Pesticide, food, and feed additive petitions: Syngenta Crop Protection, Inc.,

[Federal Register: December 16, 2005 (Volume 70, Number 241)]

[Rules and Regulations]

[Page 74679-74688]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

[DOCID:fr16de05-14]

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2005-0234; FRL-7753-4]

Acetic acid, [(5-chloro-8-quinolinyl) oxy]-, 1-methylhexyl ester (Cloquintocet-mexyl); Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

SUMMARY: EPA is granting in part, and denying in part, pesticide petition PP 4E6831 submitted by Syngenta Crop Protection, Inc. that requested certain amendments to 40 CFR 180.560 for acetic acid [(5- chloro-8-quinolinyl) oxy]-, 1-methylhexyl ester; cloquintocet-mexyl; CAS Reg. No. 99607-70-2] and its acid metabolite (5-chloro-8- quinolinoxyacetic acid). EPA issued a notice pursuant to section 408(d)(3) of FFDCA, 21 U.S.C. 346a(d)(3) in the Federal Register of June 2, 2004 (69 FR 31116) (FRL-7357-8) announcing the filing of this petition requesting that the tolerance expressions under Sec. 180.560 for wheat forage and hay be increased, the addition of tolerances for barley commodities (grain, hay, and straw), and the inclusion of a reference to the active ingredient pinoxaden. Although EPA finds it is safe to add a reference to pinoxaden and tolerances for barley (grain, hay, and straw) to this tolerance regulation, EPA does not agree that grounds exist to increase the tolerance expressions for wheat forage and hay. Thus, EPA is granting Syngenta's petition in as far as it seeks to add the reference pinoxaden and tolerances for barley (grain, hay, and straw) but is denying the request to increase the tolerance expressions for wheat forage and hay.

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DATES: This final rule is effective December 16, 2005. Objections and requests for hearings must be received on or before February 14, 2006.

ADDRESSES: To submit a written objection or hearing request follow the detailed instructions as provided in Unit VI. of the SUPPLEMENTARY INFORMATION. EPA has established a docket for this action under Docket identification (ID) number EPA-HQ-OPP-2005-0234. All documents in the docket are listed on the http://www.regulations.gov Web site. (EDOCKET,

EPA's electronic public docket and comment system was replaced on November 25, 2005, by an enhanced federal-wide electronic docket management and comment system located at http://www.regulations.gov.

Follow the on-line instructions.) Although listed in the index, some information is not publicly available, i.e., 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 either electronically in EDOCKET or in hard copy at the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall 2, 1801 S. Bell St., Arlington, VA. This docket facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The docket telephone number is (703) 305-5805.

FOR FURTHER INFORMATION CONTACT: R. Tracy Ward, Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone number: 703 308-9361; e-mail address: ward.tracyh@epa.gov.

SUPPLEMENTARY INFORMATION:

1. General Information

   1. 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:

      Crop production (NAICS 111).

      Animal production (NAICS 112).

      Food manufacturing (NAICS 311).

      Pesticide manufacturing (NAICS 32532).

      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 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.

   2. How Can I Access Electronic Copies of this Document and Other Related Information?

      In addition to using EDOCKET (http://www.epa.gov/edocket/), you may

      access this Federal Register document electronically through the EPA Internet under the ``Federal Register'' listings at http://www.epa.gov/fedrgstr/. A frequently updated electronic version of 40 CFR part 180

      is available at E-CFR Beta Site Two at http://www.gpoaccess.gov/ecfr/.

      To access the OPPTS Harmonized Guidelines referenced in this document, go directly to the guidelines at http://www.epa.gpo/opptsfrs/home/guidelin.htm/ .

