Distribution data showed that the only significant sites of residual radioactivity at 7 days post

- dose were residual carcass (0.9

- 2.2% of the administered dose) and red blood cells (0.95

- 1.53 μg equivalents/gram in blood cells for al l low dose male and female rats). Dosing regimen did not result in any apparent accumulation of residual radioactivity. Excretion data showed that urine and feces were both significant routes for elimination of metolachlor derived radioactivity Metaboli sm of metolachlor in this study was complex, with up to 32 metabolites identified in urine and/or feces. Acceptable/GuidelineS

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Page 44 of 70 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– S

- Metolachlor Guideline No. Study Type MRID No. (year)/ Classification /Doses 870.3100 90

- Day oral

toxicity rodents 43928923 (1995)

0, 30, 300, 3000 or 10000 ppm (0, 1.5, 15, 150 or 500 mg/kg/day) NOAEL = 300 ppm LOAEL = 3000 ppm based on lower body weights/body weight gains, reduced food consumption and food efficiency and increased kidney weights in males Acceptable/Guideline 870.3100 90

- Day oral

toxicity rodents 44775402 (1999)

0, 30, 300, 3000 ppm (M/F: 0, 1.90/2.13, 20.4/23.9 and 208.0/236.0 mg/kg/day0 NOAEL = 3000 ppm (equivalent to 208 mg/kg/day in males and 236 mg/kg/day in females LOAEL cannot be defined Unacceptable/Guideline 870.3150 90

- Day oral

toxicity nonrodents 43928922 (1995)

0, 300, 500, 1000 or 2000 ppm (M/F: 0, 9/10, 15.1/17.2, 31.1/31.5 or 62/74 mg/kg/day) NOAEL = 2000 ppm (M/F: 62/74 mg/kg/day) LOAEL = not established Acceptable/Non

- guideline

870.3700a Prenatal

developmental in (Tif:RAI f (SPF))
rats 43928925 (1995)

0, 5, 50, 500, or 1000 mg/kg/day S

- metolachlor (95.6% ai) in 0.5% (w/w) aqueous solution of sodium carboxymethylcellulose (gavage) GD 6

- 15 Maternal NOAEL = 50 mg/kg/day LOAEL = 500 mg/kg/day based on increased clinical signs of toxicity, decreased body weights and body weight gains and reduced food consumption and reduced food efficiency. Developmental NOAEL = 1000 mg/kg/day, highest dose tested. LOAEL = Not established Acceptable/Guideline 870.3700b Prenatal

developmental in (New Zealand White) rabbits 43928924 (1995)

0, 20, 100, or 500 mg/kg/day S

- metolachlor (89.6% ai (93.7% S isomer)) suspension in 3% corn starch (gavage) GD 7

- 19 Maternal NOAEL = 20 mg/kg/day LOAEL = 100 mg/kg/day based on clinical signs of toxicity. Developmental NOAEL = 500 mg/kg/day, highest dose tested. LOAEL = Not established Acceptable/GuidelineS

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Page 45 of 70 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– S

- Metolachlor Guideline No. Study Type MRID No. (year)/ Classification /Doses 870.5100 Gene Mutation

Salmon ella & Escherichia/Mam malian Microsome Mutagenicity Test 43928927 (1995)

78.13

- 1250.0 ug/plate In independently performed microbial mutagenicity assays, Salmonella typhimurium TA1535, TA1537, TA98, TA100 and TA102 and Escherichia coli WP2 uvr A were initially exposed to 312.5

- 5000.0 μg/plate CGA

- 77102 technical (95.6%) in the presence and absence of S9 activation. For the confirmatory trial, doses of 78.13

- 1250.0 μg/plate ±S9 were evaluated with S. typhimurium strains TA1535, TA1537, TA100 and TA102; concentrations of 312.5

- 5000.0 μg/plate ±S9 were examined with S. typhimurium TA 98 and E.coli WP2 uvr A. In general, doses  1250.0 μg/plate ±S9 were cytotoxic for S. typhimurium TA1535, TA1537, TA100 and TA102 and 5000.0 μg/plate ±S9 was slightly cytotoxic for S. typhimurium TA98 and E. coli WP2 uvr A. There was, however, no indication that CGA

- 77102 technical induced of a mutagenic effect in any tester strain either in the presence or the absence of S9 activation. Acceptable/Guideline 870.5395 Cytogenetics

Micronucleus test 43928926 (1995)

500, 1000 or 2000 mg/kg Groups of five male and five female Tif:MAGf(SPF) mice received single oral gavage administrations of 500, 1000 or 2000 mg/kg CGA 77102 technical (95.6%). Toxic signs, similar to tho se seen in the preliminary range

- finding studies (i.e., ataxia, tremors and/or hunched posture) were recorded for high

- dose males and females throughout the 48

- hour postexposure. No bone marrow cytotoxicity was seen at any dose or sacrifice time. The posit ive control induced the expected high yield of MPEs in males and females. There was, however, no evidence that CGA 77102 technical induced a clastogenic or aneugenic effect in either sex at any dose or sacrifice time. Acceptable/Guideline 870.5550 Other Effects

Unscheduled DNA synthesis 43928928 (1995)

500, 1500, 3200 (females), 5000 (males) mg/kg CGA 77102 Technical was negative for genotoxicity but positive for cellular proliferation when tested up to overtly toxic and cytotoxic doses in this in vivo / in vitro rat hepatocyte RDS/UDS assay. Acceptable/GuidelineS

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Page 46 of 70 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– S

- Metolachlor Guideline No. Study Type MRID No. (year)/ Classification /Doses 870.7485 Metabolism and

pharmacokinetics 44491401 (1996)

single dose of 0.5 (group B1) or 100 mg/kg (group D1) radiolabeled CGA

77102; 100 mg/kg/day

non

- radiolabeled CGA 77102 for 14 days followed by 0.5 mg/kg radiolabeled CGA

- 77102 (Group V1); single dose of 0.5 or 100 mg/kg radiolabeled CGA

- 77102 for bile

- cannulation study In all three dose groups (B1, D1, and V1), the seven day combined levels of radioactivity in urine were 31.1

- 36.5% for males and 40.8

- 45.5% for females; the fecal levels were 60.2

- 62.5% for males and 48.9

- 55.0% for females. Only 0.1% or less was eliminated in the expired air. The total recovery ranged from 96.5 ± 2.3% to 99.3 ± 0.9%. Irrespective of the dose and sex, there seems to be a biphasic plasma profile with two concentration maxima (C max ); a fast rising first C max was reached at 0.25

- 1 hour post dosing which was succeeded by a second C max at 8 and at 12

- 24 hours following administration of the low and high dose, respectively. Acceptable/Guideline 870.7485 Metabolism and

pharmacokinetics 44491402 (1996)

single dose of 0.5 (group B1) or 100 mg/kg (group D1) radiolabeled CGA

77102; 100 mg/kg/day

non

- radiolabeled CGA 77102 for 14 days followed by 0. 5 mg/kg radiolabeled CGA

- 77102 (Group V1); single dose of 0.5 or 100 mg/kg radiolabeled CGA

- 77102 for bile

- cannulation study (from MRID 44491401) single oral low dose (0.5 mg/kg, Group B2) of [Phenyl

- U

14 C] CGA

24705 (R/S

- Metolachlor, racemate) The 72 hour mean recovery of radioactivity in urine, feces, and carcass following administration of 0.5 mg/kg of [Phenyl

- U

14 C] CGA

- 24705 was 43.1%, 47.0%, and 7.4% in males and 54.0%, 39.4%, and 4.1% in females, respectively. In contrast, both sexes excreted

more o f the label in the feces (M:F 59.7%:53.4%) than in the urine (M:F 29.4%:39.8%) during the same period following administration of the same dose of [Phenyl

- U

14 C] CGA

- 77102 (the S

- enantiomer) (MRID 44491401). The urinary and fecal metabolite profiles, with 31 and 15 metabolite fractions, respectively, were qualitatively similar among all groups; however, there were large quantitative differences, based on the dosing formulation, on one hand, and the sex of the animal, on the other. The results clearly show that the metabolite profile in excreta and bile fluid is very complex and that Metolachlor (racemate or S

enantiomer) is extensively metabolized. Unacceptable/Guideline 870.7800 Immunotoxicity in

mice 48783301 (2012)

0, 1500, 3000 or 5000 ppm (0, 304.3, 639.5, or 1108.5 mg/kg/day NOAEL = 5000 ppm (1108.5 mg/kg/day) LOAEL = Not Established Acceptable/GuidelineS

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Page 47 of 70 A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

- Females age 13

- 49

An endpoint was not selected for Females 13

- 49 years old since no developmental effects that could be attributed to a single exposure were identified in the metolachlor/S

- me tolachlor database.

