Pesticides; tolerances in food, animal feeds, and raw agricultural commodities: sodium,
[Federal Register: September 18, 2001 (Volume 66, Number 181)]
[Rules and Regulations]
[Page 48089-48097]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr18se01-3]
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-301175; FRL-6803-2]
RIN 2070-AB78
Bispyribac-Sodium; Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
SUMMARY: This regulation establishes a tolerance for residues of bispyribac-sodium in or on rice. Valent U.S.A. Corporation (as agent for K-I Chemical U.S.A., Inc.) requested this tolerance under the Federal Food, Drug, and Cosmetic Act, as amended by the Food Quality Protection Act of 1996.
DATES: This regulation is effective September 18, 2001. Objections and requests for hearings, identified by docket control number OPP-301175, must be received by EPA on or before November 19, 2001.
ADDRESSES: Written objections and hearing requests may be submitted by mail, in person, or by courier. Please follow the detailed instructions for each method as provided in Unit VI. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, your objections and hearing requests must identify docket control number OPP-301175 in the subject line on the first page of your response.
FOR FURTHER INFORMATION CONTACT: By mail: James A. Tompkins, Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,Washington, DC 20460; telephone number: 703-305-5697; and e-mail address: tompkins.jim@epa.gov.
SUPPLEMENTARY INFORMATION:
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General Information
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Does this Action Apply to Me?
You may be affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected categories and entities may include, but are not limited to:
Examples of Categories
NAICS Codes
Potentially Affected Entities
Industry
111
Crop production 112
Animal production 311
Food manufacturing 32532
Pesticide manufacturing
This listing is not intended to be exhaustive, but rather provides a guide for readers regarding entities likely to be affected by this action. Other types of entities not listed in the table could also be affected. The North American Industrial Classification System (NAICS) codes have been provided to assist you and others in determining whether or not this action might apply to certain entities. If you have questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT.
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How Can I Get Additional Information, Including Copies of this Document and Other Related Documents?
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Electronically.You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet homepage at http://www.epa.gov/. To access this document, on the homepage select ``Laws and Regulations,'' ``Regulations and Proposed Rules,'' and then look up the entry for this document under the ``Federal Register--Environmental Documents.'' You can also go directly to theFederal Register listings at http://www.epa.gov/fedrgstr/. To access the OPPTS Harmonized Guidelines referenced in this document, go directly to the guidelines at http://www.epa.gov/opptsfrs/home/guidelin.htm. A frequently updated electronic version of 40 CFR part 180 is available at http:// www.access.gpo.gov/nara/cfr/cfrhtml_00/Title_40/40cfr180_00.html, a beta site currently under development.
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In person. The Agency has established an official record for this action under docket control number OPP-301175. The official record consists of the documents specifically referenced in this action, and other information related to this action, including any information claimed as Confidential Business Information (CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period is available for inspection in the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305-5805.
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Background and Statutory Findings
In the Federal Register of September 20, 2000 (65 FR 56901) (FRL- 6742-7), EPA issued a notice pursuant to section 408 of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a as amended by the Food Quality Protection Act of 1996 (FQPA) (Public Law 104-170) announcing the filing of
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a pesticide petition (PP) for tolerance by Valent U.S.A. Corporation (as agent for K-I Chemical U.S.A., Inc.), 1333 North California Blvd., Suite 600, Walnut Creek, CA 94569. This notice included a summary of the petition prepared by Valent U.S.A. Corporation, the registrant. There were no comments received in response to the notice of filing.
The petition requested that 40 CFR part 180 be amended by establishing a tolerance for residues of the herbicide bispyribac- sodium, sodium 2,6-bis[(4,6-dimethoxy-pyrimidin-2-yl)oxy]benzoate, in or on rice, grain and rice, straw at 0.02 part per million (ppm).
Section 408(b)(2)(A)(i) of the 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) 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) 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. . . .''
EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. For further discussion of the regulatory requirements of section 408 and a complete description of the risk assessment process, see the final rule on Bifenthrin Pesticide Tolerances (62 FR 62961, November 26, 1997) (FRL-5754-7).
