UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 21 -MAR-2013 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Sedaxane. Human Health Risk Assessment to Support New Seed Treatment 

Uses on Corn [Field, Pop, and Sweet], Crop Subgroup 6C [Pea and Bean, Dried 

Shelled, Except Soybean, Subgroup 6C], Crop Subgroup 20A [Rapeseed 

Subgroup 20A ], and Sorghum. 

PC Code: 129223 

Decision No.: 469252 

Petition No.: 2F8071 

Risk Assessment Type: Single Chemical 

Aggregate 

TXRNo.: NA 

MRIDNo.: NA 

DP Barcode: 0405099 

Registration No.: 100-1381, 100-1374 

Regulatory Action: Section 3 Registration 

Case No.: NA 

CAS No.: 874967-67-6 

40 CFR: §180.665 

FROM: . ~ ~ {) William H. Donovan, Ph.D., Risk Assesso/, 1cy(]/) /.--- ' 

Seyed 

William 

Tadayon, 

Irwin, Ph.D., 

Chemist 

Toxic<>J?gi~ 

~ 

_ W~ 

Risk Assessment Branch V 

Health Effects Division (HED) (7509P) 

THROUGH: John Liccione, Ph.D., Senior Scientist, RAB~ MichaelS. Metzger, Chief, RAB V & VII 

HED (7509P) >/r-'"11\. L / 

TO: Heather Garvie, Risk Manager 

Fungicide Branch 

Registration Division (7505P) 

Syngenta has requested registration of the fungicide sedaxane for seed treatment use on a variety 

of crops. The Registration Division of the Office of Pesticide Programs (OPP) has requested that 

HED evaluate hazard and exposure data and conduct dietary, occupational, and aggregate 

exposure assessments, as needed, to estimate the risk to human health that will result from the 

established and proposed seed treatment uses of sedaxane. 

Page 1 of75 
Sedaxane (129223) Human Health Risk Assessment D405099 

HED has evaluated the toxicity and exposure databases for sedaxane, and has conducted a 

human health risk assessment in support of the proposed uses. A summary of the findings and an 

assessment of human health risk resulting from established and proposed uses of sedaxane are 

provided in this document. The HED team members contributing to this risk assessment include 

William Irwin (hazard assessment), Seyed Tadayon (occupationaVresidential assessments), and 

William Donovan (residue chemistry, dietary exposure, and risk assessment). 

Page 2 of75 
Sedaxane (129223) Human Health Risk Assessment D405099

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Table of Contents

1.0 Executive Summary............................................................................................................. 5

2.0 HED Recommendations....................................................................................................... 6

2.1 Data Deficiencies/Conditions of Registration.................................................................. 6

2.2 Tolerance Considerations................................................................................................. 6

2.2.1 Enforcement Analytical Method............................................................................... 6

2.2.2 International Harmonization ..................................................................................... 7

2.2.3 Recommended Tolerances........................................................................................ 7

2.2.4 Revisions to Petitioned-For Tolerances.................................................................... 8

2.3 Label Recommendations.................................................................................................. 9

2.3.1 Recommendations from Residue Reviews ............................................................... 9

2.3.2 Recommendations from Occupational Assessment.................................................. 9

3.0 Introduction.......................................................................................................................... 9

3.1 Chemical Identity ............................................................................................................. 9

3.2 Physical/Chemical Characteristics................................................................................. 10

3.3 Pesticide Use Pattern...................................................................................................... 10

3.4 Anticipated Exposure Pathways..................................................................................... 10

3.5 Consideration of Environmental Justice ........................................................................ 11

4.0 Hazard Characterization and Dose-Response Assessment................................................ 11

4.1 Toxicology Studies Available for Analysis ................................................................... 11

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)................................... 12

4.2.1 Dermal Absorption ..................................................................................................... 13

4.3 Toxicological Effects ..................................................................................................... 13

4.4 Safety factor for Infants and Children (FQPA Safety Factor) ....................................... 14

4.4.1 Completeness of the Toxicology Database ................................................................ 15

4.4.2 Evidence of Neurotoxicity.......................................................................................... 15

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal............. 15

4.4.4 Residual Uncertainty in the Exposure Database......................................................... 16

4.5 Toxicity Endpoint and Point of Departure Selections.................................................... 16

4.5.1 Dose-Response Assessment ....................................................................................... 16

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ........... 17

4.5.3 Cancer Classification and Risk Assessment Recommendation.................................. 17

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment................................................................................................................................ 17

5.0 Dietary Exposure and Risk Assessment ............................................................................ 20

5.1 Metabolite/Degradate Residue Profile ........................................................................... 20

5.1.1 Summary of Plant and Livestock Metabolism Studies........................................... 20

5.1.2 Summary of Environmental Degradation ............................................................... 21

5.1.3 Comparison of Metabolic Pathways....................................................................... 21

5.1.4 Residues of Concern Summary and Rationale........................................................ 22

5.2 Food Residue Profile...................................................................................................... 22
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5.3 Water Residue Profile .................................................................................................... 23

5.4 Dietary Risk Assessment................................................................................................ 24

5.4.1 Description of Residue Data Used in Dietary Assessment..................................... 24

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................ 24

5.4.3 Acute Dietary Risk Assessment.............................................................................. 24

5.4.4 Chronic Dietary Risk Assessment .......................................................................... 25

5.4.5 Cancer Dietary Risk Assessment............................................................................ 25

5.4.6 Summary Table....................................................................................................... 25

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 25

6.1 Spray Drift...................................................................................................................... 26

7.0 Aggregate Exposure/Risk Characterization....................................................................... 26

8.0 Cumulative Exposure/Risk Characterization..................................................................... 26

9.0 Occupational Exposure/Risk Characterization .................................................................. 26

9.1 Short-/Intermediate-Term Handler Risk ........................................................................ 26

9.2 Short-/Intermediate-Term Post-Application Risk .......................................................... 32

9.2.1 Dermal Postapplication Risk................................................................................... 32

9.2.2 Inhalation Postapplication Risk .............................................................................. 32

10.0 References.......................................................................................................................... 32

Appendix A. Toxicology Profile and Executive Summaries....................................................... 35

A.1 Toxicology Data Requirements...................................................................................... 35

A.2 Toxicity Profiles............................................................................................................. 36

A.3 Hazard Identification and Endpoint Selection ............................................................... 51

A.4 Executive Summaries..................................................................................................... 53

Appendix B. Metabolism Data ..................................................................................................... 73

B1. Structures and Identity of Metabolites of Sedaxane.......................................................... 73

Appendix C. Physical/Chemical Properties................................................................................. 75

Appendix D. Review of Human Research................................................................................... 75
Sedaxane (129223) Human Health Risk Assessment D405099

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1.0 Executive Summary

Sedaxane is a pyrazole carboxamide fungicide registered for use as a seed treatment in canola, 

cereal grains (barley, oat, rye, triticale, and wheat), and soybean. The current petition (#2F8071) 

proposes to expand seed treatment uses to include corn (field, pop, and sweet), pulses (dry pea 

and bean), rape, and sorghum. This action is part of a joint review project with Health Canada’s 

Pesticide Management Regulatory Agency (PMRA). 

The sedaxane toxicology database is considered complete. The toxicological effects reported in 

the submitted animal studies such as mitochondrial disintegration and glycogen depletion in the 

liver are consistent with the pesticidal mode of action also being the mode of toxic action in 

mammals. The rat is the most sensitive species tested, and the main target tissue for sedaxane is 

the liver. Sedaxane also caused thyroid hypertrophy/hyperplasia. In the acute neurotoxicity 

(ACN) and sub-chronic neurotoxicity (SCN) studies, sedaxane caused decreased activity, 

decreased muscle tone, decreased rearing and decreased grip strength. 

There are indications of reproductive toxicity in rats such as decreased follicle counts, but these 

effects did not result in reduced fertility. In the rat, no adverse effects in fetuses were seen in 

developmental toxicity studies at maternally toxic doses. However, in the rabbit, fetal toxicity 

was observed at the same doses as the dams. Offspring effects in the reproduction study 

occurred at the same doses causing parental effects, thus there was no quantitative increase in 

sensitivity in rat pups. Sedaxane is tumorigenic in the liver in the rat and mouse, and led to 

tumors in the thyroid and uterus in the rat and was classified as “likely to be carcinogenic to 

humans.” Sedaxane was negative in the mutagenicity studies. The 28-day dermal study did not 

show systemic toxicity at the limit dose of 1000 mg/kg/day. Sedaxane has low acute toxicity by 

the oral, dermal, and inhalation routes. It is not a dermal sensitizer, causes no skin irritation and 

only slight eye irritation. 

The risk assessments were based on the most sensitive endpoints in the toxicity database, and the 

NOAELs selected for risk assessment are considered protective of potential developmental, 

neurotoxic, and immunotoxic effects for infants and children. Further, highly conservative 

exposure estimates were incorporated into the risk assessment; therefore, reduction of the 10x

Food Quality Protection Act (FQPA) safety factor to 1x is considered appropriate.

For the acute dietary risk assessment, an acute reference dose (aRfD) of 0.30 mg/kg/day was 

selected for assessment of all populations, based on a no observed adverse effect level (NOAEL)

of 30 mg/kg/day in the rat ACN study. Since the FQPA 10x factor is being reduced to 1x, the 

population adjusted dose (PAD) is equal to the RfD. For the chronic dietary risk assessment, a 

chronic reference dose (cRfD) of 0.11 mg/kg/day was selected for assessments of all 

populations, based on a NOAEL of 11 mg/kg/day from the chronic toxicity study in rats. For 

short- and intermediate-term occupational exposure scenarios involving inhalation exposure, the 

NOAEL of 30 mg/kg/day was selected from the rat acute neurotoxicity study. No non-cancer 

dermal hazard was identified for sedaxane.

The sedaxane residue chemistry database is considered complete. The nature and magnitude of 

the residue in plants and rotational crops has been adequately delineated; following a 30-day 
Sedaxane (129223) Human Health Risk Assessment D405099

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plant-back interval (PBI), no residues are expected in rotational crops. No sedaxane residues are 

expected in livestock. Adequate storage stability, method validation data and processing studies 

have been submitted. An acceptable liquid chromatography/tandem mass spectrometry 

(LC/MS/MS) analytical method is available to enforce the proposed tolerances. As part of the 

joint review process, harmonization of recommended tolerance levels was achieved. 

Environmentally, sedaxane is a moderately mobile chemical that is expected to be persistent in 

the environment in aerobic and anaerobic conditions. Based on the environmental fate 

parameters, there is the potential for sedaxane to reach drinking water resources. There are no 

monitoring data available for sedaxane; thus, drinking water concentrations were estimated using 

computer models. 

Highly conservative acute and chronic dietary (food and water) assessments using tolerance level 

residues, assuming 100% crop treated, and incorporating modeled water exposure estimates 

demonstrated that risk levels were <1% of the aPAD at the 95

th percentile exposure and <1% of 

the cPAD for the U.S. population and all population subgroups. The cancer risk estimate for the 

U.S. population was 1 × 10-6. 

There are no residential uses for sedaxane; therefore, the aggregate risk estimate for this

chemical is equivalent to the dietary risk estimate and there are no concerns for acute or chronic 

aggregate risk estimates for sedaxane. 

No non-cancer dermal hazard was identified for sedaxane; therefore occupational handler (noncancer) risks were assessed for the inhalation route of exposure only. Handler cancer risks were 

assessed for primary (i.e., commercial seed treatment which is protective of similar on-farm 

treating), hopper-box, planter-box, or slurry-box on-farm operations; and secondary handlers 

(i.e., planters) by summing potential dermal and inhalation exposures. Cancer risk estimates 

ranged from 8 × 10-10 to 2 × 10-6. Postapplication inhalation exposure is expected to be 

negligible; therefore a quantitative postapplication risk assessment was not conducted.

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, which form the basis of the 

Seed Treatment Standard Operating Procedures (SOPs), have been determined to require a 

review of their ethical conduct, have received that review, and have been determined to be 

ethical.

2.0 HED Recommendations

2.1 Data Deficiencies/Conditions of Registration

None

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method
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An adequate analytical method is available to enforce the proposed tolerances for sedaxane in 

plant commodities. A modification of the Quick, Easy, Cheap, Effective, Rugged, and Safe 

(QuEChERS) method was developed for the determination of residues of sedaxane (as its 

isomers SYN508210 and SYN508211) in/on various crops. The sedaxane isomers (SYN508210 

and SYN508211) are quantitatively determined by LC/MS/MS. The validated limit of 

quantitation (LOQ) reported in the method is 0.005 ppm for both sedaxane isomers.

A successful independent laboratory validation (ILV) study was also conducted on the modified 

QuEChERS method using samples of wheat green forage and wheat straw fortified with 

SYN508210 and SYN508211 at 0.005 and 0.05 ppm. 

Sedaxane has also been subjected to analysis by the Food and Drug Administration (FDA) multiresidue method protocols. Sedaxane is not recovered by the FDA multi-residue methods. 

The analytical standard for sedaxane, with an expiration date of June 30, 2014, is currently 

available in the EPA National Pesticide Standards Repository [personal communication from T. 

Cole of Analytical Chemistry Branch/Biological and Economic Analysis Division (ACB/BEAD)

to W. Donovan, 01/03/2013]. 

2.2.2 International Harmonization

Sedaxane is part of a joint review project with Canada. During the course of the review, the 

partners reached agreement on both the tolerance expression and the tolerance levels for 

commodities common to both countries. 

There are no Codex or Mexican maximum residue limits (MRLs) for sedaxane, and the 

recommended U.S. and Canadian MRLs are harmonized; therefore, there are no issues with 

respect to international harmonization associated with the tolerances recommended in this action. 

2.2.3 Recommended Tolerances

Table 2.2.3 summarizes the registrant’s proposed tolerances and the Agency’s final tolerance 

recommendations. The tolerance expression for sedaxane should read as follows:

Tolerances are established for residues of the fungicide sedaxane, including its 

metabolites and degradates, in or on the commodities listed below. Compliance with the 

tolerance levels specified below is to be determined by measuring only sedaxane, N-[2-

[1,1′-bicyclopropyl]-2-ylphenyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-

carboxamide, as the sum of its cis- and trans-isomers in or on the commodity.
Sedaxane (129223) Human Health Risk Assessment D405099

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Table 2.2.3. Tolerance Summary for Sedaxane.

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Foods

Corn, field, grain 0.01 0.01

Corn, pop, grain 0.01 0.01

Sorghum, grain, grain 0.01 0.01

Pea and bean, dried 

shelled, except soybean, 

subgroup 6C

0.01 0.01 This group includes: grain lupin, 

white lupin, white sweet lupin, field 

bean, kidney bean, lima bean (dry), 

navy bean, pinto bean, lepary bean, 

adzuki bean, blackeyed pea, catjang, 

cowpea, Crowder pea, moth bean, 

mung bean, rice bean, southern pea, 

urd bean, broad bean (dry), chickpea, 

guar, lablab bean, lentil, field pea, 

pigeon pea; cultivars, varieties, 

and/or hybrids of these.

Rapeseed, subgroup 20A 0.01 0.01 This group includes: Borage, 

Crambe, Cuphea, Echium, Flax seed, 

Gold of pleasure, Hare's-ear mustard, 

Lesquerella, Lunaria, Meadowfoam, 

Milkweed, Mustard seed, Oil radish, 

Poppy seed, Rapeseed, Sesame, and 

Sweet rocket; cultivars, varieties, 

and/or hybrids of these.

Corn, sweet, K+CWHR 0.01 0.01

Feedstuffs

Corn, field, forage 0.01 0.01

Corn, sweet, forage 0.01 0.01

Corn, field, stover 0.01 0.01

Corn, sweet, stover 0.01 0.01

Corn, pop, stover 0.01 0.01

Sorghum, grain, forage 0.01 0.01

Sorghum, grain, stover 0.01 0.01

Vegetable, foliage of 

legume, except soybean, 

subgroup 7A

0.01 0.01 This group includes: plant parts of 

any legume vegetable (except 

soybean) included in the legume 

vegetables group that will be used as 

animal feed.

2.2.4 Revisions to Petitioned-For Tolerances

None
Sedaxane (129223) Human Health Risk Assessment D405099

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2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

None

2.3.2 Recommendations from Occupational Assessment

None

3.0 Introduction

3.1 Chemical Identity

The structure and chemical identify for sedaxane are shown in Table 3.1. The structures for all 

metabolites discussed in this risk assessment are shown in Appendix B. 

Table 3.1. Test Compound Nomenclature.

Compound Chemical Structure

Mixture of trans (SYN508210) and cis (SYN508211) isomers

Common name Sedaxane

Company experimental name SYN524464 [mixture of trans (SYN508210) and cis (SYN508211) isomers]

IUPAC name Mixture of cis isomers 2’-[(RS,2RS)-1,1’-bicycloprop-2-yl]-3-(difluoromethyl)-

1-methylpyrazole-4-carboxanilide and trans isomer 2’-[(RS,2SR)-1,1’-

bicycloprop-2-yl]-3-(difluoromethyl)-1-methylpyrazole-4-carboxanilide

CAS name 1H-Pyrazole-4-carboxamide, N-[2-[1,1'-bicyclopropyl]-2-ylphenyl]-3-

(difluoromethyl)-1-methyl 

CAS # 874967-67-6 - Mixture of 599197-38-3 (trans isomer) and 599194-51-1 (cis 

isomer)

End-use product/EP 4.3 lb ai/gal FS formulation (Sedaxane 500FS Fungicide)

0.0667 lb sedaxane/gal FS formulation (A17511B Fungicide), MAI product 

containing sedaxane, difenoconazole, mefenoxam, and thiamethoxam

0.115 lb sedaxane/gal FS formulation (A16874F Fungicide), MAI product 

containing sedaxane, difenoconazole, and mefenoxam

Chemical Class Pyrazole Carboxamide

Known Impurities of Concern None
Sedaxane (129223) Human Health Risk Assessment D405099

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3.2 Physical/Chemical Characteristics

The physical and chemical properties, as well as a summary of relevant environmental fate 

parameters are detailed in Appendix C.

Sedaxane has a low vapor pressure (~10-7Pascal (Pa)) and is, therefore, not a volatile pesticide. 

Based on its octanol water partition coefficient, sedaxane is not expected to bioaccumulate in 

lipophilic matrices. A fish bioconcentration study confirms that accumulation does not occur. 

Sedaxane has low water solubility (14 ppm) and does not dissociate; however, environmentally, 

sedaxane is a moderately mobile chemical that is expected to be persistent in the environment in 

aerobic and anaerobic conditions. Based on the environmental fate parameters, there is the 

potential for sedaxane to reach water resources. 

3.3 Pesticide Use Pattern

The proposed use pattern for sedaxane on the various crops for which registration is sought are 

summarized in Table 3.3.

Table 3.3 Summary of Directions for Proposed New Uses of Sedaxane.

Application 

Type

Formulation

[EPA File 

Symbol No.]

Application Rate 

(lb ai/100 lb seed)

[g ai/100 kg seed]

Use Directions and Limitations

Corn (field, pop, and sweet), rapeseed subgroup 20A, sorghum

Seed treatment 4.3 lb/gal FS

[100- 1374]

0.0025-0.005

[2.5-5.0]

Do not use seed for feed, food or oil purposes. Store 

away from feeds and foodstuffs. In the event of crop 

failure or harvest of a crop grown from Vibrance 

treated seed, the field may be replanted immediately 

to canola, soybean, and cereal grains (barley, oats, rye, 

triticale, and wheat). All other crops may be planted 

no less than 30 days after planting treated seeds. 

Excess treated seed may be used for ethanol 

production only if (1) by-products are not used for 

livestock feed and (2) no measurable residues of 

pesticide remain in ethanol by-products that are used 

in agronomic practice. The maximum number of 

applications per season is 2.

0.020-0.040

[20-40] Corn only: for control of Head smut. 

Pea and bean, dried shelled, except soybean, subgroup 6C

Seed treatment 4.3 lb/gal FS

[100- 1374]

0.0025-0.005

[2.5-5.0]

As above

The use directions are adequate to allow evaluation of the residue data relative to the proposed 

use in the U.S. The proposed maximum application rates are supported by the submitted field 

trial data, although the sorghum trials were conducted using application rates higher than the 

maximum proposed label application rate. 

3.4 Anticipated Exposure Pathways
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The Registration Division has requested an assessment of human health risk to support the 

proposed new use of sedaxane on corn, pulses, and sorghum. Humans may be exposed to 

sedaxane in their diet resulting from residues present in foods grown from sedaxane treated 

seeds. Also, based on the proposed uses, it is possible that sedaxane might reach water 

resources, potentially resulting in residues in drinking water. There are no residential uses of 

sedaxane, so exposure in residential and non-occupational settings is not expected. In an 

occupational setting, applicators may be exposed while handling the pesticide prior to 

application, as well as during application. There is also potential for exposure to planters who 

are handling treated seeds. Postapplication exposures following the planting of sedaxane-treated 

seeds are unlikely because sustained levels of contact with treated seeds after planting are not

expected. This assessment considers cancer and non-cancer risks associated with the proposed 

uses of sedaxane. 

3.5 Consideration of Environmental Justice

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

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

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

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

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

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

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

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

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

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

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

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

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

for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. 

