**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460**

![](media/image1.png){width="0.875in" height="0.8388888888888889in"}

**OFFICE OF PREVENTION, PESTICIDES**

**AND TOXIC SUBSTANCES**

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

**Date:** September 5, 2008

**SUBJECT:** Trinexapac-Ethyl: Revised Human Health Assessment Scoping
Document in Support of Registration Review.

  ------------------------ ----------------------------------------------
  **PC Code:** 112602      **DP Barcode:** D356118

  **Decision No.:** 392037 **Registration No.:** NA

  **Petition No.:** NA     **Regulatory Action:** Registration Review
                           Scoping Document

  **Risk Assessment        **Case No.:** 7228
  Type:** NA               

  **TXR No.:** NA          **CAS No.:** 95266-40-3

  **MRID No.:** NA         **40 CFR:** NA
  ------------------------ ----------------------------------------------

**FROM:** Kelly Schumacher, Biologist

Douglas Dotson, Ph.D., Chemist

> Suku Oonnithan, Biologist
>
> Registration Action Branch 2

Health Effects Division (7509 P)

and

> Linda Taylor, Ph.D., Toxicologist

Reregistration Branch 1

Health Effects Division (7509 P)

and

Christina Swartz, Chemist

Registration Action Branch 2

Health Effects Division (7509 P)

**TO:** Kylie Rothwell, RM 53

Michael Goodis, RM 53

Reregistration Branch 3

Special Review and Reregistration Division (7508P)

Office of Pesticide Programs Number range CHAPTERNumber range CHAPTER

HED completed a human health scoping document for registration review of
trinexapac-ethyl, a plant growth regulator. During the development of
the Agency's preliminary work plan for registration review,
clarification of the data supporting the residential and occupational
exposure assessments was requested. This revised document addresses the
data supporting these assessments, and supersedes the 7/18/2008 scoping
document (D351407).

**Executive Summary**

Attached is the Health Effects Division's (HED) human health risk
assessment scoping document for trinexapac-ethyl to support Registration
Review. Trinexapac-ethyl is a cyclohexadione plant growth regulator
registered for non-food uses by homeowners and professional applicators
on turf grasses and on grasses grown for seed production by growers and
professional applicators. HED has considered recent updates to the
toxicology, exposure, and usage databases and the latest Agency science
policy and risk assessment methodologies and has identified numerous
deficiencies in the trinexapac-ethyl risk assessment. The toxicology
database is complete, with the exception of an immunotoxicity study
(870.7800) and acute and subchronic neurotoxicity studies (870.6200)
that are newly required by the Part 158 guidelines. The most recent
point of departure determinations are consistent with current policy,
based on the available data.

Although the use on grasses grown for seed has, in the past, been
considered a non-food use, the Agency now believes that once the seed is
harvested, the regrowth of the grass can be grazed or cut and used as
feed for cattle. Consequently, this is now considered to be a feed use.
Available data suggest that quantifiable residues of trinexapac-ethyl
may be found in animal commodities; however, no U.S. tolerances have
been established and dietary and aggregate exposure assessments have not
been conducted. Assuming that the registrant wants to support the use on
grass grown for seed, tolerances may need to be established on plant and
animal commodities. The following residue chemistry data deficiencies
must be addressed prior to determining the need/establishing
tolerances: 1) the cattle feeding study (860.1480; required to support
food uses that were later withdrawn, based on measurable residues in the
goat metabolism study) should be reviewed, 2) the plant analytical
method (860.1340) should be revised to measure conjugates, since
conjugated residues are residues of concern for both tolerance setting
and risk assessment purposes, 3) an animal analytical method (860.1340)
should be proposed and validated, since residues are expected in animal
commodities, 4) the field rotational crop study (860.1900) should be
reviewed, and 5) additional grass field trial studies (860.1500) are
required. Dietary exposure from food (if tolerances are established) and
drinking water, as well as aggregate exposure, should be assessed.

During registration review, short- and intermediate-term residential
post-application exposure, which was not previously considered, should
be assessed for 1) high contact activities of adult and toddler, 2)
mowing by adults and youth, 3) golfing by adults and youth, 4)
hand-to-mouth exposure to toddlers, 5) object-to-mouth exposure to
toddlers, and 5) incidental ingestion by toddlers. Short-term
residential handler exposure should be assessed for homeowner lawn
treatment using 1) drop/spreaders and 2) shakers. Intermediate-term
occupational handler and short-term occupational post-application
exposures, which were not previously considered, should be assessed.

Unit exposure values are not available for many of the residential and
occupational scenarios. Given the substantial revisions prescribed by
this scoping document, preliminary estimates for the residential and
occupational exposure scenarios expected to pose the highest risk were
calculated using surrogate data from the Pesticide Handlers Exposure
Database (PHED) and the draft SOPs for Residential Exposure Assessment.
These risk estimates do not indicate that the existing use patterns
exceed HED's level of concern.

**Introduction**

HED has evaluated the status of the human health assessments for
trinexapac-ethyl to determine whether sufficient data are available and
whether a new human health risk assessment is needed to support
Registration Review. Trinexapac-ethyl was first registered in 1992 and,
as a result, was not subject to the reregistration process recently
completed on August 3, 2006 for chemicals registered prior to 1984.
Additionally, no tolerances have been established for any use of
trinexapac-ethyl. Consequently, neither a Reregistration Eligibility
Decision (RED) nor a Tolerance Reregistration Eligibility Decision
(TRED) was issued. A comprehensive human health risk assessment does not
exist, but an FQPA hazard characterization was drafted in 2007 to
support proposed uses that were later rescinded. This hazard
characterization considers all available trinexapac-ethyl toxicology
studies received to date, including new studies. Existing toxicology
studies were re-evaluated (D328850). For scoping purposes, HED also
considered HED and OPPIN databases. The structure, chemical name, and
other identifiers may be found in Table 1 attached to this document;
physicochemical properties may be found in Table 2.

Trinexapac-ethyl is a cyclohexadione plant growth regulator registered
for non-food uses by homeowners and professional applicators on turf
grasses and on grasses grown for seed production by growers and
professional applicators. The registered formulations of
trinexapac-ethyl are provided in Table 3 and include emulsifiable
concentrates (ECs), wettable powder packed in water-soluble bags
(WP/WSB), and granules. Application rates are provided in Table 4. The
maximum application rate (0.88 lb ai/A) is for use on the edges of
residential and ornamental turf areas. The reentry interval (REI) for
all formulations is zero days, but there is a livestock pre-grazing
interval (PGI) of 60 days for use on grasses grown for seed.

**Hazard Identification/Toxicology**

Trinexapac-ethyl is a cyclohexadione plant growth regulator that
inhibits the biosynthesis of gibberellin (GA1), which is a phytohormone
that promotes growth of various plant organs. In mammals, the compound
is rapidly and extensively absorbed (\> 95% of the administered dose)
and rapidly eliminated (\> 85% of the administered dose eliminated
within 12 h), with no significant bioaccumulation. Significant residues
identified in the rat metabolism study were the acid metabolite of
trinexapac-ethyl (approximately 80 -- 90% of radioactivity) and the
parent compound (\<1%). These results indicate that toxicity of both the
parent and the acid metabolite has been accounted for in the submitted
toxicity studies. The acute toxicity of the technical material (Table 5)
is low via the oral, dermal, or inhalation routes of exposure
(Categories III-IV), and it is not a dermal sensitizer. The toxicity
profile of trinexapac-ethyl is attached (Table 6). With the exception of
immunotoxicity and neurotoxicity studies required by the new Part 158
guidelines, the toxicology database is complete and adequate to support
non-food and food uses.

Evidence of increased qualitative and quantitative susceptibility of the
offspring was seen in the developmental, but not the reproduction,
studies. Developmental toxicity was observed in the rat (increased
incidence of asymmetrical sternebrae) and rabbit (decreased number of
live fetuses/litter and increased post-implantation loss), with no
evidence of maternal toxicity observed at the highest dose tested in
either species. However, in the multi-generation reproduction study in
rats, the first indications of parental systemic toxicity were observed
at a lower dose level than offspring toxicity. No reproductive toxicity
was observed up to the limit dose.

The dog appears to be the most sensitive species. In adult animals, no
adverse effects were seen in rats, rabbits, or mice below the limit dose
(1000 mg/kg/day) following subchronic or chronic oral exposure. In the
dogs, however, decreased body weight gain and food consumption, diffuse
thymic atrophy, and changes in the epithelial cells of the renal tubules
were seen in the 90-day study at 516/582 mg/kg/day (males/females).
Following chronic exposure, evidence of neurotoxicity was seen at
366/356 mg/kg/day in male and female dogs, respectively, including
minimal, focal bilateral vacuolation of the dorsal medial hippocampus
and/or lateral midbrain**,** which was associated with the astrocytes
and oligodendrocytes. The lesions remained confined to the supporting
cells in the central nervous system and did not progress to more
advanced or more extensive damage of the nervous tissue. They were not
associated with other neuropathological findings or overt neurological
signs, so their biological significance is unknown. Similar lesions were
not observed in the rat (including neonates) or mouse following
subchronic or chronic dietary exposure, and there was no other evidence
in any other species tested to indicate a neurotoxicity potential. There
are no neurotoxicity studies available; therefore, both acute and
subchronic neurotoxicity studies will be required, according to the new
Part 158 guidelines. A developmental neurotoxicity study may be
required, based on the results observed in the required acute and
subchronic neurotoxicity studies.

The combined chronic toxicity/carcinogenicity study in the rat did not
demonstrate an increase in any tumor type that would be relevant to
humans. The observation of squamous cell carcinomas in the non-glandular
portion of the stomach of two males at 806 mg/kg/day does not provide
reasonable evidence of a possible deleterious effect of trinexapac-ethyl
on the pharynx and/or esophagus (non-glandular areas) of the human
because trinexapac-ethyl would not be in contact with the human tissues
for a significant period of time compared with how it would have been in
contact with the rat stomach. In the mouse, there was no evidence of
carcinogenicity. The mutagenicity database is complete, with no evidence
of mutagenicity. The cancer classification for trinexapac-ethyl is "Not
likely to be carcinogenic to humans."

Clear No Observed Adverse Effect Levels (NOAELs) have been established
for both the developmental toxicity and the neurotoxicity seen in dogs.
The acute reference dose (aRfD) is based on the most sensitive acute
endpoint observed in the database, which is from the developmental
rabbit study. It is, therefore, considered protective of all of the
developmental/offspring effects observed. Similarly, the chronic
reference dose (cRfD) is based on the most sensitive effect in the
database, which is from the chronic dog toxicity study. The NOAEL for
this study is more than 10-fold lower than the LOAEL at which
neurotoxicity is observed. Since the point of departure for the chronic
assessment is also approximately 10-fold lower than the dose levels
where developmental toxicity was seen in the developmental rabbit study,
it is considered protective for developmental and offspring toxicity.
Once the newly required data have been received and reviewed, the
appropriate FQPA safety factor will be determined.

With the exception of an ***immunotoxicity study (870.7800)*** and
***acute and subchronic neurotoxicity studies (870.6200)*** that are
newly required by the Part 158 guidelines, the toxicology database for
trinexapac-ethyl is complete. The endpoint selections and safety factors
are provided in Table 7. While the current short-term dermal and
inhalation endpoints are based on a developmental endpoint that is
appropriate for adults (NOAEL = 60 mg/kg/day), the registration review
team may wish to consider age-specific short-term dermal and inhalation
endpoints for toddlers based on the same effects (pup body weight
changes) as the short-term incidental oral endpoint (NOAEL = 594
mg/kg/day). Note that the current endpoints are highly protective for
all types of toxicity expected in toddlers with dermal or inhalation
exposure.

**Dietary Exposure**

The EPA typically establishes tolerances for residues on food and feed
commodities derived from use of pesticides on grass grown for seed.
Although trinexapac-ethyl is registered for this type of feed use and
available data suggest that quantifiable residues may be found in animal
commodities, ***no US tolerances*** have been set, and a dietary
exposure assessment has not been conducted. At the time that
trinexapac-ethyl was registered, the Agency considered grass grown for
seed to be a non-food use and did not require tolerances. Since that
time, due to the fact that grazing and/or cutting of the regrowth of the
grass once the seed is harvested may occur, this use is no longer
considered to be non-food and tolerances may be required. However, for
trinexapac-ethyl, a number of deficiencies preclude establishment of
permanent tolerances.

The nature of trinexapac-ethyl residues in grass commodities and
ruminants is understood, based on available grass, rice, and goat
metabolism studies. The available wheat metabolism study, which is not
required for use on grass, supports the findings of the grass and rice
metabolism studies. When residues measured in the goat metabolism study
are extrapolated down to a 10x feeding level, the maximum expected
residues are 0.212 ppm in liver, 2.01 ppm in kidney, 0.106 ppm in
muscle, 0.036 ppm in fat, and 0.026 ppm in milk (pm sample). Based on
these results, a ***cattle feeding study (860.1480)*** was required to
support proposed food uses that were later withdrawn. Although this
study was received, it has not yet been reviewed by the Agency. Because
there are no regulated poultry or swine feed items associated with
grasses, a poultry metabolism study is not required to set tolerances.

The residues of concern in plants and animals for both tolerance
establishment and risk assessment purposes include free and conjugated
residues of both parent and its acid metabolite, trinexapac. The data
collection method (HPLC/MS, Method 110-10) is the same as the proposed
tolerance enforcement method. The method does not determine conjugated
residues. In the grass and rice metabolism studies, significant
fractions of the trinexapac-ethyl residues in the various fractions were
conjugated. As a result, the existing ***plant analytical method
(860.1340)*** is inadequate and should be revised to include an
enzymatic and/or mild acid hydrolysis step to release conjugated
residues of trinexapac. Additionally, a confirmatory analysis must be
proposed and the method must undergo a successful independent laboratory
validation (ILV). An ***animal*** ***analytical method (860.1340)***,
with the ability to hydrolyze conjugates, must also be proposed and
validated. A ***field rotational crop study (860.1900)*** has been
received by the Agency but not reviewed. There are also deficiencies in
the number and geographic distribution of the ***grass field trial
studies (860.1500)***.

A ***dietary exposure assessment*** that includes ***drinking water
levels*** should be conducted during registration review, if the
registrant decides to support the grass grown for seed use.

**Residential Exposure**

Two granular formulations of trinexapac-ethyl are labeled for
application by homeowners to residential lawns, the use of which results
in exposure to residential handlers, as well as residential
post-application exposures to adults and children. Several other
formulations are registered for use on residential and recreational turf
areas, including golf courses, residential lawns, sport fields,
cemeteries, and edges of sidewalks, curbs, parking lots, driveways,
posts, storage buildings, pet pens, fences, trees, shrubs, flower beds,
border plants, ornamental beds, steeply sloped areas, driveways, and
fence posts. These applications are made by commercial applicators but
result in residential post-application exposures to adults and children.
When trinexapac-ethyl was first registered for residential use, the
Agency relied mainly on exposure estimates prepared by the registrant,
rather than conducting exposure assessments in-house. However, during
registration review, residential handler and post-application exposures
will be assessed as discussed below, using current policies and
procedures.

[Residential Handlers]{.underline}

Residential handler exposure scenarios include loading/applying of
granules by homeowners using a (i) broadcast/spreader, (ii)
drop/spreader, or (iii) shaker. For the purposes of this scoping
document, preliminary risk estimates were calculated for short-term
exposures resulting from the broadcast/spreader scenario, using the
maximum single application rate of 0.88 lb ai/A, where a margin of
exposure (MOE) of 100 or more is considered adequate to protect handlers
from residential exposures to trinexapac-ethyl (Table 8). The risk
estimate for short-term exposure to residential handlers who apply
granules to home lawns using a broadcast/spreader **(MOE = 18,000)**
does not exceed HED's level of concern (LOC). ***Short-term residential
handler exposure*** from homeowner lawn treatment using drop/spreaders
and shakers were not examined here, due to the ***absence of surrogate
unit exposures***, but should be assessed during registration review.

[Residential Post-Application]{.underline}

There are emulsifiable concentrates (ECs), wettable powder packed in
water-soluble bags (WP/WSB), and granular formulations of
trinexapac-ethyl registered for use on residential turf. The use of
these products results in post-application exposures to adults and
children.

For the initial registration of trinexapac-ethyl, children\'s exposure
to trinexapac-ethyl from treated turf was estimated using two
dislodgeable foliar residue (DFR) studies and assumptions about the
duration of exposure, children's body weight, etc. (C. Lewis, D180718,
December 28, 1992 and D. Hanke, D183213, January 22, 1993). These DFR
studies may be used in conjunction with the Draft SOPs for Residential
Exposure, along with the existing use patterns, to determine potential
post-application exposure and risk to children and adults associated
with use of trinexapac-ethyl formulations on turf.

***Short- and intermediate-term residential post-application exposure***
should be assessed for 1) high contact activities of adult and toddler,
2) mowing by adults and youth, 3) golfing by adults and youth, 4)
hand-to-mouth exposure to toddlers, 5) object-to-mouth exposure to
toddlers, and 5) incidental ingestion by toddlers. For this scoping
document, a preliminary assessment of the scenarios expected to pose the
highest risk was conducted according to current policy, using surrogate
data, rather than data from the human study in children. The preliminary
estimates based on surrogate data from PHED show that the short-term
post-application risks to adults, youths, and toddlers **(MOEs = 230 --
180,000)** are not of concern to HED (for MOEs, LOC ≥ 100) at the
maximum single application rate of 0.88 lb ai/A (Table 9).