2. Background and Statutory Findings

   In the Federal Register of June 22, 2004 (69 FR 31116) (FRL-7357- 8), 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 4E6831) by Syngenta Crop Protection, Inc., P.O. Box 18300, Greensboro, North Carolina, 27419-8300. This notice included a summary of the petition prepared by Syngenta Crop Protection, Inc., the petitioner. The petition requested that 40 CFR 180.560 for combined residues of the inert ingredient herbicide safener acetic acid, [(5-chloro-8- quinolinyl) oxy]-, 1-methylhexyl ester and its acid metabolite (5- chloro-8-quinolinoxyacetic acid) be amended by:

   1. Increasing the tolerance expressions in or on wheat, forage to 0.20 ppm and wheat, hay to 0.50 ppm,

   2. Adding tolerance expressions for barley, grain, hay and straw at 0.10 ppm, and

   3. By adding a reference to the active ingredient pinoxaden.

   For ease of reading this document, acetic acid, [(5-chloro-8- quinolinyl) oxy]-, 1-methylhexyl ester will be referred to as cloquintocet-mexyl. The Chemical Abstracts Service (CAS) Registry Number of cloquintocet-mexyl is 99607-70-2 and the CAS name is acetic acid, [(5-chloro-8-quinolinyl) oxy]-, 1-methylhexyl ester (9 CI).

   One comment was received on the notice of filing from a private citizen questioning whether the Agency was going to use the most current and up-to-date information and data available when writing the final rule. In developing the final rule, EPA did evaluate the information and data submitted by the petitioner as well as more recent information that was available to the Agency.

   In the final rule that EPA used to establish the existing tolerances under 40 CFR 180.560 (Federal Register of June 22, 2000 (65 FR 38757; FRL-6592[dash]4; PP7E4920), EPA determined that additional data (for plant and livestock metabolism, plant analytical methods, multiresidue methods, storage stability, crop field trials, processing studies, and rotational crops) were required before a permanent registration for cloquintocet-mexyl in or on wheat commodities could be established. Syngenta submitted data in response to the previous risk assessment. Assessments of human exposures and risks were conducted for acute and chronic dietary risk, exposure and risk to cloquintocet-mexyl residues in water, residential exposure and risk, aggregate risk, and exposure and risk to workers.

   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....''

   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 of the FFDCA and a complete description of the risk assessment process, see http://www.epa.gov/fedrgstr/EPA-PEST/1997/November/Day-26/p30948.htm .

3. Aggregate Risk Assessment and Determination of Safety

   Consistent with section 408(b)(2)(D) of FFDCA, EPA has reviewed the available scientific data and other

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   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) of FFDCA, for a tolerance for combined residues of cloquintocet-mexyl and its acid metabolite on wheat, grain and straw at 0.10 ppm; wheat, forage at 0.20 ppm; wheat, hay at 0.50 ppm; barley, grain at 0.01 ppm; and barley, hay and straw at 0.10 ppm. EPA's assessment of exposures and risks associated with establishing the tolerance follows.

   1. 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. Specific information on the studies received and the nature of the toxic effects caused by cloquintocet-mexyl as well as the no- observed-adverse-effect-level (NOAEL) and the lowest-observed-adverse- effect-level (LOAEL) from the toxicity studies are described in this section.

      1. Acute toxicity. The acute toxicity data (see Table 1) indicated that cloquintocet-mexyl (CGA 185072) has low acute oral, dermal, and inhalation toxicity (Acute Toxicity Category III) and is slightly irritating to eyes. It is not a skin irritant. However, it is a skin sensitizer.

