UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDES

                                                                        
                   AND TOXIC SUBSTANCES

	

  SEQ CHAPTER \h \r 1 MEMORANDUM

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 Type:  NA	Case No.:  7228

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			  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h
\r 1 

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

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 

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.

(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).

Occupational Handlers

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

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,"   HYPERLINK
"http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustic
e.pdf" 
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, 328853, 328898	DRAFT	Trinexapac-ethyl.  Petitions
for Registration of Use on Grasses Grown for Seed.  Summary of
Analytical Chemistry and Residue Data.  Petition Number 3F6571.

ATTACHMENTS



Common name	Trinexapac

Company experimental name	CGA-179500

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/cm3

	Water solubility (g/L at 25°C)	2.8 at pH 4.9

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, pKa	4.57

	Octanol/water partition coefficient, Log(KOW) at 25ºC	2.44 at pH 5.3

	UV/visible absorption spectrum	Neutral:	9335 L/mol·cm @ 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

	

Table 3.  Trinexapac-ethyl: Registered Formulations.

EPA Reg. Nos. 	AI %	Formul. Type 	Sites	Handler	Application             
                         Equipment	Spray vol

gal/A	Signal        word	Label    PPE

1. 100-727	97.0	tech/MP	--	--	--	--	Caution	--

2. 100-729	12.0	EC	turf	grower/comm. applicator	BP, BS, HS, SG 	22-175
Warning	B, G, E

3. 100-752	25.0	WP/WSB	turf 	 "	"	”	BP, BS, HS, SG	22-175	Caution	B, G

4. 100-930	0.01-1.0	granule	turf 	home owner/comm. appl	shaker,
fertilizer spreader *	--	Caution	none

5. 100-931	0.01-1.0	granule	turf	 "	"	”	shaker, fertilizer spreader *
--	Caution	none

6. 100-937	11.3	EC	turf	grower/comm. applicator	BP, BS, HS, SG	22-175
Caution	B, G

7. 100-949	12.0	EC	g. g. seed	 "	"	”	broadcast sprayer	10-20	Warning
B, G, E

8. 100-1241	25.5	EC	g. g. seed	 "	"	”	broadcast sprayer	10-20	Caution
B, G, E

9. 34704-1005	11.3	EC	turf	 "	"	”	BP, BS, HS, SG	22-175	Caution	B, G

10. 72112-11	11.3	EC	turf	 "	"	”	BP, BS, HS, SG	22-175	Caution	B, G

11. 72167-54	97.0	tech/MP	--	--	--	--	Caution	--

12. 73220-12	11.3	EC	turf	 "	"	”	BP, BS, HS, SG	22-175	Caution	B, G

13. 79676-24	11.3	EC	turf	 "	"	”	BP, BS, HS, SG	22-175	Caution	B, G

14. 79676-37	12.0	EC	turf	 "	"	”	BP, BS, HS, SG	22-175	Warning	B, G

15. 81943-12	11.3	EC	turf	 "	"	”	BP, BS, HS, SG	22-175	Caution	B, G

16. 81959-27	98.0	tech/MP	--	--	--	--	Caution	--

17. 83070-4	11.3	EC	turf	 "	"	”	BP, BS, HS, SG	22-175	Caution	B, G

18. MN020010	12.0	EC	seed rye grass	 "	"	”	broadcast sprayer	10-20
Warning	B, G, E

19. OR000007	12.0	EC	seed fescue	 "	"	”	broadcast sprayer	10-20
Warning	B, G, E

20. WA030007	12.0	EC	seed fescue	 "	"	”	broadcast sprayer	10-20
Warning	B, G, 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



Table 4.  Trinexapac-ethyl - Application Rates on Turf and Grasses Grown
for Seeds.

