Document ID: EPA-HQ-OPP-2007-0968-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-11-28T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

							OFFICE OF

							PREVENTION, PESTICIDES AND

							TOXIC SUBSTANCES

MEMORANDUM

DATE:  	12 June 2007  

SUBJECT:	Chlormequat Chloride. HED Human Health Risk Assessment for the
Reregistration Eligibility Decision.

PC Code:		018101		

DP Number:		D336712

Decision Number:	374840

Regulatory Action:	Reregistration Action/RED

Risk Assessment Type:	Single Chemical/No Aggregate		

FROM:	Donald Wilbur, Chemist/Risk Assessor

		Judy Facey, PhD, Toxicologist

		Elissa Reaves, PhD, Toxicologist

		Charles Smith, Environmental Scientist

		Reregistration Branch II

Health Effects Division (7509P)

THROUGH:	Alan Nielsen, Branch Senior Scientist

William Hazel, PhD, Branch Chief

Reregistration Branch II

Health Effects Division (7509P)

And

Richard Loranger, PhD, Branch Senior Scientist (RAB2)

Paula Deschamp, Branch Chief (RAB3)

Risk Assessment Review Committee (RARC)

Health Effects Division (7509P)

TO:		Tracy Perry, Chemical Review Manager

Special Review Branch

Special Review and Reregistration Division (7508P)

	Attached is the Health Effects Division’s (HED) risk assessment for
the chlormequat chloride RED. This document includes an occupational
exposure assessment from Charles Smith, toxicology and endpoint
selection from Judy Facey and Elissa Reaves, and a dietary (drinking
water only) exposure assessment from Donald Wilbur.  

Table of Contents

												Page

1.0 	Executive Summary							   	   	4	

2.0	Ingredient Profile and Uses							   	8		

	2.1	Summary of Use Patterns and Formulations				   	8

		2.1.1	End-Use Products						   	8

		2.1.2	Registered Use Categories and Sites				   	8

		2.1.3	Label Personal Protective Equipment (PPE) Requirements		8

		2.1.4	Application Methods and Rates					8

	2.2	Structure and Nomenclature						  	9

	2.3	Physical and Chemical Properties					  	10

3.0	Hazard Characterization/Assessment						  	10

	3.1	Hazard Characterization 						  	10

	3.2	Data Summary							  	12

	3.3	Mechanism of Toxicity						  	14

	3.4 	Absorption, Distribution, Metabolism, Excretion			  	14

	3.5	Evidence of Neurotoxicity		  					14

	3.6	Hazard Identification and Toxicity Endpoint Selection		  	15

		3.6.1	Acute Reference Dose (aRfD)					15

		3.6.2	Chronic Reference Dose (cRfD)					15

		3.6.3	Incidental Oral Exposure						16

		3.6.4	Dermal Absorption							16

		3.6.5	Occupational Dermal Exposure					17

		3.6.6	Occupational Inhalation Exposure					17

	3.7	Level of Concern for Margin of Exposure 				  	18

	3.8	Classification of Carcinogenic Potential					18

	3.9	Summary of Toxicological Doses and Endpoints				19

	3.10	Endocrine Disruption							  	20

	3.11	Public Health and Pesticide Epidemiology Data 				20

4.0	Drinking Water Exposure and Risk Pathway/Characterization			20

	4.1	Acute and Chronic Drinking Water Exposure and Risk			22

5.0	Dietary Exposure and Risks							  	24

6.0	Residential and Other Non-Occupational Exposures and Risks			24

			

7.0	Aggregate, Cumulative, and FQPA Assessments					24

8.0	Occupational Handler/Post Application Exposures & Risks			  	25

	8.1	Occupational Handler Exposures and Risks				  	25

		8.1.1	Data and Assumptions for Handler Exposure Scenarios	  	25	

		8.1.2	Handler Exposure Scenarios						26

		8.1.3	Non-cancer Risk Summary						27

	8.2	Occupational Post Application Exposure and Risks			  	27

		

9.0	Data Needs and Label Recommendations					  	28

Appendix A:	Toxicology Data Requirements					  	29

Appendix B:	Summaries of Toxicity Studies used in Toxicity Endpoint
Selection	30			

References										  	37

1.0	Executive Summary

	Chlormequat chloride [(2-chloroethyl) trimethylammonium chloride] is a
plant growth regulator (PGR) that belongs to the quaternary ammonium
class of chemicals.  Chlormequat chloride works through inhibition of
gibberellin hormones.  The end-use products are formulated as liquids
(soluble concentrate/liquid) and contain 11.8% of the active ingredient,
chlormequat chloride.  The product is applied to ornamental plants grown
in greenhouses, nurseries, and shadehouses.  Use is restricted to
containerized ornamentals in situations where production areas are not
under cover.  Chlormequat chloride applications are made using several
types of application equipment – including groundbooms, low pressure
handwands, backpack sprayers, and high pressure handwands.  Based on the
number of seasonal applications indicated on product labels and
information provided by the registrant, non-dietary exposures are
expected to be short- and intermediate-term in duration.  There are no
residential or food uses associated with this risk assessment and it is,
therefore, not subject to the Food Quality Protection Act (1996).  This
risk assessment is provided in support of the upcoming chlormequat
chloride RED.

Toxicology and Toxicity Endpoints for Risk Assessments

	The toxicology database for chlormequat chloride is sufficient for
hazard assessment.  The acute toxicity data indicate that chlormequat
chloride is moderately toxic (Category II) via oral and dermal routes of
exposure, and minimally toxic via acute inhalation exposure (Category
IV).  It is slightly irritating to the skin, moderately irritating to
the eye (Category IV and III, respectively) and is not a skin
sensitizer.

	Decreases in body weight and body weight gain were consistently
observed in the available oral repeat dosing studies in rats and dogs. 
Dogs appear to be the most sensitive species with clinical signs
(salivation) observed at 10 mg/kg/day (NOAEL 5 mg/kg/day) in the chronic
dog study.  Decreased body weight and gains were the only adverse
effects seen in the 90-day dietary rat study at 190 mg/kg/day (NOAEL 61
mg/kg/day).  The long-term feeding studies (carcinogenicity) also
produced decreased body weights and decreased food consumption in rats
(LOAEL 125 mg/kg/day) and in mice (LOAEL 363 mg/kg/day).  The prenatal
developmental rat study (gavage), however, produced clinical signs such
as salivation, chromorhinorrhea, as well as decreased body weight gain
and decreased food consumption at 90 mg/kg/day (NOAEL 30 mg/kg/day). 
The highest dose tested (180 mg/kg/day) caused overt toxicity within an
hour after exposure in the form of decreased motor activity, tremors,
ataxia, lacrimation, rales, gasping, body jerks, and increased
incidences of chromodacryorrhea.  There were no adverse effects noted up
to 12 mg/kg/day (highest dose tested) in the prenatal developmental
toxicity study in rabbits.  There was no quantitative or qualitative
susceptibility observed in the offspring compared to the adult animals
in the 2-generation reproduction study (rat). 

	No systemic toxicity was observed in the 21-day dermal study in rabbits
when tested up to the limit dose of 1035 mg/kg/day.  Chlormequat
chloride was irritating at 345 mg/kg/day in only female rabbits. Dermal
absorption and inhalation toxicity studies are not available.

	Carcinogenicity studies in mice and rats did not demonstrate potential
signs of carcinogenicity and chlormequat chloride was non-mutagenic in
genotoxicity studies.  Therefore, chlormequat chloride is not likely to
be a human carcinogen and a cancer risk assessment has not been
performed.

	

	Acute and subchronic neurotoxicity studies are not available for
chlormequat chloride.  Overt toxicity in the form of neurotoxic
signs/effects such as tremors, ataxia, decreased motor activity, and
body jerks were observed within an hour at the highest dose of 180
mg/kg/day with increased incidences of excess salivation at the LOAEL of
90 mg/kg/day in the developmental rat study.  Tremors and
hypersensitivity were also observed at 255 mg/kg/day in the 2-generation
reproduction rat study.  The only potential neurotoxicity signs at lower
concentrations consisted of excess salivation, which was in conjunction
with vomiting, diarrhea and decreased body weight gains in the chronic
dog study (LOAEL 10 mg/kg/day).  According to the registrant,
chlormequat chloride has the ability to act at the nicotinic cholinergic
receptor site of the neuromuscular junction.  The test material acts as
a depolarizing agent at this site, leading to muscular excitation
followed by muscle weakness.  Based on the low exposure potential from
the current use pattern (non-food/non-residential) the hazard database
is sufficient; acute and subchronic neurotoxicity tests are not required
at this time.  However, neurotoxicity studies are recommended to provide
more data regarding the neurotoxic potential of chlormequat chloride in
the event any residential or food uses are proposed in the future.

	In the available toxicity studies with chlormequat chloride, there was
no estrogen-, androgen-, and/or thyroid-mediated toxicity observed.

	Based on the toxicity, duration of exposure, and uses of chlormequat
chloride (non-food/non-residential), the following toxicity endpoints
were selected: 

Acute Dietary [Water] for general population: aRfD: 0.9 mg/kg/day
derived from a 1-day (single oral dose) NOAEL of 90 mg/kg/day in a
prenatal developmental toxicity- rat study (MRID 42246604). The 1-day
LOAEL of 180 mg/kg/day is based on overt toxicity signs (tremors,
ataxia, decreased motor activity, excess salivation) observed in dams
typically occurring within one hour after a single oral dose on GD6. 
This NOAEL/LOAEL based on 1-day effects is separate from the maternal
NOAEL/LOAEL identified from repeated dosing over 10 days (30/90
mg/kg/day).

Acute Dietary (females age 13-49):  No appropriate endpoint was
identified from the available developmental studies for this risk
assessment.

Chronic dietary (all populations): cRfD = 0.05 mg/kg/day derived from a
NOAEL of 5 mg/kg/day in a chronic toxicity - dog study (MRID 46715201).
LOAEL (mg/kg/day): 10 mg/kg/day, based on salivation (after 1 week, both
sexes), vomiting (females), diarrhea (males), and decreased body weight
gain (males).

	

Dermal (short- & intermediate-terms of exposure):  Systemic toxicity was
not observed in the 21-day dermal rabbit study up to the limit dose
(1000 mg/kg/day).  Therefore, a quantitative dermal risk assessment is
not appropriate.

Inhalation (short- & intermediate-terms of exposure): NOAEL (oral study)
= 30 mg/kg/day (Inhalation Absorption Factor = 100% of oral absorption)
from a developmental toxicity – rat study (MRID 42246604).  LOAEL = 90
mg/kg/day, based on decreased body weight gain (38-112%-GD 6-9; 21-67%
GD 6-12) and food consumption and greater incidences of increased
salivation and chromorhinorrhea.

	The uncertainty factors for chlormequat chloride are 10X for
intraspecies variability (i.e. differences among humans) and 10X for
interspecies extrapolation (differences between humans and animals). 
Therefore, a target MOE of 100 defines HED’s level of concern (LOC)
for occupational exposure assessments.

Drinking Water Exposure and Risk Estimates

	Estimated drinking water concentrations (EDWC) were provided by the
Environmental Fate and Effects Division (EFED). Monitoring data on the
concentrations of chlormequat chloride in drinking water were not
available; therefore, EFED provided modeled values for use in the
dietary risk assessment. These exposure values were generated based on
the deterministic upper bound estimates from EFED’s Tier I (F)IFRA
(I)ndex (R)eservoir (S)creening (T)ool.  (FIRST) EDWC surface water
model.  These estimates assume that 100% of the watershed is treated, as
well as that no plants are on the surface of the area that is treated
(i.e. - the entire applied product is absorbed into the soil or runs
off).

