### Famoxadone Scoping Document DP No. D423286

Page 2 of 27 E XECUTIVE 

### S UMMARY



### The HED Registration Review Team has evaluated the most recent human health assessments and database for the fungicide famoxadone, 5

- methyl

- 5

- (4

- phenoxyphenyl)

- 3

- (phenylamino)

- 2,4

- oxazolidinedione, to determine whether sufficient data are available and whether any updates are needed to support Registration Review. HED has considered the most recent human

- health risk assessments for famoxadone; updates to the toxicity, exposure, and usage databases; and current Agency sc ience policy and risk assessment methodologies to determine the scope of work necessary to support Registration Review . In addition, HED conducted a search in the open literature which yielded no new information relevant to the most recent human health ri sk assessment has been published.

Famoxadone is a fungicide belonging to the oxazolidine

- diones chemical group of quinone outside inhibitor (Qol) fungicides. It is registered for use on caneberries, peppers, tomatoes,
cucurbit vegetables , and leafy veget ables (except Brassica) , bulb vegetables , tomato es , potatoes, hops, and grapes (East of the Rocky Mountains) to control and/or manage fungal and bacterial disease. In addition, tolerances are established for ruminant livestock commodities. There are

no registered residential uses currently associated with this active ingredient (ai). Famoxadone

has one end

- use product, Tanos® Fungicide which is a water dispersible granule co

- formulated with cymoxanil.

Toxicity/Hazard The toxicity database for famoxadon e is complete except for a 90

- day inhalation toxicity study in

rats (OPPTS Guideline 870.3465)

. Famoxadone has low acute toxicity by the oral, dermal and inhalation routes, is moderately irritating to the eye and skin, and is not a skin sensitizer.

Subch ronic and chronic toxicity studies in rats, mice, dogs and monkeys caused decreased body weights and body weight gains, often accompanied by decreased food consumption and food efficiency. There were some mild changes to the liver in these studies along w ith hemolytic anemia. Microscopic lens lesions (cataracts) in female dogs, and myotonic twitches in male and female dogs, were not observed in other species and served as the basis for the human risk

assessment.

Residue Chemistry The residue chemistry database for famoxadone is considered complete with the exception of

submission of a livestock enforcement method (OPPTS Guideline 860.1340) . Provided the petitioner proposes DuPont 1452 as the tolerance

- enforcement method for livestock, further

livestock method validation will not be required ( M. Doherty, D271377 , 04/18/2003 ) . The tolerance expression in the 40 CFR § 180.587 needs to be modified according to the language recommended in the Interim Guidance on Tolerance Expressions. Harmonization of the US tolerance with the Canadian, Codex and Mexican MRLs are discussed in Section 3.0

.

Dietary Exposure The chronic dietary exposure analysis for famoxadone is a highly refined assessment, using anticipated residues, average reduction factors (e.g. washing lettuce) and percent crop treated (%CT) information (B. Hanson, D354366, 07/08/2008) . Estimated drinking water concentration (EDWC) based on modeling using PRZM/EXAMS was incorporated ( J. Lin, D347671

,

### Famoxadone Scoping Document DP No. D423286

Page 3 of 27 0 4/30/2008 ) . The estimated chronic dietary e xposure (food and water) from famoxadone does

not exceeded HED’s level of concern (i.e. > 100% of the cPAD) for the general population or any population subgroup , < 59% of the cPAD. No toxic effects resulting from a single dose

were identifie d for famoxad one; therefore, an acute dietary assessment was not required. Updated dietary exposure assessments for famoxadone may be necessary to consider the most recent consumption data, updated %CT information, and estimated drinking water concentrations

that cons ider all the residues of concern and/or changes to the famoxadone hazard.

Residential Exposure Famoxadone is not intended for use in public or residential settings so residential exposure is not expected based on the use pattern and, accordingly, a resi dential risk assessment is not required during registration review. The need for spray drift and volatilization assessments for famoxadone will be considered during registration review.

Aggregate Assessment

There are no residential uses for famoxadone. The aggregate exposure and risk i s represented by dietary risks from food and drinking water. These risks are not of concern.

Occupational Exposure The occupational exposure database is considered adequate for registration review with the exception of a dislodgeable foliar residue (DFR) study (OSCPP Guideline 875.2100) . In accordance with 40CFR158, DFR data are required for all occupational (e.g., crop, nursery, greenhouse use sites) uses that could result in post

- application expo sure to foliage. Per HED policy, a DFR study is required because the total margins of exposures (MOEs) for intermediate

term post

- application exposures are not greater than 2x the level of concern (LOC) of 300.

All of the short

- term occupational exposure scenarios for the registered use of famoxadone have been assessed adequately and there were no risk estimates of concern. However, based on the use pattern of famoxadone, the potential for intermediate

- term occupational exposures to

famoxadone exist s and h a s been assessed in one of the five past ORE assessments . Because the famoxadone dermal and inhalation endpoints selected are different for short

- and intermediate

term exposure, an updated occupational handler or post

- application exposure and risk assess ment will be required to account for intermediate

- term exposures, as well as to reflect updated policies and exposure data, or changes to famoxadone hazard.

1.0 F ORMULATIONS AND 

### U SE 

### P ATTERNS T. Chandgoyal et. al., BEAD Chemical Profile Review, 10/14/2 014 M. Doherty, D271377 , 04/18/2003 , residue chemistry chapter W. Cutchin, D323682, 11/29/2006 , residue chemistry chapter W. Cutchin, D349184, 08/18/2008 , residue chemistry chapter W. Cutchin, D 360943 , 01/26/2009, amendment to the 2008 residue chemistry ch apter



### HED used the Biological and Economics Analysis Division (BEAD) Label Data System to identify all uses of famoxadone. In addition, the BEAD Chemical Profile for Registration Review was used to characterize the use patterns of famoxadone.

### Famoxadone Scoping Document DP No. D423286

Page 4 of 27 Famoxadon e is a fungicide belonging to the oxazolidine

- diones chemical group of quinone outside inhibitor (Qol) group of fungicides. Famoxadone is registered for the control of a variety of fungal diseases including downy mildew, leaf spot; leaf blight, early and late blight, and bacterial fruit blotch. There are currently two active registrations, one technical product (EPA Reg. No. 68156

- 1) and one end

- use product (Tanos® fungicide, EPA Reg. No. 352

- 604).

Famoxadone is co

- formulated with cymoxanil and is available as water dispersible granule.

Agricultural Uses Famoxadone is registered for use on caneberries, peppers, tomatoes, cucurbit vegetables , and leafy vegetables (except Brassica) , bulb vegetables , tomato es , potatoes, hops, and grapes (East of

the R ocky Mountains).

Non

- Agricultural and Residential Uses

There are no non

- agricultural use sites registered for famoxadone.

Conclusions: The label of Tanos® Fungicide was modified to incorporate the amendments

recommended in the 2003, 2006 and 2008 resi due chemistry chapters and the subsequent amendment to the 2008 residue chemistry chapter . The current label show modifications specifying similar or lower application rates and similar or longer PHIs than those recommended for hops and grapes in the 2006 residue chemistry chapter. These modifications are considered acceptable. Also, the 2003 and 2008 resid ue chemistry chapters (including the 2009 amendment) required rotational crop restriction s which are currently listed on the product label

for Tanos® Fungicide (EPA Reg. No. 352

- 604, May 20, 2011).

