UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: 8/ 26/ 04 MEMORANDUM SUBJECT: Dimethipin: HED Chapter of the Reregistration Eligibility Decision Document ( RED). PC Code: 118901, Case #: 3063, DP Barcode: D299124.

Regulatory Action: Phase 1 Reregistration Action Risk Assessment Type: Single Chemical Aggregate FROM: Susan Stanton, Environmental Scientist Reregistration Branch 3 Health Effects Division ( 7509C)

AND John Liccione, Toxicologist Danette Drew, Chemist Seyed Tadayon, Chemist Reregistration Branch 3 Health Effects Division ( 7509C)

THROUGH: Catherine Eiden, Branch Chief Reregistration Branch 3 Health Effects Division ( 7509C)

TO: Amaris K. Johnson, MPH; Chemical Review Manager Reregistration Branch I SRRD ( 7508C) ii Table of Contents Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2.0 Ingredient Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1 Summary of Registered/ Proposed Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.2 Structure and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 2.3 Physical and Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.0 Metabolism Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.1 Comparative Metabolic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.2 Nature of the Residue in Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.2.1. Description of Primary Crop Metabolism . . . . . . . . . . . . . . . . . . . . . . . . 9 3.2.2 Description of Livestock Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation . . . . . . . . . . 11 3.3 Environmental Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.4 Tabular Summary of Metabolites and Degradates . . . . . . . . . . . . . . . . . . . . . . . 12 3.5 Toxicity Profile of Major Metabolites and Degradates . . . . . . . . . . . . . . . . . . . 13 3.6 Summary of Residues for Tolerance Expression and Risk Assessment . . . . . . . . 14 3.6.1 Tabular Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.6.2 Rationale for Inclusion of Metabolites and Degradates . . . . . . . . . . . . . 14 4.0 Hazard Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4.1 Hazard Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4.2 FQPA Hazard Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.2.1 Adequacy of the Toxicity Data Base . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.2.2 Evidence of Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.2.3 Developmental Toxicity Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.2.4 Reproductive Toxicity Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 4.2.5 Additional Information from Literature Sources . . . . . . . . . . . . . . . . . . 27 4.2.6 Pre and/ or Postnatal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 <IP_ADDRESS> Determination of Susceptibility . . . . . . . . . . . . . . . . . . . 27 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility . . . . . . . . . . . . . . . . 28 4.3 Recommendation for a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . 28 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 4.3.2 Evidence that supports not requiring a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 <IP_ADDRESS> Rationale for the UF DB ( when a DNT is recommended) . 28 4.4 Hazard Identification and Toxicity Endpoint Selection . . . . . . . . . . . . . . . . . . . 28 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 . . . . . . . . . . . . . . . . 28 4.4.2 Acute Reference Dose ( aRfD)  General Population . . . . . . . . . . . . . . . 28 4.4.3 Chronic Reference Dose ( cRfD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 iii 4.4.4 Incidental Oral Exposure ( Short and Intermediate Term) . . . . . . . . . . . . 30 4.4.5 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 4.4.6 Dermal Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . . . 30 4.4.7 Inhalation Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . 30 4.4.8 Margins of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.4.9 Recommendation for Aggregate Exposure Risk Assessments . . . . . . . . 31 4.4.10 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . 32 4.5 Special FQPA Safety Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 4.6 Endocrine disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 5.0 Public Health Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 5.1 Incident Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 5.2 Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 6.0 Exposure Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 6.1 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 6.1.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 6.1.2 Chronic Dietary Exposure and Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 6.2 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . 40 6.3.1 Home Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 6.3.2 Recreational Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 6.3.3 Other ( Spray Drift, etc.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 7.0 Aggregate Risk Assessments and Risk Characterization . . . . . . . . . . . . . . . . . . . . . 40 7.1 Acute Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.2 Short Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.3 Intermediate Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.4 Long Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.5 Cancer Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 8.0 Cumulative Risk Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 9.0 Occupational Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 9.1 Short/ Intermediate/ Long Term Handler Risk . . . . . . . . . . . . . . . . . . . . . . . . . . 44 9.2 Short/ Intermediate/ Long Term Postapplication Risk . . . . . . . . . . . . . . . . . . . . . 45 10.0 Data Needs and Label Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 10.1 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 10.2 Residue Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 10.3 Occupational and Residential Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 References: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 1 Executive Summary The Health Effects Division ( HED) of EPA's Office of Pesticide Programs has evaluated the toxicity and exposure data bases for the pesticide active ingredient dimethipin and has conducted a human health risk assessment in support of the Reregistration Eligibility Decision ( RED) for this active ingredient.

Use and Usage Information Dimethipin [ 2,3 dihydro 5,6 dimethyl 1,4 dithiin 1,1,4,4 tetraoxide] is a plant growth regulator registered for use as a preharvest cotton defoliant and herbicide, which may be applied using groundboom sprayers and fixed wing aircraft. Dimethipin inhibits the synthesis of plant proteins responsible for stomatal control. This loss of stomatal control causes leaves to rapidly lose water, stressing the plant and leading to the production of ethylene, which ultimately results in leaf abscission and defoliation of the cotton plant. Dimethipin may also be tank mixed with registered post emergence herbicides and applied as a directed spray from early post emergence through layby to control young weeds such as sicklepod and morningglory in cotton. In addition, dimethipin may be used under a Special Local Need registration in Washington state as a defoliant on non bearing apples in nurseries prior to transplanting in the field. Applications to apples are made with hand held spray equipment.

Toxicology The available toxicity data on dimethipin are adequate to assess the chemical's hazard potential. Dimethipin has moderate ( category II) acute toxicity via the oral and inhalation routes of exposure and low ( category III) acute toxicity via the dermal route. It is not an eye or skin irritant or a dermal sensitizer. Sub chronic studies in the rat and mouse showed no treatmentrelated effects on mortality, clinical signs, food consumption, hematology, clinical chemistry or pathology. Decreased body weights and body weight gains were noted in female rats administered dimethipin in the diet for 90 days. Dimethipin has relatively low chronic toxicity. The chronic studies for dimethipin indicate that reduced body weight gain, coupled with various organ effects, are the major toxic effects of long term exposure to this chemical. Observed organ effects include toxicity in the kidney, lungs, duodenum and testes of male rats and toxicity in the liver, kidney, glandular stomach, heart and aortic artery of female rats.

There is no quantitative or qualitative evidence of increased susceptibility of rat or rabbit fetuses after in utero and/ or postnatal exposure to dimethipin in the developmental and reproduction studies. Dose response relationships are well characterized and clear NOAELs/ LOAELs have been identified for the critical effects. Therefore, the special FQPA safety factor can be reduced to 1X, since the degree of concern is low and there are no residual uncertainties for pre and/ or postnatal toxicity.

No neurobehavioral alterations or evidence of neuropathological effects were observed in the available studies. Based on the weight of evidence, a developmental neurotoxicity ( DNT) study is not required for dimethipin. 2 Dimethipin has been classified as a Group C ( possible human) carcinogen by the Toxicology Peer Review Committee, based on evidence of lung adenomas and carcinomas in male CD 1 mice. There is no evidence of carcinogenicity in the rat. Calculation of a q 1 * for quantification of the cancer risk is not recommended. Dimethipin is not considered to be mutagenic, based on the results of a battery of mutagenicity studies, including a mammalian cytogenetic assay, two mouse micronucleus studies, an unscheduled DNA synthesis assay in rat hepatocytes, a bacterial gene mutation assay and a sister chromatid exchange assay in Chinese hamster ovary CHO cells.

Residue Chemistry The available residue chemistry data are adequate to assess human dietary exposure to dimethipin from the consumption of treated cottonseed commodities and associated livestock commodities. Although data have not been submitted for cotton gin byproducts ( a cattle feed item), HED assumed residues in gin byproducts equivalent to 50x the tolerance for cottonseed in calculating the dimethipin dietary burden for cattle. The 50x residue for gin byproducts is considered very conservative, and the resulting dietary exposure estimates for livestock are considered protective of the public health.

Additional storage stability data and field rotational crop studies are required to fully assess the potential for exposure to dimethipin from consumption of rotated crops. The available limited rotational crop studies indicate that dimethipin residues may occur at low levels in certain rotated crops at the established plantback interval ( 6 months). Extensive field rotational crop studies must be submitted for all crops, except leafy vegetables, for which the registrant wishes to allow a 6 month plantback interval. HED did not include rotational crops in the dietary exposure assessment for dimethipin. However, based on the low residues seen in the limited rotational crop studies (

LOQ for all crops except carrot tops), the conservative assumptions of the dietary assessment for cotton and livestock commodities ( tolerances, 100% crop treated, etc.) and the low estimated dietary risk (< 1% of the cPAD for all population subgroups), HED believes the dietary exposure assessment for dimethipin is protective of the public health.

The nature of the residue in plants and livestock is adequately understood based on metabolism studies with cotton, goats, and hens. The residue of concern for tolerance enforcement is dimethipin per se for both plant and livestock commodities. The residue of concern for risk assessment is dimethipin per se for plant commodities and livestock commodities except liver. The residues of concern for risk assessment for the liver of cattle, goats, hogs and sheep are dimethipin plus acetyl dithiane tetraoxide.

Tolerances are established under 40 CFR § 180.406 ( a) for residues of dimethipin ( 2,3 dihydro 5,6 dimethyl 1,4 dithiin 1,1,4,4 tetraoxide; CAS Reg. No. 55290 64 7) per se in/ on cotton, undelinted seed at 0.5 ppm, cotton hulls at 0.7 ppm, and the fat, meat, and meat byproducts of cattle, goats, hogs, horses, and sheep, each at 0.02 ppm. There are no tolerances established for dimethipin residues in poultry tissues or eggs as the Agency has concluded that there is no reasonable expectation of finite residues ( 40 CFR § 180.6( a)( 3)) of dimethipin in poultry commodities based on the current registered uses. 3 Tolerances for dimethipin have been reassessed. The tolerance level for undelinted cotton seed should remain at the established level ( 0.5 ppm). The established tolerance for cotton hulls should be revoked as processing studies indicate that dimethipin residues do not concentrate in cotton hulls.

Although feeding study data, reflecting exaggerated dosing levels, indicate that there is no expectation of finite residues in the fat, meat, or meat byproducts of cattle, goat, horses, hogs or sheep, HED recommends that the tolerances for dimethipin in livestock meat and meat byproducts be retained in order to harmonize with the established Codex MRLs. The U. S. tolerances for livestock meat and meat byproducts and Codex MRLs for mammalian meat and edible offal are established at 0.02 ppm, which is at or about the limit of quantitation.

The U. S. tolerances for dimethipin in the fat of cattle, goats, horses, hogs and sheep should be revoked as there is no expectation of finite residues in these commodities and there are no Codex MRLs established.

There is no U. S. tolerance for dimethipin in milk. A tolerance for milk is not required as there is no expectation of finite residues of dimethipin in milk.

For enforcement of tolerances for residues of dimethipin, PAM Vol. II lists two methods, Method I for cottonseed and Method II for livestock tissues and eggs. The stated detection limits are 0.1 ppm for cottonseed and 0.02 ppm for livestock commodities. The registrant has submitted a revised version of the enforcement method for cottonseed to include instructions for the analysis of cottonseed processed commodities, the use of toluene instead of benzene as a solvent, and a GPC cleanup step. The revised method has undergone adequate independent laboratory validation and should replace Method I for enforcement of tolerances for residues of dimethipin in/ on cottonseed.

Environmental Fate The available environmental fate data for dimethipin are adequate to assess the residues of concern in drinking water. Since no major transformation products were identified in any study, the residue of concern consists of parent dimethipin only.

The available data indicate that dimethipin is both persistent and mobile and has a high potential to leach to ground water. Since there are no monitoring data for dimethipin, human exposure to dimethipin in drinking water was assessed based on conservative, Tier 1 residue estimates for surface water and ground water generated by EFED using the FIRST and SCI GROW models, respectively. Monitoring data or information to refine the model inputs would be required to conduct a more refined drinking water assessment.

Based on the chemical and toxicological properties of dimethipin ( i. e., low volatility, lack of dermal toxicity) and the absence of any residential uses, environmental exposure to dimethipin, apart from exposure through drinking water, is not expected to be significant.

Aggregate Risk 4 A long term ( chronic) aggregate risk assessment was conducted for dimethipin. The chronic assessment considered exposures from food and water only, because there are no residential uses and no residential exposures anticipated for this chemical. An acute aggregate risk assessment was not conducted, since an endpoint attributable to a single exposure scenario was not identified for dimethipin.

The results of the deterministic, Tier 1chronic dietary assessment indicate that exposure to dimethipin from food alone is well below HED's level of concern, with estimated exposures representing < 1% of the cPAD for the U. S. population and all population subgroups, including infants and children. Since adequate water monitoring data are not available to estimate levels of dimethipin in drinking water, HED calculated DWLOCs and compared them to the modeled EDWCs for surface and ground water to determine whether aggregate chronic risks are of concern. The chronic surface and ground water EDWCs generated by FIRST and SCI GROW are below HED's calculated DWLOCs for chronic exposure to dimethipin for the U. S. population and each population subgroup. Based on these considerations, HED is reasonably certain that the chronic aggregate risk associated with the use of dimethipin does not exceed HED's level of concern for the overall U. S. population or population subgroups, including infants and children.

Occupational Exposure Occupational handlers may be exposed through the following routes during mixing, loading and application of dimethipin using aerial, groundboom or high pressure handwand equipment and during flagging operations for spray applications:

Dermal: Although dermal exposure is expected, short and intermediate term dermal endpoints were not identified due to the lack of dermal, systemic, and developmental toxicity concerns. A long term dermal endpoint was not identified; nor would long term dermal occupational exposure be expected. Therefore dermal exposure was not assessed.

Inhalation: Even though the volatility of this chemical is very low, based on the use patterns for dimethipin, both short and intermediate term inhalation exposure may occur. Long term inhalation exposure is not anticipated.

