Pesticides; tolerances in food, animal feeds, and raw agricultural commodities: Diphenylamine,

[Federal Register: December 6, 2006 (Volume 71, Number 234)]

[Proposed Rules]

[Page 70703-70709]

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

[DOCID:fr06de06-19]

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2006-0731; FRL-8104-1]

Diphenylamine; Proposed Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

SUMMARY: This document proposes to establish a tolerance for residues of diphenylamine in or on pear under the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act of 1996 (FQPA).

DATES: Comments must be received on or before February 5, 2007.

ADDRESSES: Submit your comments, identified by docket identification (ID) number EPA-HQ-OPP-2006-0731, 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 Building), 2777 S. Crystal Drive, Arlington, VA. Deliveries are only accepted during the Docket'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 telephone number is (703) 305-5805.

Instructions: Direct your comments to docket ID number EPA-HQ-OPP- 2006-0731. EPA's policy is that all comments received will be included in the docket without change and may be made available on-line at http://www.regulations.gov, including any personal information

provided, unless the comment includes information claimed to be Confidential Business Information (CBI) or other information whose disclosure is restricted by statute. Do not submit information that you consider to be CBI or otherwise protected through regulations.gov or e- mail. The Federal regulations.gov website is an ``anonymous access'' system, which means EPA will not know your identity or contact information unless you provide it in the body of your comment. If you send an e-mail comment directly to EPA without going through regulations.gov, your e-mail address will be automatically captured and included as part of the comment that is placed in the docket and made available on the Internet. If you submit an electronic comment, EPA recommends that you include your name and other contact information in the body of your comment and with any disk or CD-ROM you submit. If EPA cannot read your comment due to technical difficulties and cannot contact you for clarification, EPA may not be able to consider your comment. Electronic files should avoid the use of special characters, any form of encryption, and be free of any defects or viruses.

Docket: All documents in the docket are listed in the docket index. Although listed in the index, some information is not publicly available, e.g., 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 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 Building), 2777 S. Crystal Drive, Arlington, VA. The hours of operation of this Docket Facility are 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: Shaja R. Brothers, Registration Division (7505P), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave, NW., Washington, DC 20460- 0001; telephone number: (703) 308-3194; e-mail address: brothers.shaja@epa.gov.

[[Page 70704]]

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 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 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. To determine whether you or your business may be affected by this action, you should carefully examine the applicability provisions. 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. What Should I Consider as I Prepare My Comments for EPA?

      1. Submitting CBI. Do not submit this information to EPA through http://www.regulations.gov or e-mail. Clearly mark the part or all of the

         information that you claim to be CBI. For CBI information in a disk or CD ROM that you mail to EPA, mark the outside of the disk or CD ROM as CBI and then identify electronically within the disk or CD ROM the specific information that is claimed as CBI. In addition to one complete version of the comment that includes 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 docket. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2.

      2. Tips for preparing your comments. When submitting comments, remember to:

         i. Identify the document by docket ID number and other identifying information (subject heading, Federal Register date and page number).

         ii. Follow directions. The Agency may ask you to respond to specific questions or organize comments by referencing a Code of Federal Regulations (CFR) part or section number.

         iii. Explain why you agree or disagree; suggest alternatives and substitute language for your requested changes.

         iv. Describe any assumptions and provide any technical information and/or data that you used.

         v. If you estimate potential costs or burdens, explain how you arrived at your estimate in sufficient detail to allow for it to be reproduced.

         vi. Provide specific examples to illustrate your concerns and suggest alternatives.

         vii. Explain your views as clearly as possible, avoiding the use of profanity or personal threats.

         viii. Make sure to submit your comments by the comment period deadline identified.