EPA Reg.  No.	AI          %	Formul. Type 	Home lawns

max single

lb ai/A	Golf course

max single

lb ai/A	Res/Commerc.

max single 

lb ai/A	Edging

max single

lb ai/A	Grass gr seeds

max single

lb ai/A	

# Appl./yr 	

Max/yr

lb ai/A

1. 100-727	97.0	tech/MP	--	--	--	--	--	--	--

2. 100-729	12.0	EC	--	0.17 	0.34	0.69	--	multiple 	2.4

3. 100-752	25.0	WP/WSB	--	0.17	0.34	0.68	--	multiple 	2.7 

4. 100-930	0.01-1.0	granule	0.44	--	--	0.88	--	multiple	2.5

5. 100-931	0.01-1.0	granule	0.44	--	--	0.88	--	multiple	2.5

6. 100-937	11.3	EC	--	0.16	0.32	0.65	--	multiple	2.25

7. 100-949	12.0	EC	--	--	--	--	0.5	multiple	0.5

8. 100-1241	25.5	EC	--	--	--	--	0.45	multiple	0.5

9. 34704-1005	11.3	EC	--	0.16	0.32	0.65	--	multiple	2.25

10. 72112-11	11.3	EC	--	0.16	0.32	0.65	--	multiple	2.25

11. 72167-54	97.0	tech/MP	--	--	--	--	--	--	--

12. 73220-12	11.3	EC	--	0.16	0.32	0.65	--	multiple	2.25

13. 79676-24	11.3	EC	--	0.16	0.32	0.65	--	multiple	2.25

14. 79676-37	12.0	EC	--	0.17 	0.34	0.68	--	multiple	2.4

15. 81943-12	11.3	EC	--	0.16	0.32	0.65	--	multiple	2.25

16. 81959-27	98.0	tech/MP	--	--	--	--	--	--	--

17. 83070-4	11.3	EC	--	0.16	0.32	0.65	--	multiple	2.25

18. MN020010	12.0	EC	--	--	--	--	0.5	multiple	0.5

19. OR000007	12.0	EC	--	--	--	--	0.5	multiple	0.5

20. WA030007	12.0	EC	----	--	--	--	0.5	multiple	0.5

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



♂ LD50 = 4613 mg/kg

♀ LD50 = 4212 mg/kg

Combined LD50 = 4458 mg/kg	III

870.1200	Acute dermal [rabbit]	41563910	LD50 > 4000 mg/kg	III

870.1300	Acute inhalation [rat]	41563912	LC50 ≥ 5.3 mg/L	IV

870.2400	Acute eye irritation [rabbit]	41563914	Minimal irritant;
cleared by 72 hours	III

870.2500	Acute dermal irritation [rabbit]	41563916	Slightly irritating;
cleared by day 7	IV

870.2600	Skin sensitization [guinea pig]	41869522	Not a dermal
sensitizer	N/A



Table 6.  Subchronic, Chronic and Other Toxicity Profile of
Trinexapac-ethyl.



Guideline No./ Study Type	

MRID No. (year)

Classification /Doses	

Results

870.3100

90-Day oral toxicity [rat]	MRID 41563921 (1989)

0, 5, 50, 500, 5000, 20000 ppm

[males 0, 3, 34, 346, 1350 mg/kg/day] 

[females 0,  4, 38, 395, 1551 mg/kg/day]

acceptable/guideline	NOAEL = 20000 ppm [males 1350/females 1551
mg/kg/day

HDT



870.3150

13-week oral toxicity in nonrodent  (dog)

7-week pilot study	

MRID 41563920 (1989)

0, 50, 100, 15000, 30000 ppm

[males 0, 2.0, 34.9, 515.9, 927.1 mg/kg/day]

[females 0, 1.9, 38.8, 582.4, 890.8 mg/kg/day]

acceptable/guideline

MRID 41869523

0, 500, 5000, 15000-50000 ppm

[males 0, 22, 219, (686, 956, 734)* mg/kg/day]

[females 0, 23, 214, (680, 1373, 965)* mg/kg/day]

*15000 ppm (days 1-3); 30000 ppm (days 4-28); 50000 ppm (weeks 4-7)	

