UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

DATE: February 24, 2015 

SUBJECT: Carboxin and Oxycarboxin: 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 

Abdallah 

Bonnie 

Kidwell, 

Cropp-Kohlligian

Khasawinah, 

Risk Assessor 

Ph.D., 

, Environmental 

Toxia,l~;~~-/? Clr.At..tJ..t'.A

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 

Health 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 Health Effects 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 toxicity, exposure, and usage 

databases. The 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 limited to 

assessment of occupational exposure and risk since oxycarboxin is not registered for use on 

food/feed crops. 

Carboxin [5,6-dihydro-2-methyl-1 ,4-oxathiine-3-carboxanilide] and oxycarboxin [5,6-dihydro-2-

methyl-1,4-oxathiine-3-carboxanilide 4,4-dioxide], a sulfone analogue ofcarboxin, are members 

of the oxathiin class of systemic fungicides. Carboxin is applied to seed prior to planting for 

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

treatment uses of 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 in enclosed commercial structures such as greenhouses, shadehouses, and 

interiorscapes. There are no residential uses for either carboxin or oxycarboxin. 

The toxicology, residue chemistry, and occupational exposure databases for carboxin and 

oxycarboxin are adequate for Registration Review. HED's Hazard and Science Policy Council 

(HASPOC) concluded that an immunotoxicity, and acute and subchronic neurotoxicity studies 

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

toxicity study is required at this time. In the absence of this study, a 1 OX database uncertainty 

factor will be applied only for assessing risk for future inhalation scenarios. However, with 

additional PPE (such as a PF5 respirator) on registered labels for carboxin com seed treatment 

involving multiple activities and for oxycarboxin mixing/loading/applying 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. 

The toxicology database for oxycarboxin is limited. However, based on the close structural 

similarity of carboxin and oxycarboxin, for risk assessment purposes, the toxicity potential of 

oxycarboxin is presumed to be equivalent to that of the toxicity potential of carboxin. 

Consequently, the Point of Departures (PODs) and toxicity endpoint of concern selected for 

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

As part of Registration Review, PODs, toxicological endpoints, and uncertainty/safety factors 

used in the most recent human health risk assessments may be re-evaluated according 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 endpoints, 

points of departure, uncertainty/safety factors, and/or exposure estimates/assumptions. The 

current tolerance expression for carboxin will need to be updated to reflect the HED Interim 

Guidance on Tolerance Expressions (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 kidney 

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 male 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 the 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 mutagenicity 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 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 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 oxycarboxin 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 selectively 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 carboxin. 

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. 

Carboxin 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. Oxycarboxin 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 properties 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. The 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 

mechanically 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 assessing 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/applying 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, based 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 toxicity 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 remain 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 the 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 enzymes, 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 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 male mice at the high-dose. 

In a developmental toxicity study in rats, no developmental 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 increased 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 weight 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 adults, 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 cultures (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 wheat 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 biologically 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 exposures (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 (HIARC) (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 based 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 Adjusted 

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/carcinogenicity 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 (UFDB) for the lack of a 

repeated exposure inhalation 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 inhalation) 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: The toxicology databases for carboxin and oxycarboxin are complete, with the 

exception of a subchronic inhalation toxicity study which is now required for carboxin. Reevaluation 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 uses 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 enforcement 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) determined 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 for 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 most 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 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 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 assessment 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 is 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, if 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 setting. HED considers postapplication 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 scenarios 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 spray 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 Procedures 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 volatilization, 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 residential 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 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. It can be applied both by 

commercial seed treaters and on-farm 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 treated 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-sleeved 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/onfarm seed 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 considered 

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 Treated 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 amount 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 Treatment; 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/applicator 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 labelrequired 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 

significantly 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, 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 postapplication 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-appexposure-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). 

Conclusion: 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 data 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 SENSORPesticides, 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.

Tolerance Assessment and International Harmonization

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 updated 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 treatment 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 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 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 to 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 Database 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 ethics 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 treatment involving multiple activities and for oxycarboxin 

mixing/loading/applying 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. 

 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 cereal 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 toxicological 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 risk 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 volatilization 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

CroppKohlligian, 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.

Attachments

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 Carboxin, 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 (pKa) pKa < 0.5; very weak base MRID 42493704

Octanol/water partition coefficient 

Log(KOW)

Kow = 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 (pKa) 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(KOW)

pH Log POW

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 increased 

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

Maternal NOAEL = 75 mg/kg/day

LOAEL = 375 mg/kg/day based on increased abortions.

Developmental 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

P0 M: 0, 1, 10, 20 mg/kg/day

F: 0, 20, 300, 600 ppm

P0 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 F1 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 F1b parents due to decreased 

number of pregnancies for F2b 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 F2b male pups.

870.4100a

Chronic toxicity 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 decreased 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 nitrogen 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

Bacterial 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 sulfoxide.
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/cm2, 5 μg/cm2, or 

50 μg/cm2

A dermal absorption factor of 72%, from the combined 

radioactivity absorbed and that remaining in/on the skin at the 

10-hour exposure duration 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

Maternal 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.

Developmental 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 clastogenic 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 assay.

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 females (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<0.05), 

and increased hair loss (↑16%).

IntermediateTerm 

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

IntermediateTerm

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 %)

Residential 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%).

IntermediateTerm 

Inhalation (1 to 

6 months)

Oral study NOAEL= 

5.5 mg/kg/day

(inhalation absorption 

rate = 100 %

Residential MOE = 

1000

Occupational MOE = 

1000

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 International Residue Limits Table 

Carboxin (090201; 9/15/14)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 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-Nphenyl-, including 

metabolites determined as 

benzenamine and expressed 

as parent compound

None

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

US Canada Mexico1 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 Mexico1 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.