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

OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION



### MEMORANDUM

DATE: February 24

, 2015

SUBJECT: Carboxin and Oxycarbox i n: Human Health Scoping Document in Support of Registration Review.

PC Code: 090201 carboxin; DP Barcode: D423825

090202 oxycarboxin

Decision No.: 497186 Registration Nos.: NA

Petition No

. : NA Regulatory Action: Registration Review

Case No.: 0012 Risk Assessment Ty_p_e: NA

TXRNo.: NA CAS No.: 5234-68-4 carboxin; 5259-88

- 1 oxycarboxin

MRIDNo.: NA 40CFR: §180.301

FROM:

THROUGH:

TO: Jessica Kidwell, Risk Assessor Clr.At..tJ..t'.A

-

# ~ Abdallah Khasawinah, Ph.D.,

# Toxia,l~;~~-/?**~** Bonnie Cropp-Kohlligian

, Environmental

# Scientis~**~- ~~0**  Sue Hummel, Senior Chemist**~** 

### Ivan Nieves

, ORE 

# J _.(7) · Risk Assessment Branch 

# Yv'

Health Effects Division (7509P)

Elissa Reaves, Ph.D., Branch Chief

Risk Assessment Branch IV

Hea l th Effects Division (7509P)

Dana Friedman, Chemical Review Manager Cathryn Britton, Team Leader

Risk Management and Implementation Branch 2

Pesticide Re

- Evaluation Division (7508P)

Attached is HED's human health risk assessment scoping document for carboxin and oxycarboxin to support Registration Review.

### Carboxin & 

### Oxycarboxin Scoping Document 0423825

Executive Summary

This document summarizes the review of the Healt h E ffects Division's (HED's) human health

assessments to support the Registration Review of carboxin and oxycarboxin. T o

- · determine the

scope of work necessary to support Registration Review, HED has considered updates to Agency
science policy and risk assessment methodologies and to the t ox i city, exposure , and usage databases . T he most recent risk assessment for carboxin was completed in 2003 (D288406) for
the ,Carboxin Reregistration Eligibility Decision (RED). The most recent risk assessment for oxycarboxin was completed in 2004 (D29550 1) to support registration and was lim i ted to

assessment of occupational exposure and risk since oxycarboxin is not registere d for use on food/feed crops.

Carbox i n [5,6-dihydro

- 2

- methy l- 1

, 4-oxathiine-3-carboxanilide] and oxycarboxin [ 5,6-dihydro-2- methyl

- 1

, 4

- oxathiine-3-carboxanilide 4,4

- dioxide], a sulfone analogue ofcarboxin, a r e members
of the oxathiin class of systemic fungicides. Carboxin is applied to seed prior to plant i ng for

control of various fungi that cause seed and seedling diseases (smut, rot, and bligh t ). The seed

trea t ment uses o f carboxin are considered food/feed uses based on data that demonstrate uptake

of detectable residues in crops. Oxycarboxin is applied foliarly for control of rust diseases on ornamentals grown i n enclosed commercial structures such as greenhouses, shadehouses, and interiorscapes. There are no residential uses for eithe r carboxin or oxycarboxin.

The toxicology, residue chemistry, and occupational exposure databases for carboxin and oxycarboxin are adequate for Registration Review. HED's Hazard and Sc i ence Policy Council (HASPOC) concluded that an immuno t oxicity, and acute and subchronic neurotoxicity studies

are not required at this time for carboxin. The HASPOC concluded that a subchronic inhalation

tox i city study is requi r ed at this time. In the absence of this study, a 1 

### OX database uncertainty

factor will be applied on l y for assessing risk for future inhalation scenarios. However, with
additional PPE (such as a PF5 respirator) on registe r ed labels for carboxin com seed treatment involving multiple activities and for oxycarboxin mixing/loading/applying with a mechanically pressurized handgun, t he inhala t ion study will not be needed and the agency will waive the need

for the inhalation study, pending finalizat i on of t he modified label.

The toxicology database for oxycarboxin is limited. However, based on the close structural similarity of carboxin and oxycarboxin, for r i sk assessment purposes, the toxicity potential of oxycarboxin is presumed to be equivalent to that of the toxicity potential of carboxin. Consequently, th e Point of Departures (PODs) and t oxicity endpoint of concern selected for

carboxin will also be used for assessing risk from exposure to oxycarboxin.

As part of Regis tr ation Rev i ew, PODs, toxicological endpoints, and uncertainty/safety factors

used in the most recent human health risk assessments may be re

- evaluated accord i ng to current
HED policy

. Updated exposure and risk assessments may need to be conducted using current policy and procedures if there are any significant changes to carboxinloxycarboxin endpoin t s, points of departure, uncertainty/safety factors, and/or exposure estimates/assumptions. The

current tolerance express i on for carboxin will need to be updated to reflect the HED Interim

Guidance on Tolerance E xpressions (5/27/09, S. Knizner)

.

Page 2 of27

### Carboxin & Oxycarboxin Scoping Document D423825

Page 3 of 27 Carboxin exhibits low acute toxicity via the oral, dermal and inhalation routes of exposure. It is a slight eye irritant (Toxicity Category III). It is not a skin irritant (Toxicity Category IV) and is negative for dermal sensitization. In subchronic and chronic feeding studies in rats, the kidne y was the primary target organ. In a chronic feeding study in dogs, the primary target organ appeared to be the liver. In a carcinogenicity study in mice, dose

- related increases in the incidence of liver centrilobular hypertrophy were observed in the mid

- and high

- dose males and high

- dose females; however, this was considered to be an adaptive, rather, than an adverse response. In the female mice in this study, treatment

- related increased mortality was observed at
the mid

- and high

- dose, but not in the mal e mice at the high

- dose. There is no evidence of increased susceptibility in the developmental rat and rabbit toxicity studies or the two

- generation reproduction toxicity study in rats. There is no evidence of neurotoxicity or neurobehavioral
effects in th e current toxicity database. The FQPA safety factor was reduced to 1X. Carboxin is classified as “Not Likely to be Carcinogenic to Humans” according to the EPA Draft Proposed Guidelines for Carcinogen Risk Assessment (July 2, 1999). Although some mutagenic ity tests were positive, carboxin was negative for carcinogenicity in both rats and mice.

No acute dietary exposure and risk assessment has been conducted for carboxin since a toxicological endpoint attributable to a single oral dose was not identified in the available toxicology studies for carboxin. An unrefined chronic dietary exposure and risk assessment for food only was previously conducted using tolerance level residues, 100% crop treated and default processing factors, resulting in a dietary exposu re estimate of 36% or less of the chronic Population Adjusted Dose (cPAD) for the general U.S. population and all other population subgroups (the most highly exposed population subgroup was Children 1

- 2 years) . Drinking
water was included in the assessment as estimated environmental concentrations (EECs) from the Tier 1 FIRST model, and compared to drinking water levels of concern (DWLOC). No dietary risk of concern was identified.

The previously assessed occupational exposure scenarios for carboxin and o xycarboxin resulted in margins of exposure (MOEs) above the target MOE of 100. No occupational risk of concern
was identified.

