### (PP#0E06068), Stone Fruit (PP #2E06303), and Tomatoes (PP#1E06303) (Deschamp P, D323441, 09/23/05). Additional documents used in this scoping document are cited below.

Pyridaben [2- tert -butyl-5-(4- tert -butylbenzylthio)-4-c hloropyridazin-3(2 H )-one] is a selective

contact miticide/insecticide that controls va rious types of phytophagous mites and insects in orchards and vineyards. Pyridabe n is registered for use on tree nuts, pistachio, apple, pear, citrus fruits, grape, apricot, cherry, nectarine, peach, plum, prune, cranberry, ornamentals, and greenhouse-grown tomatoes. There are no regi stered residential uses of pyridaben.

Under the new rules for toxicity data requirements (40 CFR §158.500, 10/26/2007), an immunotoxicity study is required fo r pyridaben. Once the data have been received and reviewed, the pyridaben HED Registration Review Team will re-evaluate the sensitivity determination, as well as the points of departure and safety factors used for risk assessment purposes.

The existing residue chemistry database for pyridaben is adequate for risk assessment purposes.

There are no registered residential uses of pyridaben. There is a potential for short- and intermediate-term occupationa l handler exposure to pyridaben during mixing, loading, and applying activities. Occupati onal risk assessments have be en conducted for wettable powder formulations (in water soluble bags) and shoul d also be conducted for aqueous solution formulations. Assessments using current standard operating procedures are needed for currently registered formulations of pyridaben. New pyr idaben occupational exposure/risk assessments will be needed for Registration Review.

Occupational postapplication exposur e to pyridaben can occur via the dermal and/or inhalation routes. Postapplication exposure should be re assessed for certain pyridaben use sites using current HED policies. All other occupational e xposure scenarios were assessed adequately and do not present risks of concern.

Introduction

HED has evaluated the status of the human h ealth assessments for pyridaben to determine

whether sufficient data are available and if any updates are needed to support Registration

Review. HED has considered the most recent risk assessment for pyridaben (Deschamp P, D323441, 09/23/2005), HED and OPPIN databases for registration review. Pyridaben may be applied via handgun, airblast, gr oundboom, or chemigation (for certain use sites only) at maximum application rates of 0.5 lb ai/Acre and 0.19 lb ai per 100 gallons for greenhouse tomatoes, with a maximum of 2 applications per year for certain crops.

Hazard Identification/Toxicology Pyridaben is a selective contac t miticide/insecticide that cont rols various types of phytophagous mites and insects in orchards and vineyards. Py ridaben belongs to a cla ss of pesticides known as pyridazinones. Pyridaben affects mite and in sect metabolism by inhibiting the mitochondrial electron transport chain in target organisms (Dekeyser M, 2004 1 

### ), but its mechanism of action in mammals has not been definitively identified. Other pyridazinones affect ATP usage or generation, but their specific mechanis ms of action differ amongst the compounds.

1 Dekeyser M, Acaricide mode of action, in Pest Management Science, pp 103 -110 (2004)



### Page 2 of 28

### Pyridaben’s toxicity data base is complete, with the excepti on of a now requi red immunotoxicity study. The toxicity database for pyridaben doe s not indicate a distinct organ system being adversely affected. However, it has been shown in rats, mice, rabbits, and dogs that administration of pyridaben results in reduced body weight gain. Addi tionally, in both shortterm and long-term exposure, dogs administered pyridaben orally showed clinical signs of toxicity such as dehydration, diarrhea, food-lik e emesis, frothy emesis, soft stool, uninhibited salivation, and relaxed nictitans (membrane that functions as a third eyelid) in addition to reduced body weight gain. In an inhalation stud y, rats treated with pyrid aben showed signs of toxicity such as red dried nasal discharge, increased ano-genital staining, in addition to decreased body weight gain.

Pyridaben produced mild acute toxicity through or al, dermal, and inhalati on exposure routes. It produced slight ocular irritation but has not been shown to be a dermal irritant or sensitizer.

There are guideline acute and subc hronic neurotoxicity studies as well as developmental toxicity studies in rats and rabbits (by the oral or de rmal routes), and a multi-generation reproduction study in rats. The developmental and reproductio n studies show no effects on reproduction and no increased susceptibility of rats or rabbits to in utero and/or postnatal exposure to pyridaben as demonstrated by higher lowest-observable-adve rse-effect-levels (LOAELs) than those for maternal toxicity. In the acu te and subchronic neurotoxicity studies, moderate clinical signs were seen only at relatively high doses; the effects were suggestiv e of neurotoxicity, but there were no supportive neuropathological (g ross pathology includi ng brain weights or histopathology) effects.

Pyridaben’s mutagenicity battery indicated no evidence of genotoxic potential. Additionally, cancer studies utilizing both male and female rats do not demonstr ate any evidence of carcinogenicity. Thus, pyridaben is classified as “Not Likely to Be Carcinogenic to Humans.” 2



### The pyridaben risk assessment team has re-evalu ated all the available toxicology data along with

the most recent human health risk assessm ent (Deschamp P, D323441, 09/23/2005). The team has determined that the toxicity endpoints and points of depa rture developed in the 2005 risk assessment continue to be valid for any risk assessment purposes. A detailed listing of the endpoints, doses and uncertainty factors selected for all exposur es may be found in Attachment

4.

HED has selected an acute diet ary endpoint for the general U. S. population, including infants and children based on the rat neurotoxicity st udy where increased incidence of piloerection, hypoactivity, tremors, partially closed eyes and decreased body weight gain and food consumption were observed in both sexes. For chronic dietary exposures, HED has selected an endpoint based the 1-year dog study where increased incidence of ptyalism, emesis and soft stool and decreased body weight gain was observed in females. The Food Quality Protection Act (FQPA) requires the Agency to consider sensitiv ities of the young to chemical exposure. The pyridaben risk assessment team has reviewed the entire database for pyridaben and determined there is no residual uncertainty regarding exposur e to children at any developmental stage and

2 Memo: Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs 09/03/2009



### Page 3 of 28

### recommends that the FQPA safety factor be reduced to 1x for a ll exposure scenarios. This position continues to be valid.

An immunotoxicity study is required as part of new data requirements in the 40 CFR § 158 for pesticide registration. However, in the ab sence of a specific immunotoxicity study, EPA has evaluated the available pyridaben toxicity database to determine whether an additional database uncertainty factor is needed to account fo r potential immunotoxicity. No evidence of immunotoxicity such as altered hematology, changes in lymphoid organ weights, and aberrant histopathology, was observed in any of the available toxicity studi es. Because of the lack of evidence of immunotoxicity for pyridabe n, EPA does not believe that conducting immunotoxicity testing will result in a NOAEL less than that used to derive the current cRfD. Consequently, the EPA believes the existing da ta are sufficient for endpoint selection for exposure/risk assessment scenarios and for ev aluation of the requirements under the FQPA;

therefore an additional data base uncertainty factor does not need to be applied.

However, it must be made clear that the immune system is highly complex and, thus, studies not specifically conducted to assess immunotoxic endpoints are inadequa te to fully characterize a pesticide’s potential immunotoxicity. While da ta from hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies might offer useful information on potential immunotoxic effects, th ese endpoints alone are in sufficient to predict immunotoxicity. Therefore, an immunotoxicity study must be submitted for the risk assessment team to develop an enhanced understanding of the risks associat ed with pyridaben.