	Since chlormequat chloride has no registered food uses at this time,
dietary risk assessments were conducted for drinking water only.  Acute
and chronic dietary assessments were conducted using DEEM (DEEM-FCID™,
Ver 2.03) and the EDWCs for surface water provided by EFED.  The acute
dietary exposure estimates from drinking water are below HED’s level
of concern (< 100% aRfD) for the U.S. population and all population
subgroups at the 95th exposure percentile.  The highest exposed
population subgroup was all infants (< 1 year) at 56% of the acute RfD
of 0.9 mg/kg/day.  The chronic dietary exposure estimates from drinking
water are below HED’s level of concern (< 100% cRfD) for the U.S.
population and all population subgroups.  The highest exposed population
subgroup was all infants (< 1 year) at 13% of the chronic RfD of 0.05
mg/kg/day.  Based on the screening-level EFED assessment used to
generate the drinking water estimates, HED concludes that there is no
concern for potential acute or chronic dietary exposure from drinking
water associated with the registered non-food uses of chlormequat
chloride.

Occupational Handler/Applicator Exposure and Risk Estimates

	It has been determined that exposure to pesticide handlers is likely
during the occupational use of chlormequat chloride.  The anticipated
use patterns and current labeling indicate several occupational exposure
scenarios based on the types of equipment and techniques that can
potentially be used for chlormequat chloride applications.  Results
indicate that the occupational handler risk estimates for chlormequat
chloride do not exceed HED’s level of concern [i.e., MOEs are greater
than 100].

Post-Application Occupational Exposure and Risk Estimates

	No dermal occupational postapplication risk assessment was performed
because a dermal endpoint was not selected for chlormequat chloride as
it does not induce systemic adverse effects.  When there is no
quantitative dermal occupational postapplication risk assessment the
restricted entry interval (REI) is based on the acute toxicity of the
chemical.  The current chlormequat chloride label requires a 12-hour REI
but chlormequat chloride has been classified as Category II for acute
dermal toxicity.  In accordance with the requirements in the Worker
Protection Standards (WPS) - 40CFR170, ingredients classified as
Category II are assigned a 24-hour REI.  HED recommends that the
Registration Division (RD) ensure that the proper REI for ornamental
plants grown in greenhouses, nurseries, and shadehouses be included on
the chlormequat chloride labels.

	An inhalation occupational postapplication assessment was not performed
for chlormequat chloride due to its low vapor pressure.  However, in
nurseries and greenhouses, the WPS prohibits workers from entering the
treated area for the first four hours after an application is completed
to allow time for sprays and dusts to settle out of the air to protect
workers against postapplication inhalation exposures.

Residential Exposure and Risk Estimates

	Chlormequat chloride does not currently have any registrations for
residential use nor is it registered for use in any residential
settings.  As a result, no residential chlormequat chloride handler or
postapplication exposure is expected; therefore, such risk assessments
are not required at this time.

Environmental Justice Considerations

	Potential areas of environmental justice concerns, to the extent
possible, were considered in this 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/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

Review of Human Research

	This assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide.  These
studies, listed below, have been determined to require a review of their
ethical conduct.  The listed studies have received the appropriate
review.

The PHED Task Force, 1995.  The Pesticide Handler Exposure Database
(PHED), Version 1.1.  Task Force members Health Canada, U.S.
Environmental Protection Agency, and the National Agricultural Chemicals
Association, released February 1995.

	

Aggregate, Cumulative, and FQPA Assessments

	Chlormequat chloride does not have any food or residential uses, nor is
it assumed to share a common mode of toxicity with other substances. 
Therefore, for the purposes of this risk assessment, aggregate,
cumulative, and FQPA assessments are not applicable.

	

2.0	Ingredient Profile and Uses

2.1	Summary of Use Patterns and Formulations

		2.1.1	End-Use Products 

	

	Chlormequat chloride is a plant growth regulator that belongs to the
quaternary ammonium class of chemicals.  Chlormequat chloride works
through inhibition of gibberellin biosynthesis in the early stages of
the pathway.  This early blockage prevents the synthesis of numerous
gibberellins needed for normal plant growth and development. As a
result, internode distance is reduced thus producing thicker, stockier
growth. It is formulated as a soluble concentrate/liquid (SC/L).

2.1.2	Registered Use Categories and Sites

 

	Chlormequat chloride is currently registered for use on a wide variety
of ornamentals grown in greenhouses, shadehouses, and nurseries.  Crops
include herbaceous and woody annual and perennial plants such as
begonia, vinca, azalea, and poinsettia.  Use is restricted to
containerized ornamentals in situations where production areas are not
under cover.

2.1.3	Label Personal Protective Equipment (PPE) Requirements

 

	The current chlormequat chloride labels require that applicators and
other handlers wear the following personal protective equipment (PPE):

Long-sleeved shirt and long pants.

ch as butyl rubber ≥ 14 mils, natural rubber ≥ 14 mils, neoprene
rubber ≥ 14 mils, or nitrile rubber ≥ 14 mils.

Shoes plus socks.

2.1.4	Application Methods and Rates

 

	Chlormequat chloride applications are applied using several types of
application equipment – including groundbooms, low pressure handwands,
backpack sprayers, and high pressure handwands.  Table 2.1.4 includes a
description of application methods and rates that are currently
registered for chlormequat chloride.  The maximum recommended
application rate in the field on containerized plants is 5.5 lbs ai/A
for single applications and not more than 33.3 lbs ai/A/year total.

Table 2.1.4 Chlormequat Chloride Use Patterns and Formulations

Formulation	Use Site	Method of Application 	Use Sites	Application Rate
Label Restrictions

CYCOCEL® Plant Growth Regulator - liquid

(11.8% a.i.)

For Commercial Use

EPA Reg #241-74 	Shadehouses and nurseries	foliar spray by low pressure
handwand, backpack sprayer, or groundboom	Ornamentals	0.017 lb ai/gal

(at 2,000 ppm)

3.7 lb ai/A

(at 2,000 ppm and 

1 gal/200 ft2) or 5.5 lb ai/A (at 2,000 ppm and 1.5 gal/200 ft2 – only
for larger plants with well defined canopies)	Do not apply through any
type of irrigation equipment.  Apply only to containerized plants.  Do
not apply as a soil drench.

	Greenhouse	foliar spray by low pressure handwand, backpack sprayer
Ornamentals	0.013 lb ai/gal

(at 1,500 ppm)	Do not apply through any type of irrigation equipment.

	Greenhouse	drench by high pressure handwand	Ornamentals	0.025 lb ai/gal

(at 3,000 ppm)	Do not apply through any

type of irrigation equipment.

  HYPERLINK "http://www.etigra.com/product_chlormequat.php"  Chlormequat
E-Pro Plant Growth Regulator  - liquid

(11.8% a.i.)

For Commercial Use

EPA Reg # 81959-12 	Greenhouse	foliar spray by low pressure handwand,
backpack sprayer	Ornamentals	0.034 lb ai/gal

(at 4,000 ppm)

Greenhouse	drench by high pressure handwand	Ornamentals	0.034 lb ai/gal

(at 4,000 ppm)

	

2.2	Structure and Nomenclature

Table 2.2  Test Compound Nomenclature

Chemical Structure	

Empirical Formula	C5H13Cl2 N

Common Name	Chlormequat chloride

IUPAC Name	(2-chloroethyl)trimethylammonium chloride

CAS Name	2-chloro-N,N,N-trimethylethanaminium chloride

CAS Registry Number	999-81-5

End-use Product/EP	CYCOCEL, Chlormequat E-Pro

Chemical Class	quaternary ammonium compound

Use Type	plant growth regulator

Known Impurities of Concern	N/A

2.3	Physical and Chemical Properties

Table 2.3  Physicochemical Properties

Parameter	Value	Reference

Molecular Weight	158.1	MSDS CYCOCEL® Plant Growth Regulator by BASF
Canada, 08/15/2000

Melting Point	245ºC	MSDS CYCOCEL® Plant Growth Regulator by BASF
Canada, 08/15/2000

pH	5.14 	MSDS CYCOCEL® Plant Growth Regulator by BASF Canada,
08/15/2000

Density	1.241 g/ml	Study: Surface Tension, Density and Vapour Pressure
of Chlormequat-Chloride (PAI) by BASF Germany, 03/27/2001

Water Solubility (20° C)	74 g/100 ml	MSDS CYCOCEL® Plant Growth
Regulator by BASF Canada, 08/15/2000

Surface Tension 	70.3 mN/m	Study: Surface Tension, Density and Vapour
Pressure of Chlormequat-Chloride (PAI) by BASF Germany, 03/27/2001

Vapor Pressure ( 20°C)	 <1.0 x 10-8 mbar	Study: Surface Tension,
Density and Vapour Pressure of Chlormequat-Chloride (PAI) by BASF
Germany, 03/27/2001

Octanol/water partition coefficient, log KOW (25°C)	Not Applicable 
MSDS CYCOCEL® Plant Growth Regulator by BASF Canada, 08/15/2000

3.0	Hazard Characterization/Assessment

3.1	Hazard Characterization

	The toxicology database for chlormequat chloride is sufficient for
hazard assessment.  The toxicity profile of chlormequat chloride is
generated from acute (oral, dermal, inhalation) and repeat dosing
studies that include: subchronic (oral, dermal), developmental (oral),
reproduction (oral), chronic (oral), carcinogenicity (oral) and
mutagenicity studies.  The acute toxicity data indicate that chlormequat
chloride is moderately toxic (Category II) via oral and dermal routes of
exposure, and minimally toxic via acute inhalation exposure (Category
IV).  It is slightly irritating to the skin, moderately irritating to
the eye (Category IV and III, respectively), and is not a skin
sensitizer to guinea pigs.

			

	Decreases in body weight and body weight gain were consistently
observed in the available oral repeat dosing studies in rats and dogs. 
Dogs appear to be the most sensitive species with decreased body weight
gains (males) as well as clinical signs of toxicity including salivation
(both sexes), vomiting (females), and diarrhea (males) at 10 mg/kg/day
(NOAEL 5 mg/kg/day) in the chronic dog study.  Decreased body weight and
body weight gains were the only adverse effects observed in the 90-day
dietary rat study at 190 mg/kg/day (NOAEL 61 mg/kg/day).  The long-term
feeding studies (carcinogenicity) also produced decreased body weights
and decreased food consumption in rats (125 mg/kg/day) and in mice (363
mg/kg/day).  The prenatal developmental rat study (gavage), however,
produced clinical signs such as salivation and chromorhinorrhea, as well
as decreased body weight gain and decreased food consumption at 90
mg/kg/day (NOAEL 30 mg/kg/day).  The highest dose tested (180 mg/kg/day)
caused more severe toxicity in the form of decreased motor activity,
tremors, ataxia, lacrimation, rales, gasping, body jerks, and increased
incidences of chromodacryorrhea.  More importantly, one or more of these
clinical signs were observed in the dams typically within one hour after
the single oral dose on GD6.  There were no adverse effects noted up to
12 mg/kg/day (highest dose tested) in the prenatal developmental
toxicity study in rabbits.  

There was no quantitative or qualitative susceptibility observed in the
offspring compared to the adult animals in the 2-generation reproduction
study.  Parental effects beginning at 255 mg/kg/day (HDT) included
decreases in body weight and body weight gains with tremors and
hypersensitivity occurring mainly during lactation (NOAEL 86 mg/kg/day).
 The reproductive LOAEL was based on decreased fertility indices also at
the highest dose tested (255 mg/kg/day) with the offspring LOAEL (255
mg/kg/day) based on decreased mean litter size, body weights, and
delayed development (auditory canal opening, eye opening, and pinna
unfolding).