Introduction

Carboxin is a member of the oxathiin class of systemic fungicides

. Its apparent pesticidal mode
of action is to se lectively concentrate in fungal cells, where it inhibits succinic dehydrogenase, a respiratory enzyme in the mitochondria (Mathre, 1971, Pesticide Biochemistry and Physiology
1:216

- 224). Another member of the class is oxycarboxin, a sulfone analogue of car boxin.
Carboxin and oxycarboxin are primarily effective against the basidomycetes class of fungi which includes fungal pathogens such as rusts, smuts and bunts of cereals and the soil fungus Rhizactonia solani. Carboxin is applied to seed prior to planting for control of various fungi that cause seed and seedling diseases (smut, rot, and blight). It is available in a variety of formulations including wettable powder, dust, flowable concentrate, and ready

- to

- use liquid.
C arboxin is applied both by commercial seed treaters and on

- farm applicators. Oxycarboxin is used for control of rust diseases by foliar use on ornamentals grown in enclosed commercial structures such as greenhouses, shadehouses, and interiorscapes. Oxycarb oxin is available solely as a wettable powder formulation (Plantvax 75W, EPA Reg. No. 400

- 144). It is applied by

### Carboxin & Oxycarboxin Scoping Document D423825

Page 4 of 27 commercial applicators only. There are no registered residential uses of either carboxin or oxycarboxin. The nomenclature and physiochemical pr operties of carboxin and oxycarboxin are presented in Attachment 1.

Hazard Identification/Toxicology

The toxicology databases for carboxin and oxycarboxin are complete , with the exception of a subchronic inhalation study that is required for carboxin . Th e HASPOC concluded, based on a weight of evidence (WOE) approach and considering all the available hazard and exposure data, that an immunotoxicity, and acute and subchronic neurotoxicity studies are not required at this time for carboxin (TXR No. 0057070)

. The HASPOC concluded, based on a WOE approach that a subchronic inhalation toxicity study for carboxin is required at this time. This approach considered all of the available hazard and exposure information for carboxin and oxycarboxin, including: 1) the potential for repeated inhalation exposure to both chemicals; and 2) for
carboxin corn seed treatment involving multiple activities resulting in an MOE of 890 for
intermediate

- term exposure duration; and for oxycarboxin mixing/loading/applying with a
mech anically pressurized handgun scenario, resulting in MOEs of 610 for short term duration and 330 for intermediate term duration, at baseline (i.e., no respirator) . In the absence of this study, a 10X database uncertainty factor will be applied only for asse ssing risk for future inhalation scenarios. However, if the registrant agrees to additional mitigation (such as a PF5 respirator) on registered labels for carboxin corn seed treatment involving multiple activities and for oxycarboxin mixing/loading/applyin g with a mechanically pressurized handgun , the inhalation study will not be needed and the agency will waive the need for the inhalation study, pending finalization of the modified label.

A limited toxicology database exists for oxycarboxin; however, bas ed on the close structural similarity of carboxin and oxycarboxin, oxycarboxin is assumed to be toxicologically equivalent to carboxin for risk assessment, and endpoints for carboxin are used to assess exposure and risk to oxycarboxin. All submitted toxici ty studies for carboxin and oxycarboxin are provided in the Toxicology Profile Tables in Attachment 2.

Carboxin is rapidly and extensively absorbed, metabolized and excreted following oral administration, mostly within 24 hours. No significant residues re main after 72 hours. The major route of excretion is the urine (77

- 82% of administered dose). Only 6

- 12% of the administered dose was excreted in the feces. Percent excretion patterns are similar for high, low and repeated dose regimens and for both sexes. Major metabolites identified in the urine were hydroxylated carboxin sulfoxide, 4

- acetamidophenol, and 4

- acetamidophenol glucuronide; minor metabolites
were acetanilide and N

- acetylcysteinyl aniline. Carboxin sulfone (oxycarboxin) did not exceed
3.4% of t he administered dose in any treatment group. No parent compound (carboxin) was
found in the urine.

Carboxin exhibits low acute toxicity via oral (Toxicity Category III), inhalation (Toxicity Category IV), and dermal (Toxicity Category III) exposure. It is a slight eye irritant (Toxicity Category III). It is not a skin irritant (Toxicity Category IV) and is negative for dermal
sensitization.

### Carboxin & Oxycarboxin Scoping Document D423825

Page 5 of 27 In subchronic and chronic feeding studies in rats, the kidney was the primary target organ with effects showing increased incidence and severity with time. However, in dogs and mice, the primary target organ appeared to be the liver. In the chronic dog study liver enzy mes, cholesterol and liver weights were all increased. In addition, treatment

- related hematological changes were also observed. These changes included signs of anemia (decreased erythrocytes, hematocrit and hemoglobin; and increased mean corpuscular volume and mean corpuscular hemoglobin). In the carcinogenicity study in mice, dose

- related increases in the incidence of liver centrilobular hypertrophy were observed in the mid

- and high

- dose males and high

- dose females; however,
this was considered to be an a daptive, rather, than an adverse response. In the female mice in this study, treatment

- related increased mortality was observed at the mid

- and high

- dose, but not in the male mice at the high

- dose.

In a developmental toxicity study in rats, no developme ntal toxicity was observed in the fetuses at the highest dose tested. Decreased body weight, decreased body weight gain and decreased food consumption were noted in the dams in this study. In a developmental toxicity study in rabbits, a treatment

- related i ncreased incidence of abortions was observed at 375 mg/kg/day dose. However, it could not be determined whether the abortions were due to maternal toxicity (e.g. the result of stress) or due to an effect on developmental mechanisms. The maternal toxicity ( dams) and developmental toxicity (fetuses) were considered to be equally sensitive to the test
material. In a 2

- generation reproduction study in rats, there was no quantitative susceptibility although the effects in the offspring included decreased pup wei ght while parental effects included decreased body weight gain and kidney damage. The results of the two developmental toxicity studies and the reproduction study indicated no increased quantitative susceptibility of the fetuses or pups, as compared to adu lts, to carboxin.

Carboxin demonstrated genotoxic potential in two of five studies submitted by the registrant performed on technical grade carboxin. Positive responses were observed in an unscheduled DNA synthesis (UDS) assay in primary rat hepatocyte cu ltures (MRID 00132454) and in an in

vitro chromosomal aberration study in Chinese hamster ovary (CHO) cells with rat S

- 9 activation (MRID 45541102). In addition, a clastogenic response was demonstrated in an in vivo chromosomal aberration study in rat bone marrow cells in a study reported in the literature (Environ. Mol. Mut. 12:235

- 242, 1988, MRID 45541101). A review of the literature relating to genotoxicity of carboxin revealed it produced several types of chromosomal aberrations (including rings) in whe at and wheat

- like grains (Cytologia 45(1

- 2):169

- 175, 1980) and in barley (Acta Bot Hung 29(1

- 4):55

- 66, 1984). However, another in vivo chromosomal aberration study in rat bone marrow cells, was negative at high dose levels and a reverse gene mutation assay in S

. typhimurium was negative. HIARC concluded that there is a concern for mutagenicity but not for carcinogenicity in rats or mice. In carcinogenicity studies in male and female rats and in male and female mice, carboxin did not demonstrate any biologic ally significant evidence of carcinogenic potential. Carboxin is classified as “Not Likely to be Carcinogenic to Humans” according to the EPA Draft Proposed Guidelines for Carcinogen Risk Assessment (July 2, 1999) (TXR No. 0051928).

