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 of Hazard and Science Policy Council 

(HASPOC) Meeting of August 6, 2015: Recommendations on the Requirement 

of a 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 

40~9~~ 

THROUGH: Anwar Dunbar, Ph.D., Co-Chair ~ ?· j/,~ Jeffrey Dawson, Co-Chair 4~~~ /1 ?/ 

HASPOC r .rr )' v-----

Health Effects Division (7509P) 

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, Jeff Evans, 

John Kough, Jonathan Leshin, Michael Metzger, Ray Kent, Uma Habiba 

Presenters: Myron Ottley 

Other Attendees: -

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I. PURPOSE OF MEETING 

Bensulfuron-methyl is a systemic sulfonylurea herbicide used in the pre- and post-emergence 

control of broadleaf weeds and sedges in rice. In 2011 a Scoping Document for Registration 

Review was prepared (0389431 , S. Healy, 07/06/2011) which identified toxicity data gaps, and 

the following studies were called-in: 

• 870.7800 Immunotoxicity 

• 870.6200 Neurotoxicity Screening Battery 

• 870.3200 21 /28-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 of bensulfuron-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 of baseline 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. 

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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 of toxicity in appropriate studies. 

The chronic dietary point of departure (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 of bensulfuron-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, AL T, 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 of the studies in the database, including the acute and 28-day subchronic 

neurotoxicity studies, both of which 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 of tumors 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 

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The registrant has submitted data in place of the 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 of evidence 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 of appropriate 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 of toxicity 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 of appropriate 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 of neurotoxicity 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 of the acute neurotoxicity 

study indicates that there is no LOAEL. Preliminary review of the submitted 28-day 

neurotoxicity study also suggests that there is no LOAEL. The key deficiencies of this study are 

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that 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 of susceptibility 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 

of a 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 of the first carcinogenicity study 

and the 28-day oral study 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 dosed 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 less 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 of compound-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 

bensu lfuron-methyl (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 

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groups) pathological examination of tissues (such as adrenals, brain, ovaries/testes, 

uterus/epididymides, heart, kidneys, liver, seminal vesicles, spleen and thymus) did not reveal 

any lesions of pathological 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 of any 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 of BSM. 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 of toxicology 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 of action 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 of both 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 half the limit dose (405 mg/kg/day in females), and there were no 

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proliferative 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 of chemicals 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 

toxicity, bensulfuron does not demonstrate any effects in the thyroid. 

IV. HASPOC RECOMMENDATIONS 

Based on a WOE approach considering of all 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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