**Aggregate Risk Assessment**

An ***aggregate exposure assessment*** has not been conducted; however,
in accordance with the FQPA, when there are potential residential
exposures to a pesticide, aggregate risk assessment must consider
exposures from three major routes: oral, dermal, and inhalation. There
are three sources for these types of exposures: food, drinking water,
and residential uses. Short- and intermediate-term aggregate risk
assessment is required for trinexapac-ethyl due to potential dietary
exposure resulting from drinking water and, if tolerances are
established, from use on grasses grown for seed and potential
residential and/or recreational exposures to residues on turfgrass. The
short-term dermal and inhalation endpoints are based on decreased
fetuses/litter and increased post-implantation loss seen in a prenatal
developmental toxicity study in rabbits; the short-term incidental oral
endpoint is based on decreased F1 survival, body weights, and body
weight gains in the reproduction study.

During registration review, adult short- and intermediate-term exposure
via the dermal, inhalation, and dietary routes should be aggregated and
compared to the short- and intermediate-term endpoints from the
developmental rabbit and chronic dog studies, respectively.

For toddlers, short-term exposure via the dermal, inhalation, incidental
oral, and dietary routes should be aggregated and compared to the
short-term incidental oral endpoint from the reproduction study. It is
not appropriate to examine aggregate risk to a toddler based on a
developmental endpoint, because this form of toxicity would not occur in
a child. As previously discussed, the team may wish to select new
age-specific short-term dermal and inhalation endpoints for toddlers
based on the pup body weight changes observed in the reproduction study.
This type of toxicity could occur in toddlers via the oral, dermal, or
inhalation route. Again, note that the existing short-term dermal and
inhalation endpoints are highly conservative and protective for all
types of toxicity expected with exposure to toddlers.

**Occupational Exposure**

ECs, WP/WSB, and granular formulations of trinexapac-ethyl are applied
by commercial operators and/or growers on turf areas and grasses grown
for seeds using a variety of ground sprayers and granule spreaders
(Table 10).

[]{.mark}

[]{.mark}

[Occupational Handlers]{.underline}

During the registration of trinexapac-ethyl, the registrant provided a
short-term dislodgeable foliar residue (DFR) study for an EC
formulation. Based on that data, a short-term handler assessment was
performed, which indicated that the risks to mixer/loaders and
applicators applying the EC with a ground boom sprayer did not exceed
HED's level of concern if the handlers wore long-sleeved shirts, long
pants, and shoes with socks and gloves (C. Lewis, D180718, December 28,
1992 and D. Hanke, D183213, January 22, 1993).

For this registration review scoping document, an occupational exposure
assessment was performed using the current standards, including
surrogate values from the pesticide handlers exposure database (PHED)
and the maximum single application rate of trinexapac-ethyl on turf at
0.88 lb ai/A (Table 11). The preliminary short-term risk estimate to
loader/applicators of granules with a push-type spreader (**MOE = 420**)
does not exceed HEDs level of concern (**LOC ≤ 100**). Other short-term
occupational handler scenarios were not examined here, due to the
***absence of surrogate unit exposures***. ***Intermediate-term
exposure*** to occupational handlers should be assessed during
registration review.

[Occupational Post-Application]{.underline}

***Post-application risk to workers*** who may enter the treated field
has not been assessed at this time, but should be examined during
registration review.

**Public Health and Pesticide Epidemiology Data**

A summary report listing incidents reported to EPA for trinexapac-ethyl
will be provided for the docket. The reported incidents will be screened
in more detail during the development of the Final Work Plan for
trinexapac-ethyl.

**Tolerances and International Harmonization**

No US tolerances have been established for trinexapac-ethyl, although
the use on grasses grown for seed production is considered a feed use,
and available data suggest that quantifiable residues of
trinexapac-ethyl may be found in plant and animal commodities. Maximum
residue limits (MRLs) have not been established by Codex, Canada, or
Mexico (Table 12); however, permanent or provisional/temporary MRLs have
been established for a variety of commodities in Japan (Table 13),
Australia, New Zealand, and European countries (Table 14), as summarized
in the attached tolerance status tables.

**Environmental Justice**

Potential areas of environmental justice concerns, to the extent
possible, were considered in the human health risk assessment, in
accordance with U.S. Executive Order 12898, \"Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,\"
<http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustice.pdf>).
The Office of Pesticide Programs (OPP) typically considers the highest
potential exposures from the legal use of a pesticide when conducting
human health risk assessments, including, but not limited to, people who
obtain drinking water from sources near agricultural areas, the
variability of diets within the U.S., and people who may be exposed when
harvesting crops. Should these highest exposures indicate potential
risks of concern, OPP further refines the risk assessments to ensure
that the risk estimates are based on the best available information.

**Cumulative Risk Assessments**

The Agency has not determined whether trinexapac-ethyl shares a common
mechanism of toxicity with other chemical substances; therefore, at this
time, a cumulative assessment to support registration review is not
required.

**Human Studies**

The screening-level risks presented in this scoping document rely in
part on data from studies in which adult human subjects were
intentionally exposed to a pesticide or other chemical. These studies,
which comprise the Pesticide Handlers Exposure Database (PHED), have
been reviewed by the Agency and found to have been conducted ethically.

**Data Requirements**

During registration review, the following outstanding data requirements
should be fulfilled. See Table 9 in the Attachment of this document for
more details.

  -------------------------------------------------------------------------------
  **Outstanding Data 
  Requirements for   
  Trinexapac-ethyl   
  (PC Code 112602)** 
  ------------------ ------------------------------------------------------------
  860.1340           Plant Analytical Method

  860.1340           Animal Analytical Method

  860.1500           Crop Field Trials

  870.6200a          Acute Neurotoxicity Study

  870.6200b          Subchronic Neurotoxicity Study

  870.7800           Immunotoxicity Study
  -------------------------------------------------------------------------------

**References**

  ------------ ------------- ----------- ----------------------------------------------
  **Author**   **Barcode**   **Date**    **Title**

  Taylor, L.   D328850       1/18/2007   Trinexapac-ethyl (P. C. Code 112602): DP
                                         Barcode D328850. Transmittal of Amended Data
                                         Evaluation Records (DERs) \[Executive
                                         Summaries\] to upgrade the original DERs and
                                         Two New DERs on Trinexapac-ethyl.

  Dotson, D.   D339864       5/17/2007   Trinexapac-ethyl. Response to Registrant
                                         Proposal dated May 4, 2007 Regarding Data
                                         Deficiencies Associated with Tolerance
                                         Petitions 3F6571 (Grass Grown for Seed) and
                                         7F7203 (Wheat, Barley, and Sugarcane).

  Dotson, D.   D328850,      DRAFT       Trinexapac-ethyl. Petitions for Registration
               328853,                   of Use on Grasses Grown for Seed. Summary of
               328898                    Analytical Chemistry and Residue Data.
                                         Petition Number 3F6571.
  ------------ ------------- ----------- ----------------------------------------------

**ATTACHMENTS**

  ----------------------------------------------------------------------------------------------
  **Table 1. Chemical   
  Identity of           
  Trinexapac-ethyl.**   
  --------------------- ------------------------------------------------------------------------
  Compound              ![](media/image2.wmf){width="2.689583333333333in"
                        height="1.398611111111111in"}

  Common name           Trinexapac-ethyl

  Company experimental  CGA-163935
  name                  

  IUPAC name            ethyl
                        (*RS*)-4-cyclopropyl(hydroxy)methylene-3,5-dioxocyclohexanecarboxylate

  CAS name              ethyl 4-(cyclopropylhydroxymethylene)-3,5-dioxocyclohexanecarboxylate

  CAS registry number   95266-40-3

  PC Code               112602

  Registration review   7228
  case no.              

  Regulated metabolite  ![](media/image3.wmf){width="2.0395833333333333in"
                        height="1.3027777777777778in"}

  Common name           Trinexapac

  Company experimental  CGA-179500
  name                  

  IUPAC name            (*RS*)-4-cyclopropyl(hydroxy)methylene-3,5-dioxocyclohexanecarboxylic
                        acid

  CAS name              4-(cyclopropylhydroxymethylene)-3,5-dioxocyclohexanecarboxylic acid

  CAS registry number   104273-73-6
  ----------------------------------------------------------------------------------------------

+--------------------------+-------------------------+-----------------+
| **Table 2.               |                         |                 |
| Physicochemical          |                         |                 |
| Properties of            |                         |                 |
| Trinexapac-ethyl.**      |                         |                 |
+==========================+=========================+=================+
| Parameter                | Value                   | Reference       |
+--------------------------+-------------------------+-----------------+
| Melting point/range      | 36.1-36.6°C             | Provided in     |
|                          |                         | MRID 46809305   |
+--------------------------+-------------------------+-----------------+
| pH                       | 3.3                     |                 |
+--------------------------+-------------------------+-----------------+
| Density (20ºC)           | 1.215 g/cm^3^           |                 |
+--------------------------+-------------------------+-----------------+
| Water solubility (g/L at | 2.8 at pH 4.9           |                 |
| 25°C)                    |                         |                 |
|                          | 10.2 at pH 5.5          |                 |
|                          |                         |                 |
|                          | 21.1 at pH 8.2          |                 |
+--------------------------+-------------------------+-----------------+
| Solvent solubility       | Acetone 100% Ethanol    |                 |
|                          | 100%                    |                 |
|                          |                         |                 |
|                          | Toluene 100% n-octanol  |                 |
|                          | 100%                    |                 |
|                          |                         |                 |
|                          | n-hexane 5%             |                 |
+--------------------------+-------------------------+-----------------+
| Vapor pressure (25ºC)    | 1.62 x 10^-5^ mm Hg     |                 |
+--------------------------+-------------------------+-----------------+
| Dissociation constant,   | 4.57                    |                 |
| pK~a~                    |                         |                 |
+--------------------------+-------------------------+-----------------+
| Octanol/water partition  | 2.44 at pH 5.3          |                 |
| coefficient, Log(K~OW~)  |                         |                 |
| at 25ºC                  |                         |                 |
+--------------------------+-------------------------+-----------------+
| UV/visible absorption    | Neutral: 9335 L/mol·cm  |                 |
| spectrum                 | @ 240.2 nm              |                 |
|                          |                         |                 |
|                          | 13976 L/mol·cm @ 277.4  |                 |
|                          | nm                      |                 |
|                          |                         |                 |
|                          | Acidic: 11712 L/mol·cm  |                 |
|                          | @ 240.0 nm              |                 |
|                          |                         |                 |
|                          | 12368 L/mol·cm \@380.4  |                 |
|                          | nm                      |                 |
|                          |                         |                 |
|                          | Basic: 21320 L/mol·cm @ |                 |
|                          | 270.8 nm                |                 |
+--------------------------+-------------------------+-----------------+

[]{.mark}

> []{.mark}

+-------+----+----+------+-----------+------------+----+------+-----+
| **    |    |    |      |           |            |    |      |     |
| Table |    |    |      |           |            |    |      |     |
| 3.    |    |    |      |           |            |    |      |     |
| Tr    |    |    |      |           |            |    |      |     |
| inexa |    |    |      |           |            |    |      |     |
| pac-e |    |    |      |           |            |    |      |     |
| thyl: |    |    |      |           |            |    |      |     |
| Regis |    |    |      |           |            |    |      |     |
| tered |    |    |      |           |            |    |      |     |
| Formu |    |    |      |           |            |    |      |     |
| latio |    |    |      |           |            |    |      |     |
| ns.** |    |    |      |           |            |    |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| EPA   | AI | F  | S    | Handler   | A          | S  | Si   | La  |
| Reg.  | %  | or | ites |           | pplication | pr | gnal | bel |
| Nos.  |    | mu |      |           | Equipment  | ay | word | PPE |
|       |    | l. |      |           |            | v  |      |     |
|       |    | Ty |      |           |            | ol |      |     |
|       |    | pe |      |           |            |    |      |     |
|       |    |    |      |           |            | g  |      |     |
|       |    |    |      |           |            | al |      |     |
|       |    |    |      |           |            | /A |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| [1.   | [9 | t  | \--  | [\--]{.s  | \--        | \  | Cau  | \-- |
| 100-7 | 7. | ec |      | mallcaps} |            | -- | tion |     |
| 27]{. | 0] | h/ |      |           |            |    |      |     |
| small | {. | MP |      |           |            |    |      |     |
| caps} | sm |    |      |           |            |    |      |     |
|       | al |    |      |           |            |    |      |     |
|       | lc |    |      |           |            |    |      |     |
|       | ap |    |      |           |            |    |      |     |
|       | s} |    |      |           |            |    |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 2\.   | 12 | EC | turf | gro       | BP, BS,    | 22 | War  | B,  |
| 10    | .0 |    |      | wer/comm. | HS, SG     | -1 | ning | G,  |
| 0-729 |    |    |      | a         |            | 75 |      | E   |
|       |    |    |      | pplicator |            |    |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 3\.   | 25 | WP | turf | \" \" "   | BP, BS,    | 22 | Cau  | B,  |
| 10    | .0 | /W |      |           | HS, SG     | -1 | tion | G   |
| 0-752 |    | SB |      |           |            | 75 |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 4\.   | 0. | g  | turf | home      | shaker,    | \  | Cau  | n   |
| 10    | 01 | ra |      | ow        | fertilizer | -- | tion | one |
| 0-930 | -1 | nu |      | ner/comm. | spreader   |    |      |     |
|       | .0 | le |      | appl      | \*         |    |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 5\.   | 0. | g  | turf | \" \" "   | shaker,    | \  | Cau  | n   |
| 10    | 01 | ra |      |           | fertilizer | -- | tion | one |
| 0-931 | -1 | nu |      |           | spreader   |    |      |     |
|       | .0 | le |      |           | \*         |    |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 6\.   | 11 | EC | turf | gro       | BP, BS,    | 22 | Cau  | B,  |
| 10    | .3 |    |      | wer/comm. | HS, SG     | -1 | tion | G   |
| 0-937 |    |    |      | a         |            | 75 |      |     |
|       |    |    |      | pplicator |            |    |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 7\.   | 12 | EC | g\.  | \" \" "   | broadcast  | 1  | War  | B,  |
| 10    | .0 |    | g.   |           | sprayer    | 0- | ning | G,  |
| 0-949 |    |    | seed |           |            | 20 |      | E   |
+-------+----+----+------+-----------+------------+----+------+-----+
| 8\.   | 25 | EC | g\.  | \" \" "   | broadcast  | 1  | Cau  | B,  |
| 100   | .5 |    | g.   |           | sprayer    | 0- | tion | G,  |
| -1241 |    |    | seed |           |            | 20 |      | E   |
+-------+----+----+------+-----------+------------+----+------+-----+
| 9\.   | 11 | EC | turf | \" \" "   | BP, BS,    | 22 | Cau  | B,  |
| 34704 | .3 |    |      |           | HS, SG     | -1 | tion | G   |
| -1005 |    |    |      |           |            | 75 |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 10\.  | 11 | EC | turf | \" \" "   | BP, BS,    | 22 | Cau  | B,  |
| 721   | .3 |    |      |           | HS, SG     | -1 | tion | G   |
| 12-11 |    |    |      |           |            | 75 |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 11\.  | 97 | t  | \--  | [\--]{.s  | \--        | \  | Cau  | \-- |
| 721   | .0 | ec |      | mallcaps} |            | -- | tion |     |
| 67-54 |    | h/ |      |           |            |    |      |     |
|       |    | MP |      |           |            |    |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 12\.  | 11 | EC | turf | \" \" "   | BP, BS,    | 22 | Cau  | B,  |
| 732   | .3 |    |      |           | HS, SG     | -1 | tion | G   |
| 20-12 |    |    |      |           |            | 75 |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 13\.  | 11 | EC | turf | \" \" "   | BP, BS,    | 22 | Cau  | B,  |
| 796   | .3 |    |      |           | HS, SG     | -1 | tion | G   |
| 76-24 |    |    |      |           |            | 75 |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 14\.  | 12 | EC | turf | \" \" "   | BP, BS,    | 22 | War  | B,  |
| 796   | .0 |    |      |           | HS, SG     | -1 | ning | G   |
| 76-37 |    |    |      |           |            | 75 |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 15\.  | 11 | EC | turf | \" \" "   | BP, BS,    | 22 | Cau  | B,  |
| 819   | .3 |    |      |           | HS, SG     | -1 | tion | G   |
| 43-12 |    |    |      |           |            | 75 |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 16\.  | 98 | t  | \--  | [\--]{.s  | \--        | \  | Cau  | \-- |
| 819   | .0 | ec |      | mallcaps} |            | -- | tion |     |
| 59-27 |    | h/ |      |           |            |    |      |     |
|       |    | MP |      |           |            |    |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 17\.  | 11 | EC | turf | \" \" "   | BP, BS,    | 22 | Cau  | B,  |
| 83    | .3 |    |      |           | HS, SG     | -1 | tion | G   |
| 070-4 |    |    |      |           |            | 75 |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 18\.  | 12 | EC | seed | \" \" "   | broadcast  | 1  | War  | B,  |
| MN0   | .0 |    | rye  |           | sprayer    | 0- | ning | G,  |
| 20010 |    |    | g    |           |            | 20 |      | E   |
|       |    |    | rass |           |            |    |      |     |
+-------+----+----+------+-----------+------------+----+------+-----+
| 19\.  | 12 | EC | seed | \" \" "   | broadcast  | 1  | War  | B,  |
| OR0   | .0 |    | fe   |           | sprayer    | 0- | ning | G,  |
| 00007 |    |    | scue |           |            | 20 |      | E   |
+-------+----+----+------+-----------+------------+----+------+-----+
| 20\.  | 12 | EC | seed | \" \" "   | broadcast  | 1  | War  | B,  |
| WA0   | .0 |    | fe   |           | sprayer    | 0- | ning | G,  |
| 30007 |    |    | scue |           |            | 20 |      | E   |
+-------+----+----+------+-----------+------------+----+------+-----+

EC= emulsifiable concentrate, MP = manufacturing-use product, NA = not
applicable, WP/WSB= wettable powder packed in water-soluble bags,

PPE - B (baseline consisting of long sleeved shirt, long pants, and
shoes with socks), C (gloves), and E (eye wear)