	No systemic toxicity was observed in the 21-day dermal study in rabbits
when tested up to the limit dose of 1035 mg/kg/day.  Dermal irritation
was observed at 345 mg/kg/day in the form of erythema, edema, and
fissuring, gross lesions of treated skin (foci), and histopathological
lesions of the treated skin (acanthosis, subacute inflammation and
edema), in female rabbits only. Dermal absorption and inhalation studies
are not available.

	Carcinogenicity studies in mice and rats did not demonstrate potential
signs of carcinogenicity and chlormequat chloride was non-mutagenic in
four genotoxicity studies.  Therefore, chlormequat chloride is not
likely to be a human carcinogen and a cancer risk assessment has not
been performed.

	Acute and subchronic neurotoxicity studies are not available for
chlormequat chloride.  Overt toxicity in the form of neurotoxic
signs/effects such as tremors, ataxia, decreased motor activity, and
body jerks were observed at the highest dose of 180 mg/kg/day with
increased incidences of excess salivation at the LOAEL of 90 mg/kg/day
in the developmental rat study.  Tremors and hypersensitivity were also
observed at 255 mg/kg/day in the 2-generation reproduction rat study. 
The only potential neurotoxicity signs at lower concentrations consisted
of excess salivation, which was in conjunction with vomiting, diarrhea
and decreased body weight gains in the chronic dog study (10 mg/kg/day).
 According to the registrant, chlormequat chloride has the ability to
act at the nicotinic cholinergic receptor site of the neuromuscular
junction.  The test material acts as a depolarizing agent at this site,
leading to muscular excitation followed by muscle weakness.  Based on
the low exposure potential from the current use pattern
(non-food/non-residential) the hazard database is sufficient; acute and
subchronic neurotoxicity tests are not required at this time. However,
neurotoxicity studies are recommended to provide more data regarding the
neurotoxic potential of chlormequat chloride in the event any
residential or food uses are proposed in the future.

	In the available toxicity studies with chlormequat chloride, there was
no estrogen-, androgen-, and/or thyroid-mediated toxicity observed.

3.2	Data Summary

	Tables 3.2a and 3.2b provide a summary of the acute, subchronic and
chronic toxicity profile of the technical chlormequat chloride.  The
available and relevant toxicity studies are summarized below:

	

Table 3.2a: Acute Toxicity Profile - Chlormequat Chloride Technical
(66.1%)

Guideline No.	Study Type	MRID(s)	Results	Toxicity Category

870.1100	Acute oral toxicity –rat

(1990)	41721604	LD50 Males = 487 mg/kg

(95% C.I.= 369-643)

Females = 560 mg/kg

(95% C.I.= 399-786)

Combined = 522 mg/kg (95% C.I.= 423-646)	II

870.1200	Acute dermal toxicity-rabbit

(1990)	41721605	LD50 Males = 964 mg/kg (95% C.I.= 509-1825)

Females = 1621 mg/kg (95% C.I.= 856-3069)

Combined = 1250 mg/kg (95% C.I.= 647-2414)	

II

870.1300	Acute inhalation toxicity-rat

(1990)	41721606	LC50 => 4.57 mg/L

(males, females combined)	IV

870.2400	Primary eye irritation-rabbit

(1990)	41721607	Slight irritation.  No positive signs at 48 hours.	III

870.2500	Primary dermal irritation-rabbit

(1990)	41721608	Mildly irritating	IV

870.2600	Dermal sensitization-guinea pig

(1990)	41721609	Not a sensitizer	N/A

Table 3.2b: Subchronic, Chronic and Other Toxicity Profile for
Chlormequat Chloride

Guideline	Study Type	Dose Levels	MRID	Results

870.3100

	(1981)-90-Day oral toxicity-rat

Acceptable/Non-guideline	0, 300, 900, 2700 ppm

mg/kg/day

M: 0, 20.6, 61, 189,

F: 0, 24.4, 73, 220	00163408	NOAEL (mg/kg/day): M/F: 61.3/72.9

LOAEL (mg/kg/day): M/F: 188.5/220

based on decreased body weight (7-8%) during weeks 9-13, and an overall
decrease in body weight gains (11%) in males.

870.3200

	(1991)-21-Day dermal toxicity -rabbit

Acceptable/Guideline	mg/kg/day=

0, 115, 345, 1035	42246603	Systemic NOAEL (mg/kg/day): 1035

Systemic LOAEL (mg/kg/day): not determined

Dermal NOAEL (mg/kg/day): 115

Dermal LOAEL (mg/kg/day): 345

based on dermal irritation (erythema, edema, and fissuring), gross
lesion of treated skin (foci), and histopathological lesions in treated
skin (acanthosis, subacute inflammation and edema) in females only.

870.3700a

	(1990)-Prenatal developmental –rat

Acceptable/Guideline	mg/kg/day=

0, 30, 90, 180

(GD6-15)	42246604	Maternal NOAEL (mg/kg/day): 30

Maternal LOAEL (mg/kg/day): 90

based on decreased body weight gain (38-112% GD 6-9; 21-67% GD 6-12) and
food consumption, and increased incidences of excess salivation and
chromorhinorrhea.

Developmental NOAEL (mg/kg/day): 180

Developmental LOAEL (mg/kg/day): not determined

180 mg/kg/day (HDT): Clinical signs within 1 hour after a single oral
dose (GD6)

(BWG (36%), (BW (5-9%), ( motor activity, tremors, ataxia, lacrimation,
rales, gasping, body jerks,( incidences of chromodacryorrhea

870.3700a

	(1979)-Prenatal developmental -rabbit

Acceptable/Non-Guideline	mg/kg/day=

0, 1.5, 3.0, 6.0, 12.0	46715205	Maternal NOAEL (mg/kg/day): 12

Maternal LOAEL (mg/kg/day): not determined

Developmental NOAEL (mg/kg/day): 12

Developmental LOAEL (mg/kg/day): not determined

870.3800	(1993)-2 generation reproduction –rat

Acceptable/Guideline	ppm =

0, 300, 900, 2700

mg/kg/day =

M:  0, 28.9, 86, 255,

F:  0, 30.8, 93, 279	46715206	Maternal NOAEL (mg/kg/day): M/F: 86/ 93

Maternal LOAEL (mg/kg/day): M/F: 255/279, based on decreased body weight
and body weight gain of the P and F1 generation, and tremors and
hypersensitivity.

Reproduction NOAEL (mg/kg/day):M/F:86/93

Reproduction LOAEL (mg/kg/day): M/F: 255/279, based on decreased
fertility indices.

Offspring NOAEL (mg/kg/day): 86/ 93

Offspring LOAEL (mg/kg/day): 255/279, based on decreased mean litter
size, body weight, as well as delayed development

870.3700a

	Chronic-Dog (1993)

Acceptable/Guideline	ppm= 0, 150, 300, 1000

mg/kg/day=

0, 5, 10, 32	46715201	NOAEL (mg/kg/day): 5 mg/kg/day

LOAEL (mg/kg/day): 10 mg/kg/day, based on salivation (after 1 week, both
sexes), vomiting (females), diarrhea (males), and decreased body weight
gains (males).

32 mg/kg/day  (HDT): Apathy, staggering gait, saltatory spasm, and other
signs

870.4200	Carcinogenicity- Rats (1992)

Acceptable/Guideline	ppm= 0, 281, 937,2811

mg/kg/day = M: 0, 12, 42, 125, F: 0, 16, 55, 173	46715203	NOAEL
(mg/kg/day): M/F:43/ 55 mg/kg/day

LOAEL (mg/kg/day): M/F 125/ 172 mg/kg/ day, based on decreased body
weight (both sexes) and decreased food consumption (males)

870.4200	Carcinogenicity- mice (1994)

Acceptable/Guideline	ppm= 0, 150, 600, 2400

mg/kg/day = 0, 22, 88, 363	46715204	NOAEL (mg/kg/day): 22 mg/kg/day

LOAEL (mg/kg/day): 363 mg/kg/day, based on decreased body weight (both
sexes).

870.5100	(1990)-Bacterial Gene Mutation

Acceptable/Guideline	100, 500, 1000, 2500, 5000 μg/plate	41721610
NEGATIVE

870.5300	(1990)-In Vitro Forward Mutation

Acceptable/Guideline	500, 1250, 2500, 3500, 4500, 5000 μg/mL	41798102
NEGATIVE

870.5385	(1991)-Mammalian Bone Marrow Chromosome Aberration

Acceptable/Guideline	25, 250, 500 mg/kg	41798101	NEGATIVE

870.5550	(1990)-Unscheduled DNA Synthesis

Acceptable/Guideline	0.63, 1.25, 2.5, 4.0, 5.0, 7.5 µl/ml	

41798103	NEGATIVE

↑: increase; ↓: decrease; HDT: highest dose tested; BW: body weight;
FOB: functional observation battery

3.3	   Mechanism of Toxicity	

	Chlormequat chloride has been reported in the literature to act at the
nicotinic receptor site of the neuromuscular junction.  The test
material may act as a depolarizing agent at this site, leading to
muscular excitation followed by muscle weakness.  Acute toxicity may
lead to respiratory arrest.  Acute toxicity of chlormequat chloride has
also been reported to differ by species, which is likely due to
sensitivity to depolarizing neuromuscular blockers (Henninghausen and
Tiefenbach, 1978).

3.4	Absorption, Distribution, Metabolism, Excretion (ADME)

	A general metabolism study (870.7485) is not required under 40 CFR
158.340 because chlormequat chloride is a non-food use pesticide.

3.5	Evidence of Neurotoxicity

	Acute and subchronic neurotoxicity studies are not available for
chlormequat chloride.

Potential neurotoxicity signs/effects such as tremors, ataxia, decreased
motor activity, and body jerks were observed at the highest dose of 180
mg/kg/day with increased incidences of excess salivation at the LOAEL of
90 mg/kg/day in the developmental rat study.  Tremors and
hypersensitivity were also observed at 255 mg/kg/day of the 2-generation
reproduction rat study.  The only potential sign of neurotoxicity at
lower concentrations was excess salivation, observed 1 week post-dosing,
which was in conjunction with vomiting, diarrhea and decreased body
weight gains in the chronic dog study (10 mg/kg/day).  Apathy,
staggering gait, saltatory spasm, and other neurotoxic signs were seen
in the chronic dog study at 32 mg/kg/day.

	Although clinical signs possibly related to neurotoxicity were observed
mainly at higher doses in the repeat dosing studies and salivation was
present at 10 mg/kg/day in the chronic dog study, neurotoxicity
screening battery data are not required at this time based on the low
exposure expected from the registered uses (non-food/non-residential). 
In the event that future uses result in increased exposures such as for
any residential or food applications, then acute and subchronic
neurotoxicity studies would be required in order to address
neurotoxicity.  A developmental neurotoxicity study may also be required
depending on the effects observed in the acute and subchronic
neurotoxicity studies.

3.6	Hazard Identification and Toxicity Endpoint Selection

 

	3.6.1	Acute Reference Dose (aRfD) – General Population 

Study:  Prenatal Developmental-Rat (MRID 42246604)

1-Day oral NOAEL:  90 mg/kg/day

1-Day oral LOAEL:  180 mg/kg/day

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X
intraspecies variability)

Comments: A prenatal developmental toxicity study in rats was used to
identify the point of departure and endpoint for establishing the aRfD
of 0.9 mg/kg/day.  This study provides an appropriate endpoint after a
single oral exposure.  The oral NOAEL of 90 mg/kg/day for 1-day effects
and the LOAEL of 180 mg/kg/day is based on tremors and ataxia in dams
after a single oral dose on gestation day 6 (GD 6).  This 1-day oral
NOAEL and LOAEL is different than the maternal NOAEL (30 mg/kg/day) and
LOAEL (90 mg/kg/day) which was identified from 10 days of repeated
exposures from the prenatal developmental rat study.  Uncertainty
factors (100x) include 10X for interspecies extrapolation and 10X for
intraspecies variability.  Although an acute dietary (food) endpoint is
not necessary for this assessment, it was selected to evaluate potential
risks associated with residues in drinking water.

