Dimethomorph Human Health Risk Assessment DP No. 387381

Page 1 of 39 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

DATE : September 15, 2011

SUBJECT: Dimethomorph : Human Heal th Risk Assessment to Support Amended Use on

Grapes, Bulb Vegetables, Leafy Brassica Vegetables, and Leafy Vegetables.

PC Code: 268800 DP Barcode: D 387381

Decision No.: 437308, 443783, 443255 Registration No. : 241

- 427

Petition No.: 0F7751; 0F7800; 0F7816 Regulatory Action: Section 3 Registration

Risk A ss essment Type: Single Chemical / Aggregate Case No.: NA

T XR No.: N A CAS No.: 110488

- 70

- 5

MRID No.: N A 40 CFR: 180.493

FROM: Sheila Piper

, Chemist /Risk Assessor Yung Yang , Ph.D., Toxicologist Monica Hawkins, Ph.D., M.P.H., Environmental Health Scientist

Risk Assessment Branch VI Health Effects Division (7509P)

THROUGH: Felecia Fort , Chief

Risk Assessment Branch V I Health Effects Division (7509P)

TO: Tamue Gibson, M.S., Chemical Review Manager

Mary L. Waller, PM 21 Fungicide Branch/ Registration Division (7505P)Dimethomorph Human Health Risk Assessment DP No. 387381

Page 2 of 39 The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. BASF Corporation has requested the removal of regional restriction on grapes a nd amended the uses on bulb vegetables (crop group 3)

, leafy Brassica vegetables (crop group 5) and leafy vegetables (crop group 4).

The Registration Division (RD) of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, and aggregate exposure assessments, as needed, to

estimate the risk to human health that will resul t from the proposed use of d imethom o rph on grapes, bulb vegetables, leafy Brassica vegetables and leafy vegetables

. HED has evaluated the toxicity and exposure databases for the active ingredient, dimethomorph , and has conducted a

human health risk assess ment in support of the proposed use

. HED has determined that potential exposure could occur via the dietary and occupational pathway.

A summary of the findings and an assessment of human health risk resulting from the proposed

use for dimethomorph are provided in this document. The HED team members contributing to

this risk assessment include Monica Hawkins (occupational/residential assessments), Yung Yang (hazard evaluation ) , and Sheila Piper ( residue chemistry, dietary assessment and risk

assess ment)

. Ibrahim Abdel

- Saheb, Environmental Scientist, Environmental Risk Branch I V,

Environmental Fate and Effects Division (EFED) , provided the drinking water exposure

assessment.Dimethomorph Human Health Risk Assessment DP No. 387381

Page 3 of 39 1.0 Executive S ummary

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

2.0 HED Recommendations

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

2.1 Data D eficiencies/Conditions of Registration

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

3.0 Ingredient Profile

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

3.1 Structure and Nomenclature

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

3.2 Physical/Chemical Characteristics

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

3.3 Summary of Existing/Proposed Uses

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

4.0 Hazard Characterization and Dose

- Response Assessment

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

4.1 Hazard and Dose

- Response Characterization

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

4.1.1 Database Summary

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

4.2 Absorption, Distribution, Metabolism, Excretion (ADME)

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

4.3 FQPA Considerations

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

4.3.1 Ad equacy of the Toxicity Database

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

4.3.2 Evidence of Neurotoxicity

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

4.3.3 Developmental Toxicity Studies

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

4.3.4 Reproductive Toxicity Study

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

4.3.5 Additional Information from Literature Sources

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

4.3.6 Pre

- and/or Post

- Natal Toxicity

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

4.3.6.1 Determination of Susceptibility

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

4.3.6.2 Degree of Concern Analysis, and Residual Uncertainties for Pre

- and/or Post

Natal Susceptibility

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

4.3.7 Recommendation for a Developmental Neurotoxicity Study

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

4.4 FQPA Safety Factor for Infants and Children

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

4.5 Hazard Identification and Toxicity Endpoint Selection

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

4.5.1 Acute Reference Dose (aRfD)

- Females Age 13

- 49

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

4.5.2 Acute Reference Dose (aRfD)

- Genera l Population

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

4.5.3 Chronic Reference Dose (cRfD)

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

4.5.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

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

4.5.5 Dermal Absorption

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

4.5.6 De rmal Exposure (Short

- , Intermediate

- and Long

- Term)

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

4.5.7 Inhalation Exposure (Short

- , Intermediate

- and Long

- Term)

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

4.5.7.1 Occupational Inhalation Exposure (Short

- Term)

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

4.5.7.2 Occupational Inhalation Exposure (Intermediate

- Term)

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

4.5.8 Level of Concern (LOC) for Margin of Exposure (MOE)

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

4.5.9 Recommendation for Aggregate Exposure Risk Assessments

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

4.5.10 Classification of Carcinogenic Potential

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

4.5.11 Summary of Toxicological Doses and Endpoints for Use in Human Risk

Assessments

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

4.6 Endocrine Disruption

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

5.0 Diet ary Exposure and Risk Assessment

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

5.1 Metabolite/Degradate Residue Profile

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

5.1.1 Summary of Plant and Animal Metabolism Studies

................................ ............... 20Dimethomorph Human Health Risk Assessment DP No. 387381

Page 4 of 39 5.1.2 Summary of Environmental Degradation

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

5.1.3 Comparison of Metabolic Pathways

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

5.1.4 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

................................ ................................ ................................ ............... 22

5.3 Water Residue Profile

................................ ................................ ................................ ............. 25

5.4 Di etary Risk Assessment

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

5.4.1 Anticipated Residue and Percent Crop Treated (%CT) Information

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

5.4.2 Acute Dietary Risk Assessment

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

5.4.3 Chronic Dietary Risk Assessment

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

5.4.4 Cancer Dietary Risk Assessment

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

5.4.5 Dietary Summary Table

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

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Residential Handler Exposure

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

6.2 Residential Post

- Application Exposure

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

6.3 Spray Drift

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

6.4 Residential Bystander Post

- application Inhalation

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

7.0 Cumulative Exposure/Risk Characterization

................................ ................................ ........... 29

8.0 Occupational Exposure/Risk Characterization

................................ ........................... 29

8.1 Short

- and Intermediate

- Term Handler Risk

................................ ............................... 29

8.2 Occupational Post

- Application

................................ ................................ ................... 30

9.0 Environmental Justice Considerations

................................ ................................ ..................... 30

10.0 Data Needs and Label Recommendations

................................ .............................. 31

10.1 Toxicology

................................ ................................ ................................ .............. 31

10.2 Residue Chemistry

................................ ................................ ................................ ................... 31

11.0 References

................................ ................................ ................................ ................................ 32Dimethomorph Human Health Risk Assessment DP No. 387381

Page 5 of 39 1.0 Executive Summary

BASF Corporation is proposing an amended registration of the 4.17 lb ai/gal suspension concentrates (SC) formulation of dimethomorph (Forum® Fungicide, EPA Reg. No. 241

- 427) to reduce the preharvest intervals (PHIs) for grapes from 28 to 14 days, reduce the maximum number of applications from 5 to 4 and to expand the use from its current regionally restricted use to a
natio nal registration. In addition, the registrant is proposing amended uses on bulb vegetables (crop group 3)

, leafy Brassica vegetables (crop group 5) and leafy vegetables (crop group 4). In support of the proposed amendment, BASF Corporation, under PP 0F7751, 0F7800 and 0F7816 is proposing that the 40 CFR 180.493 be amended to reflect the following tolerances:

Grapes

................................ ................................ ... 3.5 ppm

Brassica , head and stem, subgroup 5A

................ 5.0 ppm

Brassica , leafy greens, subgroup 5B

................... 30.0 ppm Leafy Vegetable, crop group 4

........................... 16.0 pp m Green Onion

................................ ....................... 11.0 ppm

Dimethomorph, ( E,Z

)

- 4

- [3

- (4

- chlorophenyl)

- 3

- (3,4

- dimet hoxyphenyl)acryloyl]morpholine is a systemic morpholine active ingredient having fungicidal activity. Dimethomorph was developed for control of downy mildews, late blights, cr own and root rots. It is currently registered for use on bulb vegetables, cucurbit vegetables, fruiting vegetables, leafy Brassica greens, head and

stem Brassica vegetables, hops, lettuce (head and leaf), potatoes, taro, and ginseng; tolerances

have also been established on imported grapes and raisins . Its mode of action is via inhibition of sterol (ergosterol) synthesis.