Further considerations are currently in development as OPP has committed resources and 

expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

Based on the proposed use pattern, all required studies for sedaxane have been submitted. The 

available toxicology database is sufficient for assessing the toxicity and characterizing the hazard 

of the chemical. The available toxicology studies for sedaxane are listed in Table A.1 in 

Appendix A. 
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A 28-day rat toxicology study was conducted using the trans isomer, the cis isomer, and a 1:1 

mix of the isomers. Under the conditions of the study, the three sedaxane preparations were 

similar toxicologically and caused similar qualitative effects (i.e., decreased body weight, 

increased liver weight, increased cholesterol, etc.). Trans-sedaxane was considered to be slightly 

more toxic than cis-sedaxane; however, all of the major toxicology studies made use of 

SYN524464, which corresponds to commercial technical sedaxane (approximately 6:1 trans to 

cis isomer ratio). Thus, there are no concerns regarding the applicability of the toxicology 

database. 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

The absorption of sedaxane was estimated following a single gavage administration at low and 

high dose levels (1 or 80 mg/kg) to bile duct-cannulated rats. The absorption of sedaxane was 

similar between genders and at both doses, with a range of 87 - 94% (14C-pyrazole and 14Cphenyl radiolabels). 

Whole body autoradiography showed that the administered radioactivity was distributed widely 

throughout the internal organs after 5 hours; after 24 hours, levels of total radioactivity had 

decreased markedly in all tissues. Peak tissue concentrations were observed at one hour, with 

the highest concentrations of radioactivity present in the liver, kidney and fat. Elimination halflives for tissue depletion were between 0.1 and 3.2 days. Maximum plasma concentrations of 

total radioactivity were achieved at 1 - 6 hours post dose and declined with estimated terminal 

half-life values ranging from 21 - 40 hours for blood.

Sedaxane was extensively metabolized in the rat via demethylation, hydroxylation, oxidation and 

conjugation via hydroxylated metabolites, and metabolites formed by cleavage of the terminal 

cyclopropyl moiety. There were no major gender or dose related differences apparent in the 

qualitative metabolite profile for sedaxane. Little evidence of any cleavage of the molecule 

between the phenyl and pyrazole moieties was measured. The phenolic and hydroxy metabolites 

of sedaxane and desmethyl sedaxane all demonstrated conjugation with glucuronic acid, sulphate 

and glutathione.

The routes and rates of excretion were similar in rats of both genders and in both dose groups, 

with a range of 96 - 105% by seven days. The major route of excretion was via the feces 

accounting for 75 - 83% and urinary excretion ranging from 12 - 20%. In total, radioactive 

residues in tissues accounted for <0.1% of the dose and the residual carcass accounted for <0.2% 

of the dose after 7 days. 

In a repeated dose study (1 mg/kg/day) in the rat, most tissue concentrations either attained or 

were approaching steady state levels after the last of 14 doses to male rats. Following the 

cessation of dosing, all tissue concentrations declined, with no evidence of persistence. The 

elimination half-lives for tissue depletion were variable and ranged from 2 days for plasma to 33

days for the spleen.
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4.2.1 Dermal Absorption

The dermal absorption is low ≤8%, based on the findings from an in vivo dermal penetration 

study in rats. Following a 6 hour exposure to a test material preparation equivalent to a 

1/20 aqueous dilution of sedaxane end-use product, dermal absorption was 2.69% of the initial 

dose after 6 hours and 1.67% after 120 hours. Following a 6 hour exposure to a test material 

preparation equivalent to a 1/200 aqueous dilution, dermal absorption represented 8.05% of the 

dose after 6 hours and 6.92% after 120 hours. The conservative assumption is that the dermal 

absorption of sedaxane is 8.0% using dilutions similar to the end-use products. A comparison of 

the NOAELs from the rat dermal study with the rat developmental study of similar duration, 

supports that the dermal absorption is less than 10% (i.e., NOAELs >1000 and 100 mg/kg/day, 

respectively).

4.3 Toxicological Effects

Sedaxane is a pyrazole carboxamide fungicide proposed for use as a seed treatment. The 

pesticidal mode of action of this group of fungicides is inhibition of succinate dehydrogenase 

(SDH), which is a functional part of the tricarboxylic acid cycle (TCA), the mitochondrial 

electron transport chain and oxidative phosphorylation. SDH is also present in mammals and is 

an important enzyme in oxidative energy production pathways. 

Through oxidative metabolism, the mitochondria supply most of the energy in mammals needed 

for normal activity, pumping ions and generating heat. Upon mitochondrial inhibition, clear 

biological changes include lethargy, decreased activity, muscle weakness, ion imbalances (i.e.,

calcium and phosphate level alterations), hypothermia, decreased food efficiency and altered 

mitochondrial morphology. Additionally, inhibition of the citric acid cycle can cause 

hypoglycemia since some Kreb's cycle substrates are utilized for glucose synthesis and cells 

metabolize more glucose via glycolysis to meet energy demands. Mitochondrial inhibition can 

also cause glycogen depletion to generate glucose. All of these toxicological effects were 

observed in animals treated with sedaxane and the mammalian effects are consistent with the 

pesticidal mode of action.

The rat is the most sensitive species tested and the main target tissue for sedaxane is the liver, 

with effects seen in several species. Acute, sub-chronic and chronic oral toxicity studies have 

been conducted in the rat, mouse, rabbit and dog. Liver effects include hypertrophy, 

pigmentation, vacuolation, and darkened livers. However, based on the ability of sedaxane to 

inhibit energy production, the reductions of rearing, grip strength and muscle tone suggest that 

sedaxane also affects peripheral tissues. Reductions in heart mass were reported in females in 

the 90-day rat study (absolute and relative heart weights in a mitochondrial-rich tissue). Several 

studies showed reductions in bodyweight and food consumption. Sedaxane also caused thyroid 

hypertrophy/hyperplasia. At high doses, studies in three species manifested effects such as 

decreases in spleen and thymus weights (dog and rat), plus significant decreases in lymphocytes, 

WBC and monocytes (dog and mouse).

Sedaxane produced no adverse effects in rat fetuses in developmental toxicity studies at 

maternally toxic doses. However, in the rabbit, fetal toxicity was observed at the same dose as 
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the dams (i.e., decreased fetal weights, increased abortions, increased unossified sternebrae and 

13th rudimentary ribs). In reproduction studies, offspring effects occurred at the same doses 

causing parental effects, thus there was no quantitative increase in sensitivity in rat pups in the 

reproductive toxicity study. There were no single-dose effects identified in the developmental 

toxicity studies in rats or rabbits, including the abortions in the rabbit developmental study which 

occurred at GD28. There are also indications of reproductive toxicity in rats, as decreases in 

follicle count and changes in testes or ovary weight. However, these effects did not result in 

reduced functional fertility in the rat. No evidence of specific neurotoxicity was observed in 

several studies. Sedaxane caused decreased activity, decreased muscle tone, decreased rearing 

and decreased grip strength in the acute neurotoxicity (ACN) and subchronic neurotoxicity 

(SCN) studies; however, there were no supportive neuro-histopathology in any study, even at the 

highest doses tested. The Agency has a low concern for neurotoxicity based on these apical 

endpoints and the effects observed are consistent with a mitochondrial inhibitor to decrease 

energy production. Immune system toxicity was negative by the TDAR assay in the mouse. 

Sedaxane did not display systemic effects in the 28-day dermal study, even at the limit dose of 

1000 mg/kg/day.

Sedaxane causes tumors in the liver (rat and mice), and in the uterus and thyroid (rats). 

Sedaxane increased liver adenomas and thyroid tumors in male rats. The liver adenomas were 

not supported by corroborative histopathology, but the thyroid tumors were supported by 

increased follicular cell hyperplasia. In female rats, sedaxane increased both uterine adenomas 

and adenocarcinomas, but no corroborative uterine histopathology findings were present. In 

male mice, liver adenomas and carcinomas were increased, however without supporting liver 

histopathology. Sedaxane was negative in all five mutagenicity studies; however, chromosomal 

aberrations were observed at cytotoxic concentrations in one in vitro study. The HED Cancer 

Assessment Review Committee (CARC) classified sedaxane as “Likely to be Carcinogenic to 

Humans.” A linear, low-dose approach was used to extrapolate experimental animal tumor data 

for the quantitation of human cancer risk from sedaxane, with a Q1*= 4.64 x 10-3 (mg/kg/day)-1. 

Sedaxane has low acute toxicity by the oral, dermal, and inhalation routes. It is not a dermal 

sensitizer, causes no skin irritation and only slight eye irritation. Increased serum phosphate 

levels were measured in several studies (i.e. the 13-week and chronic rat studies), consistent with 

sedaxane’s inhibition of oxidative phosphorylation (i.e., phosphorylation of adenosine 

diphosphate (ADP) to adenosine-5'-triphosphate (ATP) via the electron transport chain). Ion 

imbalances in general can be a consequence of decreased energy production via decreased ATPpowered ion pump activity. Many of the listed effects of sedaxane are consistent with decreased 

mitochondrial energy production and metabolism (i.e., hypothermia, lethargy, decreased food 

efficiency, etc.). However, at higher doses, some effects of sedaxane may also be explained by 

non-specific and generalized toxicity not associated with succinate dehydrogenase inhibition. 

The CSCD465008 metabolite was negative for genotoxicity testing and is not expected to be 

more toxic than the parent. However, the 28-day study for this metabolite was performed in the 

rat while the 28-day study for sedaxane was performed in the mouse.

4.4 Safety factor for Infants and Children (FQPA Safety Factor)
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The FQPA factor for increased susceptibility to infant and children is reduced to 1X based on the 

following considerations:

1) The toxicology and exposure data bases for sedaxane are complete and adequate for 

assessing increased susceptibility under FQPA; 

2) In the rat, no adverse effects in fetuses were seen in developmental toxicity at 

maternally toxic doses. In the rabbit, fetal toxicity was observed at the same doses as 

the dam (increased unossified sternebrae and 13th rudimentary ribs and a decrease in fetal 

weights of -9% and increased abortions). In the dam, at the same doses, the effects were 

decreased body weight, decreased body weight gain, reduced food consumption, and 

decreased defecation. In reproduction studies, offspring effects occurred at the same 

doses causing parental effects; thus, there was no quantitative increase in sensitivity 

in rat pups. The LOAELs and NOAELs for the developmental and reproduction 

studies were clearly defined;

3) There are no specific concerns for neurotoxicity as observed effects were likely 

secondary to inhibition of mitochondrial energy production caused by sedaxane;

4) A developmental neurotoxicity study is not required;

5) There are no residual uncertainties in the toxicology database; and

6) Exposure assessments are conservative and will not underestimate exposure.

4.4.1 Completeness of the Toxicology Database

The toxicology database for sedaxane is considered complete for evaluating and characterizing 

its toxicity, assessing of children’s susceptibility under FQPA and selecting endpoints for the 

exposure pathways of concern. 

4.4.2 Evidence of Neurotoxicity

Acute oral (gavage) and sub-chronic oral (dietary) neurotoxicity studies in rats were conducted 

on the sedaxane technical product. No evidence of specific neurotoxicity was seen in these 

studies. Sedaxane caused changes in apical endpoints such as decreased activity, decreased 

muscle tone, decreased rearing and decreased grip strength in the ACN and SCN studies. There 

was no corroborative neuro-histopathology demonstrated in any study, even at the highest doses 

tested (i.e., 2000 mg/kg/day) and the results of the ACN and SCN studies are consistent with 

inhibition of mitochondrial energy production by sedaxane. Based on its chemical structure, its 

pesticidal mode of action and lack of evidence of neuro-histopathology in any acute and 

repeated-dose toxicity studies, sedaxane does not demonstrate potential for neurotoxicity. Since 

sedaxane did not demonstrate susceptibility to the young or specific neurotoxicity, a 

developmental neurotoxicity (DNT) study is not required.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence for increased susceptibility following pre-and or post-natal exposures to 

sedaxane based on effects seen in developmental toxicity studies in rabbits or rats. In range 

finding and definitive developmental toxicity studies in rats, neither quantitative nor qualitative 
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evidence of increased susceptibility of fetuses to in utero exposure to sedaxane was observed. In 

these studies, there were no single-dose effects. There was no evidence of increased 

susceptibility in a two-generation reproduction study in rats following pre- or post-natal exposure 

to sedaxane. There is no evidence of neuropathology or abnormalities in the development of the 

fetal nervous system from the available toxicity studies conducted with sedaxane. Clear 

NOAELs/LOAELs were established for the developmental effects seen in rats and rabbits as 

well as for the offspring effects seen in the two-generation reproduction study. The doseresponse relationship for the effects of concern is well characterized. The NOAEL used for the 

acute dietary risk assessment (30 mg/kg/day), based on effects observed in the ACN study, is 

protective of the developmental and offspring effects seen in rabbits and rats with the NOAELs 

of 100-200 mg/kg/day. Based on these considerations, there are no residual uncertainties for preand/or post-natal susceptibility; thus, a DNT study is not required.

4.4.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database for sedaxane with respect to dietary 

(food and water) exposure. Moreover, there are no registered residential uses of sedaxane in the 

U.S.

A complete database with respect to both the nature and magnitude of residues expected in food 

has been provided. The dietary food exposure assessment is based on tolerance level residues, 

and assumes 100% crop treated for all commodities, resulting in high-end estimates of dietary

food exposure. Further, highly conservative, modeled drinking estimates of exposure were 

included in the assessments. Actual exposures and risks from sedaxane in food and drinking 

water are likely to be far lower than estimated in this risk assessment. 

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary exposure scenarios to sedaxane 

are summarized below. Detailed description of the studies used as a basis for the selected 

endpoints are presented in Appendix A. 

An acute RfD is based on a NOAEL of 30 mg/kg/day selected from an ACN study in rats 

(LOAEL=250 mg/kg) based on clinical signs of toxicity (reduced activity, decreased rearing, 

initial inactivity, piloerection, ruffled fur and recumbency, decreased body weight, body weight 

gains and food consumption in males; plus weakened condition, swaying gait, decreased activity, 

reduced muscle tone and decreased locomotor activity & rearing in females). The weakened 

condition, swaying gait and decreased activity were observed on days 2-7, while the other effects 

occurred on day 1. The acute dietary dose and endpoint for the general population is protective 

for females 13+. The reproductive LOAEL for the reproduction study is 143 mg/kg/day based 

on decreased follicle counts. The NOAEL for the ACN study is 30 mg/kg: a three-fold lower 

dose. The reduced follicle counts did not result in a functional decrease in fertility; thus, the 

ACN study PoD is considered protective. An uncertainty factor of 100x (10x to account for 

interspecies extrapolation and 10x for intraspecies variation) was applied to the aRfD. 
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For acute dietary analysis of females 13+, no study was identified with an appropriate endpoint 

for this group. There were no single-dose effects identified in the developmental toxicity studies 

in rats or rabbits, including the abortions in the rabbit developmental study which occurred at 

GD28. The acute dietary POD for general population utilizing the ACN study is protective for 

this scenario.

The ACN study in rats was also considered appropriate for endpoint selection for the short- and 

intermediate-term inhalation exposure scenarios.

A chronic RfD of 0.11 mg/kg/day (NOAEL=11 mg/kg/day) was selected from a chronic 

toxicity/carcinogenicity feeding study in rats (LOAEL=67/86 mg/kg/day) based on liver and 

thyroid effects. In females, it was based on decreased body weight and body weight gain, 

increased liver weight and thyroid effects. An uncertainty factor of 100x (10x to account for 

interspecies extrapolation and 10x for intra-species variation) was applied to the cRfD. 

Because sedaxane has no residential uses, no incidental oral endpoints were selected. 

The 28-day dermal study had no systemic effects at the limit dose of 1000 mg/kg/day. 

Therefore, non-cancer dermal risk assessments are not required for sedaxane.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

As part of conducting a human health risk assessment, HED considers risks from individual 

routes of exposure (oral, dermal, and inhalation). Additionally, HED must assess aggregate risks

from dietary and residential exposures. In order to conduct an aggregate risk assessment a 

determination is made if it is appropriate to combine across routes of exposure and aggregate 

dietary risks with residential (non-occupational) risks. Because there are no residential uses for 

sedaxane, the dietary and aggregate assessments are identical. For the occupational non-cancer

risk assessment, it is not possible to combine routes of exposure due to the lack of a dermal 

toxicity endpoint. However, for the occupational cancer risk assessment, dermal and inhalation 

exposures should be combined prior to comparison to the linear slope factor selected as the 

cancer endpoint.

4.5.3 Cancer Classification and Risk Assessment Recommendation

CARC classified sedaxane as “Likely to be Carcinogenic to Humans” based on increased liver 

tumors in male mice, uterine endometrial epithelial tumors in female rats, plus increased thyroid 

follicular cell and liver tumors in male rats. In the absence of mode of action data, the CARC 

recommended low-dose, linear extrapolation for risk assessment with a Q1* value of 4.64 x10-3

(mg/kg/day)-1

.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4 summarizes the toxicological doses and endpoints selected for use in the human 
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health risk assessment for sedaxane. 
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Table 4.5.4. Summary of Toxicological Doses and Endpoints for Sedaxane for Use in Human Health Risk 

Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment Study and Toxicological Effects

Acute Dietary 

(All 

populations, 

including 

children and 

women 13-49 

years of age)

NOAEL= 

30 

mg/kg/day

UFA= 10 x

UFH=10 x

FQPA SF = 1x

Acute RfD = 

0.30 mg/kg/day

aPAD = 0.30 

mg/kg/day

Rat ACN Study

NOAEL=30 mg/kg

LOAEL=250 mg/kg based on reduced 

activity, decreased rearing, initial 

inactivity, piloerection, ruffled fur and 

recumbency, decreased BW, decreased 

BWG and food consumption (males). In 

females, weakened condition, swaying 

gait, decreased activity, reduced muscle 

tone, and decreased locomotor activity 

and rearing. The weakened condition, 

swaying gait and decreased activity were 

observed on days 2-7, while the other 

effects were on day 1.

Chronic 

Dietary (All 

Populations)

NOAEL= 

11

mg/kg/day

UFA= 10 x

UFH=10 x

FQPA SF = 1x

Chronic RfD = 

0.11

mg/kg/day

cPAD = 0.11

mg/kg/day

Chronic Rat Study 

NOAEL= 11/14 mg/kg bw/day ♂/♀

LOAEL = 67/86 mg/kg bw/day ♂/♀, in 

males based on decreased hind limb grip 

strength increased liver weight, increased 

incidences of hepatocyte hypertrophy and 

eosinophilic foci, and thyroid follicular 

cell hypertrophy, basophilic colloid, 

epithelial desquamation and increased 

phosphate levels (♂). In females, it was 

based on decreased body weight and body 

weight gain, increased liver weight and 

the same thyroid histopathology noted 

above for males.

Dermal, All 

Durations

Not applicable as the 28-day dermal study had no systemic effects at the limit dose of 1000 

mg/kg/day.

Incidental 

Oral, All 

Durations

 Not applicable as there are no residential uses of sedaxane.

Inhalation, 

Short-Term

Term (1-30 

days) 

and 

IntermediateTerm (1-6 

months)

NOAEL=30 

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF= 1x

LOC for MOE 

= 100

ACN Study

 NOAEL=30 mg/kg

LOAEL = 250 mg/kg bw, based on 

reduced activity, decreased rearing, initial 

inactivity, piloerection, ruffled fur and 

recumbency, decreased body weight, 

body weight gains and food consumption 

(♂); plus weakened condition, swaying 

gait, decreased activity, reduced muscle 

tone and decreased locomotor activity & 

rearing (♀). The weakened condition, 

swaying gait and decreased activity were 

observed on days 2-7, while the other 

effects were on day 1.
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Table 4.5.4. Summary of Toxicological Doses and Endpoints for Sedaxane for Use in Human Health Risk 

Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment Study and Toxicological Effects

Inhalation, 

Long-Term 

(>6 months)

A long-term inhalation scenario is not applicable for seed treatment uses.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Likely to be Carcinogenic to Humans” based on significant tumor increases in two 

adequate rodent carcinogenicity studies. Q1*= 4.64x10-3 (mg/kg/day)-1

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning 

of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population 

adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Livestock Metabolism Studies

5.1.1.1 Plant Metabolism Studies

Residue Chemistry Memo, D382526, D. Soderberg, 2/7/12

Plant metabolism data were submitted for corn, wheat, soybean, Swiss chard, and canola to 

support the requested seed treatment uses of sedaxane. Studies for all commodities reflected

labeling in both the phenyl and pyrazole rings. Application rates were equal to, or exaggerations 

of the currently proposed use rates, and application techniques reflect the requested use patterns. 

The metabolic pathway in wheat, soybeans, and Swiss chard is substantially similar. Insufficient 

radioactivity levels were obtained from the corn and canola samples to elucidate the metabolic 

pathways in these crops. Following seed treatment use of sedaxane in wheat, soybean, and Swiss 

chard, sedaxane metabolism may be summarized as follows: 1) oxidative metabolism of the 

phenyl and cyclopropane rings, 2) N-demethylation of the pyrazole ring and 3) cleavage between 

pyrazole and phenyl rings. Among the three crops studied, there is variation in the extent of the 

three reaction processes and the nature of the observed conjugates found.

