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

MEMORANDUM
Date: August 27,2015 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUBJECT: Bensulfuron-methyl: Summary ofHazard and Science Policy Council (HASPOC) Meeting of August 6 , 2015: Recommendations on the Requirement ofa 90-Day Subchronic Neurotoxicity Study and a Two-Year Carcinogenicity Rat Study.
PC Code: 128820 Decision No.: N/A Petition No.: N/A Risk Assessment Type: N/A TXR No.: 0057190 MRID No.: N/A FROM: Ronnie J

. Bever Jr., PhD, DABT Executive Secretary, HASPOC Health Effects Division (7509P) DP Barcode : N/ A Registration No.: N/A Regulatory Action: N/A Case No.: N/A CAS No.: 83055-99-6

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THROUGH: Anwar Dunbar, Ph.D. , Co-Chair

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# ? ·**j/,~** Jeffrey Dawson, Co-Chair**4~~~**

# /1 ?/ HASPOC 

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TO: Myron Ottley, PhD, Toxicologist Branch 3 , Risk Assessor Christine Olinger, Branch Chief Risk Assessment Branch III (RAB Ill) Health Effects Division (7509P)
MEETING ATTENDEES : HASPOC Members: Anna Lowit, Elissa Reaves , Elizabeth Mendez, JeffDawson, JeffEvans , John Kough, Jonathan Leshin, Michael Metzger, Ray Kent, Uma Habiba
Presenters: Myron Ottley
Other Attendees :
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Page I of7I. PURPOSE OF MEETING Bensulfuron-methyl is a systemic sulfonylurea herbicide used in the pre- and post-emergence control ofbroadleafweeds and sedges in rice

. In 2011 a Scoping Document for Registration Review was prepared (0389431 , S. Healy, 07/06/20 11) which identified toxicity data gaps, and the following studies were called-in:
• 870.7800 Immunotoxicity
• 870.6200 Neurotoxicity Screening Battery
• 870.3200 21 /2 8-Day Dermal Toxicity
• 870.4200 Carcinogenicity (rats only) Since that time, the requirement for the immunotoxicity study has been waived (TXR 0056723) , the requirement for the 21/28-day dermal toxicity study has been waived (TXR 0056721 ), and the requirement for the subchronic inhalation toxicity study has been waived (TXR 0052986). The registrant has submitted acute and 28-day subchronic neurotoxicity data (MRIDs 49263601, 49263602, and 49263603) which have been thoroughly screened and are currently undergoing detailed review. Finally, the registrant has submitted a waiver request for the rat carcinogenicity study under GDCI

- 128820-1121.
The Hazard Science and Policy Council (HASPOC) thus met to: 1) determine whether the submitted non-guideline 28-day subchronic neurotoxicity study (MRID 49263602) fulfills the current requirements; and 2) consider the waiver request for the carcinogenicity study in rats.

II. SUMMARY OF USE PROFILE & PREVIOUS RISK ASSESSMENT
Use Profile Bensulfuron-methyl is currently registered for use on agricultural rice production (grain and straw) to control broadleaf weeds and sedges. Due to common crayfish aquaculture in flooded rice paddies , a tolerance for crayfish was established concomitant with the tolerance establishment for rice grain and rice straw. All registered formulations ofbensulfuron-methyl (dry flowable, granular, and emulsifiable concentrate) may be applied to rice via ground or aerial equipment. Short- and intermediate-term occupational exposures are expected. There are no residential uses
. At minimum, the personal protective equipment (PPE) requirement on the labels consists ofbaseline attire (long-sleeved-shirt, long pants, and shoes plus socks) plus chemical-resistant gloves. Some labels include additional requirements for handlers to wear coveralls , chemical-resistant footwear, chemical-resistant headgear, chemical-resistant apron, and protective eyewear.