Application equipment: BP = back-pack sprayer, BS = boom sprayer, HS =
hand sprayer, and SG = spray gun

> \* = fertilizer spreaders can be either broadcast or drop spreaders
>
> []{.mark}

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><strong>Table 4. Trinexapac-ethyl - Application Rates
on Turf and Grasses Grown for Seeds.</strong></td>
</tr>
<tr class="even">
<td>EPA Reg. No.</td>
<td>AI %</td>
<td>Formul. Type</td>
<td><p>Home lawns</p>
<p>max single</p>
<p>lb ai/A</p></td>
<td><p>Golf course</p>
<p>max single</p>
<p>lb ai/A</p></td>
<td><p>Res/Commerc.</p>
<p>max single</p>
<p>lb ai/A</p></td>
<td><p>Edging</p>
<p>max single</p>
<p>lb ai/A</p></td>
<td><p>Grass gr seeds</p>
<p>max single</p>
<p>lb ai/A</p></td>
<td># Appl./yr</td>
<td><p>Max/yr</p>
<p>lb ai/A</p></td>
</tr>
<tr class="odd">
<td><span class="smallcaps">1. 100-727</span></td>
<td><span class="smallcaps">97.0</span></td>
<td>tech/MP</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
</tr>
<tr class="even">
<td>2. 100-729</td>
<td>12.0</td>
<td>EC</td>
<td>--</td>
<td>0.17</td>
<td>0.34</td>
<td>0.69</td>
<td>--</td>
<td>multiple</td>
<td>2.4</td>
</tr>
<tr class="odd">
<td>3. 100-752</td>
<td>25.0</td>
<td>WP/WSB</td>
<td>--</td>
<td>0.17</td>
<td>0.34</td>
<td>0.68</td>
<td>--</td>
<td>multiple</td>
<td>2.7</td>
</tr>
<tr class="even">
<td>4. 100-930</td>
<td>0.01-1.0</td>
<td>granule</td>
<td>0.44</td>
<td>--</td>
<td>--</td>
<td>0.88</td>
<td>--</td>
<td>multiple</td>
<td>2.5</td>
</tr>
<tr class="odd">
<td>5. 100-931</td>
<td>0.01-1.0</td>
<td>granule</td>
<td>0.44</td>
<td>--</td>
<td>--</td>
<td>0.88</td>
<td>--</td>
<td>multiple</td>
<td>2.5</td>
</tr>
<tr class="even">
<td>6. 100-937</td>
<td>11.3</td>
<td>EC</td>
<td>--</td>
<td>0.16</td>
<td>0.32</td>
<td>0.65</td>
<td>--</td>
<td>multiple</td>
<td>2.25</td>
</tr>
<tr class="odd">
<td>7. 100-949</td>
<td>12.0</td>
<td>EC</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>0.5</td>
<td>multiple</td>
<td>0.5</td>
</tr>
<tr class="even">
<td>8. 100-1241</td>
<td>25.5</td>
<td>EC</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>0.45</td>
<td>multiple</td>
<td>0.5</td>
</tr>
<tr class="odd">
<td>9. 34704-1005</td>
<td>11.3</td>
<td>EC</td>
<td>--</td>
<td>0.16</td>
<td>0.32</td>
<td>0.65</td>
<td>--</td>
<td>multiple</td>
<td>2.25</td>
</tr>
<tr class="even">
<td>10. 72112-11</td>
<td>11.3</td>
<td>EC</td>
<td>--</td>
<td>0.16</td>
<td>0.32</td>
<td>0.65</td>
<td>--</td>
<td>multiple</td>
<td>2.25</td>
</tr>
<tr class="odd">
<td>11. 72167-54</td>
<td>97.0</td>
<td>tech/MP</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
</tr>
<tr class="even">
<td>12. 73220-12</td>
<td>11.3</td>
<td>EC</td>
<td>--</td>
<td>0.16</td>
<td>0.32</td>
<td>0.65</td>
<td>--</td>
<td>multiple</td>
<td>2.25</td>
</tr>
<tr class="odd">
<td>13. 79676-24</td>
<td>11.3</td>
<td>EC</td>
<td>--</td>
<td>0.16</td>
<td>0.32</td>
<td>0.65</td>
<td>--</td>
<td>multiple</td>
<td>2.25</td>
</tr>
<tr class="even">
<td>14. 79676-37</td>
<td>12.0</td>
<td>EC</td>
<td>--</td>
<td>0.17</td>
<td>0.34</td>
<td>0.68</td>
<td>--</td>
<td>multiple</td>
<td>2.4</td>
</tr>
<tr class="odd">
<td>15. 81943-12</td>
<td>11.3</td>
<td>EC</td>
<td>--</td>
<td>0.16</td>
<td>0.32</td>
<td>0.65</td>
<td>--</td>
<td>multiple</td>
<td>2.25</td>
</tr>
<tr class="even">
<td>16. 81959-27</td>
<td>98.0</td>
<td>tech/MP</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
</tr>
<tr class="odd">
<td>17. 83070-4</td>
<td>11.3</td>
<td>EC</td>
<td>--</td>
<td>0.16</td>
<td>0.32</td>
<td>0.65</td>
<td>--</td>
<td>multiple</td>
<td>2.25</td>
</tr>
<tr class="even">
<td>18. MN020010</td>
<td>12.0</td>
<td>EC</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>0.5</td>
<td>multiple</td>
<td>0.5</td>
</tr>
<tr class="odd">
<td>19. OR000007</td>
<td>12.0</td>
<td>EC</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>0.5</td>
<td>multiple</td>
<td>0.5</td>
</tr>
<tr class="even">
<td>20. WA030007</td>
<td>12.0</td>
<td>EC</td>
<td>----</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>0.5</td>
<td>multiple</td>
<td>0.5</td>
</tr>
</tbody>
</table>

EC= emulsifiable concentrate, NA= not applicable, P/WSB= wettable powder
packed in water-soluble bags.

> []{.mark}

+--------+-------------------+-------+-----------------------+-------+
| *      |                   |       |                       |       |
| *Table |                   |       |                       |       |
| 5.     |                   |       |                       |       |
| Acute  |                   |       |                       |       |
| To     |                   |       |                       |       |
| xicity |                   |       |                       |       |
| P      |                   |       |                       |       |
| rofile |                   |       |                       |       |
| of     |                   |       |                       |       |
| Trin   |                   |       |                       |       |
| exapac |                   |       |                       |       |
| -ethyl |                   |       |                       |       |
| (9     |                   |       |                       |       |
| 7%).** |                   |       |                       |       |
+--------+-------------------+-------+-----------------------+-------+
| **Gui  | **Study Type**    | **M   | **Results**           | **Tox |
| deline |                   | RID** |                       | icity |
| No.**  |                   |       |                       | Categ |
|        |                   |       |                       | ory** |
+--------+-------------------+-------+-----------------------+-------+
| 87     | Acute oral        | 415   | ♂ LD~50~ = 4613 mg/kg | III   |
| 0.1100 | \[rat\]           | 63901 |                       |       |
|        |                   |       | ♀ LD~50~ = 4212 mg/kg |       |
|        |                   |       |                       |       |
|        |                   |       | Combined LD~50~ =     |       |
|        |                   |       | 4458 mg/kg            |       |
+--------+-------------------+-------+-----------------------+-------+
| 87     | Acute dermal      | 415   | LD~50~ \> 4000 mg/kg  | III   |
| 0.1200 | \[rabbit\]        | 63910 |                       |       |
+--------+-------------------+-------+-----------------------+-------+
| 87     | Acute inhalation  | 415   | LC~50~ ≥ 5.3 mg/L     | IV    |
| 0.1300 | \[rat\]           | 63912 |                       |       |
+--------+-------------------+-------+-----------------------+-------+
| 87     | Acute eye         | 415   | Minimal irritant;     | III   |
| 0.2400 | irritation        | 63914 | cleared by 72 hours   |       |
|        | \[rabbit\]        |       |                       |       |
+--------+-------------------+-------+-----------------------+-------+
| 87     | Acute dermal      | 415   | Slightly irritating;  | IV    |
| 0.2500 | irritation        | 63916 | cleared by day 7      |       |
|        | \[rabbit\]        |       |                       |       |
+--------+-------------------+-------+-----------------------+-------+
| 87     | Skin              | 418   | Not a dermal          | N/A   |
| 0.2600 | sensitization     | 69522 | sensitizer            |       |
|        | \[guinea pig\]    |       |                       |       |
+--------+-------------------+-------+-----------------------+-------+

