Dimethomorph Human Health Risk Assessment DP No. D416888

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D .C. 20460

MEMORANDUM

DATE: October 22

, 2014 OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

SUBJECT: Dimethomorph: Human Health Ri sk Assess ment to Support Establis hment of a Tolerance Without U .S. Registration for Papaya.

PC Code: 268800

Decision N o.: 485316

Petition No.: 3E8218

Risk Assessment Type: Sing l e Chemical / Aggregate

TXRNo

. :NA

MRIDNo

. : NA DP Barcode: 416888 Registration No. : NA Regulatory Action: Tolerance Assessment (No S3)

Case No.: NA

CAS No.: 110488-70- 5

40 CFR: 180.493

FROM: Sumitra Bose Biswas,

# C~em~t**R~** Assessor

# ~ 

# /J•**~)WU-** '
Sheila Piper

, Chemist**(J~ ~**  

# p

Yung Yang

, Ph.D., Toxicologist !{) ·**~~** __ 

### V '

Monica Hawkins, Ph. D

., M.P.H., Environme n ta l Health Scientist 11**L~>tt?U..OfUMlJ** Ri sk Assessment Branch VI

Health Effec t s Division (7509P)

,

THROUGH: D onna Davis, Acting

# Chie**Q.,u~** Risk Assessment Branch VI

H ealth Effects Division (7509P)

TO: Tamue Gibson

, M.S., Chemical Review Manager Shaja J oyner
, Product Manager

Rachel Holloman, Branch Chief Fungicide Herbic i de Br a n ch/ R eg i st ration Division (7505P)

Pa ge 1 of25Dimethomorph Human Health Risk Assessment DP No. D416888

Page 2 of 25 TABLE OF CONTENTS

1.0 Executive Summary

................................ ................................ ................................ ................... 3

2.0 HED Recommendations

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

2.1 Da ta Deficiencies

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

2.2 Tolerance Considerations

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

2.2.2 Recommended Tolerances

................................ ................................ ................................ ......... 5

2.2.3 Revisions to Petitioned

- For Tolerances

................................ ................................ .................... 5

2.3 Label Recommendations

................................ ................................ ................................ ........... 5

3.0 Introduction

................................ ................................ ................................ ................................ 6

3.1 Chemical Identity

................................ ................................ ................................ ....................... 6

3.3 Pesticide Use Pattern

................................ ................................ ................................ .................. 7

3.5 Consideration of Environmental Justice

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

4.0 Hazard Characterization and Dose

- Response Assessment

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

4.1 Summary of Toxicological Effects

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

4.2 Safety factor for Infants and Children (FQPA Safety Factor)

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

4.2.1 Completeness of the Toxicology Database

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

4.2.2 Evidence of Neurotoxicity

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

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

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

4.2.4 Residual Uncertainty in the Exposure Database

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

4.3 Toxicity Endpoint and Point of Departure Selections

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

4.3.1 Dose

- Response Assessment

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

4.3.2 Recommendation for Combining Routes of Exposures for Risk Assessment

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

4.3.3 Cancer Classification and Risk Assessment Recommendation

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

4.3.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment 12

5.1 Residue of Concern Summary and Rationale

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

5.2 Food Residue Profile

................................ ................................ ................................ ................ 15

5.3 Wa ter Residue Profile

................................ ................................ ................................ .............. 15

5.4 Dietary Risk Assessment

................................ ................................ ................................ ......... 16

5.4.1 D e s cr i p tion of R e si du e Da t a Us e d in Di e ta r y A ssess me n t

................................ ...................... 16

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ................................ . 16

5.4.3 Acute Dietary Risk Assessment

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

5.4.4 Chronic Dietary Risk Assessment

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

5.4.5 Cancer Dietary Risk Assessment

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

5.4.6 Dietary Summary Table

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

6.0 Residential Exposure/Risk Characterization

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

7.0 Aggregate Exposure/Risk Characterization

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

8.0 Cumulative Exposure/Risk Characterization

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

9.0 Occupational Exposure/Risk Characterization

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

10.0 References

................................ ................................ ................................ ................................ 19 Appendix A: Toxicology Assessment

................................ ................................ ................................ 20 Appendix B. International Residue Limits Table

................................ ................................ .............. 25Dimethomorph Human Health Risk Assessment DP No. D416888

Page 3 of 25 1.0 Executive Summary

The Registration Division requested that HED prepare a human health risk assessment for dimethomorph to support establishment of a tolerance without U.S. registration on papaya

.

Dimethomorph, ( E,Z

)

- 4

- [3

- (4

- chlorophenyl)

- 3

- (3,4

- dimetho xyphenyl)acryloyl]morpholine, is a systemic morpholine active ingredient having fungicidal activity. Dimethomorph was developed for control of downy mildew, late blight, and crown and root rot.

BASF Corporation has petitioned to establish a permanent t olerance without U.S. registration for the combined residues of fungicide dimethomorph (BAS 550 F) ( E,Z )

- 4

- [3

- (4

- chlorophenyl)

- 3

- (3,4

- dimethoxyphenyl)acryloyl]morpholine in/on imported papaya at 1.5 pp m

. The registrant has

indicated that Brazil is the only country using dimethomorph on papaya. The available Brazil ian

field trial data reflect the Brazilian use of dimethomorph in/on papaya with no more than three applications at a maximum label rate of 500 g a.i./ha (0.446 lb ai/A) during the growing sea son and 7 days of pre

- harvest interval (PHI).

The toxicology database for dimethomorph is complete, n o additional data is required. Dimethomorph has low acute toxicity by the oral, dermal, or inhalation route of exposure. It is not an eye or skin irrita nt, and is not a skin sensitizer. There is no evidence that dimethomorph is a developmental, reproductive, carcinogenic, mutagenic or immunotoxic chemical. The target organ is the liver. Dimethomorph is classified as "not likely to be carcinogenic to human s" based upon lack of evidence of carcinogenicity in rats and mice. There is no evidence of increased qualitative or quantitative susceptibility in the young and there is no evidence of neurotoxicity with dimethomorph and exposure estimates are unlikely to underestimate risk; therefore, the 10

- fold FQPA Safety Factor

can be reduced to 1x all assessments with the exception of the acute dietary assessment. The FQPA SF is retained for the acute dietary risk assessment to account for extrapolation of LOAEL to NOAEL for the acute dietary point of departure ( PoD )

. Acute and chronic dietary (food and water),

and short

- and intermediate

- term inhalation points of departure have been selected for risk

assessment. Dimethomo rp h does not pose a dermal hazard.

There a re no outstanding residue chemistry data. Based on the previous plant metabolism studies with three representative crops (potato, grape and lettuce) the qualitative nature of the dimeth omorph

residues is considered to be adequately understood. The residue of concern for the tolerance expression and risk assessment is the parent compound, dimethomorph (comprised of E and Z isomers). There are no animal feed items associated with the subject petitions. Thus, a discussion of animal metabolism is not required to support the requested new uses. Acceptable data were submitted depicting residues in target crops . These data are supported by storage stability data and were generated using adequately validated analytical methods

. Processing data are not required to support a use on papaya. There is an analytical method to enforce the proposed tolerance. There are no issues with respect to international harmonization associated with this petition. The data are adequate to suppo rt tolerance evaluation/enforcement and human health risk assessment.

