 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	

							OFFICE OF CHEMICAL SAFETY AND

	                 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)

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: 

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:

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. 

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.

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