Prometryn; Pesticide Tolerances

EPA is proposing under its own initiative that 40 CFR 180.222 be amended by establishing tolerances for residues of the herbicide prometryn, 2,4-bis(isopropylamino)-6-methylthio-s- triazine in or on carrots at 0.1 parts per million (ppm) without a U.S. registration under the Federal Insecticide Fungicide Act (FIFRA), as amended for carrots imported from Canada.

I. Risk Assessment and Statutory Findings

New section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the tolerance is ``safe.'' Section 408(b)(2)(A)(ii) defines ``safe'' to mean that ``there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.'' This includes

exposure through drinking water and in residential settings, but does not include occupational exposure. Section 408(b)(2)(C) requires EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to ``ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue. . . .'' EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. First, EPA determines the toxicity of pesticides based primarily on toxicological studies using laboratory animals. These studies address many adverse health effects, including (but not limited to) reproductive effects, developmental toxicity, toxicity to the nervous system, and carcinogenicity. Second, EPA examines exposure to the pesticide through the diet (e.g., food and drinking water) and through exposures that occur as a result of pesticide use in residential settings.

A. Toxicity

1. Threshold and non-threshold effects. For many animal studies, a dose response relationship can be determined, which provides a dose that causes adverse effects (threshold effects) and doses causing no observed effects (the ``no-observed effect level'' or ``NOEL''). Once a study has been evaluated and the observed effects have been determined to be threshold effects, EPA generally divides the NOEL from the study with the lowest NOEL by an uncertainty factor (usually 100 or more) to determine the Reference Dose (RfD). The RfD is a level at or below which daily aggregate exposure over a lifetime will not pose appreciable risks to human health. An uncertainty factor (sometimes called a ``safety factor'') of 100 is commonly used since it is assumed that people may be up to 10 times more sensitive to pesticides than the test animals, and that one person or subgroup of the population (such as infants and children) could be up to 10 times more sensitive to a pesticide than another. In addition, EPA assesses the potential risks to infants and children based on the weight of the evidence of the toxicology studies and determines whether an additional uncertainty factor is warranted. Thus, an aggregate daily exposure to a pesticide residue at or below the RfD (expressed as 100% or less of the RfD) is generally considered acceptable by EPA. EPA generally uses the RfD to evaluate the chronic risks posed by pesticide exposure. For shorter term risks, EPA calculates a margin of exposure (MOE) by dividing the estimated human exposure into the NOEL from the appropriate animal study. Commonly, EPA finds MOEs lower than 100 to be unacceptable. This 100-fold MOE is based on the same rationale as the 100-fold uncertainty factor. Lifetime feeding studies in two species of laboratory animals are conducted to screen pesticides for cancer effects. When evidence of increased cancer is noted in these studies, the Agency conducts a weight of the evidence review of all relevant toxicological data including short-term and mutagenicity studies and structure activity relationship. Once a pesticide has been classified as a potential human carcinogen, different types of risk assessments (e.g., linear low dose extrapolations or MOE calculation based on the appropriate NOEL) will be carried out based on the nature of the carcinogenic response and the Agency's knowledge of its mode of action. 2. Differences in toxic effect due to exposure duration. The toxicological effects of a pesticide can vary with different exposure durations. EPA considers the entire toxicity data base, and based on the effects seen for different durations and routes of exposure, determines which risk assessments should be done to assure that the public is adequately protected from any pesticide exposure scenario. Both short and long durations of exposure are always considered. Typically, risk assessments include ``acute,'' ``short-term,'' ``intermediate term,'' and ``chronic'' risks. These assessments are defined by the Agency as follows. Acute risk, by the Agency's definition, results from 1-day consumption of food and water, and reflects toxicity which could be expressed following a single oral exposure to the pesticide residues. High end exposure to food and water residues are typically assumed. Short-term risk results from exposure to the pesticide for a period of 1-7 days, and therefore overlaps with the acute risk assessment. Historically, this risk assessment was intended to address primarily dermal and inhalation exposure which could result, for example, from residential pesticide applications. However, since enaction of FQPA, this assessment has been expanded to include both dietary and non- dietary sources of exposure, and will typically consider exposure from food, water, and residential uses when reliable data are available. In this assessment, risks from average food and water exposure, and high- end residential exposure, are aggregated. High-end exposures from all 3 sources are not typically added because of the very low probability of this occurring in most cases, and because the other conservative assumptions built into the assessment assure adequate protection of public health. However, for cases in which high-end exposure can reasonably be expected from multiple sources (e.g. frequent and widespread homeowner use in a specific geographical area), multiple high-end risks will be aggregated and presented as part of the comprehensive risk assessment/characterization. Since the toxicological endpoint considered in this assessment reflects exposure over a period of at least 7 days, an additional degree of conservatism is built into the assessment; i.e., the risk assessment nominally covers 1-7 days exposure, and the toxicological endpoint/NOEL is selected to be adequate for at least 7 days of exposure. (Toxicity results at lower levels when the dosing duration is increased.) Intermediate-term risk results from exposure for 7 days to several months. This assessment is handled in a manner similar to the short- term risk assessment. Chronic risk assessment describes risk which could result from several months to a lifetime of exposure. For this assessment, risks are aggregated considering average exposure from all sources for representative population subgroups including infants and children.

