Thiacloprid Human Health Risk Assessment DP No. D376178

Page 3 of 53 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .... 20

6.1 Spray Drift

................................ ................................ ................................ ...................... 20

6.2 Residential Bystander Post

- Application Inhalation Exposure

................................ ....... 21

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ....... 21

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 21

9.0 Occupational Exposure/Risk Characterization

................................ ................................ .. 22

9.1 Occupational Handler Risk Estimates

................................ ................................ ............ 22

9.2 Occupational Post

- Application Risk Estimates

................................ ............................. 25

9.2.1 Dermal Post

- Application Risk Estimates

................................ ................................ 25

9.2.2 Inhalation Post

- Application Risk Estimates

................................ ........................... 26

10.0 References

................................ ................................ ................................ .......................... 27 Appendix A. Toxicology Profile and Executive Summaries

................................ ....................... 28

A.1 Toxicology Data Requirements

................................ ................................ ...................... 28

A.2 Toxicity Profiles

................................ ................................ ................................ ............. 29

A.3 Toxico logical Doses and Endpoints for Use in Human Risk Assessments

....................... 34 Appendix B. Inhalation Exposure Assessment

................................ ................................ ............ 45 Appendix C. Physical/Chemical Properties

................................ ................................ ................. 52 Appendix D. Review of Human Research

................................ ................................ ................... 53Thiacloprid Human Health Risk Assessment DP No. D376178

Page 4 of 53 1.0 Executive Summar y

The Agency has been petitioned to register the insecticide thiacloprid [ 3

- [(6

- chloro

- 3

- pyridinyl) methyl]

- 2

- thiazolidinylidene cyanamide ] on peppers and stone fruit and to establish tolerances for residues of thiacloprid in/on those commodities. Thiacloprid is proposed for foliar application to peppers and stone fruits as an aerial or airblast spray made from a 40% active ingredient (a.i.) flowable formulation (Calypso 4 Flowable). Applications would be made to stone fruits at a maximum single ap plication rate of 0.25 lb ai/A, with a minimum 7

- day retreatment interval (RTI). The total application rate would not exceed 0.38 lb a.i. /A/season and the pre

- harvest interval (PHI) would be 14 days. For peppers, the proposed label specifies a

maximum si ngle application rate of 0.094 lb ai/A, a 7

- day RTI, and a 7

- day PHI. The total application rate for peppers would not exceed 0.28 lb ai/A/season.

Thiacloprid is an insecticide that belongs to the neonicotinoid class of chemicals. The pesticidal

mode of action is the disruption of the nervous system as an inhibitor at nicotinic acetylcholine receptors. In insects, thiacloprid blocks the signals that are induced by acetylcholine at the post

synaptic membrane, resulting in nerve function impairment. The toxicological database shows neurological effects in mammals in multiple studies. However, in mammalian systems, the liver appears to be the primary target organ with some effects in the thyroid. Liver effects include enzyme changes, hypertrophy, and his topathology ; noted t hyroid effects were changes in hormone levels, weights, and follicular cell hypertrophy

. This risk assessment uses the neurological and liver/thyroid effects as the regulatory endpoints , depending on the route and duration of exposure. Given the completeness of the toxicological database, the endpoints and points of departure used for risk assessment, and the conservatisms in the assumptions used to estimate exposure, HED has reduced the required 10X Food Quality Protection Act ( FQPA )

S afety F actor to 1X. Thiacloprid is classified as, “Likely to be Carcinogenic to Humans” based on uterine tumors (rat), thyroid tumors (rat, both sexes), and ovarian tumors (mouse). A cancer
potency factor of 4.06 x 10 - 2 (mg/kg/day) - 1 was calculated base d on the increased incidence of

uterine tumors in female rats.

At this time, there are no registered or requested residential uses for this compound and the only

source of non

- occupational exposure is through food and drinking water. In estimating dietary exposure, HED has used screening

- level assumptions for the acute and chronic (non

- cancer)

assessments , and even w ith t hese highly conservative, health

- protective assumptions, estimates of exposure and risk are below HED’s level of concern. For the acute assessment, risk estimates for the general U.S. population and all population subgroups are ≤ 19 % of the population

adjusted dose (PAD) . F or the chronic assessment, risk estimates for the general U.S. population and all population subgroups are ≤ 2 6 % of the PAD. Generally, HED is concerned when risk

estimates exceed 100% of the PAD. For assessing cancer risk, HED has refined the exposure estimates by using average residue values from field trials and incorporating percent crop treated

estimates fo r some commodities , including the projected percent crop treated estimates for proposed commodities

. The upper

- bound cancer risk estimate is 2 ×10 - 6 for the general U.S. population and could be further refined in the future with the use of residue monitori ng data

.

HED h as also assessed dermal and inhalation occupational exposures to thiacloprid. Aggregate risk indices (ARIs) range from 6.9 to 240 for handler exposures and from 12 to 60 for post

-Thiacloprid Human Health Risk Assessment DP No. D376178

Page 5 of 53 application exposures. Generally

, HED has a concern when an ARI is less than one ; therefore,

the estimated ARIs are not of concern

. All ARIs were calculated assum ing baseline levels of personal protective equipment (PPE)

, with the except ion of aerial application scenarios, for

which engineering controls (closed co ckpit) are assumed by default. Cancer risk estimates for occupational activities range from 1×10 - 7 to 1×10 - 5 for handlers and from 2×10 - 4 to 4×10 - 4 for

post

- application activities

. The post

- application cancer risk estimate s are very conservative since

th ey are based on maximum application rates and Day

- 0 residue levels . W orkers are not expected to be exposed to residues at th e Day

- 0 level for all post

- application activities

.

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. See Section 3.5 and Appendix D for more

information.

2.0 HED Recommendations

There are no human health risk issues associated with the requested uses of thiacloprid on stone

fruit and peppers. Therefore, HED recommends granting the requested registrations and establishing tolerances as listed in Section 2.2

.

Furthermore, HED has reviewed the condition

- of

- registration data regarding field rotational crop studies for soybean and wheat

. The condition of registration has been fulfilled and n o rotational crop tolerances are necessary.

2.1 Data Deficiencies

An immunotoxicity study in mice and/or rats (OCSPP Guideline 870.7800) is required.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate HPLC

- MS/MS method is available for determination of thiacloprid residues in plant matrices. This method uses solvent extraction (methanol:water, 3:1, v:v), clean up on

solid

- phase extraction columns, and separation/quantification by reverse

- phase HPLC

- MS/MS.

The lowest limit of method validation

, which is the assigned limit of quantitation (LOQ), is 0.02

ppm and the calculated limit of detection (LOD) is 0.004 ppm thiacloprid. In addition t o thiacloprid, the method also detects and quantifies the amide and hydroxy

- amide metabolites

, each with an LOQ of 0.02 ppm

.

2.2.2 Recommended Tolerances

The proposed uses and the submitted data support the following tolerances for residues of thiacloprid in/ on:Thiacloprid Human Health Risk Assessment DP No. D376178

Page 6 of 53 Table 2.2.2. Summary of Proposed and Recommended Tolerances for Residues of Thiacloprid. Commodity Tolerance , ppm Comments ( Correct Commodity Definition) Proposed Recommended Pepper (bell and non

- bell) 1.1 1.0 Recommended value is harmonized with Codex

. OECD Calculation Procedure Tolerance = 0.6 ppm.

( Pepper )

F ruit, stone, group 12 0.5 0.5 Recommended value is harmonized with Codex. OECD Calculation Procedure Tolerance = 0.7 ppm.

( Fruit, stone, group 12

- 12 , except plum )

Plum

-- 0.05 OECD Calculation Procedure Tolerance = 0.05 ppm.

2.2.3 Revisions to Petitioned

- For Tolerances

The petitioned

- for tolerance levels were derived using the NAFTA MRL/Tolerance Calculation Procedures rather than the OECD procedures; therefore, there are differences between the values calculated by HED ( M. Doherty, D 406397 , 31 October 2012 ) and those from the petitioner. Furthermore, HED’s recommended tolerance levels for peppers and stone fruit (except plums) take into account existing CODEX MRLs for residues of thiacloprid in these commodities. A separate tolerance for residues in/on plu ms was not proposed but is required because of the significantly lower residues in/on plums relative to those observed in/on the other representative

stone fruit commodities.

HED notes that subsequent to review of the residue chemistry data (summarized in M. Doherty, D378298, 1 Feb 2011) submitted to support the registration and tolerance for residues in/on stone fruit, the Agency has updated Crop Group 12 to include additional commodities. In conducting this assessment, HED has included evaluation of the updated crop group (Crop Group 12

- 12) and is recommending that tolerances be set based on the revised crop group

definition.

A revised Section F should be submitted to address the following issues with the proposed

tolerances and tolerance definition:

Pe pper (bell and non

- bell) : The submitted residue data for bell peppers and non

- bell

peppers are adequate to support a Codex

- harmonized tolerance of 1.0 ppm

. A revised

Section F should be submitted in order to: (i) propose the lower recommended tolerance level and (ii) reflect the preferred Agency food and feed commodity vocabulary ( “ pepper ” )

.

Stone Fruits (Crop Group 12) : The submitted residue data for the representative

commodities of stone fruits ( cherries, peaches, and plums ) are adequate to support a Codex

- harmonized crop group tolerance of 0. 50 ppm (except plum). The petitioner

should submit a revised Section F in order to (i) reflect the preferred Agency food and feed commodity vocabulary ( “ F ruit, stone, group 12

- 12, except plum ” ) and (ii) to prov ide for a separate tolerance of 0.05 ppm for residues in/on plum

.

The tolerance definition should be revised to be in terms of the parent compound only ; i.e., for

residues of the insecticide thiacloprid , including its metabolites and degradates, in or on theThiacloprid Human Health Risk Assessment DP No. D376178

Page 7 of 53 commodities. Compliance with the tolerance levels is to be determined by measuring only thiacloprid, ( Z

)

- [3

- [(6

- chloro

- 3

- pyridinyl)methyl]

- 2

- thiazolidinylidene]cyanamide

.

2.2.4 International Harmon ization

Except for plums, the recommended tolerance levels are harmonized with existing Codex MRLs. The significantly different residue levels in the trials with plums as compared to the other representative commodities in the stone fruit crop group make it necessary to set a separate regulatory level for residues in plums.

2.3 Label Recommendations

Section B of the petition indicates that registration is being requested for both Calypso® 4

Flowable and Calypso ® 70 WG . HED understands that the 70 WG pr oduct is not actually part of the petition. A revised Section B should be submitted in which only the Calypso® 4 Flowable product is listed.

Based on the results of the submitted condition

- of

- registration field rotational crop studies with soybean and wheat, soybean and cereal grains may be added to the list of crops that may be

rotated after a 30

- day plant

- back interval.

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Test Compound Nomenclature.

Compound Chemical Structure:

Common name Thiacloprid Company experimental name Thiacloprid

IUPAC name [3

- [(6

- Chloro

- 3

- pyridinyl)methyl]

- 2

- thiazolidinylidene]cyanamide

CAS name (Z)

- [3

- [(6

- chloro

- 3

- pyridinyl)methyl]

- 2

- thiazolidinylidene]cyanamide

CAS # 111988

- 49

- 9

3.2 Physical/Chemical Characteristics

Thiacloprid has a low vapor pressure ( 8.0×10 - 10 Pa at 25°C = 6 .0 ×10 - 12 mmHg )

, indicating that inhalation exposure to gaseous material should be low. The K OW (18) indicates that the potential for thiacloprid to bioaccumulate is also low. A listing of the physico

- chemical properties of

technical

- grade thiacloprid is included in Appendix C.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 8 of 53 3.3 Pesticide Use Pattern

Table 3 .3 . Summary of Directions for Use of Thiacloprid. Applic. Timing, Type, and Equip. Formulation Applic.

Rate (lb ai/A) Max. No.

Applic.

per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Stone Fruit Group 12

- 12

Foliar application Calypso 4

Flowable 0.25 Not Specified 0.38 14 Near lakes, rivers, permanent streams, marshes or natural ponds, estuaries,

and commercial fish farm ponds: no aerial application within 100 feet; do not allow airblast spray to go beyond cultivated area. Pepper

Foliar application Calypso 4

Flowable 0.094 Not Specified 0.281 7 Near lakes, rivers, permanent streams, marshes or natural ponds, estuaries,

and commercial fish farm ponds: no aerial application within 100 feet; do not allow airblast spray to go beyond cultivated area.

The following rotational crop restrictions are specified for the 4 lb/gal SC formulation: Roots, tubers, and bulb vegetables whose tops are not used for feed may be rotated with cotton after a plan t

- back interval of 30 days. Leafy vege tables may be rotat ed after a 6

- month plant

- back interval. Do not plant any other crop in the treated area for at least one year after application

.

The R estricted

- E ntry I nterval (REI) specified on the proposed label is based on the acute toxicity

of thiacloprid

. Thiaclopr id is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. A quantitative p ost

application risk a ssessment indicates that risk estimates were not a concern on day 0 ( i.e., 12 hours following application) for all post

- application activities. Therefore, the Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post

application exposures to thiacloprid

.

The Personal Protective Equipment (PPE) statement on the proposed label requires applicators, flaggers and other handlers to wear: long

- sleeved shirt and long pants, socks, shoes, chemical

resistant gloves made of n itrile, b utyl, n eoprene and/or b arrier l a minate.

3.4 Anticipated Exposure Pathways

S ince thiacloprid may be applied directly to growing crops and application may result in thiacloprid reaching surface and ground water sources of drinking water , h umans may be exposed to residues of thiacloprid through the diet in their food and drinking water. There are no

residential uses of thiacloprid , so there is not likely to be exposure in residential or non

occupational settings. In an occupational setting, workers may be exposed via the dermal andThiacloprid Human Health Risk Assessment DP No. D376178

Page 9 of 53 inha lation routes while handling the pesticide prior to application, during application , and following application

.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in thi s human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( htt p://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population s ubgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the National Health and Nutrition Examination Survey (NHANES) What We Eat in America (WWEIA)

program, and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess d ietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products

, and associated risks for adult applicat ors and for toddlers, youths, and adults entering or playing on treated areas post

- application

, are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

Based on the proposed use patter n, the toxicology database for thiacloprid is largely complete

. In compliance with the current data requirements in the 40 CFR Part 158 for conventional pesticide registration, an immunotoxicity study in mice and/or rats is required

. However, the overall toxicity profile indicates that this chemical does not directly target the immune system; therefore, the toxicology studies that are available are adequate for conducting a risk assessment.

These include: acute lethality studies (o ral, dermal and inhalation routes); primary eye irritation, dermal irritation and sensitization; subchronic oral toxicity (rat, mouse and dog) ; rat 28

- day dermal toxicity ; rat 2 1 /28

- day inhalation toxicity (also 4

- hour and 5

- day studies); rat acute

, subchr onic, and developmental neurotoxicity; dog chronic toxicity ; rat chronic toxicity/carcinogenicity ; mouse carcinogenicity ; genotoxicity battery ; developmental toxicity (rat and rabbit) ; rat two

- generation reproductive toxicity ; dermal absorption in monkeys ; and rat general metabolism/pharmacokinetics.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 10 of 53 4.2 Absorption, Distribution, Metabolism, & Excretion (ADME)

Thiacloprid is rapidly absorbed and rapidly excreted after a series of metabolic processes, with little remaining in the tissues. In the rat metabolism study, 86

- 106% of the administered radioactivity (AR) was recovered by 48 hours . Orally, rapid absorpt ion occurred with maximum plasma concentrations 1

- 2 hours and 3

- 4 hours after dosing for 1

- and 100

- mg/kg doses, respectively . Following intravenous dosing maximum plasma concentrations occurred within 20

minutes. Distribution to tissues was extensive an d was followed by rapid removal. Excretion in urine (60

- 70%) was greater than in feces ( 30

- 40% ) and t here w ere minor gender

- related differences in the excretion time. The primary urinary metabolites were WAK 3583 (16

- 34%

AR ), 6

- CAN (7

- 9% AR ), and KNO 189 3 (4

- 12% AR ) . Other metaboli t es accounted for <4% of

the AR . The metabolic processes are : 1) hydroxylation of the thi a zolidine ring and subsequent glucuronidation (as shown by metabolite PIZ 1270), 2) hydroxylation of the cyanamide moiety (metabolite KNO 1891), 3) opening of the thiazolidine ring (e.g., metabolites KNO 2672, PIZ 1297F/WAK 6935), 4) formation of an oxazole ring (metabolite PIZ 1269X), and 6) oxidative cleavage of the methylene bridge (PIZ 1243). Only minor gender

- related quantitative

diff erences in metabolite profiles were observed. No biliary excretion studies were conducted.