A limited number of toxicology studies (acute battery, mutagenicity battery, and developmental rat and rabbit toxicity studies) were submitted for oxycarboxin (See Attachment 2). The acute toxicity battery for oxycarboxin showed results similar to carboxin . The developmental rat and

### Carboxin & Oxycarboxin Scoping Document D423825

Page 6 of 27 rabbit toxicity studies with oxycarboxin showed no increased toxicity compared to carboxin. There is no concern for mutagenicity for oxycarboxin.

Dose Response Assessment

Dietary (food and drinking water) and occupational expo sures (dermal and inhalation) are the relevant scenarios for exposure to carboxin. There are no registered residential uses of carboxin. The last evaluation of toxicity endpoints was performed by the HED Hazard Identification Assessment Review Committee (H IARC) ( TXR No

. 0051928). No applicable toxicological endpoint attributable to an acute oral dose was identified in the available toxicology studies on carboxin. Therefore, an acute dietary endpoint was not selected. The chronic oral endpoint was
selected b ased on a combined chronic feeding/carcinogenicity study in rats. The chronic Reference Dose (cRfD) is 0.008 mg/kg/day. Since the Food Quality Protection Act (FQPA) Safety Factor (SF) is not retained (i.e. 1X) for this endpoint, the chronic Population Adju sted Dose (PAD) is equivalent to the chronic RfD. The short

- , intermediate

- , and long

- term dermal endpoints were based on a 21

- day dermal toxicity study in rats with a no observed adverse effect level (NOAEL) of 400 mg/kg/day. For assessing risk via dermal exposure, the LOC is a target
MOE of 100. The short

- and intermediate

- term inhalation endpoints were selected from a developmental toxicity study in rats with a NOAEL of 10 mg/kg/day. The long

- term inhalation endpoint was selected from a chronic toxicity/c arcinogenicity study in rats with a NOAEL of 0.8 mg/kg/day. For assessing risk via inhalation exposure, the LOC is a target MOE of 1000 which includes the conventional 100X and a 10X database uncertainty factor (UF DB 

### ) for the lack of a repeated exposure in halation study. Both short and intermediate incidental oral endpoints were selected but not required for risk assessment based on the use pattern. A summary of the endpoints selected are provided in Attachment 3.

Occupational exposures (dermal and inhalat ion) are the only relevant scenarios for oxycarboxin. Oxycarboxin is assumed to be toxicologically equivalent to carboxin and endpoints selected for carboxin were used to estimate occupational exposure and risk from oxycarboxin.

Conclusion: T he toxicolo gy databases for carboxin and oxycarboxin are complete, with the exception of a subchronic inhalation toxicity study which is now required for carboxin. Re

evaluation of the toxicity endpoints and uncertainty factors for carboxin and oxycarboxin according to current policies may be necessary for Registration Review.

Dietary Exposure

The qualitative nature of the residue of carboxin in/on crops from seed treatment and in livestock is adequately understood. Carboxin is systemic and the seed treatment use s of carboxin are considered food/feed uses based on data that demonstrate uptake of detectable residues in crops. Oxycarboxin was a minor metabolite of carboxin. The HED carboxin risk assessment team
determined that the residues of concern for tolerance e nforcement and risk assessment in/on crop
and livestock commodities should include carboxin and all its metabolites convertible to aniline. Adequate analytical enforcement methods are available.

### Carboxin & Oxycarboxin Scoping Document D423825

Page 7 of 27 The HED Metabolism Assessment Review Committee (MARC) determ ined that the residues of concern in drinking water are carboxin and its sulfoxide metabolite (D279382). Oxycarboxin was a minor degradate of carboxin; however, since it is not likely to contribute significantly to estimated drinking water concentrations f or carboxin and is no more toxic than carboxin, the HED/Environmental Fate and Effects Division (EFED) carboxin risk assessment team determined that it does not need to be included as a residue of concern for the carboxin drinking

water assessment.

The m ost recent dietary exposure and risk assessment for carboxin was conducted for the RED (D289855). No acute dietary exposure and risk assessment has been conducted for carboxin
since a toxicological endpoint attributable to a single oral dose was not identi fied in the available toxicology studies for carboxin. An unrefined chronic dietary exposure and risk assessment for food only was previously conducted using tolerance level residues, 100% crop treated and default processing factors, resulting in a dietary exposure estimate of 36% or less of the chronic Population Adjusted Dose (cPAD) for the general U.S. population and all other population subgroups (the most highly exposed population subgroup was Children 1

- 2 years) . Drinking
water was included in the ass essment as estimated environmental concentrations (EECs) from the Tier 1 FIRST model, and compared to drinking water levels of concern (DWLOC) (D280763). No dietary risk of concern was identified.

Conclusion: The residue chemistry database for carboxin i s complete. A dietary exposure assessment may be needed for Registration Review if changes are made to the toxicological endpoints or Uncertainty Factors (UFs) or significant changes to the Estimated Drinking Water Concentrations (EDWCs). The assessment, i f conducted, will use the newest version of DEEM and reflect updated consumption information.

Residential Exposure

Currently, there are no residential uses of carboxin and/or oxycarboxin (limited to enclosed commercial greenhouses).

HED notes that there are no direct homeowner applications of oxycarboxin to ornamentals; however, there is a registered commercial ornamental use and the treated ornamentals could be subsequently purchased at a retail location for use in a residential sett ing. HED considers post

application exposure resulting from this scenario to be negligible for the following reasons:

(1) Considering the time from application in a commercial setting to consumer purchase at a retail location, residues are expected to decline significantly. (2) Typical activities associated with residential ornamentals (e.g., picking fruit, thinning shrubs/bushes) are anticipated to occur at some additional time after purchase and transplant, increasing the time for residues to decline. (3) In many cases, transplanted trees (especially deciduous trees) may have little to no foliage available for contact at the time of purchase and transplanting, thus decreasing the potential for dermal exposure.

Therefore, residential dermal post

- application scena rios were not assessed for the use of oxycarboxin on commercial ornamentals.

### Carboxin & Oxycarboxin Scoping Document D423825

Page 8 of 27 Residential bystander exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of oxycarboxin. The potential for s pray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedur es for Residential Risk Assessment (SOPs)

– Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non

- occupational exposure to
drift. In terms of volati lization, the agency has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

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

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

Conclusion : There are no resident ial uses currently registered for carboxin/oxycarboxin; therefore, a quantitative residential exposure risk assessment is not necessary during registration
review. The need for spray drift and volatilization risk assessment for oxycarboxin will be
examined during registration review

.

Aggregate Risk Assessment

In accordance with the Food Quality Protection Act (FQPA), HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. The aggregate risk assessment evaluates the combined risk from dietary exposure (food and water) and any non

- occupational (residential) uses. Since there are no residential uses of carboxin or oxycarboxin and since residues of oxycarboxin are not expected to occur in food and drinking water, only a dietary exposure (food and water) and risk assessment for carboxin is required under Registration Review.

Occupational Exposure

Carboxin

Carboxin is registered for use in/on various commodities including barley, beans, canola, corn, cotton, oats, onions, peanuts, rice, rye, safflower, sorghum, soybeans, triticale, and wheat. It is intended to be applied to seed prior to planting for control of vario us fungi that cause seed and seedling diseases (smut, rot, and blight). It is available in a variety of formulations including wettable powder, dust, flowable concentrate, and ready

- to

- use liquid. It can be applied both by
commercial seed treaters and on

- f arm applicators. Application rates range from 0.05

– 1.5 lb
ai/100 lb seeds.