NOAEL =  15000 ppm [males 515.9/females 582.4 mg/kg/day

LOAEL = 30000 ppm [males 927.1/females 890.8 mg/kg/day, based on
clinical signs (few feces and emaciation) decreased BWG/FC/FE in both
sexes (related to lack of palatability) and diffuse thymic atrophy 

Negative BWG in males HDT from week 5 on; HDT females from week 6 on; BW
of HDT males 81% of control/females 74% control at week 7; severe
decrease in food consumption HDT; tubular dilatation and
degeneration/regeneration of epithelial cells of renal tubules at HDT;
diffuse thymic atrophy at mid- and high-dose females and high-dose males



870.3200

21/28-Day dermal toxicity (rabbit)

	

MRID  41563922 (1989)

[46809310 (2006)]

0, 10, 100,  or 1000 mg/kg/day,

acceptable/guideline	

Systemic toxicity

NOAEL: 1000 mg/kg/day

LOAEL: Not determined

Local dermal irritation

NOAEL: 10 mg/kg/d

LOAEL: 100 mg/kg/d

 based on hyperkeratosis and subacute lymphocytic infiltrates in the
skin



870.3250

90-Day dermal toxicity

	

no study located/not required	





870.3465

90-day inhalation toxicity	

no study located on technical

	





870.3700a

Prenatal developmental in rodent [rat]	

MRID 41563923 (1988)

0, 20, 200, 1000 mg/kg/day

gestation days 6-15

acceptable/guideline	

Maternal NOAEL = 1000 mg/kg/day, highest dose tested 

Developmental NOAEL = 200 mg/kg/day

Developmental LOAEL = 1000 mg/kg/day, based on increased  incidence of
asymmetrically-shaped sternebrae 



870.3700b

Prenatal developmental in nonrodent (rabbit)	

MRID 41869524 (1990)

0, 10, 60, or 360 mg/kg/day

gestation days 7-19

acceptable/guideline	

Maternal toxicity NOAEL = 360 mg/kg/day, highest dose tested

Developmental toxicity NOAEL = 60 mg/kg/day

Developmental toxicity LOAEL = 360mg//kg/day, based on a decrease in
the mean number of fetuses/litter and an increase in post-implantation
loss



870.3800

Reproduction and fertility effects (rats)	

MRID 43128604 (1991)

0, 10, 1000, 10000, 20000 ppm

[P0 males: 0, 0.59, 59.97, 595.26, 1169.16 mg/kg/day]

[P0 females: 0, 0.75, 74.84, 736.89, 1410.08 mg/kg/day]

F1 males: 0, 0.59, 59.10, 591.76, 1254.96 mg/kg/day]

F1 females 0, 0.77, 77.17, 765.20, 1559.65 mg/kg/day]

acceptable/guideline 	

Parental toxicity NOAEL = 10000 ppm [males  593.5/females 751.1
mg/kg/day]

Parental toxicity LOAEL 20000 ppm [males 1212.1/females 1484.9
mg/kg/day], based on reduced premating and gestation body
weight/body-weight gain and food consumption

Reproductive NOAEL =  20000 ppm [males 1212/females 1484 mg/kg/day]. No
adverse treatment-related effect on reproductive parameters up to and
including 20000 ppm (HDT)

 

Offspring NOAEL = 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 generations [both sexes].



870.4100a

Chronic toxicity rodents (rat)	

MRID 42238104 (1992)

0, 10, 100, 3000, 10000, 20000 ppm

M 0, 0.38, 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	

acceptable/guideline	

Systemic toxicity NOAEL = 20000 ppm [males 806/females 1054 mg/kg/day,
highest dose tested.