2.0 H AZARD 

### I DENTIFICATION 

### /T OXICOLOGY



### With the exception of a subchronic inhalat ion toxicity study in rats, the toxicology database is

com plete for famoxadone

. HED’s Hazard Science Policy Council (HASPOC) , using weight of evidence considerations determined that this study is required since the use of an oral Point of Departure (POD) yielded Margins of Exposure that exceeded EPA’s Level of Concern by a

factor of 10 for all exposure scenarios with th e exception of mixer/loader dry flowable for aerial application (HASPOC Report TXR# 0057104 )

.

Technical grade f

amoxadone (DPX

- JE874) is white solid powder of 97.8% purity and has acute, dermal and inhalation toxicity ran ging from Toxicity Category III to IV. Famoxadone is moderately irritating to the eye and skin of the rabbit and is negative for dermal sensitization in the guinea pig.

I n subchronic and chronic feeding studies in rats, mice, dogs and Cynomolgus monkeys,

famoxadone generally caused decrea sed body weights and body weight gains, often accompanied by decreased food consumption and food efficiency. A mild regenerative hemolytic anemia was also regularly observed in these animals . S econdary effects of the anemia were frequently observed in th e spleen

, bone marrow, and the liver. Famoxadone also induced a

mild hepatotoxicity in treated animals characterized by elevated levels of clinical chemistry

enzymes indicative of liver damage and by histopathological lesions in the liver.

### Famoxadone Scoping Document DP No. D423286

Page 5 of 27 There were a dditional treatment

- related effects observed in dogs that were not observed in other species. In a 13

- week feeding study, clinical signs of neurotoxicity (myotonic twitches) were observed in male and female dogs at the highest dose tested throughout the du ration of the study.

These twitches were not observed, however, at lower doses or in the one

- year feeding study in dogs. Also, in both male and female dogs, famoxadone induced treatment

- related cataracts in the lens of the eyes, both in the 13

- week feedin g study and in the one

- year feeding study. At the lowest observed adverse effect level the cataracts were only observed in female dogs. The eye effects were observed at dose levels below those at which any other effects were observed in any other species and served as the basis for the human risk assessment

. Additional data on the eye

defect h as been recommended previously. The metabolism (toxicokinetic) studies in rats and dogs were co mpared , but no biologically significant qualitative or quantitative differences were observed in absorption, distribution, metabolism, or excretion that might help explain the differences between the species

. The registrant hypothesized that in dogs reduction of cellular ATP (resulting from inhibition of oxidative phospho rylation in mitochondria) might increase lens hydration or increase susceptibility of the eye to oxidative stress and lead to cataract formation, but there is no data to support this hypothesis.

Famoxadone is classified as "not likely to be carcinogenic t o humans" based on the lack of evidence for carcinogenicity in male and female mice and male and female rats . There is no indication of any mutagenic potential in the battery of mutagenicity studies conducted.

In an acute neurotoxicity study in rats, eq uivocal evidence of neurotoxic ity at the limit dose was noted

. A n increased incidence of palpebral (eyelid) closure was observed, but only in males and only on day 1. Other than myotonic twitching in the 13

- week feeding dog study at the high dose level, none of the other famoxadone toxicity studies

, including the subchronic neurotoxicity study in rats, revealed any evidence of treatment

- related neurotoxicity.

N o evidence of immunotoxicity was observed i n the 28

- day immunotoxicity studies in rats and

mice. In a 28

- day dermal study in rats, the observed systemic effects were very similar to those

observed in oral studies in rats. No dermal irritation was observed.

In metabolism studies in rats, f amoxadone ( ab out 40% of the administered dose) was rapidly

absorbed. Most of the administered dose (87

- 96%) was eliminated in the feces within 24 hours; very little (3

- 12%) was eliminated in the urine. Less than 1% remained in the tissues after 120 hours. Unchanged par ent (51

- 84% of the administered dose ) and two hydroxylated metabolites (IN

- KZ534 and IN

- KZ007) were the major components recovered in the feces. No unchanged parent was found in the urine. E nterohepatic circulation (about 30

- 39% of the administered

dose ) was noted ; glucuronide and sulfate conjugates of eight components (including IN

- KZ532

and IN

- ML815) were identified in the bile. No significant qualitative or quantitative differences

were observed by sex, dose level, or repeated dosing. N o biologically s ignificant qualitative differences were observed between rats and dogs in absorption, distribution, metabolism, or

excretion

.

No quantitative or qualitative evidence of increased susceptibility, as compared to adults, of rat
or rabbit fetuses to in utero exposure to f amoxadone was observed in the developmental toxicity

### Famoxadone Scoping Document DP No. D423286

Page 6 of 27 studies. No quantitative or qualitative evidence of increased susceptibility, as compared to adults,

of rat fetuses or neonates was observed in the 2

- generation reproduction study

. D evelopm ental toxicity was not observed in the rat . In the rabbit developmental toxicity study, the maternal and developmental NOAELs and LOAELs were the same. In the 2

- generation reproduction study in

rats, n o reproductive toxicity was observed and the offspring and parental toxicity NOAELs and

LOAELs were the same.

The FQPA Safety Factor is reduced (i.e.1X) since 1) there is no evidence for increased susceptibility following in utero exposures to rats and rabbits and pre/post natal exposure t o rats and 2) the toxicology data base is adequate and exposure database is complete. The PoDs selected for various exposure scenarios are listed in Attachment T able A3 .1.

Conclusions : With the exception of a subchronic inhalation study, t he toxicology database for

famoxadone is adequate to support the registration review. As part of registration review, the endpoints, doses, and uncertainty/safety factors used in the most recent risk assessment will be

re

- evaluated according to current HE D policy. In the 2003 risk assessment , HED strongly recommended that the registrant convene a Pathology Working Group to assist in resolving the uncertainty relating to the microscopic findings in the eyes of the dogs in the chronic feeding study. It was also strongly recommended that the registrant perform mechanistic studies designed to elucidate the mechanism of action of famoxadone in the eyes of dogs and other species in order to provide evidence and rationale, if possible, to support the possible

sp ecies

- specificity of this effect in dogs. To date, this information has not been received. In the absence of information to the contrary, HED considers the cataracts observed in the dog study to be pertinent to humans. It should be noted that upon reeva luation of endpoints and uncertainty factors, uncertainty factors could increase considering current policy, potentially leading to risks exceeding standard benchmarks for acceptability.

3.0 R ESIDUE 

### C HEMISTRY M. Doherty, D271377 , 04/18/2003 , residue chemistry chapter W. Cutchin, D323682, 11/29/2006 , residue chemistry chapter W. Cutchin, D349184, 08/18/2008 , residue chemistry chapter W. Cutchin, D 360943 , 01/26/2009, amendment to the 2008 residue chemistry chapter



### The metabolism of famoxadone is adequa tely understood in plants and in ruminant commodities based upon previously submitted and reviewed metabolism studies. The residue of concern for tolerance enforcement is parent famoxadone. The residue of concern for dietary assessment on

food commodities is parent famoxadone while for drinking water is parent famoxadone, and the degradates IN

- MN467 (5

- methyl

- 3

- [(2

- nitrophenyl)amino]

- 5

- (4

- phenoxyphenyl)

- 2,4

- oxazolidinedione), IN

- MN468 (5

- methyl

- 3

- [(4

- nitrophenyl)amino]

- 5

- (4

- phenoxyphenyl)

- 2,4

- oxazolidinedi one), IN

- MN968 (1

- carboxy

- 1

- (4

- phenoxyphenyl)ethyl 2

- phenylhydrazinecarboxylate monosodium salt), and IN

- JL856 (α

- hydroxy

- α

- methyl

- 4

- phenoxybenzeneacetic acid

- 2

- phenylhydrazide). Currently, tolerances are established in the 40

CFR 180.587 for residues of famoxadone in/on plant and livestock commodities.