4.2.1 Dermal Absorption

A dermal absorption study is available for thiacloprid. The study was conducted in monkeys with a 40.4% liquid formulation ( suspension co ncentrate containing 480 g a.i./L ) of thiacloprid and a 5% dermal absorption value was determined after 8 hours . It was also determine d that the absorption value is suitable for assessing other liquid formulations that are similar to the SC 480 product

, a s well as for aqueous dilutions of most thiacloprid formulations.

4.3 Toxicological Effects

Thiacloprid is an insecticide that belongs to the neonicotinoid class of chemicals. The pesticidal mode of action is the disruption of the nervous system as an i nhibitor at nicotinic acetylcholine

receptors. In insects, thiacloprid blocks the signals that are induced by acetylcholine at the post

synaptic membrane, resulting in nerve function impairment. The mammalian mode of action is

unknown.

In mammalian systems, t he liver appears to be the primary target organ with some relatively minor effects in the thyroid. Liver effects (enzyme changes, hypertrophy, and histopathology)

were noted in the 90

- day dog, 2

- generation reproduction, 2

- year rat, 2

- year mouse
, and

subchronic dermal and inhalation studies. Thyroid effects (hormone levels, weights, follicular cell hypertrophy) were noted in dog, rat

, and mouse studies. Increased prostate weight and prostatic hypertrophy were observed in the 90

- day dog study, bu t not in the 1

- year dog study. Clinical signs were also noted in dermal ( reduced motility, decreased activity, and spastic gait)

and 5 day inhalation studies ( respiratory effects, signs of ill health, piloerection, reduced mobility, tremors, and increased grip strength)

.

There was no increase in either qualitative or quantitative susceptibility of fetal animals or pups in the rabbit developmental or the 2

- generation rat reproduction studies. In the rabbitThiacloprid Human Health Risk Assessment DP No. D376178

Page 11 of 53 developmental study, decreased fetal weights wer e observed in the presence of maternal toxicity (body weight changes and decreased food consumption and fecal output). In the reproduction study in rats, decreased body weights were seen in pups at the same dose which resulted in thyroid and liver effects in maternal animals.

In the rat developmental toxicity study, there was evidence of increased qualitative susceptibility. Increased resorptions ; skeletal retardations and variations ; dysplastic humerus, radius and scapulae ; and decreased fetal weight s were seen in fetuses at the same dose resulting in less severe maternal effects (decreased body weight, body weight gain and food consumption, increased urination, and changes in water consumption). In the developmental neurotoxicity study, increased qu alitative susceptibility was also seen : D ecreased body weights in both sexes as well as altered performance in passive avoidance testing were seen in offspring animals, while deceased body weight gain and food consumption were seen in maternal animals. However, there is a low degree of concern and no residual uncertainties for the increase in qualitative susceptibility since there are well

- characterized dose responses with clear NOAELs and

LOAELs in the studies and there is no evidence of any quantitativ e s usceptibility

. Additionally, the endpoints and PODs selected for risk assessment are protective of potential developmental

effects.

Thiacloprid affects nerve function through inhibition of nicotinic acetylcholine recept ors. In the neurotoxicity studi es in rats, there was a reduction in motor and locomotor activity, slight tremors and ptosis of the eyelids, decreased hind limb grip strength, altered performance in passive avoidance testing, and altered brain morphometri cs. Increased grip strength was also

noted in a 5

- day inhalation toxicity study. There were no indications of neurotoxicity in the remainder of the submitted toxicity studies. See Section 4.4.2 for details.

A battery of genetic toxicity tests did not indicate a mutagenicity or clastog enicity concern.

Thiacloprid is classified as “Likely to be Carcinogenic to Humans” based on increased uterine

tumors in rats , thyroid follicular adenomas in rat, and ovarian tumors in mice. A cancer slope

factor of 4.06 x 10 - 2 (mg/kg/day) - 1 was calculated based on the incidence of combined uterine

tumors in female rats.

Acute lethality studies with thiacloprid indicate moderate acute toxicity via the oral route (Category II) and low toxicity via the dermal or inhalation routes (Categories II I). T here was no evidence of primary eye irritation, skin irritation, or dermal sensitization.

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

The proposed and exi sting use patterns for thiacloprid may result in dietary exposure to infants

and children. Thus, FQPA hazard considerations were addressed in HED’s evaluation of the toxicolog ical database. HED recommends that the 10x FQPA Safety Factor ( for the protection

of infants and children ) be reduced to 1x. Th is recommendation is supported by the following: 1) The toxicology database concerning infants and children is considered to be complete with the exception of an immunotoxicity study. Although an immunotoxicity study hasThiacloprid Human Health Risk Assessment DP No. D376178

Page 12 of 53 not been received by the Agency, ther e is relatively little concern as it does not appear that the chemical directly targets the immune system ; 2) Although brain morphometric changes were seen in the DNT study, the established point s of departure for risk assessment are protective of the DNT mo rphometric changes seen at the high dose. These brain effects were considered marginal and highly variable; 3) The inhalation POD is protective of potential deep lung effects, nasal irritation, and systemic effects resulting from inhalation exposure ; 4) There is no evidence of any quantitative sensitivity and there are well characterized dose

response s with clear NOAEL s and LOAEL s in the rat developmental and developmental neurotoxicity studies where increased qualitative susceptibility was seen. Additionally

, the endpoints and doses for risk assessment are protective of all adverse effects in the

database ; 5) T he dietary exposure assessment s are based on high

- end

, health protective residue levels and processing factors for foods, and upper

- bound assumptions were used to determine exposure through drinking water ; and 6) No residential exposure is expected for children.

4.4.1 Completeness of the Toxicology Database

The toxicology database concerning infants and children is considered to be complete with the

ex ception of an immunotoxicity study. Submitted studies included: developmental rat and rabbit, 2

- generation reproduction in rats as well as acute, subchronic and developmental neurotoxicity in rats. Although an immunotoxicity study has not been received b y the Agency, there is relatively little concern as it does not appear that thiacloprid directly targets the immune

system based on available studies. Although there were increases in the incidence and severity of mesenteric and mandibular lymph node vacu olization in a cancer study in mice, the effects

were seen at very high doses following long

- term treatment. Additionally, thiacloprid does not belong to a class of chemicals (e.g., the organotins, heavy metals, halogenated aromatic hydrocarbons) that wou ld be expected to be immunotoxic. Furthermore, there were no indications of immunotoxicity in other studies in the toxicology database . HED does not believe that conducting the study will result in a lower point of departure (POD) than that currently use d for overall risk assessment; therefore, a database uncertainty factor (UF DB ) is not needed to account for the lack of the study.

4.4.2 Evidence of Neurotoxicity

Acute, subchronic and developmental neurotoxicity studies in rats are available for thiacloprid. In the acute study, there were reductions in motor and locomotor activit ies in females and slight tremors and ptosis of the eyelids i n males. In the subchronic neurotoxicity study, decreased hind limb grip strength was seen in males. Increa sed grip strength was noted in a 5

- day inhalation toxicity study. In the developme ntal neurotoxicity study, altered performance in passive avoidance testing and a 4% decrease in the size of the corpus striatum region of the brain were seen in offspring a nimals at the highest dose tested. No data were received by the Agency regarding the mid

- and low

- dose brain measurements. However, the lack of a NOAEL for brain morphometric measurements in this study does not warrant an additional uncertainty factor si nce the decrease in weight is considered marginal and variable at the high dose

, and a lower doseThiacloprid Human Health Risk Assessment DP No. D376178

Page 13 of 53 would most likely result in less of an effect (the highest dose tested was 10x greater than the

lowest dose tested ), and the endpoints and PODs selected for r isk assessment are protective of the slight morphometric changes observed at the high dose . There were no indications of neurotoxicity in the remainder of the submitted toxicity studies.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Y oung Animal

In the rat developmental study, there was an increase in qualitative susceptibility based on an increase in resorptions, skeletal retardations and variations, dysplastic humerus, radius and scapulae, as well as decreased fetal weights at the s ame dose (50 mg/kg/day) at which less severe maternal effects were noted (decreased body weight, body weight gain and food consumption in addition to increased urination and changes in water consumption). In the developmental neurotoxicity study, increase d qualitative susceptibility was also seen : D ecreased body weights in both sexes as well as altered performance in passive avoidance testing were seen in offspring animals, while deceased body weight gain and food consumption were seen in maternal animals

. However, there is a low degree of concern and no residual uncertainties for the increase in qualitative susce ptibility since there is a well

- characterized dose response with clear NOAEL s and LOAEL s in the stud ies and there is no evidence of any quantita tive s usceptibility

. Additionally, the endpoints and PODs selected for risk assessment are protective of potential developmental effects.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to dietary exposure. The dietary assessments are
based on conservative

, health protective assumptions regarding exposure from food and drinking

water and are designed not to underestimate exposures

. There are no residential uses at this time and inadvertent residential exposures (i.e., spray drift and bystander exposure) have been adequately addressed (see Sections 6.1 and 6.2)

.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

The detailed descriptions of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in Appendix A.3 . Currently there are no existing or proposed residential uses of thiacloprid; however, endpoints and PODs f or residential exposure were selected to address potential future residential uses.

For acute dietary exposure assessments (all populations) , the NOAEL of 4.4 mg/kg/day from the developmental neurotoxicity study in rat s was used for risk assessment, based on offspring effects of altered performance in passive avoidance testing at a LOAEL of 25.6 mg/kg/day. The acute neurotoxicity study in rats was selected as a co

- critical study, based on reductions in motor and locomotor activity at the LOAEL of 11 mg/kg /day (NOAEL = 3.1 mg/kg/day). The effects in the studies are attributable to a single dose

, and the route and duration of exposure from these

co

- critical studies are appropriate for selection of the acute dietary endpoint. The POD and endpo int selected a re protective of the marginal and variable brain morphometric changes seen inThiacloprid Human Health Risk Assessment DP No. D376178

Page 14 of 53 the DNT study at the high dose of 40.8 mg/kg/day , as well as effects (resorptions) observed in developmental studies in rats and rabbits.

For chronic dietary exposure, the NOAE L of 1.2 mg/kg/day from the combined chronic/carcinogenicity study in rats was used for risk assessment, based on liver hypertrophy and cytoplasmic changes, thyroid hypertrophy and induction of the enzymes UDP

- Glu

- T and

aromatase

, as well as the induction of hepatic enzymes and retinal degeneration in females at the LOAEL of 2.5 mg/kg bw/day. The dose and endpoint (liver and thyroid toxicity as well as retinal degeneration in females) are appropriate since they reflect chronic (lifetime) dosing via

the ora l (diet) route. The NOAEL and LOAEL from this study are the lowest dose s in the toxicity database for chronic durations.

For short

- term incidental oral exposure, the offspring NOAEL of 4.2 mg/kg/day from the reproduction study in rats was used for risk a ssessment, based on the observed decreased pup weight during lactation at the LOAEL of 21 mg/kg/day . The endpoint selected is appropriate for the exposure duration and the population of concern (children). It is also protective of the neurotoxicity effec ts seen in the ACN, SCN and DNT studies at ≥ 11 mg/ kg/day

. At this time, there are no residential uses for thiacloprid; therefore, this exposure scenario is not relevant for

risk assessment

For short

- and intermediate

- term dermal exposure, the systemic NOAEL of 300 mg/kg/day from a subchronic dermal toxicity study was used for risk assessment, based on liver and thyroid changes, reduc ed motility, decreased activity, and spastic gait at the LOAEL of 1000 mg/kg/day.

No dermal irritation was noted in the s tudy. The developmental toxicity studies in rats and

rabbits and the reproduction study in rats were also considered for risk assessment; however,

there was no evidence o f quantitative susceptibility seen in the studies and the effects observed

in materna l animals were adequately measured in the dermal toxicity study

. Additionally, the subchronic neurotoxicity study was considered. However, the dermal equivalent dose (DED) calculated (based on 5% dermal absorption factor) for the study was higher than th e point of departure (POD) of 300 mg/kg/day from the dermal toxicity study. Therefore, the dermal toxicity study was selected and it is considered protective of potential developmental, reproductive, and neurotoxic effects.

For short

- and intermediat e

- te rm inhalation exposure, a 5

- day inhalation toxicity study in rats was used for risk assessment. The systemic NOAEL is 2 mg/m 3 . The systemic LOAEL is 20 mg/m 3 based on increased grip strength in both sexes. The portal

- of

- entry LOAEL for the 5

- day study i s 200 mg/m 3 based on bradypnea, labored breathing pattern, piloerection and decreased rectal temperature. The endpoint and systemic POD from the 5

- day study are protective of portal

- of

- entry effects in th at study, as well as both systemic and portal

- of

- en try effects noted in

a 2 1 /28

- day inhalation toxicity study. The systemic HEC was converted to a human equivalent dose (HED) of 0.24 mg/kg/day and used for risk assessment (calculations shown in Appendix B)

.

Based on the proposed use pattern for thiac loprid, long

- term dermal and inhalation exposures are not anticipated.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 15 of 53 For acute and chronic dietary risk assessments, a 100X uncertainty factor was applied (interspecies factor of 10X and intraspecies factor of 10X). For incidental oral and dermal

expos ure, the LOC for the MOE is 100 ( 10X interspecies, 10X intraspecies factors) . For inhalation risk assessments, the LOC is 30 (interspecies factor of 3X and intraspecies factor of 10X) since human equivalent calculations (HECs) were used for risk assessmen t. The interspecies factor was reduced from 10X to 3X because the HEC calculation accounts for pharmacokinetic (not pharmacodynamic) interspecies differences between animals and humans. We note, again, that the incidental oral exposure pathway is not rel evant for this risk assessment

since there are no residential uses.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For thiacloprid, dermal and inhalation exposures should be combined when assessing short

and/or intermediate

- term exposure scenarios since endpoints are based on the same toxicological effects (neurotoxicity).

4.5.3 Cancer Classification and Risk Assessment Recommendation

Thiacloprid is classified as “Likely to be Car cinogenic to Humans,” based on an increased incidence of uterine tumors in rats, thyroid follicular cell adenomas in rats (both sexes), and

ovarian tumors in the mice. A linear low

- dose approach for cancer risk was recommended for thiacloprid, a cancer sl ope factor of 4.06 × 10 - 2 (mg/kg/day) - 1 was calculated based on the

incidence of combined uterine tumors in female rats.

Previously, special studies were conducted to establish modes of action for the thyroid and

uterine tumors in rats and ovarian tumors in mice. At that time the data were determined to be inadequate. Subsequently, the r egistrant submitted additional data and proposed a new mode of action for the uterine tumors in rats. Although the proposed MOA was considered plausible, it

was conclude d that the data were inadequate to establish a non

- linear, hormonal mode of action (MOA) for the uterine tumors.

4.5.4 Summary of Points of D eparture and Toxicity Endpoints Used in Human Risk

Assessment

Table 4.5. 4

. a. Toxicological Doses and Endpoints for Thi a cloprid for Use in Dietary and Non

- Occupational

Human Health 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 All Populations NOAEL =

4.4 mg/kg/day UF A =10x

UF H = 10x FQPA SF =1x aRfD=0.0 44

mg/kg/day

a PAD=0.0 44 mg/kg/day Co

- Critical Studies

Developmental Neurotoxicity Study

- rat LOAEL=25.6 mg/kg bw based on offspring effects of altered performance in passive avoidance testing.

Acute Neurotoxicity Study

– rat LOAEL = 22 mg/kg bw based on a

reduction of motor and locomotor activity in females (NOAEL = 3.1Thiacloprid Human Health Risk Assessment DP No. D376178

Page 16 of 53 Table 4.5. 4

. a. Toxicological Doses and Endpoints for Thi a cloprid for Use in Dietary and Non

- Occupational

Human Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD/ Level

of Concern for

Risk Assessment Study and Toxicological Effects

mg/kg bw).