2. Background and Statutory Findings

   EPA on its own initiative, under section 408(e) of the FFDCA, 21 U.S.C. 346a(e), is proposing to establish a tolerance for residues of the fungicide, diphenylamine in or on pear at 5.0 parts per million (ppm). The Interregional Research Project Number 4 (IR-4) submitted a petition (PP 0E6107) for this use. However, neither IR-4 nor Atomchem North American Incorporated, the registrant, submitted all required elements of a petition in support of establishing a tolerance. Because the petition was incomplete, EPA did not publish a Notice of Filing for the petition.

   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) of the 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 the 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 the 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, consistent with section 408(b)(2) of the FFDCA, for a tolerance for residues of diphenylamine on pear at 5.0 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. The nature of the toxic effects caused by diphenylamine is discussed in Table 1 of this unit as well as the no-observed-adverse- effect-level (NOAEL) and the lowest-observed-adverse-effect-level (LOAEL) from the toxicity studies reviewed.

      [[Page 70705]]

      Table 1.--Subchronic, Chronic, and Other Toxicity

      Guideline No.

      Study Type

      Results

      870.3100

      90-Day oral toxicity

      NOAEL = 75 mg/kg/day rodents

      LOAEL = 375 mg/kg/day based on decreased body weight and body weight gain, dark urine, increased absolute spleen and liver weights, congestion in spleen, kidney, and liver, discoloration and alterations in hematological and clinical chemistry parameters.

      870.3100

      90-Day oral toxicity

      NOAEL = 2 mg/kg/day rodents

      M/F LOAEL = 94/107 mg/kg/day based on liver/ spleen alterations (extramedullary hematopoiesis in the liver, discoloration and hemosiderosis of the liver, congestion and extramedullary hematopoiesis in the spleen).

      870.3150

      90-Day oral toxicity non- M/F NOAEL = 50 mg/kg/day rodents

      LOAEL (mg/kg/day) not determined

      870.3200

      21/28-Day dermal toxicity NOAEL = 500 mg/kg/day LOAEL = 1,000 mg/kg/day based on effects in the stomach (dark foci-red foci in both sexes-6/10). Dermal: NOAEL = 1,000 mg/kg/day; LOAEL (mg/kg/day): Not determined.

      870.3700

      Prenatal developmental in Maternal NOAEL = 50 mg/kg/day rodents

      Maternal LOAEL = 100 mg/kg/daybased on decreased spleen weights and discoloration of the spleen Developmental NOAEL = 100 mg/kg/day Developmental LOAEL (mg/kg/day): Not determined

      870.3700

      Prenatal developmental in Maternal NOAEL = 100 mg/kg/day nonrodents

      Maternal LOAEL = 300 mg/kg/daybased on deceased body weight gains andfood consumption Developmental NOAEL = 300 mg/kg/day Developmental LOAEL (mg/kg/day): Not determined

      870.3800

      Reproduction and fertility Parental/Systemic NOAEL (mg/kg/day): Not effects

      determined. Parental/Systemic M/F LOAEL = 40/46 mg/kg/ day based on gross pathological findings in the spleen and microscopic findings in the kidney, liver, and spleen. Reproductive M/F NOAEL = 115/131 mg/kg/day. Reproductive M/F LOAEL = 399/448 mg/kg/day based on decreased litter size in both generations. Offspring M/F NOAEL = 40/46 mg/kg/day. Offspring M/F LOAEL = 115/131 mg/kg/day based on decreased body weight of F2 pups in late lactation.

      870.4100

      Chronic toxicity dogs NOAEL = 10 mg/kg/day LOAEL = 50 mg/kg/day based on alterations in clinical chemistry parameters (increased BUN, cholesterol, total bilirubin) and increased absolute/relative kidney, liver and spleen weights.

      870.4200

      Carcinogenicity rats

      NOAEL (mg/kg/day): Not determined. M/F LOAEL = 73/91 mg/kg/day based on histopathological lesions in the spleen. No evidence of carcinogenicity.