The 2003 residue chemistry chapter identified one deficiency that need to be resolved. The registrant was requested to propose a livestock analytical method for tolerance enforcement. The

### Famoxadone Scoping Document DP No. D423286

Page 7 of 27 data acquisit ion method, DuPont 1425, was considered adequate for enforcement. Provided the petitioner proposes DuPont 1452 as the tolerance

- enforcement method for livestock, further method validation will not be required.

Tolerances for livestock are established t o support the use of famoxadone in potato (i.e. culls and waste feedstuffs). Based on the updated Table 1 of OPPTS Guideline 860.1000

, the percentage of these feedstuff commodities in the diet of beef and dairy cattle has decreased. Therefore, the

curren t tolerances are adequate to cover residues in ruminant commodities. The need of tolerances for ruminant commodities may be re

- evaluated during registration review; however, because maximum residue limits for livestock commodities are established by Canad a at the same level it may be adequate to retain the US tolerances.

HED established interim guidance on writing tolerance expressions for enforcement purposes (S. Knizner, 27/May/2009). In order to add clarity to the language used to establish the covera ge of the tolerance expression and measurement of the level of the residue in the Raw Agricultural Commodity (RAC) the text in the 40 CFR § 180.587 should read as follows:

“(a) General. (1) Tolerances are established for residues of the fungicide famoxa done, 3

- anilino

5

- methyl

- 5

- (4

- phenoxyphenyl)

- 1,3

- oxazolidine

- 2,4

- dione, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring 3

- anilino

- 5

- methyl

- 5

- (4

- phenoxyphenyl)

- 1,3

- oxazolidine

- 2,4

- dione, in or on the commodity.”

Where possible, EPA encourages the harmonization of the US Tolerances and Maximum Residue Limits (MRLs) in key export markets. A table with the US tolerances, and the Canadi an and Codex MRLs for famoxadone is provided in Section 3.0 of Appendix B. There are currently no established Mexican MRLs for famoxadone. The US, Canadian and Codex tolerance expressions are harmonized as measurement of parent famoxadone. All US commod ities that have Canadian MRLs (fat and liver of ruminants, milk fat, caneberries, potato and tomato) are harmonized with respect to the tolerance level. The US tolerances of 0.05 ppm for cattle, goat, horse, and sheep liver are not harmonized with the Cod ex MRL of 0.5 ppm for mammalian edible offal. The US tolerance for grape raisins (4.0 ppm) and grape (2.5 ppm) are not
harmonized with the Codex MRL s as these are 5 ppm and 2 ppm, respectively. Although the field trials conducted to support the regional tolerance for grapes show residues below 2 ppm, the European field trials to support uses on imported grapes show residues ranging from 0.07 to 2.14 ppm. The US tolerance for tomato (1.0 ppm) may be harmonized with the Codex MRL if it is increased to 2 pp m; however, this would result in lack of harmonization with Canada. This information may be considered during registration review when evaluating harmonization.

Conclusions: The residue chemistry database for famoxadone is considered complete with the

ex ception of submission of a livestock enforcement method . Provided the petitioner proposes

DuPont 1452 as the tolerance

- enforcement method for livestock, further livestock method validation will not be required. The tolerance expression in the 40 CFR § 18 0.587 needs to be modified according to the language recommended in the Interim Guidance on Writing Tolerance Expressions. Recommendations on the harmonization of the US tolerance with the Codex, Canadian and Mexican MRLs will be performed as part of regi stration review.

### Famoxadone Scoping Document DP No. D423286

Page 8 of 27 4.0 D IETARY 

### E XPOSURE

B. Hanson, D 354336, 07/08/2008



### The most recent chronic dietary assessment for famoxadone was performed in 2008 to support proposed new uses a variety of crops . This analysis was conducted using the Dietary Exposure Evaluation Model (DEEM

- FCIDTM, Version 2.03) which uses food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII)

from 1994

- 1996 and 19 98. Based on toxicological considerations, acute and cancer assessments are not required.

The chronic dietary exposure analysis for famoxadone is a highly refined assessment, using anticipated residues estimated from field trial data and livestock feed ing studies, average reduction factors (e.g. washing lettuce) and percent crop treated (%CT) information. Estimated drinking water concentration of 0.189 ppb based on modeling using PRZM/EXAMS was incorporated. The estimated chronic dietary exposure (foo d and water) f rom famoxadone does

not exceed HED’s level of concern for any population subgroup. Food and water exposure occupies 47% of the cPAD for the general US population and 58% of the cPAD for adults 20

- 49 years old, the subgroup with the highest e xposure.

Conclusions: Dietary exposure assessments for famoxadone may be necessary to consider the most recent consumption data from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, updated %CT information, estimated drinking water concentrations considering all the residue of concern and/or changes in the

famoxadone toxicological points of departure and/or uncertainty factors

.

5.0 R ESIDENTIAL 

### E XPOSURE



### There are no residential uses for famoxadone, thus a residential exposure assessment is not required at this time.

Post

- application Volatilization/Spray Drift Exposure

Residential exposures resulting from off

- site transport (e.g., spray drift or volatilization) may

occur as a result of famoxadone applications to agricultural fields. Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the cas e with aerial application, but to a lesser extent, spray drift can also be a potential sourc e of exposure from the ground application methods (e.g., groundboom and airblast) employed for famoxadone

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

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information). 1


### The agency has also develop ed a policy on how to appropriately consider spray drift as a

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

### Famoxadone Scoping Document DP No. D423286

Page 9 of 27 potential source of exposure in risk assessments for pesticides. The need for a spray drift assessment for famoxadone will be considered during registration review.

Volatilization of pesticid es may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide A ct Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screeni ng Tool and a subsequent Vo latilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). Famoxadone was not included in this screening analysis however, during Registration Review, the agency will

utilize this screeni ng tool to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analyses are required for famoxadone.

Conclusions : Famoxadone is not intended for use in public or residential settings ; therefore,

residential exposure is not expected based on the use pattern a nd, accordingly, a residential risk

assessment is not required during registration review. The need for spray drift and volatilization assessments for famoxadone will be considered during registration rev iew.

6.0 A GGREGATE 

### E XPOSURE AND 

### R ISK 

### A SSESSMENT



### There are no residential uses for famoxadone and, therefore, there is no residential contribution to the aggregate risk assessment. T he aggregate exposure and risk is currently represented by dietary risks

, food and drinking water only. These risks are not of concern.

7.0 O CCUPATIONAL 

### E XPOSURE

M. Dow, D333254, 10/31/2006

M. Dow, D331977 & D332299, 9/21/2006

M

. Collantes, D288296, 4/2/2003

M

. Dow, D349187, 2/22/2008

M

. Dow, D349201, 2/22/2008



### Occupational Handlers

Famoxadone is registered for agricultural use on caneberries, peppers, tomatoes, cucurbit vegetables , and leafy vegetables (except Brassica) , bulb vegetables , tomato es , potatoes, hops, and grapes (East of the Rocky Mountains) . Based on this use profile, there is potential for short

and intermediate

- term occupationa l exposures to famoxadone during handling (mixing, loading, and applying) and post

- application activities associated with agricultural use of the chemical. Based on the current agricultural use pattern, long

- term dermal exposure is not anticipated.