Chronic All Populations including

Infants/Children NOAEL =

1.2 mg/kg/day UF A =10x

UF H =10x FQPA SF =1x cRfD =0.012

mg/kg/day

cPaD =0.012 Chronic/Carcinogenicity Study

- rat

LOAEL = 2.5/3.3 (M/F) mg/kg bw based on liver hypertrophy and cytoplasmic changes as well as induction of enzymes, thyroid epithelial hypertrophy in males and retinal degeneration in females.

Incidental Oral (Short

- Term)

Not Relevant at this

time NOAEL =

4 .2 mg/kg/day UF A =10x

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

100 (residential) Two

- Generation Reproduction Study

–

rat LOAEL = 21 mg/kg bw/day based on a decrease in pup weight during lactation.

Dermal (Short

- and

Intermediate

- Term)

Not relevant at this

time. Systemic

NOAEL

=300 mg/kg/day UF A = 10x

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

100 (residential) 21/28

– Day Dermal Study

– rat

Systemic LOAEL = 1000 mg/kg/day based on liver and thyroid effects plus clinical signs (reduc ed motility, decreased activity, and spastic gait).

No dermal irritation noted.

Cancer “Likely to be Carcinogenic to Humans” based on thyroid tumors in male rats, uterine tumors

in rats and ovarian tumors in mice. Cancer slope factor = 4.06 x 10 - 2 (mg/kg/day) - 1

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level . LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members of the human population (interspecies). FQPA SF = FQPA Safety Fact or. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

TABLE 4.5.4.b. Toxicological Doses and Endpoints for Thiacloprid for Use in Occupational Human Health

Risk Assessments Exposure /

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors L evel of Concer n

for Risk

Assessment Study and Toxicological Effects

Dermal (Short

- and

Intermediate

- Term) Systemic

NOAEL

=300 mg/kg/day UF A = 10x

UF H = 10x LOC for MOE =

100 (occupational) 21/28

– Day Dermal Study

– rat

Systemic LOAEL = 1000 mg/kg/day based on liver and thyroid effects plus clinical signs (reduc ed motility, decreased activity, and spastic gait).

No dermal irritation noted.

Inhalation

Short and

Intermediate

Durations NOAEL=2

mg/m 3
(0.002mg/L)

HEC =

0.005 mg/L (based on systemic effects) UF A = 3x

UF H = 10x LOC for MOE =

30 (occupational) 5

- day (6 hours/day) Inhalation Toxicity

Study in Rats

At the LOAEL of 20 mg/m 3 (0.02mg/L) increased grip strength was seen.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 17 of 53 HED= 0.24 mg/kg/day

Cancer “Likely to be Carcinogenic to Humans” based on thyroid tumors in male rats, uterine tumors in

rats and ovarian tumors in mice. Cancer slope factor = 4.06 x 10 - 2 (mg/kg/day) - 1

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members of the human population (interspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level

of concern. N/A = not applicable. HEC = human equivalent concentration; HED = human equivalent dose.

5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

Table 5.1. Summary of Metabolites and Degradates to be included in the Ri sk Assessment and Tolerance Expression

.

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Thiacloprid + metabolites retaining the thiazolidine ring Thiacloprid

Rotational Crop Thiacloprid + metabolites retaining the thiazolidine ring Thiacloprid

Livestock Ruminant Thiacloprid + metabolites retaining the thiazolidine ring Thiacloprid

Poultry Thiacloprid + metabolites retaining the thiazolidine ring Thiacloprid Drinking Water Thiacloprid + Amide metabolite * Not Applicable

* T he amide metabolite is only of concern for groundwater that does not undergo drinking water treatment.

HED’s Metabolism Assessment Review Committee reasoned that because thiacloprid has limiting toxic effects that are different from imidacloprid, and these effects also do not appear to be mediated by nicotinic receptors, these effects must be partly or wholly associated with the thiazolidine portion of thiacloprid (D288833, 7 April 2003). Th us, m e tabolites retainin g the intact thiazolidine ring are included in the residue definition for risk assessment.

With respect to drinking water, the registrant has provided data showing that the amide metabolite is removed by drinking water treatment processes and would, there fore, not be present in drinking water obtained from public water systems. The amide metabolite remains a residue of concern for groundwater that does not undergo drinking water treatment.

5.2 Food Residue Profile

Adequate data are available to assess the requested uses on stone fruit and peppers. In field trials, crops were treated at the maximum application rate and harvested at the shortest PHI proposed on the label. Residue results showed that quantifiable residues of thiacloprid occurred

in at le ast one sample in all studies; the amide and hydroxy amide metabolites were below the LOQ in all samples. Residues of thiacloprid declined with increasing PHI in all pepper and

stone fruit studies. The extent of the decline over time varied across the cr ops, with some crops showing extensive decline (e.g., peppers ; 0.08 ppm on Day 0, <0.01 ppm on Day 14 ) and others showing a more moderate decrease (e.g., plums ; 0.05 ppm on Day 0, 0.03 ppm on Day 28 ).Thiacloprid Human Health Risk Assessment DP No. D376178

Page 18 of 53 5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED) in the following memorandum: “ Thiacloprid: Update of the Drinking Water Exposure Assessment for Section 3 New Uses on Stone Fruits and Peppers ” (D 37618 4, G. Orrick, 07/12/2012 ) and incorporated directly into this dietary

assessment.

The surface water results from the PRZM/EXAMS models were entered in to the dietary model

for the acute, chronic, and cancer assessments. For the acute point estimate, the 1

- in

- 10

- year annual maximum c oncentration estimate of 0.018 ppm was entered . For the chronic point estimate, the 1

- in

- 10

- year annual mean concentration estimate of 0.0023 ppm was entered . For

the cancer assessment, the overall 30

- year mean concentration estimate of 0.0012 ppm was

entered

. All of these PRZM/EXAMS surface water estimates are protective of the ground water exposure estimates from the SCI

- GROW model (Table 5.3)

.

T he drinking water estimates used in this assessment have been refined to acc ount for both

percent crop ped area and for the impact of drinking water treatment processes. T hiacloprid and its amide are the only residues of concern in untreated drinking water. Following drinking water treatment, thiacloprid is the only residue of co ncern expected to be present. This is because the submitted drinking water treatment study data indicate that 1) coagulation does not remove thiacloprid or thiacloprid

- amide from source water, 2) a typical oxidant (sodium hypochlorite) removes thiacloprid

- amide (but not thiacloprid), and 3) HED has determined that the four major treatment products of thiacloprid

- amide are not residues of concern. HED determined that the treatment products of thiacloprid

- amide are not residues of concern due to the fact th at they do

not contain the thiazolidine ring. Because surface water sourced drinking water is typically treated, thiacloprid is the only compound of concern for the surface water estimates

. The ground water estimates listed below include both thiacloprid and thiacloprid

- amide as they will not always be treated, whereas the surface water estimates include only thiacloprid.

Table 5 .3 . Total Thiacloprid EDWCs in Surface Water and Ground Water for Use in Dietary Risk

Assessment Based on the Use Pattern of Maximum Exposure, Pome Fruits.

Use (maximum rate) Source PCA (%) 1

- in

- 10

- year Peak Exposure (ppb) 1

- in

- 10

- year

Annual Mean Exposure (ppb) 30

- year Mean

Exposure (ppb)

Pome fruits (0.50 lbs a.i./A/year) Surface water (treated) 91 18 2.3 1.2

Ground water (untreated) N/A 0.25 0.25 <0.25

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute and chronic analyses are based on tolerance

- level residues and 100% crop treated assumptions for both existing and proposed new uses. With the exception of empirically derived processing factors for pome fruit (apples and pears) and stone fruit (peaches and plums), default processing factors were used for all commodities. The empirical processing factors for pomeThiacloprid Human Health Risk Assessment DP No. D376178

Page 19 of 53 fruit were based on previously reviewed studies and are as follows: 0.82X all peeled apples; 0.68X for applesauce; 0.51X for dried app les and pears; 0.23X for apple juice; and 0.87X for pear juice (D. Soderberg, D289292, 23

- June

- 2003). Based on recently submitted processing studies for the new uses on stone fruit, empirically derived processing factors of 3.6X on dried peaches and 3.1X on dried plums were utilized. It is noted that the most recent (2003) dietary exposure assessment had partially refined acute and chronic assessments, which included the use of percent crop treated data and average residue field trial data. Recent change s in the toxicological endpoints and FQPA safety factor make these refinements no longer necessary for

the acute and non

- cancer chronic analyses.

The cancer analysis has been partially refined, using average residue field trial data, and percent crop treated (PCT) estimates for existing and proposed new uses as appropriate. As with the acute and chronic analyses, default processing factors were use d with the exception of pome and stone fruit commodities, where empirical processing factors were utilized as described above.

Based on the high

- end nature of field trial results and the pattern of those results, which show

non

- quantifiable residues of th e amide metabolites, the use of field

- trial thiacloprid residues in the risk assessment should adequately address the full risk assessment residue definition without correcting the values to account for all thiazolidine

- ring containing metabolites.

5.4.2 Percent Crop Treated Used in Dietary Assessment

For the acute and chronic assessments, HED assumed 100% crop treated for all registered and requested uses of thiacloprid. For the cancer assessment, estimates of percent crop treated were

used as follows: Apples

.................... 10% ( J. Alsadek

, 4 October 2012 )

Pears

......................... 5% ( J. Alsadek, 4 October 2012 )

Peaches

................... 43% (J. Alsadek, D382568, 26 September 2012 ) Peppers

................... 45% (J. Alsadek, D382568, 26 September 2012 )

5.4.3 Acute Dietary Risk Assessment

For acute exposures, the dietary r isk for the U.S. population is estimated to be 6.2 % of the a PAD

at the 95 th percentile . Acute risk s for infants <1 year old , the highest

- exposed population subgroup, is estimated to be 19 % of the a PAD at the 95 th percentile

. These risk estimates are considered to be conservative, based on unrefined tolerance

- level residues in food, 100% crop treated assumptions, and partially refined drinking water estimates to account for percent crop ped area and drinking water treatment processes.

5.4.4 Chronic Die tary Risk Assessment

For chronic exposures, the dietary risk for the U.S. population is estimated to be 5.1 % of the

cPAD. Chronic risk for children 1

- 2 years old, the highest

- exposed population subgroup, is

estimated to be 26 % of the cPAD. These risk es timates are considered to be conservative, based

on unrefined tolerance

- level residues in food, 100% crop treated assumptions, and partiallyThiacloprid Human Health Risk Assessment DP No. D376178

Page 20 of 53 refined drinking water estimates to account for percent crop treated area and drinking water

treatment processes.

5.4.5 Cancer Dietary Risk Assessment

The cancer analysis has been partially refined, using average residue field trial data, PCT

estimates for existing uses and projected PCT (PCT

new ) for proposed new uses as appropriate. As with the acute and chronic analyses, default processing factors were used with the exception

of those for pome

- and stone

- fruit commodities, where empirical processing factors were utilized

as described above. The can cer risk estimate for the U.S. population is 2 × 10 - 6 for food + water. Drinking water accounts for approximately half of this risk ( 1 × 10 - 6 )

.

5.4.6 Summary Table

Table 5.4.6 . Summary of Dietary (Food and Drinking Water) Exposure and Risk for Thiaclopri d

.

Population Subgroup Acute Dietary ( 95 th Percentile) Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.002745 6.2 0.000612 5.1 0.000049 2 × 10 - 6

All Infants (<1 year old)* 0.008329 19 0.001936 16

N/A N/A Children 1

- 2 years old* 0.007996 18 0.003106 26

Children 3

- 5 years old 0.005457 12 0.001859 16

Children 6

- 12 years old 0.003399 7.8 0.000961 8.0

Youth 13

- 19 years old 0.001901 4.3 0.000444 3.7

Adults 20

- 49 years old 0.001852 4.2 0.000380 3.2 Adults 50+ years old 0.001768 4.0 0.000414 3.5

Females 13

- 49 years old 0.001867 4.2 0.000388 3.2 *The subpopulation(s) with the highest risk estimates are bolded.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Thiacloprid does not have registered residential uses , including commercial/professional uses at

residential sites . T herefore, a risk assessment examining residential uses has not been conducted.

Potenti al spray drift and bystander inhalation exposures are discussed below.

6 .1 Spray Drift

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 less er extent, could also be a potential source of exposure from the ground application method employed for thiacloprid . 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 (see the Agency’s Spray Drift website for more information 1 ) . On a chemical by chemical basis, the Agency is now requiring interim mit igation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmThiacloprid Human Health Risk Assessment DP No. D376178

Page 21 of 53 evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a p olicy 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 s pray drift management practices to reduce off

- target drift with specific products with significant risk estimates associated with drift.

6

. 2 Residential Bystander Post

- Application Inhalation Exposure

Based on the Agency's current practices, a quantitativ e post

- application inhalation exposure

assessment is not being performed for thiacloprid at this time primarily because of the low acute

inhalation toxicity (Toxicity Category III), low vapor pressure ( 8.0 × 10 - 10 Pa at 25°C = 6 .0 × 10 - 1 2

mmHg ), and the low pr oposed use rate s ( 0.047

- 0. 25 lb ai/A). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to

volatilizati on of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 2 . The Agency is in the process of evaluating the SAP report and may, as

ap propriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

application inhalation exposure assessment for thiacloprid

.

Although quantitative exposure assessment s were not performed to address pesticide drift from neighboring treated agricultural fields or residential bystander post

- ap plication inhalation , an inhalation exposure assessment was performed for flaggers . Risk estimates for the flagger

scenario are approximately 10 - 7 and are below HED’s level of concern . This exposure scenario is representative of a wors t

- case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure scenario s
, including spray drift and bystander exposures

.

7.0 Aggregate Exposure/Risk Characterization

As previously noted, there are no uses of thiacloprid that would result in residential exposures; therefore, aggregate risk estimates are equivalent to the dietary risk estimates described in

Section 5.4.

8.0 Cumulative Exposure/Risk Characterization

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 regarding thiacloprid and any other substances

, and thiacloprid does not appear t o produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that thiacloprid has a common mechanism of toxicity with other

substances. For information regarding EPA’s efforts to det ermine which chemicals have a

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlThiacloprid Human Health Risk Assessment DP No. D376178

Page 22 of 53 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 cumu lating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

It is the policy of HED to use the best available data to assess handler and po st

- application exposure. Sources of generic data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, and the AHETF database. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisi ons of FIFRA. The standard values recommended for use in predicting exposure that are used in this assessment, known as “unit exposure” for handler activities and “transfer coefficients” for post

- application activities , are outlined in the “Occupational P esticide Handler Unit Exposure Surrogate Reference Table 3 ” and in the ExpoSAC Policy 3 4

, respectively. A dditional information on HED ’s policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency

website 5

.

9.1 Occupational Handler Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications

, and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a

ma nner specific to each application event.

Based on the proposed use patterns and labeling, HED has developed quantitative occupational handler exposure and risk estimates for the following scenarios:

• Mixing/Loading Flowable Concentrate (Liquid) for Groun dboom Application,

• Mixing/Loading Flowable Concentrate (Liquid) for Aerial Application,

• Mixing/Loading Flowable Concentrate ( Liquid) for Airblast,

• Applying Sprays with Groundboom Equipment,

• Applying Sprays with Aerial Equipment,

• Applying Sprays wit h Airblast Equipment, and

• Flagging for Aerial Applications.

Estimates of dermal and inhalation exposure were calculated for various levels of personal protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus s ocks, no protective gloves, and

no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc). The thiacloprid product labels direct mixers, loaders, applicators and other handlers to wear

3 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf

4 Available: http://www.epa.gov/pesticides/science/exposac_policy3.pdf

5 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data. htmlThiacloprid Human Health Risk Assessment DP No. D376178

Page 23 of 53 long

- sleeved shirt an d long pants, socks, shoes, chemical

- resistant gloves made of Nitrile, Butyl, Neoprene

, and/or Barrier Laminate.

