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6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 20

6.1 Spray Drift...................................................................................................................... 20

6.2 Residential Bystander Post-Application Inhalation Exposure ....................................... 21

7.0 Aggregate Exposure/Risk Characterization....................................................................... 21

8.0 Cumulative Exposure/Risk Characterization..................................................................... 21

9.0 Occupational Exposure/Risk Characterization .................................................................. 22

9.1 Occupational Handler Risk Estimates............................................................................ 22

9.2 Occupational Post-Application Risk Estimates ............................................................. 25

9.2.1 Dermal Post-Application Risk Estimates................................................................ 25

9.2.2 Inhalation Post-Application Risk Estimates ........................................................... 26

10.0 References.......................................................................................................................... 27

Appendix A. Toxicology Profile and Executive Summaries....................................................... 28

A.1 Toxicology Data Requirements...................................................................................... 28

A.2 Toxicity Profiles............................................................................................................. 29

A.3 Toxicological Doses and Endpoints for Use in Human Risk Assessments....................... 34

Appendix B. Inhalation Exposure Assessment............................................................................ 45

Appendix C. Physical/Chemical Properties................................................................................. 52

Appendix D. Review of Human Research................................................................................... 53
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1.0 Executive Summary

The Agency has been petitioned to register the insecticide thiacloprid [3-[(6-chloro-3-pyridinyl)

methyl]-2-thiazolidinylidene cyanamide] on peppers and stone fruit and to establish tolerances 

for residues of thiacloprid in/on those commodities. Thiacloprid is proposed for foliar 

application to peppers and stone fruits as an aerial or airblast spray made from a 40% active 

ingredient (a.i.) flowable formulation (Calypso 4 Flowable). Applications would be made to 

stone fruits at a maximum single application rate of 0.25 lb ai/A, with a minimum 7-day 

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

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

maximum single application rate of 0.094 lb ai/A, a 7-day RTI, and a 7-day PHI. The total 

application rate for peppers would not exceed 0.28 lb ai/A/season.

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

mode of action is the disruption of the nervous system as an inhibitor at nicotinic acetylcholine 

receptors. In insects, thiacloprid blocks the signals that are induced by acetylcholine at the postsynaptic membrane, resulting in nerve function impairment. The toxicological database shows 

neurological effects in mammals in multiple studies. However, in mammalian systems, the liver 

appears to be the primary target organ with some effects in the thyroid. Liver effects include 

enzyme changes, hypertrophy, and histopathology; noted thyroid effects were changes in 

hormone levels, weights, and follicular cell hypertrophy. This risk assessment uses the 

neurological and liver/thyroid effects as the regulatory endpoints, depending on the route and 

duration of exposure. Given the completeness of the toxicological database, the endpoints and 

points of departure used for risk assessment, and the conservatisms in the assumptions used to 

estimate exposure, HED has reduced the required 10X Food Quality Protection Act (FQPA)

Safety Factor to 1X. Thiacloprid is classified as, “Likely to be Carcinogenic to Humans” based 

on uterine tumors (rat), thyroid tumors (rat, both sexes), and ovarian tumors (mouse). A cancer 

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

uterine tumors in female rats.

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

source of non-occupational exposure is through food and drinking water. In estimating dietary 

exposure, HED has used screening-level assumptions for the acute and chronic (non-cancer) 

assessments, and even with these highly conservative, health-protective assumptions, estimates 

of exposure and risk are below HED’s level of concern. For the acute assessment, risk estimates

for the general U.S. population and all population subgroups are ≤ 19% of the populationadjusted dose (PAD). For the chronic assessment, risk estimates for the general U.S. population 

and all population subgroups are ≤ 26% of the PAD. Generally, HED is concerned when risk 

estimates exceed 100% of the PAD. For assessing cancer risk, HED has refined the exposure 

estimates by using average residue values from field trials and incorporating percent crop treated 

estimates for some commodities, including the projected percent crop treated estimates for 

proposed commodities. The upper-bound cancer risk estimate is 2×10-6for the general U.S. 

population and could be further refined in the future with the use of residue monitoring data.

HED has also assessed dermal and inhalation occupational exposures to thiacloprid. Aggregate 

risk indices (ARIs) range from 6.9 to 240 for handler exposures and from 12 to 60 for post-
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application exposures. Generally, HED has a concern when an ARI is less than one; therefore, 

the estimated ARIs are not of concern. All ARIs were calculated assuming baseline levels of 

personal protective equipment (PPE), with the exception of aerial application scenarios, for 

which engineering controls (closed cockpit) are assumed by default. Cancer risk estimates for 

occupational activities range from 1×10-7to 1×10-5for handlers and from 2×10-4to 4×10-4for 

post-application activities. The post-application cancer risk estimates are very conservative since 

they are based on maximum application rates and Day-0 residue levels. Workers are not 

expected to be exposed to residues at the Day-0 level for all post-application activities.

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. See Section 3.5 and Appendix D for more 

information.

2.0 HED Recommendations

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

fruit and peppers. Therefore, HED recommends granting the requested registrations and 

establishing tolerances as listed in Section 2.2.

Furthermore, HED has reviewed the condition-of-registration data regarding field rotational crop 

studies for soybean and wheat. The condition of registration has been fulfilled and no rotational 

crop tolerances are necessary.

2.1 Data Deficiencies

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

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate HPLC-MS/MS method is available for determination of thiacloprid residues in 

plant matrices. This method uses solvent extraction (methanol:water, 3:1, v:v), clean up on 

solid-phase extraction columns, and separation/quantification by reverse-phase HPLC-MS/MS. 

The lowest limit of method validation, which is the assigned limit of quantitation (LOQ), is 0.02 

ppm and the calculated limit of detection (LOD) is 0.004 ppm thiacloprid. In addition to 

thiacloprid, the method also detects and quantifies the amide and hydroxy-amide metabolites, 

each with an LOQ of 0.02 ppm.

2.2.2 Recommended Tolerances

The proposed uses and the submitted data support the following tolerances for residues of 

thiacloprid in/on:
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Table 2.2.2. Summary of Proposed and Recommended Tolerances for Residues of Thiacloprid.

Commodity Tolerance, ppm Comments (Correct Commodity Definition)

Proposed Recommended

Pepper (bell and non-bell) 1.1 1.0 Recommended value is harmonized with Codex. 

OECD Calculation Procedure Tolerance = 0.6 ppm.

(Pepper)

Fruit, stone, group 12 0.5 0.5 Recommended value is harmonized with Codex. 

OECD Calculation Procedure Tolerance = 0.7 ppm.

(Fruit, stone, group 12-12, except plum)

Plum -- 0.05 OECD Calculation Procedure Tolerance = 0.05 ppm.

2.2.3 Revisions to Petitioned-For Tolerances

The petitioned-for tolerance levels were derived using the NAFTA MRL/Tolerance Calculation 

Procedures rather than the OECD procedures; therefore, there are differences between the values 

calculated by HED (M. Doherty, D406397, 31 October 2012) and those from the petitioner. 

Furthermore, HED’s recommended tolerance levels for peppers and stone fruit (except plums) 

take into account existing CODEX MRLs for residues of thiacloprid in these commodities. A 

separate tolerance for residues in/on plums was not proposed but is required because of the 

significantly lower residues in/on plums relative to those observed in/on the other representative 

stone fruit commodities.

HED notes that subsequent to review of the residue chemistry data (summarized in M. Doherty, 

D378298, 1 Feb 2011) submitted to support the registration and tolerance for residues in/on 

stone fruit, the Agency has updated Crop Group 12 to include additional commodities. In 

conducting this assessment, HED has included evaluation of the updated crop group (Crop 

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

definition.

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

tolerances and tolerance definition:

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

peppers are adequate to support a Codex-harmonized tolerance of 1.0 ppm. A revised 

Section F should be submitted in order to: (i) propose the lower recommended tolerance 

level and (ii) reflect the preferred Agency food and feed commodity vocabulary

(“pepper”).

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

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

Codex-harmonized crop group tolerance of 0.50 ppm (except plum). The petitioner 

should submit a revised Section F in order to (i) reflect the preferred Agency food and 

feed commodity vocabulary (“Fruit, stone, group 12-12, except plum”) and (ii) to provide 

for a separate tolerance of 0.05 ppm for residues in/on plum.

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

residues of the insecticide thiacloprid, including its metabolites and degradates, in or on the 
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commodities. Compliance with the tolerance levels is to be determined by measuring only 

thiacloprid, (Z)-[3-[(6-chloro-3-pyridinyl)methyl]-2-thiazolidinylidene]cyanamide.

2.2.4 International Harmonization

Except for plums, the recommended tolerance levels are harmonized with existing Codex MRLs. 

The significantly different residue levels in the trials with plums as compared to the other 

representative commodities in the stone fruit crop group make it necessary to set a separate 

regulatory level for residues in plums.

2.3 Label Recommendations

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

Flowable and Calypso® 70 WG. HED understands that the 70 WG product is not actually part 

of the petition. A revised Section B should be submitted in which only the Calypso® 4 Flowable

product is listed.

Based on the results of the submitted condition-of-registration field rotational crop studies with 

soybean and wheat, soybean and cereal grains may be added to the list of crops that may be 

rotated after a 30-day plant-back interval.

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Test Compound Nomenclature. 

Compound

Chemical Structure:

Common name Thiacloprid

Company experimental name Thiacloprid

IUPAC name [3-[(6-Chloro-3-pyridinyl)methyl]-2-thiazolidinylidene]cyanamide

CAS name (Z)-[3-[(6-chloro-3-pyridinyl)methyl]-2-thiazolidinylidene]cyanamide

CAS # 111988-49-9

3.2 Physical/Chemical Characteristics

Thiacloprid has a low vapor pressure (8.0×10-10 Pa at 25°C = 6.0×10-12 mmHg), indicating that 

inhalation exposure to gaseous material should be low. The KOW (18) indicates that the potential 

for thiacloprid to bioaccumulate is also low. A listing of the physico-chemical properties of 

technical-grade thiacloprid is included in Appendix C.
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3.3 Pesticide Use Pattern

Table 3.3. Summary of Directions for Use of Thiacloprid.

Applic. Timing, 

Type, and Equip.

Formulation Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Stone Fruit Group 12-12

Foliar application Calypso 4 

Flowable 0.25 Not Specified 0.38 14

Near lakes, rivers, 

permanent streams, marshes

or natural ponds, estuaries, 

and commercial fish farm 

ponds: no aerial application 

within 100 feet; do not 

allow airblast spray to go 

beyond cultivated area.

Pepper

Foliar application Calypso 4 

Flowable 0.094 Not Specified 0.281 7

Near lakes, rivers, 

permanent streams, marshes 

or natural ponds, estuaries, 

and commercial fish farm 

ponds: no aerial application 

within 100 feet; do not 

allow airblast spray to go 

beyond cultivated area. 

The following rotational crop restrictions are specified for the 4 lb/gal SC formulation: Roots, 

tubers, and bulb vegetables whose tops are not used for feed may be rotated with cotton after a 

plant-back interval of 30 days. Leafy vegetables may be rotated after a 6-month plant-back 

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

The Restricted-Entry Interval (REI) specified on the proposed label is based on the acute toxicity 

of thiacloprid. Thiacloprid is classified as Toxicity Category III via the dermal route and 

Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. A quantitative postapplication risk assessment indicates that risk estimates were not a concern on day 0 (i.e., 12 

hours following application) for all post-application activities. Therefore, the Worker Protection 

Statement interim REI of 12 hours is adequate to protect agricultural workers from postapplication exposures to thiacloprid. 

The Personal Protective Equipment (PPE) statement on the proposed label requires applicators, 

flaggers and other handlers to wear: long-sleeved shirt and long pants, socks, shoes, chemicalresistant gloves made of nitrile, butyl, neoprene and/or barrier laminate.

3.4 Anticipated Exposure Pathways

Since thiacloprid may be applied directly to growing crops and application may result in 

thiacloprid reaching surface and ground water sources of drinking water, humans may be 

exposed to residues of thiacloprid through the diet in their food and drinking water. There are no 

residential uses of thiacloprid, so there is not likely to be exposure in residential or nonoccupational settings. In an occupational setting, workers may be exposed via the dermal and 
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inhalation routes while handling the pesticide prior to application, during application, and 

following application. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in 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 National 

Health and Nutrition Examination Survey (NHANES) What We Eat in America (WWEIA) 

program, and are used in pesticide risk assessments for all registered food uses of a pesticide. 

These data are analyzed and categorized by subgroups based on age, season of the year, ethnic 

group, and region of the country. Additionally, OPP is able to assess 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 post-application, are evaluated. Further considerations are 

currently in development as OPP has committed resources and expertise to the development of 

specialized software and models that consider exposure to bystanders and farm workers as well 

as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

Based on the proposed use pattern, the toxicology database for thiacloprid is largely complete. 

In compliance with the current data requirements in the 40 CFR Part 158 for conventional 

pesticide registration, an immunotoxicity study in mice and/or rats is required. However, the 

overall toxicity profile indicates that this chemical does not directly target the immune system; 

therefore, the toxicology studies that are available are adequate for conducting a risk assessment. 

These include: acute lethality studies (oral, dermal and inhalation routes); primary eye irritation, 

dermal irritation and sensitization; subchronic oral toxicity (rat, mouse and dog); rat 28-day 

dermal toxicity; rat 21/28-day inhalation toxicity (also 4-hour and 5-day studies); rat acute,

subchronic, and developmental neurotoxicity; dog chronic toxicity; rat chronic 

toxicity/carcinogenicity; mouse carcinogenicity; genotoxicity battery; developmental toxicity (rat 

and rabbit); rat two-generation reproductive toxicity; dermal absorption in monkeys; and rat 

general metabolism/pharmacokinetics. 
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4.2 Absorption, Distribution, Metabolism, & Excretion (ADME)

Thiacloprid is rapidly absorbed and rapidly excreted after a series of metabolic processes, with 

little remaining in the tissues. In the rat metabolism study, 86-106% of the administered 

radioactivity (AR) was recovered by 48 hours. Orally, rapid absorption occurred with maximum 

plasma concentrations 1-2 hours and 3-4 hours after dosing for 1- and 100-mg/kg doses, 

respectively. Following intravenous dosing maximum plasma concentrations occurred within 20 

minutes. Distribution to tissues was extensive and was followed by rapid removal. Excretion in 

urine (60-70%) was greater than in feces (30-40%) and there were minor gender-related 

differences in the excretion time. The primary urinary metabolites were WAK 3583 (16-34%

AR), 6-CAN (7-9% AR), and KNO 1893 (4-12% AR). Other metabolites accounted for <4% of 

the AR. The metabolic processes are: 1) hydroxylation of the thiazolidine ring and subsequent 

glucuronidation (as shown by metabolite PIZ 1270), 2) hydroxylation of the cyanamide moiety 

(metabolite KNO 1891), 3) opening of the thiazolidine ring (e.g., metabolites KNO 2672, PIZ 

1297F/WAK 6935), 4) formation of an oxazole ring (metabolite PIZ 1269X), and 6) oxidative 

cleavage of the methylene bridge (PIZ 1243). Only minor gender-related quantitative 

differences in metabolite profiles were observed. No biliary excretion studies were conducted.