870.4100b

Chronic toxicity nonrodent (dogs)	

MRID  42779402/42779401 (1991-92)

0, 40, 1000, 10000, or 20000 ppm 

[males 0, 1.56, 31.62, 356.72, or 726.65 mg/kg/day]

[females 0, 1.37, 39.54, 357.13, 783.83 mg/kg/day]	

	

acceptable/guideline	

Systemic toxicity NOAEL = 1000 ppm [males 31.62/females 39.54 mg/kg/day

Systemic toxicity LOAEL = 10000 ppm [males 365.72/females 357.13 
mg/kg/day], based on elevated serum cholesterol values in females,
mucoid feces in females and bloody feces in both sexes, and minimal,
focal vacuolation of the dorsal medial hippocampus and/or lateral
midbrain in both sexes. 





870.4200

Carcinogenicity (rat)

Sprague-Dawley

	

MRID 42238104 (1992)

0, 10, 100, 3000, 10000, 20000 ppm

M 0, 0.38, 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

acceptable/guideline	

see above under 870.4100a

There was a possible treatment related increased incidence of squamous
cell carcinoma of the forestomach in M at 20000 ppm (HDT); however, this
is not  considered toxicologically relevant to humans. 

No treatment-related difference detected in total number

of animals with tumors or in the total number of benign or malignant
tumors at 52 or 104 weeks. No treatment-related effect on the
time-dependent occurrence of tumor-bearing animals.

Not Likely to be Carcinogenic to Humans



870.4300

Carcinogenicity (mouse) 

CD-1 [Crl:CD-1

(ICR)Br] 

	

		

MRID 43128603 (1991)	

	

0, 7, 70, 1000, 3500, 7000  ppm

[males 0, 0.91, 9.01, 130.81, 450.72, 911.77 mg/kg/day]

[females 0, 1.08, 10.66, 154.08, 538.73, 1073.42 mg/kg/day]

acceptable/guideline	

Systemic toxicity NOAEL = 7000 ppm [males 911/females 1073 mg/kg/day],
the highest dose tested.

There was no treatment-related increase in tumors of any type in either
sex at dose levels up to an including 7000 ppm, the HDT

Not Likely to be Carcinogenic to Humans



870.5100

Bacterial Reverse Gene Mutation Assay

			

46809308 (2001)

Salmonella typhimurium

strains TA98, TA100, TA102,

TA1535 and TA1537

Escherichia coli strain WP2uvrA

0, 312.5, 625, 1250, 2500, or 5000 µg/plate ± S9 metabolic activation

Acceptable/guideline	

Negative acceptable/guideline





870.5300

Mouse Lymphoma Cells/Mammalian Activation Gene Forward Mutation Assay at
TK+/- locus

	

43128605 (1993

Mouse lymphoma

L5178Y cells (at the

thymidine kinase locus)

0, 7.54, 30.16, 120.62, or

1930 µg/mL for 4 hours

± S9 metabolic activation	

Negative acceptable/guideline



870.5395

Structural chromosomal aberration test -  Micronucleus Test Mouse	

41563926 (1989)

42081402 (1991)

41869527 (1991)

 M and F mouse bone marrow cells (erythrocytes)

0, 1000, 2000, or 4000 mg/kg bw (sacrifice at 16, 24, and 48 h)

Initial assay: 0 or 3000 mg/kg bw (sacrifice at 16, 24, and 48 h)

Confirmatory assay: 0, 750,

1500, or 3000 mg/kg bw

(sacrifice at 48 h)	

Negative acceptable/guideline

Significant increased frequency of micronucleated polychromatic
erythrocytes in M and sexes combined at 48 h in the initial assay;
however, values were within historical control range and not observed in
the confirmatory assay

at 3000 mg/kg bw at 48 h . In this study possible weak clastogen,
however, weight of evidence suggests

CGA-163935 not likely clastogenic.