No data on the number of exposure days per year were provided. For thiacloprid, based on the proposed use patterns and directions (e.g., 1

- 6 applications per season with a minimum 7

- 14 day spray interval depending on the use), short

- (1

- 30 days) and intermediate

- term (1

- 6 months) exposures are expected for handlers. The short

- and intermediate

- term endpoints and PODs are the same for each expo sure route ; therefore

, only short

- term h andler exposures were estimated and are considered protective for intermediate

- term exposure and risk. Long

- term exposures are not expected. For the cancer assessments, the exposure estimates assume an occupational period of 35 years out of a 78

- year lifespan. Since private growers are assumed to be exposed for fewer days per year (i.e., exposed 10 days per year ) than commercial applicators (i.e., exposed 3 0 days

per year ) , the cancer risk assessment for commercial applicators is considered protective of private growers.

The non

- cancer exposure and risk estimates for occupational handlers using thiacloprid are presented in Table 9 .1.1. For the proposed uses on peppers and stone fruits, all of the non

- cancer

occupa tional handler scenarios resulted in MOEs equal to or greater than the respective levels of concern (i.e., MOEs ≥100 for dermal and ≥30 for inhalation) at the baseline level of PPE and with the use of engineering controls for aerial applications (i.e., ass uming a closed cockpit, which is HED’s default for aerial application scenarios) . The non

- cancer dermal and inhalation risks were also combined using the ARI approach. ARIs equal to or greater than 1 are not of concern. The ARIs ranged from 6.9 to 240 a nd are not of concern. The lowest ARI of 6.9 was for handlers who apply thiacloprid to stone fruit using airblast application equipment. These ARIs would be even higher if they had been calculated assuming handlers use the PPE recommended on the proposed label.

A summary of the cancer exposure and risk estimates for pesticide handlers for the proposed crops is provided in Table 9 .1.2. Based on a cancer potency factor of 0.0406 (mg/kg/day) - 1 and

the maximum single application rates, cancer risk estimates calculated for handler activities range from 6.8 x 10 - 7 to 1.2 x 10 - 5 with either baseline PPE or engineering controls (e.g.,

enclosed c ockpit for aerial applications) assuming workers will be exposed 30 days pe r year for 35 years out of a 78

- year lifespa n

.

Table 9.1.1. Summary of Short

- and Intermediate

- Term Occupational Non

- Cancer Exposure and Risk Estimates for Thiacloprid

.

Exposure Scenario Crop Personal

Protective Equipment Dermal Inhalation

ARI 8

Dose (mg/kg/day) 4 MOE 5 Dose

(mg/kg/day) 6 MOE 7

Mixer/Loader

Flowable Concentrate (Liquid) for Groundboom Applications (AHETF) Peppers Baseline 0.0206 15,000 0.0000206 12,000 110

Flowable Concentrate (Liquid) for Aerial Applications (AHETF) Peppers Baseline 0.0905 3,300 0.0000901 2,700 24

Stone Fruits Baseline 0.2410 1,200 0.0002400 1,000 8.8

Flowable Concentrate (Liquid) for Airblast Applications (AHETF) Stone Fruits Baseline 0.0275 11,000 0.0000274 8,800 80Thiacloprid Human Health Risk Assessment DP No. D376178

Page 24 of 53 Table 9.1.1. Summary of Short

- and Intermediate

- Term Occupational Non

- Cancer Exposure and Risk Estimates for Thiacloprid

.

Exposure Scenario Crop Personal

Protective Equipment Dermal Inhalation

ARI 8

Dose (mg/kg/day) 4 MOE 5 Dose

(mg/kg/day) 6 MOE 7

Applicator Sprays for Groundboom Applications (AHETF) Peppers Baseline 0.00739 41,000 0.000032 7,500 160

Sprays for Aerial Applications (AHETF) Peppers Engineering

Controls

- Enclosed cockpit 0.00206 150,000 0.0000280 8,600 240

Stone Fruits Engineering

Controls

- Enclosed cockpit 0.00584 55,000 0.0000744 3,200 89

Sprays for Airblast Applications (AHETF) Stone Fruits Baseline 0.02840 1,400 0.0005890 410 6.9

Flagger Flagging for Aerial Applications (PHED) Peppers Baseline 0.00453 66,000 0.000144 1,700 52

Stone Fruits Baseline 0.01200 25,000 0.000383 630 19

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September, 2012); includes data from PHED/ AHETF (Level of Mitigation: Baseline, Eng. Controls , Respirator ).

2 Based on registered or proposed label ( EPA Reg. No. 264

- 806 ).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) x Conversion Factor (0.001 mg/ μ g) x Application Rate (lb ai/acre or gal) x Area Treated (A/day) / BW ( 80 kg).

5 Dermal MOE = Dermal NOAEL ( 300 mg/kg/day)/Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated (A/day) / BW ( 80 kg).

7 Inhalation MOE = Inhalation NOAEL ( 0.24 mg/kg/day)/ Inhalation Dose ( mg/kg/day).

8 ARI = 1/[(1/RI dermal ) + (1/RI inhal )] where, RI dermal = MOE dermal /100 and RI

inhal = MOE inhal / 30 . ARIs greater than 1 are not of concern.

Table 9 .1.2. Summary of Occupational Handler Cancer Exposure and Risk Estimates for Thiacloprid

. Exposure Scenario Crop Mitigation

Level LADD (mg/kg/day) Cancer

Risk Estimate 4 Dermal 1 Inhalation 2 Total 3

Flowable Concentrate (Liquid) for G roundboom Applications Peppers Baseline 7.6 x 10 - 4 7.6 x 10 - 7 2.8 x 10 - 5 1.1 x 10 - 6

Flowable Concentrate (Liquid) for Aerial Applications Peppers Baseline 3.3 x 10 - 3 3.3 x 10 - 6 1.2 x 10 - 4 5.0 x 10 - 6

Stone Fruits Baseline 8.9 x 10 - 3 8.9 x 10 - 6 3.3 x 10 - 4 1.3 x 10 - 5

Flowable Concentrate (Liquid) for Airblast Applications Stone Fruits Baseline 1.0 x 10 - 3 1.0 x 10 - 6 3.7 x 10 - 5 1.5 x 10 - 6

Sprays for Groundboom Applications Peppers Baseline 2.7 x 10 - 4 1.2 x 10 - 6 1.0 x 10 - 5 4.1 x 10 - 7

Sprays for Aerial Applications Peppers Engineering

Controls

- Enclosed cockpit 7.6 x 10 - 5 1.03 x 10 - 6 7.5 x 10 - 6 1.1 x 10 - 7

Stone Fruits Engineering

Controls

- Enclosed cockpit 2.2 x 10 - 4 2.7 x 10 - 6 2.8 x 10 - 6 3.0 x 10 - 7

Sprays for Airblast Applications Stone Fruits Baseline 2.2 x 10 - 3 2.2 x 10 - 5 3.0 x 10 - 4 1.2 x 10 - 5

Flagging for Aerial Applications Peppers Baseline 1.7 x 10 - 4 5.3 x 10 - 6 6.4 x 10 - 6 2.6 x 10 - 7

Stone Fruits Baseline 4.4 x 10 - 4 1.4 x 10 - 5 1.7 x 10 - 5 6.8 x 10 - 7

1 Dermal LADD = Dermal D ose * (30 d ays per year of exposure/365 days per year) x (35 y ears per lifetime of exposure/ 78 years of l ifetime expectancy).Thiacloprid Human Health Risk Assessment DP No. D376178

Page 25 of 53 2 Inhalation LADD = Inhalation Dose * (30 d ays per year of exposure/365 days per year) x (35 y ears per lifetime of exposure/ 78 years of l ifetime expectancy).

3 Total LADD = T otal A

bsorbed D ose [Dermal D ose + Inhalation Dose] * (30 d ays per year of exposure/365 days per year) x (35 y ears per lifetime of exposure/ 78 years of l ifetime expectancy).

4 Cancer Risk E stimates = Total LADD * Q 1 * , where Q 1 * = 4.06 x 10

- 2 (mg/kg/day)

- 1

.

9.2 Occupational Post

- Application Risk Estimates

9.2.1 Dermal Post

- Application Risk Estimates

No data regarding the number of exposure days per year were provided by the pe t itioner

. Based on the proposed use patterns and directions (e.g., 1

- 6 applications per season with a minimum 7

- 14 day spray interval dep ending on the use), short

- and intermediate

- term exposures are expected

for workers conducting post

- application activities

. Chemical

- specific dislodgeable foliar residue

data have not been submitted for thiacloprid

. Therefore, this assessment uses HED’s default assumption that 25% of the application is available for transfer on day 0 following the application and the residues dissipate at a rate of 10% each following day.

To assess cancer risk, HED assumed that private growers would be exposed 10 days per year and commercial applicators would be exposed 30 days per year. The term “private grower” means that the grower or one of the workers would apply the pesticide to land owned or operated by the grower. Commercial applicators means the applicators a re completing multiple applications for multiple clients. Furthermore, HED assume d that post

- application workers would be exposed for 35 years out of a 78

- year lifespan.

A summary of the dermal post

- application exposure and risk estimates for the propose d crops is provided in Table 9 .2. 1

. R isk estimates for the highest contact activity per crop group are shown

below. Post

- application non

- cancer dermal exposure and risk estimates resulted in MOEs greater than 100 and are not of concern on Day 0 (i.e., 12 hours after application). The dermal

non

- cancer short

- and intermediate

- term post

- application MOEs ranged from 1,200 to 6,000 for the high contact activities expected on the proposed crops (e.g., hand

- set irrigation, thinning fruit) on the day of applica tion.

Table 9.2.1. Summary of Occupational/Commercial Post

- application Non

- Cancer Risk Estimates for Thiacloprid.

Crop/Site Activities Transfer Coefficient (cm 2 /hr) DFR 1 Dermal Dose (mg/kg/day) 2 MOE on Day 0 3

Short

- and Intermediate

- term Peppers Irrigation (Hand Set) 1900 0.264 0.0502 6,000

Stone Fruits Thinning Fruit 3600 0.701 0.2520 1,200

1. DFR = Application Rate x F x (1

- D) t x 4.54E8 μg/lb x 2.47E

- 8 acre/cm 2 ; where F = 0.25 and D = 0.10 per day.

2. Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coeffi cient × 0.001 mg/μg × 8 hrs/day ] BW (80 kg). 3. MOE = POD ( 300 mg/kg/day) / Daily Dermal Dose.

Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of thiacloprid. Thiacloprid is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. A quantit ative post

- application risk

assessment indicates that risk estimates were not a concern on D ay 0 (i.e., 12 hours followingThiacloprid Human Health Risk Assessment DP No. D376178

Page 26 of 53 application) for all post

- application activities. Under 40 CFR 156.208 (c) (2) (iii), chemicals classified as Acute III or IV for acute dermal, eye irritation, and primary skin irri t ation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Standard (WPS)

interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to thiacloprid.

A summary of the post

- application cancer exposure and risk estimates for the proposed crops is provided in Table 9.2.2 . Risk estimates for the highest contact act ivity per crop group are shown below. The estimated cancer post

- application risk estimates for agricultural workers on the day of application ranged from 1.6 x 10 - 4 to 3.6 x 10 - 4 for the high contact activities (e.g., hand

- set irrigation, thinning fruit). T he se cancer risk estimates are considered conservative because the maximum single applicat ion rates and the Day

- 0 default residue values were used in the post

application cancer calculations. Additionally, the proposed PHI for the requested crops range from 7

- 14 days

, and workers conducting most high

- contact post

- application activities are no t expected to be exposed to Day

- 0 residues.

Table 9.2.2. Occupational Post

- Application Cancer Exposures and Risk Estimates for Thiacloprid. Crop Grouping/Crop Activity Days After

Treatment Dermal LADD

(mg/kg/day) 1 Cancer Risk

Estimate 2

Peppers Irrigation (Hand Set) (TC = 1900 cm 2 /hr) 0 0.004 1.6 x 10 - 4

Stone Fruits Thinning Fruit (TC =3600 cm 2 /hr ) 0 0.009 3.6 x 10 - 4

1 Dermal LADD = Dermal Dose * (30 days per year of exposure/365 days per year) x (35 years per lifetime of exposure/78 years of lifetime expectancy).

2 Cancer R isk E stimates = LADD * Q 1 * , where Q 1 * = 4.06 x 10

- 2 (mg/kg/day)

- 1

.

9.2.2 Inhalation Post

- Application Risk Estimates

Based on the Agency's current practices, a quantitative post

- application inhalation exposure

assessment is not being performed for thiacloprid primarily because of the low acute inhalation toxicity (Toxicity Category III), its vapor pressure ( 8.0 × 10 - 10 Pa at 25°C = 6 .0 × 10 - 1 2 mmHg ), and the low proposed use rate (0.047

- 0.25 lb ai/A). However, there are multiple potential sources of

post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungic ide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 6

. The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data gene rated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedu res are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment

for thiacloprid

.

6 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlThiacloprid Human Health Risk Assessment DP No. D376178

Page 27 of 53 Although a quantitative occupational post

- application inhalation exposure assessment was not performed , an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected th at these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

10.0 References

D405299. E. Holman. 31 October 2012. Thiacloprid: Acute, Chronic, and Cancer Aggregate Dietary Exposure (Food and Drinking Water) and Risk Assessment for the Section 3 Registration on Stone Fruit and Peppers.

D376184. G. Orrick. 12 July 2012. Thiacloprid: Update of the Drinking Water Exposure

Assessment for Section 3 New Uses on Stone Fruits and Peppers.

J. Alsadek, 4 October 2012. Screening Level Usage Analysis (SLUA) for Thiacloprid (014019).

D382568. J. Alsadek. 26 September 2012. Update of PCTn Values Provided Previously for Thiacloprid Use on Peaches and Stone Fruit PC# 014019.

D378298. M. Doherty. 1 February 2011

. Thiacloprid: Request for Food Uses on Stone Fruits and Peppers. Summary of Analytical Chemistry and Residue Data.

D 406397 . M. Doherty. 31 October 2012

. Thiacloprid: Request for Food Uses on Stone Fruits and Peppers. Am ended Summary of Analytical Chemistry and Residue Data.

D 406399 . Z. Figueroa. 31 October 2012 . Thiacloprid: Occupational and Residential Exposure

Assessment for Proposed Uses on Peppers and Stone Fruits.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 28 of 53 Appendix A. Toxicology Profile and Executive S ummaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for food use for thiacloprid are in Table A1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A1. Toxicology Requirements for Thiacloprid

Guideline Number and Toxicity Study 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 Sub

- chronic (Rodent)

................................ ..................... 870.3150 Oral Sub

- chronic (Non

- Rodent)

................................ ............. 870.3200 21

- Day Dermal

................................ ................................ ....... 870.3250 90

- Day Dermal

................................ ................................ ....... 870.3465 90/28

- Day Inhalation

................................ ............................. yes

yes

yes

no

yes yes

yes

yes

- yes
870.3700 Developmental Toxicity (Rodent)

................................ ......... 870.3700 Developmental Toxicity (Non

- rodent)

................................ ... 870.3800 Reproduction

................................ ................................ .......... yes

yes

yes yes

yes

yes
870.4100 Chronic Toxicity (Rodent)

................................ ..................... 870.4100 Chronic Toxicity (Non

- rodent)

................................ .............. 870.4200 Oncogenicity (Rat)

................................ ................................ . 870.4200 Oncogenicity (Mouse)

................................ ............................ 870.4300 Chronic/Oncogenicity

................................ ............................ yes

yes

yes

yes

yes yes

yes

yes

yes

yes
8 70.5100 Mutagenicity: Gene Mutation

- bacterial

............................... 870.5300 Mutagenicity: Gene Mutation

- mammalian

.......................... 870.5 375 Mutagenicity: Gene Mutation

– Structural Chromosomal

Aberrations

................................ ................................ ............ 870.5 500 Mutagenicity: Other Genotoxic Effects

................................ .. 870.5550 Mutagenicity: Other Genotoxic Effects

................................ .. yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes
870.6100 Acute Delayed Neurotoxicity (Hen)

................................ ....... 870.6100 90

- Day Neurotoxicity (Hen)

................................ .................. 870.6200 Acute Neurotoxicity Screening Battery (Rat)

........................ 870.6200 90 Day Neuro. Screening Battery (Rat)

................................ . 870.6300 Developmental Neurotoxicity

................................ ................ no

no

yes

yes

yes -

- yes

yes

yes
870.7485 General Metabolism

................................ ............................... 870.7600 Dermal Penetration

................................ ................................ . 870.7800 Immunotoxicity....................................................................... yes

yes

yes yes

yes

noThiacloprid Human Health Risk Assessment DP No. D376178

Page 29 of 53 A.2 Toxicity Profiles

Table A.2a Acute Toxicity of Thiacloprid Technical Grade Active Ingredient (TGAI) and Metabolites

Guideline

No. Study Type MRID #(S). Results Toxicity Category

870.1100 Acute Oral

- mouse 45344002 LD 50 between 100 and 140 mg/kg for

males

and 140 and 200 mg/kg

for females N/A

870.1100 Acute Oral

- rat 44927644 LD 50 621 mg/kg

- males

396 mg/kg

- females II

870.1100 Acute Oral

- rat 44927730 LD 50 between 700 and 1000 mg/kg (males)

LD 50 between 300 and 500 mg/kg (females). II

870.1100 Acute Oral

- rat

(metabolite KKO

2254

- 4

- 2) 45307404 LD 50 > 2000 mg/kg N/A

870.1100 Acute Oral

- rat

(metabolite WAK 6999) 44927737 LD 50 > 2000 mg/kg N/A

870.1100 Acute Oral

- rat

(intermediate 2

- cyaminino

- 1,3

- thiazolidin. 45307407 LD 50 > 200 mg/kg (males)

LD 50 between 200 and 2000 mg/kg (females) N/A

870.1200 Acute Dermal 44927731 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation 44927732 LC 50 > 0.481 mg/L III

870.2400 Primary Eye

Irritation 44927635 Ocular irritation resolving in 24

hours. IV

870.2500 Primary Skin

Irritation 44927635 Very slight erythema resolving in 72

hours. IV

870.2600 Dermal Sensitization 44927733 Did not indicate

sensitization . N/A

Table A.2b. Subchronic, Chronic and Other Toxicity Studies for Thiacloprid Technical.

