Notice of Filing: Pesticide Petition 7E7287

EPA Registration Division contact: Susan Stanton (703-305-5218)

Interregional Research Project #4

Pesticide Petition #7E7287

EPA has received a pesticide petition (PP#7E7287) from Interregional
Research Project #4 (IR-4), Rutgers, The State University of New Jersey,
500 College Road East, Suite 201 W, Princeton, NJ 08540 proposing,
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.438 by establishing
tolerances for residues of gamma-cyhalothrin
((S)-\[alpha\]-cyano-3-phenoxybenzyl
(Z)-(1R,3R)-3-(2-chloro-3,3,3-trifluoripropenyl)-2,2-dimethylcyclopropanecarboxylate)
in or on the raw agricultural commodity pistachio at 0.05 parts per
million (ppm) and okra at 0.2 parts per million (ppm). EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not
fully evaluated the sufficiency of the submitted data at this time or
whether the data supports granting of the petition. Additional data may
be needed before EPA rules on the petition.

*A. Residue Chemistry*

1\. *Plant metabolism.* Gamma-cyhalothrin relies on the metabolism data
conducted on lambda-cyhalothrin, which has been thoroughly tested and is
adequately understood. Gamma-cyhalothrin is a resolved isomer of the
lambda-cyhalothrin mixture.

2\. *Analytical method.* An adequate analytical method is available for
enforcement purposes. Per the Federal Register of April 8, 2004 (69
FRL-7353-4), the ICI method 81 for lamda-cyhalothrin has been validated
by EPA. Given the enantiomeric relation of gamma-cyhalothrin to
lambda-cyhalothrin and the fact that the method does not provide chiral
resolution, the method is also applicable to gamma-cyhalothrin.

3\. *Magnitude of residues.* This petition is based on existing IR-4
proposals (previously reviewed by HED) regarding crop groupings with
rational for the addition of okra to "Vegetables, fruiting, group 8
(except cucurbits)" and the additional of pistachio to "Nut, tree, group
14". Gamma-cyhalothrin has tolerances established in these related crop
groupings per Federal Register of April 8, 2004 (69 FRL-7353-4). A
tolerance of 0.05 ppm is established for the "Nut, tree, group 14" and a
tolerance of 0.2 ppm is established for the "Vegetables, fruiting, group
8 (except cucurbits)". For okra, the currently-labeled use pattern for
the fruiting vegetables will be adopted. For pistachio, the
currently-labeled use pattern for tree nuts will be used. Because the
proposed use patterns are the same, the residues should not exceed those
of currently approved uses and the tolerances are supported.

*B. Toxicological Profile* Per the Federal Register of April 8, 2004 (69
FRL-7353-4), EPA has determined the toxicological profile and endpoints
for gamma-cyhalothrin which support this petition. The toxicological
evaluation is accomplished by studies with gamma-cyhalothrin as well as
by studies on lambda-cyhalothrin and/or cyhalothrin. Because
gamma-cyhalothrin is a resolved component (single isomer) of the
registered isomer mixtures of both lambda-cyhalothrin and cyhalothrin,
much of the toxicological testing has been accomplished through existing
tests on the previous cyhalothrin mixtures (as discussed in further
detail within the Federal Register of September 27, 2002 (67 FR 60902).

1\. *Acute toxicity.* Per the Federal Register of April 8, 2004 (69
FRL-7353-4), an acute reference dose (aRfD) of 0.0025 mg/kg for
gamma-cyhalothrin is established. This value is based on: 1) an UF=100;
2) the NOEL of 0.5 mg/kg/day for the 1 and 2 day timeframe within the
chronic oral study in the dog with lambda-cyhalothrin with clinical
signs of neurotoxicity observed from day 2, 3 to 6 hour post-dose; and
3) multiplication of ½ factor based on the purity of the lambda isomer
compared to the enriched isomer gamma cyhalothrin. Given the FQPA SF=1X,
the aRfD = aPAD = 0.0025 mg/kg/day for gamma-cyhalothrin.

2\. *Genotoxicty.* Per Federal Register of February 13, 1998 (63 Number
30), genotoxicity tests for lambda-cyhalothrin were all negative: a gene
mutation assay (Ames), a mouse micronucleus assay, an in-vitro
cytogenetics assay and a gene mutation study in mouse lymphoma cells.

3\. *Reproductive and developmental toxicity.* Per Federal Register of
April 8, 2004 (69 FRL-7353-4) and Federal Register of August 15, 2007
(72 FRL-8143-1, no quantitative or qualitative evidence of increased
susceptibility of rat or rabbit fetuses to *in utero* exposure in the
developmental studies was observed. For both species, the Developmental
NOAEL = Maternal LOAEL and the values were 15 mg/kg/day in the rat and
30 mg/kg/day in the rabbit.