Acute RfD = 90 mg/kg/day = 0.9 mg/kg/day

                               100 (UF)

	Acute Reference Dose- Females age 13-49:  There is no appropriate
endpoint identified which is specific for this population subgroup.

3.6.2	Chronic Reference Dose (cRfD)

Study:  Chronic Toxicity-Dog

NOAEL:  5 mg/kg/day

LOAEL:  10 mg/kg/day

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X
intraspecies variability)

Comments:  A chronic toxicity study in dogs was used to select the dose
and endpoint for establishing the cRfD of 0.05 mg/kg/day.  This study is
the appropriate route and duration to establish a chronic dietary
endpoint.  The LOAEL of 10 mg/kg/day was based on increased salivation
(both sexes), vomiting (females), diarrhea (males), and decreased body
weight gains (males).  The NOAEL is 5 mg/kg/day.  Uncertainty factors
(100x) include: 10X interspecies extrapolation, 10X intraspecies
variability.  Although a chronic dietary endpoint for food is not
required for this assessment, it was selected to evaluate potential
risks associated with residues in drinking water.

Chronic RfD = 5 mg/kg/day = 0.05 mg/kg/day

                               100 (UF)

3.6.3	Incidental Oral Exposure

	There are no registered residential uses of chlormequat chloride.  As
exposure of children in a residential setting will not occur, selection
of an endpoint to conduct an incidental oral risk assessment has not
been made.

	3.6.4	Dermal Absorption

	There are no dermal absorption studies available for chlormequat
chloride, and the available data are insufficient to assess dermal
absorption for this chemical.  

	Although no systemic toxicity was observed in the 21-day dermal
toxicity rabbit study when tested higher than the limit dose (1035
mg/kg/day), a review of the dermal toxicology data for chlormequat
chloride suggests the potential for significant dermal irritation. 
Localized dermal toxicity was observed (days 10-21) in the 21-day dermal
rabbit study at 345 mg/kg/day in the form of dermal irritation
(erythema, edema, and fissuring), gross lesions of treated skin (foci),
and histopathological lesions in the treated skin (acanthosis, subacute
inflammation and edema) in females only.  The test substance was in
contact with the skin of the rabbit by a secured gauze dressing for 6
hours/day and 5 days/week.  The primary dermal irritation study with
rabbits also applied the pesticide to secured gauze for 4 hours.  This
single exposure produced slight irritation that was resolved by 48 hours
post-exposure.  In contrast, the pesticide was applied directly to the
skin of the rabbits for 24 hours in the acute LD50 dermal toxicity
rabbit study.  Mortality (1/10) was observed at the lowest dose of 312
mg/kg.  This increased toxicity was likely due to the direct application
and occlusion of the pesticide to the skin of the animal.  As protection
against dermal irritation from occupational handler exposures is
addressed through proper labeling and protection against dermal
irritation from occupational worker exposures is addressed by the worker
protection standard, and as dermal irritation cannot be quantified for
dermal risk assessments, it is concluded that if adequate measures are
in place to protect against dermal irritancy, (through proper labeling
language and/or worker protection standard), then quantitative risk
assessment is not necessary for pesticide chemicals meeting the above
criteria.

	The current chlormequat chloride labels require that applicators and
other handlers wear the following personal protective equipment (PPE):

Long-sleeved shirt and long pants.

Chemical resistant gloves, such as butyl rubber ≥ 14 mils, natural
rubber ≥ 14 mils, neoprene rubber ≥ 14 mils, or nitrile rubber ≥
14 mils.

Shoes plus socks.

	3.6.5	Occupational Dermal Exposure 

		Short-Term (1-30 Days) and Intermediate-Term (1-6 months)

	There were no systemic effects observed up to the limit dose of 1000
mg/kg/day in a 21-day dermal toxicity study in rabbits.  Dermal
irritation concerns are addressed by specific personal protective
equipment including long sleeved shirts, long pants, and chemical
resistant gloves.  Since no dermal hazard has been identified, a risk
assessment was not conducted.

		Long-Term Dermal (> 6 months)

A quantitative risk assessment is not appropriate since long-term
exposure is not expected based on the current use profile for
chlormequat chloride.  Chlormequat chloride is likely used in
greenhouses and nurseries throughout the year on various ornamental
species.  These uses would likely result in a series of short-term
exposures as opposed to 6 months of consecutive exposure (i.e.,
long-term exposure).

	3.6.6 	Occupational Inhalation Exposure (Short- and Intermediate-Term)

Study Selected: Prenatal Developmental Toxicity-Rat

NOAEL:  30 mg/kg/day

LOAEL:  90 mg/kg/day

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X
intraspecies variability)

Inhalation Absorption Factor: 100%

Comments: A toxicity study via the inhalation route is not available to
establish a point of departure for the occupational inhalation
assessment.  Therefore, an oral study was selected for establishing a
point of departure, namely the prenatal developmental toxicity study in
rats.  The maternal NOAEL is 30 mg/kg/day and the LOAEL is 90 mg/kg/day.
 Maternal effects were manifested as decreased body weight gain
(38-112%-GD 6-9; 21-67% GD 6-12) and food consumption and greater
incidences of increased salivation and chromorhinorrhea. Absorption via
the inhalation route is presumed to be equivalent to oral absorption
therefore, a default inhalation factor of 100% was applied to inhalation
exposures.  Uncertainty factors (100x) include: 10X interspecies
extrapolation, and 10X intraspecies variability.

Long-Term Inhalation Exposure (> 6 months)

	A quantitative risk assessment is not appropriate since long-term
exposure is not expected based on the current use profile for
chlormequat chloride.  Chlormequat chloride is likely used in
greenhouses and nurseries throughout the year on various ornamental
species.  These uses would likely result in a series of short-term
exposures as opposed to 6 months of consecutive exposure (i.e.,
long-term exposure).

3.7	Level of Concern for Margin of Exposure

	This pesticide is registered for use only in non-food and
non-residential settings and, therefore, is not subject to the Food
Quality Protection Act (1996).  There are no data gaps or other database
uncertainties associated with this chemical.  Furthermore, a
developmental neurotoxicity study is not required at this time and there
is no need for additional uncertainty factors.  Therefore, the
uncertainty factor (100X) applied was based on 10X default factors for
intraspecies variation and interspecies extrapolation.  Margins of
exposure (MOE) less than 100 are of concern to HED.

Table 3.7  Summary of the Levels of Concern (LOC) for Occupational
Exposure Risk Assessments for Chlormequat Chloride

Route/Duration	Short-Term

(1 - 30 days)	Intermediate-Term

(1 - 6 months)	Long-Term

(> 6 months)

Occupational (Worker) Exposure

Dermal	N/A	N/A	N/A

Inhalation	100	100	N/A

  N/A = Not applicable	

3.8	Classification of Carcinogenic Potential

	There were no treatment-related increases in tumors in rat and mouse
carcinogenicity studies after exposure to chlormequat chloride. 
Additionally, there was no evidence of mutagenicity noted.  Therefore,
chlormequat chloride is classified as not likely to be carcinogenic in
humans.

3.9	Summary of Toxicological Doses and Endpoints

Table 3.9a  Toxicological Doses and Endpoints for Chlormequat Chloride
for use in Dietary (Drinking Water Only) Exposure Assessment

Exposure/

Scenario	Point of Departure	Uncertainty Factors	RfD

Level of Concern	Study and Toxicological Effects

Acute Dietary (all populations)	NOAEL=

90 mg/kg/day

	UFA = 10X

UFH = 10X

	aRfD=0.9

mg/kg/day

	Prenatal Developmental-Rat (MRID 42246604)

1-Day oral LOAEL 180 mg/kg/day, based on overt toxicity signs (tremors,
ataxia) within an hour after a single oral dose in dams (GD 6).

Chronic Dietary 

(all populations)	NOAEL =

5 mg/kg/day

	UFA = 10X

UFH = 10X

	cRfD = 0.05 mg/kg/day

	Chronic Toxicity-Dog (MRID 46715201)

LOAEL (mg/kg/day): 10 mg/kg/day, based on salivation (1 week
post-dosing, both sexes), vomiting (females), diarrhea (males), and
decreased body weight gain (males).

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

lack of carcinogenic potential noted in the available studies.

Table 3.9b  Toxicological Doses and Endpoints for Chlormequat Chloride
for use in Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	RfD

Level of Concern	Study and Toxicological Effects

Dermal

(short-term, intermediate-term)	NA	NA	NA	No hazard was identified

21-day dermal toxicity study – rabbits

LOAEL = not determined, no systemic effect up to the limit dose of 1000
mg/kg/day.

Inhalation

(short-term, intermediate-term)	NOAEL = 30 mg/kg/day

100% absorption	UFA = 10X

UFH = 10X

	Occupational LOC for MOE = 100	Developmental toxicity study- rat (MRID
42246604)

LOAEL=90 mg/kg/day, based on decreased body weight gains (38-112%-GD
6-9; 21-67% GD 6-12) and food consumption and greater incidences of
increased salivation and chromorhinorrhea

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

lack of carcinogenic potential noted in the available studies.

NOAEL = no observed adverse effect level.  LOAEL = lowest observed
adverse effect level.  UF = uncertainty factor.  UFA = extrapolation
from animal to human (interspecies).  UFH = potential variation in
sensitivity among members of the human population (intraspecies).  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.

3.10	Endocrine Disruption

	EPA is required under the Federal Food Drug and Cosmetic Act (FFDCA),
as amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate."  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there were scientific
bases for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).  When the appropriate
screening and/or testing protocols being considered under the Agency’s
EDSP have been developed, there may be additional screening and/or
testing required to better characterize effects related to endocrine
disruption.  

3.11	Public Health and Pesticide Epidemiology Data 

	Public health/epidemiology data were not available for the development
of this risk assessment.	

4.0 	Drinking Water Exposure and Risk Pathway/Characterization

D336717	Tier I Drinking Water Assessment for Chlormequat Chloride in
Support of the 					Reregistration Eligibility Decision.  (M.
Echeverria, 03/19/2007)

	

	There are a number of data gaps in the chlormequat chloride
environmental fate and transport dataset.  In the absence of data,
assumptions made regarding chlormequat chloride were compared to and
supported by the environmental fate and transport data of
didecyl-dimethylammonium chloride (DDAC, PC code 69149, CAS No.
007173-51-5).  DDAC and chlormequat chloride are both quaternary
ammonium compounds that have been classified according to the Agency’s
PR Notice 88-2 (February 26, 1988) as Group I, alkyl or hydroxyalkyl
(straight chain) substituted quaternary ammonium compounds.

Chlormequat chloride has variable mobility in the environment.  Batch
equilibrium studies resulted in Freundlich sorption coefficients ranging
1.13 – 9.12 ml/g with corresponding 1/N values ranging 0.511 – 0.955
(MRIDs 46715228, 46715229).  Even though chlormequat chloride is a
cation, the correlation between cation exchange capacity (CEC) and
sorption was not significant in the batch equilibrium studies.  In a
supplemental aged column leaching study 0.3-0.5 % of the applied
radioactivity was found in the leachate after 48 hours of leaching with
4 pore volumes of 0.01 M CaCl2 in a loamy sand soil (MRID 46715230).  In
another supplemental aged column leaching study 2.5% of the applied
radioactivity was found in the leachate following 45 days of leaching
with 0.5 inches of distilled water daily through a 15 inch column filled
with a clay loam soil (MRID 124061).   In a supplemental unaged column
leaching study  < 0.1 % of applied radioactivity was found in the
leachate after leaching with 20 inches of distilled water at a rate not
exceeding 1 inch/hour through a 15 inch column filled with a sand, sandy
loam, silt loam and clay loam soil (MRID 124062).  In both of these
studies distilled water was used which could lead to dispersion of clays
that could affect soil structure.  Depending on soil, site and
meteorological conditions chlormequat chloride may be transported
off-site via runoff, leaching and/or erosion.  

