Spirotetramat Human Health Risk Assessment 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

0413575 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 16-0CT-2014 

Subject: Spirotetramat: Human Health Risk Assessment for the Proposed Use on Turfgrass 

(Sod Farms and Golf Course Turf only). 

DP Barcode: 04 13575 

Registration No.: 432-xxxx 

PC Code: 392201 

Decision No.: 478963 

Petition No.: NA 

Risk Assessment Type: Single ChemicaVAggregate 

TXRNo.: NA 

Regulatory Action: Section 3 Registration 

Case No.: 7452 

MRIDNo.: NA 

CAS No.: 203313-25-1 

40 CFR: §180.641 

From: 

Through: 

To: 

Kelly M. Lowe, Environmental Scientist 

Monique M. Perron, Sc.D., Toxicologist 

Risk Assessment Branch 1 (RAB 1) 

Health Effects Division (HED; 7509P) 

Char

George 

les 

F. 

W. 

Kramer, 

Smith II

Ph.D.

I, Branch 

, Senior 

ChiefChemist C-~ .-:-/6- --?"'(._.-;;...) .:;;::-

RABl!HED (7509P) ~ L - - ~ 

Rita Kumar, RM07 

Registration Division (RD; 7505P) 

-----

The HED ofthe Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from the proposed 

Section 3 registration use of the active ingredient (ai) spirotetramat (cis-3-(2,5-dimethlyphenyl)-

8-methoxy-2-oxo-1-azaspiro[ 4.5]dec-3-en-4-yl-ethyl carbonate]) on sod farms and golf course 

turf. 

The most recent Section 3 human health risk assessment for spirotetramat was for use on 

ornamentals in residential settings, and was completed on 29-0CT-2013 (J. Van Alstine et al., 

29-0CT-201 3; D405870). However, subsequent to completion ofthis risk assessment, the use 

on ornamentals was withdrawn by the Registrant. The risk assessment prior to the ornamental 

use was for use on taro, watercress, pomegranates, bananas, bulb vegetables, low-growing 

berries (except strawberries), bushberries, globe artichokes, fruiting vegetables, pome fruit, citrus 

fruit, pineapples, and coffee, and was completed on 17-APR-2013 (J. Van Alstine et al., 17-

Page 1 of 14 
Spirotetramat Human Health rusk Assessment 0413575 

APR-2013; 0398509). 

It has been determined that a quantitative risk assessment is not required at this time for the 

current action since the proposed uses will not impact the aggregate assessment. The aggregate 

assessment considers exposures from three major sources: food, drinking water, and residential 

exposures. A revised dietary assessment (food+ drinking water) is not needed for this 

registration request since tolerances are not required based on the proposed turfgrass use and the 

estimated drinking water concentrations (EOWCs) used in the previous dietary risk assessment 

still represent the highest estimated drinking water exposure scenarios (J. Melendez, 7-MA Y20 13; 0410121 ). In terms of residential exposures, there are no residential uses of spirotetramat 

that require a quantitative risk assessment. The proposed golf course use could result in potential 

post-application dermal exposure; however, since the last risk assessment for spirotetramat (J. 

Van Alstine et al., 29-0CT-2013; D405870), a reevaluation of the toxicological database has 

been conducted and yielded no dermal hazard. Therefore, quantification of dermal risk is not 

necessary. Furthermore, the ornamental residential use assessed in the last risk assessment was 

subsequently withdrawn by the Registrant; therefore, there is no residential component for the 

aggregate assessment of spirotetramat. 

Because of the reasons above, a quantitative risk assessment has not been completed for 

spirotetramat for the current action. A summary of the revised hazard assessment is provided 

herein since a reevaluation of the toxicological database was conducted since the last risk 

assessment. In addition, the proposed sod farm and golf course uses will result in occupational 

exposure; therefore, an occupational/residential exposure assessment was conducted and can be 

found in the following memo: K. Lowe, 16-0CT-2014; 0414958. 

Attachments: 

Attachment A. Revised Hazard Characterization and Dose-Response Assessment for Spirotetramat. 

Attachment B. Toxicology Profile and Executive Summaries 

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Spirotetramat Human Health Risk Assessment D413575

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Attachment A. Revised Hazard Characterization and Dose-Response Assessment for 

Spirotetramat.

4.0 Hazard Characterization and Dose-Response Assessment

Spirotetramat belongs to the class of cyclic ketoenol insecticides. The proposed insecticidal 

mode of action for these agents is based on inhibition of acetyl-CoA carboxylase, a key enzyme 

in fatty acid biosynthesis in eukaryotes and prokaryotes. Inhibition of lipogenesis, resulting in 

decreased lipid content (notably triglycerides and free fatty acids) in treated insects, hinders the 

ability of younger insects to develop and ultimately their ability to reproduce as adults. The 

mammalian toxicity database for spirotetramat does not indicate changes in plasma lipid 

parameters, such as plasma levels of triglycerides and cholesterol; therefore, it is unclear if this

mode of action also operates in mammals.

