Page 1 of 55 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES March 3, 2006 MEMORANDUM SUBJECT: Pendimethalin: REVISED HED Human Health Risk Assessment to Support Section 3 Registration for use on Carrots, Mint, Citrus, and Tree Nuts. PC Code: 108501; DP Barcode No.: D3125176.

Regulatory Action: Section 3 Registration Risk Assessment Type: Single Chemical Aggregate FROM: Margarita Collantes Registration Action Branch 2 Health Effects Division ( 7509C)

AND Zaida Figueroa Karlyn Bailey Christina Swartz Registration Action Branch 2 Health Effects Division ( 7509C)

THROUGH: Richard A. Loranger, Ph. D., Branch Senior Scientist Registration Action Branch 2 Health Effects Division ( 7509C)

TO: Jim Tompkins Herbicide Branch Registration Division ( 7505C) Page 2 of 55 Table of Contents 1.0 Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.0 Ingredient Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.1 Summary of Registered/ Proposed Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.2 Structure and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 2.3 Physical and Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.0 Metabolism Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.1 Comparative Metabolic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.2 Nature of the Residue in Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.2.1. Description of Primary Crop Metabolism . . . . . . . . . . . . . . . . . . . . . . . 14 3.2.2 Description of Livestock Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation . . . . . . . . . . 15 3.3 Environmental Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.4 Toxicity Profile of Major Metabolites and Degradates . . . . . . . . . . . . . . . . . . . 15 3.5 Summary of Residues for Tolerance Expression and Risk Assessment . . . . . . . . 16 3.5.1 Tabular Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4.0 Hazard Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4.1 Hazard Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4.2 FQPA Hazard Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.2.1 Adequacy of the Toxicity Data Base . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.2.2 Evidence of Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.2.3 Developmental Toxicity Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.2.4 Reproductive Toxicity Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.2.5 Additional Information from Literature Sources . . . . . . . . . . . . . . . . . . 24 4.2.6 Pre and/ or Postnatal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 <IP_ADDRESS> Determination of Susceptibility . . . . . . . . . . . . . . . . . . . 24 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility . . . . . . . . . . . . . . . . 24 4.3 Recommendation for a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . 25 4.4 Hazard Identification and Toxicity Endpoint Selection . . . . . . . . . . . . . . . . . . . 25 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 . . . . . . . . . . . . . . . . 25 4.4.2 Acute Reference Dose ( aRfD)  General Population . . . . . . . . . . . . . . . 25 4.4.3 Chronic Reference Dose ( cRfD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4.4.4 Incidental Oral Exposure ( Short and Intermediate Term) . . . . . . . . . . . . 26 4.4.5 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 4.4.6 Dermal Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . . . 26 4.4.7 Inhalation Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . 26 4.4.8 Margins of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 4.4.9 Recommendation for Aggregate Exposure Risk Assessments . . . . . . . . 27 4.4.10 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.5 Special FQPA Safety Factor . . . . . . . . . . . . . . 29 Page 3 of 55 4.6 Endocrine disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 5.0 Public Health Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 5.1 Incident Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 6.0 Exposure Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 6.1 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 6.1.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 6.1.2 Acute and Chronic Dietary Exposure and Risk . . . . . . . . . . . . . . . . . . . 31 6.2 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . 33 6.3.1 Home Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 <IP_ADDRESS> Residential Handler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 <IP_ADDRESS> Residential Postapplication . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 <IP_ADDRESS>.1 Dermal Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 <IP_ADDRESS>.2 Inhalation Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . 35 <IP_ADDRESS>.3 Oral Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 <IP_ADDRESS>.4 Aggregate Residential Exposure . . . . . . . . . . . . . . . . . 37 6.3.2 Recreational Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 6.3.3 Other ( Spray Drift, etc.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 7.0 Aggregate Risk Assessments and Risk Characterization . . . . . . . . . . . . . . . . . . . . . 39 7.1 Acute Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 7.2 Short Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 7.3 Intermediate Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 7.4 Long Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 7.5 Cancer Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 8.0 Cumulative Risk Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 9.0 Occupational Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 9.1 Agricultural and Commercial Handler Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 9.2 Agricultural Postapplication Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 9.3 Commercial Postapplication Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 10.0 Data Needs and Label Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 10.1 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 10.2 Residue Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 10.3 Occupational and Residential Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 References: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Page 4 of 55 1.0 Executive Summary A human health risk assessment has been conducted to support a proposed Section 3 registration and associated tolerances for the herbicide pendimethalin on carrots, mint, citrus and tree nuts. Pendimethalin is a selective herbicide registered for control of broadleaf weeds and grassy weed species on a variety of agricultural crops, turf and ornamentals. It is a meristematic inhibitor that interferes with the plant's cellular division of mitosis, and is generally applied early in the growing season.

Toxicology The toxicology database is adequate to support the proposed uses for pendimethalin. The scientific quality of the database for pendimethalin is relatively high and the toxicity profile can be characterized for a wide range of effects, including potential developmental, reproductive and neurotoxic effects. However, HED has requested a developmental thyroid assay to characterize thyroid effects in developing offspring, which are not typically tested in guideline studies.

The database characterizes pendimethalin as having low acute oral, dermal, and inhalation toxicity. It is classified in Toxicity Category IV for acute dermal toxicity, acute inhalation toxicity, and primary dermal irritation; Toxicity Category III for acute oral and primary eye irritation; it is not a dermal sensitizer.

The thyroid is a target organ for pendimethalin. Thyroid toxicity in chronic and subchronic rat and mouse studies was manifested as alterations in thyroid hormones ( decreased Total T4, and T3, increased percent of free T4 and T3), increased thyroid weight, and microscopic thyroid lesions.

No appropriate endpoint attributable to a single exposure was identified from the oral toxicity studies including developmental toxicity studies in rats and rabbits. Therefore, an acute reference dose ( aRfD) was not established. The following three studies: 92 day thyroid function in rats, 56 day thyroid function in rats and 14 day intra thyroid metabolism study in rats were considered together to select the dose and endpoint for establishing the chronic reference dose ( cRfD) of 0.03 mg/ kg/ day. The cRfD is derived from the NOAEL of 10 mg/ kg/ day for thyroid effects based on hormonal and histological changes in the thyroid observed at the LOAEL of 31 mg/ kg/ day and a combined uncertainty factor of 300.

The same three studies conducted in rats were used for dose and endpoint selection for all durations of dermal and inhalation exposure, with a NOAEL of 10 mg/ kg/ day, and a LOAEL of 31 mg/ kg/ day. Furthermore, these three studies were considered appropriate for dose and endpoint selection for incidental oral exposures to infants and children following application of pendimethalin in residential settings ( turf). A dermal absorption factor of 3% and an inhalation absorption factor of 100% were used. Since both dermal and inhalation endpoints were based on the same toxicological effects, these route specific Margins of Exposure ( MOEs) were combined Page 5 of 55 into a total MOE.

Pendimethalin is classified as a " Group C", possible human carcinogen, chemical based on a statistically significant increased trend and pair wise comparison between the high dose group and controls for thyroid follicular cell adenomas in male and female rats. A non quantitative approach ( i. e., non linear, RfD approach) was recommended by the Cancer Peer Review Committee since mode of action studies are available that demonstrate that the thyroid tumors are due to a thyroidpituitary imbalance.

There are no neurotoxicity studies available for pendimethalin; however, there are no neurotoxic clinical signs, changes in brain weight, or histopathology of the nervous system in any study with pendimethalin. Neurotoxicity studies for pendimethalin are not required based on the chemical characteristics.

Both the rat and rabbit developmental toxicity studies indicated no maternal or developmental toxicity at the highest doses tested, 500 mg/ kg/ day in the rat and 60 mg/ kg/ day in the rabbit. In a 2 generation rat reproduction study with pendimethalin, there was no evidence of susceptibility to offspring, with similar parental systemic and reproductive/ offspring NOAELs ( 25 mg/ kg/ day) and LOAELs ( 125 mg/ kg/ day). Systemic parental effects included decreased body weight gain and food consumption, and reproductive/ offspring effects included decreases in the number of pups born and pup body weights.

There are acceptable studies to satisfy the initial mutagenicity testing requirements for all three categories ( gene mutations, structural chromosomal aberrations, and other genotoxic effects). The positive Salmonella results in one study indicated that pendimethalin may have potential genotoxic activity. However, subsequent assays for germ cell effects ( Chinese hamster ovary cells and rat testicular cells) and additional Salmonella assays submitted to address this concern were all negative. Pendimethalin is not considered to be mutagenic.

There were no appropriate dermal absorption data available for pendimethalin; therefore, based on data from stucturally similar active ingredients which indicated a maximum dermal absorption of 2.8%, an estimate of 3% was assumed when calculating dermal risks.

FQPA and Uncertainty Factor Concerns Although it was not possible to determine the potential for susceptibility from the rat and rabbit developmental studies ( no adverse effects observed at doses tested), these studies were considered adequate, and no additional developmental toxicity studies are required. There was no evidence of qualitative or quantitative susceptibility in a 2 generation reproduction study conducted in the rat, and there was no evidence of neurotoxicity in the submitted studies. Therefore, HED has recommended the 10X special FQPA safety factor be removed ( reduced to 1X). Page 6 of 55 Hormonal changes ( alterations in thyroid weights and histopathological lesions) were observed in several studies following oral administration of pendimethalin and it is likely that these changes may cause disruption in the endocrine system. There is concern that perturbation of thyroid homeostasis may lead to hypothyroidism, and possibly result in adverse effects on the developing nervous system. Consequently, HED has recommended that a developmental thyroid assay be conducted to evaluate the impact of pendimethalin on thyroid hormones, structure, and/ or thyroid hormone homeostasis during development. Furthermore, HED has recommended that a 10X database uncertainty factor ( UF DB ) be retained pending receipt of the study.

The standard 10X intraspecies uncertainty factor and a 3X interspecies factor are applicable to pendimethalin risk assessments. The interspecies uncertainty factor of 10X was reduced to 3X due to the greater sensitivity of the adult rat to thyroid effects compared to the adult humans. Because of toxicodynamic differences in adult thyroid function that result in greater sensitivity of the adult rat to hypothyroidism compared to adult humans, the 3x ( 3.16) toxicodynamic part of the 10X can be removed leaving the 3X ( 3.16) portion for toxicokinetic interspecies differences ( Interim Guidance on Thyroid Disrupting Pesticides, dated 11/ 1/ 05). Thus, the usual 100X uncertainty factor for intra and interspecies differences is reduced to 30X. A 10X database uncertainty factor ( UF DB ) was retained pending submission of the developmental thyroid toxicity study. The level of concern ( target MOE) for occupational exposure is 30X, while the target MOE for residential exposure is 300X.

Residue Chemistry The nature of the residue in plants, livestock and rotational crops is adequately understood. Residues of concern in plants for tolerance enforcement and risk assessment purposes are the parent pendimethalin and its 3,5 dinitrobenzyl alcohol metabolite; in peanut hulls, the residue of concern also includes 2,4 dinitrobenzyl alcohol metabolite. The residue of concern in drinking water is pendimethalin, per se. The Agency has determined that there is no reasonable expectation of finite pendimethalin residues of concern in animal commodities ( 40 CFR § 180.6( a)( 3)). Tolerances for pendimethalin residues of concern in animal commodities are not needed.

In general, adequate field trials, storage stability data, analytical methods and processing studies are available to support the proposed uses on citrus, mint, tree nuts and carrots. In addition, adequate enforcement methods are available. Additional field trial data for citrus are required as a condition of registration. In general, residue data indicate that pendimethalin and metabolite residues are low or nondetectable; however, concentration has been observed in processed commodities.

Dietary Exposure Dietary risk assessments were conducted using the Dietary Exposure Evaluation Model ( DEEMFCID   ) and the LifeLine   Model, both of which use food consumption data from the USDA's Page 7 of 55 Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998. For both the DEEM FCID   and LifeLine   assessments, tolerance level residues were assumed for all food commodities with current and proposed pendimethalin tolerances, and it was assumed that all of the crops included in the analyses were treated ( i. e. 100% crop treated).

The two models provided similar estimates of chronic dietary exposure and risk. The most highly exposed population subgroup was children 1 2 years old. The chronic exposure estimate of approximately 0.002 mg/ kg/ day corresponds to 6% cPAD. Risks for the general US population and all other population subgroups were lower. Acute dietary exposure estimates were not generated, due to a lack of an acute dietary endpoint and dose for risk assessment.

Drinking Water Exposure The Environmental Fate and Effects Division ( EFED) performed a drinking water assessment for pendimethalin, based on the proposed uses considered in this assessment, as well as additional proposed uses for which residue chemistry data have been submitted but not reviewed. It was determined that the parent pendimethalin is the only significant non volatile residue, therefore, the estimated drinking water concentrations ( EDWCs) were calculated for parent pendimethalin only. For surface water sources of drinking water, the acute ( peak) water concentration is 38.8 parts per billion ( ppb), 4.8 ppb for chronic ( non cancer) and 3.8 ppb for cancer. The groundwater screening concentration was 0.024 ppb.

Residential ( non occupational) Exposure This residential exposure assessment will only re evaluate exposure resulting from residential turf/ lawn uses. A complete residential exposure assessment for pendimethaline was previously performed in the 1996 reregistration eligibility decision ( RED) document ( J. Leahy, D221532, February 20, 1996). The MOEs for residential handlers wearing baseline attire were all greater then the level concern ( MOE = 300).

Handlers Since the pendimethalin RED was issued labels for use of pendimethalin on residential turf have been revised. All turf ( ornamental, landscape, golf course, non cropland) labels appear to be for commercial use only based on the contents ( i. e. requiring mixing tanks, ground equipment for application, personal protective equipment and restricted entry intervals). However labels do not indicate for use by licenced chemical operator only. The Registration Division should confirm that proper language clarifying that these products are to be applied only by commercial or licensed operators.