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide active and other ingredients) may have an effect in humans or wildlife si milar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered ap proach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticid e active ingredients and 9 inert ingredients.

This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-applic ation agricultural scenarios.

This list should not be construe d as a list of known or likely endoc rine disruptors. Pyridaben is not among the group of 58 pesticide active ingredient s on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/dat a call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67

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### chemicals, the test guidelines, and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/.

Conclusion A newly required immunotoxi city study is needed to support re gistration review of pyridaben. HED will consider the existing toxicity database as well as all additional toxicity studies received during registration review and will reevaluate the sensitivity determination, as well as the points of departure and safety factors, used for risk assessment purposes

Residue Chemistry The existing residue chemistry database for pyridaben is adequate for risk assessment purposes. All submitted residue chemistry data have been reviewed and found sufficient to estimate and characterize dietary exposure and to support current registrations. The qualitative nature of pyridaben residues in plants and livestock is adequately understood. In the submitted plant metabolism studies (orange, apple, eggplant) pyrid aben is highly metabolized yielding minor

metabolites. The submitted livestock metabolism st udies also indicate that pyridaben is highly metabolized yielding minor meta bolites including PB-7 [2- tert -butyl-5-(4-(1-carboxy-1- methylethyl)benzylthio)-4-chloropyridazin-3(2 H )-one] and PB-9 [2- tert -butyl-5-[4(-1,1- dimethyl-2-hydroxyethyl)benzy lthio-4-chloropyridazin-3(2 H )-one]. Although these metabolism studies are adequate to support ex isting uses, if uses are proposed for grain crops and/or leafy vegetables, additional metabolism data using eith er a grain crop or leafy vegetable will be required. Adequate analytical methods exist fo r data collection and tolerance enforcement. Adequate storage stability, processed food, and plan t/animal magnitude of th e residue data exist.

Tolerances are established under 40 CFR §180.494 for residues of the insect icide pyridaben that result from agricultural uses. The permanent tolerance expression for all commodities is in terms of the parent only for plant commodities and pa rent only plus metabolites PB-7 and PB-9 for livestock commodities. Pyridaben dietary risk assessments should include the parent pyridaben and all metabolites containing the pyridazinone ring fo r plants, and parent pyridaben and its metabolites, PB-7 and PB-9, for ruminant m eat byproducts. The tolerance expression for pyridaben needs to be updated to reflect curr ent Agency policy, as follows: “Tolerances are established for residues of pyridaben, including its metabolites and degr adates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring the insecticide pyridaben [2- tert -butyl-5-(4- tert -butylbenzylthio)-4- chloropyridazin-3(2 H )-one] on the following plants, and of the insecticide pyridaben and its metabolites, [2- tert -butyl-5-(4-(1-carboxy-1-me thylethyl)benzylthio)-4-chloropyridazin-3(2 H )- one] and [2- tert -butyl-5-[4(-1,1-dimethyl-2-hydroxyet hyl)benzylthio-4-chloropyridazin-3(2 H )- one] on animals.”

Due to updated methods for calculating livestock dietary burden (June 2008), the livestock dietary burdens should be reassesse d to evaluate potential seconda ry residues of pyridaben and

its metabolites in/on livestock commodities due to consumption of feed items with pyridaben residues resulting from the established food/f eed commodities (e.g., almond hulls and wet apple pomace). The repository currently has analytical standards of parent pyridaben from both BASF and Nissan which do not expire until 2016. Howe ver, reference standards for all pyridaben

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### metabolites are not currently in stock. HED re quests that all metabolites listed in the 40 CFR §180.494 tolerance be submitted.

There are no Codex or Mexican tolerances for pyridaben and, thus, no compatibility questions exist. However, there are Canadian toleran ces for pyridaben in/on apples; cattle, meat; peaches/nectarines; sw eet cherries; tart cherries; goat, m eat; grapes; horse, meat; milk; almonds; pears; sheep, meat; strawberries; tomatoes; cu cumbers; and peppers. There are compatibility issues with Canada for some of these crops due to differences in crop grouping and livestock residue definitions (Attachment 2).

Dietary Exposure and Risks The most recent acute and chronic dietary expos ure assessments were below HED’s level of concern for the general U.S. population and all population subgroups examined (Wassell W, D316834, 05/12/2005). The dietary risk assessment incorporated all available information including usage data (percent crop treated). Perc ent crop treated estimates of agricultural uses were last provided in 2004. For registration review, th ese values will need to be updated in a new dietary exposure assessment. A comparison of previously used percent crop treated values (2004) and more recently reported values (2009) is presented in Attachment 3.

Acute A refined acute dietary exposure assessment (pr obabilistic) was conducted for pyridaben. The assumptions of this dietary exposure assessment are as follows: (1) probabilistic assessment based upon residue distribution files or anticipated-residue estimate s derived from crop field trial data were utilized for most commodities; (2) pr ocessing factors from pr ocessing studies were utilized for most processed co mmodities; and (3) percent crop treated estimates and projected

market-share estimates were utilized for most crops.

For the acute analysis, the most highly exposed population subgroup is children 1 to 2 years old. The acute exposure at the 99.9th percentile for children 1 to 2 years old is 0.0275 mg/kg/day,

which utilizes 63% of the acu te population adjusted dose (aPAD) for pyridaben. The acute dietary exposure at the 99.9t h percentile for the U.S. popula tion is 0.0110 mg/kg/day, which utilizes 25% of the aPAD for pyridaben. This as sessment is considered to be highly refined.

Chronic A partially refined chronic di etary exposure assessment was conducted for pyridaben. The assumptions of this dietary exposure assessment are as follows: (1) anticipated residue estimates were derived from proposed and established to lerance levels; and (2) percent crop treated estimates and projected market-share esti mates were utilized for most crops.

For the chronic analysis, the most highly exposed population subgroup is children 1 to 2 years old. The chronic exposure for children 1 to 2 years old is 0.00233 mg/kg/day, which utilizes 47% of the chronic population adjusted dose (c PAD) for pyridaben. The chronic dietary exposure for the U.S. population is 0.000672 mg/ kg/day, which utilizes 13% of the cPAD for pyridaben. This assessment is cons idered to be partially refined.

Drinking Water

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### Residues of concern in water c onsist of the parent compound onl y. The Environmental Fate and Effects Division (EFED) performed a screen ing level surface and ground water modeling to estimate drinking water concentrations (Coste llo K, 02/10/2004). FIRS T Version 1.1.0 modeling

was used to estimate surface water concentra tions and SCI-GROW Version 2.3 was used to estimate ground water concentrations. Modeling methodology has been modi fied since the last assessment and an updated drinking water assess ment will be needed during the registration review process to determine if pyridaben uses impact the estimated drinking water concentrations (EDWCs).

Conclusion As part of registration review, a new dietary risk assessment s hould be conducted which utilizes the most current version of the Dietary Expos ure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCIDTM, Ve rsion 2.03). The new dietary exposure assessment should also evaluate potential second ary residues of pyridaben and its metabolites in/on livestock commodities due to consumption of feed items with pyridaben residues resulting from the established food/feed commodities (e .g., almond hulls and wet apple pomace). The new dietary exposure assessment should also directly incorp orate updated drinking water estimates into the dietary risk assessment. Add itionally, should a review of the Pesticide Data Program (PDP) and percent crop treated informati on show that food residues have significantly changed, the anticipated residues may need to be revised and incorporat ed into the acute and chronic dietary risk assessments.

