Document ID: EPA-HQ-OPP-2006-0874-0014
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-11-01T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

October 5, 2006	OFFICE OF 

TXR# 0054398	PREVENTION, PESTICIDES AND

MEMORANDUM:	TOXIC SUBSTANCES   

Subject: 098801:  Response to Phase I comments from Mandava Associates. 

DP Barcode: D323828	

From:	David G Anderson

RRB-2 HED (7509P)

To:	Robert Mc Nally/Tracy Perry

SRRD (7508P)

Thru:	Alan Nielsen, BSS

RRB-2, HED (7509P)

	Phase I comments were submitted by Michael Farrow through Mandava
Associates, LLC, dated September 15, 2006.  

	Comments consisted of objection to the 3X factor in addition to the
usual 100X placed on the NOAEL of 31 mg/kg/day used in the Risk
Assessment Document for chlorflurenol-methyl ester exposure on the
grounds that: (1) It was an old pre-GLP study that was not required, (2)
the material is excreted in 24 hours, and (3) is a non-carcinogen,
non-mutagen and non-teratogen.  In addition, they request information
about whether this study and other unacceptable studies would be
included in the final RED.  

	Response by RRB-2

	As stated in chlorflurenol-methyl ester RED of July 10, 2006, in the
9th paragraph of the Executive Summary,

“Due to these ambiguous findings in the reproduction study, an
additional uncertainty factor of 3X was used when calculating human oral
risk.”

An identical explanation is given in Section 3.1.1 Database Summary, on
page 13, last paragraph, second to the last sentence, of the above
document, 

“Due to these ambiguous findings in the reproduction study, an
additional uncertainty factor of 3X was used when calculating human oral
risk.”

	The studies required for non-food use pesticides are dependent on
exposure and potential toxicity of the pesticide.  Any study showing
potential hazards to humans is evaluated.  Additional studies may be
required as needed.  In this case, potential reproductive toxicity was
ambiguously shown in a study submitted for food use purposes.  

	There was uncertainty introduced by decreased fertility at the LDT
during the parental generation of the 1st and 2nd litters and during the
two subsequent two generations for each of the 1st and 2nd litters at
all dose levels and when all generations were combined fertility was
reduced by about 27% for all dose levels.  This combined with an
excessive number of pregnant females not showing the presence of sperm
during cohabitation [29 of 479 cohabitations] cast doubt on the health
of the animals used as well as the study conduct and any conclusions
reached.  The quality and potential effects in the 2-generation
reproduction study on chlorflurenol-methyl ester (MRID# 00082867) were
judged to be relevant to the hazard assessment even if not adequate to
set a NOAEL for risk assessment.  The object of a Risk Assessment is
public protection and as such the potential effects on reproduction
could not be ignored.  

	The study was carefully evaluated.  Neither the original reviewer nor
the subsequent reviewer could determine the NOAEL for the potential
reproductive effects shown in the study.  The additional 3X factor
reflects this uncertainty.  The 3X factor could easily be eliminated by
a reproductive study showing a more definitive NOAEL.  

	The comment about chlorflurenol-methyl ester studies showing a 24 hour
excretion time, no carcinogenicity, no genotoxicity and no
teratogenicity is irrelevant, since these studies are not designed to
study reproductive effects.

	Whether the final RED will be supported by acceptable and unacceptable
studies has not been determined.  The designation of “unacceptable as
guideline study” does not mean that some data from the study can not
be used.  For instance, data from the unacceptable metabolism study
(MRID# 00082868, dated 1972) are the only data submitted supporting a 24
hour excretion time for chlorflurenol-methyl ester, however, the study
is unacceptable as a guideline metabolism study.

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