A.3.2 Acute Reference Dose (aRfD)

- General Population

Study Selected: Developmental Toxi city in Rats

- Metolachlor MRID No.: 00151941 Dose and Endpoint for Risk Assessment: POD= 300 mg/kg/day (NOAEL)

. LOAEL = 1000 mg/kg/day based on an increased incidence of death, clinical signs of toxicity (clonic and/or tonic convulsions, excessive salivation, urine

- stained abdominal fur and/or excessive lacrimation) and decreased body weight gain. Comments about Study/En dpoint/Uncertainty Factors: Since clinical signs are observed after a single oral dose of metolachlor, the duration and route of administration are appropriate for the risk assessment. Developmental effects observed are not attributable to a single expos ure and therefore, a separate acute endpoint has not been identified for females 13

- 50. Although increased incidence of death is one of the effects seen, it was seen at a dose (1000 mg/kg/day) approximately three times higher than the dose (300 mg/kg/day) selected for risk assessment; therefore, the Agency is confident that adequate safety is provided to protect the public from dietary exposure to residues of metolachlor. The total UF is 100 (10X for interspecies uncertainty factor

, 10X for intraspecies variability , 1X FQPA SF)

. Acute RfD (General Population) = aPAD= (NOAEL) 300 mg/kg = 3.0 mg/kg (UF) 100

A.3.3 Chronic Reference Dose (cRfD)

Study Selected: Chronic Feeding Study in Dogs (Metolachlor) MRID No.: 40980701, 41164501, 42218601 and 42218602 Dose and Endpoint for Risk Assessment: POD= 9.7 mg/kg/day ( NOAEL ). LOAEL = 33 mg/kg/day based on decreased body weight gain in females. Comments about Study/E ndpoint/Uncertainty Factors: This study was selected because the database shows dogs were the mo r e sensitive species and decreased body weight gain the most sensitive endpoint. The duration of 1 year and route of exposure through the feed is also
appropr iate. The total UF is 100 (10X for inte rspecies uncertainty factor and 10X for intraspecies variability).

Chronic RfD (General Population) = cPAD= (NOAEL) 9.7 mg/kg = 0.097 mg/kg (UF) 100S

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Page 48 of 70 A.3.4 Incident al Oral Exposure (Short

- T erm)

Study Selected: Developmental Toxicity Study in Rats (S

- Metolachlor) MRID No.: 43928925 Dose and Endpoint for Risk Assessment: POD = 50 mg/kg/day (maternal NOAEL ). LOAEL is 500 mg/kg/day based on increased incidence of clinical signs, decreased body weight/body weight gain, food consumption and food efficiency seen in maternal animals. Comments about Study/Endpoint/Uncertainty Factors: A short

- term incidental oral POD

was selected from a developmental toxicity study with S

- metolachlor in rats. This endpoint was based on increased incidence of clinical signs and decreased body weight/body weight gain. This study was selected because the effects were judged to be signs of fra nk toxicity and were appropriate to use for risk assessment. The NOAEL (20 mg/kg/day) from the prenatal developmental toxicity study in rabbits with S

- metolachlor (MRID 43928924) was lower than the 50 mg/kg/day from the rat developmental study. However, t he endpoint was based on weak clinical signs of toxicity (increase in little/none/soft stool observations) at 100 mg/kg/day. Although there was a dose

- related increase in this effect, it is not evidence of frank toxicity and was judged not be appropriate for risk assessment. Therefore, the rabbit study with S

metolachlor was not selected for this exposure scenario. The total UF is 100 (10X for interspecies uncertainty factor and 10X for intraspecies variability).

A.3.5 Dermal Exposure (Short

- Term)

No hazard was identified for quantification of risk following dermal exposure. In a 21

- day dermal toxicity study (MRID 41833101), no systemic toxicity was seen following repeated dermal application of metolachlor (96.4% ai) to the intact skin of five New Ze aland rabbits/sex/group at doses of 0, 10, 100 or 1000 mg/kg/day for 21 days.

A.3.6 Inhalation Exposure (Short

- and Intermediate Term)

Study Selected: Developmental Toxicity Study in Rats (S

- Metolachlor) MRID No.: 43928925 Dose and Endpoint for Risk Assessment: POD= 50 mg/kg/day ( NOAEL ). LOAEL of 500 mg/kg/day based on is based on increased incidence of clinical signs, decreased body weight/body weight gain, food consumption and food efficiency seen in maternal animals. Comments about Study/Endpoint/Uncertainty Factors: No inhalation study is available for the short

- and intermediate

- term occupational inhalation scenario s . In the absence of a route

specific study, a shor t

- and intermediate

- term inhalation exposure POD was selected from an oral developmental toxicity study in rats wi th S

- metolachlor. The endpoint selected was increased incidence of clinical signs and decreased body weight/body weight gain. This study was selected because the effects were judged to be si gns of frank toxicity and the duration of exposure is appropriate.

Since an oral study was selected, a 100% absorption factor should be applied. The total UF is 100 0 (10X for interspecies uncertainty factor

, 10X for intraspecies variability , and 10X data base UF for missing study)

.S

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Page 49 of 70 A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90

- Day Oral Toxicity

– Rat In a 90

- day subchronic oral toxicity limit study (MRID 44931710), groups of 10 male and 10 female Crl: CD BR rats were given CGA

- 354743 (L ot/Batch # KI

- 5408/6, 98% a.i.) administered in the diet at concentrations of 0, 360, 1200, 6000, or 20,000 ppm. These concentrations were equivalent to 0, 25.1, 86.2, 427.0 or 1545.0 mg/kg/day for males and 0, 28.4, 98.3, 519.0 and 1685.0 mg/kg/day for f emales. An additional 10 male and 10 female rats were given CGA

- 77102 (s

- Metolachlor)(Lot/Batch # P.501001, 98.5% a.i.) administered in the diet at 5000 ppm (equivalent to 429 mg/kg/day for males and 563 mg/kg/day for females). The study was designed to assess the subchronic oral toxicity of CGA

- 354743 technical and to compare its toxic effects with those of its parent compound, CGA

- 77102 technical.

No deaths or clinical signs of toxicity occurred during this study. In addition, no statistically signif icant changes in body weight, body weight gain, food consumption, food efficiency, ophthalmologic examination, urinalysis, or histopathology was reported for animals fed CGA

354743. Limited and sporadic statistically significant changes in hematology, cli nical chemistry, water intake and organ weight data were not dose

- dependent, and were of question able toxicological and biological importance.

Dietary exposure to CGA

- 77102 produced a statistically significant decreased body weight gain (

- 20%, p  0.01) in males during week 1 only. Females exposed to CGA

- 77102 showed decreased body weight gain (

- 19%) by week 13, but these changes were not statistically significant. The food efficiency of rats fed CGA

- 77102 was decreased relative to their respective
contr ol animals. Male and female rats had increased absolute and relative liver weights. These results are consistent with a mild liver hypertrophy in females.

Based on the data presented in this study, the NOAEL is  20,000 ppm (1543 mg/kg/day and 1685 mg/k g/day for females) for CGA

- 354743. A LOAEL could not be established. At 5000 ppm (429 mg/kg/day in males and 563 mg/kg/day in females) CGA

- 77102 , there evidence of decreased body weight gain and food efficiency, increased absolute and relative liver wei ghts and an increased incidence of hepatic centrilobular hypertrophy, although the effects were mild

. This subchronic oral toxicity study in rats is classified as Acceptable/Guideline [OPPTS 870.3100 (§82

- 1a)] and satisfies the guideline requirements.

