EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: James Tompkins, 703

- 305

- 5697 Bayer CropScience LLC PP# 9F7678 The EPA has received a pesticide petition (9F767 8) from Bayer CropScience LLC, 2 T. W. Alexander Drive, Research Triangle Park, NC 27709 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C.346a(d), to amend 40 CFR part 180. by revising tolerances for resid ues of the herbicide, bromoxy nil including its metabolites and degradates. Compliance with the tolerance levels specified is to be determined by measuring residues of bromox ynil (3,5

- dibromo

- 4

- hydrox yb enzonitrile) in or on the raw agricultural commodities [sorghum, grain] at [0.2] parts per million (ppm); [grass, hay] at [5.0] ppm; and [grass, forage] at [18] ppm. EPA has determined that the petition contains data or information regarding the elements set forth in section 408(d)(2) of the FFDCA; however, EP A has not full y evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism . The residue chemis try database for bromoxy

nil is current and complete and adequate to describe the nature and magnitude of residues for use in assessing the human dietary

exposure. Residue chemistry data supporting registration of the end use product (Huskie Herbicide) are listed in the completed EPA Data Matrix form accompanyi ng this petition. HUSKIE is a mixture of py rasulfotole, bromoxy

nil, and the safener mefenp yrdieth yl . A summary of the bromoxy

nil data follows. The nature of bromox yni l residues in plants and livestock is adequately understood. The residue of concern is bromoxy nil (3,5

- dibromo

- 4

- hydrox yb enzonitrile). 2. Analytical method . Since bromox ynil already has tolerances on sorghum and grass commodities adequate analy tical methods are in place to support the desir ed uses. 3. Magnitude of residues . Twelve field trials were conducted to measure the magnitude of total bromoxy nil residues in/on sorghum forage, grain, and stover following two foliar spray applications of HUSKIE herbicide to sorghum. Residues of bromox yn il were quantified in the harvested matrices (sorghum grain, forage and stover) following the postemergence applications of Huskie Herbicide. The HAFT bromox ynil residue in sorghum forage harvested at a 0

- day PHI was 25 ppm (maximum residue 27 ppm). The HA FT bromoxy nil residue in sorghum forage harvested at a target 7

- day PHIwas 0.58 ppm (maximum residue 0.61 ppm). The HAFT bromox yn il residue in sorghum forage harvested at ECH was 0.30 ppm (maximum residue 0.31 ppm). The HAFT bromox ynil residue in sorghum grain was 0.10 ppm (maximum residue 0.11 ppm). The HAFT bromox ynil residue in sorghum stover was 0.10 ppm (maximum residue 0.11 ppm). The bromox ynil residue decreased with time in the sorghum forage but not in sorghum stover. The decline of bromox ynil resi due with time in sorghum grain could not be assessed due to residue levels below the LOQ. Twelve field trials were conducted to measure the magnitude of bromoxy nilresidues in/on grass forage and hay following two foliar spray applications of HUSKIE herbic ide to grass. Residues of bromoxy nil were quantified in the harvested matrices (grass forage and hay) following the postemergence applications of Huskie Herbicide. The HAFT bromox ynil residue in grass forage harvested at a 0

- day PHI was 37 ppm (maximum res idue 38 ppm). The HAFT bromox yn il residue in grass forage harvested at a target 7

- day PHIwas 14 ppm (maximum residue 14 ppm). The HAFT bromox yn il residue in grass hay harvested at a target 30

- day PHI was 2.1 ppm (maximum residue 2.3 ppm). B. Toxicological Profile 1. Acute toxicity . A complete battery of acute toxicity

studies for bromox yni l (phenol) has been conducted. The acute oral toxicity study in rats resulted in a LD 50 of 81 milligrams/kilogram (mg/kg) (males) and a LD 50 of 93 mg/kg (females). The ac ute dermal toxicity

study in rabbits resulted in a LD 50 of >2,000 mg/kg for both males and females. The acute inhalation study in rats resulted in a L C 50 of 0.269 milligram/liter (mg/L) for males and 0.150 for females. The primary eye irritation study

show ed corneal opacity resolved within 3 day s, iritis resolved within 4 day s and conjuctival irritation which persisted for 10 day s. There was no irritation in the primary dermal irritation study and the dermal sensitization study in guinea pigs was negative. 2. Genotoxicty . Mutagenicity studies conducted include an unscheduled DNA sy nthesis study