4.1 Toxicology Studies Available for Analysis

The toxicology database for spirotetramat is adequate for characterization of its hazard, toxicity 

endpoint selection, and FQPA SF consideration. As part of the revised 40 CFR Toxicology Data 

Requirements, subchronic inhalation and subchronic neurotoxicity (SCN) studies are necessary 

for registered uses; however, the Hazard and Science Policy Council (HASPOC) concluded 

using a weight-of-evidence approach that these studies are not required at this time (TXR# 

0056480). Although the SCN study is not required according to HASPOC, a SCN study has 

been submitted, but not reviewed (note that there are no neurotoxic effects seen in the SCN study 

after preliminary review).

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

Absorption of orally-administered spirotetramat in rats was rapid and nearly complete. In 

females, the time to maximum plasma levels (Tmax) at the low dose tested of 2 mg/kg bw was 

estimated to be ~10 minutes, while at the high dose of 100 mg/kg bw, it was prolonged to 42 

minutes. In males, Tmax was between 0.7 and 1 hour at both dose levels. The extent of 

absorption was 89-98% by 48 hours following single low (2 mg/kg bw) and high (100 mg/kg 

bw) gavage doses, as well as repeated low doses (2 mg/kg bw). Systemic exposure estimated by 

the area under the plasma concentration-time curve (AUC) was higher for male than female rats. 

At 2 mg/kg bw (single or repeated dosing), the AUC for males was about 60% higher than 

females and much greater at the high dose. Less than 0.2% of the administered dose was 

detected in the body at 48 hours after sacrifice and the highest concentrations were detected at 

similar levels in the liver and kidney. Spirotetramat was completely metabolized in the rat since 

no parent compound was detected in the excreta. The main metabolic reaction was cleavage of 

the ester group, which resulted in formation of the major metabolite BYI 08330-enol (53-87% of 

administered dose). All other identified metabolites could be derived from the primary enol 

metabolite. Male rats exhibited much higher rates of demethylation of BYI 08330-enol to BYI 

08330-desmethyl-enol (25-37%) when compared to female rats (5-10%). Excretion of 

radioactivity was relatively rapid with 88-95% of the administered dose eliminated via urine and 

2-11% via feces by 48 hours of exposure.

4.2.1 Dermal Absorption
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A dermal-absorption factor was not needed for this risk assessment because no dermal endpoint 

was chosen (Section 4.5.1). An in vivo dermal penetration study in rats exists in the database

that can be used to estimate a dermal absorption factor in the future if needed.

4.3 Toxicological Effects

The thyroid and thymus glands were target organs in oral subchronic and chronic toxicity studies 

in the dog, which was the most sensitive species. In subchronic dog studies, lower circulating 

levels of the thyroid hormones T3 and T4 were seen in both sexes. Males exhibited the effect at 

a lower dose than females. It was noted in ADME studies that males achieve much higher 

systemic exposures than their female counterparts, which helps explain their higher sensitivity to 

spirotetramat exposure. Decreases in T4 were also observed in a one-year study in dogs at a 

lower dose as compared to subchronic exposures. The only histopathological change in the 

thyroid was a reduction in follicle size in the high-dose group, a possible indication of reduced 

amount of colloid. There were no correlative changes in thyroid weight, thyroid histopathology, 

or thyroid-stimulating hormone (TSH) in either sex. In all dog studies, there were decreases in 

thymus weights described microscopically as involution. In the one-year chronic study, the 

thymus involution was only observed in male dogs. Although the toxicology database for 

spirotetramat shows effects in the thymus gland in dogs, the results of a recently submitted and 

reviewed immunotoxicity study in rats does not indicate any functional deficits in immune 

function. Thymus involution has been demonstrated to occur when hypothyroidism is induced in 

animals, so it is reasonable to conclude that the thymus involution in dogs was secondary to the 

thyroid effects rather than a direct effect on the immune system.

In rats, the testes were the target organ following subchronic and chronic exposure to 

spirotetramat. In a subchronic study, abnormal spermatozoa and hypospermia in the epididymis, 

decreased testicular weight, and testicular degeneration and vacuolation were observed in males 

at a relatively high dose (616 mg/kg bw/day). These effects proved to be reversible in most 

animals after cessation of treatment. Following 12 or 24 months of oral exposure, abnormal 

sperm or spermatid degeneration in the testes and germ cell exfoliated debris in the epididymis 

were observed in male rats at the high dose (~400 mg/kg bw/day). In an investigative study with 

the enol metabolite of spirotetramat, spermatotoxicity, abnormal sperm, and Sertoli cell 

vacuolation were observed in the testes-epididymides of treated animals. In conjunction with the 

ADME data, which indicates that the parent chemical is completely metabolized to the enol 

metabolite, these data support the conclusion that male reproductive toxicity in rats is likely due 

to the enol metabolite of spirotetramat.