Postapplication A revised dermal postapplication exposure assessment was conducted using the turf transferable Page 8 of 55 residue data ( TTR's) from three test sites ( CA, PA, and FL) identified in the TTR study. The children's and adult's short term dermal MOEs are all greater than the level of concern of 300. All oral ( hand to mouth, object to mouth, and soil ingestion) exposure MOEs were calculated using both the TTR data and chemical specific hand press data. All oral MOEs were greater than the level of concern of 300.

Ingestion of pendimethalin granules is also a potential source of exposure because children can eat them if they are found in treated lawns or gardens. This scenario is considered an episodic scenario by the Agency ( i. e., acute oral endpoints would be used to estimate the risk). A risk assessment for this exposure scenario for children was not conducted since an acute oral toxicological endpoint of concern was not identified for this pesticide.

Residential Aggregate In evaluating the residential uses of pendimethalin, HED has combined all non dietary sources of postapplication exposure to obtain an estimate of potential aggregate exposure. These scenarios are short term in duration and consist of dermal ( adults and children) and oral ( hand to mouth, object to mouth and soil ingestion  children only) exposure. HED combines risk values resulting from separate exposure scenarios when it is likely they can occur simultaneously based on the usepattern and the behavior associated with the exposed population.

The level of concern for oral, dermal and inhalation exposure is 300. The aggregate exposure estimate for adults ( consisting of dermal exposure only) resulted in a total MOE of 740 and therefore not of concern. The aggregate residential exposure for children resulted in a total MOE ( dermal + oral) of 410 at an application rate of 2 lb ai/ acre and a MOE of 400 for an application rate of 3 lb ai/ acre. Residential aggregate exposure was not of concern.

Aggregate Risk Estimates In the current aggregate assessment, HED has considered occupational, dietary ( food and drinking water) and non occupational, non dietary postapplication exposures, including incidental oral and dermal exposures. Only dietary and non occupational exposure and risk have been included in the aggregate risk assessment. Since no toxic effects attributable to a single dose were identified for pendimethalin, an acute aggregate risk assessment was not warranted. In estimating short term aggregate risk, HED combined the chronic dietary ( food) exposure estimate and the total non dietary exposure estimates for adults and children and used the DWLOC ( drinking water level of comparison) approach to determine aggregate risk.

For all population subgroups, the short term DWLOCs range from 666 ppb ( general U. S. population) to 72 ppb ( children 1 2 years old), which are greater than the chronic ground ( 0.024 ppb) and surface water ( 5 ppb) EDWCs. Therefore, aggregate short term exposure to pendimethalin is not of concern. The chronic aggregate exposure estimate included dietary exposure only ( food + water). The chronic DWLOCs range from 423 ppb ( children 1 2 years) to Page 9 of 55 1029 ppb ( adults 50+ years) and are greater then the ground ( 0.024 ppb) and surface water ( 5 ppb) EDWCs, and are therefore not of concern.

Occupational Exposure Agricultural Handler No chemical specific data for assessing handler exposures were submitted to the Agency in support of the proposed uses; therefore, surrogate data from the Pesticide Handlers Exposure Data Base ( PHED) Version 1.1, the Outdoor Residential Exposure Task Force ( ORETF) and standard values established by the Health Effects Division ( HED) Science Advisory Council for Exposure were used for acres treated per day, body weight and the level of personal protective equipment worn by handlers.

Since both dermal and inhalation toxicological endpoints were the same for short term duration, the route specific MOEs were combined and compared to the NOAEL ( 10 mg/ kg/ day). The total MOEs for short term mixing/ loading scenarios, ranged from 50 at baseline to 1,200 using PPE level of mitigation ( single layer and gloves), and did not exceed HED's level of concern ( MOEs < 30). The total MOEs for short term applicator and flagger scenarios, at baseline level of mitigation and engineering controls for aerial application, range from 1,000 to 9,100 and do not exceed HED's level of concern ( MOEs < 30).

Commercial Handlers Commercial handler exposure estimates of applying pendimethalin to ornamentals, turf ( golf courses) and right of ways turf resulted in MOEs greater than 30 wearing either baseline attire or with the addition of gloves. Therefore, commercial handler scenarios were not of concern to HED.

Agricultural Postapplication Since these products are herbicides used mainly to control pre emergent weeds, and not applied directly to foliage, postapplication exposure is expected to be minimal. Based on this information an occupational postapplication exposure assessment was neither required nor performed.

Commercial Postapplication As indicated previously, In the 1996 RED, the following two representative post application commercial scenarios were assessed: 1) maintenance worker exposure to golf course turf, and 2) harvesting turfgrass from a sod farm. Calculations of postapplication exposure resulted in acceptable MOEs and therefore were not of concern.

Restricted Entry Interval ( REI) Page 10 of 55 The restricted entry interval ( REI) is based on the acute toxicity of pendimethalin technical material which is classified as Category III and IV for acute dermal, dermal irritation and eye irritation ( HIARC Doc. No. 014116, April 18, 2000). Acute toxicity Category III and IV chemicals for these potential hazards require a 12 hour REI. Based on the acute toxicity categories for this chemical, HED recommends that the current product labels provide a 12 hour REI.

Recommendation HED recommends in favor of the proposed uses of pendimethalin on citrus, mint, tree nuts and carrots. However, HED recommends that the registration be made conditional upon submission of additional citrus field trial data to support the citrus crop group tolerance.

HED recommends 40 CFR § 180.361 be revised to include tolerances for residues of pendimethalin and its metabolite 4[( 1 ethylpropyl) amino] 2 methyl 3,5 dinitrobenzyl alcohol in or on the following commodities:

Commodity Recommended Tolerance ( ppm) Petition Mint 0.2 7E4878 Mint Oil 1.0 7E4878 Citrus 0.1 6E4787 Citrus Oil 0.5 6E4787 Carrots 0.5 6E4603 Almond Hulls 0.4 0E6083 Tree Nuts 0.1 0E6083 Data Gaps and Deficiencies Toxicology HED has requested the submission of developmental thyroid toxicity data for adult rats and young rats following pre and post natal exposure to pendimethalin. Guidance for conducting developmental thyroid assays has been developed by HED ( Guidance for Thyroid Assays in Pregnant Animals, Fetuses and Postnatal Animals, and Adult animals, dated October 24, 2005) in cooperation with the registrant. Currently, BASF is in the process of conducting the requested thyroid study.

Residue Chemistry Page 11 of 55 Additional field trial data are needed to support the citrus crop group tolerance; the proposed uses on citrus and associated tolerances should be made conditional pending receipt of the additional grapefruit and lemon field trials.

Occupational and Residential Exposure The Agency reiterates the recommendation that agricultural handlers should wear chemical resistant gloves when mixing/ loading liquids, and when mixing/ loading and applying with a low pressure handwand.

2.0 Ingredient Profile Pendimethalin ( N( 1 ethylpropyl) 3,4 dimethyl 2,6 dinitrobenzenamine) is a herbicide used to control annual grass and broadleaf weeds and belongs to the dinitroaniline class of herbicides. As with other chemicals in this class, pendimethalin is a meristematic inhibitor that interferes with the plant's cellular division or mitosis, and it is applied early in the growing season. The petitioner is currently proposing food/ feed uses on mint, carrots, citrus fruits and tree nuts for two new end  use products: PROWL ® 3.3 EC and PROWL ® H 2 O.

2.1 Summary of Registered/ Proposed Uses Table 2.1. Summary of Pendimethalin End Use Products.

Trade Name Reg. No. ai (% of Formulation Formulation Type Target Crop Target Pests Label Date Proposed Uses Prowl ® 3.3 EC. 241 337 37.4 liquid mint, carrots, citrus fruit and tree nuts annual grasses and broadleaf weeds Feb 11, 1999 PROWL ® H2O 241 418 38.7 Mar 26, 2003 Registered Uses Pendulum 3.3 EC 241 241 emulsified conc. turf grass annual grasses and broadleaf weeds Pendulum WDG 241 340 60 WDG Pendulum 2G 241 375 2 granular Page 12 of 55 Table 2.2. Summary of Directions for Use of Pendimethalin.

Trade Name Applic. Type, and Equip. Target Crop Applic. Rate ( lb ai/ A) Max. No. Applic. per Season Max. Seasonal Applic. Rate ( lb ai/ A) PHI ( days) Use Directions and Limitations Proposed Uses Prowl ® 3.3 EC.

ground, aerial and chemigation mint 0.743 1.98 2 1.98 90 24 hour REI carrots 1.0 1 1.0 60 apply as pre emergent within 2 days after planting ; 24 hr REI citrus 1.98 3.96 2 3.96 60 24 hour REI tree nuts 60 120 PROWL ® H2O ground, aerial and chemigation mint 0.713 1.9 2 1.9 90 24 hour REI carrots 0.95 1 0.95 60 apply as pre emergent within 2 days after planting; 24 hr REI citrus 1.9 3.8 2 3,8 60 24 hour REI tree nuts 60 120 Registered Uses Pendulum 3.3 EC turf grass, sod farm, golf course 2.0 3.0 2 3.0 Turf grass may be treated at 3.0 lb ai/ acre in spring prior to germination and then repeated 6 8 weeks later. Additional applications may be made in late summer or early fall. Pendulum WDG Pendulum 2G Page 13 of 55 NO 2 O 2 N CH 3 CH 3 N H CH 3 C 2 H 5 2.3 Structure and Nomenclature TABLE 2.3. Test Compound Nomenclature Chemical Structure Empirical Formula C13H19N3O4 Common name pendimethalin Company experimental name n/ a IUPAC name N( 1 ethylpropyl) 2,6 dinitro 3,4 xylidine CAS name N( 1 ethylpropyl) 3,4 dimethyl 2,6 dinitrobenzenamine CAS Registry Number 40487 42 1 End use product/ EP Chemical Class dinitroaniline herbicide Known Impurities of Concern nitrosamines [ product chemistry data indicate these impurities are not present at levels that are of concern].

2.4 Physical and Chemical Properties Pendimethalin is an orange yellow crystalline solid with a melting point of 54 58 C. It is soluble in chlorinated hydrocarbons and aromatic solvents such as methylene chloride, acetone, and xylene, but only soluble in water at < 0.5 ppm at 20 C. Pendimethalin is stable under acidic and alkaline conditions. Page 14 of 55 TABLE 2.4. Physicochemical Properties Parameter Value Reference Molecular Weight 281.3 www. hclrss. demon. co. uk/

Melting point/ range 57.7  58C EC 7477/ VI/ 98 final, 1/ 13/ 2003 pH 4.5 7 www. aje. cc/ e_ about_ aje. htm Density 0.85 g/ ml at 25C EC 7477/ VI/ 98 final, 1/ 13/ 2003 Water solubility ( 20 C) pH4: 0.54 mg/ l pH7: 0.33 mg/ l pH10: 0.44 mg/ l EC 7477/ VI/ 98 final, 1/ 13/ 2003 Solvent solubility ( temperature not specified) n Hexane = 48.98 g/ l n   Octanol = 66.08 g/ l Dichloromethane > 800 g/ l Xylene > 800 g/ l Ethylacetate > 800 g/ l Acetone > 800 g/ l EC 7477/ VI/ 98 final, 1/ 13/ 2003 Vapor pressure ( 25 C) 1.94 x 10 3 Pa EC 7477/ VI/ 98 final, 1/ 13/ 2003 Dissociation constant, pKa 2.8 EC 7477/ VI/ 98 final, 1/ 13/ 2003 Octanol/ water partition coefficient, logPOW ( 25 C) 5.2 EC 7477/ VI/ 98 final, 1/ 13/ 2003 UV/ visible absorption spectrum 238 nm = 28775 425 nm = 5490 EC 7477/ VI/ 98 final, 1/ 13/ 2003 3.0 Metabolism Assessment 3.1 Comparative Metabolic Profile Following administration to rats, 70% of the radioactivity was excreted in the feces and 20% in the urine within 24 hours. The major portion of the radioactivity that was excreted in the feces was identified as the parent compound. Pendimethalin is metabolized in rats mainly through oxidation of the 4 methyl group attached to the benzene ring as well as oxidation of the alkyl side chain of the N substituted dinitroaniline compound. Plant and livestock metabolism data indicate there are no significant metabolites that have not been accounted for in the rat metabolism study.

3.2 Nature of the Residue in Foods 3.2.1. Primary Crop Metabolism The qualitative nature of the residue in plants is understood based on adequate studies conducted with [ 14C] pendimethalin on potatoes and sweet corn. The results of these studies are supported by additional corn, cotton, dry bean, lima bean, peanut, potato, red table beet, rice, snap bean, soybean, sugarcane, and wheat metabolism data. Pendimethalin per se and its 3,5 dinitrobenzyl Page 15 of 55 alcohol metabolite are the residues of concern ( for risk assessment and tolerance enforcement) in plants, with the exception of peanut hulls, which also include the 2,4 dinitrobenzyl alcohol metabolite.

3.2.2 Livestock Metabolism Adequate goat and poultry metabolism studies are available. The Agency has determined that there is no reasonable expectation of finite pendimethalin residues of concern in animal commodities ( 40 CFR § 180.6( a)( 3)). No additional animal metabolism, analytical methods, storage stability, and magnitude of the residue data are required. Tolerances for pendimethalin residues of concern in livestock commodities are not needed.