Because the proposed metabolic pathways for three diverse crops (cereal grain, leafy green 

vegetable, and legume vegetable) are similar, the data are adequate to define the nature of the 

residue in all plants. HED has determined that residue of concern in plants (primary and 

rotational crops) is parent sedaxane (both isomers). However, since the application techniques 

were limited to seed treatment, these data will not support foliar uses of sedaxane on agricultural 

crops, and separate metabolism studies will be needed should foliar uses be requested. 
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5.1.1.2 Livestock Metabolism Studies

Residue Chemistry Memo, D382526, D. Soderberg, 2/7/12

Livestock metabolism studies were submitted for the hen (poultry) and lactating goat (ruminant) 

for sedaxane to support the requested new uses. Studies in both animals reflected labeling in 

both the phenyl and pyrazole rings. 

Sedaxane is extensively metabolized in the hen and lactating goat. The metabolic pathways in 

poultry and ruminants appear similar. The principal routes of metabolism are oxidation resulting 

in hydroxylation of the phenyl ring or at the cyclopropane moiety. Additionally the same 

oxidations are observed following demethylation of sedaxane. Overall results also showed that 

the biotransformation pathway of sedaxane in ruminants and poultry is similar to that observed in 

the rat.

The submitted livestock metabolism studies adequately address the requirement to elucidate the 

nature of the residue in livestock for sedaxane. HED has determined that residue of concern in 

livestock is parent sedaxane (both isomers) for tolerance enforcement, while for risk assessment 

the residue definition is parent sedaxane plus CSCD658906. 

5.1.2 Summary of Environmental Degradation

Drinking Water Memo, D382528, R. Bohaty, 12/21/11

Laboratory data suggest that in the environment sedaxane is persistent. Data indicate that 

sedaxane is only susceptible to degradation via aerobic soil metabolism (laboratory soil half-life

296-400 days based on single first order kinetics) and photolysis (laboratory half-life of 46 days 

for aqueous photolysis and 253 days for soil photolysis). Aerobic biodegradation of sedaxane in 

soil does not follow single first order kinetics. In general, sedaxane concentrations decrease over 

the first 100 days; however, after 100 days, sedaxane concentrations remain steady 

(approximately 50% of the applied radioactivity) through at least 365 days. Hydrolysis, 

anaerobic soil and aquatic transformation, and aerobic aquatic metabolism are not expected to 

contribute to the dissipation of sedaxane in the environment. Terrestrial field dissipation data 

(DT50 value 114-132 days) suggest sedaxane will persist in the environment, consistent with 

laboratory metabolism and photolysis data.

5.1.3 Comparison of Metabolic Pathways

The metabolism of sedaxane in the rat is detailed in Section 4.2 and the metabolism in plants and 

livestock is discussed in Section 5.1.1. Based on the submitted data, the metabolic profile in 

plants is similar in cereal grains, leafy greens, and legumes. Metabolism in the rat and livestock 

(ruminants and poultry) is similar. The primary difference in metabolism between plants and 

animals is that in plants some cleavage of the bond between the pyrazole and phenyl rings was 

observed, while this was not seen in animals. However, due to the very low levels of these 

metabolites, combined with low concern regarding their toxicity, no additional studies are 

needed to further investigate these plant metabolites.
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5.1.4 Residues of Concern Summary and Rationale

ROCKS Memo, D387015, I. Negrón-Encarnación, 11/10/2011

ROCKS Memo, D406945, E. Holman, 12/19/2012

The HED Residues of Concern Knowledgebase Sub-committee (ROCKS) considered the 

available data on the nature and magnitude of residues in sedaxane and concluded that for plant 

seed treatment uses, the parent compound only (sum of cis and trans isomers) should be included 

for tolerance enforcement and dietary (food) risk assessment. For livestock, the residue of 

concern for tolerance enforcement is parent sedaxane; for risk assessment, parent and 

CSCD658906 comprise the residues of concern. 

Based on toxicity data provided for the pyrazole metabolites CSCD465008 and CSAA798670,

sedaxane is consistently more toxic than these metabolites in acute oral toxicity, succinate 

dehydrogenase inhibition, sub-chronic and developmental toxicity studies at doses < 500 mg/kg.

Additionally, as carcinogenicity is the primary risk driver for this assessment and is considered 

to be mainly due to parent sedaxane, the pyrazole metabolites are of reduced toxicological 

concern. Although the pyrazole metabolites may reach drinking water sources due to their 

mobility and significant half-lives, the risk assessment for sedaxane is expected to be protective 

of exposures to these metabolites. Therefore, the 2012 ROCKS meeting recommended that 

CSCD465008 and CSAA798670 no longer be considered residues of concern in drinking water.

This decision applies only to seed treatment uses.

The residues of concern for sedaxane are summarized in Table 5.1.4, below.

Table 5.1.4. Summary of Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expression1

Matrix Residues included in Risk Assessment Residues included in Tolerance 

Expression

Plants Both isomers of parent sedaxane Both isomers of parent sedaxane

Livestock Both isomers of parent sedaxane plus 

CSCD658906

Both isomers of parent sedaxane

Drinking Water Both isomers of parent sedaxane plus 

CSCD668094 and CSCD668095

Not Applicable

1 The residues of concern identified in this table apply only to seed treatment uses. 

2

Sedaxane is a mixture of cis isomer 2’-[(RS,2RS)-1,1’-bicycloprop-2-yl]-3-(difluoromethyl)-1-methylpyrazole-4-carboxanilide 

and trans isomer 2’-[(RS,2SR)-1,1’-bicycloprop-2-yl]-3-(difluoromethyl)-1-methylpyrazole-4-carboxanilide. CSCD658906 is N-

{2-[(1R,2S)-1,1'-bi(cyclopropyl)-2-yl]phenyl}-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide. CSCD668094 is N-[2-

(3-cyclopropyl-1,3-dihydroxypropyl)phenyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide; and CSCD668095 is 3-

[2-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]carbonyl}amino)phenyl]-3-hydroxypropanoic acid.

5.2 Food Residue Profile

Residue Chemistry Memo, D407472, W. Donovan, 3/12/13

The available seed treatment data on the metabolism of sedaxane in wheat, soybean, and Swiss 

chard demonstrate that residues are generally low, but do translocate throughout the plants. The 
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highest residues are generally found in the foliage or forage portions of plants, and not in the 

seeds or grains. Crop field trial residue data were consistent with the results of the plant 

metabolism studies. Specifically, the magnitude of the residue studies showed no quantifiable 

residues of sedaxane in any plant seeds or grains, but low level residues were found in some 

livestock feedstuffs associated with these plants. 

Adequate residue chemistry data have been provided for sedaxane. Sufficient field trials with 

appropriate geographic representation were submitted. Twenty-six corn trials at the maximum 

label rate showed no detectable sedaxane residues, supporting an LOQ tolerance of 0.01 ppm for 

all corn RACs. A total of 10 dry bean trials (5 in the US and 5 in Canada) showed no detectable 

sedaxane residues in any bean RAC; and a total of 13 dry pea trials (5 in the US and 8 in 

Canada) showed no detectable sedaxane residues in any pea RAC. Together, these results 

support tolerances of 0.01 ppm for Crop Subgroup 6C (seed), and for Crop Subgroup 7A 

(foliage). Twelve sorghum trials at an exaggerated rate of 8× the maximum label rate showed no 

detectable sedaxane residues, supporting tolerances of 0.01 ppm for all sorghum RACs. The 

representative crop for Crop Subgroup 20A is canola. Accordingly, the canola field trials 

reviewed previously (D382526, D. Soderberg, 2/7/12) support a tolerance level of 0.01 ppm for 

Crop Subgroup 20A. 

Two corn processing studies were conducted to determine if sedaxane residues concentrate in 

meal, flour, grits, starch, and refined oil processed from field corn grain. Following treatment of 

field corn seed at a target exaggerated rate of 120 g ai/100 kg seed (3× maximum label rate), no 

sedaxane residues were detected in corn grain or any of its processed fractions. Therefore, 

processing factors could not be calculated, and no separate tolerances are needed for any 

processed commodities from corn. 

Data analyses employed validated analytical methods and are supported by adequate storage 

stability data. Sufficient studies were submitted for corn to elucidate the fate of sedaxane in 

processed commodities derived from these crops. HED determined that the registered and 

proposed seed treatment uses of sedaxane are classified as 180.6 (a) (3), no reasonable 

expectation of finite residues with respect to residues in livestock commodities. Confined 

rotational crops studies show that the metabolism of sedaxane in rotated crops is similar to that in 

primary crops, although relatively less parent and more pyrazole-derived metabolites were 

found, particularly at PBIs longer than 30 days. Limited rotational crop field trials demonstrate 

that residues are not expected in crops planted 30 days after initially planting sedaxane-treated 

seeds; therefore, 30-day PBIs are appropriate for all crops in rotation to primary crops. 

5.3 Water Residue Profile

Drinking Water Memo, D382528, R. Bohaty, 12/21/11

Drinking Water Memo, D405391 & D407956, R. Bohaty & J. Hetrick, 03/18/13

There are no monitoring data currently available for sedaxane or its residues of concern in 

drinking water. Estimated drinking water concentrations (EDWCs) were generated using 

computer modeling methods. The screening model FIRST (FQPA Index Reservoir Screening 

Tool) was used to calculate the surface water EDWCs. Groundwater EDWCs were calculated 

using the screening model SCI-GROW (Screening Concentrations in Ground Water, version 2.3, 
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07/29/03). Groundwater EDWCs were calculated using the PRZM-Groundwater (PRZM-GW 

Version 1.0, 12/11/2012).

Maximum application rates for sedaxane as a high-end estimate of exposure in drinking water 

were modeled based on the proposed labels. In accord with recommendations of the ROCKS, 

total toxic residue levels were modeled, to include all the drinking water residues of concern, 

namely, both isomers of parent sedaxane plus CSCD668094 and CSCD668095. However, as 

CSCD668094 and CSCD668095 were only observed in aquatic photolysis studies, these residues 

were only considered as part of the surface water modeling. Surface water EDWCs were 

corrected for a percent cropped area (PCA) of 0.91. The maximum surface and ground water 

EDWCs for use in the human health risk assessment for sedaxane are shown in Table 5.3. The 

ground water values were selected for use in the dietary exposure assessment since they were 

higher than the surface water values.

Table 5.3. Maximum Estimated Surface Water and Groundwater Concentrations for Sedaxane and Major 

Degradates1.

Scenario Surface Water Conc., ppb 2 Ground Water Conc., ppb 3

Acute 4.1 9.9

Chronic & Cancer 1.2 8.4

Highest value for use in risk assessment is shown in bold.

1 EDWCs include both isomers of the parent compound in groundwater, and sedaxane plus CSCD668094 and CSCD668095 in surface water.

2

From the FIRST model.

3

From the PRZM-GW model. Chronic & cancer value is not a yearly mean but the mean concentration following breakthrough (time to 

breakthrough is 1870 days). 

5.4 Dietary Risk Assessment

Dietary Exposure Memo, D408793, W. Donovan, 2/20/13

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute and chronic dietary risk assessment used tolerance level residues for all commodities 

included in the assessments. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary risk assessment assumed 100% crop treated for all commodities 

included in the assessment.

5.4.3 Acute Dietary Risk Assessment

A highly conservative acute dietary risk assessment was conducted which used tolerance level 

residues, assumed 100 percent crop treated (% CT) for all commodities and included modeled

drinking water estimates. The estimated exposure (food and water) to the U.S. population and all 

population subgroups from the proposed new uses of sedaxane resulted in an estimated risk 

equivalent to <1% of the acute population adjusted dose (aPAD) at the 95th percentile. 
Sedaxane (129223) Human Health Risk Assessment D405099

Page 25 of 75

5.4.4 Chronic Dietary Risk Assessment

A highly conservative chronic dietary risk assessment was conducted which used tolerance level 

residues, assumed 100 percent crop treated (% CT) for all commodities, and included modeled 

drinking water estimates. The estimated exposure (food and water) to the U.S. population and all 

population subgroups from the proposed new uses of sedaxane resulted in an estimated risk 

equivalent to <1% of the chronic population adjusted dose (cPAD). 

5.4.5 Cancer Dietary Risk Assessment

The Agency has classified sedaxane as “Likely to be Carcinogenic to Humans” based on 

significant tumor increases in two adequate rodent carcinogenicity studies. Accordingly, a 

cancer dietary risk assessment was conducted, indicating a risk estimate of 1 x 10-6for the US 

population. This screening-level assessment assumed tolerance level residues, 100 percent crop 

treated (% CT) for all commodities, and included conservative modeled drinking water 

estimates. 

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Sedaxane.1

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.000604 < 1 0.000222 < 1 0.000222 1 × 10-6

All Infants (< 1 year old) 0.001784 < 1 0.000522 < 1

N/A N/A

Children 1-2 years old 0.000990 < 1 0.000363 < 1

Children 3-5 years old 0.000804 < 1 0.000321 < 1

Children 6-12 years old 0.000612 < 1 0.000231 < 1

Youth 13-19 years old 0.000505 < 1 0.000177 < 1

Adults 20-49 years old 0.000571 < 1 0.000215 < 1

Adults 50-99 years old 0.000507 < 1 0.000202 < 1

Females 13-49 years old 0.000579 < 1 0.000211 < 1

1 Highest exposure identified in bold.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization
Sedaxane (129223) Human Health Risk Assessment D405099

Page 26 of 75

Residential exposures and risk are not assessed because the proposed uses of sedaxane do not 

involve applications by homeowners or commercial applicators in residential settings and there 

are no existing or proposed residential uses.

6.1 Spray Drift

A postapplication inhalation exposure assessment is not required as exposure is expected to be 

negligible. Seed treatment assessments provide quantitative inhalation exposure assessments for 

seed treaters and secondary handlers (i.e., planters). It is expected that these exposure estimates 

would be protective of postapplication inhalation exposure scenarios; risks for these scenarios 

were not of concern.

Seed treatment operations typically utilize closed systems and do not involve spraying of 

pesticides. Therefore, any spray drift is expected to be negligible and included in the handler 

inhalation exposure assessment.

7.0 Aggregate Exposure/Risk Characterization

There are no residential uses for sedaxane; therefore the aggregate exposure and risk assessments 

include acute and chronic dietary (food and water) only and are shown in Sections 5.4.3 and 

5.4.4. There are no aggregate risk estimates of concern for the proposed new uses of sedaxane. 

Sedaxane is a member of the pyrazole carboxamide fungicides. Metabolic processes involving 

cleavage of the linkage between the pyrazole and phenyl rings of these compounds have the 

potential to produce common pyrazole-metabolites. Indeed, confined rotational crops studies for 

sedaxane, fluxapyroxad, and isopyrazam demonstrate that low levels of the following common 

metabolites form: CSCD465008, CSAA798670, and CSCC210616. However, due to the low 

levels of these compounds in rotational crops (≤0.01 ppm), and low concerns about their 

potential toxicity relative to parent molecules, any risks from aggregation of exposures to these 

metabolites across chemicals will be insignificant. 

8.0 Cumulative Exposure/Risk Characterization

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 sedaxane 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 Office of Pesticide Programs 

concerning common mechanism determinations and procedures for cumulating effects from 

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

http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Occupational/Residential Exposure Memo, D408790, S. Tadayon, 02/28/13

9.1 Short-/Intermediate-Term Handler Risk
Sedaxane (129223) Human Health Risk Assessment D405099

Page 27 of 75

Occupational handler exposure to sedaxane is expected for individuals involved in commercial 

seed treatment and on-farm seed treatment. Occupational seed treatment primary handlers may 

experience short- and intermediate-term exposure to sedaxane while performing seed treatment 

activities in commercial settings. In addition, occupational secondary handlers may experience 

short- and intermediate-term exposure while planting sedaxane-treated seeds. No chemicalspecific handler exposure data were submitted in support of this use pattern. For assessing 

commercial seed treatment and seed planting activities, unit exposure data were taken from HED 

ExpoSAC Policy 14: SOPs for Seed Treatment. The amount of active ingredient handled 

depends on the application rate (lb ai/lb seed) and the pounds of seed treated in a day (or the 

pounds of seed that can be planted in a day), all of which depend upon the seed type. Amount of 

Seed Treated or Planted per Day (Policy 15) and Interim Guidance “Amount of Commercial 

Seed Treated Per Day” (Policy 15.1). This assessment uses the Agricultural Handler Exposure 

Task Force (AHETF) surveys (01/12/2012) which were conducted in the United States and 

Canada. The main objective of this survey was to collect seed treatment throughput data for 

updating EPA HED’s Science Advisory Council for Exposure, Standard Operating Procedure 

Number 15, entitled Amount of Seed Treated or Planted per Day. Specifically, survey data were 

collected to update daily seed treatment throughput data and to characterize seed treating 

equipment and worker activities for five seed types—canola, corn, rice, soybean, and wheat. The 

AHETF survey replaces maximum equipment capacity referenced in SOP 15. 

Quantitation of non-cancer dermal exposure and risk is not required since a dermal hazard was 

not identified for sedaxane. Only inhalation exposure and risks were quantified. The 

occupational inhalation exposure assessment was completed for commercial seed treatment

facilities and for on-farm uses of hopper-box, planter-box and slurry-box. Compared to 

commercial seed treatment operations, on-farm seed treatment operations primarily utilize

similar, but smaller, machinery and treat fewer seeds per day; therefore, the risk estimates for 

commercial seed treatment facilities are protective of similar on-farm seed treatment facilities.

For the occupational cancer risk assessment, the highest exposures and risks were calculated for

on-farm hopper-box, planter-box and slurry-box operations. 

The proposed personal protective equipment (PPE) for sedaxane on all proposed labels requires 

that all mixers, loaders, applicators and other handlers wear long-sleeved shirts and long pants, 

socks plus shoes, and chemical resistant gloves (except when bagging or sewing bags of treated 

seeds).

Short- and intermediate-term handler exposures and risk estimates for seed treatment activities 

are shown in Tables 9.1.1, 9.1.2, 9.1.3 and 9.1.4, below. All inhalation risk estimates exceed an 

MOE of 100 and, therefore, are not of concern. 

Sedaxane seed treatment uses include commercial seed treatment and on-farm scenarios; the 

product use labels do not include instructions for direct application to seeds in a hopper-box, 

planter-box, or slurry-box. Nevertheless, these scenarios were included in this risk assessment 

for informational purposes. 
Sedaxane (129223) Human Health Risk Assessment D405099

Page 28 of 75

Primary Handler Cancer Risk

All cancer calculations use the maximum application rate to estimate risk. The cancer risk 

estimates for commercial primary handlers (i.e., loader/treater, bagger, sewer and multiple 

activities), hopper-box, planter-box, slurry-box; and secondary handlers (i.e., planting treated 

seed) were estimated using either baseline or PPE (single layer clothing and gloves) mitigation. 

The cancer risk estimates for hopper-box, planter-box, or slurry-box seed treatment ranged from 

3 × 10-8to 2 × 10-6, while the cancer risk estimates for commercial seed treatment ranged from 3

× 10-8to 6 × 10-7. A summary of the cancer risk estimates for primary handlers is presented in 

Table 9.1.3. 

Secondary Handler Cancer Risk

The cancer risk estimates for secondary handlers (i.e., planters) ranged from 8 × 10-10 to 4 × 10-8. 

A summary of the cancer risk estimates for secondary handlers is presented in Table 9.1.4. 