Other effects reported in rats were associated with the kidney. Kidney toxicity in the carcinogenicity 

study consisted of decreased organ weight and tubular dilation in both sexes. Similar kidney toxicity 

(decreased organ weight and histopathology) was also observed in parental animals of the F1 

generation in the two-generation rat reproduction toxicity study. 

No adverse findings were observed in mice up to the limit dose in subchronic and chronic studies

with spirotetramat.

There was no evidence of increased quantitative susceptibility of offspring following pre- or 

postnatal exposure to spirotetramat. In the rat developmental study, there is evidence of

qualitative susceptibility with reduced fetal weight and increased incidences of malformations 

and skeletal deviations observed in offspring along with decreased maternal body weight and 

food consumption at the limit dose. In the rabbit developmental study, no developmental effects 
Spirotetramat Human Health Risk Assessment D413575

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were seen. Maternal toxicity was evidenced by sacrifice of animals in moribund condition and 

clinical signs, such as alopecia, cold ears, altered fecal amount/appearance, and reddish 

excretions at the highest dose tested (160 mg/kg bw/day). Animals sacrificed in moribund 

condition displayed severe body-weight loss, reduced food consumption, clinical signs, and gross 

pathological findings at necropsy. Late abortions were noted in only one female at the mid-dose 

and two females at the high-dose. These females displayed body weight decrements and clinical 

signs before abortion that were similar to those seen in animals sacrificed in moribund condition

indicating the abortions were secondary to maternal toxicity. In the reproduction toxicity study, 

offspring effects (decreased pup body weights) were observed at the same dose as parental 

effects (body-weight decrements, decreased kidney weights, and kidney histopathology). 

Evidence of male reproductive toxicity consistent with the subchronic and chronic studies in 

adult rats was also observed in this study.

In a 28-day dermal toxicity study in rats, there were no effects (local or systemic) reported up to

the limit dose. 

Spirotetramat is classified as having low acute toxicity via the oral, dermal and inhalation routes 

(Toxicity Category III or IV). It was found to be an eye irritant and dermal sensitizer, but not a 

dermal irritant. 

In an acute neurotoxicity study in rats, the only evidence of neurotoxicity was decreased motor 

and locomotor activity which occurred only at relatively high-dose levels (200 mg/kg bw) with 

no confirmatory findings of neurological pathology. A preliminary review of a recently 

submitted SCN study in rats does not display any neurotoxic effects up to the highest dose tested.

There is no evidence of carcinogenicity in rats or mice. Spirotetramat was also negative for 

mutagenicity and clastogenicity in several standard in vivo and in vitro assays.

4.4 Safety Factor for Infants and Children (FQPA SF)

The RAB1 risk assessment team recommends that the FQPA SF be reduced to 1X for all 

exposure scenarios based on the following considerations outlined in more detail in the sections 

below: (1) the toxicology database for spirotetramat is adequate for FQPA SF consideration; (2) 

spirotetramat is not considered neurotoxic in mammals; (3) evidence of qualitative susceptibility 

to offspring is protected for by selected endpoints; and (4) the exposure databases are sufficient 

and unlikely to underestimate exposure.

4.4.1 Completeness of the Toxicology Database

The existing toxicology database for spirotetramat is complete for FQPA SF evaluation. The 

following acceptable studies are available: developmental toxicity studies in rats and rabbits, 

one- and two-generation reproduction toxicity studies in rats, and neurotoxicity studies in rats.

4.4.2 Evidence of Neurotoxicity

Although there is evidence of neurotoxicity in the acute neurotoxicity study (see section 4.3), 

concern is low since the effects are well-characterized with clearly established no-observed 

adverse-effect level (NOAEL)/lowest-observed adverse-effect level (LOAEL) values, the 

selected endpoints are protective of the observed neurotoxic effect, there are no neurotoxic 
Spirotetramat Human Health Risk Assessment D413575

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effects seen in the SCN study after preliminary review, and the existing toxicological database 

indicates that spirotetramat is not a neurotoxic chemical.

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

There was no evidence of quantitative susceptibility of offspring following pre- or postnatal 

exposure. There is evidence of qualitative susceptibility in the rat developmental study (see 

Section 4.3); however, concern is low since offspring effects were only seen at the limit dose and 

selected endpoints are protective of the offspring effects. 

4.4.4 Residual Uncertainty in the Exposure Database

The acute dietary food and drinking water exposure assessment utilizes existing and proposed 

tolerance-level residues, DEEM 7.81 default processing factors (where provided), and 100% CT 

information for all commodities. By using these screening-level assessments, actual 

exposures/risks will not be underestimated. The chronic dietary food and drinking water 

exposure assessment utilizes average field trial residues for some commodities, tolerance-level 

residues for the remaining commodities, and 100% CT. Some empirical processing factors were 

used in the chronic assessment along with DEEM 7.81 default processing factors (where 

provided). The chronic assessment is somewhat refined; however, since it is based on reliable 

data, it will not underestimate exposure/risk. The drinking water assessments utilize water 

concentration values from the watercress application scenario generated by the Tier 1 Rice 

Model v.1.0. The resulting screening-level EDWCs provide conservative, health-protective, 

high-end estimates of water concentrations that will not likely be exceeded. There are no 

residential exposures that have been quantitatively assessed for spirotetramat. 