Since no chemical specific handler exposure data are available for dimethipin, short and intermediate term inhalation exposure were assessed using data from the Pesticide Handlers Exposure Database ( PHED) Version 1.1. PHED data were used with other HED standard values for areas treated per day, body weight and the level of personal protective equipment ( PPE) and engineering controls to assess handler exposures to dimethipin. Using these assumptions, the calculated occupational handler MOEs for all exposure scenarios are greater than HED's target of 100 and are, therefore, not of concern. Short term inhalation MOEs range from 1,500 ( mixing/ loading liquids for aerial application) to 1,300,000 ( mixing/ loading liquids for highpressure handwand application). Intermediate term inhalation MOEs range from 880 ( mixing/ loading liquid for aerial application) to 770,000 ( mixing/ loading liquids for high pressure handwand application). 5 Summary Dimethipin is a relatively low toxicity pesticide whose potential routes of exposure include food and drinking water. Residential exposure to dimethipin is not expected, since there are no residential uses of this pesticide. Under the conditions of its current use on cotton and nonbearing apples, dimethipin presents little health risk to workers handling the pesticide or to the general population, including infants and children, from consumption of foods or drinking water containing dimethipin residues.

2.0 Ingredient Profile Dimethipin [ 2,3 dihydro 5,6 dimethyl 1,4 dithiin 1,1,4,4 tetraoxide] is a plant growth regulator registered for use as a preharvest cotton defoliant and herbicide. It is a member of the sulfone chemical class. Dimethipin products are registered in the U. S. to Crompton Manufacturing Company, Inc. ( parent company to Uniroyal Chemical Company, Inc.) under the trade name HARVADE ® . Currently, the 2, 3.2 and 4.9 lb./ gal. flowable concentrate formulations of dimethipin are registered for use on cotton. The products are typically applied as postemergence broadcast applications 7 to 14 days prior to harvest at an application rate of up to 0.38 lb. a. i./ acre using ground or aerial equipment. Dimethipin may also be tank mixed with registered postemergence herbicides and applied as a directed spray from early post emergence through layby to control young weeds such as sicklepod and morningglory in cotton. Application rates for postdirected weed control range from 0.23 to 0.56 lb. a. i./ acre. In addition, dimethipin may be used under a Special Local Need registration in Washington state as a defoliant on non bearing apples in nurseries prior to transplanting in the field. Applications to apples are made with hand held spray equipment at an application rate of 0.07656 lb. a. i./ acre. The Restricted Entry Interval ( REI) for workers is 48 hours for all uses. 6 2.1 Summary of Registered/ Proposed Uses Table 2.1 Summary of Directions for Use of Dimethipin SITE NAME Product/ Site Limitations Application Type ( for any Reg.# at any rate) ( aggregate)

Application Timing ( for any Reg.# at any rate)

Application Equipment ( for any Reg.# at any rate)

( aggregate) Max. Single Appl.

Rate to a Single Site ( AI unless noted otherwise) Inconvertible Label ( L) Dosages Also Present Max Seasonal Rate ( L) Dosages Also Present Max. #

Apps Per Crop Cycle ( cc)

and Year ( at any rate) Min Retmt Intv ( days)

( at any rate) PHI/ PGI/ PSI Use Limitations ( at any rate) ( May not apply to all Reg. # s within group)

COTTON ( UNSPECIFIED) Do not apply directly to water, or to areas where surface water is present or to intertidal areas below the mean high water mark.

Do not apply through any type of irrigation system.

Do not apply when drift is likely to occur.

Do not apply when wind velocity is 10 mph or greater.

Do not contaminate water by cleaning of equipment or disposal of equipment wash waters.

Do not contaminate water, food, or feed by storage or disposal.

Rotational/ plant back crop restriction.

Spray After boll opening Aircraft/ Ground .30625 lb A NS NS NS NS Geographic allowable: CA Broadcast/ Low volume spray ( concentrate)/ Spray Foliar Aircraft/ Ground .3125 lb A NS NS NS NS Geographic allowable: AL AR FL GA KS LA MO MS NC NM OK SC TN TX VA Geographic disallowable: OK TX Spray Preharvest Aircraft/ Ground .3828 lb A .5625 lb/ yr NS NS 5 Geographic allowable: AL AR FL GA LA MO MS NC OK SC TN TX VA Geographic disallowable: OK TX 7 APPLE Do not apply directly to water, or to areas where surface water is present or to intertidal areas below the mean high water mark.

Do not apply through any type of irrigation system.

Do not apply to food or feed crops within 1 year of harvest.

Do not contaminate water by cleaning of equipment or disposal of equipment wash waters.

Do not contaminate water, food, or feed by storage or disposal.

Rotational/ plant back crop restriction.

Spray Nonbearing nurserystock Sprayer .07656 lb A NS NS NS 5 Product Number( s) Contained in this Report :

000400 00155 000400 00398 000400 00505 and WA980008 8 S S CH 3 CH 3 O O O O 2.2 Structure and Nomenclature TABLE 2.2 Test Compound Nomenclature Chemical structure 2,3 dihydro 5,6 dimethyl 1,4 dithiin 1,1,4,4 tetraoxide Common name dimethipin Chemical class sulfone IUPAC name 2,3 dihydro 5,6 dimethyl 1,4 dithiine 1,1,4,4 tetraoxide CAS name 2,3 dihydro 5,6 dimethyl 1,4 dithiin 1,1,4,4 tetraoxide CAS registry number 55290 64 7 Known impurities of concern None End use products ( EPs):

400 155 4.9 lb/ gal FlC1 Harvade ®  5F Harvest Growth Regulant For Cotton 400 398 2 lb/ gal FlC Harvade ®  25F Harvest Growth Regulant For Cotton 400 505 3.2 lb/ gal EC2 Leafless ® Harvest Growth Regulant for Cotton 1 Including SLN WA980008. 2 This product also contains thidiazuron.

2.3 Physical and Chemical Properties Dimethipin is a non volatile liquid with a relatively low octanol/ water partition coefficient and high water solubility. Based on its low volatility, human exposure via the inhalation route is likely to be low. Its octanol/ water partition coefficient and high water solubility suggest that dimethipin may have relatively low bioavailability in the body and be excreted from the body fairly rapidly.

Table 2.3 Physicochemical Properties of Dimethipin Parameter Value Reference Melting point/ range 162 167

C Dimethipin RED, PC Chapter pH 4.52 at 30

C ( 1% w: v solution in 50% aqueous dioxane due to insolubility in water) Dimethipin RED, PC Chapter Density 1.5935 g/ cm3 at 23

C Dimethipin RED, PC Chapter Water solubility 0.46 g/ 100 mL at 25

C Dimethipin RED, PC Chapter Solvent solubility At 25

C: acetone 0.097 g/ mL 1 octanol 79.356 mg/ 100 mL hexane 1.664 mg/ 100 mL methanol 0.05 g/ 100 mL xylene 0.57 g/ 100 mL chloroform 7.92 g/ 100 mL Dimethipin RED, PC Chapter Table 2.3 Physicochemical Properties of Dimethipin Parameter Value Reference 9 Vapor pressure < 3.81 x 10 7 mm Hg at 24

C Dimethipin RED, PC Chapter Dissociation constant, pKa 10.88 +/ 0.39 at 25

C Dimethipin RED, PC Chapter Octanol/ water partition coefficient, Log( KOW) 0.66 at 24

C Dimethipin RED, PC Chapter UV/ visible absorption spectrum not available 3.0 Metabolism Assessment 3.1 Comparative Metabolic Profile Rat metabolism: A series of rat metabolism studies indicated that dimethipin is absorbed from the gastrointestinal tract. Following a single low oral dose, ~ 59~ 66% of the administered dose was absorbed in male and female rats, respectively. With single or multiple high doses, absorption decreased significantly (~ 37% for male and 59% for females), suggesting absorption was ratelimited Highest levels of radioactivity after administration of radiolabeled dimethipin were detected in the gastrointestinal tract, liver, kidneys and red blood cells. Following treatment, ~ 57% of a single low dose in males and ~ 63% in females was recovered in the urine 48 96 hours after treatment, while ~ 28% of the dose was recovered in the feces of these rats. Following single or multiple high doses, approximately 33% of the dose was recovered in the urine of male rats and ~ 45% in the urine of female rats 48 96 hours after dosing.

Of that amount of radiolabel recovered in the urine, ~ 77% was composed of three metabolites  R 4, R 5, and R 6. These were identified as a cysteinylglycine conjugate of the parent compound, as an N acetylcysteinyl conjugate derived from cysteinylglycine conjugate, and a reductive product of dimethipin ( 1,1,4,4 tetraoxide, 2,3 dimethyldithiane). Also identified in the urine were polar metabolites which were not further characterized. No studies were conducted to identify metabolites in the feces or bile, or determine whether radiolabel was eliminated in the expired air.

Reduced dimethipin was also identified in the poultry and ruminant metabolism studies; however, it was not found in the plant metabolism or confined rotational crop studies. The dimethipin conjugates seen in the rat metabolism study were not identified in other animal or plant matrices. However, similar amino acid conjugates were identified in both plants and livestock.

3.2 Nature of the Residue in Foods 3.2.1. Description of Primary Crop Metabolism Metabolism was studied only in cotton because dimethipin is registered only for food use on cotton. In a cotton metabolism study ( MRID 43436901), greenhouse grown cotton was treated with [ 2,3 14C] dimethipin at 1.22 lb ai/ A and 3.06 lb ai/ A ( 2.2x and 5.4x the maximum seasonal rate) two weeks prior to harvest. Total radioactive residues were 97.1 ppm in foliage and 10 0.291 ppm in seeds from plants treated at the 2.2x rate, and 341.3 ppm in foliage and 1.42 ppm in seeds from plants treated at the 5.4x rate. Matrices from the 2.2x treated plants were subjected to extraction and characterization/ identification. Dimethipin per se was found to comprise 74% of foliage radioactivity and 80% of seed radioactivity; no additional metabolites were identified.

3.2.2 Description of Livestock Metabolism Poultry: Following oral administration of [ 2,3 14C] dimethipin to hens for 5 days at 2772 ppm ( 27,720x the maximum theoretical dietary burden), the TRR were 0.12 12 ppm in egg whites, 0.34 16 ppm in egg yolks, 2.4 ppm in fat, 10 ppm in thigh muscle, 10 ppm in breast muscle, 39 ppm in kidney and 65 ppm in liver. Dimethipin per se was not detected in any poultry matrices; however, reduced dimethipin was found in all matrices except thigh muscle and fat at 0.98 7.8% TRR ( 0.21 5.0 ppm). In all matrices except liver, the predominant metabolite was Glu Cys S Harv [ S( 2,3 dimethyl 1,1,4,4 tetraoxo 1,4 dithian yl) L cysteinyl   glutamic acid] at 19 36% TRR ( 0.48 7.5 ppm); this metabolite was found in liver at 7.4% TRR ( 4.8 ppm). The most significant liver metabolite was dimethipin cysteine conjugate ( Harv S Cys) at 21.5% TRR ( 14 ppm); this metabolite was found in all other matrices except fat at 0.1 7.0% TRR ( 0.01 2.8 ppm). The major metabolic pathway proposed by the registrant involved the formation of thioethers of dimethipin; other minor pathways involved reduction and hydroxylation of dimethipin.

Ruminant:

Following oral administration of [ 2,3 14C] dimethipin to lactating goats for 5 days at 3.066, 1010.8 and 1290.0 ppm ( 0.5x, 177x and 226x the maximum theoretical dietary burden), the TRR were 0.005 0.006 ppm in milk, 0.27 ppm in liver, 0.15 ppm in kidney, 0.002 ppm in muscle and 0.001 ppm in fat from the goat dosed at 3.066 ppm; 0.68 1.20 ppm in milk, 78.5 ppm in liver, 28.4 ppm in kidney, 0.64 ppm in muscle and 0.32 ppm in fat from the goat dosed at 1010.8 ppm; and 3.13 4.26 ppm in milk, 45.0 ppm in liver, 55.2 ppm in kidney, 2.04 ppm in muscle and 0.99 ppm in fat from the goat dosed at 1290.0 ppm.

Dimethipin was not detected in milk and tissues from the goat dosed at 3.066 ppm. In milk from this goat, dimethipin cysteine conjugate ( 34.8 52.8% TRR, 0.001 0.002 ppm) was the only residue identified. In kidney, the only metabolite identified was ethane disulfonic acid ( 75.6% TRR, 0.11 ppm). In liver, two metabolites were identified: ethane disulfonic acid ( 14.6% TRR, 0.38 ppm) and acetyl dithiane tetraoxide ( 16.6% TRR, 0.045 ppm). No attempts were made to characterize/ identify radioactive residues in fat and muscle because the total radioactive residues in these tissues were 0.001 and 0.002 ppm, respectively.

The parent dimethipin was also not detected in the milk and tissues of the goats dosed at higher levels. Dimethipin cysteine conjugate was also the only residue identified in milk ( 25.2 50.6% TRR, 0.22 0.55 ppm). In kidney, ethane disulfonic acid ( 27.6% TRR, 7.8 ppm) and acetyl dithiane tetraoxide ( 32.3% TRR, 9.2 ppm) were identified. In muscle, reduced dimethipin ( 2,3 dimethyl 1,1,4,4 tetraoxo 1,4 dithiane; 21.9% TRR, 0.140 ppm) was identified. In liver, ethane disulfonic acid ( 44.8% TRR, 20.1 ppm) was identified. Based on several fractionation and 11 extraction procedures employed in the study, the registrant believes that the majority of radioactive residues in kidney and liver were covalently bound to proteins.

3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation In the submitted confined rotational crop study [ 14C] Dimethipin was applied to the soil at 0.54 lb ai/ A ( 1x the maximum seasonal rate), and rotational crops of lettuce, carrots, and barley were planted 30 and 183 days after application. Samples of immature and mature lettuce, immature and mature carrot root and top, and barley forage, grain, and straw were collected.

