UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 13 August 2009

MEMORANDUM

SUBJECT:	Clothianidin: Human Health Risk Assessment for Proposed Uses on Berries (Group 13-07H), Brassica Vegetables (Group 5), Cotton, Cucurbit Vegetables (Group 9), Fig, Fruiting Vegetables (Group 8), Leafy Green Vegetables (Group 4A), Peach, Pomegranate, Soybean, Tree Nuts (Group 14), and Tuberous and Corm Vegetables (Group 1C).

PC Code:  044309	DP Barcodes:  D355373, D362354

MRID Nos.:  See Below	Registration Nos.:  59639-150, 59639-151, 59639-152

Petition Nos.:  8F7395, 8E7460, 9F7530	Regulatory Action:  Section 3

Assessment Type:  Single Chemical Aggregate	Registration Case No.:  None

TXR No.:  None	CAS No.:  210880-92-5

40 CFR 180.586	Decision Nos.:  397135, 405608

FROM:	Michael A. Doherty, Ph.D., Chemist

		Alan Levy, Ph.D., Toxicologist

		Shih-Chi Wang, Ph.D., Biologist

		Risk Assessment Branch II

		Health Effects Division (7509P)

THROUGH:	Dennis McNeilly, Chemist

		Suku Oonnithan, Biologist

		Linnea Hansen, Ph.D., Toxicologist

		Richard A. Loranger, Ph.D., Senior Scientist

		Christina Swartz, Branch Chief

Risk Assessment Branch II

Health Effects Division (7509P)

TO:		Kable Davis/Venus Eagle (Team 01)

		Insecticide/Rodenticide Branch

		Registration Division (7505P)

		Barbara Madden

		Risk Integration, Minor Use & Emergency Response Branch

		Registration Division (7505P)

MRID No.	Study Type

47471601	860.1500 Almond

47471602	860.1500 Peppers

47471603	860.1500 Cabbage

47471604	860.1500 Cantaloupe

47471605	860.1500 Cauliflower

47471606	860.1500 Celery

47471607	860.1500/1520 Cotton

47471608	860.1500 Cucumber

47471609	860.1500 Head Lettuce

47471610	860.1500 Leaf Lettuce

47471611	860.1500 Mustard Greens

47471612	860.1500 Pecans

47471613	860.1500/1520 Soybean

47471614	860.1500 Spinach

47471615	860.1500 Summer Squash

47471616	860.1500/1520 Tomato

47578101	860.1500 Peach

47578102	860.1500 Peach

47578103	860.1500 Cranberry

47666901	860.1500 Fig

47666902	860.1500 Pomegranate

46339001	870.5300

46339002	870.5300

46339003	870.5395

46339004	Non-guideline (Unscheduled DNA Synthesis)

47506501	Non-guideline (Rat Developmental Immunotoxicity)

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc236111513 \h  5

2.0	Ingredient Profile	  PAGEREF _Toc236111514 \h  7

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc236111515 \h  7

2.2	Structure and Nomenclature	  PAGEREF _Toc236111516 \h  10

2.3	Physical and Chemical Properties	  PAGEREF _Toc236111517 \h  11

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc236111518 \h  11

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc236111519 \h  11

3.1.1	Database Summary	  PAGEREF _Toc236111520 \h  11

<IP_ADDRESS>	Studies available and considered (animal, human, general literature)	  PAGEREF _Toc236111521 \h  11

<IP_ADDRESS>	Mode of action, metabolism, toxicokinetic data	  PAGEREF _Toc236111522 \h  11

<IP_ADDRESS>	Sufficiency of studies/data	  PAGEREF _Toc236111523 \h  12

3.1.2	Toxicological Effects	  PAGEREF _Toc236111524 \h  12

3.1.3	Dose-response	  PAGEREF _Toc236111525 \h  15

3.1.4	FQPA	  PAGEREF _Toc236111526 \h  15

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF _Toc236111527 \h  15

3.3	FQPA Considerations	  PAGEREF _Toc236111528 \h  16

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc236111529 \h  16

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc236111530 \h  16

3.3.3	Developmental Toxicity Studies	  PAGEREF _Toc236111531 \h  16

3.3.4	Reproductive Toxicity Study	  PAGEREF _Toc236111532 \h  17

3.3.5	Additional Information from Literature Sources	  PAGEREF _Toc236111533 \h  17

3.3.6	Pre-and/or Postnatal Toxicity	  PAGEREF _Toc236111534 \h  17

<IP_ADDRESS>	Determination of Susceptibility	  PAGEREF _Toc236111535 \h  17

<IP_ADDRESS>	Degree of Concern Analysis and Residual Uncertainties for Pre- and/or Postnatal Susceptibility	  PAGEREF _Toc236111536 \h  17

3.3.7	Recommendation for a Developmental Neurotoxicity Study	  PAGEREF _Toc236111537 \h  18

3.3.8	Rationale for the UFDB	  PAGEREF _Toc236111538 \h  18

3.4	Safety Factor for Infants and Children	  PAGEREF _Toc236111539 \h  18

3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF _Toc236111540 \h  19

3.5.1	Acute Reference Dose (aRfD) - Females age 13-49	  PAGEREF _Toc236111541 \h  19

3.5.2	Acute Reference Dose (aRfD) - General Population	  PAGEREF _Toc236111542 \h  19

3.5.3	Chronic Reference Dose (cRfD)	  PAGEREF _Toc236111543 \h  20

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)	  PAGEREF _Toc236111544 \h  20

3.5.5	Dermal Absorption	  PAGEREF _Toc236111545 \h  21

3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)	  PAGEREF _Toc236111546 \h  21

3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)	  PAGEREF _Toc236111547 \h  22

3.5.8	Level of Concern for Margin of Exposure	  PAGEREF _Toc236111548 \h  22

3.5.9	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF _Toc236111549 \h  22

3.5.10	Classification of Carcinogenic Potential	  PAGEREF _Toc236111550 \h  22

3.5.11	Summary of Toxicological Doses and Endpoints for Use in Human Risk Assessments	  PAGEREF _Toc236111551 \h  23

3.6	Endocrine disruption	  PAGEREF _Toc236111552 \h  24

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF _Toc236111553 \h  25

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc236111554 \h  25

5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF _Toc236111555 \h  25

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc236111556 \h  25

5.1.2	Metabolism in Rotational Crops	  PAGEREF _Toc236111557 \h  26

5.1.3	Metabolism in Livestock	  PAGEREF _Toc236111558 \h  26

5.1.3	Metabolism in Livestock	  PAGEREF _Toc236111559 \h  26

5.1.4	Environmental Degradation	  PAGEREF _Toc236111560 \h  26

5.1.5	Comparative Metabolic Profile	  PAGEREF _Toc236111561 \h  26

5.1.6	Toxicity Profile of Major Metabolites and Degradates	  PAGEREF _Toc236111562 \h  27

5.1.7	Pesticide Metabolites and Degradates of Concern	  PAGEREF _Toc236111563 \h  27

5.1.8	Analytical Methodology	  PAGEREF _Toc236111564 \h  28

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc236111565 \h  28

5.1.10	Food Residue Profile	  PAGEREF _Toc236111566 \h  29

5.1.11	International Residue Limits	  PAGEREF _Toc236111567 \h  31

5.2	Dietary Exposure and Risk	  PAGEREF _Toc236111568 \h  33

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	  PAGEREF _Toc236111569 \h  34

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF _Toc236111570 \h  35

7.1	Acute Aggregate Risk	  PAGEREF _Toc236111571 \h  35

7.2	Short- and Intermediate-Term Aggregate Risk	  PAGEREF _Toc236111572 \h  35

7.3	Long-Term Aggregate Risk	  PAGEREF _Toc236111573 \h  35

7.4	Cancer Risk	  PAGEREF _Toc236111574 \h  35

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc236111575 \h  35

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc236111576 \h  36

9.1	Short- and Intermediate-Term Handler Risk	  PAGEREF _Toc236111577 \h  36

9.2	Short- and Intermediate-Term Post-Application Risk	  PAGEREF _Toc236111578 \h  40

10.0	Data Needs and Label Recommendations	  PAGEREF _Toc236111579 \h  41

10.1	Toxicology	  PAGEREF _Toc236111580 \h  41

10.2	Residue Chemistry	  PAGEREF _Toc236111581 \h  41

10.3	Occupational and Residential Exposure	  PAGEREF _Toc236111582 \h  42

References:	  PAGEREF _Toc236111583 \h  44

Appendix A:	Toxicology Assessment	  PAGEREF _Toc236111584 \h  45

A1.	Toxicology Data Requirements	  PAGEREF _Toc236111585 \h  45

A2.	Toxicity Profiles	  PAGEREF _Toc236111586 \h  46

A3.	Toxicology Executive Summaries	  PAGEREF _Toc236111587 \h  55

 1.0	Executive Summary  TC \l1 "1.0	Executive Summary

Clothianidin, (E)-N-[(2-Chloro-5-thiazolyl)methyl]-N’-methyl-N”-nitroguanidine, is a broad spectrum, systemic neonicotinoid insecticide (Group 4A insecticide) and is identical to the major metabolite (CGA-322704) of the active ingredient thiamethoxam.  Permanent tolerances are established for residues of clothianidin in/on various plant and livestock commodities [40 CFR §180.586].  Valent has submitted petitions (PP#s 8F7395 and 9F7530) proposing new uses for clothianidin formulated as a 50% water-dispersible granule (WDG; Arena® 50 WDG, EPA Reg. No. 59639-152) and a 2.13 lb/gal flowable concentrate (FlC; V-1070 2.13 SC, EPA Reg. No 59639-150) for the control of various insects on the following crops/crop groups:  Brassica leafy vegetables, cotton, cucurbit vegetables, figs, fruiting vegetables, leafy vegetables, pomegranates, soybeans and tree nuts.  In addition, Interregional Research Project No. 4 (IR-4) has submitted a separate petition (PP#8E7460) proposing new uses for Valent’s 50% WDG and 2.13 lb/gal FlC formulations on peaches and members of the low-growing berry (except strawberry) Subgroup 13-07H.  HED has sufficient information to complete a human health risk assessment for these requested uses.

The toxicological database for clothianidin is complete.  The available data indicate that there are no consistent specific target organs in mammals.  The majority of studies show decreases in body weights and body weight gains.  More severe developmental (missing lobe of the lung in the rabbit) and neurological effects in rats and mice are attributable to exposure to clothianidin; these effects serve as the basis for acute risk assessments.  Effects on body weight gain, delayed sexual maturation, decreased thymus weights, and an increase in stillbirths are the basis for assessing short-, intermediate-, and/or long-term (chronic) exposures.  Based on the completeness of the database, the observed effects, and the endpoints used for risk assessment, the FQPA Safety Factor has been reduced to 1X, leaving the 100X safety factor to account for within-species (10X) and across-species (10X) variability.  Clothianidin has been classified as not likely to be carcinogenic to humans.

The submitted residue chemistry data are relatively complete; nevertheless, more data are needed in order to recommend for the full suite of requested uses.  In spite of the lack of certain data, HED is recommending for the establishment of permanent tolerances for all of the requested crops; however, label revisions are needed prior to registration and HED is requesting residue data comparing soil and foliar applications as a condition of registration.  Bridging studies examining the effects of adjuvants and different formulations are also being requested.  Suitable analytical methods are available to enforce tolerances for residues of clothianidin.

No chemical-specific data for assessing human exposures during pesticide handling or post-application activities were submitted to the Agency in support of the requested registrations of clothianidin.  HED used surrogate data from the Pesticide Handler’s Exposure Database (PHED), in combination with HED-standard assumptions to assess exposures for crop protection uses.

The available data are adequate for assessment of exposure to clothianidin, and HED has evaluated dietary, non-dietary (i.e., residential/recreational), and occupational risks associated with the registered and requested uses of thiamethoxam.  For the dietary pathway, thiamethoxam has been included as a source of exposure to clothianidin.  All of the dietary, non-dietary, and occupational exposure estimates are based on conservative, health-protective assumptions.  The exposure estimates, especially when combined to take into account aggregate (dietary + non-dietary) exposure, may over-estimate actual exposures that are likely to occur.  Despite this, all risk estimates for clothianidin, including aggregate risk estimates, for all population groups are below HED’s level of concern.  There are no human health risk issues that preclude establishing tolerances and granting the requested registrations for clothianidin for which sufficient data have been submitted (see below).

Summary of Requested Uses Supported by Available Data for Clothianidin

Requested Use	Supported by Available Data

	Application	Formulation	Tank Mix

Adjuvant

	Foliar	Soil	WDG	FlC

	Berries (Group 13-07H)	Yes	No	Yes	No	No

Brassica Vegetables (Group 5)	Yes	No	Yes	No	No

Cotton	Yes	No	Yes	No	No

Cucurbit Vegetables (Group 9)	Yes	No	Yes	No	No

Fruiting Vegetables (Group 8)	Yes	No	Yes	No	No

Leafy Green Vegetables (Group 4A)	Yes	No	Yes	No	No

Peach	Yes	No	Yes	No	No

Soybean	Yes	No	Yes	No	Yes

Tree Nuts (Group 14)	Yes	No	Yes	No	Yes (except almond)

Tuberous and Corm Vegetables (Group 1C)	Yes	No	Yes	No	No

Fig	Yes	No	No	Yes	Yes

Pomegranate	Yes	No	No	Yes	Yes

Soybean	Seed Treatment	Yes	Yes	Not Applicable

Potato Seed Pieces	Seed Treatment	Yes	Yes	Not Applicable

Human Studies.  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 studies, which comprise the Pesticide Handlers Exposure Database (PHED) & Agricultural Re-Entry Task Force (ARTF), have been determined to require a review of their ethical conduct, and have received that review. The studies in PHED and ARTF were considered appropriate (or ethically conducted) for use in risk assessments.

Environmental Justice Considerations.  Potential areas of environmental justice concerns, to the extent possible, were considered in this 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," (http://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 subgroups 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 Continuing Survey of Food Intake by Individuals (CSFII) 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 dietary 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 applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication 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.

Provided the label revisions and revised Section F detailed in Section 10.2 are submitted, HED recommends for the requested soybean and potato seed treatments, for foliar uses as detailed in the preceding table, and for the tolerances detailed in Table 10.