	

	Overall, the major route of dissipation for chlormequat chloride
appears to be microbial degradation.  A supplemental aerobic soil
metabolism study showed that chlormequat chloride degraded with
half-lives of 30-43 days in two sandy loam and two silt loam soils (MRID
46715225).  In the study, up to 43.7% and 10.7% of the applied
radioactivity in the soil extracts was unaccounted for in two soils.  No
attempt was made to identify these transformation products and it is not
known whether or not the residues consisted of one or more components. 
Consequently, all transformation products detected at >10% of the
applied may not have been identified.  Using a total residue approach
that assumes all uncharacterized extractable residues are of equal
toxicity to chlormequat chloride results in half-lives of 32 – 132
days.  A supplemental aerobic aquatic metabolism study showed that
chlormequat chloride degraded with total system half-lives of 5-9 days
in a river water-sandy loam sediment and pond water-silt loam sediment
system (MRID 46715227).  There were no available acceptable data for
degradation of chlormequat chloride by hydrolysis or photolysis. 
Comparison to DDAC data, however, suggests that chlormequat chloride may
be hydrolytically and photolytically stable (MRID 411758-01, 411758-02).
 There are also no data for chlormequat chloride under anaerobic
conditions.  DDAC has, however, been shown to be persistent under
anaerobic conditions (MRID 422538-02).

	

	The estimated drinking water concentration (EDWC) estimates used in the
dietary risk assessment were provided by the Environmental Fate and
Effects Division (EFED) in the following memorandum: “Tier I Drinking
Water Assessment for Chlormequat Chloride in Support of Reregistration
Eligibility Decision” (M. Echeverria, D336717, 03/19/2007).    EDWCs
were incorporated into DEEM-FCID as the food forms “water, direct, all
sources” and “water, indirect, all sources.”   A summary of the
EDWCs is provided in Table 4.0.

The highest EDWC was calculated in surface water using the FIRST model
and these upper bound conservative values were used for the drinking
water analysis.  

Tier 1 EDWCs for surface water were generated by EFED from their Tier I
(F)IFRA (I)ndex (R)eservoir (S)creening (T)ool (FIRST) EDWC surface
water model

 FIRST is a screening model designed by the Environmental Fate and
Effects Division (EFED, 2001a) of the Office of Pesticide Programs to
estimate pesticide concentrations found in drinking water from surface
water sources for use in human health risk assessment.  As such, it
provides upper bound values on the concentrations that might be found in
drinking water due to the use of a pesticide.  FIRST is a single-event
model (one runoff event), but can account for spray drift from multiple
applications.  FIRST is hardwired to represent the Index Reservoir, a
standard water body used by the Office of Pesticide Programs to assess
drinking water exposure (Office of Pesticide Programs, 2002).  It is
based on a real reservoir, Shipman City Lake in Illinois, which is known
to be vulnerable to pesticide contamination.

These EDWCs were obtained from modeling using the highest use rate of
all labeled uses with an annual application rate of 33.3 lbs
a.i./A/year.

Since there were unidentified residues in the aquatic and soil
metabolism studies that may be of risk concern, a total toxic residue
approach that assumes all uncharacterized extractable residues are of
equal toxicity to the parent was used to estimate exposure.

The model and its description are available at the EPA internet site:  
HYPERLINK "http://www.epa.gov/oppefed1/models/water/" 
http://www.epa.gov/oppefed1/models/water/ .  

Table 4.0 Tier I EDWC for chlormequat chloride for ground boom spray
applications

Drinking Water Source (Model)	Use rate (lbs a.i./A/year)	EDWC (ppb)

Surface water (FIRST)

 - Acute (peak)

 - Chronic (annual mean)	

33.3

	

2574

91

Groundwater (SCI-GROW)	33.3	24

	Numerous conservative assumptions were used by EFED to generate the
EDWCs.  Based on the following, the resulting EDWCs are deterministic
upper-bound estimates.

Modeled values were used since no monitoring data are available

Assumes 100% of watershed is treated (no percent crop area data is
available, but there is a relatively low amount of chlormequat chloride
applied per year on a nationwide basis, including all indoor uses)

Assumes 100% of the product is absorbed into the ground and/or runs off
(i.e.- no plants on the surface treated, all product makes ground
contact)

Ground boom applications drive the risk even though limited usage is
expected

	

4.1	Acute and Chronic Drinking Water Exposure and Risk

D336712	Chlormequat Chloride. Screening-level Acute and Chronic Dietary
(Drinking Water Only) 			Exposure and Risk Assessment for the
Reregistration Eligibility Decision.  

		(D. Wilbur, 06/07/2007)

	

	Chlormequat chloride acute and chronic dietary exposure assessments
were conducted using the Dietary Exposure Evaluation Model software with
the Food Commodity Intake Database DEEM-FCID™, Version 2.03 which
incorporates consumption data from USDA’s Continuing Surveys of Food
Intakes by Individuals (CSFII), 1994-1996 and 1998.  The 1994-96, 98
data are based on the reported consumption of more than 20,000
individuals over two non-consecutive survey days.  For the purposes of
this risk assessment, drinking water is considered a food/foodform by
the DEEM modeling program and is treated as such.  Foods “as
consumed” (e.g., rhubarb pie with ice cream) are linked to EPA-defined
food commodities (e.g. rhubarb, peeled fruit - cooked; fresh or N/S;
baked; or wheat flour - cooked; fresh or N/S, baked) using publicly
available recipe translation files developed jointly by USDA/ARS and
EPA.  For chronic exposure assessment, consumption data are averaged for
the entire U.S. population and within population subgroups, but for
acute exposure assessment are retained as individual consumption events.
 Based on analysis of the 1994-96, 98 CSFII consumption data, which took
into account dietary patterns and survey respondents, HED concluded that
it is most appropriate to report risk for the following population
subgroups: the general U.S. population, all infants (<1 year old),
children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49,
females 13-49, and adults 50+ years old.

Acute Drinking Water Exposure Results

	Acute drinking water exposure estimates were generated based on the
deterministic upper bound estimates from EFED’s Tier I EDWC model
(FIRST).  Therefore, because of the conservative nature of this model,
it is inappropriate to assess risks based upon exposures at the 99.9th
percentile.  It is more appropriate to consider exposure at the 95th
percentile.  The acute dietary exposure estimates from drinking water
are below HED’s level of concern (< 100% aRfD) for the U.S. population
and all population subgroups at the 95th percentile.  A summary of the
results from the acute dietary exposure analysis is shown in Table 4.1.
The highest exposed population subgroup was all infants (< 1 year) at
56% of the acute RfD of 0.9 mg/kg/day.  Based on the screening-level
EFED assessment used to generate the drinking water estimates, HED
concludes that there is no concern for potential acute dietary exposure
from drinking water.

Chronic Drinking Water Exposure Results

	The chronic dietary exposure estimates from drinking water are below
HED’s level of concern (< 100% cRfD) for the U.S. population and all
population subgroups.  A summary of the results from the chronic dietary
exposure analysis is shown in Table 4.1.  The highest exposed population
subgroup was all infants (< 1 year) at 13% of the chronic RfD of 0.05
mg/kg/day.  Based on the screening-level EFED assessment used to
generate the drinking water estimates, HED concludes that there is no
concern for potential chronic dietary exposure from drinking water.

Table 4.1. Summary of Acute and Chronic Drinking Water Exposure and Risk
for Chlormequat Chloride

Population Subgroup	Acute Drinking Water

95th  Percentile	Chronic Drinking Water

	aRfD (mg/kg/day)	Dietary Exposure (mg/kg/day)	% aRfD	cRFD (mg/kg/day)
Dietary Exposure

(mg/kg/day)	% cRfD

General U.S. Population	0.9	0.13446    	15   	0.05	0.00192	3.8

All Infants (< 1 year old)

0.50696   	56    

0.00629                	13

Children 1-2 years old

0.21098   	23    

0.00285                 	5.7

Children 3-5 years old

0.19274       	21

0.00267                 	5.3

Children 6-12 years old

0.13417      	15

0.00184                 	3.7

Youth 13-19 years old

0.10909      	12  

0.00139                 	2.8

Adults 20-49 years old

0.12458    	14 

0.00179                 	3.6

Adults 50+ years old

0.11250    	13   

0.00188                 	3.8

Females 13-49 years old 

0.125285      	14

0.001783                 	3.6

5.0	 Dietary Exposure and Risks

	Chlormequat chloride has no food uses registered in the United States
at this time; thus, potential dietary exposures and risks result from
drinking water exposure only, and are summarized in Section 4.1 above.

6.0	Residential and Other Non-Occupational Exposures and Risks 

	Chlormequat chloride does not currently have any registrations for
residential use nor is it registered for use in any residential
settings.  As a result, no residential chlormequat chloride handler or
postapplication assessments are required at this time.

7.0	Aggregate, Cumulative, and FQPA Assessments

	In accordance with the FQPA, HED must consider and aggregate (add)
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, HED considers both the route and duration of exposure. 
However, since chlormequat chloride does not have food or residential
uses, an aggregate risk assessment is not applicable.

	Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mode of toxicity, EPA has not made a common
mode of toxicity finding as to chlormequat chloride and any other
substances, and chlormequat chloride does not appear to produce a toxic
metabolite produced by other substances. For the purposes of this risk
assessment, EPA has not assumed that chlormequat chloride shares a
common mode of toxicity with other substances.  Therefore, a cumulative
risk assessment is not applicable at this time.

	In addition, there are no residential or food uses associated with this
risk assessment and it is, therefore, not subject to the Food Quality
Protection Act (1996).

8.0 	Occupational Handler/Post Application Exposures & Risks

D336714	Chlormequat Chloride: Occupational and Residential Exposure
Assessment for 					the Reregistration Eligibility Decision Document. 
(C. Smith, 06/12/2007)

	There is a potential for exposure to chlormequat chloride in
occupational settings from handling chlormequat chloride products during
the application process (i.e., mixer/loaders, applicators, and
mixer/loader/applicators).  Accordingly, short- and intermediate-term
risk assessments have been completed for a number of occupational
handler scenarios.  Although postapplication exposures are expected, no
dermal occupational postapplication risk assessment was performed
because a dermal endpoint was not selected for chlormequat chloride and
no inhalation occupational postapplication assessment was performed due
to the low vapor pressure of chlormequat chloride.

8.1	Occupational Handler Exposures and Risks 

	HED uses the term “handlers” to describe those individuals who are
involved in the pesticide application process.  HED believes that there
are distinct job functions or tasks related to applications and that
exposures can vary depending on the specifics of each task. Job
requirements (e.g., amount of chemical to be used in an application),
the kinds of equipment used, the target being treated, and the level of
protection used by a handler can cause exposure levels to differ in a
manner specific to each application event. 

	8.1.1	Data and Assumptions for Handler Exposure Scenarios 

	HED uses exposure scenarios to describe the various types of handler
exposures that may occur for a specific active ingredient. The use of
scenarios as a basis for exposure assessment is very common as described
in the U.S. EPA Guidelines for Exposure Assessment (U.S. EPA; Federal
Register Volume 57, Number 104; May 29, 1992).  Information from the
current labels, use and usage information, toxicology data, and exposure
data were all key components in the development of the exposure
scenarios.  HED has developed a series of general descriptions for tasks
that are associated with pesticide applications.  Tasks associated with
occupational pesticide handlers are categorized using one of the
following terms:

Mixers and/or Loaders: These individuals perform tasks in preparation
for an application.  These individuals would mix the chlormequat
chloride and transfer it into the application equipment.

