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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

 OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

MEMORANDUM

Date: September 1, 2011

SUBJECT: Pyriofenonene - 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

TXR No.: NA CAS No.: NA

MRID No.: NA 40 CFR: NA

 

FROM: Marquea D. King, Acting ToxSAC Executive Secretary

Health Effects Division (7509P)

THROUGH: Elizabeth Mendez, ToxSAC Chair

Health Effects Division (7509P)

TO: Kit Farwell, Toxicologist

RAB III, Health Effects Division (7509P)

ToxSAC Meeting Notes for 8/11/11 Meetings on Pyriofenonene

Team Members: Kit Farwell (Toxicologist), Mike Metzger (Branch Chief)

ToxSAC Members: Abdallah Khasawinah, Marquea King, Whang Phang*, Elissa Reaves*, 

Jessica Ryman

*designated reviewers

Other Attendees: William Irwin, Khin Oo, Yung Yang, Chester Rodriguez, Alan Levy, 

Karlyn Middleton, PMRA Canada (on phone: Trisha Murray, Steve 

Wong)
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Background:

Exposure Summary

Pyriofenone is being assessed for a dietary import tolerance 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 pyriofenone. 

Occupational Exposure

There are currently no registered or proposed occupational uses of pyriofenone.

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 any 

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. Rabbit Developmental DER: 

a) Maternal Effects: The reviewer should check to see if there were particular differences in 

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). Conversely, if those does 

did not show such changes then it is likely that the abortions 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 study.

4. Dog Chronic Toxicity DER:

a) Robustness: The NOAEL is currently 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. 

Characterize the effects from the chronic dog study to explain why the rat study is more 

robust. 
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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 body of the DER states that “the decrease in food consumption in the main 

study is not considered toxicologically significant.” However, the maternal LOAEL is based on 

abortions and decreased food consumption. If the finding is not toxicologically significant, then 

it should be removed from the LOAEL statement. In addition, the developmental LOAEL for 

this study should also include the decreases in fetal weight at 300 mg/kg/day (↓17%) as part of 

the LOAEL 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 toxicity/carcinogenicity 

study with characterization as to why the chronic dog study is not as robust. Also for the chronic 

dog study 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 absence of corroborative data. a change in 

alkaline phosphatase as seen in females at 500 ppm is not considered adverse. In the subchronic 

dog study use a NOAEL of 3000 ppm (90 mg/kg/day) since the only observed effect in females 

at 3000 ppm was an increase in alkaline phosphatase with no other corroborative findings.

Incidental 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 young 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.