3.2.3 Rotational Crop Metabolism An acceptable confined rotational crop study was submitted and reviewed in conjunction with the pendimethalin RED document ( 1996). The study indicates pendimethalin residues in rotational crop matrices are extensively metabolized. Only radioactive residues of pendimethalin per se exceeded 0.01 ppm in/ on any of the mature RACs studied. Limited field rotational crop studies are not needed provided labels indicate a 90 day plantback interval ( PBI) for cereal grains, and a 270 day PBI for all other crops.

3.3 Environmental Degradation Pendimethalin dissipates in the environment through binding to soil, microbial metabolism and volatilization. In both laboratory and field studies, pendimethalin residues are tightly bound to soil and sediment particles. Pendimethalin is stable to sterile hydrolysis, soil photolysis, and anaerobic soil metabolism, but degrades slowly under aqueous photolysis. Pendimethalin forms many minor (< 10% of applied) degradates that consist primarily of an intact benzene ring with rearranged alkyl groups. Parent pendimethalin is the only significant non volatile residue expected in ground and surface water sources of drinking water.

3.4 Toxicity Profile of Major Metabolites and Degradates There are no toxicity data available for pendimethalin metabolites. For the purpose of risk assessment, the 3,5 dinitrobenzyl metabolite has been considered toxicologically equivalent to the parent. That is, for dietary risk assessment, combined residues of pendimethalin and metabolites were compared to the NOAEL for pendimethalin, per se. Page 16 of 55 3.5 Summary of Residues for Tolerance Expression and Risk Assessment 3.5.1 Tabular Summary Table 3.5. Summary of Pendimethalin Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crops Pendimethalin 3,5 dinitrobenzyl alcohol Pendimethalin 3,5 dinitrobenzyl alcohol Peanut Hulls Pendimethalin 3,5 dinitrobenzyl alcohol 2,4 dinitrobenzyl alcohol N/ A Rotational Crop N/ A N/ A Livestock Ruminant Not applicable  there is no reasonable expectation of finite residues in livestock. Poultry Drinking Water Pendimethalin Not Applicable 4.0 Hazard Characterization/ Assessment 4.1 Hazard Characterization The toxicity database for pendimethalin is adequate for the purpose of characterizing potential toxic effects following acute, short term and long term exposures via oral, dermal and inhalation routes of exposure.

The database adequately characterizes pendimethalin as having low acute oral, dermal, and inhalation toxicity. Pendimethalin is classified in Toxicity Category IV for acute dermal toxicity, acute inhalation toxicity, and primary dermal irritation; Toxicity Category III for acute oral and primary eye irritation; it is not a dermal sensitizer. The acute toxicity is summarized in Table 4.1. a.

The thyroid is a target organ for pendimethalin. Thyroid toxicity in chronic and subchronic rat and mouse studies was manifested as alterations in thyroid hormones ( decreased Total T4, and T3, increased percent of free T4 and T3), increased thyroid weight, and microscopic thyroid lesions ( including increased thyroid follicular cell height, follicular cell hyperplasia, as well as follicular cell adenomas).

The toxicology database for pendimethalin is complete with regard to pre natal developmental Page 17 of 55 toxicity in rats and rabbits; the studies are both classified as acceptable. However, a developmental thyroid study has been requested to provide additional information to evaluate thyroid toxicity in the developing fetus following pre and post natal exposure. The available data provided no indication of qualitative or quantitative susceptibility following pre natal and postnatal exposure in a 2 generation reproduction study in rats.

In a combined chronic/ carcinogenicity study in rats, the LOAEL of 250 mg/ kg/ day is based on decreased survival, body weight gain and food consumption, increased gamma glutamyl transferase and cholesterol, increase in absolute and/ or relative liver weight, generalized icterus, dark adipose tissue in females, diffusely dark thyroids and follicular cell hyperplasia of the thyroid. Thyroid tumors were observed in both male and female rats. In the carcinogenicity study in mice, the LOAEL of 622.1/ 806.99 mg/ kg/ day ( M/ F) is based on increased mortality in females, decreased body weight in females, increased absolute thyroid, liver and gall bladder weights and/ or relative body and brain weight ratios in males and females as well as amyloidosis in males. There were no tumors observed in mice.

Pendimethalin is classified as a " Group C", possible human carcinogen, chemical based on a statistically significant increased trend and pair wise comparison between the high dose group and controls for thyroid follicular cell adenomas in male and female rats. A non quantitative approach ( i. e., non linear, RfD approach) was recommended by the Cancer Peer Review Committee since mode of action studies are available that demonstrate that the thyroid tumors are due to a thyroidpituitary imbalance, and also since pendimethalin was shown to be non mutagenic in mammalian somatic cells and germ cells.

Rat metabolism data indicated pendimethalin is rapidly eliminated from the body with 70% being excreted in the feces, primarily unchanged as parent compound, and 20% in the urine within 24 hours. It is mainly metabolized through oxidation of the 4 methyl group on the benzene ring and the alkyl side chain.

There were no appropriate dermal absorption or toxicity studies available to allow an estimation of the dermal absorption by a route to route comparison of toxicity. In a previous risk assessment, dermal absorption was estimated to be no greater than 10%. This was based on structurally related chemicals ( oryzalin, trifluralin and ethalfluralin) with dermal absorption studies ( in monkeys) indicating absorption rates of 2.3%, ~ 1%, and 2.8%, respectively. The solubilities ( water) for pendimethalin and these related chemicals are also similar at 0.5 ppm, 2.5 ppm, 0.3 ppm and < 1 ppm, respectively. The upper bound value of 10% previously estimated for pendimethalin is considered very conservative. Therefore, for risk characterization purposes, a more appropriate estimate of 3% was applied. This absorption rate is comparable to those identified for related chemicals. Page 18 of 55 Table 4.1a Acute Toxicity Profile  Pendimethalin Guideline No. Study Type MRID( s) Results Toxicity Category 870.1100 Acute oral [ Rat] 00026657 LD50= 1250 mg/ kg ( m) = 1050 mg/ kg ( f) III 870.1200 Acute dermal [ Rabbit] 00026657 LD50 = > 5000 mg/ kg IV 870.1300 Acute inhalation [ Rat] 00073342 LC50 = 32 mg/ L IV 870.2400 Acute eye irritation [ Rabbit] 00026657 slight conjunctival irritation III 870.2500 Acute dermal irritation [ Rabbit] 00026657 no dermal irritation IV 870.2600 Skin sensitization [ Guinea pig ] 00153767 non sensitizer

Table 4.1b Subchronic, Chronic and Other Toxicity Profile for Pendimethalin.

Guideline No. Study Type MRID No./ Classification Dose Levels Results 870.3100 Subchronic oral rat ( 30 day) 000106754 Supplementary ppm = 0, 800, 1600, 3200 mg/ kg/ day = 0, 80, 160, 320 NOAEL = 160 mg/ kg/ day LOAEL = 320 mg/ kg/ day based on increased liver weight.

870.3100 Subchronic oral rat ( 13 week) 00156081 ppm = 0, 100, 500, 5000 mg/ kg/ day = 0, 10, 50, 500 NOAEL = 50 mg/ kg/ day LOAEL = 500 mg/ kg/ day based on decreased body weight gain and food consumption, decreased hematocrit and hemoglobin w/ increases in platelets in males, increased liver weight, red thyroids, and hypertrophy of the liver.

870.3100 Subchronic oral rat ( 13 week) 00059468 Supplementary ppm = 0, 25, 50, 100, 500, 2500 mg/ kg/ day = 0, 2.5, 5, 10, 50, 250 NOAEL = 250 mg/ kg/ day LOAEL was not determined 870.3100 Subchronic oral rat ( 13 week) 00059469 Supplementary ppm = 0, 2500 mg/ kg/ day = 0, 250 NOAEL = 250 mg/ kg/ day LOAEL was not determined 870.3100 Subchronic oral rat ( 92 day) 42054601 ppm = 0, 100, 5000 mg/ kg/ day = 0, 4.98, 245.4 NOAEL = 4.98 mg/ kg/ day LOAEL = 245.4 mg/ kg/ day based on thyroid effects Table 4.1b Subchronic, Chronic and Other Toxicity Profile for Pendimethalin.

Guideline No. Study Type MRID No./ Classification Dose Levels Results Page 19 of 55 870.3100 Subchronic oral rat ( 56 day) 43135001 ppm = 0, 500, 5000 mg/ kg/ day = 0, 31, 292 NOAEL was not determined LOAEL = 31 mg/ kg/ day based on thyroid effects 870.3100 Subchronic oral rat ( 14 day) 43135003 ppm = 0, 100, 500 mg/ kg/ day = 0, 10, 500 NOAEL = 10 mg/ kg/ day LOAEL = 500 mg/ kg/ day based on thyroid effects 870.3100 Subchronic oral dog ( 90 day) 00026672 Supplementary mg/ kg/ day = 0, 62.5, 250, 1000 NOAEL = 62.5 mg/ kg/ day LOAEL = 250 mg/ kg/ day based on body weight loss 870.3150 Subchronic oral mouse ( 30 day) 000106754 Supplementary ppm = 0, 500, 1000, 2000 mg/ kg/ day = 0, 75, 150, 300 NOAEL = 300 mg/ kg/ day LOAEL was not determined 870.3200 21 Day dermal toxicity ( rat) 00026663 mg/ kg/ day = 0, 250, 500, 1000 NOAEL = 1000 mg/ kg/ day LOAEL was not determined 870.3700a Prenatal Developmental Toxicity ( Rat) 00025752 Supplementary; but satisfactory when considered w/ rabbit developmental mg/ kg/ day = 0, 125, 250, 500 Maternal NOAEL = 500 mg/ kg/ day ( highest dose tested) Maternal LOAEL was not determined Developmental NOAEL = 500 mg/ kg/ day ( highest dose tested) Developmental LOAEL was not determined 870.3700b Prenatal Developmental Toxicity ( Rabbit) 00117444 Supplementary; Upgradeable mg/ kg/ day = 0, 15, 30, 60 Maternal NOAEL = 60 mg/ kg/ day ( highest dose tested) Maternal LOAEL was not determined Developmental NOAEL = 60 mg/ kg/ day ( highest dose tested) Developmental LOAEL was not determined Note: range finding study indicated doses $ 125 mg/ kg/ day associated with increased mortality Table 4.1b Subchronic, Chronic and Other Toxicity Profile for Pendimethalin.

Guideline No. Study Type MRID No./ Classification Dose Levels Results Page 20 of 55 870.3800 Reproduction and fertility effects ( 2 Generation Reproduction in Rats) 41725203 ppm = 0, 500, 2500, 5000 mg/ kg/ day ( M/ F) = 0, 34/ 43, 172/ 216, 346/ 436 HED RED mg/ kg/ day = 0, 25, 125, 250 HIARC Document Note: Doses were obtained from a HED pendimethalin RED and a HIARC document ( 4/ 18/ 2000) which resulted in different dose calculations for mg/ kg/ day. Consequently, doses are given as a range, based on calculations from actual chemical intake and a generic ratio ( 1: 20) of dietary intake. Parental/ Systemic NOAEL = 25 34/ 43 ( M/ F) mg/ kg/ day ( 500 ppm) Parental / Systemic LOAEL = 125 172/ 216 ( M/ F) mg/ kg/ day ( 2500 ppm) based on decreased body weight gain and food consumption.

Reproductive/ Offspring NOAEL = 25 34/ 43 ( M/ F) mg/ kg/ day ( 500 ppm) Reproductive/ Offspring LOAEL = 125 172/ 216 ( M/ F) mg/ kg/ day ( 2500 ppm) based on decreases in the number of pups born and pup weights.

870.3800 Reproduction and fertility effects 3 Generation Reproduction in Rats 00026671, 0040304, 00059470 ppm = 0, 500, 5000 mg/ kg/ day = 0, 25, 250 Parental/ Systemic NOAEL = 25 mg/ kg/ day. Parental/ Systemic LOAEL = 250 mg/ kg/ day based on decreased body weight.

Reproductive/ Offspring NOAEL = 25 mg/ kg/ day Reproductive/ Offspring LOAEL = 250 mg/ kg/ day based on decreased pup body weight gain and possible decreased pups born alive and pup survival. Table 4.1b Subchronic, Chronic and Other Toxicity Profile for Pendimethalin.

Guideline No. Study Type MRID No./ Classification Dose Levels Results Page 21 of 55 870.4100a Chronic toxicity ( Mouse) 40909901 ppm = 0, 100, 500, 5000 mg/ kg/ day ( M/ F) = 0, 12.3/ 15.6, 62.3/ 78.3, 622.1/ 806.9 NOAEL = 62.3/ 78.3 mg/ kg/ day LOAEL = 622.1/ 806.99 mg/ kg/ day based on mortality, body weight decrease, organ weight changes and amyloidosis.

870.4100b Chronic toxicity ( 2 year Oral Dog) 00058657 mg/ kg/ day = 0, 12.5, 50, 200 NOAEL = 12.5 mg/ kg/ day LOAEL = 50 mg/ kg/ day based on increased SAP, liver weights and pathology.

870.4200 Chronic Toxicity/ Carcinogenicity ( 2 year Oral Rat) 40174401 ppm = 0, 100, 500, 5000 mg/ kg/ day = 0, 5, 25, 250 NOAEL = 25 mg/ kg/ day LOAEL = 250 mg/ kg/ day based on decreased survival, body weight gain and decreased food consumption, increased gamma glutamyl transferase, cholesterol and liver weights and thyroid effects.

870.4200 Chronic Toxicity ( 2 year Oral Rat) 42027802 ppm = 0, 1250, 2500, 3750, 5000 mg/ kg/ day = 0, 51, 103, 154, 213 NOAEL was not determined LOAEL = 51 mg/ kg/ day based on non neoplastic thyroid follicular cell changes.