870.5550

Other Genotoxicity 

In vitro UDS in Primary Rat Hepatocytes	

41604205 (1987) 

41869528 (1991)

Preliminary cytotoxicity

assay: 0, 5, 10, 21, 41, 82, 164, 328, 656, 1313, 2625, or 5250 μg/mL

Initial UDS assay: 0, 0.8, 4, 20, 100, 200, or 400 μg/mL; 

Confirmatory UDS assay: 0, 4, 20, 100, 150, 200, 300, 400, or 500 μg/mL


Negative acceptable/guideline





870.6200a

Acute neurotoxicity screening battery	No study available

	

870.6200b

Subchronic neurotoxicity screening battery	No study available

	

870.6300

Developmental neurotoxicity	

No study available	





870.7485

Metabolism and pharmacokinetics 

(rat)	

MRID  41563927 (1990)

i. v. 0.91 mg/kg [14C- CGA-163935]

oral 0.97 or 166 mg/kg [14C- CGA-163935]

oral 0.97 mg/kg/day [CGA-163935] for 14 days followed by 0.97 mg/kg
[14C- CGA-163935]

acceptable/guideline	

Rapidly, extensively absorbed (both sexes) w/ >95% of administered dose
being absorbed; little potential for accumulation; >85% eliminated w/in
12 hours via urine; 2% via feces w/in 24 hours; very little or no
biliary excretion; no sex difference; free acid derivative resulting
from hydrolysis of the ester bond of parent compound is major component
in urine and feces; only other component was parent, found only in
feces.



870.7600

Dermal penetration

(rat)	

MRID 42238105 (1990)	

0, 0.01, 0.1, or 1.0 mg/cm2 [14C- CGA-163935]

single dermal dose

acceptable/guideline	

Recovery of applied dose 97%-117%; most recovered in skin washes and
urine; <1% in blood and feces; excreted in urine within 2 hours of dose

56.5% absorbed, with 21% associated with application site

dermal absorption factor 77.5%

Table 7.  Toxicological Doses and Endpoints for Trinexapac-ethyl for Use
in Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA Safety Factors	RfD, PAD,
Level of Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children)	No
appropriate endpoint found for the general population (infants and
children)

Acute Dietary

(Females 13-49 years of age)	NOAEL = 60 mg/kg

	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 1x

	Acute RfD = 0.6 mg/kg

aPAD = 0.6 mg/kg	Developmental rabbit study

LOAEL = 360 mg/kg, based on a decrease in mean number of fetuses/litter
and an increase in post-implantation loss

Chronic Dietary (All Populations)	NOAEL= 31.6 mg/kg/day

	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 1x

	Chronic RfD = 0.32

mg/kg/day

cPAD = 0.32 mg/kg/day	Chronic oral toxicity study - dog

LOAEL = 357 mg/kg/day, based on elevated serum cholesterol values in
females,  mucoid feces in females and bloody feces in both sexes, and
minimal, focal vacuolation of the dorsal medial hippocampus and/or
lateral midbrain  in both sexes

Incidental Oral (All Durations)	NOAEL= 594 mg/kg/day	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 1x

	Residential LOC for MOE = 100	Multi-generation reproduction study 

LOAEL = 1212 mg/kg/day, based on decreased F1 postnatal survival and
reduced pup body weight/body-weight gain in both generations (both
sexes)

Short-Term Dermal & Inhalation

(1-30 days)	NOAEL= 60  mg/kg/day

Dermal absorption rate = 77.5%

Inhalation absorption rate = 100%	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 1x

	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Developmental rabbit study

LOAEL = 360 mg/kg, based on a decrease in mean number of fetuses/litter
and an increase in post-implantation loss

Intermediate-Term Dermal & Inhalation

(1-6 months)	NOAEL= 31.6 mg/kg/day

Dermal absorption rate = 77.5%

Inhalation absorption rate = 100%	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 1x

	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Chronic oral toxicity study - dog

LOAEL = 357 mg/kg/day, based on elevated serum cholesterol values in
females, mucoid feces in females and bloody feces in both sexes, and
minimal, focal vacuolation of the dorsal medial hippocampus and/or
lateral midbrain  in both sexes

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” 



Table 8.  Non-cancer Short-term Exposures and Risks to Residential
Handlers from Trinexapac-ethyl Granules Applied to Turf.