Total radioactive residues accumulated above 0.01 ppm in all harvested rotational crop commodities at both plantback intervals. At the 30 day plantback interval, the highest residues were observed in barley forage ( 2.52 ppm), and the lowest residues were observed in carrot root ( immature and mature; 0.10 ppm) and barley grain ( 0.02 ppm). At the 183 day plantback interval, the highest residues were observed in carrot tops ( immature and mature; 0.508 0.705 ppm), and the lowest residues were observed in immature carrot root ( 0.017 ppm) and barley grain ( 0.018 ppm). In the 30 day plantback interval samples, dimethipin was identified in immature and mature lettuce ( 0.064 0.091 ppm), mature carrot tops ( 0.024 ppm), immature and mature carrot root ( 0.016 0.039 ppm), barley forage ( 0.025 ppm), and barley straw ( 0.012 ppm). In the 183 day plantback interval samples, dimethipin was identified in immature carrot tops ( 0.041 ppm), but was not detected in any other matrix. Metabolite H 5 ( hydroxylated dimethipin) was identified at low levels in barley straw from the 30 day plantback interval. Additional characterization data demonstrated that unidentified radioactivity generally consisted of several components, each of which comprised

0.05 ppm. Two additional metabolites, H 80 ( dimethipin cysteine conjugate) and a mercaptolactic acid conjugate, were identified in the extracts of 30 DAT immature lettuce, at 2.10% TRR ( 0.023 ppm) and 13.68% TRR ( 0.151 ppm), respectively.

The results of the confined rotational crop study indicate that dimethipin is extensively metabolized in rotational crops. The registrant proposed that dimethipin is metabolized in rotational lettuce and carrots through glutathione conjugation followed by degradation to cysteine conjugates. Further oxidation at the amino group leads to the formation of mercaptolactic acid conjugates.

3.3 Environmental Degradation Dimethipin degrades slowly under laboratory and field conditions, with the apparent primary route of dissipation in the field being leaching coupled with photodegradation at the soil surface and metabolic degradation throughout the soil column. In buffered aqueous solutions, dimethipin was stable to hydrolysis with half lives > 2 years at pHs 3 9 and photodegraded slowly to very slowly with half lives ranging from 60 days ( pH 5) to 224 days ( pH 7) at pH 5 9. In sandy loam soil, dimethipin photodegraded with a half life of 75 days. In metabolism studies, dimethipin degraded under aerobic conditions with a half life of 408 days and under anaerobic aquatic conditions with a half life of 277 days. 12 S S CH 3 CH 3 O O O O Octanol/ water partitioning ( Kow) data provided by the registrant indicate a low potential for dimethipin to accumulate in fish ( Kow for dimethipin = 0.66).

Dimethipin has very high mobility in soils ranging from sand to clay, with Freundlich adsorption coefficients of

0.09. In field studies using bare ground and cropped plots, dimethipin leached to a depth of 75 90 cm.

Volatilization is not expected to be a significant since the reported vapor pressure is < 3.87 x 10 7 mm Hg at 24  C.

No major transformation products were identified in any of the environmental fate studies. 2,3 Dihydro 5 hydroxymethyl 6 methyl 1,4 dithiin 1,1,4,4 tetraoxide ( H 5) was present as a minor transformation product ( less than 2% of the applied dimethipin) in the aquaeous photolysis study only. The saturated carboxylic acid of dimethipin was identified in the anaerobic aquatic study but was not quantified.

3.4 Tabular Summary of Metabolites and Degradates Table 3.4 Tabular Summary of Metabolites and Degradates Name Structure Study Identified (% TRR)

Dimethipin Cotton metabolism: foliage ( 74%); seed ( 80%)

Reduced Dimethipin Poultry metabolism ( 0.98 7.8% in all matrices, except thigh muscle)

Ruminant metabolism ( 21.9%, only in muscle at the high dose)

Rat metabolism ( urine)

Glu Cys S Harv:

S( 2,3 dimethyl 1,1,4,4 tetraoxo 1,4 dithian yl) L cysteinyl

 glutamic acid Poultry metabolism ( 19 36% in all matrices) Table 3.4 Tabular Summary of Metabolites and Degradates Name Structure Study Identified (% TRR)

13 SO 3 H HO 3 S S S O O O O CH 3 O S S CH 3 O O O O S CH 3 N H 2 COOH S S CH 3 O O O O S CH 3 O H COOH HARV S Cys ( dimethipin cysteine):

S( 2,3 dimethyl 1,1,4,4 tetraoxo 1,4 dithian 2 yl) L cysteine Poultry metabolism ( 0.1 7.0% in all matrices, except fat)

Ruminant metabolism ( 25.2  52.8% in milk only)

Confined rotational crop study ( 2.1% in immature lettuce only at the 30 day PBI)

Ethane disulfonic acid Ruminant metabolism ( 14.6 44.8% in liver; 27.6 75.6% in kidney)

Acetyl dithiane tetraoxide Ruminant metabolism ( 16.6% in liver at low dose; 40 50% in liver at high dose; 32.3% in kidney at high dose only)

H 80 S( 2,3 dimethyl 1,4 dithian 2 yl) 1,1,4,4 tetraoxide cysteine Confined rotational crop study ( 2.1% in immature lettuce only at the 30 day PBI)

Hydroxylated dimethipin ( H 5) N/ A Confined rotational crop study ( 0.009 ppm in barley straw only at the 30 day PBI). Aqueous photolysis study at < 2% of the applied.

Dimethipin mercaptolactic acid conjugate Confined rotational crop study ( 13.68% in immature lettuce only at the 30 day PBI)

Cysteinylglycine conjugate N/ A Rat metabolism ( urine)

N acetylcysteinyl conjugate N/ A Rat metabolism ( urine)

3.5 Toxicity Profile of Major Metabolites and Degradates Toxicity data are not available on the metabolites and degradates of dimethipin. In the absence of toxicity data or information on the precise mechanism of action of the parent compound, major metabolites/ degradates that retain the intact six membered ring structure are assumed to be of potential concern from a toxicity perspective ( personal communication, Leonard Keifer, OPPT, 3/ 9/ 04). Of the metabolites having this structure, only the acetyl dithiane tetraoxide metabolite seen in the ruminant study was found at levels indicating a potential for human exposure through the diet. The remaining metabolites having this structure were excluded from consideration in the 14 risk assessment, based on their presence in only one matrix or at low levels. Ethane disulfonic acid, a major metabolite found in the liver and kidney of ruminants, is a short chain, polar compound that is likely to be excreted rapidly in the urine. Based on its polarity and lack of structural similarity to the parent ( i. e., not a ring compound), it is not expected to be of toxicological concern.

3.6 Summary of Residues for Tolerance Expression and Risk Assessment 3.6.1 Tabular Summary Table 3.6. Summary of 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 Crop Dimethipin Dimethipin Rotational Crop Dimethipin Dimethipin Livestock Ruminant, except liver Dimethipin Dimethipin Ruminant liver Dimethipin plus acetyl dithiane tetraoxide Dimethipin Poultry not applicable  no residues expected not applicable  no tolerances required Drinking Water Dimethipin Not Applicable 3.6.2 Rationale for Inclusion of Metabolites and Degradates Primary Plant:

Dimethipin per se was found to comprise 74% of the cotton foliage TRR and 80% of the cotton seed TRR. No additional metabolites were identified. The residue of concern for the tolerance expression and risk assessment in plants is dimethipin per se.

Livestock:

Poultry: Dimethipin per se was not detected in any poultry matrices following oral administration of [ 2,3 14C] dimethipin to hens for 5 days at 2772 ppm ( 27,720x the maximum theoretical dietary burden). Reduced dimethipin was found in all matrices except thigh muscle and fat at 0.98 7.8% TRR ( 0.21 5.0 ppm). The only metabolites comprising more than 10% of the TRR for a given matrix were Glu Cys S Harv [ S( 2,3 dimethyl 1,1,4,4 tetraoxo 1,4 dithian yl) L cysteinyl   glutamic acid] at 19 36% TRR ( 0.48 7.5 ppm) and dimethipin cysteine conjugate ( Harv S Cys) at up to 21.5% TRR ( 14 ppm). Given the low levels of radioactivity found at the highly exaggerated rate, there is no reasonable expectation of finite residues of dimethipin or its metabolites in poultry. 15 Ruminant: Dimethipin per se was not detected in milk or tissues of goats following oral administration of [ 2,3 14C] dimethipin to lactating goats for 5 days at 3.066, 1018.8 and 1290.0 ppm, equivalent to 0.5x, 177x and 226x the maximum theoretical dietary burden ( MTDB).

In milk, dimethipin cysteine conjugate ( Harv S Cys) was the only residue identified at any dose level ( 34.8  52.8 % TRR, equivalent to 0.001 to 0.002 ppm at the low dose; and 25.2  50.6% TRR, equivalent to 0.22 to 0.55 ppm, at the high doses). Based on the low levels seen at 0.5x the MTDB and the conservative assumptions used to calculate the MTDB ( i. e., assumed 50x seed residue on gin byproducts in the MTDB calculation), finite residues of this metabolite would not be expected in milk.

Reduced dimethipin was identified in a single matrix, muscle, and only at the high dose ( 21.9% TRR, equivalent to 0.14 ppm). Since this metabolite was present in the rat metabolism study, is not expected to occur in muscle above the LOQ at a 1x dose and was not found in any other matrix, reduced dimethipin should not be included in the tolerance expression or risk assessment.

Ethane disulfonic acid was identified as a major metabolite in both liver and kidney, comprising more than 75% of the TRR ( 0.11 ppm) in kidney and 14.6% of the TRR ( 0.038 ppm) in liver at the low ( 0.5x) dose. However, based on the determination that this metabolite is not of toxicological concern, it should not be included in the tolerance expression or risk assessment.

Acetyl dithiane tetraoxide was identified in liver at levels above the LOQ at both the low and high doses ( 16.6% TRR, equivalent to 0.045 ppm, at the 0.5x dose). Although it occurred in only one matrix, the dimethipin Team determined that it should be included in the dimethipin risk assessment for the following reasons: ( 1) The metabolite is similar in structure to the parent compound and may be of toxicological significance, but was not present in the rat metabolism study; ( 2) It comprised more than 10% of the TRR in liver; and ( 3) It may occur in liver at levels above the LOQ. The Team concluded that acetyl dithiane tetraoxide should not be included in the tolerance expression, since ( 1) the metabolite cannot be determined by multi residue methods ( dimethipin is completely recovered using Multiresidue Methods Section 302 ( Luke Method; Protocol D)); ( 2) it was found in only one matrix at 10 20% of the TRR at the low dose; ( 3) the parent compound has relatively low toxicity; and ( 4) Codex does not include the metabolite in its regulations.

Based on the above considerations, HED concludes that the residue of concern for risk assessment is dimethipin per se in all animal commodities except liver and dimethipin plus the metabolite, acetyl dithiane tetraoxide, in the liver of ruminants. The residue of concern for the tolerance expression in animal commodities is dimethipin per se.

Rotational Crops:

In the submitted confined rotational crop study, dimethipin per se was the only residue identified at the 6 month plant back interval. Dimethipin product labels currently bear a 6 month plant back restriction. At the one month plant back interval in the confined studies, dimethipin per se and 3 metabolites were identified. Hydroxylated dimethipin ( metabolite H 5) was identified at low 16 levels ( 0.009 ppm) in a single matrix, barley straw; dimethipin cysteine conjugate ( H 80) and a mercaptolactic acid conjugate were identified in a single matrix, immature lettuce, at 0.023 ppm ( 2.1% TRR) and 0.151 ppm ( 13.68% TRR), respectively. Since these metabolites occurred at low levels ( H 5 and H 80) and/ or in one matrix only ( H 5, H 80 and the mercaptolactic acid conjugate), and since they were identified only at the 30 day plant back interval, the residue of concern for rotational crops is dimethipin per se.

Water:

No major transformation products were identified in any of the environmental fate studies. 2,3 Dihydro 5 hydroxymethyl 6 methyl 1,4 dithiin 1,1,4,4 tetraoxide ( H 5) was present as a minor transformation product ( less than 2% of the applied dimethipin) in the aquaeous photolysis study only. The saturated carboxylic acid of dimethipin was identified in the anaerobic aquatic study but was not quantified.

Toxicity information is not available for the H 5 degradate. However, based on the relatively low toxicity of the parent dimethipin and the low potential for exposure to this degradate, H 5 is not considered to be of concern for human health. Dimethipin degrades slowly in the environment, and dissipates primarily by leaching, coupled with photodegradation at the soil surface and metabolic degradation throughout the soil column. Photolysis would not occur in groundwater, and although some dimethipin would reach surface water through runoff, photolysis only occurs in the upper 2 3 inches of surface water. Therefore, little transformation of dimethipin to the H 5 degradate is expected. Based on these considerations, the residue of concern for drinking water is dimethipin per se.

4.0 Hazard Characterization/ Assessment 4.1 Hazard Characterization Acute Toxicity: The acute toxicity data base for dimethipin is considered complete for acute oral, acute dermal, acute inhalation, dermal and eye irritation, and dermal sensitization. Dimethipin has a moderate order of acute toxicity via the oral ( Category II) and inhalation routes ( Category II). It has a low order of acute toxicity via the dermal ( Category III) route of exposure. It is not an eye or skin irritant, or a dermal sensitizer. The acute toxicity data for dimethipin are summarized below in Table 4.1a.

Table 4.1a Acute Toxicity Profile  Dimethipin Guideline No. Study Type MRID( s) Results Toxicity Category 870.11 Acute Oral 42429601 LD50 = 458 mg/ kg (

) LD50 = 546 mg/ kg (  ) II 870.12 Acute Dermal 42429602 LD50 > 5000 mg/ kg III 17 870.13 Acute Inhalation 42429603 LC50 = 1.2 mg/ L. II 870.24 Primary Eye Irritation 70237 non irritant IV 870.25 Primary Dermal Irritation 42429604 non irritant IV 870.26 Dermal Sensitization 42429605 not a sensitizer   Sub chronic Toxicity: No treatment related effects on mortality, clinical signs, body weight, food consumption, pathology, hematology and clinical chemistry were observed in mice following dietary administration of doses of up to 300 mg/ kg/ day for 28 days.