870.4300 Carcinogenicity ( 18 month Oral Mouse) 40909901 ppm = 0, 100, 500, 5000 mg/ kg/ day ( M/ F) = 0, 12.3/ 15.6, 62.3/ 78.3, 622.1/ 806.9 NOAEL = 62.3/ 78.3 mg/ kg/ day LOAEL = 622./ 806.9 mg/ kg/ day based on mortality, body weight decrease, organ weight changes and amyloidosis.

870.5100 Reverse Gene Mutation Assay in Bacteria strains of S. typhimurium 00153768 50, 158, 500, 1581, 5000 µ g/ plate Positive Evidence of a 2 fold increase in number of induced mutant colonies over background at all doses from 50 to 5000 µ g/ plate 870.5100 Reverse Gene Mutation Assay in Escherichia coli WP2 43177801 25, 50, 100, 250, 500, 750 µ g/ plate Negative Table 4.1b Subchronic, Chronic and Other Toxicity Profile for Pendimethalin.

Guideline No. Study Type MRID No./ Classification Dose Levels Results Page 22 of 55 870.5100 Reverse Gene Mutation Assay in Escherichia coli WP2 43135005 50, 158, 500, 1581, 5000 µ g/ plate or 1000 µ g/ paper disk/ plate Negative 870.5100 Reverse Gene Mutation Assay in Escherichia coli WP2 43135006 50, 100, 250, 500, 750 µ g/ plate Negative 870.5300 Mammalian Cell Gene Mutation in Chinese hamster ovary 43177802 1, 5, 7.5, 10, 20, 30, 40, 50 µ g/ ml ( S9)

10, 25, 50, 75, 100, 125, 150, 175 µ g/ ml (+ S9) Negative 870.5375 Chromosomal Aberration ( CHO) 00153770 Doses ranging from 5 50 µ g/ ml Negative 870.5395 Mouse Micronucleus Study 42027801 313, 625, 1250 mg/ kg Negative 870.5550 Alkaline Elution Assay in Rats 43135007 1250, 2500, 5000 mg/ kg/ bw Negative 870.7485 Metabolism and pharmacokinetics in Rat 00046275 n/ a Pendimethalin is eliminated from body with 70% being excreted in feces primarily parent compound and 20% in urine within 24 hours.

C Some of the LOAELs/ NOAELS in Table 4.1b were previously denoted as LOELs/ NOELS in Data Evaluation Records ( DERs), the language was updated to comply with current standards without reexamining effects. As new uses for pendimethalin are submitted, DERs will be re reviewed and updated.

4.2 FQPA Hazard Considerations 4.2.1 Adequacy of the Toxicity Data Base The toxicology database for pendimethalin is adequate and complete. However, based on the hormonal changes ( alterations in thyroid weights and histopathological lesions) observed in several studies following oral administration of pendimethalin, it is likely that pendimethalin may cause disruption in the endocrine system. There is concern that perturbation of thyroid homeostasis may lead to hypothyroidism, and possibly result in adverse effects on the developing Page 23 of 55 nervous system. Consequently, HED has recommended that a developmental thyroid assay be conducted to evaluate the impact of pendimethalin on thyroid hormones, structure, and/ or thyroid hormone homeostasis during development. Furthermore, HED has recommended that a 10X database uncertainty factor ( UF DB ) of 10X be retained pending receipt of the required study.

4.2.2 Evidence of Neurotoxicity There were no neurotoxicity studies available for pendimethalin. Furthermore, there was no evidence of neurotoxic clinical signs, changes in brain weight, or histopathology of the nervous system in any study with pendimethalin. Neurotoxicity studies for pendimethalin are not required based on the chemical characteristics.

4.2.3 Developmental Toxicity Studies In the rat, the pendimethalin NOAELs for developmental and maternal toxicity are both 500 mg/ kg/ day ( highest dose tested). There were no maternal or developmental effects noted at any dose level tested. However, the study is considered adequate, and a new study is not required because in other rat studies, thyroid toxicity was seen at significantly lower doses ( 31 mg/ kg/ day) than the highest dose tested in this study, and because if thyroid parameters had been measured, maternal toxicity would likely have been demonstrated.

A rabbit toxicity study with pendimethalin did not demonstrate maternal toxicity at doses up to 60 mg/ kg/ day ( highest dose tested). The NOAEL for developmental toxicity was 60 mg/ kg/ day ( HDT). Since neither maternal nor developmental toxicity was seen at the highest dose tested, potential for increased sensitivity of the offspring could not be determined.

4.2.4 Reproductive Toxicity Study A 2 generation reproduction study ( MRID# 41725203) with pendimethalin was reviewed by HED. The pendimethalin RED and the Data Evaluation Report ( DER), concluded that the parental systemic NOAEL was 172 mg/ kg/ day [ M] and 216 mg/ kg/ day [ F] ( 2500 ppm), based on decreased body weight gain and food consumption at the LOAEL of 346 mg/ kg/ day [ M] and 436 mg/ kg/ day [ F] ( 5000 ppm). The reproductive/ offspring NOAEL was 172 mg/ kg/ day [ M] and 216 mg/ kg/ day [ F] ( 2500 ppm), based on decreased pup weight at the LOAEL of 346 mg/ kg/ day [ M] and 436 mg/ kg/ day [ F] ( 5000 ppm). The mg/ kg/ day were calculated from actual intake of chemical specific data in the DER.

Conclusions for the same 2 generation reproduction study ( MRID# 41725203) with pendimethalin in the HIARC ( 4/ 18/ 2000) indicated that the parental systemic NOAEL was 25 mg/ kg/ day ( 500 ppm), based on decreased body weight gain and food consumption at the LOAEL of 125 mg/ kg/ day ( 2500 ppm). The reproductive/ offspring NOAEL is 25 mg/ kg/ day ( 500 ppm), based on decreases in the number of pups born and pup weight at the LOAEL of 125 mg/ kg/ day ( 2500 ppm). Parental and reproductive NOAELs and LOAELs were based on a Page 24 of 55 generic ratio ( 1: 20) of dietary intake of chemical.

4.2.5 Additional Information from Literature Sources There was no additional information available from the literature.

4.2.6 Pre and/ or Postnatal Toxicity HED has concluded there is potential for pre and/ or postnatal toxicity ( thyroid) in developing offspring resulting from exposure to pendimethalin.

<IP_ADDRESS> Determination of Susceptibility There was no indication of pre/ or postnatal qualitative or quantitative increased susceptibility in the developmental studies in rats and rabbits or the 2 generation reproduction studies in rats. However, because developmental LOAELs could not be determined in the developmental studies, HED has requested developmental thyroid toxicity data, in order to determine potential thyroid toxicity following pre and/ or post natal exposure to pendimethalin.

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility HED performed a Degree of Concern Analysis because the developmental studies were not adequate to fully address the potential for susceptibility. The purpose of the Degree of Concern analysis is ( 1) to determine the level of concern for the effects observed when considered in the context of all available toxicity data; and ( 2) identify any residual uncertainties after establishing toxicity endpoints and traditional uncertainty factors to be used in the risk assessment.

If residual uncertainties are identified, then HED determines whether these residual uncertainties can be addressed by a special FQPA safety factor and, if so, the size of the factor needed.

In the case of pendimethalin, the developmental studies in rats and rabbits were acceptable but not adequate to determine the potential for thyroid toxicity during development. Consequently, there is concern for potential increased sensitivity or susceptibility in offspring regarding thyroid effects. A developmental thyroid toxicity study has been required, and the registrant has met with the Agency to discuss the conduct of the ongoing study. Pending receipt of the study, a 10X database uncertainty factor ( UF DB ) has been retained. The 10X special FQPA Factor has been reduced to 1X, however, since thyroid effects serve as the basis for endpoints for risk assessment for pendimethalin, since there were no developmental effects observed in the rat and rabbit developmental toxicity studies, and since the 10X UF DB has been retained for the lack of data in the developing thyroid. Page 25 of 55 4.3 Recommendation for a Developmental Neurotoxicity Study Because there is no concern for neurotoxicity following exposure to pendimethalin, a developmental neurotoxicity study is not needed.

4.4 Hazard Identification and Toxicity Endpoint Selection 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 The developmental toxicity rat and rabbit studies and the 2 generation rat reproduction study did not demonstrate developmental, reproductive, or offspring acute toxicity. Therefore, there is not a concern for prenatal exposure to pendimethalin following a single dose. A separate aRfD for women of childbearing age is not required.

4.4.2 Acute Reference Dose ( aRfD)  General Population No appropriate endpoint attributable to a single exposure ( dose) was identified from the oral toxicity studies including developmental toxicity studies in rats and rabbits. Therefore, an acute RfD for the general population was not established.

4.4.3 Chronic Reference Dose ( cRfD)

The following three studies: 92 day thyroid function in rats, 56 day ( 28 day treatment period) thyroid function in rats and 14 day intra thyroid metabolism study in rats were considered together to select the dose and endpoint for establishing the cRfD of 0.03 mg/ kg/ day. The cRfD is derived from the 14 day NOAEL of 10 mg/ kg/ day which is based on hormonal and histological changes in the thyroid. On this basis, the 56 day LOAEL of 31 mg/ kg/ day was established; the cRfD includes the combined uncertainty factor of 300X, based on a 3X interspecies extrapolation and a 10X for intraspecies variability ( see section 4.4.8), as well as the 10X UF DB for the lack of a developmental thyroid toxicity study.

Note: Subchronic exposure to Pendimethalin for 28 days resulted in a LOAEL of 500 ppm ( 31 mg/ kg/ day) based on several hormonal and histologic thyroid changes observed throughout the 28 day treatment period ( TSH and organ weights showed no overt changes at this dose). The NOAEL in the 92 day study was 100 ppm ( 4.98 mg/ kg/ day) while the 5000 ppm group exhibited thyroid hormonal, histologic and organ weight changes. The NOAEL in the 14 day intrathyroidal study was 100 ppm ( 10 mg/ kg/ day) with thyroid hormonal, histologic and organ weight changes also observed at 5000 ppm. The difference in the NOAELs of 4.98 mg/ kg/ day and 10 mg/ kg/ day ( both based on dietary concentrations of 100 ppm) is due to the time weighted average of compound intake. For the 14 day study, the rats received a higher dose of the compound than older rats due to increased body weight. The 14 day NOAEL of 10 mg/ kg/ day, accurately reflects a true NOAEL for thyroid effects since these effects have been demonstrated to have an early onset ( before 14 days). The three studies were considered together when establishing the Page 26 of 55 LOAEL at 31 mg/ kg/ day and the NOAEL at 10 mg/ kg/ day.

4.4.4 Incidental Oral Exposure ( Short and Intermediate Term)

The same three oral rat studies used to select endpoints and doses for risk assessment for chronic dietary, dermal and inhalation routes of exposure ( all durations) are considered applicable to endpoint selection for incidental oral exposure, since thyroid toxicity was observed after 3 days of dosing in the 14 day study. A NOAEL of 10 mg/ kg/ day was selected for all durations of oral exposure. The LOAEL of 31 mg/ kg/ day was based on several hormonal and histological thyroid changes.

4.4.5 Dermal Absorption There were no appropriate dermal absorption or toxicity studies available to allow an estimation of the dermal absorption by a route to route comparison of toxicity. In a previous risk assessment ( HIARC doc. 4/ 18/ 2000), dermal absorption was estimated to be no greater than 10%. This was based on structurally related chemicals ( oryzalin, trifluralin and ethalfluralin) with dermal absorption studies ( in monkeys) indicating absorption rates of 2.3%, ~ 1%, and 2.8%, respectively. The solubilities ( water) for pendimethalin and these related chemicals are also similar at 0.5 ppm, 2.5 ppm, 0.3 ppm and < 1 ppm, respectively. The upper bound value of 10% previously estimated for pendimethalin is considered very conservative. Therefore, for risk characterization purposes, a more appropriate estimate of 3% was applied. This absorption rate is comparable to those identified for related chemicals.

4.4.6 Dermal Exposure ( Short, Intermediate and Long Term)

The dermal endpoint and dose were selected considering three studies: 92 day thyroid function in rats, 56 day thyroid function in rats and 14 day intra thyroid metabolism study in rats. A NOAEL of 10 mg/ kg/ day was selected for all durations of dermal exposure. The LOAEL of 31 mg/ kg/ day was based on several hormonal and histological thyroid changes. Since the dermal endpoint was based on oral studies, an absorption factor of 3% was applied.

4.4.7 Inhalation Exposure ( Short, Intermediate and Long Term)

The inhalation endpoint and dose was selected considering three studies: 92 day thyroid function in rats, 56 day thyroid function in rats and 14 day intra thyroid metabolism study in rats. A NOAEL of 10 mg/ kg/ day was selected for all durations of inhalation exposure. The LOAEL of 31 mg/ kg/ day was based on several hormonal and histological thyroid changes. Since the inhalation endpoint was based on oral studies an inhalation absorption factor of 100% was applied.

4.4.8 Margins of Exposure HED has recommended retaining a 10X UF DB for pendimethalin to account for the lack of a Page 27 of 55 developmental thyroid toxicity study. The standard 10X intraspecies uncertainty factor and a 3X interspecies factor are applicable to pendimethalin risk assessments. The interspecies uncertainty factor of 10X was reduced to 3X due to the greater sensitivity of the adult rat to thyroid effects compared to the adult humans. Because of toxicodynamic differences in adult thyroid function that result in greater sensitivity of the adult rat to hypothyroidism compared to adult humans, the 3x ( 3.16) toxicodynamic part of the 10X can be removed leaving the 3X ( 3.16) portion for toxicokinetic interspecies differences ( Interim Guidance on Thyroid Disrupting Pesticides, dated 11/ 1/ 05). Thus, the usual 100X uncertainty factor for intra and interspecies differences is reduced to 30X. Therefore, the level of concern ( target MOE) for occupational exposure is 30X, while the target MOE for residential exposure is 300X because the additional 10X UF DB has been included for the lack of a developmental thyroid toxicity study.