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile

Clothianidin is a broad spectrum, systemic insecticide belonging to both the chloronicotinyl (neonicotinoid) and nitroguanidine classes of chemicals.  It is also a major metabolite of thiamethoxam.  Clothianidin acts by binding with the nicotinic acetylcholine receptor sites in insects (Group 4A insecticide), interfering with neural transmission of stimuli and eventually inhibiting reproduction of the insect.  Clothianidin Technical Insecticide was first registered in the U.S. during 2003 by Takeda, with Bayer CropScience (Bayer) acting as their Agent.  Bayer currently has six end-use products containing clothianidin that are registered only for seed treatment uses on corn, canola, cotton, rapeseed, and sorghum.  Clothianidin end-use products with direct foliar and/or soil uses on grapes, pome fruits, potatoes and tobacco were originally registered to Arvesta (now known as Arysta).  However, these products/uses have been transferred to Valent, which is now the Agent for Sumitomo Chemical Co. which owns the current registration for Technical Clothianidin.  The chemical structure and nomenclature of clothianidin and its metabolite, TMG, are listed in Table 2.2, and the physicochemical properties of technical grade clothianidin are listed in Table 2.3.

2.1	Summary of Registered/Proposed Uses  TC \l2 "2.1	Summary of Registered/Proposed Uses

Permanent tolerances are established for residues of clothianidin in/on a variety of plant commodities at levels ranging from 0.01 ppm in/on a number of crops to 1.0 ppm in/on pome fruits [40 CFR §180.586(a)].  Tolerances for clothianidin have also been established in milk at 0.01 ppm.  Time-limited tolerances have been established at 0.02 ppm in/on sugar beet roots and tops [40 CFR §180.586(b)]; these tolerances are set to expire on 12/31/09.  In addition, tolerances for indirect or inadvertent residues have been established for clothianidin at 0.02 ppm in/on non-grass animal feeds, the forage, fodder and straw of cereal grains, grass forage, fodder and hay, and soybean forage and hay [40 CFR §180.586(d)].

Valent has submitted petitions (PP#s 8F7395 and 9F7530) proposing new uses for its 50% WDG and 2.13 lb/gal FlC formulations on Brassica leafy vegetables, cotton, cucurbit vegetables, figs, fruiting vegetables, leafy vegetables, pomegranates, soybeans and tree nuts.  Valent is also proposing to amend the use directions for its 5 lb/gal FlC formulation to include a seed treatment use on potato seed pieces and soybean seeds.  In addition, IR-4 has submitted a separate petition (PP#8E7460) proposing new uses for Valent’s 50% WDG and 2.13 lb/gal FlC formulations on peaches and members of the low-growing berries subgroup, except strawberry (Subgroup 13-07H).  IR-4 is also proposing that the current use directions for potatoes on the labels for the 50% WDG and 2.13 lb/gal FlC be amended to cover all tuberous and corm vegetables (Subgroup 1C).  The use patterns associated with the requested uses are summarized in Table 2.1.

Table 2.1.	Summary of Proposed Directions for Use of Clothianidin.

Applic. Timing, Type, and Equip.1	Formulation

[EPA Reg. No.]	Applic. Rate

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations 2

Brassica Vegetables, Leafy Vegetables, Cucurbit Vegetables, and Fruiting Vegetables

Soil application at planting or post-planting 3; ground equipment	50% WDG [59639-152] 2.13 lb/gal FlC

[59639-150]	0.2	1	0.2	7	The minimum RTI for foliar applications is 10 days.

A minimum application volume is not specified.

Broadcast foliar applications as pest populations begin to build; ground equipment

0.05-0.067	NS	0.2	7

	Cotton

Broadcast foliar applications as pest populations reach threshold levels; ground equipment 	50% WDG [59639-152] 2.13 lbs/gal FlC

[59639-150]	0.05-0.067	NS	0.2	21	The minimum RTI is 7 days.

A minimum application volume is not specified.

Low Growing Berries, except Strawberry (Subgroup 13-07H)

Single post-bloom soil application as pest populations reach threshold levels; ground equipment	50% WDG [59639-152] 2.13 lbs/gal FlC

[59639-150]	0.2	1	0.2	21	The minimum RTI is 7 days for foliar applications.

A minimum application volume is not specified.

Post-bloom broadcast foliar applications as pest populations reach threshold levels; ground equipment

0.066	NS

21

	Fig

Post-bloom broadcast foliar applications as pest populations reach threshold levels; ground equipment 	50% WDG [59639-152] 2.13 lbs/gal FlC

[59639-150]	0.06-0.09	2	0.2	7	The minimum RTI is 14 days.

Apply in a minimum of 100 gal/A.

Do not allow livestock to graze on cover crops from treated orchards.

Pomegranate

Post-bloom broadcast foliar applications as pest populations reach threshold levels; ground equipment 	50% WDG [59639-152] 2.13 lbs/gal FlC

[59639-150]	0.06-0.09	2	0.2	7	The minimum RTI is 14 days.

Apply in a minimum of 100 gal/A.

Do not allow livestock to graze on cover crops from treated orchards.

Peach

Post-bloom broadcast foliar applications as pest populations reach threshold levels; ground equipment 	50% WDG [59639-152] 2.13 lbs/gal FlC

[59639-150]	0.05-0.1	NS	0.2	7	The minimum RTI is 10 days.

A minimum application volume is not specified.

Do not allow livestock to graze on cover crops from treated orchards.

Potato/ Tuber and Corm Vegetables, Subgroup 1C 4

Seed-piece treatment; spray	5 lb/gal FlC

[59639-151]

2.13 lb/gal FlC

[59639-150]	0.01 lb ai/ 100 lb seed pieces

(0.2 lb ai/A) 5	1	0.2	NA	Do not use treated seed pieces for food, feed, or fodder.

Do not apply any subsequent application of clothianidin following seed piece treatment.

In-furrow soil application at planting, or side-dress or broadcast soil application at ground-crack during hilling; ground equipment	50% WDG [59639-152] 2.13 lbs/gal FlC

[59639-150]	0.12-0.19	1	0.2	NA	The minimum RTI for foliar applications is 7 days.

A minimum application volume is not specified.

Broadcast foliar applications as pest populations reach threshold levels; ground equipment

0.03-0.05	3	0.2	14

	Soybean

Seed Treatment, commercial seed treatment equipment	5 lb/gal FlC

[59639-151]	0.05 lb ai/

100 lb seed

(0.05 lb ai/A) 6	1	0.05	NA	Do not use treated seed for feed, food or oil processing.

Broadcast foliar applications as pest populations reach threshold levels; ground equipment 	50% WDG [59639-152] 2.13 lb/gal FlC

[59639-150]	0.05-0.067	NS	0.2	21	The minimum RTI for foliar applications is 7 days.

A minimum application volume is not specified.

Do not apply foliar applications following a seed treatment with clothianidin

Tree Nuts

Broadcast foliar or chemigation applications at post bloom; ground equipment 	50% WDG [59639-152] 2.13 lb/gal FlC

[59639-150]	0.05-0.10	NS	0.2	21	The minimum RTI is 10 days.

A minimum application volume is not specified.

Do not allow livestock to graze on cover crops from treated orchards.

1	Do not apply by air.  Applications are allowed through the following types of irrigations systems:  micro (spaghetti tubes), drip, and overhead sprinklers (center pivot, solid set, hand move or moving wheel systems).  Do not apply through any irrigation system connected to the public water system.  Applications may include use of a spray adjuvant.

2	A 12-hour restricted entry interval is specified.  Do not apply to vegetable, fruit or tree nut crops during pre-bloom, bloom or when bees are actively foraging.   For all crops, do not apply a foliar application of clothianidin following a soil application; and do not apply more than 0.2 lb ai/A of clothianidin per season.

3	Soil applications can be made as either a narrow band centered on the plant row, an in-furrow spray at planting on or below the seed, a side-dress application to both sides of the row, a post-seeding drench or transplant water drench, or by chemigation into the root zone through drip, trickle, or micro-sprinkler systems.

4	The uses of the 50% WDG and 2.13 lb/gal FlC formulations on potatoes were previously approved under PP#4F6869 (DP# D303164, W. Drew, 2/1/06).

5	The use rate per acre for the potato seed piece treatment is based on a planting rate of 2,000 lb of seed pieces/acre.

6	The worst-case use rate per acre for the soybean seed treatment assumes a high planting density (200,000 plants/A) and use of larger seeds (2,000 seed/lb), which would require 100 lb of seed/A.  A more typical planting density of 160,000 seed/A using average sized seed (3,000 seed/lb) would result in a use rate of 0.026 lb ai/A.

NA = Not applicable.

NS = not specified.

2.2	Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature

The chemical structure and nomenclature of clothianidin and its TMG metabolite are summarized in Table 2.2.  Physical/chemical properties for clothianidin are summarized in Table 2.3.  Based on the available data, clothianidin has a very low vapor pressure and exposure to this chemical in the vapor phase is not expected.  The octanol/water partitioning coefficient is also quite low, indicating that clothianidin is unlikely to accumulate in fatty tissues.

Table 2.2.	Clothianidin Nomenclature.

Parent Compound

Common name	Clothianidin

Company experimental name	TI-435, V-10066

IUPAC name (E)-1-(2-Chloro-1,3-thiazol-5-ylmethyl)-3-methyl-2-nitroguanidine

CAS name (E)-N-[(2-Chloro-5-thiazolyl)methyl]-N’-methyl-N”-nitroguanidine

CAS registry number	210880-92-5 (formerly 205510-53-8)

Molecular wt.	249.68

End-use product (EP)	50% WDG (Arena® 50 WDG; EPA Reg. No. 59639-152)

2.13 lb/gal FlC (V-10170 2.13 SC; EPA Reg. No. 59639-150)

5 lb/gal FlC (V-10170 5 FS; EPA Reg. No. 59639-151)

Metabolite

Common name	Thiazolylmethylguanidine

Company experimental name	TMG

IUPAC name	N-(2-chlorothiazol-5-yl)-N´-methylguanidine

CAS Name	N-(2-chlorothiazol-5-yl)-N´-methylguanidine

CAS registry number	635283-91-9

Molecular wt.	204.68

2.3	Physical and Chemical Properties  TC \l2 "2.3	Physical and Chemical Properties

Table 2.3.	Physicochemical Properties of Clothianidin.

Parameter	Value	Reference

Melting point (ºC)	176.8	D335355, W. Drew, 10/16/07

pH at 23ºC	6.24 (1% solution/suspension)

	Density (g/cm3)	1.61 (PAI)*, 1.59 (TGAI)

	Water solubility (g/L at 20ºC)	0.327

	Solvent solubility (g/L at 25ºC)	Acetone	15.2	Dichloromethane	1.32

Ethyl acetate	2.03	Heptane 	<0.00104

Methanol	6.26	Octanol	0.938

Xylene	0.0128

	Vapor pressure (Pa at 20ºC)	1.3 x 10 -10

	Dissociation constant, pKa at 20ºC	11.09

	Octanol/water partition coefficient, Log(KOW) at 25ºC	0.7

	UV/visible absorption spectrum (Maximum, nm)	265.5 (acidic or neutral)

246.0 (basic)

	*PAI = Purified Active Ingredient; TGAI = technical grade active ingredient.

3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard Characterization/Assessment

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and Dose-Response Characterization

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary

The toxicological database for clothianidin is complete.  The scientific quality is relatively high and the toxicity profile of clothianidin can be characterized for most effects, including potential carcinogenic, mutagenic, developmental and reproductive, neurotoxic and immunotoxic effects.  Since the last risk assessment for clothianidin, the Agency has received and reviewed a developmental immunotoxicity study and four mutagenicity studies (see Appendix A3).

<IP_ADDRESS>	Studies available and considered (animal, human, general literature)  TC \l4 "<IP_ADDRESS>	Studies available and considered (animal, human, general literature)

The following studies were submitted: acute and subchronic neurotoxicity; subchronic in rats, mice and dogs; subchronic dermal, chronic/carcinogenicity in rats; carcinogenicity in mice; chronic in dogs; developmental in rats and rabbits; developmental neurotoxicity; reproduction; mutagenicity battery; metabolism (rats and mice); dermal penetration (monkeys) and immunotoxicity as well as developmental immunotoxicity.

<IP_ADDRESS>	Mode of action, metabolism, toxicokinetic data  TC \l4 "<IP_ADDRESS> Mode of action, metabolism, toxicokinetic data

Clothianidin is a major metabolite of the active ingredient thiamethoxam and is a systemic insecticide that belongs to the nitroguanidine sub-class of neonicotinoid compounds, which have agonistic activity on nicotinergic acetylcholine receptors (nAChR).  It enters through the roots and cotyledons of newly germinating seedlings and protects below- and above-ground plant parts from insect damage.

In rats, clothianidin was readily absorbed and excreted within 96 hours following a single or repeated low doses, but at a high dose, absorption became biphasic and was saturated.  The studies suggest that a multiple exposure regimen did not affect the absorption/excretion processes.  There was rapid absorption and distribution of administered radioactivity to all organs and tissues followed by rapid excretion primarily via the urine (>89% of dose) and to a lesser extent, the feces, with reduction to background levels in most tissues and organs within 24 hours.  There was a somewhat greater rate of absorption and elimination in females.  Excretory patterns did not exhibit gender-related variability but reflected the delayed absorption in the high-dose group.  The metabolites identified (primarily oxidative demethylation products and cleavage products of the nitrogen-carbon bond between the nitroimino and thiazolyl moieties) were consistent with Phase I processes of oxidation, reduction and hydrolysis.

In mice, clothianidin was readily absorbed and excreted within 168 hours following a single low dose.  Urine was the major route of excretion.  Neither clothianidin nor its metabolites appeared to exhibit potential for bioaccumulation.  Excretory patterns did not exhibit gender-related variability.  The major metabolites in both urine and feces were the parent compound (clothianidin) and TZNG [N-(2-chlorothiazol-5-ylmethyl)-N’-nitroguanidine], which resulted from N-demethylation of clothianidin.

<IP_ADDRESS>	Sufficiency of studies/data  TC \l4 "<IP_ADDRESS>	Sufficiency of studies/data

Data are sufficient for FQPA evaluation, toxicity endpoint selection and dose-response evaluation.

3.1.2	Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects

Clothianidin and its metabolites have relatively low (Category III or IV) acute toxicity via oral, inhalation and dermal routes of exposure in the rat and there is no evidence of dermal sensitization or eye irritation with the exception of the clothianidin-triazan intermediate, which is a dermal sensitizer.  The other exceptions were for technical clothianidin and the TMG metabolite via the oral route in the rat both of which were toxicity Category II.

Clothianidin induces some effects that are similar to other neonicotinoid insecticides, particularly on the liver, hematopoietic system and kidneys.

