**Docket Number OPP-2004-0147**

**Comments on EPA's Preliminary Assessment**

**Zinc Pyrithione**

**Marcia van Gemert, Ph.D. mvangemert@exponent.com**

# Exponent

We appreciate the opportunity to comment on the draft risk assessment
for zinc omadine.

After reviewing the draft documents provided in Docket Number
OPP-2004-0147, we believe there are three issues that need to be
addressed:

1\. A cumulative risk assessment should be performed based on the
existence of a common mechanism of toxicity for the zinc and sodium
pyrithione;

2\. An aggregate risk assessment should be performed for both materials;

3\. An additional 10x FQPA safety factor should be added to account for
the difference in toxicity and database between the two chemicals.

**[CUMULATIVE RISK ASSESSMENT]{.underline}**

Section 408 of the FFDCA stipulates that when determining the safety of
a pesticide chemical, EPA shall base its assessment of the risk posed by
the chemical on, among other things, available information concerning
the cumulative effects to human health that may result from dietary,
residential, or other non-occupational exposure to other substances that
have a common mechanism of toxicity. The reason for consideration of
other substances is due to the possibility that low-level exposures to
multiple chemical substances that cause a common toxic effect by a
common mechanism could lead to the same adverse health effect, as would
a higher level of exposure to any of the other substances individually.
A person exposed to a pesticide at a level that is considered safe may
in fact experience harm if that person is also exposed to other
substances that cause a common toxic effect by a mechanism common with
that of the subject pesticide, even if the individual exposure levels to
the other substances are also considered safe.

In the zinc pyrithione draft document, EPA states "EPA does not have, at
this time, available data to determine whether zince pyrithione has a
common mechanism of toxicity with other substances including sodium
pyrithione." EPA's historical statements and treatment of the pyrithione
database seem to contradict this conclusion.

The Antimicrobial Division has determined that the toxicological
databases for both the zinc and sodium pyrithione are interchangeable,
using sodium pyrithione studies to substitute for the missing zinc
pyrithione studies. This substitution is logical in light of the
conclusions published by EPA in the Federal Register on September 20,
2000 (Notice of filing for an exemption from tolerance for zinc
pyrithione). In this document, EPA clearly states that zinc pyrithione
and sodium pyrithione share a common, biologically active moiety. Since
EPA has concluded that the biologically active moiety is common between
the two molecules, it is logical that EPA would conclude that both
molecules share the same mechanism of toxicity. For this reason, EPA is
obligated to conduct a cumulative risk assessment as part of the
re-registration of zinc pyrithione.

**AGGREGATE RISK ASSESSMENT**

In the draft risk assessments, EPA has focused exclusively on exposure
and risk from zinc pyrithione. EPA has justified this by stating that
sodium pyrithione is used primarily in metal working fluids (MWF) while
zinc pyrithione is used in a variety of other applications including
paints/coatings.

This conclusion ignores marketing and technical literature generated by
the registrant for sodium pyrithione which demonstrates the facile
conversion of sodium pyrithione into zinc pyrithione. These documents
instruct commercial customers how to facilitate this conversion as well
as providing the performance benefits associated with this change. These
documents are attached as appendix I and appendix II. Weblinks for the
documents are as follows:

[www.archbiocides.com/architecturalpaints/WetDryref.asp](http://www.archbiocides.com/architecturalpaints/WetDryref.asp)

[www.archbiocides.com/architecturalpaints/sflorida.asp](http://www.archbiocides.com/architecturalpaints/sflorida.asp)

As part of the RED process for these chemicals, EPA needs to review the
composition of each sodium pyrithione product to determine if zinc oxide
is an intentionally added inert ingredient that would lead to the *in
situ* conversion to zinc pyrithione. Likewise, it is well known that
many paint producers add zinc oxide as an ingredient in their paint
formulations. Addition of sodium omadine to these paints will result in
the formation of and exposure to zinc pyrithione.

This same mechanism of conversion can be possible when sodium omadine is
used in cosmetics containing zinc chloride (see for example, US Patent
6,162,446, December 19, 2000 titled "In-situ generation of zinc
pyrithione in personal care compositions). Both of these mechanisms of
conversion will lead to increased exposure to zinc omadine, and an
underestimation of risk by EPA.

**FQPA SAFETY FACTOR**

EPA (in the notice of filing in September 20, 2000 (vol. 65, Number 183)
has stated that it considers zinc pyrithione to be a "frank
developmental toxicant". With developmental toxicity seen both in the
rat and rabbit, at maternally toxic doses (body weight gain depression
only), as well as evidence in all three 90-day studies (oral, inhalation
and dermal) of neurotoxicity, why isn't a developmental neurotoxicity
study being required for this database?

Likewise, it is conceivable that the sodium pyrithione reproduction
study should not apply to the database for zinc pyrithione. The rat
developmental NOAEL for zinc pyrithione is stated to be 0.75 mg/kg/day,
whereas the sodium pyrithione NOAEL is 5.0 mg/kg/day. This means that
zinc pyrithione is almost 7-fold more toxic than its sodium counterpart.
Then why was the sodium 2-generation reproduction study used to satisfy
the requirements for a reproduction study for zinc pyrithione, when the
NOAELs for the developmental toxicity in the rat studies are so
different and the zinc is clearly more toxic?

When taken together, the level of uncertainty associated with the
current database should justify the inclusion of an additional FQPA 10x
uncertainty factor.