Carboxin occupational exposure may occur during commercial or on farm seed treatment (i.e., loader/applicator, sewer, bagger, and multiple activities) and during planting of trea ted seed via dermal and inhalation routes. Exposure duration is considered to be of short

- (1

- 30 days) and
intermediate

- (1

- 6 months) term. Registered labels require workers to wear baseline Personal Protective Equipment (PPE) (i.e., long pants, long

- sleev ed shirt, and shoes with socks) and chemical resistant gloves.

### Carboxin & Oxycarboxin Scoping Document D423825

Page 9 of 27 All occupational registered uses have been previously assessed for the 2004 Reregistration Eligibility Decision (RED) and no risk estimates of concern were identified for commercial/on

farm see d treatment scenarios or for treated seed planting. Occupational exposure and risk estimates were conducted using maximum application rates and high

- end assumptions for amount of seed treated and planted. A target margin of exposure (MOE) of 100 was consid ered adequate for occupational exposure via dermal and inhalation routes. Exposure data used for the carboxin assessment were taken primarily from HED’s standard operating procedures (SOPs) for Seed Treatment (SOP Number 14; 2003) and for Amount of Seed Tr eated or Planted per Day (SOP Number 15; 2004) which describe rationale and scenarios for worker exposure from seed treatment and planting treated seed. For registration review this assessment will need to be revised based on updated data regarding the am ount of seed treated (AST) per day in a commercial facility, which is used in conjunction with seed treatment application rates and seed
treatment scenario

- specific “unit exposures” from SOP 14 to calculate exposure. (SOP 15.1:
Amount of Commercial Seed Tr eatment; March 2013).

Oxycarboxin

Oxycarboxin is available solely as a wettable powder formulation (Plantvax 75W, EPA Reg. No.
400

- 144). It is used as a fungicide for ornamentals grown in enclosed commercial structures such as greenhouses, shadehouses , and interiorscapes. It is intended to be applied by commercial applicators only. The last and only occupational exposure and risk assessment done for oxycarboxin was in 2004 (D295501). Occupational exposure estimates were based on a mixer/loader/applicat or scenario with a high pressure handwand at a maximum application rate of 0.011 lb ai/gal for short and intermediate term durations. A target margin of exposure (MOE) of 100 was considered adequate via the dermal and inhalation routes. With the use of lab el

required PPE (i.e., long pants, long

- sleeved shirt, shoes with socks, and gloves) MOEs for both dermal and inhalation occupational exposure to oxycarboxin were above the target MOE of 100 and, therefore, not of concern.

Occupational post

- application dermal exposure may occur after use of oxycarboxin on ornamentals. Based on the previous assessment, exposure risk estimates from post

- application activities were identified as not of concern since post

- application exposure was considered to be significan tly lower than the exposure assessed for workers handling the pesticide (1000 gal/day), calculated to be not of concern. However, exposure assessment policies have been updated as of 2012 and a screening

- level analysis based on these updates indicates that Dislodgeable Foliar Residue (DFR) data are not required, as MOEs for post

- application activities related to ornamentals are greater than 2X the level of concern (LOC) (MOEs at 0 day after treatment = 3100; LOC=100).

In accordance with 40CFR158, dislodgea ble 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. In the absence of chemical

- specific DFR data, EPA uses a default value of 25%. Since the highest estimated occupational post

- application exposure using default DFR values for oxycarboxin is minimal in comparison to the level of concern (i.e., the calculated MOE is greater than 2 times higher than the level of concern, MOE = 3100 compared

### Carboxin & Oxycarboxin Scoping Document D423825

Page 10 of 27 to the LOC of 100), EPA is waiving the 40CFR DFR data requirement. In this instance, it is unlikely that chemical

- specific DFR data would be needed to further refine exposure assessments or would add appreciably to our overall understanding of the availability of dislodgeable foliar pesticide residues for oxycarboxin.

Recommended transfer coefficients for occupational post

- application assessments are derived from ARTF exposure monitoring studies (http://www.epa.gov/pesticides/science/post

- app

exposure

- data.html). These transfer coefficients were updated in 2012 based on a reanalysis and submission of new monitoring data.

The Worker Protection Standard (WPS) Restricted Entry Interval (REI) required on the label for oxycarboxin is 12 hours. This is considered adequately protective as dermal MOEs are not of concern on the day of application, and acute toxicity is low (Toxicity Categories III and IV).

Conclusi on: The occupational exposure database is adequate to support the registration review process for carboxin and oxycarboxin. Previous occupational handler and post

- application exposure assessments did not identify risks of concern. Registration review will include updated handler and post

- application risk estimates based on current policies and if endpoints or UFs are

re

- evaluated.

Public Health and Pesticide Epidemiology Data

For this evaluation, both the OPP Incident Data System (IDS) from 2009

- 2014 and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk (SENSOR)

- Pesticides
databases from 1998

- 2010 were consulted for pesticide incident da ta on carboxin and oxycarboxin (D424015). The purpose of the database search is to identify potential patterns in the frequency and severity of the health effects attributed to carboxin and oxycarboxin exposure. Carboxin is not included in the Agricultural Health Survey (AHS), and, therefore, this study does not provide information for this report.

Six incidents of minor severity and 5 cases (severity not reported) were identified in the IDS and
the SENSOR

- Pesticides databases, respectively, for carboxin. No incidents involving oxycarboxin were reported in either of these databases. Based on the low frequency and low severity of incident cases reported for carboxin and/or oxycarboxin in both IDS and SENSOR

Pesticides, there does not appear to be a concern a t 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.

Tolerance Assessment and International Harmoniza tion

U.S. permanent tolerances for residues of carboxin and its metabolites determined as aniline and expressed as parent are established under 40 CFR §180.301 in/on a number of crop and livestock commodities. The tolerance expression will need to be upd ated to reflect the HED Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner). Additional tolerances may need to be established using available data, including a tolerance in/on cotton gin byproducts (D425015)

### Carboxin & Oxycarboxin Scoping Document D423825

Page 11 of 27 and tolerances to cover seed treatme nt uses of carboxin on mustard seed, peas (dry and succulent), rye and cereal grains, which are considered food/feed uses based on data that demonstrate uptake of detectable residues in crops. No maximum residue limits (MRLs) for
residues of carboxin have been established by Codex or Mexico. A Canadian MRL for residues
of carboxin in/on canola seed is established and is harmonized with the U.S. tolerance definition and level for this commodity. See Attachment 4.

Cumulative

Unlike other pesticides for whi ch 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 carboxin/oxycarboxin and any 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 OPP concerning common mechanism determinations and procedures for cumulating effects from
substances found t o have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

Human Studies

Past 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. These data, which include studies from the Pesticide Handlers Exposure Databa se Version 1.1 (PHED 1.1); the Agricultural Re

- entry Task Force (ARTF) database; and other registrant

- submitted exposure monitoring studies, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable et hics requirements. For certain studies that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.

Data Deficiencies and Risk Assessment Updates for Registration Review

 Toxicology: Subchronic inhalation toxicity study (Guideline No. 870.3465)

. However, if the registrant agrees to additional mitigation (such as a PF5 respirator) on registered
labels for carboxin corn seed tr eatment involving multiple activities and for oxycarboxin mixing/loading/applying with a mechanic ally pressurized handgun , the inhalation study will not be needed and the agency will waive the need for the inhalation study, pending
finalization of the modi fied label.

