Federal Register / Vol. 76, No. 235 / Wednesday, December 7, 2011 / Rules and Regulations 76309 

1999) and Executive Order 13175, 

entitled Consultation and Coordination 

with Indian Tribal Governments (65 FR 

67249, November 9, 2000) do not apply 

to this final rule. In addition, this final 

rule does not impose any enforceable 

duty or contain any unfunded mandate 

as described under Title II of the 

Unfunded Mandates Reform Act of 1995 

(UMRA) (Pub. L. 104–4). 

This action does not involve any 

technical standards that would require 

Agency consideration of voluntary 

consensus standards pursuant to section 

12(d) of the National Technology 

Transfer and Advancement Act of 1995 

(NTTAA), Public Law 104–113, section 

12(d) (15 U.S.C. 272 note). 

VII. Congressional Review Act 

The Congressional Review Act, 5 

U.S.C. 801 et seq., generally provides 

that before a rule may take effect, the 

agency promulgating the rule must 

submit a rule report to each House of 

the Congress and to the Comptroller 

General of the United States. EPA will 

submit a report containing this rule and 

other required information to the U.S. 

Senate, the U.S. House of 

Representatives, and the Comptroller 

General of the United States prior to 

publication of this final rule in the 

Federal Register. This final rule is not 

a ‘‘major rule’’ as defined by 5 U.S.C. 

804(2). 

List of Subjects in 40 CFR Part 180 

Environmental protection, 

Administrative practice and procedure, 

Agricultural commodities, Pesticides 

and pests, Reporting and recordkeeping 

requirements. 

Dated: November 21, 2011. 

Lois Rossi, 

Director, Registration Division, Office of 

Pesticide Programs. 

Therefore, 40 CFR chapter I is 

amended as follows: 

PART 180—[AMENDED] 

■ 1. The authority citation for part 180 

continues to read as follows: 

Authority: 21 U.S.C. 321(q), 346a and 371. 

■ 2. Section 180.649 is amended by 

alphabetically adding the following 

commodities to the table in paragraph 

(a)(1) to read as follows: 

§ 180.649 Saflufenacil; tolerances for 

residues. 

(a) General. (1) * * * 

Commodity Parts per 

million 

* * * * * 

Banana 1 ................................... 0.03 

Coffee, green bean 1 ................. 0.03 

* * * * * 

Mango 1 ..................................... 0.03 

* * * * * 

1 No U.S. registration as of December 7, 

2011. 

* * * * * 

[FR Doc. 2011–31394 Filed 12–6–11; 8:45 am] 

BILLING CODE 6560–50–P 

ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Part 180 

[EPA–HQ–OPP–2010–0845; FRL–8885–8] 

Isoxaflutole; Pesticide Tolerances 

AGENCY: Environmental Protection 

Agency (EPA). 

ACTION: Final rule. 

SUMMARY: This regulation establishes 

tolerances for residues of isoxaflutole in 

or on Soybean, seed and Grain, 

aspirated fractions. Bayer CropScience 

requested these tolerances under the 

Federal Food, Drug, and Cosmetic Act 

(FFDCA). 

DATES: This regulation is effective 

December 7, 2011. Objections and 

requests for hearings must be received 

on or before February 6, 2012, and must 

be filed in accordance with the 

instructions provided in 40 CFR part 

178 (see also Unit I.C. of the 

SUPPLEMENTARY INFORMATION). 

ADDRESSES: EPA has established a 

docket for this action under docket 

identification (ID) number EPA–HQ– 

OPP–2010–0845. All documents in the 

docket are listed in the docket index 

available at http://www.regulations.gov. 

Although listed in the index, some 

information is not publicly available, 

e.g., Confidential Business Information 

(CBI) or other information whose 

disclosure is restricted by statute. 

Certain other material, such as 

copyrighted material, is not placed on 

the Internet and will be publicly 

available only in hard copy form. 

Publicly available docket materials are 

available in the electronic docket at 

http://www.regulations.gov, or, if only 

available in hard copy, at the OPP 

Regulatory Public Docket in Rm. S– 

4400, One Potomac Yard (South Bldg.), 

2777 S. Crystal Dr., Arlington, VA. The 

Docket Facility is open from 8:30 a.m. 

to 4 p.m., Monday through Friday, 

excluding legal holidays. The Docket 

Facility telephone number is (703) 305– 

5805. 

FOR FURTHER INFORMATION CONTACT: 

Kathryn V. Montague, Registration 

Division (7505P), Office of Pesticide 

Programs, Environmental Protection 

Agency, 1200 Pennsylvania Ave., NW., 

Washington, DC 20460–0001; telephone 

number: (703) 305–1243; email address: 

montague.kathryn@epa.gov. 

SUPPLEMENTARY INFORMATION: 

I. General Information 

A. Does this action apply to me? 

You may be potentially affected by 

this action if you are an agricultural 

producer, food manufacturer, or 

pesticide manufacturer. Potentially 

affected entities may include, but are 

not limited to those engaged in the 

following activities: 

• Crop production (NAICS code 111). 

• Animal production (NAICS code 

112). 

• Food manufacturing (NAICS code 

311). 

• Pesticide manufacturing (NAICS 

code 32532). 