Applicators: These individuals operate application equipment during the
release of a pesticide product into the environment.  These individuals
would apply the chlormequat chloride.

Mixer/Loader/Applicators and or Loader/Applicators: These individuals
are involved in the entire pesticide application process (i.e., they do
all job functions related to a pesticide application event).  These
individuals would transfer chlormequat chloride into the application
equipment and then also apply it.

	A chemical can produce different effects based on how long a person is
exposed, how frequently exposures occur, and the level of exposure.  HED
classifies exposures up to 30 days as short-term and exposures greater
than 30 days up to several months as intermediate-term.  HED completes
both short- and intermediate-term assessments for occupational scenarios
in essentially all cases, because these kinds of exposures are likely
and acceptable use/usage data are not available to justify deleting
intermediate-term scenarios.  Based on use data and label instructions,
HED believes that occupational chlormequat chloride exposures may occur
over a few days for many use-patterns and that intermittent exposure
over several weeks also may occur.  Long-term handler exposures are not
expected to occur for chlormequat chloride based on the current use
profile.  Chlormequat chloride is likely used in greenhouses and
nurseries throughout the year on various ornamental species.  This use
would likely result in a series of short-term exposures as opposed to 6
months of consecutive daily exposure (i.e., long-term exposure).  The
same toxicological endpoint of concern (from the same developmental
study) has been selected for short- and intermediate-term inhalation
exposures to chlormequat chloride; therefore, the risk results for these
durations of exposure also are numerically identical.

	Other parameters are also defined from use and usage data such as
application rates and application frequency.  HED always completes
non-cancer risk assessments using maximum application rates for each in
order to ensure there are no concerns for each specific use.

  

	Occupational handler exposure assessments are completed by HED using
different levels of risk mitigation.  Typically, HED uses a tiered
approach.  The lowest tier is designated as the baseline exposure
scenario (i.e., long-sleeve shirt, long pants, shoes, socks, and no
respirator).  If risks are of concern at baseline attire, then
increasing levels of personal protective equipment or PPE (e.g., gloves,
double-layer body protection, and respirators) are evaluated.  If risks
remain a concern with maximum PPE, then engineering controls (e.g.,
enclosed cabs or cockpits, water-soluble packaging, and closed
mixing/loading systems) are evaluated.  This approach is used to ensure
that the lowest level of risk mitigation that provides adequate
protection is selected, since the addition of PPE and engineering
controls involves an additional expense to the user and – in the case
of PPE – also involves an additional burden to the user due to
decreased comfort and dexterity and increased heat stress and
respiratory stress.

	8.1.2	Handler Exposure Scenarios 

	It has been determined that exposure to pesticide handlers is likely
during the occupational use of chlormequat chloride in commercial
ornamental production facilities.  The anticipated use patterns and
current labeling indicate several occupational exposure scenarios based
on the types of equipment and techniques that can potentially be used
for chlormequat chloride applications. The quantitative exposure/risk
assessment developed for occupational handlers is based on the following
scenarios. 

Mixer/Loaders:

	(1) Liquid Formulations for Groundboom Applications

	Applicators:

(2) Groundboom Spray Applications

	Mixer/Loader/Applicators:

(3) Liquid Formulations: Low Pressure Handwand/HandwandBackpack Sprayer
(using PHED liquid low pressure handwand data)

(4) Liquid Formulations: High Pressure Handwand

8.1.3	Non-cancer Risk Summary

	The results indicate that all of the occupational handler risks do not
exceed HED’s level of concern [i.e., MOEs are greater than 100].  A
summary of the short- and intermediate-term risks for each exposure
scenario are presented below in Table 8.1.3.

Table 8.1.3.  Chlormequat Chloride Inhalation Occupational Handler Risks

Exposure Scenario	Crop or Target	Application Rate a	Area Treated Daily 
Baseline Inhalation Unit Exposure (ug/lb ai)	Baseline Inhalation Dose
(mg/kg/day) b	Baseline Inhalation MOE c

Mixer/Loader

Mixing/Loading Liquids Concentrates for Groundboom Applications
ornamentals: shadehouses and nurseries	5.5 lb ai/A	1 A d	1.2	0.000094
320000

3.7 lb ai/A

	0.000063	470000

Applicator

Applying Sprays via Groundboom Equipment	ornamentals: shadehouses and
nurseries	5.5 lb ai/A	1 A d	0.74	0.000058	520000

3.7 lb ai/A

	0.000039	770000

Mixer/Loader/Applicator

Mixing/Loading/Applying Liquid Concentrates with Low Pressure Handwand
(PHED)	ornamentals: shadehouses and nurseries	0.017 lb ai/gal	40 gals	30
0.00029	100000

	ornamentals: greenhouse	0.034 lb ai/gal

	0.00058	51000

	ornamentals: greenhouse	0.013 lb ai/gal

	0.00022	130000

Mixing/Loading/Applying Liquid Concentrates with a High Pressure
Handwand (only study is for greenhouse use)	ornamentals: greenhouse
0.025 lb ai/gal	1000 gals	120	0.043	700

	ornamentals: greenhouse	0.034 lb ai/gal

	0.058	510

a	Application rates are the maximum application rates determined from
EPA registered labels for chlormequat chloride

b	Average Daily Dose (mg/kg/day) = Daily Exposure * Absorption Factor /
Body Weight

c	MOE = NOAEL / Average Daily Dose (mg/kg/day)

d	Maximum area treated per day of 1 acre for groundboom applications is
based on label restrictions.

8.2	Occupational Postapplication Exposures and Risks

	No dermal occupational postapplication risk assessment was performed
because a dermal endpoint was not selected for chlormequat chloride due
to its lack of systemic toxicity via the dermal route.  When there is no
dermal occupational postapplication risk assessment, the restricted
entry interval (REI) is based on the acute toxicity of the chemical. 
The current chlormequat chloride label requires a 12-hour REI but
chlormequat chloride has been classified as Category II for acute dermal
toxicity.  In accordance with the requirements in the Worker Protection
Standards (WPS) - 40CFR170, ingredients classified as Category II are
assigned a 24-hour REI.  HED recommends that the Registration Division
(RD) ensure that the proper REI for ornamental plants grown in
greenhouses, nurseries, and shadehouses be included on the chlormequat
chloride labels.

An inhalation occupational postapplication assessment was not performed
for chlormequat chloride due to its low vapor pressure.  However, in
nurseries and greenhouses, the WPS prohibits workers from entering the
treated area for the first four hours after an application is completed
to allow time for sprays and dusts to settle out of the air to protect
workers against postapplication inhalation exposures.

9.0	Data Needs and Label Recommendations

	HED recommends that RD ensure that the current 12-hour REI on
chlormequat chloride labels be changed to a 24-hour REI in accordance
with the requirements for the Worker Protection Standards (WPS) [see
Section 8.2].

	

Appendix A: Toxicology Data Requirements

The requirements (40 CFR 158.340) for non-food use for chlormequat
chloride are presented in the following table. Use of the new guideline
numbers does not imply that the new (1998) guideline protocols were
used.

Table 1. Toxicology Data Requirements	

Technical

Test

Required	

Satisfied

870.1100	Acute Oral Toxicity	

870.1200	Acute Dermal Toxicity	

870.1300	Acute Inhalation Toxicity	

870.2400	Primary Eye Irritation	

870.2500	Primary Dermal Irritation	

870.2600	Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100	Oral Subchronic (rodent)	

870.3150	Oral Subchronic (nonrodent)	

870.3200	21/28-Day Dermal	

870.3250	90-Day Dermal	

870.3465	90-Day Inhalation		no

no

yes

no

no	yes

---

yes

---

---

870.3700a	Developmental Toxicity (rodent)	

870.3700b	Developmental Toxicity (nonrodent)	

870.3800	Reproduction		yes

no

no	yes

yes

yes

870.4100a	Chronic Toxicity (rodent)	

870.4100b	Chronic Toxicity (nonrodent)	

870.4200a	Oncogenicity (rat)	

870.4200b	Oncogenicity (mouse)	

870.4300	Chronic/Oncogenicity		no

no

no

no

no	---

yes

yes

yes

---

870.5100	Mutagenicity—Gene Mutation -bacterial	

870.5300	Mutagenicity—Gene Mutation -mammalian	

870.5385	Mutagenicity—Mammalian-chromosome aberration

870.5550              Mutagenicity—Unscheduled DNA Synthesis	yes

yes

yes

yes	yes

yes

yes

yes

870.6100a	Acute Delayed Neurotoxicity (hen)	

870.6100b	90-Day Neurotoxicity (hen)	

870.6200a	Acute Neurotoxicity  Screening Battery (rat)	

870.6200b	90 Day Neurotoxicity Screening Battery (rat)	

870.6300	Developmental Neurotoxicity		no

no

no

no

no	---

---

---

---

---

870.7485	General Metabolism	

870.7600	Dermal Penetration	no

no	---

---

Special Studies for Ocular Effects	no	---

Appendix B

Summaries of Toxicity studies used in Toxicity Endpoint Selection

Oral Subchronic Toxicity Study-Rat; OPPTS 870.3100; OECD 408

EXECUTIVE SUMMARY: In a subchronic oral toxicity study (MRID 00163408),
Chlormequat chloride (AC 38,555; 97.0% (w/w) was administered for up to
13 weeks to 10 Sprague-Dawley rats/sex/group in the diet at dose levels
of 0, 300, 900, or 2700 ppm (approximately equivalent to 0, 20.6, 61.3,
and 188.5 mg/kg/day in males and 0, 24.4, 72.9, and 220.1 mg/kg/day in
females)

No adverse treatment-related effects were noted in mortality, clinical
signs, food consumption, food efficiency, hematology, clinical
chemistry, urinalysis, organ weights, or gross or microscopic pathology.

At 2700 ppm, there were decreases (p < 0.05) in body weight (7-8%; week
9-13), and overall body weight gain (11%; week 0-13) in males. No
treatment-related effects on body weight were observed in females. 

The LOAEL is 2700 ppm (approximately equivalent to 188.5 mg/kg/day in
males and 220.1 mg/kg/day in females), based on decreased body weight
and body weight gain in males. The NOAEL is 900 ppm (approximately
equivalent to 61.3 mg/kg/day in males and 72.9 mg/kg/day in females).

This study is classified as acceptable/non-guideline and does not
satisfy the guideline requirement (OPPTS 870.3100a; OECD 408) for a
subchronic oral toxicity study in the rat based on insufficient data for
the homogeneity and stability of the test material in the diet.

Note:  Homogeneity/stability was requested for this chemical on
September 01, 2005. The registrant was unable to retrieve the data due
to the time and place where the study was conducted (1981, Japan). A
4-week feeding study determining the stability of chlormequat in animal
feed was submitted. The results showed that chlormequat chloride was
homogenous and stable for up to 32 days at room temperature. 

21-Day Dermal Toxicity; OPPTS 870.3200

EXECUTIVE SUMMARY: In a 21-day dermal toxicity study (MRID 42246603),
Chlormequat chloride (AC 38,555; 66.1% a.i.; Lot #: AC 6779-98A) was
applied to the shaved intact skin of 6 New Zealand White
rabbits/sex/dose at dose levels of 0, 115, 345, or 1035 mg/kg/day (> the
limit dose), 6 hours/day, 5 days/week for 3 weeks (15 applications). 
Doses were adjusted for purity.  Dermal irritation was evaluated daily
using a Draize-like method.  Because the initial controls were
inadvertently exposed to the test material (1035 mg/kg) for 2.5 hours on
Day 1, additional control animals (Group 5) were added to the study on
Day 2 to provide gross necropsy and histopathology data.