Acute and chronic dietary (food and drinking water) exp osure and risk assessments were conducted

which include d all existing uses as well as the proposed papaya new import use . These u nrefinedDimethomorph Human Health Risk Assessment DP No. D416888

Page 4 of 25 assessments are based on tolerance

- level residues, 100% crop treated, and DEEM default processing

factors. For food and drinking water, the acute dietary risk estimate is below HED’s level of concern (<100% of the acute population adjusted dose (a PAD)) for the general U.S. populatio n (25 % aPAD) and all population sub

- groups; the most highly exposed population subgrou p was children 3

- 5 years old (39 % aPAD) a t the 95 th percentile of exposure. The resulting food and water chronic exposure

estimates were less than HED’s level of concern ( <100% cPAD) for general U.S. population ( 16 % cPAD) and all population sub

- groups; the most highly exposed population subgroup was children 1

- 2 years old with 25 % cPAD. Dimethomorph is classified as "not likely to be carcinogenic to humans" based upon lack of evidence of carcinogenicity in rats and mice; therefore, a cancer dietary risk assessment is not required.

There are no registered or proposed residential uses, or commercial/professional uses at residential

sit es associated with dimethomorph at this time. Therefore, a quantitative residential exposure assessment is not required

. Further, since there are no residential uses, acute and chronic aggregate includes only food and water and as noted above, there are no risks of concern.

There are no occupational exposures associated with the proposed import tolerances; therefore, a new occupational exposure assessment was not conducted for this risk assessment.

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 Lo w

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

2.0 HED Recommendations

There are no residue chemistry considerations that would preclude establishment of the requested tolerance without U.S. registration for dimethomorph on papaya at 1.5 ppm

.

2.1 Data Deficiencies

There are no data deficiencies associated with the proposed tolerance without U.S. registration for dimethomorph on papaya.

2. 2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The high performance liquid chromatography with ultraviolet detection ( HPLC/UV ) method FAMS

002

- 04 has been determined to be adequate for tolerance enforcement purposes for determining residues of dimethomorph in plant commodities

. This method is adequate to enforc e the proposed papaya tolerance

. Briefly the method is described as follows. H omogenized samples are extracted with acetone and the extract is mixed with sodium chloride solution and partitioned with dichloromethane (DCM). The DCM phase is evaporated to dryness and redissolved in methanol forDimethomorph Human Health Risk Assessment DP No. D416888

Page 5 of 25 cleanup by gel permeation ch romatography. The extract is then cleaned up on a silica gel column, using acetone:n

- hexane (20:80, v:v) to elute residues. The eluate is evaporated to dryness and

redissolved in methanol for HPLC /UV analysis. The reported limit of quantitation (LOQ) is 0.01 ppm and limit of detection (LOD) is 0.002 ppm for papaya

. The method has been successfully validated. A confirmatory method is also available, Method M 2577, a gas chromatographic ( GC ) method with nitrogen phosphorus detection (NPD)

.

Dimethomorph has previously been subjected to testing via the FDA multiresidue methods protocols of PAM I. Dimethomorph was not evaluated using Protocols A and B, based on its structure. Protocol C evaluation yielded marginal results for dimethomorph. Dimethomorph is recovered using Protocol D. Protocol E evaluation of dimethomorph yielded no recovery of the analytical standard from the Florisil column using either PAM I 211.14 or 252.12 eluting systems ( D192776, D. Davis, 3/13/95 )

.

2.2. 2 Recommended Tolerances

The p roposed and recommended tolerance without U.S. registration for d imethomorph is 1.5 ppm. The current tolerance expressions are not in compliance with HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner) and should be revised as the follow ing :

Tolerances are established for the residues of the fungicide dimethomorph , including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measu ring only dimethomorph, ( E,Z ) 4

- [3

- (4

- chlorophenyl)

- 3

- (3,4

- dimethoxyphenyl)

- 1

- oxo

- 2

- propenyl]morpholine , in or on the commodity.

Table 2.2.2 . Tolerance Summary for Dimethomorph , §180.493 Commodity Established/Proposed

Tolerance (ppm) HED

- Recommended Tolerance (ppm) Comments ( correct commodity definition )
Papaya 1 1.5 1.5

1 No U.S. registration

.

2.2. 3 Revisions to Petitioned

- For Tolerances

No revision to the petitioned

- for tolerance is required.

2.2.4 International Harmonization

There are no established Canadian

, Mexican or Codex maximum residue limits (MRLs) for residues of dimethomorph in /on papaya associated with this review ; theref ore there are no issues with respect to international harmonization associated with this petition.

2.3 Label RecommendationsDimethomorph Human Health Risk Assessment DP No. D416888

Page 6 of 25 This petition is for a tolerance without U.S. registration; therefore a discussion of label recommendations is not applicable

.

3 .0 Introduction

Dimethomorph is a systemic morpholine fungicide and was developed for control of downy mildew, late blight, and crown and root rot. Its mode of action is the inhibition of sterol (ergosterol) synthesis. It is currently registered for u se on bulb vegetables, cucurbit vegetables, fruiting vegetables, leafy Brassica greens, head and stem Brassica vegetables, hops, lettuce, potatoes, taro, grapes, and ginseng. The registered application methods for dimethomorph include the use of aerial

an d ground equipment.

Tolerances are currently established for residues of dimethomorph in or on food commodities under 40 CFR 40 §180.493, at levels ranging from 0.5 to 60.0 ppm

. Tolerances are established for the

indirect or inadvertent residues of dimeth omorph under 40 CFR §180.493(d) in/on cereal grain

commodities

.

3.1 Chemical Identity

Table 3.1. Dimethomorph Nomenclature.

Chemical structure

Common name Dimethomorph

Company experimental

name BAS 550F

IUPAC name ( E,Z )

- 4

- [3

- (4

- chlorophenyl)

- 3

- (3,4

- dimethoxyphenyl)acryloyl]morpholine

CAS name 4

- [3

- (4

- chlorophenyl)

- 3

- (3,4

- dimethoxyphenyl)

- 1

- oxo

- 2

- propenyl]morpholine

CAS registry number 110488

- 70

- 5

3.2 Physical/Chemical CharacteristicsDimethomorph Human Health Risk Assessment DP No. D416888

Page 7 of 25 Dimethomorph is a colorless or grey crystalline powder that is stable under normal temperature conditions. It is stable to hydrolysis and will remain stable up to five years in the dark. It is a non

volatile fungicide that has a relatively low octanol/water partition coefficient and s olubility. Also, dimethomorph has a low soil mobility and a low leaching potential. See Table 3.2 for the physicochemical properties of dimethomorph

.

Table 3.2. Physicochemical Properties of Dimethomorph.

Parameter Value Reference

Melting point/range 125

- 149oC

DP# 316328, 7/18/05, W.

