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

[Federal Register: September 24, 2004 (Volume 69, Number 185)]

[Rules and Regulations]

[Page 57197-57207]

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

[DOCID:fr24se04-12]

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[OPP-2004-0315; FRL-7680-1]

Dimethenamid; Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

SUMMARY: This regulation establishes a tolerance for residues of dimethenamid in or on onions (dry bulb), garlic, shallots (dry bulb), tuberous and corm vegetables, sugar beets, garden beets, and horseradish. Interregional Research Project No. 4 (IR-4) requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act of 1996 (FQPA). In addition, this regulatory action is part of the tolerance reassessment requirements of section 408(q) of the FFDCA 21 U.S.C. 346a(q), as amended by the FQPA of 1996. By law, EPA is required to reassess all tolerances in existence on August 2, 1996 by August 2006. This regulatory action will count for thirteen reassessments towards this August 2006 deadline.

DATES: This regulation is effective September 24, 2004. Objections and requests for hearings must be received on or before November 23, 2004.

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 OPP-2004-0315. All documents in the docket are listed in the EDOCKET index at http://www.epa.gov/edocket. Although

listed in the index, some information is not publicly available, i.e., 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 South 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: Jim Tompkins, Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,Washington, DC 20460-0001; telephone number: (703) 305-5697; e-mail address: tompkins.jim@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), e.g., agricultural workers; greenhouse, nursery, and floriculture workers; farmers.

      Animal production (NAICS 112), e.g., cattle ranchers and farmers, dairy cattle farmers, livestock farmers.

      Food manufacturing (NAICS 311), e.g., agricultural workers; farmers; greenhouse, nursery, and floriculture workers; ranchers; pesticide applicators.

      Pesticide manufacturing (NAICS 32532), e.g., agricultural workers; commercial applicators; farmers; greenhouse, nursery, and floriculture workers; residential users.

      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.

      [[Page 57198]]

   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 March 12, 2003 (68 FR11850) (FRL-7295- 9), EPA issued a notice pursuant to section 408(d)(3) of the FFDCA, 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide petition (PP 0E6196) by Interregional Research Project No. 4 (IR-4), Technology Centre of New Jersey, Rutgers, the State University of New Jersey, 681 U.S. Highway 1 South, North Brunswick, NJ 08902-3390. The petition requested that 40 CFR 180.464 be amended by establishing a tolerance for residues of the herbicide dimethenamid, (R,S)-2-chloro-N-

   [(1-methyl-2-methoxy) ethyl] -N-(2,4-dimethyl-thien-3-yl)-acetamide, in or on onions (dry bulb), garlic, shallots (dry bulb), tuberous and corm vegetables, sugar beets, garden beets, and horseradish at 0.01 parts per million (ppm). That notice included a summary of the petition prepared by IR-4, the registrant. There were no comments received in response to the notice of filing.

   Dimethenamid was originally registered as a mixture of R and S- isomers (50:50, S:R), and tolerances for the 50:50 mixture were established for dry beans, field corn, sweet corn, peanuts, sorghum, and soybean. Manufacture of the 50:50 mixture has ceased and has been replaced by a mixture (dimethenamid-P) that is enriched in the biologically active S-isomer (90:10, S:R). Registration of the original 50:50 mixture will be cancelled when existing stock is depleted. Currently, both dimethenamid (50:50, S:R) and dimethenamid-P (90:10, S:R) are used. The petition sought to have tolerances established on a non-isomer specific bases. The existing toxicological and residue chemistry databases are established primarily on studies conducted with the 50:50 mixture. To address the uncertainty concerning qualitative or quantitative toxicological difference(s) between the original 50:50 mixture and the enriched 90:10 mixture, EPA reviewed several toxicological studies conducted using both products. EPA concluded that the dimethenamid toxicology database is adequate for the risk assessment of both dimethenamid and dimethenamid-P. Therefore, 40 CFR 180.464 is being revised to include tolerances for residues resulting from application of both dimethenamid (50:50, S:R) and dimethenamid-P (90:10, S:R).

   In addition, existing tolerances for dimethenamid were reassessed as part of the tolerance reassessment requirements of section 408(q) of the FFDCA 21 U.S.C. 346a(q), as amended by the FQPA of 1996. By law, EPA is required to reassess all tolerances in existence on August 2, 1996 by August 2006.

   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 FFDCA 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).