4.4.9 Recommendation for Aggregate Exposure Risk Assessments In accordance with the requirements of the FQPA ( 1996), HED has considered the potential for concurrent exposure to pendimethalin via oral, dermal and inhalation routes. HED estimates aggregate exposure when exposure via different routes produces the same toxicological effects. Short term oral, dermal and inhalation exposures are being regulated based on the same effects seen in the same three oral studies ( 92 day thyroid function in rats, 56 day thyroid function in rats and 14 day intra thyroid metabolism study in rats). The use of these same studies to evaluate multiple routes of exposure implicitly assumes that different routes of exposure will result in the same toxicological effects and should, therefore, be aggregated.

4.4.10 Classification of Carcinogenic Potential The HED Cancer Peer Review Committee classified pendimethalin ( 3/ 18/ 92 and re affirmed 11/ 1/ 99) as a " Group C", possible human carcinogen, chemical based on a statistically significant increased trend and pair wise comparison between the high dose group and controls for thyroid follicular cell adenomas in male and female rats. The Committee recommended a non quantitative approach ( i. e., non linear, RfD approach) since mode of action studies are available that demonstrate that the thyroid tumors are due to a thyroid pituitary imbalance, and also since pendimethalin was shown to be non mutagenic in mammalian somatic cells and germ cells. Page 28 of 55 Table 4.4. Toxicological Doses and Endpoints for Pendimethalin Human Health Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Dietary Exposure Acute Dietary ( Females 13 49) ( General US Pop.) NA NA No appropriate acute endpoint identified for these groups. There were no toxic effects attributable to a single dose.

Chronic Dietary ( all populations) NOAEL = 10 mg/ kg/ day UF = 10X ( intraspecies) 3X ( interspecies) 10X ( database UF)

Total UF = 300X Chronic RfD= 0.03 mg/ kg/ day FQPA SF = 1X cPAD = Chronic RfD FQPA SF cPAD = 0.03 mg/ kg/ day 92 day thyroid function study in rats; 56 day thyroid study in rats; 14 day intra thyroid metabolism study in rats.

LOAEL= 31 mg/ kg/ day based on hormonal and histopathological changes in the thyroid.

Incidental Oral Exposure Incidental Oral Short Term ( 1  30 days)

Intermediate Term ( 1  6 months) NOAEL = 10 mg/ kg/ day UF = 10X ( intraspecies) 3X ( interspecies) 10X ( database UF)

Total UF = 300X FQPA SF = 1X Residential LOC = 300 Occupational LOC = 30 92 day thyroid function study in rats; 56 day thyroid study in rats; 14 day intra thyroid metabolism study in rats.

LOAEL= 31 mg/ kg/ day based on hormonal and histopathological changes in the thyroid.

Dermal Exposure Dermal Short Term ( 1  30 days)

Intermediate Term ( 1  6 months)

Long Term (> 6 months) NOAEL = 10 mg/ kg/ day UF = 10X ( intraspecies) 3X ( interspecies) 10X ( database UF)

Total UF = 300X Dermal Absorption = 3% FQPA SF = 10X Residential LOC = 300 Occupational LOC = 30 92 day thyroid function study in rats; 56 day thyroid study in rats; 14 day intra thyroid metabolism study in rats.

LOAEL= 31 mg/ kg/ day based on hormonal and histopathological changes in the thyroid.

Inhalation Exposure Table 4.4. Toxicological Doses and Endpoints for Pendimethalin Human Health Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Page 29 of 55 Inhalation Short Term ( 1  30 days)

Intermediate Term ( 1  6 months)

Long Term (> 6 months) NOAEL = 10 mg/ kg/ day UF = 10X ( intraspecies) 3X ( interspecies) 10X ( database UF)

Total UF = 300X Inhalation Absorption = 100% FQPA SF = 10X Residential LOC = 300 Occupational LOC = 30 92 day thyroid function study in rats; 56 day thyroid study in rats; 14 day intra thyroid metabolism study in rats..

LOAEL= 31 mg/ kg/ day based on hormonal and histopathological changes in the thyroid.

Cancer Cancer ( oral, dermal, inhalation) Pendimethalin is considered to be a possible human carcinogen; quantitative estimate of cancer risk is not required. 2 year chronic/ carcinogenicity study in rats UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable * Refer to Section 4.5 4.5 Special FQPA Safety Factor HED has reduced the Special FQPA Safety Factor of 10X for pendimethalin to 1X. Hormonal changes ( alterations in thyroid weights and histopathological lesions) were observed in several studies following oral administration of pendimethalin and it is likely that pendimethalin may cause disruption in the endocrine system. There is concern that perturbation of thyroid homeostasis may lead to hypothyroidism, and possibly result in adverse effects on the developing nervous system. HED has recommended that a developmental thyroid assay be conducted to evaluate the impact of pendimethalin on thyroid hormones, structure, and/ or thyroid hormone homeostasis during development.

Since there was no evidence of quantitative or qualitative susceptibility in the submitted studies, and since a 10X database uncertainty factor has been retained for pendimethalin pending receipt of the required developmental thyroid toxicity study, HED reduced the 10X Special FQPA Safety Factor to 1X.

4.6 Endocrine disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following recommendations of Page 30 of 55 its Endocrine Disruptor and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP).

Based on the hormonal changes ( alterations in thyroid weights and histopathological lesions) observed in several studies following oral administration of pendimethalin, it is likely that pendimethalin may cause disruption in the endocrine system. Therefore, when additional appropriate screening and/ or testing protocols have been developed, it is recommended that pendimethalin be tested to better characterize effects related to endocrine disruption.

5.0 Public Health Data 5.1 Incident Reports A search in the Office of Pesticide Programs' Incident Data System ( 2/ 28/ 96) indicated 12 reports with 3 of these involving 5 humans ( the remainder concern fish, wildlife or domestic animals). The symptoms included signs of systemic illness: vomiting, diarrhea, chills and shakiness. Three people were hospitalized when they were exposed to a mixture of pesticides including pendimethalin and nitrogen. The database does not indicate the associated use patterns or activities in which the poisoned individuals were involved.

The California Pesticide Illness Surveillance Program for 1982 1992 contained six reports. In three the effects were systemic ( vomiting, diarrhea, etc.), two had skin effects, and one involved eye effects.

Pendimethalin ranked 41st on a list of the top 200 active ingredients for which the National Pesticide Telecommunications Network ( NPTN) received calls during 1982 1991. There were 682 calls, with 91 concerning human poisoning due to pendimethalin. HED has requested more details on the NPTN reports for review.

6.0 Exposure Characterization/ Assessment 6.1 Dietary Exposure/ Risk Pathway 6.1.1 Residue Profile Page 31 of 55 Tolerances are established for the combined residues of the herbicide pendimethalin [ N( 1 ethylpropyl) 3,4 dimethyl 2,6 dinitrobenzenamine] and its metabolite 4[( 1 ethylpropyl) amino] 2 methyl 3,5 dinitrobenzyl alcohol in or on a variety of raw agricultural commodities, including bean, lima, seed; bean, lima, succulent; bean, forage; bean, hay; corn, field, forage; corn, field, grain; corn, field, stover; corn, pop, grain; corn, sweet, forage; corn, sweet, kernel plus cob with husks removed; corn, sweet, stover; cotton, undelinted seed; garlic; onion, dry bulb; pea, succulent; peanut; peanut, hay; potato; rice, grain; rice, straw; sorghum, forage; sorghum, grain; grain; sorghum, grain, stover; soybean, forage; soybean, hay; soybean, seed; sugarcane, cane; and sunflower, seed [ all at 0.1 ppm].

The residue chemistry database to support reregistration of agricultural uses of pendimethalin, with respect to the nature of the residue in plants, livestock and rotational crops; residues to be regulated in plants for both risk assessment and tolerance enforcement; storage stability; processing studies and residue analytical methods were summarized in the 1996 residue chemistry chapter of the pendimethalin RED.

The residue chemistry data submitted to support the proposed uses ( and associated tolerances) on citrus, mint, carrots and tree nuts are generally adequate with respect to field trials, analytical methods, storage stability data and processing studies. Additional field trial data to support the proposed crop group tolerance on citrus are conditionally required. Required additional field trial data for carrots grown in CA are considered adequate. In general, residue data indicate combined residues of parent pendimethalin and its 3,5 dinitrobenzyl alcohol metabolite are very low or nondetectable. However, residues concentrate in some processed commodities, including citrus oil and mint oil.

6.1.2 Acute and Chronic Dietary Exposure and Risk ( Pendimethalin: Chronic Dietary Exposure Assessment to Support Proposed Section 3 Registration on Citrus, Mint, Carrots and Tree Nuts. Christina Swartz, 2006; DP Document Pending)

A chronic dietary risk assessment was conducted using the Dietary Exposure Evaluation Model ( DEEM FCID   , Version 2.03), which use the most recent food consumption data from USDA ( CSFII, 1994 1996 and 1998).

Tolerance level residues were assumed for all food commodities with current and proposed pendimethalin tolerances, and it was assumed that all of the crops included in the analysis were treated ( i. e., 100 % crop treated). These assumptions result in highly conservative estimates of dietary exposure and risk. In calculating dietary risk estimates, HED has compared the chronic population adjusted dose ( cPAD) to the estimated dietary exposure from DEEM FCID. Typically, HED has concerns regarding dietary risk when the exposure estimates exceed 100% of the cPAD. Even with the conservative assumptions noted above, risk estimates associated with dietary exposure to pendimethalin are significantly below HED's level of concern.

The most highly exposed population subgroup was children 1 2 years old. The chronic exposure estimate of approximately 0.002 mg/ kg/ day corresponds to 6 % cPAD. Risks for the general US Page 32 of 55 population and all other population subgroups were lower.

Table 6.1 Summary of Chronic Dietary Exposure and Risk for Pendimethalin.

Population Subgroup cPAD, mg/ kg/ day DEEM FCIDTM Exposure mg/ kg/ day % cPAD General U. S. Population 0.03 0.000710 2.4 All Infants (< 1 yr) 0.03 0.001295 4.3 Children 1 2 yrs 0.03 0.001787 6 Children 3 5 yrs 0.03 0.001608 5.4 Children 6 12 yrs 0.03 0.001105 3.7 Youth 13 19 yrs 0.03 0.000742 2.5 Adults 20 49 yrs 0.03 0.000558 1.9 Adults 50+ yrs 0.03 0.000473 1.6 Females 13 49 yrs 0.03 0.000556 1.9 C The values for the population with the highest risk for each type of risk assessment are bolded.

6.2 Water Exposure/ Risk Pathway ( Drinking Water Assessment for Pendimethalin for Bearing Citrus, Fruit and Nut Trees, Onion and Mint, James Breithaupt, 12/ 22/ 04, D310591)

Pendimethalin dissipates in the environment by binding to soil, metabolizing by microbes, and by volatilizing into air. Persistence decreased with increased temperature, increased moisture and decreased soil organic carbon. Pendimethalin residues in laboratory and field studies are tightly bound to soil and sediment particles, which is consistent with the laboratory mobility studies.

EFED estimated concentrations in drinking water using Tier II screening level surface water modeling ( PRZM EXAMS) for surface water and Tier I modeling ( SCI GROW2) for ground water. These Estimated Drinking Water Concentrations ( EDWCs) may be used for acute, chronic ( non cancer), and chronic ( cancer) exposure assessments. The PRZM EXAMS concentrations to be used for drinking water ranged from 2.2 to 38.8 ug/ L for peak values, 0.1 to 4.8 ug/ L for chronic ( non cancer), and 0.1 to 3.8 ug/ L for chronic ( cancer) exposures as summarized in Table 6.2.

The 1 in 10 year annual peak ( acute), 1 in 10 year annual mean ( non cancer chronic), and 36 year annual mean concentrations ( cancer chronic) were derived from modeling pendimethalin on the Pennsylvania apple scenario.

Based on SCI GROW modeling, the acute and chronic pendimethalin concentrations are not expected to exceed 0.024 : g/ L ( ppb) from one application of 4 lbs ai/ A. The estimated concentrations of up to 0.024 ug/ L were actually lower than the detected concentrations in ground water, ranging from 0.2 to 0.9 ppb. However, EFED does not consider pendimethalin to Page 33 of 55 be a likely ground water contaminant in most environments based on its environmental fate property of tight sorption to soil.

Parent pendimethalin is the only significant non volatile residue, therefore, the EDWCs were calculated for parent pendimethalin only.

Table 6.2. Summary of Estimated Surface and Ground Water Concentrations for Pendimethalin.

Exposure Duration Pendimethalin, per se Surface Water Conc., ppb Ground Water Conc., ppb Acute 38.8 0.024 Chronic ( non cancer) 4.8 0.024 Chronic ( cancer) 3.8 NA 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway ( Occupational and Residential Exposure for the Use of Pendimethalin Proposed Section 3 Registration for Use on Mint, Citrus Fruits, Tree Nuts, and Carrots; PC Code: 108501; DP Barcode D310952; M. Collantes and Z. Figueroa; 3/ 09/ 05)

6.3.1 Home Uses <IP_ADDRESS> Residential Handler Residential handler exposure estimates of applying pendimethalin to residential turf were previously assessed in the 1996 re registration eligibility decision ( RED) document for pendimethalin ( J. Leahy, D221532, February 20, 1996). The MOEs for residential handlers wearing baseline attire were all greater then the level of concern. Since that time registered labels for use of pendimethalin on turf have been revised. All turf ( ornamental, landscape, golf course, non cropland) labels appear to be for commercial use only based on the contents ( i. e. requiring mixing tanks, ground equipment for application, personal protective equipment and restricted entry intervals). However labels do not indicate for use by licenced chemical operator only. The Registration Division should confirm that proper language clarifying that products are to be applied only by commercial or licensed operators. A revised residential handler exposure assessment for applying pendimethalin to residential turf was not performed.

