00-21673. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food

AGENCY:

Environmental Protection Agency (EPA).

ACTION:

Notice.

SUMMARY:

This notice announces the initial filing of a pesticide petition proposing the establishment of regulations for residues of a certain pesticide chemical in or on various food commodities.

DATES:

Comments, identified by docket control number PF-958, must be received on or before September 25, 2000.

ADDRESSES:

Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I.C. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket control number PF-958 in the subject line on the first page of your response.

FOR FURTHER INFORMATION CONTACT:

By mail: Jim Tompkins, Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: [phone]; e-mail address: [e-mail].

SUPPLEMENTARY INFORMATION:

I. General Information

A. 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:

Categories	NAICS codes	Examples of 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.

B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents?

1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http://www.epa.gov/​. To access this document, on the Home Page select “Laws and Regulations” and then look up the entry for this document under the “Federal Register—Environmental Documents.” You can also go directly to the Federal Register listings at http://www.epa.gov/​fedrgstr/​.

2. In person. The Agency has established an official record for this action under docket control number PF-958. The official record consists of the documents specifically referenced in this action, any public comments received during an applicable comment period, 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 Highway, Arlington, VA, from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is [phone].

C. How and to Whom Do I Submit Comments?

You may submit comments through the mail, in person, or electronically. To ensure proper receipt by EPA, it is imperative that you identify docket control number PF-958 in the subject line on the first page of your response.

1 . By mail. Submit your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.

2 . In person or by courier. Deliver your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is [phone].

3. Electronically. You may submit your comments electronically by e-mail to: “[e-mail],” or you can submit a computer disk as described above. Do not submit any information electronically that you consider to be CBI. Avoid the use of special characters and any form of encryption. Electronic submissions will be accepted in Wordperfect 6.1/8.0 or ASCII file format. All comments in electronic form must be identified by docket control number PF-958. Electronic comments may also be filed online at many Federal Depository Libraries.

D. How Should I Handle CBI That I Want to Submit to the Agency?

Do not submit any information electronically that you consider to be CBI. You may claim information that you submit to EPA in response to this document as CBI by marking any part or all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public version of the official record. Information not marked confidential will be included in the public version of the official record without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person identified under FOR FURTHER INFORMATION CONTACT.

E. What Should I Consider as I Prepare My Comments for EPA?

You may find the following suggestions helpful for preparing your comments:

1. Explain your views as clearly as possible.

2. Describe any assumptions that you used.

3. Provide copies of any technical information and/or data you used that support your views.

4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide.

5. Provide specific examples to illustrate your concerns.

6. Make sure to submit your comments by the deadline in this notice.

7. To ensure proper receipt by EPA, be sure to identify the docket control number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation.

II. What Action is the Agency Taking?

EPA has received a pesticide petition as follows proposing the establishment and/or amendment of regulations for residues of a certain pesticide chemical in or on various food commodities under section 408 of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a. EPA has determined that this petition contain data or information regarding the elements set forth in section 408(d)(2); however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules on the petition.

List of Subjects

• Environmental protection
• Agricultural commodities
• Feed additives
• Food additives
• Pesticides and pests
• Reporting and recordkeeping requirements

Dated August 11, 2000.

Peter Caulkins,

Acting Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

The petitioner summary of the pesticide petition is printed below as required by section 408(d)(3) of the FFDCA. The summary of the petition was prepared by the petitioner and represents the view of the petitioner. The petition summary announces the availability of a description of the analytical methods available to EPA for the detection and measurement of the pesticide chemical residues or an explanation of why no such method is needed.

American Cyanamid Company

9F5092

EPA has received a pesticide petition 9F5092 from American Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400 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 establishing tolerances for residues of the herbicide ( ±)-2-4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1-H-imidazol-2-yl-5-methyl-3-pyridinecarboxylic acid (also known as imazapic), applied as either the free acid or the ammonium salt, and its metabolite ( ±)-2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1-H-imidazol-2-yl]-5-hydroxymethyl-3-pyridinecarboxylic acid, both free and conjugated, in or on the raw agricultural commodities grass forage at 35 parts per million (ppm), and grass hay at 15 ppm. Tolerances are also proposed for ( ±)-2-4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1-H-imidazol-2-yl-5-methyl-3-pyridinecarboxylic acid and its free hydroxymethyl metabolite alone in milk, meat of cattle, sheep, goats, and horses, fat of cattle, sheep, goats, and horses, meat by-products (except kidney) of cattle, sheep, goats, and horses at 0.1 ppm and kidney of cattle, sheep, goats, and horses at 2.0 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, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The qualitative nature of the residues of imazapic in grass is adequately understood. Based on results of a grass metabolism study conducted with a representative of this crop group, Bermuda grass, residues of concern for tolerance setting purposes in grass are parent imazapic and its hydroxymethyl metabolite, both free and glucose conjugated.