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 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 residues of dimethenamid on onions (dry bulb), garlic, shallots (dry bulb), tuberous and corm vegetables, sugar beets, garden beets, and horseradish at 0.01 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 dimethenamid are 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.

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

      Guideline No.

      Study Type

      Results

      870.1100

      Acute oral/rats [Sprague LD50 = 429 mg/kg for males LD50 = 531 mg/kg Dawley] dimethenamid-P for females (90:10 S:R isomers)

      LD50 = 480 mg/kg for both sexes Toxicity category II

      870.1100

      Acute oral/rats [Sprague LD50 = 500 mg/kg. The mean for both sexes Dawley] dimethenamid Toxicity category II (50:50 S:R isomers)

      [[Page 57199]]

      870.1200

      Acute dermal/rabbits

      LD50 = > 2,000 mg/kg dimethenamid-P (90:10 S:R Toxicity category III isomers)

      870.1200

      Acute dermal/rabbits

      LD50 = > 2,000 mg/kg dimethenamid (50:50 S:R Toxicity category III isomers)

      870.1300

      Acute inhalation [Sprague LC50 = 2.2 mg/L Dawley] dimethenamid-P Toxicity category III (90:10 S:R isomers)

      870.1300

      Acute inhalation/rats LC50 = 4.99 mg/L [Wistar] dimethenamid Toxicity category III (50:50 S:R isomers)

      870.2400

      Acute eye irritation

      Minimally irritating rabbits dimethenamid-P Toxicity category III (90:10 S:R isomers)

      870.2400

      Acute eye irritation/ Minimally irritating rabbits dimethenamid Toxicity category III (50:50 S:R isomers)

      870.2500

      Acute dermal irritation Minimally irritating rabbits dimethenamid-P Toxicity category IV (90:10 S:R isomers)

      870.2500

      Acute dermal irritation/ Minimally irritating rabbits dimethenamid Toxicity category IV (50:50 S:R isomers)

      870.2600

      Skin sensitization [Guinea Mild skin senstizer Pigs] dimethenamid-P (90:10 S:R isomers)

      870.2600

      Skin sensitization [Guinea Mild skin senstizer Pigs] dimethenamid (50:50 S:R isomers)

      870.3100

      Subchronic Feeding/Sprague NOAEL= 37/40(M/F) mg/kg/day [500 ppm] Dawley Rat dimethenamid-P LOAEL= 110/125 (M/F) mg/kg/day [1,500 ppm] (90:10 S:R isomers)

      based on decreased body weight (bwt) and bwt gain in males and females, increased gamma-glutamyl transferase in both sexes, increased cholesterol in males, increased absolute and relative liver weight and periportal hepatocytic hypertrophy and periportal eosinophilic inclusions in males, centrilobular hypertrophy in females and liver necrosis in females

      870.3100

      Subchronic Feeding/Sprague NOAEL= 33.5/40.1 (M/F) mg/kg/day [500 ppm] Dawley rat dimethenamid LOAEL= 98/119 (m/f) mg/kg/day [1,500 ppm] (50:50 S:R isomers)

      based on decreased bwt and bwt gain, increased total protein in males; in females, increased cholesterol, increased liver weight and centrilobular hepatocytic enlargement

      870.3150

      Subchronic oral toxicity NOAEL = 4.72/4.98 (M/F) mg/kg/day [100 ppm (dog) dimethenamid (50:50 ] S:R isomers)

      LOAEL = 33.6/39.7 (M/F) mg/kg/day [750 ppm] based on decreased bwt and bwt gain in females, increased relative liver weight in both sexes, increased periportal vacuolation in both sexes and dilation of liver sinusoids in females

      870.3200

      21/28-Day dermal toxicity NOAEL = 50 mg/kg/day (rabbit) dimethenamid LOAEL = 150 mg/kg/day based on decreased (50:50 S:R isomers)

      blood phosphate in both sexes [15% at 150mg/kg/day and 15% at 500 mg/kg/day] [p 44123502. S. dimethenamid-P (90:10 S:R typhimurium TA100 was exposed to 100-5,000 isomers)

      [mu]g/plate +/- S9 Assay was negative

      870.5100

      Bacterial Reverse mutation Exposed to 100-5,000 [mu]g/plate, +/- S9, dimethenamid-P (90:10 S:R in a plate incorporation assay. isomers)