4.2.1 Dermal Absorption

A dermal absorption study is available for thiacloprid. The study was conducted in monkeys 

with a 40.4% liquid formulation (suspension concentrate containing 480 g a.i./L) of thiacloprid 

and a 5% dermal absorption value was determined after 8 hours. It was also determined that the 

absorption value is suitable for assessing other liquid formulations that are similar to the SC 480 

product, as well as for aqueous dilutions of most thiacloprid formulations.

4.3 Toxicological Effects

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

mode of action is the disruption of the nervous system as an inhibitor at nicotinic acetylcholine 

receptors. In insects, thiacloprid blocks the signals that are induced by acetylcholine at the postsynaptic membrane, resulting in nerve function impairment. The mammalian mode of action is 

unknown. 

In mammalian systems, the liver appears to be the primary target organ with some relatively 

minor effects in the thyroid. Liver effects (enzyme changes, hypertrophy, and histopathology) 

were noted in the 90-day dog, 2-generation reproduction, 2-year rat, 2-year mouse, and 

subchronic dermal and inhalation studies. Thyroid effects (hormone levels, weights, follicular 

cell hypertrophy) were noted in dog, rat, and mouse studies. Increased prostate weight and

prostatic hypertrophy were observed in the 90-day dog study, but not in the 1-year dog study. 

Clinical signs were also noted in dermal (reduced motility, decreased activity, and spastic gait) 

and 5 day inhalation studies (respiratory effects, signs of ill health, piloerection, reduced 

mobility, tremors, and increased grip strength).

There was no increase in either qualitative or quantitative susceptibility of fetal animals or pups

in the rabbit developmental or the 2-generation rat reproduction studies. In the rabbit 
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developmental study, decreased fetal weights were observed in the presence of maternal toxicity 

(body weight changes and decreased food consumption and fecal output). In the reproduction 

study in rats, decreased body weights were seen in pups at the same dose which resulted in

thyroid and liver effects in maternal animals. 

In the rat developmental toxicity study, there was evidence of increased qualitative susceptibility. 

Increased resorptions; skeletal retardations and variations; dysplastic humerus, radius and 

scapulae; and decreased fetal weights were seen in fetuses at the same dose resulting in less 

severe maternal effects (decreased body weight, body weight gain and food consumption, 

increased urination, and changes in water consumption). In the developmental neurotoxicity 

study, increased qualitative susceptibility was also seen: Decreased body weights in both sexes 

as well as altered performance in passive avoidance testing were seen in offspring animals, while 

deceased body weight gain and food consumption were seen in maternal animals. However, 

there is a low degree of concern and no residual uncertainties for the increase in qualitative 

susceptibility since there are well-characterized dose responses with clear NOAELs and 

LOAELs in the studies and there is no evidence of any quantitative susceptibility. Additionally, 

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

effects.

Thiacloprid affects nerve function through inhibition of nicotinic acetylcholine receptors. In the 

neurotoxicity studies in rats, there was a reduction in motor and locomotor activity, slight 

tremors and ptosis of the eyelids, decreased hind limb grip strength, altered performance in 

passive avoidance testing, and altered brain morphometrics. Increased grip strength was also 

noted in a 5-day inhalation toxicity study. There were no indications of neurotoxicity in the 

remainder of the submitted toxicity studies. See Section 4.4.2 for details.

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

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

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

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

tumors in female rats.

Acute lethality studies with thiacloprid indicate moderate acute toxicity via the oral route 

(Category II) and low toxicity via the dermal or inhalation routes (Categories III). There was no 

evidence of primary eye irritation, skin irritation, or dermal sensitization.

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

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

and children. Thus, FQPA hazard considerations were addressed in HED’s evaluation of the 

toxicological database. HED recommends that the 10x FQPA Safety Factor (for the protection 

of infants and children) be reduced to 1x. This recommendation is supported by the following:

1) The toxicology database concerning infants and children is considered to be complete 

with the exception of an immunotoxicity study. Although an immunotoxicity study has 
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not been received by the Agency, there is relatively little concern as it does not appear 

that the chemical directly targets the immune system;

2) Although brain morphometric changes were seen in the DNT study, the established 

points of departure for risk assessment are protective of the DNT morphometric changes 

seen at the high dose. These brain effects were considered marginal and highly variable; 

3) The inhalation POD is protective of potential deep lung effects, nasal irritation, and 

systemic effects resulting from inhalation exposure;

4) There is no evidence of any quantitative sensitivity and there are well characterized dose 

responses with clear NOAELs and LOAELs in the rat developmental and developmental 

neurotoxicity studies where increased qualitative susceptibility was seen. Additionally, 

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

database;

5) The dietary exposure assessments are based on high-end, health protective residue levels 

and processing factors for foods, and upper-bound assumptions were used to determine 

exposure through drinking water; and

6) No residential exposure is expected for children. 

4.4.1 Completeness of the Toxicology Database 

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

exception of an immunotoxicity study. Submitted studies included: developmental rat and 

rabbit, 2-generation reproduction in rats as well as acute, subchronic and developmental 

neurotoxicity in rats. Although an immunotoxicity study has not been received by the Agency, 

there is relatively little concern as it does not appear that thiacloprid directly targets the immune 

system based on available studies. Although there were increases in the incidence and severity 

of mesenteric and mandibular lymph node vacuolization in a cancer study in mice, the effects 

were seen at very high doses following long-term treatment. Additionally, thiacloprid does not 

belong to a class of chemicals (e.g., the organotins, heavy metals, halogenated aromatic 

hydrocarbons) that would be expected to be immunotoxic. Furthermore, there were no 

indications of immunotoxicity in other studies in the toxicology database. HED does not believe 

that conducting the study will result in a lower point of departure (POD) than that currently used

for overall risk assessment; therefore, a database uncertainty factor (UFDB) is not needed to 

account for the lack of the study.

4.4.2 Evidence of Neurotoxicity

Acute, subchronic and developmental neurotoxicity studies in rats are available for thiacloprid. 

In the acute study, there were reductions in motor and locomotor activities in females and slight 

tremors and ptosis of the eyelids in males. In the subchronic neurotoxicity study, decreased hind 

limb grip strength was seen in males. Increased grip strength was noted in a 5-day inhalation 

toxicity study. In the developmental neurotoxicity study, altered performance in passive 

avoidance testing and a 4% decrease in the size of the corpus striatum region of the brain were 

seen in offspring animals at the highest dose tested. No data were received by the Agency 

regarding the mid- and low-dose brain measurements. However, the lack of a NOAEL for brain 

morphometric measurements in this study does not warrant an additional uncertainty factor since 

the decrease in weight is considered marginal and variable at the high dose, and a lower dose 
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would most likely result in less of an effect (the highest dose tested was 10x greater than the 

lowest dose tested), and the endpoints and PODs selected for risk assessment are protective of 

the slight morphometric changes observed at the high dose. There were no indications of 

neurotoxicity in the remainder of the submitted toxicity studies.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

In the rat developmental study, there was an increase in qualitative susceptibility based on an 

increase in resorptions, skeletal retardations and variations, dysplastic humerus, radius and 

scapulae, as well as decreased fetal weights at the same dose (50 mg/kg/day) at which less severe 

maternal effects were noted (decreased body weight, body weight gain and food consumption in 

addition to increased urination and changes in water consumption). In the developmental 

neurotoxicity study, increased qualitative susceptibility was also seen: Decreased body weights 

in both sexes as well as altered performance in passive avoidance testing were seen in offspring 

animals, while deceased body weight gain and food consumption were seen in maternal animals. 

However, there is a low degree of concern and no residual uncertainties for the increase in 

qualitative susceptibility since there is a well-characterized dose response with clear NOAELs

and LOAELs in the studies and there is no evidence of any quantitative susceptibility. 

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

developmental effects.

4.4.4 Residual Uncertainty in the Exposure Database

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

based on conservative, health protective assumptions regarding exposure from food and drinking 

water and are designed not to underestimate exposures. There are no residential uses at this time

and inadvertent residential exposures (i.e., spray drift and bystander exposure) have been 

adequately addressed (see Sections 6.1 and 6.2).

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The detailed descriptions of the toxicity studies used for selecting toxicity endpoints and points 

of departure for various exposure scenarios are presented in Appendix A.3. Currently there are 

no existing or proposed residential uses of thiacloprid; however, endpoints and PODs for 

residential exposure were selected to address potential future residential uses.

For acute dietary exposure assessments (all populations), the NOAEL of 4.4 mg/kg/day from the 

developmental neurotoxicity study in rats was used for risk assessment, based on offspring 

effects of altered performance in passive avoidance testing at a LOAEL of 25.6 mg/kg/day. The 

acute neurotoxicity study in rats was selected as a co-critical study, based on reductions in motor 

and locomotor activity at the LOAEL of 11 mg/kg/day (NOAEL = 3.1 mg/kg/day). The effects 

in the studies are attributable to a single dose, and the route and duration of exposure from these 

co-critical studies are appropriate for selection of the acute dietary endpoint. The POD and 

endpoint selected are protective of the marginal and variable brain morphometric changes seen in 
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the DNT study at the high dose of 40.8 mg/kg/day, as well as effects (resorptions) observed in 

developmental studies in rats and rabbits. 

For chronic dietary exposure, the NOAEL of 1.2 mg/kg/day from the combined 

chronic/carcinogenicity study in rats was used for risk assessment, based on liver hypertrophy 

and cytoplasmic changes, thyroid hypertrophy and induction of the enzymes UDP-Glu-T and 

aromatase, as well as the induction of hepatic enzymes and retinal degeneration in females at the 

LOAEL of 2.5 mg/kg bw/day. The dose and endpoint (liver and thyroid toxicity as well as 

retinal degeneration in females) are appropriate since they reflect chronic (lifetime) dosing via 

the oral (diet) route. The NOAEL and LOAEL from this study are the lowest doses in the 

toxicity database for chronic durations.

For short-term incidental oral exposure, the offspring NOAEL of 4.2 mg/kg/day from the 

reproduction study in rats was used for risk assessment, based on the observed decreased pup 

weight during lactation at the LOAEL of 21 mg/kg/day. The endpoint selected is appropriate for 

the exposure duration and the population of concern (children). It is also protective of the 

neurotoxicity effects seen in the ACN, SCN and DNT studies at ≥ 11 mg/kg/day. At this time, 

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

risk assessment

For short- and intermediate-term dermal exposure, the systemic NOAEL of 300 mg/kg/day from 

a subchronic dermal toxicity study was used for risk assessment, based on liver and thyroid 

changes, reduced motility, decreased activity, and spastic gait at the LOAEL of 1000 mg/kg/day. 

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

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

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

in maternal animals were adequately measured in the dermal toxicity study. Additionally, the 

subchronic neurotoxicity study was considered. However, the dermal equivalent dose (DED) 

calculated (based on 5% dermal absorption factor) for the study was higher than the point of 

departure (POD) of 300 mg/kg/day from the dermal toxicity study. Therefore, the dermal 

toxicity study was selected and it is considered protective of potential developmental, 

reproductive, and neurotoxic effects.

For short- and intermediate-term inhalation exposure, a 5-day inhalation toxicity study in rats 

was used for risk assessment. The systemic NOAEL is 2 mg/m3. The systemic LOAEL is 20 

mg/m3based on increased grip strength in both sexes. The portal-of-entry LOAEL for the 5-day 

study is 200 mg/m3based on bradypnea, labored breathing pattern, piloerection and decreased 

rectal temperature. The endpoint and systemic POD from the 5-day study are protective of 

portal-of-entry effects in that study, as well as both systemic and portal-of-entry effects noted in 

a 21/28-day inhalation toxicity study. The systemic HEC was converted to a human equivalent 

dose (HED) of 0.24 mg/kg/day and used for risk assessment (calculations shown in Appendix B). 

Based on the proposed use pattern for thiacloprid, long-term dermal and inhalation exposures are 

not anticipated.
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For acute and chronic dietary risk assessments, a 100X uncertainty factor was applied 

(interspecies factor of 10X and intraspecies factor of 10X). For incidental oral and dermal 

exposure, the LOC for the MOE is 100 (10X interspecies, 10X intraspecies factors). For 

inhalation risk assessments, the LOC is 30 (interspecies factor of 3X and intraspecies factor of 

10X) since human equivalent calculations (HECs) were used for risk assessment. The 

interspecies factor was reduced from 10X to 3X because the HEC calculation accounts for 

pharmacokinetic (not pharmacodynamic) interspecies differences between animals and humans. 

We note, again, that the incidental oral exposure pathway is not relevant for this risk assessment 

since there are no residential uses.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For thiacloprid, dermal and inhalation exposures should be combined when assessing shortand/or intermediate-term exposure scenarios since endpoints are based on the same toxicological 

effects (neurotoxicity). 

4.5.3 Cancer Classification and Risk Assessment Recommendation

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

incidence of uterine tumors in rats, thyroid follicular cell adenomas in rats (both sexes), and 

ovarian tumors in the mice. A linear low-dose approach for cancer risk was recommended for 

thiacloprid, a cancer slope factor of 4.06×10-2(mg/kg/day)-1 was calculated based on the 

incidence of combined uterine tumors in female rats. 

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

uterine tumors in rats and ovarian tumors in mice. At that time the data were determined to be 

inadequate. Subsequently, the registrant submitted additional data and proposed a new mode of 

action for the uterine tumors in rats. Although the proposed MOA was considered plausible, it 

was concluded that the data were inadequate to establish a non-linear, hormonal mode of action 

(MOA) for the uterine tumors. 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4. a. Toxicological Doses and Endpoints for Thiacloprid for Use in Dietary and Non-Occupational

Human Health Risk Assessments

Exposure/ Scenario Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD/ Level 

of Concern for 

Risk Assessment

Study and Toxicological Effects

Acute Dietary

All Populations

NOAEL = 

4.4

mg/kg/day 

UFA=10x

UFH = 10x

FQPA SF =1x

aRfD=0.044

mg/kg/day

aPAD=0.044

mg/kg/day

Co-Critical Studies

Developmental Neurotoxicity Study-rat

LOAEL=25.6 mg/kg bw based on 

offspring effects of altered performance 

in passive avoidance testing.