Type of Study/Guide line Study Title/

Classification /Doses MRID Results

870.3100

90

- Day oral toxicity

- rats (diet) / 0, 25, 100, 400, or 1600 ppm.

0 and 1600 ppm (5 week recovery groups) Acceptable/Guideline

mg/kg/day [m/f] : 0/0, 1.9/2.0, 7.3/7.6, 28.6/35.6, 123.2/160.6 44927714 (1997) NOAEL = 400 ppm ( 28.6 mg/kg/day in males; 160 .6 mg/kg/day in females).

LOAEL = 16 00 ppm ( 123.2 mg/kg/day in males; 35.6 mg/kg/day in females) based on decreased body weight throughout treatment.

44927633 (1995)Thiacloprid Human Health Risk Assessment DP No. D376178

Page 30 of 53 Table A.2b. Subchronic, Chronic and Other Toxicity Studies for Thiacloprid Technical.

Type of Study/Guide line Study Title/

Classification /Doses MRID Results

870.3100

90

- Day oral toxicity

- mice (diet) Supplemental amendment:

additional histopath ology and immunochemistry Acceptable/Guideline 0, 50, 250, 1250 or 6250 ppm

mg/kg/day [m/f] : 0/0, 19.9/27.2, 102.6/139.1, 542.4/704.3,

2819.9/3351.0 44927634 (1995) NOAEL < 50 ppm (27.2 mg/kg/day) in

females.

LOAEL = 50 ppm (27.2 mg/kg/day) in

females based on adrenal X

- zone changes in

females.

NOAEL = 250 ppm (102.6 mg/kg/day) in

males. LOAEL = 1250 ppm (542.4 mg/kg/day) in males based on liver effects (weight and hypertrophy).

870.3150

90

- Day oral toxicity in non rodents

– dog (diet)Range

finding Acceptable/Guideline

0, 250, 1000 or 4000 ppm or 0, 8.5, 34.9, 68 mg/kg/day for males and 0, 8.9, 34.7 or 65.3 mg/kg/day for females.

20

- 25 weeks old at week

- 2

high

- dose: days 1

- 4, 4000 ppm

days 5

- 14, 0 ppm

days 15

- end, 2000

ppm 250 ppm = 8.7 mg/kg/day (M&F average)

1000 ppm =34.8 mg/kg/day

2000 ppm = 66.7 mg/kg/day 44927709 (1998) 44927747 (1997) NOAEL = 250 ppm (8.5 for males and 8.9

mg/kg/day for fe males). LOAEL = 1000 ppm (~34.9 mg/kg/day) based mainly on liver enzyme changes, thyroid hormone level (T4) and binding capacity changes and increased prostatic weight and prostatic hypertrophy.

870.3200

21/28

- Day dermal toxicity

– rat Acceptable/Non

- Guideline

0, 100, 300 or 1000 mg/kg/day.

(5/sex/dose; Guideline requires 10/sex/dose) 44927701 (1997) NOAEL = 300 mg/kg/day (in females) LOAEL = 1000 mg/kg/day based on liver and thyroid effects and clinical signs ( reduc ed motility, decreased activity, and spastic gait )

. No dermal irritation.

870.3465

21/ 28

- Day inhalation toxicity

– rat (solid aerosol dust) Acceptable/Guideline

0, 2, 18.2 and 143/4 mg/m 3

5 hours/day, 6 days/week (4 weeks)

[nominal highest dose tested = 200 mg/m 3 for days 0

- 7, 100 mg/m 3 for days 8

- 28] 44927715 (1998)

SYSTEMIC

NOAEL = 2 0 mg/m 3.
LOAEL = 200 mg/m 3 based on liver (hypertrophy, increased liver enzymes, and necrosis) and thyroid (hypertrophy and slight increases in thyroid hormone) effects.

PORTAL

- OF

- ENTRY

NOAEL = 100 mg/m 3

LOAEL = 200 mg/m 3 based on respiratory

distress ( bradypnea, piloerection, and decreased rectal temperature )

.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 31 of 53 Table A.2b. Subchronic, Chronic and Other Toxicity Studies for Thiacloprid Technical.

Type of Study/Guide line Study Title/

Classification /Doses MRID Results

Concentration of 200 mg/m 3 reduced to 100 mg/m 3 due to marked respiratory distress and decreased body weight gain. Rectal temperature reduced only at 200 mg/m 3 ; slight to severe slow breathing both sexes at 200/100 mg/m 3

. 870.3465

5

- Day inhalation toxicity

– rat (solid aerosol dust) Acceptable/Non

- Guideline 0, 2, 20 and 200mg/m 3
5 days, 6 hours/day (16 day recovery period) 44927736 (1995) SYSTEMIC

NOAEL = 2 mg/m 3
LOAEL = 20 mg/m 3 based on increased grip strength in both sexes.

RESPIRATORY IRRITATION

NOAEL = 20 mg/m 3
LOAEL = 200 mg/m 3 based on bradypnea, labored breathing pattern, piloerection and decreased rectal temperature.

870.3465

4

- Hour inhalation toxicity

– rat (solid aerosol dust) Acceptable/Non

- Guideline 0, 80, 481, 1523 and 2535 mg/m 3 44927736 (1995) Irritation NOAEL = 80 mg/m 3
Irritation LOAEL = 481 mg/m 3 based on tremors, apathy, hypothermia, ungroomed haircoat, decreased bodyweight and piloerection (du ration of signs up to day 6).

In females only, mortality ≥ 1523 mg/m 3

. Necropsy showed relationship between lethality and lung damage; no mention of microscopic tissue examination.

870.3700a Prenatal developmental

- rats (gavage) Acceptable/Guideline 0, 2, 10 or 50 mg/kg/day. 44927741 (1997) Maternal Toxicity: NOAEL = 10 mg/kg/day LOAEL = 50 mg/kg/day based on decreased body weights, body weight gains, food consumption, increased urination, and changes in water consumption. Developmental Toxicity: NOAEL = 10 mg/kg/day LOAEL = 50 mg/kg/day based on increased resorptions (complete and late), skeletal retardations, variations (wavy ribs and asymmetrical sternebrae), and malformations (dysplastic humerus, radius, and scapulae)

an d on decreased fetal weights.

870.3700b Prenatal developmental

- rabbits (gavage) Acceptable/Guideline 0, 2, 10 or 45 mg/kg/day. 44939201 (1996) Maternal Toxicity: NOAEL = 2 mg/kg/day LOAEL = 10 mg/kg/day based on decreased body weight gains, food consumption, and fecal output. Developmental Toxicity:Thiacloprid Human Health Risk Assessment DP No. D376178

Page 32 of 53 Table A.2b. Subchronic, Chronic and Other Toxicity Studies for Thiacloprid Technical.

Type of Study/Guide line Study Title/

Classification /Doses MRID Results

NOAEL = 2 mg/kg/day LOAEL = 10 mg/kg/day based on decreased fetal weights.

At 45 mg/kg/day, 2 abortions and 3 total resorptions (24 ra bbits).

870.3800 Reproduction and fertility

effects

– rat (diet)

- Range

finding Acceptable/Guideline 0, 50, 300 or 600 ppm.

mg/kg/day:

pre

- mating [m/f] : 0/0, 3.5/4.2, 21/26, 41/51

gestation: 0, 3.7, 22, 43

lactation: 0, 6.8, 42, 86 44927702 (1997) 44927638 (1995) Parental/Systemic:

NOAEL = 50 ppm (3.5 mg/kg/day in males) LOAEL = 300 ppm (21 mg/kg/day based on increased liver and thyroid weights and on hepatocytomegaly, liver necrosis, and thyroid follicular cell hypertrophy Reproductive : NOAEL = 50 ppm (4.2 mg/kg/day in females) LOAEL = 300 ppm (26 mg/kg/day) based on dystocia (abnormal or difficult labor). Offspring: NOAEL = 50 ppm (4.2 mg/kg/day in females) LOAEL = 300 ppm (21 mg/kg/day in females) based on decreased pup weight during lactation.

870.4100b

Chronic toxicity

- dogs (diet) Acceptable/Guideline 0, 40, 100, 250 or 1000 ppm.

mg/kg/day [m/f] = 0/0, 1.42/1.39, 3.60/3.27, 8.88/8.30,

34.42/33.80

27

- 32 weeks old at day 0

26

- week interim sacrifice of 3 males/group (0, 100 and 1000 ppm) 44927716 (1998) No firm LOAEL was established for this chronic feeding study with dogs. There were no effects that were of sufficient magnitude or consistency to justify that they were definite responses to treatment. Certain effects noted in the subchronic dog study on the prostate and other male organs and an apparent effect on uterine weight in the subchronic dog study were not seen in this chronic study. This may be because the dogs in this study had reached maturity. (see 15 week study, MRID 44927709, Guideline 870.3150).

26

- week interim sacrifice. No effects reported on any parameter.

870.4200 Carcinogenicity

- mice (diet)

– 2 years Acceptable/Guideline 0, 30, 1250 or 2500 ppm.

mg/kg/day [m/f] : 0/0, 5.7/10.9, 234.1/475.3, 546.4/872.5 44927710 (1998) 44927711 (1998) NOAEL = 30 ppm (5.7 mg/kg/day in males

and 10.9 mg/kg/day in females). LOAEL = 1250 ppm (234.1 mg/kg/day in

males and 475.3 mg/kg/day in females) based on liver toxicity and microscopic lymph node changes in both sexes and

increased X

- zone vacuolization of the adrenal glands in female mice. Evidence of carcinogenicity bas ed on

increased incidence of ovarian luteomas.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 33 of 53 Table A.2b. Subchronic, Chronic and Other Toxicity Studies for Thiacloprid Technical.

Type of Study/Guide line Study Title/

Classification /Doses MRID Results

870.4300 Combined chronic feeding and carcinogenicity

- rats. (diet) Acceptable/Guideline 0, 25, 50, 500 or 1000 ppm.

mg/kg/day [m/f] : 0/0, 1.2/1.6, 2.5/3.3, 25.2/33.5, 51.7/69.1 44927712 (1998) NOAEL = 25 ppm (1.2 mg/kg/day in males and 1.6 mg/kg/day in females). LOAEL = 50 ppm (2.5 mg/kg/day in males and 3.3 mg/kg/day in females) based on liver toxicity (hepatocellular hypertrophy and cytoplasmic change and increased enzyme activity), thyroid f

ollicular epithelial hyper

trophy in males and oculotoxicity (retinal atrophy) in females. Evidence of carcinogenicity based on increased incidence of thyroid follicular cell adenomas in males and possibly also in

females and increased incidence of uterine tumors (adenocarcinomas)

870.6200a

Acute neurot oxicity screening battery

– rat (gavage) Supplemental study Acceptable/Guideline 0, 3.1, 11, 22, 53 or 109 mg/kg/day (doses in one or the other study). 44927703 (1997) 44927704 (1998) NOAEL = 3.1 mg/kg/day

LOAEL = 11 mg/kg/day in females based on reductions in motor and locomotor activity.

In males, the LOAEL was 22 mg/kg bw (based on FOB observations of slight tremors and ptosis of the eyelids on the day of treatment), and the NOAEL of 11 mg/kg

bw.

870.6200b Subchronic neurotoxicity screening battery

- rat (diet) Acceptable/Guideline 0, 50, 400 or 1600 ppm.

mg/kg/day [m/f] : 0/0, 2.94/3.41, 24.2/27.9, 101/115 44927645 (1997) NOAEL = 400 ppm (24.2 mg/kg/day in males and 27.9 mg/kg/day in females). LOAEL = 1600 (101 mg/kg/day in males and 115 mg/kg/day in females) based on decreased body weight gains and food consumption in both sexes and decreased hindlimb grip strength in mal es.

870.6300 Developmental neurotoxicity

– rat (diet) Acceptable/Non

- guideline. 0, 50, 300, or 500 ppm (0, 4.4, 25.6, and 40.8 mg/kg/day during gestation; 0, 8.2, 49.4, and 82.8 mg/kg/day during lactation). 45516601(2001) Maternal NOAEL = 50 ppm (4.4 mg/kg/day) LOAEL = 300 ppm (25.6 mg/kg/day based on deceased body weight gain and food consumption during early gestation (GD 0

- 6).

Offspring NOAEL = 50 ppm (4.4 mg/kg/day) LOAEL = 300 ppm (25.6 mg/kg/day) based on decreased pre

- weani ng and post

- weaning body weights in both sexes as well as altered performance in passive avoidance testing.

Changes in brain morphometrics at 500ppm

870.7485 Metabolism and pharmaco

kinetics

- rat Acceptable/Guideline 44927609 (1998)

Toxicokinetics

and metabolism 44927605 (1996) Recovery was 86

- 106%. Orally, rapid

absorption with maximum plasma

concentrations at 1

- 2 hours and 3

- 4 hours forThiacloprid Human Health Risk Assessment DP No. D376178

Page 34 of 53 Table A.2b. Subchronic, Chronic and Other Toxicity Studies for Thiacloprid Technical.

Type of Study/Guide line Study Title/

Classification /Doses MRID Results

44927612 (1997) 1 and 100 mg/kg doses; intravenously,

within 20 minutes. Rapid excretion. Minor gender

- related differences in excretion time. Extensive tissue distribution with rapid removal. Hydroxylation of thiazolidine ring with glucuronidation. Hydroxylation of cyanamid moiety. Opening of thiazolidine ring. Formation of exazole ring. Oxidation and methyl ation of thiazolidine ring. Oxidative cleavage of methylene bridge. Minor gender

- related quantitative differences in metabolite profiles.

870.7600. Dermal absorption

- monkeys. Acceptable/Guideline 45846701

45846702 A 5% dermal absorption value is appropriate

for estimating the risk resulting from dermal exposure to Thiacloprid formulated as a 40.4% liquid formulation (SC 480). This 5% value is also appropriate for other liquid thiacloprid formulations that are simi lar to the SC 480 liquid formulation product tested and for aqueous dilutions of most thiacloprid

formulations.