Page 2 of?Endpoints and PODs Used in the Last Risk Assessment In the previous risk assessment (D 1238880, William Wassell, 11/2011997), toxicity endpoints and PODs for dermal and inhalation exposures (short-, intermediate- , and long-term) , and acute dietary exposures were not selected because of an absence oftoxicity in appropriate studies. The chronic dietary point ofdeparture (POD) was the No Observed Adverse Effect Level (NOAEL) of750 ppm (21.4 and 19

.9 mg/kg/day in males and females, respectively) in a oneyear dog study. The Lowest Observed Adverse Effect Level (LOAEL) of7500 ppm (237.3 and 222.6 mg/kg/day in males and females, respectively) was based on the discoloration and inflammation ofthe oral mucosa, elevated alkaline phosphatase, SGPT (ALT), and liver weights , and brown pigment in biliary canaliculi in both sexes. The Food Quality Protection Act (FQPA) Safety Factor was reduced to I X at that time, because no susceptibility was observed in the available prenatal developmental studies (rat and rabbit) or the multi-generation rat reproduction study.
Toxicitv Profile The primary target organ ofbensulfuron-methyl toxicity is the liver. Effects in the mouse included enlarged livers, nodules and masses in the liver, and increased liver weight accompanied by liver elevated alkaline phosphatase, ALT, AST and histological lesions at the highest dose tested (HOT- 455 mg/kg/day)

. Similar hepatotoxicity, as well as irritation of oral mucosa, was also observed in the chronic dog study at 23 7 mg/kg/day and above. Adaptive, non-adverse changes in liver histopathology were observed in the chronic rat study at 305/405 mg/kg/day (HOT in males/females). Similar to chronic studies, liver effects were seen in the 90- day subchronic toxicity studies in the mouse and dog at similar dose levels with NOAELs of 132 and 32 mg/kg/day, respectively. The acute dermal toxicity indicates that the LDso for bensulfuron-methyl is >2000 mg/kg

. There is no dermal penetration study on bensulfuronmethyl.
Submitted reproductive and developmental toxicity studies reviewed for the weight-of-evidence determination did not suggest that bensulfuron-methyl is a developmentally toxic

. Therefore, there are no susceptibility concerns
. Bensulfuron-methyl did not produce evidence of neurotoxicity in any ofthe studies in the database, including the acute and 28-day subchronic neurotoxicity studies, both ofwhich included dosing up to and exceeding the limit dose. These two studies are currently undergoing detailed review. Bensulfuron-methyl is not mutagenic in bacteria or cultured mammalian cells

. Bensulfuron-methyl is not considered likely to be carcinogenic to humans because there is no evidence of increased incidence oftumors in rats or mice under the experimental conditions tested. Bensulfuron-methyl has low acute toxicity. It is classified as toxicity category IV for oral and inhalation exposure and toxicity category III for dermal exposure. Bensulfuron-methyl is classified as toxicity category IV for primary eye and skin irritation and is not a dermal sensitizer.
Ill. STUDY WAIVER RECOMMENDATION AND REQUEST
Subchronic Neurotoxicity Study

Page 3 of7The registrant has submitted data in place ofthe required 90-day subchronic neurotoxicity study for bensulfuron-methyl. The data comes from a special28-day study conducted in rats (MRID 49623602) in which animals were assessed for neurotoxicity. With respect to considering whether the requirement for the 90-day neurotoxicity study (SCN) can be waived for bensulfuron-methyl , the RAB III risk assessment team used WOE approach:

• Lack ofevidence for neurotoxicity in the bensulfuron-methyl database of toxicology studies:
In an available rat acute neurotoxicity study (MRID 49623601, currently under detailed review) bensulfuron-methyl was administered as a single oral gavage dose of2000 mg /kg in corn oil to 10 Wistar rats/sex/dose group ofappropriate age. No mortality, clinical signs , effects on body weight or food consumption was observed. No changes in FOB parameters or neurohistopathology were observed

. Bensulfuron-methyl did not produce a neurotoxic effect at the limit dose. The NOAEL was 2000 mg/kg, and the LOAEL was not established. This study is considered acceptable, non-guideline because, although the required three dose levels were not used, the absence oftoxicity at the limit dose indicates that lower dose levels were not needed.
In an available rat 28-day study (MRID 49623601, currently under detailed review), Wistar rats (5/sex/dose group ofappropriate age) were dosed with bensulfuron-methyl in the diet at 0, 750 , 10,000, 12,500 and 15,000 ppm (0, 632, 858, 1061, and 1281 mg/kg/day males , and 0, 704,934, 1260, and 1376 mg/kg/day females) for 28 days. No effects on mortality, clinical signs, body weight or food consumption were noted. No changes in FOB parameters or neurohistopathology were observed. In this non-guideline, 28-day study, bensulfuron-methyl did not produce any neurotoxic effects at any levels up to and including the limit dose. The NOAEL was 1281 

### I 1376 mg/kg/day in males 

### I females , and the LOAEL was not established. This study did not follow the guideline requirement oftesting for 90 days

. However, because no toxicity (including neurotoxicity) was seen at levels above the limit dose , the data are considered useful for risk assessment, and classified as acceptable, non-guideline
There was no evidence ofneurotoxicity in the other repeated dose studies in the available bensulfuron-methyl toxicity database.