T he toxicology database for dimethomorph is complete ; no additional data are required for risk

assessment. T he Agency believes that the current toxicological database is adequate to evaluate

the hazards associated with these amended uses.

Dimethom orph has l ow acute toxicity via the oral and dermal routes of exposure. The available

data for dimethomorph do not show evidence of neurotoxicity, and a developmental neurotoxicity study is not warranted at this time. An acute neurotoxicity study was not submitted; however, HED believe s that conducting an acute neurotoxicity stud y is unlikely to

add value to t he risk assessment or identify a lower point of departure for risk assessment. Therefore, an acute neutoxicity study is not needed at this time

.

Metabolism studies in the rat indicate that dimethomorph is extensively absorbed, metabolized

and excreted t hrough the urine and feces (80

- 90%)

. 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 wasDimethomorph Human Health Risk Assessment DP No. 387381

Page 6 of 39 due to radioactivity in the lumenal contents. Urinary metabolites resulted from demethylation of the dimethoxyphenyl ring and oxidation of the morpholine ring.

No appropriate toxicological endpoints attributable to a single exposure were identified in oral studies. Because no acute toxicity endpoints were identified, risks from acute exposure are not of concern to HED. Chronic risk is regulated based on effects seen in body weight decrements

and liver effects in the female rat. Dimethomorph has be en classified as showing no evidence of human carcinogenicity. Therefore, cancer risk from dimethomorph is not of concern to HED.

The dose for short

- term exposure is the maternal NOAEL established in the rat developmental toxicity study, whereas the dose for intermediate

- term exposure is the NOAEL established in the

90

- day dog feeding study. In a 28

- day rat dermal toxicity study, the NOAEL was 1000 mg/kg/day (the highest dose test, HDT) with no toxic effect seen. Since no toxicity was observed

at the limi t dose, risk assessment for dermal exposure is not necessary . Inhalation absorption is assumed to be 100 percent. At this time, there are no residential uses for dimethomorph. Therefore, discussion of dermal and inhalation toxicity are unnecessary for th is risk assessment with respect to residential exposures.

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

we ll as a two

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

- generation reproductive toxicity studies, that were observed at lower doses than those which produ ced toxic effects in the parents. No developmental toxicity was demonstrated in the rabbit developmental toxicity study.

Because of these reasons the 10

- fold FQPA Safety Factor, to account for enhanced sensitivity of infants and children, was reduced to 1.

An acute endpoint was not selected for dimethomorph; therefore, the Agency conducted only a chronic dietary (food and drinking water) exposure and risk assessment. Chronic dietary risks are not of concern for the U.S. population and all subpopulatio ns. For food and drinking water, the chronic aggregate d ietary risk was calculated at 14 % of the cPAD (chronic population adjusted dose). The exposure estimate for the most highly exposed subpopul ation (children 1

- 2 years) is 27 % of the cPAD.

There are no residential uses for dimethomorph at this time, nor are any proposed. Also, t here are no registered or proposed uses of dimethomorph that would result in treatment of recreational areas. Therefore, assessment for residential handler and post

- application exposures is not required at this time

.

Since there are no acute endpoints of concern, an acute aggregate risk assessment was not conducted. There are currently no registered residential uses associated with dimethomorph; therefore, no short

- and intermediate

- term aggregate risk assessments are required.

HED has assessed occupational exposures to dimethomorph . These assessments includeDimethomorph Human Health Risk Assessment DP No. 387381

Page 7 of 39 scenarios for mixer s, loader s, applicator s and flaggers, and for post

- ap plication exposure of

workers arising from scouting, harvesting, and other cultivation

- related activities . For all of

these scenarios , risk estimates are below HED’s level of concern (MOEs ≥ 100). The label restricted entry interval (REI) of 12

- hour is appropriate and in compliance of the Worker Protection Standard requirements.

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 studies, which compr ise the Pesticide Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force ARTF) database, have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethical.

2.0 HED Recom mendations

Provided the registrant submits a revised Section F (see Table 10.2 )

, there are no human health risks of concern that would preclude the establishment or revision of tolerances for the residue of dimethomorph under 40 CFR 180.493 as follows:

Grapes

................................ ................................ ... 4.0 ppm Grape raisins

................................ ......................... 6.0 ppm

Brassica , head and stem, subgroup 5A

................ 5.0 ppm

Brassica , leafy greens, subgroup 5B

................... 30.0 ppm Leafy Vegetable except Brassica

, sub group 4 A.. 20.0 ppm

Leaf Petioles

, subgroup 4B

................................ . 15.0 ppm

Onion bulb

................................ ........................... 0.6 ppm

Green Onion

................................ ....................... 15. 0 ppm

2.1 Data Deficiencies/Conditions of Registration

The following data should be submitted with future uses:

RESIDUE CHEMISTRY

860.1200 Directions for Use

Section B of the labels should be amended to prohibit rotation to cereal grains. Also, the

crop rotation restriction will need to be revised to specify a 7 month plant back interval (PBI) for soybean and other legume vegetables ; all other crops can be planted 12 months after the last application

.

Note to RD: Please delete the expired footnote in the 40 CFR 180.493 for grape raisin that states, ―There are no US registrations as of March 4, 2009, for the use ofDimethomorph Human Health Risk Assessment DP No. 387381

Page 8 of 39 dimethomorph on grapes grown for raisin production.‖ The registrant is requesting

national toleranc es for grapes and the raisin tolerance of 6.0 ppm can remain for US registration.

860.190 0 Field Accumulation in Rotational Crops

Limited field trials for wheat (20 trials) should be conducted and the geographic representation should be the same as that r equired to establish a t olerance on wheat as listed in the OPPTS Guideline 860.1500. [ Note: Limited field trials for wheat are not required if the registrant agree s to label amend ments prohibit ing rotation to cereal grains ]

2. 2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate enforcement method is available for dimethomorph , Method FAMS 002

- 04, which utilizes high pressure liquid chromatography with ultraviolet detection (HPLC/UV). The reported limit s of quantitation (LOQs) rang e from 0.010 to 0.050 ppm, depending on the sample matrix. The method has been successfully validated by BEAD’s Analytical Chemistry Branch (ACB). A confirmatory method is also available, Method M 2577, a gas

- chromatography method with nitrogen/phosphoru s detection (GC/NPD). Also, dimethomorph has previously been subjected to testing via the FDA multiresidue methods protocols of PAM 1 and dimethomorph is recovered using Protocol D. A LC/MS/MS method (BASF Method No 575/0) for dimethomorph has been deter mined to be adequate for data collection in/on grapes, bulb vegetables, leafy Brassica vegetables and leafy vegetables. The LOQ is 0.01 ppm.

2.2.2 International Harmonization

There are no Canadian nor Mexican maximum residue limits (MRLs) established fo r residues of dimethomorph in crops associated with this review. Codex MRLs have been finalized for grapes and raisins at 2 and 5 ppm, respectively. The Codex MRLs are not harmonized with the established US tolerances in grapes and raisins (3.5 and 6.0 p pm, respectively), which are based on European residue data.

3 .0 Ingredient Profile

Dimethomorph is a systemic fungicide used for the control of downy mildews, late blights, and

crown and root rots.

3.1 Structure and NomenclatureDimethomorph Human Health Risk Assessment DP No. 387381

Page 9 of 39 Table 3 .1 : Test Compound 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

End

- use product (EP) BAS 550 11F ( F ORUM ® Fungicide (4.17 ai /gal SC formulation); EPA Reg. No.