Special studies Several special studies conducted to attempt to establish a mode of action for the induction of thyroid tumors in rats based on increased thyroid hormone metabolism and activation of the liver/pituitary/thyroid axis, induction of uterine tumors in rats and ovary tumors in mice and dystocia in rats were presented. Since these studies are not required for registration, they are not being listed here. Please refer to the MTARC review (TXR # 0051476 and dated February 19, 2003) for both the

list of these and HED’s interpretation of these studies. Also March 26, 2033 CARC memo, TXR # 0051705); November 16, 2011 CARC memo, TXR # 0056114)

A.3 Toxicological Doses and Endpoints for Use in Human Risk Assessments

Hazard Identification and Endpoint Selection

A) Acute Reference Dose (aRfD)

- Acute Reference Dose (aRfD) general population, including infants and children

Studies Selected: Co

- critical studies: Developmental Neurotoxicity Study in the Rat and Acute Neurotoxicity study in Rats

MRID Nos.: 455166 01 (DNT); 44927703, and 44927704 (ACN)

Dose and Endpoint for Risk Assessment: Offspring NOAEL = 4.4 mg/kg/day from the DNT study based on offspring effects of altered performance in passive avoidance testing at a LOAEL of 25.6 mg/kg/day. In the ACN study, the NOAEL = 3.1 and the LOAEL = 11 mg/kg/day in females based on reductions in motor and locomotor activity.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 35 of 53 Uncertainty Factor(s): 100X [10 interspecies; 10X intraspecies] FQPA SF = 1X Comments about Study/Endpoint/Uncertainty Factor : The route and duration of exposure

from these co

- critical studies are appropriate for selection of the acute dietary endpoint. The toxicity could occur following a single exposure and is appropriate for this exposure scenario. Regulating at the higher NOAEL of 4.4 m g/kg/day from the DNT study is protective of both the effects seen at the LOAEL of 11 mg/kg/day in the ACN study (which is a gavage study) and at the LOAEL of 25.6 mg/kg/day in the DNT study. It would also be protective of the marginal

and variable brain morphometric changes seen in the DNT at the high dose of 40.8 mg/kg/day

. Toxic effects (resorptions) appropriate for acute dietary exposure, females ages 13

- 49, were seen in developmental toxicity studies in rats and rabbits at ≥ 45 mg/kg/day. However, t hese effects were observed at higher doses than effects seen in the acute neurotoxicity and the developmental neurotoxicity studies. Therefore, the dose and endpoints from the neurotoxicity studies were selected and considered protective of potential acute toxicity for all populations (general (including infants and children) and females ages 13 to 49).

aRfD = aPAD = 4.4 mg/kg/day = 0.044 mg/kg/day

100

B) Chronic Reference Dose (cRfD)

Study Selected : Chronic/Carcinogenicity Study

– rat (OCSPP 870.4300)

MRID No. 44927712

Dose and Endpoint for Establishing a RfD: NOAEL = 1.2/1.6 mg/ kg /day (M/F) based on liver hypertrophy and cytoplasmic changes, thyroid hypertrophy and induction of the enzymes UDP

Glu

- T and aromatase as well as the induc tion of hepatic enzymes and retinal degeneration in females at the LOAEL of 2.5 mg/ kg /day.

Uncertainty Factor(s): 100X [10 interspecies; 10X intraspecies] FQPA SF = 1X,

Comments on Study/Endpoint/Uncertainty Factors:

The dose and endpoint (liver and thyroid toxicity as well as retinal degeneration in females) reflect chronic (lifetime) dosing via the oral (diet) route. The NOAEL/LOAEL in the rat is the lowest dose in the toxicity database for chronic durations. The c hronic rat study was therefore considered to be the most appropriate for chronic dietary dose and endpoint selection.

Chronic RfD = cPAD = 1.2 mg/kg/day (NOAEL) = 0.012 mg/kg /day 100 (UF)

C) Incidental Oral Exposure (Short

- Term)

Study Selected:

– 2

- Generation Reproduction Study in RatsThiacloprid Human Health Risk Assessment DP No. D376178

Page 36 of 53 MRID No.: 44927702 and 44927638

Dose and Endpoint for Risk Assessment: Offspring NOAEL = 4.2 mg/kg/day. The Offspring LOAEL = 21 mg/kg/day based on decreased pup weight during lactation.

Uncertainty Factor(s): LOC for MOE = 100. 100X [10 interspecies; 10X intraspecies]; FQPA

SF = 1X.

Comments about Study/Endpoint/Uncertainty Factor : The endpoint selected is appropriate for the exposure duration and the population of concern (children). It is also protectiv e of the neurotoxicity effects seen in the ACN, SCN and DNT studies. Given that there are no residential uses, this exposure scenario is not relevant at this time.

D) Dermal Exposure (Short

- and Intermediate Term)

- All Populations

Study Selected : 28 Day Dermal Study

– rat (OCSPP 870.3200)

MRID No .: 44927701

Dose and Endpoint for Establishing the RfD : Systemic NOAEL = 300 mg/ kg /day. Systemic effects observed at the LOAEL of 1000 mg/ kg /day (limit dose) were liver and thyroid changes plus clinical signs of reduced motility, decreased a ctivity and spastic gait in females. No dermal

irritation was noted at 1000 mg/kg/day (limit dose).

Uncertainty Factor(s): LOC for MOE = 100. 100X [10 interspecies; 10X intras pecies]; FQPA

SF = 1X.

Comments on Study/Endpoint/Uncertainty Factors : This study is appropriate for the route and duration of exposure. The developmental toxicity studies in rats and rabbits and the reproduction study in rats were also considered for risk assessment ; however, there was no evidence o f quantitative susceptibility seen in the studies and the effects observed in maternal animals were adequately measured in the dermal toxicity study

. Additionally, the subchronic neurotoxicity study was cons idered. However, the dermal equivalent dose (DED) calculated (based on 5% dermal absorption factor) for the study was higher than the point of departure (POD) of 300 mg/kg/day from the dermal toxicity study. Therefore, the dermal toxicity study was selec ted and it is considered protective of potential developmental, reproductive, and neurotoxic effects.

E) Inhalation Exposure (Short and Intermediate Term) (See Appendix B for Inhalation Assessment Methodology and HEC assessment array)

Study Selected: 5

- day (6 hours per day) inhalation toxicity study in rats

MRID No: MRIDs 44927715 Dose and Endpoint for Risk Assessment : NOAEL=2 mg/ m 3 (0.002 mg/L); HEC = 0.005 mg/L; HED=0.24 mg/kgThiacloprid Human Health Risk Assessment DP No. D376178

Page 37 of 53 Uncertainty Factor: 30x (3x interspecies extrapolation, 10x intrasp ecies variability, 1x FQPA Safety Factor )

Study/Endpoint: In a 5

- day/6 hours per day nose

- only inhalation study in male and female Wistar rats (10/sex/group), Thiacloprid

, 97.2% a.i., was administered as a solid aerosol dust at average target concentrati ons of 0, 2, 20 or 200 mg/m 3 . After the 5 exposure days, the animals were observed during a 16

- day recovery period. The systemic LOAEL is 20 mg/m 3 and is based on increased grip strength in both sexes. The systemic NOAEL is 2.0 mg/m 3 . The portal

- of

entry LOAEL i s 200 mg/m 3 and is based on bradypnea, labored breathing pattern, piloerection and decreased rectal temperature. The portal

- of

- entry NOAEL is 20 mg/m 3

.

Table 1. Table of systemic and portal

- of

- entry endpoints and PODs for s hort

- and intermediate term occupational exposure based on a 5 day (6 hours exposure/day)

inhalation toxicity study. Effect Endpoint HEC ( 5 day stud y ) HED ( 5 day study ) Systemic 0.005 mg/L 0.24 mg/kg The systemic LOAEL of 20 mg/m 3 is based on increased grip strength in both sexes. The systemic NOAEL is 2 mg/m. 3

Portal

- of

- entry: pulmonary (PU) 0.008 mg/L 0.38 mg/kg The portal

- of

- entry LOAEL i s 200 mg/m 3 and is based on bradypnea, labored breathing pattern, piloerection and decreased rectal temperature. The portal

- of

- entry NOAEL is 20 mg/m 3

. Effect Endpoint HEC ( 21/ 28 day stud y ) HED ( 21/ 28 day study ) Systemic 0.048mg/L 2.3 mg/ kg

Portal

- of

- entry: pulmonary (PU) 0.042mg/L 2.0 mg/kg The systemic LOAEL is 200 mg/m 3 based on liver (hypertrophy, increased liver enzymes, and necrosis) and thyroid effect s (increased weights, minor increases thyroid hormones, and hypertrophy). The systemic NOAEL is 20 mg/m 3. The portal

- of

- entry LOAEL is 200 mg/m 3
based on respiratory distress (bradypnea, piloerection, and decreased rectal temperature ) . The NOAEL is 100 mg/m 3

.

Dose and Endpoint for Risk Assessment ( O ccupational): The HEC of 0.005 mg/L was based on systemic effects (increased grip strength) seen in a 5

- day inhalation toxicity study. The systemic HEC is also protective of the portal

- of

- entry effects noted in the study at a higher dose. The observed effect is consistent with the pesticidal mode of action for thiacloprid, disruption of the

nervous s ystem as an inhibitor at nicotinic acetylcholine receptors. T he duration of exposure in

the 5

- day inhalation toxicity study is appropriate for short

- term risk assessments. For

intermediate

- term risk assessment, the 5 day study was also selected and cons idered protective of the systemic and portal

- of entry effects noted in the 21/ 28 day inhalation toxicity study since the

HECs in the 21/ 28 day stud y w ere higher (i.e., less sensitive). A MOE of 30 defines HEDs level of concern in accordance with the guid ance provided in the RfC methodology.

Occupational Long

- Term Inhalation Exposures

Long

- Term inhalation studies are currently unavailable for thiacloprid. However, based on the proposed use pattern for t hiacloprid, long

- term inhalation exposure is not anticipated.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 38 of 53 Residential Inhalation Exposures (all durations)

Based on the use pattern residential inhalation exposure is not anticipated.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 39 of 53 A. 4

. Executive Summaries for new or revised DERs

90

- DAY RAT STUDY (DIET) [MRID 44927714]

UPDATED EXECUTIVE SUMMARY : In a 90

- day oral toxicity study (1997, MRID 44927714) Thiacloprid (98.6% a.i., batch # NLL 3351

- 13) was administered to 10 SPF

- bred Wistar rats/sex/dose in the diet at dose levels of 0, 25, 100, 400, or 1600 ppm (equivalent to 0, 1.9, 7.3, 28.6, and 123.2 mg/ kg /day in males and 0, 2.0, 7.6, 35.6, and 160.6 mg/ kg /day in females). Recovery groups (0 and 1600 ppm) with the same number of rats were observed for an

additional five weeks without treatm ent.

No animals died during the study. Moderate hepatocellular hypertrophy associated with a fine granular to vesicular structure of the perinuclear cytoplasm was seen in 9/10 males and 2/10 females of the 400 ppm group and in all 1600 ppm animals. Af ter the recovery period, minimal hepatocellular hypertrophy without cytoplasmic change was seen in 3/10 of the 1600 ppm males. There was no evidence of cell proliferation in the liver. Body weights of the 1600 ppm groups were significantly lower than thos e of controls throughout the study, and overall body weight gains were decreased by 22

- 24%. There were no treatment

- related food consumption, ophthalmology, or hematology findings. At the end of treatment, serum cholesterol and total protein were increase d up to 84% and 11%, respectively, but returned to normal levels following the recovery period. Hepatic enzyme activities were elevated in the 400 (especially males) and 1600 ppm groups, but returned to normal levels following the recovery period. Absolute liver weights were increased by up to 21% in the 1600 ppm groups. Absolute thyroid weight increased 67% in 1600 ppm males, but no microscopic thyroid changes were seen. There were no significant differences in liver or thyroid weights of the control or t reated groups after the recovery period. T he LOAEL is 1600 ppm (123.2 mg/kg/day in males, 160.6 g/kg/day in females) based on decreased body weight throughout the treatment period (14

- 16%). The NOAEL is 400 ppm (28.6 mg/kg/day in males, 35.6 mg/kg/day in f emales)

.

This study is Acceptable (Guideline) and satisfies the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3100; OECD 408) in rats.

Note: This updated executive summary revises the previous NOAEL /LOAEL determined for thiacloprid that were incorrectly reported in the DER.

28

- DAY DERMAL STUDY IN RATS [MRID 44927701]

UPDATED EXECUTIVE SUMMARY : In a 28

- day dermal toxicity study (1997, MRID 44927701), YRC 2894 (thiacloprid, 97.2% a.i.; Batch/Lot #: 290894) was applied to the shaved intact skin of 5 Hsd Cpb: WU rats/sex/dose at dose levels of 0, 100, 300, or 1000 mg/kg bw/day, 6 hours/day for 5 d ays/week during the first 3 weeks and 7 days/week during the fourth week. An additional 5 rats/sex were necropsied after a two

- week recovery period in the 0 and 1000 mg/kg/day groups.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 40 of 53 Mortality, dermal effects, body weight, body weight gain, food consump tion, hematology, and clinical chemistry were not adversely affected by treatment. There was one female which displayed at least some transient clinical signs (i.e. decreased motility) that would be expected of thiacloprid.

Moderate hepatocellular cent rilobular hypertrophy in combination with a more homogeneously structured cytoplasm was noted in males at control (0/5), 100 (1/5), 300 (3/5 and 1000 (5/5 and also 3/5 females) mg/kg/day. In the recovery group, centrilobular hypertrophy was still noted i n the high dose group males (2/5). At 1000 mg/kg, hypertrophy of the follicular epithelium in the thyroid was noted in 3/5 males and 2/5 females ( vs. 0/5 controls), and increased colloid vacuolation and foamy cytoplasm were noted in 1/5 males ( vs. 0/5 con trols). In the recovery group, 1/5 males each at 1000 mg/kg displayed hypertrophy of the follicular epithelium and round cell infiltration. Significant increases 0.05) in liver weights were noted in males (relative [to body] incr. 17%) and females (abs olute and relative incr. 12

- 14%). In addition, absolute liver weight was increased 13% in males, but without statistical significance. The LOAEL is 1000 mg/kg/day based on liver and thyroid effects and clinical signs ( reduced motility, decreased activit y, and spastic gait) . The NOAEL is 300 mg/kg/day.

This study is classified as Acceptable/Non

- guideline and satisfies the guideline requirement (OPPTS 870.3200; OECD 410) for a 28

- day dermal toxicity study in rats.

Note: This updated executive summary upgrades the previous classification fo r thiacloprid from Unacceptable ( Guideline ) to Acceptable ( Non

- guideline ) . Although the guideline study requires 10 animals/sex and this study used only 5 animals/sex, it satisfies the guideline requirement (O PPTS 870.3200; OECD 410) for a 28

- day dermal toxicity study in rats

. Additionally, the NOAEL/LOAEL statement has been revised.

21/28

- DAY INHALATION STUDY IN RATS (INCLUDES 4

- HOUR AND 5

- DAY STUDIES) [MRID 44927715, 44927636]

UPDATED EXECUTIVE SUMMARY : In a subacute inhalation toxicity study (1998, MRID 44927715 and 1995, MRID 44927636), YRC 2894 (thiacloprid; 96.8

- 97.2% a.i., Batch No.

29089 4) as a solid aerosol dust was ad ministered to 10 Wistar rats/sex/concentration by dynamic

nose

- only exposure a t target concentrations of 0, 2, 20, or 200/100 mg/m 3 (achieved mean analytical dosages of 0, 2, 18.2, and 143.4 mg/m 3 ) for 6 hours per day, 5 days/week for a total of 28 days (20 exposures). The achieved MMAD was ~ 2.9 μM. The high dose animals were

exp osed to 200 mg/m 3 for study Days 0

- 7, then exposed to 100 mg/m 3 for Days 8

- 28 due to marked respiratory distress and decreased body weight gain observed at the initial concentration.

There were no treatment

- related effects on mortality, urinalysis, bod y weights, and ophthalmoscopic , neurologic, and macroscopic changes. Rectal temperature was decreased while exposed to 200 mg/m 3 but was normal when the dose was reduced.