Residential Exposure

Residential Handlers Pyridaben is not currently registered for use by ho meowners or in residen tial settings; therefore, no residential handler exposure is expected.

Residential Post Application Pyridaben is not currently registered for use by homeowners or in re sidential settings. Postapplication exposure resulting from volatilization or spray drift is expected to be unlikely to occur as pyridaben is not applied aerially, whic h increases the likelihood of exposure resulting from spray drift.

Conclusion Because pyridaben is not registered for use in residential settings, there is currently no risk concern for residential exposure. If exposure data and met hodologies for estimating exposure have changed for issues such as volatilization, spray drif t and track-in from fi eld applications to residential settings, then a new expos ure assessment may be requested.

Aggregate Risk Assessment

Since there are no residential uses of pyridaben, there is no concer n for short- and intermediateterm aggregate risk from the residential pathwa y. Aggregated exposure/risk from the food and drinking water pathways are presented above.

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### Occupational Exposure Pyridaben is registered for use on various raw agricultural commodities (RACs) and ornamentals. There is a potenti al for short- and intermediate-t erm exposure to pyridaben during mixing, loading, and applying activities. Occupati onal risk assessments have been conducted for wettable powder formulations (in water soluble bags); however pyrid aben is also available as an aqueous solution. Modifications to the occupati onal handler exposure assessment are needed. A new occupational handler risk assessment will be needed for registration review.

Occupational Handlers Attachment 5 summarizes the occupational scenario s that exist for pyridab en and whether or not each scenario has been previously assessed. Attachment 5 summarizes the occupational risks for pyridaben that have been prev iously assessed. All pyridaben labels require long pants, longsleeved shirts, shoes plus socks, gloves (chemical resistant), and goggles or a face shield. Some labels also require a respir ator for handling ac tivities (EPA Regist ration Numbers: 81880-5, 33906-23, 81880-4, 33906-19, 33960-21, and 81880-3).

Data sources that have been used in previous occupational assessments include PHED for unit exposure values. For registered uses of pyridaben for mixer loader scenar ios no risks of concern were identified (Arthur J, D261499, 11/30/1999; Arthur J, D261499, 09/11/2003). For uses on stone fruits and greenhouse tomato es the total short- and intermediate-term combined dermal and inhalation margins of exposure (MOEs; assessed with gloves and open cab) ranged from 110 to 36,000, resulting in no risks of concern to HED (Arthur J, D261499, 09/11/2003). For pyridaben use on citrus, apples, apricots, cherries, pears, peaches, plums, almonds, pistachios, grapes, and cranberries, the total short- and intermediate -term combined dermal and inhalation MOEs (assessed with gloves and open cab) ranged from 170 to 14,000, resulting in no risks of concern to HED (Arthur J, D261499, 11/30/1999). For the use sites allowing airblast application, the mixer/loader and applicator scenarios should be assessed with wettabl e powder and aqueous solutions. Use sites registered with aqueous solution, include tree nuts, stone fruits, and pistachios.

Occupational Postapplication Occupational postapplication exposur e to pyridaben can occur via the dermal and/or inhalation routes. Postapplication exposure is expected to occur for short- and intermediate-term durations. Long-term exposure is not expected even for gr eenhouse tomato use sites because a maximum of two applications per growing season are permitted and are separated by a 30-day treatment

interval.

The pyridaben technical material is classified as Toxicity Category III for acute dermal, acute inhalation, and primary eye irritation. Per th e Worker Protection Standard (WPS), a 12-hour restricted entry interval (REI) is required for chemicals clas sified under Toxicity Category III. However, using the short- and intermediate-ter m dermal toxicity endpoints and data from two dislodgeable foliar residue (DFR) studie s (MRID No. 436804-25, MRID No. 440292-03) with pyridaben, MOEs for post-application exposure exceed HED’s level of concern at the 12 hour REI for certain crops and activitie s. Longer REIs are needed to reach the level of concern (LOC) of 100 for certain crops in California where diss ipation was the slowest of the sites studied (Attachment 5). In conjunction with Registration Reviews, pyridaben labels should be revised to

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### incorporate the additional REIs in California for tree crops (REI of 5 days in CA, almonds and pistachios REI of 12 hours for mechanical operations and 10 days for hand/manual activities), grapes (13 days in CA), and cranberries (12 hou rs). Using the short- and intermediate-term dermal toxicity endpoints and data from the DF R study with pyridaben use on California citrus, the MOEs for all major postapplication activitie s for stone fruits reach the LOC of 100 on the day of treatment, Day 0, for all crops and, ther efore, do not exceed HED’s level of concern.

Inhalation exposure is expected to be negligible for most postappl ication scenarios. However, due to the enclosed nature of gr eenhouses, the airborne concentra tion of volatile or semi-volatile pesticides may result in concerns for gree nhouse workers following application of such pesticides. The WPS for Agricult ural Pesticides contains requ irements for protecting workers and bystanders from inhalation exposures durin g and after greenhouse ap plications through the use of ventilation requirements.

Based on the Agency's current practices, a qua ntitative postapplication inhalation exposure assessment was not performed for pyridaben at this time. However, volatilization of pesticides may be a potential source of postapplication inhalation exposure to i ndividuals nearby to pesticide applications. The Agency sought e xpert advice and input on issues related to volatilization of pesticid es from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html). The Agency is currently evaluating the SAP report and may, as appropriate, develop policies and procedures to identify whether to incorpor ate postapplication inhala tion exposure into the Agency’s risk assessments, and methods to assess postapplication inhalati on exposure. If new policies or procedures are implemented, the Agen cy may revisit the need for a quantitative postapplication inhalation exposur e assessment for pyridaben.

Conclusion The following occupational exposure scenarios lis ted below will need to be assessed or reassessed for Registration Review using current ORE policies and currently established toxicity endpoints. All other occupational exposure scen arios do not need to be revised and do not present risks of concern. At the time of the registration review ri sk assessment, if exposure data and methodologies for estimating exposure have changed for issues such as spray drift, volatilization, and track-in from field applications to residential settings these inputs will be incorporated into the assessment. Add itionally, if toxicity endpoints related to occupational/residential exposure change, the risk assessment may need to be revised.

ORE Assessments Needed

• New occupational risk assessments will be need ed to assess mixer/loader and applicator exposure from airblast app lication to citrus, tree nuts (Crop Group 14), apples, stone fruits (Crop Group 12), cranberry, grapes, pear, and pistachio.

• A new occupational risk assessment, includi ng postapplication exposure, will be needed for pyridaben application to ornamentals as the use site has not previously been assessed.

• The new occupational risk assessment for almonds should reflect current HED acres

treated values.

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### • Aqueous solution products need to be assesse d for tree nuts, stone fruits, pistachio, and

pears.

Public Health and Pesticide Epidemiology Data The OPP Incident Data System (IDS) a nd the Centers for Disease Control and Prevention/National Institute for Occupational Sa fety and Health (CDC/N IOSH) Sentinel Event Notification System for Occupational Risk-Pestic ides (SENSOR) database were consulted for pesticide incident data on th e active ingredient pyridaben (S . Recore and K. Oo, DP374530, 20 May 2010).