      870.4300

      Carcinogenicity mice

      M/F NOAEL = 29/25 mg/kg/day. M/F LOAEL = 147/138 mg/kg/day based on reduced body weight and body weight gains, changes in hematological parameters, spleen and kidney lesions and increased clinical signs of toxicity. No evidence of carcinogenicity

      870.5100

      Gene mutation

      Negative

      870.5300

      Cytogenetics

      Weakly mutagenic in the presence of metabolic activation

      870.5395

      Other effects

      Negative

      [[Page 70706]]

      870.7485

      Metabolism and

      Terminal distribution data showed no pharmacokinetics

      significant residual activity in tissues 168 hours post-dose for both the low and high oral dose groups: Urine was the major route for excretion. Recovery after 168 hours: Single/repeated low dose = urine 68-81% (both sexes) single high dose = 73-74% Male rats excreted a greater percentage of diphenylamine derived activity at the low dose, while female rats showed greater excretion in feces at this dose. At the high dose, the percentage eliminated in urine was equivalent in both males and females. Metabolites-urine: Dihydroxylated conjugates of diphenylamine, mono- hydroxylated sulfate conjugates of diphenylamine, monohydroxylated glucuronide conjugates of diphenylamine. Metabolites-feces: Parent chemical and 4- hydroxydiphenylamine, which comprised 0.5- 3% administered dose in both sexes.

   2. 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 intra species 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 (SF).

      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 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 diphenylamine used for human risk assessment is shown in Table 2 of this unit:

      Table 2.--Summary of Toxicological Dose and Endpoints for Diphenylamine 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

      Acute Dietary (Females 13-50 years of N/A

      N/A

      An acute reference dose age)

      for females aged 13-50 has not been established. Developmental toxicity studies in rats and rabbits and a 2- generation reproduction study in rats did not demonstrate evidence of toxicity attributable to a single dose.

      Acute Dietary (General population N/A

      N/A

      An endpoint including infants and children)

      attributable to a single dose was not identified from the available database.

      Chronic Dietary (All populations) NOAEL = 10 mg/kg/day FQPA SF = 1X

      Chronic Toxicity - Dog UF = 100 Chronic RfD = cPAD = chronic RfD/FQPA LOAEL = 50 mg/kg/day 0.1 mg/kg/day.

      SF = 0.1 mg/kg/day. based on alterations in clinical chemistry parameters (increased BUN, cholesterol, total bilirubin) and increased absolute/ relative kidney, liver, and spleen weights.

      [[Page 70707]]

      Short-Term Dermal (1 to 30 days) Dermal (or oral) study LOC for MOE = 100

      21-Day Dermal - Rabbit (Residential)........................ NOAEL= 500 mg/kg/day... (Residential).......... LOAEL = 1,000 mg/kg/day based on effects in the stomach (dark red foci in both sexes).

      Intermediate-Term Dermal (1 week to Dermal (or oral) study LOC for MOE = 100

      21-Day Dermal- Rabbit several months)

      NOAEL = 500 mg/kg/day (Residential).......... LOAEL = 1,000 mg/kg/day (Residential)........................

      based on effects in the stomach (dark red foci in both sexes).

      Short-Term Inhalation (1 to 30 days) Inhalation (or oral) LOC for MOE = 100

      Developmental Toxicity (Residential)........................ study

      (Residential).......... Rat NOAEL = 50 mg/kg/day

      LOAEL = 100 mg/kg/day (inhalation absorption

      based on increased rate = 100%).

      spleen weights and discoloration of the spleen.

      Intermediate-Term Inhalation (1 week Inhalation (or oral) LOC for MOE = 100

      Developmental Toxicity to several months)

      study

      (Residential).......... Rat (Residential)........................ NOAEL = 50 mg/kg/day

      LOAEL = 100 mg/kg/day (inhalation absorption

      based on increased rate = 100%).

      spleen weights and discoloration of the spleen.

      Cancer (oral, dermal, inhalation) N/A

      N/A

      Classification: This chemical is ``not likely'' to be a human carcinogen.

