![](media/image1.png){width="0.78125in" height="0.78125in"}**UNITED
STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460**

**OFFICE OF PREVENTION, PESTICIDES**

**AND TOXIC SUBSTANCES**

Number range CHAPTER**[MEMORANDUM]{.underline}**

December 20, 2006

**SUBJECT:** Allethrins: HED Response to Comments by Valent BioSciences
Corporation on HED Chapter of Reregistration Eligibility Decision
Document.

**PC Codes:** Bioallethrin (0040003), Esbiol (004004), Esbiothrin
(004007), and Pynamin Forte (004005)

**DP Barcode:** D334056

**FROM:** Kit Farwell, DVM, Risk Assessor

Toiya Goodlow, Chemist, Dietary Exposure

Tim Dole, C.I.H., Occupational and Residential Exposure Assessor

Reregistration Branch 1

Health Effects Division (7509P)

**TO:** Molly Clayton, Chemical Review Manager

Reregistration Branch 3

Special Review and Reregistration Division (7508P)

**THROUGH:** Jeff Dawson

Reregistration Branch 1

Health Effects Division (7509P)

**I. CONCLUSIONS**

The HED allethrin risk assessment team reviewed comments made by Valent
Biosciences Corporation on the HED Chapter of the Reregistration
Eligibility Decision Document. Several minor corrections to the risk
assessment were identified and are described below. The overall
conclusions in the RED have not changed.

**II. COMMENTS MADE BY VALENT BIOSCIENCES AND HED RESPONSES**

**Valent 1**. [FQPA safety factor of 10X]{.underline} for dietary and
residential exposure is unnecessary. Was a dose analysis conducted in
order to determine the need for a safety factor? The data base is
complete except for a Developmental Neurotoxicity (DNT) study. Based on
these data, a 10X safety factor seems excessive in that the NOEL from a
DNT study would not be expected to be 10X less than that used in the
risk assessments. A safety factor of 3X would still seem to be
conservative because \"the end points for risk assessment were at the
same or lower doses at which developmental and reproductive toxicity
occurred, there were no concerns for sensitivity of offspring.\" In
addition, acute and sub-chronic neurotoxicity studies were conducted on
s-bioallethrin. Although the sub-chronic study was deemed unacceptable
due to a lack of positive control data, it does serve as an indication
that the NOEL will most likely be considerably higher than any used in
the risk assessments. Therefore, we believe a 3X FQPA safety factor is
more than adequate to account for the lack of this study.

**HED response**: The NOAEL (no observed adverse effect level) from the
developmental neurotoxicity study cannot be determined until the study
is conducted. The 10x database uncertainty factor is applied because the
NOAEL from the developmental neurotoxicity (DNT) study could be lower
than NOAELs from the studies selected for endpoints. The NOAEL from the
DNT study may also be lower than NOAELs from the developmental or
reproductive toxicity studies. The quotation for \"no concerns for
sensitivity of offspring\" is in reference only to the NOAELs for
developmental and reproductive studies. In the past, HED has conducted
dose analyses to determine the need for a database safety factor but
this is not the current HED policy.

**Valent 2**. [Acute Dietary Risk Assessment]{.underline}: The
assumption that 100% of food handling establishments (FHE) will be
treated with a space spray is unreasonable. Usage data provided by
Valent BioSciences Corporation demonstrate that on average over a
seven-year period, less than 5,000 lbs of bioallethrin, esbiothrin and
s-bioallethrin combined were used in the professional pest control
market (including food and non-food areas). Even if the usage of these
compounds were to increase dramatically, 100% FHE treatment is not
realistic. We agree that it is impossible to estimate the number of FHEs
in the US or the percent of those that may apply insecticides in a
similar manner. However, we believe that the same 20% FHE treatment used
in the chronic dietary risk assessment should also be used in the acute.