For IDS, no incidents were report ed occurring in the United States from 2002 to the present for the single chemical only (pyridaben ). For NIOSH SENSOR from 1998 to 2006, there are 11 cases reported for pyridaben in the database. Of these cases, 4 were reviewed because, in these cases, pyridaben was used as a single chemical onl y and had a certainty cla ssification of definite, probable, or possible, as these cases provide more certain inform ation about the potential effects of pyridaben exposure. All of th e reviewed cases were classified as low or moderate severity. The health effects reported include: two cases of ocular symptoms (50%), two cases of gastrointestinal symptoms (50%), one case of neurological symptoms (25%), and one case of respiratory symptoms (25%). Pr oportions relate to the total number of symptoms, not the total number of cases, i.e ., an individual may report multiple symptoms to the database. One of these cases was bystander exposure to pyridaben. A 33 year old pregnant female was exposed while performing a greenhouse insp ection. She experienced ocular a nd respiratory symptoms. In three cases the details are unknown. Pyridaben is not included in the AHS , and therefore not considered in this report.

Based on the low severity and low number of inci dent cases, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to

monitor the incident information and if a con cern is triggered, additional analysis will be

included in the risk assessment.

Environmental Justice Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, “Federal Actions

to Address Environmental Just ice in Minority Populations an d Low-Income Populations,” http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf. The Office of Chemical Safety and Pollution Prevention (OC SPP) typically considers the highest potential exposures from the legal use of a pesticide wh en conducting human health risk assessments, including, but not limited to, pe ople who obtain drinking water fr om sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvesting crops. Should these high exposures indicate potential risks of concern, OCSPP will further

refine the risk assessments to ensure that th e risk estimates are based on the best available

information.

Cumulative The Agency has not determined whether pyridaben shares a common mechanism of toxicity with

other chemical substances. Pr ior to a final Registration Revi ew decision for pyridaben, the

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### Agency will determine if there is any new information, such as new hazar d or exposure data or information on changes to the use pattern, which would affect the cumulative risk assessment. Should the Agency determine that new inform ation on pyridaben is available that could potentially impact the cumulative risk assessment a nd result in a risk of c oncern, the Agency will

revisit the cumulative risk assessment.

Human Studies Past pyridaben risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to de termine their dermal and inhalation exposure. Many such studies, involving exposur e to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) Databa se. EPA has reviewed all the studies supporting these multi-pesticide generic exposure databa ses, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevai ling at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on

these studies.

Data Requirements HED does not anticipate that additional residue chemistry, toxicology or occupational/residential exposure data will be required for the pyridaben registration review process, with the exception of the following study listed below:

• Immunotoxicity Study (OPPTS 870. 7800) (See Attachment 6)

Page 11 of 28

### References

1. Deschamp P, Amendment to HED Human Health Risk Assessment: Pyridaben in/on Hops (PP#1E06226), Tropical Fruit (PP#3E06460), Strawberries (PP#0E06068), Stone Fruit (PP#2E06303), and To matoes (PP#1E06303) ; DP Barcode: D323441 (2005)

2. Wassell W, Pyridaben in/on Hops (PP#1E06226), Tropical Fruit (PP#3E06460), Strawberries (PP#0E06068), Stone Fruit (PP#2E06303), and Tomatoes (PP#1E06303).

HED Human Health Risk Assessment ; DP Barcode: D316833 (2005)

3. Wassell W, PP#6F4651/FAP#6H5745, PP#9E6002, PP#7F4881 and PP#5F4543; Pyridaben (OracleTM Miticide/Insecticide, EPA Reg. No. 7969-125) in/on Apples, Cranberry, Peach, Nectarine, Plum, Prune, Cherry, Apri cot, Grape, Pistachio, Citrus and Tree Nuts Crop Groups and Livestock Commodities ; DP Barcode: D264767 (2000)

4. Cutchin W, ID#98MA0006 SECTION 18 EXEMPTION FOR TH E USE OF PYRIDABEN ON

CRANBERRIES IN MASSACHUSETTS ; DP Barcode: D245233 (1998)

5. Kramer G, Risk Assessment for Use of the New Chem ical Insecticide Pyridaben in/on Citrus, Apples, Pears, Almonds, Peaches, Plums and Grapes ; DP Barcode: D233114, D233166, D233164, D234191, D 233248, D233250, D233 244, D233247, D233 252, D233522, and

D227535

6. Cimino P, ID# 96DE0007 SECTION 18 EXEMPTION FOR USE OF PYRIDABEN ON APPLES IN THE STATE OF DELAWARE; DP Barcode : D227688

7. Madden B, Pyridaben (129105): Risk Assessment fo r an Experimental Use Permit (7969- EUP-GA) for Use of Pyridabe n on Apples (5G4589/5H5731) ; DP Barcode: D220682 and

D220683

8. Arthur J, Petition# 6F4721: Occupati onal and Residential Risk Assessment to Support New Uses of Pyridaben on Stone Fruits (Crop Group 12), Hops, Strawberries, Tropical Fruit and

Greenhouse Tomatoes ; DP Barcode: D261499

9. Arthur J, Occupational and Residential Risk Assessm ent to Support Request for a Section 3 Registration of the Pyridaben on Citrus, Apples, Apricots, Cherries, Pears, Peaches, Plums, Almonds, Pistachios, Grapes and Cranberries ; DP Barcode: D261499

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### Attachments

1. Chemical Identity and Physiochemical Properties

2. International Residue Limit Summary (IRLS)

3. Percent Crop Treated Data Comparison

4. Endpoint Selection Table and Toxicity Profile

5. Occupational Exposure Tables

6. Data Call-In Table

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### Attachment 1: Chemical Identity and Physiochemical Properties

Pyridaben Structure and Nomenclature.

Chemical Structure

Empirical Formula C 19 H 25 ClN 2 OS

Common Name Pyridaben (ANSI approved)

Company Experimental Name BAS 300

IUPAC Name 2- tert -butyl-5-(4- tert -butylbenzylthio)-4-chloropyridazin-3(2 H )-one

CAS Name 4-chloro-2-(1,1-dimethylethyl)-5-[[[4-(1,1 -dimethylethyl)phenyl]methyl]thio ]- 3(2 H }- Pyridazinone CAS Registry Number 96489-71-3

End-Use Product/EP Pyramite Miticide/Insecticide (EPA Reg. No. 7969-124) Nexter Miticide/Insecticide (EPA Reg. No. 7969-106)

Chemical Class pyridazinone class of pesticides

Known Impurities of Concern None

Physiochemical Properties of Pyridaben.