Acute Neurotoxicity Study – rat

LOAEL = 22 mg/kg bw based on a 

reduction of motor and locomotor 

activity in females (NOAEL = 3.1 
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Table 4.5.4. a. Toxicological Doses and Endpoints for Thiacloprid for Use in Dietary and Non-Occupational

Human Health Risk Assessments

Exposure/ Scenario Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD/ Level 

of Concern for 

Risk Assessment

Study and Toxicological Effects

mg/kg bw).

Chronic

All Populations 

including

Infants/Children

NOAEL = 

1.2 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF =1x

cRfD =0.012

mg/kg/day

cPaD =0.012

Chronic/Carcinogenicity Study- rat

LOAEL = 2.5/3.3 (M/F) mg/kg bw

based on liver hypertrophy and 

cytoplasmic changes as well as 

induction of enzymes, thyroid epithelial 

hypertrophy in males and retinal 

degeneration in females.

Incidental Oral

(Short-Term)

Not Relevant at this 

time

NOAEL = 

4.2 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF =1x

LOC for MOE = 

100

(residential)

Two-Generation Reproduction Study –

rat

LOAEL = 21 mg/kg bw/day based on a 

decrease in pup weight during lactation.

Dermal

(Short-and 

Intermediate-Term)

Not relevant at this 

time.

Systemic 

NOAEL 

=300 

mg/kg/day 

UFA= 10x

UFH = 10x

FQPA SF =1x

LOC for MOE = 

100

(residential)

21/28 – Day Dermal Study – rat

Systemic LOAEL = 1000 mg/kg/day 

based on liver and thyroid effects plus 

clinical signs (reduced motility, 

decreased activity, and spastic gait). 

No dermal irritation noted. 

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

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

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

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (intraspecies). UFH = potential variation in 

sensitivity among members of the human population (interspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable.

 

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

Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal

(Short-and 

Intermediate-Term)

Systemic 

NOAEL 

=300 

mg/kg/day 

UFA= 10x

UFH = 10x

LOC for MOE = 

100

(occupational)

21/28 – Day Dermal Study – rat

Systemic LOAEL = 1000 mg/kg/day 

based on liver and thyroid effects plus 

clinical signs (reduced motility, 

decreased activity, and spastic gait). 

No dermal irritation noted. 

Inhalation 

Short and 

Intermediate

Durations

NOAEL=2 

mg/m3

(0.002mg/L)

HEC = 

0.005 mg/L

(based on 

systemic 

effects)

UFA= 3x

UFH = 10x

LOC for MOE = 

30

(occupational)

5-day (6 hours/day) Inhalation Toxicity 

Study in Rats 

At the LOAEL of 20 mg/m3(0.02mg/L) 

increased grip strength was seen. 
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HED=0.24 

mg/kg/day

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

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

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

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (intraspecies). UFH = potential variation in 

sensitivity among members of the human population (interspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

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

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression.

Matrix Residues included in Risk Assessment Residues included in 

Tolerance Expression

Plants Primary Crop Thiacloprid + metabolites retaining the thiazolidine ring Thiacloprid

Rotational Crop Thiacloprid + metabolites retaining the thiazolidine ring Thiacloprid

Livestock Ruminant Thiacloprid + metabolites retaining the thiazolidine ring Thiacloprid

Poultry Thiacloprid + metabolites retaining the thiazolidine ring Thiacloprid

Drinking Water Thiacloprid + Amide metabolite* Not Applicable

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

HED’s Metabolism Assessment Review Committee reasoned that because thiacloprid has 

limiting toxic effects that are different from imidacloprid, and these effects also do not appear to 

be mediated by nicotinic receptors, these effects must be partly or wholly associated with the 

thiazolidine portion of thiacloprid (D288833, 7 April 2003). Thus, metabolites retaining the 

intact thiazolidine ring are included in the residue definition for risk assessment.

With respect to drinking water, the registrant has provided data showing that the amide 

metabolite is removed by drinking water treatment processes and would, therefore, not be 

present in drinking water obtained from public water systems. The amide metabolite remains a 

residue of concern for groundwater that does not undergo drinking water treatment. 

5.2 Food Residue Profile

Adequate data are available to assess the requested uses on stone fruit and peppers. In field 

trials, crops were treated at the maximum application rate and harvested at the shortest PHI 

proposed on the label. Residue results showed that quantifiable residues of thiacloprid occurred 

in at least one sample in all studies; the amide and hydroxy amide metabolites were below the 

LOQ in all samples. Residues of thiacloprid declined with increasing PHI in all pepper and 

stone fruit studies. The extent of the decline over time varied across the crops, with some crops 

showing extensive decline (e.g., peppers; 0.08 ppm on Day 0, <0.01 ppm on Day 14) and others 

showing a more moderate decrease (e.g., plums; 0.05 ppm on Day 0, 0.03 ppm on Day 28).
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5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the 

Environmental Fate and Effects Division (EFED) in the following memorandum: “Thiacloprid: 

Update of the Drinking Water Exposure Assessment for Section 3 New Uses on Stone Fruits and 

Peppers” (D376184, G. Orrick, 07/12/2012) and incorporated directly into this dietary 

assessment.

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

for the acute, chronic, and cancer assessments. For the acute point estimate, the 1-in-10-year 

annual maximum concentration estimate of 0.018 ppm was entered. For the chronic point 

estimate, the 1-in-10-year annual mean concentration estimate of 0.0023 ppm was entered. For 

the cancer assessment, the overall 30-year mean concentration estimate of 0.0012 ppm was 

entered. All of these PRZM/EXAMS surface water estimates are protective of the ground water 

exposure estimates from the SCI-GROW model (Table 5.3). 

The drinking water estimates used in this assessment have been refined to account for both 

percent cropped area and for the impact of drinking water treatment processes. Thiacloprid and 

its amide are the only residues of concern in untreated drinking water. Following drinking water 

treatment, thiacloprid is the only residue of concern expected to be present. This is because the 

submitted drinking water treatment study data indicate that 1) coagulation does not remove 

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

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

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

treatment products of thiacloprid-amide are not residues of concern due to the fact that they do 

not contain the thiazolidine ring. Because surface water sourced drinking water is typically 

treated, thiacloprid is the only compound of concern for the surface water estimates. The ground 

water estimates listed below include both thiacloprid and thiacloprid-amide as they will not 

always be treated, whereas the surface water estimates include only thiacloprid. 

Table 5.3. Total Thiacloprid EDWCs in Surface Water and Ground Water for Use in Dietary Risk 

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

Use (maximum rate) Source PCA 

(%)

1-in-10-year 

Peak Exposure 

(ppb)

1-in-10-year 

Annual Mean 

Exposure (ppb)

30-year Mean 

Exposure (ppb)

Pome fruits

(0.50 lbs a.i./A/year)

Surface water (treated) 91 18 2.3 1.2

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

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute and chronic analyses are based on tolerance-level residues and 100% crop treated 

assumptions for both existing and proposed new uses. With the exception of empirically derived 

processing factors for pome fruit (apples and pears) and stone fruit (peaches and plums), default 

processing factors were used for all commodities. The empirical processing factors for pome 
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fruit were based on previously reviewed studies and are as follows: 0.82X all peeled apples; 

0.68X for applesauce; 0.51X for dried apples and pears; 0.23X for apple juice; and 0.87X for 

pear juice (D. Soderberg, D289292, 23-June-2003). Based on recently submitted processing 

studies for the new uses on stone fruit, empirically derived processing factors of 3.6X on dried 

peaches and 3.1X on dried plums were utilized. It is noted that the most recent (2003) dietary 

exposure assessment had partially refined acute and chronic assessments, which included the use 

of percent crop treated data and average residue field trial data. Recent changes in the 

toxicological endpoints and FQPA safety factor make these refinements no longer necessary for 

the acute and non-cancer chronic analyses.

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

crop treated (PCT) estimates for existing and proposed new uses as appropriate. As with the 

acute and chronic analyses, default processing factors were used with the exception of pome and 

stone fruit commodities, where empirical processing factors were utilized as described above.

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

non-quantifiable residues of the amide metabolites, the use of field-trial thiacloprid residues in 

the risk assessment should adequately address the full risk assessment residue definition without 

correcting the values to account for all thiazolidine-ring containing metabolites.

5.4.2 Percent Crop Treated Used in Dietary Assessment

For the acute and chronic assessments, HED assumed 100% crop treated for all registered and 

requested uses of thiacloprid. For the cancer assessment, estimates of percent crop treated were 

used as follows:

Apples....................10% (J. Alsadek, 4 October 2012)

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

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

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

5.4.3 Acute Dietary Risk Assessment

For acute exposures, the dietary risk for the U.S. population is estimated to be 6.2% of the aPAD

at the 95th percentile. Acute risks for infants <1 year old, the highest-exposed population 

subgroup, is estimated to be 19% of the aPAD at the 95th percentile. 

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

residues in food, 100% crop treated assumptions, and partially refined drinking water estimates 

to account for percent cropped area and drinking water treatment processes.

5.4.4 Chronic Dietary Risk Assessment

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

cPAD. Chronic risk for children 1-2 years old, the highest-exposed population subgroup, is 

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

on unrefined tolerance-level residues in food, 100% crop treated assumptions, and partially 
Thiacloprid Human Health Risk Assessment DP No. D376178

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refined drinking water estimates to account for percent crop treated area and drinking water 

treatment processes.

5.4.5 Cancer Dietary Risk Assessment

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

estimates for existing uses and projected PCT (PCTnew) for proposed new uses as appropriate. 

As with the acute and chronic analyses, default processing factors were used with the exception 

of those for pome- and stone-fruit commodities, where empirical processing factors were utilized 

as described above. The cancer risk estimate for the U.S. population is 2×10-6for food + water. 

Drinking water accounts for approximately half of this risk (1×10-6). 

5.4.6 Summary Table

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

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

% cPAD*

Dietary 

Exposure

(mg/kg/day)

Risk

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

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

N/A N/A

Children 1-2 years old* 0.007996 18 0.003106 26

Children 3-5 years old 0.005457 12 0.001859 16

Children 6-12 years old 0.003399 7.8 0.000961 8.0

Youth 13-19 years old 0.001901 4.3 0.000444 3.7

Adults 20-49 years old 0.001852 4.2 0.000380 3.2

Adults 50+ years old 0.001768 4.0 0.000414 3.5

Females 13-49 years old 0.001867 4.2 0.000388 3.2

*The subpopulation(s) with the highest risk estimates are bolded. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

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

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

Potential spray drift and bystander inhalation exposures are discussed below.

6.1 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for thiacloprid. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information1). On a 

chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial 

applications that must be placed on product labels/labeling. The Agency has completed its 

 

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. 

pesticide registrants, and is developing a policy on how to appropriately apply the data and the 

AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast,

and ground hydraulic methods. After the policy is in place, the Agency may impose further 

refinements in spray drift management practices to reduce off-target drift with specific products 

with significant risk estimates associated with drift.

6.2 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

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

inhalation toxicity (Toxicity Category III), low vapor pressure (8.0×10-10 Pa at 25°C = 6.0×10-12

mmHg), and the low proposed use rates (0.047-0.25 lb ai/A). However, volatilization of 

pesticides may be a source of post-application inhalation exposure to individuals nearby 

pesticide applications. The Agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 20102. The Agency is in the process of evaluating the SAP report and may, as 

appropriate, develop policies and procedures to identify the need for and, subsequently, the way 

to incorporate post-application inhalation exposure into the Agency's risk assessments. If new 

policies or procedures are developed, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for thiacloprid.

Although quantitative exposure assessments were not performed to address pesticide drift from 

neighboring treated agricultural fields or residential bystander post-application inhalation, an 

inhalation exposure assessment was performed for flaggers. Risk estimates for the flagger 

scenario are approximately 10-7and are below HED’s level of concern. This exposure scenario 

is representative of a worst-case inhalation (drift) exposure and may be considered protective of 

most outdoor agricultural and commercial post-application inhalation exposure scenarios, 

including spray drift and bystander exposures.

7.0 Aggregate Exposure/Risk Characterization

As previously noted, there are no uses of thiacloprid that would result in residential exposures; 

therefore, aggregate risk estimates are equivalent to the dietary risk estimates described in 

Section 5.4.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding 

regarding thiacloprid and any other substances, and thiacloprid does not appear to produce a 

toxic metabolite produced by other substances. For the purposes of this tolerance action, 

therefore, EPA has not assumed that thiacloprid has a common mechanism of toxicity with other 

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

 

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

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common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

It is the policy of HED to use the best available data to assess handler and post-application

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

data, include PHED 1.1, and the AHETF database. Some of these data are proprietary (e.g., 

AHETF data), and subject to the data protection provisions of FIFRA. The standard values 

recommended for use in predicting exposure that are used in this assessment, known as “unit 

exposure” for handler activities and “transfer coefficients” for post-application activities, are 

outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table3” and 

in the ExpoSAC Policy 34, respectively. Additional information on HED’s policy on use of 

surrogate data, including descriptions of the various sources, can be found at the Agency 

website5. 

9.1 Occupational Handler Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications, and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event.

Based on the proposed use patterns and labeling, HED has developed quantitative occupational 

handler exposure and risk estimates for the following scenarios:

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

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

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

• Applying Sprays with Groundboom Equipment,

• Applying Sprays with Aerial Equipment,

• Applying Sprays with Airblast Equipment, and

• Flagging for Aerial Applications.

Estimates of dermal and inhalation exposure were calculated for various levels of personal 

protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of 

clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and 

no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, 

etc). The thiacloprid product labels direct mixers, loaders, applicators and other handlers to wear 

 

3 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

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

5 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
Thiacloprid Human Health Risk Assessment DP No. D376178

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long-sleeved shirt and long pants, socks, shoes, chemical-resistant gloves made of Nitrile, Butyl, 

Neoprene, and/or Barrier Laminate.