Decreased body weights and body weight gains were noted in female rats administered dimethipin in the diet for 90 days ( LOAEL = 131 mg/ kg/ day; NOAEL = 3.1 mg/ kg/ day). A LOAEL for male rats was not established ( NOAEL = 220 mg/ kg/ day). There were no treatment related effects on mortality, clinical signs, food consumption, hematology, clinical chemistry, or pathology.

Chronic Toxicity: The toxicity database for dimethipin indicates that reduced body weight gain, coupled with various organ effects in multiple species, are the major toxic effects of this chemical.

In a 104 week dietary study in the rat, effects were observed in males treated with 77.6 mg/ kg/ day ( mid dose) and 161 mg/ kg/ day ( high dose), and in females treated with 50.3 mg/ kg/ day ( mid dose) and 103 mg/ kg/ day ( high dose). Liver toxicity was indicated by increased incidences of bile duct cysts in the high dose male and female groups, bile duct hyperplasia in the mid and high dose female groups, eosinophilic altered foci in the high dose male group, and elevated serum cholesterol levels in males. Chronic progressive nephropathy was exacerbated in mid and high dose rats of both sexes as evidenced by increased incidence and severity of the lesion. The mean absolute kidney weight was elevated in high dose male rats. Toxicity in the gastrointestinal tract was manifested by elevated incidences and severity of epithelial hyperplasia in the nonglandular stomach in high dose male rats, mineralization in the glandular stomach of mid and high dose female rats, epithelial hyperplasia of the duodenum in mid and high dose males and high dose females, and crypt abscesses in the duodenum of mid and high dose male rats. In addition testicular lesions occurred in male rats fed the mid and high doses, and epididymal hypospermia occurred in high dose males. Effects occurring only in females included cardiovascular toxicity ( mineralization of the heart and aortic artery ( mid and high doses)) and brain degeneration ( high doses). The NOAEL in males is 2.18 mg/ kg/ day, and in females is 1.75 mg/ kg/ day.

In a carcinogenicity study, male mice administered 286 mg/ kg/ day dimethipin in the diet exhibited increased mononuclear inflammatory cell foci in the trachea, decreased body weight gain, and decreased food efficiency. The NOAEL is 400 ppm for males ( 56 mg/ kg/ day). A LOAEL was not determined for females. The NOAEL for female mice was 2000 ppm ( 341 mg/ kg/ day).

In a 52 week dietary toxicity study in the dog, decreased body weight gain, reduced food consumption, and a negative food efficiency were observed in males and females at 98.98 18 mg/ kg/ day and 92.87 mg/ kg/ day, respectively. NOAELs of 29.85 mg/ kg/ day ( males) and 34.42 mg/ kg/ day ( females) were identified.

Developmental/ Reproductive Toxicity: Available developmental toxicity data provided no indication of increased susceptibility ( quantitative or qualitative) of rats or rabbits to in utero and/ or postnatal exposure to dimethipin. No treatment related external, visceral, or skeletal malformations/ variations were noted in a rat developmental toxicity study.

In a two generation rat reproduction study, decreased body weights and/ or body weight gains were apparent in the F 1a, F 2a, and F 2b pups. The offspring toxicity LOAEL was 800 ppm ( 35.5 115.7 mg/ kg/ day for males and 31.2 120.3 mg/ kg/ day for females). The offspring toxicity NOAEL was 200 ppm ( 9.2 28.7 mg/ kg/ day for males and 11.8 29.0 mg/ kg/ day for females). Maternal toxicity consisted of decreased body weight and body weight gain ( LOAEL is 800 ppm for F 0 and F 1 females ( 31.2 120.3 mg/ kg/ day). The NOAEL is 200 ppm for F 0 and F 1 females ( 11.8 29.0 mg/ kg/ day). No effects were noted in the males [ NOAEL

800 ppm for F 0 and F 1 males ( 35.5 115.7 mg/ kg/ day)].

Carcinogenicity/ Mutagenicity: Dimethipin has been classified as a Group C ( possible human) carcinogen by the HED Cancer Peer Review Committee. The classification was based on evidence of lung adenomas and carcinomas in male CD 1 mouse. The Committee concluded that the original rat study was not conducted at a high enough dose and recommended that a new study be conducted. The results of the new study indicated no evidence of carcinogenicity in the rat. Calculation of a q1* was not recommended for dimethipin.

Dimethipin was negative in a mammalian cytogenetic assay ( chromosome aberration in Chinese hamster ovary CHO cells), in two mouse micronucleus studies, in an unscheduled DNA synthesis assay in rat hepatocytes, in a bacterial ( Salmonella typhimurium/ E. coli) gene mutation assay, and in a sister chromatid exchange assay in Chinese hamster ovary CHO cells.

Subchronic and chronic toxicity data for dimethipin are summarized in Table 4.1b.

Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3100 90 Day oral toxicity ( rat) 43065901 ( 1993)

Acceptable/ guideline 0, 40, 1750, or 3500 ppm M: 0, 2.5, 108, and 220 mg/ kg/ d F: 0, 3.1, 131, and 260 mg/ kg/ d NOAEL = 3.1 mg/ kg/ day (

) ; 220 mg/ kg/ day (  )

LOAEL = 131 mg/ kg/ day (

) , based on decreased body weight and body weight gain. LOAEL (  ) not identified. Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 19 870.3200 21/ 28 Day dermal toxicity ( rat) 41944901 ( 1991)

Acceptable/ Guideline 0, 10, 100, or 1000 mg/ kg bw/ day systemic NOAEL = 1000 mg/ kg/ day systemic LOAEL = not identified 870.3700a Prenatal developmental in Rat 93089032; 93089009 ( 1990)

Unacceptable/ Guideline ( Upgradable)

0, 30, 80, or 160 mg/ kg bw/ day Maternal NOAEL = 30 mg/ kg/ day LOAEL = 80 mg/ kg/ day based on decreased maternal body weight gain..

Developmental NOAEL = 160 mg/ kg/ day LOAEL = Not Identified.

870.3700b Prenatal developmental in Rabbit 93089033 ( 1981), 93089010 ( 1990), 44988701 ( 1999)

Unacceptable/ Guideline ( Upgradable)

0, 7.5, 20, or 40 mg/ kg bw/ day Maternal NOAEL = 20 mg/ kg/ day LOAEL = 40 mg/ kg/ day based on decreased body weight gain..

Developmental NOAEL = 40 mg/ kg/ day 870.3800 Reproduction and fertility effects ( Rat) 93089034 ( 1982), 93089011 ( 1990)

Acceptable/ Guideline 0, 50, 200, or 800 ppm Parental/ Systemic NOAEL = 200 ppm for F0 and F1 females ( 11.8 29.0 mg/ kg/ day) and

800 ppm for F0 and F1 males ( 35.5 115.7 mg/ kg/ day).

LOAEL = 800 ppm for F0 and F1 females ( 31.2 120.3 mg/ kg/ day) based on decreased body weights and body weight gains and was not identified for males.

Offspring NOAEL = 200 ppm ( 9.2 28.7 mg/ kg/ day for males and 11.8 29.0 mg/ kg/ day for females).

LOAEL = 800 ppm ( 35.5 115.7 mg/ kg/ day for males and 31.2 120.3 mg/ kg/ day for females) based on decreased body weights and/ or body weight gains by the F1a, F2a, and F2b pups. Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 20 870.4100b Chronic toxicity ( dog) 93089030 ( 1990), 93089008 ( 1981)

Unacceptable/ Guideline ( Upgradable)

0, 100, 300, or 3000 ppm M: 0, 8.92, 29.85, and 98.98 mg/ kg bw/ day F: 0, 10.33, 34.42, and 92.87 mg/ kg bw/ day for females NOAEL = 29.85 mg/ kg/ day (

) ; 34.42 mg/ kg/ day (  )

LOAEL = 98.98 mg/ kg/ day (

) ; 92.87 mg/ kg/ day (  ) , based on decreased body weight gain, reduced food consumption and negative food efficiency.

870.4200 Carcinogenicity ( rat) 43897601 ( 1996)

Acceptable/ Guideline M: 0, 40, 1750, or 3500 ppm ( 0, 1.75, 77.6, or 161 mg/ kg/ day)

F: 0, 40, 875, or 1750 ppm ( 0, 2.18, 50.3, or 103 mg/ kg/ day) NOAEL = 1.75 mg/ kg/ day (

) ; 2.18 mg/ kg/ day (  )

LOAEL = 77.6 mg/ kg/ day (

) ; 50.3 mg/ kg/ day (  ) , based on toxicity in the kidney, lungs, duodenum, and testes of male rats and depressed body weight gain and toxicity in the liver, kidney, glandular stomach, heart, and aortic artery of female rats.

No evidence of carcinogenicity.

870.4300 Carcinogenicity ( mouse) 93089031 ( 1981), 93089008 ( 1990)

Acceptable/ Guideline 0, 80, 400, or 2000 ppm M: 0, 11.3, 56, or 286 mg/ kg bw/ day F: 0, 13.3, 68, or 341 mg/ kg bw/ day NOAEL = 56 mg/ kg/ day (

) ; 341 mg/ kg/ day (  )

LOAEL = 286 mg/ kg/ day (

) , based on increased mononuclear inflammatory cell foci in the trachea, decreased body weight gain, and decreased food efficiency; LOAEL not identified in females.

Carcinogenicity  Marginally significant ( p< 0.044) increase in the incidences of lung carcinomas and adenomas combined compared to the control group and a significant positive trend for lung adenomas in male mice. Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 21 Gene Mutation: In vitro sister chromatid exchange ( SCE) assay in Chinese hamster ovary CHO cells 870.5900 3089036 ( 1981)

93089015 ( 1990)

42282705 ( 1992)

Acceptable/ Guideline 0, 3.1, 9.3, 27.8, 83.3, 250.0 or 750.0 µ g/ mL with metabolic activation ( S9 mix): 0, 1.56, 3.13, 6.25, 12.50, 25.00 or 50.00 µ g/ mL without S9 mix. There was no evidence of SCE induction over background.

Gene Mutation: In vitro Bacterial Gene Mutation ( Bacterial system, Salmonella typhimurium; E. coli)/ mammalian activation gene mutation assay 870.5100 93089035 ( 1990)

93089012 ( 1990)

Acceptable/ Guideline 0, 1, 10, 100, 500, 1000, 2500, 5000 or 10,000 µ g/ plate in the presence and absence of mammalian metabolic activation ( S9 mix) There was no evidence of induced mutant colonies over background.

Gene Mutation: In Vitro Mammalian Cells in Culture Gene Mutation assay in L5178Y mouse lymphoma cells 870.5300 93089041 ( 1981)

93089029 ( 1990)

Unacceptable/ Guideline 0, 1.56, 12.5, 25.0, 50.0 or 75.0 µ g/ mL without metabolic activation ( S9 mix); and 0, 12.5, 50.0, 75.0, 100.0 or 150.0 µ g/ mL with S9 mix. In the second assay, 0, 25.0, 50.0, 75.0, 100.0, 150.0 or 200.0 µ g/ mL with S9 mix only There was an indication of mutant induction in the presence of S9 mix but only at very cytotoxic doses of Harvade ( N252).

Cytogenetics: In vivo Mammalian Cytogenetics  Micronucleus Assay 870.5395 40479602 ( 1984)

93089014 ( 1990)

Acceptable/ Guideline M: 0, 22.0, 73.3 or 220.0 mg/ kg F: 0, 30, 100 or 300 mg/ kg There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow from either sex at any dose. Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 22 Cytogenetics: In Vivo Mammalian Cytogenetics  Erythrocyte Micronucleus assay in mice 870.5395 41708201 ( 1986)

Acceptable/ Guideline 0 or 220 mg/ kg There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in mouse bone marrow at any harvest time.

Other Genotoxicity: Unscheduled DNA Synthesis in Rat Hepatocytes/ Mam malian Cells  in vivo/ in vitro Procedure 870.5550 40479601 ( 1987)

93089016 ( 1990)

Acceptable/ Guideline 0, 100, 300 or 1000 mg/ kg There was no evidence that Harvade increased the incidence of UDS over the solvent control values indicating no induction of DNA damage.

870.6200a Acute neurotoxicity screening battery Not available N/ A 870.6200b Subchronic neurotoxicity screening battery Not available N/ A Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 23 870.7485 Metabolism and pharmacokinetics ( species) 41323301 ( 1987), 41323302 ( 1987), 41612401 ( 1989), 93089017 ( 1990), and 93089018 ( 1990),

Unacceptable/ Guideline A series of metabolism studies indicated that dimethipin is absorbed from the gastrointestinal tract. Following a single low oral dose, ~ 59~ 66% of the administered dose was absorbed in male and female rats, respectively. With single or multiple high doses, absorption decreased significantly (~ 37% for male and 59% for females), suggesting absorption was rate limited. Highest levels of radioactivity after administration of radiolabeled dimethipin were detected in the gastrointestinal tract, liver, kidneys and red blood cells. Following treatment, ~ 57% of a single low dose in males and ~ 63% in females was recovered in the urine 48 96 hours after treatment while ~ 28% of the dose was recovered in the feces of these rats. Following single or multiple high doses, approximately 33% of the dose was recovered in the urine of male rats and ~ 45% in the urine of female rats 48 96 hours after dosing.

Of that amount of radiolabel recovered in the urine, ~ 77% was composed of three metabolites identified as R 4, R 5, and R 6. These were identified as a cysteinylglycine conjugate of the parent compound, as an N acetylcysteinyl conjugate derived from cysteinylglycine conjugate, and a reductive product of dimethipin ( 1,1,4,4 tetraoxide, 2,3 dimethyldithiane). Also identified in the urine were polar metabolites which were not further characterized. No studies were conducted to identify metabolites in the feces or bile, or whether radiolabel was eliminated in the expired air.