Acute neurotoxicity studies were conducted in rats and mice following exposure by gavage.  Comparing these two studies, mice appear to be more sensitive than rats.  In the acute neurotoxicity rat study, FOB effects, including decreased arousal as well as decreased motor and locomotor activity, were seen at the LOAEL on Day 0 in males.  Effects at dose levels above the LOAEL in the rat study included tremors, slightly uncoordinated gait, effects on pupil response and righting reflex, and decreases in both temperature and ataxia.  In the acute neurotoxicity study in mice, effects were also observed on Day 0 in males (no female mice were tested), but they occurred at lower doses than those that produced neurotoxic effects in rats.  Effects seen at the LOAEL in this mouse study included transient signs of decreased spontaneous motor activity, tremors and deep respirations.  At higher dose levels, the following were observed: decreases in reactivity, grooming and muscle tone; prone position; staggering gait; mydriasis; and hypothermia.

In rats only, a subchronic neurotoxicity study was conducted following dietary exposure.  In contrast to the acute neurotoxicity study described previously, no indications of neurotoxicity were noted in the subchronic study.  Slightly decreased food consumption, body weights and body weight gains were the only observed effects.

In subchronic oral studies in rats and dogs, decreases in body weight and body weight gain were observed.  In addition, dogs also displayed decreased white blood cells, albumin and total protein, as well as some anemia, and they appeared to be more sensitive than rats.  Male dogs were more sensitive than females.  No effects were observed up to the limit dose in the 28-day dermal study in rats.

Chronic feeding studies were conducted in the dog, rat and mouse.  Anemia was observed in the dog.  In the rat, decreased body weight and food consumption, interstitial gland hyperplasia in the ovary, increased lymphohistiocytic infiltrate and altered hepatocellular eosinophilic foci of the liver were observed in females; decreased body weight and food consumption, slightly increased incidences of pelvic mineralization, and transitional cell hyperplasia in the kidney, mottled livers, and altered hepatocellular eosinophilic foci in the liver were observed in male rats.  In the mouse, decreases in body weight and body weight gain in females and increases in vocalization in both sexes were the only observed effects.  Anemia, only in females, was observed at the highest dose tested in dogs.

A comparison of the subchronic and chronic feeding studies in rats showed that a wider spectrum of effects was observed in the chronic study, even though the NOAELs and LOAELs in these two studies were similar.  Thus, it appears that there may be more toxicity in rats when exposure is over a longer period of time.  In contrast, administration to the dog for a longer period of time does not appear to result in any additional effects or effects at lower doses.

There was an increase in quantitative susceptibility in the developmental neurotoxicity study.  Effects in the offspring were observed at a lower dose than the dose which caused toxicity in the maternal animals.  However, this increased susceptibility does not require an additional 10X uncertainty factor because endpoints selected for assessment of risks to infants and children are at doses below the offspring NOAEL observed in this study and thus are protective of these effects.  Maternal effects included decreased body weights, body weight gains and food consumption.  Effects seen in the offspring included decreased body weights, body weight gains, motor activity and acoustic startle response in females.

No increased quantitative or qualitative susceptibility was observed in the developmental rat or rabbit studies.  In the rat, no developmental toxicity was observed at the highest dose tested, although this dose induced decreases in body weight gain and food consumption in the dams.  In the rabbit, premature deliveries, decreased gravid uterine weights, an increase in litter incidence of a missing lobe of the lung and a decrease in the litter average for ossified sternal centra per fetus were noted at a dose level at which maternal death, a decrease in food consumption and clinical signs (scant feces and orange urine) were observed.  The developmental effects in this study are not considered to be quantitatively more severe than the maternal effects because they occurred at the same dose and they are not considered to be qualitatively more severe because death occurred in the dams.

Increased quantitative susceptibility was observed in the two-generation reproduction study since the offspring NOAEL was lower than the parental NOAEL.  The LOAEL for offspring toxicity is based on decreased body weight gains, delayed sexual maturation (males), decreased absolute thymus weights in F1 pups of both sexes, and an increase in stillbirths in both generations.  The parental systemic LOAEL is based on decreased absolute body weights and body weight gains with decreased absolute and relative thymus weights in both sexes.

In the rat chronic carcinogenicity study, an apparent increase in thyroid c-cell tumors was observed in females.  A statistical analysis revealed that the increase in these tumors did not appear to be significant, especially when carcinomas and adenomas were combined.  An increased incidence of hepatocellular carcinomas at the low and high doses were just outside historical control incidences for the same testing laboratory (only 2 studies) but were within the historical control range for the animal supplier.  In addition, there was no dose-response.  Also, there was no continuum (i.e., no preneoplastic lesions and no adenomas).  There was no evidence of an increase of tumors in mice.  Therefore, clothianidin is classified as not likely to be carcinogenic to humans.

In the mutagenicity studies, none of the intermediates or metabolites appeared to have genotoxic potential under the conditions of the studies, but the studies for the technical material gave mixed results.  Some of the batches of test material were positive and some were negative.  HED had requested that the composition of the test materials used in the mutagenicity studies be investigated to determine whether or not the differences in composition may have affected the results from the studies.  To address the request, additional mutagenicity studies were performed and it was determined that there was no concern because clothianidin was neither clastogenic nor aneugenic in the mouse bone marrow micronucleus assay up to a toxic oral dose (100 mg/kg); also, there was no induction of unscheduled DNA synthesis (UDS) in the livers of Wistar male mice when administered at the limit dose of 2000 mg/kg.

In some of the toxicity studies, there was evidence of possible effects on the immune system.  Decreased absolute and relative thymus and spleen weights were observed in multiple studies.  In addition, juvenile rats in the two-generation reproduction study appeared to be more susceptible to these effects.  The thymus is involved in the production of T cells, whose function is to recognize and respond to foreign antigens.  The spleen serves an important function in clearing the blood of infectious organisms.  A guideline immunotoxicity study showed no evidence of clothianidin-mediated immunotoxicity in adult rats, in the form of a T-cell dependent anti-Sheep Red Blood Cell (SRBC) forming cell response, at doses lower than those resulting in generalized signs of toxicity (e.g., decreases in body weight).  However, since effect in the offspring occurred at lower doses in the two-generation study, HED concluded that the lack of effects on immunotoxicity in adults did not alleviate concerns for immunotoxicity in the offspring.  A developmental immunotoxicity study was required and demonstrated no susceptibility with respect to immunotoxicity.

In a dermal absorption study in monkeys, absorption was calculated as 0.24% (±0.11%).  This value was determined by adding the radioactivity recovered from urinary excretion, fecal excretion and from cage/pan/chair wash debris.  Adjustment of the direct absorption determination was not necessary because recovery from the dermal dose was >90%.  A value of 1% dermal absorption has been recommended as appropriate for use in risk assessment.  This estimation takes into account any variability that would have likely occurred with testing several dose levels.  The mouse single dose and rat single and multiple dose metabolism studies indicated that oral absorption was in the range of 90% or greater.  Therefore, any extrapolation from the oral to the dermal route using the dermal absorption factor is not likely to underestimate anticipated adverse effects.

3.1.3	Dose-response  TC \l3 "3.1.3	Dose-response

The database on clothianidin indicates no consistent specific target organs at the doses tested.

Decreases in body weights and body weight gains were consistently observed among species and at different dosing durations.  Clinical signs of neurotoxicity were exhibited in both rats and mice in the single dose (gavage) studies; however, no indications of neurotoxicity were observed in the subchronic (dietary) rat study.  In a developmental neurotoxicity study in rats, decreased body weights, body weight gains, motor activity and acoustic startle response amplitude (females) were seen in offspring at doses lower than those resulting in maternal toxicity.  Although the NOAELs were similar for the subchronic and chronic feeding studies in the rat, a greater spectrum of effects was observed in the chronic study.  Dogs dosed for 3 months or 1 year exhibited clinical signs of anemia.   The only observed effects in mice following chronic dietary administration were increases in vocalization and decreases in body weight and body weight gains.  There was no evidence of increased quantitative or qualitative susceptibility of rat or rabbit fetuses in developmental studies; however, increased quantitative susceptibility of rat pups was seen in both the reproduction and developmental neurotoxicity studies.  The degree of concern for both of these studies is low because the observed effects are well characterized and there are clear NOAELs.

3.1.4	FQPA  TC \l3 "3.1.4	FQPA

See Sections 3.3 and 3.4.

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)  TC \l2 "3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

In rats, clothianidin was readily absorbed and excreted within 96 hours.  Females showed a greater rate of absorption.  Metabolites were primarily oxidative demethylation and cleavage products.

In mice, absorption and excretion were complete within 168 hours with urine as the major excretory route.  No bioaccumulation was apparent.  Parent and TZNG metabolite were noted in urine and feces.

A dermal absorption study in the monkey indicated that absorption was 0.24%.

3.3	FQPA Considerations  TC \l2 "3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database  TC \l3 "3.3.1	Adequacy of the Toxicity Database

The database for evaluating in utero or postnatal susceptibility is adequate for evaluation of the FQPA safety factor.  The following acceptable studies are available:

	Developmental toxicity studies in rats and rabbits

	Two-generation reproduction study in rats

	Developmental neurotoxicity study in rats

	Developmental immunotoxicity study in rats

3.3.2	Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of Neurotoxicity

Clothianidin was tested in the following three rat neurotoxicity studies: acute, 90-day and developmental.  In addition, a neurotoxicity/pharmacology single dose study was performed in mice.

In the acute neurotoxicity study, decreased arousal, motor activity and locomotor activity were observed; however, in the subchronic study, the LOAEL was based on decreased body weights, body weight gains and food consumption with no evidence of neurotoxicity.

In the developmental neurotoxicity study, the maternal effects included decreased body weights, body weight gains and food consumption; whereas, in the offspring, decreased body weights, body weight gains, motor activity and acoustic startle response in females were observed at a lower dose than the dose required to induce effects in the dams.

In the single dose mouse study, transient signs of decreased spontaneous motor activity, tremors and deep respirations were observed.

No signs of neurotoxicity were observed in the remainder of the toxicity studies.

3.3.3	Developmental Toxicity Studies  TC \l3 "3.3.3	Developmental Toxicity Studies

In the gavage developmental studies, there is no evidence of increased quantitative or qualitative susceptibility of rat or rabbit fetuses to in utero exposure to clothianidin.  The developmental NOAELs are either higher than or equal to the maternal NOAELs.  The toxicological effects in fetuses are not considered to be more severe than those in the dams or does.

In the rat developmental neurotoxicity study, there was evidence of increased quantitative susceptibility, because offspring effects were observed at lower doses than doses at which maternal effects were observed; however, the effects were not considered to be more severe.  The maternal NOAEL was 43 mg/kg/day with the LOAEL being 142 mg/kg/day based on decreased body weight, body weight gain and food consumption.  For offspring, the NOAEL was 13 mg/kg/day and the LOAEL was 43 mg/kg/day based on decreases in body weights, body weight gains, motor activity and acoustic startle response in females.  Nonetheless, HED considers the degree of concern for the developmental neurotoxicity study to be low and there are no residual uncertainties for pre- and/or postnatal toxicity because the observed effects are well characterized and there are clear NOAELs/LOAELs.

3.3.4	Reproductive Toxicity Study  TC \l3 "3.3.4	Reproductive Toxicity Study

Increased quantitative susceptibility was observed in the two-generation reproduction study, in which offspring toxicity (decreased body weight gains, delayed sexual maturation in males, decreased absolute thymus weights in F1 pups of both sexes and an increase in stillbirths in both generations) was seen at a dose lower than that which caused parental toxicity consisting of decreased body weight gains as well as decreased thymus weights (absolute and relative).

3.3.5	Additional Information from Literature Sources  TC \l3 "3.3.5 Additional Information from Literature Sources

None.

3.3.6	Pre-and/or Postnatal Toxicity  TC \l3 "3.3.6	Pre-and/or Postnatal Toxicity

<IP_ADDRESS>	Determination of Susceptibility  TC \l4 "<IP_ADDRESS>	Determination of Susceptibility

While no increased quantitative or qualitative susceptibility was observed in either of the developmental rat or rabbit studies, increased quantitative susceptibility was observed in both the developmental neurotoxicity and rat reproduction studies.  In the developmental neurotoxicity study, offspring toxicity (decreased body weight gains, motor activity and acoustic startle response) was seen at a lower dose than the dose what caused maternal toxicity.  However, HED determined that the degree of concern for the developmental neurotoxicity study is low and there are no residual uncertainties for pre- and/or postnatal toxicity because the observed effects are well characterized and there are clear NOAELs/LOAELs.

In the two-generation reproduction study, offspring toxicity (decreased body weight gains, delayed sexual maturation in males, decreased absolute thymus weights in F1 pups of both sexes and an increase in stillbirths in both generations) was seen at a dose lower than that which caused parental toxicity.

Immunotoxicity and developmental immunotoxicity studies were performed and neither showed any changes in the immune system parameters examined.

<IP_ADDRESS>	Degree of Concern Analysis and Residual Uncertainties for Pre- and/or Postnatal Susceptibility  TC \l4 "<IP_ADDRESS>	Degree of Concern Analysis and Residual Uncertainties for Pre- and/or Postnatal Susceptibility

There is low concern for an increase in quantitative or qualitative susceptibility in rats or rabbits in the developmental studies.  In the rat study, no developmental effects were noted in the highest dose tested; whereas, there was a decrease in maternal body weights and body weight gains as well as food consumption.  In the rabbit developmental study, maternal death occurred as the same dose as the fetal findings.  In the rat developmental neurotoxicity study, although there were neurotoxic signs in the offspring (decreased motor activity and acoustic startle response in females) at a dose lower than the maternal effects, the degree of these findings was considered to be minor and there would be little or no concern because the doses selected for risk assessment are protective of the effects observed in the developmental neurotoxicity study.

In the two-generation reproduction study, the offspring NOAEL (based on LOAEL findings of delayed sexual maturation in F1 males and an increase in stillbirth in both generations) was at a dose lower than the parental NOAEL (based on decreased body weights, body weight gains and thymus weights).  There was an increased quantitative susceptibility in this study, but the degree of concern is low because the study NOAEL and LOAEL have been selected for risk assessment purposes for relevant exposure routes and durations.  In addition, the potential immunotoxic effects observed in the study have been further characterized with the submission of a developmental immunotoxicity study, which showed no evidence of susceptibility.

3.3.7	Recommendation for a Developmental Neurotoxicity Study  TC \l3 "3.3.7	Recommendation for a Developmental Neurotoxicity Study

A developmental neurotoxicity study was submitted and reviewed by the Agency (see Section 3.3.2).