The only findings observed at 20 mg/m 3 were an increase in the liver enzyme, aminopyrine

- N

demethylase (N

- DEM) and minimal to slight hepatocyte hypertrophy in the males (5/10). These observations were also noted at a greater incidence in the 200/100 mg/m 3 males and females. AtThiacloprid Human Health Risk Assessment DP No. D376178

Page 41 of 53 200/100 mg/m 3 , a slight to moderate piloerection and s light to severe bradypnea were observed throughout treatment in both males and females. Liver enzymatic activity of p

- nitroanisole

- O

demethylase (O

- DEM) and cytochrome P450 (P450) were increased (p 0.01) in both sexes. Absolute and relative (to body and brain) liver weights were elevated (p 0.01) in females, while relative (to body) liver weights were elevated (p 0.01) in males. Minimal single cell necrosis and fat deposition in the liver were observed in the controls and treated animals; a minor incr ease in the incidence of these findings was observed in the liver of both sexes at 200/100 mg/m 3 (3

- 5/10 treated vs. 1

- 3/10 controls). Findings in the thyroid at 200/100 mg/m 3 included slight hypertrophy of the thyroidal epithelium in males (2/10 treated vs. 0/10 controls), and statistically insignificant increases in absolute and relative thyroid weights in males and females (incr. 28

- 40%) and in triiodothyronine (T3) and thyroxine (T4) in the females (incr. 12

- 26%). The systemic LOAEL is 200 mg/m 3 bas ed on liver (hypertrophy, increased liver enzymes, and necrosis) and thyroid effect (increased weights, minor increases thyroid hormones, and hypertrophy). The systemic NOAEL is 20 mg/m 3. The portal

- of

- entry LOAEL is 200 mg/m 3 based on respiratory dis tress (bradypnea, piloerection, and decreased rectal
temperature ) . The NOAEL is 100 mg/m 3 . Histological evaluation of the respiratory tract (i.e. larynx, nose and nasal passage) did not reveal any treatment related change. Serial sections were not perfo rmed on the nose/nasal regions.

5 DAY STUDY: The systemic LOAEL is 20 mg/m 3 based on increased grip strength in both sexes. The systemic NOAEL is 2.0 mg/m 3 . The portal

- of

- entry LOAEL is 200 mg/m 3
and was based on bradypnea, labored breathing pattern, piloerection and decreased rectal temperature. The portal

- of

- entry NOAEL is 20 mg/m. 3

This study is Acceptable (Guideline) and satisfies the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3100; OECD 408) in rats.

Note: This updated ex ecutive summary revises the previous NOAELS /LOAELS determined for thiacloprid in both the 5 day and 28 day inhalation studies.

In the 4

- hour study, t he systemic LOAEL of 481 mg/m 3 was based on tremors, apathy, hypothermia, ungroomed haircoat , decreased bodyweight and piloerection as well as mortality at the next concentration (1533 mg/m 3 ). The systemic NOAEL is 80 mg/m3. The portal

- of

- entry LOAEL of 481 mg/m 3 was based on bradypnea, dyspnea, labored breathing pattern, rales, nose/snout area with red encrustations, salivation, mydrias is and chromodacryorrhea. The portal

- of

- entry NOAEL i s 80 mg/m 3

.

This subacute inhalation toxicity study in the rat is Acceptable (G uideline ) and satisfies the guideline requirement for a subchronic inhalatio n study OCSPP 870.3465; OECD 413 in

the rat

.

DEVELOPMENTAL NEUROTOXICITY STUDY IN RATS (DIET) [MRID 45516601]

EXECUTIVE SUMMARY : In a developmental neurotoxicity study (MRID 45516601) YRC 2894 (Thiacloprid; 99.2% a.i., 898013001) was administered to 25 f emale Crl:CD ® (SD)IGS BR

VAF/Plus ® rats per dose in the diet at dose levels of 0, 50, 300, or 500 ppm (0, 4.4, 25.6, and 40.8 mg/kg/day during gestation; 0, 8.2, 49.4, and 82.8 mg/kg/day during lactation) fromThiacloprid Human Health Risk Assessment DP No. D376178

Page 42 of 53 gestation day (GD) 0 through lactation day (LD) 22. The day that litter delivery was completed was designated postnatal day (PND) 1 (or LD 1). Body weight and food consumption data were recorded for dams. Detailed clinical observations, including assessments of autonomic function,

were conducted dai ly during gestation and on LD 1, 5, 8, 14, and 22. Dams were killed and necropsied on LD 22. On PND 5, litters were standardized to yield 5 males and 5 females (as closely as possible), and 10 randomly selected pups/sex/group were subjected to detailed c linical examination outside the home cage. On PND 12, pups were randomly assigned to each of the following four subsets: 1) fixed brain weights and/or neuropathological evaluation on PND 12 (10/sex/group); 2) passive avoidance testing (on PND 23

- 25 and 30

- 32) and water maze testing (on PND 59

- 63 and 66

- 70) ( 20/ sex/group); 3) motor activity testing (on PND 14, 18, 22, and 58

- 60) and auditory startle habituation (on PND 23 and 59

- 61) (20/sex/group); 4) detailed clinical exam outside the home cage on PND 12 a nd weekly during the postweaning period (20/sex/group), fixed brain weights and neuropathological evaluation on PND 68

- 79 (10/sex/group). In addition, the pups from subsets 2

- 4 were observed for the age of attainment of balanopreputial separation or vagin al patency (60/sex/group).

There were no treatment

- related effects on maternal survival, clinical or functional observations, reproductive function, or gross pathology at any dietary level. Treatment

- related decreases (p 0.05) in maternal body weight ga in were observed in the 300 and 500 ppm dams during GDs

0

- 6 ( 31

- 56%), and in the 500 ppm dams during LDs 1

- 4 ( 67%). Treatment

- related decreases in food consumption (p 0.01) were also noted in the 300 and 500 ppm dams during GDs 0

- 6 ( 16

- 30%) and in the 500 ppm dams during LD 4

- 7 ( 11%). Significant decreases (p 0.01) in relative food consumption on GD 0

- 6 at 300 ( 14%) and 500 ppm ( 27%) support the conclusion that the effects on body weight gain in early gestation were not solely related to palatabilit y.

The maternal LOAEL is 300 ppm (25.6 mg/kg/day), based on decreased body weight gain and food consumption during early gestation (GD 0

- 6). The maternal NOAEL is 50 ppm (4.4 mg/kg/day).

Offspring survival, assessments of autonomic function, watermaze, brain weights, and qualitative histopathology were unaffected by treatment. Suggestive effects on motor activity and auditory startle were seen in the 300 and 500 ppm groups. Increased incidences (p 0.01) of malaligned incisors and chromodacryorrhea were observed at postpartum week 10 in 500 ppm offspring. These findings were considered to be treatment

- related, perhaps a latent expression of a developmental anomaly.

Pre

- weaning body weights were decreased (p 0.01) in both sexes at 300 and 500 ppm on PN Ds

8

- 22 ( 5

- 15%). In addition, postweaning body weights were decreased (p 0.01) at 300 ( 5

- 15%) and 500 ( 4

- 13%) ppm. Increased (p 0.05) time to preputial separation was noted in the 300 and 500 ppm male pups when compared to controls (48.2 days each tre ated vs. 46.7 days controls). In addition, time to vaginal opening was delayed in the 500 ppm females (34.7 days treated vs. 33.4 days controls).

The corpus striatum ( 4%) and corpus callosum ( 14%) were smaller (p 0.05) in the 500 ppm males when compare d to controls on PND 12. Additionally, at study termination, the corpusThiacloprid Human Health Risk Assessment DP No. D376178

Page 43 of 53 striatum ( 4%) and dentate gyrus ( 5%) were smaller (p 0.05) in the 500 ppm males when compared to controls. Non

- significant decreases were also noted in females for corpus callosum measures at PND 12 and for corpus callosum measures at termination, supporting the position

that the effects in males are related to tre atment. In male offspring, at the highest dose tested (500 ppm; 40 mg/kg/day), the corpus striatum (4%) and corpus callo sum (14%) were smaller (p<0.05) when compared to controls on PND 12. At study termination (PND 63

- 79), the corpus striatum (4%) and dentate gyrus (5%) were smaller (p<0.05) when compared to controls. The changes observed at the high dose were attributed t o treatment. In spite of these changes at the high dose brain morphometric analyses were not performed at the mid

- and low

- dose groups. However, it is determined that the concern is low for the lack of brain morphometric

measurements at the mid and low dose groups based on the following considerations: 1) the only consistent change was the decrease in corpus callosum in the male pups at both time periods (i.e., at PND 12 and termination; 2) at both time periods the magnitude of the change is small (4%)

whic h well could be within the differences that could occur from embedding the brains at different times; 3) decreases in the corpus striatum were not seen in female pups at either time periods; and 4) there is a pervasive lack of biological plausibility that changes would be seen at the low dose (4 mg/kg/day) which is 10

- fold lower than the dose (40 mg/kg/day) that caused a

small decrease.

The offspring LOAEL is 300 ppm (25.6 mg/kg/day), based on decreased preweaning and postweaning body weights in both sex es and delayed sexual maturation in the males, and altered performance in passive avoidance testing. The offspring NOAEL is 50 ppm (4.4 mg/kg/day).

This study is classified Acceptable (Non

- guideline) and does not satisfy the guideline requirement for a d evelopmental neurotoxicity study in rats (OPPTS 870.6300, §83

- 6); OECD 426 (draft). However, the study can be used for regulatory purposes

C. STUDY DEFICIENCIES:

- The method used for the evaluation of f unctional behavior was not adequately described

in the text of the report. The procedures used were not described, including whether the same technicians were used throughout testing, where the testing was done (including whether the animals were removed from the cage), what the environmental conditions were (e.g., noise level, etc.), whether scoring criteria were used for the measured parameters, or the duration of the observation period for open field observations.

- During the period of 10/23/00 to 12/22/00, the humidity in the animal room was outside

th e targeted range of 30

- 70% on numerous occasions. There were 7 incidences of >70% humidity, 270 incidences of <30% humidity.

- The lack of habituation of motor activity for the adult rats should be explained.

- Session 1/Trial 1 latency data should be reporte d for water maze testing. Additionally, more complete reporting of individual learning and memory test results would facilitate the interpretation of these data.

- The termination of adult offspring (subset 4) was conducted on PND 68

- 79. An explanation for this wide range of ages at termination (i.e., a span of 11 days) should be provided.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 44 of 53 - Measurements were made bilaterally for a number of areas of the brain in both PND 12 and adult offspring (see report pages 728 and 779), but only the mean values were

r eported. Values for linear brain measurements that were recorded, but not included in the current report, should be submitted.

- Acceptable positive control data were not provided.

COMPLIANCE : Signed and dated GLP, Quality Assurance, Data Confidentiality, and Flagging statements were provided.

Note: This updated executive summary upgrades the previous classification for the developmental neurotoxicity study from Unacceptable/Guideline to Acceptable/Non

guideline. Additionally, more characterization has been added regarding the morphometric chan ges observed in the study.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 45 of 53 A ppendix B. Inhalation Exposure Assessment

Human respiratory data are not available for the thiacloprid inhalation risk assessment. Therefore, the methods and dosimetry equations described in EPA’s reference concentration (RfC) guidance (1994) are suited for calculating human equivalent concentrations (HECs) and for use in margin of exposure (MOE) calculations. Compared to the methods previously used by OPP, the dosimetry equations in the RfC guidance more appropriately ad dress different properties of gases and particles, different properties of reactive and non

- reactive compounds, and explicitly consider some differences in the structure of the respiratory tract between laboratory animals and humans. As performed by HED f or other inhalation studies, OPP has used the dosimetry equations from the RfC guidance to develop HECs to estimate acute, short

- , and intermediate

- term inhalation risk to thiacloprid.

In the risk assessment, endpoint selection for inhalation exposure w as based on the effects occurring at the lowest HEC derived from animal data using the RfC methodology. When conducting inhalation risk assessments, the magnitude of the UFs applied is dependent on the methodology used to calculate risk. For studies i n this risk assessment with inhalation animal data, UFs are based on the RfC methodology developed by the Office of Research and Development (ORD) for the derivation of inh alation reference concentration s (RfCs) and human equivalent concentrations (HECs) f or use in MOE calculations. Since the RfC methodology takes into consideration the pharmacokinetic (PK) differences but not pharmacodynamic (PD)

differences , the UF for interspecies extrapolation may be reduced to 3X (to account for the PD differences) wh ile the UF for intraspecies variation is retained at 10X 7 . Thus, the UF when using the RfC methodology is customarily 30X.

For t hiacloprid, HED believes exposures can be short

- (1

- 30 days) or intermediate

- (1 to 6 months) term in duration. Long

- term exp osures are not anticipated based on proposed labeled

uses. Acute and long term exposures are not expected

.

For the short

- and intermediate

- term scenarios, inhalation data from the 5 day inhalation rodent study was the most sensitive study for determining HECs. In the RfC methodology, different HECs may be calculated for the same experimental NOAEL due to:

1. Different algorithms are used to derive HECs for systemic versus port

- of

- entry effects. Typically, HECs are calculated separately for systemic versus port

- of

entry effect. For thiacloprid, both port

- of

- entry irritation and systemic toxicity were observed in the studies. However, the systemic HEC calculations were more

conservative and used for risk assessment. Additionally, the systemi c HEC calculations are protective of port

- of entry effects.

2. 

### Ti me adjustments are traditionally needed for non

- occupational (bystander) versus occupational exposure scenarios. Traditionally, HECs for non

occupational exposure are based on the number of hours an individual may be at home. Therefore, the most conserva tive estimate of hours spent at home would be 24 hours/day and 7 days/week. In comparison, the average work week for an

7 A 3X UF for interspecies extrapolation is retained to account for the PD differences between a nimals and humans which are not accounted for in the RfC methodology.Thiacloprid Human Health Risk Assessment DP No. D376178

Page 46 of 53 occupational worker is 8 hours/day and 5 days/week. The HEC array table reflects the time adjustment in the calculations (Tables 1 and 2).

Available Inhalation Toxicity Studies

4 Hour Inhalation Toxicity Study in Rats, MRID 44927636 In a preliminary 4

- hour nose

- only inhalation study in male and female Wistar rats (number/sex/group not indicated), thiacloprid (97.2% a.i., Batch No. 290 894) was administered as a solid aerosol dust at average concentrations of 80, 481, 1523 and 2535 mg/m 3 . In females only, mortality was noted at 1523 and 2535 mg/m 3 post

- exposure days 1

- 7 (necropsy showed relationship between lethality and lung damage; no mention of microscopic tissue examination). The systemic LOAEL of 481 mg/m 3 was based on tremors, apathy, hypothermia, ungroomed haircoat, decreased bodyweight and piloerection as well as mortality at the next concentration (1533 mg/m 3 ). The sys temic NOAEL is 80 mg/m3. The portal

- of

- entry LOAEL of 481 mg/m 3 was based on bradypnea, dyspnea, labored breathing pattern, rales, nose/snout area with red encrustations, salivation, mydriasis and chromodacryorrhea. The portal

- of

- entry NOAEL is 80 mg/m 3

.