      Insolubility seen at 333 and 5,000 [mu]g/ plate, but no toxicity at any dose +/- S9 Assays were negative with both bacteria + S9, however, - S9 induced 1.5 fold increases at 333 [mu]g/plate and 4.1 fold increases in reverents in TA100 strain at 5000 [mu]g/plate. This mutagenic response was reproducible at 100 to 5,000 [mu]g/ plate

      870.5100

      Bacterial Reverse mutation Strains tested at 1000-10,000 [mu]g/plate, dimethenamid-P (90:10 S:R S9 and 1,000-6,500 [mu]g/plate, + S9. isomers)

      Cytotoxicity and precipitation were noted at higher doses Test was negative, +/- S9

      870.5300

      Mammalian cell mutation Chinese hamster ovary (CHO) cells were dimethenamid-P (90:10 S:R exposed to 100-400 [mu]g/mL, - S9, and 100- isomers)

      450 [mu]g/mL, + S9. Slight cytotoxicity was seen at the highest dose and severe toxicity was seen at >= 500 [mu]g/mL Test was negative for mutagenic effects, +/- S9

      870.5395

      Mouse erythrocyte

      CD-1 mice dosed at 710 mg/kg in two daily micronucleus test

      doses. LD50 = 1,417 mg/kg. Bone marrow dimethenamid (50:50 S:R erythrocytes harvested 24 and 48 hours isomers)

      later Test negative

      870.5395

      Mouse erythrocyte

      Mice dosed 0-1,000 mg/kg in single doses. micronucleus test

      Mice showed no toxicity; only one mouse dimethenamid (50:50 S:R died isomers)

      Test negative

      870.5375

      Chromosomal aberration Cells in 125-150 [mu]g/mL, - S9 and 400 to test dimethenamid (50:50 500 [mu]g/mL, + S9; all doses were S:R isomers)

      cytotoxic. Study needs repeating at none cytotoxic doses. Test considered equivocally positive

      870.5550

      Unscheduled DNA

      Cell in 1.0-100 nl/mL. No cytotoxicity was (deoxyribonucleic acid) seen Synthesis (UDS) in rat Test was negative hepatocytes dimethenamid (50:50 S:R isomers)

      870.5550

      UDS in rat hepatocytes Fisher 344 rat administered SAN 582H doses dimethenamid (50:50 S:R of 158 or 500 mg/kg. Sampled 2-4 and 12-14 isomers)

      hours after dosing. Only 0.2-3.6% cells in repair, but negative control was less than zero Test was negative for UDS at 158 and 500 mg/ kg

      870.5550

      UDS in rat hepatocytes SAN 582H administered at 0.01 to 50 [mu]g/ dimethenamid (50:50 S:R mL. Unscheduled DNA synthesis was seen isomers)

      well below cytotoxic doses. Unequivocally positive for UDS Test positive

      870.5550

      UDS in rat hepatocytes SAN 582H administered at 0.0128 to 1,000 dimethenamid (50:50 S:R [mu]g/mL to rat primary cultures of isomers)

      hepatocytes. Doses at 1,000 [mu]g/mL were cytotoxic. No UDS was noted Test negative for UDS

      870.5450

      Dominant Lethal

      Male Charles River (CR) rats (40-55) dimethenamid (50:50 S:R administered SAN 582H in single oral doses isomers)

      of 275, 550, or 1,100 mg/kg were mated starting at 10 weeks to 40-55 female undosed CR rats. Increased dead implants at week 1 and week 2 may suggest a dominant lethal effect. These were mostly late implant deaths, which some consultants claim are not characteristic of a dominant lethal effect

      870.5450

      Dominant Lethal

      Male Sprague Dawley rats (40-60) dimethenamid (50:50 S:R administered SAN 582H in single oral doses isomers)

      of 275, 550, or 1,100 mg/kg were mated starting the day after dosing in Trial 1 and 2 days after dosing in Trial 2 to 80- 120 female undosed Sprague Dawley rats . Each male was mated to 2 females over a five day sequence. Results equivocal Note: Both the high dose rabbit and rat developmental studies showed increased late and early resorptions

      [[Page 57202]]

      870.5375

      Cytogenetics in CHO cells CHO cells were exposed to 2-120 [mu]g/mL - dimethenamid-P(90:10 S:R S9; cytotoxic at >= 120 [mu]g/mL. CHO isomers)

      cells were exposed to 15-120 [mu]g/mL + S9; cytotoxic at >= 500 [mu]g/mL Assay was negative +/- S9

