Document ID: EPA-HQ-OPP-2005-0145-0048
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-03-28T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date:  2/13/08

							

MEMORANDUM

SUBJECT:	Boscalid:  Addendum to the July 10, 2007 Human Risk Assessment
to Support a Section 3 Use on Endive, an Amendment to the Tolerances for
Strawberries and Berries, Crop Group 13, and an Increase in Tolerances
in/on Cucumber and Vegetable, Root, Subgroup 1A, except Sugar Beet,
Garden Beet, Radish, and Turnip.

PC Code:  128008, Petition Nos:  5E7013, 5F6986

DP Barcode:  348571

							

FROM:	Donna S. Davis, Chemist/Risk Assessor	

		Reregistration Branch 1

		Health Effects Division (7509P)

THROUGH:	Michael S. Metzger, Chief	

		Reregistration Branch 1

		Health Effects Division (7509P)

TO:		Shaja Brothers/Barbara Madden/Dan Rosenblatt

RIMUERB/Registration Division (7505P)

	and

Bryant Crowe/Tony Kish/Cynthia Giles-Parker

Fungicide Branch/Registration Division (7505P)

BACKGROUND

On July 10, 2007, the Alternative Risk Integration and Assessment (ARIA)
Team in the Registration Division of the Office of Pesticide Programs
(OPP) issued a human health risk assessment for the active ingredient,
boscalid, to support a Section 3 use on endive, an amendment to the
tolerances for strawberries and berries, crop group 13, and an increase
in tolerances in/on the cucumber and vegetable, root, subgroup 1A,
except sugar beet, garden beet, radish, and turnip (D327906, B. Hanson).
 Subsequent to completion of the risk assessment, the Agency received an
objection to a previously proposed final rule for another use of the
same chemical.  As part of the process of responding to that objection,
the Health Effects Division (HED) re-reviewed the toxicity database for
boscalid and discovered two errors in the Hazard Identification
Assessment Review Committee (HIARC) report cited in the ARIA memorandum.
 This memorandum serves as an addendum to the July ARIA risk assessment,
and also as documentation to correct the most recent HIARC document (A
Levy, 3/7/2003, TXR No. 0051613) and HED risk assessment (Y. Donovan,
9/8/2003, D290022).  Further, this addendum captures more completely an
accurate discussion of the FQPA SF for boscalid.  Lastly, this addendum
addresses the completeness of the residue chemistry database to support
the uses cited in the July 2007 risk assessment.

This addendum supersedes the prior cited documents with respect to
discussion of the boscalid toxicity database and hazard
characterization, the FQPA safety factor and the completeness of the
residue chemistry database.  All other aspects of the July 2007 human
health risk assessment remain unchanged.

TOXICITY CONSIDERATIONS

Error Correction for the 2-Generation Reproduction Study in Rats

In reviewing the 2-generation reproduction study in rats, the human
health risk assessments issued in September 2003 and July 2007 indicated
that body weight effects seen in the second generation pups were seen
only at the high dose.  This statement is in error since the effects
were seen at both the mid and high doses in the study in the second
generation pups.

Error Correction for the Developmental Neurotoxicity Study 

Prior documentation has noted that body weight effects occurred only at
the limit dose.  However, EPA notes that transient effects were seen in
the pups in one sex at the mid-dose (statistically significant decreases
in bodyweight on post-natal days 1 -3 but the animals had recovered by
day 11).  

Boscalid Regulatory Endpoints

The endpoints used for risk assessment purposes are briefly summarized
below.  HED notes that no change in endpoints has occurred from those
endpoints used in the September 2003 and July 2007 human health risk
assessments.

An acute endpoint was not selected since there were no adverse effects
seen in the database, including the developmental toxicity studies,
attributable to a single exposure of boscalid.  The chronic dietary
endpoint, incidental oral endpoint, dermal, and inhalation endpoints
were all selected from three co-critical studies, the chronic rat study,
the rat carcinogenicity study and a one-year feeding study in dogs.  The
dose selected for regulation of oral, dermal and inhalation risk at all
durations, for all populations is the NOAEL of 21.8 mg/kg/day based on
thyroid and hepatic toxicity seen in rats and dogs at higher dose
levels.  A dermal absorption factor of 15% was derived from an in vivo
dermal penetration study in the rat.  An inhalation absorption factor of
100% was assumed for the inhalation risk assessments.  