241

- 427 )

3.2 Physical/Chemical Characteristics

Table 3 .2 : Physical and Chemical Properties

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) water, pH 5 19 mg/L water, pH 7 18 mg/L water, 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 25oC

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 availableDimethomorph Human Health Risk Assessment DP No. 387381

Page 10 of 39 3 .3 Summary of Existing/Proposed Uses

BASF Corporation has submitted draft label language to support the amended use of dimethomorph on grapes. The amended label would reduce the PHI for grapes from 28 to 14 days, reduce the maximum number of applications from 5 to 4 and to expand the use from its current regionally restricted use to a national registration. In addition, the registran t is proposing

amended uses on bulb vegetables, leafy Brassica vegetables (crop group 5) and leafy vegetables (crop group 4) as a 4.17 lb ai/gal SC formulation (EPA Reg. No. 241

- 427)

. This is a new

formulation (SC) being proposed for dimethomorph. There is an existing FlC formulation (EPA Reg. No. 241

- 427). T hese end

- use products (EPs) may be applied by aerial, airblast or ground sprays, or via chemigation. The proposed ne w uses are summarized in Table 3 .3.

TABLE 3 .3. Summary of Directions for the Proposed Uses of Dimethomorph. Use Timing; Type; Equipment Formulation

[EPA File #] Applic.

Rate (lb ai/A) Max # of Applic.

per Season Max

Seasonal Applic. Rate (lb ai/A) PHI

(Days) Use Directions and

Limitations

Grapes

Post

- emergence; Foliar; ground

or aerial 4.17 lb ai/gal

SC [241

- 427] 0.20 4 0.80 14 Do Not use less than 20 gal of water per acre for ground and 5 gal of water for aerial applications. The minimum application

interval for Forum is 7 days.

Brassica Leafy Vegetables

Post

- emergence; Foliar; ground

or aerial 4.17 lb ai/gal

SC [241

- 427] 0.20 3 0.60 0 Do n ot use less than 20 gal of water per acre for ground and 5 gal of water for aerial applications.

The minimum application interval

for Forum is 7 days.Dimethomorph Human Health Risk Assessment DP No. 387381

Page 11 of 39 TABLE 3 .3. Summary of Directions for the Proposed Uses of Dimethomorph. Use Timing; Type; Equipment Formulation

[EPA File #] Applic.

Rate (lb ai/A) Max # of Applic.

per Season Max

Seasonal Applic. Rate (lb ai/A) PHI

(Days) Use Directions and

Limitations

Leafy (Except Brassica ) Vegetables

Post

- emergence; Foliar; ground

or aerial 4.17 lb ai/gal

SC [241

- 427] 0.20 3 0.60 0 Do n ot use less than 20 gal of water per acre for ground and 5 gal of water for aerial applications.

The minimum application interval for Forum is 7 days.

Bulb Onion

Post

- emergence; Foliar; ground

or aerial 4.17 lb ai/gal

SC [241

- 427] 0.20 3 0.60 0 Do n ot use less than 20 gal of water per acre for ground and 5 gal of water for aerial applications.

The minimum application interval for Forum is 5 days

4 .0 Hazard Characterization and Dose

- Response Assessment

4 .1 Hazard and Dose

- Response Characterization

Table A.2.1 (in Appendix A) summarizes the acute toxicity of the technical grade of dimethomorph. As demonstrated, technical dimethomorph is relatively non

- toxic when administered acutely to laboratory animals. Table A.2.2 (in Appendix A) summarizes the subchronic, chronic and other toxicity of the technical grade of dimethomorph.

4 .1.1 Database Summary

T he toxicology database for dimethomorph is complete ; no additional studies are required for

risk assessment. The to xicity profile of dimethomorph can be characterized for most effects, including potential carcinogenic, mutagenic, developmental, immunotoxic, and neurotoxic effects. The doses and endpoints for use in human health risk assessments are summarized in

Table 4.5.11. Previously, a s part of the new EPA guideline requirements (40CFR §158) , acuteDimethomorph Human Health Risk Assessment DP No. 387381

Page 12 of 39 and subchronic neurotoxicity studies, as well as an immunotoxicity study we re required . Studies for 21/28 day dermal toxicity, immunotoxicity, subchronic neurotoxicity w ere submitted. However, an acute neurotoxicity study was not submitted. There were no neurotoxic effects seen at the highest dose tested in a subchronic neurotoxicity study. The available data for dimethomorph also do not show evidence of neurotoxicity

. H ED believe s that conducting an

acute neurotoxicity stud y is unlikely to add value to the risk assessment or identify a lower point of departure for risk assessment. Therefore, an acute neurotoxicity study is not needed at this

time.

4 .2 Absorption, Dist ribution, Metabolism, Excretion (ADME)

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 excretio n of metabolites in the urine and bile. Saturation of absorption following single high doses ( 500 mg/kg ) was indicated by large amounts (roughly 50% ) of radioactivity in the feces being associated with parent compound. For low

- or high

- dose treatment, ur inary 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 no more than 1% for most tissues

, although the liver exhibited slightly higher levels ( 1.4% ). H igher levels in the gastrointestinal tract organs w ere caused by radioactivity in the lumenal contents. Urinary metabolites resulted from demethylation of the dimethoxyphenyl ring

, and oxidation of the morpholine ring. Bi liary excretion exhibited first

- order kinetics with a low

- dose ( 10 mg/kg )

half

- life of approximately 3 hours

, 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 e xcretion 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.

4 .3 FQPA Considerations

4 .3.1 Ad equacy of the Toxicity Database

The database is adequate to characterize potential pre

- and/or post

- natal risk for infants and

children . Developmental toxicity studies in rats and rabbits, a nd reproduction studies in rats a re available for FQPA assessment

. Based on the toxicity profile for dimethomorph, a developmental neurotoxicity study in rats is not required.

4 .3.2 Evidence of Neurotoxicity

There is a subchronic neurotoxicity studies available while an acute neurotoxicity study was not submitted. There was no evidence of neurotoxicity observed in any of the submitted studies for dimethomorph.Dimethomorph Human Health Risk Assessment DP No. 387381

Page 13 of 39 4 .3.3 Developmental Toxicity Studies

In a developmental toxicity study in rats, reductions in body weight, body weight gain, and food consumption were seen in maternal animals at the LOAEL of 160 mg/kg/day (NOAEL = 60 mg/kg/day). Increased post

- implanta tion loss was also seen at 160 mg/kg/day. In a developmental toxicity study in rabbits, increased incidence of abortion was observed at the LOAEL of 650 mg/kg/day (NOAEL = 300 mg/kg/day). No effects were observed in pups at doses of up to 650 mg/kg/day.

4 .3.4 Reproductive Toxicity Study

In a multi

- generation reproductive toxicity study, the P generation animals were mated in a one

to

- one ratio, and given the test material for 15 weeks before they were mated . Selection of the parents for the F 1 generation was made shortly after weaning on day 21 post

- partum. The P 1 animals were mated when they were approximately 21 weeks of age, while the F 1 generation was mated at about 15 weeks of age.

No clinical sig ns or necropsy findings which could be associated with administration of the test material were noted at any dose level in parental animals. At 1000 ppm, P generation females weighed consistently less than controls throughout the 15 week pre

- mating period (p<0.05). Statistically significant reductions in food consumption were also noted in 1000 ppm females during the pre

- mating period. In F 1 females, body weights were slightly lower in all the dose groups but differences were not statistically significan t. At the 1000 ppm level, during several intervals of the pre

- mating period, female weight gain was reduced (p<0.05). No effects were apparent in males of the P or F 1 generations. For parental systemic toxicity, the NOAEL was 300 ppm, and the LOAEL was 1000 ppm, based upon decreased body weights and body weight gains.

Reproductive indices were not affected by treatment at any dose level or mating. The percentage of pups with incisor eruption was noted at the 1000 ppm dose level in the F 1 , F 2a and F 2b generations with non

- significant delays observed at the lower dose levels. During the second mating of the F 1 generation to produce the F 2b generation, a large number of inseminated females failed to deliver. This finding appeared to occur in a dose

- r elated manner at all dose levels but was not apparent during other matings. It should be noted that the prostate gland was apparently affected by the test material in the dog chronic feeding study, and the organ was not weighed in the chronic rat study. No organ weight data were presented for the prostate gland in this reproduction study but no dose

- related histopathology data were apparent in this study. For reproductive toxicity, the NOAEL was 300 ppm, and the LOAEL was 1000 ppm, based upon

decreased i ncisor eruption on day 10 postpartum.Dimethomorph Human Health Risk Assessment DP No. 387381

Page 14 of 39 4 .3.5 Additional Information from Literature Sources

There is no additional information available from the literature to influence FQPA safety

find ings.

