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The toxicity database is adequate to support existing registrations and registration review with 

the exception of an immunotoxicity study, as well as acute neurotoxicity studies as specified in 

the new 40 CFR Part 158 data requirements. The Food Quality Protection Act (FQPA) Safety 

Factor (SF) will need to be re-evaluated for future actions. In the previous risk assessments, only 

the chronic dietary endpoint was selected (see Attachment 2). For Registration Review, 

endpoints for the occupational and residential (if necessary) exposure scenarios (dermal and 

inhalation of all durations) will be evaluated and selected based upon the available data. 

The dietary-exposure database is adequate to support the existing registrations. However, a new 

dietary assessment will be required during registration review using current exposure models 

[i.e., Dietary Exposure Evaluation Model software with the Food Commodity Intake Database 

(DEEM-FCIDTM)] and incorporating potential changes to the pyrithiobac sodium tolerances 

estimated drinking water concentrations.

EFED provided ground and surface water exposure estimates by using the Generic Expected 

Environmental Concentration (GENEEC) model. The Tier 1 exposure estimate for surface water is 

7.76 ppb (chronic) and for ground water is 0.778 ppb. 

The most recent human-health risk assessment included a comprehensive assessment of 

aggregate exposure, and no risks of concern were identified (Memo, D235143, G. Kramer, 

7/15/97). Based on the available data and assumptions used for dietary/water (aggregate) 

exposure and risk estimates, the population group estimated to be the most highly exposed to 

pyrithiobac sodium was children (1-6 years old), with a risk estimate from combined sources 

equaling <0.2% of the RfD. The Carcinogenicity Peer Review Committee (CPRC) determined 

that the classification for pyrithiobac sodium should be group C (possible human carcinogen) 

and that a low-dose extrapolation methodology (Q1*) should be applied to the animal data to 

determine the most protective human risk estimate (Taylor et al., TXR #0011668, 05-SEP-08). 

This decision was based on evidence of increased incidences of liver tumors in the CD-1 male 

mouse that were statistically significant at more than one dosea and exceeded the historical 

control range, and increases in rare kidney tumors in male Crl:CDBR rats. Upper-bound lifetime 

cancer risk from the proposed use of pyrithiobac sodium on cotton was 2.3 x 10-7 for adult males. 

An upper-bound potency factor (Q1*) of 1.05 x 10-3 (mg/kg/day)-1 and a 70-year lifetime 

exposure were assumed in this calculation. 

The residue chemistry database is sufficient to support the current registrations. The following 

issues should be addressed in registration review: 1) determination of the residues of concern in 

livestock for both the tolerance expression and risk assessment, 2) HED review of the residue 

data for cotton gin byproducts (MRID# 44373801), and 3) reevaluation of the cotton seed and 

gin byproduct tolerances. 

There are no established Canadian, Mexican, or Codex maximum residue limits (MRLs) for 

residues of pyrithiobac sodium. Therefore, issues of compatibility with respect to U.S. 

tolerances and Canadian, Mexican, and Codex MRLs do not exist.

 a

Questions regarding the lack of response in the male mouse liver at the highest dose could not be resolved by the CPRC. 
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There is sufficient information available to assess occupational handler exposure. Because there 

were no short- and intermediate-term dermal or inhalation endpoints identified at the time of the 

last risk assessment, short- and intermediate-term occupational exposure assessments were not 

conducted. Estimated excess lifetime carcinogenic risks for mixer/loaders and applicators were 

calculated and were not of concern to HED. If changes are made to the toxicological endpoint 

selection, occupational handler scenarios may need to be assessed for short- and intermediateterm exposure durations. In addition, an updated occupational handler cancer assessment for 

both registered formulations following current procedure is required. 

There is sufficient information available to assess occupational post-application exposure. Postapplication dermal and inhalation exposures have not been previously assessed. A postapplication inhalation exposure assessment may be needed pending changes to Agency policies 

and procedures. Pending final determination of proposed changes to the hazard assessment, a 

dermal post-application exposure assessment may be required for post-application activities such 

as weeding and scouting since pyrithiobac sodium can be applied post-emergence, up to 60 days 

before harvesting. An occupational cancer post-application assessment will need to be 

conducted during Registration Review.

Data needs and risk assessment updates required under registration review for pyrithiobac 

sodium are as follows:

Toxicology:

• The toxicity endpoint/dose selection along with the FQPA SF will need to be reevaluated according to current policy.

• The following studies are required as specified in the revised 40 CFR Part 158:

o Guideline 870.3465 90-day inhalation toxicity study,

o Guideline 870.7800 immunotoxicity, and

o Guideline 870.6200 acute neurotoxicity.

Residue Chemistry:

• Determination of the residues of concern in livestock for both the tolerance expression 

and risk assessment.

• HED review of the residue data for cotton gin byproducts (MRID# 44373801; Guideline 

860.1500).

• Re-evaluation of the cottonseed and gin byproduct tolerances.