No data on the number of exposure days per year were provided. For thiacloprid, based on the 

proposed use patterns and directions (e.g., 1-6 applications per season with a minimum 7-14 day 

spray interval depending on the use), short- (1-30 days) and intermediate-term (1-6 months)

exposures are expected for handlers. The short- and intermediate-term endpoints and PODs are 

the same for each exposure route; therefore, only short-term handler exposures were estimated

and are considered protective for intermediate-term exposure and risk. Long-term exposures are 

not expected. For the cancer assessments, the exposure estimates assume an occupational period 

of 35 years out of a 78-year lifespan. Since private growers are assumed to be exposed for fewer 

days per year (i.e., exposed 10 days per year) than commercial applicators (i.e., exposed 30 days 

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

private growers.

The non-cancer exposure and risk estimates for occupational handlers using thiacloprid are 

presented in Table 9.1.1. For the proposed uses on peppers and stone fruits, all of the non-cancer 

occupational handler scenarios resulted in MOEs equal to or greater than the respective levels of 

concern (i.e., MOEs ≥100 for dermal and ≥30 for inhalation) at the baseline level of PPE and 

with the use of engineering controls for aerial applications (i.e., assuming a closed cockpit, 

which is HED’s default for aerial application scenarios). The non-cancer dermal and inhalation 

risks were also combined using the ARI approach. ARIs equal to or greater than 1 are not of 

concern. The ARIs ranged from 6.9 to 240 and are not of concern. The lowest ARI of 6.9 was 

for handlers who apply thiacloprid to stone fruit using airblast application equipment. These 

ARIs would be even higher if they had been calculated assuming handlers use the PPE 

recommended on the proposed label.

A summary of the cancer exposure and risk estimates for pesticide handlers for the proposed 

crops is provided in Table 9.1.2. Based on a cancer potency factor of 0.0406 (mg/kg/day)-1and 

the maximum single application rates, cancer risk estimates calculated for handler activities 

range from 6.8 x 10-7to 1.2 x 10-5 with either baseline PPE or engineering controls (e.g., 

enclosed cockpit for aerial applications) assuming workers will be exposed 30 days per year for 

35 years out of a 78-year lifespan. 

Table 9.1.1. Summary of Short- and Intermediate-Term Occupational Non-Cancer Exposure and Risk 

Estimates for Thiacloprid. 

Exposure Scenario Crop

Personal 

Protective 

Equipment

Dermal Inhalation

ARI8 Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7

Mixer/Loader

Flowable Concentrate 

(Liquid) for Groundboom 

Applications (AHETF)

Peppers Baseline 0.0206 15,000 0.0000206 12,000 110

Flowable Concentrate 

(Liquid) for Aerial 

Applications (AHETF)

Peppers Baseline 0.0905 3,300 0.0000901 2,700 24

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

Flowable Concentrate 

(Liquid) for Airblast 

Applications (AHETF)

Stone Fruits Baseline 0.0275 11,000 0.0000274 8,800 80
Thiacloprid Human Health Risk Assessment DP No. D376178

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Table 9.1.1. Summary of Short- and Intermediate-Term Occupational Non-Cancer Exposure and Risk 

Estimates for Thiacloprid. 

Exposure Scenario Crop

Personal 

Protective 

Equipment

Dermal Inhalation

ARI8 Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7

Applicator

Sprays for Groundboom 

Applications (AHETF) Peppers Baseline 0.00739 41,000 0.000032 7,500 160

Sprays for Aerial 

Applications (AHETF)

Peppers

Engineering 

Controls -

Enclosed cockpit

0.00206 150,000 0.0000280 8,600 240

Stone Fruits

Engineering 

Controls -

Enclosed cockpit

0.00584 55,000 0.0000744 3,200 89

Sprays for Airblast 

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

Flagger

Flagging for Aerial 

Applications (PHED)

Peppers Baseline 0.00453 66,000 0.000144 1,700 52

Stone Fruits Baseline 0.01200 25,000 0.000383 630 19

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September, 2012); includes data from PHED/AHETF 

(Level of Mitigation: Baseline, Eng. Controls, Respirator).

2 Based on registered or proposed label (EPA Reg. No.264-806).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated 

(A/day) / BW (80 kg).

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

6

Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated 

(A/day) / BW (80 kg).

7

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

8 ARI = 1/[(1/RIdermal) + (1/RIinhal)] where, RIdermal = MOEdermal/100 and RIinhal = MOEinhal/30. ARIs greater than 1 are not of concern.

Table 9.1.2. Summary of Occupational Handler Cancer Exposure and Risk Estimates for Thiacloprid. 

Exposure Scenario Crop Mitigation 

Level

LADD (mg/kg/day) Cancer

Risk Estimate4 Dermal1 Inhalation 2 Total 3

Flowable Concentrate 

(Liquid) for Groundboom

Applications 

Peppers Baseline 7.6 x 10-47.6 x 10-72.8 x 10-51.1 x 10-6

Flowable Concentrate 

(Liquid) for Aerial 

Applications 

Peppers Baseline 3.3 x 10-33.3 x 10-61.2 x 10-45.0 x 10-6

Stone Fruits Baseline 8.9 x 10-38.9 x 10-63.3 x 10-41.3 x 10-5

Flowable Concentrate 

(Liquid) for Airblast 

Applications 

Stone Fruits Baseline 1.0 x 10-31.0 x 10-63.7 x 10-51.5 x 10-6

Sprays for Groundboom 

Applications Peppers Baseline 2.7 x 10-4

1.2 x 10-61.0 x 10-54.1 x 10-7

Sprays for Aerial 

Applications 

Peppers

Engineering 

Controls -

Enclosed cockpit

7.6 x 10-51.03 x 10-67.5 x 10-61.1 x 10-7

Stone Fruits

Engineering 

Controls -

Enclosed cockpit

2.2 x 10-42.7 x 10-62.8 x 10-63.0 x 10-7

Sprays for Airblast 

Applications Stone Fruits Baseline 2.2 x 10-3

2.2 x 10-53.0 x 10-41.2 x 10-5

Flagging for Aerial 

Applications 

Peppers Baseline 1.7 x 10-45.3 x 10-66.4 x 10-62.6 x 10-7

Stone Fruits Baseline 4.4 x 10-41.4 x 10-51.7 x 10-56.8 x 10-7

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

expectancy).
Thiacloprid Human Health Risk Assessment DP No. D376178

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2

Inhalation LADD = Inhalation Dose * (30 days per year of exposure/365 days per year) x (35 years per lifetime of exposure/78 years of lifetime 

expectancy).

3 Total LADD = Total Absorbed Dose [Dermal Dose + Inhalation Dose] * (30 days per year of exposure/365 days per year) x (35 years per 

lifetime of exposure/78 years of lifetime expectancy).

4 Cancer Risk Estimates = Total LADD * Q1*

, where Q1* = 4.06 x 10-2(mg/kg/day)-1.

9.2 Occupational Post-Application Risk Estimates

9.2.1 Dermal Post-Application Risk Estimates

No data regarding the number of exposure days per year were provided by the petitioner. Based

on the proposed use patterns and directions (e.g., 1-6 applications per season with a minimum 7-

14 day spray interval depending on the use), short- and intermediate-term exposures are expected 

for workers conducting post-application activities. Chemical-specific dislodgeable foliar residue 

data have not been submitted for thiacloprid. Therefore, this assessment uses HED’s default 

assumption that 25% of the application is available for transfer on day 0 following the 

application and the residues dissipate at a rate of 10% each following day. 

To assess cancer risk, HED assumed that private growers would be exposed 10 days per year and 

commercial applicators would be exposed 30 days per year. The term “private grower” means 

that the grower or one of the workers would apply the pesticide to land owned or operated by the 

grower. Commercial applicators means the applicators are completing multiple applications for 

multiple clients. Furthermore, HED assumed that post-application workers would be exposed for 

35 years out of a 78-year lifespan.

A summary of the dermal post-application exposure and risk estimates for the proposed crops is 

provided in Table 9.2.1. Risk estimates for the highest contact activity per crop group are shown 

below. Post-application non-cancer dermal exposure and risk estimates resulted in MOEs 

greater than 100 and are not of concern on Day 0 (i.e., 12 hours after application). The dermal 

non-cancer short- and intermediate-term post-application MOEs ranged from 1,200 to 6,000 for 

the high contact activities expected on the proposed crops (e.g., hand-set irrigation, thinning 

fruit) on the day of application. 

Table 9.2.1. Summary of Occupational/Commercial Post-application Non-Cancer Risk Estimates for 

Thiacloprid.

Crop/Site Activities Transfer Coefficient 

(cm2/hr) DFR1 Dermal Dose (mg/kg/day)2 MOE on Day 03

Short- and Intermediate-term

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

Stone Fruits Thinning Fruit 3600 0.701 0.2520 1,200

1. DFR = Application Rate x F x (1-D)tx 4.54E8 μg/lb x 2.47E-8 acre/cm2; where F = 0.25 and D = 0.10 per day.

2. Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day] BW (80 kg).

3. MOE = POD (300 mg/kg/day) / Daily Dermal Dose. 

Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of thiacloprid. 

Thiacloprid is classified as Toxicity Category III via the dermal route and Toxicity Category IV 

for skin irritation potential. It is not a skin sensitizer. A quantitative post-application risk 

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

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application) for all post-application activities. Under 40 CFR 156.208 (c) (2) (iii), chemicals 

classified as Acute III or IV for acute dermal, eye irritation, and primary skin irritation are 

assigned a 12-hour REI. Therefore, the [156 subpart K] Worker Protection Standard (WPS) 

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

exposures to thiacloprid.

A summary of the post-application cancer exposure and risk estimates for the proposed crops is 

provided in Table 9.2.2. Risk estimates for the highest contact activity per crop group are shown 

below. The estimated cancer post-application risk estimates for agricultural workers on the day 

of application ranged from 1.6 x 10-4to 3.6 x 10-4for the high contact activities (e.g., hand-set 

irrigation, thinning fruit). These cancer risk estimates are considered conservative because the 

maximum single application rates and the Day-0 default residue values were used in the postapplication cancer calculations. Additionally, the proposed PHI for the requested crops range

from 7-14 days, and workers conducting most high-contact post-application activities are not 

expected to be exposed to Day-0 residues. 

Table 9.2.2. Occupational Post-Application Cancer Exposures and Risk Estimates for Thiacloprid.

Crop 

Grouping/Crop Activity Days After Treatment

Dermal LADD 

(mg/kg/day)1

Cancer Risk 

Estimate2

Peppers Irrigation (Hand Set) 

(TC = 1900 cm2/hr) 0 0.004 1.6 x 10-4

Stone Fruits Thinning Fruit

(TC =3600 cm2/hr ) 0 0.009 3.6 x 10-4

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

expectancy).

2 Cancer Risk Estimates = LADD * Q1*

, where Q1* = 4.06 x 10-2(mg/kg/day)-1.

9.2.2 Inhalation Post-Application Risk Estimates

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment is not being performed for thiacloprid primarily because of the low acute inhalation 

toxicity (Toxicity Category III), its vapor pressure (8.0×10-10 Pa at 25°C = 6.0×10-12 mmHg), and 

the low proposed use rate (0.047-0.25 lb ai/A). However, there are multiple potential sources of 

post-application inhalation exposure to individuals performing post-application activities in 

previously treated fields. These potential sources include volatilization of pesticides and 

resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and 

received the SAP’s final report on March 2, 20106. The Agency is in the process of evaluating 

the SAP report as well as available post-application inhalation exposure data generated by the 

ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, 

subsequently, the way to incorporate occupational post-application inhalation exposure into the 

Agency's risk assessments. If new policies or procedures are put into place, the Agency may 

revisit the need for a quantitative occupational post-application inhalation exposure assessment 

for thiacloprid.

 

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

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Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

10.0 References

D405299. E. Holman. 31 October 2012. Thiacloprid: Acute, Chronic, and Cancer Aggregate 

Dietary Exposure (Food and Drinking Water) and Risk Assessment for the Section 3 

Registration on Stone Fruit and Peppers.

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

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

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

D382568. J. Alsadek. 26 September 2012. Update of PCTn Values Provided Previously for 

Thiacloprid Use on Peaches and Stone Fruit PC# 014019.

D378298. M. Doherty. 1 February 2011. Thiacloprid: Request for Food Uses on Stone Fruits 

and Peppers. Summary of Analytical Chemistry and Residue Data.

D406397. M. Doherty. 31 October 2012. Thiacloprid: Request for Food Uses on Stone Fruits 

and Peppers. Amended Summary of Analytical Chemistry and Residue Data.

D406399. Z. Figueroa. 31 October 2012. Thiacloprid: Occupational and Residential Exposure 

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

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for thiacloprid are in Table A1. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A1. Toxicology Requirements for Thiacloprid

Guideline Number and Toxicity Study Required Satisfied

870.1100 Acute Oral Toxicity................................................................

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

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

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

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

870.2600 Dermal Sensitization ..............................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Sub-chronic (Rodent).....................................................

870.3150 Oral Sub-chronic (Non-Rodent).............................................

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

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

870.3465 90/28-Day Inhalation .............................................................

yes

yes

yes

no

yes

yes

yes

yes

-

yes

870.3700 Developmental Toxicity (Rodent).........................................

870.3700 Developmental Toxicity (Non-rodent)...................................

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

yes

yes

yes

yes

yes

yes

870.4100 Chronic Toxicity (Rodent) .....................................................

870.4100 Chronic Toxicity (Non-rodent) ..............................................

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity: Gene Mutation - bacterial ...............................

870.5300 Mutagenicity: Gene Mutation - mammalian ..........................

870.5375 Mutagenicity: Gene Mutation – Structural Chromosomal 

Aberrations ............................................................................

870.5500 Mutagenicity: Other Genotoxic Effects..................................

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.6100 Acute Delayed Neurotoxicity (Hen).......................................

870.6100 90-Day Neurotoxicity (Hen) ..................................................

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

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

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

no

no

yes

yes

yes

-

-

yes

yes

yes

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

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

870.7800 Immunotoxicity.......................................................................

yes

yes

yes

yes

yes

no
Thiacloprid Human Health Risk Assessment DP No. D376178

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A.2 Toxicity Profiles

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

Guideline

No.

Study Type MRID #(S). Results Toxicity Category

870.1100 Acute Oral-mouse 45344002 LD50 between 100 

and 140 mg/kg for 

males

and

140 and 200 mg/kg 

for females

N/A

870.1100 Acute Oral- rat 44927644 LD50

621 mg/kg - males

396 mg/kg - females

II

870.1100 Acute Oral -rat 44927730 LD50 between 700 

and 1000 mg/kg 

(males)

LD50 between 300 

and 500 mg/kg 

(females).