4 .3.6 Pre

- and/or Post

- Natal Toxicity

4 .3.6.1 Determination of Susceptibility

The available data do not provide evidence of any increased susceptibility in the offspring in either of the two developmental toxicity studies, nor in the two

- generation reproduction study. In none of these studies was any toxicity seen in the offspring which occurred at doses lower than in the parents.

4 .3.6.2 Degree of Concern Analysis

, and Residual Uncertainties for Pre

- and/or Post

- N atal Susceptibility

The purposes of the Degree of Concern analysis are to determine the level of concern for the

effects observed ( when considered in the context of all available toxicity data ), and to identify any residual uncertainties ( after establishing toxicity endpoints

, and traditional uncertainty

factors to be used in the risk assessment ) . If residual uncertainties are identified, then HED determines whether these residual uncertainties can be addressed by a n FQPA safety factor

, and if so, the size of the safety facto r needed.

T here are no residual uncertainties with regard to pre

- and/or post

- natal toxicity following in

utero exposure to rats or rabbits

, and pre and/or post

- natal exposures to rats

. Therefore, it is recommended that the FQPA safety factor be reduc ed to 1 x; no additional safety factors are needed ( see S ection 4 .4 , below ).

4 .3.7 Recommendation for a Developmental Neurotoxicity Study

None of the submitted studies indicate that dimethomorph is a neurotoxic chemical. Neither the subchronic nor chronic toxicity studies in rats or dogs, nor the developmental toxicity studies indicated that the nervous system was affected by treatment with dimethomorph. There is no indication that dimethomorph is a neurotoxic chemical, and there are no residual uncertainties regarding pre

- and/or post

- natal toxicity following dimethomorph exposure . Therefore, a developmental neurotoxicity study is not req uired, and there is no need for additional uncertainty

factors.

4.4 FQPA Safety Factor for Infants and Children

Initially (4 May 1998), HED determined that a safety factor was necessary, based on t he lack of environmental fate data required for the drinking water exposure assessment of dimethomorph.Dimethomorph Human Health Risk Assessment DP No. 387381

Page 15 of 39 However, EFED assured HED that, even assuming the worst possible model input parameters for dimethomorph, risk levels for drinking water exposure are n ot of concern. Considering this inormation, on 8 June 1998, HED recommended that the 10x Safety Factor be removed. Additionally:

1. The developmental and reproductive toxicity data did not indicate increased susceptibility of rats or rabbits to in ut ero and/or post

natal exposure to dimethomorph,

2. T here is no evidence of neurotoxicity,

3

. T he dietary (food only) exposure assessment did not indicate a concern for potential risk to infants and children, even though unrefined field study data are use d, resulting in an overestimate of dietary exposure, and

4

. T here are currently no registered residential uses for dimethomorph.

4.5 Hazard Identification and Toxicity Endpoint Selection

4.5.1 Acute Reference Dose (aRfD)

- Females Age 13

- 49

No appropriate endpoint was identified.

Comments about Study/Endpoint/Uncertainty Factors: 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 RfD (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 identif ied in other oral studies. Consequently, it was determined that there was no basis for selecting a dose and endpoint for an acute RfD.

4.5.2 Acute Reference Dose (aRfD)

- General Population

No appropriate endpoint was identified.

Comments about Study/Endpoint/Uncertainty Factors: No appropriate toxicological endpoints attributable to a single exposure were identified in oral studies. Consequently, there was no basis for selecting a dose and endpoint for an acute RfD. An acute dietary risk assessment is not required for any segment of the US population, including infants and children.

4.5.3 Chronic Reference Dose (cR fD )

Studies Selected: Chronic Toxicity

- Rat/Carcinogenicity

- Rat

MRID N umbers : 42233912 and 42233916Dimethomorph Human Health Risk Assessment DP No. 387381

Page 16 of 39 Dose and Endpoint for Risk Assessmen t: NOAEL= 11 mg/kg/day Uncertainty Factor: 100 x (10x interspecies extrapolation, 10x intraspecies variability)

Chronic RfD = 11 mg/kg/day (NOAEL) = 0.1 mg/kg/day

100 (UF)

Comments about Study/Endpoint/Uncertainty Factors: The d ata evaluation r ecords (DERs) for

the rat chronic

, and rat carcinogenicity studies (MRIDs #42233912 and #42233916) established comparable NOAELs (11 .9 versus 11.3 mg/kg/day) and endpoints of increased incidences of pigmented or hypertrophied hepatocytes

, and ―ground glass‖ foci in livers of female rats. Females appeared to be more sensitive in these studies.

Dose and Endpoint for Establishing the RfD : NOAEL= 11 mg/kg/day based on decreased body weight and statistically significant increases in liver lesions in female rats at 46.3 mg/kg/day (LOAEL).

4.5.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

There are no residential uses for dimethomorph, so a toxicity endpoint for incidental oral exposure is not necessary.

4.5.5 Dermal Absorption

The total amount of dimethomorph absorbed (expressed as a percent of the [ 14 C]

- dose) by rats at various times following dermal administration of [ 14 C]

- dimethomorph at 7.73 (0.15 mg/cm 2 ) or 79.62 mg/kg (1.58 mg/cm 2 ) is less than 5% of the dose, and it appears that the absorption is concentration dependent. Dermal absorption was 0.05%, 0.07% and 0.27% of the administered dose in rats 4, 8 and 24 hours after dermal treatment at 7.73 mg/kg, res pectively. Dermal absorption was 0.02%, 0.16% and 0.12% of the dose 4, 8 and 24 hours after dermal treatment at 79.62 mg/kg, respectively. Dermal absorption was approximately 0.4 and 1 mg/kg in terms of weight equivalent at 7.73 and 79.62 mg/kg, respecti vely. Six days after dermal treatment, the percent total absorption of the dose at 7.73 and 79.62 mg/kg was 4.76 and 1.20%, respectively. Mean percent recovery of 14 C for dose levels of 7.73 and 79.62 mg/kg was 10 4.1% and 92.1%, respectively. The m ajori ty of the radioactivity was found in skin swabs and gauze wash (80.9 to 81.8%). The percent of the dose in the skin decreased with dose, being 17.5 % at 7.73 mg/kg, and 9.99% at 79.62 mg/kg.

The dermal absorption coefficient factor is 5%.Dimethomorph Human Health Risk Assessment DP No. 387381

Page 17 of 39 4.5.6 De rmal Exposure (Short

- , Intermediate

- and Long

- Term)

There is a 28

- day dermal toxicity study in rats available. The NOAEL was 1000 mg/kg/day (the highest dose test, HDT) with no toxic ef fect was seen. Since no toxicity was observed at the limit dose, risk assessment for short

- and intermediated

- term occupational dermal exposure is not necessary. The current use pattern does not indicate a concern for long

- term exposure/risk, and no long

- t erm uses are proposed. Therefore, risk assessment for long

- term dermal exposure is not

needed.

4.5.7 Inhalation Exposure (Short

- , Intermediate

- and Long

- Term)

There are no inhala tion studies, except for the acute toxicity study (MRID #43917246). Therefore, the oral NOAELs were selected for short

- and intermediate

- term inhalation risk assessments. The use pattern does not indicate a concern for long

- term exposure/risk.

4.5.7.1 Oc cupational Inhalation Exposure (Short

- Term) Study Selected: Developmental Toxicity

- Rat

MRID N umbers : 42233919 and 44175302 Dose and Endpoint for Risk Assessment: NOAEL= 60 mg/kg/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors: No inhalation toxicity studies are available. The maternal toxicity NOAEL is 60 mg/kg/day, based on decreased body weight, decreased body weight gain, and decreased food consumption at 160 mg/kg/day (LOAEL) in an oral developmental toxicity study. The effects seen in the dams during gestation days 10

- 15 (after 4

- 5 dosings) are appropriate to use for sh ort

- term exposure periods (1

- 30 days). Since an oral NOAEL was selected, the inhalation exposure component (μg ai/day) using 100% absorption rate should be converted to an equivalent oral dose (mg/kg/day) in calculating the risk for inhalation exposure.