Famo xadone can be applied via groundboom, airblast sprayer, or fixed wing aircraft at a maximum application rate of 0.19

- 0.25 lb ai/A. Famoxadone is registered for use as a dry flowable formulation (EPA Reg. No. 352

- 604). The personal protective equipment (P PE) on the

### Famoxadone Scoping Document DP No. D423286

Page 10 of 27 dry flowable product labels is coveralls, chemical resistant gloves, shoes with socks, and no respirator.

Five assessments were previously completed for famoxadone

. For occupational handlers, MOE(s) greater than 100 are not of concern to HED . All short term combined dermal and inhalation occupational exposure risk estimates are not of concern with use of currently required PPE (i.e., coveralls, chemical resistant gloves, and shoes with socks). Among all famoxadone registered crops the lowest handler MOE was 1,960 for mixing/loading for aerial applications of

famoxadone to caneberries, peppers, tomatoes, cucurbit vegetables , and leafy vegetables (except Brassica) , bulb vegetables , tomato es , potatoes, hops, and grapes (East of the Rocky Mountain s)

.

Famoxadone, a fungicide, can be applied at a re

- tr eatment interval ranging from 5 to 10 days

, and labeling currently recommends rotation with other fungicidal active ingredients to prevent

resistance. Further , it is reasonable to assume that large agribusiness and/or commercial applicators will apply famoxadone for several weeks within a specific region. Therefore, HED

recommends the assessment of both short

- and intermediate

- term exposures and risks for

famox adone. Only one previously completed assessment considered intermediate

- term exposure s (DP288296, 04/02/2003). Among all famoxadone crops considered in this assessment, the lowest

handler MOE was 380 for (include scenario and crop). During registration re view an

intermediate

- term occupational exposure assessment will be required for the uses of famoxadone not previously assessed

.

Recommended unit exposures for occupational handler assessments have generally been derived only from the Pesticide Handlers Ex posure Database (PHED). However, recently both the Outdoor Residential Exposure Task Force (ORETF) and the Agricultural Handler Exposure Task Force (AHETF) have produced pesticide handler exposure monitoring data that the Agency is using in place of PHED (http://www.epa.gov/pesticides/science/handler

- exposure

- data.html). As more reliable data become available, the Agency will continue to replace existing data. Reviewers should incorporate new exposure monitoring data, as necessary, during registration

rev iew.

Occupational Post

- application

HED uses the term post

- application to describe exposures that occur when individuals are present and conducting work functions in an environment that has been previously treated with a pesticide (also referred to as re

- entry exposure). Based on the use profile of famoxadone, there may be the potential for post

- application exposures. Several risk assessments have been previously completed which assess the potential for occupational post

- application exposures.

For the cu rrently registered product, EPA Reg. No. 352

- 604, the resulting short

- term post

application MOEs ranged from 310 to 830 on the day of application. As stated above, only one of the previous 5 occupational risk assessments conducted for famoxadone assessed

i ntermediate

- term exposures (DP288296, 04/02/2003). Estimated i ntermediate

- term post

application MOEs for this assessment ranged from 170 to 4

, 800. The previous assessments adequately address all short

- term occupational post

- application exposure scenarios for the currently registered product. However, for the reasons described above for occupational

### Famoxadone Scoping Document DP No. D423286

Page 11 of 27 handlers, HED recommends the assessment of intermediate

- term post

- application exposures for famoxadone during registration review.

In accordance with 40CFR § 158, the following data are required for all occupational or residential pesticide uses: dislodgeable foliar residue (DFR) data are required for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and vegetable g ardens, pick your own farms, retail tree farms) uses that could result in post

- application exposure to foliage; and turf transferable residue (TTR) data are required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or res idential turf uses that could result in post

application exposure to turf. Per HED policy, a DFR study is required because the total margins of exposures (MOEs) for intermediate

- term post

- application exposures are not greater than 2x

the level of concern (LOC) of 300. It should be noted that short

- term occupational post

application MOEs are greater than 2X the LOC.

Restricted Entry Interval (REI)

Based on the criteria of the Worker Protection Standard (WPS) the Restricted Entry Interval (REI) for famoxa done is 12 hours as is required by the currently registered product. This REI is in accordance with the most recent occupational post

- application assessments which identified acceptable risks on the day of product application.

Conclusions: The occupati onal exposure database is adequate to support the registration review process for famoxadone, with the exception of a DFR study. All of the short

- term occupational exposure scenarios for the registered use of famoxadone have been assessed adequately and th ere were no risk estimates of concern. However, based on the use pattern of famoxadone, the potential for intermediate

- term occupational exposur es to famoxadone exists and has not been assessed. Because the famoxadone dermal and inhalation endpoints selec ted are different for

short

- and intermediate

- term exposure, an updated occupational handler or post

- application exposure and risk assessment will be required to account for intermediate

- term exposures, as well as to reflect updated policies and exposure data, or changes to famoxadone hazard.

8.0 P UBLIC 

### H EALTH AND 

### P ESTICIDE 

### E PIDEMIOLOGY 

### D ATA
E. Evans and S. Recore, D 423541, 10/28/2014



### T he OPP Incident Data System (IDS)

, and the Centers for Disease Control and Prevention / National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases were consulted for pesticide incident data on the active ingredients famoxadone (PC Code: 113202)

.

For the M ain IDS, from January 1, 200 9 to August 12, 2014, there were 0 incidents reported involving famoxadone. In A ggregate IDS , from January 1, 200 9 to August 12, 2014, there were 2 incidents reported involving famoxadone

. These incidents were classified as minor severity. Overall, there are few incidents involving famoxadone reported to IDS. A query of SENSOR

Pesticides from 1998

- 2010 identifies no cases invo lving famoxadone

. Famoxadone is not included in the Agricultural Health Study, and therefore thi s study does not provide information for this report.

### Famoxadone Scoping Document DP No. D423286

Page 12 of 27 HED has evaluated the available incident data and concludes that based on the low frequency and low severity of incident cases reported for famoxadone in both IDS and SENSOR

- Pesticides,

there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

9.0 E NVIRONMENTAL 

### J USTICE



### 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 L ow

- 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 acc ording to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption,

and activities in and around the home that invol ve 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 ar e performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, 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 specialized software and models that consider exposure to bystanders and farm workers

, as well as lifest yle and traditional dietary patterns among specific subgroups.

10.0 C UMULATIVE 

### R ISK 

### A SSESSMENT



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

to famoxadone and any other substances and famoxadone does not appear to produ ce a toxic metabolite produced by other substances. EPA has not assumed that famoxadone has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and t o evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative

.

### Famoxadone Scoping Document DP No. D423286

Page 13 of 27 11.0 H UMAN 

### S TUDIES



### Past famoxadone risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED, the Outdoor Residential Exposure Task Force (ORETF) Database, and the Agricultural Reentry Task Force (ART F) Database. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relativ e to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.

12.0 D ATA 

### R EQUIREMENTS



### Hazard/Toxicity

- A 90

- day inhalation toxicity study in the rat (OPPTS Guideline 870.3465) is required

based on the re commendations of 40 CFR §158 by the decision of the HASPOC ( 01/08/2015 ).

Residue Chemistry

- The registrant was asked to propose a livestock enforcement method ( OPPTS Guideline 860.1340) . Provided the petitioner proposes DuPont 1452 as the tolerance

- enforcement method for livestock, further livestock method validation will not be required (M. Doherty, D271377 , 04/18/2003)

.

Occupational Exposure

- Dislodgeable Foliar Residue (DFR) Study (OPPTS Guideline 875.2100).