870.3100 90

- Day Oral Toxicity

– Rat

In a subchronic oral feeding study, (MRID 44929509), CGA

- 51202 technical (100% a.i.; batch No. JD 7069/3) was fed to groups of 10 male and 10 female albino rats at dose levels of 0, 300, 1000, or 15,000 ppm for 3 mon ths. The average achieved doses for the corresponding groupsS

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Page 50 of 70 were 0, 18.7, 62.1, and 1000 mg/kg bodyweight for males, and 0, 20.6, 67.3, and 1020 mg/kg for females.

All animals survived to study termination and no treatment

- related clinical signs were ob served. There were no treatment

- related effects on body weight, food consumption, ophthalmoscopic parameters, or urinalysis. Platelet counts were decreased 16% (p<0.01) in high

- dose males. Total protein in high

- dose males (5% decrease, p<0.01) and femal es (4% decrease, N.S.) was slightly decreased due to decreased globulin in males and decreased albumin and globulin fractions in females. These effects were not considered biologically significant. There were no
treatment

- related organ weight effects or macroscopic or microscopic lesions. Under the conditions of this study, the NOAEL is 15,000 ppm in the diet (1000 mg/kg for males, 1020 mg/kg for females, limit dose) based on no biologically significant effects. A LOAEL was not identified.

This subchron ic toxicity study in rats (82

- 1) is classified as Acceptable/Guideline. It satisfies the guideline requirement for a subchronic dietary toxicity study in rodents.

870.3150 90

- Day Oral Toxicity

– Dog

In a subchronic oral toxicity study (MRID5 00032174 and 43244001), metolachlor (96.8% ai) was administered in the diet to Beagle dogs (8/sex/group for control and high dose groups; 6/sex/group for low

- and mid

- dose groups) at dose levels of 0, 100, 300 or 1000 ppm (males: 0, 2.92, 9.71 and 29.61 mg/kg/day, respectively; females: 0, 2.97, 8.77 and 29.42 mg/kg/day, respectively) for six months. There were no deaths or clinical signs of toxicity. Mean body weight gain was decreased during weeks 0

- 13 and 0

- 26 i n the 1000 ppm group males (55

- 63% decrease) and females (44

- 50% decrease), although the changes were not statistically significant. Mean overall food consumption was not affected in the 1000 ppm group males but was slightly decreased (9%) in the 1000 ppm females. There was a significant decrease in the activated partial thromboplastin time (APTT) in the 300 and 1000 ppm group males and 300 ppm group females but the findings were not considered toxicologically significant because the decrease was slight and not dose

- related. Alkaline phosphatase was signifcantly increased in the 300 ppm and 1000 ppm group males and females at week 26; however, the effect was not considered toxicologically significant due to the small magnitude of the increase and the lack of accompanying necropsy findings. The LOAEL was 1000 ppm (males/females: 29.61/29.42 mg/kg/day) based on decreased body weight gain. The NOAEL was 300 ppm (maLes/females: 9.71/8.77 mg/kg/day).

870.3150 90

- Day Oral Toxicity

– Dog

In a 90

- day subchronic o ral toxicity study (MRID 44931709), CGA

- 354743 technical ( m etabolite of metolachlor) (Batch Nos. KI

- 5408/4 and KI

- 5408/5, 99% a.i.) was administered to 4 pure bred beagle dogs/sex/dose by capsule at dose levels of 0, 50, 200, 500, and 1000 mg/kg/day for 13 weeks. An additional group of 4 males and 4 females received parent compound (CGA

- 77102 technical, Batch No. P.501001, 98.5% a.i.) at 200 mg/kg/day for 13 weeks.S

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Page 51 of 70 There were no significant treatment related effects on mortality, body weight, food consu mption, food conversion ratios, ophthalmological findings, hematology and urinalysis parameters, or gross and histopathological findings. Vomiting did occur at a higher incidence in females treated with 1000 mg/kg/day of CGA

- 354743. Clinical signs in anim als treated with CGA

- 77102 included vomiting, salivation and hematuria. Mean alkaline phosphatase activity was slightly increased in males receiving 1000 mg/kg/day CGA

- 354743 at weeks 7 and 13 to levels which were less than double the pretest mean for this group. This finding correlated with slightly increased absolute liver weights, but there were no corresponding histopathological findings, or toxicologically significant increases in other biochemistry parameters. In females, mean ALP activities remaine d within the reference range for untreated animals and mean GGT activity exceeded the reference range only at week 13 and only for the 500 mg/kg/day CGA

- 354743 group. Absolute liver weights and liver weights relative to body weights were increased in fema les receiving 500 and 1000 mg/kg/day. In the absence of corresponding histopathological findings or biologically significant increases in biochemistry parameters consistent with adverse hepatic effects, this finding is not considered toxicologically signi ficant.

Mean ALP and GGT activities were significantly increased in both sexes at weeks 7 and 13 given CGA

- 77102. In addition, ALT activity of males was increased at weeks 7 and 13. Absolute and relative liver weights were significantly increased in mal es and females. There were small increases in the incidences and severity of bile duct hyperplasia, perilobular fatty change in the livers of both sexes, and cystic hyperplasia of the gallbladder occurred only in the parent compound group.

The results appear to indicate that CGA

- 354743 may have effects (vomiting, slight increases in ALT and liver weight) similar to those of its parent compound, CGA

- 77102; however, at the limit dose, 1000 mg/kg/day, the effects observed were so slight and of questionable toxicological significance in CGA

- 35743

- treated dogs that a definitive comparison of the two compounds cannot be made.

Based on the data presented in this study, the LOAEL was not determined, and the NOAEL was greater than or equal to 1000 mg/kg/da y.
This subchronic oral toxicity study in dogs is classified as Acceptable/Guideline and satisfies the guideline requirements for a subchronic oral study [OPPTS: 870.3150 (§82

- 1b)] in dogs since the limit dose was tested.

870.3200 21/28

- Day Dermal Tox icity

– Rat

In a 21

- day dermal toxicity study (MRID 41833101), no systemic toxicity was seen following repeated dermal application of metolachlor (96.4% ai) to the intact skin of five New Zealand rabbits/sex/group at doses of 0, 10, 100 or 1000 mg/kg/day for 21 days.

The Systemic LOAEL = not observed. The Systemic NOAEL = 1000 mg/kg/day.S

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Page 52 of 70 870.3465 90

- Day Inhalation

– Rat

Data gap.

A.4.2 Prenatal Developmental Toxicity

There was no evidence of maternal or developmental toxicity in the rat prenatal developmental study with CGA 354743 or CGA 51202 at the limit dose of 1000 mg/kg/day.

870.3700a Prenatal Developmental Toxicity Study

– Rat

In a prenatal developmental toxicity study (MRID 00151941), metolachlor (96.4% a.i.) in 0.5% (w/v) aqueous hydroxy methylcellulose was administered by gavage (10 mL/kg) to 25 presumed pregnant BR rats from gestation days (GD) 6 through 15, inclusive, at dose levels of 0, 30, 100, 300 or 1000 mg/kg/day. The animals were sacrificed on GD 20 and the fetuses examined for e vidence of developmental effects.

There were four treatment

- related deaths in animals treated at 1000 mg/kg/day. Clinical signs of toxicity, including clonic and/or toxic convulsions, excessive salivation, urine

- stained abdominal fur and/or excessive lacr imation, were observed in animals treated at 1000 mg/kg/day. There was also an increase in excessive salivation in the 300 mg/kg/day group. However, as this effect was most likely due to gastric irritation and there was no other evidence of treatment

relat ed toxicity, the finding is not considered toxicologically significant. Body weight gain was significantly decreased in the 1000 mg/kg/day group during GD 6

- 16, GD 6

- 20and GD 0

- 20. Food consumption was not affected. In the 1000 mg/kg/day group, there were a slightly decreased number of implantations per dam, decreased live fetuses/dam and increased number of resorptions/dam. There was also a statistically significant decrease in mean fetal body weight.