5

- da y (6 hours per day) Inhalation Toxicity Study in Rats, MRID 44927636

In a 5

- day/6 hours per day nose

- only inhalation study in male and female Wistar rats (10/sex/group), Thiacloprid (YRC 2894), 97.2% a.i., was administered as a solid aerosol dust at

averag e target concentrations of 0, 2, 20 or 200 mg/m 3 (achieved analytical doses of 0, 1.97, 19 or 205 mg/m 3 ). After the 5 exposure days, the animals were observed during a 16

- day recovery period. There were no adverse respiratory signs ≤ 20 mg/m 3 . At 200 mg /m 3 , the only noted inhalation changes were upper respiratory tract irritation and a decrease in rectal temperature. All changes were reversible within the 2

- week post

- exposure observation period. The following clinical signs were noted in the 200 mg/m 3 group on treatment days 0

- 5: bradypnea, labored breathing pattern, piloerection, reduced mobility, ungroomed fur, tremors, flaccid appearance, mydriasis and emaciation. In addition, rectal temperatures were decreased on day 0 in both sexes. Body weights and food consumption were decreased on days 4 and/or 7. A dose related

increase in grip strength was observed in the 20 and 200 mg/m 3 rats of both sexes. At an interim sacrifice on day 7, there were increased incidences of gray

- white foci in the lungs of the 20 mg/m 3 females (1/5 vs. 0/5 in controls) and black spleens in the 20 and 200 mg/m 3 females (4/5

each vs. 0/5 controls). No gross lesions were observed at the terminal sacrifice on day 21. The systemic LOAEL is 20 mg/m 3 based on increased grip strength in both sexes. The systemic NOAEL is 2.0 mg/m 3 ). The portal

- of

- entry LOAEL is 200 mg/m 3 and was based on bradypnea, labored breathing pattern, piloerection and decreased rectal temperature. The portal

- of

- entry NOAEL is 20 mg/m. 3

28 day (20 exposures) Inhalation Toxicity Study in Rats, MRID 44927715 In a subacute inhalation toxicity study, thiacloprid (96.8

- 97.2% a.i., Batch No. 290894) as a solid aerosol dust was administered to 10 Wistar rats/sex/concentration by dynam ic nose

- only exposure at target concentrations of 0, 2, 20, or 200/100 mg/m 3 (achieved mean analytical dosages of 0, 2, 18.2, and 143.4 mg/m 3 ) for 6 hours per day, 5 days/week for a total of 28 days (20 exposures). The achieved MMAD was ~ 2.9 μM. The hig h dose animals were exposed to 200 mg/m 3 for study Days 0

- 7, then exposed to 100 mg/m 3 for Days 8

- 28 due to markedThiacloprid Human Health Risk Assessment DP No. D376178

Page 47 of 53 respiratory distress and decreased body weight gain observed at the initial concentration. There

were no treatment

- related effects on mort ality, urinalysis, body weights, and ophthalmoscopic

, neurologic, and macroscopic changes. Rectal temperature was decreased while exposed to 200 mg/m 3 but was normal when the dose was reduced . T he only findings observed at 20 mg/m 3

were a minor increase i n liver enzyme, aminopyrine

- N

- demethylase (N

- DEM) and minimal to slight hepatocyte hypertrophy in the males (5/10). These observations were noted at a greater incidence in the 200/100 mg/m 3 males and females. At 200/100 mg/m 3 , a slight to moderate piloere ction and slight to severe bradypnea were observed throughout treatment in both males and females. Liver enzymatic activity of p

- nitroanisole

- O

- demethylase (O

- DEM) and cytochrome P450 (P450) were increased (p 0.01) in both sexes. Absolute and relative ( to body and brain) liver weights were elevated (p 0.01) in females, while relative (to body) liver weights were elevated ( p 0.01) in males. Minimal single cell necrosis and fat deposition in the liver were observed in the controls and treated animals; a minor increase in the incidence of these findings was observed in the liver of both sexes at 200/100 mg/m 3 (3

- 5/10 treated vs. 1

- 3/10 controls). Findings in the thyroid at 200/100 mg/m 3 included slight hypertrophy of the thyroidal epithelium in males (2 /10 treated vs. 0/10 controls), and statistically insignificant increases in absolute and relative thyroid weights in males and females (incr. 28

- 40%) and in triiodothyronine (T3) and thyroxine (T4) in the females (incr. 12

- 26%). The systemic LOAEL

is 20 0 mg/m 3 based on liver (hypertrophy , increased liver enzymes, and necrosis) and thyroid effect (increased weights, minor increases thyroid hormones, and hypertrophy)

. The systemic NOAEL is 2 0 mg/m 3. The portal

- of

- entry LOAEL is 200 mg/m 3 based on

resp iratory distress (bradypnea, piloerection, and decreased rectal temperature . The NOAEL is 100 mg/m 3 . Histological evaluation of the respiratory tract (i.e. larynx, nose and nasal passage) did not reveal any treatment related change. Serial sections were not performed on the nose/nasal regions.

Methodologies for Human

- Equivalent Concentration (HEC) Calculations. The RfC methodology applies a dosimetric adjustment that takes into consideration not only the differences in ventilation rate (MV) but also the physicochemical properties of the inhaled compound, the type of toxicity observed ( e.g. systemic vs. port of entry) and the pharmacokinetic (PK) but not pharmacodynamic (PD) differences between animals and humans. Based on the EPA’s RfC guidance (1994), the methodology for RfCs derivation is an estimate of the quantitative dose

- response assessment of chronic non

- cancer toxicity for individual inhaled

chemicals and includ es dosimetric adjustment to account for the species

- specific relationships of exposure concentration to deposited/delivered dose. This adjustment is influenced by the physicochemical properties of the inhaled compound as well as the type of toxicity observ ed ( e.g. systemic vs. port of entry), and takes into consideration the PK differences between animals

and humans. Though the RfC methodology was developed to estimate toxicity of inhaled chemicals over a lifetime, it can be used for other inhalation expos ures ( e.g. acute and short

- term exposures) since the dosimetric adjustment incorporates mechanistic determinants of disposition that can be applied to shorter duration of exposures provided the assumptions underlying the methodology are still valid. These assumptions, in turn, vary depending on the type of toxicity observed. Thus the derivation of a HEC for inhaled gases is described by the following equation:Thiacloprid Human Health Risk Assessment DP No. D376178

Page 48 of 53 Where:

POD study : Point of departure identified in the critical toxicology study

D animal exposu re : Duration of daily animal exposure (hrs/day)

D anticipated exposure : Anticipated daily human duration of exposure (hrs/day)

W animal exposure : Duration of weekly animal exposure (days/week)

W anticipated exposure : Anticipated weekly human duration of expos ure (days/week) RGDR: Regional Gas Dose Ratio

Calculations used to estimate the inhalation risk to humans from aerosols are dependent not on the RGDR as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies using aerosols charact erize particulate exposure by defining the particulate diameter (mass median aerodynamic diameter [MMAD]) and the geometric standard deviation (σ g ), which is then used to determine the RDDR. The RDDR is a multiplicative factor used to adjust an

observed i nhalation particulate exposure concentration of an animal (A) to the predicted inhalation particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the rth region or target tissue.

RDDR
r = (RDD

r

/Normalizing Factor) A (RDD

r /Normalizing Factor) H

As with calculations for gases, the regions and potential target tissues are the three respiratory regions ( extrathoracic (ET), tracheobronchial (TB), and pulmonary (PU ). The RDDR is easily

calcul ated by using a software program designed specifically for computing the RDDR from the

MMAD and σ g defined from an aerosol inhalation study. The values for the species

- specific parameters used to calculate the RDDR are provided in the EPA document “Method s for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry.”

RDDRs for Thiacloprid

Because the respired material used in the thiacloprid inhalation studies is an aerosol, the RD DR ratio, which incorporates MMAD and σ, is appropriate to use for HEC calculation (see below)

. The “RDDR.exe” software program was used to obtain the following RDDR values:

4 hour inhalation study : Systemic RDDR= 3.26, Pulmonary (PU) RDDR = 0.56. The inputs for the program are : MMAD =3.0; σ = 1.7; default BW for Wistar Rats =187g; S tandard human BW information (i.e., 70 kg ).

5 day inhalation study : Systemic RDDR= 3.11, Pulmonary (PU) RDDR = 0.52. The inputs for the program are : MMAD =3.30; σ =1.80; default BW for Wistar Rats =187g; S tandard h uman BW information (i.e., 70 kg ).Thiacloprid Human Health Risk Assessment DP No. D376178

Page 49 of 53 28 day (20 exposures) inhalation study : Systemic RDDR= 3.2, Pulmonary (PU) RDDR = 0.56. The inputs for the program are : MMAD =2.9; σ =1.84; default BW for Wistar Rats =187g;

S tandard human BW information (i.e., 70 kg ).

Appendix B/Table 1 : HEC Array for Occupational Risk Assessment §

Relevant Study LOAEL (mg/ L ) NOAEL

(mg/ L ) Da Dh Wa Wh RDDR HEC (mg/ L ) inter intra Total

UF

A cute Exposure

Inhalation

– Rat (MRID44927636)

1

- Day (4 hour) Systemic 0. 48 0.0 8 4 8 1 1 3.26 0.130 3 10 30X

PU 0. 48 0.0 8 4 8 1 1 0.56 0.022 3 10 30X

Short

- & Intermediate

- Term Exposure

Inhalation

– Rat (MRID44927636) 5

- day Systemic 0.0 2 0.00 2 6 8 5 5 3.11 0.005 3 10 30X

PU 0. 20 0.0 2 6 8 5 5 0.52 0.008 3 10 30X

Inhalation

– Rat (MRID 44927715)

21/ 28

- day Systemic 0.20 0.0 2 6 8 5 5 3.18 0.048 3 10 30X

PU 0.20 0.10 6 8 5 5 0.56 0.042 3 10 30X

Long Term Exposure: Not appropriate for thiacloprid

Appendix B/Table 2 : HEC Array for Non

- Occupational Risk Assessment §

Relevant Study LOAEL (mg/ L ) NOAEL

(mg/ L ) Da Dh Wa Wh RDDR HEC (mg/ L ) inter intra UF

Acute Exposure

Inhalation

– Rat (MRID 44927636)

1

- Day (4 hour) Systemic 0. 48 0.0 8 4 24 1 1 3.26 0.044 3 10 30X

PU 0. 48 0.0 8 4 24 1 1 0.56 0.008 3 10 30X

Short

- & Intermediate

- Term Exposure

Inhalation

– Rat (MRID 44927636) 5

- day , 6

- hours/day Systemic 0.0 2 0.00 2 6 24 5 7 3.11 0.001 3 10 30X

PU 0. 20 0.0 2 6 24 5 7 0.52 0.002 3 10 30X

Inhalation

– Rat ( MRID 44927715)

21/ 28

- day Systemic 0.20 0.02 6 24 5 7 3.18 0.011 3 10 30X

PU 0.20 0.10 6 24 5 7 0.56 0.010 3 10 30X

L ong Term Exposure: Not appropriate for thiaclopridThiacloprid Human Health Risk Assessment DP No. D376178

Page 50 of 53 Key for Array Tables

LOAEL : Lowest observed adverse effect level

Da : Daily animal exposure (hrs/day)

Wa : Weekly animal exposure (days/week)

RRDR : Regional Deposited Dose Ratio

inter : interspecies extrapolation uncertainty factor Dh : Anticipated daily human exposure (hrs/day)

Wh : Anticipated weekly human exposure (days/week)

HC: Human Concentration

HEC : Human Equivalent Concentration

intra : intraspecies variation uncertainty factor

UF : Other uncerta inty factor(s)

PU: P ulmonary

§ Bolded studies used for endpoint selection.

Calculation of the Human Equivalent Concentrations (HEC) and Human Equivalent Doses

Human Equivalent Concentrations (HECs) Human Equivalent Concentrations (HEC) = rat NOAEL*(daily duration adjustment)*weekly daily duration adjustment *RDDR

Occupationa l HECs Systemic HEC

- 4 hour inhalation study: = 0.08 mg/L * (4hr/8hr)*(1)*3.26 = 0.130 mg/L Pulmonary HEC

- 4 hour inhalation study: = 0.08 mg/L * (4hr/8hr)*(1)*0.56 = 0. 0 22 mg/L Systemic HEC

- 5 day inhalation study: = 0.002 mg/L * (6hr/8hr)*(1)*3.11= 0.005 mg/L Pulmonary HEC 5 day inhalation study: = 0.02 mg/L * (6hr/8hr)*(1)*0.52= 0.008 mg/L Systemic HEC

- 28 day (20 exposures) inhalation study: = 0.02 mg/L * (6hr/8hr)*(1)*3.18= 0.048 mg/L Pulmonary HEC

- 28 day (20 exposures) inhalation study: = 0.100 mg/L * (6hr/8hr)*(1)*0.56=

0.042 mg/L

Non

- Occupational HECs (calculated but not used for the current risk assessment) Systemic HEC

- 4 hour inhalation study: = 0.08 mg/L * (4hr/24hr)*(1)*3.26= 0.044 mg/L Pulmonary HEC

- 4 hour inhalation study: = 0.08 mg/L * (4hr/24hr)*(1)*0.56= 0.008 mg/L Systemic HEC

- 5 day inhalation study: = 0.002 mg/L * (6hr/24hr)*(0.71)*3.11= 0.001 mg/L Pulmonary HEC 5 day inhalation study: = 0.02 mg/L (6hr/24hr)*(0.71)*0.52= 0.002 mg/L Systemic HEC

- 28 day (20 exposures) inhalation study: = 0.02 mg/L * (6hr/24hr)*(0.71)*3.18=

0.011 mg/L Pulmonary HEC

- 28 day (20 exposures) inhalation study: = 0. 100 mg/L * (6hr/24hr)*(0.71)*0.56=

0.010 mg/L

Human Equivalent Doses Using the HECs calculated a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) for use in risk assessment was conducted as follows: HED = HEC value (mg/L)* absorption* human specific conversion factor ( L/hr/kg) *daily duration (hours)*Activity Factor

Where:

A absorption: ratio of deposition and absorption in respiratory tract compared to absorption by the oral route ; 100% assumed

CF Conversion Factor: A L/hr/kg factor which accounts for respiratory volume and body weight for a given species and strain (Table 1 of guidance document).

D Duration: Duration of daily animal or human exposure (hours).

AF Activity Factor: Animal default is 1.

Occupational HEDsThiacloprid Human Health Risk Assessment DP No. D376178

Page 51 of 53 Systemic HED

- 4 hour inhalation study: = 0.130 mg/L *(1)*(6)*(8hrs)*(1) = 6.24 mg/kg Pulmonary HED

- 4 hour inhalation study: = 0.022 mg/L *(1)*(6)*(8hrs)*(1) = 1.06 mg/kg Systemic HED

- 5 day inhalation study: = 0.005 mg/L *(1)*(6)*(8hrs)*(1) = 0.24 mg/kg Pulmonary HED 5 day inhalation study: = 0.008 mg/L *(1)* (6)*(8hrs)*(1) = 0.38 mg/kg Systemic HED

- 28 day (20 exposures) inhalation study: = 0.0 48 mg/L *(1)*(6)*(8hrs)*(1) = 2.3 mg/kg Pulmonary HED

- 28 day (20 exposures) inhalation study: = 0.042 mg/L *(1)*(6)*(8hrs)*(1) = 2.02 mg/kg

Non

- Occupational HEDs (calculated but not used for the current assessment) Systemic HED

- 4 hour inhalation study : = 0.044 mg/L *(1)*(6)*(24hrs)*(1) = 6.34 mg/kg Pulmonary HED

- 4 hour inhalation study: = 0.008 mg/L *(1)*(6)*(24hrs)*(1) = 1.15 mg/kg Systemic HED

- 5 day inhalation study: = 0.001 mg/L *(1)*(6)*(24hrs)*(1) = 0.144 mg/kg Pulmonary HED 5 day inhalation study: = 0.002 mg/L *(1)*(6)*(24hrs)*(1) = 0.288 mg/kg Systemic HED

- 28 day (20 exposures) inhalation study: = 0. 011 mg/L *(1)*(6)*(24hrs)*(1) = 1.6 mg/kg Pulmonary HED

- 28 day (20 exposures) inhalation study: = 0. 0 10 mg/L *(1)*(6)*(24hrs)*(1) = 1.44 mg/kgThiacloprid Human Health Risk Assessment DP No. D376178

Page 52 of 53 Appendix C . Physical/Chemical Properties

Physicochemical Properties of the Technical Grade Thiacloprid

Parameter Value Melting point/range 136° C pH 7.40 at 20° C Density 1.46 g/mL at 20° C
Water solubility ( g/L @ 20  ̊ C) 0. 185
Solvent solubility (g/L) n

- Heptane: < 0.1 Xylene: 0.30

1

- Octanol:1.4

2

- Propanol: 3.0 Ethyl acetate: 9.4 Polyethylene glycol (PEG): 42

Acetonitrile: 52

Acetone: 64 Dimethylsulfoxide (DMSO): 150

Dichloromethane: 160 Vapor pressure at 20 & 25° C 2

. 3x10(

- 9 ) Pa at 20° C [1.75x10(

- 11) mmHg ] 8x10(

- 10) Pa at 25° C [6.0x10(

- 12) mmHg ] Dissociation constant (pK

a ) AI has no basic or acidic properties in aqueous solutions Octanol/water partition coefficient Log(K OW )

K OW 1.26 at 20° C

18 UV/visible absorption spectrum λ max Extinction coefficient

295

- 300 nm 49.1828

301

- 305 nm 39.3463Thiacloprid Human Health Risk Assessment DP No. D376178

Page 53 of 53 Appendix D . Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from PHED 1.1; the AHETF database; and the A RTF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the

Human Studies Review Boar d. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 8

.

8 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html