• The tolerance expression for pyrithiobac sodium residues needs to be updated to reflect 

current Agency policy: “Tolerances are established for residues of the herbicide 

pyrithiobac sodium, including its metabolites and degradates, in or on the commodities in 

the table below. Compliance with the tolerance levels specified below is to be 

determined by measuring only pyrithiobac sodium (2-chloro-6-[(4,6-dimethoxy-2-

pyrimidinyl)thio]benzoic acid), in or on the following commodities:”

Dietary Exposure:

• A new dietary assessment will be required during registration review using current 

exposure models (i.e., DEEM-FCIDTM) and incorporating potential changes to the 

pyrithiobac sodium tolerances and estimated drinking water concentrations.
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Occupational Exposure:

• A revised occupational exposure assessment to include changes to the toxicological 

endpoints, additional scenarios, and current policies. 

Introduction

Pyrithiobac sodium is an ALS inhibiting herbicide and is currently registered by DuPont for a 

Section 3 use as a pre-emergent or post-emergence broadcast treatment to cotton (the only 

registered food use). In addition, the States of TN and NC have Section 24(c) registrations for 

use on kenaf (non-food). The registered products include the soluble-powder formulation 

Staple® (EPA Reg. No. 352-576), containing 85% pyrithiobac sodium packaged in water-soluble 

bags; and the SC formulation Staple® LX (EPA Reg. No. 352-613), containing pyrithiobac 

sodium at a concentration of 3.2 lb ai/gal. Use on cotton is limited to one or two pre-emergent or 

post-emergence applications at a maximum rate of 0.1275 lb ai/A. There are no registered or 

proposed residential uses.

Hazard Identification/Toxicology

Pyrithiobac sodium is the active ingredient in a low use rate herbicide (Staple®) for postemergence weed control for cotton. Its mechanism of action prevents cell division and growth 

due to inhibition of the plant enzyme acetolactate synthase, which catalyzes the first step in the 

synthesis of branch-chain amino acids (valine, leucine, and isoleucine). This hazard summary is 

based upon the hazard characterization from the most recent human-health risk assessment for 

pyrithiobac sodium (Memo, D235143, G. Kramer, 7/15/97).

Pyrithiobac sodium was of low acute toxicity (Toxicity Category III or IV) via the oral, dermal,

and inhalation routes of exposure. It was not a dermal sensitizer, or a dermal irritant. It was 

irritating to the eyes of rabbits (Toxicity Category II). 

Pyrithiobac sodium was well absorbed from the gastrointestinal tract (69-83% for both sexes), 

and rapidly excreted with 90% of the compound being eliminated within 48 hours. In low- and

high-dose groups, as well as low-repeated-dose groups, pyrithiobac sodium was cleared within 

72 hours. In both low- and high-dose groups, pyrithiobac sodium was not detectable in any of 

the tissues tested 120 hours post-dosing. 

By the oral route of exposure, pyrithiobac sodium caused toxicity in several organs with the liver 

being the most prominent. Liver toxicity occurred in the mouse, rat, and dog for both subchronic 

and chronic durations. Effects included increased liver weights (absolute and relative) in all 

species, histopathological indicators of injury (focal cystic degeneration and foci/focus 

hepatocellular alterations; all species), hepatic peroxisomal β oxidation (mice and rats), and 

hepatocellular neoplasms (adenomas or carcinomas) in males (mice).

Kidney toxicity was also observed in the mouse, rat, and dog following chronic exposures. 

Histopathological indicators of injury in the kidney included inflammatory and degenerative 

microscopic lesions (female rats), increased incidence of glomerular nephropathy in both sexes 

(mice), increased incidence of infarct in the kidneys of males (mice), and unspecified 

microscopic findings in dogs. Kidney tumors were observed in both male and female rats at the 
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highest doses tested. There were also mild changes in urinalysis in both sexes (rats), and clinical 

signs suggestive of urinary tract dysfunction (rats). 

Decreased body-weight gains were observed in all species. Hematotoxic effects were observed 

in the mouse and the dog including decreased red blood cell counts, hemoglobin concentrations, 

hematocrit levels, white blood cells, neutrophils, and lymphocytes. Increased thyroid weights 

were observed in the dog and keratopathy (corneal opacity) of the eye occurred in the rat. 

There was no increased qualitative or quantitative fetal susceptibility following oral 

administration of pyrithiobac sodium in the prenatal developmental toxicity studies. In the rat, 

maternal effects which were mild (decreased food consumption and stained fur) occurred at 

lower doses than fetal effects which were not considered adverse (increased skeletal variations at 

the high dose with no dose response). In the rabbit, maternal and fetal effects occurred at the 

same dose. Maternal effects included deaths, decreased body-weight gain and feed consumption, 

and an increase in early resorptions. Developmental effects included decreased fetal body 

weights. In the rat two-generation reproduction study, effects in parental groups included 

decreased body weight, body-weight gain, and food efficiency. These effects occurred at lower 

doses than the offspring effects. Offspring effects included decreased pup body weight. No 

reproductive effects were observed.

In a 21-day dermal toxicity study in rabbits, pyrithiobac sodium caused toxicity at the high dose 

of 1,200 mg/kg/day. These effects consisted of decreased body-weight gains as well as 

acanthosis (diffuse epidermal hyperplasia) and hyperkeratosis (thickening of the stratum 

corneum). 