The maternal toxicity LOAEL was 1000 mg/kg/day based on an increased incidence of death, clinical signs of toxicity (clonic and/or toxic convulsions, excessive salivation, urine

stained abdominal fur and/or excessive lacrimation) and decreased body weight gain. The NOAEL was 300 mg/kg/day. The developmenta l toxicity LOAEL was conservatively established at 1000 mg/kg/day based on slightly decreased number of implantations per dam, decreased number of live fetuses/dam, increased number of resorptions/dam and significant decrease in mean fetal body weight. The NOAEL was 300 mg/kg/day.

870.3700a Prenatal Developmental Toxicity Study

– Rat

In a developmental (teratology) study (MRID# 43928925), rats (Strain: Tif: RAI f (SPF)) received either 0, 5, 50, 500, or 1000 mg/kg/day S

- metolachlor (95.6% a.i.) suspension in 0.5% (w/w) aqueous solution of sodium carboxymethylcellulose by oral gavage from gestation days 6 through 15.

No treatment related mortality was noted. There was a dose related increase in clinical signs seen as all 500 and 1000 mg/kg/day animals and 9/24 of the 50mg/kg/day animals exhibited as pushing head through bedding for about one hour. This was noted throug hout theS

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Page 53 of 70 dosing period and may be an indication of neurotoxicity. The 500 and 1000 mg/kg/day dose groups had lower overall body weights at gestation days 15 and 21 and gained less weight than the control during the dosing period (gestation days 6

- 16) and f or the calculated periods of gestation days 6

- 21 and 0

- 21, also for corrected body weight gains from gestation days 6

- 21. Also the 500 and 1000 mg/kg/day dose groups had reduced food consumption during the dosing period (gestation days 6

- 16, statistically significantly different), reduced food consumption following the dosing period and for the overall periods (gestation days 6

- 21 and 0

- 2 1). This is also reflected in reduced food efficiency for the same periods (6

- 16, 6

- 21, 6

- 21, and 0

- 21).

The maternal toxicity NOEL was 50 mg/kg/day with a LOEL of 500 mg/kg/day based on increased clinical signs of toxicity, decreased body weights and body weight gains and reduced food consumption and reduced food efficiency. No significant treatment related developmental toxicity was noted at the dose levels tests. The developmental toxicity was equal to or greater than 1000 mg/kg/day, a LOEL was not reached.

870.3700a Prenatal Developmental Toxicity Study

– Rat

In a developmental toxicity study (MRID 44931711), 28 pr esumed pregnant Wistar B: Hanlbm:WIST rats per group were administered CGA 354743 Technical (98%; Batch No. KI

5408/6) by gavage in 0.5% aqueous sodium carboxymethylcellulose in 0.1% aqueous polysorbate 80 at doses of 0, 250, 500, or 1000 mg/kg/day on gest ation days (GD) 6

- 15, inclusive. Controls were treated with 0.5% sodium carboxymethylcellulose in 0.1% aqueous polysorbate 80 (vehicle). On GD 21, dams were sacrificed, subjected to gross necropsy, and all fetuses examined externally. Approximately one

- half of each litter was processed for visceral examination and the remaining one

- half was processed for skeletal examination. All animals survived to terminal sacrifice. No clinical signs of toxicity were observed in any animal. Maternal body weights, bo dy weight gains, and food consumption were similar between the treated and control groups throughout the study. Maternal necropsy was unremarkable.

Therefore, the maternal toxicity NOAEL is  1000 mg/kg/day and the maternal toxicity LOAEL was not identifi ed.

No differences were observed between the treated and control groups for number of corpora lutea, number of implantation sites, live fetuses/dam, pre

- and post

- implantation losses, fetal body weights, or fetal sex ratios.

No treatment

- related external , visceral, or skeletal malformations/variations were observed in any fetus from any group.

The high dose is equivalent to the limit dose for developmental toxicity studies.

Therefore, the developmental toxicity NOAEL is  1000 mg/kg/day and the developme ntal toxicity LOAEL was not identified.

This study is classified as Acceptable/Guideline and satisfies the requirements for a developmental toxicity study [870.3700 (§83

- 3a)] in rats.S

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Page 54 of 70 870.3700a Prenatal Developmental Toxicity Study

- Rat

In a developme ntal toxicity study (MRID 44929510), 24 presumed pregnant Tif: RAI f (SPF) (hybrids of RII/1  RII/2) rats per group were administered CGA 51202 Technical (100%; Batch No. JD 7069/3) by gavage in 0.5% aqueous sodium carboxy methylcellulose solution at dos es of 0, 10, 100, or 1000 mg/kg/day on gestation days (GD) 6

- 15, inclusive. Controls were treated with 0.5% sodium carboxymethylcellulose (vehicle). On GD 21, dams were sacrificed, subjected to gross necropsy, and all fetuses examined externally. Approx imately one

- half of each litter was processed for visceral examination and the remaining one

- half was processed for skeletal examination.

One low

- dose animal was sacrificed moribund on GD 20 with a urogenital infection. All other animals survived to terminal sacrifice. No clinical signs of toxicity were observed in any animal. Maternal body weights and body weight gains were similar between the treated and control groups throughout the study. Food consumption was not affected by treatment. Materna l necropsy was unremarkable.

Therefore, the maternal toxicity NOAEL is  1000 mg/kg/day and the maternal toxicity LOAEL was not identified.

No differences were observed between the treated and control groups for number of corpora lutea, number of implanta tion sites, live fetuses/dam, pre

- and post

- implantation losses, fetal body weights, or fetal sex ratios.

No treatment

- related external, visceral, or skeletal malformations/variations were observed in any fetus from any group.

The high dose is equivalent to the limit dose for developmental toxicity studies.

Therefore, the developmental toxicity NOAEL is  1000 mg/kg/day and the developmental toxicity LOAEL was not identified.

This study is classified as Acceptable/Guideline and satisfies the requirements for a develop

mental toxicity study [870.3700 (§83

- 3a)] in rats.

870.3700b Prenatal Developmental Toxicity Study

– Rabbit

In a developmental (teratology) study (MRID# 43928924), sexually mature virgin female New Zealand White, S.P.F. Rabbits (Strain: Ha r:PF/CF(NZW)BR) from H.A.R.E., Rabbits for Research, Hewitt, N.J. Received either 0, 20, 100, or 500 mg/kg/day CGA

- 77102 Technical (Lot No. FL

- 830813 with a purity of 89.6% (93.7% S isomer) suspension in 3% corn starch containing 0.5% Tween 80 by oral gava ge from gestation days 7 through 19.

No treatment related mortality was noted. There was a dose related increase in little/none/soft stool observations at the 100 and 500 mg/kg/day dose levels. The 500 mg/kg/day dose groupS

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Page 55 of 70 had lower overall body weight s at gestation days 19, 29 and corrected body weights at day 29 gained less weight than the control during the dosing period (gestation days 7

- 19) with a rebound weight gain following the dosing period (gestation days 19

- 29), an indicator of toxicity. Thi s group also had lower overall weight gain for the calculated periods of gestation days 7

- 29, 0

- 29 and corrected body weight gains for 0

- 29. This was supported by reduced food consumption during the dosing period (gestation days 7

- 19) and for the overall periods (gestation days 7

- 28 and 0

- 28) with a rebound in food consumption following dosing (gestation days 19

- 28) at the 500 mg/kg/day dose level. This is also reflected in reduced food efficiency for the same periods (719, 7

- 28, and 0

- 28) and increased f ood efficiency following dosing (19

- 28) at the 500 mg/kg/day dose level. The maternal toxicity NOEL was 20 mg/kg/day with a LOEL of 100 mg/kg/day based on clinical signs of toxicity.

No significant treatment related developmental toxicity was noted at th e dose levels tests. The developmental toxicity was equal to or greater than 500 mg/kg/day, a LOEL was not reached.

This study is classified as Acceptable

- Guideline and satisfies the guideline requirements [870.3700 (§83

- 3b)] for a teratology study in ra bbits.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

- Rat In a two

- generation reproduction study (MRID 00080897), metolachlor (95.4% a.i.) was administered in the diet to two consecutive generations of 15 male/30 female CD albino rats at dose levels of 0, 30, 300 or 1000 ppm (F 0 males: 0, 2.4, 23.5 and 75.8 mg/kg/day; F 0 females: 0, 2.5, 26.0 and 85.7 mg/kg/day; F 1 males: 0, 2.3, 23.7 and 76.6 mg/kg/day; F 1 females: 0, 2.6, 25.7 and 84.5 mg/kg/day).