This listing is not intended to be 

exhaustive, but rather to provide a guide 

for readers regarding entities likely to be 

affected by this action. Other types of 

entities not listed in this unit could also 

be affected. The North American 

Industrial Classification System 

(NAICS) codes have been provided to 

assist you and others in determining 

whether this action might apply to 

certain entities. If you have any 

questions regarding the applicability of 

this action to a particular entity, consult 

the person listed under FOR FURTHER

INFORMATION CONTACT. 

B. How can I get electronic access to 

other related information? 

You may access a frequently updated 

electronic version of EPA’s tolerance 

regulations at 40 CFR part 180 through 

the Government Printing Office’s e-CFR 

site at http://ecfr.gpoaccess.gov/cgi/t/ 

text/text-idx?&c=ecfr&tpl=/ecfrbrowse/ 

Title40/40tab_02.tpl. To access the 

harmonized test guidelines referenced 

in this document electronically, please 

go to http://www.epa.gov/ocspp and 

select ‘‘Test Methods and Guidelines.’’ 

C. How can I file an objection or hearing 

request? 

Under FFDCA section 408(g), 21 

U.S.C. 346a, any person may file an 

objection to any aspect of this regulation 

and may also request a hearing on those 


sroberts on DSK5SPTVN1PROD with RULES
76310 Federal Register / Vol. 76, No. 235 / Wednesday, December 7, 2011 / Rules and Regulations 

objections. You must file your objection 

or request a hearing on this regulation 

in accordance with the instructions 

provided in 40 CFR part 178. To ensure 

proper receipt by EPA, you must 

identify docket ID number EPA–HQ– 

OPP–2010–0845 in the subject line on 

the first page of your submission. All 

objections and requests for a hearing 

must be in writing, and must be 

received by the Hearing Clerk on or 

before February 6, 2012. Addresses for 

mail and hand delivery of objections 

and hearing requests are provided in 40 

CFR 178.25(b). 

In addition to filing an objection or 

hearing request with the Hearing Clerk 

as described in 40 CFR part 178, please 

submit a copy of the filing that does not 

contain any CBI for inclusion in the 

public docket. Information not marked 

confidential pursuant to 40 CFR part 2 

may be disclosed publicly by EPA 

without prior notice. Submit a copy of 

your non-CBI objection or hearing 

request, identified by docket ID number 

EPA–HQ–OPP–2010–0845, by one of 

the following methods: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the on-line 

instructions for submitting comments. 

• Mail: Office of Pesticide Programs 

(OPP) Regulatory Public Docket (7502P), 

Environmental Protection Agency, 1200 

Pennsylvania Ave. NW., Washington, 

DC 20460–0001. 

• Delivery: OPP Regulatory Public 

Docket (7502P), Environmental 

Protection Agency, Rm. S–4400, One 

Potomac Yard (South Bldg.), 2777 S. 

Crystal Dr., Arlington, VA. Deliveries 

are only accepted during the Docket 

Facility’s normal hours of operation 

(8:30 a.m. to 4 p.m., Monday through 

Friday, excluding legal holidays). 

Special arrangements should be made 

for deliveries of boxed information. The 

Docket Facility telephone number is 

(703) 305–5805. 

II. Summary of Petitioned-For 

Tolerance 

In the Federal Register of December 

15, 2010 (75 FR 78240) (FRL–8853–1), 

EPA issued a notice pursuant to section 

408(d)(3) of FFDCA, 21 U.S.C. 

346a(d)(3), announcing the filing of a 

pesticide petition (PP 0F7750) by Bayer 

CropScience, 2 T.W. Alexander Dr., 

Research Triangle Park, NC 27709. The 

petition requested that 40 CFR 180.537 

be amended by establishing tolerances 

for combined residues of the herbicide 

isoxaflutole, 5-cyclopropyl-4-(2- 

methylsulfonyl-4- 

trifluoromethylbenzoyl) isoxazole and 

its metabolite 1-(2-methylsulfonyl-4- 

trifluoromethylphenyl)-2-cyano-3- 

cyclopropyl propane-1,3-dione, (RPA 

202248), calculated as the parent 

compound, in or on soybean at 0.05 

parts per million (ppm), and soybean, 

aspirated grain fractions at 0.25 ppm. 

That notice referenced a summary of the 

petition prepared by Bayer CropScience, 

the registrant, which is available in the 

docket, http://www.regulations.gov. 

There were no comments received in 

response to the notice of filing. 

Based upon review of the data 

supporting the petition and the 

preferred crop terminology, EPA has 

made two changes to the requested 

tolerances. First, EPA has changed the 

commodity descriptions for the 

tolerances to soybean, seed and grain, 

aspirated fractions. Second, EPA is 

raising the grain, aspirated fractions 

tolerance from 0.25 ppm to 0.30 ppm. 

III. Aggregate Risk Assessment and 

Determination of Safety 

Section 408(b)(2)(A)(i) of FFDCA 

allows EPA to establish a tolerance (the 

legal limit for a pesticide chemical 

residue in or on a food) only if EPA 

determines that the tolerance is ‘‘safe.’’ 

