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EXECUTIVE SUMMARY

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 science 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 risk 

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 vegetables (except Brassica), bulb vegetables, tomatoes, 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 famoxadone 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. 

Subchronic 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 with 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, 
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04/30/2008). The estimated chronic dietary exposure (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 identified for famoxadone; 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 consider 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 residential 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 is 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 exposure to foliage. Per HED 

policy, a DFR study is required because the total margins of exposures (MOEs) for intermediateterm 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 exists and has been assessed in one of the five past ORE assessments. Because the 

famoxadone dermal and inhalation endpoints selected are different for short- and intermediateterm 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. 

1.0 FORMULATIONS AND USE PATTERNS 

T. Chandgoyal et. al., BEAD Chemical Profile Review, 10/14/2014

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, D360943, 01/26/2009, amendment to the 2008 residue chemistry chapter

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. 
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Famoxadone 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, tomatoes, potatoes, hops, and grapes (East of 

the Rocky 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 residue 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 residue chemistry chapters (including the 2009 

amendment) required rotational crop restrictions which are currently listed on the product label 

for Tanos® Fungicide (EPA Reg. No. 352-604, May 20, 2011). 

2.0 HAZARD IDENTIFICATION/TOXICOLOGY

With the exception of a subchronic inhalation toxicity study in rats, the toxicology database is 

complete 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 the exception of mixer/loader dry flowable for aerial 

application (HASPOC Report TXR# 0057104).

Technical grade famoxadone (DPX-JE874) is white solid powder of 97.8% purity and has acute, 

dermal and inhalation toxicity ranging 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.

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

famoxadone generally caused decreased 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. Secondary effects of the anemia 

were frequently observed in the 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. 
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There were additional 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 duration 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 feeding 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 has been recommended previously. The metabolism (toxicokinetic) studies in rats and 

dogs were compared, 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 phosphorylation 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 to 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, equivocal evidence of neurotoxicity at the limit dose was 

noted. An 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. 

No evidence of immunotoxicity was observed in 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, famoxadone (about 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 parent (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. Enterohepatic 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. No biologically significant 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 famoxadone was observed in the developmental toxicity 
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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. Developmental 

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, no 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 to 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 Table A3.1. 

Conclusions: With the exception of a subchronic inhalation study, the 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 HED 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 

species-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 reevaluation of endpoints and uncertainty 

factors, uncertainty factors could increase considering current policy, potentially leading to risks 

exceeding standard benchmarks for acceptability. 

3.0 RESIDUE CHEMISTRY

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, D360943, 01/26/2009, amendment to the 2008 residue chemistry chapter

The metabolism of famoxadone is adequately 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-

oxazolidinedione), 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 
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data acquisition 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 to 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 

current 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 Canada 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 coverage 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 famoxadone, 3-anilino5-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 Canadian 

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 commodities 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 Codex 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 MRLs 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 ppm; 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 

exception 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 § 180.587 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 registration review. 
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4.0 DIETARY EXPOSURE

B. Hanson, D354336, 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 1998. 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 feeding 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 (food and water) from 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 exposure. 

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 RESIDENTIAL EXPOSURE

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 case with 

aerial application, but to a lesser extent, spray drift can also be a potential source of exposure 

from the ground application methods (e.g., groundboom 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 developed a policy on how to appropriately consider spray drift as a 

 

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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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 pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization 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 screening 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 and, 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 review. 

6.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

There are no residential uses for famoxadone and, therefore, there is no residential contribution 

to the aggregate risk assessment. The aggregate exposure and risk is currently represented by 

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

7.0 OCCUPATIONAL EXPOSURE 

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, tomatoes, potatoes, hops, 

and grapes (East of the Rocky Mountains). Based on this use profile, there is potential for shortand intermediate-term occupational 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. 

Famoxadone 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 (PPE) on the 
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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, tomatoes, potatoes, hops, and grapes (East of the Rocky Mountains). 

Famoxadone, a fungicide, can be applied at a re-treatment interval ranging from 5 to10 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 

famoxadone. Only one previously completed assessment considered intermediate-term exposures

(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 review 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 Exposure 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 

review.

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 currently registered product, EPA Reg. No. 352-604, the resulting short-term postapplication 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 

intermediate-term exposures (DP288296, 04/02/2003). Estimated intermediate-term postapplication 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 
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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 gardens, 

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 residential turf uses that could result in postapplication 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 postapplication 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 famoxadone 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 occupational 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 there 

were no risk estimates of concern. However, based on the use pattern of famoxadone, the 

potential for intermediate-term occupational exposures to famoxadone exists and has not been 

assessed. 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 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 PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA 

E. Evans and S. Recore, D423541, 10/28/2014

The 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 Main IDS, from January 1, 2009 to August 12, 2014, there were 0 incidents reported 

involving famoxadone. In Aggregate IDS, from January 1, 2009 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 SENSORPesticides from 1998-2010 identifies no cases involving famoxadone. Famoxadone is not 

included in the Agricultural Health Study, and therefore this study does not provide information 

for this report.
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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 ENVIRONMENTAL JUSTICE

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates 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 involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups, and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, 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 lifestyle and traditional dietary patterns among specific 

subgroups.

