### 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

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Risk Assessment Branch VII

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### ;\- Health Effects Division (7509P)

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### 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 fo llowing 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 author s did not provide a ra tionale for their dose selection, and 3) the thyroid appears to be a target organ for th is 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 c ontains 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 highe r than 1 mg/kg/day and therefor e, any effects observed would likely occur at doses greater than 1 mg/kg/da y, which would not provide the most sensitive point of departure (POD). The developm ental 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 developm ental neurotoxicity study in rats.

Uncertainty Factor(s): 1000X (10X for inte rspecies 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 dura tions. The route of exposure (in the feed) is appropriate for this exposure scenario and this endpoi nt is protective of effects observed at higher doses. The FQPA safe ty factor of 10X has been retained due to a need for a comparative thyroid study for fipronil as discussed below.

### Page 3 of 3 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 UF A = 10x UF H =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 OralIntermediateTerm NOAEL = 0.05 mg/kg/day UF A = 10x UF H =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 es timated 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 ad verse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animals to humans (interspecies). UF H = potential variation in sensitivity among member s of the human population (intraspecies). UF L = LOAEL to NOAEL uncertainty factor. FQPA SF = FQ PA 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.