4.2 FQPA Hazard Considerations 4.2.1 Adequacy of the Toxicity Data Base The toxicology database is adequate for the evaluation of risks to infants and children. Relevant studies include developmental toxicity studies in the rat and rabbit and a 2 generation reproductive toxicity study in the rat. 24 25 4.2.2 Evidence of Neurotoxicity No neurobehavioral alterations or evidence of neuropathological effects were observed in the available studies.

4.2.3 Developmental Toxicity Studies Developmental Rat Study EXECUTIVE SUMMARY: In a developmental toxicity study ( MRID 93089032; 93089009), N252 Technical ( 99.2% a. i., Lot # D10370) in corn oil was administered to groups of at least 25 BLU:( SD) BR ( Sprague Dawley) rats/ dose by gavage at dose levels of 0, 80, 400, or 800 mg/ kg bw/ day from days 6 through 15 of gestation. A positive control group of 29 rats was administered 250 mg/ kg bw/ day aspirin from gestation days ( GD) 6 15. Because of excessive deaths of the dams, the dose levels of 400 and 800 mg/ kg/ day N252 Technical were terminated, and the dose groups of 30 and 160 mg/ kg/ day were added. Therefore, the test groups were as follows: groups of 28, 25, 25, or 26 SD rats were administered N252 Technical by gavage at dose levels of 0, 30, 80, or 160 mg/ kg bw/ day, respectively, from days 6 through 15 of gestation. On GD 20, all dams were sacrificed, subjected to gross necropsy, and all fetuses examined externally. The total numbers of fetuses examined ( number of litters) were 262 ( 21), 243 ( 22), 261 ( 22), and 243 ( 22), for the 0, 30, 80, 160 mg/ kg bw/ day groups, respectively, and 196 ( 19) for the 250 mg/ kg/ day aspirin group. Approximately one third of the fetuses were examined viscerally, and the other two thirds of the fetuses were examined for skeletal malformations/ variations.

At the discontinued dose levels of 400 and 800 mg/ kg/ day, maternal toxicity consisted of urine seepage, bloody vaginal discharge, decreased activity, weight loss, and death.

No treatment related deaths or clinical signs were observed in dams in the 0, 30, 80, or 160 mg/ kg/ day groups. The 30 and 160 mg/ kg/ day dose groups exhibited statistically decreased mean absolute body weights throughout the study, including GD 0 ( 90 and 93% of controls, respectively; p< 0.05 as analyzed by the reviewer using ANOVA followed by Dunnet's test). These lower mean absolute body weights suggest that these animals were younger than the original animals used at study initiation. The 80 and 160 mg/ kg/ day dose groups did have biologically significant decreases in mean body weight gains over the treatment interval of GD 6 15 ( 77 and 71% of controls, respectively; statistical analysis not conducted). Body weight gains during the post dosing interval of GD 15 20 were comparable to controls.

Food consumption values were not recorded, and no gross pathological findings were noted during the limited gross necropsy of treated dams.

The maternal LOAEL is 80 mg/ kg bw/ day based on decreased maternal body weight gain during the dosing interval. The maternal NOAEL is 30 mg/ kg bw/ day. 26 No definitive N252 Technical related effects on pregnancy rates, number of corpora lutea, pre or postimplantation losses, resorptions/ dam, fetuses/ litter, fetal body weights, or fetal sex ratios were observed in the treated groups as compared with the controls.

No N252 Technical related external, visceral, or skeletal malformations/ variations were observed. The developmental NOAEL is

160 mg/ kg bw/ day, and a developmental LOAEL could not be established.

The study is classified Unacceptable/ Guideline ( upgradable), and does not satisfy the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in the rat because data on test material stability, homogeneity, and concentration in the dosing medium were not provided. This study may be upgraded and found to be acceptable if the missing data are obtained.

Developmental Rabbit Study EXECUTIVE SUMMARY: In a developmental toxicity study ( MRID 93089033) N252 technical ( 98.3% a. i., batch/ lot # D10894) was administered to 16 female Dutch belted rabbits/ dose by gavage at dose levels of 0, 7.5, 20, or 40 mg/ kg bw/ day from days 6 through 27 of gestation. Additional information on test article identity was provided in MRID 93089010. Historical control data ( MRID 44988701) from 36 studies conducted between 1977 1983 included observations from uterine examination; results were given as percent of fetuses and litters affected. On GD 28, all surviving does were sacrificed and examined grossly. Each fetus was weighed and examined for external abnormalities. Fetuses were examined viscerally, including sex determination. The brain was examined by a mid coronal slice, and the heart was dissected by a modification of the Staples method. The eviscerated, skinned carcasses were processed for skeletal examination.

All animals survived to GD 28. One doe in each of the control, mid, and high dose groups aborted on or prior to termination on GD 28 and was sacrificed. No treatment related clinical signs of toxicity were observed in any animal and gross necropsy was unremarkable. No differences in absolute body weights were found between the treated and control groups at any time during the study. However, weight gain by the high dose group was less than that of the controls throughout the treatment interval. The high dose group had a mean weight loss after the initiation of dosing ( GD 6 12) and an overall weight gain for the treatment interval only 2% of the control level.

Therefore, the maternal toxicity LOAEL for N252 in rabbits is 40 mg/ kg/ day based on decreased body weight gain and the maternal toxicity NOAEL is 20 mg/ kg/ day.

No statistically significant differences were noted between the treated and control groups for numbers of corpora lutea, implantations, live fetuses, or resorptions, fetal sex ratios, or pre or post implantation losses. Fetal body weights were similar between the treated and control 27 groups. No dose or treatment related external or visceral malformations/ variations were observed in any fetus from any group. The slight increase in the incidence of scoliosis was not considered treatment related based on historical control data.

Therefore, the developmental toxicity NOAEL for N252 in rabbits is 40 mg/ kg/ day.

The developmental toxicity study in the rabbit is classified Unacceptable/ Guideline ( upgradable) and does not satisfy the guideline requirements for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in rabbits. The dosing solutions were not analyzed for homogeneity, stability, or concentration. These data may have been submitted separately, but were not available to the reviewer.

4.2.4 Reproductive Toxicity Study EXECUTIVE SUMMARY: In a two generation reproduction study ( MRID 93089034), N252 ( Dimethipin; 99.7% a. i., lot # D10894) was administered to 15 male and 25 female CD ® ( SD) BR rats/ dose in the diet at concentrations of 0, 50, 200, or 800 ppm. Additional information on test article identity was provided in MRID 93089011. Two litters were produced in each generation; F 1 animals were randomly selected from the B litters. The animals were mated 1: 2 ( male: female) within dose groups. Premating compound intake ( mean values) for the treated F 0 parental animals were 2.5 7.7, 9.4 28.7, and 39.4 115.7 mg/ kg/ day, respectively, for males and 3.1 7.4, 12.7 29.0, and 51.1 120.3 mg/ kg/ day, respectively, for females. Premating doses for the treated F 1 parental animals were 2.4 6.1, 9.2 24.8, and 35.5 96.0 mg/ kg/ day, respectively, for males and 3.0 5.9, 11.8 24.9, and 31.2 96.4 mg/ kg/ day, respectively, for females. F 0 and F 1 parental animals were administered test or control diet for 15 or 17 weeks, respectively, prior to mating, throughout mating, gestation, and lactation of two litters, and until sacrifice.

No treatment related deaths, clinical signs of toxicity, or gross or microscopic lesions were observed in any animal during the study. No effects on body weights, body weight gains, or food consumption were observed in the low and mid dose groups of either generation.

Body weights and body weight gains of the high dose F 0 and F 1 females were significantly ( p

0.05 or 0.01) less than those of the controls during premating. Absolute body weights for the F 0 females were 91 93% of controls during weeks 9 15 and for the F 1 females were 89 94% of controls during weeks 7 17. Weekly body weight gains for the F 0 females were not affected by treatment, however, overall premating weight gain by the high dose group was 89% of the control group level. Body weight gains for the F 1 animals were less than control levels for weeks 2, 4, and 11 with overall premating weight gain by the high dose group 80% of the control group level. The lower absolute body weights for high dose females of both generations continued into gestation and lactation of both litters. Food consumption by the high dose F 0 females was significantly ( 92 94% of controls; p

0.05 or 0.01) less than that of the controls for premating weeks 6 and 8 10. Food consumption by the high dose F 1 females was significantly ( p

0.05 or 0.01) less than that of the controls for premating weeks 6 9 ( 91 94% of controls), 11 15 ( 89 91% of controls), and 17 ( 54% of controls). The parental systemic LOAEL is 800 ppm for F0 and 28 F1 females ( 31.2 120.3 mg/ kg/ day) based on decreased body weights and body weight gains and was not identified for males. The parental systemic NOAEL is 200 ppm for F0 and F1 females ( 11.8 29.0 mg/ kg/ day) and

800 ppm for F0 and F1 males ( 35.5 115.7 mg/ kg/ day).

No treatment related differences in mating, fertility, or gestation indices were seen between the treated and control groups of either generation during the production of both litters. The precoital interval and the gestation length of the treated groups were comparable to the control groups during the production of both litters in both generations. The reproductive toxicity NOAEL for males and females is

800 ppm ( 35.5 115.7 and 31.2 120.3 mg/ kg/ day, respectively) and the reproductive toxicity LOAEL was not identified.

For the A and B litters of the F 1 and F 2 generations, live birth and viability indices, mean litter sizes, sex ratios, and frequency and type of clinical signs were similar between the treated and control groups. Absolute body weights of all low and mid dose pups and high dose F 1b and F 2a pups were not affected by treatment. High dose F 1a pups had significantly ( p

0.01) lower body weights on lactation days 14 and 21 compared with the controls as a result of weight gains 79 84% of the control group levels during lactations days 4 21. Body weight gains of the high dose F 2a pups were 83% of controls ( p

0.05) for lactation days 14 21. Body weight of the high dose F 2b pups were significantly ( 84 86%; p

0.05) less than those of the controls on lactation days 4 14 due to a weight gain of 75% ( p

0.01) of the control level on day 4. No dose or treatmentrelated differences were seen in organ weights or gross or microscopic lesions between treated and control weanlings of either generation. The offspring toxicity LOAEL is 800 ppm ( 35.5 115.7 mg/ kg/ day for males and 31.2 120.3 mg/ kg/ day for females) based on decreased body weights and/ or body weight gains by the F1a, F2a, and F2b pups. The offspring toxicity NOAEL is 200 ppm ( 9.2 28.7 mg/ kg/ day for males and 11.8 29.0 mg/ kg/ day for females).

This study is Acceptable/ Guideline and satisfies the guideline requirement for a two generation reproduction study ( OPPTS 870.3800; OECD 416) in rats.

4.2.5 Additional Information from Literature Sources No additional information was identified from literature sources.

4.2.6 Pre and/ or Postnatal Toxicity <IP_ADDRESS> Determination of Susceptibility There is no indication of increased susceptibility of fetuses or offspring in the developmental and reproduction studies. 29 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility There is no degree of concern and there are no residual uncertainties. Although the developmental toxicity studies are unacceptable ( upgradable pending receipt of absent data on homogeneity, stability, and concentration), the missing data will not impact the conclusions of the studies. No quantitative or qualitative sensitivity was observed in the rat and rabbit developmental studies or in the 2 generation reproduction study in the rat. Based on the lack of evidence of pre and/ or postnatal susceptibility resulting following exposure to dimethipin, and considering the lack of residual uncertainties for pre and/ or postnatal toxicity, no special FQPA safety factor is needed ( i. e., 1X). There is no concern for developmental neurotoxicity resulting from exposure to dimethipin.

4.3 Recommendation for a Developmental Neurotoxicity Study 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study There was no evidence of developmental toxicity in the developmental toxicity studies in the rat and rabbit. No neurobehavioral alterations or evidence of neuropathological effects were observed in the available studies.

4.3.2 Evidence that supports not requiring a Developmental Neurotoxicity study None.

<IP_ADDRESS> Rationale for the UFDB ( when a DNT is recommended)

Not applicable. A Developmental Neurotoxicity study is not recommended.

4.4 Hazard Identification and Toxicity Endpoint Selection 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 An endpoint attributable to a single exposure was not identified from the available database.

4.4.2 Acute Reference Dose ( aRfD)  General Population 30 An endpoint attributable to a single exposure was not identified from the available database.

4.4.3 Chronic Reference Dose ( cRfD)

The chronic reference dose ( cRfD) for the general population was selected from a combined chronic toxicity/ carcinogenicity feeding study in the rat. The proposed study is suitable for a chronic exposure duration. The endpoint was based on toxicity in the kidney, lungs, duodenum, and testes of male rats and depressed body weight gain and toxicity in the liver, kidney, glandular stomach, heart, and aortic artery of female rats. The LOAEL in males is 77.6 mg/ kg/ day and the LOAEL in females is 50.3 mg/ kg/ day. The NOAEL in males is 1.75 mg/ kg/ day and the NOAEL in females is 2.18 mg/ kg/ day. The chronic RfD was derived from the NOAEL of 2.18 mg/ kg/ day in females. Application of an uncertainty factor of 100 results in a chronic RfD of 0.0218 mg/ kg/ day.

EXECUTIVE SUMMARY: In a chronic toxicity study ( MRID 43897601), Harvade ® Technical ( 98.5% a. i.) was administered in the diet to 60 male rats ( Crl: CD ® BR/ VAF/ Plus) at concentrations of 0, 40, 1750, or 3500 ppm ( 0, 1.75, 77.6, or 161 mg/ kg/ day) and 60 female rats at concentrations of 0, 40, 875, or 1750 ppm ( 0, 2.18, 50.3, or 103 mg/ kg/ day) for 104 weeks. Ten animals per sex per dose were killed at 12 months for interim evaluations.