Cutchin pH Not applicable; not soluble in water

Density 1.318 g/cm 3 at 20oC

Water solubility (20oC) pH 5 19 mg/L pH 7 18 mg/L pH 9 16 mg/L

Solvent solubility (20oC) n

- hexane 0.11 mg/mL

methanol 39.0 mg/mL

toluene 49.5 mg/mL

acetone 100 mg/mL

dichloromethane 461 mg/mL

Vapor pressure E

- isomer: 9.7 x 10

- 7 Pa at 25oC

Z

- isomer: 1.0 x 10

- 6 Pa at 2 5oC

Dissociation constant, pK

a Not determinable (the solubility of dimethomorph is very low, and the

ionized and nonionized forms have identical absorption coefficients)

Octanol/water partition coefficient, Log(K OW ) E

- isomer: K

ow = 430 (log K

ow = 2.63) at

20oC

Z

- isomer: K

ow = 543 (log K

ow = 2.73) at

20oC

UV/visible absorption spectrum Not available

3 .3 Pesticide Use Pattern

BASF Corporation has petitioned to establish a permanent tolerance without U.S. registration for the residues of dimethomorph (BAS 550 F) in/on imported papaya grown in Brazil. The registrant has indicated that Brazil is the only country using dimethomorph on papaya. For use on the requested crop dimethomorph is formulated as a 500 g ai/kg wettable po wder. The proposed foreign use pattern of dimethomorph under the field condition in Brazil is summarized in Table 3.3.Dimethomorph Human Health Risk Assessment DP No. D416888

Page 8 of 25 Table 3.3. Summary of Proposed Directions for Dimethomorph Applic. Timing, Type, and Equip. Formulation Applic.

Rate (lb ai/A) Max. No.

Applic.

per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Papaya

Post

emergence; Foliar ; ground 50% ai WP

500g/kg 0.446

lb/ ai/A 4 1.78 lb ai/A 7 Do not exceed the

number of 3 application per

calendar year at a total

rate between 0.357 lb

ai/A and 0.446 lb ai/A, and a PHI of 7 days.

3.4 Anticipated Exposure Pathways

H umans may be exposed to dimethomorph in food and drinking water, since dimethomorph may be applied directly to growing crops and application may result in dimethomorph reaching surface and ground water drinking water sources. There are no residential uses for this chemical. While there is the potential for occupation exposure to workers applying dimethomorph from the domestically registered uses, there is no increased worker exposure expected from this new use since no domestic registration is sought for t he use on papaya.

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 Actio ns 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

as sessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and wa ter consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture under the National Health

and Nutrition Examination Survey, What We E at in America, (NHANES/WWEIA). These food consumption patterns 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,

eth nic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups

, and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

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

- application are evaluated. Exposure risk estimates were not

of concern. Further considerations are currently in development

, as OPP has committed resourcesDimethomorph Human Health Risk Assessment DP No. D416888

Page 9 of 25 and expertise to the development of specialized software and mode ls that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

The most recent risk assessment for dimethomorph (D399514, 3/6/2012) was conducted prior to the receipt and review of an acute neurotoxicity (ACN) study. This study has been reviewed and the findings incorporated into this risk assessment.

T he toxicolo gy database for dimethomorph is complete, no additional data is required. The current 40 CFR Part 158 Toxicology Data Requirement requires a subchronic inhalation study for dimethomorph ; however, the Hazard and S cience Policy Council (HASPOC) determined th at based on a weight

- of

- evidence (WOE) approach, a subchronic inhalation study is not required to support the registered uses of dimethomorph (TXR#0056964, 2014) at this time. The scientific quality of the database for dimethomorph is relatively high and the toxicity profile can be characterized for a wide range of effects, including potential developmental, reproductive, neurotoxic, carcinogenic, and

immunotoxic effects.

4. 1 Summary of Toxicological Effects

Dimethomorph has low acute toxicity by the o r al, dermal, or inhalation route of exposure. It is not an eye or skin irritant, and is not a skin sensitizer. There is no evidence that dimethomorph is a developmental , reproductive, carcinogenic, mutagenic or immunotoxic chemical

.

No biologically significant effect was observed in the rat subchronic oral toxicity study while decreased body weight and increased incidence of arteritis in male rats and decreased body weights and increased incidence of “ground

- glass” foci in livers of f emale rats were observed in the rat chronic toxicity study. In the dog subchronic oral toxicity study, decreased absolute and relative prostate weights, and slight liver effects were observed. No toxicity was observed at the limit dose in

the rat 28

- day de rmal toxicity study. The developmental toxicity studies showed no increased sensitivity to offspring of either rats or rabbits as demonstrated by NOEL’s equal to or higher than those producing toxicity in the maternal animals. Likewise, in the two generati on reproduction study, there was no toxicity to the offspring at doses lower than that causing parental toxicity.

In an acute neurotoxicity study, functional observational battery ( FOB ) findings and reduced motor activity were observed. However, t hese f indings were considered an impairment of the overall condition of the animals following treatment, rather than direct neurotoxic effects of the dimethomorph exposure. No neurotoxic effects were observed in the subchronic neurotoxicity study

in rats and the re is no evidence of neurotoxicity throughout the dimethomorph toxicity database

. There was no evidence of i mmunotoxicity in the guideline i mmunotoxicity study

.

Dimethomorph is classified as "not likely to be carcinogenic to hu m ans" based upon lack of

ev idence of carcinogenicity in rats and mi ce. Therefore, a cancer risk assess m ent is not required.

4. 2 Safety factor for Infants and Children (FQPA Safety Factor)Dimethomorph Human Health Risk Assessment DP No. D416888

Page 10 of 25 The toxicity database is complete, there is no evidence of increased qualitative or quantitative susceptibility in the young, there is no evidence of neurotoxicity with dimethomorph and exposure estimates are unlikely to underestimate risk; therefore, the 10

- fold FQPA Safety Factor can be

reduced to 1 x for all assessments except the acute dietary assessment

. The FQPA SF is retained for the acute dietary risk assessment to account for extrapolation of LOAEL to NOAEL for the acute dietary PoD.

4. 2 .1 Complet eness o f the Toxicology Database

The toxic ology database for dimethomorph is complete and adequate to support risk assessments. All part 158 data requirements have either been satisfied or waived for this chemical.

4. 2 .2 Evidence of N eurotoxicity

In an acute neurotoxicity study, FOB findings and reduced motor activity were observed at 250 mg/kg and doses above on Day 0 only. These findings were considered an impairment of the overall condition of the animals following treatment, rather than direct neurotoxic effects of the dimethomorph exposure based on the absence of any neurohistopathological changes in the treated

animals and the transient nature of the observed FOB and neurobehavioral assessments. In a subchronic neurotoxicity study, no neuroto xic effects were observed in rats fed dimethomorph up to the highest dose tested at 2400 ppm (178/204 mg/kg/day for males/females, respectively) for 90 days. In addition, the toxicology database does not reveal any evidence of neurotoxic clinical signs,

ch anges in brain weight, or histopathology of the nervous system in any study with dimethomorph.

4. 2 .3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

The toxicology data on dimethomorph provides no indication of enhanced sensitivity of infants and children based on the results from developmental studies conducted with rats and rabbits as well as a

two

- generation reproduction study conducted with rats. There were no toxic effects observed in either the rat developmental tox icity or the rat two

- generation reproductive toxicity studies that were lower than doses which produced toxic effects in the paren ts. No developmental toxicity was demonstrated in the rabbit developmental toxicity study.