B. Aggregate Exposure

In examining aggregate exposure, FFDCA section 408 requires that EPA take into account available and reliable information concerning exposure from the pesticide residue in the food in question, residues in other foods for which there are tolerances, residues in groundwater or surface water that is consumed as drinking water, and other non- occupational exposures through pesticide use in gardens, lawns, or buildings (residential and other indoor uses). Dietary exposure to residues of a pesticide in a food commodity are estimated by multiplying the average daily consumption of the food forms of that commodity by the tolerance level or the anticipated pesticide residue level. The Theoretical Maximum Residue Contribution (TMRC) is an estimate of the level of residues consumed daily if each food item contained pesticide residues equal to the tolerance. In evaluating food exposures, EPA takes into account varying consumption patterns of major identifiable subgroups of consumers, including infants and

children. The TMRC is a ``worst case'' estimate since it is based on the assumptions that food contains pesticide residues at the tolerance level and that 100% of the crop is treated by pesticides that have established tolerances. If the TMRC exceeds the RfD or poses a lifetime cancer risk that is greater than approximately one in a million, EPA attempts to derive a more accurate exposure estimate for the pesticide by evaluating additional types of information (anticipated residue data and/or percent of crop treated data) which show, generally, that pesticide residues in most foods when they are eaten are well below established tolerances. Percent of crop treated estimates are derived from federal and private market survey data. Typically, a range of estimates are supplied and the upper end of this range is assumed for the exposure assessment. By using this upper end estimate of percent of crop treated, the Agency is reasonably certain that exposure is not understated for any significant subpopulation group. Further, regional consumption information is taken into account through EPA's computer- based model for evaluating the exposure of significant subpopulations including several regional groups, to pesticide residues. For this pesticide, the most highly exposed population subgroup (non-nursing infants >1 year old) was not regionally based.

II. Aggregate Risk Assessment and Determination of Safety

Consistent with section 408(b)(2)(D), EPA has reviewed the available scientific data and other relevant information in support of this action, EPA has sufficient data to assess the hazards of prometryn, and to make a determination on aggregate exposure, consistent with section 408(b)(2), for a tolerance for residues of prometryn and its metabolite on carrots at 0.1 ppm. EPA's assessment of the dietary exposures and risks associated with establishing the tolerance follows.