**HED response**: It is HED policy that refined dietary assessments are
to be conducted only after dietary exposure and risk estimates for a
pesticide exceed the Agency's level of concern (i.e. \>100% of the
population adjusted dose (PAD)). The Agency utilizes a tiered approach
when assessing dietary risks proceeding from more to less conservative
assumptions. Assessments can be refined with the incorporation of field
trial data, monitoring data and percent crop treated information.
However, these refinements are only necessary after assessments assuming
the theoretical maximum contribution of a pesticide have exceeded the
Agency's level of concern. The dietary exposure analysis for allethrins
result in acute dietary risk estimates that are below the Agency's level
of concern assuming 100% of food handling establishments are treated.
The highest exposure and risk estimates were for children 1-2 years old,
which utilized 90% of the aPAD. Therefore, a refined acute dietary
assessment is not necessary at this time.

**Valent 3**. [Chronic Dietary Risk Assessment]{.underline}: The Agency
used a NOEL of 6 mg/kg/day to establish the chronic reference dose. This
was obtained from a 6-month sub-chronic dog feeding study conducted on
Bioallethrin. This study may be pertinent to assess intermediate-term
exposure. But, we do not believe this study is pertinent to chronic risk
because other longer term and more pertinent data are available. The
NOELS ranged from 13 mg/kg/day in the pynamin forte rat reproduction
study to 214 mg/kg/day in the esbiothrin chronic mouse study. Worst case
for the chronic dietary risk assessment is the 13 mg/kg/day with a
resulting reference dose of 0.013 (if a 10X safety factor is used).
However, since we believe a 3X safety factor is more than adequate, a
reference dose of no lower than 0.043 should be used. (We are not at
this time proposing a RfD of 0.043 as we have not been able to conduct a
full detailed review of the tox data base. We are simply stating that we
believe this to be the worst case possible based on this limited
review.)

**HED response**: The NOAEL of 6 mg/kg/day from the 6-month dog study
was based on microscopic liver changes at the LOAEL of 36 mg/kg/day. Dog
studies range in duration from 3 months for a subchronic study to 12
months for a chronic study. The dog study selected for an endpoint is
closer in length to a chronic study than a subchronic study and is of
appropriate duration for a chronic endpoint. The studies mentioned above
were assessed, but the study with the lowest appropriate NOAEL was
picked to assess risk for chronic dietary exposure.

**Valent 4. a.** [Indoor Surface Treatment]{.underline} -- The exposure
durations of 4 hours on vinyl and 8 hours on carpet seem excessive. Are
these standard figures? Has the Agency considered the rapid
photodegradation of the allethrins? The degradation rate of allethrins
has been estimated to be 7-15 minutes in sunlight and approximately 2
hours in total darkness. Also, data on resmethrin, a similar pyrethroid
demonstrate a half-life in seawater of 22 minutes and 47 minutes in
distilled water. Even assuming some lack of light and slower degradation
on other surfaces, 4 and 8 hour exposure durations seem overly
conservative.

**HED response**: The exposure durations of 4 hours on vinyl and 8 hours
on carpet are from ExpoSAC Policy #12 "Recommended Revisions to the
Standard Operating Procedures (SOPS) for Residential Exposure
Assessments." Although these values are listed under the exposure
scenario "Dermal Exposure from Indoor Pesticide Use (8.2)", these values
are also applicable for incidental oral exposures because they are based
upon exposure times from the Exposure Factors Handbook which are not
specific to the route of exposure.

HED has not seen the allethrin degradation data. HED has considered the
photodegradation data for pyrethrin, which is a structurally similar to
allethrin, from Study #99-020-PY01 "Fate of Pyrethrins and Piperonyl
Butoxide in a Representative Household Fogger Formulation Exposed to
Various Indoor and Outdoor Conditions". This study indicated that the
half life of pyrethrin residues exposed to fluorescent light is 38 or 70
days on ceramic tiles and 10.2 or 23.1 days on percale cloth, depending
upon the specific isomers considered (PYI or PYII). These same data
indicated that the half life for the tile and percale cloth control
samples that were stored in the dark was 46 or 42.5 days and 11.7 or
23.4 days, respectively.