No compound-related effects on mortality, clinical signs, body weight,
body weight gain, food consumption, hematology, clinical chemistry, or
organ weights were observed.

In the 345 mg/kg/day group, dermal irritation characterized by erythema,
edema, and fissuring was observed in 1-2 females, a gross lesion (foci)
was seen in one female, and histopathological lesions in the treated
skin (mild acanthosis and minimal subacute inflammation and edema) in
another female.

At 1035 mg/kg/day, dermal irritation (erythema, edema, fissuring, and
eschar) was also observed in 1-3 females.  Gross lesions were limited to
foci in the treated skin in 2 males and 1 female. Minimal to mild
histopathological effects observed in the treated skin in both sexes
included: (i) acanthosis (2 males and 4 females); (ii) subacute
inflammation (2 males and 1 female); and (iii) edema (2 males and 3
females).  Additionally, a single male displayed minimal fibrosis of the
treated skin.

The systemic LOAEL is not determined and the systemic NOAEL is 1035
mg/kg/day (> the limit dose).

The dermal LOAEL is 345 mg/kg/day based on dermal irritation, gross
lesion of the treated skin, acanthosis, subacute inflammation, and edema
in females.  The dermal NOAEL is 115 mg/kg/day.

This study is classified as acceptable/guideline and satisfies the
guideline requirement (OPPTS 870.3200; OECD 410) for a 21-day dermal
toxicity study in rabbits.

Developmental Toxicity Study-Rat; OPPTS 870.3700a; OECD 414

		

EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 42246604),
Chlormequat chloride (AC 38,555; 66.1% a.i., doses adjusted for purity;
Lot # AC 6779-98A)  in reverse osmosis membrane processed deionized
water was administered daily via oral gavage to 25 presumed pregnant
Sprague-Dawley (Crl:CD®BR VAF/Plus®) rats/group at a dose volume of 10
mL/kg at dose levels of 0, 30, 90, or 180 mg/kg/day from gestation day
(GD) 6 through 15.  All surviving dams were killed on GD 20; their
fetuses were removed by cesarean section and examined.

There were no treatment-related effects on mortality or gross pathology.

At > 90 mg/kg/day, clinical signs of toxicity included increased
incidences of excesses salivation (7-21 treated dams vs 0 controls) and
chromorhinorrhea (2-3 treated dams vs 0 controls).  Clinical signs first
occurred for the 90 mg/kg/day dams after the second dose (GD 7) and for
the 180 mg/kg/day dams after the first dose (GD 6).  Additionally at 180
mg/kg/day, decreased motor activity, tremors, ataxia, lacrimation,
rales, gasping, body jerks, and increased incidences of
chromodacryorrhea were observed.

At > 90 mg/kg/day, maternal body weight gains were decreased (p< 0.05)
during GD 6-9 (38-112%) and GD 6-12 (21-67%).  Additionally at 180
mg/kg/day, body weight gains were decreased (p< 0.01) during GD 7-8
(144%), 8-9 (103%), and 9-12 (38%), resulting in decreased (36%; p<
0.01) body weight gains for the overall (GD 6-16) treatment interval. 
Furthermore, body weights at this dose were decreased (5-9%) beginning
on GD 8 and continuing until termination.  During the post-treatment
interval, body weight gains of the treated groups were comparable to
controls.  Gravid uterine weights of the treated groups were comparable
to controls.  Thus, body weight gains from the beginning of treatment
until termination (GD 6-20) were decreased (p< 0.01) whether uncorrected
(13%) or corrected (39%) for gravid uterine weight.

At 90 mg/kg/day, decreases (7-16%; p < 0.05) in absolute (g/rat/day) and
relative (to body weight) food consumption (g/kg/day) were observed
during GD 7-8, 6-9, and 6-12.  Additionally at this dose, absolute food
consumption was decreased during GD 9-12.  At 180 mg/kg/day, absolute
and relative food consumption were decreased (7-34%; p < 0.05)
throughout the treatment interval.  During the post-treatment interval,
absolute food consumption was comparable to controls, and relative food
consumption was increased (8%; p < 0.01) compared to controls.  

The maternal LOAEL is 90 mg/kg/day based on increased incidences of
excess salivation and chromorhinorrhea and decreased body weight gains
and food consumption.  The maternal NOAEL is 30 mg/kg/day.

There were no abortions, premature deliveries, complete litter
resorptions, or dead fetuses.  There were no treatment-related effects
on the numbers of litters, live fetuses, early resorptions, late
resorptions, or on the sex ratio or post-implantation loss.  There were
no treatment-related effects on fetal body weights or on skeletal
ossification, indicating no effect on fetal growth or development. 
There were no treatment-related external, visceral, or skeletal
malformations or variations.

The developmental LOAEL is not determined and the developmental NOAEL is
180 mg/kg/day.

This study is classified acceptable/guideline (OPPTS 870.3700a) and
satisfies the guideline requirements for a developmental study in the
rat.

  SEQ CHAPTER \h \r 1 

Developmental Toxicity Study-Rabbit; OPPTS 870.3700b; OECD 414

EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 46715205),
Chlormequat chloride (99% a.i.; Lot # 78/557/78/639) in distilled water
was administered daily via oral gavage (10 mL/kg) to groups of 14-21
artificially inseminated Himalayan (ChBB:HM) rabbits/dose at dose levels
of 0, 1.5, 3.0, 6.0, or 12.0 mg/kg/day on gestation days (GD) 6-18.  All
surviving does were killed on GD 28; their fetuses were removed by
cesarean section and examined.

Maternal toxicity

There were no treatment-related effects observed on mortality, clinical
signs, or gross pathology.

rnal absolute body weights for all treatment groups were comparable to
the control group throughout the study.  Mean food consumption was
decreased (p≤0.05) in all treatment groups during GD 6-18 (12-17%),
resulting in decreased (not significant; NS) overall (GD1-28) food
consumption (8%).  The decrease in food consumption observed in treated
groups can not be verified since individual food consumption data was
not reported; therefore, it can not be determined whether the decrease
in food consumption is indeed an effect of treatment.

The maternal LOAEL is not determined and the maternal NOAEL is 12.0
mg/kg/day.

Developmental toxicity

There were no treatment-related external, visceral, or skeletal
malformations or variations observed.  In addition, there were no
effects of treatment observed on numbers of litters, live fetuses,
resorptions (early, late, or complete litter), sex ratio, or
post-implantation loss.  No treatment-related effects were observed on
fetal body weight or crown-rump length, or placental weight.  

The developmental LOAEL is not determined and the developmental NOAEL is
12.0 mg/kg/day.

This developmental toxicity study in the rabbit is classified
acceptable/non-guideline and does not satisfy the guideline requirement
(OPPTS 870.3700b; OECD 414) for a developmental toxicity study in
rabbits.  The frequency of preparation of the test formulations and
homogeneity, stability, and concentration analyses were not provided. 
In addition, a LOAEL was not determined and the animals could have
tolerated a higher dose.    

Reproduction and Fertility Effects-Rat; OPPTS 870.3800; OECD 416

		

EXECUTIVE SUMMARY: In a multigeneration reproduction toxicity study
(MRID 46715206), chlormequat chloride (67.4% a.i., dose levels adjusted
for purity; Batch No. 82-0767) was administered continuously in the diet
to Wistar rats (24 rats/sex/dose) at dose levels of 0, 300, 900, or 2700
ppm (approximately equivalent to 0, 28.9, 86.4, and 254.6 mg/kg/day in
males and 0, 30.8, 93.4, and 279.3 in females).    SEQ CHAPTER \h \r 1
The P animals were given test article diet formulations for 10 weeks
prior to mating and throughout mating to produce the F1a litters, and
throughout gestation and lactation for females; they were subsequently
mated again to produce a second litter (F1b retained only until
weaning).  After weaning, F1a animals (24/sex/dose) were selected to
become the parents of the F2 generation and were given the same
concentration test formulation as their parents.  F1 animals were given
test formulations for 14 weeks prior to mating and throughout mating to
produce the F2 litters, and throughout gestation and lactation for
females.  In addition to the typical parameters examined in a
reproductive toxicity study, clinical chemistry parameters were examined
in 12 female F1 rats/dose.

No treatment-related adverse effect was observed in the parents on
mortality, food consumption, mating or gestation indices, gestation
duration, clinical chemistry, or on gross or histological pathology.

At 900 ppm in the P generation dams, mean body weight gain was decreased
during lactation of 

the first litter by 52% (p≤0.01) and second litter by 72% (NS; Table
3a).  These decreases in body

weight gains were not associated with decreased body weights at 900 ppm.
 

At 2700 ppm, increased incidences of tremor and hypersensitivity were
observed during lactation.  Decreased body weights and body weight gains
were observed in the females of the P and F1 generations, generally
throughout the study but usually most severe during lactation. 
Decreased body weight gains were observed during pre-mating in the P
generation only, and in gestation and lactation in both generations. 

The LOAEL for parental toxicity is 2700 ppm (approximately equivalent to
254.6 mg/kg/day in males and 279.3 mg/kg/day in females), based on
decreased body weights and body weight gains of the P and F1
generations, and increased incidences of tremor and hypersensitivity. 
The NOAEL is 900 ppm (approximately equivalent to 86.4mg/kg/day in males
and 93.4 mg/kg/day in females).

No treatment-related effect was observed on male or female mating
indices. 

Fertility was decreased in the 2700 ppm group at each mating.  The
fertility index was 75-83% in the treated groups compared to concurrent
controls (96-100%) and historical controls (88-100%). However, fertility
was reevaluated in those animals that were not observed to be fertile,
and most of the animals were proven fertile.  In the P generation, only
one 2700 ppm female did not prove its fertility.  In the F1 generation,
one 300 ppm male was not reevaluated due to a technical error; one 900
ppm female, one 2700 ppm male, and one 2700 ppm female did not prove to
be fertile.  However, an effect of treatment may have been diluted by
mating treated rats with controls for this re-evaluation.  

The LOAEL for reproductive performance is 2700 ppm (approximately
equivalent to 254.6 mg/kg/day in males and 279.3 mg/kg/day in females),
based on decreased fertility indices.  The NOAEL is 900 ppm
(approximately equivalent to 86.4 mg/kg/day in males and 93.4 mg/kg/day
in females).

  SEQ CHAPTER \h \r 1 No treatment-related effect was observed on number
of pups born dead; live birth, viability, or lactation indices; sex
ratio; acoustic startle and pupil constriction responses; or gross or
histological pathology

≤0.01) mean litter size was observed at Days 0 (34%) and 4 before
culling (30%) in the F1a litter.  On Days 0 and 4 (before culling), mean
litter size was also decreased (NS) in the F1b (9-14%) and F2 (16-17%)
litters. 

At 2700 ppm, decreased (p≤0.01) body weights were observed in the F1a
generation on PND 14 and 21 (13-18%).  Decreased (p≤0.05) body weights
were observed in the F2 generation on PND 7, 14, and 21 (12-26%).  

At 2700 ppm in the F1a, F1b, and F2 generations, fewer (p≤0.01) pups
were noted with pinna unfolding (80-84% treated vs 91-98% controls),
auditory canal opening (84-91% vs 97-99%), and eye opening (77-81% vs
94-100%).  In addition, fewer (p≤0.05) pups demonstrated the gripping
reflex at 2700 ppm in the F1a generation (95% treated vs 100% controls),
but the frequency was similar to controls in the F1b and F2 generations.

The LOAEL for offspring toxicity is 2700 ppm (approximately equivalent
to 254.6 mg/kg/day in males and 279.3 mg/kg/day in females), based on
decreased mean litter size, body weight, as well as delayed development.
The NOAEL is 900 ppm (approximately equivalent to 86.4 mg/kg/day in
males and 93.4 mg/kg/day females).