3.3.8	Rationale for the UFDB (when a DNT is recommended)  TC \l3 "3.3.8 Rationale for the UFDB

No database uncertainty factor is required (see Section 3.3.2)

3.4	FQPA Safety Factor for Infants and Children  TC \l2 "3.4	Safety Factor for Infants and Children

It is recommended that the 10X FQPA safety factor for the protection of infants and children be reduced to 1X.  There is no increased qualitative or quantitative susceptibility in the rat or rabbit developmental toxicity studies.  In the rat developmental neurotoxicity study, there was evidence of quantitative susceptibility, but the NOAEL and LOAEL were well characterized and the doses and endpoints selected for risk assessment are protective of the observed susceptibility.

In the two-generation reproduction study, there was increased quantitative susceptibility as the offspring NOAEL was below the parental NOAEL.  There was a clear difference between the NOAEL and the LOAEL.  The observed susceptibility in the reproduction study and the potential immunotoxicity observed in the study was the basis for the retention of a 10X database uncertainty factor (UFDB) for the lack of the developmental immunotoxicity study in previous risk assessments.  However, the submitted developmental immunotoxicity study demonstrated no treatment-related effects.

With the submission of an acceptable immunotoxicity study, HED has concluded the 10X FQPA safety factor can be removed (reduced to 1X).  The toxicity database is complete; despite evidence of quantitative susceptibility in several studies, the degree of concern for the susceptibility is low because:

Doses and endpoints selected for risk assessment are protective of the observed effects.

The dietary food exposure assessment is not likely to underestimate exposure/risk.

The dietary drinking water assessment utilizes water concentration values generated by models and associated modeling parameters that are designed to provide conservative, health protective, high-end estimates of concentrations in water that are not likely to be exceeded.

The residential exposure assessment was conducted using standard, health-protective assumptions.

3.5	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5 Hazard Identification and Toxicity Endpoint Selection

3.5.1	Acute Reference Dose (aRfD) - Females age 13-49  TC \l3 "3.5.1 Acute Reference Dose (aRfD) - Females age 13-49

Study Selected: Developmental Toxicity Study – rabbit (OPPTS 870.3700)

MRID No.: 45422713, 45422712

Dose and Endpoint for Establishing aRfD:  Developmental NOAEL = 25 mg/kg/day based on an increased litter incidence of a missing lobe of the lung observed at the LOAEL of 75 mg/kg/day.

Uncertainty Factor(s): An UF of 100 was applied to account for inter-species extrapolation (10X) and intra-species variation (10X).

Comments on Study/Endpint/Uncertainty Factors:

The acute dietary endpoint for females in the 13 to 49 year age group is based on an increased litter incidence of a missing lobe of the lung.  This developmental effect is presumed to occur following a single oral dose and is considered an appropriate endpoint for this population subgroup (i.e., women who could potentially be pregnant).  Other effects observed at 75 mg/kg/day were premature deliveries, decreased gravid uterine weights and decreased litter average for ossified sternal centra per fetus; however, these are not considered to be single-dose effects.

	Acute RfD = 25 mg/kg/day (NOAEL) = 0.25 mg/kg/day

				100 (UF)

3.5.2	Acute Reference Dose (aRfD) - General Population  TC \l3 "3.5.2 Acute Reference Dose (aRfD) - General Population

Study Selected:  Special neurotoxicity/pharmacology study in mice	 (Non-guideline)

MRID No.:  45422823

Dose and Endpoint for Establishing aRfD:  NOAEL = 25 mg/kg/day based on transient signs of decreased spontaneous motor activity, tremors and deep respirations observed at the LOAEL of 50 mg/kg/day.

Uncertainty Factor(s): An UF of 100 was applied to account for inter-species extrapolation (10X) and intra-species variation (10X).

Comments on Study/Endpoint/Uncertainty Factors:  The acute dietary endpoint for the general population is based on transient signs of decreased spontaneous motor activity, tremors and deep respirations in the mouse following a single oral dose.  This endpoint is considered appropriate for the general population (including infants and children) because the effects were observed following a single dose and the route of administration (oral) is appropriate for dietary considerations.

	Acute RfD =    25 mg/kg/day (NOAEL)   = 0.25 mg/kg/day

			              100 (UF)

3.5.3	Chronic Reference Dose (cRfD)  TC \l3 "3.5.3	Chronic Reference Dose (cRfD)

Study Selected:  2-Generation Reproduction Toxicity Studies—rat  (OPPTS 870.3800)

MRID No.:  45422714; 45422715 and 45422716

Dose and Endpoint for Establishing cRfD: NOAEL = 9.8 mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and an increase in stillbirths in both generations observed at the LOAEL of 31.2 mg/kg/day.

Uncertainty Factor(s):  An UF of 100 was applied to account for inter-species extrapolation (10X) and intra-species variation (10X).

Comments on Study/Endpoint/Uncertainty Factors:

The chronic dietary endpoint is based on offspring effects in the two-generation reproduction study: decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and an increase in stillbirths in both generations.  This endpoint is considered applicable for chronic dietary exposure because the route of administration (oral) is appropriate for dietary considerations.  The study and endpoint were selected because they are protective of effects observed in all the other available studies that could be selected for chronic dietary exposure assessment.

	Chronic RfD =    9.8 mg/kg/day (NOAEL)   = 0.098 mg/kg/day

			              100 (UF)

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)   TC \l3 "3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected:  2-Generation Reproduction Study - rat	(OPPTS 870.3800)

MRID No.:  45422714, 45422715 and 45422716

Dose and Endpoint for  Risk Assessment:  NOAEL = 9.8 mg/kg/day based on decreased body weight gains and delayed sexual maturation and decreased absolute thymus weights in F1 pups in both generations at the LOAEL of 31.2 mg/kg/day.

Uncertainty Factor(s): An UF of 100 was applied to account for inter-species extrapolation (10X) and intra-species variation (10X).

 Comments on Study/Endpoint:

This endpoint is based on an oral study, which is the route of interest for an incidental oral risk estimate.  The study and endpoint were selected because they are protective of effects observed in all the other available studies.  The endpoint is appropriate for all durations, as the effect may be a result of either short- and/or longer-term exposure.  In addition, it is appropriate for incidental oral exposure because it is based on offspring effects from the reproduction study.

3.5.5	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption

Dermal Absorption Factor:  1%.

In a dermal penetration study (MRID 45868001), TI-435 [Clothianidin] as the FS 600 formulation (10% a.i.) [nitroimino-14C] TI- 435), was administered to five male Rhesus monkeys.  Test material was applied to a shaved area (4 cmX 6 cm) of the skin on the back of each animal.  The total dose was contained in 100 ml of test substance and was applied at a dose of 6.13 ug/cm2.  Animals were exposed for 8 hours, and then the application sites were washed.  Subjects were monitored for 120 hours.  Urine and feces were collected for the exposure and the subsequent monitoring periods.

3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)  TC \l3 "3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)

Study Selected:  2-Generation Reproduction Toxicity Studies - rat (OPPTS 870.3800)

MRID No.:  45422714, 45422715 and 45422716

Dose and Endpoint for Risk Assessment: The NOAEL = 9.8 mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and an increase in stillbirths in both generations observed at the LOAEL of 31.2 mg/kg/day

Comments on Study/Endpoint:  This endpoint is based on an oral study.  No dermal studies are available.  Therefore, an oral study is selected to estimate risk using a route-to-route extrapolation.  The study and endpoint were selected because it is protective of effects observed in all the available studies.  The endpoint is appropriate for all durations as the effect may be a result of either short- and/or longer-term exposure.  Because an oral study was selected, the dermal absorption factor of 1% should be used for dermal risk assessment.

3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)  TC \l3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)

Study Selected:  2-Generation Reproduction Toxicity Study - rat (OPPTS 870.3800)

MRID No.:  45422714, 45422715 and 45422716

Dose and Endpoint for Risk Assessment:  The NOAEL = 9.82 mg/kg/day based on

Decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and an increase in stillbirths in both generations observed at the LOAEL of 31.2 mg/kg/day.

Uncertainty Factor(s): An UF of 100 was applied to account for inter-species extrapolation (10X) and intra-species variation (10X).

Comments about the Study/Endpoint:  This endpoint is based on an oral study.  No inhalation studies are available.  Therefore, an oral study is selected to estimate risk using a route-to-route extrapolation.  The study and endpoint were selected because they are protective of effects observed in all the available studies.  The endpoint is appropriate for all durations as the effect may be a result of either short- and/or longer-term exposure.  Absorption via inhalation is assumed to be equivalent to absorption via the oral route, i.e., 100% dermal absorption is assumed in risk assessment.

3.5.8	Level of Concern for Margin of Exposure  TC \l3 "3.5.8	Level of Concern for Margin of Exposure

Table 3.5.8.   Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	100

Inhalation	100	100	100

Residential Exposure

Dermal	100	100	N/A

Inhalation	100	100	N/A

Incidental Oral	100	100	N/A

3.5.9	Recommendation for Aggregate Exposure Risk Assessments  TC \l3 "3.5.9	Recommendation for Aggregate Exposure Risk Assessments

According to FQPA (1996), when there are potential residual exposures to a pesticide, an aggregate risk assessment must consider exposures from 3 major routes: oral, dermal, and inhalation.

For all durations, oral, dermal, and inhalation exposures may be aggregated because of the selection of a common endpoint for these routes of exposure.

3.5.10	Classification of Carcinogenic Potential  TC \l3 "3.5.10 Classification of Carcinogenic Potential

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), the clothianidin is classified as “Not Likely to be Carcinogenic to Humans.”

A statistical analysis showed that the increase in thyroid c-cell tumors in female rats was not significant, especially when carcinomas and adenomas were combined.  The increased incidence of hepatocellular carcinomas in male rats at the low and high doses are just outside historical control incidences for the same testing laboratory (only 2 studies) but are within the historical control range for the animal supplier.  In addition, there was no dose-response and there is no continuum (i.e. no preneoplastic lesions and no adenomas).  Based on these factors, it was determined that there was no evidence of carcinogenicity in rats.  There was no evidence of carcinogenicity in mice.

3.5.11	Summary of Toxicological Doses and Endpoints for Use in Human Risk Assessments  TC \l3 "3.5.11	Summary of Toxicological Doses and Endpoints for Use in Human Risk Assessments

Table 3.5.1a.  Summary of Toxicological Doses and Endpoints for Clothianidin for Use in Dietary and Non-Occupational Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	Level of Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary

Females age

13-49 	NOAEL =

25 mg/kg/day	UFA = 10X

UFH = 10X

SFFQPA =1

 	aRfD=0.25 mg/kg/day

aPAD=0.25 mg/kg/day	Rabbit developmental  study

LOAEL = 75 mg/kg/day based on increased litter incidence of a missing lobe of the lung

Acute Dietary

General population	NOAEL =

25 mg/kg/day	UFA = 10X

UFH = 10X

SFFQPA  = 1	aRfD = 0.25

mg/kg/day

aPAD 0.25

mg/kg/day	Special neurotoxicity/pharmacol

study in mice

LOAEL = 50 mg/kg/day based on transient signs of decreased spontaneous motor activity, tremors and deep respirations

Chronic Dietary

All populations including infants and children	NOAEL=

9.8 mg/kg/day  	UFA = 10X

UFH = 10X

SFFQPA =1	cRfD=0.098 mg/kg/day

cPAD=0.098 mg/kg/day	2-Generation reproduction study

LOAEL = 31.2 mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and increased stillbirths in both generations

Incidental Oral (short and intermediate term)	NOAEL=

9.8 mg/kg/day	UFA= 10X

UFH= 10X

SFFQPA=1	MOE= 100 (residential and occupational)	2-Generation reproduction study

LOAEL= 31.2  mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups

Dermal (all durations) 	Oral study NOAEL=

9.8 mg/kg/day

(dermal absorption = 1%)	UFA= 10X

UFH= 10X

SFFQPA=1	MOE= 100 (residential and occupational)	2-Generation reproduction study

LOAEL = 31.2 mg/kg/day based on  decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and increased stillbirths in both generations

Inhalation (all durations)

	Oral study NOAEL=

9.8 mg/kg/day

(inhalation absorption = 100% of oral absorption)	UFA= 10X

UFH= 10X

SFFQPA=1	MOE= 100 (residential and occupational)	2-Generation reproduction study

LOAEL = 31.2 mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and increased stillbirths in both generations

Cancer (oral, dermal, inhalation)	“Not Likely to be Carcinogenic to Humans”

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.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key date (i.e., lack of a critical study).  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.

Table 3.5.1a.  Summary of Toxicological Doses and Endpoints for Clothianidin for Use in Occupational Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA Safety Factors	Level of Concern for Risk Assessment	Study and Toxicological Effects

Dermal (all durations) (Adults)	Oral study NOAEL=

9.8 mg/kg/day

(dermal absorption = 1%)	UFA= 10X

UFH= 10X

SFFQPA=1	MOE= 100 (residential and occupational)	2-Generation reproduction study

LOAEL = 31.2 mg/kg/day based on  decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and increased stillbirths in both generations

Inhalation (all durations)

	Oral study NOAEL=

9.8 mg/kg/day

(inhalation absorption = 100% of oral absorption)	UFA= 10X

UFH= 10X

SFFQPA=1	MOE= 100 (residential and occupational)	2-Generation reproduction study

LOAEL = 31.2 mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and increased stillbirths in both generations

Cancer (oral, dermal, inhalation)	“Not Likely to be Carcinogenic to Humans”

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.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key date (i.e., lack of a critical study).  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.

3.6	Endocrine disruption  TC \l2 "3.6	Endocrine disruption

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

When the appropriate screening and/or testing protocols being considered under the Agency’s EDSP have been developed, clothianidin may be subjected to additional screening and/or testing to better characterize effects related to possible endocrine disruption.

Although there are possible endocrine effects associated with clothianidin, there are no specific studies being requested at this time because the effects have been characterized in an acceptable 2-generation reproduction study with a clear NOAEL and LOAEL as well as in developmental studies, and the chronic reference dose (cRfD) selected for clothianidin risk assessments is considered protective of the observed possible endocrine effects.  To the extent that new or revised tests are developed in connection with the EDSP that can provide more information on endocrine effects, EPA will consider whether further testing of clothianidin is appropriate.

4.0	Public Health and Pesticide Epidemiology Data  TC \l1 "4.0	Public Health and Pesticide Epidemiology Data

No public health or epidemiological data were used for this risk assessment.

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary Exposure/Risk Characterization

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1 Pesticide Metabolism and Environmental Degradation

The metabolism of clothainidin in primary crops, rotational crops, livestock, and rats was evaluated by the Metabolism Assessment Review Committee (MARC) in 2003.  The clothianidin risk assessment team concurs with the findings of the MARC regarding the residues of concern for risk assessment and tolerance enforcement (Table 5.1.7).