2. Analytical method. Practical analytical methods for detecting and measuring the residues of concern in grass and animal commodities are submitted to EPA with this petition. The analytical methods for grass commodities, milk, meat, and meat by-products are based on capillary electrophoresis with limits of quantitation (LOQ) of 0.5 ppm for grass commodities, 0.01 ppm for milk, and 0.05 ppm for meat and meat by-products. Measurement of imazapic residues in milk fat and tissue fat is accomplished by high performance liquid chromatography/positive ion electro spray ionization tandem mass spectrometry (LC/MS). The validated LOQ of the method is 0.01 ppm for milk fat and 0.05 ppm for tissue fat. These independently validated methods are appropriate for the enforcement purposes of this petition.

3. Magnitude of residues. A total of 13 field trials was conducted with representative grasses for this crop group at the proposed use rate for imazapic on grass. The residue values based on the proposed label use pattern and reported from these field trials were all less than the proposed tolerances of 35 ppm for grass forage and 15 ppm for grass hay. No processing study is included with this petition as grasses from pasture and rangeland have no processed commodities according to the EPA residue chemistry test guidelines.

B. Toxicological Profile

1. Acute toxicity. Imazapic technical is considered to be nontoxic (toxicity category IV) to the rat by the oral route of exposure. In an acute oral toxicity study in rats, the LD₅₀ value of imazapic technical was greater than 5,000 milligrams/kilograms body weight (mg/kg bwt) for males and females. The results from an acute dermal toxicity study in rabbits indicate that imazapic is slightly toxic (toxicity category III) to rabbits by the dermal route of exposure. The dermal LD₅₀ value of imazapic technical was greater than 2,000 mg/kg bwt for both male and female rabbits. Imazapic technical is considered to be nontoxic (toxicity category IV) to the rat by the respiratory route of exposure. The 4-hour LC₅₀ value was greater than 5.52 mg/L (analytical) for both males and females. Imazapic technical was shown to be non-irritating to rabbit skin (toxicity category IV) and minimally irritating to the rabbit eye (toxicity category III). Based on the results of a dermal sensitization study, imazapic technical is not considered a sensitizer in guinea pigs.

2. Genotoxicty. Imazapic technical was tested in a battery of four in vitro and one in vivo genotoxicity assays measuring several different endpoints of potential genotoxicity. Collective results from these studies indicate that imazapic does not pose a mutagenic or genotoxic risk.

3. Reproductive and developmental toxicity. The developmental toxicity study in Sprague Dawley rats conducted with imazapic technical showed no evidence of teratogenic effects in fetuses and no evidence of developmental toxicity. Thus, imazapic is neither a developmental toxicant nor a teratogen in the rat. In the rat developmental toxicity study with imazapic technical, the no observed adverse effect level (NOAEL) for maternal toxicity and developmental toxicity was 1,000 mg/kg bwt/day, the highest dose tested.

Results from a developmental toxicity study in New Zealand White rabbits with imazapic technical also indicated no evidence of teratogenicity or developmental toxicity. Thus, imazapic technical is neither a developmental toxicant nor a teratogen in the rabbit. In the rabbit developmental toxicity study, the NOAEL for maternal toxicity was 350 mg/kg bwt/day, based on decreased food consumption and body weight gain at 500 mg/kg bwt/day, the next highest dose tested. The NOAEL for developmental toxicity was determined by EPA to be 500 mg/kg bwt/day; the excessive mortality in dams at 700 mg/kg bwt/day (the highest dose tested) resulted in too few fetuses that were available for evaluation.

The results from the two-generation reproduction toxicity study in rats with imazapic technical support a NOAEL for parental toxicity of 20,000 ppm (or approximately 1,344 mg/kg bwt/day, calculated from food consumption data), the highest concentration tested. The NOAEL for growth and development of the offspring is also 20,000 ppm, or 1,344 mg/kg bwt/day. Results from the reproduction study and the developmental toxicity studies conducted with imazapic technical show no increased sensitivity to developing offspring as compared to parental animals, because the NOAELs for growth and development of offspring were equal to or greater than the NOAELs for parental toxicity.

4. Subchronic toxicity. A short-term (21-day) dermal toxicity study in rabbits was conducted with imazapic technical. No dermal irritation or abnormal clinical signs were observed at dose levels up to and including 1,000 mg/kg bwt/day (highest dose tested), supporting a NOAEL for dermal irritation and systemic toxicity of 1,000 mg/kg bwt/day. In a subchronic (13-week) dietary toxicity study in rats with imazapic technical, no signs of systemic toxicity were noted, supporting a NOAEL of 20,000 ppm (or approximately 1,625 mg/kg bwt/day, calculated from food consumption data), the highest concentration tested. The requirement for a subchronic dietary toxicity study in non-rodents is satisfied by the one-year dietary toxicity study in dogs.