Treatment related ( statistically significant ( p< 0.05 or < 0.01), biologically significant, and doserelated effects occurred in the liver, kidney, lungs, and gastrointestinal tract at the mid and highdose levels for male ( 1750 and 3500 ppm) and female rats ( 875 and 1750 ppm). Effects were seen also in the cardiovascular system and brain of females and in the reproductive organs of males receiving the mid and high doses. High dose male rats weighed up to 14% less than controls up to week 102 of the study and 20% less at week 104; mid dose females weighed up to16% less than controls and the high dose females weighed up to19% less than controls during the study. Body weight gain was depressed by 24% in the high dose male group and by 13 and 29% in the mid and high dose female groups overall compared with controls. There was no accompanying decrease in food consumption. Liver toxicity was indicated by increased incidences of bile duct cysts in the high dose male and female groups, bile duct hyperplasia in the mid and high dose female groups, eosinophilic altered foci in the high dose male group, and elevated serum cholesterol levels in males. Chronic progressive nephropathy was exacerbated in mid and high dose rats of both sexes as evidenced by increased incidence and severity of the lesion. The mean absolute kidney weight was elevated in high dose male rats. Toxicity in the gastrointestinal tract was manifested by elevated incidences and severity of epithelial hyperplasia in the nonglandular stomach in high dose male rats, mineralization in the glandular stomach of mid and high dose female rats, epithelial hyperplasia of the duodenum in mid and high dose males and high dose females, and crypt abscesses in the duodenum of mid and high dose male rats. In addition testicular lesions occurred in male rats fed the mid and high doses, and epididymal hypospermia occurred in high dose males. Effects occurring only in females included cardiovascular toxicity ( mineralization of the heart and aortic artery ( mid and high doses)) and brain degeneration ( high doses). No treatment related clinical signs of toxicity, ophthalmic effects, hematologic effects, or changes in urinalysis parameters occurred in male or females rats 31 fed the test material. There were no treatment related effects in male or female rats fed 40 ppm of the test material.

The LOAEL is 1750 ppm ( 77.6 mg/ kg/ day) for males and 875 ppm ( 50.3 mg/ kg/ day) for females, based on toxicity in the kidney, lungs, duodenum, and testes of male rats and depressed body weight gain and toxicity in the liver, kidney, glandular stomach, heart, and aortic artery of female rats. The corresponding NOAEL is 40 ppm ( 1.75 and 2.18 mg/ kg/ day, respectively) for male and female rats.

There was no evidence of potential carcinogenicity of the test material in this study. No neoplastic lesions showed increased incidences that were significantly different from the incidences observed in control animals. The doses were adequate for testing carcinogenicity based on treatment related toxicity seen in the mid and high dose groups.

This study is classified as acceptable and it satisfies the guideline requirements for a combined chronic toxicity/ oncogenicity study ( § 83 5). There were no noteworthy deficiencies in this study.

Uncertainty Factor( s): 100 ( 10X for intraspecies variation, 10X for interspecies extrapolation).

Comments about Study/ Endpoint/ Uncertainty Factor: This endpoint is of the appropriate route and duration of exposure and applies to the population of concern.

4.4.4 Incidental Oral Exposure ( Short and Intermediate Term)

Incidental oral endpoints were not selected since there are no residential uses.

4.4.5 Dermal Absorption No dermal absorption studies on dimethipin are available.

4.4.6 Dermal Exposure ( Short, Intermediate and Long Term)

Short and Intermediate Term Dermal Endpoints: No hazard was identified; therefore, no quantification is required. Systemic toxicity was not seen at the limit dose in a dermal toxicity study in the rat. Additionally, there are no developmental concerns.

Long Term Dermal Endpoints: Based on use pattern, no long term dermal exposure is anticipated.

4.4.7 Inhalation Exposure ( Short, Intermediate and Long Term) 32 Short Term Inhalation Endpoint: The short term inhalation endpoint was based on the maternal NOAEL of 20 mg/ kg/ day identified in an oral developmental rabbit study. The maternal LOAEL of 40 mg/ kg/ day was based on decreased body weight gain.

Comments about Study/ Endpoint: This study was selected for determination of the short term inhalation endpoint because the duration of the study is appropriate to a short term exposure scenario and a clear NOAEL was identified for the endpoint.

Intermediate Term Inhalation Endpoint: The 2 generation reproduction study in the rat was used for the selection of the intermediate term inhalation endpoint, which was based on a parental systemic NOAEL of 11.8 mg/ kg/ day ( F0 and F1 females). The LOAEL for F0 and F1 females ( 31.2 120.3 mg/ kg/ day) was based on decreased body weights and body weight gains.

Comments about Study/ Endpoint: This study was selected for determination of the intermediateterm inhalation endpoint because the duration of the study is appropriate to an intermediate term exposure scenario and a clear NOAEL was identified for the endpoint.

Long Term Inhalation Endpoint: Based on use pattern, no long term inhalation exposure is anticipated.

4.4.8 Margins of Exposure The target Margins of Exposure ( MOEs) for occupational exposure risk assessments are as follows:

Route of Exposure Duration of Exposure Short Term ( 1 30 Days) Intermediate Term ( 1  6 Months) Long Term (> 6 Months)

Dermal       Inhalation 100 100   For occupational exposure, short term and intermediate term inhalation exposure risk assessments, a MOE of 100 is required. The MOE is based on the conventional uncertainty factor of 100X ( 10X for intraspecies variation and 10X for interspecies extrapolation).

There are no residential uses at the present time.

4.4.9 Recommendation for Aggregate Exposure Risk Assessments 33 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 this case, since dimethipin is registered only for agricultural uses, no residential exposures are anticipated. Therefore, the aggregate exposure risk assessment for dimethipin considers only exposures and risks from residues of dimethipin in food and drinking water.

4.4.10 Classification of Carcinogenic Potential Dimethipin has been classified as a Group C ( possible human) carcinogen by the Toxicology Peer Review Committee. The classification was based on evidence of lung adenomas and carcinomas in male CD 1 mouse. The Committee concluded that the original rat study was not conducted at a high enough dose and recommended that a new study be conducted. The results of the new study indicated no evidence of carcinogenicity in the rat. Calculation of a q1* was not recommended for dimethipin, based on the weight of evidence ( i. e., tumors at the HDT in only one sex, strain, species and only one experiment; weak mutagenicity of dimethipin; and lack of structural congener information).

Table 4.4. Summary of Toxicological Doses and Endpoints for Chemical for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary ( females 13 49) Not applicable. Not applicable. No appropriate acute endpoint identified for these groups ( i. e., no toxic effect attributable to a single dose identified). Acute Dietary ( general population)

Chronic Dietary ( all populations) NOAEL = 2.18 mg/ kg/ day UF = 100 ( 10x for intraspecies variation, 10x for interspecies extrapolation)

Chronic RfD = 0.0218 mg/ kg/ day 1X cPAD = 0.0218 mg/ kg/ day ( cRfD/ FQPA SF = cPAD = 0.0218/ 1 = 0.0218) ChronicToxicity/ Carcinogenicity Study in the Rat LOAEL = 50.3 mg/ kg/ day , based on toxicity in the kidney, lungs, duodenum, and testes of male rats and depressed body weight gain and toxicity in the liver, kidney, glandular stomach, heart, and aortic artery of female rats.

Incidental Oral Short Term ( 1  30 days) Not applicable. Not applicable. Not required  no residential uses. Table 4.4. Summary of Toxicological Doses and Endpoints for Chemical for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects 34 Incidental Oral Intermediate Term ( 1  6 months)

Dermal Short Term ( 1  30 days) Not applicable. Not applicable. No hazard was identified; therefore no quantification is required. Systemic toxicity not seen at the limit dose in a Dermal Toxicity Study. Additionally, there are no developmental concerns and no anticipated residential exposure. Residential Occupational Dermal Intermediate Term ( 1  6 months)

Not applicable. Not applicable. Not required  no residential uses. Residential Occupational Not applicable. Not applicable. No hazard was identified; therefore no quantification is required. Systemic toxicity not seen at the limit dose in a Dermal Toxicity Study. Additionally, there are no developmental concerns.

Dermal Long Term (> 6 mos.) Not applicable Not applicable No residential uses. Based on use pattern, no long term occupational exposure is anticipated. Residential Occupational Inhalation Short Term ( 1  30 days) NOAEL = 20 mg/ kg/ day 1X LOC: MOE = 100 ( 10x for intraspecies variation, 10x for interspecies extrapolation) Developmental Study in the Rabbit LOAEL = 40 mg/ kg/ day, based on decreased body weight gain.

Occupational Residential Not applicable Not applicable Not required  no residential uses. Table 4.4. Summary of Toxicological Doses and Endpoints for Chemical for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects 35 Inhalation Intermediate Term ( 1  6 months) NOAEL = 11.8 mg/ kg/ day 1X LOC: MOE = 100 ( 10x for intraspecies variation, 10x for interspecies extrapolation) Two generation reproduction study in the rat LOAEL = 31.2 120.3 mg/ kg/ day, based on decreased bodyweight/ bodyweight gain in F0 & F1 females. Occupational Residential Not applicable. Not applicable. Not required  no residential uses.

Inhalation Long Term (> 6 months)

Residential Not applicable. Not applicable. Not required  no residential uses and no long term inhalation exposure anticipated.

Occupational Not applicable Not applicable Based on use pattern, no long term occupational exposure is anticipated.

Cancer ( oral, dermal, inhalation) Classification: Class C  quantification not recommended.

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 * Refer to Section 4.5 4.5 Special FQPA Safety Factor Based on the above discussed hazard and exposure data, no special FQPA safety factor is needed ( i. e., 1X) and there are no residual uncertainities for pre and/ or post natal toxicity.

 The dietary food exposure assessment utilizes tolerance level or higher residues and 100% crop treated ( CT) information for all commodities. By using these screening level assessments, chronic exposures/ risks will not be underestimated. 36  The dietary drinking water assessment ( Tier 1 estimates) utilizes values generated by models and associated modeling parameters which are designed to provide conservative, health protective, high end estimates of water concentrations.

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 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).

In the available toxicity studies on dimethipin, there was no estrogen, androgen, and/ or thyroid mediated toxicity. When additional appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, dimethipin may be subjected to further screening and/ or testing to better characterize effects related to endocrine disruption.

5.0 Public Health Data 5.1 Incident Reports According to a review of dimethipin incident reports ( Jerome Blondell, 05/ 20/ 04, DP293579), relatively few incidents of illness have been reported due to dimethipin. This conclusion is based on information from the following data sources:

I. OPP Incident Data System ( 1992 to the present) : No reports II. Poison Control Center Data  1993 through 2001: There was only one report of an exposure to dimethipin. This occupational exposure involved a forty three year old man who ingested the product and reported throat irritation and itching. No further information on the disposition of the case was reported.

III. California Data  1982 through 2002: No reports 37 IV. National Pesticide Information Center: On the list of the top 200 chemicals for which NPIC received calls from 1984 1991, inclusively, dimethipin was not reported to be involved in human incidents.

V. National Institute of Occupational Safety and Health's Sentinel Event Notification System for Occupational Risks ( NIOSH SENSOR) 1998 2002: No reports VI. Scientific Literature: No scientific literature was located concerning acute poisoning due to exposure to dimethipin.

5.2 Other Dimethipin is not included in the Agricultural Health Survey ( AHS) Applicator questionnaire and is not on the current National Health and Nutrition Examination Survey ( NHANES) list.

6.0 Exposure Characterization/ Assessment 6.1 Dietary Exposure/ Risk Pathway 6.1.1 Residue Profile The nature of the residue in plants and livestock is adequately understood based on metabolism studies with cotton, goats, and hens. The residue of concern for tolerance enforcement is dimethipin per se for both plant and livestock commodities. The residue of concern for risk assessment is dimethipin per se for plant commodities and livestock commodities except liver. The residues of concern for risk assessment for the liver of cattle, goats, hogs and sheep are dimethipin plus acetyl dithiane tetraoxide. A conservative residue value for liver for risk assessment purposes was calculated by multiplying the total amount of dimethipin and acetyl dithiane tetraoxide ( 0.0 ppm dimethipin and 0.045 ppm) found in the liver in the ruminant metabolism study at 1/ 2x the maximum theoretical dietary burden ( MTDB) for cattle by 2 ( 0.045 ppm x 2 = 0.09, rounded to 0.1ppm).

Tolerances are established under 40 CFR § 180.406 ( a) for residues of dimethipin ( 2,3 dihydro 5,6 dimethyl 1,4 dithiin 1,1,4,4 tetraoxide; CAS Reg. No. 55290 64 7) per se in/ on cotton, undelinted seed at 0.5 ppm, cotton hulls at 0.7 ppm, and the fat, meat, and meat byproducts of cattle, goats, hogs, horses, and sheep, each at 0.02 ppm. There are no tolerances established for dimethipin residues in poultry tissues or eggs as the Agency has concluded that there is no reasonable expectation of finite residues ( 40 CFR § 180.6( a)( 3)) of dimethipin in poultry commodities based on the current registered uses.

Crop field trials conducted in several different states indicate that residues of dimethipin are not likely to exceed the established tolerance of 0.5 ppm in/ on cottonseed when dimethipin is used 38 according to label directions. Processing studies indicate that residues of dimethipin do not concentrate in cottonseed meal, hulls, or refined oil. The field trial and processing studies for dimethipin satisfy the reregistration requirements for these magnitude of the residue studies.

Data must be submitted for cotton gin byproducts, a cattle feed item. In the absence of data, HED assumed residues in gin byproducts of 50x the cottonseed tolerance in calculating the maximum theoretical dietary burden ( MTDB) for cattle. The 50x value is considered worst case and is based on a comparison of established tolerances for cottonseed and cotton gin byproducts for pesticides where separate tolerances for cottonseed and gin byproducts have been established.

Feeding study data, reflecting exaggerated dosing levels, indicate that there is no expectation of finite residues in the fat, meat, or meat byproducts of cattle, goats, horses, hogs or sheep. However, HED recommends that the tolerances for dimethipin in livestock meat and meat byproducts be retained in order to harmonize with the established Codex MRLs. The U. S. tolerances for livestock meat and meat byproducts and Codex MRLs for mammalian meat and edible offal are established at 0.02 ppm, which is at or about the limit of quantitation. HED recommends that tolerances for dimethipin in the fat of cattle, goats, horses, hogs and sheep be revoked as there is no expectation of finite residues in these commodities and there are no Codex MRLs established. There is no U. S. tolerance for dimethipin in milk. A tolerance for milk is not required as there is no expectation of finite residues of dimethipin in milk.