10.0 CUMULATIVE RISK ASSESSMENT

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 produce 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 to evaluate the 

cumulative effects of such chemicals, see the policy statements released by EPA’s Office of 

Pesticide Programs concerning common mechanism determinations and procedures for 

cumulating effects from substances found to have a common mechanism on EPA’s website at 

http://www.epa.gov/pesticides/cumulative.
Famoxadone Scoping Document DP No. D423286

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11.0 HUMAN STUDIES

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 (ARTF) 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 relative 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 DATA REQUIREMENTS

Hazard/Toxicity

- A 90-day inhalation toxicity study in the rat (OPPTS Guideline 870.3465) is required

based on the recommendations 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 Protection 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, Brussels, 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 (Commission 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

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Appendix A: Toxicology Profile 

A.1 Toxicology Data Requirements 

The requirements to support current uses of famoxadone are in the table below. These 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

No

No

yes

yes

yes

yes

yes

NA

No1

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/Carcinogenicity...................................... 

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 erythrocyte micronucleus 

test............................................. 

yes

yes

yes

No

yes

yes

yes 

yes

No

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 Developmental Neuro. ................................................ 

No

No

yes

yes

No

No

No

yes

yes

No

870.7485 General Metabolism......................................... 

870.7600 Dermal Penetration.......................................... 

870.7800 Immunotoxicity..........................................

yes

No

yes

yes

No

yes

1 Data required per HASPOC meeting 01/08/2015.

NA = not applicable.
Famoxadone Scoping Document DP No. D423286

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A.2 Toxicity Profiles

Table A2.1Famoxadone Acute Toxicity Profile

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

870.1100 Acute oral [rat] 44303407 LD50 > 5000 mg/kg M/F IV

870.1100 Acute oral [mouse] 44303408 LD50 > 5000 mg/kg M/F IV

870.1200 Acute dermal [rabbit] 44303409 LD50 > 2000 mg/kg M/F III

870.1300 Acute inhalation [rat] 44303410 LD50 > 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 A2.2Famoxadone 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) 

Unacceptable/nonguideline

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

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Table A2.2Famoxadone 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 on 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.

870.3200 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 resorptions per doe.
Famoxadone Scoping Document DP No. D423286

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Table A2.2Famoxadone 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 870.4200

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 in 

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

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Table A2.2Famoxadone 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 based 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, also 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 micronucleus 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

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Table A2.2Famoxadone 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 single 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 

decreased 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 (HIARC, 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 after 120 

hours. Unchanged parent (51-84% of AD) and 

2 hydroxylated metabolites (IN-KZ534 and INKZ007) 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 conjugates 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

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Table A2.2Famoxadone 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 recovered 

in the feces, but later (>24 hrs.) unchanged 

parent (12-35% of radioactivity in feces), INKZOO7 (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 INKZ532 and IN-KZ534 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 

weight, 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)

Acceptable/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

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Appendix A.3. Famoxadone Endpoints and Doses for Risk Assessment

Table A3.1 Summary of Toxicological Doses and Endpoints for famoxadone for Use in Dietary and NonOccupational 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

UFA= 10x

UFH=10x

UFL=10 X

FQPA SF= 1x

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 ShortTerm (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. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = 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

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Table A3.2 Summary of Toxicological Doses and Endpoints for famoxadone 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 ShortTerm (1-30 

days)

Oral Study 

NOAEL=

10.0

mg/kg/day

Dermal 

Absorption 

rate = 5%

UFA=10x

UFH=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 

IntermediateTerm (1-6 

months)

Oral Study 

LOAEL< 

1.4

mg/kg/day

Dermal 

Absorption 

rate = 5%

UFA=10x

UFH=10x

Occupational LOC 

for MOE = 300a

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%)

UFA=10x

UFH=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 

Intermediateterm (1-6 

months)

Oral Study 

LOAEL< 

1.4

mg/kg/day

(inhalation 

absorption 

rate = 

100%)

UFA=10x

UFH=10x

Occupational LOC 

for MOE = 300a

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. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = 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

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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 D204 = 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, pKa Expected to be weakly basic. The dissociation 

constant could not be measured or inferred 

from solubility or octanol water partition 

coefficient.

O

N

O

O

N

H

O

H3C
Famoxadone Scoping Document DP No. D423286

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Table 2. Physicochemical Properties of Famoxadone.

Parameter Value Reference

Octanol/water partition coefficient, 

Log(KOW)

pH Log Kow ± 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
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3.0 International Residue Limits 

Famoxadone (PC Code 113202)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

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 Mexico1 Codex2

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, raisin1 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

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Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

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 the 

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