Potential neurotoxicity was examined in a combined subchronic toxicity/ neurotoxicity/onegeneration reproduction study. All of relevant criteria by today’s guidelines were measured, 

including the functional-observation-battery (FOB) testing, motor-activity measurements, as well 

as determination of changes in central and peripheral nervous system morphometry 

(neuropathology). The only potentially significant finding was a 5% decrease in absolute brain 

weights of males at the highest dose tested and increased relative brain weights. There was also 

a slight decrease in forelimb and hindlimb grip strength and landing foot splay in males at the 

highest dose tested. The author did not consider these neurotoxic effects, but a decrease in 

muscle strength associated with decreased body weights ~10%. No other of neurotoxicity were 

observed up to the highest dose tested (1,376 mg/kg/day), which was comparable to the limit 

dose by the current criteria (1,000 mg/kg/day). There is no acute neurotoxicity screening battery 

study or an immunotoxicity study available for pyrithiobac sodium. 

Of the battery of tests used to determine genotoxicity, the micronucleus test was the only study 

that demonstrated DNA damage due to treatment with pyrithiobac sodium. All other assays 

were negative.

The CPRC met on July 12, 1995 to discuss and evaluate the weight-of-the-evidence on 

pyrithiobac sodium with particular reference to its carcinogenic potential. The CPRC concluded 

that pyrithiobac sodium should be classified as Group C, possible human carcinogen, and 

recommended that a low-dose-extrapolation model be applied to the animal data due to liver and 

kidney adenomas/adenocarcinomas observed in the male rat. The estimate of unit risk, Q1*, was 
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converted to human equivalents by the use of body weights of 0.35 kg for rats, 70 kg for humans, 

and the 3/4's scaling factorb for interspecies extrapolation.

FQPA Considerations: The pre- and post-natal toxicology database for pyrithiobac sodium is 

complete with respect to current toxicological data requirements. The results of these studies 

indicated that infants and children were not more sensitive to exposure, based on the results of 

the oral rat and rabbit developmental toxicity studies and the two-generation reproductive 

toxicity study in rats. Thus, there was minimal concern for developmental or reproductive 

toxicity. No additional uncertainty factor for increased sensitivity in infants and children was 

required.

The requirement for the subchronic neurotoxicity study under the revised 40 CFR Part 158 is 

satisfied by the combined subchronic oral/neurotoxicity/1-generation reproductive study (MRID 

42856931). The level of concern for neurotoxicity is low despite the lack of a newer study, 

because there was little evidence for neurotoxic effects in the combined study. What is observed 

in that study is not considered adverse and occurred at a level greater than the current limit dose 

(1,000 mg/kg bw/day). There is currently no available acute neurotoxicity or immunotoxicity 

study for pyrithiobac sodium. 

The policy for evaluation of the FQPA SF was revised after completion of the previous risk 

assessments for pyrithiobac sodium (see Hotsheet #30, 2008), and thus for registration review, 

the FQPA SF will need to be evaluated based upon the available data for pyrithiobac sodium. 

Three new studies need to be submitted and added to the database (acute neurotoxicity, 

immunotoxicity, and inhalation toxicity) which may also affect this SF for future registrations. 

Immunotoxicity: An immunotoxicity study is required as a part of revised data requirements in 

the 40 CFR Part 158 for conventional pesticide registration. Because the immune system is 

highly complex, studies not specifically conducted to assess immunotoxic endpoints are 

inadequate to characterize a pesticide’s potential immunotoxicity. While data from hematology, 

lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies 

may offer useful information on potential immunotoxic effects, these endpoints alone are 

insufficient to predict immunotoxicity. In the absence of required studies, EPA may use a 

database uncertainty factor of up to 10X. An immunotoxicity study on pyrithiobac sodium 

should be conducted. Once all data have been received and reviewed, the pyrithiobac sodium 

Registration Review Team recommends that the points of departure and SFs used for risk 

assessment purposes be reexamined and a new risk assessment done, if necessary.

Endocrine Disruption: As required by FIFRA and the Federal Food, Drug, and Cosmetic Act 

(FFDCA), EPA reviews numerous studies to assess potential adverse outcomes from exposure to 

chemicals. Collectively, these studies include acute, subchronic, and chronic toxicity, including 

assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or 

systemic toxicity. These studies include endpoints that may be susceptible to endocrine 

influence, including effects on endocrine target organ histopathology, organ weights, estrus 

cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in 

offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that 

assess growth, developmental and reproductive effects in different taxonomic groups. As part of 

its most recent registration decision, EPA reviewed these data and selected the most sensitive 

 b

From memorandum, “Deriving Q1

*

s Using the Unified Interspecies Scaling Factors,” P.A. Fenner-Crisp, Director-HED, 7/1/94.
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endpoints for relevant risk assessment scenarios from the existing hazard database. However, as 

required by FFDCA section 408(p), pyrithiobac sodium is subject to the endocrine screening part 

of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Pyrithiobac 

sodium is not among the group of 58 pesticide active ingredients on the initial list to be screened 

under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP 

orders/data call-ins, requiring the submission of EDSP screening assays for pyrithiobac sodium. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website: http://www.epa.gov/endo/.

Conclusions

The toxicity database is adequate to support existing registrations and registration review with 

the exception of an immunotoxicity study, as well as acute neurotoxicity studies as specified in 

the new 40 CFR Part 158 data requirements. A guideline 90-day inhalation study will also be 

required. The FQPA SF will need to be re-evaluated. In the previous risk assessments, only the 

chronic dietary endpoint was selected (see Attachment 2). For Registration Review, endpoints 

for the occupational and residential (if necessary) exposure scenarios (dermal and inhalation of 

all durations) will be evaluated and selected based upon the available data. 