<IP_ADDRESS> Residential Postapplication In the 1996 RED, the following three representative post application scenarios were assessed: 1) toddler exposure to residential turf; 2) maintenance worker exposure to golf course turf; and 3) harvesting turfgrass from a sod farm. Of these three scenarios, toddler exposure to residential turf grass is the only scenario considered as residential exposure. This scenario was representative of the worst case postapplication exposure to residential populations, including children, following Page 34 of 55 applications to residential and recreational turf areas or ornamental plantings. Based on postapplication calculations using surrogate data, HED concluded that the MOEs were unacceptable at the 3 lb a. i./ acre rate and required a reduction in maximum use rate from 3 to 2 lb a. i./ acre on residential and recreational area turf grass. Since that time, application rates have been reduced to 2 lb. a. i./ acre for residential turf. Furthermore chemical specific turf transferable residue ( TTR) and hand press data have been submitted to the Agency and reviewed in support of the use of pendimethalin on residential lawns. HED has provided the following revised postapplication exposure assessment for use of pendimethalin on residential lawns.

<IP_ADDRESS>.1 Dermal Exposure and Risk Chemical specific WDG turf transferable residue ( TTR) data have been submitted to the Agency and reviewed in support of assessing dermal exposure to adults and children.

The level of concern for non occupational dermal exposure is 300. Using the TTR data for the Pendulum WDG formulation, children's short term dermal MOEs calculated at a rate of 3.0 lb ai/ A ranged from 440 to 910. For adults, short term dermal MOEs ranged from 740 to 1500. All dermal short term MOEs were greater than 300 and therefore did not exceed HED's level of concern ( LOC). A summary of the dermal exposure and MOEs are included as Tables 6.3a and b.

Table 6.3 a: Summary Table of Short term Dermal Exposure for Children ( Tier 1)

State TTR 1 ( µ g/ cm2) ( mg/ µ g) TC 2 ( cm2/ hr) ET 3 ( hrs) Dermal Absorption BW ( kg) Daily Dose 4 ( mg/ kg/ day) NOAEL ( mg/ kg/ day) MOE 5 CA 1.1 0.001 5200 2 0.03 15 0.0228 10 440 PA 0.756 0.0157 640 FL 0.538 0.011 910 1. TTR = transferable residues based on Pendulum WDG TTR study ( MRID 449699 01) 2. Tc = transfer coefficient based on HED Residential SOPs 3. ET = exposure time based on HED Residential SOPs 4. Dose = TTR ( ug/ cm2) x 0.001 ( mg/ ug) x Tc ( cm2/ hr) x ET ( hrs/ day) x dermal absorp BW 5. Dermal MOE = Short term NOAEL ( 10 mg/ kg/ day) Daily Dose Page 35 of 55 Table 6.3b: Summary Table of Short term Dermal Exposure for Adults ( Tier 1)

State TTR 1 ( µ g/ cm2) ( mg/ µ g) TC 2 ( cm2/ hr) ET 3 ( hrs) Dermal Absorption BW ( kg) Dose 4 ( mg/ kg/ day) NOAEL ( mg/ kg/ day) MOE 5 CA 1.1 0.001 14500 2 0.03 70 0.0136 10 740 PA 0.756 0.009 1100 FL 0.538 0.00668 1500 1. TTR = transferable residues based on Pendulum WDG TTR study ( MRID 449699 01) 2. Tc = transfer coefficient based on HED Residential SOPs 3. ET = exposure time based on HED Residential SOPs 4. Dose = TTR ( ug/ cm2) x 0.001 ( mg/ ug) x Tc ( cm2/ hr) x ET ( hrs/ day) x dermal absorp ( mg/ kg/ day) BW 5. MOE = Short term NOAEL ( 10 mg/ kg/ day) Daily Dose <IP_ADDRESS>.2 Inhalation Exposure Since there are no indoor residential uses and only outdoor turf uses associated with these products, inhalation exposure resulting from outdoor uses is expected to be negligible. Therefore, a postapplication inhalation exposure assessment was not required.

<IP_ADDRESS>.3 Oral Exposure and Risk The NOAEL of 10 mg/ kg/ day was used to calculate MOEs for children's oral exposure for handto mouth, object to mouth, and soil ingestion. To further refine oral exposure estimates, HED used hand press residue data to estimate oral MOEs. The level of concern for non occupational oral exposure is 300.

All oral ( hand to mouth, object to mouth, and soil ingestion) exposures were greater than 300 and therefore are not of concern to HED. The MOEs calculated for hand to mouth exposures using the rate of 2.0 lb ai/ A resulted in an MOE of 7,700. The MOEs for object to mouth and soil ingestion exposure were 130,000 and 100,000 respectively. MOEs calculated for hand tomouth exposures using the rate of 3.0 lb ai/ A resulted in an MOE of 5,300. The MOEs for object to mouth and soil ingestion exposure were 85,000 and 67,000 respectively. A summary of the oral MOEs is provided in Table 6.3c.

Ingestion of pendimethalin granules is also a potential source of exposure because children can eat them if they are found in treated lawns or gardens. This scenario is considered to be episodic, and therefore acute oral endpoints would be used to estimate the risk. A risk assessment for this exposure scenario for children was not conducted since an acute oral toxicological endpoint of concern was not identified for pendimethalin. Page 36 of 55 Table 6.3c: Summary of Oral Exposure for Pendimethalin ( Tier 1) Hand to Mouth 1 Rate ( lbai/ A ) SR 0 TTR a ( µ g/ cm2) Grt a ( µ g/ cm2) Srt a ( µ g/ g) ( mg/ µ g) b or ( g/ ug) c SA ( cm2/ event) IgR ( cm2/ day)

d or ( mg/ day) e FQ ( events/ hr ) SEF ET ( hrs) BW ( kg) Dose f ( mg/ kg/ day) MOE 2.0 22.4 0.049 NA NA 1E 3 b 20 NA 20 0.5 2 15 0.0013 7700 3.0 33.6 0.74 0.0019 5300 Object to Mouth 2 2.0 NA NA 0.0471 NA 1E 3 b NA 25 NA NA NA 15 0.0000785 130,000 3.0 0.07 0.0001178 85,000 Soil Ingestion 3 2.0 NA NA NA 15 1E 6 c NA 100 NA NA NA 15 0.0001 100,000 3.0 22.5 0.00015 67,000 Total Oral Dose 5 and MOE 6 2.0 0.001479 6800 3.0 0.00217 4600 Notes:

0. SR = Surface Residue = 2 lb ai/ A x 11.2 = 22.4 1a. TTR = application rate ( 2 lb ai/ A) x conversion factor ( 11.22 µ g/ cm2 ) x % transferability ( 0.0022) for gauze wipe 1f. Hand to mouth Dose = TTR t ( ug/ cm2) x SA ( cm2/ event) x SEF x FQ ( events/ hr) x 1.0E 3 mg/ ug x ET ( hrs/ day)

Body Weight ( kg)

2a. GRt = application rate ( 2 lb ai/ A) x ( 11.22 µ g/ cm2 ) x % transferability ( 0.0021) aerosol OT solution sample 2f. Object to mouth Dose = GR t ( ug/ cm2) x IgR ( cm2/ day) x 1.0E 3 mg/ ug Body Weight ( kg)

3a. Srt = application rate ( 2 lb ai/ A) x ( 11.22 µ g/ cm2 ) x % transferability ( 1.0) x 0.67 cm2/ g soil 3f Oral Dose t = SR t ( ug/ g) * IgR ( 100 mg/ day) * CF1( 10 3 g/ mg) x ( 10 3 mg/ ug)

Body Weight ( kg)

4. TTR, Grt, and Srt values are cited from 2001 ORE memo for Pendimethalin ( D270528)

5. Total Dose = Hand to mouth dose + Object to mouth dose + Soil ingestion dose 6. Total Oral MOE =_ 1 Or NOAEL ( 10 mg/ kg/ day)

1 1 1 Hand to Mouth Dose + Object to Mouth Dose + Soil Ingestion Dose Hand to Mouth MOE + Object to Mouth MOE + Soil Ingestion MOE Page 37 of 55 <IP_ADDRESS>.4 Aggregate Residential Exposure In evaluating the residential uses of pendimethalin, HED has combined all non dietary sources of postapplication exposure to obtain an estimate of potential aggregate exposure. These scenarios are short term in duration and consist of dermal ( adults and children) and oral ( hand to mouth, object to mouth and soil ingestion  children only) exposure. HED combines risk values resulting from separate exposure scenarios when it is likely they can occur simultaneously based on the usepattern and the behavior associated with the exposed population.

A Tier 1 aggregate exposure estimate for adults ( consisting of dermal exposure only) resulted in a total MOE of 740 which is greater than the level of concern of 300 and therefore not of concern ( Table 6.3d). The adult total MOE of 740 was based on using the TTR from California test site and 3% dermal absorption factor. Since the California test site resulted in the lowest dermal MOE, it was determined to represent the worst case scenario. In assessing the aggregate residential exposure for children, HED also used the California TTR data, hand press data and 3% dermal absorption factor for determining dermal exposure to children. This resulted in a total MOE ( dermal + oral) of 410 for an application rate of 2 lb ai/ acre and 400 for an application rate of 3 lb ai/ acre, both of which are greater than 300 and therefore not of concern. This information is also summarized in Table 6.3d. Page 38 of 55 Table 6.3d: Aggregate Risk Resulting from Residential Exposure to Pendimethalin ( Tier 1)

Exposure Scenario Population TTR (( ug/ cm2) 1 Dermal Dose 2 ( mg/ kg/ day) Dermal MOE 3 Inhalation MOE Total Oral Dose4 ( mg/ kg/ day) Oral MOE3 Total Dose Total MOE 4 Turf Grass adults 1.1 0.0136 a 740 NA NA NA 0.0136 740 children 0.0228 b 440 NA 0.0015 6800 0.0243 410 0.0022 4600 0.025 400 Notes:

1. TTR values based on Pendulum WDG TTR study ( MRID 449699 01)

2a. See Table 4 2b. See Table 5 3. Dermal MOE = Average of dermal MOEs for adults and children calculated from TTR data from CA, PA and FL ( see Tables 4 and 5)

4. Oral Dose = Hand to mouth dose + Object to mouth dose + Soil ingestion dose ( See Table 6)

5. Oral MOE = _ 1 Hand to Mouth MOE + Object to Mouth MOE + Soil Ingestion MOE 6. Total MOE = _ 1 OR NOAEL ( 10 mg/ kg/ day)

____ 1______ + 1 Dermal Dose + Total Oral Dose ( Hand to Mouth Dose + Object to Mouth Dose + Soil Ingestion Dose)

Dermal MOE Oral MOE Page 39 of 55 6.3.2 Recreational Uses In the 1996 RED, handler and postapplication exposures were assessed for maintenance worker exposure to golf course turf. As indicated previously, children's exposure to residential turfgrass was also assessed and determined to represent the worst case exposure resulting from residential populations, including children, following applications to residential and recreational turf areas or ornamental plantings. Therefore a residential exposure assessment for golf course exposures has not been included in this assessment.

6.3.3 Other ( Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for pendimethalin. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U. S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off target drift with specific products with significant risks associated with drift.

7.0 Aggregate Risk Assessments and Risk Characterization In accordance with the FQPA, HED must consider and aggregate ( add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e. g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

In evaluating the proposed uses of pendimethalin, HED has combined dietary ( food) and nondietary ( turf grass) sources of exposure to obtain an estimate of potential aggregate exposure. The non dietary scenarios in the aggregate assessment include dermal exposure for adults and children as well as incidental oral exposures ( hand and object to mouth transfer of residues and ingestion of soil) for children only.

HED acknowledges that the aggregate exposure and risk estimates for children are likely to overestimate actual exposures since our estimates assume simultaneous, constant exposures from dietary and non dietary sources. An assessment that takes into account the timing of source Page 40 of 55 specific exposures and the likelihood of their co occurring would be expected to produce more realistic and lower exposure and risk estimates.

For most pesticide active ingredients, water monitoring data are considered inadequate to determine surface and ground water drinking water exposure estimates, so model estimates have been used to estimate residues in drinking water ( EDWCs). In order to determine if aggregate risks are of concern, HED then calculates drinking water levels of comparison, or DWLOCs. The DWLOC is the maximum amount of a pesticide in drinking water that would be acceptable in light of combined exposure from food and residential pathways. The calculated DWLOCs are then compared to the EDWCs provided by EFED; if model derived EDWCs exceed the DWLOCs for surface or ground water, there may be a concern for dietary exposure to residues in drinking water, and monitoring data may be required.

7.1 Acute Aggregate Risk No toxic effects attributable to a single dose were identified for pendimethalin. Therefore, an acute risk assessment is not warranted for this chemical.