4. 2 .4 Residual Uncertainty in the Exposure Datab ase

The acute and chronic dietary exposure assessment assumed 100% of the proposed and registered

crops were treated , and incorporated tolerance level residues for all uses. The dietary (food and drinking water) exposure assessment does no t underestimate the potential exposure for infants, children, or women of child bearing age.

4. 3 Toxicity Endpoint and Point of D eparture Selections

4. 3 .1 Dose

- Response AssessmentDimethomorph Human Health Risk Assessment DP No. D416888

Page 11 of 25 Acute Dietary Endpoint for the General Population : In an acute neurotoxicity study in rats (MRID 48980106), reduced motor activity was observed at the lowest dose tested (LOAEL=250 mg/kg). The route and a single exposure of this study are appropriate for acute dietary risk assessment. The UF is 1000x (10x for interspe cies extrapolation, 10x for intraspecies variation and, FQPA SF L of 10x for extrapolation of LOAEL to NOAEL). The acute population adjusted dose (aPAD) for general population is 0.25 mg/kg.

Acute Dietary Endpoint for Female 13

- 49 Years of Age : No endpoint was selected for this population (female 13

- 49 years of ages). The developmental toxicity NOAEL of 60 mg/kg/day from a developmental toxicity study in rats, based on post

- implantation loss at 160 mg/kg/day, was considered for establishing the acute point o f departure (PoD) for females 13

- 49. However, it was determined that this endpoint was not appropriate for use in this risk assessment, since the effect at the high dose was minimal and was not supported by a decrement in litter size (12.4 fetuses per dam in the control, compared to 11.3 fetuses per dam at the high dose). The maternal effects (decreased body weight gain and food consumption) were not considered to be attributable to a single exposure, and thus not appropriate for this risk assessment. No appropriate toxicological endpoints attributable to a single exposure were identified in other oral studies. Consequently, it was determined that there was no basis for selecting a dose and endpoint for an acute PoD for females 13

- 49 years of age.

Chron ic Dietary Endpoint for the General Population : The rat chronic and carcinogenicity studies (MRIDs #42233912 and #42233916) have comparable NOAELs (11 .9 versus 11.3 mg/kg/day) and endpoints with increased incidences of pigmented or hypertrophied hepatocyte s
, and “ground glass”

foci in livers of female rats at LOAELS of 99.9 and 46.3 mg/kg/day, respectively. Females appeared

to be more sensitive in these studies. Therefore the studies were considered co

- critical in establishing a PoD for chronic dietary risk assessment. An UF of 100x (10x for interspecies extrapolation and 10x for intraspecies variation) is applied to the NOAEL of 11 mg/kg/day to obtain a chronic reference dose ( cRfD ) of 0.1 mg/kg/day. The FQPA factor is reduced to1x

. The chronic population adjusted dose (cPAD) is 0.1 mg/kg/day.

Incidental Oral Exposure (Short

- and Intermediate

- Term) : There is no residential use for dimethomorph, so a toxicity end point for incidental oral exposure has not been established

.

Dermal Exposure (Short

- , Intermediate

- , and Long

- Term) : There is a 28

- day dermal toxicity study in rats (MRID# 48326908). The NOAEL was 1000 mg/kg/day (the highest dose test, HDT) with no

toxic effect seen. Since no toxicity was observed at the limit dose for dermal exposure and no developmental toxicity concern has been identified

, a quantitative dermal risk assessment for short

and intermediated

- term occupational

, dermal exposure is not necess ary. The re are currently no registered uses for dimethomorph that result in long

- term dermal exposure, therefore

, a long

- term
dermal risk assessment is not needed.

Inhalation Exposure ( S hort

, Intermediate

- , and Long

- Term) : There was no inhalation study av ailable except the acute inhalation study (Toxicity Category III). A subchronic toxicity study in dogs (MRID# 42233908) was selected for short and intermediated

- term inhalation exposure. The NOAEL is 15 mg/kg/day, the LOAEL is 43 mg/kg/day based on decrea sed absolute and relative prostate weights. Since an oral study was selected, the inhalation exposure component (μg ai/day) using 100% absorption rate should be converted to an equivalent oral dose (mg/kg/day) for riskDimethomorph Human Health Risk Assessment DP No. D416888

Page 12 of 25 assessments Th e re are currently no r egister e d uses for d imethomorph that result in long

- term
inhalation exposure, therefore, a long

- term inhalation risk assessment is not required.

4. 3 .2 Recommendation for Combining Routes of Exposures for Risk Assessment

D imethomorph does not pose a dermal risk; therefore quantification of dermal risk is not r equired.

O ral and inhalation exposure can be combined since route specific inhalation data is not available, and inhalation toxicity is evaluated based on oral studies.

4. 3 .3 Cancer Classifi cation and Risk Assessment Recommendation

The Hazard Identification Assessment Review Committee (HIARC) has classified d imethomorph as "not likely to be carcinogenic to hu m ans" based upon lack of evidence of carcinogenicity in rats and

mi ce (HIARC Memo, M ay 13, 1998) . Therefore, a cancer risk assess m ent is not required.

4. 3 .4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

Table TABLE 4 .5. 4. 1 Summary of Toxicological Doses and Endp oints for Use in Dimethomorph Human

Health Risk Assessments. Exposure
Scenario Point of Departure

,

Uncertainty/FQPA Safety

Factors LOC for Risk

Assessment Study and Toxicological

Effects

Acute Dietary ( G eneral P opulation) L OAEL = 250 mg/kg/day

UF A = 10x

UF H = 10x FQPA SF L = 10x aRfD= 0.25 mg/kg aPAD=0.25 mg/kg MRID 48980106

Acute Neurotoxicity Study LOAEL=250 mg/kg/day

based on reduced motor activity in both sexes.

Acute Dietary ( F emales 13

- 49) No appropriate endpoint was

identified including developmental to xicity studies in

rats and rabbits. Not applicable

. No study selected.

Chronic Dietary ( All P opulations) NOAEL = 11 mg/kg/day

UF A = 10x

UF H = 10x FQPA SF = 1x cRfD= 0.1 mg/kg/d

cPAD = 0.1 mg/kg/d MRID 42233912, 42233916

Carcin ogenicity s tudy in r at s. LOAEL = 46.3 mg/kg/day

, based on decreased body weight and increases in liver

lesions in female rats.

Incidental Oral

- All time periods Not applicable.

No registered residential uses. Not applicable No study selected.

Dermal Short

- and

Intermediate

- Term No toxicity was observed at the

limit dose in a 28

- day dermal toxicity study. No quantitative

risk assessment is necessary. Not applicable

. No study selected.

Dermal Long

- Term (> 6 M onths) No long

- term exposure. Not applicable

. No study selected

.