+---------+---+--------+-------------+---+-----------+---------------------+---+
| **Table |   |        |             |   |           |                     |   |
| 6.      |   |        |             |   |           |                     |   |
| Subc    |   |        |             |   |           |                     |   |
| hronic, |   |        |             |   |           |                     |   |
| Chronic |   |        |             |   |           |                     |   |
| and     |   |        |             |   |           |                     |   |
| Other   |   |        |             |   |           |                     |   |
| T       |   |        |             |   |           |                     |   |
| oxicity |   |        |             |   |           |                     |   |
| Profile |   |        |             |   |           |                     |   |
| of      |   |        |             |   |           |                     |   |
| Trine   |   |        |             |   |           |                     |   |
| xapac-e |   |        |             |   |           |                     |   |
| thyl.** |   |        |             |   |           |                     |   |
+=========+===+========+=============+===+===========+=====================+===+
| **Gu    |   | **MRID |             |   | **        |                     |   |
| ideline |   | No.    |             |   | Results** |                     |   |
| No./    |   | (y     |             |   |           |                     |   |
| Study   |   | ear)** |             |   |           |                     |   |
| Type**  |   |        |             |   |           |                     |   |
|         |   | **Cl   |             |   |           |                     |   |
|         |   | assifi |             |   |           |                     |   |
|         |   | cation |             |   |           |                     |   |
|         |   | /D     |             |   |           |                     |   |
|         |   | oses** |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | MRID   |             |   | NOAEL =   |                     |   |
| 70.3100 |   | 41     |             |   | 20000 ppm |                     |   |
|         |   | 563921 |             |   | \[males   |                     |   |
| 90-Day  |   | (1989) |             |   | 135       |                     |   |
| oral    |   |        |             |   | 0/females |                     |   |
| t       |   | 0, 5,  |             |   | 1551      |                     |   |
| oxicity |   | 50,    |             |   | mg/kg/day |                     |   |
| \[rat\] |   | 500,   |             |   |           |                     |   |
|         |   | 5000,  |             |   | HDT       |                     |   |
|         |   | 20000  |             |   |           |                     |   |
|         |   | ppm    |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | \      |             |   |           |                     |   |
|         |   | [males |             |   |           |                     |   |
|         |   | 0, 3,  |             |   |           |                     |   |
|         |   | 34,    |             |   |           |                     |   |
|         |   | 346,   |             |   |           |                     |   |
|         |   | 1350   |             |   |           |                     |   |
|         |   | mg/kg  |             |   |           |                     |   |
|         |   | /day\] |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | \[f    |             |   |           |                     |   |
|         |   | emales |             |   |           |                     |   |
|         |   | 0, 4,  |             |   |           |                     |   |
|         |   | 38,    |             |   |           |                     |   |
|         |   | 395,   |             |   |           |                     |   |
|         |   | 1551   |             |   |           |                     |   |
|         |   | mg/kg  |             |   |           |                     |   |
|         |   | /day\] |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | ac     |             |   |           |                     |   |
|         |   | ceptab |             |   |           |                     |   |
|         |   | le/gui |             |   |           |                     |   |
|         |   | deline |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | MRID   |             |   | NOAEL =   |                     |   |
| 70.3150 |   | 41     |             |   | 15000 ppm |                     |   |
|         |   | 563920 |             |   | \[males   |                     |   |
| 13-week |   | **(*   |             |   | 515.      |                     |   |
| oral    |   | *1989) |             |   | 9/females |                     |   |
| t       |   |        |             |   | 582.4     |                     |   |
| oxicity |   | 0, 50, |             |   | mg/kg/day |                     |   |
| in      |   | 100,   |             |   |           |                     |   |
| no      |   | 15000, |             |   | LOAEL =   |                     |   |
| nrodent |   | 30000  |             |   | 30000 ppm |                     |   |
| (dog)   |   | ppm    |             |   | \[males   |                     |   |
|         |   |        |             |   | 927.      |                     |   |
| 7-week  |   | \      |             |   | 1/females |                     |   |
| pilot   |   | [males |             |   | 890.8     |                     |   |
| study   |   | 0,     |             |   | m         |                     |   |
|         |   | 2.0,   |             |   | g/kg/day, |                     |   |
|         |   | 34.9,  |             |   | based on  |                     |   |
|         |   | 515.9, |             |   | clinical  |                     |   |
|         |   | 927.1  |             |   | signs     |                     |   |
|         |   | mg/kg  |             |   | (few      |                     |   |
|         |   | /day\] |             |   | feces and |                     |   |
|         |   |        |             |   | em        |                     |   |
|         |   | \[f    |             |   | aciation) |                     |   |
|         |   | emales |             |   | decreased |                     |   |
|         |   | 0,     |             |   | BWG/FC/FE |                     |   |
|         |   | 1.9,   |             |   | in both   |                     |   |
|         |   | 38.8,  |             |   | sexes     |                     |   |
|         |   | 582.4, |             |   | (related  |                     |   |
|         |   | 890.8  |             |   | to lack   |                     |   |
|         |   | mg/kg  |             |   | of        |                     |   |
|         |   | /day\] |             |   | pala      |                     |   |
|         |   |        |             |   | tability) |                     |   |
|         |   | ac     |             |   | and       |                     |   |
|         |   | ceptab |             |   | diffuse   |                     |   |
|         |   | le/gui |             |   | thymic    |                     |   |
|         |   | deline |             |   | atrophy   |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | MRID   |             |   | Negative  |                     |   |
|         |   | 41     |             |   | BWG in    |                     |   |
|         |   | 869523 |             |   | males HDT |                     |   |
|         |   |        |             |   | from week |                     |   |
|         |   | 0,     |             |   | 5 on; HDT |                     |   |
|         |   | 500,   |             |   | females   |                     |   |
|         |   | 5000,  |             |   | from week |                     |   |
|         |   | 15000  |             |   | 6 on; BW  |                     |   |
|         |   | -50000 |             |   | of HDT    |                     |   |
|         |   | ppm    |             |   | males 81% |                     |   |
|         |   |        |             |   | of        |                     |   |
|         |   | \      |             |   | contro    |                     |   |
|         |   | [males |             |   | l/females |                     |   |
|         |   | 0, 22, |             |   | 74%       |                     |   |
|         |   | 219,   |             |   | control   |                     |   |
|         |   | (686,  |             |   | at week   |                     |   |
|         |   | 956,   |             |   | 7; severe |                     |   |
|         |   | 734)\* |             |   | decrease  |                     |   |
|         |   | mg/kg  |             |   | in food   |                     |   |
|         |   | /day\] |             |   | co        |                     |   |
|         |   |        |             |   | nsumption |                     |   |
|         |   | \[f    |             |   | HDT;      |                     |   |
|         |   | emales |             |   | tubular   |                     |   |
|         |   | 0, 23, |             |   | d         |                     |   |
|         |   | 214,   |             |   | ilatation |                     |   |
|         |   | (680,  |             |   | and       |                     |   |
|         |   | 1373,  |             |   | degener   |                     |   |
|         |   | 965)\* |             |   | ation/reg |                     |   |
|         |   | mg/kg  |             |   | eneration |                     |   |
|         |   | /day\] |             |   | of        |                     |   |
|         |   |        |             |   | e         |                     |   |
|         |   | \      |             |   | pithelial |                     |   |
|         |   | *15000 |             |   | cells of  |                     |   |
|         |   | ppm    |             |   | renal     |                     |   |
|         |   | (days  |             |   | tubules   |                     |   |
|         |   | 1-3);  |             |   | at HDT;   |                     |   |
|         |   | 30000  |             |   | diffuse   |                     |   |
|         |   | ppm    |             |   | thymic    |                     |   |
|         |   | (days  |             |   | atrophy   |                     |   |
|         |   | 4-28); |             |   | at mid-   |                     |   |
|         |   | 50000  |             |   | and       |                     |   |
|         |   | ppm    |             |   | high-dose |                     |   |
|         |   | (weeks |             |   | females   |                     |   |
|         |   | 4-7)   |             |   | and       |                     |   |
|         |   |        |             |   | high-dose |                     |   |
|         |   |        |             |   | males     |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | MRID   |             |   | *         |                     |   |
| 70.3200 |   | 41     |             |   | *Systemic |                     |   |
|         |   | 563922 |             |   | t         |                     |   |
| 21      |   | (1989) |             |   | oxicity** |                     |   |
| /28-Day |   |        |             |   |           |                     |   |
| dermal  |   | \[46   |             |   | NOAEL:    |                     |   |
| t       |   | 809310 |             |   | 1000      |                     |   |
| oxicity |   | (2     |             |   | mg/kg/day |                     |   |
| (       |   | 006)\] |             |   |           |                     |   |
| rabbit) |   |        |             |   | LOAEL:    |                     |   |
|         |   | 0, 10, |             |   | Not       |                     |   |
|         |   | 100,   |             |   | d         |                     |   |
|         |   | or     |             |   | etermined |                     |   |
|         |   | 1000   |             |   |           |                     |   |
|         |   | mg/k   |             |   | **Local   |                     |   |
|         |   | g/day, |             |   | dermal    |                     |   |
|         |   |        |             |   | irr       |                     |   |
|         |   | ac     |             |   | itation** |                     |   |
|         |   | ceptab |             |   |           |                     |   |
|         |   | le/gui |             |   | NOAEL: 10 |                     |   |
|         |   | deline |             |   | mg/kg/d   |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   |        |             |   | LOAEL:    |                     |   |
|         |   |        |             |   | 100       |                     |   |
|         |   |        |             |   | mg/kg/d   |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   |        |             |   | based on  |                     |   |
|         |   |        |             |   | hyper     |                     |   |
|         |   |        |             |   | keratosis |                     |   |
|         |   |        |             |   | and       |                     |   |
|         |   |        |             |   | subacute  |                     |   |
|         |   |        |             |   | ly        |                     |   |
|         |   |        |             |   | mphocytic |                     |   |
|         |   |        |             |   | in        |                     |   |
|         |   |        |             |   | filtrates |                     |   |
|         |   |        |             |   | in the    |                     |   |
|         |   |        |             |   | skin      |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | no     |             |   |           |                     |   |
| 70.3250 |   | study  |             |   |           |                     |   |
|         |   | locat  |             |   |           |                     |   |
| 90-Day  |   | ed/not |             |   |           |                     |   |
| dermal  |   | re     |             |   |           |                     |   |
| t       |   | quired |             |   |           |                     |   |
| oxicity |   |        |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | no     |             |   |           |                     |   |
| 70.3465 |   | study  |             |   |           |                     |   |
|         |   | l      |             |   |           |                     |   |
| 90-day  |   | ocated |             |   |           |                     |   |
| inh     |   | on     |             |   |           |                     |   |
| alation |   | tec    |             |   |           |                     |   |
| t       |   | hnical |             |   |           |                     |   |
| oxicity |   |        |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 87      |   | MRID   |             |   | **M       |                     |   |
| 0.3700a |   | 41     |             |   | aternal** |                     |   |
|         |   | 563923 |             |   | NOAEL =   |                     |   |
| P       |   | (1988) |             |   | 1000      |                     |   |
| renatal |   |        |             |   | m         |                     |   |
| develo  |   | 0, 20, |             |   | g/kg/day, |                     |   |
| pmental |   | 200,   |             |   | highest   |                     |   |
| in      |   | 1000   |             |   | dose      |                     |   |
| rodent  |   | mg/    |             |   | tested    |                     |   |
| \[rat\] |   | kg/day |             |   |           |                     |   |
|         |   |        |             |   | **Develo  |                     |   |
|         |   | ges    |             |   | pmental** |                     |   |
|         |   | tation |             |   | NOAEL =   |                     |   |
|         |   | days   |             |   | 200       |                     |   |
|         |   | 6-15   |             |   | mg/kg/day |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | ac     |             |   | **Develo  |                     |   |
|         |   | ceptab |             |   | pmental** |                     |   |
|         |   | le/gui |             |   | LOAEL =   |                     |   |
|         |   | deline |             |   | 1000      |                     |   |
|         |   |        |             |   | m         |                     |   |
|         |   |        |             |   | g/kg/day, |                     |   |
|         |   |        |             |   | based on  |                     |   |
|         |   |        |             |   | increased |                     |   |
|         |   |        |             |   | incidence |                     |   |
|         |   |        |             |   | of        |                     |   |
|         |   |        |             |   | asy       |                     |   |
|         |   |        |             |   | mmetrical |                     |   |
|         |   |        |             |   | ly-shaped |                     |   |
|         |   |        |             |   | s         |                     |   |
|         |   |        |             |   | ternebrae |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 87      |   | MRID   |             |   | **M       |                     |   |
| 0.3700b |   | 41     |             |   | aterna**l |                     |   |
|         |   | 869524 |             |   | *         |                     |   |
| P       |   | (1990) |             |   | *toxicity |                     |   |
| renatal |   |        |             |   | NOAEL** = |                     |   |
| develo  |   | 0, 10, |             |   | 360       |                     |   |
| pmental |   | 60, or |             |   | m         |                     |   |
| in      |   | 360    |             |   | g/kg/day, |                     |   |
| no      |   | mg/    |             |   | highest   |                     |   |
| nrodent |   | kg/day |             |   | dose      |                     |   |
| (       |   |        |             |   | tested    |                     |   |
| rabbit) |   | ges    |             |   |           |                     |   |
|         |   | tation |             |   | **Develo  |                     |   |
|         |   | days   |             |   | pmenta**l |                     |   |
|         |   | 7-19   |             |   | *         |                     |   |
|         |   |        |             |   | *toxicity |                     |   |
|         |   | ac     |             |   | NOAEL** = |                     |   |
|         |   | ceptab |             |   | 60        |                     |   |
|         |   | le/gui |             |   | mg/kg/day |                     |   |
|         |   | deline |             |   |           |                     |   |
|         |   |        |             |   | **Deve    |                     |   |
|         |   |        |             |   | lopmental |                     |   |
|         |   |        |             |   | toxicity  |                     |   |
|         |   |        |             |   | LOAEL** = |                     |   |
|         |   |        |             |   | 360mg    |                     |   |
|         |   |        |             |   | //kg/day, |                     |   |
|         |   |        |             |   | based on  |                     |   |
|         |   |        |             |   | a         |                     |   |
|         |   |        |             |   | decrease  |                     |   |
|         |   |        |             |   | in the    |                     |   |
|         |   |        |             |   | mean      |                     |   |
|         |   |        |             |   | number of |                     |   |
|         |   |        |             |   | fetus     |                     |   |
|         |   |        |             |   | es/litter |                     |   |
|         |   |        |             |   | and an    |                     |   |
|         |   |        |             |   | increase  |                     |   |
|         |   |        |             |   | in        |                     |   |
|         |   |        |             |   | post-imp  |                     |   |
|         |   |        |             |   | lantation |                     |   |
|         |   |        |             |   | loss      |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | MRID   |             |   | *         |                     |   |
| 70.3800 |   | 43     |             |   | *Parental |                     |   |
|         |   | 128604 |             |   | toxicity  |                     |   |
| Repro   |   | (1991) |             |   | NOAEL** = |                     |   |
| duction |   |        |             |   | 10000 ppm |                     |   |
| and     |   | 0, 10, |             |   | \[males   |                     |   |
| fe      |   | 1000,  |             |   | 593.      |                     |   |
| rtility |   | 10000, |             |   | 5/females |                     |   |
| effects |   | 20000  |             |   | 751.1     |                     |   |
| (rats)  |   | ppm    |             |   | mg        |                     |   |
|         |   |        |             |   | /kg/day\] |                     |   |
|         |   | \[P0   |             |   |           |                     |   |
|         |   | males: |             |   | *         |                     |   |
|         |   | 0,     |             |   | *Parental |                     |   |
|         |   | 0.59,  |             |   | toxicity  |                     |   |
|         |   | 59.97, |             |   | LOAEL**   |                     |   |
|         |   | 5      |             |   | 20000 ppm |                     |   |
|         |   | 95.26, |             |   | \[males   |                     |   |
|         |   | 1      |             |   | 1212.     |                     |   |
|         |   | 169.16 |             |   | 1/females |                     |   |
|         |   | mg/kg  |             |   | 1484.9    |                     |   |
|         |   | /day\] |             |   | mg/       |                     |   |
|         |   |        |             |   | kg/day\], |                     |   |
|         |   | \[P0   |             |   | based on  |                     |   |
|         |   | fe     |             |   | reduced   |                     |   |
|         |   | males: |             |   | premating |                     |   |
|         |   | 0,     |             |   | and       |                     |   |
|         |   | 0.75,  |             |   | gestation |                     |   |
|         |   | 74.84, |             |   | body      |                     |   |
|         |   | 7      |             |   | weight/bo |                     |   |
|         |   | 36.89, |             |   | dy-weight |                     |   |
|         |   | 1      |             |   | gain and  |                     |   |
|         |   | 410.08 |             |   | food      |                     |   |
|         |   | mg/kg  |             |   | co        |                     |   |
|         |   | /day\] |             |   | nsumption |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | F1     |             |   | **Repro   |                     |   |
|         |   | males: |             |   | ductive** |                     |   |
|         |   | 0,     |             |   | **NOAEL** |                     |   |
|         |   | 0.59,  |             |   | = 20000   |                     |   |
|         |   | 59.10, |             |   | ppm       |                     |   |
|         |   | 5      |             |   | \[males   |                     |   |
|         |   | 91.76, |             |   | 121       |                     |   |
|         |   | 1      |             |   | 2/females |                     |   |
|         |   | 254.96 |             |   | 1484      |                     |   |
|         |   | mg/kg  |             |   | mg/       |                     |   |
|         |   | /day\] |             |   | kg/day\]. |                     |   |
|         |   |        |             |   | No        |                     |   |
|         |   | F1     |             |   | adverse   |                     |   |
|         |   | f      |             |   | treatmen  |                     |   |
|         |   | emales |             |   | t-related |                     |   |
|         |   | 0,     |             |   | effect on |                     |   |
|         |   | 0.77,  |             |   | rep       |                     |   |
|         |   | 77.17, |             |   | roductive |                     |   |
|         |   | 7      |             |   | p         |                     |   |
|         |   | 65.20, |             |   | arameters |                     |   |
|         |   | 1      |             |   | up to and |                     |   |
|         |   | 559.65 |             |   | including |                     |   |
|         |   | mg/kg  |             |   | 20000 ppm |                     |   |
|         |   | /day\] |             |   | (HDT)     |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | ac     |             |   | **Of      |                     |   |
|         |   | ceptab |             |   | fspring** |                     |   |
|         |   | le/gui |             |   | **NOAEL** |                     |   |
|         |   | deline |             |   | = 10000   |                     |   |
|         |   |        |             |   | ppm       |                     |   |
|         |   |        |             |   | \[males   |                     |   |
|         |   |        |             |   | 593.      |                     |   |
|         |   |        |             |   | 5/females |                     |   |
|         |   |        |             |   | 751.1     |                     |   |
|         |   |        |             |   | mg        |                     |   |
|         |   |        |             |   | /kg/day\] |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   |        |             |   | **        |                     |   |
|         |   |        |             |   | Offspring |                     |   |
|         |   |        |             |   | LOAEL** = |                     |   |
|         |   |        |             |   | 20000 ppm |                     |   |
|         |   |        |             |   | \[males   |                     |   |
|         |   |        |             |   | 1212.     |                     |   |
|         |   |        |             |   | 1/females |                     |   |
|         |   |        |             |   | 1484.9    |                     |   |
|         |   |        |             |   | mg/       |                     |   |
|         |   |        |             |   | kg/day\], |                     |   |
|         |   |        |             |   | based on  |                     |   |
|         |   |        |             |   | decreased |                     |   |
|         |   |        |             |   | F1        |                     |   |
|         |   |        |             |   | postnatal |                     |   |
|         |   |        |             |   | survival  |                     |   |
|         |   |        |             |   | and       |                     |   |
|         |   |        |             |   | reduced   |                     |   |
|         |   |        |             |   | pup body  |                     |   |
|         |   |        |             |   | weights   |                     |   |
|         |   |        |             |   | in both   |                     |   |
|         |   |        |             |   | ge        |                     |   |
|         |   |        |             |   | nerations |                     |   |
|         |   |        |             |   | \[both    |                     |   |
|         |   |        |             |   | sexes\].  |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 87      |   | MRID   |             |   | *         |                     |   |
| 0.4100a |   | 42     |             |   | *Systemic |                     |   |
|         |   | 238104 |             |   | toxicity  |                     |   |
| Chronic |   | (1992) |             |   | NOAEL =** |                     |   |
| t       |   |        |             |   | 20000 ppm |                     |   |
| oxicity |   | 0, 10, |             |   | \[males   |                     |   |
| rodents |   | 100,   |             |   | 80        |                     |   |
| (rat)   |   | 3000,  |             |   | 6/females |                     |   |
|         |   | 10000, |             |   | 1054      |                     |   |
|         |   | 20000  |             |   | m         |                     |   |
|         |   | ppm    |             |   | g/kg/day, |                     |   |
|         |   |        |             |   | highest   |                     |   |
|         |   | M 0,   |             |   | dose      |                     |   |
|         |   | 0.38,  |             |   | tested.   |                     |   |
|         |   | 3.87,  |             |   |           |                     |   |
|         |   | 115.6, |             |   |           |                     |   |
|         |   | 392.7, |             |   |           |                     |   |
|         |   | 805.7  |             |   |           |                     |   |
|         |   | mg/    |             |   |           |                     |   |
|         |   | kg/day |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | F 0,   |             |   |           |                     |   |
|         |   | 0.49,  |             |   |           |                     |   |
|         |   | 4.88,  |             |   |           |                     |   |
|         |   | 147.4, |             |   |           |                     |   |
|         |   | 494.0, |             |   |           |                     |   |
|         |   | 1054   |             |   |           |                     |   |
|         |   | mg/    |             |   |           |                     |   |
|         |   | kg/day |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | ac     |             |   |           |                     |   |
|         |   | ceptab |             |   |           |                     |   |
|         |   | le/gui |             |   |           |                     |   |
|         |   | deline |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 87      |   | MRID   |             |   | *         |                     |   |
| 0.4100b |   | 42779  |             |   | *Systemic |                     |   |
|         |   | 402/42 |             |   | toxicity  |                     |   |
| Chronic |   | 779401 |             |   | NOAEL** = |                     |   |
| t       |   | (19    |             |   | 1000 ppm  |                     |   |
| oxicity |   | 91-92) |             |   | \[males   |                     |   |
| no      |   |        |             |   | 31.6      |                     |   |
| nrodent |   | 0, 40, |             |   | 2/females |                     |   |
| (dogs)  |   | 1000,  |             |   | 39.54     |                     |   |
|         |   | 10000, |             |   | mg/kg/day |                     |   |
|         |   | or     |             |   |           |                     |   |
|         |   | 20000  |             |   | *         |                     |   |
|         |   | ppm    |             |   | *Systemic |                     |   |
|         |   |        |             |   | toxicity  |                     |   |
|         |   | \      |             |   | LOAEL** = |                     |   |
|         |   | [males |             |   | 10000 ppm |                     |   |
|         |   | 0,     |             |   | \[males   |                     |   |
|         |   | 1.56,  |             |   | 365.7     |                     |   |
|         |   | 31.62, |             |   | 2/females |                     |   |