      870.5395

      Cytogenetics; mouse

      Mice (5/sex) were exposed to i.p. erythrocyte microncleus injections of 103, 205, 410 mg/kg test dimethenamid-P

      Assay was negative, indicating no (90:10 S:R isomers)

      clastogenic or aneugenic response

      870.5550

      UDS in mammalian cell Cells tested at 7.8-125 [mu]g/mL. culture dimethenamid-P Cytotoxicity and insolubility were seen at (90:10 S:R isomers)

      >= 250 [mu]g/mL Test was negative for UDS

      870.6200

      Acute neurotoxicity

      Not required screening battery dimethenamid-P (90:10 S:R isomers)

      870.6200

      Acute neurotoxicity

      Not required screening battery dimethenamid (50:50 S:R isomers)

      870.6200

      Subchronic neurotoxicity Not required screening battery dimethenamid-P (90:10 S:R isomers)

      870.6300

      Developmental

      Not required neurotoxicity dimethenamid-P (90:10 S:R isomers)

      870.7485

      Metabolism and

      Not required pharmacokinetics (species) dimethenamid-P (90:10 S:R isomers)

      870.7600

      Dermal penetration

      Not required (species) dimethenamid-P (90:10 S:R isomers)

      870.7600

      Dermal penetration

      Not required (species) dimethenamid (50:50 S:R isomers)

   2. Toxicological Endpoint

      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.

      Three other types of safety or uncertainty factors may be used: ``Traditional uncertainty factors;'' the ``special FQPA safety factor;'' and the ``default FQPA safety factor.'' By the term ``traditional uncertainty factor,'' EPA is referring to those additional uncertainty factors used prior to FQPA passage to account for database deficiencies. These traditional uncertainty factors have been incorporated by the FQPA into the additional safety factor for the protection of infants and children. The term ``special FQPA safety factor'' refers to those safety factors that are deemed necessary for the protection of infants and children primarily as a result of the FQPA. The ``default FQPA safety factor'' is the additional 10X safety factor that is mandated by the statute unless it is decided that there are reliable data to choose a different additional factor (potentially a traditional uncertainty factor or a special FQPA safety factor).

      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 an UF of 100 to account for interspecies and intraspecies differences and any traditional uncertainty factors deemed appropriate (RfD = NOAEL/UF). Where a special FQPA safety factor or the default FQPA safety factor is used, 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 safety factor.

      For non-dietary risk assessments (other than cancer) the UF is used to

      [[Page 57203]]

      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). An example of how such a probability risk is expressed would be to describe the risk as one in one hundred thousand (1 X 10-\5\), one in a million (1 X 10-\6\), or one in ten million (1 X 10-\7\). 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 dimethenamid used for human risk assessment is shown in Table 2. of this unit:

      Table 2.--Summary of Toxicological Dose and Endpoints for Dimethenamid for Use in Human Risk Assessment.

      Dose Used in Risk Assessment,

      Special FQPA SF and Exposure Scenario

      Interspecies and Level of Concern for Study and Toxicological Intraspecies and any Risk Assessment

      Effects Traditional UF

      Acute Dietary (Females 13-49 years of NOAEL = 75 mg/kg/day FQPA SF = 1X

      Developmental Toxicity age) Based on [RS] data

      UF = 100............... aPAD = acute RfD / FQPA in rabbits Acute RfD = 0.75 mg/kg/ SF = 0.75 mg/kg/day. Maternal; LOAEL = 150 day.

      mg/kg/day based on abortions and decreased body weight gain and food consumption Developmental; LOAEL = 150 mg/kg/day based on post-implantation loss

      Chronic Dietary (All populations) NOAEL= 5 mg/kg/day FQPA SF = 1X

      Chronic/rats Based on [RS] data

      UF = 100............... cPAD = chronic RfD / LOAEL = M/F; 36/49 mg/ Chronic RfD = 0.05 mg/ FQPA SF = 0.05 mg/kg/ kg/day based on kg/day.

      day.

      decreased body weight and body weight gain in both sexes, increased food conversion ratios in females, and increased microscopic hepatic lesions in both sexes