II

870.1100 Acute Oral - rat

(metabolite KKO 

2254-4-2)

45307404 LD50 > 2000 mg/kg N/A

870.1100 Acute Oral - rat

(metabolite WAK 

6999)

44927737 LD50 > 2000 mg/kg N/A

870.1100 Acute Oral - rat

(intermediate 2-

cyaminino-1,3-

thiazolidin.

45307407 LD50 > 200 mg/kg 

(males)

LD50 between 200 

and 2000 mg/kg 

(females)

N/A

870.1200 Acute Dermal 44927731 LD50 > 2000 mg/kg III

870.1300 Acute Inhalation 44927732 LC50 > 0.481 mg/L III

870.2400 Primary Eye 

Irritation

44927635 Ocular irritation 

resolving in 24 

hours.

IV

870.2500 Primary Skin 

Irritation

44927635 Very slight erythema 

resolving in 72 

hours.

IV

870.2600 Dermal Sensitization 44927733 Did not indicate 

sensitization .

N/A

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

Type of Study/Guide line Study Title/

Classification /Doses

MRID Results

870.3100

90-Day oral toxicity - rats 

(diet)/

0, 25, 100, 400, or 1600 ppm.

0 and 1600 ppm (5 week 

recovery groups)

Acceptable/Guideline

mg/kg/day [m/f]: 0/0, 1.9/2.0, 

7.3/7.6, 28.6/35.6, 123.2/160.6

44927714 (1997) NOAEL = 400 ppm (28.6 mg/kg/day in 

males; 160.6 mg/kg/day in females). 

LOAEL = 1600 ppm (123.2 mg/kg/day in 

males; 35.6 mg/kg/day in females) based on 

decreased body weight throughout treatment. 

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

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

Type of Study/Guide line Study Title/

Classification /Doses

MRID Results

870.3100 

90-Day oral toxicity - mice 

(diet) 

Supplemental amendment: 

additional histopathology and 

immunochemistry

Acceptable/Guideline

0, 50, 250, 1250 or 6250 ppm

mg/kg/day [m/f]: 0/0, 19.9/27.2, 

102.6/139.1, 542.4/704.3, 

2819.9/3351.0 

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

females.

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

females based on adrenal X-zone changes in 

females. 

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

males.

LOAEL = 1250 ppm (542.4 mg/kg/day) in 

males based on liver effects (weight and 

hypertrophy). 

870.3150

90-Day oral toxicity in non 

rodents – dog (diet)Rangefinding 

Acceptable/Guideline 

0, 250, 1000 or 4000 ppm or 0, 

8.5, 34.9, 68 mg/kg/day for 

males and 0, 8.9, 34.7 or 65.3 

mg/kg/day for females. 

20-25 weeks old at week -2

high-dose: days 1-4, 4000 ppm

 days 5-14, 0 ppm

 days 15-end, 2000 

ppm

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

average)

1000 ppm =34.8 mg/kg/day

2000 ppm = 66.7 mg/kg/day 

44927709 (1998) 

44927747 (1997) NOAEL = 250 ppm (8.5 for males and 8.9 

mg/kg/day for females). 

LOAEL = 1000 ppm (~34.9 mg/kg/day) 

based mainly on liver enzyme changes, 

thyroid hormone level (T4) and binding 

capacity changes and increased prostatic 

weight and prostatic hypertrophy.

870.3200

21/28-Day dermal toxicity –

rat

Acceptable/Non-Guideline 

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

(5/sex/dose; Guideline requires 

10/sex/dose)

44927701 (1997) NOAEL = 300 mg/kg/day (in females)

LOAEL = 1000 mg/kg/day based on liver 

and thyroid effects and clinical signs

(reduced motility, decreased activity, and 

spastic gait).

No dermal irritation.

870.3465

21/28-Day inhalation 

toxicity – rat (solid aerosol 

dust)

Acceptable/Guideline 

0, 2, 18.2 and 143/4 mg/m3

5 hours/day, 6 days/week (4 

weeks)

[nominal highest dose tested = 

200 mg/m3for days 0-7, 100 

mg/m3for days 8-28]

44927715 (1998)

SYSTEMIC

NOAEL = 20 mg/m3.

LOAEL = 200 mg/m 3based on liver 

(hypertrophy, increased liver enzymes, and 

necrosis) and thyroid (hypertrophy and slight 

increases in thyroid hormone) effects. 

PORTAL-OF-ENTRY

NOAEL = 100 mg/m3

LOAEL = 200 mg/m3based on respiratory 

distress (bradypnea, piloerection, and 

decreased rectal temperature).
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Table A.2b. Subchronic, Chronic and Other Toxicity Studies for Thiacloprid Technical.

Type of Study/Guide line Study Title/

Classification /Doses

MRID Results

Concentration of 200 mg/m3reduced to 100 

mg/m3due to marked respiratory distress 

and decreased body weight gain. Rectal 

temperature reduced only at 200 mg/m3; 

slight to severe slow breathing both sexes at 

200/100 mg/m3.

870.3465

5-Day inhalation toxicity –

rat (solid aerosol dust)

Acceptable/Non-Guideline 

0, 2, 20 and 200mg/m3

5 days, 6 hours/day (16 day 

recovery period)

44927736 (1995) SYSTEMIC

NOAEL = 2 mg/m3

LOAEL = 20 mg/m3based on increased grip 

strength in both sexes.

RESPIRATORY IRRITATION

NOAEL = 20 mg/m3

LOAEL = 200 mg/m3based on bradypnea, 

labored breathing pattern, piloerection and 

decreased rectal temperature.

870.3465

4-Hour inhalation toxicity –

rat (solid aerosol dust)

Acceptable/Non-Guideline 

0, 80, 481, 1523 and 2535 

mg/m3

44927736 (1995) Irritation NOAEL = 80 mg/m3

Irritation LOAEL = 481 mg/m3based on 

tremors, apathy, hypothermia, ungroomed 

haircoat, decreased bodyweight and 

piloerection (duration of signs up to day 6).

In females only, mortality ≥ 1523 mg/m3. 

Necropsy showed relationship between 

lethality and lung damage; no mention of 

microscopic tissue examination.

870.3700a

Prenatal developmental -

rats 

(gavage) 

Acceptable/Guideline 

0, 2, 10 or 50 mg/kg/day.

44927741 (1997) Maternal Toxicity: 

NOAEL = 10 mg/kg/day

LOAEL = 50 mg/kg/day based on decreased 

body weights, body weight gains, food 

consumption, increased urination, and 

changes in water consumption. 

Developmental Toxicity:

NOAEL = 10 mg/kg/day

LOAEL = 50 mg/kg/day based on increased 

resorptions (complete and late), skeletal 

retardations, variations (wavy ribs and 

asymmetrical sternebrae), and malformations 

(dysplastic humerus, radius, and scapulae) 

and on decreased fetal weights. 

870.3700b

Prenatal developmental -

rabbits (gavage)

Acceptable/Guideline

0, 2, 10 or 45 mg/kg/day. 44939201 (1996) Maternal Toxicity:

NOAEL = 2 mg/kg/day

LOAEL = 10 mg/kg/day based on decreased 

body weight gains, food consumption, and 

fecal output. 

Developmental Toxicity:
Thiacloprid Human Health Risk Assessment DP No. D376178

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

Type of Study/Guide line Study Title/

Classification /Doses

MRID Results

NOAEL = 2 mg/kg/day

LOAEL = 10 mg/kg/day based on decreased 

fetal weights. 

At 45 mg/kg/day, 2 abortions and 3 total 

resorptions (24 rabbits).

870.3800

Reproduction and fertility 

effects – rat (diet)-Rangefinding

Acceptable/Guideline

0, 50, 300 or 600 ppm. 

mg/kg/day: 

pre-mating [m/f]: 0/0, 3.5/4.2, 

21/26, 41/51

gestation: 0, 3.7, 22, 43

lactation: 0, 6.8, 42, 86

44927702 (1997)

44927638 (1995) Parental/Systemic:

NOAEL = 50 ppm (3.5 mg/kg/day in males)

LOAEL = 300 ppm (21 mg/kg/day based on 

increased liver and thyroid weights and on 

hepatocytomegaly, liver necrosis, and 

thyroid follicular cell hypertrophy

Reproductive:

NOAEL = 50 ppm (4.2 mg/kg/day in 

females)

LOAEL = 300 ppm (26 mg/kg/day) based on 

dystocia (abnormal or difficult labor). 

Offspring:

NOAEL = 50 ppm (4.2 mg/kg/day in 

females)

LOAEL = 300 ppm (21 mg/kg/day in 

females) based on decreased pup weight 

during lactation. 

870.4100b

Chronic toxicity - dogs 

(diet)

Acceptable/Guideline

0, 40, 100, 250 or 1000 ppm.

mg/kg/day [m/f] = 0/0, 

1.42/1.39, 3.60/3.27, 8.88/8.30, 

34.42/33.80

27-32 weeks old at day 0

26-week interim sacrifice of 3 

males/group (0, 100 and 1000 

ppm)

44927716 (1998) No firm LOAEL was established for this 

chronic feeding study with dogs. There were 

no effects that were of sufficient magnitude 

or consistency to justify that they were 

definite responses to treatment. Certain 

effects noted in the subchronic dog study on 

the prostate and other male organs and an 

apparent effect on uterine weight in the 

subchronic dog study were not seen in this 

chronic study. This may be because the dogs 

in this study had reached maturity. (see 15 

week study, MRID 44927709, Guideline 

870.3150).

26-week interim sacrifice. No effects 

reported on any parameter.

870.4200

Carcinogenicity - mice 

(diet) – 2 years

Acceptable/Guideline

0, 30, 1250 or 2500 ppm. 

mg/kg/day [m/f]: 0/0, 5.7/10.9, 

234.1/475.3, 546.4/872.5

44927710 (1998)

44927711 (1998) 

NOAEL = 30 ppm (5.7 mg/kg/day in males 

and 10.9 mg/kg/day in females). 

LOAEL = 1250 ppm (234.1 mg/kg/day in 

males and 475.3 mg/kg/day in females) 

based on liver toxicity and microscopic 

lymph node changes in both sexes and 

increased X-zone vacuolization of the

adrenal glands in female mice.

Evidence of carcinogenicity based on

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

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

Type of Study/Guide line Study Title/

Classification /Doses

MRID Results

870.4300

Combined chronic feeding 

and carcinogenicity - rats. 

(diet)

Acceptable/Guideline

0, 25, 50, 500 or 1000 ppm. 

mg/kg/day [m/f]: 0/0, 1.2/1.6, 

2.5/3.3, 25.2/33.5, 51.7/69.1

44927712 (1998) NOAEL = 25 ppm (1.2 mg/kg/day in males 

and 1.6 mg/kg/day in females). 

LOAEL = 50 ppm (2.5 mg/kg/day in males 

and 3.3 mg/kg/day in females) based on liver 

toxicity (hepatocellular hypertrophy and 

cytoplasmic change and increased enzyme 

activity), thyroid follicular epithelial hypertrophy in males and oculotoxicity (retinal 

atrophy) in females.

Evidence of carcinogenicity based on 

increased incidence of thyroid follicular cell 

adenomas in males and possibly also in 

females and increased incidence of uterine

tumors (adenocarcinomas) 

870.6200a

Acute neurotoxicity 

screening battery – rat 

(gavage)

Supplemental study

Acceptable/Guideline

0, 3.1, 11, 22, 53 or 109 

mg/kg/day (doses in one or the 

other study).

44927703 (1997)

44927704 (1998) NOAEL = 3.1 mg/kg/day

LOAEL = 11 mg/kg/day in females based on 

reductions in motor and locomotor activity. 

In males, the LOAEL was 22 mg/kg bw 

(based on FOB observations of slight 

tremors and ptosis of the eyelids on the day 

of treatment), and the NOAEL of 11 mg/kg

bw.

870.6200b

Subchronic neurotoxicity 

screening battery - rat (diet)

Acceptable/Guideline

0, 50, 400 or 1600 ppm.

mg/kg/day [m/f]: 0/0, 2.94/3.41, 

24.2/27.9, 101/115

44927645 (1997) NOAEL = 400 ppm (24.2 mg/kg/day in 

males and 27.9 mg/kg/day in females). 

LOAEL = 1600 (101 mg/kg/day in males 

and 115 mg/kg/day in females) based on 

decreased body weight gains and food 

consumption in both sexes and decreased 

hindlimb grip strength in males. 

870.6300

Developmental 

neurotoxicity – rat (diet)

Acceptable/Non-guideline.

0, 50, 300, or 500 ppm (0, 4.4, 

25.6, and 40.8 mg/kg/day during 

gestation; 0, 8.2, 49.4, and 82.8 

mg/kg/day during lactation).

45516601(2001) Maternal

NOAEL = 50 ppm (4.4 mg/kg/day) 

LOAEL = 300 ppm (25.6 mg/kg/day based 

on deceased body weight gain and food 

consumption during early gestation (GD 0-

6).

Offspring

NOAEL = 50 ppm (4.4 mg/kg/day)

LOAEL = 300 ppm (25.6 mg/kg/day) based 

on decreased pre-weaning and post-weaning 

body weights in both sexes as well as altered 

performance in passive avoidance testing.

Changes in brain morphometrics at 500ppm 

870.7485

Metabolism and pharmacokinetics - rat

Acceptable/Guideline 44927609 (1998)

Toxicokinetics 

and metabolism

44927605 (1996)

Recovery was 86-106%. Orally, rapid 

absorption with maximum plasma 

concentrations at 1-2 hours and 3-4 hours for 
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Table A.2b. Subchronic, Chronic and Other Toxicity Studies for Thiacloprid Technical.

Type of Study/Guide line Study Title/

Classification /Doses

MRID Results

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

within 20 minutes. Rapid excretion. Minor 

gender-related differences in excretion time. 

Extensive tissue distribution with rapid 

removal. Hydroxylation of thiazolidine ring 

with glucuronidation. Hydroxylation of 

cyanamid moiety. Opening of thiazolidine 

ring. Formation of exazole ring. Oxidation 

and methylation of thiazolidine ring. 

Oxidative cleavage of methylene bridge. 

Minor gender-related quantitative 

differences in metabolite profiles. 

870.7600. 

Dermal absorption -

monkeys.

Acceptable/Guideline 45846701

45846702 A 5% dermal absorption value is appropriate 

for estimating the risk resulting from dermal 

exposure to Thiacloprid formulated as a 

40.4% liquid formulation (SC 480). This 

5% value is also appropriate for other liquid 

thiacloprid formulations that are similar to 

the SC 480 liquid formulation product tested 

and for aqueous dilutions of most thiacloprid 

formulations. 