|         |   | 3      |             |   | 357.13    |                     |   |
|         |   | 56.72, |             |   | mg/       |                     |   |
|         |   | or     |             |   | kg/day\], |                     |   |
|         |   | 726.65 |             |   | based on  |                     |   |
|         |   | mg/kg  |             |   | elevated  |                     |   |
|         |   | /day\] |             |   | serum     |                     |   |
|         |   |        |             |   | ch        |                     |   |
|         |   | \[f    |             |   | olesterol |                     |   |
|         |   | emales |             |   | values in |                     |   |
|         |   | 0,     |             |   | females,  |                     |   |
|         |   | 1.37,  |             |   | mucoid    |                     |   |
|         |   | 39.54, |             |   | feces in  |                     |   |
|         |   | 3      |             |   | females   |                     |   |
|         |   | 57.13, |             |   | and       |                     |   |
|         |   | 783.83 |             |   | bloody    |                     |   |
|         |   | mg/kg  |             |   | feces in  |                     |   |
|         |   | /day\] |             |   | both      |                     |   |
|         |   |        |             |   | sexes,    |                     |   |
|         |   | ac     |             |   | and       |                     |   |
|         |   | ceptab |             |   | minimal,  |                     |   |
|         |   | le/gui |             |   | focal     |                     |   |
|         |   | deline |             |   | va        |                     |   |
|         |   |        |             |   | cuolation |                     |   |
|         |   |        |             |   | of the    |                     |   |
|         |   |        |             |   | dorsal    |                     |   |
|         |   |        |             |   | medial    |                     |   |
|         |   |        |             |   | hi        |                     |   |
|         |   |        |             |   | ppocampus |                     |   |
|         |   |        |             |   | and/or    |                     |   |
|         |   |        |             |   | lateral   |                     |   |
|         |   |        |             |   | midbrain  |                     |   |
|         |   |        |             |   | in both   |                     |   |
|         |   |        |             |   | sexes.    |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | MRID   |             |   | see above |                     |   |
| 70.4200 |   | 42     |             |   | under     |                     |   |
|         |   | 238104 |             |   | 870.4100a |                     |   |
| C       |   | (1992) |             |   |           |                     |   |
| arcinog |   |        |             |   | There was |                     |   |
| enicity |   | 0, 10, |             |   | a         |                     |   |
| (rat)   |   | 100,   |             |   | possible  |                     |   |
|         |   | 3000,  |             |   | treatment |                     |   |
| Sprague |   | 10000, |             |   | related   |                     |   |
| -Dawley |   | 20000  |             |   | increased |                     |   |
|         |   | ppm    |             |   | incidence |                     |   |
|         |   |        |             |   | of        |                     |   |
|         |   | M 0,   |             |   | squamous  |                     |   |
|         |   | 0.38,  |             |   | cell      |                     |   |
|         |   | 3.87,  |             |   | carcinoma |                     |   |
|         |   | 115.6, |             |   | of the    |                     |   |
|         |   | 392.7, |             |   | fo        |                     |   |
|         |   | 805.7  |             |   | restomach |                     |   |
|         |   | mg/    |             |   | in M at   |                     |   |
|         |   | kg/day |             |   | 20000 ppm |                     |   |
|         |   |        |             |   | (HDT);    |                     |   |
|         |   | F 0,   |             |   | however,  |                     |   |
|         |   | 0.49,  |             |   | this is   |                     |   |
|         |   | 4.88,  |             |   | not       |                     |   |
|         |   | 147.4, |             |   | c         |                     |   |
|         |   | 494.0, |             |   | onsidered |                     |   |
|         |   | 1054   |             |   | toxico    |                     |   |
|         |   | mg/    |             |   | logically |                     |   |
|         |   | kg/day |             |   | relevant  |                     |   |
|         |   |        |             |   | to        |                     |   |
|         |   | ac     |             |   | humans.   |                     |   |
|         |   | ceptab |             |   |           |                     |   |
|         |   | le/gui |             |   | No        |                     |   |
|         |   | deline |             |   | treatmen  |                     |   |
|         |   |        |             |   | t-related |                     |   |
|         |   |        |             |   | d         |                     |   |
|         |   |        |             |   | ifference |                     |   |
|         |   |        |             |   | detected  |                     |   |
|         |   |        |             |   | in total  |                     |   |
|         |   |        |             |   | number    |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   |        |             |   | of        |                     |   |
|         |   |        |             |   | animals   |                     |   |
|         |   |        |             |   | with      |                     |   |
|         |   |        |             |   | tumors or |                     |   |
|         |   |        |             |   | in the    |                     |   |
|         |   |        |             |   | total     |                     |   |
|         |   |        |             |   | number of |                     |   |
|         |   |        |             |   | benign or |                     |   |
|         |   |        |             |   | malignant |                     |   |
|         |   |        |             |   | tumors at |                     |   |
|         |   |        |             |   | 52 or 104 |                     |   |
|         |   |        |             |   | weeks. No |                     |   |
|         |   |        |             |   | treatmen  |                     |   |
|         |   |        |             |   | t-related |                     |   |
|         |   |        |             |   | effect on |                     |   |
|         |   |        |             |   | the       |                     |   |
|         |   |        |             |   | time-     |                     |   |
|         |   |        |             |   | dependent |                     |   |
|         |   |        |             |   | o         |                     |   |
|         |   |        |             |   | ccurrence |                     |   |
|         |   |        |             |   | of        |                     |   |
|         |   |        |             |   | tumo      |                     |   |
|         |   |        |             |   | r-bearing |                     |   |
|         |   |        |             |   | animals.  |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   |        |             |   | **Not     |                     |   |
|         |   |        |             |   | Likely to |                     |   |
|         |   |        |             |   | be        |                     |   |
|         |   |        |             |   | Car       |                     |   |
|         |   |        |             |   | cinogenic |                     |   |
|         |   |        |             |   | to        |                     |   |
|         |   |        |             |   | Humans**  |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | MRID   |             |   | *         |                     |   |
| 70.4300 |   | 43     |             |   | *Systemic |                     |   |
|         |   | 128603 |             |   | toxicity  |                     |   |
| C       |   | (1991) |             |   | NOAEL** = |                     |   |
| arcinog |   |        |             |   | 7000 ppm  |                     |   |
| enicity |   | 0, 7,  |             |   | \[males   |                     |   |
| (mouse) |   | 70,    |             |   | 91        |                     |   |
|         |   | 1000,  |             |   | 1/females |                     |   |
| CD-1    |   | 3500,  |             |   | 1073      |                     |   |
| \[C     |   | 7000   |             |   | mg/       |                     |   |
| rl:CD-1 |   | ppm    |             |   | kg/day\], |                     |   |
|         |   |        |             |   | the       |                     |   |
| (I      |   | \      |             |   | highest   |                     |   |
| CR)Br\] |   | [males |             |   | dose      |                     |   |
|         |   | 0,     |             |   | tested.   |                     |   |
|         |   | 0.91,  |             |   |           |                     |   |
|         |   | 9.01,  |             |   | There was |                     |   |
|         |   | 1      |             |   | no        |                     |   |
|         |   | 30.81, |             |   | treatmen  |                     |   |
|         |   | 4      |             |   | t-related |                     |   |
|         |   | 50.72, |             |   | increase  |                     |   |
|         |   | 911.77 |             |   | in tumors |                     |   |
|         |   | mg/kg  |             |   | of any    |                     |   |
|         |   | /day\] |             |   | type in   |                     |   |
|         |   |        |             |   | either    |                     |   |
|         |   | \[f    |             |   | sex at    |                     |   |
|         |   | emales |             |   | dose      |                     |   |
|         |   | 0,     |             |   | levels up |                     |   |
|         |   | 1.08,  |             |   | to an     |                     |   |
|         |   | 10.66, |             |   | including |                     |   |
|         |   | 1      |             |   | 7000 ppm, |                     |   |
|         |   | 54.08, |             |   | the HDT   |                     |   |
|         |   | 5      |             |   |           |                     |   |
|         |   | 38.73, |             |   | **Not     |                     |   |
|         |   | 1      |             |   | Likely to |                     |   |
|         |   | 073.42 |             |   | be        |                     |   |
|         |   | mg/kg  |             |   | Car       |                     |   |
|         |   | /day\] |             |   | cinogenic |                     |   |
|         |   |        |             |   | to        |                     |   |
|         |   | ac     |             |   | Humans**  |                     |   |
|         |   | ceptab |             |   |           |                     |   |
|         |   | le/gui |             |   |           |                     |   |
|         |   | deline |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | 46     |             |   | **N       |                     |   |
| 70.5100 |   | 809308 |             |   | egative** |                     |   |
|         |   | (2001) |             |   | ac        |                     |   |
| Ba      |   |        |             |   | ceptable/ |                     |   |
| cterial |   | *Salm  |             |   | guideline |                     |   |
| Reverse |   | onella |             |   |           |                     |   |
| Gene    |   | typhim |             |   |           |                     |   |
| M       |   | urium* |             |   |           |                     |   |
| utation |   |        |             |   |           |                     |   |
| Assay   |   | s      |             |   |           |                     |   |
|         |   | trains |             |   |           |                     |   |
|         |   | TA98,  |             |   |           |                     |   |
|         |   | TA100, |             |   |           |                     |   |
|         |   | TA102, |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | TA1535 |             |   |           |                     |   |
|         |   | and    |             |   |           |                     |   |
|         |   | TA1537 |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | *Esche |             |   |           |                     |   |
|         |   | richia |             |   |           |                     |   |
|         |   | coli*  |             |   |           |                     |   |
|         |   | strain |             |   |           |                     |   |
|         |   | WP2    |             |   |           |                     |   |
|         |   | *uvr*A |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | 0,     |             |   |           |                     |   |
|         |   | 312.5, |             |   |           |                     |   |
|         |   | 625,   |             |   |           |                     |   |
|         |   | 1250,  |             |   |           |                     |   |
|         |   | 2500,  |             |   |           |                     |   |
|         |   | or     |             |   |           |                     |   |
|         |   | 5000   |             |   |           |                     |   |
|         |   | µg     |             |   |           |                     |   |
|         |   | /plate |             |   |           |                     |   |
|         |   | ± S9   |             |   |           |                     |   |
|         |   | met    |             |   |           |                     |   |
|         |   | abolic |             |   |           |                     |   |
|         |   | acti   |             |   |           |                     |   |
|         |   | vation |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | Ac     |             |   |           |                     |   |
|         |   | ceptab |             |   |           |                     |   |
|         |   | le/gui |             |   |           |                     |   |
|         |   | deline |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | 43     |             |   | **N       |                     |   |
| 70.5300 |   | 128605 |             |   | egative** |                     |   |
|         |   | (1993  |             |   | ac        |                     |   |
| Mouse   |   |        |             |   | ceptable/ |                     |   |
| L       |   | Mouse  |             |   | guideline |                     |   |
| ymphoma |   | ly     |             |   |           |                     |   |
| C       |   | mphoma |             |   |           |                     |   |
| ells/Ma |   |        |             |   |           |                     |   |
| mmalian |   | L5178Y |             |   |           |                     |   |
| Act     |   | cells  |             |   |           |                     |   |
| ivation |   | (at    |             |   |           |                     |   |
| Gene    |   | the    |             |   |           |                     |   |
| Forward |   |        |             |   |           |                     |   |
| M       |   | thy    |             |   |           |                     |   |
| utation |   | midine |             |   |           |                     |   |
| Assay   |   | kinase |             |   |           |                     |   |
| at      |   | locus) |             |   |           |                     |   |
| TK^+/-^ |   |        |             |   |           |                     |   |
| locus   |   | 0,     |             |   |           |                     |   |
|         |   | 7.54,  |             |   |           |                     |   |
|         |   | 30.16, |             |   |           |                     |   |
|         |   | 1      |             |   |           |                     |   |
|         |   | 20.62, |             |   |           |                     |   |
|         |   | or     |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | 1930   |             |   |           |                     |   |
|         |   | µg/mL  |             |   |           |                     |   |
|         |   | for 4  |             |   |           |                     |   |
|         |   | hours  |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | ± S9   |             |   |           |                     |   |
|         |   | met    |             |   |           |                     |   |
|         |   | abolic |             |   |           |                     |   |
|         |   | acti   |             |   |           |                     |   |
|         |   | vation |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | 41     |             |   | **N       |                     |   |
| 70.5395 |   | 563926 |             |   | egative** |                     |   |
|         |   | (1989) |             |   | ac        |                     |   |
| Str     |   |        |             |   | ceptable/ |                     |   |
| uctural |   | 42     |             |   | guideline |                     |   |
| chro    |   | 081402 |             |   |           |                     |   |
| mosomal |   | (1991) |             |   | Si        |                     |   |
| abe     |   |        |             |   | gnificant |                     |   |
| rration |   | 41     |             |   | increased |                     |   |
| test -  |   | 869527 |             |   | frequency |                     |   |
| Micro   |   | (1991) |             |   | of        |                     |   |
| nucleus |   |        |             |   | micro     |                     |   |
| Test    |   | M and  |             |   | nucleated |                     |   |
| Mouse   |   | F      |             |   | poly      |                     |   |
|         |   | mouse  |             |   | chromatic |                     |   |
|         |   | bone   |             |   | ery       |                     |   |
|         |   | marrow |             |   | throcytes |                     |   |
|         |   | cells  |             |   | in M and  |                     |   |
|         |   | (e     |             |   | sexes     |                     |   |
|         |   | rythro |             |   | combined  |                     |   |
|         |   | cytes) |             |   | at 48 h   |                     |   |
|         |   |        |             |   | in the    |                     |   |
|         |   | 0,     |             |   | initial   |                     |   |
|         |   | 1000,  |             |   | assay;    |                     |   |
|         |   | 2000,  |             |   | however,  |                     |   |
|         |   | or     |             |   | values    |                     |   |
|         |   | 4000   |             |   | were      |                     |   |
|         |   | mg/kg  |             |   | within    |                     |   |
|         |   | bw     |             |   | h         |                     |   |
|         |   | (sac   |             |   | istorical |                     |   |
|         |   | rifice |             |   | control   |                     |   |
|         |   | at 16, |             |   | range and |                     |   |
|         |   | 24,    |             |   | not       |                     |   |
|         |   | and 48 |             |   | observed  |                     |   |
|         |   | h)     |             |   | in the    |                     |   |
|         |   |        |             |   | con       |                     |   |
|         |   | I      |             |   | firmatory |                     |   |
|         |   | nitial |             |   | assay     |                     |   |
|         |   | assay: |             |   |           |                     |   |
|         |   | 0 or   |             |   | at 3000   |                     |   |
|         |   | 3000   |             |   | mg/kg bw  |                     |   |
|         |   | mg/kg  |             |   | at 48 h . |                     |   |
|         |   | bw     |             |   | In this   |                     |   |
|         |   | (sac   |             |   | study     |                     |   |
|         |   | rifice |             |   | possible  |                     |   |
|         |   | at 16, |             |   | weak      |                     |   |
|         |   | 24,    |             |   | c         |                     |   |
|         |   | and 48 |             |   | lastogen, |                     |   |
|         |   | h)     |             |   | however,  |                     |   |
|         |   |        |             |   | weight of |                     |   |
|         |   | Confir |             |   | evidence  |                     |   |
|         |   | matory |             |   | suggests  |                     |   |
|         |   | assay: |             |   |           |                     |   |
|         |   | 0,     |             |   | C         |                     |   |
|         |   | 750,   |             |   | GA-163935 |                     |   |
|         |   |        |             |   | not       |                     |   |
|         |   | 1500,  |             |   | likely    |                     |   |
|         |   | or     |             |   | cla       |                     |   |
|         |   | 3000   |             |   | stogenic. |                     |   |
|         |   | mg/kg  |             |   |           |                     |   |
|         |   | bw     |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | (sac   |             |   |           |                     |   |
|         |   | rifice |             |   |           |                     |   |
|         |   | at 48  |             |   |           |                     |   |
|         |   | h)     |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | 41     |             |   | **N       |                     |   |
| 70.5550 |   | 604205 |             |   | egative** |                     |   |
|         |   | (1987) |             |   | ac        |                     |   |
| Other   |   |        |             |   | ceptable/ |                     |   |
| Genot   |   | 41     |             |   | guideline |                     |   |
| oxicity |   | 869528 |             |   |           |                     |   |
|         |   | (1991) |             |   |           |                     |   |
| *In     |   |        |             |   |           |                     |   |
| vitro*  |   | Preli  |             |   |           |                     |   |
| UDS in  |   | minary |             |   |           |                     |   |
| Primary |   | cytoto |             |   |           |                     |   |
| Rat     |   | xicity |             |   |           |                     |   |
| Hepa    |   |        |             |   |           |                     |   |
| tocytes |   | assay: |             |   |           |                     |   |
|         |   | 0, 5,  |             |   |           |                     |   |
|         |   | 10,    |             |   |           |                     |   |
|         |   | 21,    |             |   |           |                     |   |
|         |   | 41,    |             |   |           |                     |   |
|         |   | 82,    |             |   |           |                     |   |
|         |   | 164,   |             |   |           |                     |   |
|         |   | 328,   |             |   |           |                     |   |
|         |   | 656,   |             |   |           |                     |   |
|         |   | 1313,  |             |   |           |                     |   |
|         |   | 2625,  |             |   |           |                     |   |
|         |   | or     |             |   |           |                     |   |
|         |   | 5250   |             |   |           |                     |   |
|         |   | μg/mL  |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | I      |             |   |           |                     |   |
|         |   | nitial |             |   |           |                     |   |
|         |   | UDS    |             |   |           |                     |   |
|         |   | assay: |             |   |           |                     |   |
|         |   | 0,     |             |   |           |                     |   |
|         |   | 0.8,   |             |   |           |                     |   |
|         |   | 4, 20, |             |   |           |                     |   |
|         |   | 100,   |             |   |           |                     |   |
|         |   | 200,   |             |   |           |                     |   |
|         |   | or 400 |             |   |           |                     |   |
|         |   | μg/mL; |             |   |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | Confir |             |   |           |                     |   |
|         |   | matory |             |   |           |                     |   |
|         |   | UDS    |             |   |           |                     |   |
|         |   | assay: |             |   |           |                     |   |
|         |   | 0, 4,  |             |   |           |                     |   |
|         |   | 20,    |             |   |           |                     |   |
|         |   | 100,   |             |   |           |                     |   |
|         |   | 150,   |             |   |           |                     |   |
|         |   | 200,   |             |   |           |                     |   |
|         |   | 300,   |             |   |           |                     |   |
|         |   | 400,   |             |   |           |                     |   |
|         |   | or 500 |             |   |           |                     |   |
|         |   | μg/mL  |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 87      |   | No     |             |   |           |                     |   |
| 0.6200a |   | study  |             |   |           |                     |   |
|         |   | ava    |             |   |           |                     |   |
| Acute   |   | ilable |             |   |           |                     |   |
| neurot  |   |        |             |   |           |                     |   |
| oxicity |   |        |             |   |           |                     |   |
| sc      |   |        |             |   |           |                     |   |
| reening |   |        |             |   |           |                     |   |
| battery |   |        |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 87      |   | No     |             |   |           |                     |   |
| 0.6200b |   | study  |             |   |           |                     |   |
|         |   | ava    |             |   |           |                     |   |
| Sub     |   | ilable |             |   |           |                     |   |
| chronic |   |        |             |   |           |                     |   |
| neurot  |   |        |             |   |           |                     |   |
| oxicity |   |        |             |   |           |                     |   |
| sc      |   |        |             |   |           |                     |   |
| reening |   |        |             |   |           |                     |   |
| battery |   |        |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | No     |             |   |           |                     |   |
| 70.6300 |   | study  |             |   |           |                     |   |
|         |   | ava    |             |   |           |                     |   |
| Develo  |   | ilable |             |   |           |                     |   |
| pmental |   |        |             |   |           |                     |   |
| neurot  |   |        |             |   |           |                     |   |
| oxicity |   |        |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | MRID   |             |   | Rapidly,  |                     |   |
| 70.7485 |   | 41     |             |   | ex        |                     |   |
|         |   | 563927 |             |   | tensively |                     |   |
| Met     |   | (1990) |             |   | absorbed  |                     |   |
| abolism |   |        |             |   | (both     |                     |   |
| and     |   | i\. v. |             |   | sexes) w/ |                     |   |
| ph      |   | 0.91   |             |   | \>95% of  |                     |   |
| armacok |   | mg/kg  |             |   | adm       |                     |   |
| inetics |   | \[     |             |   | inistered |                     |   |
|         |   | ^14^C- |             |   | dose      |                     |   |
| (rat)   |   | CGA-16 |             |   | being     |                     |   |
|         |   | 3935\] |             |   | absorbed; |                     |   |
|         |   |        |             |   | little    |                     |   |
|         |   | oral   |             |   | potential |                     |   |
|         |   | 0.97   |             |   | for       |                     |   |
|         |   | or 166 |             |   | accu      |                     |   |
|         |   | mg/kg  |             |   | mulation; |                     |   |
|         |   | \[     |             |   | \>85%     |                     |   |
|         |   | ^14^C- |             |   | e         |                     |   |
|         |   | CGA-16 |             |   | liminated |                     |   |
|         |   | 3935\] |             |   | w/in 12   |                     |   |
|         |   |        |             |   | hours via |                     |   |
|         |   | oral   |             |   | urine; 2% |                     |   |
|         |   | 0.97   |             |   | via feces |                     |   |
|         |   | mg/    |             |   | w/in 24   |                     |   |
|         |   | kg/day |             |   | hours;    |                     |   |
|         |   | \[     |             |   | very      |                     |   |
|         |   | CGA-16 |             |   | little or |                     |   |
|         |   | 3935\] |             |   | no        |                     |   |
|         |   | for 14 |             |   | biliary   |                     |   |
|         |   | days   |             |   | e         |                     |   |
|         |   | fo     |             |   | xcretion; |                     |   |
|         |   | llowed |             |   | no sex    |                     |   |
|         |   | by     |             |   | di        |                     |   |
|         |   | 0.97   |             |   | fference; |                     |   |
|         |   | mg/kg  |             |   | free acid |                     |   |
|         |   | \[     |             |   | d         |                     |   |
|         |   | ^14^C- |             |   | erivative |                     |   |
|         |   | CGA-16 |             |   | resulting |                     |   |
|         |   | 3935\] |             |   | from      |                     |   |
|         |   |        |             |   | h         |                     |   |
|         |   | ac     |             |   | ydrolysis |                     |   |
|         |   | ceptab |             |   | of the    |                     |   |