Section 408(b)(2)(A)(ii) of FFDCA 

defines ‘‘safe’’ to mean that ‘‘there is a 

reasonable certainty that no harm will 

result from aggregate exposure to the 

pesticide chemical residue, including 

all anticipated dietary exposures and all 

other exposures for which there is 

reliable information.’’ This includes 

exposure through drinking water and in 

residential settings, but does not include 

occupational exposure. Section 

408(b)(2)(C) of FFDCA requires EPA to 

give special consideration to exposure 

of infants and children to the pesticide 

chemical residue in establishing a 

tolerance and to ‘‘ensure that there is a 

reasonable certainty that no harm will 

result to infants and children from 

aggregate exposure to the pesticide 

chemical residue * * *.’’ 

Consistent with section 408(b)(2)(D) 

of FFDCA, and the factors specified in 

section 408(b)(2)(D) of FFDCA, EPA has 

reviewed the available scientific data 

and other relevant information in 

support of this action. EPA has 

sufficient data to assess the hazards of 

and to make a determination on 

aggregate exposure for isoxaflutole 

including exposure resulting from the 

tolerances established by this action. 

EPA’s assessment of exposures and risks 

associated with isoxaflutole follows. 

A. Toxicological Profile 

EPA has evaluated the available 

toxicity data and considered its validity, 

completeness, and reliability as well as 

the relationship of the results of the 

studies to human risk. EPA has also 

considered available information 

concerning the variability of the 

sensitivities of major identifiable 

subgroups of consumers, including 

infants and children. 

Isoxaflutole exhibited low acute 

toxicity via oral, dermal, and inhalation 

routes of exposure and it is not a dermal 

sensitizer. In long-term studies via the 

oral route, isoxaflutole caused ocular 

toxicity in rats, hepatotoxicity 

(including liver tumor formation) and 

thyroid tumors in rats and mice, and 

hematotoxicity (toxicity to blood) in 

dogs and mice at high doses. The liver 

and ocular toxicities observed in rats 

were consistent with the mode of action 

of isoxaflutole in mammals (i.e., 

inhibition of the hepatic enzyme 4- 

hydroxyphenylpyruvate dioxygenase 

(HPPD)) that leads to a buildup of 

tyrosine in the blood and the eye. 

Developmental toxicity was observed 

in rats and rabbits primarily as growth 

retardations, including delays in 

skeletal ossification, effects that have 

been observed with other HPPD 

inhibitors (e.g., pyrasulfotole). There 

was no evidence of reproductive 

toxicity in the 2-generation reproductive 

toxicity study in rats; however, both 

adults and offspring exhibited ocular 

and liver toxicities as seen in long-term 

studies. 

In the acute and subchronic 

neurotoxicity studies in rats, mild 

changes in functional-observation 

battery (FOB) parameters (grip strength 

and/or landing foot splay) were 

observed in adult animals. However, 

similar effects were not observed either 

in pregnant animals or in offspring in a 

developmental neurotoxicity (DNT) 

study in rats. In both maternal animals 

and offspring, changes in body weight 

and/or food consumption were the 

primary effects seen in the DNT study 

and at the same dose tested. Decreased 

brain weights were observed in 

offspring on post-natal day (PND) 11 at 

the high dose only, but not at a later 

time point, an indicator of a 

developmental delay and/or a secondary 

effect of the decreased body weight. 

Although morphometric analyses were 

not performed in the study, there were 

no effects on pup swimming ability, 

learning, memory, motor activity, or 

auditory startle response at any dose, 

nor was there any evidence of 

neuropathology in the study at any 

dose. As a result, the missing 

morphometric measurements, while 

required, are unlikely to affect the 

tentative lowest-observed adverse-effect 

level (LOAEL) of the study (highest dose 

tested). 

Isoxaflutole was negative in a variety 

of genotoxicity screening assays. In 

carcinogenicity studies, isoxaflutole 


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induced liver and thyroid tumors in rats 

and liver tumors in mice. Isoxaflutole 

was classified as ‘‘likely to be a human 

carcinogen.’’ The method of 

quantification was linear cancer slope 

factor (Q1*). 

Specific information on the studies 

received and the nature of the adverse 

effects caused by isoxaflutole as well as 

the no-observed-adverse-effect-level 

(NOAEL) and the lowest-observedadverse-effect-level (LOAEL) from the 

toxicity studies can be found at http:// 

www.regulations.gov in document 

‘‘Isoxaflutole. Section 3 Registration for 

Use on Soybeans. Human-Health Risk 

Assessment,’’ p. 13 in docket ID number 

EPA–HQ–OPP–2010–0845. 

B. Toxicological Points of Departure/ 

Levels of Concern 

Once a pesticide’s toxicological 

profile is determined, EPA identifies 

toxicological points of departure (POD) 

and levels of concern to use in 

evaluating the risk posed by human 

exposure to the pesticide. For hazards 

that have a threshold below which there 

is no appreciable risk, the toxicological 

POD is used as the basis for derivation 

of reference values for risk assessment. 