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Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D), 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, consistent with section 408(b)(2), for a tolerance for residues of bispyribac-sodium on rice at 0.02 ppm. EPA's assessment of exposures and risks associated with establishing the tolerance follows.
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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. The nature of the toxic effects caused by bispyribac-sodium are discussed in the following Table 1 as well as the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL) from the toxicity studies reviewed.
Table 1.--Subchronic, Chronic, and Other Toxicity
Guideline No.
Study Type
Results
870.3100
90-Day oral toxicity
NOAEL = 71.9/79.9 mg/kg/day (M/F) rodents (rat)
LOAEL = 724.0/790.8 mg/kg/day (M/F), based on decreased body weight gain, increased absolute and relative liver weights, increased alkaline phosphatase and gamma- GTP, and increased incidence of grossly dilated bile duct lumen in males, and microscopic lesions in the liver, biliary system and urinary bladder in both sexes.
870.3100
90-Day oral toxicity
NOAEL = 68.6/79.0 mg/kg/day (M/F) rodents (mouse)
LOAEL = 699.1/806.1 mg/kg/day (M/F), based on liver cell swelling and slight liver cell granulation in females
870.3150
90-Day oral toxicity in NOAEL = 100 mg/kg/day nonrodents (dog)
LOAEL = 600 mg/kg/day (M/F), based on increased salivation and slight proliferation of intrahepatic bile duct
870.3200
21/28-Day dermal toxicity NOAEL = 1,000 mg/kg/day (M/F) (rat)
LOAEL >1,000 mg/kg/day (M/F). No systemic toxicity or dermal irritation noted.
870.3700
Prenatal developmental in Maternal rodents (rat)
NOAEL = 1,000 mg/kg/day LOAEL = >1,000 mg/kg/day Developmental NOAEL = 1,000 mg/kg/day LOAEL = >1,000 mg/kg/day
870.3700
Prenatal developmental in Maternal nonrodents (rabbit)
NOAEL = 100 mg/kg/day LOAEL = 300 mg/kg/day, based on lethargy, diarrhea, and decreased body weight gain in the range finding study Developmental NOAEL = 300 mg/kg/day LOAEL was not established
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870.3800
Reproduction and fertility Parental/Systemic effects (rats)
NOAEL = 1.5 mg/kg/day LOAEL = 75.7 mg/kg/day (M/F), based on trace to mild choledocus Reproductive NOAEL = 759.0 mg/kg/day LOAEL = >759 mg/kg/day Offspring NOAEL = 75.7 mg/kg/day LOAEL = 759 mg/kg/day (M/F), based on decreased body weights, body weight gains, and liver weights, and increased incidence of consolidation and circumscribed areas in the liver
870.4100
Chronic toxicity (dogs) NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day (M/F), based on dose- related increase in intrahepatic bile duct hyperplasia and liver granulation in females
870.4300
Combined chronic toxicity/ NOAEL = 10.9 mg/kg/day carcinogenicity rodents LOAEL = 194.5 mg/kg/day (M), based on (rat)
macrosopic (yellowish liver, dilated choledochus lumen), microscopic (cellular infiltration, vacuolic changes in the bile ducts), and clinical signs (morbundity, wasting, piloerection, subnormal temperature, and decreased spontaneous motor activity. No evidence of carcinogenicity
870.4300
Carcinogenicity (mice) NOAEL = 14.1/17.4 (M/F) mg/kg/day LOAEL = 353.0/447.8 mg/kg/day (M/F), based on decreased body weight gain, and food efficiency, and increased incidence of microscopic lesions in the liver and gall bladder (M) No evidence of carcinogenicity
870.5100
Gene mutation - reverse There was no evidence of induced mutant gene mutation assay in colonies over background bacteria
870.5375
Cytogenetics - in vitro Not clastogenic with or without S9 mammalian cytogenetic activation, at any dose tested assay
870.5395
Other effects - in vivo Did not induce micronucleated polychromatic mammalian cytogenetic erythrocytes (PMCEs) in bone marrow at any assay
dose
870.5500
Other genotoxic effects - No zones of inhibition and the differential bacterial DNA damage and killing index suggesting potential DNA repair test
damage
870.5550
Other genotoxic effects - Did not induce UDS at any dose UDS synthesis in mammalian cell culture
870.7485
Metabolism and
A series of rat metabolism studies with pharmacokinetics (rat) 14CPy-bispyribac-sodium and 14C-Bn- bispyribac-sodium indicated that pretreatment, dose level, sex and position of the radiolabel made little effect on the absorption, distribution, elimination and metabolism. It was readily absorbed by male and female rats following intravenous or oral dosing. The total recovery of the administered radioactivity was 95.8 - 101.6% for all treatment groups. Most of the dose (>43%) of the administered dose was excreted in feces within 48 hours and essentially complete within 5 days. Less than 2% of the administered dose remained in the carcass and tissues and 14Cpy-bispyribac-sodium and Parent and 3 metabolites identified with of 14C-Bn-bispyribac-sodium administration. The parent compound, bispyribac-sodium, was the major component identified in the feces (37 - 69% of the dose) and urine (5 - 41% of the dose), in both sexes. Metabolites identified in the excreta constituted 8.3 - 14.6% and unknown metabolites constituted 0.7 - 5.2% of the dose.