      Carcinogenicity Based on [RS] data Classified as a Group C N/A

      Chronic risk assessment (possible human

      protective of any carcinogen)

      potential carcinogenic risk

   3. Exposure Assessment

      1. Dietary exposure from food and feed uses. Tolerances have been established (40 CFR 180.464) for the residues of dimethenamid, in or on a variety of raw agricultural commodities. Risk assessments were conducted by EPA to assess dietary exposures from dimethenamid in food as follows:

         i. Acute exposure. Acute dietary risk assessments are performed for a food-use pesticide, if a toxicological study has indicated the possibility of an effect of concern occurring as a result of a one-day or single exposure. In conducting the acute dietary risk assessment EPA used the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID\TM\), which incorporates food consumption data as reported by respondents in the United States Department of Agriculture (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 acute exposure assessments: The residue estimate for each food commodity was the tolerance for that crop (0.01 ppm) and each crop was assessed as if 100% of the crop has been treated with dimethenamid.

         ii. Chronic exposure. In conducting the chronic dietary risk assessment EPA used the DEEM-FCID\TM\, which incorporates food consumption data as reported by respondents in the USDA 1994-1996 and 1998 CSFII, and accumulated exposure to the chemical for each commodity. The following assumptions were made for the chronic exposure assessments: The residue estimate for each food commodity was the tolerance for that crop (0.01 ppm) and each crop was assessed as if 100% of the crop has been treated with dimethenamid.

         iii. Cancer. Dimethenamid (50:50 S:R isomers) was classified as a group ``C'' (possible human carcinogen). The Agency concluded that the chronic risk assessment, making use of the cPAD, to be protective of any potential carcinogenic risk. Dimethenamid is at best a weak carcinogen. An intermediate dose showed marginally significant results (p = 0.056) with liver adenomas one species (rat) and one sex (males). The incidence of liver tumors was just slightly increased from the level in the historical control data. Higher doses did not demonstrate the occurrence of liver adenomas significantly different from the controls. No dose-related tumors were seen in the mouse carcinogenicity study, and a battery of mutagenicity studies with dimethenamid-P (90:10 S:R isomers) were negative or equivocal for genetic mutations including unscheduled DNA synthesis.

      2. Dietary exposure from drinking water. The Agency lacks sufficient monitoring exposure data to complete a comprehensive dietary exposure analysis and risk assessment for dimethenamid in drinking water. Because the Agency does not have comprehensive monitoring data, drinking water concentration estimates are made by reliance on simulation or modeling taking into account data on the physical characteristics of dimethenamid.

         [[Page 57204]]

         The Agency uses the Generic Estimated Environmental Concentration (GENEEC) or the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) to estimate pesticide concentrations in surface water and SCI-GROW, which predicts pesticide concentrations in groundwater. In general, EPA will use GENEEC (a tier 1 model) before using PRZM/EXAMS (a tier 2 model) for a screening-level assessment for surface water. The GENEEC model is a subset of the PRZM/EXAMS model that uses a specific high-end runoff scenario for pesticides. GENEEC incorporates a farm pond scenario, while PRZM/EXAMS incorporate an index reservoir environment in place of the previous pond scenario. The PRZM/EXAMS model includes a percent crop area factor as an adjustment to account for the maximum percent crop coverage within a watershed or drainage basin.

         None of these models include consideration of the impact processing (mixing, dilution, or treatment) of raw water for distribution as drinking water would likely have on the removal of pesticides from the source water. The primary use of these models by the Agency at this stage is to provide a screen for sorting out pesticides for which it is unlikely that drinking water concentrations would exceed human health levels of concern.

         Since the models used are considered to be screening tools in the risk assessment process, the Agency does not use estimated environmental concentrations (EECs), which are the model estimates of a pesticide's concentration in water. EECs derived from these models are used to quantify drinking water exposure and risk as a %RfD or %PAD. Instead drinking water levels of comparison (DWLOCs) are calculated and used as a point of comparison against the model estimates of a pesticide's concentration in water. DWLOCs are theoretical upper limits on a pesticide's concentration in drinking water in light of total aggregate exposure to a pesticide in food, and from residential uses. Since DWLOCs address total aggregate exposure to dimethenamid they are further discussed in the aggregate risk sections in Unit III.E.

         Based on the PRZM/EXAMS and SCI-GROW models, the EECs of dimethenamid for acute exposures are estimated to be 49 parts per billion (ppb) for surface water and 0.42 ppb for groundwater. The EECs for chronic exposures are estimated to be 7.9 ppb (non-cancer exposure) and 5.1 ppb (cancer exposure) for surface water and 0.42 ppb for groundwater.