**Valent 4. a.** [High Application Rate]{.underline} - The high
application rate of 1 gallon of 3% active ingredient per 1000 sq. ft. is
based on an error on the product labeling. The actual rate should have
been 1.0 ounce of 3% active ingredient per 1000 sq. ft. (ULV treatment).
These use directions will be corrected or deleted from the product
labeling. The next highest rate would then be 1 gallon of 1.5% active
ingredient per 1000 sq. ft. (1021-1478).

**HED response**: HED concurs with this comment and will delete this
rate from the risk assessment when a revised product label is received
and approved.

**Valent 4. b**. [Indoor Space Spray]{.underline} -- An exposure
duration of 2 hours is used. This seems excessive in that the particles
would not be expected to remain air born for such a long period. Also,
labeling language, \[such as 1) leave the treated area immediately, 2)
keep area closed for 15 minutes, 3) ventilate treated area thoroughly,
4) do not re-enter until sprays have dissipated\] can virtually
eliminate post application inhalation exposure. The Agency conducted
occupational inhalation exposure risks with and without a dust mask or
respirator. The residential inhalation exposure risk should likewise be
assessed taking into account use with and without label mitigation
statements.

**HED response**: The exposure duration of 2 hours is based upon the air
concentration data that were submitted in Volume 18 of the NDETF Study,
"Measurement of Air Concentration, Dermal Exposure, and Deposition of
Pyrethrin and Piperonyl Butoxide Following the Use of an Aerosol Spray".
The air concentrations measured at the five foot level ranged from 0.1
mg/m^3^ at (Time 0 to 5 minutes) to 0.012 mg/m^3^ at (Time 90 to 120
minutes). The two hour time weighted average air concentration was 0.019
mg/m^3^. HED acknowledges that the above data were collected in a
non-ventilated room to measure the impact of aerosol settling and that
actions required by the label would reduce exposures. HED did not
attempt to assess the effect of the label requirements at this point
because the application rate was not clearly defined and would have a
greater impact on the exposures. Once the application rate is better
defined, HED will re-consider the effects of the label requirements.

**Valent 4. c**. [Hand-Held Yard & Patio Foggers / Total Release Yard &
Patio Foggers]{.underline} -- The exposure duration of 3 (children) to 5
(adults) hours is excessive. It is hard to imagine particles remaining
air born for that length of time in an outdoor setting. In addition,
photodegradation would also play a significant role in reducing the
exposure duration. Again, post application inhalation exposure following
this use can be virtually eliminated with label language, such as,
vacate the treated area after application, do not re-enter until sprays
have dissipated. Residential inhalation exposure risk should be assessed
taking into account use with and without label mitigation statements.

**HED response**: HED concurs that the many of the aerosols released by
the foggers would not remain airborne in the treated area for 3 to 5
hours after application. To account for particle settling and
dispersion, HED used a dilution factor of 100 as outlined in the
Residential SOP 7.0 "Inhalation Doses among Adults and Children after
Pesticide Applications (e.g., Foggers) Outside of a Residence for the
Purpose of Short Term Pest Control". This dilution factor also accounts
for the effect of label requirements. HED did not attempt to account for
photo-degradation because it was assumed that the foggers would be used
in the evening when insect pests such as mosquitoes are most active.

**Valent 4. d**. [Pet Treatments]{.underline} -- The risk assessments
are confusing since the formulation and use type are not included in
most areas. The use of shampoos is below the LOC but for RTU sprays, it
is not. Please incorporate the type of formulation used in each of the
assessments to clarify what types of formulations/uses are of concern.

**HED response**: The source of exposure for treated pets has been
clarified in Table 13 -- Allethrin Residential Post Application Risk
Summary. There was also a typo at the bottom of page 35 which indicated
that there were no MOEs of concern for toddlers playing with pets after
treatment with spray formulations. This typo has been corrected to
indicate that there is a risk concern for intermediate term exposure
where the MOE of 650 is below the target MOE (i.e. LOC) of 1000.