Non-guideline
Serum bile acids (mice) Bile acids increased 115% and slight cecal enlargement in 9/10 treated mice
Non-guideline
Reversibility (mice)
Bispyribac-sodium was associated with liver lesions, bile duct hyperplasia and dilated gall bladders in subchronic and oncogenicity studies were not replicated in this reversibility study
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Non-guideline
Serum bile acids (rat) Total bile acids increased 1,072% (12- fold). The concentration of glycocholic acid, taurocholic acid, deoxycholic acid increased 2,127%, 2,991% and 138%, respectively, where as chenodeoxy cholic acid levels were similar to controls. Hyodeoxycholic acid was reduced from 34.0% to 3.3 of the total bile acids. Treatment altered the degree of conjugation; hyodeoxycholic acid increased 84% and deoxycholic acid increased 1,133%.
Non-guideline
Reversibility (rat)
Bispyribac-sodium was associated with urinary bladder epithelial hyperplasia in subchronic study and bile duct hyperplasia, enlarged bile ducts, and liver cell hypertrophy and fibrosis in chronic study. Upon removal of bispyribac- sodium from the diet, resulted complete recovery in liver enzymes, food consumption, food efficiency, body weights, however, muscular hypertrophy of choledocus was still evident. The study did not duplicate urinary bladder lesions noted in the subchronic study.
870.5100
Gene mutation - reverse Metabolite DesMe-2023 did not induce gene mutation assay in mutantcolonies over background bacteria
870.5100
Gene mutation - reverse Metabolite 2,4-dihydroxy-6-mehtoxy gene mutation assay in pyrimidine did not induce mutant colonies bacteria
over background
870.5100
Gene mutation - reverse Metabolite KIH-2023-M-8-Na did not induce gene mutation assay in mutant colonies over background bacteria
870.5100
Gene mutation - reverse Metabolite KIH-2023-M-9-Na did not induce gene mutation assay in mutant colonies over background bacteria
870.5100
Gene mutation - reverse Metabolite BIX-180 did not induce mutant gene mutation assay in colonies over background bacteria
870.5100
Gene mutation - reverse Metabolite Me2BA did not induce mutant gene mutation assay in colonies over background bacteria
870.5100
Gene mutation - reverse Metabolite KIH-2023-I-1 did not induce gene mutation assay in mutant colonies over background bacteria
870.5100
Gene mutation - reverse Metabolite KIH-2023-I-2 did not induce gene mutation assay in mutant colonies over background bacteria
870.5100
Gene mutation - reverse Metabolite KIH-2023-I-4 did not induce gene mutation assay in mutant colonies over background bacteria
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Toxicological Endpoints
The dose at which no adverse effects are observed (the NOAEL) from the toxicology study identified as appropriate for use in risk assessment is used to estimate the toxicological level of concern (LOC). However, the lowest dose at which adverse effects of concern are identified (the LOAEL) is sometimes used for risk assessment if no NOAEL was achieved in the toxicology study selected. An uncertainty factor (UF) is applied to reflect uncertainties inherent in the extrapolation from laboratory animal data to humans and in the variations in sensitivity among members of the human population as well as other unknowns. An UF of 100 is routinely used, 10X to account for interspecies differences and 10X for intraspecies differences.