A 3-generation reproduction test in the rat covering cyhalothrin,
lambda-cyhalothrin and gamma-cyhalothrin indicated a reproductive NOAEL
of 5 mg/kg/day, the reproductive LOAEL was not established and the
Offspring NOAEL/LOAEL was 1.5 mg/kg/day. Offspring toxicity (decreased
body weight and body weight gain) was observed in the reproduction study
at the same dose level as parental toxicity; these effect are not
considered to be more several than the effects in the parent.

4\. *Subchronic toxicity.* Per the Federal Register of April 8, 2004 (69
FRL-7353-4), the short-term incidental oral exposure scenario is to be
evaluated against a NOAEL of 0.1 mg/kg/day with a residential MOE of
100; this was based on observations with the chronic oral study in the
dog for lambda-cyhalothrin. However for this tolerance petition for food
use on okra and pistachios, this endpoint is not applicable.

5\. *Chronic toxicity.* Per the Federal Register of April 8, 2004 (69
FRL-7353-4), a chronic reference dose (cRfD) of 0.001 mg/kg for
gamma-cyhalothrin is established. This value is based on: 1) an UF=100;
2) the NOAEL of 0.1 mg/kg/day from the chronic oral study in the dog
with lambda-cyhalothrin; and 3) and no adjustment for the relative
amounts of the lambda isomer compared to the gamma-cyhalothrin. Given
the FQPA SF=1X, the cRfD = cPAD = 0.001 mg/kg/day for gamma-cyhalothrin.
For all routes (oral, dermal and inhalation), gamma-cyhalothrin has been
classified as "not likely to be Carcinogenic to Humans"; no cancer
assessment is needed.

6\. *Animal metabolism.* Per the Federal Register of April 8, 2004 (69
FRL-7353-4), the rat model indicates 55% of the oral dose is absorbed
and then extensively metabolized. The ester is cleaved to the
cyclopropylcarboxylic acid and a phenoxybenzyl derivative. Comparison of
multi and single dose studies indicates distribution and excretion rates
are similar. With the exception of accumulation of unchanged compound in
the fat with chronic dosing, cyhalothrin is rapidly metabolized and
excreted.

7\. *Metabolite toxicology*. Per Federal Register of February 13, 1998
(63 Number 30), the metabolism of lambda-cyhalothrin in livestock was
studied in the goat, chicken and cow; only unchanged parent is the major
residue component of toxicological concern in meat and milk.

8. *Endocrine disruption*. No studies have been conducted to investigate
the potential of gamma-cyhalothrin to induce estrogenic or other
endocrine effects. However, no evidence of such effects has been noted
in the battery of toxicity studies which have been conducted on
cyhalothrin/lambda-cyhalothrin.

*C. Aggregate Exposure*

1\. *Dietary exposure.* The agency has conducted an extensive assessment
of the aggregate exposure for lambda-cyhalothrin reported in the Federal
Register of September 27, 2002 (FR 65 60902) (FRL-7200-1). The EPA
recently conducted a refined exposure assessment to cover new uses for
lambda-cyhalothrin per Federal Register of August 15, 2007 (72
FRL-8143-1). In the Federal Register of April 8, 2004 (69 FRL-7353-4),
the EPA concluded that risk assessments on lambda-cyhalothrin
sufficiently covers gamma-cyhalothrin and "no new aggregate risk
assessment is needed for gamma-cyhalothrin". Their conclusion is based
on the following: 1) gamma-cyhalothrin is the isolated active of
lambda-cyhalothrin, 2) the residue data from comparison studies showed
that residues "from the gamma uses are, on average , no more than half
of those of lambda-cyhalothrin" and 3) the toxicological endpoints
selected for gamma-cyhalothrin are not less than half those selected for
lambda-cyhalothrin.

i\. *Food.* The lambda-cyhalothrin assessment in the Federal Register of
August 15, 2007 (72 FRL-8143-1) includes Tier I worse-case assumptions
of 100 PCT and tolerance level values for residues on pistachio and
okra. Dietary exposure for the resolved isomer gamma-cyhalothrin has
already been implicitly assessed; there is no new data and the
assessment need not be repeated.

ii\. *Drinking water.* The lambda-cyhalothrin assessment in the Federal
Register of August 15, 2007 (72 FRL-8143-1) includes a modeled estimate
for acute water exposure of 5.35 ppb and a modeled estimate for chronic
water exposure of 0.130 ppb. Exposure to the resolved isomer
gamma-cyhalothrin has already been implicitly assessed; there is no new
data and no new assessment is needed.