 Additional tolerances may need to be established using available data, including a tolerance in/on cotton gin byproducts (D425015) and tolerances to cover seed treatment uses of carboxin on mustard seed, peas (dry and succulent), rye and cerea l grains. The tolerance expression will need to be updated to reflect the HED Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner).

 A new dietary exposure and risk assessment may need to be conducted if there are changes to the carboxin toxicolo gical points of departure (PODs) or Uncertainty Factors

### Carboxin & Oxycarboxin Scoping Document D423825

Page 12 of 27 (UFs) or significant changes to the Estimated Drinking Water Concentrations (EDWCs). The assessment, if conducted, will use the newest version of DEEM and reflect updated consumption information. If additional tolerances are established to cover seed treatment uses of carboxin on mustard seed, peas (dry and succulent), rye and/or cereal grains, a new dietary exposure and risk assessment will be needed.

 Updated occupational/residential exposure and ris k assessments may be conducted if there are any significant changes to carboxin PODs, Food Quality Protection Act safety factor or other uncertainty factors, standard operating procedures, or exposure data or assumptions. The need for spray drift and vola tilization risk assessment for oxycarboxin will be examined during registration review

.

### Carboxin & Oxycarboxin Scoping Document D423825

Page 13 of 27 References

Table 1. Memoranda Relevant to Registration Review.

Author Barcode Date Title

Cropp

Kohlligian, B. D425015 2/5/2015 

### Carboxin. Cotton Gin Byproducts. Summary of Analytical Chemistry and Residue Data.

Daiss, R D289855 8/7/2003 Carboxin Chronic Dietary Exposure Assessment
for the Reregistration Eligibility
Decision Document

Daiss, R. D288406 12/17/2003 Carboxin HED Risk Assessment for Reregistration Eligibility Document (RED)

Daiss, R. D295501 11/19/04 Oxycarboxin Occupational Exposure and Risk

Assessment

Dotson, D. D279382

TXR No.
0050292 12/19/01 Carboxin in/on Canola and Dry Bulb Onions.
Conclusions of the 11/27/2001 Meeting of the
Metabolism Assessment Review Committee.

Jones, R.D. D280763 2/1/2002 Tier I Estimated Drinking Water Concentrations
for Carboxin in Support of the Registration of New

Uses on Canola and Onions.

Ramasamy, S. TXR No.

0051928 6/5/2003 Carboxin

– Report of the Hazard Identification

Assessment Review Committee

Recore, S. D424015 11/20/2014 Carboxin and Oxycarboxin: Tier I Review of

Human Incidents

US EPA 9/2004 Reregistration Eligibility Decision for Carboxin.
Office of Prevention, Pesticides and Toxic
Substances. EPA 738

- R

- 04

- 015.

Leshin, J. TXR No.

0057070 1/8/2015 Carboxin : Summary of Hazard and Science Policy
Council (HASPOC) Meeting of October 9, 2014:
Recommendations on the requirement of a 28

- day
inhalation study, neurotoxicity (acute and subchronic), and immunotoxicity studies.



### Attachment s

Attachment 1. Chemical Identity of Carboxin, Oxycarboxin and Metabolites Attachment 2. Toxicity Profile Tables Attachment 3. Carboxin Endpoints and Doses for Risk Assessment
Attachment 4. Carboxin International Residue Limits Table

### Carboxin & Oxycarboxin Scoping Document D423825

Page 14 of 27 Attachment 1. Chemical Identity of Ca rboxin, Oxycarboxin and Metabolites

Chemical Identity and Physicochemical Properties Table

TABLE A1.1. Nomenclature

Compound

Carboxin (PC Code 090201) Chemical Structure

Common name Carboxin

IUPAC name 5,6

- dihydro

- 2

- methyl

- 1,4

- oxathiine

- 3

- carboxanilide

CAS name 5,6

- dihydro

- 2

- methyl

- N

- phenyl

- 1,4

- oxathiin

- 3

- carboxamide

CAS # 5234

- 68

- 4

Compound

Oxycarboxin (PC Code 090202)

Common name Oxycarboxin

IUPAC name 5,6

- dihydro

- 2

- methyl

- 1,4

- oxathiine

- 3

- carboxanilide 4,4

- dioxide

CAS name 5,6

- dihydro

- 2

- methyl

- N

- phenyl

- 1,4

- oxathiin

- 3

- carboxamide 4,4

- dioxide

CAS # 5259

- 88

- 1

Metabolite

Carboxin sulfoxide (PC Code None)

### Carboxin & Oxycarboxin Scoping Document D423825

Page 15 of 27 Common Name Carboxin sulfoxide

IUPAC name 5,6

- dihydro

- 2

- methyl

- 1,4

- oxathiine

- 3

- carboxanilide 4

- oxide

CAS name 5,6

- dihydro

- 2

- methyl

- N

- phenyl

- 1,4

- oxathiin

- 3

- carboxamide 4

- oxide

CAS # 17757

- 70

- 9

TABLE A1.2. Physicochemical Properties of the Technical Grade of Carboxin

Parameter Value Reference

Melting point/range Two ranges given. 91.5

- 92.5 and

98.1

- 100 C Carboxin Registration

Standard

pH 5.89; approximately 1 % solution at

20 C MRID 42493706

Density 1.7 grams/mL Carboxin Registration

Standard

Water solubility (25 C) 0.017 gr/100 gr water Carboxin Registration

Standard

Solvent solubility (mg/L at 25 C) 60 in acetone; 21 in methanol; 11 in

ethanol Carboxin Registration

Standard

Vapor pressure at 25 C 1.9 X 10

- 7 mm Hg MRID 42493703

Dissociation constant ( pK a ) pK
a < 0.5; very weak base MRID 42493704

Octanol/water partition coefficient Log(K OW ) K
ow = 148.4 MRID 42493705

### Carboxin & Oxycarboxin Scoping Document D423825

Page 16 of 27 TABLE A1.2. Physicochemical Properties of the Technical Grade of Carboxin

Parameter Value Reference

UV/visible absorption spectrum Not available

TABLE A1.3. Physicochemical Properties of Technical Grade of Oxycarboxin.

Parameter Value Reference

Melting point/range 127.5

- 129 D348580

pH 4.25 ± 2.8; 1% solution

Density 1.4145 g/cc, % COV = 0.24

Water solubility (25 C) 0.0014 g/mL D355356

Solvent solubility (25 C) 0.0837 g/mL in acetone; 8.85 μg/mL in

hexane

Vapor pressure at 25 C <4.2 X 10

- 8 mm Hg D363246

Dissociation constant (pK
a ) The dissociation constant (pKa) of purified oxycarboxin could not be determined by OECD Test Method #112, as no changes in the spectra were observed that could be attributed to the dissociation of oxycarboxin. Calculated pKa values based on the structure of oxycarboxin indicated there will be no D348580

### Carboxin & Oxycarboxin Scoping Document D423825

Page 17 of 27 ionization at environmentally significant pH’s.