13.0 REFERENCES

(1) Heywood, R. (1999) Famoxadone (DPX

- JE874) Relevance of Ocular Findings in

Animals for Human Risk. E.I. du Pont de Nemours and Company, DuPont Agricultural Products, Global Technology Division , Wilmington, Delaware, Laboratory Project ID:

DuPont

- 3351, August 30, 1999, MRID 44946216. Unpublished.

(2) MacKenzie, S.A. (1998) Comparative Aspects of Human, Primate, and Canine Lens and Lenticular Opacities. E.I. du Pont de Nemours and Company, DuPont Agricultural Products, Wilmington, Delaware. Laboratory Project ID: DuPont

- 1441, August 27, 1998,

MRID 44946214. Unpublished.

### Famoxadone Scoping Document DP No. D423286

Page 14 of 27 (3) European Commission, Health & Consumer Protecti on Directorate

- General (2001) Opinion of the Scientific Committee on Plants on Specific Questions from the Commission Concerning the Evaluation of Famoxadone [DPX

- JE874] in the Context of

Council Directive 91/414/EEC. Directorate C

- Scientific Opinions, Bru ssels, Belgium.

SCP/F AMOX/002

- Final, September 5, 2001, MRID 45833802. Published. (Document provided to EPA by DuPont).

(4) European Commission, Directorate

- General Health & Consumer Protection (2002)

Review Report for the Active Substance Famoxadone (Commis sion Working Document).

Directorate E

- Public, Animal and Plant Health, Brussels, Belgium. 6505NII99

- Final, September 18, 2002, MRID 45833803. Published. (Document provided to EPA by DuPont).

(5) Pletcher, JM. (2002) Relevance of Famoxadone (DPX

- JE874) Induced Cataracts in Dogs

to Human Health (Memorandum to Edwin Budd & Joycelyn Stewart/HED/EP A). Pathology Associates, A Charles River Company, Frederick Maryland. October 25, 2002,

MRID 45833801. Unpublished.

### Famoxadone Scoping Document DP No. D423286

Page 15 of 27 Appendix A: Toxicology Profile

A.1 Toxicology D ata Requirement s

The requirements to support current uses of famoxadone are in the table below. The se are the requirements (40 CFR

158. 500 ) for food use for famoxadone

.

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity............................................
870.1200 Acute Dermal Toxicity.......................................
870.1300 Acute Inhalation Toxicity...................................
870.2400 Primary Eye Irritation.

....................................... 870.2500 Primary Dermal Irritation...................................
870.2600 Dermal Sensitization......................................... yes
yes
yes
yes
yes
yes yes

yes
yes
yes
yes
yes

870.3100 Oral Subchronic (rodent)...................................
870.3150 Oral Subchronic (nonrodent).............................
870.3200 21

- Day Dermal..................................................
870.3250 90

- Day Dermal...............

................................... 870.3465 90

- Day Inhalation.............................................. yes N o N o
yes
yes yes

yes
yes NA
No 1

870.3700a Developmental Toxicity (rodent)....................... 870.3700b Developmental Toxicity (nonrodent)................
870.3800 Reproduction.................................................. yes
yes
yes yes

yes
yes

870.4100a Chronic Toxicity (rodent)................................... 870.4100b Chronic Toxicity (nonrodent)............................ 870.4200a Oncogenicity (rat)............................................. 870.4200b Oncogenicity (mouse)......................................
870.4300 Chronic/ Carcin ogenicity...................................... No
No
No
No yes

yes
yes
yes
yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial.........
870.5300 Mutagenicity

— Gene Mutation

- mammalian.....
870.5375 Mutagenicity

— Structural Chromosomal

Aberrations...................................................... 870.5385 Mutagenicity

— Mammalian Bone Marrow

Chromosomal Aberration Test..........................
870.5395 Mutagenicity

— Mammalian erythroc yte micronucleus

test............................................. yes
yes

yes

No

yes yes

yes

yes

N o

yes

870.6100a Acute Delayed Neurotox. (hen)........................ 870.6100b 90

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

- Day Neuro. Screening Battery (rat)...............
870.6300 Develop mental Neuro

. ................................................ No
No

yes
yes N o No

No

yes
yes N o

870.7485 General Metabolism.........................................
870.7600 Dermal Penetration.......................................... 870.7800 Immunotoxicity.......................................... yes N o
yes yes

N o
yes

1 Data required per HASPOC meeting 01/08/2015. NA = not applicable.

### Famoxadone Scoping Document DP No. D423286

Page 16 of 27 A.2 Toxicity Profiles

Table A2.1 F amoxadone Acute Toxicity Profile

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 44303407 LD 50 > 5000 mg/kg M/F IV

870.1100 Acute oral [mouse ] 44303408 LD 50 > 5000 mg/kg M/F IV

870.1200 Acute dermal [rabbit] 44303409 LD 50 > 2000 mg/kg M/F III

870.1300 Acute inhalation [rat] 44303410 LD 50 > 5.3 mg/L M/F IV

870.2400 Acute eye irritation [rabbit] 44303411 Moderate irritation III

870.2500 Acute dermal irritation [rabbit] 44303412 Mild irritation IV

870.2500 Acute dermal irritation [rabbit] 44946205 Moderate irritation III

870.2600 Skin sensitization [guinea pig] 44303413 Negative NA

Table A2.2 F amoxadone Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral

toxicity (rat) 44302415, 44302416,

44946206,44946207 (1995) Acceptable/guideline 0,50,200,800,1600 ppm M: 0, 3.3, 13.0, 52.1, 106 mg/kg/day F: 0,4.2, 16.6, 65.7, 130 mg/kg/day NOAEL = M: 3.3 mg/kg/day. F: 4.2 mg/kg/day. LOAEL = M: 13.0 mg/kg/day based on mild hemolytic/in rats anemia and decreased glucose. F: 16.6 mg/kg/day based on decreased body weight gain, decreased food consumption, decreased food efficiency, mild hemolytic anemia and decreased globulin.

870.3100 28

- Day oral

toxicity (rat) 44946207 (1996)

Acceptable/non

- guideline 0,100, 200, 300, 400, 500, 600 ppm NOAEL = M: 300 ppm. F: 400 ppm.

LOAEL = M: 400 ppm based on increased alkaline phosphatase, aspartate

aminotransferase and increased sorbitol dehydrogenase. F: 500 ppm based on increased sorbitol dehydrogenase and decreased triglycerides.

870.3100 14

- Day oral

toxicity (rat) 44967201 (1992)

Unac ceptable/non

guideline 0, 100, 1000, 5000, 20000 ppm M: 0, 9.0, 86, 428, 1629 mg/kg/day F: 0, 8.9, 81, 440, 1589 mg/kg/day NOAEL = M: 9.0 mg/kg/day. F: 8.9 mg/kg/day LOAEL = M: 86 mg/kg/day based on hepatotoxicity in the liver. F: 81 mg/kg/day

based on decreased body weight, decreased body weight gain, decreased food consumption and hepatotoxicity in the liver.

### Famoxadone Scoping Document DP No. D423286

Page 17 of 27 Table A2.2 F amoxadone Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral

toxicity (mouse) 44302417,44302418,

44946208 (1994) Acceptable/guideline 0, 35, 350, 3500, 7000

ppm M: 0, 5.9, 62.4, 534, 1149 mg/kg/day P: 0, 8.2, 79.7, 757, 1552 mg/kg/day NOAEL = M: 62.4 mg/kg/day. F: 79.7 mg/kg/day. LOAEL = M: 534 mg/kg/day based on mild hemolytic anemia with secondary responses in spleen and mild hepatotoxicity in the liver. F: 757 mg/kg/day based o n mild hemolytic anemia with secondary responses in spleen and mild hepatotoxicity in the liver.