Cancer Risk Characterization

To estimate the LADD (Lifetime Average Daily Dose) the maximum application rate, the 

number of days worked per year, and the number of years one would be exposed during a 

working lifetime are needed. Each one of these variables depends upon many factors. For 

example, the number of days worked per year must correspond to the days worked when the 

pesticide of concern has been applied. Additionally, the residue dissipation over the work 

interval should be estimated. Without an estimate for residue dissipation one needs to assume 

(unrealistically) that the worker is exposed to the highest residue value in the seed treatment 

facility. For sedaxane, a screening estimate was developed because lifetime use data are not 

available. The screening level estimate assumed: (1) that commercial seed treaters would be 

exposed to sedaxane on treated corn seed for 180 consecutive days per year, and for 90 days per 

year for all other seed types; (2) no residue dissipation; (3) maximum application rate; and (4) a 

seed treater would be exposed for 35 years. These assumptions are consistent with 

recommendations from the Exposure Science Advisory Committee (ExpoSAC) and information

from the National Agricultural Statistics Service. Due to these high-end assumptions, HED 

believes that the cancer risk estimates are conservative. 
Page 29 of 75

Table 9.1.1 Non-Cancer Risk for Seed-Treatment Handlers

Exposure 

Scenario 

(Scenario #)

PPE Dermal 

Unit 

Exposure 

(mg/lb ai)

Inhalation 

Unit 

Exposure 

(mg/lb ai) 

Seed Type Application 

Rate

(lb ai per 100 

lb seed)

Amount 

Treateda

(lb seed 

treated per 

day)

Daily

Inhalation

Dose 

(mg/kg/day)b

Short -Term 

Inhalation 

MOEc 

Commercial: Loader/Applicator

Loading/Applying

Liquids for

Seed Treatment

SL, G 0.023 0.00034 Corn (smut treatment) 0.04 339,500 (ST) 0.00058 52,000

Sorghum (AHETF Wheat Data) 0.005 360,000 (ST) 0.000077 390,000

Rapeseed (AHETF Canola data) 125,000(ST) 0.000027 1,100,000

Peas and Bean (AHETF Soybeans Data) 281,250(ST) 0.00006 500,000

Commercial: Sewer

Sewing Seeds after 

Seed treatment

SL, 

no G

0.0062 0.00023 Corn (smut treatment) 0.04 339,500 (ST) 0.00039 77,000

Sorghum (AHETF Wheat Data) 0.005 360,000 (ST) 0.000052 580,000

Rapeseed (AHETF Canola data) 125,000(ST) 0.000018 1,700,000

Peas and Bean (AHETF Soybeans Data) 281,250(ST) 0.00004 740,000

Commercial: Bagger

Bagging Seeds 

after Seed 

treatment

SL, 

no G

0.0091 0.00016 Corn (smut treatment) 0.04 339,500 (ST) 0.00027 110,000

Sorghum (AHETF Wheat Data) 0.005 360,000 (ST) 0.000036 830,000

Rapeseed (AHETF Canola data) 125,000(ST) 0.000013 2,400,000

Peas and Bean (AHETF Soybeans Data) 281,250(ST) 0.000028 1,100,000

Multiple Activities Worker

Multiple Activities 

for Seed treatment

SL,G 0.042 0.0016 Corn (smut treatment) 0.04 339,500 (ST) 0.0027 11,000

Sorghum (AHETF Wheat Data) 0.005 360,000 (ST) 0.00036 83,000

Rapeseed (AHETF Canola data) 125,000(ST) 0.000125 240,000

Peas and Bean (AHETF Soybeans Data) 281,250(ST) 0.00028 780,000

Hopper-box, Planter-box, Slurry-box

Hopper-box, 

Planter-box, or 

Sslurry-box

SL, 

no G

12.6 0.0012 Corn (smut treatment) 0.04 3000 0.000018 1,700,000

Sorghum 0.005 800 0.0000006 50,000,000

Rapeseed 320 0.00000024 130,000,000

Peas 16000 0.000012 2,500,000

Beans 4960 0.0000015 20,000,000

a Daily amounts treated values are based on the information on Expo SAC policies 15 and 15.1

b Daily inhalation dose (mg/kg/d) = (unit exposure (mg/lb ai) * application. rate (lb ai/lb seed) * daily amounts treated / body weight (80 kg).

c Short- and intermediate -term inhalation MOE = NOAEL (30 mg/kg/day) / daily inhalation dermal dose. 
Sedaxane (129223) Human Health Risk Assessment D405099

Page 30 of 75

Table 9.1.2 Non-Cancer Risk for Handler-Seed Planters

Exposure Scenario 

(Scenario #)

Mitigation 

Level

Inhalation Unit 

Exposure 

(mg/lb ai)

Seed Type Application Rate

(lb ai per 100lb 

seed)

Amount 

Planteda

Daily

Inhalation

Doseb(mg/kg/day)

Short-Term 

Inhalation MOEc 

Seed Planters

Planting Treated Seed Corn 0.04 3,000 0.000051 590,000

Potato seed pieces 0.0025 800,000 0.00085 35,000

Sorghum 0.005 800 0.0000017 1,800,000

Rapeseed 0.005 320 0.00000068 4,400,000

Peas 0.005 16000 0.000034 880,000

Bean 0.005 4960 0.000011 2,800,000

a Daily amounts treated values are based on the information on Expo SAC policy 15. 1

b Daily inhalation dose (mg/kg/d) = (unit exposure (mg/lb ai) * application. rate (lb ai/lb seed) * daily amounts treated / body weight (80 kg).

c Short-term and intermediate-term inhalation MOE = NOAEL (30 mg/kg/d) / daily inhalation dose. 

Table 9.1.3 Primary Handler Cancer Risk for Sedaxane

Crop Dermal Dose a

(mg/kg/day)

Inhalation Dose a

(mg/kg/day)

Combined 

ADD b

(mg/kg/day)

LADDc

(mg/kg/day)

Cancer Riskd

Commercial : Mixer/Loader/Treater (G, No respirator)

Corn 2.30E-04 4.25E-05 2.73E-04 6.03E-05 3E-07

Sorghum 2.07E-04 3.83E-05 2.45E-04 2.71E-05 1E-07

Rapeseed 1.44E-04 2.66E-05 1.70E-04 1.88E-05 9E-08

Beans 2.30E-04 4.25E-05 2.73E-04 3.02E-05 1E-07

Peas 2.30E-04 4.25E-05 2.73E-04 2.65E-05 1E-07

Commercial :Sewer (Baseline)

Corn 6.20E-05 2.88E-05 9.08E-05 2.01E-05 9E-08

Sorghum 5.58E-05 2.59E-05 8.17E-05 9.04E-06 4E-08

Rapeseed 3.88E-05 1.80E-05 5.67E-05 6.28E-06 3E-08

Beans and peas 6.20E-05 2.88E-05 9.08E-05 1.00E-05 5E-08

Commercial :Bagger (Baseline)

Corn 9.10E-05 2.00E-05 1.11E-04 2.46E-05 1E-07

Sorghum 8.19E-05 1.8E-05 9.99E-05 1.11E-05 5E-08
Sedaxane (129223) Human Health Risk Assessment D405099

Page 31 of 75

Table 9.1.3 Primary Handler Cancer Risk for Sedaxane

Crop Dermal Dose a

(mg/kg/day)

Inhalation Dose a

(mg/kg/day)

Combined 

ADD b

(mg/kg/day)

LADDc

(mg/kg/day)

Cancer Riskd

Rapeseed 5.69E-05 1.25E-05 6.94E-05 7.68E-06 4E-08

Beans and peas 9.10E-05 2.00E-05 1.11E-04 1.23E-05 6E-08

Multiple Activities (G, no respirator)

Corn 4.20E-04 2.00E-05 6.20E-04 1.37e-04 6E-07

Sorghum 3.78E-04 1.80E-04 5.58E-04 6.17E-05 3E-07

Rapeseed 2.63E-04 1.25E-04 3.88E-04 4.29E-05 2E-07

Beans and peas 4.20E-04 2.00E-04 6.20E-04 6.86E-05 3E-07

Hopper-box, Planter-box, Slurry-box

Corn 1.51E-03 1.80E-06 1.51E-03 5.58E-05 3E-07

Sorghum 5.04E-04 6.00E-07 5.05E-04 1.86E-05 9E-08

Rapeseed 2.02E-04 2.40E-07 2.02E-04 7.44E-06 3E-08

Beans 3.12E-03 3.72E-06 3.13E-03 1.15E-04 5E-07

Peas 1.01E-02 1.20E-05 1.01E-02 3.72E-04 2E-06

a. Unit exposure (mg ai/lb of seed) x Application Rate (0.00005lb ai/lb of seed) x the amount of seed planted/day (lbs) // body weight (80kg)

b. ADD (mg/kg/day) = [Dermal Dose (mg/kg/day) x 8%DA]+ Inhalation Dose (mg/kg/day)

c. LADD (mg/kg/day) = ADD x [(180 days (corn) 90 days (all other crops) /yr Commercial)/ (365 days/yr)] x (35 yrs/78yrs)

d Cancer Risk = LADD x Q* ( 4.64 x 10-3 mg/kg/day)-1

Table 9.1.4: Planter Cancer Risk for Sedaxane

Crop Dermal Dose a

(mg/kg/day) (glove) Inhalation Dose a(mg/kg/day) No 

respirator

Planters ADDb

(mg/kg/day)

Planters / LADDc

(mg/kg/day)

Planters

Cancer Risk d

Corn 5.1E-05 3.0E-04 3.51E-05 1.29E-06 6E-09

Sorghum 1.00E-05 1.70E-06 1.17E-05 4.32E-07 2E-09

Rapeseed 4.00E-06 6.80E-07 4.68E-06 1.73E-07 8E-10

Beans 6.20E-05 1.05E-05 2.34E-04 8.63E-06 4E-08

Peas 2.00E-04 3.40E-05 7.25E-05 2.68E-06 1E-08

a. Unit exposure (mg ai/lb of seed) x Application Rate (0.00005lb ai/lb of seed) x the amount of seed planted/day (lbs) / body weight (80kg)

b. ADD (mg/kg/day) = [Dermal Dose (mg/kg/day) x 8%DA]+ Inhalation Dose (mg/kg/day)

c. Planter LADD (mg/kg/day) = ADD x [(30 days/yr)/ (365 days/yr)] x (35 yrs/78yrs)

d Planter Cancer Risk = LADD x Q* ( 4.64 x 10-3 mg/kg/day)-1
Sedaxane (129223) Human Health Risk Assessment D405099

Page 32 of 75

9.2 Short-/Intermediate-Term Post-Application Risk

9.2.1 Dermal Postapplication Risk

The potential for post-application exposures following the planting of sedaxane-treated seeds is 

unlikely. Sustained levels of contact with treated seed after it has been placed in the soil or 

other planting media would not be expected because no routine cultural practice required for the 

production of agricultural commodities involves such an activity as defined in the no/low contact 

criteria in the Worker Protection Standard (WPS). Also, as no dermal hazard has been identified, 

no quantitative post-application assessment is required for exposure to treated seeds that have 

already been planted.

The proposed labels require that workers wear long-sleeved shirt, long pants, shoes, socks and 

chemical-resistant gloves when opening bags of treated seed or loading/pouring the treated seed. 

No additional PPE requirements are necessary for labeling of treated seed. Certain tasks, even 

though they are not routine, may involve contact with the soil subsurface (e.g., repair of certain 

irrigation equipment) and they are covered by the REI. Therefore, the REI is based on the acute 

toxicity of the active ingredients. Note that REI recommendations include consideration of only 

sedaxane. A 12-hour REI is appropriate for sedaxane-treated seeds, although the Worker 

Protection Standard (WPS) allows workers to enter treated areas without restriction if there will 

be no worker contact with the treated seeds in the soil or planting media. If longer REIs are 

appropriate for any co-formulant(s) in the end-use product, those values should supersede the 

REI recommendation for sedaxane. 

9.2.2 Inhalation Postapplication Risk

A postapplication inhalation exposure assessment is not required as exposure is expected to be 

negligible. Seed treatment assessments provide quantitative inhalation exposure assessments for 

seed treaters and secondary handlers (i.e., planters). These exposure estimates are protective of 

any postapplication inhalation exposure scenarios.

10.0 References

Toxicology Reference

Author: Jessica Kidwell

Date: May 18, 2011

TXR No.: 0055854

Title: Sedaxane: Report of the Cancer Assessment Review Committee.

Author: Jessica Kidwell

Date: January 24, 2012 

Title: Sedaxane - ToxSAC Meeting on December 1, 2011.
Sedaxane (129223) Human Health Risk Assessment D405099

Page 33 of 75

Product Chemistry Reference

Author: Akiva Abramovitch

Date: November 2, 2011

DP Number: D382350

Title: Product Chemistry Review of Sedaxane Technical. 

Residue Chemistry References

Author: Ideliz Encarnacion

Date: November 10, 2011

DP Number: D387015

Title: Sedaxane Seed Treatment. Report of the Residues of Concern Knowledgebase 

Subcommittee (ROCKS). 

Author: Elizabeth Holman

Date: December 19, 2012

DP Number: D406945

Title: Sedaxane Seed Treatment Drinking Water Revisit. Report of the Residues of 

Concern Knowledgebase Subcommittee (ROCKS). 

Author: David Soderberg

Date: February 7, 2012

DP Number: D382526

Title: Sedaxane. Application for Section 3 Registration for Seed Treatment Use on 

Canola, Cereal Grains (Barley, Oats, Rye, Triticale, and Wheat), and Soybean. 

Summary of Analytical Chemistry and Residue Data.

Author: William Donovan

Date: March 12, 2013

DP Number: D407472

Title: Sedaxane. Petition fo the Establishment of Permanent Tolerances for Seed 

Treatment Use on Corn [Field, Pop, and Sweet], Crop Subgoup 6C [Pea and 

Bean, Dried Shelled, Except Soybean, Subgroup 6C], Crop Subgroup 20A 

[Rapeseed Subgroup 20A], and Sorghum. Summary of Analytical Chemistry and 

Residue Data.

Drinking Water Assessment

Author: Rochelle Bohaty

Date: December 21, 2011

DP Number: D382528

Title: Drinking Water Assessment for the Registration of Sedaxane.

Author: Rochelle Bohaty & James Hetrick

Date: March 18, 2013
Sedaxane (129223) Human Health Risk Assessment D405099

Page 34 of 75

DP Number: D405391 & D407956

Title: Drinking Water Assessment for the Proposed New Use of Sedaxane as a Seed 

Treatment on Corn, Sorghum, Dried Shelled Pea and Bean (Subgroup 6C; except 

soybean), Rapeseed (Subgroup 20A) and Potato.

Dietary Exposure Assessment

Author: William Donovan

Date: February 20, 2013

DP Number: D408793

Title: Sedaxane. Acute, Chronic, and Cancer Aggregate Dietary (Food and Drinking 

Water) Exposure and Risk Assessments to Support New Seed Treatment Uses on 

Corn [Field, Pop, and Sweet], Crop Subgoup 6C [Pea and Bean, Dried Shelled, 

Except Soybean, Subgroup 6C], Crop Subgroup 20A [Rapeseed Subgroup 20A], 

and Sorghum.

Occupational Assessment References

Author: Seyed Tadayon

Date: February 28, 2013

DP Number: D408790

Title: Sedaxane: Occupational and Residential Exposure/Risk Assessment of Sedaxane 

for Seed Treatment Uses on Rapeseed, Sorghum, Crop Group 6A (except 

soybean), Corn, and Potato Seed Piece.

Science Advisory Council for Exposure (ExpoSAC) Policy 14: Standard Operating Procedures 

(SOPs) for Seed Treatment (May 1, 2003).

ExpoSAC Policy 15: Amount of Seed Treated or Planted per Day (March 2, 2004).
Sedaxane (129223) Human Health Risk Assessment D405099

Page 35 of 75

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The toxicological data requirements (40 CFR 158.340) for food uses for sedaxane are in Table 

A1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols 

were used.

Table A.1 Sedaxane Toxicology Data Requirements

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity ...........................................................

870.1200 Acute Dermal Toxicity.......................................................

870.1300 Acute Inhalation Toxicity...................................................

870.2400 Primary Eye Irritation.........................................................

870.2500 Primary Dermal Irritation...................................................

870.2600 Dermal Sensitization

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Sub-chronic (rodent) ..................................................

870.3150 Oral Sub-chronic (non-rodent)...........................................

870.3200 21/28-Day Dermal..............................................................

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

870.3465 90-Day Inhalation ..............................................................

yes

yes

yes

no

no

yes

yes

yes

---

---

870.3700a Developmental Toxicity (rodent) .......................................

870.3700b Developmental Toxicity (non-rodent)................................

870.3800 Reproduction......................................................................

yes

yes

yes

yes 

yes 

yes

870.4100a Chronic Toxicity (rodent)....................................................

870.4100b Chronic Toxicity (non-rodent) ............................................

870.4200a Oncogenicity (rat) ...............................................................

870.4200b Oncogenicity (mouse).........................................................

870.4300 Chronic/Oncogenicity .........................................................

yes

yes 

yes 

yes 

yes

yes

yes 

yes

yes 

yes

870.5100 Mutagenicity--Gene Mutation - bacterial

870.5300 Mutagenicity--In vitro, Mammalian cells

870.5375 Mutagenicity--Structural Chromosomal Aberration

870.5395 Mutagenicity--In Vivo Mammalian Cytogenetics

yes

yes 

yes 

yes 

yes

yes 

yes 

yes

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

870.6100b 90-Day Neurotoxicity (hen) ................................................

870.6200a Acute Neurotox. Screening Battery (rat).............................

870.6200b 90-Day Neurotox. Screening Battery (rat) ..........................

870.6300 Developmental Neurotoxicity .............................................

no

no

yes

yes

no

---

---

yes 

yes

---

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

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

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

yes

CR

yes

yes

yes

yes

CR: Conditionally Required.

---: Not Provided.
Sedaxane (129223) Human Health Risk Assessment D405099

Page 36 of 75

A.2 Toxicity Profiles

A.2.1 Sedaxane Acute Toxicity

Study Type MRID(s) Results

US EPA 

Toxicity 

Category

870.1100

Acute Oral, Rat 

MRID 

47473366

LD50 = 5000 

mg/kg/bw

(95% CI 

2513-9210)

Females

III

870.1200

Acute Dermal, 

Rat

MRID 

47473367

LD50 > 5000 

mg/kg/bw IV

870.1300

Acute 

Inhalation, Rat

MRID 

47473368

LC50 >5.24 

mg/L IV

870.2400

Acute Eye 

irritation, rabbit

MRID 

47473370

Minimally 

irritating IV

870.2500

Acute Dermal 

Irritation, Rabbit

MRID 

47473369 Non-irritating IV

870.2600

Skin 

sensitization, 

mouse LLNA

MRID 

47473371 Negative Not a skin sensitizer

A.2.2 Metabolite CSCD465008 Acute Toxicity

Study Type MRID(s) Results

US EPA 

Toxicity 

Category

870.1100

Acute Oral, Rat 

CSCD465008

Metabolite

MRID 

47473366

LD50 > 2000 

mg/kg/bw

Females

III
Sedaxane (129223) Human Health Risk Assessment D405099

Page 37 of 75

A.2.2 Sub-chronic, Chronic, Other Toxicity

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

Rat Sub-chronic 

Oral Toxicity 

28-day CSCD465008 Metabolite, 

Rat

(Oral-dietary)

MRID 47746827

Acceptable/Non-Guideline

0, 2000, 6000, 12000 ppm

♂: 0, 175, 497, 1018 mg/kg 

bw/day 

♀: 0, 176, 525, 1107 mg/kg 

bw/day 

No treatment-related effects on survival, 

clinical signs, body weights, food 

consumption, FOB, motor activity, 

ophthalmoscopy, hematology, clinical 

chemistry, organ weights, urinalysis or 

histopathology. No treatment-related 

effects on cytochrome P450 content, 7-

ethoxyresorufin O-dealkylation 

(CYP1A1/2) or 7-pentoxyresorufin Odealkylation (CYP2B1/2) were observed.

NOAEL= 497/1107 mg/kg/day

LOAEL= 1018/ND mg/kg/day, 

based on decreased kidney weights

28-day Comparative Isomer 

Toxicity, Rat (trans isomer, cis 

isomer and a racemic 1:1 cis-trans 

mixture of sedaxane)

(Oral-dietary)

MRID 47473372.

Acceptable/Non-Guideline

0, 500, 2000, 5000 ppm

SYN508210: ♂ 0, 47.0, 187.4, 

438.2 mg/kg bw/day, ♀ 0, 48.4, 

177.1, 384.3 mg/kg bw/day

SYN508211: ♂ 0, 45.9, 182.7, 

438.2 mg/kg bw/day, ♀ 0, 47.6, 

179.6, 435.8 mg/kg bw/day

SYN524464: ♂ 0, 47.5, 181.2, 

444.6 mg/kg bw/day, ♀ 0, 46.7, 

181.1, 428.1 mg/kg bw/day 

SYN508210 (trans), SYN508211 (cis) and 

SYN524464 (1:1 cis-trans mixture) had

similar effects on body weight, liver weight 

and cholesterol levels, however, the trans 

form had a slightly more effect. The cis 

form at 435.8-438.2 mg/kg/day decreased 

heart weight significantly in both genders 

(a tissue with high mitochondrial content).

All isomers caused increased 16β 

hydroxylation of testosterone, consistent 

with being potent inducers of CYP 2B 

isoforms. The 3 test compounds caused 

decreases in 16α and 2α hydroxylation in 

males but increases in females. Both 16α 

and 2α are markers for the cytochrome 

isoenzyme CYP 2C11. The above findings 

were supported by increased CYP 2B and 

CYP 3A contents. The weakly increased 

EROD activity suggests that SYN508210, 

SYN508211 and SYN524464 do not act as 

polycyclic aromatic hydrocarbon-type 

inducers.

Toxicokinetics: Tmax =12-20 h; no 

obvious differences between the trans and 

cis isomers; Cmax and AUC were ~10-fold 

lower in the cis isomer group vs. trans 

isomer group.
Sedaxane (129223) Human Health Risk Assessment D405099

Page 38 of 75

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

870.3100

90-day Rat, Sedaxane 

(Oral-Diet)

MRID #47473375.

Acceptable/Guideline

0, 250, 1000, 4000 ppm

♂: 0, 18.6, 72.9, 299.6 mg/kg 

bw/day

♀: 0, 21.4, 85.7, 315.3 mg/kg 

bw/day 

NOAEL = 72.9/85.7 mg/kg/day ♂/♀

LOAEL = 299.6/315.3 mg/kg/day, based 

on decreased body weights, food 

consumption and food efficiency, increased 

total protein, increased liver weight, 

centrilobular hypertrophy and pigmentation 

in the liver in both sexes, plasma albumin 

in males and increased platelet counts, 

increased plasma cholesterol and decreased 

heart weights in females.

870.3100

13-Week Rat, Sedaxane

(Oral-Diet)

MRID 47473376

Acceptable/Guideline

0, 300, 2000, 4000 ppm

♂: 0, 24.8, 168.0, 325.1 mg/kg 

bw/day

♀: 0, 28.3, 186.0, 349.8 mg/kg 

bw/day

NOAEL=24.8/28.3 mg/kg/day ♂/♀

LOAEL= 168.0/186.0 mg/kg/day ♂/♀,

based on decreased body weight and body 

weight gain in females and decreased 

forelimb grip strength in both sexes. Dose 

spacing not a good as other 90-day study.