4.5.7.2 Occupational Inhalation Exposure (Intermediate

- Term) Study Selected: Subchronic Toxicity

- Dog

MRID N umber : 422339081 Dose and Endpoint for Risk Assessment: NOAEL= 15 mg/kg/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors: The NOAEL is 15 mg/kg/day, based on decreased absolute and relative prostate weight, and possible threshold liver effects at the LOAEL of 43 mg/kg/day in a subchronic oral feeding study in dogs. Since a subchronic oral study was selected, the inhalation e xposure component (μg ai/day) using 100% absorption rate should be converted to an equivalent oral dose (mg/kg/day) for intermediate

- term (30 days to 6 months) risk assessments.Dimethomorph Human Health Risk Assessment DP No. 387381

Page 18 of 39 The current use pattern does not indicate a concern for long

- term exposure/risk, and no long

term uses are proposed.

4.5.8 Level of Concern (LOC) for Margin of Exposure (MOE)

Target MOEs are 100 for occupational inhalation (short

- and intermediate

- term) exposures.

TA BLE 4 .5.8 Summary of LOCs for Dimethomorph Risk Assessment.

Route of Exposure Short

- Term

(1

- 30 Days) Intermediate

- Term

(1

- 6 Months) Long

- Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal NA* NA* NA*

Inhalation 100 100 NA

Residential Exposure

Dermal NA NA NA

Inhalation NA NA NA

Incidental Oral NA NA NA

* NA = Not Applicable.

4.5.9 Recommendation for Aggregate Exposure Risk Assessments

There 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.

4.5.10 Classification of Carcinogenic Potent ial

In a carcinogenicity study in rat, there was no evidence of increased incidence of any neoplasms at the doses tested. The chemical was tested at adequate dosage, based on the high incidence o f arteritis in males, and the pronounced decrease in body weight in females at the mid

- and high

dose levels.

In a carcinogenicity study in mice, there was no dose

- related decrease in survival, or in any parameter examined on necropsy. The LOAEL for systemic toxicity was 1000 mg/kg/day, based on decreased body weight gain in males. The NOAEL was 100 mg/kg/day. There was no evidence of carcinogenicity. The high dose tested (1000 mg/kg/day), while probably not the maximum tolerated dose, especially in females, is the maximum dose required by the test guidelines for a dietary oncogenicity study.Dimethomorph Human Health Risk Assessment DP No. 387381

Page 19 of 39 Dimethomorph h as been classified as ―not likely‖ to be a human carcinogen.

4.5.11 Summary of Toxicological Doses and Endpoints for Use in Human Risk

Assessments

The toxi city endpoints pertinent to an assessment of risk for dimethomorph are summarized in

Table 4 .5.11, below.

Table TABLE 4 .5.11 Summary of Toxic ological Doses and Endpoints 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 ( F emales 13

- 49) No endpoint attributable to a

single dose was identified

. Not applicable

. No study selected.

Acute Dietary ( G eneral P opulation) No endpoint attributable to a

single dose was identified

. Not applicable

. No study selected

.

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

UF A = 10x

UF H = 10x FQPA SF = 1

UF = 100 cPAD =

NOAEL ÷ UF = 0.1 mg/kg/day 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.

Dermal Short

- and

Intermediate

- Term No toxicity was observed at the

limit dose in a 28

- day dermal toxicity study. No risk assessment

is necessary. Not applicable

. No study selected.

Dermal Long

- Term (> 6 M onths) No long

- term exposure or risk. Not applicable

. No study selected

.

Inhalation Short

- Term (1

- 30 D ays) O ral study NOAEL=

60 mg/kg/day (inhalation absorption factor = 100%) LOC for MOE < 100 Developmental t oxicity s tudy

in r at s. LOAEL = 160 mg/kg/day based on decreased body weight, body weight gain, and food consumption.

Inhalation

Intermediate

- Term (1

- 6 M onths) O ral study NOAEL= 15 mg/kg/day (inhalation absorption factor = 100%) L OC for MOE < 100 Subchronic feeding s tudy in

d ogs

. LOAEL = 43 mg/kg/day based on

decreased absolute and relative prostate weight

, and possible threshold liver

effects. Inhalation Long

- Term (>6 M onths) No long

- term exposure or risk. 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 inDimethomorph Human Health Risk Assessment DP No. 387381

Page 20 of 39 sensitivity among members of the human population (intraspecies). FQPA SF = F QPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). MOE = margin of exposure. LOC = level of concern.

4.6 Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) ―may have an effect in humans that is similar to an effect produced by a natu rally occurring estrogen, or other such endocrine effects as the Administrator may designate.‖ Following recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there was a scientific basis for inc luding, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC’s recommendation to include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone system s may be added to the Endocrine Disruptor Screening Program (EDSP).

When additional appropriate screening and/or testing protocols being considered under the Agency’s EDSP have been developed, dimethomorph may be subjected to further screening

and/or te sting 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: http://www.epa.gov/endo/.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5 .1.1 Summary of Plant and Animal Metabolism Studies

Plant Metabolism Studies

The qualitative nature of dimethomorph residues in plants is adequately understood based on metabolism studies conducted in three dissimilar crops (potatoes, grapes and lettuce ). The residue of concern for the tolerance expression and risk assessment is the parent compound, dimethomorph (comprised of E and Z isomer s).

Animal Metabolism Studies

Based on the results of metabolism studies in ruminants and poultry, and a cattle feeding study, tolerances are not required for residues in meat, milk, poultry nor eggs as a result of ingestion ofDimethomorph Human Health Risk Assessment DP No. 387381

Page 21 of 39 dimethomorph residues in the livestock feed . Furthermore, there are no significant livestock feedstuffs associated with the proposed uses on grapes, bulb vegetables, Brassica leafy vegetables and leafy vegetables. As a result , tolerances for residues of dimethomorph in

livestock commodities need not be established.

5 .1.2 Summary of Environmental Degradation

The residue of concern in drinking water is dimethomorph (comprised of E and Z isomers).

D imethomorph is not expected to be affected by abiotic degradation process es, 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 moderately persistent in an aerobic soil (half

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

Laboratory studies on mobility of dimethomorph indicated low to medium mobility in soil systems, in accordance with McCall et al (1981). The results of the field dissipation study appear to confirm the low to medium mobility inferred from laboratory studies. H owever, episodes of high rain fall were shown to increase downward mobility in the field soil profile

.

5 .1.3 Compar ison of Metabolic Pathways

Oral administration of dimethomorph (10 mg/kg single dose; 10 mg/kg 14

- day repeated dose; 10 mg/kg 7

- day repeated dose; 500 mg/kg single dose) 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 inferr ed by the rapid excretion of metabolites in the urine and bile

. Saturation of absorption following single high doses (500 mg/kg) was indicated by large amounts ( 50%) of radioactivity in the feces being associated with parent compound

. For low

- and high

- dose treatment s , urinary

excretion in female rats tended to be up to 2

- fold greater (in low

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

- dimethomorph

- derived radioactivity was generally 1% for

most tissues

, although the liver exhibit ed slightly higher levels (1.4%)

, and higher levels in the gastrointestinal tract organs was owing to radioactivity 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 half

- life of approximately 3 hours

, and a high

- dose 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

.

5 .1.4 Residues of Concern Summary and RationaleDimethomorph Human Health Risk Assessment DP No. 387381

Page 22 of 39 TABLE 5 .1. 4 Summary of Metabolites and Degradates to Be Included in Risk Assessment and

Tolerance Expression

Matrix Residues I ncluded in Risk

Assessment Residues I ncluded in Tolerance Expression

Plants Primary crops Dimethomorph Dimethomorph

Rotational crops

Livestock Ruminants NA* NA

Poultry Drinking water Dimethomorph NA * NA = Not Applicable.

5 .2 Food Residue Profile

Processed Food and Feed

The Agency does not require residue data for any processed commodities associated with bulb vegetables, and Brassica leafy vegetables and leafy vegetables. Processing study data for grapes were submitted previously in conjunction with the tolerance petitions requesting use on imported grapes (PP#2E4054 and PP#7F4816). These data indicated that dimethomorph residues do not concentrate in grape juice but do concentrate in raisins. Applying the average concentration factor of 1.8 to the highest theoretical field trial value (i.e., the HAFT prorated to a 1x application rate) obtained in field t rials (i.e., 3.07 ppm which was obtained in the previous Spanish field trials) yields a maximum theoretical residue level in raisins of 5.5 ppm. This value supports a tolerance of 6.0 ppm in raisins. (The highest field trial value reported in the most

re cent grape study for national registration is 1.86 ppm).