Octanol/water partition coefficient Log(K OW ) pH Log P OW

6.8 1.2

9.1 1.2

4.0 1.2

UV/visible absorption spectrum Neutral and Acidic solution

17,293 L/mol*cm at 206 nm

13,811 L/mol*cm at 254 nm

Basic solution

25,390 L/mol*cm at 206 nm

16,502 L/mol*cm at 254 nm

### Carboxin & Oxycarboxin Scoping Document D423825

Page 18 of 27 Attachment 2. Toxicity Profile Tables

Table A2.1. Acute Toxicity profile of carboxin

GDLN Study Type MRID Results Tox Category

870.1100 Acute Oral

Rats 4317140 (1992) M: LD50 = 2588 mg/kg

F: LD50 = 3080 mg/kg III

870.1200 Acute Dermal

Rabbits 43171402 (1992) M: LD50 > 4000 mg/kg

F: LD50 > 4000 mg/kg III

870.1300 Acute Inhalation

Rats 43171403 (1993) M: LC50 > 4.7 mg/L

F: LC50 > 4.7 mg/L IV

870.2400 Primary Eye Irritation

Rabbits 43171404 (1992) Slightly Irritating III

870.2500 Primary Skin Irritation

Rabbits 43171405 (1992) Not Irritating IV

870.2600 Dermal Sensitization

Guinea Pigs
Vitavax

- 25DB (25% carboxin) 00105980 (1982) Negative for dermal sensitization N/A

Table A2.2. Acute Toxicity profile of Oxycarboxin

GDLN Study Type MRID Results Tox Category

870.1100 Acute Oral

Rats 43980701 (1996) M: LD50 = 5816 mg/kg

F: LD50 = 1632 mg/kg III

ont870.12
00 Acute Dermal

Rabbits 43980702 (1996) M: LD50 > 5000 mg/kg

F: LD50 > 5000 mg/kg IV

T
870.1300 Acute Inhalation

Rats 42712601 (1993) M: LC50 >

F: LC50 >

870.1300 Acute Inhalation

Rats
Plantvax 75W 43981203 (1995) M: LC50 > 2 mg/L

F: LC50 > 2 mg/L IV

870.2400 Primary Eye Irritation

Rabbits 43980703 (1996) Slightly Irritating III

870.2500 Primary Skin Irritation

Rabbits 43980704 (1996) Not Irritating IV

870.2600 Dermal Sensitization

Guinea Pigs 43980705 (1996) Negative for dermal sensitization N/A

### Carboxin & Oxycarboxin Scoping Document D423825

Page 19 of 27 Table A2.3. Carboxin Subchronic, Chronic and Other Toxicity Profile

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

870.3100a
90

- Day oral toxicity in rats 45695501 (2002) Acceptable/guideline M: 0, 5.5, 10.5, 16 mg/kg/day F: 0, 6, 12, 37 mg/kg/day
42391106 (1987) Acceptable/non

- guideline (range

- finding) 0, 200, 800, 2000 ppm M & F: 0, 10, 40, 100 mg/kg/day NOAEL = Males 5.5 mg/kg/day Females 12.1
LOAEL = 10.5 mg/kg/day based histopathological changes in the kidneys

NOAEL = Males: not identified; Females: 10 mg/kg/day
LOAEL = Males: 10 mg/kg/day based on chronic nephritis, increased urea nitrogen, increased creatinine; Females: 40 mg/kg/day based on chronic nephritis

870.3150
90

- Day oral toxicity in dogs 45695502 (2002) Acceptable/Guideline M:0, 5.3, 7.9, 34.4 mg/kg/day F: 0, 5.9, 9.0, 17.7 mg/kg/day Females: NOAEL= 9 mg/kg/day (F); 34.4 mg/kg/day (HDT) (M) LOAEL=17.7 mg/kg/day based on increased uterine/cervix and ovarian weights (F); No LOAEL observed for males

870.3200
21/28

- Day dermal toxicity in

rats 45695503 (2002) Acceptable/guideline M & F: 0, 30, 400, 1000 mg/kg/day NOAEL = Males: 400 mg/kg/day; Females: 1000 mg/kg/day
LOAEL = Males: 1000 mg/kg/day based on tubular degeneration and tubular mineralization

.

870.3465
90

- Day inhalation toxicity in

rats Requirement for a subchronic inhalation toxicity study was waived by HASPOC (TXR No. 0057070).

870.3700a Prenatal developmental in

rats 45261401 (1989) Acceptable/guideline F: 0, 10, 90, 175 mg/kg/day Maternal NOAEL = 10 mg/kg/day
LOAEL = 90 mg/kg/day based on decreased body weights (↓5

- 8% on GD 16, P<0.05) and body weight gain during GDs 6

- 16 (  25

- 45%, p=not statistically significant), decreased food consumption during GDs 6

- 16 (  7%, P<0.05), and incr eased hair loss (↑16%). Developmental NOAEL = 175 mg/kg/day
LOAEL = not identified

870.3700b Prenatal developmental in
rabbits 00086054, 42391104, 42391105 (1981) Acceptable/guideline F: 0, 75, 375, 750 mg/kg/day Materna l NOAEL = 75 mg/kg/day
LOAEL = 375 mg/kg/day based on increased abortions. Developmenta l NOAEL = 75 mg/kg/day
LOAEL = 375 mg/kg/day based on increased abortions.

870.3800 Reproduction and fertility
effects in rats 41922601, 42391107 (1991) Acceptable/guideline M: 0, 20, 200, 400 ppm P 0 M: 0, 1, 10, 20 mg/kg/day F: 0, 20, 300, 600 ppm

P 0 F: 0, 1, 15, 30 mg/kg/day Parental NOAEL = Males and Females: 1 mg/kg/day
LOAEL = Males: 10 mg/kg/day based on decreased body weight gains in F 1 parents, gross and histopathological changes in kidneys; Females: 15 mg/kg/day based on equivocal histopathological changes in kidneys. Reproductive NOAEL = Males: 10 mg/kg/day; Females: 15 mg/kg/day
LOAEL = Males: 20 mg/kg/day; Females: 30 mg/kg/day based on decreased fertility indices for F 1b parents due to decreased number of pregnancies for F 2b generation.

### Carboxin & Oxycarboxin Scoping Document D423825

Page 20 of 27 Table A2.3. Carboxin Subchronic, Chronic and Other Toxicity Profile

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

Offspring NOAEL = Males: 10 mg/kg/day; Females: 15 mg/kg/day
LOAEL = Males: 20 mg/kg/day; Females: 30 mg/kg/day based on decreased body weights for F 2b male pups.

870.4100a
Chronic to xicity in rats NA; see 870.4300 NA

870.4100b Chronic toxicity in dogs 41882901, 42391103 (1991) Acceptable/guideline 0, 40, 500, 3000/5000/7500

ppm M: 0, 1.1, 16, 158 mg/kg/day F: 0, 1.3, 15, 170 mg/kg/day NOAEL = Males: 16 mg/kg/day; Females: 1.3 mg/kg/day
LOAEL = Males: 158 mg/kg/day based on decreased RBC, hematocrit and hemoglobin, increased MCH and MCV, increased alkaline phosphatase and cholesterol, increased liver weights; Females: 15 mg/kg/day based on de creased body weight gains.