Mouse Sub-chronic 

Oral Toxicity

28-day Mouse, Sedaxane

(Oral-Diet)

MRID 47473373.

Acceptable/Non-Guideline

0, 1000, 5000, 7000 ppm

♂: 0, 178, 920, 1268 mg/kg/day

♀: 0, 248, 1150, 1800 mg/kg/day

NOAEL=920 mg/kg/day

LOAEL=1268 mg/kg/day, based on 

decreased serum calcium levels and 

increased triglycerides in males.

870.3100

90-day Mouse, Sedaxane

(Oral-Diet)

MRID 47473377.

Acceptable/Guideline

0, 500, 3500, 7000 ppm

♂: 0, 80, 567, 1167 mg/kg/day

♀: 0, 112, 810, 1455 mg/kg/day 

NOAEL=567/1455 mg/kg/day ♂/♀

LOAEL=1167/NA mg/kg/day based on 

decreased body weight, body weight gains, 

food efficiency, total bilirubin, and 

increased adjusted liver and testes weights. 

Also based on decreased white blood cells 

and lymphocytes.
Sedaxane (129223) Human Health Risk Assessment D405099

Page 39 of 75

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

Dog Sub-chronic 

Oral Toxicity

28-day Dog, Sedaxane

(Oral-Capsule)

MRID 47473374

Acceptable/Non-Guideline

0, 50, 100, 300 mg/kg/day

NOAEL= 50 mg/kg/day

LOAEL= 100 mg/kg/day, based on liver 

vacuolation at 100 mg/kg/day (♀) and at 

300 mg/kg/day (♂).

870.3150

90-day Dog, Sedaxane

(Oral-Capsule)

MRID 47473378. 

Acceptable/Guideline

0, 50, 150, 400 mg/kg/day

NOAEL = 150/Not determined mg/kg 

bw/day ♂/♀

LOAEL = 400/50 mg/kg bw/day ♂/♀, 

based on decreased body weight, body 

weight gain, food consumption, 

lymphocyte counts, , spleen weights (♂); 

decreased body weight and body weight 

gain (preceded by body weight loss) (♀)

At 150 mg/kg bw/day, decreased 

leukocytes, lymphocytes and monocytes 

(♀).

At 400 mg/kg bw/day, also decreased 

spleen weights (♀)

Rat 28-Day Dermal 

Toxicity 

870.3200

Rat, Sedaxane

MRID 47473380

Acceptable/Guideline

0, 100, 300, 1000 mg/kg bw/day

NOAEL= 1000 mg/kg/day

LOAEL= Not determined, no systemic 

effects

Rat Prenatal 

Developmental 

Toxicity 

Preliminary Rat Study - Sedaxane

(Oral-Gavage)

MRID 47473391

Acceptable/Non-Guideline

0, 200, 500, 750 mg/kg bw/day

Maternal NOAEL= Not determined

Maternal LOAEL=200 mg/kg/day, based 

on decreased body weight gains and food 

consumption.

At 500 mg/kg bw/day (exceeded MTD), 

decreased body weight and food 

consumption, body weight loss; decreased 

activity, ruffled fur, poor clinical condition, 

lateral recumbency, uncoordinated 

movements)-animals were sacrificed for 

humane reasons prior to study termination. 

At 750 mg/kg bw/day, one death (GD 11).

Fetal NOAEL/LOAEL = Not determined
Sedaxane (129223) Human Health Risk Assessment D405099

Page 40 of 75

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

870.3700a

Definitive Rat Developmental 

Study - Sedaxane

(Oral-Gavage)

MRID 47473392.

Acceptable/Guideline

0, 25, 100, 200 mg/kg bw/day 

Maternal NOAEL= 100 mg/kg bw/day

Maternal LOAEL= 200 mg/kg bw/day, 

based on decreased body weight, body 

weight gain, food consumption.

Fetal NOAEL = 100 mg/kg bw/day

Fetal LOAEL = 200 mg/kd/day based on 

decreased fetal weights

Rabbit Prenatal 

Developmental 

Toxicity 

Preliminary Rabbit 

Developmental Study - Sedaxane

(Oral-Gavage)

MRID 47473393.

Acceptable/Non-Guideline

0, 100, 300, 500 mg/kg/day

Maternal NOAEL=100 mg/kg/day

Maternal LOAEL=300 mg/kg/day, 

based on increased liver weight 

(histopathology was not conducted), 

decreased defecation, decreased body 

weight gain/body weight loss, food 

consumption.

At 500 mg/kg bw/day, increased liver 

weight (histopathology was not 

conducted), decreased defecation, 

decreased body weight gain/body weight 

loss, food consumption; increased 

mortality (2♀ on GD 16; 1♀ delivered 

early on GD 29), preceded by BW loss, 

decreased food consumption, decreased 

defecation and/or soft stool.

Fetal NOAEL = 500 mg/kg/day

Fetal LOAEL= ND, No adverse effects at 

any dose level based on a limited number 

of parameters assessed.

870.3700b

Definitive Rabbit Developmental 

Study- Sedaxane

(Oral-Gavage)

MRID 47473394.

Acceptable/Guideline

0, 25, 100, 200 mg/kg bw/day

Maternal NOAEL= 100 mg/kg/day

Maternal LOAEL= 200 mg/kg/day, based 

on abortions, decreased body weight 

gain/body weight loss, reduced food 

consumption, defecation.

Fetal NOAEL = 100 mg/kg/day

Fetal LOAEL = 200 mg/kg/day, based on 

increased unossified sternebrae and 13th 

rudimentary ribs and a decrease in fetal 

weights (-9%) and increased abortions.
Sedaxane (129223) Human Health Risk Assessment D405099

Page 41 of 75

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

Rat Reproduction 

and Fertility Effects 

Preliminary Rat Reproduction 

Study- Sedaxane

(Oral-Diet)

MRID 47473389. 

Acceptable/Non-Guideline

0, 500, 1500, 3600 ppm

(~0, 50, 150, 360 mg/kg bw/day; 

assuming that 0.100 ppm = 1 

mg/kg bw/day)

Parental NOAEL= 50 mg/kg/day

Parental LOAEL= 150 mg/kg/day,

based on decreased body weight, body 

weight gains, food consumption (♀); 

increased liver weights, abnormally 

darkened livers (♀). 

At 360 mg/kg bw/day (exceeded MTD), 

decreased body weight, body weight gains, 

food consumption; increased liver weights, 

abnormally darkened livers (♀).

Repro NOAEL= 150 mg/kg/day

Repro LOAEL= 360 mg/kg/day

(exceeded MTD), based on decreased 

mean implantation sites, number of pups 

born; increased number of pup deaths (LD 

0-4); decreased mean litter size, viability 

index, lactation index; increased missing 

pups (presumed cannibalized).

Offspring NOAEL= 50 mg/kg/day

Offspring LOAEL= 150 mg/kg/day, based 

on decreased body weights, increased liver 

weights.

At 360 mg/kg bw/day (exceeded MTD), 

decreased body weight and body weight 

gains, increased liver weights.
Sedaxane (129223) Human Health Risk Assessment D405099

Page 42 of 75

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

870.3800

Definitive Rat Reproduction 

Study- Sedaxane

(Oral-Diet)

MRID 47473390.

Acceptable/Guideline

0, 200, 500, 1500 ppm 

P generation: ♂ 0, 16, 41, 120 

mg/kg bw/day; ♀ 0, 18, 46, 143 

mg/kg bw/day

F1 generation: ♂ 0, 17, 43, 134 

mg/kg bw/day; ♀ 0, 19, 47, 141 

mg/kg bw/day

Parental 

NOAEL= 500 ppm (41/46 mg/kg bw/day 

♂/♀)

LOAEL = 1500 ppm (120/143 mg/kg 

bw/day ♂/♀) body weight gain (P ♀ 

premating), food consumption (P ♂ 

premating; ♀ throughout), decreased 

ovarian weights (F1 ♀). 

Repro NOAEL = 14.3 mg/kg/day, based 

on the LOAEL and a 10X UF due to 

missing follicle data

Repro LOAEL= Not determined/143 

mg/kg bw/day ♂/♀, based on decreased 

primordial (P gen), growing and antral 

follicles (F1 gen) and corpora lutea (P and 

F1 gen); increase in lactational diestrous, 

increased implantation loss.

No follicle counts at two intermediate 

doses, thus a 10X UF is applied to 

determine the NOAEL.

Offspring NOAEL = 43/47 mg/kg/day, 

(500 ppm)

Offspring LOAEL= 134/141 mg/kg/day

(1500 ppm), based on decreased pup body 

weights, increased liver weight 

(histopathology not conducted), decreased 

spleen weight (histopathology not 

conducted). 

 

Chronic Dog 

Toxicity 

(1 Year)

870.4100a

Sedaxane

(Oral-Capsule)

MRID 47473379.

Acceptable/Guideline

0, 15, 50, 200 mg/kg bw/day

NOAEL = 50 mg/kg/day

LOAEL = 200 mg/kg bw/day based on 

decreased body weights, body weight gains 

and food consumption, decreased spleen 

weights in both sexes, plus decreased 

glucose levels and decreased testes weight 

in males. Hypoglycemia can be an 

indication of mitochondrial inhibition in 

the liver.

Mice 

Carcinogenicity 

(CD-1)

870.4200b

Sedaxane

(Oral-Diet)

MRID 47473388.

Acceptable/Guideline

NOAEL= NOAEL = 157/185 mg/kg/day 

♂/♀

LOAEL = 900/1001 mg/kg/day ♂/♀, based 

on decreased body weight, body weight 

gains, food efficiency; increased incidences 

of hepatocellular adenomas, carcinomas 

and combined hepatocellular adenomas 
Sedaxane (129223) Human Health Risk Assessment D405099

Page 43 of 75

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

0, 200, 1250, 7000 ppm

♂: 0, 25, 157, 900 mg/kg/day

♀: 0, 29, 185, 1001 mg/kg/day

and/or carcinomas (♂).

Rat Chronic 

Toxicity/ 

Carcinogenicity

870.4300

Sedaxane

(Oral-Diet)

MRID 47473386.

Acceptable/Guideline

0, 200, 1200, 3600 ppm

♂ 0, 11, 67, 218 mg/kg bw/day

♀: 0, 14, 86, 261 mg/kg bw/day 

NOAEL= 11/14 mg/kg bw/day ♂/♀

LOAEL = 67/86 mg/kg bw/day ♂/♀, based 

on increased liver weight, increased 

incidences of hepatocyte hypertrophy and 

eosinophilic foci, and thyroid follicular cell 

hypertrophy, basophilic colloid and 

epithelial desquamation, plus increased 

phosphate levels (oxidative 

phosphorylation inhibition)(♂). In females, 

it was based on decreased body weight and 

body weight gain, increased liver weight 

and the same thyroid histopathology noted 

above for males.

At 218/261 mg/kg bw/day, decreased food 

efficiency Wk 1-13; decreased body 

weight, bodyweight gain, increased GGT 

(marginal), glucose, phosphate, increased 

thyroid follicular cell adenomas & liver 

hepatocellular adenomas (♂); decreased 

food consumption, increased hepatocyte 

hypertrophy and pigment, thyroid follicular 

cell hyperplasia, thymus epithelial tubular 

hyperplasia, kidney 

inflammation/inflammatory cell 

infiltration; decreased vaginal mucification, 

increased uterine adenocarcinomas (♀).

Bacterial Reverse 

Mutation Test 

870.5100

Sedaxane

MRID47473381 

Acceptable/Guideline

Doses up to 5000μg/plate (with 

and without activation)

Negative. There was no evidence of 

induced reverse mutations with or without 

activation.
Sedaxane (129223) Human Health Risk Assessment D405099

Page 44 of 75

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

870.5100 

CSCD465008 (metabolite)

MRID 47746852. 

Acceptable/Guideline

Doses up to 5000 μg/plate (with 

and without activation)

Negative. There was no evidence of 

induced reverse mutations with or without 

activation.

In vitro mammalian 

cell gene mutation 

test

870.5300

Sedaxane

MRID 47473383. 

Acceptable/Guideline

4 hr (without activation): 6.9-82.5 

(Exp. 1), 20-90 μg/mL (Exp. 2)

4 hr (with activation): 13.8-110.0 

(Exp.1), 20.0-100.0 μg/mL (Exp. 

2)

Negative. There was no evidence of gene 

mutations with or without activation.

870.5300

CSCD465008 (metabolite)

MRID 47746856. 

Acceptable/Guideline

4 hr (with or without activation): 

110-1760μg/mL

Negative. There was no evidence of gene 

mutations with or without activation.

In vitro mammalian 

chromosome 

aberration test

870.5375

Sedaxane

MRID 47473382. 

Acceptable/Guideline

6 hr (without activation): 52.4-

200 μg/mL; 6hr (with activation): 

65.5-250μg/mL; 24 hrs (without 

activation): 41.9-160 μg/mL

Negative.
Sedaxane (129223) Human Health Risk Assessment D405099

Page 45 of 75

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

870.5375

CSCD465008 (metabolite)

MRID 47746860.

Acceptable/Guideline

4 or 22 hr (without activation): 

574.7-1760μg/mL; 4 hr (with 

activation): 328.4-1005.7μg/mL 

(Exp. 1), 574.7-1760.0 μg/mL 

(Exp. 2)

Negative. There was no evidence of 

chromosomal aberrations with or without 

activation.

Mammalian 

erythrocyte 

micronucleus testMouse

870.5395

Sedaxane

MRID 47473384.

Acceptable/Guideline

♂: 0, 500, 1000, 2000mg/kg bw

Negative. There was no significant increase 

in the frequency of micro-nucleated 

polychromatic erythrocytes.

Unscheduled DNA 

Synthesis

870.5550

Sedaxane 

MRID 47473385.

Acceptable/Guideline

0, 500, 1000, 2000 mg/kg bw

Negative. The test material did not induce 

UDS in primary rat hepatocytes up to 2000 

mg/kg.

Acute Neurotoxicity 

Screening Battery–

Rat (Sprague 

Dawley)

Preliminary Rat ACN Study

Sedaxane

(Oral-Gavage)

MRID 47473395.

Acceptable/Non-Guideline

0, 80, 1000, 2000 mg/kg bw

NOAEL= Not determined

LOAEL= 80 mg/kg,

based on increased piloerection (2-8 h postdose); hunched posture, spasms, reduced 

activity also noted sporadically

At 1000 and 2000 mg/kg bw, increased 

piloerection (2-8 h ♂, beyond day 4 ♀ 

post-dose); hunched posture, spasms, 

reduced activity, reduced activity, hunched 

posture, spasms, piloerection, 

uncoordinated movements (peak effect at 3 

h post-dose), decreased body weight and 

body weight gains. 
Sedaxane (129223) Human Health Risk Assessment D405099

Page 46 of 75

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

870.6200a

Rat ACN Study

Sedaxane

(Oral-Gavage)

MRID 47473396.

Acceptable/Guideline

0, 30, 250, 2000 mg/kg bw

NOAEL = 30 mg/kg bw 

LOAEL = 250 mg/kg bw, based on 

reduced activity, decreased rearing, initial 

inactivity, piloerection, ruffled fur and 

recumbency, decreased body weight, body

weight gains and food consumption (♂); 

plus weakened condition, swaying gait, 

decreased activity, reduced muscle tone 

and decreased locomotor activity & rearing 

(♀).The weakened condition, swaying gait 

and decreased activity were observed on 

days 2-7, while the other effects were on 

day 1.

Hypothermia occurred at 2000 mg/kg.

Sub-Chronic 

Neurotoxicity 

Screening Battery–

Rat

28-Day

Preliminary SCN Study -

Sedaxane

(Oral-Diet)

MRID 47473397.

Acceptable/Non-Guideline

0, 500, 2000, 5000 ppm 

♂ 0, 37.8, 153.5, 360.1 mg/kg 

bw/day 

♀ 0, 40.1, 156.4, 338.8 mg/kg 

bw/day 

NOAEL= 37.8 mg/kg/day

LOAEL= 153.5/156.4 mg/kg/day, 

based on decreased food efficiency, body 

weight (♀), body weight gain (♀), food 

consumption (♀). 

At 360.1/338.8 mg/kg bw/day ♂/♀, 

decreased body weight, body weight gain, 

food consumption. No neurobehavioral 

were performed in this range-finding study.

870.6200b

90-Day SCN Rat Study

Sedaxane

(Oral-Diet)

MRID 47473398.

Acceptable/Guideline

0, 300, 1000, 4000 ppm 

♂ 0, 19.7, 66.0, 260.0 mg/kg 

bw/day ♀ 0, 24.3, 79.7, 302.9 

mg/kg bw/day 

NOAEL = 66.0/79.7 mg/kg bw/day ♂/♀

LOAEL = 260.0/302.9 mg/kg bw/day ♂/♀,

based on decreased body weight, body 

weight gains, food consumption, food 

efficiency, as well as reduced locomotor 

activity.
Sedaxane (129223) Human Health Risk Assessment D405099

Page 47 of 75

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

870.7485

Rat Metabolism and 

Pharmacokinetics

870.7485

Rat Excretion and Tissue 

Distribution-Sedaxane

(Oral-Gavage)

MRID 47473359.

Acceptable/Guideline

Metabolism-Single Dose Oral

Recoveries of radioactivity ranged between 

96.3-104.9% AD, with no significant 

differences in tissue distribution or 

excretion between the dose levels. The 

primary route of excretion of [pyrazole14C]-SYN524464 was via the feces in both 

sexes, with urinary excretion slightly 

higher in females. The absorbed 

radioactivity was rapidly distributed 

throughout the tissues and rapidly cleared 

without accumulation of radio-labelled 

SYN524464 in the tissues. 

870.7485

Rat Pharmacokinetics-Sedaxane

(Oral-Gavage)

MRID 47473355.

Acceptable/Guideline

Metabolism-Single Dose Oral

A mean of 91.6% or 97.2% AD was 

eliminated in urine and feces over 72 h by 

male and female rats. The major route of 

elimination was via the feces; however, 

urinary elimination was also an important 

route of excretion in both sexes and 

slightly more pronounced in females 

compared to males.

Recoveries of radioactivity ranged between 

91.5-101.1% AD. Concentrations of 

[pyrazole-5-

14C]-SYN524464 were slightly 

higher in plasma than in whole blood at 

most time points, suggesting that total 

radioactivity was relatively evenly 

distributed between them.

In general, Tmax was achieved at 1-6 h post 

dose and declined with estimated terminal 

half-life values ranging from 22.65-28.76 

h. Terminal half-life values of 20.71-39.86 

h were obtained for blood. 

There were no apparent differences in the 

AUC and Cmax values between genders, or 

between the dose levels. As doses of 

[pyrazole-5-

14C]-SYN524464 were 

increased from 1 to 80 mg/kg bw, systemic 

exposure to total radioactivity exhibited a 

118-140 fold increase but, due to the 

observed variability in the concentrations 

for individual rats, this was not considered 

significant. 
Sedaxane (129223) Human Health Risk Assessment D405099

Page 48 of 75

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

870.7485

Excretion in Bile Duct 

Cannulated Rats (pyrazole label) -

Sedaxane

(Oral-Gavage)

MRID 47473357.

Acceptable/Guideline

The majority of the administered 

radioactivity was excreted within the first 

day post-dose for both dose levels. 

Absorption was estimated to be 87-89% 

AD in males and 88-92% AD and females. 

Fecal excretion and gastrointestinal tract 

contents were less than 7% AD. Biliary 

excretion represented the predominant 

excretion route for both sexes at 79-82% 

AD. Urinary excretion of the absorbed 

dose was limited, accounting for 

approximately 6-7% AD in males and 7-

10% AD in females. 

870.7485

Excretion in Bile Duct 

Cannulated Rats (phenyl label) -

Sedaxane

(Oral-Gavage)

MRID 47473360.

Acceptable/Guideline

There were no significant differences in 

absorption and elimination patterns 

between dose levels or between genders. 

For both dose groups, the majority of the

administered radioactivity was excreted 

within the first day post-dose and biliary 

excretion represented about 79-85% AD, 

with urinary excretion , accounting for 

approximately 5-8% AD. Absorption was 

estimated to be 87-94% AD (urine 

radioactivity, cage washes, bile and 

residual carcass) with fecal excretion and 

GI tract contents were less than 7% AD.
Sedaxane (129223) Human Health Risk Assessment D405099

Page 49 of 75

Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

870.7485

Rat Tissue Depletion-Sedaxane

(Oral-Gavage)

MRID 47473358.

Acceptable/Guideline

The tissue distribution of a single oral dose 

of 1 or 80 mg [pyrazole-5-

14C]-SYN524464/kg bw was extensive. 

Plasma half-lives ranged from 25.84-32.33 

h for both dose group and half-lives in the 

whole blood ranged from 29.49-40.10 h. 

Tissue concentrations of radioactivity were 

highest at 1-1.5 h for low dose and 5 h for 

high dose with progressively decreased 

thereafter with elimination half lives of 

0.1-3.2 days. Most mean tissue 

concentrations were near the limit of 

reliable measurement by 96 h post dose. 

The high levels of radioactivity in the 

gastrointestinal tract and its contents were 

consistent with the established biliary 

elimination and fecal excretion of 

SYN524464 metabolites. There were no 

pronounced gender differences in tissue 

distribution, depletion profiles, or half-lives 

of elimination in the plasma or whole 

blood. 