Inhalation Short

- and

Intermediate

- Term (1

- 6 M onths) Oral, NOAEL= 15 mg/kg/day

(inhalation absorption factor = 100%) LOC = 100 MRID 42233908

Subchronic feeding s tudy in

d ogs

. LOAEL = 43 mg/kg/day based on decreasedDimethomorph Human Health Risk Assessment DP No. D416888

Page 13 of 25 Table TABLE 4 .5. 4. 1 Summary of Toxicological Doses and Endp oints for Use in Dimethomorph Human

Health Risk Assessments. Exposure
Scenario Point of Departure

,

Uncertainty/FQPA Safety

Factors LOC for Risk

Assessment Study and Toxicological

Effects

absolute and relative prostate weight s

. Inhalation Long

- Term (>6 M onths) No long

- term exposure. Not applicable

. No study selected

.

Cancer ( O ral, D ermal,

I nhalation) Classification : This chemical is classified as “not likely” to be a human carcinogen.

Point of Departure (POD) = data point or estimated point, 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 adver se effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor.

UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = F QPA Safety Factor. FQPA SF L = extrapolation from LOAEL to NOAEL. RfD= reference dose. PAD = population adjusted dose (a = acute, c = chronic). LOC = level of concern.

4.3.5 Endocrine Disruption Screening Program

As required by FIFRA and FFDCA, EPA rev iews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and ge neral or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reprodu ctive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of the reregistration decision for dimethomorph, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), trifluralin is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a

“natural ly occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potent ial of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the n ext stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals,

which contains 58 pesticide active ingredients and 9 inert ingredients. When additional appropriate screening and/or testing protocols being considered under the Agency’s EDSP have been developed,Dimethomorph Human Health Risk Assessment DP No. D416888

Page 14 of 25 dimethomorph may be subjected to further screening and/or testing to better characterize effects related to endocrine disruption . For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit

our website: htt p://www.epa.gov/endo/.

5.0 Dietary Exposure and Risk Assessment

5.1 Residue of Concern Summary and Rationale

5.1.1 Summary of Plant and Animal Metabolism Studies No new plant metabolism studies were submitted for imported papaya. Based on the previous

m etabolism studies with three representative crops (potato, grape and lettuce) the qualitative nature of the dimethomorph residues in papaya is considered to be adequately understood (D192776 & D219530, D. Davis, 3/31/95 and 10/31/95) . In all three studies, parent dimethomorph was the predominant residue. The residue of concern for the tolerance expression and risk assessment is the parent compound, dimethomorph (comprised of E and Z isomers).

T here are no livestock feedstuffs items associated with the subj ect petition. Therefore, a discussion of animal metabolism is not required to support the proposed tolerance.

5.1. 2 Summary of Environmental Degradation

D imethomorph is not expected to be affected by abiotic degradation processes, such as hydrolysis and photolysis, in soil or under aquatic conditions. Biotic transformation appears to be the major route of dissipation in the environment. Dimethomorph was m oderately persistent in an aerobic soil (half

- life = 117 days). There are strong indications that significantly more rapid dissipation may occur under anaerobic conditions in soil and aquatic systems.

The residue of concern in drinking water for risk assessment purposes is the parent compound, dimethomorph, com prised of E and Z isomers (D349254; Jose Luis Melendez; 3 September 2008).

5.1 .3 Comparison of Metabolic Pathways

The registrant has previously submitted acceptable studies depicting the meta bolic fate of dimethomorph in plants, rats and livestock. Dimethomorph is the predominant residue in both plants and animals according to the metabolism studies.

Metabolism appears to be similar in a variety of plant commodities. Based on the plant metab olism study, unchanged parent is the only significant component of the total residue in grapes, potatoes and lettuce and other representative rotational crops. The predominant residue (dimethomorph) was mostly found as a surface residue in most plants, wi th negligible systemic translocation, while in potato only low residues were found in tubers (almost all in the peel), suggesting that translocation from treated aerial parts to the tuber is negligible. The major metabolic pathways are demethylationDimethomorph Human Health Risk Assessment DP No. D416888

Page 15 of 25 of the 4

- methoxy group of the dimethoxyphenyl ring followed by conjugate formation, the other being the stepwise degradation of the morpholine ring.

Dimethomorph is extensively metabolized in rats by demethylation of one of the methoxy groups

and formation of O

- conjugate and degradation products of morpholine ring opening. Unchanged parent dimethomorph was the only detect in rats. Lactating goat study shows that 90% of the administered dose was excreted in feces and urine and radioactivity in the edible organs and tissues was readily and almost completely extracted, indicating that dimethomorph or its metabolites were not bound in the organs and tissues. The major component of the extractable residue in liver, muscle and fat was the unchanged parent. The metabo lic pathway for dimethomorph in the lactating goat is similar to that for rats, and involves the demethylation of one of the phenolic methoxy

- groups, with an alternative pathway being the cleavage of the morpholine

- ring. Extractability of Total

Radioactiv e Residues (TRR) in laying hens was high and predominant residue was the parent compound. The metabolic pathways observed in laying hens also similar to the goat and rats study.

5.1. 4 Residues of Concern Summary and Rationale

TABLE 5.1.4 Summary of Me tabolites and Degradates to Be Included in Risk Assessment and

Tolerance Expression

Matrix Residues Included in Risk

Assessment Residues Included in Tolerance Expression

Plants Primary crops Dimethomorph Dimethomorph

Rotational crops

Livestock Ruminants Dimethomorph NA*

Poultry Drinking water Dimethomorph NA*

*NA

- Not Applicable

5.2 Food Residue Profile

No new plant metabolism studies were submitted. The results from the previously plant metabolism studies indicate that the major component of the extractable residue was unchanged parent dimethomorph in both fruit and leaves

, and that residues are generally low. The highest residues are generally found in the foliage (leaves) of plant s, and not in the fruit itself . The residue is expected to be a surface residue consisting of primarily parent compound . The available m etabolism data in plants shows that dimethomorph undergoes limited translocation or degradation

.

5 .3 Water Residue P rofile

There are no uses associated with this petition that would impact U.S. water resources. For the aggregate risk assessment, HED has considered the currently registered domestic use that will result in the highest estimated drinking water concentrat ion (EDWC). EFED has determine d that broccoli (representative of brassica head and stem) is the use with the major exposure and highest percent

crop area (I. Abdel

- Saheb, D387377, 7/27/11) . The EDWCs for dimethomorph were calculatedDimethomorph Human Health Risk Assessment DP No. D416888

Page 16 of 25 based on a maximum application rate of 1.4 lb ai/A/season for broccoli. Water residues were incorporated in to the dietary risk assessment for food categories “water, direct, all sources” and “water, indirect, all sources.” The groundwater value was gener ated using the Screening Concentration in Groundwater (SCI

- GROW) Model and the surface water values were generated using a Tier 1 broccoli model . The surface water estimate was used for both acute and chronic assessment (81.1 ppb for acute and 24.7 ppb fo r chronic) because these values were higher than the groundwater value. According to a personal conversation between Donna Davis (HED) and Mark Corbin (EFED) on 8/21/2014, PRZM

- GW was not run for this chemical and the EDWCs would probably be a little high er than the current surface water number. However, Mark agreed that since there is no risk issue for this chemical, the old drinking water numbers are good for this action. In

future new PRZM

- GW numbers will be used for domestic use. The models and the d escriptions are

available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

TABLE 5

. 3 Maximum Tier 1 Estimated Drinking Water Concentration (EDWCs) for Drinking Water Risk Assessment Based on Aerial Application of Dimetho morph.