5. Chronic toxicity. A one-year dietary toxicity study was conducted with imazapic technical in Beagle dogs at dietary concentrations of 0, 5,000, 20,000, and 40,000 ppm. In this study, the NOAEL for systemic toxicity was less than 5,000 ppm or approximately 158 mg/kg bwt/day (137 mg/kg bwt/day for males and 180 mg/kg bwt/day for females), calculated from food consumption data, based on a slight skeletal myopathy, characterized by degeneration/necrosis of single fibers (minimal severity) and lymphocyte/macrophage infiltration in skeletal muscle, in males and females, and slightly decreased serum creatinine in females at 5,000 ppm (lowest concentration tested).

The skeletal myopathy observed at 5,000 ppm was considered of minimal toxicological significance because the limited presence and the minimal severity of skeletal myopathy was evident in only a few fibers out of hundreds evaluated per section per animal. Further, these focal myopathies of minimal severity were not consistently diagnosed in all skeletal muscles sites examined per dog (i.e., vastus and abdominal muscles, diaphragm and esophagus). Moreover, no clinical observations indicative of muscle dysfunction were noted in any animal in the study. Finally, although the skeletal myopathy noted at 40,000 ppm (highest concentration tested) was associated with increases in creatine kinase, aspartate aminotransferase and lactate dehydrogenase, no statistically or biologically significant increases in these serum enzymes were noted during the study period for animals in the 5,000 ppm group. As such, the minimal myopathy diagnosed microscopically at 5,000 ppm was not considered to impair or adversely affect the functional capacity of the affected skeletal muscles.

In a 2-year chronic dietary oncogenicity and toxicity study in rats conducted with imazapic technical, the NOAEL for oncogenicity and chronic systemic toxicity was 20,000 ppm (approximately 1,133 mg/kg bwt/day, calculated from food consumption data), the highest concentration tested. An 18-month chronic dietary oncogenicity and toxicity study in mice with imazapic technical supports a NOAEL for oncogenicity and for chronic systemic toxicity of 7,000 ppm (or approximately 1,288 mg/kg bwt/day, calculated from food consumption data), the highest concentration tested.

The EPA has classified imazapic as a group E carcinogen (evidence of non-carcinogenicity for humans) based on the absence of treatment-related tumors in acceptable carcinogenicity studies in both rats and mice.

6. Animal metabolism. The rat and goat metabolism studies indicate that the qualitative nature of the residues of imazapic in animals is adequately understood. In the rat metabolism study conducted with radio labeled AC 263222 (imazapic technical) no detectable radioactivity was excreted via expired air. In both the rat and goat metabolism studies, urinary excretion was the primary elimination route with 95% and 81.7% of the radioactivity, respectively, excreted in the urine. The major component in the urine from both studies was the unchanged parent compound.

There was no significant bioaccumulation of radioactivity in the tissues from the rat metabolism study. In the goat metabolism study, blood and tissue samples taken following sacrifice at approximately 23 hours after the last dose contained less than 0.01% of the administered radioactivity, and the entire milk sample contained less than 0.03% of the administered radioactivity. As with the residues in other samples from the rat and goat metabolism studies, the major residue in the goat tissue and milk samples was parent compound. A hen metabolism study is not required, because grasses from pasture or rangelands are not used as significant feedstuff for poultry according to the EPA residue chemistry test guidelines.

7. Metabolite toxicology. Metabolism studies in grass and peanuts indicate that the only significant metabolite is the hydroxymethyl metabolite of imazapic, both free and glucose conjugated. The hydroxymethyl metabolite has also been identified in minor quantities in the rat metabolism study and in a previously submitted goat metabolism study. No additional toxicologically significant metabolites were detected in any of the plant or animal metabolism studies.

8. Endocrine disruption. Collective organ weight data and histopathological findings from the two-generation rat reproductive study, as well as from the subchronic and chronic toxicity studies in three different animal species, demonstrate no apparent estrogenic effects or treatment-related effects of imazapic on the endocrine system.