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Tables 4.5.4.1 and 4.5.4.2 summarize the toxicological doses and endpoints selected for human

health risk assessment. Since the last risk assessment, dermal and inhalation exposure endpoints 

have been updated. 

Acute Dietary Endpoint (General Population): The acute dietary endpoint was based on clinical 

signs and decreased motor activity observed in the acute neurotoxicity study at the LOAEL of 

200 mg/kg bw (NOAEL = 100 mg/kg bw). The acute population-adjusted dose (aPAD) of 1.0 

mg/kg bw/day is derived from the NOAEL of 100 mg/kg bw and a 100-fold uncertainty factor

(10X for interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF).

Chronic Dietary (All Populations): The chronic dietary endpoint was based on the thymus 

involution in males in the chronic dog study at the LOAEL of 20 mg/kg bw/day (NOAEL = 5 

mg/kg bw/day). The chronic population-adjusted dose (cPAD) of 0.05 mg/kg bw/day is derived 

from the NOAEL of 5 mg/kg bw/day and a 100-fold uncertainty factor (10X for interspecies 

extrapolation, 10X for intraspecies variation, and 1X for FQPA SF).

Dermal (Short- and Intermediate-Term): A dermal endpoint was not selected. Dermal endpoints 

were chosen in previous risk assessments; however, reevaluation of the toxicological database 

yielded no dermal hazard. Since there is no concern for enhanced sensitivity/susceptibility to 

offspring from spirotetramat exposure, the effects of concern in adults and offspring are 
Spirotetramat Human Health Risk Assessment D413575

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adequately assessed in the dermal toxicity study where no adverse dermal or systemic effects 

were observed up to the limit dose.

Inhalation (Short- and Intermediate-Term): The 90-day oral toxicity study in dogs was selected 

to evaluate inhalation exposures (NOAEL = 32 mg/kg bw/day). The LOAEL of 72 mg/kg 

bw/day is based on depressed red blood cell parameters, thymus atrophy, and decreased food 

consumption. The LOC for inhalation exposure scenarios is for MOEs <100 (10X for

interspecies extrapolation and 10X for intraspecies variation). Since the NOAEL for inhalation 

risk assessment was chosen from an oral study, it was assumed that toxicity via the inhalation 

route is equivalent to oral toxicity. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Since there are no dermal endpoints for spirotetramat, dermal and inhalation exposures do not 

need to be combined for occupational assessments.

4.5.3 Cancer Classification and Risk Assessment Recommendation

There is no evidence of carcinogenicity in chronic toxicity/carcinogenicity studies performed in 

rats and mice. Spirotetramat has been classified as “not likely to be carcinogenic to humans” 

based on lack of evidence for carcinogenicity in rodent studies. 

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

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Dietary and NonOccupational Human Health Risk Assessments. 

Exposure Scenario POD Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC for 

Risk Assessment

Study and Relevant 

Toxicological Effects

Acute Dietary (General 

Population, including 

Infants and Children)

NOAEL = 

100

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

aRfD = aPAD = 1.0 

mg/kg/day

Acute neurotoxicity (rat)

LOAEL = 200 mg/kg based on 

clinical signs and decreased 

motor activity in males.

Chronic Dietary (All 

Populations)

NOAEL = 5

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

cRfD = cPAD = 0.05 

mg/kg/day

Chronic toxicity (dog)

LOAEL = 20 mg/kg/day based 

on thymus involution in males.

Dermal

Short- and 

Intermediate- Term (1-

30 days and 1-6 

months)

In a dermal toxicity study in rats, no adverse effects were observed up to the limit dose. Since there 

is no evidence of increased susceptibility, a dermal assessment is not needed.

Inhalation

Short- and 

Intermediate- Term (1-

30 days and 1-6 

months)

NOAEL = 32

mg/kg/day 

Inhalation 

toxicity is 

considered 

equivalent to 

oral toxicity.

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential LOC for 

MOE =100

90-Day oral toxicity (dog)

LOAEL = 72 mg/kg/day [F] 

based on depressed RBC 

parameters (red blood cell count, 

hemoglobin level and 

hematocrit), thymus atrophy and 

decreased food consumption.

Cancer (Oral, Dermal, 

Inhalation)

Classification: “not likely to be carcinogenic to humans” based on lack of evidence of 

carcinogenicity in rats and mice.

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential variation in sensitivity among 

members of the human population (intraspecies), FQPA SF = FQPA Safety Factor, NOAEL = no-observed adverse-effect level, LOAEL = 

lowest-observed adverse-effect level, RfD = reference dose (a = acute, c = chronic), PAD = population-adjusted dose, LOC = level of concern.
Spirotetramat Human Health Risk Assessment D413575

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Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Occupational Human

Health Risk Assessments.