Drinking Water Source [Model

Used] Crop Use [Rate Modeled] EDWC (ppb)

Groundwater [SCI

- GROW] Broccoli [1.4 lb ai/A] Acute and Chronic 0.264

Surface Water [FIRST] Broccoli [1.4 lb ai/A] Acute 81.1

Broccoli [1.4 lb ai/A] Chronic 24.7

5 .4 Dietary Risk Assessment

5.4.1 D e s cr i p tion of R e si du e Da t a Us e d in Di e ta r y A ssess me n t

An updated a cute and chronic dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16 . This software uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutr ition Examination Survey, What We Eat in America, (NHANES/WWEIA). The unrefined acute and chronic analyses are based

on tolerance

- level residues, 100% crop treated assumptions for all commodities

, and DEEMTM default processing factors or empirical processing factors where available. The drinking water estimates provided by EFED are modeled estimates, and were generated using the most conservative

model available for the existing uses. The unrefined acute and chronic approach to dietary risk exposure analysis will not underestimate risk to the general U.S. population or any population subgroup

.

5 .4. 2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated refinements were not used in this assessment.Dimethomorph Human Health Risk Assessment DP No. D416888

Page 17 of 25 5 .4. 3 Acute Dietary Risk Assessment

The acute analysis for all population subgroups, including infants and children, was unrefined and

used tolerance

- level residues and 100% crop

- treated (PCT). The resulting acute food and drinking

water risk estimates are below HED’s level of concern (<100% aPAD) at the 95 th percentile of the exposure distribution for the general U.S. population ( 25% aPAD), and all population subgroups

. The most highly

- exposed population subgroup was children 3 to 5 years old which utilized 39 % of

the aPAD at t he 95th percentile of exposure. Thus, acute dietary exposure to dimethomorph for all population subgroups is not of concern. The detailed results for the general population and all population subgroups is shown in Table 5.4 .6, below.

5 .4. 4 Chronic Dietary Risk Assessment

The chronic dietary (food and drinking water) risk estimate utilizes 16 % of the chronic population

adjusted dose (cPAD) for the U.S. population. The estimated risk for the most highly exposed population subgroup (children 1

- 2 years) is 25 % of the cPAD. Thus, chronic dietary exposure to dimethomorph for all population subgroups is not of concern. The detailed results for the general population and all population subgroups are shown in Table 5.4 .6, below.

5 .4. 5 Cancer Dietary Risk Assessm ent

Dimethomorph is classified as a “not likely” human carcinogen. A cancer dietary exposure analysis is not required.

5 .4. 6 Dietary Summary Table

The acute and chronic dietary risks for dimethomorph are summarized below.

Table 5. 4. 6 Summary of the Dietary Exposure and Risk Estimates for Dimethomorph 1

Population Subgroup Acute Assessment (95 th Percentile) Chronic Assessment

aPAD mg/kg/day Exposure

Estimate mg/kg/day %

aPAD cPAD

mg/kg/day Exposure

Estimate mg/kg/day % cPAD

U.S. Population

0.25 0.063603 25

0.1 0.016379 16

All infants 0.052513 21 0.009773 9.8

Children 1

- 2 yrs 0.086871 35 0.025425 25

Children 3

- 5 yrs 0.096278 39 0.022638 23

Children 6

- 12 yrs 0.054574 22 0.013773 14

Youth 13

- 19 yrs 0.048841 20 0.011315 11

Adults 20

- 49 yrs 0.064193 26 0.016698 17

Adults 50

- 99 yrs 0.063408 25 0.017084 17

Females 13

- 49 yrs 0.067352 27 0.016670 17Dimethomorph Human Health Risk Assessment DP No. D416888

Page 18 of 25 1 The populations with the greatest risk estimates are bolded.

6.0 Residential Exposure/Risk Characterization

There are no registered or proposed residential uses, or commercial/professional uses at residential sites associated with dimethomorph; therefore, a quantitative residential exposure assessment is not required for this risk assessment.

7. 0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate

assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and durati on of

exposure.

For dimethomorph, t here are currently no registered residential uses, nor are any proposed. Therefore, at this time, dietary (food + water) exposure is the only component of an aggregate exposure analysis and risk assessment. As shown i n Sections 5.4.3 and 5.4.4, there are no aggregate dietary (food plus water) risks of concern for dimethomorph.

8.0 Cumulative Exposure/Risk Characterization

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 as to dimethomorph and any other substances and dimethomorph does not appear to p roduce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA

has not assumed that dimethomorph has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determi ne 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 cumulati ng effects from substances found to have a common mechanism on EPA’s

website at http://www.epa.gov/pesticides/cumulative/

.

9.0 Occupational Exposure/Risk Characterization

There are no occupational exposures associated with the proposed import tolerances; therefore, a new occupational exposure assessment was not conducted for this import tolerance petition on

papayas.Dimethomorph Human Health Risk Assessment DP No. D416888

Page 19 of 25 1 0 .0 References

Residue Chemistry References Dimethomorph : Petition for the Establishment of Tolerances Without U.S. Registration on Papaya. Summary of Analytical Chemistry and Residue Data. DP Barcode D 423323 ; S. Biswas;

10/ 22 /2014 Dimethomorph: Human Health Risk Assessment to Support Amended proposed Use on

G rapes, Bulb Vegetables, Leafy Brassica Vegetables, and Leafy Vegetables. PC Code 268800; DP Barcode D387381; S. Piper; 09/15/2011. Addendum to Dimethomorph: Human Health Risk Assessment to Support Amended proposed Use on Grapes, Bulb Vegetables, Leafy B rassica Vegetables, and Leafy Vegetables. PC Code 268800; DP Barcode D399514; S. Piper; 03/06 /2012

. Drinking Water Assessment

D imethomorph: D rinking Water Assessment for the Amended Directions for Use of Dimethomorph in Brassica Subgroups 5A & 5B, and Green Onions, Use on Grapes; Dimethomorph New Use on Leafy Vegetables; New ai Ametoctradin Coformulated with Dimethomorph for (non

- food use and food uses) in Human Health Risk Assessment; D387377, I.

Abdel

- Saheb, 7/25/11. Dietary Exposure Assessm ent Dimethomorph : Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Establishment of Tolerances for Residues of Dimethomorph in/on Imported Papaya. DP Barcode D 423324 ; S. Biswas; 10/ 22 /2014

. Dimethomorph : Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Proposed Amended Uses for Grapes, Leafy Vegetables, Leafy Brassica Vegetables and Bulb Vegetables. Barcode D393434; S. Piper; 09/07/2011Dimethomorph Human Health Risk Assessment DP No. D416888

Page 20 of 25 Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40CFR §158.340) for food use of dimethomorph are in Table A.1, below. Use of

the n ew guideline numbers does not imply that the new (1998) guideline protocols were used.

TABLE A.1 Toxicology Data Requirements for Dimethomorph.