870.4200a Oncogenicity in rats NA; see 870.4300 NA

870.4200b Oncogenicity in mice 00114139, 42533301, 42533302 (1982) Acceptable/guideline 0, 50, 2500, 5000 ppm M: 0, 8, 385, 752 mg/kg/day F: 0, 9, 451, 912 mg/kg/day NOAEL = Males: 752 mg/kg/day; Females: 9 mg/kg/day
LOAEL = Males: not identified; Females: 451 mg/kg/day based on increased mortality.

Dose

- related increases in the incidence of liver centrilobular hypertrophy were observed in the mid

- and high

- dose males and high

- dose females; however, this was considered to be an adaptive, rather, than an adverse response. Negative for carcinogenicity.

870.4300
Combined Chronic/ Oncogenicity in rats 41882902, 42391101, 42391102, 42391106 (1991) Acceptable/guideline

M: 0, 20, 200, 400 ppm M: 0, 0.8, 9, 17 mg/kg/day F: 0, 20, 300, 600 mg/kg/day F: 0, 1.0, 16, 34 mg/kg/day NOAEL = Males: 0.8 mg/kg/day; Females: 1.0 mg/kg/day
LOAEL = Males: 9 mg/kg/day based on decreased body weight and body weight gain, increased urea nit rogen and creatinine, increased water consumption and urine volume, decreased urine specific gravity, histopathological changes in kidneys; Females: 16 mg/kg/day based on histopathological changes in kidneys. Negative for carcinogenicity.

870.5100

Bacter ial reverse mutation assay (Ames test) 00132453 (1982) Acceptable/guideline seven concentrations ranging from 1 to 5000 μg /plate Negative with or without S

- 9 activation at 5000 μg /plate and
less.

870.5300

In vitro mammalian gene mutation assay NA NA

870.5375

In vitro mammalian
chromosome aberration (CHO cells) 45541102 (1982) Acceptable/guideline 17 to 1670 μg /mL (±S

- 9) Negative without S

- 9 activation.

Positive with S

- 9 activation. Highly significant increases in
chromosomal aberrations at several toxic dose levels ranging from 400 to 1400 μg/mL.

### Carboxin & Oxycarboxin Scoping Document D423825

Page 21 of 27 Table A2.3. Carboxin Subchronic, Chronic and Other Toxicity Profile

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

870.5385

In vivo mammalian chromosome aberration (rat bone marrow) 00132455 (1983) Unacceptable/guideline M&F: 200, 660, 2000 mg/kg (single oral dose) Negative at all dose levels up to 48

- hours post

- dosing.

Study is unacceptable due to lack of clinical toxicity, lack of a multiple dosing schedule, and/or lack of evidence of transport to target tissue.

870.5385

In vivo mammalian chromosome aberration (rat bone marrow) 00152339 (1985) Acceptable/guideline M&F: 750, 2000, 4000 mg/kg/day (single oral dose) M&F: 100, 400, 800 mg/kg/day (5

- day, oral) Negative at all dose levels tested.

870.5385

In vivo mammalian chromosome aberration (rat bone marrow) 45541101 (1988)
Published article

M : 95.5, 191, 382 mg/kg (two intraperitoneal doses at 24

- hour interval) Positive. Dose

- related statistically significant increased percent

of aberrant cells at  191 mg/kg/day.

870.5395 Mammalian (mouse) erythrocyte micronucleus test NA NA

870.5450 Dominant lethal assay in rats NA;

-----

870.5550 UDS in primary rat hepatocytes 00132454 (1982) Acceptable/guideline 0.513 to 256 μg/mL Positive. Dose

- dependent positive responses were observed at treatment levels from 5.13 to 103 μg/mL in the absence of moderate to severe toxicity.

870.6200a Acute neurotoxicity screening battery in rats NA Requirement for an acute neurotoxicity study was waived by HASPOC (TXR No. 0057070).

870.6200b Subchronic neurotoxicity screening battery in rats NA Requirement for a subchronic neurotoxicity study was waived by HASPOC (TXR No. 0057070).

870.6300 Developmental neurotoxicity NA NA

870.7485
Metabolism and pharmacokinetics in rats 42656501, 42656502 (1992

- 1993) Acceptable/guideline M & F: 5 mg/kg ( single low dose and 15 repeated doses), 150 mg/kg (single high dose) Following oral treatment of rats with [phenyl

- UL

- C 14 ] carboxin

, approximately 78.3

- 81.1% and 77.0

- 81.5% of the low and high doses, respectively, were recovered. Urine was the major route of excretion. The major urinary metabolites were 4

- acetamidophenol and its glucuronide, acetanilide, and hydroxylated carboxin su lfoxide.

### Carboxin & Oxycarboxin Scoping Document D423825

Page 22 of 27 Table A2.3. Carboxin Subchronic, Chronic and Other Toxicity Profile

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

870.7600 Dermal penetration 45926001 (2003) Acceptable/Guideline 0, 0.5 μg/cm 2 , 5 μg/cm 2 , or 50 μg/cm 2 A dermal absorption factor of 72%, from the combined radioactivity absorbed and that remaining in/on the skin at the
10

- hour exposure duratio n for the low dose, would be
considered a conservative estimate for use in risk assessment (no information to determine whether/extent to which material remaining in/on skin continues to be absorbed post wash).

870.7800 Immunotoxicity HASPOC granted the waiver for an Immunotoxicity study (TXR No. 0057070)

Table A2.4 . Oxycarboxin Subchronic, Chronic and Other Toxicity Profile

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

870.3700a Prenatal developmental in

rats 00105991 (1982) Acceptable/guideline F: 0, 25, 100, 200 mg/kg/day Maternal NOAEL = 100 mg/kg/day LOAEL = 200 mg/kg/day based on slight decrease in the mean body weight and a slight increase in toxic symptoms. Developmental NOAEL = 25 mg/kg/day
LOAEL = 100 mg/kg/day based on the incidence of litters with mean fetal weight of 3.0 g or less and the incidence of fetuses and litters with reduced skull ossification and misaligned
sternebrae.
Note: This DER needs to be revised.

870.3700b Prenatal developmental in
rabbits 43069401 (1993) Acceptable/guideline F: 0, 15, 150, 750 mg/kg/day oxycarboxin Materna l NOAEL = 150 mg/kg/day LOAEL = 750 mg/kg/day based on significant depressions in mean body weight and body weight gains during gestation as
well as significant depressions in food consumption. Developmenta l NOAEL = 150 mg/kg/day LOAEL = 750 mg/kg/day based on significant depressions in fetal weights and elevations in the incidence of several developmental alterations including forked scapulae, absent azygous lobe of the lung and gallbladder hypoplasia.

870.5100
Bacterial reverse mutation assay (Ames test) 43527602 (1995) Acceptable/guideline Oxycarboxin was negative with or without S

- 9 activation at 5000 μg/plate and less.

870.5300

In vitro mammalian gene mutation assay 43527601 (1995) Acceptable/guideline Oxycarboxin (up to 400 ug/ml) was positive in an in vitro mammalian forward gene mutation assay with L5178Y TK+/

- mouse lymphoma cells with S

- 9 metabolic activation, suggesting clastoge nic activity. It was negative in the absence
of S

- 9 metabolic activation.