PODs are developed based on a careful 

analysis of the doses in each 

toxicological study to determine the 

dose at which no adverse effects are 

observed (the NOAEL) and the lowest 

dose at which adverse effects of concern 

are identified (the LOAEL). Uncertainty/ 

safety factors are used in conjunction 

with the POD to calculate a safe 

exposure level—generally referred to as 

a population-adjusted dose (PAD) or a 

reference dose (RfD)—and a safe margin 

of exposure (MOE). For non-threshold 

risks, the Agency assumes that any 

amount of exposure will lead to some 

degree of risk. Thus, the Agency 

estimates risk in terms of the probability 

of an occurrence of the adverse effect 

expected in a lifetime. For more 

information on the general principles 

EPA uses in risk characterization and a 

complete description of the risk 

assessment process, see http:// 

www.epa.gov/pesticides/factsheets/ 

riskassess.htm. 

A summary of the toxicological 

endpoints for isoxaflutole used for 

human risk assessment is shown in the 

Table of this unit. 

TABLE 1—SUMMARY OF TOXICOLOGICAL DOSES AND ENDPOINTS FOR ISOXAFLUTOLE FOR USE IN HUMAN HEALTH RISK

ASSESSMENT

Exposure/scenario Point of departure and 

uncertainty/safety factors 

RfD, PAD, LOC for risk assessment Study and toxicological effects 

Acute dietary (Females 13–49 

years of age).

LOAEL = 5 milligrams/kilograms/ 

day (mg/kg/day) 

UFA = 10x 

UFH = 10x 

FQPA SF = 3 (includes UFL) 

Acute RfD = aPAD = 0.02 mg/kg/ 

day.

Prenatal developmental toxicity 

(rabbit) LOAEL = 5 mg/kg/day 

based on mg/kg/day based on 

increased incidence of fetuses 

with 27th pre-sacral vertebrae. 

Acute dietary (General population 

including infants and children).

NOAEL = 125 mg/kg 

UFA = 10x 

UFH = 10x 

FQPA SF = 1x 

Acute RfD = aPAD = 1.25 mg/kg Acute neurotoxicity (rat) LOAEL = 

500 mg/kg based on significant 

decreases in hind limb grip 

strength and landing foot splay 

on day 15. 

Chronic dietary (All populations) .... NOAEL= 2 mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 1x 

Chronic RfD = cPAD = 0.02 mg/ 

kg/day.

Combined chronic toxicity/carcinogenicity (rat) LOAEL = 20 mg/ 

kg/day based on liver, thyroid, 

ocular, and nervous system toxicity (M) and liver toxicity (F). 

Cancer (Oral, dermal, inhalation) .. Classification: ‘‘Likely to be Carcinogenic to Humans’’. Q1* (mg/kg/day)-1 of 1.14 x 10-2 from the male CD–1 

mouse liver for the linear low-dose extrapolation based on statistically significant increases in liver tumors in 

both sexes of mice and rats. 

UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population 

(intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account 

for the absence of data or other data deficiency. FQPA SF = Food Quality Protection Act Safety Factor. PAD = population adjusted dose (a = 

acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. 

C. Exposure Assessment 

1. Dietary exposure from food and 

feed uses. In evaluating dietary 

exposure to isoxaflutole, EPA 

considered exposure under the 

petitioned-for tolerances as well as all 

existing isoxaflutole tolerances in 40 

CFR 180.537. EPA assessed dietary 

exposures from isoxaflutole in food as 

follows: 

i. Acute exposure. Quantitative acute 

dietary exposure and risk assessments 

are performed for a food-use pesticide, 

if a toxicological study has indicated the 

possibility of an effect of concern 

occurring as a result of a 1-day or single 

exposure. 

Such effects were identified for 

isoxaflutole. In estimating acute dietary 

exposure, EPA used food consumption 

information from the United States 

Department of Agriculture (USDA) 

1994–1996 and 1998 Nationwide 

Continuing Surveys of Food Intake by 

Individuals (CSFII). As to residue levels 

in food, EPA assumed that 100% of the 

crop was treated and that for all 

commodities residues were at tolerance 

levels. 

ii. Chronic exposure. In conducting 

the chronic dietary exposure assessment 

EPA used the food consumption data 

from the USDA 1994–1996 and 1998 

CSFII. As to residue levels in food, EPA 

assumed that 100% of the crop was 

treated and that for all commodities 

residues were at tolerance levels. 

iii. Cancer. EPA determines whether 

quantitative cancer exposure and risk 

assessments are appropriate for a fooduse pesticide based on the weight of the 

evidence from cancer studies and other 

relevant data. If quantitative cancer risk 

assessment is appropriate, cancer risk 

may be quantified using a linear or 

nonlinear approach. If sufficient 

information on the carcinogenic mode 

of action is available, a threshold or 

non-linear approach is used and a 

cancer RfD is calculated based on an 

earlier non-cancer key event. If 

carcinogenic mode of action data are not 

available, or if the mode of action data 


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76312 Federal Register / Vol. 76, No. 235 / Wednesday, December 7, 2011 / Rules and Regulations 

determines a mutagenic mode of action, 

a default linear cancer slope factor 

approach is utilized. Based on the data 

summarized in Unit III.A., EPA has 

concluded that isoxaflutole should be 

classified as ‘‘Likely to be Carcinogenic 

to Humans’’ and a linear approach has 

been used to quantify cancer risk. 

In conducting the cancer dietary 

exposure assessment EPA used the same 

food consumption data from the USDA 

and assumptions for residue levels in 

food as the Chronic Exposure in Unit III. 