Special studies Several special studies conducted to attempt to establish a mode of action for the induction of thyroid 

tumors in rats based on increased thyroid hormone metabolism and activation of the 

liver/pituitary/thyroid axis, induction of uterine tumors in rats and ovary tumors in mice and dystocia 

in rats were presented. Since these studies are not required for registration, they are not being listed 

here. Please refer to the MTARC review (TXR # 0051476 and dated February 19, 2003) for both the 

list of these and HED’s interpretation of these studies. Also March 26, 2033 CARC memo, TXR # 

0051705); November 16, 2011 CARC memo, TXR # 0056114)

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

Hazard Identification and Endpoint Selection

A) Acute Reference Dose (aRfD) - Acute Reference Dose (aRfD) general population, 

including infants and children

Studies Selected: Co-critical studies: Developmental Neurotoxicity Study in the Rat and Acute 

Neurotoxicity study in Rats

MRID Nos.: 45516601 (DNT); 44927703, and 44927704 (ACN) 

Dose and Endpoint for Risk Assessment: Offspring NOAEL = 4.4 mg/kg/day from the DNT 

study based on offspring effects of altered performance in passive avoidance testing at a LOAEL 

of 25.6 mg/kg/day. In the ACN study, the NOAEL = 3.1 and the LOAEL = 11 mg/kg/day in 

females based on reductions in motor and locomotor activity.
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Uncertainty Factor(s): 100X [10 interspecies; 10X intraspecies] FQPA SF = 1X

Comments about Study/Endpoint/Uncertainty Factor: The route and duration of exposure 

from these co-critical studies are appropriate for selection of the acute dietary endpoint. The 

toxicity could occur following a single exposure and is appropriate for this exposure scenario. 

Regulating at the higher NOAEL of 4.4 mg/kg/day from the DNT study is protective of both the 

effects seen at the LOAEL of 11 mg/kg/day in the ACN study (which is a gavage study) and at 

the LOAEL of 25.6 mg/kg/day in the DNT study. It would also be protective of the marginal 

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

Toxic effects (resorptions) appropriate for acute dietary exposure, females ages 13-49, were seen 

in developmental toxicity studies in rats and rabbits at ≥ 45 mg/kg/day. However, these effects 

were observed at higher doses than effects seen in the acute neurotoxicity and the developmental 

neurotoxicity studies. Therefore, the dose and endpoints from the neurotoxicity studies were 

selected and considered protective of potential acute toxicity for all populations (general 

(including infants and children) and females ages 13 to 49). 

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

100

B) Chronic Reference Dose (cRfD) 

Study Selected: Chronic/Carcinogenicity Study – rat (OCSPP 870.4300)

MRID No. 44927712

Dose and Endpoint for Establishing a RfD: NOAEL = 1.2/1.6 mg/kg/day (M/F) based on liver 

hypertrophy and cytoplasmic changes, thyroid hypertrophy and induction of the enzymes UDPGlu-T and aromatase as well as the induction of hepatic enzymes and retinal degeneration in 

females at the LOAEL of 2.5 mg/kg/day.

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

Comments on Study/Endpoint/Uncertainty Factors:

The dose and endpoint (liver and thyroid toxicity as well as retinal degeneration in females) 

reflect chronic (lifetime) dosing via the oral (diet) route. The NOAEL/LOAEL in the rat is the 

lowest dose in the toxicity database for chronic durations. The chronic rat study was therefore 

considered to be the most appropriate for chronic dietary dose and endpoint selection. 

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

100 (UF)

C) Incidental Oral Exposure (Short-Term)

Study Selected: –2-Generation Reproduction Study in Rats
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MRID No.: 44927702 and 44927638

Dose and Endpoint for Risk Assessment: Offspring NOAEL = 4.2 mg/kg/day. The Offspring 

LOAEL = 21 mg/kg/day based on decreased pup weight during lactation.

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

SF = 1X.

 

Comments about Study/Endpoint/Uncertainty Factor: The endpoint selected is appropriate 

for the exposure duration and the population of concern (children). It is also protective of the 

neurotoxicity effects seen in the ACN, SCN and DNT studies. Given that there are no residential 

uses, this exposure scenario is not relevant at this time.

D) Dermal Exposure (Short- and Intermediate Term) - All Populations 

Study Selected: 28 Day Dermal Study – rat (OCSPP 870.3200)

MRID No.: 44927701

Dose and Endpoint for Establishing the RfD: Systemic NOAEL = 300 mg/kg/day. Systemic 

effects observed at the LOAEL of 1000 mg/kg/day (limit dose) were liver and thyroid changes 

plus clinical signs of reduced motility, decreased activity and spastic gait in females. No dermal 

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

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

SF = 1X. 

Comments on Study/Endpoint/Uncertainty Factors: This study is appropriate for the route and 

duration of exposure. The developmental toxicity studies in rats and rabbits and the reproduction

study in rats were also considered for risk assessment; however, there was no evidence of 

quantitative susceptibility seen in the studies and the effects observed in maternal animals were 

adequately measured in the dermal toxicity study. Additionally, the subchronic neurotoxicity 

study was considered. However, the dermal equivalent dose (DED) calculated (based on 5% 

dermal absorption factor) for the study was higher than the point of departure (POD) of 300 

mg/kg/day from the dermal toxicity study. Therefore, the dermal toxicity study was selected and 

it is considered protective of potential developmental, reproductive, and neurotoxic effects.

E) Inhalation Exposure (Short and Intermediate Term) 

(See Appendix B for Inhalation Assessment Methodology and HEC assessment array)

Study Selected: 5-day (6 hours per day) inhalation toxicity study in rats 

MRID No: MRIDs 44927715 

Dose and Endpoint for Risk Assessment: NOAEL=2 mg/ m3(0.002 mg/L); HEC = 0.005 

mg/L; HED=0.24 mg/kg
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Uncertainty Factor: 30x (3x interspecies extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor)

Study/Endpoint: In a 5-day/6 hours per day nose-only inhalation study in male and female 

Wistar rats (10/sex/group), Thiacloprid, 97.2% a.i., was administered as a solid aerosol dust at 

average target concentrations of 0, 2, 20 or 200 mg/m3. After the 5 exposure days, the animals 

were observed during a 16-day recovery period. The systemic LOAEL is 20 mg/m3and is based 

on increased grip strength in both sexes. The systemic NOAEL is 2.0 mg/m3. The portal-ofentry LOAEL is 200 mg/m3

and is based on bradypnea, labored breathing pattern, piloerection 

and decreased rectal temperature. The portal-of-entry NOAEL is 20 mg/m3.

Table 1. Table of systemic and portal-of-entry endpoints and PODs for short- and 

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

inhalation toxicity study.

Effect Endpoint HEC (5 day study) HED (5 day study)

Systemic 0.005 mg/L 0.24 mg/kg

The systemic LOAEL of 20 mg/m3is based on increased grip strength in both sexes. The 

systemic NOAEL is 2 mg/m.3

Portal-of-entry: pulmonary (PU) 0.008 mg/L 0.38 mg/kg

The portal-of-entry LOAEL is 200 mg/m3and is based on bradypnea, labored breathing pattern, 

piloerection and decreased rectal temperature. The portal-of-entry NOAEL is 20 mg/m3.

Effect Endpoint HEC (21/28 day study) HED (21/28 day study)

Systemic 0.048mg/L 2.3 mg/kg

Portal-of-entry: pulmonary (PU) 0.042mg/L 2.0 mg/kg

The systemic LOAEL is 200 mg/m3based on liver (hypertrophy, increased liver enzymes, and 

necrosis) and thyroid effects (increased weights, minor increases thyroid hormones, and 

hypertrophy). The systemic NOAEL is 20 mg/m 3. The portal-of-entry LOAEL is 200 mg/m3

based on respiratory distress (bradypnea, piloerection, and decreased rectal temperature). The 

NOAEL is 100 mg/m3.

Dose and Endpoint for Risk Assessment (Occupational): The HEC of 0.005 mg/L was based on 

systemic effects (increased grip strength) seen in a 5-day inhalation toxicity study. The systemic 

HEC is also protective of the portal-of-entry effects noted in the study at a higher dose. The 

observed effect is consistent with the pesticidal mode of action for thiacloprid, disruption of the 

nervous system as an inhibitor at nicotinic acetylcholine receptors. The duration of exposure in 

the 5-day inhalation toxicity study is appropriate for short- term risk assessments. For 

intermediate-term risk assessment, the 5 day study was also selected and considered protective of 

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

HECs in the 21/28 day study were higher (i.e., less sensitive). A MOE of 30 defines HEDs level 

of concern in accordance with the guidance provided in the RfC methodology. 

 

Occupational Long-Term Inhalation Exposures

Long-Term inhalation studies are currently unavailable for thiacloprid. However, based on the 

proposed use pattern for thiacloprid, long-term inhalation exposure is not anticipated. 
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Residential Inhalation Exposures (all durations)

Based on the use pattern residential inhalation exposure is not anticipated. 
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A. 4. Executive Summaries for new or revised DERs

90-DAY RAT STUDY (DIET) [MRID 44927714]

UPDATED EXECUTIVE SUMMARY: In a 90-day oral toxicity study (1997, MRID 

44927714) Thiacloprid (98.6% a.i., batch # NLL 3351-13) was administered to 10 SPF-bred 

Wistar rats/sex/dose in the diet at dose levels of 0, 25, 100, 400, or 1600 ppm (equivalent to 0, 

1.9, 7.3, 28.6, and 123.2 mg/kg/day in males and 0, 2.0, 7.6, 35.6, and 160.6 mg/kg/day in 

females). Recovery groups (0 and 1600 ppm) with the same number of rats were observed for an 

additional five weeks without treatment. 

No animals died during the study. Moderate hepatocellular hypertrophy associated with a fine 

granular to vesicular structure of the perinuclear cytoplasm was seen in 9/10 males and 2/10 

females of the 400 ppm group and in all 1600 ppm animals. After the recovery period, minimal 

hepatocellular hypertrophy without cytoplasmic change was seen in 3/10 of the 1600 ppm males. 

There was no evidence of cell proliferation in the liver. Body weights of the 1600 ppm groups 

were significantly lower than those of controls throughout the study, and overall body weight 

gains were decreased by 22-24%. There were no treatment-related food consumption, 

ophthalmology, or hematology findings. At the end of treatment, serum cholesterol and total 

protein were increased up to 84% and 11%, respectively, but returned to normal levels following 

the recovery period. Hepatic enzyme activities were elevated in the 400 (especially males) and 

1600 ppm groups, but returned to normal levels following the recovery period. Absolute liver 

weights were increased by up to 21% in the 1600 ppm groups. Absolute thyroid weight 

increased 67% in 1600 ppm males, but no microscopic thyroid changes were seen. There were 

no significant differences in liver or thyroid weights of the control or treated groups after the 

recovery period. The LOAEL is 1600 ppm (123.2 mg/kg/day in males, 160.6 g/kg/day in 

females) based on decreased body weight throughout the treatment period (14-16%). The 

NOAEL is 400 ppm (28.6 mg/kg/day in males, 35.6 mg/kg/day in females).

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

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

Note: This updated executive summary revises the previous NOAEL /LOAEL determined 

for thiacloprid that were incorrectly reported in the DER. 

28-DAY DERMAL STUDY IN RATS [MRID 44927701]

UPDATED EXECUTIVE SUMMARY: In a 28-day dermal toxicity study (1997, MRID 

44927701), YRC 2894 (thiacloprid, 97.2% a.i.; Batch/Lot #: 290894) was applied to the shaved 

intact skin of 5 Hsd Cpb: WU rats/sex/dose at dose levels of 0, 100, 300, or 1000 mg/kg bw/day, 

6 hours/day for 5 days/week during the first 3 weeks and 7 days/week during the fourth week. 

An additional 5 rats/sex were necropsied after a two-week recovery period in the 0 and 1000 

mg/kg/day groups.
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Mortality, dermal effects, body weight, body weight gain, food consumption, hematology, and 

clinical chemistry were not adversely affected by treatment. There was one female which 

displayed at least some transient clinical signs (i.e. decreased motility) that would be expected of 

thiacloprid. 

Moderate hepatocellular centrilobular hypertrophy in combination with a more homogeneously 

structured cytoplasm was noted in males at control (0/5), 100 (1/5), 300 (3/5 and 1000 (5/5 and 

also 3/5 females) mg/kg/day. In the recovery group, centrilobular hypertrophy was still noted in 

the high dose group males (2/5). At 1000 mg/kg, hypertrophy of the follicular epithelium in the 

thyroid was noted in 3/5 males and 2/5 females (vs. 0/5 controls), and increased colloid 

vacuolation and foamy cytoplasm were noted in 1/5 males (vs. 0/5 controls). In the recovery 

group, 1/5 males each at 1000 mg/kg displayed hypertrophy of the follicular epithelium and 

round cell infiltration. Significant increases 0.05) in liver weights were noted in males 

(relative [to body] incr. 17%) and females (absolute and relative incr. 12-14%). In addition, 

absolute liver weight was increased 13% in males, but without statistical significance. The 

LOAEL is 1000 mg/kg/day based on liver and thyroid effects and clinical signs (reduced 

motility, decreased activity, and spastic gait). The NOAEL is 300 mg/kg/day. 

This study is classified as Acceptable/Non-guideline and satisfies the guideline requirement 

(OPPTS 870.3200; OECD 410) for a 28-day dermal toxicity study in rats. 

Note: This updated executive summary upgrades the previous classification for thiacloprid 

from Unacceptable (Guideline) to Acceptable (Non-guideline). Although the guideline study 

requires 10 animals/sex and this study used only 5 animals/sex, it satisfies the guideline 

requirement (OPPTS 870.3200; OECD 410) for a 28-day dermal toxicity study in rats. 

Additionally, the NOAEL/LOAEL statement has been revised. 

21/28-DAY INHALATION STUDY IN RATS (INCLUDES 4-HOUR AND 5-DAY 

STUDIES) [MRID 44927715, 44927636]

UPDATED EXECUTIVE SUMMARY: In a subacute inhalation toxicity study (1998, MRID 

44927715 and 1995, MRID 44927636), YRC 2894 (thiacloprid; 96.8-97.2% a.i., Batch No. 

290894) as a solid aerosol dust was administered to 10 Wistar rats/sex/concentration by dynamic 

nose-only exposure at target concentrations of 0, 2, 20, or 200/100 mg/m3 (achieved mean 

analytical dosages of 0, 2, 18.2, and 143.4 mg/m3) for 6 hours per day, 5 days/week for a total of 

28 days (20 exposures). The achieved MMAD was ~ 2.9 μM. The high dose animals were 

exposed to 200 mg/m 3 for study Days 0-7, then exposed to 100 mg/m 3 for Days 8-28 due to 

marked respiratory distress and decreased body weight gain observed at the initial concentration. 