Residue Chemistry

The nature of the residue in cotton is understood, based on metabolism studies with cotton 

treated with pyrithiobac sodium. The HED Metabolism Assessment Review Committee 

(MARC) determined that the residue of concern for both the tolerance expression and risk 

assessment is pyrithiobac sodium per se. The nature of the residue in livestock is understood 

based on metabolism studies with goats and hens. The residues of concern in livestock were not 

determined due to the low potential for exposure. 

A high-performance liquid chromatography/ultraviolet (HPLC/UV) method (Method AMR 

2816-93, Revision 2; MRID# 43193401) is available for the enforcement of the cottonseed 

tolerance. The recoveries reported by the registrant and in the Independent Laboratory

Validation (ILV) were acceptable. The limit of quantitation (LOQ) is 0.010 ppm. This method 
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has undergone a successful Petition Method Validation (PMV) by Agency chemists at the 

Analytical Chemistry Laboratory/Biological and Economics Analysis Division (ACL/BEAD). A 

liquid chromatography with tandem mass spectroscopy (LC-MS/MS) method (AMR 3954-96 2; 

MRID# 44373802) is available for enforcement of the cotton gin byproduct tolerance. This 

method has also undergone a successful PMV. 

Pyrithiobac sodium was tested with the FDA Multiresidue Method Testing (MRM) Protocols. 

Protocols A, D, and E were not applicable. Protocol C was not suitable due to insufficient 

response. Protocol B afforded a 43% recovery for a 0.2-ppm fortification and a 0% recovery for 

a 0.02-ppm fortification.

Adequate crop field trial data are available to support the cottonseed tolerance. Residues of

pyrithiobac sodium were <LOQ in all cottonseed samples from 14 residue trials. The tolerances 

will be reevaluated as part of registration review. HED has not reviewed the residue data for 

cotton gin byproducts (MRID# 44373801).

No livestock feeding studies have been submitted. Due to the low potential for exposure, these 

studies are not required. 

Adequate confined rotational crop studies have been submitted. The MARC determined that the 

residue of concern for both the tolerance expression and risk assessment is pyrithiobac sodium 

per se. These data indicated that plantback intervals (PBIs) of at least 30 days for all nonregistered crops are appropriate for pyrithiobac sodium; no rotational crop tolerances are 

required. HED recently approved the use of DuPont Staple® Plus Herbicide (EPA Reg. No. 352-

606; 40.2% glyphosate as the isopropylamine salt and 1.7% pyrithiobac sodium) which permits 

the rotation of glyphosate-tolerant field corn and soybeans following application to glyphosatetolerant cotton. Since the rotational crops (corn and soybean) are planted at intervals of >30 

days, additional residue chemistry data were not required to support this use.

Conclusions

The residue chemistry database is sufficient to support the current registrations. The following 

issues should be addressed in registration review: 1) determination of the residues of concern in 

livestock for both the tolerance expression and risk assessment, 2) HED review of the residue 

data for cotton gin byproducts (MRID# 44373801), and 3) reevaluation of the cotton seed and 

gin byproduct tolerances.

Dietary Exposure

The most recent chronic dietary-exposure assessment (food only) was performed in conjunction 

with the 7/15/97 human-health risk assessment conducted by HED (D235143, G. Kramer). 

Dietary risk assessments were conducted using the Dietary Risk Evaluation System (DRES). 

The chronic analysis assumed 100 percent crop treated (%CT), and tolerance-level residues for 

all commodities. The resulting chronic and cancer risk estimates were not of concern to HED. 

The most highly exposed population was children 1-6 years old, utilizing <0.1% of the cPAD. 

The cancer analysis was performed using an upper-bound potency factor (Q1*) and highly 

conservative exposure assumptions (i.e., 100% CT, and tolerance-level residues for all 

commodities). The resulting cancer risk estimate, 1 x 10-9 for the general U.S. population, was 

not of concern to HED. 
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EFED provided ground and surface water exposure estimates (Memo, R. Jones; 6/30/97). 

Pyrithiobac sodium concentrations in surface water were estimated by using the Generic Expected 

Environmental Concentration (GENEEC) model. The Tier 1 exposure estimate for surface water is 

7.76 ppb (chronic) and for ground water is 0.778 ppb. Based on a water consumption of 2 L/d for a 

70-kg adult (male) and of 1 L/d for a 10-kg child (1-6 years), the worst-case estimate of residues in 

drinking water (7.76 ppb) resulted in an exposure of 2.2 x 10-4 mg/kg/day for adults and 7.8 x 10-4

mg/kg/day for children. These exposure values correspond to: a) <0.1% of the cPAD for adult 

males and 0.1% of the cPAD for children (1-6 years); and b) a cancer risk for adult males of 2.3 x 

10-7.

Conclusions

The dietary-exposure database is adequate to support the existing registrations. However, a new 

dietary assessment will be required during registration review using current exposure models 

(i.e., DEEM-FCIDTM) and incorporating potential changes to the pyrithiobac sodium tolerances

and estimated drinking water concentrations.

Residential Exposure

There are currently no registered residential uses of pyrithiobac sodium. Therefore, residential 

handler and post-application exposures have not been assessed. 