      3. From non-dietary exposure. The term ``residential exposure'' is used in this document to refer to non-occupational, non-dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets).

         Dimethenamid is not registered for use on any sites that would result in residential exposure.

      4. Cumulative effects from substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider ``available information'' concerning the cumulative effects of a particular pesticide's residues and ``other substances that have a common mechanism of toxicity.''

         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 dimethenamid and any other substances. Dimethenamid 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 dimethenamid 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 (OPP) concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's web site at http://www.epa.gov/pesticides/cumulative/.

   4. Safety Factor for Infants and Children

      1. In general. Section 408 of 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 based on reliable data 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. In applying this provision, EPA either retains the default value of 10X when reliable data do not support the choice of a different factor, or, if reliable data are available, EPA uses a different additional safety factor value based on the use of traditional uncertainty factors and/or special FQPA safety factors, as appropriate.

      2. Prenatal and postnatal sensitivity. No offspring pre- or postnatal susceptibility to either dimethenamid (50:50 S:R isomers) or dimethenamid-P (90:10 S:R isomers) was seen in a rabbit or two rat developmental studies and reproduction study. There is low concern for pre- or postnatal toxicity since the developmental effects from the [S] and [RS] mixture are similar and occur at similar doses.

      3. Conclusion. There is a complete toxicity data base for dimethenamid and exposure data are complete or are estimated based on data that reasonably accounts for potential exposures. EPA determined that the safety factor for dimethenamid should be 100 (10X safety factor for interspecies extrapolation and 10X for intraspecies variation). The additional FQPA SF was removed taking into account the low concerns and lack residual uncertainties with regard to prenatal and postnatal toxicity and the completeness of the toxicity and exposure data base.

   5. Aggregate Risks and Determination of Safety

      To estimate total aggregate exposure to a pesticide from food, drinking water, and residential uses, the Agency calculates DWLOCs which are used as a point of comparison against EECs. DWLOC values are not regulatory standards for drinking water. DWLOCs are theoretical upper limits on a pesticide's concentration in drinking water in light of total aggregate exposure to a pesticide in food and residential uses. In calculating a DWLOC, the Agency determines how much of the acceptable exposure (i.e., the PAD) is available for exposure through drinking water (e.g., allowable chronic water exposure (mg/kg/day) = cPAD - (average food + residential exposure)). This allowable exposure through drinking water is used to calculate a DWLOC.

      A DWLOC will vary depending on the toxic endpoint, drinking water consumption, and body weights. Default body weights and consumption values as used by the EPA's Office of Water are used to calculate DWLOCs: 2 liter (L)/70 kg (adult male), 2L/60 kg (adult female), and 1L/10 kg (child). Default body weights and drinking water consumption values vary on an individual basis. This variation will be taken into account in more refined screening-level and quantitative

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      drinking water exposure assessments. Different populations will have different DWLOCs. Generally, a DWLOC is calculated for each type of risk assessment used: Acute, short-term, intermediate-term, chronic, and cancer.

      When EECs for surface water and ground water are less than the calculated DWLOCs, OPP concludes with reasonable certainty that exposures to the pesticide in drinking water (when considered along with other sources of exposure for which OPP has reliable data) would not result in unacceptable levels of aggregate human health risk at this time. Because OPP considers the aggregate risk resulting from multiple exposure pathways associated with a pesticide's uses, levels of comparison in drinking water may vary as those uses change. If new uses are added in the future, OPP will reassess the potential impacts of residues of the pesticide in drinking water as a part of the aggregate risk assessment process.

      1. Acute risk. The dimethenamid aPAD is 0.75 mg/kg/day (applicable to child bearing females only (females 13-49 years old) (Table 3.). The estimated acute (one day) aggregate exposure of females 13-49 years of age (0.006857 mg/kg/day) utilizes less than 1% of the dimethenamid aPAD. For the other population subgroups, an appropriate acute endpoint attributed to a single dose was not available in the toxicity data base including the developmental toxicity studies.

      Table 3.--Aggregate Risk Assessment for Acute Exposure to Dimethenamid

      Surface Ground Population Subgroup

      aPAD (mg/ % aPAD Water EEC Water EEC Acute DWLOC kg)

      (Food) (ppb)

      (ppb)

      (ppb)

      Females 13-49 yrs

      0.75