There were no treatment-related effects on mortality, urinalysis, body weights, and 

ophthalmoscopic, neurologic, and macroscopic changes. Rectal temperature was decreased while 

exposed to 200 mg/m3 but was normal when the dose was reduced. 

The only findings observed at 20 mg/m3 were an increase in the liver enzyme, aminopyrine-Ndemethylase (N-DEM) and minimal to slight hepatocyte hypertrophy in the males (5/10). These 

observations were also noted at a greater incidence in the 200/100 mg/m3 males and females. At 
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200/100 mg/m3, a slight to moderate piloerection and slight to severe bradypnea were observed 

throughout treatment in both males and females. Liver enzymatic activity of p-nitroanisole-Odemethylase (O-DEM) and cytochrome P450 (P450) were increased (p 0.01) in both sexes. 

Absolute and relative (to body and brain) liver weights were elevated (p 0.01) in females, while 

relative (to body) liver weights were elevated (p 0.01) in males. Minimal single cell necrosis 

and fat deposition in the liver were observed in the controls and treated animals; a minor increase 

in the incidence of these findings was observed in the liver of both sexes at 200/100 mg/m3(3-

5/10 treated vs. 1-3/10 controls). Findings in the thyroid at 200/100 mg/m3included slight 

hypertrophy of the thyroidal epithelium in males (2/10 treated vs. 0/10 controls), and statistically 

insignificant increases in absolute and relative thyroid weights in males and females (incr. 28-

40%) and in triiodothyronine (T3) and thyroxine (T4) in the females (incr. 12-26%). The 

systemic LOAEL is 200 mg/m 3based on liver (hypertrophy, increased liver enzymes, and 

necrosis) and thyroid effect (increased weights, minor increases thyroid hormones, and 

hypertrophy). The systemic NOAEL is 20 mg/m 3. The portal-of-entry LOAEL is 200 

mg/m3based on respiratory distress (bradypnea, piloerection, and decreased rectal 

temperature). The NOAEL is 100 mg/m3. Histological evaluation of the respiratory tract (i.e. 

larynx, nose and nasal passage) did not reveal any treatment related change. Serial sections were 

not performed on the nose/nasal regions.

5 DAY STUDY: The systemic LOAEL is 20 mg/m3based on increased grip strength in 

both sexes. The systemic NOAEL is 2.0 mg/m3. The portal-of-entry LOAEL is 200 mg/m3

and was based on bradypnea, labored breathing pattern, piloerection and decreased rectal 

temperature. The portal-of-entry NOAEL is 20 mg/m.3

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

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

Note: This updated executive summary revises the previous NOAELS /LOAELS 

determined for thiacloprid in both the 5 day and 28 day inhalation studies.

In the 4-hour study, the systemic LOAEL of 481 mg/m3 was based on tremors, apathy, 

hypothermia, ungroomed haircoat, decreased bodyweight and piloerection as well as 

mortality at the next concentration (1533 mg/m3). The systemic NOAEL is 80 mg/m3. The 

portal-of-entry LOAEL of 481 mg/m3 was based on bradypnea, dyspnea, labored breathing 

pattern, rales, nose/snout area with red encrustations, salivation, mydriasis and 

chromodacryorrhea. The portal-of-entry NOAEL is 80 mg/m3.

 

This subacute inhalation toxicity study in the rat is Acceptable (Guideline) and satisfies the 

guideline requirement for a subchronic inhalation study OCSPP 870.3465; OECD 413 in 

the rat.

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

EXECUTIVE SUMMARY: In a developmental neurotoxicity study (MRID 45516601) YRC 

2894 (Thiacloprid; 99.2% a.i., 898013001) was administered to 25 female Crl:CD®(SD)IGS BR 

VAF/Plus®rats per dose in the diet at dose levels of 0, 50, 300, or 500 ppm (0, 4.4, 25.6, and 

40.8 mg/kg/day during gestation; 0, 8.2, 49.4, and 82.8 mg/kg/day during lactation) from 
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gestation day (GD) 0 through lactation day (LD) 22. The day that litter delivery was completed 

was designated postnatal day (PND) 1 (or LD 1). Body weight and food consumption data were 

recorded for dams. Detailed clinical observations, including assessments of autonomic function, 

were conducted daily during gestation and on LD 1, 5, 8, 14, and 22. Dams were killed and 

necropsied on LD 22. On PND 5, litters were standardized to yield 5 males and 5 females (as 

closely as possible), and 10 randomly selected pups/sex/group were subjected to detailed clinical 

examination outside the home cage. On PND 12, pups were randomly assigned to each of the 

following four subsets: 1) fixed brain weights and/or neuropathological evaluation on PND 12 

(10/sex/group); 2) passive avoidance testing (on PND 23-25 and 30-32) and water maze testing 

(on PND 59-63 and 66-70) (20/sex/group); 3) motor activity testing (on PND 14, 18, 22, and 58-

60) and auditory startle habituation (on PND 23 and 59-61) (20/sex/group); 4) detailed clinical 

exam outside the home cage on PND 12 and weekly during the postweaning period 

(20/sex/group), fixed brain weights and neuropathological evaluation on PND 68-79 

(10/sex/group). In addition, the pups from subsets 2-4 were observed for the age of attainment of 

balanopreputial separation or vaginal patency (60/sex/group).

There were no treatment-related effects on maternal survival, clinical or functional observations, 

reproductive function, or gross pathology at any dietary level. Treatment-related decreases 

(p 0.05) in maternal body weight gain were observed in the 300 and 500 ppm dams during GDs 

0-6 ( 31-56%), and in the 500 ppm dams during LDs 1-4 ( 67%). Treatment-related decreases 

in food consumption (p 0.01) were also noted in the 300 and 500 ppm dams during GDs 0-6 

( 16-30%) and in the 500 ppm dams during LD 4-7 ( 11%). Significant decreases (p 0.01) in 

relative food consumption on GD 0-6 at 300 ( 14%) and 500 ppm ( 27%) support the 

conclusion that the effects on body weight gain in early gestation were not solely related to 

palatability.

The maternal LOAEL is 300 ppm (25.6 mg/kg/day), based on decreased body weight gain 

and food consumption during early gestation (GD 0-6). The maternal NOAEL is 50 ppm 

(4.4 mg/kg/day).

Offspring survival, assessments of autonomic function, watermaze, brain weights, and qualitative 

histopathology were unaffected by treatment. Suggestive effects on motor activity and auditory 

startle were seen in the 300 and 500 ppm groups. Increased incidences (p 0.01) of malaligned 

incisors and chromodacryorrhea were observed at postpartum week 10 in 500 ppm offspring. 

These findings were considered to be treatment-related, perhaps a latent expression of a 

developmental anomaly. 

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

8-22 ( 5-15%). In addition, postweaning body weights were decreased (p 0.01) at 300 ( 5-

15%) and 500 ( 4-13%) ppm. Increased (p 0.05) time to preputial separation was noted in the 

300 and 500 ppm male pups when compared to controls (48.2 days each treated vs. 46.7 days 

controls). In addition, time to vaginal opening was delayed in the 500 ppm females (34.7 days 

treated vs. 33.4 days controls).

The corpus striatum ( 4%) and corpus callosum ( 14%) were smaller (p 0.05) in the 500 ppm 

males when compared to controls on PND 12. Additionally, at study termination, the corpus 
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striatum ( 4%) and dentate gyrus ( 5%) were smaller (p 0.05) in the 500 ppm males when 

compared to controls. Non-significant decreases were also noted in females for corpus callosum 

measures at PND 12 and for corpus callosum measures at termination, supporting the position 

that the effects in males are related to treatment. In male offspring, at the highest dose tested 

(500 ppm; 40 mg/kg/day), the corpus striatum (4%) and corpus callosum (14%) were smaller 

(p<0.05) when compared to controls on PND 12. At study termination (PND 63-79), the corpus 

striatum (4%) and dentate gyrus (5%) were smaller (p<0.05) when compared to controls. The 

changes observed at the high dose were attributed to treatment. In spite of these changes at the 

high dose brain morphometric analyses were not performed at the mid-and low-dose groups. 

However, it is determined that the concern is low for the lack of brain morphometric 

measurements at the mid and low dose groups based on the following considerations: 1) the only 

consistent change was the decrease in corpus callosum in the male pups at both time periods (i.e., 

at PND 12 and termination; 2) at both time periods the magnitude of the change is small (4%) 

which well could be within the differences that could occur from embedding the brains at 

different times; 3) decreases in the corpus striatum were not seen in female pups at either time 

periods; and 4) there is a pervasive lack of biological plausibility that changes would be seen at 

the low dose (4 mg/kg/day) which is 10-fold lower than the dose (40 mg/kg/day) that caused a 

small decrease. 

The offspring LOAEL is 300 ppm (25.6 mg/kg/day), based on decreased preweaning and 

postweaning body weights in both sexes and delayed sexual maturation in the males, and 

altered performance in passive avoidance testing. The offspring NOAEL is 50 ppm (4.4 

mg/kg/day).

This study is classified Acceptable (Non-guideline) and does not satisfy the guideline 

requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6); OECD 

426 (draft). However, the study can be used for regulatory purposes

C. STUDY DEFICIENCIES: 

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

in the text of the report. The procedures used were not described, including whether the 

same technicians were used throughout testing, where the testing was done (including 

whether the animals were removed from the cage), what the environmental conditions 

were (e.g., noise level, etc.), whether scoring criteria were used for the measured 

parameters, or the duration of the observation period for open field observations.

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

the targeted range of 30-70% on numerous occasions. There were 7 incidences of >70% 

humidity, 270 incidences of <30% humidity.

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

- Session 1/Trial 1 latency data should be reported for water maze testing. Additionally, 

more complete reporting of individual learning and memory test results would facilitate 

the interpretation of these data.

- The termination of adult offspring (subset 4) was conducted on PND 68-79. An 

explanation for this wide range of ages at termination (i.e., a span of 11 days) should be 

provided. 
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- Measurements were made bilaterally for a number of areas of the brain in both PND 12 

and adult offspring (see report pages 728 and 779), but only the mean values were 

reported. Values for linear brain measurements that were recorded, but not included in 

the current report, should be submitted.

- Acceptable positive control data were not provided.

COMPLIANCE: Signed and dated GLP, Quality Assurance, Data Confidentiality, and 

Flagging statements were provided.

Note: This updated executive summary upgrades the previous classification for the 

developmental neurotoxicity study from Unacceptable/Guideline to Acceptable/Nonguideline. Additionally, more characterization has been added regarding the 

morphometric changes observed in the study.
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Appendix B. Inhalation Exposure Assessment

Human respiratory data are not available for the thiacloprid inhalation risk assessment. 

Therefore, the methods and dosimetry equations described in EPA’s reference concentration 

(RfC) guidance (1994) are suited for calculating human equivalent concentrations (HECs) and 

for use in margin of exposure (MOE) calculations. Compared to the methods previously used by 

OPP, the dosimetry equations in the RfC guidance more appropriately address different 

properties of gases and particles, different properties of reactive and non-reactive compounds, 

and explicitly consider some differences in the structure of the respiratory tract between 

laboratory animals and humans. As performed by HED for other inhalation studies, OPP has 

used the dosimetry equations from the RfC guidance to develop HECs to estimate acute, short-, 

and intermediate-term inhalation risk to thiacloprid. 

In the risk assessment, endpoint selection for inhalation exposure was based on the effects 

occurring at the lowest HEC derived from animal data using the RfC methodology. 

When conducting inhalation risk assessments, the magnitude of the UFs applied is dependent on 

the methodology used to calculate risk. For studies in this risk assessment with inhalation animal 

data, UFs are based on the RfC methodology developed by the Office of Research and 

Development (ORD) for the derivation of inhalation reference concentrations (RfCs) and human 

equivalent concentrations (HECs) for use in MOE calculations. Since the RfC methodology 

takes into consideration the pharmacokinetic (PK) differences but not pharmacodynamic (PD) 

differences, the UF for interspecies extrapolation may be reduced to 3X (to account for the PD 

differences) while the UF for intraspecies variation is retained at 10X7. Thus, the UF when using 

the RfC methodology is customarily 30X.

For thiacloprid, HED believes exposures can be short- (1-30 days) or intermediate- (1 to 6 

months) term in duration. Long-term exposures are not anticipated based on proposed labeled 

uses. Acute and long term exposures are not expected.

For the short- and intermediate-term scenarios, inhalation data from the 5 day inhalation rodent 

study was the most sensitive study for determining HECs. In the RfC methodology, different 

HECs may be calculated for the same experimental NOAEL due to:

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

effects. Typically, HECs are calculated separately for systemic versus port-ofentry effect. For thiacloprid, both port-of-entry irritation and systemic toxicity 

were observed in the studies. However, the systemic HEC calculations were more 

conservative and used for risk assessment. Additionally, the systemic HEC 

calculations are protective of port-of entry effects.

2. Time adjustments are traditionally needed for non-occupational (bystander) 

versus occupational exposure scenarios. Traditionally, HECs for nonoccupational exposure are based on the number of hours an individual may be at 

home. Therefore, the most conservative estimate of hours spent at home would 

be 24 hours/day and 7 days/week. In comparison, the average work week for an 

 

7 A 3X UF for interspecies extrapolation is retained to account for the PD differences between animals and humans 

which are not accounted for in the RfC methodology. 
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occupational worker is 8 hours/day and 5 days/week. The HEC array table 

reflects the time adjustment in the calculations (Tables 1 and 2).

Available Inhalation Toxicity Studies

4 Hour Inhalation Toxicity Study in Rats, MRID 44927636

In a preliminary 4-hour nose-only inhalation study in male and female Wistar rats 

(number/sex/group not indicated), thiacloprid (97.2% a.i., Batch No. 290894) was administered 

as a solid aerosol dust at average concentrations of 80, 481, 1523 and 2535 mg/m3. In females 

only, mortality was noted at 1523 and 2535 mg/m3post-exposure days 1-7 (necropsy showed 

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

The systemic LOAEL of 481 mg/m3 was based on tremors, apathy, hypothermia, 

ungroomed haircoat, decreased bodyweight and piloerection as well as mortality at the 

next concentration (1533 mg/m3). The systemic NOAEL is 80 mg/m3. The portal-of-entry

LOAEL of 481 mg/m3 was based on bradypnea, dyspnea, labored breathing pattern, rales, 

nose/snout area with red encrustations, salivation, mydriasis and chromodacryorrhea. The 

portal-of-entry NOAEL is 80 mg/m3.