FQPA Safety Factor Discussion for Boscalid

As noted in the September 2003 and July 2007 human health risk
assessments, EPA has concluded that an additional safety factor beyond
the standard inter- and intra-species extrapolation-based safety factor
of 100 is not required for the protection of infants and children.  This
conclusion remains unchanged; however, a more accurate and complete
rationale is provided as follows.

The toxicity database for boscalid is complete.  The toxicity studies
for boscalid show it generally to have low mammalian toxicity. 

In considering the toxicity database and the need for an additionally
safety factor to protect infants and children, the Agency carefully
considered the toxicity data for evidence of increased qualitative or
quantitative susceptibility to boscalid in young animals.  

As noted above, in the 2-generation reproduction study in rats, body
weight effects were seen in the mid and high doses in the second
generation male pups.  However, the degree of concern is low for the
quantitative evidence of susceptibility seen in this study, since the
body weight effects were seen in only one sex and only after dosing for
two generations.  There is a clear NOAEL for the body weight effects
seen in the rat 2-generation reproduction study and EPA is regulating
based on a point of departure below where these effects are seen.

As noted above, in the developmental neurotoxicity study, transient body
weight effects were seen in one sex at post-natal days 1 - 4 with the
animals recovering by post-natal day 11.  Body weight effects were also
seen in the high dose, which was the limit dose. The degree of concern
for these effects are low since the effects are either transient in
nature or occurred at the limit dose and EPA is regulating based on a
point of departure below where these effects are seen.

While qualitative sensitivity was seen in the rabbit developmental
study, the fetal effects were seen only at the limit dose in the
presence of maternal toxicity.  Further, since EPA is regulating based
on a point of departure which is an order of magnitude below where these
effects are seen in the rabbit developmental study, EPA concludes that
the qualitative sensitivity evidenced in the fetuses in the rabbit
developmental study does not require retention of the 10X children’s
safety factor.

Finally, EPA has conservatively estimated human exposure to boscalid,
relying on worst case exposures in food (assuming all registered crops
contain residues at the tolerance level), and conservative models as
well as pesticide-specific data in estimating exposure from residues in
drinking water and from residential  uses.

Based on the considerations above, EPA concludes that it has reliable
data showing that infants and children would be safe without the
application of an addition 10X safety factor for boscalid.

In summary the FQPA safety factor has been reduced to 1X for this
assessment for the following reasons:

EPA has a complete toxicity database for boscalid. 

The toxicity studies for boscalid show it generally to have low
mammalian toxicity. 

Data involving the testing of young animals did show increased
quantitative sensitivity in the young with regard to body weight effects
and qualitative sensitivity in one developmental study. However, clear
NOAELs were identified for all of these effects. Moreover, the body
weight effects at the LOAELs in these studies were either transient or
inconsistent and qualitative sensitivity occurred at the limit dose in
the presence of maternal toxicity. 

EPA concludes that there are no residual uncertainties for pre and/or
post-natal toxicity.  The NOAEL used for various risk assessments would
address the body weight effects seen at higher doses in the
developmental and reproductive studies. 

EPA has conservatively estimated human exposure to boscalid, relying on
worst case exposures in food(assuming all registered crops contain
residues at the tolerance level), and conservative models as well as
pesticide-specific data in estimating exposure from residues in drinking
water and from residential uses.

RESIDUE CHEMISTRY CONSIDERATIONS

In the July 2007 human health risk assessment, in the Executive Summary,
Under  the subsection titled FQPA Assessment, there is a statement that
the “…residue chemistry and environmental fate databases are
relatively complete…”  HED wishes to clarify that the term
“relatively complete” is a reflection of the writing style of the
author.  Having reexamined the chemistry and fate databases, the Agency
concludes that the databases are complete with respect to the requested
new uses and amendments to uses that are the subject of the July 2007
risk assessment.  

Addendum to Boscalid Human Health Risk Assessment	D348571

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