Test Technical

Required Satisified

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 (non

- rodent)

870.3200 21/28

- Day Dermal

870.3250 90

- Day Dermal

870.3465 90

- Day Inhalation yes

yes

yes

no

yes yes

yes

yes

no waived 1

870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (non

- rodent)

870.3800 Reproduction yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (non

- rodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation (bacterial) 870.5300 Mutagenicity

— Gene Mutation (mammalian) 870.5375 Mutagenicity

— Structural Chromosomal Aberrations 870.5395 Mutagenicity

— Other Genotoxic Effects 870.5500 Mutagenicity

— Other Genoto xic Effects yes

yes

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 Developmental Neurotoxicity no

no

yes

yes

no no

no

yes

yes

no

870.7485 General Metabolism

870.7600 Dermal Penetration 870.7800 Immunotoxicity yes

no

yes yes

yes

yes

1 The requirement for a subchronic inhalation study is waived

.Dimethomorph Human Health Risk Assessment DP No. D416888

Page 21 of 25 A.2 Toxicity Profiles

TABLE A.2.1 Acute Toxicity Profile for Dimethomorph.

Guideline

Number Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [Rat] 42233902 LD 50 = 3900 (3300

- 4500) mg/kg (M,F) III
870.1200 Acute dermal [Rat] 42233903 LD 50 ≥ 5000 mg/kg IV

870.1300 Acute inhalation [Rat] 42233904 LC 50 ≥ 4.24 mg/L III

870.2400 Acute eye irritation [Rabbit] 42233905 Conjunctival irritation clearing in 4 days III

870.2500 Acute dermal irritation [Rabbit] 42233907 No irritation reported IV

870.2600 Skin sensitization [Guinea pig] 42233906 Not a sensitizer

TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Dimethomorph.

Guideline Number/ Study Type MRID(s) [year]/

Classification/Doses Results

870.3100

90

- Day oral toxicity [dog] 42233908 [1991]

Acceptable/guideline 0, 150, 450, 1350 ppm M: 0, 5, 15, 43 mg/kg/day F: 0, 6, 15, 44 mg/kg/day NOAEL = 15 mg/kg/day LOAEL = 43 mg/kg/day based on decrease in the absolute

and relative prostate weights.

870.3150

90

- Day oral toxicity [rat] 42233910 [1991]

Core minimum 0, 40, 200, 1000 ppm M: 0, 2.9, 14.2, 73 mg/kg/day F: 0, 3.2, 15.8, 82 mg/kg/day NOAEL >73/82 [M/F] mg/kg/day LOAEL was not established in this study, because the highest dose tested produced no biologically significant

effects.

870.3200

28

- day dermal toxicity [rat] 48326908[2010]

Acceptable/guideline 0,100,300,1000 mg/kg/day 6 hr/day 5day/wk [M/F] NOAEL=1000 mg/kg/day [M/F]

No effects seen at the limit dose

870.3700a

Prenatal developmental [rabbit] 42233918 [1989]

Unacceptable/core supplemental [Initial rating] 0, 135, 300, 650 mg/kg/day Maternal NOAEL = 300 mg/kg/day LOAEL = 650 mg/kg/day based on an increased incidence of abortion confirmed in a range

- finding study. Developmental NOAEL could not be determined.

LOAEL could not be determined.

870.3700b

Prenatal developmental [rabbit] 44175303

Acceptable Information supplemental to

MRID# 42233918 Matern al NOAEL = 300 mg/kg/day LOAEL = 650 mg/kg/day based on an increased incidence of abortion confirmed in a range

- finding study. Developmental NOAEL =650 mg/kg/day [highest dose tested].

LOAEL could not be determined

- no effects observed at highest dose tested.

870.3700c

Prenatal developmental [rat] 42233919 [1989]

Unacceptable/core supplemental [Initial rating] 0, 20, 60, 160 mg/kg/day Materna l NOAEL = 60 mg/kg/day LOAEL = 160 mg/kg/day based on reductions in food consumption, mean body weights and body weight gain. Developmenta l NOAEL could not be determined

LOAEL = could not be determined.

870.3700d

Prenatal developmental [rat] 44175302

Acceptable Information supplemental to

MRID# 42233919 Materna l NOAEL = 60 mg/kg/day LOAEL = 160 mg/kg/day based on reductions in food consumption, mean body weights and body weight gains. Developmenta l NOAEL = 60 mg/kg/day LOAEL = 160 mg/kg/day based on the incidence of post implantation lossDimethomorph Human Health Risk Assessment DP No. D416888

Page 22 of 25 TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Dimethomorph.

Guideline Number/ Study Type MRID(s) [year]/

Classification/Doses Results

870.3800 Reproduction and fertility effects [rat] 42233920 [1990]

Acceptable/guideline 0, 100, 300, 1000 ppm M: 0,6.9,20.8,69 mg/kg/day F: 0, 8.0,24,79.3 mg/kg/day Parental/Systemic NOAEL = 20.8/24 (M/F) mg/kg/day LOAEL = 69/79.3 (M/F) mg/kg/day based on decreased body weights and body weight gains. Reproductive NOAEL = 20.8/24 (M/F) mg/kg/day LOAEL = 69/79.3 (M/F) mg/kg/day based on decreased incisor eruption on day 10 postpartum. Offspring NOAEL was not reported LOAEL was not reported.

870.4100a Chronic toxicity [rat] 42233912 [1991]

Acceptable/guideline 0, 150, 450, 1350 ppm M: 0, 9.4, 36.2, 99.9 mg/kg/day F: 0, 11.9, 57.7, 157.8 mg/kg/day NOAEL = 36.2/11.9 [M/F] mg/kg/day LOAEL = 57.7/99.9 [M/F] mg/kg/day based on decreased body weight and increased incidence of arteritis in male rats and decreased body weight and significant increased incidence of "ground

- glass" foci in the liver in female rats.

870.4100b Chronic toxicity [dog] 42233911 [1991]

Acceptable/guideline 0, 150, 450, 1350 ppm M: 0, 4.9, 14.7, 44.6 mg/kg/day F: 0, 5.0, 15.7, 47.0 mg/kg/day NOAEL = 14.7 mg/kg/day LOAEL = 44.6mg/kg/day based on decreased prostate weight.

870.4200 Carcinogenicity [rat] 42233916 [1991]

Acceptable/guideline 0, 200, 750, 20000 ppm M: 0, 8.8, 33.9, 94.6 mg/kg/day F: 0, 11.3, 46.3, 132.5 mg/kg/day NOAEL [systemic] = 33.9/11.3 [ M/F] mg/kg/day LOAEL [systemic] = 94.6/46.3 [M/F] mg/kg/day based on decreased body weight, gross and microscopic lesions in blood vessels, and liver lesions in males and decreased body weight, gross and microscopic lesions blood vessels, bone marrow hype rcellularity, and liver lesions in females. There was no evidence of carcinogenicity

870.4300 Carcinogenicity [mouse] 42233914 [1991]

Acceptable/guideline 0, 10, 100, 1000 mg/kg/day NOAEL = 100 mg/kg/day LOAEL [systemic] = 1000 mg/kg/day based on decreased body weight gaisn in males. There was no evidence of carcinogenicity

Gene Mutation

870.5100a 42233921 [1985]

Acceptable Negative for inducing reverse gene mutation in either

Salmonella his

- mutants or E. coli trp

- cells exposed beyond precipitatin g concentrations [500 ug/plate], up to the limit dose, 5000 ug/plate, w/without metabolic

activation.