Residential Bystander Post-application Inhalation Exposure: Based on the Agency's current 

practices, a quantitative residential bystander post-application inhalation exposure assessment 

was not performed for pyrithiobac sodium at this time. However, volatilization of pesticides 

may be a potential source of post-application inhalation exposure to individuals nearby to 

pesticide applications. The Agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) 

Scientific Advisory Panel (SAP)in December 2009. The Agency received the SAP’s final report 

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

Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative post-application 

inhalation exposure assessment for pyrithiobac sodium.

Spray Drift: Spray drift is always a potential source of exposure to residents nearby to spraying 

operations. This is particularly the case with aerial application, but, to a lesser extent, could also 

be a potential source of exposure from the ground application method employed for pyrithiobac 

sodium. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices 

and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical-by-chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT® computer model 

to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic 

methods. After the policy is in place, the Agency may impose further refinements in spray-drift-
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management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

Conclusions

Residential handler and post-application exposures are not permitted by the label and have not 

been previously assessed, nor are they expected. Because there are currently no registered 

residential uses, an assessment is not required at this time; however, the need for residential postapplication exposure assessments will be re-evaluated based on current Agency policy at the 

time of the risk assessment. 

Aggregate Risk Assessment

Chronic Risk: Based on the available data and assumptions used for dietary/water and risk 

estimates, the population group estimated to be the most highly exposed to pyrithiobac sodium 

are children (1-6 years old), with a risk estimate from combined sources equaling <0.2% of the 

RfD (dietary = <0.1% + drinking water = 0.1% + non-occupational = 0%).

Cancer Risk: The upper-bound lifetime cancer risk from the proposed use of pyrithiobac 

sodium on cotton is 2.3 x 10-7 (dietary = <1 x 10-9

+ drinking water = 2.3 x 10-7 + nonoccupational = 0). An upper-bound potency factor (Q1*) of 1.05 x 10-3 (mg/kg/day)-1 and a 70-

year lifetime exposure were assumed in this calculation. 

Conclusions

A new aggregate risk assessment will be required during registration review to incorporate the 

revised dietary assessment. 

Occupational Exposure

Pyrithiobac sodium is registered only for use on cotton and kenaf. A summary of occupational 

uses is listed in Attachment 4.

Occupational Handlers: HED has determined that occupational handlers are likely to be 

exposed to pyrithiobac sodium residues from the registered use on cotton. Because there were 

no short- and intermediate-term dermal or inhalation endpoints identified at the time of the last 

risk assessment (G. Kramer, D235143, 15-JUL-97), short- and intermediate-term occupational 

exposure assessments were not conducted. There was a cancer endpoint, and a cancer 

assessment was conducted for mixers/loaders and applicators handling the soluble powder 

formulation (packaged in water-soluble bags). Estimated lifetime carcinogenic risks for 

mixer/loaders and applicators were calculated and were not of concern to HED.

The previous assessment only assessed exposure/risk for the soluble powder formulation 

(packaged in water-soluble bags) and was not conducted using current assumptions and inputs. 

Revised occupational handler assessments would need to be performed for the following 

scenarios associated with use on cotton:

• mixer/loader scenarios for groundboom, aerial, and banded application of wettable 

powder (packaged in water-soluble bags) and liquid formulations; and 
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• applicator scenarios for aerial, groundboom, and banded application of sprays.

Conclusions

There is sufficient information available to assess occupational handler exposure. If changes are 

made to the toxicological endpoint selection, the scenarios listed above may need to be assessed 

for short- and intermediate-term exposure durations. In addition, an updated cancer assessment 

for both registered formulations following current procedure is required. Recommended unit 

exposures for occupational handler assessments have generally been derived only from PHED. 

However, recently both the ORETF and AHETF have produced pesticide handler exposure 

monitoring data that the Agency is using in place of PHED 

(http://www.epa.gov/pesticides/science/handler-exposure-data.html). As more reliable data 

become available (such as that from the AHETF and ORETF), the Agency will continue to 

replace existing data. Reviewers should incorporate new exposure monitoring data, as 

necessary, during Registration Review.

Occupational Post-Application: An occupational post-application dermal exposure assessment 

was not conducted for the last risk assessment because no short- and intermediate-term dermal 

endpoints were selected. In addition, a cancer post-application assessment was not conducted for 

pyrithiobac sodium.

Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment was not performed for pyrithiobac sodium. However, there are multiple 

potential sources of post-application inhalation exposure to individuals performing postapplication activities in previously treated fields. These potential sources include volatilization 

of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency 

sought expert advice and input on issues related to volatilization of pesticides from its FIFRA 

SAP in December 2009. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for pyrithiobac sodium. 