         Table 1.--Acute Toxicity Data on Cloquintocet-mexyl

         GDLN

         Study Type

         Results

         81-1

         Acute Oral-Rat LD50>2,000 mg/kg (M&F)

         81-1

         Acute Oral-Mouse LD50>2,000 mg/kg (M&F)

         81-2

         Acute Dermal-Rat LD50> 2,000 mg/kg

         81-3

         Acute Inhalation- LC50>0.935 [mu]g/L Rat

         81-4

         Primary Eye

         Slight eye Irritation-Rabbit irritant

         81-5

         Primary Skin

         Non-irritant Irritation-Rabbit

         81-6

         Dermal

         Skin sensitizer Sensitization- Guinea pig

      2. Subchronic and chronic toxicity. Available toxicity studies are described in Table 2.

         i. Systemic toxicity. The primary target organs for subchronic exposure of cloquintocet-mexyl (CGA 185072) are the liver and the renal system. In a 90-day feeding study in rats, increased incidence of urinary bladder hyperplasia and increased serum bilirubin were observed in males at doses >= 1,000 ppm (equivalent to 64 mg/kg/day). This observation was supported by a 28-day oral gavage study in rats where renal papillary necrosis and inflammation with fibrosis were observed at doses >= 100 mg/kg/day. In a 28-day dermal toxicity study in rats, mottled or reddish livers accompanied by histopathological changes including necrosis and fibrosis were observed in two of five females exposed to 1,000 mg/kg/day of cloquintocet-mexyl (CGA 185072). In a 90- day feeding study in dogs, liver toxicity was evidenced by observations of liver necrosis and perivascular inflammatory cell infiltration. In the one-year dog study, increased relative liver weight and increased chronic interstitial nephritis were observed. It is notable that in the two-year chronic toxicity study in rats, no renal or liver toxicity was reported; however, there was an increase in lymphoid hyperplasia of the thymus in male rats and an increase in thyroid follicular epithelial hyperplasia in female rats at 73 mg/kg/day.

         ii. Developmental/reproductive toxicity. There was no evidence of developmental or reproductive toxicity for cloquintocet-mexyl. The data demonstrate no increased sensitivity of rats or rabbits to in utero or early post-natal exposure to cloquintocet-mexyl (CGA 185072). NOAELs for maternal/parental toxicity were either less than or equal to the NOAELs for fetal or reproductive toxicity.

         iii. Carcinogenicity. In accordance with the EPA Proposed EPA Weight-of-the-Evidence Categories, August 1999 cloquintocet-mexyl was classified as not likely to be a human carcinogen. Carcinogenicity studies in rats and mice did not show increased incidence of spontaneous tumor formation. With negative mutagenic test battery, it is suggested that cloquintocet-mexyl (CGA 185072) is not likely to be a human carcinogen.

         iv. Mutagenicity. Studies indicate that cloquintocet-mexyl is not mutagenic in bacteria (Salmonella typhimurium or Escherichia coli) or cultured mammalian cells (Chinese hamster V79 lung fibroblasts). There is also no evidence of clastogenicity either in vitro or in vivo. Similarly, cloquintocet-mexyl did not induce unscheduled DNA synthesis (UDS) in primary rat hepatocytes.

         v. Neurotoxicity. There is no evidence of neurotoxicity based on observations in toxicity studies. Acute and subchronic neurotoxicity studies are not available for cloquintocet-mexyl; additional neurotoxicity testing is not being required at this time.

         vi. Metabolism. Metabolism studies in rats indicated that approximately 40% of the administered dose of cloquintocet-mexyl was absorbed through the gastrointestinal tract and subsequently excreted via the urine. Fecal excretion accounted for approximately 60% of the administered dose. The chemical was rapidly eliminated (more than 80% of the administered dose) via feces and urine within 48 hours post- dosing. Sex, dosing regime, and dose levels had little effect on the excretion pattern. Excretion patterns were similar between the biliary cannulated and non-cannulated animals indicating that there was no enterohepatic circulation of the chemical. Three days after administration, tissue radioactivity accounted for less than 0.3% of the administered dose (or was non-detectable) and was not detectable in the expired air. At day three post-dosing, most tissue residues of radioactivity were below the limit of detection. The major metabolic pathway of cloquintocet-mexyl was ester hydrolysis to yield 5-chloro-8- quinolinoxy acetic acid, the major metabolite in the fecal and urinary pools.