- rat primary

hepatocy tes (negative); in vitro transformation assay

- mouse cells (negative); sister chromosomal exchange study

- CHO cells (negative); forward mutation stu dy

- mouse lymphoma cells (negative without activation and positive with activation); DNA repair test

- E. Coli (positive); in vitro chromosomal aberration (negative without activation and positive with activation); two separate micronucleus assays (both negat ive); forward mutation

- CHO cells (negative); and Salmonella ty phimurium reverse mutation assay

(negative with and without activation). Therefore, bromoxynil (phenol) and DBHA are non

- mutagenic. 3. Reproductive and developmental toxicity . A teratology study was conducted with rats administered (orally) bromoxy nil phenol at dose levels of 0, 4, 12.5, or 40 mg/kg/day . The maternal no

- observed

- effect level (NOAEL) and lowest

- observedadverse

effect level (LOAEL) are 12.5 and 40 mg/kg/day respectivel y. The devel opmental NOAEL and L OAEL are 4.0 and 12.5 mg/kg/day , respectively . Maternal body weights and food consumption were reduced in the high dose group. Fetal effects observed were reduced body weight, with associated decreases in ossification. An increase in 14 th ribs was observed in the mid and high dose levels. A teratology study was conducted with rats administered (orally) bromoxy nil phenol at dose levels of 0, 5, 15, or 35 mg/kg/day . The maternal NOAEL and LOAEL are 5.0 and 15 mg/kg/day , respectivel y. The f

etotoxicity

and developmental NOAEL and LOAEL are less than 5 and 5 mg/kg/day , respectively . Significant maternal mortality and decreased body

weight gain were associated with the high dose, indicating that the maximum tolerance dose was exceeded. Decrease s in maternal body weight gain were also observed in the mid and low dose levels. At the mid

- dose level a statisticall y significant increase in the number of fetuses with supernumerary ribs, a common fetal variant was observed. A teratology study was condu cted with rats administered (orally) bromoxy nil phenol at dose levels of 0, 1.7, 5, or 15 mg/kg/day. The maternal NOAEL and LOAEL are 5 and 15 mg/kg/day , respectivel y. The developmental NOAEL and LOAELare 5 and 15 mg/kg/day ,respectivel y. This study was c lassified as unacceptable, primaril y due to reporting

deficiencies. A teratology study was conducted with rabbits administered (orally) bromox yn il phenol at dose levels of 0, 15, 30, or 60 mg/kg/day . The maternal NOAEL and LOAEL are 15 and 30 mg/kg/day , re spectively . The developmental NOAEL and LOAEL are less than 15 and 15 mg/kg/day , respectively . Significant body weight gain decrements were reported at the two highest dose levels along with observed decreases in food consumption. The severe maternal toxic ity among high dose dams was associated with fetotoxicity

and teratogenicity. A slight, nonsignificant increase in supernumerary ribs was reported at the mid and low dose levels. A teratology study was conducted with mice administered (orally) bromox yn il p henol at dose levels of 0, 11, 32, or 96 mg/kg/day . Maternal mortality was observed at 32 and 96 mg/kg/day . Fetal body weight was decreased at the top dose level, associated with a decrease in caudal vertebral ossification and an increase in supernumerary ribs. The maternal NOAEL and L OAEL are 11 and 32 mg/kg/day

respectivel y. The developmental NOAEL and LOAELare 32 and 96 mg/kg/day , respectively . A reproduction study was conducted with rats administered (orally) bromoxy nil phenol at dose levels of 0, 0.8, 4, or 21 mg/kg/day in the diet. The s ys temic adult rat NOAEL is 4 mg/kg/day and the LOAEL is 21 mg/kg/day