Conclusions

There is sufficient information available to assess occupational post-application exposure. Postapplication dermal and inhalation exposures have not been previously assessed. A postapplication inhalation exposure assessment may be needed pending changes to Agency policies 

and procedures. Pending final determination of proposed changes to the hazard assessment, a 

dermal post-application exposure assessment may be required for post-application activities such 

as weeding and scouting since pyrithiobac sodium can be applied post-emergence, up to 60 days 

before harvesting. A cancer post-application assessment will need to be conducted during 

Registration Review. Recommended exposure data for occupational post-application 

assessments have recently been updated (http://www.epa.gov/pesticides/science/post-appexposure-data.html). Reviewers should incorporate new post-application exposure data, as 

necessary, during Registration Review.
Pyrithiobac Sodium Registration Review Human-Health Assessment Scoping Document

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Public Health and Pesticide Epidemiology Data

For this evaluation, the OPP Incident Data System (IDS) was utilized for pesticide-incident data 

on the active ingredient pyrithiobac sodium. The purpose of the database search is to identify 

potential patterns on the frequency and severity of the health effects attributed to pyrithiobac 

sodium exposure. The IDS includes reports of alleged human health incidents from various 

sources, including mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) 

Section 6 (a) (2) reports from registrants, other federal and state health and environmental 

agencies and individual consumers. Since 1992, OPP compiles these reports in IDS. IDS 

contains reports from across the U.S. and most incidents have all relevant product information 

recorded. Reports submitted to the IDS represent anecdotal reports or allegations only, unless 

otherwise stated in the report. The AHS is a high quality, prospective epidemiology study 

evaluating the link between pesticide use and various health outcomes including cancer. The 

AHS includes private and commercial pesticide applicators and their spouses. If there are AHS 

findings relevant to a particular pesticide going through registration review, the Agency will 

ensure they are considered in the problem formulation/scoping phase of the process and, if 

appropriate, fully reviewed in the risk assessment phase of the process. The AHS includes 

information on use of 50 different pesticide active ingredients commonly used in agriculture.

IDS records incidents resulting in higher severity outcomes in more detail, in a module called the 

Main IDS module. This system stores incident data for death, major and moderate incidents, and 

it includes more details about the location, date, and nature of the incident. Main IDS incidents 

involving only one pesticide are considered to provide more certain information about the 

potential effects of exposure from the pesticide. The less severe human incidents (minor, 

unknown, or no effects outcomes) are reported by registrants as counts called aggregate 

summaries and are recorded in a separate module called Aggregate IDS. 

In Aggregate IDS, from January 1, 2006 to March 23, 2011 there are zero incidents involving 

pyrithiobac sodium. For the Main IDS, from January 1, 2006 to March 23, 2011, there are zero 

cases reported that involve the active ingredient pyrithiobac sodium. Pyrithiobac sodium is not 

included in the AHS, and therefore does not provide information for this report.

Conclusions

There are no incident cases reported for pyrithiobac sodium in either the Main or Aggregate IDS 

module. There does not appear to be a concern at this time that would warrant further 

investigation. The Agency will continue to monitor the incident information and if a concern is 

triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR 180.487) are summarized in Attachment 5. There 

are no established Canadian, Mexican, or Codex MRLs for residues of pyrithiobac sodium. 

Therefore, issues of compatibility with respect to U.S. tolerances and Canadian, Mexican, and 

Codex MRLs do not exist. 
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Environmental Justice

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

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.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP 

typically considers the highest potential exposures from the legal use of a pesticide when 

conducting human-health risk assessments, including, but not limited to, people who obtain 

drinking water from sources near agricultural areas, the variability of diets within the U.S., and 

people who may be exposed when harvesting crops. Should these highest exposures indicate 

potential risks of concern, OPP further refines the risk assessments to ensure that the risk 

estimates are based on the best available information.

Human Studies

Past pyrithiobac sodium risk assessments rely in part on data from studies in which adult 

human subjects were intentionally exposed to a pesticide to determine their dermal and 

inhalation exposure. Many such studies, involving exposure to many different pesticides, 

comprise generic pesticide exposure databases such as PHED, the Outdoor Residential 

Exposure Task Force (ORETF) Database, and the Agricultural Reentry Task Force (ARTF) 

Database. EPA has reviewed all the studies supporting these multi-pesticide generic exposure 

databases, and has found no clear and convincing evidence that the conduct of any of them was 

either fundamentally unethical or significantly deficient relative to the ethical standards 

prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule 

for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and 

there is no regulatory barrier to continued reliance on these studies.

Data Requirements/Risk Assessment Updates

Toxicology:

• The toxicity endpoint/dose selection along with the FQPA SF will need to be reevaluated according to current policy.

• The following studies are required as specified in the revised 40 CFR Part 158:

o Guideline 870.3465 90-day inhalation toxicity study,

o Guideline 870.7800 immunotoxicity, and

o Guideline 870.6200 acute neurotoxicity.

Residue Chemistry:

• Determination of the residues of concern in livestock for both the tolerance expression 

and risk assessment.

• HED review of the residue data for cotton gin byproducts (MRID# 44373801; Guideline 

860.1500).

• Re-evaluation of the cottonseed and gin byproduct tolerances.

• The tolerance expression for pyrithiobac sodium residues needs to be updated to reflect 

current Agency policy: “Tolerances are established for residues of the herbicide 

pyrithiobac sodium, including its metabolites and degradates, in or on the commodities in 

the table below. Compliance with the tolerance levels specified below is to be 
Pyrithiobac Sodium Registration Review Human-Health Assessment Scoping Document

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determined by measuring only pyrithiobac sodium (2-chloro-6-[(4,6-dimethoxy-2-

pyrimidinyl)thio]benzoic acid), in or on the following commodities:”

Dietary Exposure:

• A new dietary assessment will be required during registration review using current 

exposure models (i.e., DEEM-FCIDTM) and incorporating potential changes to the 

pyrithiobac sodium tolerances and estimated drinking water concentrations.