Parameter Value

Molecular Weight 364.9

Melting point/range 111-112°C

pH 6.81 in a solution containing 90.1 mg/L

Density 1.03 kg/L at 20°C

Water solubility (20°C) 0.012 μg/mL

Solvent solubility (20°C to 25°C) 57 g/L in ethanol 10 g/L in hexane 390 g/L in xylene 320 g/L in cyclohexane

110 g/L in benzene 63 g/L in n-octanol 460 g/L in acetone

Vapor pressure 1.9 x 10 -6 mmHg at 20°C (0.25 mPa at 20°C)

8.21 x 10 -5 mm Hg at 25 ̊ C
Dissociation constant, pKa N/A

Octanol/water partition coefficient, log(K OW ) Log K OW = 6.37 (at 23°C)



### Page 14 of 28Pyridaben Residues of Concern fo r Tolerance Setting Purposes.

Residue CAS Name Structure

Pyridaben 4-chloro-2-(1,1-dimethylethyl)-5-[[[4-(1,1- dimethylethyl)phenyl]methyl]thio]-3(2 H )- pyridazinone

PB-7 2- tert -butyl-5-[4-(1-carboxy-1-methylethyl) benzylthio]-4-chloropyridazin-3(2 H )-one

PB-9 2- tert -butyl-5-[4-(1,1-dimethyl-2-hydroxyethyl) benzylthio]-4-chloropyridazin-3(2 H )-one



### Page 15 of 28

### Attachment 2: International Residue Limit Summary (IRLS)

Summary of US and International Tol erances and Maximum Residue Limits.

US Canada Mexico 1 Codex

Residue Definition:

40 CFR 180.494

pyridaben [2- tert -butyl-5-(4- tert

butylbenzylthio)-4-chloropyridazin-3(2 H )-one]

on plant commodities , and

pyridaben [2- tert -butyl-5-(4- tert

butylbenzylthio)-4-chloropyridazin-3(2 H )-one] and its metabolites (2- tert -butyl-5-(4-(1- carboxy-1-methylethyl)benzylthio)-4- chloropyridazin-3(2 H )-one] and (2- tert -butyl-5- [4(-1,1-dimethyl-2-hypdroxyethyl)benzylthio-4- chloropyridazin-3(2 H )-one) on animal

commodities 4-chloro-2-(1,1- dimethylethyl)-5-[[[4- (1,1- dimethylethyl)phenyl] methyl]thio]-3(2 H )- pyridazinone None

Commodity Tolerance (ppm) /Max imum Residue Limit (mg/kg) Commodity US Canada Mexico 1 Codex
Almond, hulls 4.0 None Apple 0.5 0.5 Apple, wet pomace 0.75

Canistel 0.10
Cattle, fat 0.05
Cattle, meat 0.05 0.05 Cattle, meat byproducts 0.05

Citrus 0.5 Citrus, dried pulp 1.5
Citrus, oil 10.0

Fruit, stone, group 12 2.5 1.5 peaches/ nectarines

1.3

sweet cherries

1.3

tart cherries
Goat, fat 0.0
Goat, meat 0.05 0.05 Goat, meat byproducts 0.05 Grape 1.5 0.3 Hog, fat 0.05 Hog, meat 0.05 Hog, meat byproducts 0.05 Hop, dried cones 10.0
Horse, fat 0.05
Horse, meat 0.05 0.05 Horse, meat byproducts 0.05 Mango 0.10

Milk 0.01 0.01

Nut, tree, group 14 0.05 0.05

almonds Papaya 0.10



### Page 16 of 28Summary of US and International Tol erances and Maximum Residue Limits.

US Canada Mexico 1 Codex

Pear 0.75 0.75

Pistachio 0.05 Sapodilla 0.10 Sapote, black 0.10 Sapote, mamey 0.10 Sheep, fat 0.05 Sheep, meat 0.05 0.05 Sheep, meat byproduct 0.05 Star apple 0.10 Strawberry 2.5 2.0

Tomato 0.15 0.15 Cranberry (regional) 0.5

Cucumbers

- 0.1 Peppers

- 1.0

1 Mexico adopts US tolerances and/or Codex MRLs for its import/export purposes.



### Page 17 of 28

### ATTACHMENT 3: Percent Crop Treated Data Comparison

Percent Crop Treated Data Comparison for Pyridaben Percent Crop Treated Percent Crop Treated
Crop 2004 Avg. 2009 Avg. 2004 Max. 2009 Max.

1 Almonds <2.5 <2.5 4 5

2 Apples 10 10 20 20

3 Cherries <2.5 <2.5 4 7

4 Grapefruit 15 25 35 40

5 Grapes 5 5 10 10

6 Lemons <2.5 <1 4 <2.5

7 Nectarines (CA only) 9 4 (CA only) 15 10

8 Olives (CA only) <1 NA (CA only) 1 NA

9 Oranges 5 5 8 10

10 Peaches 5 <2.5 8 5

11 Pears 15 15 22 30

12 Pistachios (CA only) <1 NA (CA only) 1 NA

13 Prunes & Plums 5 <2.5 8 5

14 Sugar Beets (CA only) <1 NA (CA only) 1 NA

15 Tangelos (CA only) 13 20 (CA only) 20 25

16 Tangerines 15 35 25 60

17 Walnuts <2.5 <2.5 4 5

Page 18 of 28

### Attachment 4: Endpoint Select ion Table and Toxicity Profile

Summary of Toxicological Doses and Endpoints for Pyridaben for Use in Human Risk Assessments.

Exposure Scenario Point of Departure Uncertainty / FQPA Safety

Factors RfD, PAD, Level of

Concern for Risk

Assessment Study and Toxicological Effects

Acute Dietary (Females 13-50 years of age) N/A N/A N/A No study applicable to a single oral exposure has been identified

Acute Dietary (General population including infants and children) NOAEL = 44 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1X Acute RfD = 0.44 mg/kg/day

aPAD = 0.44 mg/kg/day Acute Neurotoxicity – Rat

LOAEL = 80 mg/kg/day Based on: Increased incidence of piloerection, hypoactivity, tremors and partially closed eyes. Decreased body weight gain and food consumption

Chronic Dietary (All populations) LOAEL = 0.5 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1X Chronic RfD = 0.005 mg/kg/day

cPAD = 0.005 mg/kg/day Chronic Feeding – Dog

LOAEL = 0.5 mg/kg/day Based on: Increased incidence of ptyalism, emesis and soft stool Decreased body weight gain in females

Short-Term Incidental Oral (1-30 days) NOAEL = 5 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1X LOC for MOE

Residential = 100 Occupational = N/A Developmental – Rabbit

Maternal LOAEL = 15 mg/kg/day

Based on: Increase in abortions. De crease in maternal body weight, body weight gain, food consumption

Intermediate-Term

Incidental Oral (1-6 months) NOAEL = 1.0 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1X LOC for MOE

Residential = 100 Occupational = N/A 90-Day Feeding – Dog LOAEL = 4.0 mg/kg/day Based on: Increased incidence of ptyalism. Decreased body weight gain

Short-Term Dermal (1-6 months) NOAEL = 100 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1X LOC for MOE

Residential = 100 Occupational = 100 21-Day Dermal – Rat LOAEL = 300 mg/kg/day Based on: Decreased body weight gain

Intermediate-Term

Dermal (1-6 months) NOAEL = 100 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1X LOC for MOE

Residential = 100 Occupation = 100 21-Day Dermal – Rat LOAEL = 300 mg/kg/day Based on: Decreased body weight gain

Long-Term Dermal (>6 months) LOAEL = 0.5 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1X LOC for MOE

Residential = 100 Occupation = 100 Chronic Feeding – Dog LOAEL = 0.5 mg/kg/day Based on: Increase incidence of ptyalism, emesis and soft stools and in F: Decreased body weight gain

Short-Term

Inhalation (1-30 days) NOAEL =

0.261 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1X LOC for MOE

Residential = 100 Occupation = 100 30-Day Inhalation – Rat LOAEL = 0.783 mg/kg/day