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	Metabolism in Primary Crops

Adequate plant metabolism studies are available reflecting the application of [14C]-clothianidin as a seed treatment to corn and sugar beets, as foliar applications to apples, and as soil and foliar applications to tomatoes.  The metabolic profiles in the tested primary crops were similar, in that the highest level residue was the parent, clothianidin, with the exception of mature sugar beet tops.  The metabolic profile from the study with apple is indicative of the metabolic profile in other plants and is believed to proceed as follows:  (i) hydrolysis of clothianidin to form TZMU; (ii) N-demethylation of clothianidin to form TZNG; (iii) hydroxylation of clothianidin to form THMN and subsequent glucosylation to form THMN-Glc; (iv) N-demethylation of TZMU to form TZU; (v) denitrification of clothianidin to form TMG; (vi) loss of the thiazolyl-methyl moiety (C-N bond cleavage) from clothianidin to form MNG and reduction of MNG (vii) denitrification of MNG to form MG; and (viii) N-demethylation of MNG to form NTG.  See D260059 (L. Croteau and Y. Donovan, 25 April 2003) for the chemical structures of the various clothianidin metabolites.

5.1.2	Metabolism in Rotational Crops  TC \l3 "5.1.2	Metabolism in Rotational Crops

Adequate confined and limited field rotational crop studies are available.  The metabolism of clothianidin in primary and rotational crops is similar.  Clothianidin, TZNG, and MNG are the ROCs in rotational crops for risk assessment.  Clothianidin is the ROC for the tolerance expression.

5.1.3	Metabolism in Livestock  TC \l3 "5.1.3	Metabolism in Livestock

The nature of clothianidin residues in livestock is adequately understood based on acceptable goat and hen metabolism studies.  Metabolism in livestock involves numerous demethylation and denitrification reactions.    TC \l3 "5.1.3	Metabolism in Livestock The ROCs for risk assessment are parent and the metabolites TZU, TZG, TZNG, ATMG-pyruvate (ruminants), and ATG-acetate (poultry).  For tolerance enforcement, clothianidin is the only ROC.

5.1.4	Environmental Degradation TC \l3 "5.1.4	Environmental Degradation

The fate and disposition of clothianidin in the environment suggest that it is persistent and mobile, stable to hydrolysis, and has potential to leach to ground water, as well as runoff to surface waters.  The high persistence of clothianidin (aerobic soil metabolism and terrestrial field dissipation half-lives ranging from half a year to several years) may cause accumulation of the chemical in soils following repeated uses.

5.1.5	Comparative Metabolic Profile TC \l3 "5.1.5	Comparative Metabolic Profile

The metabolism of clothianidin is complex, with a few major (> 10% of the total radioactive residues) and numerous minor metabolites.  The list of terminal residues is fairly consistent across plants, goats, hens, and rats, although the designation of major vs. minor metabolites varies depending on the test species.

Table 5.1.5.  Overview of clothianidin metabolic profile in plant and animal matrices.

Residue	Rat	Hen	Goat	Corn	Sugar Beet	Rotational Crops	Apple	Tomato

Clothianidin	(	(	(	(	(	(	(	(

ACT**	(

	ATG-Ac

(*

ATG-Pyr

(

ATMG-Pyr

	(*

	ATMT

(

CTCA**	(

	(

MG	(

(	(	(	(	(

	MNG	(	(	(	(	(	(*	(	(

MTCA**	(

	NTG	(	(	(	(	(	(	(

	THMN	(

(

	THMN-Glc

	(

	TMG	(	(	(	(	(* (tops)	(	(

	TMHG

	(

	TMT

(

TZG	(	(*	(*

	TZMU	(

(	(	(	(	(

	TZNG	(	(*	(*	(	(	(*	(	(

TZU	(	(*	(*	(	(	(	(

	UREA	(	(	(

	* 	major metabolites

**	ACT, MTCA, CTCA did not show up in hen and goat because only the nitroimino label was used.  There are also no acute studies with these metabolites.

5.1.6	Toxicity Profile of Major Metabolites and Degradates TC \l3 "5.1.6 Toxicity Profile of Major Metabolites and Degradates

Acute toxicity and genotoxicity data are available for ATG-acetate, ATMG-pyruvate, TMG, TZMU, TZNG, and MNG. The toxicity of ATG-acetate and ATMG-pyruvate appears to be similar to that of clothianidin.  Acute toxicity tests using LD50 levels indicate that TMG, TZMU, and TZNG may be somewhat more toxic than clothianidin.  Structurally, these three metabolites are nearly identical to clothianidin, differing only in the loss of a nitro and/or methyl group.  The points of departure used for risk assessment are well below the LD50 levels observed in the acute toxicology studies.  Given that and the structural similarity between these metabolites and clothianidin, HED is assuming that these compounds are toxicologically equivalent to clothianidin with respect to the endpoints being used for risk assessment.

5.1.7	Pesticide Metabolites and Degradates of Concern TC \l3 "5.1.7 Pesticide Metabolites and Degradates of Concern

Table 5.1.7.  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.

Matrix	Residues included in Risk Assessment	Residues included in Tolerance Expression

Plants

	Primary Crop	Leafy and Root/Tuber Vegetables:  Parent + TMG

Other crops: Parent	Parent

	Rotational Crop	Parent, TZNG, MNG	Parent

Livestock

	Ruminant	Parent, TZU, TZG, TZNG, ATMG-Pyr	Parent

	Poultry	Parent, TZU, TZG, TZNG, ATG-Ac	Parent

Drinking Water	Parent	Not Applicable

Based on the available metabolism studies, HED concluded that the nature of the residue has been adequately delineated, and that parent only is the residue of concern (ROC) to be used for the tolerance expression for primary crops.  HED had previously determined that future new uses on root crops and/or leafy vegetables will require analysis for residues of TMG along with parent in field trial samples and that TMG should be included as a ROC for risk assessment if significant levels of TMG were observed.  In the current submission, residues of TMG were shown to occur in leafy vegetables at levels approximately 10-fold below those of clothianidin.

5.1.8	Analytical Methodology  TC \l3 "5.1.8	Analytical Methodology

Adequate LC/MS/MS methods are available for both collecting residue chemistry data and enforcing tolerances for clothianidin residues in plant (Bayer Methods 00552 and 109240-1) and animal (Bayer Method 00624) commodities.  The validated limit of quantitation (LOQ) for clothianidin in plant commodities is 0.010 ppm, except for wheat straw (0.020 ppm), and the validated LOQs are 0.010 ppm in milk and 0.020 ppm in animal tissues.  All three of these methods have been reviewed by BEAD’s Analytical Chemistry Laboratory (ACL), approved for tolerance enforcement, and forwarded to FDA for inclusion in PAM Volume II.  More recently, another LC/MS/MS method (Morse Method #Meth-164) was proposed for enforcing tolerances and collecting data on residues of clothianidin and TMG in grape and potato commodities.  This method is similar to Method 00552 and involves extraction of residues with acetonitrile/water, cleanup using solid phase extraction (SPE) cartridges, and the separate analysis of clothianidin and TMG by LC/MS/MS.  The validated LOQ for each analyte is 0.02 ppm in all grape and potato matrices, except for potato chips and raisins (with LOQs of 0.04 ppm).  The method was adequately validated in conjunction with the field trials and processing studies and has undergone a successful independent laboratory validation (ILV) trial.

5.1.9	Drinking Water Residue Profile TC \l3 "5.1.9	Drinking Water Residue Profile

The Environmental Fate and Effects Division (EFED) provided Tier I Estimated Drinking Water Concentrations (EDWCs) for clothianidin in surface water and in ground water for use in human health risk assessments (J. Meléndez, D360266, 4 August 2009).  The simulation model FIRST was used to calculate the surface water EDWCs, and the SCI-GROW model was used to calculate the groundwater EDWC.  No clothianidin monitoring data were available.  Although clothianidin is a major metabolite of thiamethoxam in plants and in animals, it was not found in thiamethoxam environmental fate studies.  Therefore, exposure to clothianidin in drinking water due to thiamethoxam uses is not expected.  For the simulation models, the application rate of 0.4 lbs a.i./A for turfgrass was used.  This rate is the highest of all the proposed and existing uses.  The EDWCs for clothianidin in surface waters are 7.29 ppb for acute risk scenarios and 1.35 ppb for chronic risk.  Clothianidin EDWCs in groundwater are not expected to exceed 5.88 ppb.  Typically, HED uses the higher of the surface or groundwater estimates for each duration when assessing dietary risk (e.g., 7.29 ppb from surface water for acute exposures and 5.88 ppb from groundwater for chronic exposures).

Table 5.1.9	Summary of Estimated Surface Water and Groundwater Concentrations for Clothianidin.

Scenario	Surface Water Conc., ppb a	Groundwater Conc., ppb b

Acute	7.29	5.88

Chronic (non-cancer)	1.35	5.88

a From the Tier I FIRST model.  Input parameters are based on use of clothianidin on turf grass.

b From the SCI-GROW model assuming a maximum seasonal use rate of 0.4 lb ai/A, a Koc of 84, and a half-life of 744 days.

5.1.10	Food Residue Profile  TC \l3 "5.1.10	Food Residue Profile

Valent has submitted field trial data on celery, lettuce (head and leaf), spinach, cauliflower, cabbage, mustard greens, tomatoes, peppers, cucumbers, cantaloupes, squash, pecans, almonds, figs, pomegranates, cotton and soybeans supporting the proposed uses of clothianidin (50% WDG and 2.13 lb/gal FlC) on leafy vegetables, Brassica vegetables, fruiting vegetables, cucurbit vegetables, tree nuts, figs, pomegranates, cotton and soybeans.  In addition, IR-4 has submitted field trial data on cranberries and peach supporting the proposed uses of clothianidin (50% WDG and 2.13 lb/gal FlC) on the low-growing berries, except strawberry, Subgroup (13-07H) and peaches.

The field trial data submitted by Valent supporting repeated foliar applications of the 50% WDG or 2.13 lb/gal FlC formulations of clothianidin are adequate, although the maximum single application rate used in the field trials was higher (1.5X) than the proposed rate, with the exceptions of the tree nut, fig and pomegranate field trials.  For both the 50% WDG and 2.13 lb/gal FlC formulations, the maximum proposed single foliar application rate is 0.05-0.067 lb ai/A for all crops except tree nuts (0.1 lb ai/A), figs (0.09 lb ai/A) and pomegranates (0.09 lb ai/A), and the maximum seasonal application rate is 0.2 lb ai/A for all proposed crops.  However, in each trial, the WDG or FLC formulation was applied twice at a rate of 0.1 lb ai/A (1.5X proposed single rate for most crops) for a total of 0.2 lb ai/A (1X proposed seasonal rate).  With the exceptions of the field trial data on tree nuts, figs and pomegranates, the residue data from Valent’s current field trials are likely to slightly over estimate clothianidin residues.

For the proposed foliar applications, an adequate number of tests were conducted using the 50% WDG or 2.13 lb/gal FlC formulation on the required representative crops in the appropriate geographic regions at ~1X the proposed maximum seasonal rate, and the appropriate commodities were collected from each test around the proposed PHIs.  Samples from all the field trials were analyzed using adequate LC/MS/MS methods, and the available storage stability data support the sample storage durations and conditions.  As the proposed use directions are identical for the 50% WDG and 2.13 lb/gal formulations, and the PHIs for the foliar applications are >7 days, the residue data for the WDG or FlC formulations will also support the use of either the FlC or WDG formulations (per pending OECD residue chemistry guidelines) on low-growing berries, tree nuts, cotton, and soybean.  For foliar applications, HED will generally allow for translation of residue data between water-diluted formulations (other than ECs, Mcap, and oil-dispersion formulations) when the proposed PHI is >7 days and residues are shown to decline at longer post-treatment intervals (per draft, pending OECD guidelines).  Therefore, HED has no objections to the translation of formulation-specific residue data for the proposed uses on tuberous and corm vegetables, cotton, berries, soybeans, and tree nuts.  However, for the other crops HED is requesting that bridging trials be completed and submitted in order to evaluate the residue levels resulting from these two formulations for uses with a 7-day PHI.  Adequate residue data were provided for TMG in/on leafy and Brassica vegetables commodities as required.

In addition to the formulation issue, several other deficiencies were noted in Valent’s field trial data.  First, with the exceptions of the fig and pomegranate field trials, none of the other field trials included the use of any adjuvants in the spray mix, although the proposed labels allow for the use of spray adjuvants.  The foliar applications were applied at a slightly exaggerated single rate (1.5X).  HED has evidence that adjuvants can have a significant impact on residue levels, potentially increasing them by 4- to 5-fold relative to residues resulting from the same use without adjuvants.  Therefore, the 1.5X application rate is not sufficient to address the impact of adjuvants on residue levels.  HED requests that bridging trials be conducted to show the impact of adjuvants on residue levels (three trials per representative crop) and that in the mean time, the proposed label be revised to disallow the use of spray adjuvants with clothianidin foliar treatments, with the exception of applications to figs, pomegranates, and tree nuts except almonds (due to residues in/on almond hulls).

Second, no residue data were submitted on soybean forage and hay following the proposed foliar applications.  The label should be revised to prohibit the feeding of soybean forage and hay to livestock.

at ≥21 days following a single soil application at 0.2 lb ai/A are likely to be less than or equal to the residues resulting from repeated foliar applications totaling 0.2 lb ai/A, insufficient data are available to make this determination.  Based on the submitted soil application data, HED also assumes that the desired PHI for soil applications is 21 days, as in the studies, rather than the currently specified 7-day PHI.

Data are insufficient to support the soil application use patterns requested. In order to support this use pattern, HED recommends bridging studies be conducted to examine the effects of application mode (soil vs. foliar) on residue levels.  Given the number of variables involved with the requested uses (adjuvant use, formulation effects, and soil vs. foliar application), HED further recommends that the design of these trials be discussed with HED prior to their initiation.

Although no field trial data were submitted by Valent supporting the use of the 5 lb/gal FlC formulation as a seed (soybean) or seed-piece treatment (potatoes), no new residue data are required as the existing residue data on soybeans and potatoes will support the proposed uses.  For potatoes, adequate field trial data are available supporting an identical use for the 2.13 lb/gal FlC formulation (DP# 303164, W. Drew, 2/1/06); these data will support the same use for the 5 lb/gal FlC formulation.

For soybeans, the submitted field trial data reflecting foliar applications at up to 0.2 lb ai/A/season will cover the proposed seed treatment use, as the proposed use rate from the seed treatment would result in a worst-case field rate of 0.05 lb ai/A.  Given the longer harvest interval and lower use rate for the seed treatment, and the fact that residues in/on soybean seeds were detectable in only one soybean seed sample (0.016 ppm) at 21 days following the foliar applications, HED concludes that the proposed seed treatment is unlikely to result in residues greater than those resulting from the foliar use.