. The reproductive NOAEL is 21 mg/kg/day , and the LOAEL is greater than 21 mg/kg/day . The postnatal developmental NOAEL is 4 mg/kg/day , and the LOAEL is 21 mg/kg/day . Body weight gain decrements were reported. However, no adverse effects on fertility , fecundit y, reproductive performance or pre and postnatal development were observed. A reproduction study was conducted with rats administered (orally) bromoxy nil phenol at dose levels of 0, 1.5, 5, or 15 mg/kg/day in the diet. The sy stemic rat NOAEL is 1.5 mg/kg/day , and the LOAEL is 5 mg/kg/day . The reproductive NOAEL is 15 mg/kg/day , and the LOAEL is greater than 15 mg/kg/day . The offspring developmental NOAE L is 5 mg/kg/day and the LOAEL is 15 mg/kg/day . Body weight gain decrements were reported. However, no adverse effects on fertility , fecundity , reproductive performance or pre and postnatal development were observed. Based on the studies discussed abo ve, it is concluded that bromoxy nil is not teratogenic at doses that are not maternally

toxic. In addition, bromoxy nil is not considered a reproductive toxicant and shows no evidence of endocrine effects. 4. Subchronic toxicity . In a 12

- week range

- finding study , bromox ynil (phenol) was administered in the diets of male and female CD

- 1 mice at dose levels of 0, 1.3, 3.9, 13, 39, 130, or 390 mg/kg/day . For male mice, the NOAEL is 3.9 mg/kg/day and the LOEL is 13 mg/kg/day

based on increased liver weights and hepatocellular hy pertrophy

. In female mice, the NOAEL is 13 mg/kg/day

and the LOEL is 39 mg/kg/day based on increased liver weights, hepatocellular h yp ertrophy , hepatocellular degeneration, and hepatocellular vacuolization. In a 13

- week subchronic feeding study , bromoxy nil (phenol) was administered in the diet to male and female Sprague

- Dawley rats at dose levels of 0, 28, 58, or 168 mg/kg/day . For male rats, the NOAEL is 28 mg/kg/day and the LOEL is 58 mg/kg/day

based on decreased body weight gain, increas ed ALT and increased alkaline phosphatase. For female rats, no NOAEL was determined in this study and the LOEL is 35 mg/kg/day based on decreased body weight gain. In a 13

- week range
- finding study, bromox yn il (phenol) was administered orally to male and fe male dogs at doses of 0, 1, 5, 8, 12, 16, 20, 30, 40, or 50 mg/kg/day . For males, no NOAEL was determined and the LOEL is 1 mg/kg/day based on decreased body weight gain. Forfemales, the NOAEL is 1 mg/kg/day and the NOAELis 5 mg/kg/day based on decreased body weight gain, panting and liquid feces. In a 21 day subchronic dermal study , bromox yn il (phenol) was applied to skin of male and female New Zealand white rabbits at doses of 0, 30, 300, or 1,000 mg/kg/day for 6 hours/day , 5 day s/week. Treatment produc ed no observable dermal or s ys temic toxicity therefore the NOAEL is 1,000 mg/kg/day

. 5. Chronic toxicity . A 1

- ye ar oral study was conducted with dogs administered bromox yn il (phenol) at dose levels of 0, 0.1, 0.3, 1.5, and 7.5 mg/kg/day in capsules. The NO AEL/LOAEL is 1.5 mg/kg/day for both females and males based on decreased body weight gain, decreased RBC count, decreased hemoglobin, decreased PCV, and increased liver weights. The chronic dog study was determined to be the most appropriate study for sett ing the Reference Dose (RfD) of 0.015 mg/kg/day (includes a hundredfold safet y factor). A 2

- year combined chronic toxicity /carcinogenicity

study was conducted with rats administered (oral) dosages of 0, 60, 190, or 600 ppm (0, 2.6, 8.2, or 28 mg/kg/day in males; 0, 3.3, 11.0, or 41 mg/kg/day in females) bromoxy

nil phenol in the diet. In males the no

- observed

- effect

- level (NOAEL) for s ys temic toxicity is 2.6 mg/kg/day , and the lowest

- observable

- adverse

- effect

- level (LOAEL) is 8.2 mg/kg/day . In females, the N OAEL is 3.3 mg/kg/day, and the LOAEL is 11.0 mg/kg/day . This study did not demonstrate an y increase in tumor incidences in either male or female rats. A 2