870.7485

Rat Investigation of the Nature 

and Identity of Radio-labeled 

Metabolites-Sedaxane

(Oral-Gavage)

MRID 47473356.

Acceptable/Guideline

The major metabolites were the trans para 

phenol CSCD658906 and the desmethyl 

trans para phenol CSCD659087 which 

together with the equivalent cis para phenol 

isomers. SYN524464 was extensively 

metabolized by rats through demethylation, 

hydroxylation, oxidation and conjugation 

pathways resulting in a number of 

hydroxylated metabolites and metabolites 

formed by cleavage of the terminal 

cyclopropyl moiety. Glucuronic acid, 

sulphate and glutathione conjugates were 

also formed. CSCD659090 and 

CSCD668404 accounted for approximately 

half the administered dose. 
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Acute, Sub-chronic, Chronic, and Other Toxicity Profile – Sedaxane Technical

Study Type

MRID No. / Classification/ 

Doses Results

870.7485

Tissue Distribution and 

Elimination in the Rat - Repeated 

Dose -Sedaxane

(Oral-Gavage)

MRID 47473362.

Acceptable/Guideline

The majority of the oral administered 

radioactivity was excreted via the feces at 

60.9% AD over the 24 h collection period, 

with urinary excretion at 13.0% AD. 

Recovery of administered radioactivity was 

incomplete by 24 h post-dose with a mean 

of 75.7% AD. Similar results were 

obtained after 14 daily dosings, with some 

of the dosing from day 13 also contributing 

to the day 14 elimination.

Tissue concentrations of radioactivity were 

highest at 24 h following the fourteenth 

and final dose with the exception of whole 

blood and plasma, for which the highest 

mean concentrations were observed 24 h 

after the tenth dose. The liver and kidney 

had the highest levels after 14 daily 

dosings, respectively. Most mean tissue 

concentrations appeared either to have 

attained or to be approaching steady state 

kinetics by the end of the 14 day dosing 

period. The high levels of radioactivity in 

the gastrointestinal tract and its contents 

were consistent with the established biliary 

elimination and fecal excretion of 

SYN524464 metabolites. There were no 

pronounced sex differences in tissue 

distribution, depletion profiles, or half-lives 

of elimination in the plasma or whole 

blood.

ImmunotoxicityMouse (CD-1)

870.7800

Sedaxane

(Oral-Diet)

MRID 47473405.

Acceptable/Guideline

0, 62.5, 250 and 1000 mg/kg/day

NOAEL =1080.1 mg/kg bw/day

LOAEL = Not determined, no decrease in 

TDAR response, Spleen and thymus 

weight changes not statistically significant 

(high coefficients of variation noted for 

IgM data)
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A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) – All Populations

Study Selected: Acute Neurotoxicity Study 

MRID No.: 47473396

Executive Summary: See Appendix A, Guideline [§ 870.6200a]

Dose and Endpoint for Establishing aRfD: The NOAEL of 30 mg/kg/day is based on clinical 

signs of reduced activity, decreased rearing, initial inactivity, piloerection, ruffled fur and 

recumbency, decreased body weight, body weight gains and food consumption in males at the 

LOAEL of 250 mg/kg. The weakened condition, swaying gait and decreased activity were 

observed on days 2-7, while the other effects were on day 1.

UF(s): A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies 

variation (10X).

Comments on Study/Endpoint/UFs: This study provides the lowest NOAEL in the database 

considered to be valid for an acute effect and is protective for any potential adverse effects in 

humans, including the Females 13+ category. A preliminary ACN study with a LOAEL of 80 

mg/kg/day (LDT) based on increased piloerection (2-8 hrs postdosing), hunched posture, spasms, 

and reduced activity provides confidence in the NOAEL/LOAEL (30/250 mg/kg/day, which is a 

large dose spread) for the definitive ACN study. The 28-day dog study was also considered with 

a higher NOAEL of 50 mg/kg/day, however, the only effect at 250 mg/kg/day was liver 

vacuolation at 100 mg/kg/day. The 28-day mouse study had a very high NOAEL of 920 

mg/kg/day. A separate endpoint for Females 13+ is not required. There were no single dose 

effects identified in the developmental toxicity studies, including the abortions seen in the 

developmental toxicity study in rabbits. 

aRfD = 30 mg/kg/day (NOAEL) = 0.30 mg/kg/day

 100 (UF)

A.3.2 Chronic Reference Dose (cRfD) – All Populations

Study Selected: Chronic Toxicity/Carcinogenicity (Feeding)/Rat

MRID No.: 47473386

Executive Summary: See Appendix A, Guideline [§ 870.4300]

Dose and Endpoint for Establishing cRfD: The NOAEL was 11 mg/kg/day and the LOAEL = 

67/86 mg/kg bw/day based on increased liver weight, increased serum phosphate, increased 

incidences of hepatocyte hypertrophy and eosinophilic foci, and thyroid follicular cell 

hypertrophy, basophilic colloid and epithelial desquamation (♂). In females, it was based on 
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decreased body weight and body weight gain, increased liver weight and the same thyroid 

histopathology noted for males.

UF(s): A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies variation (10X).

Comments about Study/Endpoint/UF: This study provides the lowest NOAEL in the database 

(most sensitive endpoint) and will also provide the most protective limits for human effects. The 

chronic dog study was also considered, however, the NOAEL was higher at 50 mg/kg/day with a 

LOAEL of 200 mg/kg/day based on decreased body weights, body weight gains and food 

consumption, decreased spleen weights in both sexes, plus decreased glucose.

cRfD = 11 mg/kg/day (NOAEL) = 0.11 mg/kg/day

 100 (UF)

A.3.3 Incidental Oral– All Durations

Study Selected: Acute Neurotoxicity Study 

MRID No.: 47473396

Executive Summary: See Appendix A, Guideline [§ 870.6200a]

Dose and Endpoint for Establishing aRfD: The NOAEL of 30 mg/kg/day is based on clinical 

signs of reduced activity, decreased rearing, initial inactivity, piloerection, ruffled fur and 

recumbency, decreased body weight, body weight gains and food consumption in males at 250 

mg/kg. The weakened condition, swaying gait and decreased activity were observed on days 2-7, 

while the other effects were on day 1.

UF(s): A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies 

variation (10X).

Comments on Study/Endpoint/UFs: This study provides the lowest NOAEL in the database 

considered to be valid for this exposure and duration, thus is protective for any potential adverse 

effects in humans (i.e. 90-day rat study, SCN study, chronic dog study). The 28-day dog study 

was also considered with a higher NOAEL of 50 mg/kg/day, however, the only effect at 250 

mg/kg/day was liver vacuolation at 100 mg/kg/day. The 28-day mouse study had a very high 

NOAEL of 920 mg/kg/day. The 2-generation reproductive toxicity study in rats, which is 

typically used for this endpoint, with an offspring NOAEL of 41 mg/kg/day (offspring LOAEL 

of 120 mg/kg/day) is also an appropriate study to use for this endpoint. However, the NOAELs 

of 30 and 41 mg/kg/day are similar and the NOAEL of 30 mg/kg/day from the ACN is protective 

of all effects, including all sensitivities. In the future the ACN endpoint could be aggregated.

A.3.4 Dermal--- All Durations
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A dermal assessment is not required. The 28-day dermal study had no systemic effects at 

the limit dose of 1000 mg/kg/day and dermal exposure is limited for a seed treatment.

A.3.5 Inhalation– All Durations

Study Selected: Acute Neurotoxicity Study 

MRID No.: 47473396

Executive Summary: See Appendix A, Guideline [§ 870.6200a]

Dose and Endpoint for Establishing aRfD: The NOAEL of 30 mg/kg/day is based on clinical 

signs of reduced activity, decreased rearing, initial inactivity, piloerection, ruffled fur and 

recumbency, decreased body weight, body weight gains and food consumption in males at the 

LOAEL of 250 mg/kg.

UF(s): A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies 

variation (10X).

Comments on Study/Endpoint/UFs: There is no inhalation study available. This study 

provides the lowest NOAEL in the database considered to be valid for this exposure and 

duration, thus is protective for any potential adverse effects in humans (i.e. 90-day rat study, 

SCN study, chronic dog study, chronic rat study). The 28-day dog study was also considered 

with a higher NOAEL of 50 mg/kg/day, however, the only effect at 250 mg/kg/day was liver 

vacuolation at 100 mg/kg/day. The 28-day mouse study had a very high NOAEL of 920 

mg/kg/day. 

A.4 Executive Summaries

A.4.1 Sub-chronic Toxicity

870.3100 90-Day Oral Toxicity – Rat

In a sub-chronic toxicity study (MRID #47473375), SYN524464 (98.2% a.i.) was administered 

to 12 HsdRccHan:WIST (Han Wistar) rats/sex/dose in diet at dose levels of 0, 250, 1000 or 4000 

ppm (equal to 0, 18.6, 72.9, 299.6 mg/kg bw/day in males and 0, 21.4, 85.7, 315.3 mg/kg bw/day 

in females) for 90 days.

There were no treatment related clinical signs or ophthalmoscopy findings observed at any dose 

level tested. Functional observation battery assessments and motor activity were not affected by 

treatment. There were no treatment related macropathology findings.

Body weight, food consumption and food efficiency were decreased in the high-dose group when 

compared to controls. Platelet counts were slightly higher for high-dose females. Plasma 

triglycerides and total protein were increased in both sexes at the high-dose. Plasma cholesterol 

was increased in high-dose females. Increased absolute and adjusted liver weights, associated 

with centrilobular hypertrophy and increased pigmentation in the liver, were seen in both sexes 
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at 4000 ppm. Treatment-related decreased absolute and adjusted heart weights were observed in 

high-dose females. 

The LOAEL is 299.6/315.3 mg/kg bw/day males/females, based on decreased body weights, 

food consumption and food efficiency, increased total protein, increased liver weight, 

centrilobular hypertrophy and pigmentation in the liver in both sexes, plasma albumin in males 

and increased platelet counts, increased plasma cholesterol and decreased heart weights in 

females. The NOAEL is 72.9 mg/kg bw/day for males and 85.7 mg/kg bw/day for females. 

This sub-chronic toxicity study in the rat is acceptable and satisfies the guideline requirement for 

a sub-chronic oral study (OPPTS 870.3100; OECD 408) in rats. 

870.3100 13-Week Oral Toxicity – Rat

In a sub-chronic toxicity study (MRID #47473376), groups of 10 male and 10 female 

Crl:WI(Han) (Han Wistar) rats were fed diets containing 0, 300, 2000 or 4000 ppm (0, 24.8, 

168.0, 325.1 mg/kg bw/day in males and 0, 28.3, 186.0, 349.8 mg/kg bw/day in females) 

SYN524464 for a period of at least 90 days. SYN524464 administered daily in the diet for 90 

days at doses of up to 325.1 or 349.8 mg/kg bw/day was generally well tolerated with no 

mortality and no treatment related clinical signs during weekly examinations.

In male and female animals treated at 325.1 and 349.8 mg/kg bw/day, respectively, body weight, 

body weight gain and food consumption were significantly decreased. In females, body weight 

and body weight gain were decreased at 186.0 mg/kg bw/day. In detailed FOB examinations, 

males treated at 325.1 mg/kg bw/day showed a statistically significant increase in hunched 

posture and piloerection when observed in the arena. Significant decreases were observed in 

forelimb grip strength in males at 168.0 and 325.1 mg/kg bw/day and females at 186.0 and 349.8 

mg/kg bw/day. Decreased hind limb grip strength was observed in females at 349.8 mg/kg 

bw/day. No treatment related effects were observed on motor activity or any other functional 

observation battery parameter.

At 325.1 and 349.8 mg/kg bw/day administered to males and females, respectively, gamma 

glutamyl transferase was increased in both sexes, triglycerides and total protein were increased in 

males and cholesterol levels were increased in females. Phosphate levels were statistically 

significantly higher than control values by 29% in 325.1 mg/kg bw/day males. 

No treatment related effects were observed at necropsy. Absolute liver weights and liver weights 

adjusted for body weight were increased at the high-dose in males and females. Mild to 

moderate centrilobular hepatocyte hypertrophy was observed at the high-dose accompanied by 

minimal to mild hepatocyte pigmentation in both sexes. Minimal to moderate diffuse thyroid 

follicular cell hypertrophy was observed in 5 males at 325.1 mg/kg bw/day and 1 female at 349.8 

mg/kg bw/day.

The LOAEL is 168.0 mg/kg bw/day in males and 186.0 mg/kg bw/day in females, based on 

decreased body weight and body weight gain in females and decreased forelimb grip strength in 

both sexes. The NOAEL is 24.8 mg/kg bw/day in males and 28.3 mg/kg bw/day in females. 
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This sub-chronic toxicity study in the rat is acceptable and satisfies the guideline requirement for 

a sub-chronic oral study (OPPTS 870.3100; OECD 408) in rats.

870.3100 90-Day Oral Toxicity – Mouse 

In a sub-chronic toxicity study (MRID#47473377), SYN524464 (95.3% a.i.) was administered in 

diet to groups of CD-1 mice (10/sex) at dose levels of 0, 500, 3500 or 7000 ppm (0, 80, 567, and 

1167 mg SYN524464/kg/day for males and 0, 112, 810, and 1455 mg SYN524464/kg/day for 

females, correspondingly) for 90 days.

There were no treatment-related mortalities, clinical signs, hematology, clinical chemistry, gross 

pathology or histopathology. At 7000 ppm (1167 mg/kg/day), males had treatment-related lower 

body weight and body weight gain, and lower food utilization. Treatment-related decreased 

white blood cell and lymphocyte counts were also observed at this dose level.

The LOAEL was 7000 ppm in males (1167 mg/kg/day) based on the decreased body weight, 

lower body weight gain and food utilization, total bilirubin, increased liver and testes weights, as 

well as decreased white blood cell and lymphocyte counts. The NOAEL was 3500 ppm in males 

(567 mg/kg/day). The NOAEL in females was 7000 ppm, the highest dose tested (1455 

mg/kg/day), as no treatment-related effects were observed. The LOAEL for females was not 

determined.

This sub-chronic toxicity study in the mouse is acceptable and satisfies the guideline requirement 

for a sub-chronic oral study (OPPTS 870.3100; OECD 408) in mice. 

870.3150 90-Day Oral Toxicity – Dog

In a 13-week dog study (MRID #47473378), SYN524464 (95.3% a.i.) was administered to 4 

Beagle dogs/sex/dose by capsule at dose levels 0, 50, 150 or 400 mg/kg bw/day.

There were no treatment-related effects on survival, clinical signs, ophthalmoscopic parameters, 

veterinary examinations (patellar reflex, pupillary light reflex, corneal reflex), urinalysis, gross 

pathology or histopathology.

Body weight loss was observed during the first week of treatment in males and females at 150 

mg/kg/day. Body weights and cumulative body weight gains remained lower than control in both 

sexes at 400 mg/kg/day and in females at 150 mg/kg/day throughout the study. Decreased body 

weights were also seen in 50 mg/kg bw/day females starting around day 71/85 and were 

associated with slightly decreased body weight gains. In high-dose males, decreased body 

weights were only observed from Days 71 onwards, while in females body weights were 

decreased compared to controls through most of the study period particularly at the high dose 

level. At 400 mg/kg bw/day, these findings were associated with decreased food consumption. 

The above findings were considered to be treatment-related and adverse. 
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Statistically identified lower total leukocyte, lymphocyte and monocyte counts in females at 

150 mg/kg/day and lower total leukocytes in males at 400 mg/kg/day were noted during week 

13, and were considered to be adverse. Decreased mean absolute and relative spleen weights 

were observed in males and females. 

The LOAEL in females is 50 mg/kg bw/day, based on body weight loss (Week 1) and decreased 

body weight gains. The NOAEL in females was not established. The LOAEL in males is 400 

mg/kg bw/day, based on decreased body weight, body weight gains and food consumption, 

decreased lymphocyte counts, as well as decreased spleen weights. The NOAEL in males is 150 

mg/kg bw/day.

This study in dogs is acceptable and satisfies the guideline requirement for a 90-day oral toxicity 

study in dogs (OPPTS 870.3150; OECD 409). 

870.3200 21/28-Day Dermal Toxicity – Rat 

In a repeat-dose dermal toxicity study (MRID#47473380), SYN524464 95.3% (a.i.) was applied 

to the shaved skin of 10 HanRcc:WIST (SPF) rats/sex/dose at dose levels of 0, 100, 300 or 1000 

mg/kg bw/day, 6 hours/day for 5 days/week during a 28-day period. A functional observational 

battery (FOB) including grip strength and locomotor activity measurements was conducted 

during the last week of treatment before the dermal administration for that day. 

Ophthalmoscopic examinations were performed in all animals during acclimatization and during 

week 4 in animals of the control and high dose groups. 

There were no treatment-related effects on mortality, body weight, food consumption, clinical 

signs of toxicity, FOB parameters, ophthalmology, hematology, clinical chemistry, organ 

weights or gross and histologic pathology. 

The LOAEL was not established. The NOAEL is 1000 mg/kg bw/day.

This dermal toxicity study in the rat is acceptable and satisfies the guideline requirement for a 

repeat-dose dermal toxicity study (OPPTS 870.3250 rat); OECD 410 in the rat. 

870.3465 90-Day Inhalation – Rat 

Due to extremely high inhalation MOEs of 37,000 or greater, a 90-day inhalation study is not 

required.

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat Range Finding Study
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In a range-finding developmental toxicity study (MRID #47473391), SYN524464 (95.3% a.i.) 

was administered to 10 mated female Wistar rats/dose by gavage in 0.5% CMC (high viscosity)

at dose levels of 0, 200, 500, or 750 mg/kg bw/day from days 6 through 20 of gestation. 

The dams in the groups receiving 500 and 750 mg/kg/day were sacrificed prior to study 

termination due to ethical reasons. Signs of decreased activity and generally poor clinical 

condition were noted, and food and body weight gains were statistically significantly reduced.

Decreased corrected for gravid uterine weight body weight gain and food consumption were 

considered to be treatment-related and adverse at 200 mg/kg bw/day.

The maternal NOAEL was not determined.

The maternal LOAEL was 200 mg/kg/day, based on decreased body weight gains and food 

consumption.At 500 mg/kg bw/day (exceeded MTD), decreased body weight and food 

consumption, body weight loss; decreased activity, ruffled fur, poor clinical condition, lateral 

recumbency, uncoordinated movements)-animals were sacrificed for humane reasons prior to 

study termination. 

At 750 mg/kg bw/day, there was one death (GD 11).

The fetal NOAEL or LOAEL were not determined.

This study is an acceptable/non-guideline study for range-finding purposes.

870.3700a Prenatal Developmental Toxicity Rat Definitive Study

In a developmental toxicity study (MRID #47473392), SYN524464 (95.3% a.i.) was 

administered to 24 mated female Han Wistar rats/dose by gavage at dose levels of 0, 25, 100 or 

200 mg/kg bw/day in 0.5% CMC high viscosity from days 6 through 20 of gestation. 

There were no treatment-related effects on survival, clinical signs or Caesarean section 

parameters in maternal animals. At 200 mg/kg bw/day, decreased body weight gains or body 

weight loss and decreased food consumption were observed. These findings were considered to 

be treatment-related and adverse.

The maternal LOAEL is 200 mg/kg bw/day, based on decreased body weight gains/body weight 

loss and reduced food consumption. The maternal NOAEL is 100 mg/kg bw/day. 

At 200 mg/kg/day, the mean weights of female fetuses were statistically significantly lower than 

controls and considered this finding to be treatment-related. There were no treatment-related 

external, visceral or skeletal malformations or variations.

There were no treatment-related external, visceral or skeletal malformations or variations. 

The developmental LOAEL was 200 mg/kg bw/day, based on decreased female fetal weights. 

The developmental NOAEL is 100 mg/kg bw/day.
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The developmental toxicity study in the rat is classified acceptable and satisfies the guideline 

requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rats. 

870.3700b Prenatal Developmental Toxicity Study – Rabbit Range Finding Study

In a range-finding developmental toxicity study (MRID #47473393), SYN524464 (95.3% a.i.) 

was administered to 10 time-mated female New Zealand White rabbits in 0.5% (w/v) aqueous 

high viscosity carboxymethylcellulose (CMC) from gestation days 7 through 28, at doses of 0, 

100, 300, 500 mg/kg/day. There were no treatment-related effects on gravid uterine weights or 

gross pathology in maternal animals. 

Maternal toxicity was manifested by moribundity in the 500 mg/kg/day group, as 2 females were 

euthanized on gestation day (GD) 16 following excessive body weight loss, reduced food 

consumption and decreased defecation. One female was sacrificed after it delivered early on GD 

29. Compared to the control group, a dose-related increase in the incidence of decreased 

defecation was noted among surviving females in the 300 and 500 mg/kg/day groups at the daily 

examinations. Treatment-related decreased body weight gains/body weight loss and reduced 

food consumption were noted at doses 300 mg/kg bw/day. A dose-related increase in mean 

absolute and relative (to net body weight) liver weight was noted at all dose levels.

There were no treatment-related external or visceral malformations or variations.

The maternal NOAEL was 100 mg/kg/day. The maternal LOAEL was 300 mg/kg/day, based on 

increased liver weight (histopathology was not conducted), decreased defecation, decreased body 

weight gain/body weight loss, food consumption.