Based on: Increased incidence of dried red nasal discharge. Decreased body weight gain and albumin levels



### Page 19 of 28Summary of Toxicological Doses and Endpoints for Pyridaben for Use in Human Risk Assessments.

Exposure Scenario Point of Departure Uncertainty / FQPA Safety

Factors RfD, PAD, Level of Study and Toxicological Effects

Concern for Risk

Assessment

Intermediate-Term Inhalation (1-6 months) NOAEL =

0.261 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1X LOC for MOE

Residential = 100 Occupation = 100 30-Day Inhalation – Rat LOAEL = 0.783 mg/kg/day

Based on: Increased incidence of dried red nasal discharge. Decreased body weight gain and albumin levels

Long-Term

Inhalation (>6 months) NOAEL =

0.261 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1X LOC for MOE

Residential = 100 Occupation = 100 30-Day Inhalation – Rat LOAEL = 0.783 mg/kg/day

Based on: Increased incidence of dried red nasal discharge. Decreased body weight gain and albumin levels

Cancer (Oral, Dermal, and Inhalation) Chemical classified as “Group E” Based on lack of evidence of carcinogenicity in ma le and female rats and male and female mice.

For additional information see HIAR C memorandum dated 22 June 1998.

UF = Uncertainty Factor, UFDB = Uncertainty Factor in the database, FQPA SF = Special FQPA Safety Factor,

NOAEL = No Observed Adverse Effect Level, LOAEL = Lowest Observed Adverse Eff ect Level, PAD = Population Adjusted Dose (a = acu te, c = chronic), RfD = Reference Dose, MOE = Margin of Exposure, LOC = Level of Concern, N/A = Not Applicable

Subchronic, Chronic, and Other Toxicity Profile of Pyridaben Technical.

Guideline

No. Study Type MRID No. (year) / Doses / Classification Results

90-Day Oral Toxicity in

Rodents (Rat) 42680126 (1988) 0, 30, 65, 155, 350 ppm M: 0, 2.3, 4.94, 11.55, 25.71 mg/kg/day F: 0, 2.64, 5.53, 12.84, 27.68 mg/kg/day Acceptable / Guideline NOAEL = M: 4.94, F: 2.64 mg/kg/day

LOAEL = M: 11.55, F: 5.53 mg/kg/day Based on in M and F: Decreased body weight gain, food consumption, and food efficiency 870.3100

90-Day Oral Toxicity in

Rodents (Mouse) 43064101 (1988) 0, 30, 90, 270, 810 ppm M: 0, 4.07, 13.02, 40.09, 119.2 mg/kg/day F: 0, 4.92, 14.65, 43.14, 124.6 mg/kg/day Acceptable / Guideline NOAEL = M: 4.07, F: 4.92 mg/kg/day LOAEL = M: 13.02, F: 14.65 mg/kg/day Based on in M and F: Decreased body weight gain

42680127 (1989) 0, 0.5, 1.0, 4.0, 16.0 mg/kg/day Acceptable / Guideline NOAEL = 1.0 mg/kg/day LOAEL = 4.0 mg/kg/day Based on in M and F: Decreased body weight gain and clinical signs such as ptyalism, emesis, soft stool/diarrhea and trembling 870.3150 90-Day Oral Toxicity in

Nonrodents (Dog)

42680128 (1989) 0, 2.4, 12, 60, 300 mg/kg/day Supplementary NOAEL = <2.4 mg/kg/day

LOAEL = ≤ 2.4 mg/kg/day Based on decreased body weight gain



### Page 20 of 28Subchronic, Chronic, and Other Toxicity Profile of Pyridaben Technical.

Guideline

No. Study Type MRID No. (year) / Doses / Classification Results

870.3200 21/28-Day Dermal Toxicity (Rat) 42680130 (1992) 0, 30, 100, 300, 1000 mg/kg/day Acceptable / Guideline Dermal NOAEL = >1000 mg/kg/day

LOAEL = Not Established

Systemic NOAEL = 100 mg/kg/day LOAEL = 300 mg/kg/day Based on F: Decrease in body weight

870.3250 90-Day Dermal Toxicity N/A Study not available

870.3465 30-Day Inhalation Toxicity (Rat)

In place of: 90-Day Inhalation Toxicity 42680131 (1989) 0, 0.00087, 0.003, 0.010 g/L Acceptable / Non-Guideline NOAEL = 0.00087 mg/L (0.227 mg/kg) LOAEL = 0.003 mg/L (0.783 mg/kg) Based on in M and F: Clinical signs of toxicity observed were dried red nasal discharge and increased yellow ano-genital staining and in F only: Decreased body weight and body weight gain

870.3700a Prenatal Developmental in

Rodents (Rat) 42680139 (1988) 0, 2.5, 5.7, 13.0, 30.0 mg/kg/day Acceptable / Guideline Maternal NOAEL = 4.7 mg/kg/day LOAEL = 13 mg/kg/day Based on decrease in body weight , body weight gain and food consumption

Developmental NOAEL = 13 mg/kg/day LOAEL = 30 mg/kg/day Based on decrease in fetal weights and incomplete ossification in

selected bones

870.3700b Prenatal Developmental in

Nonrodents (Rabbit) 42680142 (1988) 0, 1.5, 5, 15 mg/kg/day Acceptable / Guideline Maternal NOAEL = 5 mg/kg/day LOAEL = 15 mg/kg/day Based on decreases in body weight , body weight gain and food consumption, and abortions

Developmental NOAEL = 5 mg/kg/day LOAEL = 15 mg/kg/day

Based on an increase in abortions and an increase in the “12/13" and

“13/13" ribs



### Page 21 of 28Subchronic, Chronic, and Other Toxicity Profile of Pyridaben Technical.

Guideline

No. Study Type MRID No. (year) / Doses / Classification Results

Prenatal Development in

Nonrodents [Dermal] (Rabbit); 43680416 0, 70, 170, 450 mg/kg/day Acceptable / Guideline Maternal

Dermal NOAEL for dermal toxicity = not established LOAEL for dermal toxicity = 70 mg/kg/day

Based on skin reactions.

Systemic NOAEL = 70 mg/kg/day LOAEL = 170 mg/kg/day Based on body weight loss and decreased food consumption.