The existing tolerance for dimethomorph residues in raisins was established to support use of dimethomorph on grapes grown outside the US ; therefore, the tolerance should remain in 40CFR §180.493[a ] for US registration.

Storage Stability

Freezer storage stability data are available which demonstrate that residues of dimethomroph are stable under frozen storage conditions for up to 24 months in/on grapes, potatoes, broccoli, spinach and canola (D 381831; S. Piper; 09 / 31 /2011 )

.

Meat, Milk, Poultry, and EggsDimethomorph Human Health Risk Assessment DP No. 387381

Page 23 of 39 The Agency has determined that no livestock feeding studies are needed to determine secondary

transfer of dimethomorph residues of concern in milk, eggs, and edible tissues. Therefore, data requirements pertaining to meat, milk, poultry, and eggs are not relevant to this tolerance petition.

Rotational Crops

Based on previous data, HED concluded that the residue of concern in rotational crops is dimethomorph per se and that the following PBI s would be appropriate for dimethomorph uses at total seasonal rates of 1 lb ai/A (the maximum seasonal rate at the time): (1) 0 days for potato (the only registered crop use at the time); (2) 30 days for wheat, barley, oats

, Brassica leafy vegetables

, an d root/tuber/bulb vegetables ; (3) 7 months for corn, rice, sorghum

, soybeans

, and other legume vegetables ; and (4) 12 months for all other crops (D323873, D.Rate, 10/29/08).

The results from the latest limited field trial study have shown that followin g three broadcast applications to the soil targeting 0.198

- 203 lb ai/A application at a 4

- 6 day RTI, resulting in a

total rate of 0.598

- 0.607 lb ai/A/season. No quantifiable residues of dimethomorph were observed in rotational crops (lettuce and radish) planted up to 4 months after the last application, with the exception of wheat forage, hay and straw. Quantifiable dimethomorph residues were observed in wheat forage (0.03 ppm), hay (0.04 ppm), and straw (0.20 ppm) planted for up to 4

months after the las t application. If the limited field studies indicate that quantifiable residues will occur, rotational crop tolerances will be required . The data show higher residues at longer PBI, and tolerances may be needed in the cereal group, grain commodities except grain. Therefore, limited field trials for wheat (20 trials) commodities should be conducted and the geographic representation should be the same as that required to establish a tolerance on wheat

as listed in the OPPTS Guideline 860.1500. The labels must be amended to prohibit rotation to cereal grains. These rotational crop restriction s on cereal grains are needed until additional field

trial data are submitted. Also, a PBI of 7 months for soybean and other legume vegetables

should remain

, and 12 months for all other crops

.

Crop Field Trials

BASF Corporation has submitted a request to revise the use pattern for dimethomorph on grapes, bulb vegetables, leafy vegetables and Brassic a leafy vegetables using the Forum® Fungicide as a

foliar s uspension concentrate (SC) formulation containing the active ingredient dimethomorph. Dimethomorph is currently registered for up to five foliar broadcast applications to grapes at 0.2 lb ai/A, for a maximum seasonal rate of 1.0 lb ai/A, with a 7

- day mini mum re

- treatment interval (RTI) and a 28

- day pre

- harvest interval (PHI). However, this registration is regionally restricted and the use is limited to Rocky Mountains. The registrant has submitted a Section 3 registration to remove the regional restrictio n, change the PHI from 28 days to 14 days and change the maximum number of applications from 5 to 4. Previously, to support the proposed uses forDimethomorph Human Health Risk Assessment DP No. 387381

Page 24 of 39 dimethomorph on grapes in the U.S., IR

- 4 is relying on European field trial data submitted to

establish the c urrent import tolerance for dimethomorph residues in/on grape (PP#s 2E4054 and 7F4816). The available data will support a tolerance with national registration for residues of dimethomorph in/on grapes at 3.5 ppm and raisins at 6.0 ppm. The registrant has provided grape field trial data reflecting a 14

- day PHI.

Field trial data were submitted on bulb vegetables, leafy vegetables and Brassic a leafy vegetables using the Forum® Fungicide as a foliar suspension concentrate (SC) formulation containing the act ive ingredient dimethomorph. At each test location, three broadcast foliar applications of a tank mix of suspension concentrate (SC) formulations containing the active ingredient dimethomorph were made to bulb vegetables, leafy vegetables and Brassic a lea fy vegetables targeting 0.200 lb ai/A/application (maximum seasonal rate of 0.80 lb ai/ha/application) harvested at 0 days after the last application.

The submitted residue data for grapes, bulb vegetables, leafy vegetables and Brassic a leafy vegetables are adequate. The residue data were entered into the Agency’s OECD MRL

calculator . The tolerance spreadsheet recommends a tolerance of 4.0 ppm (instead of the proposed 3.5 ppm) for residues in/on grapes; 5.0 ppm in/on Brassica , head and stem, CG 5A; 30.0 ppm in/on Brassica , leafy greens, CG 5B; 20.0 ppm in/on leafy vegetables except Brassica CG 4A and 15.0 ppm for leaf petioles CG 4B ( instead of the proposed 16.0 ppm) ; 15.0 ppm (instead of the proposed 11 ppm) in/on green onion a nd 0.6 ppm in/on onion bulb

.

Table 5.2: Summary of Dimethomorph Residue Data from Field Trials

Matrix Total

Applic.

Rate (lb a.i./A) PHI

(days) n Min. Max. HAFT a Median (STMdR ) b Mean (STMR)

c Std.

Dev.

Conc. Spray (Treatment 2) Grape, fruit 0.79

- 0.82 14

- 15 13 0.05 1.83 1.83 0.4 0.65 0.61 Dilute Spray (Treatment 3) Grape, fruit 0.79

- 0.83 14

- 15 13 0.11 1.86 1.86 0.65 0.74 0.53 Both Sprays (Treatment 2& 3) Grape, fruit 0.79

- 0.83 14

- 15 26 0.05 1.86 1.67 0.50 0.69 0.56

Bulb onion,

bulb 0.662

- 0.711 0 20 0.04 0.40 0.39 0.13 0.15 0.11

Green onion 0.662

- 0.696 0 6 1.34 6.60 5.36 1.79 2.90 2.06

Overall bulb veg. (bulb and green onion) 0.662

- 0.711 0 26 0.04 6.60 5.36 0.18 0.79 1.50

Leaf Lettuce,

leaves 0.672

- 0.693 0 18 2.04 10.53 9.88 4.94 5.53 2.63

Head Lettuce, 0.671

- 0.687 0 16 1.07 4.10 4.10 1.925 2.12 0.95Dimethomorph Human Health Risk Assessment DP No. 387381

Page 25 of 39 fresh, WWL Spinach,

leaves 0.668

- 0.704 0 16 4.20 11.47 11.26 8.15 7.80 2.31

Celery,leaf

stalk 0.672

- 0.692 0 18 1.25 8.82 8.21 2.435 3.30 2.23

Broccoli, (Flower head

and stem) 0.663

- 0.721 0 20 0.19 2.14 2.05 1.11 1.22 0.59

Cabbage, head (Fresh with wrapper leaves) 0.662

- 0.684 0 20 0.13 4.61 4.26 0.94 1.17 1.14

Cabbage,

head Fresh

without

wrapper leaves) 0.662

- 0.694 0 20 <0.01 0.56 0.50 0.08 0.13 0.15

Mustard greens(leaves) 0.659

- 0.681 0 14 3.44 19.25 15.79 8.37 9.77 4.56

Brassica leafy veg. (all RAC types) 0.659

- 0.779 0 54 <0.01 19.25 15.79 1.37 3.42 4.48

For residue values below the LOQ, the LOQ (0.01 ppm) was used for calculation of the HAFT, median, mean, and standard

deviation.

a HAFT = Highest Average Field Trial value.

b STMdR = Supervised Trial Median Residue.

c STMR = Supervised Trial Mean Residue.