A. 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 prometryn are discussed below. 1. A rat acute oral study with a LD50 of 1,802 milligrams/kilogram (mg/kg) for males and a LD50 of 2,076 mg/kg for females 2. A 28-day mice pilot feeding study with a No Observed Effect Level (NOEL) of 450 milligrams/kilogram/day (mg/kg/day) and a Lowest Observed Effect Level (LOEL) of 1,500 mg/kg/day based on decreased body weights. 3. A 21-day dermal toxicity study with a NOEL and LOEL greater than of 1,000 mg/kg/day the highest dose tested (HDT). 4. A 102-week chronic feeding/carcinogenicity study in mice with a Systemic NOEL of 100 mg/kg/day for females and a Systemic LOEL of 300 mg/kg/day for females based on decreased body weight gain. No effects were observed in males. Although significant toxicity was observed only in females, the Health Effects Division Reference Dose (RfD) committee considered the study adequate since (1) levels were close to one-half the limit dose in mice; (2) no effects were noted in the study to warrant repeating the study at high dose levels; and (3) all tumors noted with other members of the s-triazine class were mainly in rats and not mice. 5. A 2-year rat chronic feeding/carcinogenicity study with a Systemic NOEL of 29.45 mg/kg/day for males and 37.25 mg/kg/day for females and a Systemic LOEL of 60.88 mg/kg/day for males and 80.62 mg/ kg/day for females based on decreased body weight and body weight gain and an increase in the incidence of renal lesions (mineralized concretions) in males. prometryn was not oncogenic under the conditions of the study. 6. A 106-week dog feeding study with a NOEL of 3.75 mg/kg/day and a LOEL of 37.5 mg/kg/day based on degenerative hepatic changes, renal tubule degeneration, and bone marrow atrophy. Prometryn was not oncogenic under the conditions of the study. 7. A developmental toxicity study in rats with a Maternal and Developmental NOEL of 50 mg/kg and a Maternal LOEL of 250 mg/kg based on salivation and decreases in body weight and food consumption. The Developmental LOEL is 250 mg/kg/day based on significantly decreased and incomplete ossification in the sternebrae and metacarpals. 8. A developmental toxicity study in rabbits with a Maternal and Developmental NOEL of 12 mg/kg/day and a Maternal LOEL of 72 mg/kg based on based on decreased food consumption, and the Developmental LOEL of 72 mg/kg/day, based on increased fetal resorptions. 9. A two-generation reproduction study in rats with a Parental Systemic NOEL of 0.6 mg/kg/day in males and 0.7 mg/kg/day in females and a Parental Systemic LOEL of 47.8 mg/kg/day in males and 53.6 mg/kg/ day in females based on decreased food consumption, body weight and body weight gain. The Reproductive Systemic NOEL is 0.65 mg/kg/day and the Reproductive Systemic LOEL is approximately 50 mg/kg/day, based on decreased pup weight. 10. An Ames salmonella test, prometryn was negative for gene mutation up to cytotoxic solubility limits (1,000-2,000 g/ plate). A chromosomal aberration in vivo Chinese hamster bone marrow test, prometryn was negative for nuclear anomalies (micronuclei) when animals were dosed orally up to 5,000 mg/kg. Prometryn was negative for bacterial DNA repair and gene mutation up to precipitating levels (1,000 g/plate). An unscheduled DNA synthesis test prometryn was negative (measured as UDS) in rat hepatocytes cultured in vitro up to cytotoxic levels (156.25 g/mL). 11. Rat metabolism studies showed that radio labeled prometryn is distributed in blood greater than spleen greater than lungs (the three highest tissues measured). Distribution is not dosage-dependant. It is extensively metabolized with less than 2% of recovered 14C radioactivity representing the parent compound. Twenty-eight metabolites were identified in the urine, and 28 in the feces. Ten metabolites were identified in both urine and feces. Prometryn is excreted predominantly in the urine and feces, with slightly higher concentrations in the urine. The 7-day recovery of 14C radioactivity averaged 95% for all dosing groups.

B. Toxicological Endpoints

1. Acute toxicity. The developmental NOEL of 12 mg/kg/day from a developmental study was recommend for the acute dietary risk assessment. 2. Short - and intermediate - term toxicity. The developmental NOEL of 12 mg/kg/day from a developmental study was recommend for the short- and intermediate- term dermal and inhalation risk assessments. 3. Chronic toxicity. EPA has established the RfD for prometryn at 0.04 mg/kg/day. This RfD is based on upon the chronic feeding study in dogs with a NOEL of 3.75 mg/kg/day with a 100-fold safety factor to account for interspecies extrapolation and intraspecies variability. 4. Carcinogenicity. The Health Effects Division Reference Dose (RfD) Committee classified prometryn as a

Group E chemical (no evidence of human carcinogenic potential).

