UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

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 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:  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:  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 – 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 - 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 – 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/m3 at (Time 0 to 5 minutes) to 0.012 mg/m3 at (Time 90 to
120 minutes).  The two hour time weighted average air concentration was
0.019 mg/m3.  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 – 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 – 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.  

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