Occupational Exposure:

• A revised occupational exposure assessment to include changes to the toxicological 

endpoints, additional scenarios, and current policies.

References

Table 1. Memoranda Relevant to Registration Review.

Author Barcode Date Title

S. Robbins - 9/25/95

HED Risk Assessment for Use of Pyrithiobac Sodium 

(sodium 2-chloro-6-[(4,6-dimethoxypyrimidin-2-

yl)thio]benzoate) in or on Cotton.

E. Haeberer - 9/8/95 Dietary Exposure Analysis for the Proposed Use of 

Pyrithiobac Sodium in/on Cotton.

G. Kramer 235143 7/15/97 Tolerance Petition for Residues of Pyrithiobac Sodium 

in/on Cotton.

G. Kramer 197524 7/13/94 PP# 3G04244. New Chemical - Pyrithiobac sodium in or on 

cotton. Revisions to Analytical Enforcement Method. 

G. Kramer 197524 3/17/94

PP# 3G04244. New Chemical - Pyrithiobac sodium in or on 

cotton. Results of the Petition Method Validation (PMV) of 

the Analytical Enforcement Method. 

G. Kramer 202039 4/29/94 PP# 3G04244. New Chemical - Pyrithiobac sodium in or on 

cotton. Revised Analytical Enforcement Method. 

G. Kramer

195332, 

197661, 

198415, 

201378

6/13/94

PP# 3G04244. New Chemical - Pyrithiobac sodium in or on 

cotton. Evaluation of residue and analytical data for an 

EUP and temporary tolerances. 

G. Kramer - 5/25/95 Pyrithiobac sodium. Issues to be presented to the HED 

Metabolism Committee on 6/1/95.

G. Kramer 215241 6/6/95 PP# 4F04391. Pyrithiobac sodium in or on cotton. 

Amendment of 5/5/95. 

G. Kramer 216002 6/21/95 HED Metabolism Committee Meeting of 6/1/95. 

Pyrithiobac sodium. PP# 4F04391. 

T. Bloem 278999 11/8/01 ID# 4F04391 - Application of Pyrithiobac-Sodium to 

Cotton. Results of Petition Method Validation (PMV). 

T. Bloem

271399 1/9/01 PP# 0F04391 - Application of Pyrithiobac-Sodium to 

Cotton. Petition Method Validation (PMV) Request. 

Chemical 078905. 

T. Bloem

357880 10/29/08 Glyphosate and Pyrithiobac Sodium. Amended Section 3 

Registration to Permit the Rotation to Glyphosate-Tolerant 

Field Corn and Glyphosate-Tolerant Soybean Following 

Application to Glyphosate-Tolerant Cotton and Revision of 

the Field Corn Tolerance Expression. Summary of 

Analytical Chemistry and Residue Data.
Pyrithiobac Sodium Registration Review Human-Health Assessment Scoping Document

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Attachments:

Attachment 1: Chemical Identity Table.

Attachment 2: Pyrithiobac Sodium Endpoint Selection Tables.

Attachment 3: Exposure Potential for Adult and Child Aggregate Risk Estimates.

Attachment 4: Occupational Use Patterns/Exposure Scenarios for Pyrithiobac Sodium.

Attachment 5: Pyrithiobac Sodium International Residue Limit Status Sheet. 

cc: A. Nowotarski (RAB1), G. Kramer (RAB1), A. Dunbar (RAB1)

RDI: RAB1 (5/11/11), J. Fowle (5/16/11)

G.F. Kramer:S10957:PY-S:(703)305-5079:7509P:RAB1
Pyrithiobac Sodium Registration Review Human-Health Assessment Scoping Document

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Attachment 1: Chemical Identity Table.

Pyrithiobac Sodium Compound Nomenclature.

Compound

N

O

CH3

O

H3C

S

Cl

O

OH

Common name pyrithiobac (PC code 078905)

Company experimental name --

CAS name 2-chloro-6-[(4,6-dimethoxy-2-pyrimidinyl)thio]benzoic acid

IUPAC 2-chloro-6-(4,6-dimethoxypyrimidin-2-ylthio)benzoic acid

CAS registry number 123342-93-8 (acid) 123343-16-8 (sodium salt)
Pyrithiobac Sodium Registration Review Human-Health Assessment Scoping Document

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Attachment 2: Pyrithiobac Sodium Endpoint Selection Table (information taken last risk 

assessment: G. Kramer, D235143, 15-JUL-97).

Endpoint Selection Table for Pyrithiobac Sodium

Exposure/

Scenario

Point of 

Departure Uncertainty/FQPA SFs

RfD, PAD, 

LOC for Risk 

Assessment

Study and Toxicological Effects 

Chronic Dietary 

(All 

Populations)

NOAEL= 

58.7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

cRfD = 0.58 

mg/kg/day

cPAD = 0.58 

mg/kg/day

Chronic Toxicity Study in Rats

LOAEL = 200 mg/kg/day (M), 918 

mg/kg/day (F) based on decreased body 

weight, body weight gain, decreases in 

hematocrit and red blood cells, and treatment 

related hematuria.