C. Aggregate Exposure

1. Dietary exposure. The potential dietary exposure to imazapic has been calculated from the proposed tolerances for use on grasses and from the previously established tolerance for peanuts. These very conservative chronic dietary exposure estimates used the tolerance value for peanuts and the proposed tolerance values for meat and milk. In addition, these estimates assume that 100% of the peanut crop and all meat and milk contain imazapic residues.

i. Food. Using the assumptions discussed above, the theoretical maximum residue concentration (TMRC) values of imazapic were calculated for the U.S. general population and subgroups. Based on the peanut tolerance and the proposed tolerances for meat and milk, the TMRC values for each group are 0.000778 mg/kg bwt/day for the general U.S. population; 0.001257 mg/kg bwt/day for all infants; 0.001524 mg/kg bwt/day for non-nursing infants; 0.002878 mg/kg bwt/day for children 1 to 6 years of age, and 0.001430 mg/kg bwt/day for children 7 to 12 years of age. Potential exposure to residues of imazapic in food will be restricted to intake of peanuts, peanut butter, peanut oil, meat, meat byproducts, and milk.

ii. Drinking water. As a screening-level assessment for aggregate exposure, the U.S. EPA evaluates a drinking water level of comparison (DWLOC), which is the maximum concentration of a chemical in drinking water that would be acceptable in light of total aggregate exposure to that chemical. Based on the chronic reference dose (RfD) of 0.5 mg/kg bwt/day and the EPA's default factors for body weight and drinking water consumption, the DWLOCs have been calculated to assess the potential dietary exposure from residues of imazapic in water. For the adult population, the chronic DWLOC was 17,473 and for children the DWLOC was estimated to be 4,971 parts per billion (ppb).

Chronic drinking water exposure analyses were calculated using EPA models for Screening Concentration in Groundwater (SCI-GROW) for ground water and Generic Expected Environmental Concentration (GENEEC) for surface water. The calculated peak GENEEC value is 5.58 ppb and the SCI-GROW value is 0.56 ppb. For the U.S. adult population, the estimated exposures of imazapic residues in surface water and ground water are approximately 0.03% and 0.003%, respectively, of the DWLOC. The estimated exposures of children to imazapic residues in surface water and ground water are approximately 0.1% and 0.01%, respectively, of the DWLOC. Therefore, the exposures to drinking water from imazapic use are negligible.

2. Non-dietary exposure. Imazapic products are not currently registered or requested to be registered for residential or urban use; therefore, the estimate of residential exposure is not relevant to this tolerance petition.

D. Cumulative Effects

Imazapic is a member of the imidazolinone class of herbicides. Other compounds of this class are registered for use in the U.S. However, the herbicidal activity of the imidazolinones is due to the inhibition of acetohydroxy acid synthase (AHAS), an enzyme only found in plants. AHAS is part of the biosynthetic pathway leading to the formation of branched chain amino acids. Animals lack AHAS and this biosynthetic pathway. This lack of AHAS contributes to the low toxicity of the imidazolinone compounds in animals. We are aware of no information to indicate or suggest that imazapic has any toxic effects on mammals that would be cumulative with those of any other chemical. Therefore, for the purposes of this tolerance petition no assumption has been made with regard to cumulative exposure with other compounds having a common mode of action.

E. Safety Determination

1. U.S. population. The RfD represents the level at or below which daily aggregate exposure over a lifetime will not pose appreciable risks to human health. Results from the 1-year chronic dietary toxicity study in dogs supports the lowest observed effect level (LOAEL) of 5,000 ppm, equivalent to approximately 137 mg/kg bwt/day for males. The EPA applied an uncertainty or safety factor of 300 to the LOAEL based on a safety factor of 100 to account for interspecies extrapolation and intraspecies variability, and an additional factor of 3 to account for the lack of a NOAEL in the chronic dog study. Applying a safety factor of 300 to this LOAEL of 137 mg/kg bwt/day results in the RfD of 0.50 mg/kg bwt/day. The chronic dietary exposure of 0.00078 mg/kg bwt/day for the general U.S. population will utilize only 0.2% of the RfD of 0.5 mg/kg bwt/day. EPA generally has no concern for exposures below 100% of the RfD. Due to the low toxicity of imazapic, an acute exposure dietary risk assessment is not warranted. The complete and reliable toxicity data base, the low toxicity of the molecule, and the conservative chronic dietary exposure assumptions support the conclusion that there is a “reasonable certainty of no harm” from the proposed use of imazapic on grasses and the currently registered crop, peanuts.

2. Infants and children. The conservative dietary exposure estimates previously presented will utilize 0.3% of the RfD for all infants, for the non-nursing infant group, and for children ages 7 to 12. The chronic dietary exposures for children 1 to 6 years of age, the most highly exposed subgroup, will utilize only 0.6% of the RfD. Results from the two-generation reproduction study in rats and the developmental toxicity studies in rabbits and rats indicate no increased sensitivity to developing offspring when compared to parental toxicity. These results also indicate that imazapic is neither a developmental toxicant nor a teratogen in either the rat or rabbit. Therefore, an additional safety factor is not warranted, and the RfD of 0.5 mg/kg bwt/day, which utilizes a 300-fold safety factor is appropriate to ensure a reasonable certainty of no harm to infants and children.

F. International Tolerances

There are no Codex maximum residue levels established or proposed for residues of imazapic from use on grasses.