C. Exposures and Risks

1. From food and feed uses. Tolerances have been established (40 CFR 180.222(a)) for the residues of prometryn, 2,4-bis(isopropylamino)- 6-methylthio-s-triazine, in celery at 0.5 ppm; corn forage, fresh corn and corn grain at 0.25 ppm; cotton at 1 ppm: cottonseed at 0.25 ppm; and pigeon peas at 0.25 ppm.. Tolerances with regional registration have been established (40 CFR 180.222(b)) for the residues of prometryn in dill at 0.3 ppm and parsley at 0.1 ppm. Risk assessments were conducted by EPA to assess dietary exposures and risks from prometryn as follows: i. Acute exposure and risk. Acute dietary risk assessments are performed for a 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. The Margin of Exposure (MOE) value for females (13 years and older) was 1,200,000. This value is significantly higher than the Agency's level of concern of 100 which is adequate to ensure protection for females 13 and older.. ii. Chronic exposure and risk. Assuming 100% of the crop are treated and residues are at tolerance levels the theoretical maximum residue contribution (TMRC) from the established and proposed tolerances is 0.000056 mg/kg/day and utilizes less than 1% of the RfD for the U.S. Population. For exposure of the most highly exposed subgroup in the population, non-nursing infants, the TMRC is 0.0016 mg/ kg/day which utilizes less than 1% of the RfD. 2. From drinking water. Despite the potential for exposure through drinking water, EPA has concluded that the percentage of the RfD that will be utilized by dietary exposure (including drinking water exposure) to residues of prometryn does not exceed 100% for any of the population subgroups. Considering food only, the population subgroup with the largest percentage of the RfD occupied is 0.0000056 mg/kg/day at opp-docket@epamail.epa.gov.

Electronic comments must be submitted as an ASCII file avoiding the use of special characters and any from of encryption. The official record for this rulemaking, as well as the public version, as described above will be kept in paper from. Accordingly, EPA will transfer any copies of comments received electronically into printed, paper from as they are received and will place the paper copies in the official rulemaking record which will also include all comments submitted directly in writing. The official rulemaking record is the paper record maintained at the Virginia address in ``ADDRESSES'' at the beginning of this document.

VI. Regulatory Assessment Requirements

Under Executive Order 12866 (58 FR 51735, Oct. 4, 1993), the Agency must determine whether the regulatory action is ``significant'' and therefore subject to all the requirements of the Executive Order (i.e., Regulatory Impact Analysis, review by the Office of Management and Budget (OMB)). Under section 3(f), the order defines ``significant'' as those actions likely to lead to a rule (1) having an annual effect on the economy of $100 million or more, or adversely and materially affecting a sector of the economy, productivity, competition, jobs, the environment, public health or safety, or State, local or tribal governments or communities (also known as ``economically significant''); (2) creating serious inconsistency or otherwise interfering with an action taken or planned by another agency; (3) materially altering the budgetary impacts of entitlement, grants, user fees, or loan programs; or (4) raising novel legal or policy issues arising out of legal mandates, the President's priorities, or the principles set forth in this Executive Order. Pursuant to the terms of this Executive Order, EPA has determined that this proposed rule is not ``significant'' and is therefore not subject to OMB review. Pursuant to the requirements of the Regulatory Flexibility Act (Pub. L. 96-354, 94 Stat. 1164, 5 U.S.C. 601-612), the Administrator has determined that regulations establishing new tolerances or raising tolerance levels or establishing exemptions from tolerance requirements do not have a significant economic impact on a substantial number of small entities. A certification statement to this effect was published in the Federal Register of May 4, 1981 (46 FR 24950).

List of Subjects in 40 CFR Part 180

Environmental protection, Administrative practice and procedure, Agricultural commodities, Pesticides and pests, Reporting and recordkeeping requirements.

Dated: February 17, 1998.

James Jones, Director, Registration Division, Office of Pesticide Programs. Therefore, it is proposed that 40 CFR Part 180 be amended as follows:

PART 180--[AMENDED]

1. The authority citation for part 180 continues to read as follows:

Authority: 21 U.S.C. 346a and 371.

2. In Sec. 180.222 by amending paragraph (a) by alphabetically adding the following commodity to the table to read as follows:

Sec. 180.222 Prometryn; tolerances for residues.

(a) * * *

------------------------------------------------------------------------ Parts per Commodity million ------------------------------------------------------------------------ * * * * * * * Carrots1................................................... 0.1 * * * * * * * ------------------------------------------------------------------------ \1\There are no U.S. registrations as of February 25, 1998 for use on carrots.

* * * * *

[FR Doc. 98-4804 Filed 2-24-98; 8:45 am] BILLING CODE 6560-50-F