870.5395 Mammalian (mouse) erythrocyte micronucleus test 43527603 (1995) Acceptable/guideline ♂157, 313, 625 mg/kg (ip) Death, prostration, lethargy in high dose males, lethargy in mid dose males and females, and high dose females. No death in high dose females. Oxycarboxin up to toxic doses of 625 mg/kg

### Carboxin & Oxycarboxin Scoping Document D423825

Page 23 of 27 Table A2.4 . Oxycarboxin Subchronic, Chronic and Other Toxicity Profile

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

♀ 110, 220, 440 mg/kg (ip) (males) or 440 mg/kg (females) was negative in a mouse
micronucleus as say. 870.5550 Unscheduled DNA Synthesis
in mammalian cells in vitro

. Primary cultures of rat hepatocytes 44453301 (1997) Acceptable/guideline Tested up to 400 μg/ml Oxycarboxin (Plantvax technical) did not induce a significant
increase in the mean number of net nuclear grain counts in isolated rat hepatocytes. The test material was considered negative in this study.

### Carboxin & Oxycarboxin Scoping Document D423825

Page 24 of 27 Attachment 3. Carboxin/Oxycarboxin Endpoints and Doses for Risk Assessment

The points of departure, uncertainty factors, and toxicity endpoints are presented in the following

tables.

Table A3.1. Toxicity Endpoints of Carboxin/Oxycarboxin

Exposure

Scenario Dose Used in Risk

Assessment, UF Special FQPA SF and

Level of Concern for

Risk Assessment Study and Toxicological Effects

Acute Dietary

(All Population Subgroups) No toxicological endpoint attributable to a single oral dose was identified in the available toxicology

studies on carboxin that would be applicable to f emales (13

- 50 years) or to the general population (including infants and children).

Chronic Dietary

(All populations) NOAEL= 0.8 mg/kg/day

UF = 100

Chronic RfD =

0.008 mg/kg/day FQPA SF = 1X

cPAD =

chronic RfD

FQPA SF

= 0.008 mg/kg/day Chronic feeding/ carcinogenicity, rats

LOAEL = 9 mg/kg/day based on decreased body weight and body weight gain; kidney damage (including secondary effects)

Short

- Term

Incidental Oral

(1

- 30 days) NOAEL= 10 mg/kg/day Residential MOE =

100

Occupational = NA Developmental toxicity, rats (MRID 45261401)

LOAEL = 90 mg/kg/day based on decreased body weights (↓5

- 8% on GD 16, p<0.05) and body weight gain during GDs 6

- 16 (  25

- 45%, not statistically significant), decreased food consumption during GDs 6

- 16 (  7%, p<0.0 5), and increased hair loss (↑16%).

Intermediate

Term

Incidental Oral

(1

- 6 months) NOAEL= 5.5 mg/kg/day Residential MOE =

100

Occupational = NA Sub chronic oral toxicity, rats

LOAEL = 10.5 mg/kg/day based on increased incidence and degree of chronic nephropathy

Short

- Term

Dermal

(1 to 30 days) Dermal study NOAEL=

400 mg/kg/day

(dermal absorption rate = not required ) Residential MOE =

100

Occupational MOE =

100 28 day dermal toxicity, rats

LOAEL = 1000 mg/kg/day based on tubular degeneration and tubular mineralization in male kidneys

Dermal study NOAEL= 28 day dermal toxicity, rats

### Carboxin & Oxycarboxin Scoping Document D423825

Page 25 of 27 Table A3.1. Toxicity Endpoints of Carboxin/Oxycarboxin

Exposure

Scenario Dose Used in Risk

Assessment, UF Special FQPA SF and

Level of Concern for

Risk Assessment Study and Toxicological Effects

Intermediate

Term

Dermal (1 to 6 months) 400 mg/kg/day

(dermal absorption rate = not required) Residential MOE =

100

Occupational MOE =

100 LOAEL = 1000 mg/kg/day based on tubular degeneration and tubular mineralization in male kidneys

Short

- Term Inhalation (1 to 30 days) Oral study NOAEL= 10

mg/kg/day

(inhalation absorption

rate = 100 %) Residenti al MOE =

1000

Occupational MOE =

1000 Developmental toxicity, rats (MRID 45261401)

LOAEL = 90 mg/kg/day based on decreased body weights (↓5

- 8% on GD 16, p<0.05) and body weight gain during GDs 6

- 16 (  25

- 45%, not statistically significant), decreased food consumption during GDs 6

- 16 (  7%, p<0.05), and increased hair loss (↑16%).

Intermediate

Term Inhalation (1 to 6 months) Oral study NOAEL=

5.5 mg/kg/day

(inhalation absorption

rate = 100 % Residential MOE =

1000

Occupational MOE =

100 0 Sub chronic oral toxicity, rats

LOAEL = 10.5 mg/kg/day based on increased incidence and degree of chronic nephropathy

Cancer (oral, dermal, inhalation) Classified as “Not Likely to be Carcinogenic to Humans”

Long term exposure duration scenarios were not assessed based on use patterns. There are no residential uses/ exposures of carboxin or oxycarboxin so residential exposures are not assessed.

### Carboxin & Oxycarboxin Scoping Document D423825

Page 26 of 27 Attachment 4. Carboxin Int ernational Residue Limits Table

Carboxin (090201; 9/15/14)

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

40 CFR 180.301:

Plant: Combined residues of carboxin (5,6

- dihydro

- 2

- methyl

- 1,4

- oxathiin

- 3

- carboxanilide)
and its metabolites determined as aniline and expressed as parent compound.

Livestock: Combined residues of carboxin (5,6

- dihydro

- 2

- methyl

- 1,4

- oxathiin

- 3

- carboxanilide) and its metabolites determined

as aniline and expressed as parent compound. 1,4

- oxathiin

- 3

- carboxamide, 5,6

- dihydro

- 2

- methyl

- N

phenyl

- , including
metabolites determined as benzenamine and expressed as parent compound None

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

US Canada Mexico 1 Codex Barley, grain 0.2 Barley, straw 0.2 Bean, dry, seed 0.2 Bean, succulent 0.2 Canola, seed 0.03 0.03 Cattle, fat 0.05 Cattle, meat byproducts 0.1 Cattle, meat 0.05 Corn, field, forage 0.2 Corn, field, grain 0.2 Corn, field, stover 0.2 Corn, pop, grain 0.2 Corn, pop, stover 0.2 Corn, sweet, forage 0.2 Corn, sweet, kernel plus cob with
husks removed 0.2

Corn, sweet, stover 0.2 Cotton, undelinted seed 0.2 Egg 0.05 Goat, fat 0.05 Goat, meat byproducts 0.1 Goat, meat 0.05 Hog, fat 0.05 Hog, meat byproducts 0.1 Hog, meat 0.05 Horse, fat 0.05 Horse, meat byproducts 0.1 Horse, meat 0.05

Milk 0.05 Oat, forage 0.5 Oat, grain 0.2 Oat, straw 0.2 Onion, bulb 0.2

### Carboxin & Oxycarboxin Scoping Document D423825

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

Peanut 0.2 Peanut, hay 0.2 Poultry, fat 0.1 Poultry, meat byproducts 0.1 Poultry, meat 0.1 Rice, grain 0.2 Rice, straw 0.2 Safflower, seed 0.2 Sheep, fat 0.05 Sheep, meat byproducts 0.1 Sheep, meat 0.05 Soybean, seed 0.2 Wheat, forage 0.5 Wheat, grain 0.2 Wheat, straw 0.2 Completed: M. Negussie; 09/16/14

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