Pyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 2 of 20 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 exi sting 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

- FCID TM )] and incorporating pote ntial 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 include d 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 an d 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) deter mined that the classification for pyrithiobac s odium should be group C (possible human carcinogen) and that a low

- dose extrapolation methodology (Q 1 *) 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 dose a and exceeded the historical control range, and increases in rare kidne y tumors in male Crl:CDBR rats. Upper

- bound lifetime cancer risk from the proposed use of pyrithiobac sodium on cotton wa s 2.3 x 10 - 7 for adult males

. An upper

- bound potency factor (Q 1 *) 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 c oncern 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 Canad ian, 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.Pyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 3 of 20 There is sufficient information available to a ssess 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

- a nd intermediate

term 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

- app lication exposure. Post

application dermal and inhalation exposures have not been previously assessed. A post

application inhalation exposure assessment may be needed pending changes to Agency policies and procedures. Pending final determination of prop osed 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 n o ccupational 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 s election along with the FQPA SF will need to be re

evaluated 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 i mmunotoxicity , 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# 4 4373801 ; Guideline 8 6 0. 15 00 ).

**•** 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 herb icide 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

- py rimidinyl)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

- FCID TM ) and incorporating potential changes to the pyrithiob ac sodium tolerances and estimated drinking water concentrations.Pyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 4 of 20 Occupational Exposure:

**•** A revised occupational exposure assessment to include changes to the toxicological endpoints, additional scenarios, and current policies.

Introduction

Pyrithioba c 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) reg istrations 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 res idential uses.

Hazard Identification/Toxicology

Pyrithiobac sodium is the active ingredient in a low use rate herbicide (Staple ® ) for post

emergence 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 as sessment for pyrithiobac sodium (Memo, D235143, G. Kramer

, 7/15/97).

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

, and inhalation routes of exposure. It wa s not a dermal sensitizer, or a dermal irritant. It wa s irritating to the eyes of rabbits ( Toxicity Category II).

Pyrithiobac s odium 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 ex posure, 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 rel ative) 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 male s (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 glom erular 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 thePyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 5 of 20 highest doses tested. There were also mi ld 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 re d 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 staine d 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 dea ths, 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 weig ht, 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, pyri thiobac 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 neurotox icity was examined in a combined subchronic toxicity/ neurotoxicity/one

generation reproduction study . All of relevant criteria by today’s guidelines were measured, including the functional

- observation

- battery (FOB) testing, motor

- activity measurements, a s 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 decrease d body weights ~10%. No other of neurotoxicity were observed up to the highest dose tested (1,376 mg/kg/day), which w as 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 negativ e.

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. Th e estimate of unit risk, Q 1 *, wasPyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 6 of 20 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 factor b for interspecies extrapolation.

FQPA Considerations : The pre

- and post

- natal toxicology database for pyrithiobac sodium is complete with respect to current toxicological data re quirements. The results of these studies indicate d that infants and children we re 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 wa s minimal concern for developmental or reproductive toxicity. No additional uncertainty factor for increased sensitivity in infants and children wa s required

. The requirement for the subchronic neurotoxicity study under the revised 40 CFR P art 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 new er study, because there wa s little evidence for neurotoxic effects i n 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 s odium.

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. T hree 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 immunotox icity 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 t o 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 reviewe d, 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 Fo od, 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, neurot oxicity, 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 mat uration, 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 Q 1 * s Using the Unified Interspecies Scaling Factors, ” P.A. Fenner

- Crisp, Director

- HED, 7/1/94.Pyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 7 of 20 endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), pyrithiobac sodiu m 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 wildli fe 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 batte ry 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 caus ed 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 c all

- 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. According ly, 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

c hemicals, 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 durat ions) 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 co tto n treated with pyrithiobac sodium. The HED Metabolism Assessment Review Comm ittee (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 28 16

- 93, Revision 2; MRID# 431934 01) is available for the enforcement of the cottonseed tol erance. The recoveries reported by the registrant and in the Independent Lab oratory Validation (ILV) we re acceptable. The limit of quantitation (LOQ) is 0.010 ppm. This methodPyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 8 of 20 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 b yproduct 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

re sponse. 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 cott onseed 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 non

registered crops are appropriate for pyrithiobac sodium ; no rotational crop tolerances are required. HED recently approved the use of DuPont Staple ® Plus Herbicide (EP A 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 soybean s following application to glyphosate

tolerant cotton. Since the rotational crops (corn an d 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 cott on 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 ( D 235143 , G. Kramer ). D ietary risk asses sments 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 we re not of concern to H ED. The most highly exposed population was children 1