5 .3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provide d by the

E nvironmental Fate and Effects Division (E FED ) in the following memorandum: ―The Amended Directions for use of Dimethomorph in Brassica subgroup 5A&5B, Green Onions, Grapes, Leafy Vegetables, New ai Ametoctradin Cofomulated with Dimethomorph (non

- food uses and food uses) for use in Human Health Risk Assessment‖ (I. Abdel

- Saheb, D387377, 7/27/11) and incorporated directly into th e dietary assessment.

The Agency lacks sufficient monitoring exposure data to complete a comprehensive dietary exposure anal ysis and risk assessment for dimethomorph in drinking water. Because the Agency does not have comprehensive monitoring data, drinking water concentration estimates are made by reliance on simulation or modeling, taking into account data on the physical ch aracteristics of dimethomorph.

The estimated drinking water concentrations (EDWCs) for dimethomorph were calculated based on a maximum application rate of 1.4 lb ai/A/season. For the proposed crop applications, the chronic EDWC in ground water was 0.26 4 ppb, from Tier 1 SCI

- GROW modeling. The chronicDimethomorph Human Health Risk Assessment DP No. 387381

Page 26 of 39 EDWC in surface water, from Tier 1 FIRST modeling, was 24.7 ppb based on applications of the

chemical to broccoli

. Surface water concentrations were estimated using the Tier II model

Pesticide Root Zone M odel 3 (PRZM3; ver. 3.12.2; 5/2/2005)/Exposure Analysis Modeling System (EXAMS; ver. 2.98.04.06; 4/25/2005 )

. The model and its description are available at the

EPA internet site : http://www.epa.gov/o ppefed1/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 Anticipated Residue and Percent Crop Treated (%CT) Information

Anticipated residues and percent crop treated information were not used in this dietary exposure and risk assessment conducted to support the amended uses on grapes, bulb vegetables, Brassica leafy vegetables and leafy vegetables using t he the Forum® Fungicide as a foliar suspension concentrate (SC) formulation containing the active ingredient dimethomorph

.

5 .4.2 Acute Dietary Risk Assessment

No toxic effects attributable to a single dose of dimethomorph were observed in the toxicology database; therefore, an acute dietary exposure and risk assessment for this chemical was not

conducted.

5 .4.3 Chronic Dietary Risk AssessmentDimethomorph Human Health Risk Assessment DP No. 387381

Page 27 of 39 The unrefined chronic dietary risk assessment used tolerance level residues, included modeled drinking water estimates, assumed 100% crop treated, and incorporated DEEM default

proc essing factors. This highly conservative risk assessment showed no risks of concern (<100% of the chronic population adjusted dose (cPAD)) fo r the U.S. general p opulation or any population subgroup . The estimated exposure to the U.S. general p opulation res ulted in a risk equivalent to 14 % of the c PAD. The estimated exposure to children 1

– 2 years of age, the most highly exposed population su bgroup , res ulted in a risk equivalent to 27 % of the cPAD. Results

for all population subgroup are summarized in Table 5.4.5 , below.

5 .4.4 Cancer Dietary Risk Assessment

Dimethomorph is classified as ―Not Likely to be Carcinogenic to Humans‖, therefore, a cancer dietary exposure assessment was not conducted.

5 .4.5 Dietary Summary Table

Table 5

. 4.5 Summary of Dietary Exposure and Risk for Dimethomorph

Population Subgroup Acute Dietary Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population

N/A 13 % 14%

N/A All Infants (< 1 year old) 13 % 11%

Children 1

- 2 years old 0.027 6534 27%

Children 3

- 5 years old 0.021 379 22%

Children 6

- 12 years old 0.013 515 14%

Youth 13

- 19 years old 0.010 199 10%

Adults 20

- 49 years old 0.01 2865 13%

Adults 50+ years old 0.013 144 13 %

Females 13

- 49 years old 0.012 569 13%

The population with the highest exposure is in bold.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

6.1 Residential Handler ExposureDimethomorph Human Health Risk Assessment DP No. 387381

Page 28 of 39 There are no residential uses for dimethomorph at this time, nor are any proposed. Also, t here are no registered or proposed uses of dimethomorph that would result in treatment of recreational areas. Therefore, assessment for residential handler and post

- application exposures is not required at this time

.

6.2 Residential Post

- Application Ex posure

See Section 6.1 above.

6.3 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for dimethomorph. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applicati ons that must be placed on product labels/labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to re duce off

- target drift and risks associated with aerial as well as other applic ation types where appropriate.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighbor ing treated agricultural fields, an inhalation exposure assessment was performed for occupational flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure scenarios

.

6.4 Residential Bystander Post

- application Inhalation

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

- application inhalation exposure assessment was not performed for dimethomorph at this time primarily because of the low acute inhalation toxicity (Toxicity Category III). However, volatilization of pesticides may be a potential source of post

- application inhalation exposure to individuals nearby to pesticide applicatio ns. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory PanelDimethomorph Human Health Risk Assessment DP No. 387381

Page 29 of 39 (SAP) in December 2009. The Agency received the SAP’s final report on M arch 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). 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 incor porate post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for dimethomorph.

7.0 Cumula tive Exposure/Risk Characterization

The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. The Agency determined that there was insufficient evidence to suggest d imethomorph shares a common mechanism of toxicity with

other chemical 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 po licy statements released by EPA’s Office of Pesticide Program 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/

.

8.0 Occupational Exposure/Risk Characterization

8.1 Short

- and Intermediate

- Term Handler Risk

The registrant, BASF Corporation, has submitted a Section 3 registration application for proposed amended uses of the active ingredient (ai) dimethomorph on g rapes, leafy vegetables,

Brassica leafy vegetables, and bulb and green onions.

Handler Exposure

In 2000 and 2008, HED conducted occupational and residential exposure assessments for use of dimethomorph on a variety of agricultural crops including: tomato es, ginseng, grape, lima bean, and turnip greens (Shih

- chi Wang, D265380, 7/25/00 and Suku Oonnithan, D350234, 10/24/08). The maximum allowable application rate for all of these crops is 0.2 lb active ingredient (ai)/Acre. The typical application equipme nt for dimethomorph includes ground, aerial, and chemigation equipment In general, t he estimated non

- cancer short

- and intermediate

- term total margin of exposures (MOEs) from the 2000 and 2008 assessments to mixers, loaders, applicators, and flaggers did not exceed the Agency’s level of concern (MOEs ≥ 100) if the handlers wear baseline personal protective equipment (PPE) consisting of long sleeved shirt, long pants, and shoes with socks and chemical resistant gloves.Dimethomorph Human Health Risk Assessment DP No. 387381

Page 30 of 39 In addition, in the 2000 and 2008 ass essments, quantification of the short

- term dermal risk was performed using a developmental toxicity rat study. The intermediate

- term dermal risk was based on a subchronic toxicity dog study. At the time, no dermal toxicity studies were available (W

. Drew, DP349253, 11/6/08). Recently, a 28

- day dermal toxicity study was submitted to HED that was considered acceptable. The NOAEL from the study was 1000 mg/kg/day (the highest dose tested) with no effects shown. Since no toxicity was observed at the limit d ose, a quantitative occupational dermal risk assessment for short

- and intermediate

- term ex posure is no longer necessary.

The proposed amended uses of dimethomorph on grapes, leafy vegetables, Brassica leafy vegetables, and bulb and green onions would not result in a change in the maximum application

rate or the application equipment that would be used compared to what has already been assessed. Therefore, an updated occupational handler exposure asses sment for the proposed

amended uses is not required at this time.

8.2 Occupational Post

- Application

In 2000 and 2008, HED conducted a post

- application exposure assessment for workers when they enter dimethomorph

- treated fields for a variety of agricultural crops including: tomatoes, ginseng, grapes, lima bea ns, and turnip greens (S.Wang, D265380, 7/25/00 and S. Oonnithan, D350234, 10/24/08). In general, the estimated short

- and intermediate

- term dermal MOEs for the occupational post

- application activities did not exceed the Agency’s level of concern (MOEs ≥ 100). These assessments confirmed that the restricted entry interval (REI) of 12 hours on the dimethomorph labels is adequate to protect the workers who may enter the treated fields to do

any crop related activities.