7.2 Short Term Aggregate Risk In estimating short term aggregate risk, HED combined the chronic dietary ( food) exposure estimate and the total non dietary ( residential) exposure estimate for adults and children. The chronic dietary exposure estimate reflects average dietary exposure and serves as an estimate of dietary exposure that co occurs with potential short term non dietary exposure to adults and children. The short term aggregate exposures for adults and children at application rates of 3 and 2 lb ai/ acre were greater than the EDWC for groundwater or surface water and therefore, were not of concern. Short term aggregate risk estimates for pendimethalin are summarized in Table 7.2. Page 41 of 55 Table 7.2. Short Term and/ or Intermediate Term Aggregate Risk and DWLOC Calculations Population Short Term Scenario NOAEL mg/ kg/ day Target MOE1 Max Exposure2 mg/ kg/ day Average Food Exposure mg/ kg/ day Residential Exposure3 mg/ kg/ day Aggregate MOE ( food and residential) 4 Max Water Exposure5 mg/ kg/ day Ground Water EDWC6 ( ppb) Surface Water EDWC6 ( ppb) Short

Term DWLOC7 ( µ g/ L)

Adult Male ( U. S. Population) 10 300 0.0333333 0.000710 0.014 699 0.019023 0.024 5 666 Adult Female ( Females 13+) 10 300 0.0333333 0.000473 0.016 607 0.016860 506 Child ( 1 2 yrs) 10 300 0.0333333 0.001787 0.024 383 0.007246 72 0.025 370 0.006300 95 1 Target MOE = 300 based on a total UF of 100 ( 10X intraspecies, 3X interspecies, 10X Database).

2 Maximum Exposure ( mg/ kg/ day) = NOAEL/ Target MOE 3 Residential Exposure = [ Oral exposure + Dermal exposure + Inhalation Exposure]

4 Aggregate MOE = [ NOAEL ÷ ( Avg Food Exposure + Residential Exposure)]

5 Maximum Water Exposure ( mg/ kg/ day) = Target Maximum Exposure  ( Food Exposure + Residential Exposure)

6 The crop producing the highest level was used.

7 DWLOC( µ g/ L) = [ maximum water exposure ( mg/ kg/ day) x body weight ( kg)]

[ water consumption ( L) x 10 3 mg/ µ g]

Body Weight = 70 kg for adults, 10 Kg for children; Water consumption = 2L for adults, 1L for children.

8Exposure refers to the highest dietary exposure. Page 42 of 55 7.3 Intermediate Term Aggregate Risk Based on the currently requested uses, there are no scenarios that are likely to result in intermediate term exposure ( 30 180 days, continuous). Therefore, HED has not conducted an intermediate term risk assessment for pendimethalin.

7.4 Long Term Aggregate Risk The dietary exposure ( food) pathway is the only source of exposure to pendimethalin that is expected to be long term ( 180  365 days). Therefore, the long term aggregate exposure and risk estimates are equivalent to the chronic dietary exposure and risk estimates discussed in Section 6.1.2. The chronic aggregate exposure is provided in Table 7.4 for convenience. For all population subgroups, the chronic DWLOC is greater than the chronic ground and surface water EDWC; therefore, aggregate chronic exposure to pendimethalin is not expected to exceed HED's level of concern.

Table 7.4. Aggregate Risk Assessment for Chronic ( Non Cancer) Exposure to Pendimethalin.

Population Subgroup Chronic Scenario cPAD mg/ kg/ day Chronic Food Exp mg/ kg/ day Max Chronic Water Exp mg/ kg/ day1 Ground Water EDWC ( ppb) 2 Surface Water EDWC ( ppb) 2 Chronic DWLOC ( ppb) 3 U. S. Population 0.03 0.000710 0.02929 0.024 4.8 1025 All Infants (< 1 year old) 0.0001295 0.02987 448 Children 1 2 years 0.001787 0.028213 423 Children 3 5 years 0.001608 0.0284 426 Children 6 12 0.001105 0.028895 433 Youth 13 19 0.000742 0.02926 1024 Adults 20 49 0.000558 0.029442 1030 Females 13+ 0.000473 0.0295 885 Adults 50+ years 0.000556 0.0294 1029 1Maximum Chronic Water Exposure ( mg/ kg/ day) = [ Chronic PAD ( mg/ kg/ day)  Chronic Dietary Exposure ( mg/ kg/ day)] 2 See Table 6.2 Estimated Surface and Groundwater Concentrations 3 Chronic DWLOC( µ g/ L) = [ maximum chronic water exposure ( mg/ kg/ day) x body weight ( kg)] [ water consumption ( L) x 10 3 mg/ µ g] body weights ( 70 kg adult male; 60 kg adult female; 10 kg child) Page 43 of 55 7.5 Cancer Aggregate Risk The HED Cancer Peer Review Committee classified pendimethalin as a " Group C", possible human carcinogen based on thyroid follicular cell adenomas in the rats. The committee recommended a non quantitative approach ( i. e., non linear, RfD approach) therefore, a quantitative cancer aggregate risk assessment was not required.

8.0 Cumulative Risk Characterization/ Assessment 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 pendimethalin and any other substances and pendimethalin 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 pendimethalin 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/.

9.0 Occupational Exposure/ Risk Pathway ( Occupational and Residential Exposure for the Use of Pendimethalin Proposed Section 3 Registration for Use on Mint, Citrus Fruits, Tree Nuts, and Carrots; PC Code: 108501; DP Barcode D310952; M. Collantes and Z. Figueroa; 3/ 09/ 05)

9.1 Agricultural and Commercial Handlers The following two agricultural ( PROWL ® 3.3 EC and PROWL ® H 2 O) and commercial ( Pendulum 3.3 EC and Pendulum AquaCap) products have been assessed for occupational exposure.

PROWL ® 3.3 EC contains 37.4% of the active ingredient ( a. i.) pendimethalin, while PROWL ®

H 2 O Herbicide contains 38.7% active ingredient. Both products are formulated as liquids, used as an agricultural herbicide on mint, citrus fruits, tree nuts, and carrots and applied by chemigation, ground and aerial equipment. The proposed application rates for PROWL ® 3.3 EC range from 0.743 to 3.96 lbs active ingredient ( ai) per acre. A maximum seasonal application rates are also specified as 1.98 lb a. i./ A/ season for mint, 1.0 lb a. i./ A/ season for carrots, and 3.96 lb a. i./ A/ season for citrus fruits and tree nuts. The proposed application rates for Prowl ® H 2 O range from 0.713 to 3.80 lbs active ingredient ( ai) per acre. The maximum seasonal application rates are also specified as 1.90 lb a. i./ A/ season for mint, 0.95 lb a. i./ A/ season for carrots, and 3.80 lb a. i./ A/ season for citrus fruits and tree nuts.

Pendulum 3.3 EC herbicide contains 37.4% of the active ingredient ( a. i.) pendimethalin, while Page 44 of 55 Pendulum AquaCap herbicide contains 38.7 % pendimethalin. Both products are formulated as liquids, used to control weeds in turfgrass, ornamentals, landscape, ground maintenance, golf courses, sod farms and noncrop land areas. Both products are applied by ground equipment, backpack and hand gun sprayers applied at a maximum rate of 3 lbs a. i. per acre.

Based on the number of seasonal applications indicated on these product labels, and information provided by the registrant, handler exposures are expected to be short term in duration.

Chemical specific data for assessing exposure during pesticide handling activities were not submitted to the Agency in support of this Section 3 application. It is HED policy to use data from the Pesticide Handlers Exposure Database ( PHED) Version 1.1 to assess handler exposures for regulatory actions when chemical specific data are not available ( HED Science Advisory Council for Exposure, SOP Number .007, January 1999).

Occupational handler exposure assessments were completed by HED using baseline and single layer of personal protective equipment ( PPE). The baseline clothing level for occupational exposure scenarios is generally an individual wearing long pants, a long sleeved shirt, no chemical resistant gloves, and no respirator. The first level of mitigation generally applied is PPE. As reflected in the calculations included herein, PPE may involve the use of single layer of clothing, chemical resistant gloves, and no respirator.

9.1.2 Exposure and Risk Summaries of the non cancer ( MOEs) short term risks for handlers at the baseline and PPE levels are included in Table 9. Calculations for handler exposure were performed for the highest application rate per crop to represent the worst case scenario. Since both dermal and inhalation toxicological endpoints were the same for the short term duration, the route specific MOEs were combined and compared to the NOAEL ( 10 mg/ kg/ day). The total MOEs for short term mixing/ loading scenarios ranged from 50 at baseline to 1,200 using PPE ( single layer and gloves), and did not exceed HED's level of concern ( MOEs < 30). The total MOEs for short term applicator and flagger scenarios, at baseline level of mitigation and engineering controls for aerial, range from 1,000 to 9,100 and do not exceed HED's level of concern ( MOEs < 30). The total MOEs for short term mixer/ loader/ applicator using PPE ( single layer clothes and gloves) ranged from 40 to 2,800 and did not exceed HED's level of concern ( MOEs < 30).

The handler exposure estimates in this assessment are based on a central tendency estimate of unit exposure and an upper percentile assumption for the application rate, and are assumed to be representative of high end exposures. The uncertainties associated with this assessment stem from the use of surrogate exposure data ( e. g., differences in use scenario and data confidence) and assumptions regarding the amount of chemical handled. The estimated exposures are believed to be reasonable high end estimates based on observations from field studies and professional judgement. It should be noted that for mixing/ loading scenarios, gloves are requested. Page 45 of 55 9.2 Agricultural Postapplication No postapplication data were submitted in support of this registration action. Based on the number of seasonal applications indicated on the proposed product labels, and information provided by the registrant, postapplication exposures are expected to be short term in duration for all agricultural crops. Furthermore, since these products are herbicides used to mainly control pre emergent weeds, and not applied directly to foliage, postapplication exposure is expected to be minimal. Based on this information a postapplication exposure assessment was neither required nor performed.

9.3 Commercial Postapplication The following two representative post application commercial scenarios: 1.) maintenance worker exposure to golf course turf, and 2.) harvesting turfgrass from a sod farm were assessed in the 1996 RED. Surrogate Foliar Dislodgeable Residue ( FDR) data were used to assess golf course and sod farm turf postapplication exposure. Calculations of postapplication exposure resulted in acceptable MOEs and therefore were not of concern to HED.

Restricted Entry Interval ( REI) The restricted entry interval ( REI) is based on the acute toxicity of pendimethalin technical material which is classified as Category III and IV for acute dermal, dermal irritation and eye irritation ( HIARC Doc. No. 014116, April 18, 2000). Acute toxicity Category III and IV chemicals for these potential hazards require a 12 hour REI. Based on the acute toxicity categories for this chemical, HED recommends that the current product labels provide a 12 hour REI. Page 46 of 55 Table 9 : Short term Handler Exposure and Risk for Pendimethalin Exposure Scenario Crop Mitigation Level Dermal Unit Exposure ( mg/ lb ai) Inhalation Unit Exposure (: g/ lb ai) Application Rate ( lb ai/ A) Amount Treated ( acres/ day) Dermal Dose ( mg/ kg/ day) a Inhalation Dose b ( mg/ kg/ day) Dermal MOE c Inhalation MOE d Total Dose e Total MOE f Mixer/ Loader Liquid for Aerial application carrots Baseline 2.9 1.2 ( 0.0012 mg/ lb ai) 1.0 350 0.435 0.0060 23 1,700 0.441 22 Single layer,

gloves 0.023 0.00345 0.0060 2900 1,700 0.00945 1100 Liquid for Grourndboom Application mint Baseline 2.9 1.2 ( 0.0012 mg/ lb ai) 1.98 80 0.196 0.0027 50 3,700 0.198 50 Liquid for Grourndboom Application citrus Baseline 2.9 1.2 ( 0.0012 mg/ lb ai) 3.96 80 0.39 0.0054 25 1,900 0.39 25 Single layer,

gloves 0.023 0.00312 0.0054 3,200 1,900 0.00852 1200 Liquid for Groundboom Application carrots Baseline 2.9 1.2 ( 0.0012 mg/ lb ai) 1.0 80 0.099 0.0014 30 100 0.1 100 Liquid for Groundboom Application tree nuts Baseline 2.9 1.2 ( 0.0012 mg/ lb ai) 3.96 80 .4 0.0054 25 1,900 0.4 25 Single layer,

gloves 0.023 0.00312 0.0054 3,200 1,900 0.0085 1200 Liquid for Groundboom Application turfgrass, sod, golf course, ornamentals,

landscape, grounds maintenance, noncroplands Baseline 2.9 0.0012 mg/ lb ai 3.0 200 ( sod farm) 0.75 0.0103 13 970 0.76 13 Single layer,

gloves 0.023 0.006 0.0103 1700 970 0.0163 610 Liquid for Chemigation Application Citurs Fruits Baseline 2.9 1.2 ( 0.0012 mg/ lb ai) 3.96 350 1.7 0.024 6 416 1.7 6 Single layer,

gloves 0.023 0.0136 0.024 740 416 0.037 270 Table 9 : Short term Handler Exposure and Risk for Pendimethalin Exposure Scenario Crop Mitigation Level Dermal Unit Exposure ( mg/ lb ai) Inhalation Unit Exposure (: g/ lb ai) Application Rate ( lb ai/ A) Amount Treated ( acres/ day) Dermal Dose ( mg/ kg/ day) a Inhalation Dose b ( mg/ kg/ day) Dermal MOE c Inhalation MOE d Total Dose e Total MOE f Page 47 of 55 Liquid for Chemigation application carrots Baseline 2.9 1.2 ( 0.0012 mg/ lb ai) 1.0 350 0.435 0.0060 30 1,700 0.441 22 Single layer,

gloves 0.023 1.0 0.00345 0.0060 2900 1,700 0.00945 1100 Liquid for Chemigation application tree nuts Baseline 2.9 1.2 ( 0.0012 mg/ lb ai) 3.96 350 1.7 0.024 6 416 1.7 6 Single layer,