At 500 mg/kg bw/day, the following effects occured: increased liver weight (histopathology was 

not conducted), decreased defecation, decreased body weight gain/body weight loss, food 

consumption; increased mortality (2♀ on GD 16; 1♀ delivered early on GD 29), preceded by 

BW loss, decreased food consumption, decreased defecation and soft stool.

The fetal NOAEL was 500 mg/kg/day.The fetal LOAEL was not determined, no adverse effects 

at any dose level based on a limited number of parameters assessed.

Based on the results of this study, dose levels of 300 mg/kg bw/day were considered to be 

excessive for a main (definitive) developmental toxicity study in rabbits.

This study is acceptable/non-guideline study for range-finding purposes.

870.3700b Prenatal Developmental Toxicity- Rabbit Definitive Study

In a developmental toxicity study (MRID #47473394), SYN524464 (95.3% a.i.) was 

administered to 25 time-mated female New Zealand White rabbits/dose by gavage in 0.5% high 

viscosity carboxymethylcellulose (CMC) at dose levels of 0, 25, 100, or 200 mg/kg bw/day from 

days 7 through 28 of gestation. 

There were no treatment-related effects on maternal survival or gross pathology.
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Increased abortions were noted in 2 females at 200 mg/kg bw/day on GD 24 or 28 and 1 female 

delivered early on GD 29. These findings were preceded by body weight loss or decreased body 

weight gains, decreased or no food consumption and reduced fecal output, thus not considered to 

be a single-dose effect. Similar body weight effects were noted in females at scheduled necropsy. 

The maternal LOAEL is 200 mg/kg bw/day based on increased abortions decreased body weight 

gains or body weight loss, reduced food consumption and decreased defecation. The maternal 

NOAEL is 100 mg/kg bw/day.

The developmental LOAEL is 200 mg/kg bw/day, based on increased abortions, unossified 

sternebrae and 13th rudimentary ribs. The developmental NOAEL is 100 mg/kg bw/day.

The developmental toxicity study in the rabbit is classified acceptable and satisfies the guideline 

requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414)

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat Range Finding Study

In a 1-generation reproduction study (MRID#47473389), SYN524464 (95.3% a.i.) was 

administered to 10 Wistar rats/sex/dose in diet at dose levels of 0, 500, 1500, or 3600 ppm 

(estimated to be equal to 0, 50, 150 or 360 mg/kg bw/day) for 10 weeks before mating through to 

weaning of the F1 generation. After the F1 generation pups were weaned (lactation day (LD) 28 

of age), up to 3/sex/litter from control, 500 and 1500 ppm groups were retained post weaning 

until LD 35. High dose (3600 ppm) pups/litters were not retained after Day 28 of lactation due 

to excessive toxicity. The F1 generation received SYN524464 in the diet at the same nominal 

dose level as the P generation they were selected from.

Parental toxicity: 

There were no treatment-related effects on survival, clinical signs, reproductive parameters (precoital interval, number of copulation plugs, fertility, gestation duration, number of litters) or 

gross pathology.

At doses greater than or equal to 1500 ppm, decreased body weight, body weight gains and food 

consumption were observed in maternal animals. At necropsy, increased mean liver weights and 

increased incidences of abnormally darkened livers were noted. These findings were considered 

to be treatment-related and adverse. In males, treatment-related decreased body weight, body 

weight gains and food consumption were only observed at 3600 ppm.

The parental NOAEL was 50 mg/kg/day. The parental LOAEL was 150 mg/kg/day,

based on decreased body weight, body weight gains, food consumption (♀); increased liver 

weights, abnormally darkened livers (♀).

Reproductive toxicity: 

There were no treatment-related effects on live birth index or sex ratio.
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At 3600 ppm, a number of reproductive parameters were affected and included decreased mean 

implantation sites, decreased number of pups born, increased number of pup deaths (LD 0-4), 

decreased mean litter size, decreased viability and lactation indices, and increased number of 

missing pups (presumed cannibalized). These findings were considered to be treatment-related 

and adverse.

The reproductive NOAEL was 150 mg/kg/day. The reproductive LOAEL was 360 mg/kg/day

(exceeded MTD), based on the following: decreased mean implantation sites, number of pups 

born; increased number of pup deaths (LD 0-4); decreased mean litter size, viability index, 

lactation index; increased missing pups (presumed cannibalized).

Offspring toxicity: 

There were no treatment-related gross pathological effects.

At 3600 ppm, marked decreased body weight and body weight gains were noted in offspring 

before weaning and after weaning until LD 35. Due to the increased pup toxicity observed at 

this dose level, the pups were kept with their damss until LD 28 at which time, they were 

sacrificed. At necropsy, increased liver weights were observed in high dose pups compared to 

controls and were considered to be treatment-related. This dose level was considered to 

approximate the MTD for this type of study.

At 1500 ppm, decreased pup body weights and increased liver weights were observed, and were 

considered to be treatment-related and adverse. No treatment-related offspring effects were 

observed at 500 ppm.

The offspring NOAEL was 50 mg/kg/day. The offspring LOAEL was 150 mg/kg/day, based on 

decreased body weights and increased liver weights.

At 360 mg/kg bw/day (exceeded MTD), decreased body weight and body weight gains and 

increased liver weights were also observed.

Due to marked effects on body weight in P females, low F1 generation pup body weights and 

poor pup survival, a dietary level of 3600 ppm was considered to be in at or in excess of a 

maximum tolerated dose (MTD) in this study.

This study is acceptable/non-guideline study for use as range-finding.

870.3800 Reproduction and Fertility Effects – Rat Definitive Study

In a 2-generation reproduction study (47473390), SYN524464 (95.3% a.i.) was administered to 

25 Wistar rats/sex/dose in diet at dose levels of 0, 200, 500 or 1500 ppm (P generation: 0, 16, 41, 

120 mg/kg bw/day in males; 0, 18, 46, 143 mg/kg bw/day in females; F1 generation: 0, 17, 43, 

134 mg/kg bw/day in males; 0, 19, 47, 141 mg/kg bw/day in females). Due to less than optimal 

pup health, the high dose P generation dams and their F1 pups remained together until lactation 

day (LD) 28.

In parental animals, there were no treatment-related effects on survival, clinical signs, food 

efficiency, estrous cycle length or periodicity, sperm parameters, or reproductive performance 
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(pre-coital interval, # copulation plugs, fertility, gestation duration, # litters). In offspring, there 

were no treatment-related effects on pup viability, litter parameters (including sex ratio), clinical 

signs, preputial separation or gross pathology.

At 120 mg/kg bw/day, decreased body weights were observed in F1 males during the premating 

period and in females throughout the study. In P generation females, the body weight effects 

were associated with decreased body weight gains. During the premating period in P generation 

males and throughout the study in both generations of females, the body weight decrements were 

associated with decreased food consumption.

Upon necropsy, increased liver weights, enlarged livers (females only) and increased incidence 

and severity of centrilobular heptocellular hypertrophy were noted in the high dose parental 

animals and were considered to be adaptive. At 1500 ppm, decreased ovary weights in F1

generation females were considered to be adverse.

The parental LOAEL is 1500 ppm (120 mg/kg bw/day in males and 141 mg/kg bw/day in 

females), based on decreased body weights, body weight gains and food consumption in both 

sexes and decreased ovary weights in F1 generation females. The parental NOAEL is 500 ppm 

(41 mg/kg bw/day in males and 43 mg/kg bw/day in females). 

Treatment-related decreased primordial follicle counts in the P generation females and decreased 

growing and antral follicle counts in the high dose F1 generation females were observed. These 

findings were associated with decreased corpora lutea counts in both generations. The changes in 

ovarian follicle counts were associated with increased incidences of females in lactational 

diestrous. The study authors attributed the lack of estrous cyclicity in high dose females to a 

prolonged suckling period by the pups secondary to systemic toxicity. Review of the individual 

animal data by the reviewer did not show a clear correlation between the presence of lactational 

diestrus in dams and decreased follicle counts. However, only a limited subset (N=10) of high 

dose females was subjected to a quantitative follicle count. Amongst the high dose females 

assessed, only 4 of them were in lactational diestrus. Of these females, only female #385 

appeared to have lower follicle counts compared to controls and cycling females in the same 

dose group. The remaining females in the high dose group were cycling and had decreased 

follicle counts compared to the concurrent controls. Overall, based on the weight of evidence of 

related ovarian effects occurring at the high dose level in this 2-generation reproductive toxicity 

study and the presence of treatment-related endocrine effects throughout the sedaxane 

toxicological database, these findings were considered to be treatment-related and adverse. The 

Ovarian follicle counts were not performed at the low and mid dose levels and consequently, a 

clear NOAEL cannot be established for this endpoint. There were no outstanding concerns 

surrounding the lack of ovarian follicle data at lower doses, since there was no effect on fertility.

The reproductive LOAEL was not determined in males and is 1500 ppm (143 mg/kg bw/day) in 

females. The reproductive NOAEL in males is 1500 ppm (120 mg/kg bw/day) and was not 

determined in females since critical parameters, i.e. ovarian follicle counts, were not measured at 

200 and 500 ppm. However, a reproductive NOAEL of 14.3 mg/kg/day was derived for females 

by applying a 10X factor to extrapolate from the female LOAEL value of 143 mg/kg/day. 
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The statistical increase in post-implantation loss at 3600 ppm (143 mg/kg bw/day) was 

considered adverse. At 143 mg/kg bw/day, treatment-related decreased pup body weights were 

observed. Delayed vaginal patency (F1) and increased anogenital distance in F2 female pups were 

noted at the same dose level and were considered to be equivocal, based on the small magnitude 

of the changes. Treatment-related increased absolute and/or relative liver weights and spleen 

weights were observed in both generations of pups and were considered to be treatment-related 

(histopathology was not conducted). 

The offspring NOAEL is 43/47 mg/kg/day. The offspring LOAEL is 1500 ppm (134/141 mg/kg 

bw/day), based on based on a 21% decrease in spleen weights in both sexes, plus a 15% decrease 

in food consumption, and decreased pup body weights, , post implantation loss in F1 females. 

The F2 ano-genital distance change of only 8% not considered adverse. 

This study is acceptable and satisfies the guideline requirement for a 2-generation reproductive 

study (OPPTS 870.3800; OECD 416) in rats. However, critical parameters (ovarian follicle 

counts) were not assessed at 200 or 500 ppm and consequently, a clear reproductive NOAEL 

could not be established in females, thus was estimated from the LOAEL value.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat – See A.4.5

870.4100b Chronic Toxicity – Dog

In a 52-week dog study (MRID #47473379), SYN524464 (95.3% a.i.) was administered to 4 

Beagle dogs/sex/dose by capsule at dose levels of 0, 15, 50, 200 mg/kg bw/day.

There were no treatment-related effects on survival, clinical signs, ophthalmoscopic parameters, 

veterinary examinations (patellar reflex, pupillary light reflex, corneal reflex), hematology, 

urinalysis, organ weights or gross pathology or histopathology.

At 200 mg/kg bw/day, decreased body weights were observed in both sexes with the effect being 

more pronounced in females. Body weight loss occurred during Week 1 of the study. Following 

an extended feeding period, animals consumed more food but a pattern of decreased body weight 

gains was observed for the remainder of the study. The body weight effects were associated with 

decreased food consumption. Treatment-related clinical chemistry findings included decreased 

glucose levels in males. Decreased absolute and relative testes weights at 200 mg/kg bw/day and 

were considered to be treatment-related. Decreases in mean spleen weights in both sexes at 200 

mg/kg bw/day and considered to be adverse.

The LOAEL is 200 mg/kg bw/day based on decreased body weights, body weight gains and food 

consumption in both sexes, decreased glucose levels in males, decreased testes weights and 

decreased spleen weights in both sexes. The NOAEL is 50 mg/kg bw/day.
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This study is classified as acceptable/guideline and satisfies the guideline requirements for a 

chronic toxicity study (non-rodent).

A.4.5 Carcinogenicity

870.4300 Carcinogenicity/Chronic Study – Rat

In a chronic toxicity study (MRID #47473386), SYN524464 (95.3% a.i.) was administered to 52 

Crl:WI(Han) (Han Wistar) rats/sex/dose in diet at dose levels of 0, 200, 1200 or 3600 ppm (0, 

11, 67 or 218 mg/kg bw/day in males and 0, 14, 86 or 261 mg/kg bw/day in females; designated 

as control, low, mid or high dose respectively) for at least 104 consecutive weeks. In addition, a 

toxicity study comprising 12 Han Wistar rats/sex/dose were included and dosed in an identical 

fashion for a period of 52 consecutive weeks.

There were no treatment-related effects on survival, clinical signs, ophthalmoscopic parameters, 

motor activity, urinalysis or gross pathology.

A decrease in bodyweight and bodyweight gain was observed in males at 218 mg/kg bw/day and 

in females at 86 and 261 mg/kg bw/day. A corresponding decrease in food consumption and 

food efficiency was observed in both sexes at the high-dose. 

The only treatment-related effect observed in the Functional Observation Battery (FOB) was 

decreased hindlimb grip strength in males at 67 and 218 mg/kg bw/day. This finding was 

considered to be equivocal. Increased gamma glutamyl transferase (GGT), glucose and 

phosphate levels were observed in males at 218 mg/kg bw/day. Increased phosphate is 

considered to be treatment related at 67 mg/kg bw/day in males.

A dose related statistically significant increase in absolute and adjusted liver weight, (adjusted 

for body weight by covariate analysis) was seen at 67/86 mg/kg bw/day M/F. In males, this 

was associated with increased hepatocyte hypertrophy and eosinophilic foci. At the high-dose 

level, minimal to moderate centrilobular hepatocyte hypertrophy and increased incidence of 

pigment in centrilobular or mid-zonal hepatocytes in the liver were seen at week 52 in both sexes 

and only in females at week 104. Increased incidences of thyroid follicular cell hypertrophy and 

epithelial desquamation were seen in both sexes dosed at 67 or 86 mg/kg bw/day and above. 

Increased epithelial tubular hyperplasia of the thymus was observed in high-dose females. 

Increased incidences of thyroid follicular cell adenomas and liver hepatocellular adenomas were 

observed at 218 mg/kg bw/day. An increased incidence of uterine adenocarcinomas was 

observed in females at 261 mg/kg bw/day. These tumors were considered to be treatment-related 

by the Canada PMRA and US EPA. 

The NOAEL is 11 mg/kg bw/day in males and 14 mg/kg bw/day in females. The LOAEL is 67 

mg/kg bw/day in males, increased liver weight, increased incidences of hepatocyte hypertrophy 

and eosinophilic foci, and thyroid follicular cell hypertrophy, basophilic colloid and epithelial 

desquamation. The LOAEL is 86 mg/kg bw/day in females, based on decreased body weight 
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and body weight gain, increased liver weight and the same thyroid histopathology noted above 

for males.

There was evidence of carcinogenicity after treatment with SYN524464 at 218 mg/kg bw/day in 

males and 261 mg/kg bw/day in females. Dosing was considered to be adequate, but not 

excessive, to assess the carcinogenicity of sedaxane. 

This chronic study in the rat is acceptable and satisfies the guideline requirement for a chronic 

oral study (OPPTS 870.4300), OECD 453 in rat. 

870.4200b Carcinogenicity (Feeding) – Mouse

In a carcinogenicity study (MRID #47473388), SYN524464 (Sedaxane) (95.3% a.i.) was 

administered in diet to groups of CD-1 mice (50/sex/group) at dose levels of 0, 200, 1250 or 

7000 ppm (0, 25, 157, and 900 mg SYN524464/kg/day for males and 0, 29, 185, and 1001 mg 

SYN524464/kg/day for females) for 80 weeks.

Dietary administration of SYN524464 at 7000 ppm (900/1001 mg/kg bw/day M/F) resulted in 

treatment-related lower body weights and body weight gains for males and females. The body 

weight decrements were not considered to be adverse since they were less than 10%.

Treatment-related increased incidences of hepatocellular adenomas and/or carcinomas were seen 

in male mice at 7000 ppm (900/1001 mg/kg bw/day M/F), a dose level that approached a limit 

dose, compared to controls No treatment-related neoplastic or non-neoplastic micropathological 

changes of the liver were observed at lower doses in males or in females. Dosing was considered 

to be adequate based on decreased body weight/gains and decreased food utilization in the initial 

stages of the study.

The LOAEL for SYN524464 was 7000 ppm for both sexes (900 mg/kg/day for males and 1001 

mg/kg/day for females) based on lower body weights body weight gains and food efficiency. The 

NOAEL for SYN524464 was 1250 ppm for both sexes (157 mg /kg/day in males and 185 mg 

/kg/day in females).

There was evidence of carcinogenicity after treatment with SYN524464 at 900 mg/kg bw/day in 

males. In both males and female rats, the high dose of 7000 ppm was considered to be adequate 

to assess the carcinogenicity of sedaxane.

This carcinogenicity study in the mouse is acceptable and satisfies the guideline requirement for 

a carcinogenicity study (OPPTS 870.4200; OECD 451) in mice. 

A.4.6 Mutagenicity

Sedaxane was negative in the mutagenicity studies. However, chromosomal aberrations were 

observed at cytotoxic concentrations in one in vitro study. 
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Study Dose Levels Result

In vitro studies 

870.5100

Bacterial Reverse Mutation

MRID#1897888

Sokolowski, A (2009)

0-5000 μg/plate Negative

870.5375

In vitro Cytogenetics

MRID#47473382

Bohnenberger S (2009)

0 – 216.8 μg/mL Negative 

870.5300

Mammalian cell gene mutation (mouse 

lymphoma)

MRID #47473383

Wollny H-E (2009)

0-110 μg/mL Negative

In vivo studies

870.5395

Mouse Bone Marrow Micronucleus 

Assay

MRID#47473384

Reichenbach M (2010)

0-2000 mg/kg bw Negative

870.5550

Unscheduled DNA synthesis – Rat 

Liver

MRID#4743385

Durward R (2009)

0-2000 mg/kg bw Negative

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study – Hen - NA

870.6200a Acute Neurotoxicity Screening Battery-Rat Range Finding Study

In a range-finding acute neurotoxicity study (MRID #47473395), groups of unfasted 7-8 week 

old HanRcc:Wistar (SPF) rats (3/sex) were given a single oral dose of SYN524464 (95.3% a.i.) 

in 0.5% w/v carboxymethylcellulose (CMC), high viscosity grade, in distilled water at doses of 

0, 80, 1000 or 2000 mg/kg bw and observed for 8 days. A limited functional observation battery 

(FOB) was performed on all animals on day 1 at approximately hourly intervals for 8 hours, and 

once daily on days 2 to 8. There were no treatment-related effects on survival or gross pathology.

Treatment-related reduced activity, hunched posture, spasms, piloerection and uncoordinated 

movements were observed after dosing at 1000 mg/kg bw/day, with a peak effect at 3 hours 

post-dose. In females, incidences of piloerection persisted beyond day 4. Treatment-related 

decreased body weight and body weight gains were also observed for several days post-dosing 

but resolved by the end of the study. At 80 mg/kg bw, piloerection was observed from 2-8 hours 

post-dose on day 1 only; hunched posture, spasms and reduced activity were also noted 

sporadically on day 1.
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A NOAEL was not determined. The LOAEL was 80 mg/kg, based on increased piloerection (2-

8 h post-dose); hunched posture, spasms, reduced activity also noted sporadically

At 1000 and 2000 mg/kg bw, increased piloerection (2-8 h ♂, beyond day 4 ♀ post-dose); 

hunched posture, spasms, reduced activity, reduced activity, hunched posture, spasms, 

piloerection, uncoordinated movements (peak effect at 3 h post-dose), decreased body weight 

and body weight gains.

Based on the results of this preliminary study, a single oral dose of 2000 mg/kg SYN524464 

would be an appropriate high dose for an acute neurotoxicity study in the rat. The estimated time 

of peak effect is 3 hours after dosing.

The study is classified as acceptable/non-guideline for a range-finding acute neurotoxicity study

870.6200a Acute Neurotoxicity Screening Battery-Rat Definitive Study

In an acute neurotoxicity study (MRID #47473396), groups of unfasted young adult 

HanRcc:Wistar (SPF) rats (10/sex) were given a single oral dose of SYN524464 (95.3% a.i.) in 

0.5% w/v carboxymethylcellulose (CMC), high viscosity grade at doses of 0, 30, 250 or 2000 

mg/kg bw and observed for 15 days. Neurobehavioral assessment (functional observation battery 

and motor activity testing) was performed in 10 animals/sex/group on Days 1 (approximately 2-4 

hours after dosing), 8 and 15. At study termination, 5 animals/sex/group were euthanized and 

perfused in situ for neuropathological examination. Of the perfused animals, all animals in each 

group were subjected to histopathological evaluation of brain and peripheral nervous system 

tissues. 

There were no treatment-related effects on landing foot splay, brain weights, gross pathology or 

neuropathology.

At 2000 mg/kg bw, clinical signs of toxicity were observed in both males (4/10) and females 

(3/10); these animals were sacrificed moribund at 6 hours post-dose. In female survivors, 

treatment-related decreased body weight and body weight gains and reduced food consumption 

were noted. Associated clinical signs included in both sexes included bradynpea and hunched 

posture. In males, increased incidences of rough coat, weakened condition, hunched posture, 

reduced muscle tone were observed; increased incidences of ruffled fur, prostration, hunched 

posture and abnormal gait were noted in females. All clinical signs occurred during Week 1 postdose. Treatment-related decreased grip strength in both the fore- and hind-limbs were observed 

in high dose animals on day 1.