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

In a 5-day/6 hours per day nose-only inhalation study in male and female Wistar rats 

(10/sex/group), Thiacloprid (YRC 2894), 97.2% a.i., was administered as a solid aerosol dust at 

average target concentrations of 0, 2, 20 or 200 mg/m3(achieved analytical doses of 0, 1.97, 19 

or 205 mg/m3). After the 5 exposure days, the animals were observed during a 16-day recovery 

period. There were no adverse respiratory signs ≤ 20 mg/m3. At 200 mg/m3, the only noted 

inhalation changes were upper respiratory tract irritation and a decrease in rectal temperature. 

All changes were reversible within the 2-week post-exposure observation period. The following 

clinical signs were noted in the 200 mg/m3group on treatment days 0-5: bradypnea, labored 

breathing pattern, piloerection, reduced mobility, ungroomed fur, tremors, flaccid appearance, 

mydriasis and emaciation. In addition, rectal temperatures were decreased on day 0 in both 

sexes. Body weights and food consumption were decreased on days 4 and/or 7. A dose related 

increase in grip strength was observed in the 20 and 200 mg/m3rats of both sexes. At an interim 

sacrifice on day 7, there were increased incidences of gray-white foci in the lungs of the 20 

mg/m3females (1/5 vs. 0/5 in controls) and black spleens in the 20 and 200 mg/m3females (4/5 

each vs. 0/5 controls). No gross lesions were observed at the terminal sacrifice on day 21. The 

systemic LOAEL is 20 mg/m3based on increased grip strength in both sexes. The systemic 

NOAEL is 2.0 mg/m3). The portal-of-entry LOAEL is 200 mg/m3and was based on 

bradypnea, labored breathing pattern, piloerection and decreased rectal temperature. The 

portal-of-entry NOAEL is 20 mg/m.3

28 day (20 exposures) Inhalation Toxicity Study in Rats, MRID 44927715

In a subacute inhalation toxicity study, thiacloprid (96.8-97.2% a.i., Batch No. 290894) as a solid 

aerosol dust was administered to 10 Wistar rats/sex/concentration by dynamic nose-only 

exposure at target concentrations of 0, 2, 20, or 200/100 mg/m3 (achieved mean analytical 

dosages of 0, 2, 18.2, and 143.4 mg/m3) for 6 hours per day, 5 days/week for a total of 28 days 

(20 exposures). The achieved MMAD was ~ 2.9 μM. The high dose animals were exposed to 

200 mg/m 3 for study Days 0-7, then exposed to 100 mg/m 3 for Days 8-28 due to marked 
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respiratory distress and decreased body weight gain observed at the initial concentration. There 

were no treatment-related effects on mortality, urinalysis, body weights, and ophthalmoscopic, 

neurologic, and macroscopic changes. Rectal temperature was decreased while exposed to 200 

mg/m3 but was normal when the dose was reduced. The only findings observed at 20 mg/m3 

were a minor increase in liver enzyme, aminopyrine-N-demethylase (N-DEM) and minimal to 

slight hepatocyte hypertrophy in the males (5/10). These observations were noted at a greater 

incidence in the 200/100 mg/m3 males and females. At 200/100 mg/m3, a slight to moderate 

piloerection and slight to severe bradypnea were observed throughout treatment in both males 

and females. Liver enzymatic activity of p-nitroanisole-O-demethylase (O-DEM) and 

cytochrome P450 (P450) were increased (p 0.01) in both sexes. Absolute and relative (to body 

and brain) liver weights were elevated (p 0.01) in females, while relative (to body) liver 

weights were elevated ( p 0.01) in males. Minimal single cell necrosis and fat deposition in the 

liver were observed in the controls and treated animals; a minor increase in the incidence of these 

findings was observed in the liver of both sexes at 200/100 mg/m3(3-5/10 treated vs. 1-3/10 

controls). Findings in the thyroid at 200/100 mg/m3included slight hypertrophy of the thyroidal 

epithelium in males (2/10 treated vs. 0/10 controls), and statistically insignificant increases in 

absolute and relative thyroid weights in males and females (incr. 28-40%) and in 

triiodothyronine (T3) and thyroxine (T4) in the females (incr. 12-26%). The systemic LOAEL 

is 200 mg/m 3based on liver (hypertrophy, increased liver enzymes, and necrosis) and 

thyroid effect (increased weights, minor increases thyroid hormones, and hypertrophy). 

The systemic NOAEL is 20 mg/m 3. The portal-of-entry LOAEL is 200 mg/m3based on 

respiratory distress (bradypnea, piloerection, and decreased rectal temperature. The 

NOAEL is 100 mg/m3. Histological evaluation of the respiratory tract (i.e. larynx, nose and 

nasal passage) did not reveal any treatment related change. Serial sections were not performed 

on the nose/nasal regions.

Methodologies for Human-Equivalent Concentration (HEC) Calculations.

The RfC methodology applies a dosimetric adjustment that takes into consideration not only the 

differences in ventilation rate (MV) but also the physicochemical properties of the inhaled 

compound, the type of toxicity observed (e.g. systemic vs. port of entry) and the pharmacokinetic 

(PK) but not pharmacodynamic (PD) differences between animals and humans. Based on the 

EPA’s RfC guidance (1994), the methodology for RfCs derivation is an estimate of the 

quantitative dose-response assessment of chronic non-cancer toxicity for individual inhaled 

chemicals and includes dosimetric adjustment to account for the species-specific relationships of 

exposure concentration to deposited/delivered dose. This adjustment is influenced by the 

physicochemical properties of the inhaled compound as well as the type of toxicity observed 

(e.g. systemic vs. port of entry), and takes into consideration the PK differences between animals 

and humans. Though the RfC methodology was developed to estimate toxicity of inhaled 

chemicals over a lifetime, it can be used for other inhalation exposures (e.g. acute and short-term 

exposures) since the dosimetric adjustment incorporates mechanistic determinants of disposition 

that can be applied to shorter duration of exposures provided the assumptions underlying the 

methodology are still valid. These assumptions, in turn, vary depending on the type of toxicity 

observed. Thus the derivation of a HEC for inhaled gases is described by the following 

equation:
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Where:

PODstudy: Point of departure identified in the critical toxicology study

Danimal exposure: Duration of daily animal exposure (hrs/day)

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

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

Wanticipated exposure: Anticipated weekly human duration of exposure (days/week)

RGDR: Regional Gas Dose Ratio

Calculations used to estimate the inhalation risk to humans from aerosols are dependent not on 

the RGDR as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies 

using aerosols characterize particulate exposure by defining the particulate diameter (mass 

median aerodynamic diameter [MMAD]) and the geometric standard deviation (σg), which is 

then used to determine the RDDR. The RDDR is a multiplicative factor used to adjust an 

observed inhalation particulate exposure concentration of an animal (A) to the predicted 

inhalation particulate exposure concentration for a human (H) that would be associated with the 

same dose delivered to the rth region or target tissue.

RDDRr = (RDDr/Normalizing Factor)A

 (RDDr/Normalizing Factor)H 

As with calculations for gases, the regions and potential target tissues are the three respiratory 

regions (extrathoracic (ET), tracheobronchial (TB), and pulmonary (PU). The RDDR is easily 

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

MMAD and σg defined from an aerosol inhalation study. The values for the species-specific 

parameters used to calculate the RDDR are provided in the EPA document “Methods for 

Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry.”

RDDRs for Thiacloprid 

Because the respired material used in the thiacloprid inhalation studies is an aerosol, the RDDR 

ratio, which incorporates MMAD and σ, is appropriate to use for HEC calculation (see below). 

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

4 hour inhalation study: Systemic RDDR= 3.26, Pulmonary (PU) RDDR = 0.56. The inputs for 

the program are: MMAD=3.0; σ=1.7; default BW for Wistar Rats =187g; Standard human BW 

information (i.e., 70 kg). 

5 day inhalation study: Systemic RDDR= 3.11, Pulmonary (PU) RDDR = 0.52. The inputs for 

the program are: MMAD=3.30; σ=1.80; default BW for Wistar Rats =187g; Standard human 

BW information (i.e., 70 kg). 

HEC = POD * D 

D 

* W

W

study * RGDR animal exposure (hrs/ day)

human exposure (hrs/ day)

animal exposure (days / wk)

human exposure (days/ wk)
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28 day (20 exposures) inhalation study: Systemic RDDR= 3.2, Pulmonary (PU) RDDR = 0.56. 

The inputs for the program are: MMAD=2.9; σ=1.84; default BW for Wistar Rats =187g; 

Standard human BW information (i.e., 70 kg). 

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

Relevant Study LOAEL

(mg/L)

NOAEL

(mg/L)

Da Dh Wa Wh RDDR HEC 

(mg/L)

inter intra Total

UF

Acute Exposure

Inhalation – Rat 

(MRID44927636)

1-Day (4 hour)

Systemic 0.48 0.08 4 8 1 1 3.26 0.130 3 10 30X

PU 0.48 0.08 4 8 1 1 0.56 0.022 3 10 30X

Short-& Intermediate-Term Exposure

Inhalation –Rat

(MRID44927636) 5-

day 

Systemic 0.02 0.002 6 8 5 5 3.11 0.005 3 10 30X

PU 0.20 0.02 6 8 5 5 0.52 0.008 3 10 30X

Inhalation – Rat

(MRID 44927715) 

21/28-day

Systemic 0.20 0.02 6 8 5 5 3.18 0.048 3 10

30X

PU 0.20 0.10 6 8 5 5 0.56 0.042 3 10

 30X

Long Term Exposure: Not appropriate for thiacloprid

Appendix B/Table 2: HEC Array for Non-Occupational Risk Assessment§ 

Relevant Study LOAEL

(mg/L)

NOAEL

(mg/L)

Da Dh Wa Wh RDDR HEC 

(mg/L)

inter intra UF

Acute Exposure

Inhalation – Rat 

(MRID 44927636)

1-Day (4 hour)

Systemic 0.48 0.08 4 24 1 1 3.26 0.044 3 10 30X

PU 0.48 0.08 4 24 1 1 0.56 0.008 3 10

30X

Short-& Intermediate-Term Exposure

Inhalation –Rat

(MRID 44927636) 5-

day , 6-hours/day

Systemic 0.02 0.002 6 24 5 7 3.11 0.001 3 10 30X

PU 0.20 0.02 6 24 5 7 0.52 0.002 3 10 30X

Inhalation – Rat

(MRID 44927715) 

21/28-day

Systemic 0.20 0.02 6 24 5 7 3.18 0.011 3 10

30X

PU 0.20 0.10 6 24 5 7 0.56 0.010 3 10

30X

Long Term Exposure: Not appropriate for thiacloprid
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Key for Array Tables

LOAEL: Lowest observed adverse effect level

Da: Daily animal exposure (hrs/day)

Wa: Weekly animal exposure (days/week)

RRDR: Regional Deposited Dose Ratio

inter: interspecies extrapolation uncertainty factor

Dh: Anticipated daily human exposure (hrs/day)

Wh: Anticipated weekly human exposure (days/week)

HC: Human Concentration

HEC: Human Equivalent Concentration

intra: intraspecies variation uncertainty factor

UF: Other uncertainty factor(s)

PU: Pulmonary 

§ Bolded studies used for endpoint selection.

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

Human Equivalent Concentrations (HECs)

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

daily duration adjustment *RDDR 

Occupational HECs

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

Pulmonary HEC- 4 hour inhalation study: = 0.08 mg/L * (4hr/8hr)*(1)*0.56= 0.022 mg/L

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

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

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

mg/L

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

0.042 mg/L

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

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

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

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

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

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

0.011 mg/L

Pulmonary HEC-28 day (20 exposures) inhalation study: = 0.100 mg/L * (6hr/24hr)*(0.71)*0.56= 

0.010 mg/L

Human Equivalent Doses

Using the HECs calculated a conversion of the inhalation concentration to a dose (mg/L to 

mg/kg/day) for use in risk assessment was conducted as follows: 

HED = HEC value (mg/L)* absorption* human specific conversion factor (L/hr/kg) *daily 

duration (hours)*Activity Factor

Where: 

A absorption: ratio of deposition and absorption in respiratory tract compared to absorption 

by the oral route; 100% assumed

CF Conversion Factor: A L/hr/kg factor which accounts for respiratory volume and body 

weight for a given species and strain (Table 1 of guidance document).

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

AF Activity Factor: Animal default is 1.

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

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

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

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

Systemic HED-28 day (20 exposures) inhalation study: = 0.048 mg/L*(1)*(6)*(8hrs)*(1) =2.3

mg/kg

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

2.02 mg/kg

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

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

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

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

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

Systemic HED-28 day (20 exposures) inhalation study: = 0.011 mg/L *(1)*(6)*(24hrs)*(1) = 1.6

mg/kg

Pulmonary HED-28 day (20 exposures) inhalation study: = 0.010 mg/L*(1)*(6)*(24hrs)*(1) = 

1.44 mg/kg
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Appendix C. Physical/Chemical Properties

Physicochemical Properties of the Technical Grade Thiacloprid

Parameter Value 

Melting point/range 136° C 

pH 7.40 at 20° C

Density 1.46 g/mL at 20° C

Water solubility (g/L @ 20 ̊C) 0.185

Solvent solubility (g/L) n-Heptane: < 0.1

Xylene: 0.30

1-Octanol:1.4

2-Propanol: 3.0

Ethyl acetate: 9.4

Polyethylene glycol (PEG): 42

Acetonitrile: 52

Acetone: 64

Dimethylsulfoxide (DMSO): 150

Dichloromethane: 160

Vapor pressure at 20 & 25° C 2.3x10(-9) Pa at 20° C [1.75x10(-11) mmHg]

8x10(-10) Pa at 25° C [6.0x10(-12) mmHg]

Dissociation constant (pKa) AI has no basic or acidic properties in aqueous solutions

Octanol/water partition coefficient 

Log(KOW)

KOW

1.26 at 20° C

18

UV/visible absorption spectrum λ max Extinction coefficient

295-300 nm 49.1828

301-305 nm 39.3463 
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Appendix D. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

PHED 1.1; the AHETF database; and the ARTF database are (1) subject to ethics review 

pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable 

ethics requirements. For certain studies, the ethics review may have included review by the 

Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, 

can be found at the Agency website8.

 

8

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

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