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         Table 2.--Toxicity Profile Summary Table for Cloquintocet-mexyl

         Guideline No.

         Study Type

         Results

         870.3100

         28-Day oral in NOAEL = 10 mg/kg/ rodents

         day LOAEL = 100 mg/kg/ day based on microscopic kidney lesions

         870.3100

         28-Day oral in NOAEL = 10 mg/kg/ rodents.

         day (females only) LOAEL = 400 mg/kg/ day based on transient decrease in body weight gain, microscopic alterations of the pituitary and thyroid and possibly increased SGPT.

         870.3100

         13 week oral in NOAEL = M: 150 ppm rodents

         (9.7 mg/kg), F= 6,000 ppm (=407 mg/ kg/day). LOAEL = M - 1,000 ppm (6.9 mg/kg); F >= 6,000 ppm (>= 407 mg/kg/day), based on urinary bladder hyperplasia, kidney hydronephrosis and increased serum bilirubin in males.

         870.3150

         90-Day oral in non- NOAEL = 100 ppm (M: rodent

         2.9 mg/kg/day; F: 3.3 mg/kg/day). LOAEL = 1,000 ppm (M and F: 30.2 mg kg/day) based on perivascular mixed inflammatory cell infiltrates and multicellular multifocal necrosis of the liver and thymic atrophy

         870.3200

         28-Day dermal NOAEL = 200 mg/kg/ toxicity

         day LOAEL = 1,000 mg/kg/ day based on mottled or reddish livers accompanied by histopathological changes including necrosis and fibrosis

         870.3700

         Prenatal

         Maternal NOAEL = developmental in 100 mg/kg/day rodent

         LOAEL = 400 mg/kg/ day based on clinical signs and decrease in body weight gain and food consumption. Developmental NOAEL = 100 mg/kg/day LOAEL = 400 mg/kg/ day based on the higher incidence of skeletal variants and decrease in fetal body weights in the high dose group.

         870.3700

         Prenatal

         Maternal NOAEL = 60 developmental in mg/kg/day nonrodent

         Maternal LOAEL = 300 mg/kg/day based on maternal toxicity (death) in the high dose group only. Developmental NOAEL = 300 mg/kg/day Developmental LOAEL >= 300 mg/kg/day

         870.3800

         2 Generation

         Parental/Systemic Reproduction

         NOAEL = 5,000 ppm (M: 370.7; F: 442.8 mg/kg/day) Parental/Systemic LOAEL =10,000 ppm (M: 721.7 ; F: 846.9 mg/kg/day), based on decreased body weight, deceased food consumption, and pathological changes in the kidney (dilated renal pelvis, nephrolith, hydronephrosis, urethral constrictions) and urinary bladder (cytoliths, hyperemia, cystitis and urothelial hyperplasia). Reproductive NOAEL = 10,000 ppm (721.7 mg/kg/day). Reproductive LOAEL >= 10,000 ppm (721.7 mg/kg/day) Developmental NOAEL = 5,000 ppm (442.8 mg/kg/day) Developmental LOAEL = 10,000 (846.9 mg/ kg/day) based on decreased pup weight and dilated renal pelvis.

         870.4100

         Chronic toxicity NOAEL = 1500 ppm in nonrodent

         (M: 43, F: 45 mg/ kg/day) LOAEL = 15,000/ 10,000 ppm (M: 196 F:216 mg/kg/day) based on decreased body weight/weight gain and food consumption, anemia, increased serum iron, protein alterations, bone marrow hypoplasia and possibly decreased testes/ prostate weights and interstitial nephritis.

         870.4200

         Carcinogenicity in NOAEL = 1,000 ppm mice

         (M: 111; F: 102 mg/ kg/day) LOAEL = 5,000 ppm (M: 583; F: 520 mg/ kg/day) based on decreased body weight/weight gain in both sexes, urinary bladder lesions (chronic inflammation, ulceration, calculus and submucosa edema) in males and possibly slightly increased water consumption in both sexes. Negative for oncogenicity.