- year combined feeding/carcinogenicity study was conducted with rats administered bromox yn il phenol in the diet at dose levels of 0, 10, 30, or 100 ppm (0, 0.5, 1.5, or 5 mg/kg/day). In both males and females, the NOAEL and LOEL for s ys temic toxicity was 5 mg/kg/day

and >5 mg/kg/day , respectively . At the highest dose tested, increased liver weights were ob served at 12 months, but not at 24 months. This study was considered negative for carcinogenicity . An 18 month carcinogenicity study was conducted with mice administered bromoxy nil phenol at dose levels of 0, 10, 30, or 100 ppm (0, 1.3, 3.9, or 13 mg/kg/day) in the diet. For males, dose related increases in h yperplastic nodules and liver adenomas/carcinomas were observed which were statistically significant at the 100 ppm. Increased relative liver weights were also observed. In females, increased absolute l iver weights and relative liver and kidney weights were observed. The study was considered negative for carcinogenicity for females. An 18 month carcinogenicity study was conducted with mice administered bromoxy nil phenol at dose levels of 0, 20, 75, or 30 0 ppm (0, 3.1, 12 or 46 mg/kg/day in males and 0, 3.7, 14, or 53 mg/kg/day in females). Mice given 300 ppm had significantly increased absolute and relative liver weights. Histopathology

of the liver revealed increased hepatocellular h yp ertroph y, hepatocel lular degeneration, necrosis of individual hepatocy tes, and pigment accumulation in hepatocytes and Kupffer cells. Male mice had statisticall y significant increased numbers of hepatocellular adenomas and carcinomas at 20 ppm, but not 75 ppm. In contrast, n o significant increase in tumor incidence was observed for female mice by pair

- wise anal ys is. The trend test was significant for adenomas or carcinomas in females, onl y at p<0.05, not p<0.01 as would be appropriate for this type of tumor. The trend is due entirel y to the high dose group and therefore is of questionable validity . It is concluded that bromox yn il is a weak, single sex, single species, non

- metastic, single target organ carcinogen, inducing hepatocellular tumors in male mice exposed to 300 ppm f or 18 months. These tumors and associated histopathological findings are consistentwith secondary mechanisms such as peroxisome proliferation, a mechanism known to have marked species differences and questionable relevance for humans. Therefore, the data are not suitable for quantitative risk assessment. A threshold safety factor approach is more appropriate and is commonly used for single sex, single species carcinogens such as bromox yn il that are thought to work through secondary mechanisms. For the purp oses of this tolerance petition, risk assessments have been performed using a low dose linear extrapolation model (Q 1 * is 1.03 x 10

- 1 ). 6. Animal metabolism . Results of a bromox ynil metabolism study with the rat (octanoate) demonstrated that 2 mg/kg of radiolabeled bromoxy nil octanoate was rapidly absorbed, h ydrol yz ed to bromoxy nil phenol, distributed, and excreted in rats following repeated oral administration. The urine was the major route of excretion, representing 80.24% of the administered dose in male s and 67.91% in females at 7 day s post

- dosing. Tissue distribution was similar for both sexes with the highest radioactivity recovered in the liver and kidney . Similar results were obtained in a separate rat metabolism study conducted with bromox ynil heptanoate. 7. Metabolite toxicology . DBHA (3,5

- dibromo

- 4

- hydrox yb enzoic acid) is a major plant metabolite of bromox yn il only in bromoxy

nil

- resistant transgenic cotton. Acute oral toxicity testing with DBHA in rats resulted in an LD 50 of >2,000 mg/kg. Acute der mal toxicity testing with DBHA in rabbits resulted in an LD 50 of >2,000 mg/kg. The primary dermal irritation study

with DBHA in rabbits indicated DBHA to be a slight irritant, and DBHA was not a dermal sensitizer in Guinea pigs. Mutagenicity studies conduc ted with DBHA include a Salmonella ty phimurium reverse mutation assay (negative with and without activation); micronucleus assay (negative); and TK+/

- mouse ly mphoma assay (negative with and without metabolic activation). In subchronic feeding studies in the rat, DBHA was administered by oral gavage to groups of Sprague