Gene Mutation

870.5100b 42233926 [1989]

Acceptable Negative for inducing reverse gene mutation in

Salmonella TA strains and E. coli WP2 uvr A exposed, with/without activation, up to 5000 ug/plate.

In vitro mammalian cell gene mutation

test
870.5300a 42233923 [1987]

Acceptable Negative for inducing forward mutation at the hypoxanthine

- guanine phosphoribosyl transferase locus in

Chines e hamster lung [V79] cells treated up to cytotoxic
levels [230 ug/mL/

- S9; 300 ug/mL/+S9]

. In vitro mammalian cell gene mutation

test
870.5300b 42233927 [1991]

Acceptable Negative for inducing forward mutation at the hypoxanthine

- guanine phosphoribosyl tra nsferase [HGPRT] locus in Chinese hamster lung [V79] exposed, with/without activation, up to cytotoxic concentrations [180 ug/mL/

- S9; 333 ug/mL/+S9].Dimethomorph Human Health Risk Assessment DP No. D416888

Page 23 of 25 TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Dimethomorph.

Guideline Number/ Study Type MRID(s) [year]/

Classification/Doses Results

In vitro mammalian

chromosome

aberration test

870.5375a 42233924 [1986]

Unacceptable Reportedly positive for chromosome aberrations at the highest doses tested [160 ug/mL/

- S9; 170 ug/mL/+S9].

In vitro mammalian

chromosome

aberration test

870.5375b 42233925 [1987]

Acceptable [Confirmatory repeat of Study LMP

- 180 C, MRID

422339

- 24]. Positive for increased chr omosome aberrations at high doses [160 ug/mL/

- S9; 170 ug/mL/+S9].

In vitro mammalian

chromosome

aberration test

870.5375c 42233928 [1991]

Acceptable Presumptively [weakly] positive, but only in activated cultures treated at the HDT, in human lymphocyte cultures treated up to the highly toxic dose, 422 ug/mL; negative in

the absence of activation at all doses.

Mammalian erythrocyte

micronucleus test

870.5395a 42233930 [1991]

Acceptable Negative for inducing micronuclei in bone marrow cells of

mice admini stered test article i.p. up to severely toxic levels [200 mg/kg].

Mammalian erythrocyte

micronucleus test

870.5395b 42233931 [1989]

Acceptable Negative for inducing micronuclei in bone marrow cells of mice treated orally at the limit dose, 5000 mg/kg.

M utagenicity

- DNA damage/repair in

vitro

870.5500 42233922 [1986]

Unacceptable Reportedly negative for inducing unscheduled DNA synthesis [as measured by liquid scintillation counting] in rat hepatocytes cultured [for only 3 hours] at doses up to

250 ug/mL, a weakly cytotoxic level.

Other Effects

- Morphologic

transformation of

cells in culture

870.8800 42233929 [1986]

Acceptable Negative for transformation in Syrian hamster embryo cells treated, in the presence and absence of activation, up
to cytot oxic concentrations [265 ug/mL/+S9; 50 ug/mL/

- S9]Dimethomorph Human Health Risk Assessment DP No. D416888

Page 24 of 25 TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Dimethomorph.

Guideline Number/ Study Type MRID(s) [year]/

Classification/Doses Results

870.6200 Acute neurotoxicity [rat] 48980106 (2011)

Acceptable/non

- guideline 0, 250, 500, 2000 mg/kg NOAEL<250 mg/kg, LOAEL=250 mg/kg based on decreased motor activity, impairment of gait and rearing in

bot h sexes.

870.6200

Subchronic neurotoxicity [rat] 48326902 [2004]

Acceptable/guideline 0,300, 800, 2400 ppm M:0,21.7,58.7,177.9 mg/kg/day F:0,25.7,69.6,204 mg/kg/day Systemic NOAEL= 58.7/69.9 mg/kg/day (M/F), LOAEL=177.9/204 mg/kg/day based on decreases in body weight and weight gains. Neurotoxicity NOAEL= 177.9/204 mg/kg/day (HDT) No evidence of neurotoxicity.

870.7485

Metabolism and pharmacokinetics [rat] 42233932 [1994]

Acceptable 10 mg/kg single dose; 10 mg/kg 14

- day repeated dose; 10 mg/kg 7

- day repea ted dose; 500 mg/kg single dose Oral administration of dimethomorph results in rapid

excretion into the urine and feces of rats. For all treatment protocols, most [80

- 90%] of the radiolabel administered was excreted in the feces. A considerably smaller amount [6

- 16%] was excreted in the urine and only minimal levels [0.1

- 0.4%] were detected in the organs and tissues. Rapid absorption may be inferred by the rapid excretion of metabolites in the urine and bile. Saturation of absorption following single h igh doses [500 mg/kg] was indicated by large amounts [  50%] of radioactivity in the feces being associated with parent compound. For low

- or high

- dose treatment, urinary excretion in female rats tended to be greater [up to 2

- fold in low

- dose rats] than that of male rats. Retention of dimethomorph or [ 14 C]

- dimethomorph

derived radioactivity was generally  1% for most tissues although the liver exhibited slightly higher levels [1.4%] and higher levels in the gastrointestinal tract organs was

due to radioa ctivity in the lumenal contents. Urinary metabolites resulted from demethylation of the dimethoxyphenyl ring and oxidation of the morpholine ring. Biliary excretion exhibited first

- order kinetics with a

low

- dose [10 mg/kg] half

- life of approximately 3 ho urs and a high

- dose [500 mg/kg] half

- life of 11 hours for males and about 6 hours for females. Biliary metabolites accounted for most of the fecal excretion following low

dose treatment. The major biliary metabolites were glucuronides of one and possibly two of the compounds produced by demethylation of the dimethoxyphenyl ring. The report provided a proposed metabolic pathway for dimethomorph.

870.7600 Dermal penetration [rat] 43917221 [1995]

Acceptable/guideline 7.73 [2.5% w/v aqueous suspension] or 7 9.62 [25% w/v aqueous suspension] mg/kg. The dermal absorption coefficient factor is 5%.

870.7800 Immunotoxicity [rat] 48326901 (2010)

Acceptable/guideline 0,300,800,2400 ppm [M] 0, 23,61,184 mg/kg/day NOAEL = 2400 ppm (184 mg/kg/day, HDT)

No evidence of immunotoxicity.Dimethomorph Human Health Risk Assessment DP No. D416888

Page 25 of 25 Appendix B. International Residue Limits Table



### Dimethomorph ( 268800; 08/ 12/2014 )

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex

40 CFR 180.493:

Plants /Livestock : dimethomorph, ( E,Z ) 4

- [3

- (4

- chlorophenyl)

- 3

- (3,4

- dimethoxyphenyl)

- 1

- oxo

- 2

- propenyl]morpholine ( E,Z )

- 4

- [3

- (4

- chlorophenyl)

- 3

- (3,4

- dimethoxyphenyl)

- 1

- oxo

- 2

- propenyl]morpholine dimethomorph (sum of isomers)

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex
Imported Papaya 1.5

Completed: M. Negussie; 08/12/14

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.