         870.4300

         Combined chronic/ NOAEL = F: 100 ppm oncogenicity in (4.3 mg/kg/day) M: rat

         1,000 ppm (36.4 mg/ kg/day) LOAEL = F: 1,000 ppm (41.2 mg/kg/ day); M: 2,000 ppm ( 81.5 mg/kg/day) based on increased incidence of thyroid follicular epithelial hyperplasia in females and based on lymphoid hyperplasia of the thymus in males.

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         870.5100

         Gene Mutation Testing up to 5,000 [mu]g/plate with or without S9 microsomes produced no evidence that CGA 185072 technical induced a mutagenic effect in any strain. Negative mutagen

         870.5200

         Gene Mutation There was no evidence mutagenic effect at any dose (up to 500 [mu]g/ plate) with or without S9 activation. Negative mutagen.

         870.5315

         Human Lymphocytes Human lymphocytes in vitro

         were exposed in vitro up to 75 [mu]g/mL with or without S9 activation showed no evidence that CGA 185072 induced a cytogenetic effects. at any dose. Negative mutagen.

         870.5395

         Micronucleus Test Chinese hamsters dosed from 625 to 2,500 mg/kg showed no evidence that CGA 185072 induced a clastogenic or aneugenic effect in either sex at any dose or sacrifice time. Negative mutagen.

         870.5550

         DNA Repair Human Cultured human Fibroblasts

         fibrocytes were exposed in vitro to up to 60 [mu]g/ mL for 5 hrs. and scored for silver grains in the nucleus. There was no evidence that CGA 185072 technical in the absence of S9 activation induced a genotoxic response.

         870.5550

         DNA Repair Rat Primary rat Hepatocytes

         hepatocytes expose to 200 [mu]g/mL for 16-18 hour and scored for nuclear grains showed no evidence that CGA 185072 technical induced a genotoxic response. Negative mutagen.

         870.7485

         Metabolism and Absorption after a pharmacokinetics single low oral dose (50 mg/kg bw), was between 40.2% (males) and 35.6% (females). The major metabolite in the 0 to 24 hour fecal and urinary pools was determined to be quinolinoxy acetic acid, reference material CGA 153433, accounting for approximately 95% of the recovered radioactivity.

         870.7485

         Metabolism and The major metabolic pharmacokinetics pathway of CGA 185072 was determined to be hydrolysis of the ester group, resulting in the formation of 5- chloro-8- quinolinoxy acetic acid. The major metabolic pathway was not significantly affected by sex, dose level or dosing regime.

   2. Toxicological Endpoints

      A summary of the toxicological endpoints for cloquintocet-mexyl used for human risk assessment is shown below in Table 3.

      1. Acute dietary exposure. An acute reference dose (RfD) was selected for the subpopulation of females 13-50 years old. This acute RfD of 1 mg/kg/day is based on the no-observable-adverse-effect-level (NOAEL) of 100 mg/kg/day selected from a developmental toxicity in rats (MRID 44387429) where an increased incidence of skeletal variants and decreased fetal body weight was observed at 400 mg/kg/day. [The NOAEL of 100 mg/kg/day is divided by uncertainty factors (UF) for inter- species extrapolation (10x) and intra-species variability (10x).] Based on the conservative assumption that developmental toxicity could occur following a single exposure to a pregnant female, this endpoint is appropriate for acute risk assessment for females 13-50 years old.

      An acute RfD for the general population was not identified. Based on the available toxicology data, toxic effects observed in oral toxicity studies could not be attributed to a single dose (exposure) for population subgroups other than females 13-50 years old. No acute or subchronic neurotoxicity studies are available for cloquintocet- mexyl at this time. No other neurotoxic effects were observed in available toxicity studies. It is also noteworthy that the acute oral LD50for male and female rats for technical grade cloquintocet-mexyl (98% a.i.) is