Cancer (oral, 

dermal, 

inhalation)

The CPRC classified as Group C - possible human carcinogen - and recommended that a low-doseextrapolation model be applied to the animal data (Q1*), due to liver and kidney adenomas/ adenocarcinomas 

observed in the male rat. The estimation of unit risk, Q1* (mg/kg/day)-1 of pyrithiobac sodium, based upon 

the male rat kidney tubular (adenomas and/or adenocarcinomas) tumors, is 1.05 x 10-3 (mg/kg/day)-1 in 

human equivalents. 1

 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, NOAEL = no-observed adverse-effect 

level, LOAEL = lowest-observed adverse-effect level, cRfD = chronic reference dose, cPAD = chronic population-adjusted dose, 

MOE = margin of exposure, LOC = level of concern.
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Attachment 3: Exposure Potential for Adult and Child Aggregate Risk Estimates.

(From D235143, G. Kramer; 7/15/97)

Chronic dietary exposure estimates (DRES) for pyrithiobac sodium are summarized below. The 

registered pyrithiobac sodium uses result in a Theoretical Maximum Residue Contribution 

(TMRC) that is equivalent to the following percents of the RfD:

U.S. Population (48 States) <0.1%

Hispanics <0.1%

Non-Hispanic Others <0.1%

Non-Nursing Infants (<1 year old) <0.1%

Females (13+ years, pregnant) <0.1%

Females (13+ years, nursing) <0.1%

Children (1-6 years old) <0.1%

Children (7-12 years old) <0.1%

Dietary Cancer Risk. An upper-bound potency factor (Q1*) of 1.05 x 10-3 (mg/kg/day)-1 

and a 70-year lifetime exposure were assumed in this calculation. Upper-bound lifetime 

cancer risk from the proposed use of pyrithiobac sodium on cotton is less than 1 x 10-9; it 

appears that cancer risk from this use is negligible.

EFED provided ground and surface water exposure estimates (Memo, R. Jones; 6/30/97). 

Pyrithiobac sodium concentrations in surface water were estimated by using the GENEEC model. 

The Tier 1 exposure estimate for surface water is 7.76 ppb (chronic) and for ground water is 0.778 

ppb. Based on and water consumption of 2 L/d for a 70-kg adult (male) and of 1 L/d for a 10-kg 

child (1-6 years), the worst-case estimate of residues in drinking water (7.76 ppb) results in the 

following risks:

Adult (Male) Exposure = (chemical concentration in μg/L)*(10-3 mg/μg)*(2 L/day) ÷ (70 kg body 

weight)

Child (1-6 years) Exposure = (chemical concentration in μg/L)*(10-3 mg/μg)*(1 L/day) ÷ (10 kg 

body weight)

Adult exposure is thus calculated to be 2.2 x 10-4 mg/kg/day and exposure for children is calculated 

to be 7.8 x 10-4 mg/kg/day. These exposure values correspond to: a) <0.1% of the cPAD for adult 

males and 0.1% of the cPAD for children (1-6 years); and b) a cancer risk for adult males of 2.3 x 

10-7.

Chronic Aggregate Risk: Based on the available data and assumptions used for 

dietary/water/residential exposure and risk estimates, the population group estimated to be the 

most highly exposed to pyrithiobac sodium are children (1-6 years old), with a risk estimate from 

combined sources equaling <0.2% of the RfD (dietary = <0.1% + drinking water = 0.1% + nonoccupational = 0%).

Cancer Aggregate Risk: Based on an upper-bound potency factor (Q1*) of 1.05 x 10-3

(mg/kg/day)-1 and a 70-year lifetime exposure, lifetime cancer risk from the proposed use of 

pyrithiobac sodium on cotton is 2.3 x 10-7 (dietary = <1 x 10-9

+ drinking water = 2.3 x 10-7 + 

non-occupational = 0) for adult males.
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Attachment 4: Occupational Use Patterns/Exposure Scenarios for Pyrithiobac Sodium.

Summary of Representative Occupational Use Patterns, Formulations, and Application Rates for 

Pyrithiobac Sodium.

Crop / Site Equipment Form

Max App 

Rate Qty 

(lb/A)

Mixer/

Loader 

Covered?

Applicator

Scenario 

Covered?

COTTON Aircraft WP (WSP) 0.095625 N N

COTTON Band sprayer WP (WSP) 0.095625 N N

COTTON Ground WP (WSP) 0.095625 N N

COTTON Aircraft L 0.095760 N N

COTTON Band sprayer L 0.095760 N N

COTTON Ground L 0.095760 N N

KENAF Aircraft WP (WSP) 0.06375 N N

KENAF Band sprayer WP (WSP) 0.06375 N N

KENAF Ground WP (WSP) 0.06375 N N
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Attachment 5: Pyrithiobac Sodium International Residue Limit Status Sheet.

International Residue Limits 

Pyrithiobac Sodium (078905; 4/29/11)

Summary of U.S. and International Tolerances and Maximum Residue Limits.

Residue Definition:

U.S. Canada Mexico2 Codex

40 CFR 180.487:

Plant: pyrithiobac sodium, (sodium 2-

chloro-6-[(4,6-dimethoxypyrimidin-2-

yl)thio]benzoate)

Livestock: NA

None None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

U.S. Canada Mexico2 Codex

Cotton, gin byproducts 0.15

Cotton, undelinted seed 0.02

Completed: M. Negussie; 05/03/2011

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

2 Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.