|         |   | le/gui |             |   | ester     |                     |   |
|         |   | deline |             |   | bond of   |                     |   |
|         |   |        |             |   | parent    |                     |   |
|         |   |        |             |   | compound  |                     |   |
|         |   |        |             |   | is major  |                     |   |
|         |   |        |             |   | component |                     |   |
|         |   |        |             |   | in urine  |                     |   |
|         |   |        |             |   | and       |                     |   |
|         |   |        |             |   | feces;    |                     |   |
|         |   |        |             |   | only      |                     |   |
|         |   |        |             |   | other     |                     |   |
|         |   |        |             |   | component |                     |   |
|         |   |        |             |   | was       |                     |   |
|         |   |        |             |   | parent,   |                     |   |
|         |   |        |             |   | found     |                     |   |
|         |   |        |             |   | only in   |                     |   |
|         |   |        |             |   | feces.    |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| 8       |   | MRID   |             |   | Recovery  |                     |   |
| 70.7600 |   | 42     |             |   | of        |                     |   |
|         |   | 238105 |             |   | applied   |                     |   |
| Dermal  |   | (1990) |             |   | dose      |                     |   |
| pene    |   |        |             |   | 97%-117%; |                     |   |
| tration |   | 0,     |             |   | most      |                     |   |
|         |   | 0.01,  |             |   | recovered |                     |   |
| (rat)   |   | 0.1,   |             |   | in skin   |                     |   |
|         |   | or 1.0 |             |   | washes    |                     |   |
|         |   | mg     |             |   | and       |                     |   |
|         |   | /cm^2^ |             |   | urine;    |                     |   |
|         |   | \[     |             |   | \<1% in   |                     |   |
|         |   | ^14^C- |             |   | blood and |                     |   |
|         |   | CGA-16 |             |   | feces;    |                     |   |
|         |   | 3935\] |             |   | excreted  |                     |   |
|         |   |        |             |   | in urine  |                     |   |
|         |   | single |             |   | within 2  |                     |   |
|         |   | dermal |             |   | hours of  |                     |   |
|         |   | dose   |             |   | dose      |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   | ac     |             |   | 56.5%     |                     |   |
|         |   | ceptab |             |   | absorbed, |                     |   |
|         |   | le/gui |             |   | with 21%  |                     |   |
|         |   | deline |             |   | a         |                     |   |
|         |   |        |             |   | ssociated |                     |   |
|         |   |        |             |   | with      |                     |   |
|         |   |        |             |   | ap        |                     |   |
|         |   |        |             |   | plication |                     |   |
|         |   |        |             |   | site      |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   |        |             |   | dermal    |                     |   |
|         |   |        |             |   | a         |                     |   |
|         |   |        |             |   | bsorption |                     |   |
|         |   |        |             |   | factor    |                     |   |
|         |   |        |             |   | 77.5%     |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| **Table |   |        |             |   |           |                     |   |
| 7.      |   |        |             |   |           |                     |   |
| Toxico  |   |        |             |   |           |                     |   |
| logical |   |        |             |   |           |                     |   |
| Doses   |   |        |             |   |           |                     |   |
| and     |   |        |             |   |           |                     |   |
| En      |   |        |             |   |           |                     |   |
| dpoints |   |        |             |   |           |                     |   |
| for     |   |        |             |   |           |                     |   |
| Tr      |   |        |             |   |           |                     |   |
| inexapa |   |        |             |   |           |                     |   |
| c-ethyl |   |        |             |   |           |                     |   |
| for Use |   |        |             |   |           |                     |   |
| in      |   |        |             |   |           |                     |   |
| Human   |   |        |             |   |           |                     |   |
| Health  |   |        |             |   |           |                     |   |
| Risk    |   |        |             |   |           |                     |   |
| Assessm |   |        |             |   |           |                     |   |
| ents.** |   |        |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| **Expo  | * |        | **Uncer     | * |           | **Study and         |   |
| sure/** | * |        | tainty/FQPA | * |           | Toxicological       |   |
|         | P |        | Safety      | R |           | Effects**           |   |
| **Sce   | o |        | Factors**   | f |           |                     |   |
| nario** | i |        |             | D |           |                     |   |
|         | n |        |             | , |           |                     |   |
|         | t |        |             | P |           |                     |   |
|         | o |        |             | A |           |                     |   |
|         | f |        |             | D |           |                     |   |
|         | D |        |             | , |           |                     |   |
|         | e |        |             | L |           |                     |   |
|         | p |        |             | e |           |                     |   |
|         | a |        |             | v |           |                     |   |
|         | r |        |             | e |           |                     |   |
|         | t |        |             | l |           |                     |   |
|         | u |        |             | o |           |                     |   |
|         | r |        |             | f |           |                     |   |
|         | e |        |             | C |           |                     |   |
|         | * |        |             | o |           |                     |   |
|         | * |        |             | n |           |                     |   |
|         |   |        |             | c |           |                     |   |
|         |   |        |             | e |           |                     |   |
|         |   |        |             | r |           |                     |   |
|         |   |        |             | n |           |                     |   |
|         |   |        |             | f |           |                     |   |
|         |   |        |             | o |           |                     |   |
|         |   |        |             | r |           |                     |   |
|         |   |        |             | R |           |                     |   |
|         |   |        |             | i |           |                     |   |
|         |   |        |             | s |           |                     |   |
|         |   |        |             | k |           |                     |   |
|         |   |        |             | A |           |                     |   |
|         |   |        |             | s |           |                     |   |
|         |   |        |             | s |           |                     |   |
|         |   |        |             | e |           |                     |   |
|         |   |        |             | s |           |                     |   |
|         |   |        |             | s |           |                     |   |
|         |   |        |             | m |           |                     |   |
|         |   |        |             | e |           |                     |   |
|         |   |        |             | n |           |                     |   |
|         |   |        |             | t |           |                     |   |
|         |   |        |             | * |           |                     |   |
|         |   |        |             | * |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| Acute   | N |        |             |   |           |                     |   |
| Dietary | o |        |             |   |           |                     |   |
| (       | a |        |             |   |           |                     |   |
| General | p |        |             |   |           |                     |   |
| Popu    | p |        |             |   |           |                     |   |
| lation, | r |        |             |   |           |                     |   |
| in      | o |        |             |   |           |                     |   |
| cluding | p |        |             |   |           |                     |   |
| Infants | r |        |             |   |           |                     |   |
| and     | i |        |             |   |           |                     |   |
| Ch      | a |        |             |   |           |                     |   |
| ildren) | t |        |             |   |           |                     |   |
|         | e |        |             |   |           |                     |   |
|         | e |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | d |        |             |   |           |                     |   |
|         | p |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | f |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | u |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | d |        |             |   |           |                     |   |
|         | f |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | r |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | h |        |             |   |           |                     |   |
|         | e |        |             |   |           |                     |   |
|         | g |        |             |   |           |                     |   |
|         | e |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | e |        |             |   |           |                     |   |
|         | r |        |             |   |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | l |        |             |   |           |                     |   |
|         | p |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | p |        |             |   |           |                     |   |
|         | u |        |             |   |           |                     |   |
|         | l |        |             |   |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | ( |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | f |        |             |   |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | s |        |             |   |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | d |        |             |   |           |                     |   |
|         | c |        |             |   |           |                     |   |
|         | h |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | l |        |             |   |           |                     |   |
|         | d |        |             |   |           |                     |   |
|         | r |        |             |   |           |                     |   |
|         | e |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | ) |        |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| Acute   | N |        | UF~A~= 10x  | A |           | *Developmental      |   |
| Dietary | O |        |             | c |           | rabbit study*       |   |
|         | A |        | UF~H~ = 10x | u |           |                     |   |
| (       | E |        |             | t |           | LOAEL = 360 mg/kg,  |   |
| Females | L |        | FQPA SF     | e |           | based on a decrease |   |
| 13-49   | = |        | (UF~DB~)=   | R |           | in mean number of   |   |
| years   | 6 |        | 1x          | f |           | fetuses/litter and  |   |
| of age) | 0 |        |             | D |           | an increase in      |   |
|         | m |        |             | = |           | post-implantation   |   |
|         | g |        |             | 0 |           | loss                |   |
|         | / |        |             | . |           |                     |   |
|         | k |        |             | 6 |           |                     |   |
|         | g |        |             | m |           |                     |   |
|         |   |        |             | g |           |                     |   |
|         |   |        |             | / |           |                     |   |
|         |   |        |             | k |           |                     |   |
|         |   |        |             | g |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   |        |             | a |           |                     |   |
|         |   |        |             | P |           |                     |   |
|         |   |        |             | A |           |                     |   |
|         |   |        |             | D |           |                     |   |
|         |   |        |             | = |           |                     |   |
|         |   |        |             | 0 |           |                     |   |
|         |   |        |             | . |           |                     |   |
|         |   |        |             | 6 |           |                     |   |
|         |   |        |             | m |           |                     |   |
|         |   |        |             | g |           |                     |   |
|         |   |        |             | / |           |                     |   |
|         |   |        |             | k |           |                     |   |
|         |   |        |             | g |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| Chronic | N |        | UF~A~= 10x  | C |           | *Chronic oral       |   |
| Dietary | O |        |             | h |           | toxicity study -    |   |
| (All    | A |        | UF~H~ = 10x | r |           | dog*                |   |
| Popul   | E |        |             | o |           |                     |   |
| ations) | L |        | FQPA SF     | n |           | LOAEL = 357         |   |
|         | = |        | (UF~DB~)=   | i |           | mg/kg/day, based on |   |
|         | 3 |        | 1x          | c |           | elevated serum      |   |
|         | 1 |        |             | R |           | cholesterol values  |   |
|         | . |        |             | f |           | in females, mucoid  |   |
|         | 6 |        |             | D |           | feces in females    |   |
|         | m |        |             | = |           | and bloody feces in |   |
|         | g |        |             | 0 |           | both sexes, and     |   |
|         | / |        |             | . |           | minimal, focal      |   |
|         | k |        |             | 3 |           | vacuolation of the  |   |
|         | g |        |             | 2 |           | dorsal medial       |   |
|         | / |        |             |   |           | hippocampus and/or  |   |
|         | d |        |             | m |           | lateral midbrain in |   |
|         | a |        |             | g |           | both sexes          |   |
|         | y |        |             | / |           |                     |   |
|         |   |        |             | k |           |                     |   |
|         |   |        |             | g |           |                     |   |
|         |   |        |             | / |           |                     |   |
|         |   |        |             | d |           |                     |   |
|         |   |        |             | a |           |                     |   |
|         |   |        |             | y |           |                     |   |
|         |   |        |             |   |           |                     |   |
|         |   |        |             | c |           |                     |   |
|         |   |        |             | P |           |                     |   |
|         |   |        |             | A |           |                     |   |
|         |   |        |             | D |           |                     |   |
|         |   |        |             | = |           |                     |   |
|         |   |        |             | 0 |           |                     |   |
|         |   |        |             | . |           |                     |   |
|         |   |        |             | 3 |           |                     |   |
|         |   |        |             | 2 |           |                     |   |
|         |   |        |             | m |           |                     |   |
|         |   |        |             | g |           |                     |   |
|         |   |        |             | / |           |                     |   |
|         |   |        |             | k |           |                     |   |
|         |   |        |             | g |           |                     |   |
|         |   |        |             | / |           |                     |   |
|         |   |        |             | d |           |                     |   |
|         |   |        |             | a |           |                     |   |
|         |   |        |             | y |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| Inc     | N |        | UF~A~= 10x  | R |           | *Multi-generation   |   |
| idental | O |        |             | e |           | reproduction study* |   |
| Oral    | A |        | UF~H~ = 10x | s |           |                     |   |
| (All    | E |        |             | i |           | LOAEL = 1212        |   |
| Dur     | L |        | FQPA SF     | d |           | mg/kg/day, based on |   |
| ations) | = |        | (UF~DB~)=   | e |           | decreased F1        |   |
|         | 5 |        | 1x          | n |           | postnatal survival  |   |
|         | 9 |        |             | t |           | and reduced pup     |   |
|         | 4 |        |             | i |           | body                |   |
|         | m |        |             | a |           | weight/body-weight  |   |
|         | g |        |             | l |           | gain in both        |   |
|         | / |        |             | L |           | generations (both   |   |
|         | k |        |             | O |           | sexes)              |   |
|         | g |        |             | C |           |                     |   |
|         | / |        |             | f |           |                     |   |
|         | d |        |             | o |           |                     |   |
|         | a |        |             | r |           |                     |   |
|         | y |        |             | M |           |                     |   |
|         |   |        |             | O |           |                     |   |
|         |   |        |             | E |           |                     |   |
|         |   |        |             | = |           |                     |   |
|         |   |        |             | 1 |           |                     |   |
|         |   |        |             | 0 |           |                     |   |
|         |   |        |             | 0 |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| Sho     | N |        | UF~A~= 10x  | R |           | *Developmental      |   |
| rt-Term | O |        |             | e |           | rabbit study*       |   |
| Dermal  | A |        | UF~H~ = 10x | s |           |                     |   |
| &       | E |        |             | i |           | LOAEL = 360 mg/kg,  |   |
| Inh     | L |        | FQPA SF     | d |           | based on a decrease |   |
| alation | = |        | (UF~DB~)=   | e |           | in mean number of   |   |
|         | 6 |        | 1x          | n |           | fetuses/litter and  |   |
| (1-30   | 0 |        |             | t |           | an increase in      |   |
| days)   | m |        |             | i |           | post-implantation   |   |
|         | g |        |             | a |           | loss                |   |
|         | / |        |             | l |           |                     |   |
|         | k |        |             | L |           |                     |   |
|         | g |        |             | O |           |                     |   |
|         | / |        |             | C |           |                     |   |
|         | d |        |             | f |           |                     |   |
|         | a |        |             | o |           |                     |   |
|         | y |        |             | r |           |                     |   |
|         |   |        |             | M |           |                     |   |
|         | D |        |             | O |           |                     |   |
|         | e |        |             | E |           |                     |   |
|         | r |        |             | = |           |                     |   |
|         | m |        |             | 1 |           |                     |   |
|         | a |        |             | 0 |           |                     |   |
|         | l |        |             | 0 |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | b |        |             | O |           |                     |   |
|         | s |        |             | c |           |                     |   |
|         | o |        |             | c |           |                     |   |
|         | r |        |             | u |           |                     |   |
|         | p |        |             | p |           |                     |   |
|         | t |        |             | a |           |                     |   |
|         | i |        |             | t |           |                     |   |
|         | o |        |             | i |           |                     |   |
|         | n |        |             | o |           |                     |   |
|         | r |        |             | n |           |                     |   |
|         | a |        |             | a |           |                     |   |
|         | t |        |             | l |           |                     |   |
|         | e |        |             | L |           |                     |   |
|         | = |        |             | O |           |                     |   |
|         | 7 |        |             | C |           |                     |   |
|         | 7 |        |             | f |           |                     |   |
|         | . |        |             | o |           |                     |   |
|         | 5 |        |             | r |           |                     |   |
|         | % |        |             | M |           |                     |   |
|         |   |        |             | O |           |                     |   |
|         | I |        |             | E |           |                     |   |
|         | n |        |             | = |           |                     |   |
|         | h |        |             | 1 |           |                     |   |
|         | a |        |             | 0 |           |                     |   |
|         | l |        |             | 0 |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | b |        |             |   |           |                     |   |
|         | s |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | r |        |             |   |           |                     |   |
|         | p |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | r |        |             |   |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | e |        |             |   |           |                     |   |
|         | = |        |             |   |           |                     |   |
|         | 1 |        |             |   |           |                     |   |
|         | 0 |        |             |   |           |                     |   |
|         | 0 |        |             |   |           |                     |   |
|         | % |        |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| Int     | N |        | UF~A~= 10x  | R |           | *Chronic oral       |   |
| ermedia | O |        |             | e |           | toxicity study -    |   |
| te-Term | A |        | UF~H~ = 10x | s |           | dog*                |   |
| Dermal  | E |        |             | i |           |                     |   |
| &       | L |        | FQPA SF     | d |           | LOAEL = 357         |   |
| Inh     | = |        | (UF~DB~)=   | e |           | mg/kg/day, based on |   |
| alation | 3 |        | 1x          | n |           | elevated serum      |   |
|         | 1 |        |             | t |           | cholesterol values  |   |
| (1-6    | . |        |             | i |           | in females, mucoid  |   |
| months) | 6 |        |             | a |           | feces in females    |   |
|         | m |        |             | l |           | and bloody feces in |   |
|         | g |        |             | L |           | both sexes, and     |   |
|         | / |        |             | O |           | minimal, focal      |   |
|         | k |        |             | C |           | vacuolation of the  |   |
|         | g |        |             | f |           | dorsal medial       |   |
|         | / |        |             | o |           | hippocampus and/or  |   |
|         | d |        |             | r |           | lateral midbrain in |   |
|         | a |        |             | M |           | both sexes          |   |
|         | y |        |             | O |           |                     |   |
|         |   |        |             | E |           |                     |   |
|         | D |        |             | = |           |                     |   |
|         | e |        |             | 1 |           |                     |   |
|         | r |        |             | 0 |           |                     |   |
|         | m |        |             | 0 |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | l |        |             | O |           |                     |   |
|         | a |        |             | c |           |                     |   |
|         | b |        |             | c |           |                     |   |
|         | s |        |             | u |           |                     |   |
|         | o |        |             | p |           |                     |   |
|         | r |        |             | a |           |                     |   |
|         | p |        |             | t |           |                     |   |
|         | t |        |             | i |           |                     |   |
|         | i |        |             | o |           |                     |   |
|         | o |        |             | n |           |                     |   |
|         | n |        |             | a |           |                     |   |
|         | r |        |             | l |           |                     |   |
|         | a |        |             | L |           |                     |   |
|         | t |        |             | O |           |                     |   |
|         | e |        |             | C |           |                     |   |
|         | = |        |             | f |           |                     |   |
|         | 7 |        |             | o |           |                     |   |
|         | 7 |        |             | r |           |                     |   |
|         | . |        |             | M |           |                     |   |
|         | 5 |        |             | O |           |                     |   |
|         | % |        |             | E |           |                     |   |
|         |   |        |             | = |           |                     |   |
|         | I |        |             | 1 |           |                     |   |
|         | n |        |             | 0 |           |                     |   |
|         | h |        |             | 0 |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | l |        |             |   |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | b |        |             |   |           |                     |   |
|         | s |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | r |        |             |   |           |                     |   |
|         | p |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | r |        |             |   |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | e |        |             |   |           |                     |   |
|         | = |        |             |   |           |                     |   |
|         | 1 |        |             |   |           |                     |   |
|         | 0 |        |             |   |           |                     |   |
|         | 0 |        |             |   |           |                     |   |
|         | % |        |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+
| Cancer  | C |        |             |   |           |                     |   |
| (oral,  | l |        |             |   |           |                     |   |
| dermal, | a |        |             |   |           |                     |   |
| inha    | s |        |             |   |           |                     |   |
| lation) | s |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | f |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | c |        |             |   |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | : |        |             |   |           |                     |   |
|         | " |        |             |   |           |                     |   |
|         | N |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | l |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | k |        |             |   |           |                     |   |
|         | e |        |             |   |           |                     |   |
|         | l |        |             |   |           |                     |   |
|         | y |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | b |        |             |   |           |                     |   |
|         | e |        |             |   |           |                     |   |
|         | C |        |             |   |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | r |        |             |   |           |                     |   |
|         | c |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | g |        |             |   |           |                     |   |
|         | e |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | i |        |             |   |           |                     |   |
|         | c |        |             |   |           |                     |   |
|         | t |        |             |   |           |                     |   |
|         | o |        |             |   |           |                     |   |
|         | H |        |             |   |           |                     |   |
|         | u |        |             |   |           |                     |   |
|         | m |        |             |   |           |                     |   |
|         | a |        |             |   |           |                     |   |
|         | n |        |             |   |           |                     |   |
|         | s |        |             |   |           |                     |   |
|         | " |        |             |   |           |                     |   |
+---------+---+--------+-------------+---+-----------+---------------------+---+