gloves 0.023 3.96 0.0136 0.024 740 416 0.037 270 Applicator Sprays for Aerial application carrots Baseline 0.005 0.068 ( 0.000068 mg/ lb ai) 1.0 350 0.00075 0.00034 13,000 29,000 0.0011 9,100 Sprays for Groundboom application mint Baseline 0.014 0.74 ( 0.00074 mg/ lb ai) 1.98 80 0.0009 0.0017 11,000 5,900 0.0026 3,800 Sprays for Groundboom application citrus fruit Baseline 0.014 0.74 ( 0.00074 mg/ lb ai) 3.96 80 0.0019 0.0033 5,300 3,000 0.0052 1,900 Sprays for Groundboom application carrots Baseline 0.014 0.74 ( 0.00074 mg/ lb ai) 1.0 80 0.00048 0.00085 21,000 12,000 0.00133 7,500 Sprays for Groundboom application tree nuts Baseline 0.014 0.74 ( 0.00074 mg/ lb ai) 3.96 80 0.0019 0.0033 5,300 3,000 0.0052 1,900 Sprays for Groundboom application turfgrass, sod,, golf course, ornamentals,

landscape, grounds maintenance, noncroplands Baseline 0.014 0.00074 mg/ lb ai 3.0 200 ( sod farm) 0.0036 0.0063 2800 1600 0.0099 1,000 Flagger Table 9 : Short term Handler Exposure and Risk for Pendimethalin Exposure Scenario Crop Mitigation Level Dermal Unit Exposure ( mg/ lb ai) Inhalation Unit Exposure (: g/ lb ai) Application Rate ( lb ai/ A) Amount Treated ( acres/ day) Dermal Dose ( mg/ kg/ day) a Inhalation Dose b ( mg/ kg/ day) Dermal MOE c Inhalation MOE d Total Dose e Total MOE f Page 48 of 55 Liquid for Aerial application carrots Baseline 0.011 0.35 ( 0.00035 mg/ lb ai) 1.0 350 Acres/ day 0.00165 0.00175 6,100 5,700 0.0034 2,900 Mixer/ loader/ Applicator Backpack ( PHED) turfgrass, sod,, golf course, ornamentals,

landscape, grounds maintenance, noncroplands resdiental lawn Single layer and gloves 2.5 0.03 mg/ lb ai 3.8 lb ai/ gal 40 gal/ day 0.16 0.065 63 150 0.225 40 Lawn Handgun Sprayer ( ORETF) 0.5 0.0019 mg/ lb ai 3 lb ai/ acre 5 acres 0.0032 0.0004 3,100 25,000 0.0036 2,800 a. Dermal Dose ( mg/ kg/ day) = Rate ( lb ai/ A) x UE ( mg / lb ai ) x DA ( 0.03) x Acres Treated ( A/ day) d. Inhalation MOE = Inhalation NOAEL ( 10 mg/ kg/ day)

BW ( 70 kg) Inhalation Dose ( mg/ kg/ day)

b. Inhalation Dose ( mg/ kg/ day) = Rate ( lb ai/ A) x UE ( mg / lb ai ) x Acres Treated ( A/ day) e. Total Dose ( mg/ kg/ day) = Dermal Dose ( mg/ kg/ day) + Inhalation Dose BW ( 70 kg)

c. Dermal MOE = Dermal NOAEL ( 10 mg/ kg/ day) f. Total MOE = NOAEL ( 10 mg/ kg/ day) / Total Dose ( mg/ kg/ day)

Dermal Dose ( mg/ kg/ day) Page 49 of 55 10.0 Data Needs and Label Requirements 10.1 Toxicology HED has requested the submission of developmental thyroid toxicity data for adult rats and young rats following pre and post natal exposure to pendimethalin.

10.2 Residue Chemistry Residue chemistry data are adequate to support the proposed uses on mint, tree nuts and carrots; however, as a condition of registration, additional residue data are required to support the proposed citrus crop group tolerance. Specifically, grapefruit field trial data from Regions 3, 6 and 10 ( one test each), and lemon field trial data from Region 10 ( two tests) are needed.

10.3 Occupational and Residential Exposure The Agency reiterates the recommendation that agricultural handlers should wear chemicalresistant gloves when mixing/ loading liquids, and when mixing/ loading and applying with a low pressure handwand. Page 50 of 55 References Endpoint selection document:

Pendimethalin  Revisit to HIARC in Response to Registrant Rebuttal; S. Williams Foy; PC Code 108501: HED DOC NO. 014116; April 18, 2000 Dietary Exposure Memo:

Pendimethalin: Chronic Dietary Exposure Assessment to Support Proposed Section 3 Registration on Citrus, Mint, Carrots and Tree Nuts; C. Swartz, 3/ 7/ 2005; PC Code: 108501, DP Number: D313734.

Residue Chemistry Memoranda Product and Residue Chemistry Chapters for the Pendimethalin Reregistration Eligibility Decision ( RED) Document. CBRS No.: 16592 DP Barcode No.: D221531 Chemical No.: 108501 Reregistration Case No.: 0187; Bonnie Kohlligian, 12/ 12/ 95 Residue Chemistry Data Reviews:

PP# 6E4787. Request for the use of Pendimethalin on Citrus. Evaluation of Analytical Method and Magnitude of the Residue Data. DP Barcode: D238469; W. D. Cutchin, 7/ 26/ 99.

PP# 0E6083. Request for the use of Pendimethalin on Tree Nuts including Pistachios. Evaluation of Analytical Method and Magnitude of the Residue Data. W. D. Cutchin, 9/ 1/ 2000 Pendimethalin ( Prowl ® ) on Carrots; N. Dodd, 3/ 26/ 1996.

Occupational and Residential Exposure Memo:

Occupational and Residential Exposure for the Use of Pendimethalin Proposed Section 3 Registration for Use on Mint, Citrus Fruits, Tree Nuts, and Carrots; PC Code: 108501; DP Barcode D310952; M. Collantes and Z. Figueroa; 3/ 09/ 05 Reregistration Eligibility Document Pendimethalin Reregistration Eligibility Document; D221532; J. Leahy; 02/ 20/ 96 Page 51 of 55 Appendices 1.0 TOXICOLOGY DATA REQUIREMENTS HED has requested the submission of developmental thyroid toxicity data for adult rats and young rats following pre and post natal exposure to pendimethalin.

2.0 NON CRITICAL TOXICOLOGY STUDIES Refer to the 3/ 18/ 96 HED RED Chapter for additional details.

3.0 METABOLISM CONSIDERATIONS The nature of the residue in plants, livestock and rotational crops is adequately understood. Metabolism studies identified and discussed in the 3/ 18/ 96 RED chapter support the currently proposed uses on carrots, mint, tree nuts, and citrus. Rotational crop tolerances are not needed, provided labels specify rotational crop plantback intervals of 90 days for cereal grains, and 270 days for all other crops.

4.0 ANALYTICAL METHODOLOGY Adequate methods are available for data collection and tolerance enforcement for existing and proposed uses of pendimethalin. Methods I through IV in PAM Vol. II are gas chromatography/ electron capture ( GC/ ECD) methods. Methods used for data collection are essentially the same as the PAM Vol. II methods, and have been adequately validated.

The FDA PESTDATA database ( PAM Volume I, Appendix I) indicates that pendimethalin is completely recovered (> 80%) by Multiresidue Methods Section 302 ( Luke method; Protocol D) and 303 ( Mills, Onley, Gaither method; Protocol E, nonfatty), and partially recovered ( 50 80%) by Multiresidue Method Section 304 ( Mills fatty food method; Protocol E, fatty).

5.0 SUMMARY OF MAGNITUDE OF RESIDUE ( MOR) STUDIES Magnitude of the residue data have been submitted and reviewed in conjunction with the proposed new uses. Adequate data support the proposed uses on mint, tree nuts and carrots. HED had required the submission of an additional field trial in CA to support the use on carrots; the required study has been submitted to the Agency, and a preliminary review indicates that data are acceptable, and are consistent with the previously submitted studies, which support the proposed tolerance of 0.5 ppm. Page 52 of 55 Additional field trial data are required to support the proposed citrus crop group tolerance: grapefruit field trial data from Regions 3, 6 and 10 ( one test each), and lemon field trial data from Region 10 ( two tests). These data are considered confirmatory, and a time limited tolerance should be established pending receipt of the data.

In general, residue data indicate combined residues of parent pendimethalin and its 3,5 dinitrobenzyl alcohol metabolite are very low or nondetectable. In nutmeats, combined residues were < 0.1 ppm, the combined LOQ; these data have not been summarized in the tables below.

Field Trial Data Results for Citrus Crops MRID Location Application Data Residues ( ppm)

Total Rate ( lb ai/ A) PHI Pendimethalin 3,5 dinitrobenzyl alcohol Total Orange 44103901 FL 6.0 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 44312201 CA 6.0 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 CA 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 50 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 FL 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 FL 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 FL 6.0 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 5.4 49 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 FL 6.0 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 FL 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 FL 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 TX 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 44103904 CA 4.0 60 < 0.05 < 0.05 < 0.10 12.0 < 0.005 < 0.005 < 0.010 FL 4.0 58 < 0.05 < 0.05 < 0.10 12.0 < 0.005 < 0.005 < 0.010 Grapefruit 44103902 FL 6.0 1 0.008, 0.007 < 0.005, < 0.005 0.013, 0.012 44312202 CA 6.0 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 FL 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 44103904 CA 4.0 60 < 0.05 < 0.05 < 0.10 12.0 < 0.05 < 0.05 < 0.10 FL 2.0 + 4.0 < 0.05 < 0.05 < 0.10 6.0 + 6.0 < 0.05 < 0.05 < 0.10 Field Trial Data Results for Citrus Crops MRID Location Application Data Residues ( ppm)

Total Rate ( lb ai/ A) PHI Pendimethalin 3,5 dinitrobenzyl alcohol Total Orange 44103901 FL 6.0 1 < 0.005, < 0.005 < 0.005, < 0.005 < 0.010, < 0.010 Page 53 of 55 TX 2.0 + 4.0 < 0.05 < 0.05 < 0.10 6.0 + 6.0 < 0.05 < 0.05 < 0.10 Lemon 44103903 AZ 6.0 1 0.006, 0.006 < 0.005, < 0.005 0.011, 0.011 44312203 CA 6.0 1 0.009, < 0.005 < 0.005, < 0.005 0.014, < 0.010 FL 1 0.019, 0.018 < 0.005, < 0.005 0.024, 0.023 44103904 AZ 4.0 55 < 0.05 < 0.05 < 0.10 12.0 < 0.05 < 0.05 < 0.10 CA 4.0 59 < 0.05 < 0.05 < 0.10 12.0 < 0.005 < 0.005 < 0.010 Field Trial Data Results for Mint Location/ Mint Variety Rate ( lb ai/ A) PHI Residues ( ppm)

Pendimethalin 3,5 dinitrobenzyl alcohol metabolite Total OR Native spearmint 2.0 145 0.052, 0.054 < 0.05, < 0.05 0.10, 0.10 10.0 < 0.05, < 0.05 < 0.05, < 0.05 < 0.10, < 0.10 WA Black Mitchum 2.0 124 < 0.05, < 0.05 < 0.05, < 0.05 < 0.10, < 0.10 10.0 < 0.05, 0.076 < 0.05, < 0.05 < 0.10, 0.13 Page 54 of 55 Field Trial Data Results for Almond Hulls MRID Location Total Rate ( lb ai/ A) PHI Residues ( ppm)

Pendimethalin 3,5 dinitrobenzyl alcohol Total 44983301 CA 5.58 ( 0.9x) 128 < 0.05 < 0.05 < 0.1 CA 5.62 ( 0.9x) 128 < 0.05 < 0.05 < 0.1 CA 6.01 ( 1x) 111 < 0.05 < 0.05 < 0.1 CA 6.01 ( 1x) 116 0.11 < 0.05 0.16 CA 5.99 ( 1x) 116 0.21 < 0.05 0.26 44983305 CA 4.0 ( 0.7x) 60 0.13 < 0.05 0.18 90 0.19 < 0.05 0.24 12.0 ( 2x) 60 0.06 < 0.05 0.11 90 0.08 < 0.05 0.13 CA 4.0 ( 0.7x) 90 < 0.05 < 0.05 < 0.10 120 0.29 < 0.05 0.34 12.0 ( 2x) 90 0.42 < 0.05 0.47 120 0.62 < 0.05 0.67 Field Trial Data Results for Carrots Location Application Rate ( lbs ai/ A) PHI ( days) Residues ( ppm)

Pendimethalin 3,5 dinitrobenzyl alcohol Total WA 1 + 1 2 + 2 59 59 < 0.05 0.080 < 0.05 < 0.05 < 0.1 0.13 MI 1 + 1 2 + 2 61 61 < 0.05 0.064 < 0.05 < 0.05 < 0.1 0.114 MD 1 + 1 2 + 2 46 46 < 0.05 0.088 < 0.05 < 0.05 < 0.1 0.138 NJ 1 + 1 2 + 2 61 61 < 0.05 0.054 < 0.05 < 0.05 < 0.1 0.104 FL 1 + 1 2 + 2 60 60 < 0.05 0.080 0.29 0.44 0.34 0.52 CA 1 + 1 2 + 2 51 51 0.058 0.10 0.096 < 0.05 0.154 0.15 Field Trial Data Results for Carrots Location Application Rate ( lbs ai/ A) PHI ( days) Residues ( ppm)

Pendimethalin 3,5 dinitrobenzyl alcohol Total Page 55 of 55 TX 1 + 1 2 + 2 60 60 0.10 0.16 < 0.05 < 0.05 0.15 0.21 6.0 INTERNATIONAL CONSIDERATIONS There are no established or proposed Codex MRLs for pendimethalin residues. Therefore, there are no questions of compatibility with respect to Codex MRLs and U. S. tolerances.