Exposure Scenario POD Uncertainty Factors LOC for Risk 

Assessment Study and Toxicological Effects

Dermal

Short- and 

Intermediate- Term (1-

30 days and 1-6 

months)

In a dermal toxicity study in rats, no adverse effects were observed up to the limit dose. Since there 

is no evidence of increased susceptibility, a dermal assessment is not needed.

Inhalation

Short- and 

Intermediate- Term (1-

30 days and 1-6 

months)

NOAEL = 32

mg/kg/day 

Inhalation 

toxicity is 

considered 

equivalent to 

oral toxicity.

UFA = 10X

UFH = 10X Occupational LOC for 

MOE =100

90-Day oral toxicity (dog)

LOAEL = 72 mg/kg/day [F] 

based on depressed RBC 

parameters (red blood cell count, 

hemoglobin level and 

hematocrit), thymus atrophy and 

decreased food consumption.

Cancer (oral, dermal, 

inhalation)

Classification: “not likely to be carcinogenic to humans” based on lack of evidence of 

carcinogenicity in rats and mice.

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential variation in sensitivity among 

members of the human population (intraspecies), NOAEL = no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect level, 

MOE = margin of exposure, LOC = level of concern.
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Attachment B. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for spirotetramat are presented below.

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21/28-Day Dermal

870.3250 90-Day Dermal

870.3465 90-Day Inhalation

yes

yes

yes

no

no1

yes

yes

yes

-

-

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction and Fertility Effects

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5300 Mutagenicity—Gene Mutation - mammalian

870.5400 Mutagenicity—Structural Chromosomal Aberrations

870.5500 Mutagenicity—Other Genotoxic Effects

yes

yes

yes

no

yes

yes

yes

-

870.6100a Acute Delayed Neurotox. (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat)

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

870.6300 Develop. Neurotoxicity

no

no

yes

no

no

-

-

yes

yes

-

870.7485 General Metabolism

870.7600 Dermal Penetration

yes

yes

yes

yes

1 The Hazard and Science Policy Council (HASPOC) met on 04-OCT-2012 (TXR# 0056480) and concluded that a repeated exposure inhalation 

toxicity study is not required for spirotetramat at this time. 
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A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile – Spirotetramat Technical. 

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral (rat) 46904527 LD50 >2000 mg/kg (F) III

870.1200 Acute dermal (rat) 46904529 LD50 >2000 mg/kg 

(M&F) III

870.1300 Acute inhalation (rat) 46904530 LC50 >4.183 mg/L 

(M&F) IV

870.2400 Primary eye irritation (rabbit) 46904531

Corneal opacity and iritis 

(grade 1); cleared by day 

8

II

870.2500 Primary dermal irritation (rabbit) 46904532 Negative IV

870.2600 Dermal sensitization (mouse) 46904565 Positive (LLNA) N/A

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat Technical.

Guideline 

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

870.3100 28-Day oral toxicity 

(mouse)

46904536 (2001) Acceptable/nonguideline

0, 500, or 5000 ppm (equivalent to 

0, 136.5, or 1415 mg/kg bw/day 

[M])

NOAEL = 5000 ppm (1415 mg/kg/day [M]).

LOAEL not observed.

870.3100 90-Day oral toxicity 

(mouse)

46904539 (2005) 

Acceptable/guideline

0, 70, 350, 1700, or 7000 ppm 

(equivalent to 0/0, 12.8/16, 

59.6/72.4, 300/389, or 1305/1515 

mg/kg bw/day [M/F])

NOAEL = 7000 ppm (1305/1515 mg/kg/day [M/F]).

LOAEL not observed.

870.3100 28-Day oral toxicity 

(rat)

46904537 (1998) Acceptable/nonguideline

0, 500 or 5000 ppm (equivalent to 

0, 47.3, or 501.8 mg/kg bw/day [F])

NOAEL = 5000 ppm (501.8 mg/kg/day [F]).

LOAEL not observed.

870.3100 90-Day oral toxicity 

(rat)

46904538 (2005) 

Acceptable/guideline

0, 150, 600, 2500, or 10000 ppm 

(equivalent to 0/0, 9/11, 26/46, 

148/188, or 616/752 mg/kg bw/day 

[M/F])

NOAEL = 2500 ppm (148/188 mg/kg/day [M/F]).

LOAEL = 10000 ppm (616/752 mg/kg/day [M/F]), 

based on decreased body weight, abnormal 

spermatozoa and hypospermia in the epididymis, 

decreased testicular weight, and testicular 

degeneration and vacuolation in males, and alveolar 

macrophages in both sexes.

870.3150 28-Day oral toxicity 

(dog)

46904572 (2004)

Acceptable/non-guideline

0, 100, 400, 1600, or 6400 ppm 

(equivalent to 0/0, 3/3, 13/12, 

42/70, or 104/127 mg/kg/day 

[M/F])

NOAEL = 1600 ppm (42/70 mg/kg/day [M/F]).

LOAEL = 6400 ppm (104/127 mg/kg/day [M/F]) 

based on decreased thymus size and weight as well as 

decreased body weight and food consumption, which 

resulted in emaciation.