> []{.mark}

+--------+------+-------+------+-------+---------+----------+------+
| *      |      |       |      |       |         |          |      |
| *Table |      |       |      |       |         |          |      |
| 8.     |      |       |      |       |         |          |      |
| Non-   |      |       |      |       |         |          |      |
| cancer |      |       |      |       |         |          |      |
| Shor   |      |       |      |       |         |          |      |
| t-term |      |       |      |       |         |          |      |
| Exp    |      |       |      |       |         |          |      |
| osures |      |       |      |       |         |          |      |
| and    |      |       |      |       |         |          |      |
| Risks  |      |       |      |       |         |          |      |
| to     |      |       |      |       |         |          |      |
| Resid  |      |       |      |       |         |          |      |
| ential |      |       |      |       |         |          |      |
| Ha     |      |       |      |       |         |          |      |
| ndlers |      |       |      |       |         |          |      |
| from   |      |       |      |       |         |          |      |
| Trin   |      |       |      |       |         |          |      |
| exapac |      |       |      |       |         |          |      |
| -ethyl |      |       |      |       |         |          |      |
| Gr     |      |       |      |       |         |          |      |
| anules |      |       |      |       |         |          |      |
| A      |      |       |      |       |         |          |      |
| pplied |      |       |      |       |         |          |      |
| to     |      |       |      |       |         |          |      |
| T      |      |       |      |       |         |          |      |
| urf.** |      |       |      |       |         |          |      |
+--------+------+-------+------+-------+---------+----------+------+
| Ex     | App  | Appl. | D    | I     | Sho     | Sh       | T    |
| posure | lica | rate, | erm. | nhal. | rt-term | ort-term | otal |
|        | tion | max   | unit | unit  | dermal  | In       | Sh   |
| Sc     | E    | si    | exp  | exp   | ^3^     | halation | ort- |
| enario | quip | ngle, |      |       |         | ^4^      | term |
|        | ment | lb    | m    | mg/lb |         |          | MOE  |
|        |      | ai/A  | g/lb | a     |         |          | ^5^  |
|        |      |       | ai   | i.^2^ |         |          |      |
|        |      |       | .^1^ |       |         |          |      |
+--------+------+-------+------+-------+---------+----------+------+
| load   | b    | 0.88  | 0.68 | 0.    | Exp.    | Exp.     | 18   |
| ing/ap | road |       |      | 00091 | 0.0033  | 0.000006 | ,000 |
| plying | cast |       |      |       |         |          |      |
| gr     | spre |       |      |       |         |          |      |
| anules | ader |       |      |       |         |          |      |
+--------+------+-------+------+-------+---------+----------+------+
|        |      |       |      |       | MOE     | MOE      |      |
|        |      |       |      |       | 18,000  | 1.0E+07  |      |
+--------+------+-------+------+-------+---------+----------+------+

1\. & 2. Dermal value is for short pants and short sleeves (worst case
scenario). Both unit exposures are geometric means from ORETF Study OMA
003 (G. Bangs, April 30, 2001).

3\. Dermal exposure = \[unit exp \* appl. rate \* area treated/day
(0.5A) \* derm. absorp. rate (77.5%) \] / body wt. (70 kg). Short-term
dermal MOE = short-term dermal NOAEL (60 mg/kg/day) / dermal exposure.

4\. Inhal. exposure = \[unit exp \* appl. rate \* area treated/day
(0.5A) \* inhal. absorp. rate (100.0%) \] / body wt. (70 kg). Short-term
inhalation MOE = short-term inhalation NOAEL (60 mg/kg/day) / inhal.
exposure.

5\. Total MOE + 1/\[(1/dermal MOE) + (1/inhal. MOE)\]. The corresponding
LOC of MOE is 100.

+----------------+------------+------------+------------+------------+
| **Table 9.     |            |            |            |            |
| Po             |            |            |            |            |
| st-application |            |            |            |            |
| Short-term     |            |            |            |            |
| Risks to       |            |            |            |            |
| Adults,        |            |            |            |            |
| Youths, and    |            |            |            |            |
| Toddlers from  |            |            |            |            |
| Tr             |            |            |            |            |
| inexapac-ethyl |            |            |            |            |
| Applied to     |            |            |            |            |
| Residential    |            |            |            |            |
| Turf.**        |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Exposure       | Routes of  | Transfer   | Short-term | S          |
|                | Exposure   | c          | Exposures  | hort.-term |
| Scenario ^1^   |            | oefficient | (          | MOE ^4^    |
|                |            |            | mg/kg/day) |            |
|                |            | (cm^2^/hr) | ^3^        |            |
|                |            | ^2^        |            |            |
+----------------+------------+------------+------------+------------+
| Adults , high  | dermal     | 14,500     | 0.0182     | 330        |
| contact        |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Adults, mowing | dermal     | 3,400      | 0.0430     | 1,400      |
+----------------+------------+------------+------------+------------+
| Adults,        | dermal     | 500        | 0.0126     | 4,700      |
| golfing        |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Youth, mowing  | dermal     | 3,400      | 0.0661     | 910        |
+----------------+------------+------------+------------+------------+
| Youth, golfing | dermal     | 500        | 0.0194     | 3,100      |
+----------------+------------+------------+------------+------------+
| Toddlers, high | dermal     | 5,200      | 0.2628     | 230        |
| contact        |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Toddlers,      | incidental | NA         | 0.0130     | 46,000     |
| hand-to-mouth  | oral       |            |            |            |
+----------------+------------+------------+------------+------------+
| Toddlers,      | incidental | NA         | 0.0033     | 180,000    |
| object-to-     | oral       |            |            |            |
| mouth          |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Toddlers, soil | incidental | NA         | 0.0437     | 14,000     |
| ingestion      | oral       |            |            |            |
+----------------+------------+------------+------------+------------+

1\. Applicable scenarios were selected from Residential SOP Apr. 5, 2000
(Draft).

2\. Residential SOP 1997 (Draft).

3\. Algorithms are from Lowe, K.M., D334752, March 01, 2007. The max.
single appl. rate used was 0.88 lb ai/A (Table 2).

4\. Short-term MOE = short-term dermal NOAEL (60 mg/kg/day) / dermal
exposure or short-term incidental oral NOAEL (594 mg/kg/day) /
incidental ingestion.

> []{.mark}
>
> []{.mark}
>
> []{.mark}

+---+----------------------------+------------+-----------------------+
| * |                            |            |                       |
| * |                            |            |                       |
| T |                            |            |                       |
| a |                            |            |                       |
| b |                            |            |                       |
| l |                            |            |                       |
| e |                            |            |                       |
| 1 |                            |            |                       |
| 0 |                            |            |                       |
| . |                            |            |                       |
| T |                            |            |                       |
| r |                            |            |                       |
| i |                            |            |                       |
| n |                            |            |                       |
| e |                            |            |                       |
| x |                            |            |                       |
| a |                            |            |                       |
| p |                            |            |                       |
| a |                            |            |                       |
| c |                            |            |                       |
| - |                            |            |                       |
| e |                            |            |                       |
| t |                            |            |                       |
| h |                            |            |                       |
| y |                            |            |                       |
| l |                            |            |                       |
| : |                            |            |                       |
| O |                            |            |                       |
| c |                            |            |                       |
| c |                            |            |                       |
| u |                            |            |                       |
| p |                            |            |                       |
| a |                            |            |                       |
| t |                            |            |                       |
| i |                            |            |                       |
| o |                            |            |                       |
| n |                            |            |                       |
| a |                            |            |                       |
| l |                            |            |                       |
| a |                            |            |                       |
| n |                            |            |                       |
| d |                            |            |                       |
| R |                            |            |                       |
| e |                            |            |                       |
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| i |                            |            |                       |
| d |                            |            |                       |
| e |                            |            |                       |
| n |                            |            |                       |
| t |                            |            |                       |
| i |                            |            |                       |
| a |                            |            |                       |
| l |                            |            |                       |
| H |                            |            |                       |
| a |                            |            |                       |
| n |                            |            |                       |
| d |                            |            |                       |
| l |                            |            |                       |
| e |                            |            |                       |
| r |                            |            |                       |
| E |                            |            |                       |
| x |                            |            |                       |
| p |                            |            |                       |
| o |                            |            |                       |
| s |                            |            |                       |
| u |                            |            |                       |
| r |                            |            |                       |
| e |                            |            |                       |
| S |                            |            |                       |
| c |                            |            |                       |
| e |                            |            |                       |
| n |                            |            |                       |
| a |                            |            |                       |
| r |                            |            |                       |
| i |                            |            |                       |
| o |                            |            |                       |
| s |                            |            |                       |
| . |                            |            |                       |
| * |                            |            |                       |
| * |                            |            |                       |
+---+----------------------------+------------+-----------------------+
| S | Exposure                   | Max single | Comments              |
| c |                            | appl rate  |                       |
| e | Scenarios                  | lb ai/A    |                       |
| n |                            |            |                       |
| . |                            |            |                       |
| \ |                            |            |                       |
| # |                            |            |                       |
+---+----------------------------+------------+-----------------------+
|   | **[Grower/Commercial uses  |            |                       |
|   | on turf and grass grown    |            |                       |
|   | for seeds]{.smallcaps}**   |            |                       |
+---+----------------------------+------------+-----------------------+
| \ | **Mixing / Loading**       |            |                       |
| - |                            |            |                       |
| - |                            |            |                       |
+---+----------------------------+------------+-----------------------+
| 1 | open mixing/loading of EC  | 0.68       |                       |
|   | for BP, BS, HS, SG         |            |                       |
+---+----------------------------+------------+-----------------------+
| 2 | open mixing/loading of     | \"         |                       |
|   | WP/WSBs for BP, BS, HS, SG |            |                       |
+---+----------------------------+------------+-----------------------+
| \ | **Applying**               | \--        |                       |
| - |                            |            |                       |
| - |                            |            |                       |
+---+----------------------------+------------+-----------------------+
| 3 | applying ECs using         | 0.68       |                       |
|   | back-pack sprayer          |            |                       |
+---+----------------------------+------------+-----------------------+
| 4 | applying ECs using boom    | \"         |                       |
|   | sprayer                    |            |                       |
+---+----------------------------+------------+-----------------------+
| 5 | applying ECs using hand    | \"         |                       |
|   | gun                        |            |                       |
+---+----------------------------+------------+-----------------------+
| 6 | applying ECs using spray   | \"         |                       |
|   | gun                        |            |                       |
+---+----------------------------+------------+-----------------------+
| 7 | applying WP spray using    | \"         |                       |
|   | back-pack sprayer          |            |                       |
+---+----------------------------+------------+-----------------------+
| 8 | applying WP spray using    | \"         |                       |
|   | boom sprayer               |            |                       |
+---+----------------------------+------------+-----------------------+
| 9 | applying WP spray using    | \"         |                       |
|   | hand gun                   |            |                       |
+---+----------------------------+------------+-----------------------+
| 1 | applying WP spray using    | \"         |                       |
| 0 | spray gun                  |            |                       |
+---+----------------------------+------------+-----------------------+
| \ | **Mixing / Loading /       | \--        |                       |
| - | Applying**                 |            |                       |
| - |                            |            |                       |
+---+----------------------------+------------+-----------------------+
| 1 | open mixing/loading and    | 0.68       |                       |
| 1 | applying ECs using         |            |                       |
|   | back-pack sprayer          |            |                       |
+---+----------------------------+------------+-----------------------+
| 1 | open mixing/loading and    | \"         |                       |
| 2 | applying ECs using boom    |            |                       |
|   | sprayer                    |            |                       |
+---+----------------------------+------------+-----------------------+
| 1 | open mixing/loading and    | \"         |                       |
| 3 | applying ECs using hand    |            |                       |
|   | gun                        |            |                       |
+---+----------------------------+------------+-----------------------+
| 1 | open mixing/loading and    | \"         |                       |
| 4 | applying ECs using spray   |            |                       |
|   | gun                        |            |                       |
+---+----------------------------+------------+-----------------------+
| 1 | open mixing/loading and    | \"         |                       |
| 5 | applying WP using          |            |                       |
|   | back-pack sprayer          |            |                       |
+---+----------------------------+------------+-----------------------+
| 1 | open mixing/loading and    | \"         |                       |
| 6 | applying WP using boom     |            |                       |
|   | sprayer                    |            |                       |
+---+----------------------------+------------+-----------------------+
| 1 | open mixing/loading and    | \"         |                       |
| 7 | applying WP using hand gun |            |                       |
+---+----------------------------+------------+-----------------------+
| 1 | open mixing/loading and    | \"         |                       |
| 8 | applying WP using spray    |            |                       |
|   | gun                        |            |                       |
+---+----------------------------+------------+-----------------------+
| \ | **[residential -           | \--        |                       |
| - | home-owner                 |            |                       |
| - | uses]{.smallcaps}**        |            |                       |
+---+----------------------------+------------+-----------------------+
| 1 | loading/applying granules  | 0.88       | residential handler   |
| 9 | using shaker               |            |                       |
+---+----------------------------+------------+-----------------------+
| 2 | loading/applying granules  | \"         | \"\" \"\"             |
| 0 | using spreader/broadcast   |            |                       |
+---+----------------------------+------------+-----------------------+
| 2 | loading/applying granules  | \"         | \"\" \"\"             |
| 1 | using spreader/dropper     |            |                       |
+---+----------------------------+------------+-----------------------+
|   |                            |            |                       |
+---+----------------------------+------------+-----------------------+

> []{.mark}

[]{.mark}

+--------+------+-------+------+-------+---------+---------+-------+
| *      |      |       |      |       |         |         |       |
| *Table |      |       |      |       |         |         |       |
| 11.    |      |       |      |       |         |         |       |
| Non-   |      |       |      |       |         |         |       |
| cancer |      |       |      |       |         |         |       |
| Shor   |      |       |      |       |         |         |       |
| t-term |      |       |      |       |         |         |       |
| Exp    |      |       |      |       |         |         |       |
| osures |      |       |      |       |         |         |       |
| and    |      |       |      |       |         |         |       |
| Risks  |      |       |      |       |         |         |       |
| to     |      |       |      |       |         |         |       |
| Occupa |      |       |      |       |         |         |       |
| tional |      |       |      |       |         |         |       |
| Ha     |      |       |      |       |         |         |       |
| ndlers |      |       |      |       |         |         |       |
| from   |      |       |      |       |         |         |       |
| Trin   |      |       |      |       |         |         |       |
| exapac |      |       |      |       |         |         |       |
| -ethyl |      |       |      |       |         |         |       |
| Gr     |      |       |      |       |         |         |       |
| anules |      |       |      |       |         |         |       |
| A      |      |       |      |       |         |         |       |
| pplied |      |       |      |       |         |         |       |
| to     |      |       |      |       |         |         |       |
| T      |      |       |      |       |         |         |       |
| urf.** |      |       |      |       |         |         |       |
+--------+------+-------+------+-------+---------+---------+-------+
| Ex     | App  | Max   | D    | I     | Sho     | Sho     | Total |
| posure | lica | s     | erm. | nhal. | rt-term | rt-term | short |
| Sc     | tion | ingle | unit | unit  | dermal  | Inh     | -term |
| enario | E    | appl. | exp  | exp   | ^3^     | alation | MOE   |
|        | quip | rate, | m    |       |         | ^4^     | ^5^   |
|        | ment | lb    | g/lb | µg/lb |         |         |       |
|        |      | ai/A  | ai   | a     |         |         |       |
|        |      |       | .^1^ | i.^2^ |         |         |       |
+--------+------+-------+------+-------+---------+---------+-------+
| Loade  | s    | 0.88  | 2.9  | 6.3   | Exp.    | Exp.    | 420   |
| r/appl | prea |       |      |       | 0.141   | 0       |       |
| icator | der, |       |      |       |         | .000396 |       |
| of     | push |       |      |       |         |         |       |
| gr     | type |       |      |       |         |         |       |
| anules |      |       |      |       |         |         |       |
+--------+------+-------+------+-------+---------+---------+-------+
|        |      |       |      |       | MOE 425 | MOE     |       |
|        |      |       |      |       |         | 1.5E+05 |       |
+--------+------+-------+------+-------+---------+---------+-------+

1\. & 2. Unit exposures are from PHED for single layer clothing and no
gloves.