   3. Exposure Assessment

      1. Dietary exposure from food and feed uses. The residue of concern in plants and livestock for the tolerance enforcement and risk assessment is parent diphenylamine. Tolerances are established in 40 CFR 180.190(a) for diphenylamine residues in/on apple at 10 ppm and apple, wet pomace at 30 ppm. Diphenylamine (EC or SC/L) is applied to apples (pre- or post-harvest) as a spray, dip or drench application. Additionally, tolerances are established at 0.01 ppm in milk, meat, fat, and meat byproducts (except liver) of cattle, goat, horse, and sheep, and at 0.1 ppm in liver of these animals. Risk assessments were conducted by EPA to assess dietary exposures from diphenylamine in food as follows:

         i. Acute exposure. There were no toxic effects attributable to a single dose. An endpoint of concern was not identified to quantitate an acute-dietary risk to the U.S. general population or to the subpopulation females 13-50 years old. Therefore, an acute aggregate exposure assessment was not performed.

         ii. Chronic exposure.In conducting this chronic dietary risk assessment the Dietary Exposure Evaluation Model (DEEM\TM\) analysis evaluated the individual food consumption as reported by respondents in the USDA 1994-1996 and 1998 Nationwide Continuing Surveys of Food Intake by Individuals (CSFII) and accumulated exposure to the chemical for each commodity. The following assumptions were made for the chronic exposure assessments: The chronic dietary exposure analysis was based on tolerance level residues, DEEM (Version 7.81) default processing factors, an empirical processing factor for apple juice, and 100% crop treated assumptions.

         iii. Cancer. Diphenylamine was classified as ``not likely to be a human carcinogen;'' therefore, a cancer dietary exposure analysis was not performed.

      2. Dietary exposure from drinking water. Diphenylamine uses are post-harvest; therefore, residues in drinking water are not relevant to this risk assessment.

      3. Dietary exposure from non-dietary exposure. Diphenylamine is not registered for use on any sites that would result in residential exposure. Therefore a residential exposure risk assessment was not performed.

      4. Cumulative effects from substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of the 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.''

         Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to diphenylamine and any other substances and diphenylamine does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that diphenylamine has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/ .

   4. Safety Factor for Infants and Children

      1. In general. Section 408 of the FFDCA provides that EPA shall apply an additional tenfold 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 data base on toxicity and exposure unless EPA determines that a different margin of safety will be safe for infants and children. Margins of safety are incorporated into EPA risk assessments either directly through use of a MOE analysis or through using uncertainty (safety) factors in calculating a dose level that poses no appreciable risk to humans.

      2. Prenatal and postnatal sensitivity. There is no indication of increased sensitivity of rats or rabbits to in utero and postnatal exposure to diphenylamine. In prenatal

         [[Page 70708]]

         developmental toxicity studies in rats and rabbits, no evidence of developmental toxicity was observed. In a 2-generation reproduction study, offspring toxicity (decreased body weight) was seen only in the presence of maternal toxicity.

      3. Conclusion. EPA recommended the FQPA safety factor be reduced to 1X for the following reasons:

         i. There is a complete toxicity data base for diphenylamine;

         ii. The toxicity database showed no increase in susceptibility in fetuses and pups with in utero and postnatal exposure, and

         iii. The dietary food exposure assessment is based on recommended tolerance-level residues (except those processed commodities for which processing factors were used) and assumes 100% crop treated for all commodities, which resulted in very high-end estimates of dietary exposure.

   5. Aggregate Risks and Determination of Safety

      1. Acute risk. There were no toxic effects attributable to a single dose. An endpoint of concern was not identified to quantitate an acute- dietary risk to the U.S. general population or to the subpopulation females 13-50 years old. Therefore, diphenylamine is not expected to pose an acute risk.

      2. Chronic risk. Using the exposure assumptions described in this unit for chronic exposure, EPA has concluded that exposure to diphenylamine from food will utilize 12% of the cPAD for the U.S. population, 69% of the cPAD for all infants