870.3150 90-Day oral toxicity 

(dog)

46904541 (2005) 

Acceptable/guideline

0, 150, 300, 1200, or 4000/2500 

ppm (equivalent to 0/0, 5/6, 9/10, 

33/32, or 81/72 mg/kg bw/day)

NOAEL = 1200 (32 mg/kg/day) [F] & 2500 ppm (81 

mg/kg/day) [M].

LOAEL = 2500 ppm (72 mg/kg/day) [F] based on 

decreased food consumption, depressed RBC 

parameters (red blood cell count, hemoglobin level.

and hematocrit), and thymus atrophy.

870.3200 28-Day dermal toxicity 

(rat)

46904542 (2006)

Acceptable/guideline

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

(limit dose)

NOAEL = 1000 mg/kg/day.

LOAEL not established.

870.3700a Prenatal developmental 

(rat)

46904543 (2004)

Acceptable/guideline

0, 20, 140, or 1000 mg/kg bw/day

Maternal NOAEL = 140 mg/kg/day.

LOAEL = 1000 mg/kg/day based on impaired food 

consumption, transient body weight loss, and reduced 

final body weight.

Developmental NOAEL = 140 mg/kg/day.

LOAEL = 1000 mg/kg/day based on reduced fetal 

weight and increased incidences of malformations and 

skeletal variations.
Spirotetramat Human Health Risk Assessment D413575

Page 11 of 14

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat Technical.

Guideline 

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

870.3700b Prenatal developmental 

(rabbit)

46904544 (2004)

Acceptable/guideline

0, 10, 40, or 160 mg/kg bw/day

Maternal NOAEL = 40 mg/kg/day.

LOAEL = 160 mg/kg/day based on sacrifice of 

animals in moribund condition and clinical signs

Developmental NOAEL = 160 mg/kg/day.

LOAEL not observed.

870.3800 1-gen. reproduction and 

fertility effects

(rat) – range finding

46904571 (2006)

Acceptable/non-guideline

0, 200, 500, 6000, or 10000 ppm 

(equivalent to 0/0, 10.5/12.8, 

27.8/31.4, 320.1/384.1, or 

537.9/645.7 mg/kg bw/day [M/F])

Parental/Systemic NOAEL = 500 ppm (27.8 and 

31.4 mg/kg bw/day [M/F]).

LOAEL = 6,000 ppm (320.1 and 384.1 mg/kg bw/day 

[M/F]) based on decreased terminal body weight (F1

males).

Reproductive NOAEL = 500 ppm (27.8 mg/kg 

bw/day [M]) and 10,000 ppm (645.7 mg/kg/day) [F].

LOAEL = 6,000 ppm (320.1 mg/kg bw/day [M]) 

based on decreased sperm motility and progression 

and increased abnormal sperm cells in the F1 males.

Offspring NOAEL = 500 ppm (27.8 and 31.4 mg/kg 

bw/day [M/F]).

LOAEL = 6,000 ppm (320.1 and 384.1 mg/kg bw/day 

[M/F]) based on decreased body weight during 

lactation in F1 pups.

870.3800 2-gen. reproduction and 

fertility effects

(rat)

46904546 (2006)

Acceptable/guideline

0, 250, 1,000, or 6,000 ppm 

(equivalent to 0/0, 17.2/20, 

70.7/82.5, or 419.3/484.7 mg/kg 

bw/day [M/F])

Parental/Systemic NOAEL = 1000 ppm (70.7/82.5 

mg/kg/day [M/F]).

LOAEL = 6000 ppm (419.3/484.7 mg/kg/day [M/F]) 

based on decreases in body weight (F1 males and 

females), and food consumption during lactation (Pand F1-generation females), and kidney 

histopathology and decreased kidney weights (F1

males and females).

Reproductive NOAEL = 1000 ppm (70.7 mg/kg/day) 

[M] & 6000 ppm (484.7 mg/kg/day) [F].

LOAEL = 6000 ppm (419.3 mg/kg/day) [M] based on 

abnormal sperm cells and decreased reproductive 

performance in the F1 males.

Offspring NOAEL = 1000 ppm (70.7/82.5 

mg/kg/day [M/F]).

LOAEL = 6000 ppm (419.3/484.7 mg/kg/day [M/F]) 

based on decreased body weight during lactation in 

both F1 and F2 generations.

870.4100 Chronic toxicity (1 year; 

dog)

46904548 (2006)

Acceptable/guideline

0, 200, 600, or 1800 ppm 

(equivalent to 0/0, 6/5, 20/19, or 

55/48 mg/kg/day [M/F])

NOAEL = 200 ppm (6 mg/kg/day) [M] & 1800 ppm

(48 mg/kg/day) [F].

LOAEL = 600 ppm (20 mg/kg/day) [M] based on 

thymus involution [M] and not observed [F].