• Evidence for neurotoxicity in the database of toxicology studies for other similar chemicals: The ISTEP database identified four other sulfonylurea herbicides for which neurotoxicity data were available : flazasulfuron , imazosulfuron, prosulfuron, and trifloxysulfuron sodium. The neurotoxicity observed in these studies is summarized in Table 1 and shows that these sulfonylureas are not neurotoxic.

• Risk assessment considerations:
In the previous risk assessment, the chronic point of departure was based upon liver effects which were considered adaptive and these effects. Preliminary review ofthe acute neurotoxicity study indicates that there is no LOAEL. Preliminary review ofthe submitted 28-day neurotoxicity study also suggests that there is no LOAEL. The key deficiencies ofthis study are

Page 4 of7that 3 rats/sex/group were used, and the study was carried out only for 28-days as opposed to 90- days

. All measurements required for a guideline study were measured (FOB, changes in motor activity and neuro-histopathology)

. The HASPOC concluded, based on a weight of evidence (WOE) approach, that a 90-day subchronic neurotoxicity study is not required at this time. This approach considered the following evidence: (1) No significant neurotoxicity was observed in the bensulfuron-methyl database, including the two non-guideline neurotoxicity studies submitted; (2) there is no evidence of neurotoxicity in the analogs examined except at very high dose levels (2: 1 000 mg/kg/day); and (3) there is no evidence ofsusceptibility in the prenatal developmental and multi-generation reproduction studies with bensulfuron-methyl; so, there is no concern for neurotoxicity potential in progeny
. Carcinogenicity Study in Rats
In the last bensulfuron-methyl scoping document (038943 1, S

. Healy, 7/6 /2011), an acceptable carcinogenicity study in rats was identified as a data gap , because the previously submitted study (MRID 40089316) was determined to be inadequate to assess carcinogenicity, due to the absence ofa LOAEL. In response to the ensuing Generic Data Call-In (#GDCI-128820-11 21), the registrant has submitted a waiver request. Support for the waiver request comes from a 28-day oral subchronic study (MRID 49623602) in which dose levels up to 128111376 mg/kg/day in males/females failed to produce significant toxicity. Details ofthe first carcinogenicity study and the 28-day oral st udy are presented below : Chronic/Carcinogenicity Study CMRID No. 40089316) In a chronic feeding/carcinogenicity study in rats , groups of 80 male and 80 female Crl:CD (SD)BR rats were do sed with INF-5384 (95 and 95.9% bensulfuron-methyl) in their feed at doses ofO, 50, 750, or 7500 ppm. These doses were equivalent to 0, 2.0, 30, or 309 mg/kg/day in males, and 0, 2

.7, 40, or 405 mg/kg/day in females

. Clinical anomalies were observed only at the 7500 ppm dose. Histopathologic lesions included diffuse fatty changes in male livers , and centrilobular hepatocellular hypertrophy and centrilobular hepatocyte cytoplasmic basophilia margination in both sexes
. These lesions were seen at the 1-year and terminal sacrifices , but were les s frequent at the terminal sacrifice. In the absence of corroborative elevated liver enzyme levels in serum, these lesions are considered to be evidence of normal hepatic adaptive function. There was no evidence ofcompound-related neoplasia in any tissue found in the rats. The NOAEL was 7500 ppm (309 and 405 mg/kg/day in males and females, respectively) and the LOAEL was not established. 28-day feeding subchronic study CMRID 49623602) In a 28-day toxicity study, male and female Sprague Dawley rats were exposed to b ensu lfuron-methy l (BSM) at dietary concentrations ofO, 7500, 10,000, 12,500 and 15 ,000 ppm (equivalent to 0, 631 , 858 , 1060 and 1280 mg/kg/day, respectively, for males ; 0, 703 , 934 , 1259 and 1375 mg/kg/day, respectively , for females) for period of28 consecutive days. No mortality was observed during the treatment period nor were any clinical signs of toxicity or treatment related changes in FOB parameters observed in any group of animals during the treatment period. Gross (all groups) and microscopic (control and high BSM