At 250 and 2000 mg/kg bw, evidence of toxicity included clinical observations such as reduced 

activity, decreased rearing, as well as increased initial inactivity and piloerection in both sexes. 

Treatment-related increased incidences of ruffled fur and recumbency were observed in males, 

while in females, noted clinical observations included weakened condition, swaying gait, 

decreased activity and reduced muscle tone. Treatment-related decreased body weight and body 

weight gains and reduced food consumption were noted in males at this dose level. No treatment-
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related findings were evident in any of the surviving rats during the second week of the study. At 

2000 mg/kg, there was a decrease in rectal temperature.

At study termination, no neurohistopathological lesions were present. The 2000 mg/kg bw dose 

level slightly exceeded the desired high dose for an acute neurotoxicity study but the study was 

still considered to be acceptable. 

The LOAEL is 250 mg/kg bw in males, based on reduced activity, decreased rearing, initial 

inactivity, piloerection in both sexes; ruffled fur and recumbency, decreased body weight, body 

weight gains and food consumption. The NOAEL is 30 mg/kg bw/day in males. The LOAEL in 

females is 30 mg/kg bw based on decreased forelimb grip strength, but the NOAEL was not 

established.

The study is classified as an acceptable/guideline study for an acute neurotoxicity study in rats 

(870.6200). 

870.6200b Sub-chronic Neurotoxicity Screening Battery-Rat Range Finding Study

In a range-finding sub-chronic neurotoxicity study (MRID #47473397), SYN524464 

(95.3% a.i.) was administered to 8 Wistar rats/sex/group via the diet at dose levels of 0, 

500, 2000 or 5000 ppm (equal to 0, 37.8, 153.5, 360.1 mg/kg bw/day in males and 0, 

40.1, 156.4, 338.8 mg/kg bw/day in females) for 28 days. No neurobehavioral 

assessments were performed in this range-finding test. At study termination, all animals 

were euthanized and subjected to a gross examination. 

All rats survived until scheduled termination. There were no treatment-related effects on clinical 

signs, detailed behavioral observations or gross pathology. 

Reduced food intake and decreased body weight and body weight gains were observed in males 

and females at 5000 ppm (360.1/338.8 mg/kg bw/day M/F) and females at 2000 ppm (156.4 

mg/kg bw/day). Food efficiency was decreased in males and females at 2000 ppm (153.5/156.4 

mg/kg bw/day M/F). There were no treatment-related effects in either sex at 500 ppm (37.8/40.1 

mg/kg bw/day M/F).

The NOAEL was 37.8 mg/kg/day. The LOAEL was 153.5/156.4 mg/kg/day, 

based on decreased food efficiency, body weight (♀), body weight gain (♀), food consumption 

(♀). 

At 360.1/338.8 mg/kg bw/day ♂/♀, decreased body weight, body weight gain, food 

consumption. No neurobehavioral were performed in this range-finding study.

The study is classified as acceptable/non-guideline study as a range-finding sub-chronic 

neurotoxicity study in rats.

870.6200b Sub-chronic Neurotoxicity Screening Battery- Rat Definitive Study
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In a sub-chronic neurotoxicity study (MRID #47473398), SYN524464 (95.3% a.i.) was 

administered to 12 HanRcc:WIST (SPF) rats/sex/group in the diet at 0, 300, 1000 or 4000 ppm

(equal to 0, 19.7, 66.0, 260.0 mg/kg bw/day in males and 0, 24.3, 79.7 or 302.9 mg/kg bw/day in 

females) for 92 days. Detailed clinical observations were performed on all animals once prior to 

study start and once weekly thereafter. Furthermore, a neurobehavioral assessment including a 

functional observation battery (FOB) and quantitative assessments of landing foot splay, sensory 

perception and muscle weakness, and an assessment of locomotor activity were performed in all 

animals once prior to study start, and in weeks 2, 5, 9 and 13.

At study termination, 5 animals/sex/group were sacrificed and perfused in situ for the assessment 

of brain weight, macroscopic changes and neuropathological examination. All perfused animals 

of the high dose and control groups were subjected to histopathological evaluation of brain and 

peripheral nervous system tissues. Any remaining un-perfused animals were sacrificed and 

discarded. 

There were no treatment-related effects on survival, clinical signs, detailed behavioral 

observations, ophthalmoscopic parameters, FOB, body temperature, grip strength, landing foot 

splay, brain weight, gross pathology or neuropathology.

Treatment-related decreases in body weight, body weight gains, food consumption and food 

efficiency were observed at the high dose level (260.0 mg/kg bw/day in males, 302.9 mg/kg 

bw/day in females) throughout the study period. Decreases in mean locomotor activity (total 

distance travelled) were noted at the same dose level and were considered to be treatment-related 

and adverse. 

The LOAEL is 260.0/302.9 mg/kg bw/day M/F, based on decreased body weight, body weight 

gains, food consumption and food efficiency, as well as reduced locomotor activity. The 

NOAEL is 66.0/79.7 mg/kg bw/day M/F.

The study is classified as acceptable as an acute neurotoxicity study in rats (870.6200).

870.6300 Developmental Neurotoxicity Study 

- NA -

A.4.8 Metabolism

870.7485 Metabolism - Rat

Excretion and Tissue Distribution in the Rat Following Single Oral Administration of 1 mg or 80 

mg [Pyrazole-5-

14C]-SYN524464/kg (MRID #47473359)

Recoveries of radioactivity ranged between 96.3-104.9% AD, with no significant differences in 

tissue distribution or excretion between the dose levels. The primary route of excretion of 
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[pyrazole14C]-SYN524464 was via the feces in both sexes, with urinary excretion slightly 

higher in females. The absorbed radioactivity was rapidly distributed throughout the tissues and 

rapidly cleared without accumulation of radio-labelled SYN524464 in the tissues. 

The study is classified as acceptable as a metabolism study in rats (870.7485).

Pharmacokinetics in the Rat following a Single Oral Administration of 1 mg or 80 mg [Pyrazole5-

14C]-SYN524464/kg (MRID #47473355)

A mean of 91.6% or 97.2% AD was eliminated in urine and feces over 72 h by male and female 

rats. The major route of elimination was via the feces; however, urinary elimination was also an 

important route of excretion in both sexes and slightly more pronounced in females compared to 

males.

Recoveries of radioactivity ranged between 91.5-101.1% AD. Concentrations of [pyrazole-5-

14C]-SYN524464 were slightly higher in plasma than in whole blood at most time points, 

suggesting that total radioactivity was relatively evenly distributed between them.

In general, Tmax was achieved at 1-6 h post dose and declined with estimated terminal half-life 

values ranging from 22.65-28.76 h. Terminal half-life values of 20.71-39.86 h were obtained for 

blood. 

There were no apparent differences in the AUC and Cmax values between genders, or between the 

dose levels. As doses of [pyrazole-5-

14C]-SYN524464 were increased from 1 to 80 mg/kg bw, 

systemic exposure to total radioactivity exhibited a 118-140 fold increase but, due to the 

observed variability in the concentrations for individual rats, this was not considered significant.

The study is classified as acceptable as a metabolism study in rats (870.7485).

Excretion in Bile Duct Cannulated Rats Following Single Oral Administration of 1 mg or 80 mg 

[Pyrazole-5-

14C]-SYN524464/kg (MRID #47473357)

The majority of the administered radioactivity was excreted within the first day post-dose for 

both dose levels. Absorption was estimated to be 87-89% AD in males and 88-92% AD and 

females. Fecal excretion and gastrointestinal tract contents were less than 7% AD. Biliary 

excretion represented the predominant excretion route for both sexes at 79-82% AD. Urinary 

excretion of the absorbed dose was limited, accounting for approximately 6-7% AD in males and 

7-10% AD in females. 

The study is classified as acceptable as a metabolism study in rats (870.7485).

Excretion in Bile Duct Cannulated Rats Following Single Oral Administration of 1 mg or 80 mg 

[Phenyl-U14C]-SYN524464/kg (MRID #47473360)

There were no significant differences in absorption and elimination patterns between dose levels 

or between genders. For both dose groups, the majority of the administered radioactivity was 
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excreted within the first day post-dose and biliary excretion represented about 79-85% AD, with 

urinary excretion , accounting for approximately 5-8% AD. Absorption was estimated to be 87-

94% AD (urine radioactivity, cage washes, bile and residual carcass) with fecal excretion and GI 

tract contents were less than 7% AD.

The study is classified as acceptable as a metabolism study in rats (870.7485).

Tissue Depletion in the Rat Following Single Oral Administration of 1 mg or 80 mg [Pyrazole-5-

14C]-SYN524464/kg (MRID #47473358)

The tissue distribution of a single oral dose of 1 or 80 mg [pyrazole-5-

14C]-SYN524464/kg bw 

was extensive. Plasma half-lives ranged from 25.84-32.33 h for both dose group and half-lives 

in the whole blood ranged from 29.49-40.10 h. Tissue concentrations of radioactivity were 

highest at 1-1.5 h for low dose and 5 h for high dose with progressively decreased thereafter with 

elimination half lives of 0.1-3.2 days. Most mean tissue concentrations were near the limit of 

reliable measurement by 96 h post dose. The high levels of radioactivity in the gastrointestinal 

tract and its contents were consistent with the established biliary elimination and fecal excretion 

of SYN524464 metabolites. There were no pronounced sex differences in tissue distribution, 

depletion profiles, or half-lives of elimination in the plasma or whole blood.

The study is classified as acceptable as a metabolism study in rats (870.7485).

Investigation of the Nature and Identity of Radiolabelled Metabolites Present in Plasma, Urine, 

Faeces and Bile Collected from Rats Following Oral Administration of [14C]-SYN524464 

(MRID #47473356)

The major metabolites were the trans para phenol CSCD658906 and the desmethyl trans para 

phenol CSCD659087 which together with the equivalent cis para phenol isomers. SYN524464 

was extensively metabolized by rats through demethylation, hydroxylation, oxidation and 

conjugation pathways resulting in a number of hydroxylated metabolites and metabolites formed 

by cleavage of the terminal cyclopropyl moiety. Glucuronic acid, sulphate and glutathione 

conjugates were also formed. CSCD659090 and CSCD668404 accounted for approximately half 

the administered dose. 

The study is classified as acceptable as a metabolism study in rats (870.7485).

Tissue Distribution and Elimination in the Rat Following Repeated Daily Oral Administration of 

1 mg [Pyrazole-5-

14C]-SYN524464/kg (MRID #47473362)

The majority of the oral administered radioactivity was excreted via the feces at 60.9% AD over 

the 24 h collection period, with urinary excretion at 13.0% AD. Recovery of administered 

radioactivity was incomplete by 24 h post-dose with a mean of 75.7% AD. Similar results were 

obtained after 14 daily dosings, with some of the dosing from day 13 also contributing to the day 

14 elimination.
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Tissue concentrations of radioactivity were highest at 24 h following the fourteenth and final 

dose with the exception of whole blood and plasma, for which the highest mean concentrations 

were observed 24 h after the tenth dose. The liver and kidney had the highest levels after 14 

daily dosings, respectively. Most mean tissue concentrations appeared either to have attained or 

to be approaching steady state kinetics by the end of the 14 day dosing period. The high levels of 

radioactivity in the gastrointestinal tract and its contents were consistent with the established 

biliary elimination and fecal excretion of SYN524464 metabolites. There were no pronounced 

sex differences in tissue distribution, depletion profiles, or half-lives of elimination in the plasma 

or whole blood.

The study is classified as acceptable as a metabolism study in rats (870.7485).

870.7600 Dermal Absorption – Rat 

The objective of this study (MRID #47473632) was to investigate the in vivo dermal absorption 

of [14C]-SYN524464 through rat skin. Dose preparations equivalent to a SYN524464 FS 

Formulation concentrate (A16148C) and two aqueous end-use dilutions thereof (nominally 1/20 

and 1/200) were prepared and supplied by Dermal Technology Laboratory Ltd. Each dose 

application site of 10 cm

2

per rat was defined and protected by an O-ring glued to the clipped 

skin surface. For each dose preparation, 100 μL was applied to the skin of each of sixteen 

animals per dose level (48 rats in total), corresponding to nominal doses of 50, 2.5 and 0.25 mg 

[

14C]-SYN524464 per rat. Each dosing device incorporated a non-occlusive gauze cover. The 

dermal absorption of radioactivity was followed during a 6 hour exposure interval after 

application and over a total time course of 120 hours. Rats were housed individually in 

metabolism cages for the collection of excreta.

The application sites on all rats were washed after the 6 hour exposure interval with soap and 

water to remove the unabsorbed dose. Urine, faeces and a cage wash were collected from each 

cage after the skin wash and at intervals for the duration of each experiment. Sub-groups of four 

rats were terminated immediately after the 6 hour exposure interval and after 24, 72 and 

120 hours. Cardiac blood samples were collected under terminal anaesthesia. The liver, kidneys 

and representative samples of adipose tissue and muscle were taken for analysis. Each 

application skin site was excised and sequentially tape-stripped to remove the stratum corneum. 

All samples, including residual carcasses were analyzed for radioactivity.

The group mean achieved doses were 56.5 mg (491 kBq), 2.51 mg (509 kBq) and 0.250 mg 

(519 kBq) of [14C]-SYN524464 per rat for the formulation concentrate, 1/20 dilution and 1/200 

dilution respectively. These compared well with the target doses.

In the experiment with the formulation concentrate, most of the applied radioactivity remained 

unabsorbed following the 6 hour exposure interval and was readily washed from the skin surface 

using mild soap solution and water. Approximately 0.15% of the dose was associated with the 

skin and stratum corneum of the application site following the 6 hour skin wash; this declined to 

0.07% after 120 hours, showing that the residues could be absorbed. The absorbed dose 

amounted to 0.08% after 6 hours, 0.10% after 24 hours, 0.17% after 72 hours and 0.24% after 

120 hours. The dermal absorption, calculated by adding the potentially absorbable dose 
Sedaxane (129223) Human Health Risk Assessment D405099

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(application site skin and stratum corneum) with the absorbed dose, was 0.23%, 0.23%, 0.30 and 

0.31% after 6, 24, 72 and 120 hours, respectively.

Following dermal exposure to the 1/20 aqueous dilution for 6 hours, a mean of 96.3% of the 

applied radioactivity was removed by skin washing. In the rats terminated at 6 hours, the 

radioactivity present in the stratum corneum and skin beneath the application sites amounted to 

1.47% of the dose. This declined slightly to 0.41% after 120 hours, which was evidence that 

residues could be absorbed. The absorbed dose amounted to 1.22% after the 6 hour exposure 

period, 0.89% after 24 hours, 3.11% after 72 hours and 1.25% after 120 hours. The dermal 

absorption, calculated by adding the potentially absorbable dose (application site skin and 

stratum corneum) with the absorbed dose, was 2.69%, 1.68%, 3.75% and 1.67% after 6, 24, 72 

and 120 hours, respectively.

Following application of the 1/200 aqueous dilution, a mean of 93.6% of the applied 

radioactivity was readily washed from the skin surface after the 6 hour exposure interval (in rats 

terminated at 6 hours), and was readily washed from the skin surface. The potentially absorbable 

skin residue declined from 4.55% of the dose after 6 hours to 2.04% after 120 hours. The 

percentage of dose absorbed from this dilution accounted for 3.51, 4.31, 3.90 and 4.88% of the 

dose after 6, 24, 72 and 120 hours respectively. The dermal absorption, calculated by adding the 

potentially absorbable dose with the absorbed dose, was 8.05%, 6.72%, 5.19% and 6.92% after 

6, 24, 72 and 120 hours, respectively.

Following a dermal exposure interval of 6 hours to SYN524464 FS formulation concentrate 

(A16148C), virtually all of the applied dose was readily removed from the skin surface by mild 

skin washing. Dermal absorption of SYN524464 accounted for 0.23% of the dose after 6 hours 

and 0.31% after 120 hours. Following a 6 hour exposure to a 1/20 aqueous dilution, dermal 

absorption represented 2.69% of the dose after 6 hours and 1.67% after 120 hours. Following a 

6 hour exposure to a 1/200 aqueous dilution, dermal absorption represented 8.05% of the dose 

after 6 hours and 6.92% after 120 hours. 

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID #47473405), SYN524464 (95.3% a.i.,) was administered to 

10 Crl:CD1 (ICR) male mice/dose in the diet at concentrations of 0, 500, 2000 or 5500 ppm (0, 

93, 367.3 or 1080.1 mg/kg bw/day) for 28 consecutive days. An additional group of mice were 

administered the positive control substance, cyclophosphamide monohydrate (CPS), via 

intraperitoneal injection (50 mg/kg/day) for 4 consecutive days (study days 24 through 27). The 

vehicle control and positive control groups (Groups 1 and 5, respectively) were offered the basal 

diet for a minimum of 28 consecutive days. All mice were immunized with an intravenous 

injection of sRBC on study day 24, approximately 96 hours prior to the scheduled necropsy. All 

animals were euthanized on study day 28. 

All animals survived to the scheduled necropsy. There were no test substance-related clinical 

observations. There were no test substance-related effects on body weights, food consumption, 
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or macroscopic findings. There was an increase in relative spleen weights and gross and relative 

thymus weights in high-dose animals, but not statistically significant. In the antibody formation 

cell assay, there was an increase in antibody formation at 5500 ppm. 

Sedaxane did not elicit immunosuppressant effects. The positive control cyclophosphamide 

demonstrated response of the assay to a known immunotoxicant. 

NOAEL=1080 mg/kg/day, LOAEL=Not determined, no decrease in TDAR assay, spleen and 

thymus weight changes not statistically significant (high coefficients of variation noted for IgM 

data).

Appendix B. Metabolism Data

B1. Structures and Identity of Metabolites of Sedaxane

Appendix B.1. Test Compound Nomenclature.

Compound Chemical Structure

Common name: Sedaxane

CAS name: N-[2-[1,1′-bicyclopropyl]-2-

ylphenyl]-3-(difluoromethyl)-1-methyl-1Hpyrazole-4-carboxamide

IUPAC Name: Mixture of cis isomers 2’-

[(RS,2RS)-1,1’-bicycloprop-2-yl]-3-

(difluoromethyl)-1-methylpyrazole-4-

carboxanilide and trans isomer 2’-[(RS,2SR)-

1,1’-bicycloprop-2-yl]-3-(difluoromethyl)-1-

methylpyrazole-4-carboxanilide Mixture of trans (SYN508210) and cis (SYN508211) isomers

Company name: CSCD658906

IUPAC Name: N-{2-[(1R,2S)-1,1'-

bi(cyclopropyl)-2-yl]phenyl}-1-methyl-3-

(trifluoromethyl)-1H-pyrazole-4-

carboxamide

Company name: CSCC210616

IUPAC Name: 3-(difluoromethyl)-1Hpyrazole-4-amide
Sedaxane (129223) Human Health Risk Assessment D405099

Page 74 of 75

Appendix B.1. Test Compound Nomenclature.

Compound Chemical Structure

Company name: CSCD465008

IUPAC Name: 3-(difluoromethyl)-1Hpyrazole-4-carboxylic acid

OH

O

N

N

H

HF2C

Company name: CSAA798670

IUPAC Name: 3-(difluoromethyl)-1-methyl1H-pyrazole-4-carboxylic acid

OH

O

N

N

HF2C

CH3

Company name: CSCD668094

IUPAC Name: N-[2-(3-cyclopropyl-1,3-

dihydroxypropyl)phenyl]-3-(difluoromethyl)-

1-methyl-1H-pyrazole-4-carboxamide

NH

O

N

N

HF2C

CH3

HO

HO

Company name: CSCD668095

IUPAC Name: 3-[2-({[3-(difluoromethyl)-1-

methyl-1H-pyrazol-4-

yl]carbonyl}amino)phenyl]-3-

hydroxypropanoic acid

NH

O

N

N

HF2C

CH3

HO O

HO
Sedaxane (129223) Human Health Risk Assessment D405099

Page 75 of 75

Appendix C. Physical/Chemical Properties

Table C.1. Physicochemical Properties of Sedaxane. 

Parameter Value Reference

Melting point 121.4  ̊C

D382350, A. 

Abramovitch, 

11/2/2011

pH 5.9 at 1.0 % w/v (25 °C)

Density 1.23x 103kg/m3at 20°C corresponding 

to a relative density of 1.23

Water solubility 14 mg/L

Solvent solubility (at 25°C) Acetone – 410 g/L

Dichloromethane – 500 g/L

Ethyl acetate hexane – 200 g/L

Methanol – 410 mg/L

Octanol – 110 g/L

Toluene – 20 g/L

Vapor pressure At 20°C, 6.5x10-8Pa 

At 25°C, 1.7x10-7Pa

Dissociation constant (pKa) No pKa found in the range of 1.0 to 12.0 

by spectro-photometric titration of a 

solution of sedaxane in water

Octanol/water partition coefficient 

Log(KOW)

log KOW @ 25°C = 3.3

Henry’s Law Constant At 25°C, 4.0 x10-6Pa m

3

/mol

UV/visible absorption spectrum Neutral, acidic and basic solutions:

max = 225, 265, and 295 nm

Appendix D. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, which form the basis of the 

Seed Treatment SOPs, have been determined to require a review of their ethical conduct, have 

received that review, and have been determined to be ethical.