870.4100 Chronic toxicity

(1 year; rat)

46904547 (2005)

Acceptable/guideline

0, 250, 3500, or 7500/12000 ppm 

(M/F) (equivalent to 0/0, 13.2/18, 

189/255, or 414/890 mg/kg bw/day 

[M/F])

NOAEL = 250 ppm (13.2 mg/kg/day) [M] & 3500 

ppm (255 mg/kg/day) [F].

LOAEL = 3500 ppm (189 mg/kg/day)[M] based on 

dose-dependent increase in alveolar macrophages; & 

12000 ppm (890 mg/kg/day)[F] based on decreased 

body weight, alveolar macrophages, discoloration of 

the lung, and yellow/brown staining of the perigenital 

area and tail.

870.4200 Carcinogenicity

(rat)

46904549 (2006)

Acceptable/guideline

0, 250, 3500, or 7500/12000 ppm 

(M/F) (equivalent to 0/0, 12.5/16.8,

169/229, or 373/823 mg/kg bw/day 

[M/F])

NOAEL = 250 ppm (12.5/16.8 mg/kg/day [M/F]).

LOAEL = 3500 ppm (169/229 mg/kg/day [M/F]) 

based on decreased kidney weight and renal tubular 

dilation.

No evidence of carcinogenicity.

870.4200 Carcinogenicity

(mouse)

46904550 (2006)

Acceptable/guideline

0, 70, 1700, or 7000/6000 ppm 

(M/F) (equivalent to 0/0, 10.9/13.7, 

263/331, or 1022/1319 mg/kg/day 

[M/F])

NOAEL = 7000/6000 ppm (1022/1319 mg/kg/day 

[M/F]).

LOAEL not observed.

No evidence of carcinogenicity.
Spirotetramat Human Health Risk Assessment D413575

Page 12 of 14

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat Technical.

Guideline 

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

870.5100 Bacterial Gene 

Mutation

46904551 (2006)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, or 5000 

μg/plate +/- S9 activation

Negative.

870.5100 Bacterial Gene 

Mutation

46904552 (2002)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, or 5000 

μg/plate +/- S9 activation

Negative.

870.5300 Mammalian Gene 

Mutation

46904553 (2002)

Acceptable/guideline

0, 2.5, 5, 10, 20, 30, 40, 50, 60, 70, 

or 80 g/mL (-S9)

0, 20, 40, 60, 80, 92, 100, 108, 116, 

120, 124, 132, or 140 g/mL (+S9)

Negative.

870.5375 In vitro mammalian 

chromosome aberration

46904554 (2002)

Acceptable/guideline

0, 10, 12, 24, 30, 48, or 50 μg/mL (-

S9) 

0, 20, 40, or 80 μg/mL (+S9)

Weakly clastogenic at cytotoxic concentrations only.

870.5375 In vitro mammalian 

chromosome aberration

46904555 (2003)

Unacceptable/guideline

0, 30, 50, 70, 90, or 110 μg/mL (-

S9)

0, 40, 60, 80, 100, or 120 μg/mL 

(+S9)

N/A

870.5395 In vivo erythrocyte 

micronucleus assay 

(mouse)

46904556 (2002)

Acceptable/guideline

0, 125, 250, or 500 mg/kg bw

Negative.

870.5385 In vivo bone marrow 

chromosomal aberration 

assay (mouse)

46904558 (2003)

Acceptable/guideline

0, 125, 250, or 500 mg/kg bw

Negative.

870.5550 In vivo/in vitro UDS 

assay (rat hepatocytes)

46904557 (2003)

Acceptable/guideline

0, 1000, or 2000 mg/kg bw

Negative.

870.6200a Acute neurotoxicity 

screening battery

46904560 (2005)

Acceptable/guideline

0, 50, 100, 200, 500, or 2000 mg/kg 

bw

NOAEL = 100 mg/kg/day.

LOAEL = 200 mg/kg/day based on clinical signs 

(males and females) and decreased motor activity 

(males).

870.6200b Subchronic 

neurotoxicity screening 

battery

48958802 (2012) Pending formal review.

870.7485 Metabolism and 

pharmacokinetics

(rat)

46904504 (2006)

Acceptable/guideline

2 or 100 mg/kg bw (single)

2 mg/kg bw (repeat)

Absorption: 89-98% after 48 hrs (no significant 

differences among low-dose, high-dose, and repeateddose tests).

Distribution: AUC0-∞ (measure of systemic exposure) 

slightly higher for males than females; <0.2% of 

administered dose detected in body 48 hrs after 

sacrifice; highest equivalent concentrations detected 

in liver and kidney.

Metabolism: parent compound undetected in urine 

and feces of all tests; main metabolic reaction was 

cleavage of the ester group which resulted in 

formation of the primary metabolite BYI 08330-enol 

(53-87% of administered dose); all other identified 

metabolites could be derived from enol; male rats 

exhibited much higher rates of demethylation of BYI 

08330-enol to BYI 08330-desmethyl-enol (25-37%) 

vs. females rats (5-10%).

