1 **UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460**

**OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION**  **MEMORANDUM Date:**  Septe mber 1 , 2011 **SUBJECT: P**  **yriofenone n**  **e** - ToxSAC Meeting on August 11, 2011 **PC Code:** 028828 **DP Barcode:** NA **Decision No.:** NA **Registration No. :**  NA **Petition No.:** NA **Regulatory Action:** NA **Risk Assessment Type:** Single Chemical Aggregate **Case No.:** NA T **XR No.:** NA **CAS No.:** NA **MRID No.:** NA **40 CFR:** NA **FROM:** Marquea D. King , Acting ToxSAC Executive Secretary

Health Effects Division (7509P) **THROUGH:** El i z abeth Mendez , ToxSAC Chair

Health Effects Division (7509P) **TO :**  Kit Farwell , Toxicologist

RAB I II, Health Effects Division (7509P) ToxSAC Meeting Notes for 8 / 11 / 1 1 Meetings on Py riofenonen e Team Members : Kit Farwell ( T oxicologist ) , Mike Metzger (Branch Chief) ToxSAC Members : Abdallah Khasawinah, Marque a King, Whang Phang * , Elissa Reaves * ,

Jessica Ry

man *designated reviewers Other Attendees : William Irwin, Khin Oo, Yung Yang, Chester Rodriguez, Alan Levy ,

Karl yn Middleton, PMRA Canada (on phone: Trisha Murray , Steve Wong)2

**Background: Exposure S**  **ummary** Py riofenone is being assessed for a dietary import tol erance and is being reviewed as a joint review with PMRA, which had the lead for toxicity reviews. The PMRA reviews have undergone secondary

review by

HED and appropriate changes have been made . Both the HED and PMRA toxicologists agree on NOAELs and interpretation of the studies and there are no differences between the two agencies in their respective DERs. Use Pattern Not provided. Residential Exposure There are currently

no registered or proposed residential uses of p yriofenone

. Occupational Exposure There are currently

no registered or proposed occupational uses of p yriofenone

. **I .**  **General Comments**  1. The toxicologist should provide additional details in the hazard characterization regarding the details of the microscopic changes and/or lesions . Also background on the hazard and an y information on the mode of action would be useful. 2. In the toxicity

profile table, clarify

that the rabbit developmental toxicity seen was treatment related and adverse but not considered acute. 3 . Ra bbi t Developmental DER: a) Maternal Effects: The reviewer should check to see if there w ere particular differences i n food consumption for does euthanized with signs of abortion. If food consumption was affected in the two high dose treated animals then it is possible that the abortions in these animals were not due to an acute exposure but rather secondary to a sustained decrease in maternal food consumption (indicative of maternal distress)

. Conversel y, if those does did not show such changes then it is likely that the abortio n s are due to an acute effect

. If the latter is the case, then the ToxSAC recommends establishing an acute RfD for females of reproductive age based on abortions seen in this stu dy

. 4. Dog Chronic Toxicity

DER: a) Robustness: The N OAEL is currentl y 14 mg/kg/day based on liver toxicity while the rat chronic toxicity

study is 9 mg/kg/day

based on an increased incidence of nephropathy

. C haracterize the effects from the chronic dog s tudy to explain why

the rat study

is more robust.3

5. The committee noted a number of inconsistencies between the toxicity profile table, the NOAEL/LOAELs statements in DERs and

– in some instances

– discrepancies between executive summaries and text in the body of the DER. As an example, in the developmental study in rats, the bod y of the DER states that “the decrease in food consumption in the main study is not considered toxicologically significant.” However, the maternal L OAEL is based on abortions and decreased food consumption. I f the finding is not toxicologically significant, then it should be removed from the L OAEL statement. In addition, the developmental L OAEL for this study should also include the decreases in fetal weight at 300 mg/kg/day ( ↓ 17%) as part of the L OAEL statement **. II.**  **Questions for the ToxSAC:** 1) Please comment on the endpoint

. ToxSAC Response : Acute: please see rabbit developmental comment above. Chronic Dietary : Use a NOAEL of 9 mg/kg/day from the rat chronic toxici ty /carcinogenicit y study with characterization as to why the chronic dog stud y is not as robust. Also for the chronic dog stud y use the NOAEL of 500 ppm (14 mg/kg/day) and a LOAEL of 3000 ppm (84/86 mg/kg/day , males and females , respectively). In the ab sence of corroborative data. a change in alkaline phosphatase as seen in females at 500 ppm is not considered adverse. In the subchronic dog stud y use a NOAEL of 3000 ppm (90 mg/kg/day) since the onl y observed effect in females at 3000 ppm was an increase in alkaline phosphatase with no other corroborative findings.
In cidental Oral

– N/A FQPA: The committee concurred with the risk assessment team’s recommendation that the FQPA factor be reduced to 1X. No enhanced susceptibility of the y oung was noted in the available developmental or reproductive toxicity studies . In addition, endpoint selection is based on the most sensitive endpoint and population available and thus is protective for the developmental/offspring effects noted in the database.