Although additional field trial data are being requested from Valent, the available data support tolerances of clothianidin at 3.0 ppm on leafy vegetables, 1.9 ppm on Brassica vegetables, 0.2 ppm on fruiting vegetables, undelinted cottonseed, and pomegranates, 0.06 ppm on cucurbit vegetables, 0.05 ppm on figs, 0.01 ppm on tree nuts and pistachios, 1.5 ppm on almond hulls, 4.5 ppm on cotton gin byproducts, and 0.02 ppm on soybean seed.  (Note: although TMG residue data will be used for risk assessment, the tolerance for primary crop uses will continue to include only the parent compound for enforcement purposes)

The submitted residue data for TMG in/on leafy and Brassica vegetables and cotton gin byproducts are adequate, and the ratio of clothianidin residues to TMG residues was relatively consistent for a given crop, generally showing that residues of clothianidin are 10X higher than TMG residues.

The field trial data submitted by IR-4 supporting the use of clothianidin (WDG) on peaches and low-growing berries (except strawberry) are also adequate, although the peach field trials used an exaggerated single application rate (2X).  An adequate number of tests were conducted on peaches and cranberries using the WDG formulation in the appropriate geographic regions at ~1X the proposed maximum seasonal rate.  The appropriate commodities were collected from each test at the proposed PHIs.  Samples from all the field trials were analyzed using an adequate LC/MS/MS method, and the analyses are supported by the available storage stability data.  Although no field trial data were submitted supporting the use of the FlC formulation on berries, the available residue data for the WDG formulation will be translated to support the FlC formulation as the proposed PHI for the foliar applications is 21 days for these crops.  However, bridging data are required for use of the FlC product on peaches.

The available peach and cranberry field trial data support the proposed tolerances of 0.70 ppm for peaches and 0.01 ppm for low-growing berries, except strawberry (Subgroup 13-07H).  However, for purposes of international harmonization, HED is recommending a tolerance level of 0.80 ppm for residues of clothianidin in/on peaches.

5.1.11	International Residue Limits TC \l3 "5.1.11	International Residue Limits

Except for potatoes and peach/stone fruit there are currently no established or proposed Codex, Canadian, or Mexican maximum residue limits (MRLs) for clothianidin on the requested crops/crop groups.  For potato and peach/stone fruit commodities, HED’s recommended tolerances are in accord with established/recommended Canadian MRLs.  Therefore, harmonization with international MRLs is not an issue with this petition.  An International Residue Limit Status Sheet follows.

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: (E)-N-[(2-Chloro-5-thiazolyl)methyl]-N’-methyl-N”-nitroguanidine Common Name: Clothianidin	X Proposed tolerances

 Reevaluated tolerance

 Other	Date: 2/16/09

Codex Status (Maximum Residue Limits)	U. S. Tolerances

X No Codex proposal step 6 or above

 No Codex proposal step 6 or above for the crops requested 	Petition Numbers: 8F7395, 8E7460,  and 9F7530

DP Numbers: 355896, 360842, and 362499

Other Identifier: PC Code 044309

Residue definition (step 8/CXL):  NA	Reviewer/Branch: M. Doherty/RAB II

	Residue definition: Clothianidin

Crop (s)	MRL (mg/kg)	Crop(s) 	Recommended Tolerance (ppm)

Vegetable, leafy, except brassica, Group 4	3.0

Vegetable, brassica, leafy, Group 5	1.9

Vegetable, fruiting, Group 8	0.2

Vegetable, cucurbits, Group 9	0.06

Fig	0.05

Nut, tree nuts, Group 14	0.01

Pistachio	0.01

Pomegranate	0.20

Almond, hulls	1.5

Cotton, undelinted seed	0.20

Cotton, gin byproducts	4.5

Soybean, seed	0.02

Peach	0.70

Berry, low-growing, except strawberry, Subgroup 13-07H	0.01

	Limits for Canada	Limits for Mexico

( No Limits

X No Limits for the crops requested	X  No Limits

(   No Limits for the crops requested

Residue definition: Clothianidin	Residue definition:  NA

Crop(s)	MRL (mg/kg)	Crop(s)	MRL (mg/kg)

  SEQ CHAPTER \h \r 1 Field corn grain	0.01

Popcorn grain	0.01

Rapeseed (canola)	0.01

Sweet corn kernel plus cob with husk removed	0.01

Milk	0.01

	Notes/Special Instructions:  Potato commodities were recently given MRLs by Canada, as follows:  Tubers (0.3 ppm), chips (0.6 ppm), and granules/flakes (1.5 ppm).  PMRA (Canada) is currently reviewing a petition to establish tolerances on stone fruit, which includes peaches.  HED’s recommended tolerance of 0.7 ppm is harmonized with PMRA’s recommended MRL for stone fruit.

5.2	Dietary Exposure and Risk TC \l2 "5.2	Dietary Exposure and Risk

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted (M. Doherty, D364363, 11 August 2009) using the Dietary Exposure Evaluation Model DEEM-FCID™, Version 2.03 which uses food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.  The analyses were performed to support Section 3 registration requests for clothianidin and thiamethoxam.

Both the acute and chronic assessments are based on tolerance-level residues, assume 100% crop treated, and include estimates for residues of clothianidin in drinking water.  Clothianidin is a major metabolite of thiamethoxam, and these analyses include thiamethoxam as a source of clothianidin exposure.  These assessments address requests for new uses of clothianidin as foliar treatments on berries (Subgroup 13-07H), Brassica vegetables (Group 5), cotton, cucurbit vegetables (Group 9), figs, fruiting vegetables (Group 8), leafy vegetables (Group 4), peaches, pomegranates, soybeans, tuberous and corm vegetables (Subgroup 1C), tree nuts (Group 14); as seed treatments on root and tuber vegetables (Group 1), bulb vegetables (Group 3), leafy greens (Subgroup 4A), Brassica leafy vegetables (Subgroup 5B), fruiting vegetables (Group 8), cucurbit vegetables (Group 9), and cereal grains (except rice; Group 15); and new uses of thiamethoxam on rice, sugar beets, and tropical fruits.

Based on highly conservative, health-protective assumptions, the aggregate dietary risk estimates are below HED’s level of concern (100% of the population-adjusted dose, PAD) for all durations and population subgroups.  For the acute assessment, the maximum estimated risk is for 23% of the acute PAD (aPAD).  Similarly, the maximum estimated risk for the chronic assessment is for children 1-2 years of age at 19% of the chronic PAD (cPAD).  Clothianidin is not a human carcinogen; therefore, cancer risk is not an issue for this chemical.  Dietary exposure and risk estimates are summarized in Table 5.2, below.

Table 5.2.  Summary of Dietary Exposure and Risk Estimates for Clothianidin.

Population Subgroup	Acute (95th Pecentile of Exposure)	Chronic

	Exposure, mg/day	Risk, % aPAD	Exposure, mg/day	Risk, % cPAD

U.S. Population (total)	0.015348	6	0.004582	5

All infants (< 1 year)	0.048192	19	0.012680	13

Children 1-2 yrs	0.057589	23	0.018429	19

Children 3-5 yrs	0.039621	16	0.012188	12

Children 6-12 yrs	0.018222	7	0.005801	6

Youth 13-19 yrs	0.011109	4	0.003194	3

Adults 20-49 yrs	0.010491	4	0.003229	3

Adults 50+ yrs	0.010650	4	0.003438	4

Females 13-49 yrs	0.010991	4	0.003325	3

The population subgroup(s) with the highest exposure/risk estimates are shown in bold.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC \l1 "6.0	Residential (Non-Occupational) Exposure/Risk Characterization

The non-occupational/residential exposure/risk assessment is based on the HED’s previous assessment (M. Dow, D296176, 24 February 2004).  The results of this assessment are summarized as follow:

There is a registered use for clothianidin on turf and, therefore, residential and recreational post-application exposures are possible.

Although residential handler exposure is not expected from the currently registered or proposed uses of clothianidin, owing to the absence of products registered or proposed for homeowner use, the exposure estimates in Table 6 (below) do include adult exposure from commercial application to turfgrass via granular push-type spreader.  Therefore, this represents an overestimate of total exposure.

The MOEs for the residential post-application exposures/risks range from 1,300 to 490,000 (Table 6.0).  MOE values greater than 100 are considered adequate to protect adults and children from residential non-dietary post-application exposures to clothianidin.  The estimated MOE’s are based upon conservative assumptions and are >1000; therefore, the estimated risks from residential non-dietary post-application exposures do not exceed HED’s level of concern.

Table 6.0.  Summary of Residential Post-Application Exposure and Risk Estimates.

Activity	Exposure (Dose)

mg a.i./kg bw/day	MOE

Adult dermal application	0.000026	370000

Adult dermal post-application turf contact	0.00108	9100

Adult golfer post-application turf contact	0.000075	130000

Adult combined	0.001181	8300

Toddler oral hand to mouth from contacting treated turf	0.0059	1700

Toddler incidental oral ingestion of treated soil	0.00002	490000

Toddler dermal post-application turf contact	0.00155	6300

Toddler combined	0.00747	1300

Spray drift is always a potential source of exposure to residents nearby spraying operations.  This is particularly the case with aerial application but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for clothianidin.  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.  The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift and risks associated with aerial as well as other application types where appropriate.

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0 Aggregate Risk Assessments and Risk Characterization

7.1	Acute Aggregate Risk TC \l2 "7.1	Acute Aggregate Risk

Other than dietary exposure, there are no other sources of exposure that constitute an acute exposure scenario; therefore, acute aggregate exposure and risk estimates are equivalent to the acute dietary exposure and risk estimates summarized in Table 5.2 and are below HED’s level of concern.

7.2	Short- and Intermediate-Term Aggregate Risk TC \l2 "7.2	Short- and Intermediate-Term Aggregate Risk

All of the short- and intermediate-term aggregate MOEs are greater than 100 (Table 7.2) and, therefore, represent risks that are below HED’s level of concern.

Table 7.2.  Summary of the Short- and Intermediate-Term Aggregate Exposure and Risk Estimates for Clothianidin.

Population Subgroup	Total Residential Exposure, mg/kg/day	Chronic Dietary Exposure, mg/kg/day	Aggregate Exposure1, mg/kg/day	MOE2

U.S. Population (total)	0.001181	0.004582	0.005763	1700

All infants (< 1 year)	0.00747	0.012680	0.020150	480

Children 1-2 yrs	0.00747	0.018429	0.025899	380

Children 3-5 yrs	0.00747	0.012188	0.019658	500

Children 6-12 yrs	0.001181	0.005801	0.006982	1400

Youth 13-19 yrs	0.001181	0.003194	0.004375	2200

Adults 20-49 yrs	0.001181	0.003229	0.004410	2200

Adults 50+ yrs	0.001181	0.003438	0.004619	2100

Females 13-49 yrs	0.001181	0.003325	0.004506	2200

The population subgroup with the highest estimated exposure/risk is bolded.

1 Aggregate Exposure = Residential Exposure + Chronic Dietary Exposure

2 Aggregate MOE = NOAEL (9.8 mg/kg/day) ÷ Aggregate Exposure (mg/kg/day)

7.3	Long-Term Aggregate Risk TC \l2 "7.3	Long-Term Aggregate Risk

Other than dietary exposure, there are no other sources of exposure that constitute a long-term exposure scenario; therefore, long-term aggregate exposure and risk estimates are equivalent to the chronic dietary exposure and risk estimates summarized in Table 5.2 and are below HED’s level of concern.

7.4	Cancer Risk TC \l2 "7.4	Cancer Risk

Clothianidin has been classified as “not likely to be carcinogenic to humans.”  Therefore, cancer risk is not a concern for this chemical.

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "8.0	Cumulative Risk Characterization/Assessment

Clothianidin is a member of the neonicotinoid class of pesticides and is a major metabolite of another neonicotinoid, thiamethoxam.  Structural similarities or common effects do not constitute a common mechanism of toxicity.  Evidence is needed to establish that the chemicals operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002).  Although clothianidin and thiamethoxam bind selectively to insect nicotinic acetylcholine receptors (nAChR), the specific binding site(s)/receptor(s) for clothianidin, thiamethoxam and the other neonicotinoids are unknown at this time.  Additionally, the commonality of the binding activity itself is uncertain, as preliminary evidence suggests that clothianidin operates by direct competitive inhibition, while thiamethoxam is a non-competitive inhibitor.  Furthermore, even if future research shows that neonicotinoids share a common binding activity to a specific site on insect nAChRs, there is not necessarily a relationship between this pesticidal action and a mechanism of toxicity in mammals.  Structural variations between the insect and mammalian nAChRs produce quantitative differences in the binding affinity of the neonicotinoids towards these receptors which, in turn, confers the notably greater selective toxicity of this class towards insects, including aphids and leafhoppers, compared to mammals.  While the insecticidal action of the neonicotinoids is neurotoxic, the most sensitive regulatory endpoint for clothianidin is based on unrelated effects in mammals, including changes in body and thymus weights, delays in sexual maturation, and still births.  Additionally, the most sensitive toxicological effect in mammals differs across the neonicotinoids (such as testicular tubular atrophy with thiamethoxam, and mineralized particles in thyroid colloid with imidacloprid).  Thus, there is currently no evidence to indicate that neonicotinoids share common mechanisms of toxicity, and EPA is not following a cumulative risk approach based on a common mechanism of toxicity for the neonicotinoids.  For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity, and to evaluate the cumulative effects of such chemicals, see the policy statements concerning common mechanism determinations, and procedures for cumulating effects from substances found to have a common mechanism, released by OPP on EPA’s website at   HYPERLINK "http://www.epa.gov/pesticides/cumulative/"  http://www.epa.gov/pesticides/cumulative/ .

Note that because clothianidin is a major metabolite of thiamethoxam, EPA has combined exposure to clothianidin resulting both from thiamethoxam use, and from use of clothianidin as an active ingredient, and has compared this aggregate exposure estimate to relevant endpoints for clothianidin.  Labeling for formulations containing either of these compounds specifies that other neonicotinoid insecticides are not to be applied during the growing season (i.e., a crop treated with clothianidin will not be treated with thiamethoxam).  Given that, in combination with the assumption of 100% crop treated for both the acute and chronic dietary assessments, obviates the need to do a combined assessment for crops with approved uses of both clothianidin and thiamethoxam.

9.0	Occupational Exposure/Risk Pathway  TC \l1 "9.0	Occupational Exposure/Risk Pathway

Based on the proposed use patterns, handler and post-application exposures to clothianidin may occur.  In terms of duration, exposures are expected to be of short- or intermediate-term duration; long-term (> 6 months) exposures are not expected to occur.

