Document ID: EPA-HQ-OPP-2006-0239-0040
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-22T04:00Z

APPENDIX H

PRODUCT FORMULATIONS CONTAINING MULTIPLE ACTIVE INGREDIENTS

The Agency does not routinely include, in its risk assessments, an
evaluation of mixtures of active ingredients, either those mixtures of
multiple active ingredients in product formulations or those in the
applicator’s tank. In the case of the product formulations of active
ingredients (that is, a registered product containing more than one
active ingredient), each active ingredient is subject to an individual
risk assessment for regulatory decision regarding the active ingredient
on a particular use site. If effects data are available for a formulated
product containing more than one active ingredient, they may be used
qualitatively or quantitatively,.

Acute oral toxicity data (i.e., LD50 values) from mammalian studies for
formulated products that contain fomesafen and one or more additional
active ingredients are summarized below.

Currently, the Agency’s guidance for assessing the potential risk of
chemical mixtures is limited to human health applications (USEPA 2000).
However, the guidance includes principles for evaluating mixtures to
assess potential interactive effects that are generally applicable.
Consistent with EPA’s Overview Document (USEPA 2004), the Agency’s
mixture guidance (USEPA 2000) discusses limitations in quantifying the
risk of specified mixtures when there is differential degradation,
transport and fate of chemical components following environmental
release or application. The LD50 values are potentially useful only to
the extent that a wild mammal would consume plants or animals
immediately after these dietary items were directly sprayed by the
product. Increasing time post application, the differential rates of
degradation, transport, etc. for the active ingredients in the
formulation only permit a qualitative discussion of potential acute risk
(USEPA 2004).

As discussed in USEPA (2000) a quantitative component-based evaluation
of mixture toxicity requires data of appropriate quality for each
component of a mixture. In this mixture evaluation LD50s, with
associated 95% confidence intervals, are needed for the formulated
product. The same quality of data is also required for each component of
the mixture. Given that many of the formulated products do not have LD50
values of the required quality and since LD50 values are not available
for all the components of these formulations a quantitative analysis of
potential interactive effects is not possible.

While a quantitative evaluation of the data is not possible with
currently accepted scientific methods, as a screening tool, a
qualitative analysis can be used to indicate if formulated products
exhibit interactive effects (e.g., synergism or antagonism). In the case
of fomesafen, a qualitative examination of the trends in LD50 values,
with the associated confidence intervals, across the range of percent
active ingredient, show no discernable trends in potency that would
suggest synergistic (i.e., more than additive) or antagonistic (i.e.,
less than additive) interactions. In addition, when the product LD50s,
and associated confidence intervals, are adjusted for the percent
fomesafen (a conservative assumption that attributes all of the observed
toxicity of the formulated product to fomesafen) in 4 out of the 9 cases
these adjusted 95% confidence intervals overlap with the confidence
values of the LD50 value of fomesafen. In the other instances the
adjusted LD50s and/or the confidence intervals are within a factor of 2;
given the overall variability of the available acute toxicity data these
differences are not considered biologically significant. Based on this
qualitative evaluation of the best available data and the Agency’s
existing guidance it is reasonable to conclude that these formulations
are reflecting an independent additive toxicity response and not an
interactive effect. Given that the active and inert ingredients would
not be expected to have similar mechanisms of action, metabolites or
toxicokinetic behavior it is also reasonable to conclude that an
assumption of dose-addition would be inappropriate. Consequently, an
assessment of fomesafen’s potential effect on the CRLF when it is
co-formulated with other active ingredients can be based on the toxicity
of fomesafen.



Pesticide Products Formulated with Fomesafen and Other Pesticide Active
Ingredients

FOMESAFEN PRODUCTS ,

	Product	Adjusted For Active Ingredient

Product/Trade Name	EPA Reg.No.	% Fomesafen	LD50 (mg/kg)	CI (mg/kg	LD50
(mg/kg)	CI (mg/kg)

Prefix	100-1268	10.1	5000	2865-8390	NA Limit Dose	NA Limit Dose

BAS 530 04	7969-82	29	>1210	NA	NA	NA

Faster	7969-83	29.8	1470	1000-2160	NA	NA

 Overview of the Ecological Risk Assessment Process in the Office of
Pesticide Programs, Environmental Protection Agency (January 2004)
(Overview Document).

 Memorandum to Office of Prevention, Pesticides and Toxic Substance, US
EPA conveying an evaluation by the U.S. Fish and Wildlife Service and
National Marine Fisheries Service of an approach to assessing the
ecological risks of pesticide products (January 2004).

 From registrant submitted data to support registration. Compiled by
Office of Pesticide Programs Environmental Fate and Effects Division.

 Fomesafen: Female LD50 = 3863 mg/kg; CI= not reported. Male LD50: not
reported.