3\. Dermal exposure = \[unit exp \* appl. rate \* area treated/day (5A)
\* derm. absorp. rate (77.5%) \] / body wt. (70 kg). Short-term dermal
MOE = Short term dermal NOAEL (60 mg/kg/day) / dermal exposure.

4\. Inhal. exposure = \[(unit exp/1000) \* appl. rate \* area
treated/day (5A) \* inhal. absorp. rate (100.0%) \] / body wt. (70 kg).
Short-term inhalation MOE = Short-term inhalation NOAEL (60 mg/kg/day) /
inhal. exposure.

5\. Total short-term MOE + 1/\[(1/dermal MOE) + (1/inhal. MOE)\]. The
corresponding LOC of MOE is 100.

[]{.mark}

[Tolerance/MRL Tables]{.underline}

  --------------------- -------------- ----------- ------------ --------------- -----------
  **Table 12. Summary                                                           
  of US and                                                                     
  International                                                                 
  Tolerances and                                                                
  Maximum Residue                                                               
  Limits for                                                                    
  Trinexapac-ethyl.**                                                           

  **Commodity**         **Tolerances                                            
                        or MRLs**                                               

                        **US**         **Codex**   **Canada**   **Australia**   **New
                                                                                Zealand**

  Sugar cane            None           None        None         0.05 mg/kg      None

  Rye, straw and        None           None        None         3 mg/kg         None
  fodder, dry                                                                   

  Sugar cane, fodder    None           None        None         1 mg/kg         None

  Sugar cane, forage    None           None        None         1 mg/kg         None

  Cereal grain          None           None        None         None            0.05 mg/kg
  --------------------- -------------- ----------- ------------ --------------- -----------

+-----------------------------------+----------------+----------------+
| **Table 13. Summary of Japanese   |                |                |
| (Provisional) Maximum Residue     |                |                |
| Limits for Trinexapac-ethyl.**    |                |                |
|                                   |                |                |
| *MRLs are established for the sum |                |                |
| of residues of trinexapac-ethyl   |                |                |
| and trinexapac calculated as      |                |                |
| trinexapac-ethyl.*                |                |                |
+-----------------------------------+----------------+----------------+
| **Commodity**                     | **MRLs (ppm)** | **             |
|                                   |                | Classification |
|                                   |                | of MRL**       |
+-----------------------------------+----------------+----------------+
| Rice (brown rice)                 | 0.5            |                |
+-----------------------------------+----------------+----------------+
| Numerous commodities, including   | 0.02           | provisional    |
| grains                            |                |                |
+-----------------------------------+----------------+----------------+

  -------------------------------------------------------------------------------------
  **Table 14. Summary                                                      
  of European Union                                                        
  *Temporary* Maximum                                                      
  Residue Limits for                                                       
  Trinexapac-ethyl.                                                        
  (Annex III to                                                            
  European Commission                                                      
  N 396/2005)**                                                            
  ------------------- ---------------------------------------------------- ------------
  Code number         Groups and examples of individual products to which  Trinexapac
                      the MRLs apply                                       

  0100000             1\. FRUIT FRESH OR FROZEN; NUTS                      0.050

  0211000             \(a\) Potatoes                                       0.050

  0212000             \(b\) Tropical root and tuber vegetables             1.000

  0213000             \(c\) Other root and tuber vegetables except sugar   1.000
                      beet                                                 

  0220000             \(ii\) Bulb vegetables                               1.000

  0230000             \(iii\) Fruiting vegetables                          1.000

  0240000             \(iv\) Brassica vegetables                           1.000

  0250000             \(v\) Leaf vegetables & fresh herbs                  1.000

  0260000             \(vi\) Legume vegetables (fresh)                     1.000

  0270000             \(vii\) Stem vegetables (fresh)                      1.000

  0280000             \(viii\) Fungi                                       1.000

  0290000             (ix). Sea weeds                                      1.000

  0300010             Beans                                                10.000

  0300020             Lentils                                              0.050

  0300030             Peas                                                 0.050

  0300040             Lupins                                               0.050

  0300990             Others                                               0.050

  0401010             Linseed                                              0.050

  0401020             Peanuts                                              0.050

  0401030             Poppy seed                                           0.050

  0401040             Sesame seed                                          0.050

  0401050             Sunflower seed                                       0.050

  0401060             Rape seed                                            2.000

  0401070             Soya bean                                            0.050

  0401080             Mustard seed                                         0.050

  0401090             Cotton seed                                          0.050

  0401100             Pumpkin seeds                                        0.050

  0401110             Safflower                                            0.050

  0401120             Borage                                               0.050

  0401130             Gold of pleasure                                     0.050

  0401140             Hempseed                                             0.050

  0401150             Castor bean                                          0.050

  0401990             Others                                               0.050

  0402000             \(ii\) Oilfruits                                     0.050

  0500000             5\. CEREALS                                          0.500

  0600000             6\. TEA, COFFEE, HERBAL INFUSIONS AND COCOA          0.050

  0700000             7\. HOPS (dried) , including hop pellets and         0.050
                      unconcentrated powder                                

  0800000             8\. SPICES                                           0.050

  0900000             9\. SUGAR PLANTS                                     0.050

  1000000             10\. PRODUCTS OF ANIMAL ORIGIN-TERRESTRIAL ANIMALS   0.050
  -------------------------------------------------------------------------------------

[DCI Tables]{.underline}

+-----------------------------------------------------------------------+
| **Guideline Number: 860.1340**                                        |
|                                                                       |
| **Study Title: Plant Analytical Method and Animal Analytical Method** |
+-----------------------------------------------------------------------+
| **Rationale for Requiring the Data**                                  |
+-----------------------------------------------------------------------+
| *Data Collection*                                                     |
|                                                                       |
| Residue analytical methods are used to validate the residue field     |
| trial studies in plant and animal commodities. Data collection        |
| methods are necessary for all pesticides used on edible crops/animals |
| and resultant produce, and for products (e.g., meat, milk) from       |
| animals that may consume treated crops. The trinexapac-ethyl          |
| registrant submitted a plant analytical method (HPLC/MS, Method       |
| 110-10); however, this method does not determine conjugated residues. |
| The residues of concern in plants and animals for both tolerance      |
| enforcement and risk assessment purposes include free and conjugated  |
| residues of both parent and its acid metabolite, trinexapac. This     |
| determination is based on the results of grass and rice metabolism    |
| studies in which significant fractions of the trinexapac-ethyl        |
| residues in the various fractions were conjugated. The Agency         |
| recommends that the registrant revise the existing method to include  |
| an enzymatic and/or mild acid hydrolysis step to release conjugated   |
| residues of trinexapac. Additionally, a confirmatory analysis must be |
| proposed, and the method must undergo a successful independent        |
| laboratory validation (ILV). The Agency also recommends that the      |
| registrant develop and validate an animal analytical method that has  |
| the ability to hydrolyze conjugates.                                  |
|                                                                       |
| *Enforcement*                                                         |
|                                                                       |
| Plant and animal analytical methods submitted by the registrant must  |
| be suitable for use by various Federal and State enforcement          |
| agencies. The Food and Drug Administration (FDA) collects these       |
| methods and then publishes them to be used for enforcement purposes.  |
+-----------------------------------------------------------------------+
| **Practical Utility of the Data**                                     |
+-----------------------------------------------------------------------+
| **How will the data be used?**                                        |
|                                                                       |
| *Data Collection*                                                     |
|                                                                       |
| The methods will be used to validate the residue field trials, which  |
| can then be used to establish tolerances and assess dietary risk.     |
|                                                                       |
| *Enforcement*                                                         |
|                                                                       |
| EPA will review the submitted plant and animal analytical methods and |
| determine their suitability as enforcement methods. If suitable, EPA  |
| will forward the methods to FDA. The enforcement analytical methods   |
| are published by FDA and are available to all regulatory laboratories |
| for use in monitoring the specific pesticide concentrations in foods  |
| and feeds. They are a necessary tool for tolerance enforcement and    |
| residue monitoring and, as such, are essential in the efforts to      |
| ensure a safe food supply for the consumer.                           |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **Guideline Number: 860.1500**                                        |
|                                                                       |
| **Study Title: Crop Field Trials**                                    |
+-----------------------------------------------------------------------+
| **Rationale for Requiring the Data**                                  |
+-----------------------------------------------------------------------+
| **Trinexapac-ethyl was considered a non-food use when originally      |
| registered in 1992. Tolerances were not established because it was    |
| not expected that detectable residues would be present in             |
| agricultural commodities. However, recently submitted data show that  |
| residues are detected in plant and animal commodities when used on    |
| grasses grown for seed. Therefore, tolerances need to be established  |
| for this use.**                                                       |
|                                                                       |
| Crop field trials are required for each commodity/commodity group     |
| according to guidelines that take into account where the crop is      |
| grown and how much of the crop is grown. In general, the OPPTS Series |
| 860 Guidelines, Section 1500, provide the recommended distribution    |
| and numbers of field trials for the various crops. For grasses grown  |
| for seed, however, OPP has a separate guidance document that is       |
| currently in draft status. The document is entitled: Additional       |
| Guidance on the Crop -- 'Grasses Grown for Seed' (dated 09/2000). As  |
| with the 860 Guidelines, the additional guidance document provides    |
| the recommended number of field trials and their geographic           |
| distribution. In the United States, a significant fraction of the     |
| grasses grown for seed are grown in the Pacific Northwest. As a       |
| result, the guidance document has separate recommendations depending  |
| on whether the registrant wishes to obtain a national registration or |
| a regional Pacific Northwest registration. Regardless of which type   |
| of registration the registrant is requesting, the two RACs, forage    |
| and hay, need to be analyzed.                                         |
|                                                                       |
| For a national registration, the draft guidance document recommends   |
| that a total of 8 field trials be performed on representative         |
| varieties (specifically, 3 trials in EPA Growing Zone 12, 2 trials in |
| Zone 11, and 3 trials in Zone 5). For a regional Pacific Northwest    |
| registration, the draft guidance document recommends that a total of  |
| 5 field trials be performed on representative varieties               |
| (specifically, 3 trials in EPA Growing Zone 12 and 2 trials in Zone   |
| 11).                                                                  |
|                                                                       |
| The registrant originally submitted the results of 9 field trials     |
| that were performed in Regions 5, 10, 11, and 12. If stored samples   |
| of both forage and hay from these trials are available, and if        |
| storage stability of the residues can be demonstrated over the        |
| storage interval, the samples may be re-analyzed using the updated    |
| analytical method. The registrant may submit the results of these     |
| trials, and HED will evaluate their adequacy.                         |
+-----------------------------------------------------------------------+
| **Practical Utility of the Data**                                     |
+-----------------------------------------------------------------------+
| **How will the data be used?**                                        |
|                                                                       |
| These data will allow EPA to set enforceable tolerance levels that    |
| farmers and producers will be able to rely upon for trade and         |
| commerce. The farmers and producers depend upon EPA to set            |
| appropriate tolerance levels in conjunction with label directions     |
| (which can include restrictions on use of additives) that would       |
| prevent legal uses from producing over-tolerance residues, and        |
| thereby resulting in crop seizure. Once the tolerance levels are      |
| determined, dietary risk will be assessed.                            |
|                                                                       |
| **How could the data impact the Agency\'s future decision-making?**   |
|                                                                       |
| These data might help in granting future new use requests.            |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **Guideline Number: 870.6200**                                        |
|                                                                       |
| **Study Title: Acute & Subchronic Neurotoxicity**                     |
+-----------------------------------------------------------------------+
| **Rationale for Requiring the Data**                                  |
+-----------------------------------------------------------------------+
| The acute and subchronic neurotoxicity studies are a new data         |
| requirement under 40 CFR Part 158 as a part of the data requirements  |
| for registration of a pesticide (food and non-food uses).             |
|                                                                       |
| The Neurotoxicity Test Guideline (OPPTS 870.6200) prescribes          |
| functional and structural neurotoxicity testing and is designed to    |
| evaluate the potential of a repeated chemical exposure to produce     |
| adverse effects on the nervous system. Although some information on   |
| neurotoxicity may be obtained from standard guideline toxicity study  |
| data, studies not specifically conducted to assess neurotoxic         |
| endpoints may be inadequate to characterize a pesticide's potential   |
| neurotoxicity. While data on clinical signs of toxicity or            |
| histopathology in routine chronic or subchronic toxicity studies may  |
| offer useful information on potential neurotoxic effects, these       |
| endpoints alone may be insufficient to detect more subtle             |
| neurological effects.                                                 |
+-----------------------------------------------------------------------+
| **Practical Utility of the Data**                                     |
+-----------------------------------------------------------------------+
| **How will the data be used?**                                        |
|                                                                       |
| Neurotoxicity studies provide critical scientific information needed  |
| to characterize potential hazard to the human population on the       |
| nervous system from pesticide exposure. Since epidemiologic data on   |
| the effects of chemical exposures of trinexapac-ethyl on neurologic   |
| parameters are limited and may be inadequate to characterize a        |
| pesticide's potential neurotoxicity in humans, animal studies are     |
| used as the most sensitive endpoint for risk assessment. These animal |
| studies can be used to select endpoints and doses for use in risk     |
| assessment of all exposure scenarios and are considered a primary     |
| data source for reliable reference dose calculation.                  |
|                                                                       |
| **How could the data impact the Agency\'s future decision-making?**   |
|                                                                       |
| If the neurotoxicity studies show that the test material poses either |
| a greater or a diminished risk than that given in the interim         |
| decision's conclusion, the risk assessments for the test material may |
| need to be revised to reflect the magnitude of potential risk derived |
| from the new data.                                                    |
|                                                                       |
| If the Agency does not have these data, a 10X database uncertainty    |
| factor may be applied for conducting a risk assessment from the       |
| available studies.                                                    |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **Guideline Number: 870.7800**                                        |
|                                                                       |
| **Study Title: Immunotoxicity**                                       |
+-----------------------------------------------------------------------+
| **Rationale for Requiring the Data**                                  |
+-----------------------------------------------------------------------+
| The immunotoxicity study is a new data requirement under 40 CFR Part  |
| 158 as a part of the data requirements for registration of a          |
| pesticide (food and non-food uses).                                   |
|                                                                       |
| The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes         |
| functional immunotoxicity testing and is designed to evaluate the     |
| potential of a repeated chemical exposure to produce adverse effects  |
| (i.e., suppression) on the immune system. Immunosuppression is a      |
| deficit in the ability of the immune system to respond to a challenge |
| of bacterial or viral infections such as tuberculosis (TB), Severe    |
| Acquired Respiratory Syndrome (SARS), or neoplasia. Because the       |
| immune system is highly complex, studies not specifically conducted   |
| to assess immunotoxic endpoints are inadequate to characterize a      |
| pesticide's potential immunotoxicity. While data from hematology,     |
| lymphoid organ weights, and histopathology in routine chronic or      |
| subchronic toxicity studies may offer useful information on potential |
| immunotoxic effects, these endpoints alone are insufficient to        |
| predict immunotoxicity.                                               |
+-----------------------------------------------------------------------+
| **Practical Utility of the Data**                                     |
+-----------------------------------------------------------------------+
| **How will the data be used?**                                        |
|                                                                       |
| Immunotoxicity studies provide critical scientific information needed |
| to characterize potential hazard to the human population on the       |
| immune system from pesticide exposure. Since epidemiologic data on    |
| the effects of chemical exposures on immune parameters are limited    |
| and are inadequate to characterize a pesticide's potential            |
| immunotoxicity in humans, animal studies are used as the most         |
| sensitive endpoint for risk assessment. These animal studies can be   |
| used to select endpoints and doses for use in risk assessment of all  |
| exposure scenarios and are considered a primary data source for       |
| reliable reference dose calculation. For example, animal studies have |
| demonstrated that immunotoxicity in rodents is one of the more        |
| sensitive manifestations of TCDD                                      |
| (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental,            |
| reproductive, and endocrinologic toxicities. Additionally, the EPA    |
| has established an oral reference dose (RfD) for tributyltin oxide    |
| (TBTO) based on observed immunotoxicity in animal studies (IRIS,      |
| 1997).                                                                |
|                                                                       |
| **How could the data impact the Agency\'s future decision-making?**   |
|                                                                       |
| If the immunotoxicity study shows that the test material poses either |
| a greater or a diminished risk than that given in the interim         |
| decision's conclusion, the risk assessments for the test material may |
| need to be revised to reflect the magnitude of potential risk derived |
| from the new data.                                                    |
|                                                                       |
| If the Agency does not have these data, a 10X database uncertainty    |
| factor may be applied for conducting a risk assessment from the       |
| available studies.                                                    |
+-----------------------------------------------------------------------+