Exposure

Scenario	Application Equipment	Appl. rate, max single, lb ai/A          
    	Derm. unit exp

 mg/lb ai.1	Inhal. unit exp

mg/lb ai.2	Short-term          dermal 3	Short-term         Inhalation 4
Total Short-term MOE 5

loading/applying granules 	broadcast spreader	0.88	0.68	0.00091	Exp.
0.0033	Exp.	0.000006	18,000





	MOE	18,000	MOE	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.  Post-application Short-term Risks to Adults, Youths, and
Toddlers from Trinexapac-ethyl Applied to Residential Turf.

Exposure

Scenario 1	Routes of                      Exposure                
Transfer coefficient

(cm2/hr) 2	Short-term Exposures (mg/kg/day) 3	Short.-term               
           MOE 4

Adults , high contact	dermal	14,500	0.0182	330

Adults, mowing	dermal	3,400	0.0430	1,400

Adults, golfing	dermal	500	0.0126	4,700

Youth, mowing	dermal	3,400	0.0661	910

Youth, golfing	dermal	500	0.0194	3,100

Toddlers, high contact	dermal	5,200	0.2628	230

Toddlers, hand-to-mouth	incidental oral	NA	0.0130	46,000

Toddlers, object-to- mouth	incidental oral	NA	0.0033	180,000

Toddlers, soil ingestion	incidental oral	NA	0.0437	14,000

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.

 



Table 10.  Trinexapac-ethyl:  Occupational and Residential Handler
Exposure Scenarios.

Scen . #	Exposure

 Scenarios	Max single appl rate             lb ai/A	Comments

	Grower/Commercial uses on turf       and grass grown for seeds



--	 Mixing / Loading  



1	open mixing/loading of EC for BP, BS, HS, SG	0.68

	2	open mixing/loading of WP/WSBs for BP, BS, HS, SG	"

	--	Applying 	--

	3	applying ECs using back-pack sprayer	0.68

	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	"

	10	applying WP spray using spray gun	"

	--	Mixing / Loading / Applying	--

	11	open mixing/loading and applying ECs using back-pack sprayer	0.68

	12	open mixing/loading and applying ECs using boom sprayer	"

	13	open mixing/loading and applying ECs using hand gun	"

	14	open mixing/loading and applying ECs using spray gun	"

	15	open mixing/loading and applying WP using back-pack sprayer	"

	16	open mixing/loading and applying WP using boom sprayer	"

	17	open mixing/loading and applying WP using hand gun	"

	18	open mixing/loading and applying WP using spray gun	"

	--	residential - home-owner uses	--

	19	loading/applying granules using shaker	0.88	residential handler

20	loading/applying granules using spreader/broadcast	"	    ""          
""                

21	loading/applying granules using spreader/dropper	"	    ""          
""





	



Table 11.  Non-cancer Short-term Exposures and Risks to Occupational
Handlers from Trinexapac-ethyl Granules Applied to Turf.

Exposure       Scenario	Application Equipment	Max single appl. rate, lb
ai/A               	Derm. unit exp  mg/lb ai.1	Inhal. unit exp

µg/lb ai.2	Short-term          dermal 3	Short-term         Inhalation 4
Total short-term MOE 5

Loader/applicator of granules  	spreader,         push type          
0.88		2.9 	6.3	Exp.	0.141		Exp.	0.000396	420





	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.



Tolerance/MRL Tables

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 fodder, dry	None	None	None	3 mg/kg	None

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 grains	0.02	provisional



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 the MRLs
apply	Trinexapac

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 beet	1.000

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 unconcentrated
powder	0.050

0800000	8. SPICES	0.050

0900000	9. SUGAR PLANTS	0.050

1000000	10. PRODUCTS OF ANIMAL ORIGIN-TERRESTRIAL ANIMALS	0.050



DCI Tables

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?

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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.



Page   PAGE  8  of   NUMPAGES  27 