There were no deaths in the F 0 generation. Two females of the F 1 generation died during the pre

mating period, one in the 300 ppm group at 32 days and the other in the 1000 ppm group at 52 days. One female in the 300 ppm group was found dead on gestation day 19 and a control grou p female was sacrificed in a moribund condition on lactation day 1. Based on necropsy examinations, none of the deaths was treatment

- related. There were no treatment

- related clinical signs of toxicity in either generation. Body weight, body weight gain and food consumption were unaffected in the F 0 generation. In the F 1 generation, food consumption was significantly decreased in females of the 1000 ppm group at several timepoints; however, there was no effect on body weight/body weight gain. Therefore, this finding was not considered toxicologically significant. There were no treatment

- related effects on organ weights or gross/microscopic necropsy examinations in either generation.

There was no evidence of a treatment

- related effect on any of the reproducti ve parameters for either generation. Offspring body weight was significantly decreased in the F 1 litter on lactation days 14 and 21 (91

- 96% of control value) and in the F 2 litter on lactation days 4, 7, 14 and 21S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 56 of 70 (92

- 95% of control value). Although the magnitude of the decrease is small, the finding is regarded as toxicologically significant.

The parental toxicity LOAEL was not established. The NOAEL was 1000 ppm (F 0 males/females: 75.8/85.7 mg/kg/day; F 1 males/females: 76.6/84.5 mg/kg/day).

The reprod uctive toxicity LOAEL was not established. The NOAEL was 1000 ppm (F 0 males/females: 75.8/85.7 mg/kg/day; F 1 males/females: 76.6/84.5 mg/kg/day).

The offspring LOAEL was conservatively established at 1000 ppm (F 0 males/females: 75.8/85.7 mg/kg/day; F 1 male s/females: 76.6/84.5 mg/kg/day) based on decreased body weight in F 1 and F 2 litters . The NOAEL is 300 ppm (F 0 males/females: 23.5/ 26.0 mg/kg/day; F 1 males/females: 23.7/25.7 mg/kg/day).

The study is classified as Acceptable/guideline and satisfies the gu ideline requirements for a multi

- generation reproduction study in rats (83

- 4; OPPTS 870.3800).

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

– Rat See Carcinogenicity section below.

870.4100b Chronic Toxicity

- Dog In a chronic toxicity study (MRIDs 40980701, 41164501, 42218601 and 42218602), metolachlor (97% a.i.) was administered in the diet to Beagle dogs (6/sex/group for control and high dose groups; 4/sex/group for low

- and mid

- dose groups) at dose levels of 0, 100, 300 or 1000 ppm (males: 0, 3.5, 9.7 and 32.7 mg/kg/day, respectively; females: 0, 3.6, 9.7 and 33.0 mg/kg/day, respectively) for one year. Two dogs of each sex in the control and high

- dose group designated as recovery animals were treated for 52 weeks and were then allow ed a 4

- week recovery period. An additional 4 dogs/sex/group were treated at the same dose levels and sacrificed at 13 weeks.

There were no treatment

- related deaths or clinical signs of toxicity. Mean body weight gain was decreased in the 1000 ppm group f emales, considering both all animals (5

- 17% decrease) and only those treated for 52 weeks (5

- 17% decrease). Alkaline phosphatase was significantly increased in the 1000 ppm females at weeks 12, 26 and 40; however, the increase was not considered toxicologi cally significant due to the small magnitude of the effect and the lack of accompanying necropsy findings.

The LOAEL was 1000 ppm for females (33.0 mg/kg/day) based on decreased body weight gain. The NOAEL was 300 ppm (9.7 mg/kg/day). The LOAEL for males was not established. The NOAEL for males was 1000 ppm (32.7 mg/kg/day).

The study is classified as Acceptable/guideline and satisfies the guideline requirements for a chronic toxicity study in dogs (83

- 1; OPPTS 870.4100).S

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Page 57 of 70 A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study

- rat In a chronic toxicity/carcinogenicity study (MRID 00129377), metolachlor (95.3%), was administered in the diet to 60 CD

- Crl:CD albino rats/sex/group at dose levels of 0, 30, 300 or 3000 ppm (0, 1.5, 15 or 150 mg/kg/day ) for two years. An additional 10 rats/sex/group were administered either 0 ppm or 3000 ppm in the diet for 12 months; 5 rats/sex/group were sacrificed after treatment and the remaining 5/sex/group were allowed to recover for four weeks and then sacrifice d. Comparable mortality were observed in the treated and control animals. There were no treatment

- related clinical signs of toxicity. Mean body weight gain was slightly decreased in the 3000 ppm females (6

- 17% decrease) throughout the study; the changes were not statistically significant. Mean food consumption was slightly decreased (4

- 9% decrease) in the 3000 ppm females; the decrease was not statistically significant. Absolute, relative and liver

- to

brain weight were increased (7%, 13%, and 5%, respe ctively) in the 3000 ppm males. These increases were also observed in the 3000 ppm males after four

- week recovery period. However, the toxicological significance of the finding is questionable as there were no accompanying clinical pathology or histologi c changes.

For chronic toxicity, in males, the NOAEL was 3000 ppm (150 mg/kg/day), a LOAEL was not established. For females, the NOAEL was 300 ppm (15 mg/kg/day) and the LOAEL was 3000 ppm (150 mg/kg/day) based on slightly decreased body weight gain and food
consump tion.

The study is classified as acceptable/guideline and satisfies the guideline requirements for a chronic toxicity study in rats (83

- 1; OPPTS 870.4200a).

870.4200b Carcinogenicity (feeding)

- Mouse In a carcinogenicity study (MRID 00117597 6 ), met olachlor (reported to be 95% a.i.) was administered in the diet to 68 CD

- 1 mice/sex/group at doses of 0, 300, 1000 or 3000 ppm (0, 45, 150 or 450 mg/kg/day, based on 1ppm equals 0.150 mg/kg/day). Eight mice/sex/group were sacrificed at 12 and 18 months. H igh dose females had a significant increased mortality rate due to a number of deaths during the first few weeks of treatment (control: 24/52; high dose females: 34/52 at termination). Although the deaths were possibly attributable to a viral infection, t he contribution of the test material can not be dismissed. Body weight was statistically significantly decreased (91

- 95% of control value) throughout the study in the 3000 ppm males and during the latter half of the study in the 3000 ppm females (93

- 95%). Body weight gain was consistently decreased in the 3000 ppm males (48

- 48%) and females (59

- 86%). Food consumption was comparable between treated and control group until week 90 of treatment, at which time the 3000 ppm males consumed 10% less than contr ols. The decrease was statistically significant at weeks 98, 102 and 104. There was no significant effect on female food consumption. There was

6 According to the Second Peer Review of Metolachlor (April 17, 1991), a mouse carcinogenicity study (MRIDs 00042725, 00084003) conducted by Industrial Biotest (validated by EPA)at doses of 0, 30, 1000 and 3000 ppm also showed no evidence of carcinogenic effects.S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 58 of 70 no evidence of treatment

- related effect on hematology or clinical chemistry parameters. Organ weight was no t affected except for a dose

- related decrease in absolute and relative weight of the seminal vesicles of males which was statistically significant at the high dose. However, there was no effect on testes weight and no accompanying histological changes in the seminal vesicles; therefore, the toxicological significance of the finding is questionable. There were no treatment

related microscopic changes. There were no treatment

- related increases in tumor incidence in the study.

The NOAEL was 1000 ppm (150 mg/kg/day) and the LOAEL was 3000 ppm (450 mg/kg/day) based on possible treatment

- related deaths in females and decreased body weight/body weight gain in males and females.

The study is classified as acceptable/guideline and satisfies the guideline requi rements for a carcinogenicity toxicity study in mice (83

- 5; OPPTS 870.4200).