9.1	Short- and Intermediate-Term Handler Risk  TC \l2 "9.1	Short- and Intermediate-Term Handler Risk

Handler exposures may occur during foliar and seed-treatment uses.  Exposure and risk estimates for handlers are based on SOPs developed by HED’s Exposure Science Advisory Council and on data in the Pesticide Handler’s Exposure Database (PHED).  Handler exposure and risk estimates are summarized in Table 9.1.1 and 9.1.2, below, for the foliar and seed treatment uses, respectively.  For a complete description of the handler exposure analysis, see D363340 (S. Wang, 17 June 2009).

There are 12 handler scenarios that are expected to result in the highest exposure for the proposed foliar and seed-treatment uses:

Mixing/Loading Dry Flowable for Ground-boom Applications (Scenario 1)

Mixing/Loading Dry Flowable for Airblast Applications (Scenario 2)

Mixing/Loading Dry Flowable for Chemigation (Scenario 3)

Mixing/Loading Liquid for Ground-boom Applications (Scenario 4)

Mixing/Loading Liquid for Airblast Applications (Scenario 5)

Mixing/Loading Liquid for Chemigation (Scenario 6)

Applying Sprays with Ground-boom Equipment (Scenario 7)

Applying Sprays with Airblast Equipment (Scenario 8)

Loading (Open)/Applying Liquid for Seed Treatment (Scenario 9)

Sewing Seeds after Seed Treatment (Scenario 10)

Bagging Seeds after Seed Treatment (Scenario 11)

Multiple Activities Worker for Seed Treatment (Scenario 12)

All of the resulting occupational handler MOEs are greater than 100, indicating that risks associated with the above exposure scenarios are below HED’s level of concern.

Table 9.1.  Occupational Handler Risk Estimates for the Requested Foliar Uses of Clothianidin.

Exposure Scenario (Scenario #)	Personal Protective Equip.a	Dermal Unit Exposureb (mg/lb ai)	Inhalation Unit Exposurec   (ug/lb ai)	Crop Application Rate

(lb ai/A)	Amount Treatedd

(A/day)	Daily

Dermal

Dosee (mg/kg/day)	Daily

Inhalation

Dosef (mg/kg/day)	Combined

Daily Doseg (mg/kg/day)	MOEh

Mixer/Loader

Dry Flowables for

ground-boom (1)	Baseline	0.066	0.77	Vegetables, Cott/Soybn, Cranberry i 0.06             	80         200         80	4.53 E-5 0.000113     4.53 E-5	5.28 E-5  0.000132    5.28 E-5      	9.81 E-5  0.000245    9.81 E-5 100,000  40,000  100,000

Dry Flowables for

airblast (2)

Baseline	0.066	0.77	Tree nuts, Figs/Pomgnt Peach i	0.1	40	3.77 E-5 0.000044	0.000082	120,000

Dry Flowables for

chemigation (3)	Baseline	0.066	0.77	Vegetables, Cranberry	0.2	350 0.00066	0.00077	0.00143	6,900

Liquid for

ground-boom (4)	Baseline	2.9	1.2	Vegetables, Cott/Soybn, Cranberry i 0.06             	80         200         80	0.001989   0.004971    0.001989     	8.23 E-5  0.000206    8.23 E-5  	0.0021      0.0052    0.0021	4,700         1,900         4,700

Liquid for

airblast (5)	Baseline	2.9	1.2	Tree nuts, Figs/Pomgnt Peach i	0.1	40 0.001657	6.86 E-5	0.0017	5,700

Liquid for

chemigation (6)	Baseline	2.9	1.2	Vegetables, Cranberry	0.2	350	0.029 0.0012	0.030	320

Applicator

Sprays with

ground-boom  (7)	Baseline	0.014	0.74	Vegetables, Cott/Soybn, Cranberry i 0.06	80         200         80	9.6 E-6   0.000024      9.6 E-6	5.07 E-5  0.000127     5.07 E-5	0.000060  0.00015     0.000060	160,000  65,000   160,000

Sprays with

airblast (8)	Baseline	0.36	4.5	Tree nuts, Figs/Pomgnt Peach i	0.1	40 0.000206	0.000257	0.00046	21,000

a	Baseline consists of long-sleeve shirt, long pants, shoes, and socks and no respirator.  PPE consists of long-sleeve shirt, long pants, shoes, socks, chemical-resistant gloves, and no respirator.

b	Baseline Dermal Unit Exposure represents long pants, long sleeved shirt, no gloves, open mixing/loading, and open cab tractors, as appropriate.

c	Baseline Inhalation Exposure represents no respiratory protection, open mixing/loading, and open cab tractors, as appropriate.

d	Daily acres treated values are from EPA estimates of acreage that could be treated or volume handled in a single day for each exposure scenario of concern, based on the application method and formulation/packaging type.

e	Daily dermal dose (mg/kg/d) =  [unit dermal exposure (mg/lb ai) * dermal absorption (0.01) * application rate (lb ai/acre) * daily acres treated /  body weight (70 kg).

f	Daily inhalation dose (mg/kg/d) = (unit exposure (µg/lb ai) * (1mg/1000 µg) conversion * application rate (lb ai/acre) * daily acres treated / body weight (70 kg).

g	Combined daily dose = daily dermal dose + daily inhalation dose.

h	MOE = NOAEL (9.8 mg/kg/d) / combined daily dose.  UF = 100.

i                Vegetables=brassica veg+cucurbit veg+fruiting veg+leafy veg; Cott=cotton; Soybn=soybean; Pomgnt=pomegranate.

Table 9.2.  Occupational Handler Risk Estimates for the Requested Soybean Seed-Treatment Use of Clothianidin.

Exposure Scenario (Scenario #)

Personal Protective Equipment

Dermal Unit Exposure (mg/lb ai)

Inhalation Unit Exposure   (mg/lb ai)

Seed Species

Application Rate

(lb ai  per lb seed)

Amount Treateda

(lb seed trt per day)

Daily

Dermal

Dose b (mg/kg/day)

Daily

Inhalation

Dosec (mg/kg/day)

Combined Daily Dosed  (mg/kg/day)

MOEe

Loader/Applicator

Loading/Applying

Liquids for

Seed Treatment (9)

Single Layer, Gloves	0.023	0.00034	Soybean  	0.0005	718,000	0.0012 0.0017	0.0029	3,400

Sewer

Sewing Seeds after Seed treatment (10)

Single Layer,

No Gloves	0.0062	0.00023	Soybean  	0.0005	718,000	0.00032	0.0012	0.0015 6,500

Bagger

Bagging Seeds after Seed treatment (11)

Single Layer,

No Gloves	0.0091	0.00016	Soybean  	0.0005	718,000	0.00047	0.00082	0.0013 7,600

Multiple Activities Worker

Multiple Activities for Seed treatment (12)

Single Layer, Gloves	0.042	0.0016	Soybean  	0.0005	718,000	0.0022	0.0082 0.0104	950

a	Daily amounts treated values are based on the information provided by the Registrant through Registration Division.

b	Daily dermal dose (mg/kg/d) =  [unit dermal exposure (mg/lb ai) * dermal absorption (0.01) * application rate (lb ai/lb seed) * daily amounts treated /  body weight (70 kg).

c	Daily inhalation dose (mg/kg/d) = (unit exposure (mg/lb ai) * application. rate (lb ai/lb seed) * daily amounts treated / body weight (70 kg).

d	Combined daily dose (mg/kg/d) =  Daily dermal dose (mg/kg/d) + Daily inhalation dose (mg/kg/d).

e	MOE = NOAEL (9.8  mg/kg/d) / combined daily dose.  UF = 100.

9.2	Short- and Intermediate-Term Post-Application Risk  TC \l2 "9.2 Short- and Intermediate-Term Post-Application Risk

Post-application exposures may occur during farming activities in treated fields as well as from the handling of treated seeds (secondary seed handling).  As with the handler occupational exposure and risk estimates, the post-application risk estimates are detailed in the assessment by S. Wang (D 363340, 17 June 2009).  All post-application MOEs are greater than 100 and reflect risk estimates that are below HED’s level of concern.  The post-application MOEs are summarized in Tables 9.2.1 and 9.2.2.

Table 9.2.1.  Post-Application Risk Estimates Associated with the Requested Foliar Uses of Clothianidin at Zero Days after Treatment.

Crop	Application Rate

(lb ai/A)	Work Activity	Transfer Coefficientsa (cm2/hr)	DFRc

(µg/cm2)	Daily Dosed (mg/kg/day)	 MOE e

Cotton,

Soybean	0.06	irrigation, scouting, thinning, weeding immature plants	100 0.135	0.000015	640,000

irrigation, scouting, weeding mature plants	1500	0.135	0.00023	42,000

Cranberry	0.06	irrigation, scouting, weeding, pruning, thinning	400 0.135	0.000062	160,000

harvesting, hand pruning, pinching, training	1500	0.135	0.00023	42,000

Brassica Veg. Cucurbit Veg. Leafy  Veg.	0.06	irrigation, scouting, thinning, weeding immature plants	500	0.135	0.000077	130,000

irrigation, and scouting mature plants	1500	0.135	0.00023	42,000

hand harvesting,  pruning, and thinning mature plants	2500	0.135	0.00038 25,000

Fruiting Veg.	0.06	irrigation, scouting, thinning, weeding immature plants	500	0.135	0.000077	130,000

irrigation, and scouting mature plants	700	0.135	0.00011	91,000

hand harvesting, pruning, staking, tying	1000	0.135	0.00015	64,000

Figs,         Peach	0.1	propping	100	0.224	0.000026	380,000

irrigation, scouting, weeding 	1000	0.224	0.00026	38,000

Harvesting, pruning, training, tying	1500	0.224	0.00038	25,000

Pomegranate	0.1	propping	100	0.224	0.000026	380,000

irrigation, scouting, hand weeding, harvesting, pruning, training 	1500 0.224	0.00038	25,000

Thinning, tying	3000	0.224	0.00077	13,000

Tree Nuts 	0.1	irrigation, scouting, thinning, weeding	500	0.224	0.00013 76,000

harvesting/poling, pruning, thinning	2500	0.224	0.00064	15,000

a	Transfer coefficient from Science Advisory Council for Exposure: Policy Memo #003 "Agricultural Transfer Coefficients," 05/07/98.

b	Day after treatment represents approximately 12 hours following application  when sprays have dried.

c	DFR = Application Rate (lb ai/acre)X Fraction of active ingredient that remains on the foliage when sprays have dried X 4.54E8 µg/lbX 24.7E-9 acre/cm2.

d	Daily dose = DFR (µg/cm2)X TC (cm2/hr)X conversion factor (1 mg/1,000 µg)X exposure time (8 hrs/day)X dermal absorption (0.01) / body weight (70 kg).

e	MOE = NOAEL (9.8 mg/kg/day) / daily dose (mg/kg/day).

Table 9.2.2.  Risk Estimate for Secondary Seed Handlers of Treated Soybean Seed.

Mitigation Level	Dermal Unit Exposure (mg/lb ai)	Inhalation Unit Exposure   (mg/lb ai)	Application Rate

(lb ai  per lb seed)	Amount Planteda

(lb seed pnted/day)	Daily

Dermal

Dose b (mg/kg/day)	Daily

Inhalation

Dosec (mg/kg/day)	Combined Daily Dosed (mg/kg/day) 	MOEe

Single Layer, Gloves	0.25	0.0034	0.0005	12,000	0.00021	0.00029	0.0005 20,000

a	Daily amounts planted values are based on the information provided by the Registrant through Registration Division.

b	Daily dermal dose (mg/kg/d) =  [unit dermal exposure (mg/lb ai) * dermal absorption (0.01) * application rate (lb ai/lb seed) * daily amounts treated /  body weight (70 kg).

c	Daily inhalation dose (mg/kg/d) = (unit exposure (mg/lb ai) * application. rate (lb ai/lb seed) * daily amounts treated / body weight (70 kg).

d	Combined daily dose (mg/kg/d) =  Daily dermal dose (mg/kg/d) + Daily inhalation dose (mg/kg/d).

e	MOE = NOAEL (9.8 mg/kg/d) / combined daily dose.  UF = 100.

10.0	Data Needs and Label Recommendations  TC \l1 "10.0	Data Needs and Label Recommendations

10.1	Toxicology  TC \l2 "10.1	Toxicology

None.

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry

	•	Label directions for Valent’s 50% WDG and 2.13 lb/gal FlC formulations should be amended to include rotational crop restrictions.

	•	Label directions for Valent’s 50% WDG and 2.13 lb/gal FlC formulations should be revised to remove the soil application for vegetable crops.

	•	Label directions for both the seed treatment and foliar application uses on soybeans should be amended to prohibit the grazing or feeding for soybean forage and hay to livestock.

	•	Label directions for all crops except fig, pomegranate, soybeans and tree nuts (excluding almonds) should be revised to prohibit the use of adjuvants.  If the petitioner wants to allow the use of adjuvants, side-by-side trials should be conducted.  HED recommends that the petitioner consult with the Agency prior to conducting any such trials.

	•	To support the use of clothianidin (WDG or FlC) as a soil application on vegetable crops, bridging studies are required on selected vegetable crops to compare residues resulting from soil vs. foliar applications.  Additional field trials are required on leaf lettuce, mustard greens, peppers, and cucumbers (3 tests for each crop).  In each test, clothianidin (WDG or FlC) should be applied separately to side-by-side plots as either a single soil application at 0.2 lb ai/A, or as three foliar applications at 0.067 lb ai/A/application at a RTI of 7 days, for a total of 0.2 lb ai/A/season.  Samples of each commodity should be harvested at 21 DAT for the soil application and at 7 DAT for the foliar applications.  The foliar applications should also include the use of spray adjuvants in each test.  If residues resulting from the soil application are greater than those coming from the foliar use, a full set of trials reflecting residues from soil applications will be required.

	•	The available field trial data reflect the use of the WDG formulation on leafy vegetables, Brassica vegetables, fruiting vegetables, cucurbit vegetables, peaches, low-growing berries (except strawberry), tree nuts, cotton, and soybeans; and of the FlC formulation on figs and pomegranates.  Of these, translation between formulations for the foliar uses on cotton, berries, legume vegetables, and tree nuts is appropriate since the PHI for these uses is greater than one week.  For the other uses, side-by-side trials should be conducted to demonstrate equivalency of formulations, with respect to residue levels, if registrations for both formulations are desired.  Due to these formulation issues and the adjuvant issues noted above, HED recommends that the petitioner consult with the Agency prior to initiating any side-by-side residue trials.