Adequate enforcement methodology is available to enforce dimethipin tolerances. PAM Vol. II lists two methods, Method I for cottonseed and Method II for livestock tissues and eggs. The stated detection limits are 0.1 ppm for cottonseed and 0.02 ppm for livestock commodities.

6.1.2 Chronic Dietary Exposure and Risk Reference: Dimethipin Chronic Dietary Exposure Assessment for the Reregistration Eligibility Decision, DP Barcode: D303935, Susan Stanton, 08/ 18/ 04 A chronic dietary risk assessment was conducted using the Lifeline Model Version 2.0 and the Dietary Exposure Evaluation Model ( DEEM FCID   ) , Version 2.03, which use food consumption data from the USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998. In this analysis the chronic dietary exposure and risk estimates resulting from food intake were determined for the general U. S. population and various population subgroups. An endpoint of concern attributable to a single dose was not identified for dimethipin; therefore, an acute RfD was not established and an acute dietary risk assessment was not conducted.

The resulting food exposure estimates using the Lifeline   software were less than 1% of the cPAD for the U. S. population and all population subgroups. Dimethipin food exposure was estimated at 0.000042 mg/ kg/ day for the U. S. population (< 1% of the cPAD) and 0.000083 mg/ kg/ day (< 1% 39 of the cPAD) for the most highly exposed population subgroup ( children, 3 5 years old). DEEMFCID yielded similar results.

The chronic analysis assumed 100% crop treated, DEEM   ( ver 7.76) default processing factors, and tolerance level residues ( Tier 1) for all commodities, except the liver of cattle, goats, hogs and sheep.

Liver: The residues of concern for risk assessment in liver are dimethipin and its metabolite, acetyl dithiane tetraoxide. A conservative residue value for liver was calculated by multiplying the total amount of dimethipin and acetyl dithiane tetraoxide ( 0.0 ppm dimethipin and 0.045 ppm acetyl dithiane tetraoxide) found in the liver in the ruminant metabolism study at 1/ 2x the maximum theoretical dietary burden ( MTDB) for cattle by 2 and rounding to 0.1 ppm ( 0.045 ppm x 2 = 0.09, rounded to 0.1ppm). This value is considered conservative because of the worst case assumptions that went into calculation of the MTDB for cattle. Residue data for the cattle feed item, cotton gin byproducts, have not been submitted; however, it is unlikely that residues of dimethipin in cotton gin byproducts would exceed residues in cotton seed by more than a factor of 50X. A review of existing tolerances for 13 pesticides with both cotton seed and cotton gin byproducts tolerances found a 1X to 50X difference between cotton seed and cotton gin byproducts tolerances with an average difference of 22X. Based on this information, the MTDB of dimethipin to cattle was calculated assuming a worst case estimate of residues of dimethipin in/ on cotton gin byproducts at 25 ppm ( equivalent to 50X the cotton seed tolerance of 0.5 ppm) ( Dimethipin, Residue Chemistry Considerations for Reregistration Eligibility Decision, Case No. 3063. DP Barcode: 293580, Danette Drew, 07/ 22/ 04). The MTDB of dimethipin to cattle is also considered conservative, because it assumes cotton gin byproducts would comprise 20% of the diet of all beef and dairy cattle. In fact, cotton gin byproducts is a relatively minor feed item of significance in certain regional areas only. In most areas, cotton gin byproducts would be a minor contributor or non contributor to the diet of beef and dairy cattle. This is especially true for dimethipin, since less than 5% of the cotton crop is treated. It should be noted that HED is currently reviewing public comments regarding the feeding of cotton gin byproducts to livestock and may revise ( i. e., lower) its estimate of the maximum amount in livestock diets in the future. 40 Table 6.1. Result of Chronic Dietary Exposure and Risk Estimates for Dimethipin Population Subgroupa cPAD ( mg/ kg/ day) Exposure ( mg/ kg/ day) b % cPAD Lifeline DEEMFCID Lifeline DEEMFCID General U. S. Population 0.0218 0 0.00004 < 1.0 < 1.0 All Infants (< 1 year old) 0 0.00002 < 1.0 < 1.0 Children 1 2 years old 0.0001 0.00008 < 1.0 < 1.0 Children 3 5 years old 0.0001 0.00009 < 1.0 < 1.0 Children 6 12 years old 0.0001 0.00006 < 1.0 < 1.0 Youth 13 19 years old 0 0.00004 < 1.0 < 1.0 Adults 20 49 years old 0 0.00004 < 1.0 < 1.0 Adults 50+ years old 0 0.00003 < 1.0 < 1.0 Females 13 49 years old 0 0.00003 < 1.0 < 1.0 a The values for the population with the highest risk are bolded.

b Reported to 2 significant figures.

6.2 Water Exposure/ Risk Pathway References: Tier I Estimated Environmental Concentrations of Dimethipin, for use in Human Health Risk Assessment; DP Barcode: D293574, Larry Liu, 06/ 22/ 04; Personal Communications  Larry Liu and Michael Barrett ( 8/ 19/ 04 & 8/ 20/ 04)

Water models were used to assess potential exposure to dimethipin from consumption of contaminated drinking water. Tier 1 Estimated Environmental Concentrations ( EECs) for dimethipin were generated using FIRST for surface water and SCI GROW for groundwater. FIRST is a relatively new screening model which provides high end estimates of the concentrations that might be found in a small drinking water reservoir due to use of the pesticide. Input parameters for FIRST were based on application to cotton at the maximum seasonal rate of 0.562 lb. a. i./ A. SCI GROW is a screening model which provides worst case estimates of groundwater concentrations if the pesticide is used at the maximum allowable rate in areas where groundwater is exceptionally vulnerable to contamination.

Using input parameters for FIRST and SCI GROW of a maximum seasonal use rate of 0.562 lb ai/ A, a K oc of 1, and a half life of 408 days, the Tier 1 acute and chronic ( non cancer) EECs for dimethipin in surface water are 11.9 ppb and 7.3 ppb, respectively. The Tier 1EEC ( acute and chronic) for dimethipin in ground water is 423.2 ppb. The disparity between estimated levels of dimethipin in ground and surface water may be attributed to dimethipin's physico chemical properties and the limitations of the drinking water screening models. Dimethipin has an extremely low adsorption coefficient ( Koc = 1) indicating a high leaching potential. It is also very persistent, as indicated by its aerobic soil metabolism half life of 408 days. These characteristics of high mobility and persistence account, in part, for the relatively high estimated residue level in groundwater. 41 The high residue estimate for groundwater is also due, in part, to the limitations of the SCIGROW model itself. Dimethipin's K oc value of 1 is very low and outside the range of K oc values used in the development of SCI GROW. According to EFED's Dr. Michael Barrett, the developer of SCI GROW, the model tends to overestimate leaching below a K oc of 10; and it is more appropriate to run the model using a K oc of 10 as a reasonable worst case in estimating residues of dimethipin in groundwater. When the model is re run with a K oc of 10, the resulting estimated concentration of dimethipin in groundwater is 99 ppb, compared to 423 ppb using a K oc of 1.

Based on the conservative, screening nature of the SCI GRO model and the limitations on its reliability for pesticides with very low K oc values, HED believes the EEC of 99 ppb is a more reliable estimate of dimethipin residues in ground water and should therefore be used for determining risk from consumption of dimethipin contaminated drinking water.

6.3 Residential ( Non Occupational) Exposure/ Risk Pathway Dimethipin is registered for use only on the agricultural site, cotton. There are no residential uses and, therefore, no anticipated exposures in or around homes or recreational areas.

6.3.1 Home Uses  Not applicable.

6.3.2 Recreational Uses  Not applicable.

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 dimethipin. 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 42 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.

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 An acute aggregate risk assessment was not conducted because an endpoint of concern attributable to a single dose was not identified.

7.2 Short Term Aggregate Risk A short term aggregate risk assessment was not conducted because there are no existing or proposed residential uses for dimethipin.

7.3 Intermediate Term Aggregate Risk An intermediate term aggregate risk assessment was not conducted because there are no existing or proposed residential uses for dimethipin.

7.4 Long Term Aggregate Risk A long term ( chronic) aggregate risk assessment was conducted for dimethipin. The chronic assessment considered exposures from food and water only, because there are no residential uses and no residential exposures anticipated for this chemical. Since adequate water monitoring data are not available to estimate levels of dimethipin in drinking water, HED calculated DWLOCs and compared them to the modeled EDWCs for surface and ground water to determine whether aggregate chronic risks are of concern.

The results of the deterministic, Tier 1 dietary exposure assessment indicate that dietary exposures to dimethipin in food are very low and well below HED's level of concern ( 100% of the cPAD). Dimethipin food exposure is estimated at 0.000042 mg/ kg/ day for the U. S. population (< 1% of 43 the cPAD) and 0.000083 mg/ kg/ day (< 1% of the cPAD) for the most highly exposed population subgroup ( children, 3 5 years old) using the LifeLine model. DEEM FCID yielded nearly identical results.

HED used the LifeLine exposure estimates to calculate chronic DWLOCs for the U. S. population and various population subgroups. The calculated DWLOCS ranged from 762 ppb for adults to 217 ppb for children. The Tier 1 chronic surface water EDWC ( 7.3 ppb) generated by EFED is well below HED's calculated DWLOCs for chronic exposure to dimethipin for the U. S. population and each population subgroup. The chronic ground water EDWC ( 99 ppb) generated by SCI GROW using a K oc value of 10 is also below HED's calculated DWLOCs for the U. S. population and all population subgroups.

Based on these considerations, HED is reasonably certain that the chronic aggregate risk associated with the use of dimethipin does not exceed HED's level of concern for the overall U. S. population or population subgroups, including infants and children.

Table 7.4 summarizes the estimated chronic aggregate exposures to dimethipin residues.

Table 7.4. Aggregate Risk Assessment for Chronic ( Non Cancer) Exposure to Dimethipin Population Subgroup1 Chronic Scenario cPAD mg/ kg/ day Chronic Food Exp mg/ kg/ day Max Chronic Water Exp mg/ kg/ day2 Ground Water EDWC ( ppb) 3 Surface Water EDWC ( ppb) 3 Chronic DWLOC ( ppb)

U. S. Population 0.0218 0 0.021758 99 7.3 762 All Infants (< 1 year old) 0.0218 0 0.021785 99 7.3 218 Children 1 2 years 0.0218 0 0.021724 99 7.3 217 Children 3 5 years 0.0218 0 0.021717 99 7.3 217 Children 6 12 0.0218 0 0.02174 99 7.3 217 Youth 13 19 0.0218 0 0.021757 99 7.3 653 Adults 20 49 0.0218 0 0.021762 99 7.3 762 Females 13 49 years 0.0218 0 0.021757 99 7.3 653 Table 7.4. Aggregate Risk Assessment for Chronic ( Non Cancer) Exposure to Dimethipin Population Subgroup1 Chronic Scenario cPAD mg/ kg/ day Chronic Food Exp mg/ kg/ day Max Chronic Water Exp mg/ kg/ day2 Ground Water EDWC ( ppb) 3 Surface Water EDWC ( ppb) 3 Chronic DWLOC ( ppb)

44 Adults 50+ years 0.0218 0 0.021763 99 7.3 762 1Body wts. used to calculate DWLOCs: 70 kg ( U. S. Population, Adults 20 49 years and Adults 50+ years); 60 kg ( Females 13 49 years and Youth 13 19 years); and 10 kg. ( Infants and Children). Water consumption was assumed to be 2 L/ day for adults and youths ( 13 19) and 1 L/ day for infants and children.

2Maximum Chronic Water Exposure ( mg/ kg/ day) = [ Chronic PAD ( mg/ kg/ day)  Chronic Dietary Exposure ( mg/ kg/ day)]

3 Based on application to cotton at the maximum seasonal rate of 0.562 lb. a. i./ A. and a K oc value of 10. The K oc of 10 was used instead of dimethipin's K oc value of 1 to adjust for SCI GROW's tendency to overestimate residues for chemicals with low K oc values.

4 Chronic DWLOC(  g/ L) = [ maximum chronic water exposure ( mg/ kg/ day) x body weight ( kg)]

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

7.5 Cancer Risk Quantification of the cancer risk is not recommended for dimethipin. Therefore, an aggregate cancer assessment was not conducted.

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 dimethipin and any other substances and dimethipin 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 dimethipin 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/. 45 9.0 Occupational Exposure/ Risk Pathway Reference: Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document for Dimethipin. DP Barcode D332596. S. Tadayon. 06/ 08/ 04.

9.1 Short/ Intermediate/ Long Term Handler Risk Occupational handlers may be exposed through the following routes during mixing, loading and application of dimethipin using aerial, groundboom or high pressure handwand equipment and during flagging operations for spray applications:

Dermal: Although dermal exposure is expected, short and intermediate term dermal endpoints were not identified due to the lack of dermal, systemic, and developmental toxicity concerns. A long term dermal endpoint was not identified; nor would long term dermal occupational exposure be expected. Therefore dermal exposure was not assessed.

Inhalation: Even though the volatility of this chemical is very low, based on the use patterns for dimethipin, both short and intermediate term inhalation exposure may occur. Long term inhalation exposure is not anticipated. A shortterm inhalation endpoint was selected based on the maternal NOAEL of 20 mg/ kg/ day from an oral developmental rabbit study. The maternal LOAEL of 40 mg/ kg/ day was based on decreased body weight gain. An intermediate term inhalation endpoint was selected using the NOAEL of 11.8 mg/ kg/ day ( F0 and F1 females) from a 2 generation reproduction study in the rat. The LOAEL for F0 and F1 females ( 31.2 120.3 mg/ kg/ day) was based on decreased body weights and body weight gains.