- Dawley rats for 28 day s at dose levels of 25, 50, 100 and 250 mg/kg/day . No toxicologically meaningful changes were observed in an y of the parameters measured in this study . The NOAEL and LO AEL for this study

were 250 and >250 mg/kg/day , respectivel y. C. Aggregate Exposure Assessments were conducted to evaluate potential risks due to chronic and acute dietary exposure of the U.S. population and selected population subgroups to residues of bro moxy nil. These assessments included current and proposed uses of bromoxy nil including the increased use rates on sorghum and grass grown for seed. Exponent Inc.'s Dietary

Exposure Evaluation Model (DEEM

- FCID , Version 2.14), which is licensed to Bayer, was used to estimate the chronic and acute dietary exposure. This software uses the food consumption data from the 1994

- 1998 USDA Continuing Survey s of Food Intake by Individuals (CSFII 1994

- 1998). The aRfD for the general U.S. population, including infants and children, was 0.08 mg/kg/day

based on a NOAEL of 8 mg/kg/day and an uncertainty

factor of 100. The aRfD for Females 13

- 49 was 0.004 mg/kg/day based on a NOAEL of 4 mg/kg/day and an uncertaint y factor of 1000. The cRfD was 0.015 mg/kg/day based on a NOAE L of 1.5 mg/kg/day

and an uncertainty

factor of 100. The cancer assessment was based on a Q* of 0.103 (mg/kg/day)

- 1

. i. Dietary (food and water) exposure . For the purpose of estimating the potential human dietary

exposure resulting from bromox yni l use on s orghum and grass grown for seed in addition to all current uses under the existing tolerances, anticipated residues ofbromox yn il were used for all crops except cotton where anticipated residues of

bromox yn il and DBHA were used. Based on the use of these e xposure data and the above reference doses the acute exposure was equivalent to approximately 3.7% of the acute reference dose (food and water) for the US Population and 48.6% of the aPAD for females 13

- 49. The chronic cancer risk of bromoxy nil, i.e., the upper
- bound human risk estimate for the general (U.S.) population represented by all sources of bromoxy

nil exposure is approximately 2.8 x 10

- 6 (food and water). Water exposure is based on the USEPA

- derived acute EDWC of 12.3 ppb and chronic EDWC of 0.24 p pb. D . Cumulative Effects There are no reliable data suggesting that an y toxic effect that might be caused by bromox yn il would be cumulative with those of any other compound. Further, bromoxy nil does not appear to produce a toxic metabolite that is produce d by other substances. Therefore, consideration of potential cumulative effects is not appropriate at this time. E. Safety Determination 1. U.S. population . Using the present acute reference doses for bromox ynil (0.08 mg/kg/day

for the US Population) and a chronic RfD for bromox ynil of 0.015 mg/kg/day the total bromoxy

nil exposure (food and water) was equal to 3.7% of the acute RfD and 0.2% of the chronic RfD for the US Population. The cancer risk for the US Population is 2.8 x 10

- 6 . Therefore, the dietary exposure estimates are below EPA's level of concern for the overall U.S. population. 2. Females 13

- 49 . Using the acute bromox ynil reference dose for females 13

- 49 of 0.004 mg/kg/day

and a chronic RfD for bromoxy nil of 0.015 mg/kg/day the total bromox yn il e xposure (food and water) was equal to 48.9% of the acute RfD and 0.1% of the chronic RfD for Females 13

- 49. Therefore, the acute and chronic dietary exposure estimates are below EPA's level of concern for Females 13

- 49. 3. Infants and children . To estimate dietary risk for other population subgroups (i.e., infants and children) an acute reference dose of 0.08 mg/kg/day and a chronic reference dose of 0.015 mg/kg/day were used. Two multi

- generation rodent reproduction studies demonstrated that there were no adverse effects on reproductive performance, fertility , fecundit y, pup survival, or pup development. Maternal and developmental NOAELs and LOAELs were comparable indicating no increase susceptibility of developing organisms. No evidence of endocrine effect s was noted in an y study . It is therefore concluded that bromoxy nil poses no additional risk for infants and children and no additional uncertainty factor is warranted. Dietary assessment based on the above acute and chronic reference doses resulted in tot al exposure (food and water) equal to 8.6% of the acute RfD (Infants) and 0.6% of the chronic reference dose (Children 1

- 2) for the most exposed population subgroup. F. International Tolerances There are no Codex tolerances established for bromoxy nil resid ues, therefore international compatibility is not considered to be an issue at this time.