C. 1. ii., of this unit. 

2. Dietary exposure from drinking 

water. The Agency used screening level 

water exposure models in the dietary 

exposure analysis and risk assessment 

for isoxaflutole in drinking water. These 

simulation models take into account 

data on the physical, chemical, and fate/ 

transport characteristics of isoxaflutole. 

Further information regarding EPA 

drinking water models used in pesticide 

exposure assessment can be found at 

http://www.epa.gov/oppefed1/models/ 

water/index.htm. 

Based on the First Index Reservoir 

Screening Tool (FIRST) and Screening 

Concentration in Ground Water (SCI– 

GROW) models, the estimated drinking 

water concentrations (EDWCs) of 

isoxaflutole and metabolite RPA 202248 

are estimated to be 8.68 parts per billion 

(ppb) for surface water and 0.255 ppb 

for ground water for acute exposures, 

1.26 ppb for surface water and 0.255 

ppb for ground water for chronic 

exposures for non-cancer assessments, 

and 0.53 ppb for surface water and 

0.255 ppb for ground water for cancer 

assessments. 

Modeled estimates of drinking water 

concentrations were directly entered 

into the dietary exposure model. For 

acute dietary risk assessment, the water 

concentration value of 8.68 ppb was 

used to assess the contribution to 

drinking water. For chronic dietary risk 

assessment, the water concentration of 

value 1.26 ppb was used to assess the 

contribution to drinking water. For 

cancer dietary risk assessment, the 

water concentration of value 0.53 ppb 

was used to assess the contribution to 

drinking water. 

3. From non-dietary exposure. The 

term ‘‘residential exposure’’ is used in 

this document to refer to nonoccupational, non-dietary exposure 

(e.g., for lawn and garden pest control, 

indoor pest control, termiticides, and 

flea and tick control on pets). 

Isoxaflutole is not registered for any 

specific use patterns that would result 

in residential exposure. 

4. Cumulative effects from substances 

with a common mechanism of toxicity. 

Section 408(b)(2)(D)(v) of FFDCA 

requires that, when considering whether 

to establish, modify, or revoke a 

tolerance, the Agency consider 

‘‘available information’’ concerning the 

cumulative effects of a particular 

pesticide’s residues and ‘‘other 

substances that have a common 

mechanism of toxicity.’’ 

Pyrasulfotole, mesotrione, 

isoxaflutole, and topramezone belong to 

a class of herbicides that inhibit the 

liver enzyme HPPD, which is involved 

in the catabolism (metabolic 

breakdown) of tyrosine (an amino acid 

derived from proteins in the diet). 

Inhibition of HPPD can result in 

elevated tyrosine levels in the blood, a 

condition called tyrosinemia. HPPD 

inhibiting herbicides have been found to 

cause a number of toxicities in 

laboratory animal studies including 

ocular, developmental, liver and kidney 

effects. Of these toxicities, the ocular 

effect (corneal opacity) is highly 

correlated with the elevated blood 

tyrosine levels. In fact, rats dosed with 

tyrosine alone show ocular opacities 

similar to those seen with HPPD 

inhibitors. Although the other toxicities 

may be associated with chemically 

induced tyrosinemia, other mechanisms 

may also be involved. 

There are marked differences among 

species in the ocular toxicity associated 

with inhibition of HPPD. Ocular effects 

following treatment with HPPD 

inhibitor herbicides are seen in the rat 

but not in the mouse. Monkeys also 

seem to be recalcitrant to the ocular 

toxicity induced by HPPD inhibition. 

The explanation of this species-specific 

response in ocular opacity is related to 

the species differences in the clearance 

of tyrosine. A metabolic pathway exists 

to remove tyrosine from the blood that 

involves a liver enzyme called tyrosine 

aminotransferase (TAT). In contrast to 

rats where ocular toxicity is observed 

following exposure to HPPD-inhibiting 

herbicides, mice and humans are 

unlikely to achieve the levels of plasma 

tyrosine necessary to produce ocular 

opacities because the activity of TAT in 

these species is much greater compared 

to rats. Thus, humans and mice have a 

highly effective metabolic process for 

handling excess tyrosine. 

HPPD inhibitors (e.g., nitisinone) are 

used as an effective therapeutic agent to 

treat patients suffering from rare genetic 

diseases of tyrosine catabolism. 

Treatment starts in childhood but is 

often sustained throughout patient’s 

lifetime. The human experience 

indicates that a therapeutic dose (1 mg/ 

kg/day dose) of nitisinone has an 

excellent safety record in infants, 

children, and adults and that serious 

adverse health outcomes have not been 

observed in a population followed for 

approximately a decade. Rarely, ocular 

effects are seen in patients with high 

plasma tyrosine levels; however, these 

effects are transient and can be readily 

reversed upon adherence to a restricted 

protein diet. This indicates that an 

HPPD inhibitor in and of itself cannot 

easily overwhelm the tyrosine-clearance 

mechanism in humans. 

Therefore, due to an efficient 

metabolic process to handle excess 

tyrosine, exposure to environmental 

residues of HPPD inhibiting herbicides 

is unlikely to result in high blood levels 

of tyrosine and ocular toxicity in 

humans; and EPA has concluded that a 

cumulative risk assessment with other 

HPPD inhibitors is unnecessary. 