Excretion: 88-95% of administered dose eliminated 

via urine and 2-11% via feces within 48 hrs.

870.7485 Metabolism and 

pharmacokinetics

46904561 (2006)

Acceptable/guideline

At 1000 mg/kg bw: Absorption and excretion less 

than low dose, with 27% of dose excreted in urine 
Spirotetramat Human Health Risk Assessment D413575

Page 13 of 14

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat Technical.

Guideline 

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

(rat) 2 or 1000 mg/kg bw (single) after 24 hours (18% in feces); plasma radioactivity 

slightly higher than in liver and kidney; these results 

are consistent with saturation of cellular transport 

mechanisms. Tissue radioactivity decreased from 1 to 

24 hours post dose. Metabolism profile qualitatively 

similar to that of the low-dose group; BYI 08330-enol 

was most prominent metabolite; similar to low-dose 

group, BYI 08330-desmethyl-enol levels greater in 

urine than in plasma and organs.

870.7600 In vivo dermal 

penetration

(rat)

46904563 (2006)

Acceptable/guideline 

100, 15, or 5 μg ai/cm2(OD150 

formulation)

Dermal absorption = 10%.

870.7800 Immunotoxicity

(rat)

48525901 (2011)

Acceptable/guideline

500, 2500, or 12,000 ppm 

(equivalent to 33, 164, or 795

mg/kg/day)

The functional immunotoxicity NOAEL is 12,000 

ppm (equivalent to 795 mg/kg/day, the highest dose 

tested); the LOAEL was not established.

The systemic toxicity LOAEL for spirotetramat in 

male rats is 12,000 ppm (equivalent to 795 mg/kg 

bw/day) based on decreased body weights, lowered 

food consumption, lower thymus weight, and 

observations of atrophic thymus. The NOAEL for 

systemic toxicity is 2500 ppm (equivalent to 164 

mg/kg bw/day)

Special 

study

Male reproductive 

toxicity 

46904569 (2005)

Acceptable/non-guideline

1000 mg/kg bw/day (3, 10, 21, or 

41 days)

Primary testicular effects on or after day 10 were 

degeneration of round and elongating spermatids 

(stage 7-8 and 9-14, respectively), decreased sperm 

count, and increased numbers of aberrant/abnormal 

spermatozoa in the epididymis.

Table A.2.3. Toxicity Profile – Metabolites.

Guideline 

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

Exploratory 

study

10-day gavage (enol 

metabolite)

46904601 (2006)

Acceptable/non-guideline

800 mg/kg bw/day

No treatment related effects; only limited parameters 

measured; histopathology not evaluated.

Special study 21-day gavage (enol 

metabolite)

47070901 (2006)

Acceptable/non-guideline

800 mg/kg bw/day

Clinical signs of toxicity and testicular/spermatotoxicity.

870.5100 Bacterial Gene 

Mutation

(ketohydroxy 

metabolite)

46904594 (2005)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, or 

5000 μg/plate +/- S9 activation

Negative.

870.7485 Metabolism and 

Pharmacokinetics (rat)

(ketohydroxy 

metabolite)

46904595 (2006)

Acceptable/guideline

2 mg/kg bw (single)

Absorption: ≥55% after 48 hrs. 

Distribution: highest concentrations detected in GI tract, 

liver, and kidney; <0.2% of administered dose detected 

in body 48 hrs post dose.

Metabolism: parent compound undetected in urine and 

trace amounts in feces; main metabolic reaction was 

oxidative demethylation of cyclohexyl-O-methyl group 

to form desmethyl-ketohydroxy metabolite (15% of 

administered dose); all other identified metabolites could 

be derived from desmethyl-ketohydroxy metabolite.

Excretion: 54% of administered dose eliminated via 

urine and 44% via feces within 48 hrs.

870.5100 Bacterial Gene 

Mutation

(desmethylketohydroxy 

metabolite)

46904597 (2006)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, or 

5000 μg/plate +/- S9 activation

Negative.
Spirotetramat Human Health Risk Assessment D413575

Page 14 of 14

Table A.2.3. Toxicity Profile – Metabolites.

Guideline 

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

870.5100 Bacterial Gene 

Mutation

(dihydroxy metabolite)

46904599 (2005)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, or 

5000 μg/plate +/- S9 activation

Negative.

870.7485 Metabolism and 

Pharmacokinetics (rat)

(enol glucoside 

metabolite)

46904602 (2006)

Acceptable/non-guideline

0.1 mg/kg bw (single; 1 rat)

Absorption: 54% after 48 hrs.

Distribution: plasma concentrations peaked 4 hrs post 

dose; 1% of administered dose detected in body 48 hrs 

post dose.

Metabolism: parent compound detected in feces (21%); 

main metabolite was enol (64% of administered dose).

Excretion: 53% of administered dose eliminated via 

urine and 44% via feces within 48 hrs.

870.5100 Bacterial Gene 

Mutation

(monohydroxy 

metabolite)

46904604 (2005)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, or 

5000 μg/plate +/- S9 activation

Negative.