Page 5 of7groups) pathological examination oftissues (such as adrenals, brain, ovaries/testes, uterus/epididymides, heart, kidneys, liver, seminal vesicles , spleen and thymus) did not reveal any lesions ofpathological significance. Based on the results of this study, the LOAEL for BSM Technical is greater than 15 ,000 ppm in the diet, equivalent to 1280 mg/kg/day for males and 1375 mg/kg/day for females , which exceed the limit dose

. Registrant ' s Rationale for a Waiver for the Rat Carcinogenicity Study The registrant states: " Considering the lack ofany specific organ toxicity for BSM at such high dietary concentrations, it is clear that conducting a new carcinogenicity study in rats at a limit dose of 1000 mg/kg/day or approximately ll ,000 ppm would not be expected to provide further information regarding the carcinogenicity potential ofBSM. This observation coupled with the very low chronic dietary consumption for BSM in treated commodities ( < 1% ofthe cPAD for General US population , infants and children) strongly supports a conclusion that a new carcinogenicity study at the 1000 mg/kg/day would be a waste of financial and animal resources ."

• Evidence for carcinogenicity in the database oftoxicology studies for other similar chemicals:
HED has assigned a cancer classification to 21 other sulfonylurea herbicides. From Table 2 below, it is evident that none has been classified as " Likely to Be Carcinogenic to Humans"

. Three (orthosulfamuron, tribenuron, trisulfuron-methyl) have been classified "Suggestive Evidence of Carcinogenic Potential" with the RID approach to quantitation recommended for risk assessments , and one (sulfosulfuron) is considered " Not Likely to Be Carcinogenic to Humans below a Defined Range" based on mode ofaction data. Additionally, the team used the National Institute of Health' s Chem!Dplus tool and identified orthosulfamuron (84% similar to bensulfuron-methyl) as being the most structurally similar chemical to bensulfuron-methyl within the Agency's database. Orthosulfamuron caused thyroid follicular cell adenomas and carcinomas in male (but not female) rats at 500 and l 000 mg/kg/day. While the liver was a target organ ofboth bensulfuron-methyl and orthorsulfamuron, with similar increases in enzyme activity and liver weights, bensulfuron-methyl toxicity did not include adverse effects on the thyroid as was seen with orthosulfamuron, such as thyroid hypertrophy, enlarged thyroids , and thyroid follicular cell adenomas. Orthosulfamuron also caused nephrotoxicity which was not seen with bensulfuron-methyl. Both chemicals tested negative in the mutagenicity battery.
Other close structural analogs identified by ChemiDplus such as trisulfuron and mesosulfuronmethyl, both 79% similar to bensulfuron-methyl, were not carcinogenic in laboratory rats and m1ce.
The HASPOC determined that an additional rat carcinogenicity study is NOT required at this time based on the following weight of evidence considerations:

• While the liver is a target organ following bensulfuron-methyl treatment, there were no significant adverse effects on the liver (or any other organ) after dosing in rats for two years up to about halfthe limit dose (405 mg/kg/day in females) , and there were no

Page 6 of7proliferative lesions observed in the rats or mice at these high levels

. Therefore, testing at higher dose levels is not expected to provide useful data for risk assessment.

• Data on several sulfonylurea analogs indicate that this class ofchemicals does not normally produce proliferative tumors in rats and mice, and is not likely to be carcinogenic to humans. Data on the closest structural analog to bensulfuron, orthosulfamuron, produced thyroid tumors in male rats only at high dose levels (500 and 1000 mg/kg/day)

. While both bensulfuron and orthosulfamuron demonstrate liver tox icity, bensulfuron does not demonstrate any effects in the thyroid

. 

### IV. HASPOC RECOMMENDATIONS
Based on a WOE approach considering ofall the available hazard and exposure information for bensulfuron-methyl, the HASPOC concludes that the 90-day subchronic neurotoxicity and the rat carcinogenicity studies are not required at this time

.

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