UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: April 27, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Fipronil. Requirement for a Comparative Thyroid Assay, and Limited Review to 

Determine Incidental Oral Endpoints. 

PC Code: 129121 

Decision No.: 502763 

Petition No.: NA 

Risk Assessment Type: NA 

TXR No.: 00054036 

MRIDNo.: NA 

DP Barcode: 426426 

Registration No.: NA 

Regulatory Action: NA 

Case No.: NA 

CAS No.: 120068-37-3 

40 CFR: 180.517 

FROM: Michael S. Metzger, Chief .. ti /) { () Risk Assessment Branch VII ,1 ~ · ()_. ~ /~· ;\-

Health Effects Division (7509P) -

TO: Garland Waleko 

Risk Management and Implementation Branch 2 

Pesticide Re-evaluation Division (7508P) 

I. ACTION REQUESTED 

Review the fipronil database for selection of endpoints for Incidental Oral exposure scenarios for 

short- and intermediate-term duration exposures, and determine if a new developmental rabbit 

toxicity study and a comparative thyroid assay (CT A) are required. 

II. BACKGROUND 

Fi pro nil [ 5-amino-1-(2, 6-dichloro-4-( trifl uoromethyl) pheny 1 )-4-( ( 1,R, S )-

trifl uoromethy l )sulfin y l )-1-H-pyrazole-3-carbonitrile] is a broad-spectrum insecticide belonging 

to the pyrazole class of insecticides. Fipronil is available in a number of different formulations, 

including liquid, granular, dust, bait stations, and aerosol products. It is used agriculturally as a 

foliar and a seed treatment in a number of settings (i.e. turf, ornamentals, greenhouses etc.), and 

used as a termiticide treatment both commercially and residentially. There are also registered 

residential uses (pet and termiticide uses and fire ant control) for fipronil. A limited review was 
Page 2 of 3

and the LOAEL was not determined. Concerns were identified with the methodology used 

in the rabbit developmental toxicity study and the rabbit developmental study was not 

selected for risk assessment purposes. The following issues with the study were identified: 

1) the the highest dose tested was 1 mg/kg/day and this dose did not sufficiently challenge 

the animals, 2) the study authors did not provide a rationale for their dose selection, and 3) 

the thyroid appears to be a target organ for this chemical and thyroid measurements were not 

performed in this study. However, HED will not ask for a new developmental rabbit study 

because the fipronil database contains several studies in the rat including the developmental 

neurotoxicity, a developmental toxicity y and the 2-generation reproductive toxicity studies, 

and the NOAELs are all well below 1 mg/kg/day. In addition, the dosing in a new study in 

rabbits would need to be higher than 1 mg/kg/day and therefore, any effects observed would 

likely occur at doses greater than 1 mg/kg/day, which would not provide the most sensitive 

point of departure (POD). The developmental rabbit study is classified as 

Acceptable/Nonguideline. 

III. CONCLUSIONS

Endpoint Selection 

Incidental Oral (Short- and Intermediate-term) 

Study Selected: Developmental Neurotoxicity Study in rats 

MRID Number: 44039002, 44501102, 44501103 

Dose and Endpoint for Risk Assessment: 0.05 mg/kg/day, based on decreased pup weight at 

a LOAEL of 0.9 mg/kg/day in the developmental neurotoxicity study in rats. 

Uncertainty Factor(s): 1000X (10X for interspecies variability, 10X for intraspecies 

variability, 10X for FQPA SF). 

Comments about Study/Endpoint/Uncertainty Factor: 

The developmental neurotoxicity study was selected because it provides the most sensitive 

oral endpoint for both the short- and the intermediate-term durations. The route of exposure 

(in the feed) is appropriate for this exposure scenario and this endpoint is protective of 

effects observed at higher doses. The FQPA safety factor of 10X has been retained due to a 

need for a comparative thyroid study for fipronil as discussed below. 
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Summary of Toxicological Doses and Endpoints for Fipronil for Use in 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 

Incidental Oral 

Short-Term 

NOAEL = 

0.05 

mg/kg/day 

UFA = 10x 

UFH =10x 

FQPA = 10x LOC = 1000

Developmental Neurotoxicity Study 

MRIDs 44039002, 44501102, 

44501103) in the rat 

Developmental LOAEL = 0.9 

mg/kg/day for decreased pup 

weight. 

Incidental Oral 

IntermediateTerm 

NOAEL = 

0.05 

mg/kg/day 

UFA = 10x 

UFH =10x 

FQPA = 10x LOC = 1000

 Developmental Neurotoxicity 

Study MRIDs 44039002, 44501102, 

44501103) in the rat 

Developmental LOAEL = 0.9 

mg/kg/day for decreased pup 

weight. 

Point of Departure (POD) = A data point or an estimated point 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 animals to humans (interspecies). 

UFH = potential variation in sensitivity among members of the human population (intraspecies). UFL = 

LOAEL to NOAEL uncertainty factor. FQPA SF = FQPA Safety Factor. cPAD = chronic population 

adjusted dose. RfD = reference dose. N/A = not applicable. 

Comparative Thyroid Study 

A comparative thyroid study is needed because the thyroid is a target in adults and there has 

not been an assessment of thyroid function in the young. An additional 10x FQPA safety 

factor is needed due to the lack of a comparative thyroid study.