Handler exposure and risk were estimated for the following scenarios: ( 1) mixing/ loading liquids for aerial application, ( 2) mixing/ loading liquids for groundboom application , ( 3) mixing/ loading liquids for high pressure handwand application, ( 4) aerial spray application, ( 5) groundboom spray application, ( 6) high pressure handwand spray application and ( 7) flagging for spray applications.

No chemical specific handler exposure data were submitted to the Agency in support of the reregistration of dimethipin. It is the policy of HED to use data from the Pesticide Handlers Exposure Database ( PHED) Version 1.1, as presented in the PHED Surrogate Exposure Guide ( 8/ 98), when chemical specific monitoring data are not available. PHED data were used with other HED standard values for areas treated per day, body weight and the level of personal protective equipment ( PPE) to assess handler exposures to dimethipin. For all exposure scenarios except aerial spray application, baseline PPE ( i. e., no respirator) were assumed. This assumption is consistent with PPE requirements on dimethipin labels ( gloves, but not respirators, are 46 required). For aerial spray application ( fixed wing aircraft), HED assumed the use of engineering controls ( i. e., closed cockpit). Engineering controls were assumed because of the insufficient number of data points for fixed wing, open cockpit aircraft in the PHED.

Using the above assumptions, all of the calculated occupational handler MOEs are greater than HED's target of 100 and, therefore, are not of concern. Short term inhalation MOEs range from 1,500 ( mixing/ loading liquids for aerial application) to 1,300,000 ( mixing/ loading liquids for highpressure handwand application). Intermediate term inhalation MOEs range from 880 ( mixing/ loading liquid for aerial application) to 770,000 ( mixing/ loading liquids for high pressure handwand application).

Table 9.1.1 Short and Intermediate Term Occupational Exposure and Risk Estimates for Dimethipin. The short term inhalation NOAEL is 20 mg/ kg/ day. The long term inhalation NOAEL is 11.8 mg/ kg/ day.

Exposure Scenario ( Scenario #) Crop Daily Area Treated ( Acres or Gals./ Day) Daily Inhalation Dose ( mg/ kg/ day) Short Term Inhalation MOE Intermediat e Term Inhalation MOE Mixer/ Loader Mixing/ loading Liquids for Aerial Application ( 1) Cotton 1200 acres 0.013 1,500 880 Mixing/ loading Liquids for Groundboom Application ( 2) 200 acres 0.0022 8,900 5,300 Mixing/ loading Liquids for High pressure Handwand Application ( 3) Apple 1,000 gals. 0.000015 1,300,000 770,000 Applicator Aerial Spray Application ( 4) Cotton 1200 0.00076 26,000 ( engineering control) 15,000 ( engineering control)

Groundboom Spray Application ( 5) Cotton 200 0.0014 14,000 8,500 High pressure Handwand Spray Application ( 6) Apple 1,000 gals. 0.001 20,000 12,000 Flagger Flagging for Spray Applications ( 7) Cotton 350 0.0011 17,000 10,000 9.2 Short/ Intermediate/ Long Term Postapplication Risk EPA did not assess risk from occupational postapplication dermal exposure, since no short or intermediate term dermal endpoint of concern was identified and long term dermal exposures are 47 not expected for tasks involving cotton use patterns. Postapplication inhalation exposure is expected to be negligible; therefore, a risk assessment for this route was also not conducted.

The toxicity categories of the active ingredient for acute dermal toxicity, eye and skin irritation potential are used to determine the interim REI ( Restricted entry Interval). The classification of dimethipin in category III for dermal irritation potential requires a 12 hour REI.

10.0 Data Needs and Label Requirements 10.1 Toxicology  870.3700a: Data must be submitted on test material stability, homogeneity, and concentration in the dosing medium.

 870.3700b: Data must be submitted on test material stability, homogeneity, and concentration in the dosing medium.

 870.4100b: Data must be submitted on historical controls, and diet homogeneity and stability.

10.2 Residue Chemistry  860.1500: Data must be submitted depicting dimethipin residues in cotton gin byproducts which include burrs, leaves, stem, lint, immature seeds and sand ( dirt) obtained from ginning cotton.

 860.1850: To demonstrate the storage stability of the samples used in the supplemental confined rotational crop submission, the registrant must submit additional data/ information comparing the chromatographic profiles of the stored samples with those of the original analyses ( see D219060and D223855, DERs 4376801, 43768202, and 43931301).

 860.1900: Additional storage stability data are required to support the limited field rotational crop studies ( see D225417, DERs 43979102 and 43979101). HED notes that crop field trial data for cotton gin byproducts and extensive field rotational crop studies are required; storage stability data to support those studies will be required unless samples are analyzed within one month of collection.

 860.1900: The available limited rotational crop studies indicate the potential for dimethipin residues in certain rotated crops at the established plantback interval ( 6 months). Extensive field rotational crop studies must 48 be submitted for all crops, except leafy vegetables, for which the registrant wishes to allow a 6 month plantback interval. In the submitted studies, residues of dimethipin were below the LOQ (< 0.02 ppm) to 0.031 ppm in lettuce, < 0.02 ppm in carrot roots, 0.034 0.071 ppm in carrot tops, 0.027 0.039 ppm in wheat forage, < 0.02 ppm in wheat grain, and < 0.02 0.023 ppm in wheat straw planted one month after application of dimethipin. Residues of dimethipin were below the LOQ (< 0.02 ppm) in lettuce, < 0.02 0.024 ppm in carrot roots, < 0.02 0.180 ppm in carrot tops, < 0.02 ppm in oat forage, < 0.02 ppm in oat grain, and < 0.02 0.021 ppm in oat straw planted six months after dimethipin application. At both plantback intervals, residues were highest in carrot tops.

10.3 Occupational and Residential Exposure  None References:

Dimethipin, Residue Chemistry Considerations for Reregistration Eligibility Decision, Case No. 3063. DP Barcode: 293580, Danette Drew, 07/ 22/ 04 Dimethipin Chronic Dietary Exposure Assessment for the Reregistration Eligibility Decision, DP Barcode: D303935, Susan Stanton, 08/ 18/ 04 Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document for Dimethipin, DP Barcode D332596, S. Tadayon, 06/ 08/ 04 Tier I Estimated Environmental Concentrations of Dimethipin for use in Human Health Risk Assessment; DP Barcode: D293574, Larry Liu, 06/ 22/ 04 49 Appendices 1.0 TOXICOLOGY DATA REQUIREMENTS The requirements ( 40 CFR 158.340) for food use for dimethipin are in Table 1. Use of the new guideline numbers does not imply that the new ( 1998) guideline protocols were used.

Test Technical Required Satisfied 870.1100 Acute Oral Toxicity . . . . . . . . . . . . . . .

870.1200 Acute Dermal Toxicity . . . . . . . . . . . . .

870.1300 Acute Inhalation Toxicity . . . . . . . . . . .

870.2400 Primary Eye Irritation . . . . . . . . . . . . . .

870.2500 Primary Dermal Irritation . . . . . . . . . . .

870.2600 Dermal Sensitization . . . . . . . . . . . . . . . yes yes yes yes yes yes yes yes yes yes yes yes 870.3100 Oral Subchronic ( rodent) . . . . . . . . . . .

870.3150 Oral Subchronic ( nonrodent) . . . . . . . .

870.3200 21 Day Dermal . . . . . . . . . . . . . . . . . . .

870.3250 90 Day Dermal . . . . . . . . . . . . . . . . . . .

870.3465 90 Day Inhalation . . . . . . . . . . . . . . . . . yes yes yes no no yes yes yes

870.3700a Developmental Toxicity ( rodent) . . . . .

870.3700b Developmental Toxicity ( nonrodent) . . .

870.3800 Reproduction . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes 870.4100a Chronic Toxicity ( rodent) . . . . . . . . . . .

870.4100b Chronic Toxicity ( nonrodent) . . . . . . . .

870.4200a Oncogenicity ( rat) . . . . . . . . . . . . . . . .

870.4200b Oncogenicity ( mouse) . . . . . . . . . . . . . .

870.4300 Chronic/ Oncogenicity . . . . . . . . . . . . . . yes yes yes yes yes yes yes yes yes yes Test Technical Required Satisfied 50 870.5100 Mutagenicity   Gene Mutation  bacterial . . . . . . . . . . . . . . . . . . . . . . . .

870.5300 Mutagenicity   Gene Mutation  mammalian . . . . . . . . . . . . . . . . . . . . . .

870.5xxx Mutagenicity   Structural Chromosomal Aberrations . . . . . . . . . . . . . . . . . . . . . .

870.5550 Mutagenicity   Other Genotoxic Effects yes yes yes yes yes yes yes yes 870.6100a Acute Delayed Neurotox. ( hen) . . . . . .

870.6100b 90 Day Neurotoxicity ( hen) . . . . . . . . .

870.6200a Acute Neurotox. Screening Battery ( rat)

870.6200b 90 Day Neuro. Screening Battery ( rat)

870.6300 Develop. Neuro . . . . . . . . . . . . . . . . . . no no no no no

870.7485 General Metabolism . . . . . . . . . . . . . . .

870.7600 Dermal Penetration . . . . . . . . . . . . . . . . yes no yes

Special Studies for Ocular Effects Acute Oral ( rat) . . . . . . . . . . . . . . . . . . . . . .

Subchronic Oral ( rat) . . . . . . . . . . . . . . . . . .

Six month Oral ( dog) . . . . . . . . . . . . . . . . . . no no no

2.0 NON CRITICAL TOXICOLOGY STUDIES STUDY TYPE: Carcinogenicity feeding  mouse [ OPPTS 870.4200b ( § 83 2( b))]; OECD 451.

EXECUTIVE SUMMARY: In a 18 month oral carcinogenicity study ( MRID 93089031), N252 ( 97.8% a. i., Lot # BL 8461) was administered to a total of 50 CD ®  1 mice/ sex/ dose in the diet at concentrations of 0, 80, 400, or 2000 ppm ( equivalent to 0, 11.3, 56, or 286 mg/ kg bw/ day for males and 0, 13.3, 68, or 341 mg/ kg bw/ day for females).

There were no treatment related effects on mortality. The body weight gain of males at 2000 ppm was 75% ( p< 0.05) of the control after 13 weeks of treatment and 81% after 18 months. The body weight gain in females at 2000 ppm was 80% ( NS) of the control at 13 weeks and comparable to the controls at 18 months. Food efficiency over the first 53 weeks of the study was decreased by 23% in males at 2000 ppm compared to the control. Food consumption was comparable to the control groups. Erythrocyte counts were increased by 19 25% in treated mice compared to the control groups, but the difference was statistically significant only in females at 51 80 ppm. Increases in hematocrit and hemoglobin concentration were also seen in treated mice, but the changes were not significantly different from the control. No significant treatment related changes were seen in absolute or relative ( to body weight) organ weights. Microscopic examination revealed significantly increased incidences of tracheal mononuclear inflammatory cell foci in males at 2000 ppm ( 26%, p< 0.05) compared to the control group ( 8%). Increased inflammatory cell foci incidences were not seen in treated females compared to the control group.

A number of findings were negatively correlated with treatment including incidences of liver microgranulomas and nonsuppurative pericholangitis in males; pulmonary perivascular lymphoid hyperplasia and focal pneumonitis, dilated kidney tubules, regenerative kidney tubule epithelium, and cystic ovarian follicles in females.

The LOAEL for N252 in male mice is 2000 ppm ( 286 mg/ kg/ day) based on increased mononuclear inflammatory cell foci in the trachea, decreased body weight gain, and decreased food efficiency. A LOAEL was not determined for females. The NOAEL is 400 ppm for males ( 56 mg/ kg/ day) and 2000 ppm for females ( 341 mg/ kg/ day).

Treatment of CD ®  1 male mice with a dietary level of 2000 ppm N252 for 18 months resulted in a marginally significant ( p< 0.044) increase in the incidences of lung carcinomas and adenomas combined compared to the control group and a significant positive trend for lung adenomas.

This carcinogenicity study in the mouse is Acceptable/ Guideline and satisfies guideline requirements for a carcinogenicity study [ OPPTS 870.4200b; OECD 451] in mice. Although toxicity and neoplastic effects were seen in males, the animals, and especially females, could have tolerated higher doses. A comparison of tumor incidences in historic controls would have been helpful.

STUDY TYPE: Chronic toxicity  dog feeding OPPTS 870.4100b [ § 83 1b] OECD 452.

EXECUTIVE SUMMARY: In a chronic toxicity study ( MRID 93089030), N252 ( 99.7% a. i., Control D  10894) was administered to 6 beagle dogs/ sex/ dose in the diet at concentrations of 0, 100, 300, or 3000 ppm ( equivalent to 0, 8.92, 29.85, and 98.98 mg/ kg bw/ day for males and 0, 10.33, 34.42, and 92.87 mg/ kg bw/ day for females, respectively) for 52 weeks. An independent summary ( MRID 93089007) of the materials/ methods and results of the aforementioned primary study was also available and concurred with the study reports conclusions.

At 3000 ppm N252, females showed a statistically significant decrease in body weight gain ( 20.8% at 52 weeks; p < 0.01) and males exhibited a statistically significant decrease ( 7.8% at 52 weeks; p< 0.05). Food consumption was markedly reduced in females and moderately reduced in males at 3000 ppm. Irregular heartbeat was observed in most of the 3000 ppm dogs prior to sacrifice. Four dogs in the 3000 ppm treatment group ( 1 male and 3 females) died or were sacrificed in extremis during the study; the deaths could not be directly attributed to the treatment. Although the deaths could not be directly attributed to the treatment based upon the 52 clinical chemistry and gross pathology correlates, food efficiency was negative for both males and females in the high dose group thereby suggesting a compound related effect. There were no remarkable treatment related gross or microscopic lesions, and no alterations in hematologic and clinical chemistry parameters in any of the dogs. Relative weights of various organs were significantly increased ( p < 0.05 or p < 0.01) in both male and female dogs in the 1000 and 3000 ppm treatment groups. However, corresponding absolute organ weights were not significantly increased compared to controls, indicating increased relative organ weights were likely a function of decreased body weight.