For dietary risk assessment (other than cancer) the Agency uses the UF to calculate an acute or chronic reference dose (acute RfD or chronic RfD) where the RfD is equal to the NOAEL divided by the appropriate UF (RfD = NOAEL/UF). Where an additional safety factor is retained due to concerns unique to the FQPA, this additional factor is applied to the RfD by dividing the RfD by such additional factor. The acute or chronic Population Adjusted Dose (aPAD or cPAD) is a modification of the RfD to accommodate this type of FQPA Safety Factor.
For non-dietary risk assessments (other than cancer), the UF is used to determine the LOC. For example, when 100 is the appropriate UF (10X to account for interspecies differences and 10X for intraspecies differences) the LOC is 100. To estimate risk, a ratio of the NOAEL to exposures (margin of exposure (MOE) = NOAEL/exposure) is calculated and compared to the LOC.
The linear default risk methodology (Q*) is the primary method currently used by the Agency to quantify carcinogenic risk. The Q* approach assumes that any amount of exposure
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will lead to some degree of cancer risk. A Q* is calculated and used to estimate risk which represents a probability of occurrence of additional cancer cases (e.g., risk is expressed as 1 x 10-\6\ or one in a million). Under certain specific circumstances, MOE calculations will be used for the carcinogenic risk assessment. In this non-linear approach, a ``point of departure'' is identified below which carcinogenic effects are not expected. The point of departure is typically a NOAEL based on an endpoint related to cancer effects though it may be a different value derived from the dose response curve. To estimate risk, a ratio of the point of departure to exposure (MOEcancer= point of departure/exposures) is calculated. A summary of the toxicological endpoints for bispyribac- sodium used for human risk assessment is shown in the following Table 2:
Table 2.--Summary of Toxicological Dose and Endpoints for Bispyribac-sodium for Use in Human Risk Assessment
FQPA SF* and Level of Exposure Scenario
Dose Used in Risk
Concern for Risk Study and Toxicological Assessment, UF
Assessment
Effects
Chronic dietary (all populations) NOAEL = 10 mg/kg/day FQPA SF = 1x
Chronic toxicity study UF = 100............... cPAD = chronic RfD
dog Chronic RfD = 0.1 mg/kg/ FQPA SF. LOAEL = 100 mg/kg/day day.
= 0.1 mg/kg/day........ based on dose-related increases in hyperplasia of the intrahepatic bile ducts in males and females and granulation of the liver in the females.
Short-term incidental oral (1-30 NOAEL = 100 mg/kg/day LOC for MOE = 100
Developmental toxicity days) (residential)
(residential, includes study - rabbit the FQPA SF).
Maternal LOAEL = 300 mg/ kg/day based on lethargy, diarrhea and decreased body weight gain in the range finding study
Intermediate-term incidental oral (1- NOAEL = 100 mg/kg/day LOC for MOE = 100
90-Day feeding study - 6 months) (residential)
(residential, includes dog the FQPA SF)
LOAEL = 600 mg/kg/day based upon salivation and slight proliferation of intrahepatic bile duct
Short-term inhalation (1-30 days) Oral study
LOC for MOE = 100
Developmental toxicity (occupational/residential)
NOAEL = 100 mg/kg/day (occupational)
study - rabbit (inhalation absorption LOC for MOE = 100
Maternal LOAEL = 300 mg/ rate = 100%).
(residential, includes kg/day based on the FQPA SF).
lethargy, diarrhea and decreased body weight gain.
Intermediate-term inhalation (1-6 Oral study
LOC for MOE = 100
90-Day feeding study - months) (occupational/residential) NOAEL = 100 mg/kg/day (Occupational)
dog (inhalation absorption LOC for MOE = 100
LOAEL = 600 mg/kg/day rate = 100%).
(residential, includes based upon salivation the FQPA SF).
and slight proliferation of intrahepatic bile duct
Long-term inhalation (01-23227Filed9-17-01; 8:45 am] BILLING CODE 6560-50-S
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