2\. *Non-dietary exposure*. The newly proposed tolerances for
gamma-cyhalothrin on pistachios and okra are dietary uses and there is
no increase in the non-dietary exposure potential previously included in
the recent exposure assessment Federal Register of August 15, 2007 (72
FRL-8143-1). The existing residential uses were assessed by the agency
via a screening-level approach to address the risks associated with the
use of the aerosol can product of lambda-cyhalothrin purchased by
homeowners. This use is assumed to have the highest exposure potential
of all the residential uses. No new assessment is needed for
gamma-cyhalothrin.

*D. Cumulative Effects*

For the purpose of this request, it has been assumed that the
cyhalothrins (i. e., cyhalothrin, gamma-cyhalothrin and
lambda-cyhalothrin) do not have a common mechanism of toxicity with
other substances.

*E. Safety Determination* In a recent exposure assessment Federal
Register of August 15, 2007 (72 FRL-8143-1), the proposed uses of
gamma-cyhalothrin on okra and pistachios was implicitly covered by the
assessment for lambda-cyhalothrin, which already assumed 100 percent
crop treated (PCT) for okra and pistachios. EPA concluded there is a
reasonable certainly that no harm will result to the general population
of infants and children for lambda-cyhalothrin. Because
gamma-cyhalothrin is a resolved isomer of lambda-cyhalothrin, the risk
has already been implicitly assessed and no new assessment is needed.

1\. *U.S. population.* In a recent exposure assessment Federal Register
of August 15, 2007 (72 FRL-8143-1), the agency determined the acute
dietary exposure from food and water to lambda-cyhalothrin to occupy 46%
of the aPAD and 17% of cPAD for the general US population. EPA concluded
that food, water and residential exposures result in aggregate MOEs of
140 to 490. Because the MOEs are greater than 100, there were no
concerns for aggregate exposure. There is no additional new exposure to
be added to this model; gamma-cyhalothrin has already been implicitly
assessed through the use of 100 PCT for lambda-cyhalothrin and no new
assessment is needed.

2\. *Infants and children*. Per Federal Register of August 15, 2007 (72
FRL-8143-1), EPA has reviewed a DNT for lambda-cyhalothrin (MRID
46449102); while the study has been deemed technically unacceptable, the
EPA is not requiring a repeat of the study. Instead a 10X factor has
been applied to the NOAEL of 4 mg/kg bw/day to arrive at a 0.4 mg/kg
bw/day. This value is similar to the acute and chronic NOAELs. EPA
concluded that use of the NOAELs from the dog study is protective of
infants and children and the FQPA SF=1.

In the exposure assessment of Federal Register of August 15, 2007 (72
FRL-8143-1), the agency determined the acute dietary exposure from food
and water to lambda-cyhalothrin to occupy 61% of the aPAD for all
infants as the most highly exposed populations subgroup. The chronic
assessment for children indicated that children (1-2 years old) were the
most highly exposed subpopulation with potential exposure at 50% of
cPAD. Because the projected exposures are less than 100% of the PAD,
there is a reasonable certainty of no harm.

*F. International Tolerances*

A review of national websites and the Homologa MRL database reveals that
for nuts and fruiting vegetables there are no MRLs outside the US which
have been specifically established for gamma cyhalothrin. MRLS are
fairly harmonized for the related isomers of lambda-cyhalothrin per the
table below. In addition, there are Codex maximum residue levels pending
for residues of cyhalothrin, as the sum of all isomers, in or tree nuts
(shelled and unshelled) at 0.05 ppm. For Canada, treenuts including
pistachios are covered based on the "negligible" residue clause of
Canadian Food and Drug Act Regulations (B.15.002(1).

  -------------------- ----------------------- ------------- -------- ------
  Active               Country                 Commodity     Value    Unit

  Lambda-cyhalothrin   US, Canada, EU, Mexico  Tomatoes      0.1      ppm

  Gamma-cyhalothrin    US                      Tomato        0.1      ppm

  Lambda-cyhalothrin   Mexico                  Peppers       0.2      ppm

  Lambda-cyhalothrin   EU                      Peppers       0.1      ppm

  Lambda-cyhalothrin   US                      Peppers       0.2      ppm
  and                                                                 
  Gamma-cyhalothrin                                                   

  Gamma-cyhalothrin    US                      Treenuts      0.05     ppm

  Lambda-cyhalothrin   EU, US                  Treenuts and  0.05     ppm
                                               Pistachio              
  -------------------- ----------------------- ------------- -------- ------

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