870.3150 90

- Day oral

toxicity (dog) 44302419,44302420

(1995) Acceptable/guideline 0, 40, 300, 1000/600 ppm M: 0, 1.3, 10.0,23.8/21.2 mg/kg/day F: 0, 1.4, 10.1, 23.3/20.1 mg/kg/day NOAEL = M: 1.3 mg/kg/day. F: <1.4 mg/kg/day. LOAEL = M: 10.0 mg/kg/day based on lens cataracts in eyes; at 23.8/21.2 mg/kg/day, also myotonic twitches (starting on day 21), decreased body weight, decreased body weight gain, decreased food consumption, decreased food efficiency, slight anemia and hyperkalemia. F: 1.4 mg/kg/day based on lens cataracts in eyes; at 10.1 mg/kg/day, no additional effects; at 23.3/20.1 mg/kg/day,

same effects as for males at 23.8/21.2 mg/kg/day.

87 0.3200 28

- Day dermal

toxicity (species) 44946209 (1998)

Acceptable/guideline M&F: 0, 250,500,1000 mg/kg/day NOAEL = M: 250 mg/kg/day. F: 1000 mg/kg/day. LOAEL = M: 500 mg/kg/day based on increased alkaline phosphatase, increased

alanine amino

- transferase, increased sorbitol dehydrogenase and mild hepatotoxicity in the liver. F: none (>1000 mg/kg/day). No dermal

irritation in M or F.

870.3465 90

- Day inhalation

toxicity (species) Data required per HASPOC meeting

01/08/2015

870.3700 Prenatal

developmental in

rats 44302426,44946217

(1999) Acceptable/guideline F: 0, 125,250,500,1000 mg/kg/day Maternal NOAEL = 250 mg/kg/day LOAEL = 500 mg/kg/day based on transient decreased body developmental weight gain and decreased food consumption. Developmental NOAEL = 1000 mg/kg/day LOAEL = none (> 1000 mg/kg/day)

870.3700 Prenatal

developmental in

rabbit 44946218,44946219

(1999) Acceptable/guideline F: 0, 100, 350, 1000 mg/kg/day Maternal NOAEL = 350 mg/kg/day LOAEL = 1000 mg/kg/day based on abortions, decreased body weight, decreased body weight gain, decreased food consumption and

abnormal stools. Developmental NOAEL = 350 mg/kg/day LOAEL = 1000 mg /kg/day based on abortions

and equivocal increases in postimplantation loss and mean resorption s per doe.

### Famoxadone Scoping Document DP No. D423286

Page 18 of 27 Table A2.2 F amoxadone Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3800 Reproduction and

fertility effects (rat) 44302428 (1995)

Acceptable/guideline 0, 20, 200, 800 ppm M: 0, 1.1, 11.3, 44.7 mg/kg/day F: 0, 1.5, 14.2,53.3 mg/kg/day Parental/Systemic NOAEL = M/F: 11.3/14.2 mg/kg/day

LOAEL = M/F: 44.7/53.3 mg/kg/day based on decreased body weight, decreased body weight gain, decreased food consumption and hepatotoxicity in the liver. Reproductive NOAEL = M/F: 44.7/53.3 mg/kg/day LOAEL = M/F: none (>44.7/53.3 mg/kg/day) Offspring NOAEL = M/F: 11.3114.2 mg/kg /day LOAEL = M/F: 44.7/53.3 mg/kg/day based on decreased body weights for F 1 and F 2 pups throughout lactation.

870.4100 Chronic toxicity

rat See 870.4 2 00

870.4100 Chronic toxicity

dog 44302422 (1996)

Acceptable/guideline 0, 10, 20, 40, 300 ppm

M: 0, 0.3, 0.6, 1.2,8.8 mg/kg/day F: 0, 0.3, 0.6, 1.2,9.3 mg/kg/day NOAEL = M: 1.2 mg/kg/day. F: 1.2 mg/kg/day LOAEL = M: 8.8 mg/kg/day based on lens cataracts in eyes. F: 9.3 mg/kg/day based on lens cataracts in eyes. No other adverse effects were observed i n M or F.

870.4100 Chronic toxicity in

Cynomolgus monkeys 44946210 (1997)

Acceptable/guideline M&F: 0, 1, 100 1000 mg/kg/day (gavage) (1

- year) NOAEL = M: 100 mg/kg/day. F: 100 mg/kg/day LOAEL = M: 1000 mg/kg/day based on mild hemolytic anemia with secondary responses in spleen, liver and kidney, and sinus dilatation in spleen. F: 1000 mg/kg/day based on mild hemolytic anemia with secondary responses in spleen, liver and kidney, and sinus dilatation in spleen. No evidence of lens cataracts in eyes of

M or F.

870.4200 Carcinogenicity

mouse 44302424,44302425,

44946211 (1996) Acceptable/guideline 0, 5, 50, 700, 2000 ppm M: 0, 0.7, 6.8, 96, 274 mg/kg/day F: 0,1.0, 9.8,130,392 mg/kg/day NOAEL = M: 96 mg/kg/day. F: 130 mg/kg/day LOAEL = M: 274 mg/kg/day based on slight hepatotoxicity in the liver; no anemia. F: 392 mg/kg/day based on amyloidosis and slight hepatotoxicity in the liver; no anemia. No evidence of carcinogenicity in M or F.

### Famoxadone Scoping Document DP No. D423286

Page 19 of 27 Table A2.2 F amoxadone Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.4300 Combined

Chronic/ Carcinogenicity

rat 44302430,44302431,

44946212,44946213 (1996) Acceptable/guideline 0, 10, 40, 200, 400 ppm M: 0, 004, 1.6, 804, 16.8 mg/kg/day F: 0, 0.5, 2.2, 10.7, 23.0 mg/kg/day NOAEL ~ M: 8.4 mg/kg/day. F: 2.2 mg/kg/day

LOAEL ~ M: 16.8 mg/kg/day base d on slight hemolytic anemia with compensatory erythropoiesis and secondary responses in spleen and bone marrow, and mild hepatotoxicity in the liver. F: 10.7 mg/kg/day based on decreased body weight gain and slight hemolytic anemia; at 23.0 mg/kg/day, a lso secondary responses to anemia in spleen, bone marrow and/or liver, and mild hepatotoxicity in the liver. No evidence of carcinogenicity in M or F.

870.5100 Bacterial reverse

gene mutation with

S. typhimurium/

E. coli 44302433 (1995)

Acceptable Negative without and with S

- 9 activation up to limit dose of 5000 μg/plate.

870.5300 In vitro

mammalian cell forward gene mutation assay (CHO

cells/HGPRT locus) 44302436 (1994)

Acceptable Negative without and with 5

- 9 activation up to

the limit of solubility (in DMSO) of 30 μg/mL.

870.5300 In vitro

mammalian cell forward gene mutation assay (CHO

cells/HGPRT locus) 44946220 (1999)

Acceptable Negative without and with S

- 9 activation up to cytotoxic concentrations (2:200 μg/mL without

S

- 9 and 2:150 μg/mL with S

- 9).

870.5375. In vitro

mammalian aberration (human lymphocytes) 44302435 (1994)

Acceptable Positive (weak clastogenic effect) without S

- 9

activation Statistically significant increases in percentage

of aberrant chromosome cells at several dose levels ranging from 5

- 15 μg/mL. Cytotoxicity was observed at 10

- 18 μg/mL. Negative with S

- 9 activation.