D. Safety Factor for Infants and 

Children 

1. In general. Section 408(b)(2)(C) of 

FFDCA provides that EPA shall apply 

an additional tenfold (10X) margin of 

safety for infants and children in the 

case of threshold effects to account for 

prenatal and postnatal toxicity and the 

completeness of the database on toxicity 

and exposure unless EPA determines 

based on reliable data that a different 

margin of safety will be safe for infants 

and children. This additional margin of 

safety is commonly referred to as the 

FQPA Safety Factor (SF). In applying 

this provision, EPA either retains the 

default value of 10X, or uses a different 

additional safety factor when reliable 

data available to EPA support the choice 

of a different factor. 

2. Prenatal and postnatal sensitivity. 

Developmental toxicity was observed in 

rats and rabbits as growth retardations 

including delays in skeletal ossification; 

effects that have been observed with 

other HPPD inhibitors (e.g., 

pyrasulfotole). There was evidence of 

increased susceptibility in the rabbit 

study in the form of increased incidence 

of fetuses with 27th pre-sacral vertebrae 

at a dose much lower than those causing 

maternal deficits in body weight and 

food consumption. Neither the rat 

developmental study nor the rat 2- 

generation reproductive toxicity studies 

revealed any evidence of increased 

susceptibility. However, both adults and 

offspring in the 2-generation 

reproductive toxicity study exhibited 

ocular and liver toxicities seen in longterm studies. 

3. Conclusion. EPA has determined 

that reliable data show the safety of 

infants and children would be 

adequately protected if the FQPA SF 

were reduced to 1x for all exposure 

scenarios, except acute dietary for 

females 13–49 years of age for which an 

FQPA SF is retained but reduced to 3X. 


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Federal Register / Vol. 76, No. 235 / Wednesday, December 7, 2011 / Rules and Regulations 76313 

That decision is based on the following 

findings: 

i. The toxicity database for 

isoxaflutole is complete. 

ii. There are not residual concerns 

regarding neurotoxicity, including 

developmental neurotoxicity, based on 

the results of acute, subchronic, and 

developmental neurotoxicity studies. 

iii. There is no evidence that 

isoxaflutole results in increased 

susceptibility following in utero 

exposure in a rat developmental study 

or in young rats in the 2-generation 

reproduction study. However, there was 

evidence of increased susceptibility 

following in utero exposure in a rabbit 

developmental study and a NOAEL for 

developmental effects was not identified 

in that study. To address the concern for 

increased in utero susceptibility and the 

lack of a NOAEL in the rabbit study, this 

study was selected for the acute dietary 

endpoint for females of 13–49 years of 

age and a 3X FQPA SF was retained for 

that population subgroup. Use of a 3X 

FQPA SF applied to the LOAEL yielded 

a point of departure that is comparable 

to the point of departure for the chronic 

dietary exposure scenario and the 

offspring effects in the rat 2-generation 

reproductive toxicity study. Therefore, 

all dietary exposure scenarios are 

considered protective of developmental 

effects. 

iv. There are no residual uncertainties 

identified in the exposure databases. 

EPA made the very conservative, healthprotective assumption that all 

commodities for which tolerances exist 

or are proposed contain residues at the 

tolerance level. Additionally, EPA made 

conservative (protective) assumptions in 

the ground and surface water modeling 

used to assess exposure to isoxaflutole 

in drinking water. These assessments 

will not underestimate the exposure and 

risks posed by isoxaflutole. 

E. Aggregate Risks and Determination of 

Safety 

EPA determines whether acute and 

chronic dietary pesticide exposures are 

safe by comparing aggregate exposure 

estimates to the acute PAD (aPAD) and 

chronic PAD (cPAD). For linear cancer 

risks, EPA calculates the lifetime 

probability of acquiring cancer given the 

estimated aggregate exposure. Short-, 

intermediate-, and chronic-term risks 

are evaluated by comparing the 

estimated aggregate food, water, and 

residential exposure to the appropriate 

PODs to ensure that an adequate MOE 

exists. 

1. Acute risk. Using the exposure 

assumptions discussed in this unit for 

acute exposure, the acute dietary 

exposure from food and water to 

isoxaflutole will occupy 2.4% of the 

aPAD for females 13 to 49 years old, the 

population group receiving the greatest 

exposure. 

2. Chronic risk. Using the exposure 

assumptions described in this unit for 

chronic exposure, EPA has concluded 

that chronic exposure to isoxaflutole 

from food and water will utilize 1% of 

the cPAD for all infants (<1 year old) the 

population group receiving the greatest 

exposure. There are no residential uses 

for isoxaflutole. 

3. Short-term risk. A short-term 

adverse effect was identified; however, 

isoxaflutole is not registered for any use 

patterns that would result in short-term 

residential exposure. Short-term risk is 

assessed based on short-term residential 

exposure plus chronic dietary exposure. 

Because there is no short-term 

residential exposure and chronic dietary 

exposure has already been assessed 

under the appropriately protective 

cPAD (which is at least as protective as 

the POD used to assess short-term risk), 

no further assessment of short-term risk 

is necessary, and EPA relies on the 

chronic dietary risk assessment for 

evaluating short-term risk for 

isoxaflutole. 