In addition, in the 2000 and 2008 assessments, quantification of the short

- term dermal risk was performed using a developmental toxicity rat study. The intermediate

- term dermal risk was based on a subchronic toxicity dog study. At the time, no dermal toxicity studies were available ( W . Drew, DP349253, 11/6/08). Recently, a 28

- day dermal toxicity study was submitted to HED that was considered acceptable. The NOAEL from the study was 1000 mg/kg/day (the highest dose tested) with no effects shown. Since no toxicity was observed at the limit dose, a quantitative occupational dermal risk assessment for short

- and intermediate

- term ex posure is no longer necessary.

The proposed amended uses of dimethomorph on grapes, leafy vegetable s, Brassica leafy vegetables, and bulb and green onions would not result in a change in the maximum application

rate compared to what has already been assessed. Therefore, an updated occupational post

application exposu re assessment for the proposed amend ed uses is not required at this time.

9 .0 Environmental Justice ConsiderationsDimethomorph Human Health Risk Assessment DP No. 387381

Page 31 of 39 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 risks to population subgroups from pesticide exposures that are based on pat terns 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 patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

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

post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of spec ialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

10.0 Data Needs and Label Recommendations

10.1 Toxicology

No additional toxicological data are required at this time.

10.2 Residue Chemistry

The following residue chemistry deficiencies have been identified.

860.1200 Directions for Use

Section B of the labels should be amended to prohibit rotation to cereal grains. Also, the crop

rotation restriction will need to be revised to specify a 7 month plant back interval (PBI) for soybean and other legume vegetables ; all other crops can be planted 12 months after the last application

.Dimethomorph Human Health Risk Assessment DP No. 387381

Page 32 of 39 Note to RD: Please delete the expired footnote in th e 40 CFR 180.493 for grape raisin that states, ―There are no US registrations as of March 4, 2009, for the use of dimethomorph on grapes grown for raisin production.‖ The registrant is requesting national tolerances for grapes

and the raisin tolerance of 6.0 ppm can remain for US registration.

860.1550 Proposed Tolerances

The proposed tolerances must be re vised as specified in Table 10.2.

Table 10.2. Tolerance Summary for Dimethomorph

Commodity Established Tolerance (ppm) Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct

Commodity Definition
Tolerances to be established under §180.493 Grapes 3.5 1 3.5 4.0

Brassica , head and stem, subgroup 5A 2.0 5.0 5.0

Brassica , leafy greens, subgroup 5B 20.0 30.0 30.0

Leafy Vegetable

except Brassica

, sub group 4 A 10.0 (lettuce) 16.0 20.0

Leaf Petioles

, sub group 4 B NA 16.0 15.0

Onion bulb 2.0 11.0 0.6

Green Onion 2.0 11.0 15.0
Grape, raisin 6.0 2

-- 6.0

1 Tolerances for regional registration under 40 CFR 180.493(c)

2 There are no U.S. registration s as of March 4, 2009, for the use of dimethomorph on grapes grown for
raisin production

860.190 0 Field Accumulation in Rotational Crops

Limited field trials for wheat (20 trials) should be conducted and the geographic representation

sho uld be the same as that required to establish a t olerance on wheat as listed in the OPPTS

Guideline 860.1500. [ Note: Limited field trials for wheat are not required if the registrant agree s to label amend

ments prohibit ing rotation to cereal grains ]

11.0 ReferencesDimethomorph Human Health Risk Assessment DP No. 387381

Page 33 of 39 DP#: 381813 Subject: Dimethomorph. Application for Proposed Amended Use on Grapes

(PP# 0F7751); and the Section 3 Registration Action on the Bulb Vegetables (PP#0F7800 ) ; Leafy Brassica Vegetables (PP#0F7800 ) ; and Leafy Vegetables (PP#0F7816). S ummary of Analytical Chemistry and Residue Data.

From: S.Piper

To: T. Gibson, M. Waller

Date: 09/ 31 / 11

MRIDs: 47700109, 47700113, 47700114, 47700115, 47700105

DP#: 349253 Subject: 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

. From: S.Piper

To: T. Gibson, M. Waller

Date: 09 /07 / 11

MRIDs: NA

DP#: 192776 Subject: PP#2E4054

. Dimethomorph (in/on Grapes, Pot atoes, Animal Tissues and Milk

.

Review of Plant and Animal Metabolism Data, Analytical Methods, Crop Field Trials, Ruminant Feeding Study Data and Storage Stability Data to Support the

Establishment of an Import Tolerance for a New Chemical

. From: D. Davi s To: K

. Scanlon/L

. Cole

Date: 03/13/95

MRIDs: 42233942

DP#: 237101 Subject: PP# 7F4816

. Tolerance Petitions for the Use of Dimethomorph on Domestic and

Imported Tomatoes, Imported Grapes and Imported Hop Evaluation of Residue Chemistry and Analytical Methodology

. From: D. Dotson

To: M. Waller / T. Stowe

Date: 035/104/00

MRIDs: 44271201

- 202; 44388001, 44348901, 44457602, 44457607

- 44993001Dimethomorph Human Health Risk Assessment DP No. 387381

Page 34 of 39 APPENDIX A: TOXICOLOGY ASSESSMEN T

A.1 Toxicology Data Requirements

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

Use of th e new guideline numbers does not imply that the new (1998) guideline protocols were

used.

TABLE A.1 Toxicology Data Requirements for Dimethomorph.

Test Technical

Required Conducted

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

no yes

yes

yes

no

no

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

no 1

yes

no

870.7485 General Metabolism

870.7600 Dermal Penetration 870.7800 Immunotoxicity yes

no

yes yes

yes

yesDimethomorph Human Health Risk Assessment DP No. 387381

Page 35 of 39 1. The requirement for an acute neurotoxicity screening battery (rat) is waived.

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 sensitizerDimethomorph Human Health Risk Assessment DP No. 387381

Page 36 of 39 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 weights of the prostate and possible threshold

liver effects.

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

Acc eptable Information supplemental to

MRID# 42233918 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 =650 mg/kg/day [highest dose tested].

LOAEL could no t 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 gain. Developmenta l NOAEL = 60 mg/kg/day LOAEL = 160 mg/kg/day based on the incidence of post implantation loss

870.3800 Reprodu ction and fertility effects [rat] 42233920 [1990]

Acceptable/guideline 0, 100, 300, 1000 ppm Parental/Systemic NOAEL = 300 ppm LOAEL = 1000 ppm based on decreased body weights and body weight gains. Reproductive NOAEL = 300 ppm LOAEL = 1000 ppm based on de creased 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 liv er in female rats.

870.4100b Chronic toxicity 42233911 [1991]

Acceptable/guideline NOAEL = 14.7 mg/kg/day LOAEL = 44.6mg/kg/day based on decreased prostateDimethomorph Human Health Risk Assessment DP No. 387381

Page 37 of 39 TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Dimethomorph.

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

Classification/Doses Results

[dog] 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 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 hypercellularity, a nd 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 g ain 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 precipitating 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, u p 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 Chinese hamster lung [V79] cells treated up to cytot oxic
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 transferase [HGPRT] locus in Chinese hamster lung [V79] exposed, with/without activation, up to cytotoxic concentrations [180 ug/mL/

- S9; 333 ug/mL/+S9].

In vitro mammalian

chromosome

aberration test

870.5375a 42233924 [1986]

Unacceptable Reportedly positive for chro mosome 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 chromosome 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 [199 1]

Acceptable Negative for inducing micronuclei in bone marrow cells of mice administered 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.Dimethomorph Human Health Risk Assessment DP No. 387381

Page 38 of 39 TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Dimethomorph.

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

Classification/Doses Results

Mutagenicity

- DNA damage/repair in

vitro

870.5500 42233922 [1986]

Unacceptable Reportedly negative for inducing unscheduled DNA synthesis [as measured by liquid scinti llation 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 h amster embryo cells treated, in the presence and absence of activation, up to cytotoxic concentrations [265 ug/mL/+S9; 50 ug/mL/

- S9]

870.6200

Subchronic neurotoxicity [rat] 48326902 [2004]

Acceptable/guideline 0,60,600,6000 ppm M:0,4.2,43.8,432.9 mg/kg/day F:0,5.0,50.9,510.1 mg/kg/day NOAEL= 432.9/510.1 mg/kg/day (M/F), 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 repeated 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 smal ler 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 sing le high 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] tha n 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 radi oactivity 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 hours 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 possib ly 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 79.62 [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. 387381

Page 39 of 39