	•	A revised Section F should be submitted amending the proposed tolerances to reflect the recommendations made by HED in Table 10.  Additionally, the tolerance expression should be revised to read as follows:

		Tolerances are established for residues of the insecticide clothianidin, including its metabolites and degradates, in or on the commodities in the table below as a result of the application of clothianidin.  Compliance with the tolerance levels specified below is to be determined by measuring only clothianidin [(E)-N-[(2-Chloro-5-thiazolyl)methyl]-N’-methyl-N”-nitroguanidine] in or on the commodity.

Although additional field trial data are being requested, sufficient data are available to support permanent tolerances on the requested commodities.  HED recommends establishing permanent tolerances for residues of clothianidin as detailed in Table 10.  Note that HED is currently evaluating other petitions for clothianidin requesting registration of seed-treatment uses.

10.3	Occupational and Residential Exposure  TC \l2 "10.3	Occupational and Residential Exposure

None.

Table 10. 	Tolerance Summary for Clothianidin

Commodity	Proposed/Existing

Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;

Correct Commodity Definition

Leafy vegetables, Crop Group 4	3.5	3.0	Adequate data from the foliar application use are available on lettuce (head and leaf), celery and spinach.

Vegetable, leafy, except brassica, Group 4

Brassica (Cole) vegetables, Crop Group 5	3.0	1.9	Adequate data from the foliar application use are available on cabbage, cauliflower and mustard greens.

Vegetable, brassica, leafy, Group 4

Fruiting vegetables, Crop Group 8	0.25	0.20	Adequate data from the foliar application use are available on tomatoes and peppers (Bell and non-Bell).

Vegetable, fruiting, Group 8

Cucurbits vegetables, Crop Group 9	0.05	0.06	Adequate data from the foliar application use are available on cucumbers, cantaloupes and summer squash.

Vegetable, cucurbits, Group 9

Crop Sub-Group 13-07H	0.01	0.01	Adequate data are available on cranberries.

Berry, low-growing, except strawberry, Subgroup 13-07H

Tree nuts, Crop Group 14	0.01	0.01	Adequate data are available on almonds and pecans.  Nut, tree, Group 14.

A separate tolerance is also required for Pistachio.

Pistachio	None	0.01

	Almond, hulls	1.5	1.5	Adequate data are available on almonds.

Fig	0.05	0.05	Adequate data are available on figs.

Pomegranate	0.20	0.20	Adequate data are available on pomegranates.

Peach	0.70	0.80	Adequate data are available on peaches.  0.8 ppm is being recommended for harmonization purposes.

Cotton, seed	0.25	0.20	Adequate data are available on cotton.

Cotton, undelinted seed

Cotton, gin byproducts

Cotton, gin byproducts	4.5	4.5

	Cotton, meal	0.25	None	Adequate cotton seed processing data are available.  As residues were reduced in meal, hulls and oil, separate tolerances are not required.

Cotton, hulls	0.25	None

	Cotton, refined oil	0.01	None

	Soybean, seed	0.03	0.02	Adequate data are available

Soybean, hulls	0.35	None	Adequate soybean processing data are available indicating that quantifiable residues are unlikely to occur in soybean processed fractions

Soybean, meal	0.07	None

	Soybean, oil	0.01	None

	Tomato, paste	0.08	None	Adequate processing data are available on tomato indicating that separate tolerances are not required for tomato puree and paste.

Tomato, puree	0.07	None

	Vegetable, tuberous and corm, Subgroup 1C	0.05	0.3	Adequate residue data are available on potatoes to support a subgroup tolerance on tuberous and corm vegetables.

Once the subgroup tolerance is established the separate tolerance on potatoes can be deleted.  The recommended tolerances are harmonized with current and/or pending MRLs in Canada, and are based on seed piece treatments.  That use produces the highest residue.

Potato	0.05	delete

	Potato, chips	None	0.6

	Potato, granules/flakes	None	1.5

References:  TC \l1 "References:

D260059.	Clothianidin- Briefing Memorandum for Meeting of Metabolism Assessment Review Committee.  Y. Donovan, et al.  25 April 2003

D296176.	Clothianidin - Exposure/Risk Assessment for the Proposed New Uses of Clothianidin on Turfgrass, Landscape Ornamentals and Tobacco.  M. Dow.  24 February 2004.

D303164.	Clothianidin. Tolerance Petition Requesting Food Use of the Insecticide Clothianidin on Grapes, Potatoes, Sorghum, and Cotton (Section 3 Registration). Summary of Analytical Chemistry and Residue Data.  W. Drew.  1 February 2006.

D335355.	Clothianidin. Tolerance Petition Requesting the Establishment of Permanent Tolerances (Associated with Section 3 Registration) for Food/Feed Use of the Insecticide as a Seed Treatment on Sugar Beets. Resolution of Rotational Crop Data Deficiency. Summary of Analytical Chemistry and Residue Data.  W. Drew.  16 October 2007.

D355896.	Clothianidin; Petitions for Tolerances and Uses on Berries Subgroup 13-07H, Brassica Vegetables, Cotton, Cucurbit Vegetables, Figs, Fruiting Vegetables, Leafy Vegetables, Peaches, Pomegranates, Soybeans, Tuberous and Corm Vegetables, and Tree Nuts.  Summary of Analytical Chemistry and Residue Data.  M. Doherty.  30 July 2009

D363340.	Clothianidin: Occupational and Residential Exposure/Risk Assessment of Clothianidin for Section 3 Registration of New Uses on Vegetables, Cotton, Soybean, Tree Nuts, Figs, Pomegranate, Cranberry and Peach.  S. Wang.  17 June 2009.

D364363.	Clothianidin Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments.  M. Doherty.  11 August 2009.

Appendix A:	Toxicology Assessment  TC \l1 "Appendix A:	Toxicology Assessment

A1.	Toxicology Data Requirements TC \l2 "A1.	Toxicology Data Requirements

The requirements (40 CFR 158.340) for food uses for clothianidin are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity

870.1200    Acute Dermal Toxicity

870.1300    Acute Inhalation Toxicity

870.2400    Primary Eye Irritation

870.2500    Primary Dermal Irritation

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)

870.3150    Oral Subchronic (nonrodent)

870.3200    21-Day Dermal

870.3250    90-Day Dermal

870.3465    90-Day Inhalation		yes

yes

yes

no

no	yes

yes

yes

-

-

870.3700a  Developmental Toxicity (rodent)

870.3700b  Developmental Toxicity (nonrodent)

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)

870.4100b  Chronic Toxicity (nonrodent)

870.4200a  Oncogenicity (rat)

870.4200b  Oncogenicity (mouse)

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial

870.5300    Mutagenicity—Gene Mutation - mammalian

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations

870.5xxx    Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)

870.6100b  90-Day Neurotoxicity (hen)

870.6200a  Acute Neurotox. Screening Battery (rat)

870.6200b  90-Day Neuro. Screening Battery (rat)

870.6300    Develop. Neuro		no

no

yes

yes

yes	-

-

yes

yes

yes

870.7485    General Metabolism

870.7600    Dermal Penetration

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

yes

yes	yes

yes

yes

Special Studies

Developmental Immunotoxicity

yes

yes

A2.	Toxicity Profiles TC \l2 "A2.	Toxicity Profiles

Table A.2.1	Acute Toxicity Profile - Clothianidin Technical, Intermediates, and Metabolites

  SEQ CHAPTER \h \r 1 Test Material	Guideline No.	Study Type	MRID(s) Results	Toxicity Category

  SEQ CHAPTER \h \r 1 Technical	870.1100	Acute oral - rat	45422621	LD50 > 5000 mg/kg	IV

BN0230M  Metabolite	870.1100	Acute oral - rat	45422628	LD50 > 2000 mg/kg (♂+♀)	III

BN0335E2 Metabolite	870.1100	Acute oral - rat	45422623	LD50 > 2000 mg/kg (♂+♀)	III

MAI

Metabolite	870.1100	Acute oral - rat	45422629	LD50 = 758 mg/kg (♀)

Males not more susceptible	III

Clothianidin-CCMT-

Adduct Intermediate	870.1100	Acute oral - rat	45422630	LD50 > 2000 mg/kg (♂+♀)	III

Clothianidin-Hexahydropyrimidine Intermediate	870.1100	Acute oral - rat 45422631	LD50 > 2000 mg/kg (♂+♀)	III

Clothianidin-Triazan Intermediate	870.1100	Acute oral - rat	45422632 LD50 > 2000 mg/kg (♂+♀)	III

TMG Metabolite	870.1100	Acute oral - rat	45422625	LD50 < 550 mg/kg (♂)

LD50 = 567 mg/kg (♀)	II

TZMU Metabolite	870.1100	Acute oral - rat	45422624	LD50 = 1424 mg/kg (♂)

LD50 = 1282 mg/kg (♀)	III

TZNG Metabolite	870.1100	Acute oral - rat	45422626	LD50 > 1450 mg/kg (♂)

LD50 = 1481mg/kg (♀)	III

Technical	870.1100	Acute oral - mouse	45422622	LD50 = 389 mg/kg (♂;

95% C.I. = 380-475)

LD50 = 465 mg/kg (♀;

95% C.I. =   SEQ CHAPTER \h \r 1 384-561)

LD50 = 425 mg/kg (♂+♀;

95% C.I. =   SEQ CHAPTER \h \r 1 380-475)	II

Technical	870.1200	Acute dermal - rat	45422634	LD50 > 2000 mg/kg	III

Technical	870.1300	Acute inhalation	45422636	LC50 >   SEQ CHAPTER \h \r 1 5.538 mg/L (♂+♀)	IV

Technical	870.2400	Acute eye irritation	45422701	  SEQ CHAPTER \h \r 1 Slightly irritating to the eye	IV

Clothianidin-CCMT- Adduct Intermediate	870.2400	Acute eye irritation 45422814	  SEQ CHAPTER \h \r 1 Not irritating to the eye	IV

Clothianidin-Triazan Intermediate	870.2400	Acute eye irritation	45422819   SEQ CHAPTER \h \r 1 Not irritating to the eye	IV

Technical	870.2500	Acute dermal irritation	45422703	  SEQ CHAPTER \h \r 1 Not irritating to the skin	IV

Clothianidin-CCMT- Adduct Intermediate	870.2500	Acute dermal irritation 45422813	  SEQ CHAPTER \h \r 1 Not irritating to the skin	IV

Clothianidin-Triazan Intermediate	870.2500	Acute dermal irritation 45422820	  SEQ CHAPTER \h \r 1 Not irritating to the skin	IV

Technical	870.2600	Skin sensitization	45422705	  SEQ CHAPTER \h \r 1 Is not a sensitizer under conditions of study	N/A

Clothianidin-CCMT- Adduct Intermediate	870.2600	Skin sensitization 45422815	  SEQ CHAPTER \h \r 1 Is not a sensitizer under conditions of study	N/A

Clothianidin-Triazan Intermediate	870.2600	Skin sensitization	45422821	  SEQ CHAPTER \h \r 1 Is a sensitizer under conditions of study	N/A

Table A.2.2.	  Subchronic, Chronic and Other Toxicity Profile  for Clothianidin

Guide line	Study Title	MRID	Results

870.3100	90-Day Oral Toxicity - rat (diet)	45422809

(2000)

45422708

(4-week)

Acceptable/

guideline

ppm=0, 150, 500  & 3000

mg/kg/day (M/F)=0/0, 9.0/10.9, 27.9/34.0, 202.0/254.2	NOAEL =   SEQ CHAPTER \h \r 1 27.9/34.0 mg/kg/day   SEQ CHAPTER \h \r 1 (M/F)

LOAEL =   SEQ CHAPTER \h \r 1 202.0/254.2 mg/kg/day (M/F)

based on   SEQ CHAPTER \h \r 1 decreased BW and BW gain.

870.3150	13-Week Oral Toxicity- dog (diet)	45422810

2000

45422808

2000

4-week

45422811

1998

palatability

Acceptable/

guideline

ppm=0, 325, 650, 1500 & 2250

mg/kg/day

(M/F)=0/0, 9.2/9.6, 19.3/21.2, 40.9/42.1, 58.2/61.8  	NOAEL = 19.3/42.1 mg/kg/day (M/F)

LOAEL = 40.9/61.8 mg/kg/day (M/F) based on thinness, decreased body weight, body weight gain and anemia (1 M); and on decreased white blood cells, albumin, and total protein (F).

870.3200	28-Day Dermal Toxicity - rat	45422707 (2000)

Acceptable/

guideline

mg/kg/day= 0, 100, 300 & 1000	NOAEL = 1000 mg/kg/day (HDT)

LOAEL = Not established

870.3700a	Developmental Toxicity- rat (gavage)	45422711 (1998)

45422710 (1998)

range-finding

Acceptable/

guideline

mg/kg/day=0, 10, 40 & 125	Maternal NOAEL = 10 mg/kg/day

Maternal LOAEL = 40 mg/kg/day based on decreased body weight gain and food consumption.

Developmental NOAEL = 125 mg/kg/day (HDT)

Developmental LOAEL = Not established

870.3700b	Developmental Toxicity- rabbit (gavage)	45422713 (1998)

45422712 (1998)

range-finding

Acceptable/

guideline

mg/kg/day=0, 10, 25, 75 & 100	Maternal NOAEL = 25 mg/kg/day

Maternal LOAEL = 75 mg/kg/day based on increased incidences of clinical signs (scant feces and orange urine), mortalities, decreased food consumption, early delivery, abortion, and decreased body weight gain.

Developmental NOAEL = 25 mg/kg/day

Developmental LOAEL = 75 mg/kg/day based on premature deliveries, decreased gravid uterine weights, an increased litter incidence of a missing lobe of the lung, and decreased litter average for ossified sternal centra per fetus.

870.3800	Reproduction (2- Generation)- rat (diet)	45422715 (2000)

45422714 (2000)

pilot

45422716

(2001)

supplemental

45422825 (1999)

rat feed

45422826

(1999)

rat feed

Acceptable/

guideline

ppm=0, 150, 500 & 2500

mg/kg/day

(M/F)=0/0, 9.8/10.7, 31.2/34.3,163.4/188.8	Parental/Systemic NOAEL = 31.2/36.8 mg/kg/day (M/F)

Parental/Systemic LOAEL = 163.4/188.8 mg/kg/day (M/F) based on decreased body weight, body weight gain, and absolute and relative thymus weights.

Reproductive NOAEL = 31.2/188.8 mg/kg/day (M/F)

Reproductive LOAEL = 163.4/not established mg/kg/day (M/F) based on decreased sperm motility and increased number of sperm with detached heads in both generations.

Offspring NOAEL = 9.8/11.5 mg/kg/day (M/F)