A.4.6 Mutagenicity There was no evidence of mutagenicity in vitro or in vivo with either CGA 354743 or CGA 51202. Mutagenicity Studies with CGA 354743

Gene Mutation 870.5100 Sal monella/Escheri chia bacterial reverse mutation assay 44931712 (1996)

acceptable/guideline 312.5, 625.0, 1250.0, 2500.0 and 5000.0 μg/plate in the presence and absence of mammalian metabolic activation (S9

- mix) Strains TA98, TA100, TA102, TA1535 and

TA1537 of S. typhimurium and strain WP2(uvrA) of E. coli were exposed to CGA

- 354743 tech. in DMSO at con cen trations of 312.5

- 5000.0 μg/plate in the presence and absence of mammalian metabolic activation (S9

- mix). T here was no evidence of induced mutant colonies over background.

Gene Mutation 870.5300 mammalian cell gene mutation assay at the HPRT locus, Chinese hamster V79 cells 44991102 (1999)

acceptable/guideline concentrations of 185.19, 555.56, 1666.67, 500 0.00 μg/mL in the presence and absence of mammalian metabolic activation (S9

- mix). Chinese hamster V79 cells in culture were exposed

to CGA

- 354743 tech. in bidistilled water at concentrations of 185.19

- 5000.00 μg/mL in the presence and absence of mamma lian metabolic activation (S9

- mix). There was suggestive (statistical) evidence of a possible induction of mutant colonies over background; however, the results are unlikely to be biologically significant because the absolute numbers of mutant colonies

we re low and within the testing laboratory’s historical solvent control ranges.

Cytogenetics 870.5395 44931713 (1998)

acceptable/guideline Five mice/sex/dose were treated once each via oral

gavage with CGA

- 354743 tech. at doses of 1250

-S

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Page 59 of 70 Micronucleus assay in mouse bone marrow cells 1250, 2500 and 5000

mg/kg body weight 5000 mg/kg body weight. There was no significant

increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any dose or trea tment time.

Other Effects 870.5503, Unscheduled DNA Synthesis 44931714 (1998)

acceptable/guideline concentrations of 9.77, 39.06, 156.25, 625.00, 2500.00, 5000.00 μg/mL Primary rat hepatocyte cultures were exposed to

CGA

- 354743 tech in bidistilled water at concentrations of 9.77

- 5000.00 μg/mL for 16 to 18 hours in an initial assay and to concentrations of 78.13

- 2500 μg/mL for 16 to 18 hours in a confirmatory assay. There was no evidence that unscheduled DNA synthesis, as determined by radioactiv e tracer procedures (nuclear silver grain counts), was induced.

Mutagenicity Studies with CGA 51202

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

Classification /Doses Results

Gene Mutation 870.5100 Salmonella/Escheri chia bacterial reverse mutation assay 44929512 (1992)

acceptable/guideline 312.5, 625, 1250, 2500, 5000 ug/plate Strains TA98, TA100, TA1535 and TA1537 of S.

typhimurium and strain WP2(uvrA) of E. coli were exposed to CGA

- 51202 technical in DMSO
at concen tra tions of 312.5

- 5000.0 μg/plate in the presence and absence of mammalian metabolic activation.

There was no evidence of induced mutant colonies over background.

Cytogenetics 870.5395, Micronucleus assay in mouse bone marrow cells MRID 44929511

(1992) 600, 1200 or 2400 mg/kg acceptable/guideline Five mice/sex/dose were treated once via oral

gavage with CGA

- 51202 technical at doses of 600

- 2400 mg/kg body weight. There was no biologically significant increase in the frequency of micronucleated poly chromatic erythrocytes in bone marrow after any dose or treatment time used in the study.

Gene Mutation 870.5300 MRID 45001201

(1999) CGA 51202 tech. was tested up to cytotoxic

concentrations. Statistically significant increases in mean mutant frequency were seen in the in itialS

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Page 60 of 70 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

mammalian cell gene mutation assay at the HPRT locus, Chinese hamster V79 cells 500, 1000, 2000 or

4000 ug/mL in initial assay; 375, 750, 1500 or 3000 ug/mL in confirmatory assay, in the presence and absence of mammalian metabolic activation (S9

- mix). assay with S9

- mix at 500 μg/mL (6.66 x 10 6 ) and

1000 μg/mL (5.56 x 10 6 ) compared to the solvent control value of 4.02 x 10 6 and without S9

- mix at 500 μg/mL (15.35 x 10 6 ) compared to the solvent control value of 12.90 x 10 6 . The increases were smal l and the actual mean mutant frequencies were within the range of historical solvent control values. No positive dose

- response was seen and no statistically significant increases in mean mutant frequencies were seen in the confirma tory assay. The solven t and positive controls induced the appropriate response. There was no evidence of a biologically significant induction of mutant colonies over background.

A.4.8 Metabolism

870.7485 Metabolism

- Rat

In a metabolism study (MRID 44931715), groups of three male and three female rats were each given [phenyl

- U

14 C] CGA 77102 (batch no. ILS

- 143.1; purity 98.9%) and non

- radiolabeled CGA 77102 (batch no. AMS 757

- 101; purity 99.8%) to provide a total single oral dose of 0.5 or 100 mg/kg. Urinary and fecal e xcretion were monitored over 72 hours and major metabolites identified and quantified. The study focused on evaluating the presence of the metabolites CGA 354743, CGA 368208, and CGA 357704 in the excreta of rats.

There were no deaths or overt signs of to xicity attributed to the test material. Actual adminis

tered doses were 3

- 8% greater than nominal. Overall recovery of administered radio activity was an acceptable 93.83

- 99.18%. Urinary excretion and carcass burden data implied that absorption
was appr oximately 38

- 49% of the administered dose. Most (86.5

- 91.7%) of the radioactivity recovered at 72 hours post was associated with the urine and feces. The available data suggested that urinary excretion was slightly greater in female rats than male rats (42% for low

- and high

dose females as compared to 30% and 32% of low

- and high

- dose males, respectively), and fecal elimination was expectedly less (approximately 13

- 15%) for females than for males. However, the small sample size (three rats per sex) pre cludes a definitive assessment of gender

- specific differences in excretory pattern. Time

- course data for absorption and excretion were not provided. Based upon the residual radioactivity in the carcasses, accumulation in the tissues was less than 10% of t he administered dose at 72 hours after administration.S

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Page 61 of 70 Both urinary and fecal metabolites were identified and quantified. For both routes of elimina

tion, three major metabolites were identified but none represented more than 0.25% of the administered d ose. Characterization of these metabolites and comparison to known reference standards revealed them to be CGA 357704, CGA 354743, and CGA 368208. In the feces, CGA 357704 and CGA 354743 represented a notably greater percent of the administered dose than in the urine. The amounts of CGA 368208 were similar in the feces and urine. Biliary excretion experiments were not performed and, therefore, no assessment can be made regarding biliary or gut microflora as the source of these biotransformation product s in the feces.

This metabolism study in rats is Acceptable/Non

- guideline . Although not satisfying the requirements for a Metabolism and Pharmacokinetics study [OPPTS 870.7485 (85

- 1)], the study was well designed and conducted, and provided supplemental data regarding the quantitation and identification of urinary and fecal metabolites in rats given a single oral dose of CGA 77102.

Executive Summary : In a metabolism study (MRIDs 44931716 and 44931717), groups of four male and female and six male Tif: RAI f (SPF) rats were given single oral doses of [Phenyl

- U

14 C]

- CGA

- 376944 (0.5 mg/kg nominal; Batch No. ILS

- 125.4 radiochemical purity >95.5%), for the metabolism and bile

- duct cannulation studies, respectively.

There were no deaths or overt signs of toxici ty that could be attributed to the test material. Weight loss in bile

- duct cannulated rats was attributed to surgical trauma. Radioactivity inventory indicated an acceptable 96.46

- 99.01% recovery of the administered dose among the experimental groups. Ba sed on urinary excretion, biliary excretion, and carcass burden, 17.35% of the administered radioactivity was absorbed following a single oral dose of 0.5 mg/kg of [Phenyl

- U

14 C]

- CGA

- 376944. Absorption was rapid but limited and most of the absorbed radioa ctivity (92.3%) was excreted within 24 hours; primarily in the bile. At 72 hours, measurable radioactivity was found only in the liver of non

- cannulated rats. Carcass burdens accounted for <0.01% of the administered dose at necropsy.