Developmental NOAEL = 170 mg/kg/day LOAEL = 450 mg/kg/day Based on retarded fetal growth and in creased incidence of incompletely

ossified skulls

870.3800 Reproduction and Fertility Effects (Rat) 42680144 (1990) 0, 10, 28, 80 ppm M: 0, 0.78, 2.20, 6.31 mg/kg/day F: 0, 0.94, 2.41, 7.82 mg/kg/day Acceptable / Guideline Parental NOAEL = M: 2.20, F: 2.41 mg/kg/day LOAEL = M: 6.31, F: 7.82 mg/kg/day Based on in M and F: Decreased body weight gain and food efficiency

Reproductive NOAEL = M: 6.31, F: 7.82 mg/kg/day LOAEL = M: >6.31, F: >7.82 mg/kg/day

Based on in M and F: No effect on reproductive parameters at the dose levels tested in this study

Offspring NOAEL = M: 2.2, F: 2.41 mg/kg/day LOAEL = M: 6.31, F: 7.82 mg/kg/day Based on decreased pup body weights from PND 7-25 and decreased pup body weight gains throughout lactation

42680134 (1990) 0, 1.0, 4.0, 16.0, 32.0 mg/kg/day Acceptable / Guideline NOAEL = Not Established LOAEL = 1.0 mg/kg/day Based on in M and F: Clinical signs such as thinness, dehydration, diarrhea, food-like emesis, frothy emesis, soft stool, ptyalism and relaxed nictitans and in F only: Decreased body weight gain 870.4100b Chronic toxicity (Dog)

42680135 (1991) 0, 0.5 mg/kg/day Acceptable / Guideline (with MRID# 42680134) NOAEL = Not Established LOAEL = 0.5 mg/kg/day Based on in M and F: Clinical signs of toxicity such as Ptyalism, emesis, soft stools and in F onl y: Decreased body weight gain

870.4200b Carcinogenicity (Mouse) 42680137 (1990) 0, 2.5, 8, 25, 80 ppm M: 0, 0.27, 0.81, 2.78, 8.88 mg/kg/day F: 0, 0.29, 0.91, 2.78, 9.74 mg/kg/day Acceptable / Guideline NOAEL = M: 2.78, F: 2.78 mg/kg/day. LOAEL = M: 8.88, F: 9.74 mg/kg/day Based on in M and F: Decreased body weight gain and food efficiency and in M only: Changes in or gan weights, and changes in histopathology

No evidence of carcinogenicity



### Page 22 of 28Subchronic, Chronic, and Other Toxicity Profile of Pyridaben Technical.

Guideline

No. Study Type MRID No. (year) / Doses / Classification Results

870.4300 Combined Chronic Toxicity/ Carcinogenicity (Rat) 42680132 (1990) 0, 4, 10, 28 120 ppm M: 0, 0.16, 0.4, 1.13, 5 mg/kg/day; F: 0, 0.2, 0.54, 1.6, 6.52 mg/kg/day Acceptable / Guideline NOAEL = M: 1.13, F: 1.6 mg/kg/day LOAEL = M: 5, F: 6.52 mg/kg/day Based on in M and F : Decreased body weight gain and in M only:

Decreased ALT

No evidence of carcinogenicity

870.5100 Bacterial Reverse

Mutation Test (Salmonella typhimurium, Escherichia coli) 42680145 (1986)

Series of doses ≤ 5000 μg/plate in presence

or absence of S9 metabolic activation Acceptable / Guideline Negative in two independent bacter ial/mammalian microsome reverse mutation assays

870.5300 In vitro

Mammalian Cell

Gene Mutation

Test (Chinese Hamster V79 Cells) 42680149 (1989)

Series of test concentrations ≤ 50 μg/mL (limit solubility) in th e presence or absence

of S9 metabolic activation Unacceptable / Guideline Negative for inducing forward gene mutations at the HGPRT locus

870.5375 In vitro

Mammalian

Chromosome

Aberration Test (Chinese Hamster Lung Cells) 42680148 (1989)

Series of doses ≤ 50 ug/mL in presence or

absence of S9 metabolic activation Acceptable / Guideline Negative for inducing structural chromosome aberrations

870.5395 Mammalian Erythrocyte

Micronucleus Test (Mouse) 42680147 (1988)

Series of doses ≤ 140 mg/kg Acceptable / Guideline Negative micronucleus inducti on in the bone marrow cells

870.5500 Bacterial DNA Damage or Repair

Tests (Escherichia coli) 42680146 (1986)

Series of doses ≤ 10000 ug/mL in presence

or absence of S9 metabolic activation Acceptable / Guideline Negative for inducing primary DNA da mage in Escherichia coli repair

deficient strains WP 67 or CM871.

Cytotoxicity was not demonstrated for the DNA competent strain (WP2) or the DNA deficient strains at any dose.

870.6200a Acute Neurotoxicity Screening Battery (Rat) 43680412 (1995)

Nominal Doses 0, 50, 100, 200 mg/kg

Actual Doses M: 0, 44.3, 79.6, 190 mg/kg F: 0, 44.5, 99.7, 190 mg/kg Acceptable / Guideline NOAEL = 50 mg/kg M: 44.3, F: 44.5 mg/kg LOAEL = 100 mg/kg M: 79.6, F: 99.7 mg/kg Based on in M and F: Clinical signs of toxicity (piloerection, hypoactivity, tremors, and partially closed eyes), and decreased food consumption and body weight gain

870.6200b Subchronic Neurotoxicity Screening Battery (Rat) 43680413 (1995) 0, 30, 100, 350 ppm M: 0, 2.5, 8.5, 28.8 mg/kg F: 0, 2.8, 9.3, 31.1 mg/kg Acceptable / Guideline NOAEL = M: 8.5, F: 9.3 mg/kg/day LOAEL = M: 28.8, F: 31.1 mg/kg/day

Based on in M and F: Decreases in body weight, body weight gain, food consumption and food efficiency



### Page 23 of 28Subchronic, Chronic, and Other Toxicity Profile of Pyridaben Technical.

Guideline

No. Study Type MRID No. (year) / Doses / Classification Results

870.6300 Developmental Neurotoxicity N/A Study Is Not Required.

Amendment to HED Human Health Risk Assessment: Pyridaben in/on Hops (PP#1E06226), Tropical Fruit (PP#3E06460), Strawberries (PP#0E06068), Stone Fruit (PP#2E06303), and Tomatoes (PP#1E06303)

“Further evaluation of the toxicity database and the entire weight of

evidence has lead to the conclusion that the FQPA Safety Factor be reduced to 1X and a developmen tal neurotoxicity study not be required.”

870.7485 Metabolism and

Pharmacokinetics (Rat) 43258901 (1994) Single Dose: 3, 30 mg/kg 14 Doses (1 Dose per Day): 3 mg/kg/day Acceptable / Guideline Absorption of an oral dose of NC-129 was fairly rapid but incomplete at all dose levels. The presence of a significant percentage of excreted radioactivityin bile at the high dose (20-30%) indicates that some of the

absorbed test material was excreted by this route and/or reabsorbed

from the intestinal tract for s ubsequent biliary elimination.

The gastrointestinal tract was a major site for distribution.

Metabolism Urinary, fecal and liver metabolites of 14-C-NC-129 were isolated and identified. At the low dose, the main urinary component from

administration of Pz-labeled test material was the P-9 metabolite ormercapturic acid conjugate of pyridazinone moiety. The B-11 and B15 metabolites were the main components in urine after administration

of Bz-labeled test material. In feces, the main component observed

after administration of both the Pz- and Bz-labeled test material and representing approximately 20% of the dose, was unmetabolized parent compound. Some evidence of gluduronide conjugates of NC-19 was observed for bilary metabolites, but no definitive characterization could be performed. The liver contained several metabolites from

adinistration of either Pz- or Bz -labeled test material, but these comprised 1.6% or less of the dose.

Elimination Feces were the major route for elimination, 80-97% AD, across all dose groups for both labels. At the high dos e, it seems that some of the dose (20-30% AD) was excreted thr ough the biliary elimination.