- 6 year s old

, utilizing <0 .1% of the cPAD. The cancer analysis was performed using an upper

- bound potency factor (Q 1 *) 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, wa s not of concern to HED.Pyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 9 of 20 EFED provided ground and surface water exposure estimates (Memo, R. Jones; 6/30/97). Pyrithiobac sodium concentratio ns 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) result ed 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 corr espond 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 ne w dietary assessment will be required during registration review using current exposure models (i.e., DEEM

- FCID TM ) and incorporat ing 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
p ractices, 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 t o 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 200 9. 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 ident ify the need for and, subsequently, the way to incorporate 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 post

- application inhal ation 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 metho d 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/labe ling. 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

-Pyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 10 of 20 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 residentia l uses, an assessment is not required at this time ; however, the need for residential post

application 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 u pper

- 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 + n on

occupational = 0). A n upper

- bound potency factor (Q 1 *) 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 occupati onal 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, D2351 43, 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 w ater

- 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 app lication of wettable powder (packaged in water

- soluble bags) and liquid formulations; andPyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 11 of 20 **•** 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 fol lowing 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 OR ETF), 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 quan titative 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 post

application 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 fro m 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

- applicati on 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 inf ormation available to assess occupational post

- application exposure. Post

application dermal and inhalation exposures have not been previously assessed. A post

application inhalation exposure assessment may be needed pending changes to Agency policies

an d 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

- app

exposure

- data.html). Reviewers should incorporate new post

- application exposure data, as necessary, during Registration Review.Pyrithiobac Sodium Registration Review Human

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Page 12 of 20 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 al legations 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 app licators 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 revie wed 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 m ore 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 mo dule 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.

Tolera nce 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 compat ibility with respect to U.S. tolerances and Canadian, Mexican, and Codex MRLs do not exist.Pyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 13 of 20 Environmental Justice

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

- health risk assessment, in accord ance 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 highes t 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 peopl e 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 p yrithiobac 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 pestici des, 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 gener ic 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 ap plicable 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 re

evaluated 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 i mmunotoxicity, 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 8 6 0. 15 00 ).

**•** 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 r esidues 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 bePyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 14 of 20 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

- FCID TM ) and incorporating potential chang es 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.

Referen ces

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

Page 15 of 20 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 Statu s Sheet

.

cc: A. Nowotarski (RAB1), G. Kramer (RAB1), A. Dunbar (RAB1) RDI: RAB1 ( 5 / 11 /1 1 ) , J. Fowle ( 5 / 16 /11) G.F. Kramer:S10957:PY

- S:(703)305

- 5079:7509P:RAB1Pyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 16 of 20 Attachment 1: Chemical Identity Table

.

Pyrithiobac Sodium Compound Nomenclature.

Compound N O C H 3

O C H 3 S

Cl O

O H

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

Page 17 of 20 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 SF s RfD, PAD, L O C for Risk Assessment Study and Toxicological Effects

Chronic Dietary (All Populations) NOAEL= 58.7 mg/kg/day UF A = 10x UF H =10x FQPA SF= 1x c RfD = 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

- dose

extrapolation model be applied to the animal data (Q 1 *), due to liver and kidney adenomas/ adenocarcinomas observed in the male rat. The estimation of unit risk, Q 1 * (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/k g/day) - 1 in human equivalents.
1 UF = uncertainty factor, UF A = extrapolation from animal to human (interspecies), UF H = 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, c RfD = chronic reference dose, c PAD = chronic population

- adjusted dose, MOE = margin of exposure, LOC = level of concern

.Pyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 18 of 20 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 sodi um 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 (Q 1 *) 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 pp b (chronic) and for ground water is 0.778
pp b . 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 pp b ) results in the fol lowing 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 calcula ted 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

mo st 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 Aggregate Risk : Based on an upper

- bound potency factor (Q 1 *) 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

.Pyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 19 of 20 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 NPyrithiobac Sodium Registration Review Human

- Health Assessment Scoping Document

Page 20 of 20 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 Mexico 2 Codex 40 CFR 180.487: Plant: pyrithiobac sodium, (sodium 2

- chloro

- 6

- [(4,6

- dimethoxypyrimidin

- 2

- yl)thio]benzoate) Livestock: NA None None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) U.S. Canada Mexico 2 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.