Fecal elimination was the major route of excretion, accounting for most of the administered oral dose in non

- cannulated rats (94.24

- 96.27%). Fecal excretion was rapid with 98.8

- 99.2% of the fecal excretion occurring within 24 hours post

- dosing. Urinary excreti on, accounted for only 2.1

- 4.4% of the dose in non

- cannulated rats and 5.3% in bile

- duct cannulated rats. Urinary excretion was rapid and nearly complete within 24 hours of dosing. Biliary excretion repre

sented 11.5% of the administered dose at 48 hours . The majority of biliary excretion (99.2%) occurred within 24 hours after dosing. In bile

- duct cannulated animals, an additional 76.8% of the administered dose was excreted in the feces. Based on these data, biliary excretion is a contributor to fecal elimination of the test material. This appears consistent with the occurrence of enterohepatic circulation via the hepatic portal system and bile

- duct. Only a minor percentage of the dose (5.3%) appeared to enter the systemic circulation where it was rap idly excreted by the kidneys. No biologically relevant gender

- related differences were detected in the oral dose
groups.
Blood pharmacokinetic parameters could not be calculated due to low blood concentrations and rapid clearance of the administered dose . Blood levels of radioactivity peaked in both sexes within one hour post

- dosing.S

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Page 62 of 70 It is evident from the results of this study that the test material undergoes limited but rapid absorp tion and nearly complete excretion within 24 hours. The primary ro ute of excretion is via the feces with biliary excretion products representing about 15.0% of the fecal excretion pro

ducts. At the dose tested, [ 14 C]

- CGA

- 376944 exhibits little potential for accumulation in the tissues. There were no significant gender

- related differences in absorption and disposition of the test material. The unchanged test material accounted for >90% of the dose in both males and females. The unknown metabolites of urine and feces, separated by TLC accounted for 0.2

- 2.8% of the admin istered radioactivity and were not characterized further.

This combined metabolism study in rats is Acceptable/Guideline and satisfies the requirements for a Metabolism and Pharmacokinetics study [OPPTS 870.7485 (§85

- 1)].

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID 48783301), S

- Metolachlor (98.6% a.i., Lot # CAB9J054)

was administered in the diet for 28 consecutive days (Days 0

- 27) to female Crl:CD

- 1 (ICR) mice (10 animals/dose) at doses of 0, 1500, 3000 or 5000 ppm ( 0, 304.3, 639.5 or 1108.5 mg/kg/day, respectively). Four days prior to sacrifice, animals in all groups were immunized with a suspension of sheep red blood cells (SRBC) by intravenous injection (1 x 108 SRBC/animal, 0.2 mL/animal dose volume). Animals in the positive control group received intraperitoneal injections of cyclophosphamide (50 mg/kg bw/day) on Days 24

- 27. All animals were evaluated for mortality, clinical signs, body weight changes, and gross pathology. On Day 28, animals were sacrificed an d spleens were collected. Spleen cell suspensions were prepared, spleen cell counts were performed, and the numbers of specific IgM antibody

- forming cells directed towards the SRBC antigen were determined to measure the humoral immune response using the

s plenic Antibody

- Forming Cell (AFC) assay. There were no treatment

- related effects on clinical observations, body weight , body weight gain, food consumption, and spleen or thymus weights. A higher liver weight (absolute and adjusted) was noted at all dos age levels of S

- Metolachlor, with significant differences noted in the mid and high doses. The NOAEL for systemic toxicity in female mice is 5000 ppm (actual dose of 1108.5 mg/kg/ bw/day); the LOAEL was not determined, tested above the limit dose.

For i mmunotoxicity, there were no statistically significant treatment

- related effects on anti

SRBC AFC response. A high inter

- individual variability was noted in all the treatment groups as well as in the control group. Examination of individual animal data d id not show any trend or distribution that would demonstrate significant suppression of the anti

- SRBC AFC response. The positive control group showed a statistically significant reduction in the anti

- SRBC AFC response, confirming the validity of the immun otoxicity assay.

A natural killer (NK) cell activity assay was not performed. The toxicology database for S

metolachlor does not reveal any evidence of treatment

- related effects on the immune system.S

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Page 63 of 70 The overall weight of evidence suggests that this che mical does not directly target the immune system. Under HED guidance, a NK cell activity assay is not required at this time.

Under the conditions of this study, the NOAEL for immunotoxicity in female mice is 5000 ppm (actual dose of 1108.5 mg/kg/ bw/day) . The LOAEL for immunotoxicity was not determined.

This immunotoxicity study is classified acceptable/guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in the mice.S

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Page 64 of 70 Appendix B. Field Trial Summaries

Table B.1. Summary of Residues from Cantaloupe Field Trials with S

- Metolachlor. Crop Matrix Trt 1 Total

Application Rate (lb ai/A) [kg ai/ha] PHI

(days) n 2 S

- Metolachlor residues 3 (ppm)

Min. 4 Max. 4 LAFT

5 HAFT

5 Media

n 5 Mean

5 SD 5

Cantalou
pe 2 1.26

- 1.33

[1.42

- 1.49] 27

- 33 9 <0.13 0 0.391 <0.13

0 <0.322 0.130 0.165 0.06 46 3 1.26

- 1.34 [1.42

- 1.50] 8 <0.13 0 0.170 <0.13

0 0.166 0.130 0.135 0.01 27

1 TRT 2 reflected foliar broadcast application, and TRT 3 reflected application banded to row middles.

2 n = number of field trials.

3 Combined residues of SYN

- 506357 and SYN

- 508500 in parent equivalents.

4 Values based on total number of samples.

5 Values based on per

- trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ (converted to parent equivalents) are assumed to be at the LOQ (0.130 ppm).

Table B.2. Summary of Residues from Summer Squash Field Trials with S

- Metolachlor

. Crop Matrix TRT

No. 1 Total Application Rate lb ai/A (g ai/ha) PHI

(day s) n 2 S

- Metolachlor residues 3 (ppm)

Min. 4 Max. 4 LAFT

5 HAF T 5 Medi

an 5 Mean

5 SD 5

Summer squash 02 0.66

- 0.72

(735

- 802) 30

-

75 9 <0.13

0 <0.13 0 <0.13 0 <0.13 0 0.130 0.130 N/A

03 1.24

- 1.35 (1393

- 1513) 9 <0.13 0 <0.13 0 <0.13 0 <0.13 0 0.130 0.130 N/A

04 0.65

- 0.70 (724

- 788) 21

-

50 9 <0.13

0 <0.13 0 <0.13 0 <0.13 0 0.130 0.130 N/A

05 1.28

- 1.36 (1436

- 1528) 9 <0.13 0 <0.13 0 <0.13 0 <0.13 0 0.130 0.130 N/A

1 TRTs 2 and 3 reflected preemergence application, and TRTs 4 and 5 reflected foliar application.

2 n = number of field trials.

3 Combined residues of SYN

- 506357 and SYN

- 508500 in parent equivalents.