870.7800 Immunotoxicity N/A Study Is Required But Not Available



### Page 24 of 28

### Attachment 5: Occupational Exposure Tables

Occupational Mixer/Loader and Applicator Exposu re Scenarios for Registered Uses of Pyridaben

Crop/Use Site Application Equipment

Assessed Possible Application

Types Formulation Types Risk

Assessment

Needed Notes

Citrus Hand-gun, airblast, groundboom Hand-gun, airblast, groundboom WP in Water Soluble Bags No N/A

Ornamentals N/A Ground Equipment WP in Water Soluble Bags Yes No prior risk assessment completed

Almond* Hand-gun, airblast, groundboom Hand-gun, airblast, groundboom WP in Water Soluble Bags and Aqueous

Solution Yes Assessed 30 acres treated in 1999, however using crop specific estimates of farm size. Also used larger unit exposures, and will

therefore result in lower MOEs. Assessment needed for liquid formulation

Apple Hand-gun, airblast, groundboom Hand-gun, airblast, groundboom WP in Water Soluble Bags No N/A

Cherry** Hand-gun, airblast, groundboom Hand-gun, airblast, groundboom WP in Water Soluble Bags and Aqueous

Solution Yes Assessment needed for liquid formulation

Cranberry Hand-gun, airblast, groundboom Hand-gun, airblast, groundboom also

chemigation WP in Water Soluble Bags Yes Assessment needed for chemigation application (M/L only)

Grapes Hand-gun, airblast, groundboom Hand-gun, airblast, groundboom WP in Water Soluble Bags No N/A

Pear Hand-gun, airblast, groundboom Hand-gun, airblast, groundboom WP in Water Soluble Bags No N/A

Pistachio Hand-gun, airblast, groundboom Hand-gun, airblast, groundboom WP in Water Soluble Bags and Aqueous

Solution Yes Assessment needed for liquid formulation

Tomato (Greenhouse) M/L high pressure handwand, M/L

airblast, M/L groundboom, A high pressure handwand, A airblast, A, groundboom M/L high pressure handwand, M/L

airblast, M/L groundboom, A high pressure handwand, A airblast, A, groundboom WP in Water Soluble Bags Yes PHED unit exposure for "high pressure handwand" was used because it most closely matched the"handgun" scenario for pyridaben application to greenhouse

tomatoes and was therefore used 6 oz per 100 gal listed on the label. 21.3 oz

= 1.0 lb ai from master label. 6.0oz max single application rate listed on this label =

0.28 lb ai/acre, did not assess M/L/A

*Representative of the tree-nut crop group, includes Almond, Beech Nut, Brazil Nut, Butternut, Cashew, Chestnut, Chinquapin, Fi lbert (hazelnut), Hickory Nut, Macadamia Nut, Pecan, Walnut

**Representative of stone fruits group, incl uding apricot, cherry (sweet and tart), n ectarine, peach, plum, plumcot, and prune (fresh)



### Page 25 of 28

### Page 26 of 28 Summaries of Occupational Post Applic ation Risk of Pyridaben by Use Site

Crop/Use Site DP#, Date Maximum

Transfer

Coefficient DFR (μg/cm 2 ) MOE Maximum REI required (italic is California-Specific)

Citrus 261499, 1999 10,000 0.865 100 5 days

Ornamentals N/A N/A N/A N/A N/A

Almond* 261499, 1999 10,000 0.867 100 10 days for hand/manual activities

Apple 261499, 1999 10,000 0.865 100 5 days

261499, 1999 10,000 0.865 100 5 days Cherry**

261499, 1999 3,000 1.11 260 5 days

Cranberry 261499, 1999 4,000 0.267 200 12 hours

Grapes 261499, 1999 15,000 0.58 100 13 days

Pear 261499, 1999 10,000 0.865 100 5 days

Pistachio 261499, 1999 10,000 0.867 100 10 days for hand/manual activities

Tomato (Greenhouse) 261499, 2003 1,000 1.11 790 12 h

*Representative of the tree-nut crop group, includes Almond, Beech Nut, Brazil Nut, Butternut, Cashew, Chestnut, Chinquapin, Fi lbert (hazelnut), Hickory Nut, Macadamia Nut, Pecan, Walnut

**Representative of stone fruits group, incl uding aprictot, cherry (sweet and tart), nectarine, peach, plum, plumcot, and prune (fresh)Page 27 of 28Summary of Representative Occupational Handler Exposure Scenarios and Risks for Pyridaben (all using Water Soluble Bags and Gloves)Unit Exposure (mg/lb ai)1Dose (mg/kg/day)2Short/Intermediate TermRisk (MOE)3ExposureScenarioAssessedDP#MaximumApplicationRate AssessedAcresTreated(acres/day)DermalInhalationDermalInhalationDermalInhalationTotal Risk(MOE)4Mixer/LoaderWP forhandgunsprayerD261499,11/30/990.5100.00980.000240.00070.000017140,00015,00014,000WP for AirblastsprayerD261499,11/30/990.5400.00980.000240.00280.00006936,0003,8003,400WP forGroundboomD261499,11/30/990.5800.00980.000240.00560.0001418,0001,9001,700WP for HighPressureHandwandD261499,9/11/030.191000gallons0.00980.000240.000270.0000065370,00040,00036,000ApplicatorHand GunSprayer5D261499,11/30/990.5101.30.00390.0930.000281,100930500ApplicationAirBlast OpenCabD261499,11/30/990.5800.360.00450.1030.0013970200170GroundboomSprayer (opencab)D261499,11/30/990.5800.0170.000740.0080.0004212,500620600High PressureHandwand6D261499,19/11/20030.191000gallons1.80.0790.0490.00212,000120110GroundboomSprayer (opencab)D261499,19/11/20030.5800.0140.000740.0080.0004212,5006206001Unless otherwise specified, unit exposure values are for workers wearing baseline clothing, (i.e., long-sleeved shirt, long pants, shoes and socks)2Daily Dose =[Application Rate (lb ai/A) x Acres Treated (A/day) x Unit Exposure(mg/lb ai handled)]/Body Weight3MOE = NOAEL/Daily Dose. Short and Intermediate-term Dermal NOAEL=100 mg/kg/day.Short and Intermediate-term Inhalation NOAEL=0.261 mg/kg/day4Total Risk MOE = 1/(1/MOEdermal + 1/MOEinhalation)5PHED unit exposure for "right-of-way sprayer" most closely matches the hand gun scenario for pyridaben application and is therefore used here.6PHED unit exposure for "high-pressure handwand" most closely matches the "hand-gun"scenario for pyridaben application on greenhouse tomatoes, and is therefore used here.

### Attachment 6: Data Call-In Table

Guideline Number: 870.7800 Study Title : Immunotoxicity Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non-food uses).

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produc e adverse effects (i.e., suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies assessing functional immunotoxic endpoints are helpful in fully characterizing a pesticide’s potential immuno toxicity. These data will be used in combination with data from hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies to characterize potential immunotoxic effects.

Practical Utility of the Data

How will the data be used?

These animal studies can be used to se lect endpoints and doses for use in ri sk assessment of all exposure scenarios and are considered a primary data source for reliable refere nce dose calculation. For exam ple, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8- tetrachlorodibenzo-p-dioxin) among developmental, reprod uctive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tr ibutyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Ag ency's future decision-making?

If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for th e test material may need to be revised to reflect the magnitude of potential risk derived from the new data.

If the Agency does not have this data, a 10X database uncertainty factor may be applied for conducting a risk

assessment from the available studies.



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