4. Intermediate-term risk. An 

intermediate-term adverse effect was 

identified; however, isoxaflutole is not 

registered for any use patterns that 

would result in intermediate-term 

residential exposure. Intermediate-term 

risk is assessed based on intermediateterm residential exposure plus chronic 

dietary exposure. Because there is no 

intermediate-term residential exposure 

and chronic dietary exposure has 

already been assessed under the 

appropriately protective cPAD (which is 

at least as protective as the POD used to 

assess intermediate-term risk), no 

further assessment of intermediate-term 

risk is necessary, and EPA relies on the 

chronic dietary risk assessment for 

evaluating intermediate-term risk for 

isoxaflutole. 

5. Aggregate cancer risk for U.S. 

population. The aggregate cancer risk 

assessment for the general population 

takes into account exposure estimates 

from dietary consumption of 

isoxaflutole from food and drinking 

water sources. Average food plus water 

source dietary exposure was used. 

Estimated cancer risk for the U.S. 

population includes infants and 

children. The aggregate cancer risk 

estimate for isoxaflutole is 8 × 10¥7. 

This risk estimate is based, in part, on 

the conservative assumption that 100% 

of all crops for which isoxaflutole is 

registered or proposed for registration 

are treated. Additional refinement using 

percent crop treated estimates would 

result in a lower estimate of cancer risk. 

EPA generally considers cancer risks 

in the range of one in one million (1 × 

10¥6) or less to be negligible. 

Accordingly, EPA has concluded the 

cancer risk for all existing isoxaflutole 

uses and the uses associated with the 

tolerances established in this action is 

negligible. 

6. Determination of safety. Based on 

these risk assessments, EPA concludes 

that there is a reasonable certainty that 

no harm will result to the general 

population, or to infants and children 

from aggregate exposure to isoxaflutole 

residues. 

IV. Other Considerations 

A. Analytical Enforcement Methodology 

Adequate enforcement methodology 

(liquid chromatography with tandem 

mass spectrometry (LC/MS/MS) method 

(IS–004–P10–02)) is available to enforce 

the tolerance expression. 

The method may be requested from: 

Chief, Analytical Chemistry Branch, 

Environmental Science Center, 701 

Mapes Rd., Ft. Meade, MD 20755–5350; 

telephone number: (410) 305–2905; 

email address: residuemethods@epa.

gov. 

B. International Residue Limits 

In making its tolerance decisions, EPA 

seeks to harmonize U.S. tolerances with 

international standards whenever 

possible, consistent with U.S. food 

safety standards and agricultural 

practices. EPA considers the 

international maximum residue limits 

(MRLs) established by the Codex 

Alimentarius Commission (Codex), as 

required by FFDCA section 408(b)(4). 

The Codex Alimentarius is a joint U.N. 

Food and Agriculture Organization/ 

World Health Organization food 

standards program, and it is recognized 

as an international food safety 

standards-setting organization in trade 

agreements to which the United States 

is a party. EPA may establish a tolerance 

that is different from a Codex MRL; 

however, FFDCA section 408(b)(4) 

requires that EPA explain the reasons 

for departing from the Codex level. 

The Codex has not established a MRL 

for isoxaflutole. 

V. Conclusion 

Therefore, tolerances are established 

for residues of isoxaflutole, (5- 

cyclopropyl-4-isoxazolyl) [2- 

(methylsulfonyl)-4- 

(trifluoromethyl)phenyl] methanone and 

its metabolite 1-(2-methylsulfonyl-4- 

trifluoromethylphenyl)-2-cyano-3- 

cyclopropyl propane-1,3-dione, in or on 


sroberts on DSK5SPTVN1PROD with RULES
76314 Federal Register / Vol. 76, No. 235 / Wednesday, December 7, 2011 / Rules and Regulations 

soybean, seed and grain, aspirated 

fractions at 0.05 ppm and 0.30 ppm, 

respectively. 

VI. Statutory and Executive Order 

Reviews 

This final rule establishes tolerances 

under section 408(d) of FFDCA in 

response to a petition submitted to the 

Agency. The Office of Management and 

Budget (OMB) has exempted these types 

of actions from review under Executive 

Order 12866, entitled Regulatory 

Planning and Review (58 FR 51735, 

October 4, 1993). Because this final rule 

has been exempted from review under 

Executive Order 12866, this final rule is 

not subject to Executive Order 13211, 

entitled Actions Concerning Regulations 

That Significantly Affect Energy Supply, 

Distribution, or Use (66 FR 28355, May 

22, 2001) or Executive Order 13045, 

entitled Protection of Children From 

Environmental Health Risks and Safety 

Risks (62 FR 19885, April 23, 1997). 

This final rule does not contain any 

information collections subject to OMB 

approval under the Paperwork 

Reduction Act (PRA), 44 U.S.C. 3501 et 

seq., nor does it require any special 

considerations under Executive Order 

12898, entitled Federal Actions to 

Address Environmental Justice in 

Minority Populations and Low-Income 

Populations (59 FR 7629, February 16, 

1994). 