4 Values based on total number of samples.

5 Values base d on per

- trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ (converted to parent equivalents) are assumed t o be at the LOQ (0.13 ppm). N/A = Not applicable.S

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Page 65 of 70 TABLE B.3. Summary of Residue Data from Crop Field Trials with S

- Metolachlor. Commodit
y Total

Applic. Rate (lb ai/A) [kg ai/ha] Treatment PHI

(days ) Analyte Residue Levels (ppm) 1

n Min. Max. HAF

T 2 Median (STMd R) Mean (STM R) Std. Dev. 3

Cucumber 0.89

- 1.00

[1.00

- 1.12] Post

emergence 32

- 52 CGA

49751 22 <0.05 <0.05 0.05 0.05 0.05

--

CGA

37913 22 <0.05 <0.05 0.05 0.05 0.05

--

Total 22 <0.10 <0.13 0.13 0.13 0.13

-- 1.22

- 1.31 [1.36

- 1.47] Post

e mergence 32

- 52 CGA

49751 20 <0.05 <0.05 0.05 0.05 0.05

--

CGA

37913 20 <0.05 <0.05 0.05 0.05 0.05

--

Total 20 <0.13 <0.13 0.13 0.13 0.13

-- 0.92

- 1.00 [1.03

- 1.12] Pre

emergence 45

- 76 CGA

49751 21 <0.05 <0.05 0.05 0.05 0.05

--

CGA

37913 21 <0.05 <0.05 0.05 0.05 0.05

--

Total 21 <0.13 <0.13 0.13 0.13 0.13

-- 1.22

- 1.36 [1.36

- 1.51] Pre

emergence 45

- 76 CGA

49751 20 <0.05 <0.05 0.05 0.05 0.05

--

CGA

37913 20 <0.05 <0.05 0.05 0.05 0.05

--

Total 20 <0.13 <0.13 0.13 0.13 0.13

-- 1 For statistical calculations, the LLMV (0.05 ppm for each analyte) was used for values reported as <LLMV in Table C.3. Total residues are expressed as parent equivalents by using the following equation. CGA

- 49751 x 1.14 + CGA

- 37913 x 1.47 = total metolac hlor equivalents.
2 HAFT = Highest Average Field Trial.
3 Standard deviation is not calculated when all samples have nonquantifiable residues.S

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Page 66 of 70 Table B.4. Summary of Residues from Head Lettuce Field Trials with S

- Metolachlor. Crop Matrix TR

T No. 1 Total Application Rate (lb ai/A) PHI

(days) n 2 S

- Metolachlor Residues 3 (ppm)

Min. 4 Max. 4 LAFT

5 HAFT

5 Media

n 5 Mean

5 SD 5

Head Lettuce 02 1.283

- 1.331 18

- 21 7 <0.13 0 <0.183 <0.13

0 <0.182 0.134 0.141 0.01 83 03 1.988

- 2.059 18

- 21 7 <0.13 0 0.414 <0.13

0 0.412 0.276 0.272 0.09 34 04 0.988

- 1.030 18

- 21 7 <0.13 0 <0.365 <0.13

0 <0.340 0.155 0.198 0.09 40

1 TRTs 02 and 03 reflected soil or foliar broadcast at transplant + mid/late

- season foliar application. TRT 04 reflected a single mid/late season foliar application.

2 n = number of field trials.

3 Combined residues of SYN

- 506357 and SYN

- 508500 in parent equivalents.

4 Values based on total number of samples.

5 Values based on per

- trial averages. LAFT = lowest average field trial, HAFT = highest average f ield trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ (converted to parent equivalents) are assumed to be at the LOQ (0.13 ppm).

Table B.5. Summary of Residues from Leaf Lettuce Field Trials with S

- Metolachlor. Crop Matrix TRT No. 1 Total Application Rate (lb ai/A) PHI

(days) n 2 S

- Metolachlor residues 3 (ppm)

Min. 4 Max. 4 LAFT

3 HAFT

3 Media

n 3 Mean

3 SD 3

Leaf lettuce 02 0.64

- 0.66 27

- 28 6 <0.13 0 0.519 <0.13

0 0.501 0.186 0.244 0.14 6 03 & 05 0.92

- 1.04 25

- 30 8 <0.13 0 1.415 <0.13

0 1.228 0.320 0.462 0.39 0 04 & 06 1.28

- 1.33 20

- 30 8 <0.13 0 0.758 <0.13

0 0.754 0.163 0.255 0.21 3 07 2.01

- 2.03 20

- 21 2 0.338 1.050 0.351 1.021 0.686 0.686 0.47 3 08 1.00

- 1.02 20

- 21 2 <0.13 1 1.275 <0.14

7 1.173 0.660 0.660 0.72 6

1 TRTs 02 and 03 reflected preemergence application, TRT 04 reflected preemergence + foliar application, TRTs 05 and 08 reflected a single foliar application, and TRTs 06 and 07 reflected at

transplant + foliar application.

2 n = number of field trials.

3 Combined residues of SYN

- 506357 and SYN

- 508500 in parent equivalents.

4 Values based on total number of samples.

5 Values based on per

- trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, S D = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ (converted to parent equivalents) are assumed to be at the LOQ (0.13 ppm).S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 67 of 70 Table B.6. Summary of Residues from Strawberry Field Trials with S

- Metolachlor

. Crop Matrix Total

Application Rate (lb ai/A) PHI

(day s) n 1 S

- Metolachlor residues 3 (ppm)

Min. 2 Max. 2 LAFT 3 HAFT
3 Median

3 Mean 3 SD 3

Strawberr
y 1.19

- 1.23 24

- 33 8 <0.13

0 <0.13 4 <0.130 <0.132 0.130 0.130 0.001

2.38

- 2.50 24

-

33 8 <0.13

0 < 0.25 2 <0.130 <0.244 0.133 0.152 0.041

1 n = number of field trials.
2 Values based on total number of samples.
3 Combined residues of SYN

- 506357 and SYN

- 508500 in parent equivalents.
4 Values based on per

- trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ (converted to parent equivalents) a re assumed to be at the LOQ (0.130 ppm).

Table B.7. Summary of Residue Data in/on Sunflower Seed from Crop Field Trials with S

Metolachlor. Total Applic. Rate (lb ai/A) Applic. Method a PHI (days) Combined S

- Metolachlor Residue Levels (ppm)
Minimu

m Maximum HAFT Mean Std. Dev.
2.0 Preplant Incorp. (PPI) 122

- 147 <0.08 <0.26 0.22 0.14 b 0.07

2.0 Broadcast

Preemergence 107

-

147 <0.08 <0.49 0.47 0.26 b 0.17

2.0 PPI or Preemergence 107

- 147 <0.08 <0.49 0.47 0.20 c 0.14

a A single application of S

- metolachlor (7.64 lb/gal EC) was made at planting for all tests.
b N = 8. (The replicates from the trials were individually included in the statistics.)

c N = 16. (The replicates from the trials were individually included in the sta tistics.)S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 68 of 70 TABLE B.8. Summary of Total Residue Data for Peppers and Tomatoes from Crop Field Trials using S

- Metolachlor (7.6 lb/gal EC) 1

Commodi ty Total

Rate (lb a.i./A) PHI

(days) Combined SYN508500 and SYN506357 Residue Levels (ppm) 2

n Min. Max. HAFT
3 Median (STMdR 4 ) Mean

(STMR 5 ) Std.

Dev.

Bell Pepper 1.65

-

1.79 39

-

125 60 <0.08 <0.08 <0.08 <0.08 <0.08 <0.08

Hot Pepper 1.63

-

1.75 60

-

124 32 <0.08 <0.08 <0.08 <0.08 <0.08 <0.08

Tomato 1.62

-

1.75 36

-

120 10 6 < 0.08 <0.08 <0.08 <0.08 <0.08 <0.08

1 Three different application regimes were used; either a preplant incorporated or foliar applications. The data for each type of application were pooled as residues were identical.
2 Residues are expressed as S

- Metolachlor equivalents. The LOQ is 0.05 ppm for SYN508500, 0.03 ppm for SYN506357, and 0.08 ppm for combined residues.
3 HAFT = Highest Average Field Trial.
4 STMdR = Supervised Trial Median Residue.S

- Metolachlor Human Health Risk Assessment DP No. D425168

Page 69 of 70 Appendix C. Physical/Chemical Properties

Table C1. Physico

- Chemical Properties Parameter Value Reference Molecular Weight

MRID 47121701 (DP#s 332846, etc., 10/21/08, D. McNeilly) pH 7.8 at 25 oC (1% aqueous dispersion) Water solubility (20°C) 0.48 g/L

Solvent solubility (20°C to 25°C) Completely miscible with methanol, acetone, toluene, n

- octanol,

n

- hexane, ethyl acetate, and dichloromethane Vapor pressure (25°C) 2.8 x 10

- 5 mm Hg

Dissociation constant, pKa No dissociation constant in pH range 2

- 12 Octanol/water partition coefficient, log K OW (25°C) 3.05 at 25 oC

Soil Half

- life (or other relevant information from EFED Drinking water assessment)S

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Page 70 of 70 Appendix D. 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 the PHED 1.1, and the AHETF 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

. [ 7 ]

7 http://www.epa.gov/pesticides/science/handler

- exposure - data.html and http://www.epa.gov/pesticides/science/post

- app - exposure - data.html