This study is classified as acceptable/guideline and satisfies the
guideline requirement (OPPTS 870.3800; OECD 416) for a two-generation
reproduction study in the rat.

  SEQ CHAPTER \h \r 1 

Oral Chronic Toxicity study -Dog; OPPTS 870.4100; OECD 452

		

EXECUTIVE SUMMARY: In a chronic toxicity study (MRID 46715201),
Chlormequat chloride (67.4% a.i., dose levels adjusted for purity, Batch
#: 82-0767) was administered to 5 beagle dogs/sex/dose in the diet for
52 weeks at doses of 0, 150, 300, or 1000 ppm (approximately equivalent
to 0, 5, 10, and 32 mg/kg/day). 

There were no treatment-related adverse effects observed on food
consumption, food efficiency, ophthalmoscopic examination, brain
cholinesterase, hematology, clinical chemistry, urinalysis, organ
weights, gross pathology, or histopathology.  

At 300 ppm and above, incidences of salivation were increased in the
males (3-5 treated vs. 0 controls) and females (2-5 treated vs. 0
controls).  Diarrhea was observed in the males at these doses (2-5
treated vs. 0 controls), and vomiting was noted in a single female at
300 ppm.  At 300 ppm, cumulative body weight gain was decreased (5-36%;
not significant [NS]) in males beginning on Day 21 and lasting until Day
231 where it had become comparable to controls.

At 1000 ppm, treatment-related deaths were observed in one male on Day
42 and one female on Day 20.  Histopathological examination in these
animals revealed moderate or marked serous lung edema.  Also, marked
depletion of thymic lymphocytes was noted in the male and multiple
thymic hemorrhages were noted in the female.  All other animals survived
until scheduled sacrifice.  Clinical signs of neurotoxicity were
observed in the animals that died, including:  emaciation, apathy,
staggering gait, lateral position, saltatory spasm, and vomitus in the
male and unsteady gait in the female.  Additionally at 1000 ppm,
cumulative body weight gain was decreased (90-133% [NS]) in males mostly
due to one animal which died on Day 42.  After the death of this animal,
body weight gain was still decreased (14-31%; [NS]) during Days 42-364. 

The LOAEL is 300 ppm (approximately equivalent to 10 mg/kg/day), based
upon salivation (both sexes), vomiting (in females), and diarrhea (in
males), and decreases in body weight gains in males. The NOAEL is 150
ppm (approximately equivalent to 5 mg/kg/day).  

This study is classified as acceptable/guideline and satisfies the
guideline requirement (OPPTS 870.4100b, OECD 452) for a chronic oral
toxicity study in dogs.

Bacterial Reverse Mutation Assay; OPPTS 870.5100; OECD 471

EXECUTIVE SUMMARY: In two fully independent and two  partial microbial
mutagenicity assays (MRID 41721610) , cultures of five
histidine-deficient (auxotrophic his -),  strains of Salmonella
typhimuriumn (TA98, TA100, TA1535, TA1537, and TA1538) and the
typtophan-deficient (auxotrophic try -) strain (WP2  uvrA)  of
Escherichia coli were exposed in the presence and absence of metabolic
activation for 48 hours by plate incorporation to the test material (CL
38,555, Batch AC6779-98A, 66.1%) at  5 concentrations ranging from 100
to 5000 ug/plate, as follow:  Two initial and repeat  “full” assays,
 i.e., testing the entire battery of six bacterial strains indicated
above; as well as testing twice only those strains to determine the
reproducibility of suspected spurious positive results obtained in the
full trials.  In addition to assaying the vehicle, water (negative
control), the tester strains were exposed to strain specific mutagens 
(as  positive  controls).   At harvest, the numbers of  revertant
colonies (his +, try +) in tester strains were compared to the number of
colonies in vehicle controls, and the incidences in positive controls
versus negative controls were employed to determine the adequacy of the
assays.  Significant increases in revertant colonies were to be recorded
as positive responses, and would represent induced mutagenic events.

Single non-concentration-related positive responses were found in
treated TA1537 at 100 ug/plate and in TA1538  at 1000 ug/plate  in the 
S9-activated portion  of  the first full trial,  as well as in TA1535 at
100 ug/plate in the second full trial, both without activation,  as well
as under S9-activated conditions.  These increases were considered
non-biological, since they were not observed in two “partial” assays
of these three strains.  All positive controls responded with marked
increases in revertants.

Thus, CL 38,555 (chlormequat-chloride) may be considered non-mutagenic
in this battery of bacterial tester strains when assayed up to the limit
dose (5000 ug/plate  ± S9).

This study is classified as acceptable/guideline and satisfies the
requirement for FIFRA Test Guideline 84-2 for in vitro mutagenicity
(bacterial reverse gene mutation) data.

In Vitro Mammalian Cell Gene Mutation Test; 870.5300, OECD 476

						

EXECUTIVE SUMMARY: In independent mammalian cell forward gene mutation
assays (MRID 41798102), cultures of Chinese hamster ovary (CHO) cells,
heterozygous at the hypoxanthine-guanine phosphoribosyl transferase
locus (hgprt+/hgprt -), were exposed for 5 hours to CL 38,555 (Batch No.
AC 6779-98A, 66.1% a.i., dissolved in sterile water, SW.), in the
presence (+S9) and absence (-S9) of an exogenous metabolic activation
system (±S9), at six concentrations ranging from 500 to 5000 ug/mL. 
These concentrations were selected from a previous screening test, which
indicated that the test article was not cytotoxic below 3500 ug/mL.   In
addition to cultures exposed to SW (representing the vehicle, negative,
control), additional cultures were treated with the mutagens
ethylmethanesulfonate (EMS, 200 ug/mL) and 7, 12-dimethylbenzanthracene
(DMBA 3.5 ug/mL) to serve as positive controls for, respectively,  the
non-activated and S9-activated test series.  All cultures were exposed
to the substituted purine nitrogenous base, 6-thioguanine (TG).  Mutant
cells (tgprt -/tgprt - ) have lost their ability to incorporate TG and 
survive while all other gene variants, homozygates (+/+) and any
remaining heterozygotes (+/-), incorporate this altered purine analog
and die.

Results obtained in the first S9-activated  assay (Trial I), and in both
nonactivated (-S9) assays (Trials I and II) demonstrated that CL 38,555
does not induce forward mutations at the HGPRT-locus when exposed to
concentrations up to 5000 ug/mL.  In Trial II, 2500 ug/mL alone had a
limited positive response, but is not deemed a truly biological response
since a linear concentration associated with this increase was absent,
and this single increase was not observed in Trial I.

Therefore, CL 38,555 is considered negative for mutation in this test
system.

This study is classified as acceptable/guideline and satisfies the
requirement for in vitro gene mutation for FIFRA Test Guideline 84-2
(forward mutation) data.

 Mammalian Bone Marrow Chromosome Aberration Test; OPPTS 870.5385

EXECUTIVE SUMMARY: In a  mammalian cytogenetic assay (MRID 41798101),
Sprague-Dawley rats  (5M:5F per group) were  administered the test
material [CL(AC) 38,555, Batch AC 6779-98A, 66.1% a.i., in sterile water
(SW)]  at acute oral doses of 125, 250 and 500 mg/kg, and bone marrow
cells were collected  12, 24 and 48 hours later.   The characteristic
array of chromosome aberrations in test groups was compared to that of
the vehicle control rats.  In addition to 5M and 5F administered the
vehicle and sacrificed at the same harvest time as the test groups (to
represent the vehicle, “negative” control),  a  group of 5M:5F was 
given a single administration of the mutagen, cyclophosphamide (CP, 40
mg/kg), and sacrificed at 24 hours.   Two to three hours before
harvesting, all cultures were administered colchicine, which arrests
cell division at metaphase.

Deaths occurred at the highest test dose:  One male from the 12-hour
harvest, and 3 females from the 24-hour harvest.  Other signs of
toxicity included:   Salivation; nose-bleeding; diarrhea.

There was no evidence (or a dose related positive response) of an
increased number of abnormal metaphases of test substance-treated
animals over background.  The CP animals responded with marked increases
in aberrations. 

This study is classified as acceptable/guideline and satisfies the
requirement for FIFRA Test Guideline 84-2 for in vivo cytogenetic data.

Unscheduled DNA Synthesis; OPPTS 870.5550

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H-thymidine (specific activity, 20 Ci/mM)  for 18 hrs.   Following an
autoradiographic procedure, the cells were scored for silver grain
counts, an indirect measure of UDS.

In a preliminary range-finding test, exposure to the test article for 18
hrs at 10 concentration levels of  0.08 to 100 uL/mL, both the average
number of viable cells in  replicate cultures, and the Relative Cell
Survival (RCS) of treated  compared to vehicle control groups, were
calculated.  Based on the results indicating that concentrations of  (50
uL/mL were lethal and the RCS was 8.3% at 10 and 41.7% at 5.0 ul/mL, 7.5
uL/mL was selected as the highest concentration for the main
(definitive) UDS assay.

There was no evidence (or a dose-related positive response) that
unscheduled DNA synthesis, as determined by radioactive tracer
procedures [nuclear silver grain counts] was induced.

This study is classified as acceptable/guideline and satisfied the
requirement for FIFRA Test Guideline 84-2 for other genotoxic
mutagenicity data.

References

D312082	Chlormequat Chloride: Human Health Risk Assessment for the
Proposed Use as a 		Plant Growth Regulator on Containerized Ornamental
Plants in Commercial 			Nurseries, Greenhouses, and Shade Houses.  (Z.
Figueroa, 10/12/2006)

D336712	Chlormequat Chloride. Screening-level Acute and Chronic Dietary
(Drinking 			Water Only) Exposure and Risk Assessment for the
Reregistration Eligibility 			Decision.  (D. Wilbur, 06/07/2007)

D336714	Chlormequat Chloride: Occupational and Residential Exposure
Assessment for 			the Reregistration Eligibility Decision Document.  

		(C. Smith, 06/12/2007)

D336717	Tier I Drinking Water Assessment for Chlormequat Chloride in
Support of the 			Reregistration Eligibility Decision.  (M. Echeverria,
03/19/2007)

Henninghausen G. and Tiefenbach B. 1978. Abstract: Mechanism of acute
toxic effects of 	chlorocholine chloride and 2-chloroethyl phosphonic
acid (Ethephon). Arch. Exp. 	Veterinar. Med. 32(4): 609-621.

U.S. EPA, February 10, 1998 Draft Standard Operating Procedures for
Residential Exposure 

	Assessments.  U.S. Environmental Protection Agency, Office of Pesticide
Programs.

U.S. EPA, 1998.  PHED Surrogate Exposure Guide, V1.1.  U.S.
Environmental Protection

	Agency, Office of Pesticide  Programs, August 1998.

U.S. EPA SAP, “Exposure Data Requirement for Assessing Risks from
Pesticide Exposure of 

	Children”, SAP Meeting of March 8, 1999, page 60. 

U.S. EPA, 1999, “Use of Values from the PHED Surrogate Table and
Chemical-Specific Data.”  

	Science Advisory Council for Exposure, Policy.007, U.S. Environmental
Protection Agency,  

	Office of Pesticide Programs.

U.S. EPA, August 7, 2000, "Agricultural Default Transfer Coefficients"
Science Advisory 

	Council for Exposure, SOP 003.1, .U.S. Environmental Protection Agency,
 Office of 

	Pesticide Programs.

U.S. EPA, July 5, 2000, “Standard Values for Daily Acres Treated in
Agriculture” HED Science 

	Advisory Council for Exposure, Policy.009, U.S. Environmental
Protection Agency, Office 

	of Pesticide Programs.

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