Since tolerances and exemptions that 

are established on the basis of a petition 

under section 408(d) of FFDCA, such as 

the tolerance in this final rule, do not 

require the issuance of a proposed rule, 

the requirements of the Regulatory 

Flexibility Act (RFA) (5 U.S.C. 601 et 

seq.) do not apply. 

This final rule directly regulates 

growers, food processors, food handlers, 

and food retailers, not States or tribes, 

nor does this action alter the 

relationships or distribution of power 

and responsibilities established by 

Congress in the preemption provisions 

of section 408(n)(4) of FFDCA. As such, 

the Agency has determined that this 

action will not have a substantial direct 

effect on States or tribal governments, 

on the relationship between the national 

government and the States or tribal 

governments, or on the distribution of 

power and responsibilities among the 

various levels of government or between 

the Federal Government and Indian 

tribes. Thus, the Agency has determined 

that Executive Order 13132, entitled 

Federalism (64 FR 43255, August 10, 

1999) and Executive Order 13175, 

entitled Consultation and Coordination 

with Indian Tribal Governments (65 FR 

67249, November 9, 2000) do not apply 

to this final rule. In addition, this final 

rule does not impose any enforceable 

duty or contain any unfunded mandate 

as described under Title II of the 

Unfunded Mandates Reform Act of 1995 

(UMRA) (Pub. L. 104–4). 

This action does not involve any 

technical standards that would require 

Agency consideration of voluntary 

consensus standards pursuant to section 

12(d) of the National Technology 

Transfer and Advancement Act of 1995 

(NTTAA), Public Law 104–113, section 

12(d) (15 U.S.C. 272 note). 

VII. Congressional Review Act 

The Congressional Review Act, 5 

U.S.C. 801 et seq., generally provides 

that before a rule may take effect, the 

agency promulgating the rule must 

submit a rule report to each House of 

the Congress and to the Comptroller 

General of the United States. EPA will 

submit a report containing this rule and 

other required information to the U.S. 

Senate, the U.S. House of 

Representatives, and the Comptroller 

General of the United States prior to 

publication of this final rule in the 

Federal Register. This final rule is not 

a ‘‘major rule’’ as defined by 5 U.S.C. 

804(2). 

List of Subjects in 40 CFR Part 180 

Environmental protection, 

Administrative practice and procedure, 

Agricultural commodities, Pesticides 

and pests, Reporting and recordkeeping 

requirements. 

Dated: November 21, 2011. 

Lois Rossi, 

Director, Registration Division, Office of 

Pesticide Programs. 

Therefore, 40 CFR chapter I is 

amended as follows: 

PART 180—[AMENDED] 

■ 1. The authority citation for part 180 

continues to read as follows: 

Authority: 21 U.S.C. 321(q), 346a and 371. 

■ 2. Section 180.537 is amended in 

paragraph (a) by revising the 

introductory text and alphabetically 

adding the following commodities to the 

table to read as follows: 

§ 180.537 Isoxaflutole; tolerances for 

residues. 

(a) General. Tolerances are 

established for residues of the herbicide, 

isoxaflutole, 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 the sum of isoxaflutole 

((5-cyclopropyl-4-isoxazolyl) [2- 

(methylsulfonyl)-4- 

(trifluoromethyl)phenyl] methanone) 

and its metabolite 1-(2-methylsulfonyl4-trifluoromethylphenyl)-2-cyano-3- 

cyclopropyl propan-1,3-dione (RPA 

202248), calculated as the 

stoichiometric equivalent of 

isoxaflutole, in or on the commodity: 

Commodity Parts per 

million 

*****

Grain, aspirated fractions ........... 0.30 

Soybean, seed ............................ 0.05 

* * * * * 

[FR Doc. 2011–31397 Filed 12–6–11; 8:45 am] 

BILLING CODE 6560–50–P 

ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Part 300 

[EPA–HQ–SFUND–2000–0003; FRL–9500–9] 

National Oil and Hazardous 

Substances Pollution Contingency 

Plan; National Priorities List: Deletion 

of the Palmer Barge Line Superfund 

Site 

AGENCY: Environmental Protection 

Agency. 

ACTION: Direct final rule. 

SUMMARY: The Environmental Protection 

Agency (EPA) Region 6 is publishing a 

direct final Notice of Deletion of the 

Palmer Barge Line (PBL) Superfund Site 

located in Port Arthur, Texas (Jefferson 

County), from the National Priorities 

List (NPL). The NPL, promulgated 

pursuant to Section 105 of the 

Comprehensive Environmental 

Response, Compensation, and Liability 

Act (CERCLA) of 1980, as amended, is 

an appendix of the National Oil and 

Hazardous Substances Pollution 

Contingency Plan (NCP). This direct 

final deletion is being published by EPA 

with the concurrence of the State of 

Texas, through the Texas Commission 

on Environmental Quality, because EPA 

has determined that all appropriate 

response actions at these identified 

parcels under CERCLA, other than 

operation, maintenance, and Five-Year 

Reviews, have been completed. 

However, this deletion does not 

preclude future actions under 

Superfund. 

DATES: This direct final deletion is 

effective February 6, 2012 unless EPA 

receives adverse comments by January 

6, 2012. If adverse comments are 

received, EPA will publish a timely 

withdrawal of the direct final deletion 


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