870.5375 In vitro

mammalian aberration (human lymphocytes) 44302434 (1995)

Acceptable Positive (weak clastogenic effect) without S

- 9

activation. Statistically significant increases in percentage

of aberrant chromosome cells at several dose levels ranging from 15

- 30 μg/mL. Cytotoxicity

was observed at 20

- 30μg/mL. Negative with S

- 9 activation.

870.5395 In vivo micro

nucleus assay in mice (bone marrow cells) 44302439 (1994)

Acceptable Negative at single oral doses of up to limit dose of 5000 mg/kg

870.5550 in vitro

Unscheduled DNA synthesis (primary rat hepatocytes) 44302438 (1994)

Acceptable Positive response (increased net nuclear grain

counts observed at several treatment levels ranging from 0.05

- 10 μg/mL. Cytotoxicity was observed at 10 μg/mL

### Famoxadone Scoping Document DP No. D423286

Page 20 of 27 Table A2.2 F amoxadone Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.5550 in vitro

Unscheduled DNA synthesis (primary rat hepatocytes) 44302437 (1994)

Acceptable Negative at treatment levels up to 10μg/mL. Cytotoxicity was observed at 10 μg/mL

870.5550 in vitro

Unscheduled DNA synthesis (primary rat hepatocytes) 44946222 (1999)

Acceptable Negative at treatment levels up to 5.0μg/mL. Cytotoxicity was observed at 2.5 and 5.0 μg/mL

870.5550 in vivo/in vitro

Unscheduled DNA synthesis (in primary rat hepatocytes

derived from male rats given single

oral doses of 800 or 2000 mg/kg of Famoxadone) 44946221 (1998)

Acceptable Negative at sin gle oral doses of up to 2000 mg/kg. No marked increases in net nuclear grain counts or percentage of cells in repair in hepatocyte cultures.

870.6200 Acute

neurotoxicity screening battery

rat 44302414 (1995)

Acceptable M&F: 0,500, 1000,2000 mg/kg (gavage) NOAEL = M: 1000 mg/kg. F: 2000 mg/kg LOAEL = M: 2000 mg/kg based on decreased body weight gain, decreased food consumption (on days 1

- 2) and palpebral (eyelid) closure (on day 1 only). F: none (>2000 mg/kg).

870.6200 Subchronic

neurotoxicity screening battery

rat 44302421 (1995)

Acceptable 0, 50, 200, 800 ppm M: 0, 2.9, 11.7, 47 mg/kg/day F: 0, 3.7, 14.4, 59 mg/kg/day NOAEL = M: 11.7 mg/kg/day. F: 14.4 mg/kg/day LOAEL = M: 47 mg/kg/day based on decreased body weight, decreased body weight gain, decreased food consumption and

decre ased food efficiency. F: 59 mg/kg/day based on decreased body weight, decreased body weight gain, decreased food consumption

and decreased food efficiency. No evidence of neurotoxicity in M or F.

870.6300 Developmental

neurotoxicity Not required (HI ARC, 12/12/02)

870.7485 Metabolism and

pharmacokinetics (species) 44302440,44302441,

and 44302442 (1995

- 1997) Acceptable/guideline M&F: 5 mg/kg (single low dose and 15 repeated doses), 100 mg/kg (single high dose) Famoxadone was rapidly absorbed, but only

about 40% of the administered dose (AD) was absorbed. Most of the AD (87

- 96%) was eliminated in the feces within 24 hours; very rats little (3

- 12%) was eliminated in the urine.

Less than 1% remained in the tissues af ter 120 hours. Unchanged parent (51

- 84% of AD) and 2 hydroxylated metabolites (IN

- KZ534 and IN

KZ007) were the major components recovered in the feces. No unchanged parent was found in the urine. An enterohepatic circulation (about

30

- 39% of the AD) was observed; glucuronide and sulfate conjuga tes of 8 components (including IN

- KZ532 and IN

- ML815) were identified in the bile. No significant qualitative or quantitative differences were observed for sex, dose level, or repeated dosing.

### Famoxadone Scoping Document DP No. D423286

Page 21 of 27 Table A2.2 F amoxadone Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.7485 Metabolism and

pharmacokinetics (dogs

– males only) 44302443, 44946227

(1996

- 1998) Acceptable/non

- guideline M: 15 mg/kg (single oral gavage dose) Only about 80% of the total administered dose (AD) of Famoxadone was recovered. Famoxadone was rapidly absorbed, but absorption was limited. Most of the AD (62 %)

was eliminated in the feces within 24 hours; very little (about 8% ) was eliminated in the

urine. Less than 1% remained in the tissues after 96 hours. Initially, unchanged parent (94

- 97% of radio

- activity in feces) was recovere d in the feces, but later ( >24 h rs. ) unchanged parent (12

- 35% of radioactivity in feces), IN

KZOO7 (21

- 33% of radioactivity in feces) and

IN

- ML815 (4

- 9% of radioactivity in feces) were recovered. Even later (>48 hrs), trace amounts of the hydroxylated metabolites IN

KZ532 and IN

- KZ5 34 were also identified in the feces. No unchanged parent was found in the urine, but up to 8 unknown regions of radioactivity (each <2% of the AD) were

observed.

870.7600 Dermal penetration

(rat) Not available

870.7800 Immunotoxicity

(rats ) 44946223 (1999)

Acceptable/guideline 0, 50, 100,200, 800 ppm M:0, 4, 7, 14, 55 mg/kg/day F: 0, 4, 8, 16, 57 mg/kg/day NOAEL = M: 14 mg/kg/day. F: 16 mg/kg/day LOAEL = M: 55 mg/kg/day based on decreased body weight, decreased body weight gain, decreased food consumption, decreased food efficiency and increased spleen weights (probably due to increased pigment in spleen). F: 57 mg/kg/day based on decreased body

w eight, decreased body weight gain, decreased food consumption, decreased food efficiency and increased spleen weights (probably due to increased pigment in spleen). No evidence of immunotoxicity in M or F.

870.7800 Immunotoxicity

( mice) 44946225 (1999)

Ac ceptable/guideline 0, 50, 350, 2000, 7000

ppm M:0, 8, 55, 327, 1186 mg/kg/day F: 0, 11, 72, 417, 1664 mg/kg/day NOAEL = M: 1186 mg/kg/day. F: 417 mg/kg/day LOAEL = M: none (>1186 mg/kg/day). F: 1664 mg/kg/day based on increased spleen weights (probably due to increased pigment in spleen). No evidence of immunotoxicity in M

or F.

### Famoxadone Scoping Document DP No. D423286

Page 22 of 27 Appendix A. 3. Famoxadone Endpoints and Doses for Risk Assessment

Table A3.1 Summary of Toxicological Doses and Endpoints for f amoxadone for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population, including

Infants and Children) No toxicological endpoint attributable to a single oral dose was identified in the available

toxicology studies with famoxadone

Acute Dietary (Females 13

- 49 years of age) No toxicological endpoint attributable to a single oral dose was identified in the available

toxicology studies with famoxadone

Chronic Dietary (All Populations) NOAEL

< 1.4 mg/kg/day UF A = 10 x

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

= 0.0014 mg/kg/day

cPAD =

0.0014 mg/kg/day 13

- Week Feeding Study in Dogs

LOAEL = 1.4 mg/kg/day based on microscopic lens lesions (cataracts) in eyes of female dogs. A NOAEL could not be determined since 1.4 mg/kg/day

was the lowest dose tested

Incidental

Oral (All Durations) No residential uses for famoxadone have been proposed

Dermal Short

Term (All

Durations No residential uses for famoxadone have been proposed

Inhalation

Short

- Term ( All

Durations ) No residential uses for famoxadone have been proposed

Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic in humans

.

Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose

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

reference dose.

### Famoxadone Scoping Document DP No. D423286

Page 23 of 27 Table A3.2 Summary of Toxicological Doses and Endpoints for f amoxadone for Use in Occupational

Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Dermal Short

Term (1

- 30 days) Oral Study

NOAEL=

10.0 mg/kg/day

Dermal Absorption

rate = 5% UF A =10x

UF H =10x Occupational LOC

for MOE = 100 13

- Week Feeding Study in Dogs

LOAEL = 23.3 mg/kg/day based on myotonic twitches in male and female dogs starting on study day 21

Dermal

Intermediate

Term (1

- 6 months) Oral Study

L OAEL <
1.4 mg/kg/day

Dermal Absorption

rate = 5% UF A =10x

UF H =10x Occupational LOC

for MOE = 300 a 13

- Week Feeding Study in Dogs

LOAEL = 1.4 mg/kg/day based on microscopic lens lesions (cataracts) in eyes of female dogs. A NOAEL could not be determined since 1.4 mg/kg/day

was the lowest dose tested

Inhalation

Short

- Term (1

- 30 days) Oral Study

NOAEL=

10.0 mg/kg/day (inhalation absorption

rate = 100%) UF A =10x

UF H =10x Occupational LOC

for MOE = 100 13

- Week Feeding Study in Dogs

LOAEL = 23.3 mg/kg/day based on myotonic twitches in male and female dogs starting on study day 21

Inhalation

Intermediate

term (1

- 6 months) Oral Study

L OAEL <
1.4 mg/kg/day (inhalation absorption

rate = 100%) UF A =10x

UF H =10x Occupational LOC

for MOE = 300 a 13

- Week Feeding Study in Dogs

LOAEL = 1.4 mg/kg/day based on microscopic lens lesions (cataracts) in eyes of female dogs. A NOAEL could not be determined since 1.4 mg/kg/ day

was the lowest dose tested

Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic in humans

.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from a nimal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

a = Additional 3x database uncertainty factor because of the use of a LOAEL, rather than a NOAEL, was used.

### Famoxadone Scoping Document DP No. D423286

Page 24 of 27 Appendix B: Chemistry

1.0 Identification of Active Ingredient

Table 1. Famoxadone Nomenclature.

Chemical structure

Common name Famoxadone

Company experimental name DPX

- JE874

IUPAC name 3

- anilino

- 5

- methyl

- 5

- (4

- phenoxyphenyl)

- 1,3

- oxazolidine

- 2,4

- dione

CAS name 5

- methyl

- 5

- (4 phenoxyphenyl)

- 3

- (phenylamino)

- 2,4

- oxazolidinedione

CAS registry number 131807

- 57

- 3

End

- use product (EP) Tanos® Fungicide (EPA Reg. No. 352

- 604), a DF formulation which contains 25% ai famoxadone and 25% ai cymoxanil.



### 2.0 Physical and Chemical Properties

Table 2. Physicochemical Properties of Famoxadone.

Parameter Value Reference

Melting point/range 140.3

- 141.8°C DP#s 271377 and 287253, 4/18/03, M. Doherty PH 6.56 at 20°C

Density D 20 4 = 1.310 g/mL

Water solubility pH g/L

unbuffered 52

2 143

3 191

5 243

7 111

9 38
Solvent solubility Solvent g/L

acetone 274

acetonitrile 125

dichloromethane 239 ethyl acetate 125

hexane 0.0476

methanol 10.0

1

- octanol 1.87

Toluene 13.3

Vapor pressure 6.4×10

- 4 mPa (4.8×10

- 9 mm Hg)

Dissociation constant, pK

a Expected to be weakly basic. The dissociation

constant could not be measured or inferred from solubility or octanol water partition

coefficient.

### Famoxadone Scoping Document DP No. D423286

Page 25 of 27 Table 2. Physicochemical Properties of Famoxadone.

Parameter Value Reference

Octanol/water partition coefficient, Log(K OW ) pH Log K ow ± SD

3.0 4.59 ± 0.06

5.0 4.80 ± 0.13

7.0 4.65 ± 0.40

9.0 5.55 ± 0.26
UV/visible absorption spectrum Not available

### Famoxadone Scoping Document DP No. D423286

Page 26 of 27 3.0 International Residue Limits



## Famoxadone (PC Code 113202 )

Summary of US and International Tolerances and Maximum Residue Limits
Residue Definition :
US Canada Mexico 1 

### Codex 2



### 40 CFR 180.587: (a) General. famoxadone (3

- anilino

- 5

- methyl

- 5

- (4

- phenoxyphenyl)

- 1,3

- oxazolidine

- 2,4

- dione) 

### 5

- methyl

- 5

- (4

- phenoxyphenyl)

- 3

- (phenylamino)

- 2,4

- oxazolidinedione Famoxadone

The residue is

fat soluble.

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

US Canada Mexico 1 

### Codex 2

Caneberry subgroup 13

- 07A 10 10 blackberries, loganberries, raspberries

, wild raspberries
Cattle, fat 0.02 0.02

Cattle, liver 0.05 0.05 0.5 edible offal (mammalian)
Cilantro, leaves 25
Goat, fat 0.02 0.02

Goat, liver 0.05 0.05 0.5 edible offal (mammalian)

Grape, raisin 1 4.0 5 dried grapes (=currants, raisins and sultanas) Hop, dried cone 80
Horse, fat 0.02 0.02

Horse, liver 0.05 0.05 0.5 edible offal (mammalian) Milk, fat (reflecting negligible residues in whole milk) 0.06 0.06 0.03 F

Onion, bulb, subgroup 3

- 07A 0.45
Onion, green, subgroup 3

- 07B 40

Potato 0.02 0.02 0.02 (*) Sheep, fat 0.02 0.02 Sheep, liver 0.05 0.05 0.5 edible offal (mammalian) Spinach 50

Tomato 1.0 1 2 Vegetable, cucurbit, group 9 0.30 0.2 cucumber, squash summer Vegetable, fruiting, group 8, except

tomato 4.0

Vegetable, leafy, except Brassica, group 4, except spinach 25

MRLs with No US Equivalent Barley 0.2 Barley straw and fodder, dry 5 Eggs 0.01 (*)

### Famoxadone Scoping Document DP No. D423286

Page 27 of 27 Summary of US and International Tolerances and Maximum Residue Limits
Residue Definition :
US Canada Mexico 1 

### Codex 2

Grape pomace, dry 7 Meat (from mammals other than

marine mammals) 0.5 (fat)

Poultry meat 0.01 (*) Poultry, edible offal of 0.01 (*)

Wheat 0.1 Wheat bran, unprocessed 0.2 Wheat straw and fodder, dry 7

Completed: M. Negussie; 10/22/2014

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

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on t he fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.



### (c) Tolerances with a regional registrations. Tolerances with a regional registration as defined in §180.1(l) are established for the residues of the fungicide famoxadone, 3

- anilino

- 5

- methyl

- 5

- (4

- phenoxyphenyl)

- 1,3

- oxazolidine

- 2,4

- dione) in or on the raw agricultural commodities:

Commodity Parts per million 

### Codex

Grape 2.5 

### 2