United States
Environmental Protection
Agency
Office of Prevention, Pesticides
and Toxic Substances
(7501C)
r/EPA
Description of Chemical
Chemical Name:
Common Name:
Trade Name:
Chemical Class:
EPA Chemical Code:
Chemical Abstracts
Service (CAS) Number:
Year of Initial Registration:
Pesticide Type:
U.S. Producer:
Pesticide
Fact Sheet
Name of Chemical: Macleaya Extract
Reason for Issuance: New Chemical
Date Issued: September 19, 2002
Active components are: Sanguinarine chloride: [1,3]
benzodioxolo [5,6-c] phenanthridinium-13-methyl chloride
and Chelerythrine chloride: [1,3] benzodioxolo [5,6-c]
phenanthridinium-l,2-dimethoxy-12-methyl chloride.
Macleaya Extract
Qwel (CTI 13-19B) Liquid Concentrate
Quaternary benzophenanthridine alkaloids (QBA)
069095
112025-60-2
2002
Fungicide
Camas Technologies, Inc.
P.O. Boxl357
Broomfield, CO 80038
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Use Pattern and Formulations
Qwel (CTI 13-19B) Liquid Concentrate is a liquid product containing 1.5% of the active
ingredient (ai) macleaya extract (0.125 Ib ai/gallon). Qwel is applied as a spray mist for the
control of powdery mildew and Alternaria and Septoria leafspots on a variety of ornamental
plants in enclosed commercial greenhouses. Dosage rates vary from 3 to 5 fl.oz./lO gallons
water applied to 2,000 sq. ft. for small plants or 1,250 tol,500 sq. ft. for roses and other larger
plants. Applications are repeated at 8 -10 day intervals.
Science Findings
Summary Science Statement
EPA has concluded from the review of the supporting data that there are no risks of
concern from the use of macleaya extract. The end-use product is in Toxicity Category I because
of primary eye irritation concerns. Based upon the use pattern for this product, the only
toxicological concern would be related to worker exposure. Risk from exposure of workers
(applicators and other handlers) was below the Agency's level of concern. No food uses are
proposed for the product so there would be no dietary exposure. Additionally, since the product
will be used in enclosed greenhouses, there would be no exposure through drinking water. The
product will not be registered for residential or homeowner uses so there would be no non-
occupational exposure expected, including exposure of infants or children. The Agency
concluded that the use of macleaya extract on the labeled ornamental plants in enclosed
greenhouses is unlikely to present a significant threat to non-target organisms or the
environment.
Physical/Chemical Properties
Physical and Chemical Properties for Technical Grade Active Ingredient
Requirement
Color
Physical State
Odor
Storage Stability
Corrosion Characteristics
pH
Melting Point/
Melting Range
Result or Deficiency
Orange
Free-flowing powder
Nasal irritant
Greater than one year
Non-corrosive
3. 29 (1.0% solution)
237-258° C
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Physical and Chemical Properties for Technical Grade Active Ingredient
Requirement
Density/
Relative Density/
Bulk Density
Solubility
Result or Deficiency
0.43 g/ml
Water: 1.2%(w/v)
Methanol: 2.5% (w/v)
Toluene: <0.002%
Acetone: <0.002%
Toxicitv Profile:
Acu t e Toxicity Profile of Macleaya Extract
GDLN
81-1
81-2
81-3
81-4
81-5
81-6
Study Type
Acute Oral
Acute Dermal - rabbit
Acute Inhalation
Primary Eye Irritation
Primary Skin
Irritation
Dermal Sensitization
MRID
44525106
44525107
44525108
_
-
-
Results
Males:= 1016 mg/kg in corn oil);
1544 mg/kg (CMC)
Females:= 629 mg/kg in corn oil;
960 mg/kg (CMC)
LD,0 > 2000 mg/kg
Males:< 0.22 mg/L
Females:> 0.22 mg/L and < 0.52 mg/L
Not conducted
Not conducted
Not conducted
Tox
Categor
y
III
III
II
_
-
N/A
Toxicity Studies other than Acute Toxicity:
Guideline No./Study
Type
MRID No.
(year)/Classiflcation/Doses
Results
870.3100
13-Week feeding - rat
(Sanguinaria Extract:
(44.5% sanguinarine
chloride and 78.6%
alkaloid))
45400502
1987/Unacceptable guideline
0,50, 100, 200, 300, or 400
mg/kg/day by gavage (20 mL/kg)
NOAEL: Not established
LOAEL: 50 mg/kg/day (decreased overall body weight
gain, labored breathing and rales in both sexes (LOT)).
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Toxicity Studies other than Acute Toxicity:
Guideline No./Study
Type
MRID No.
(year)/Classification/Doses
Results
870.3100
13-Week feeding -
monkey (Sanguinarine
Chloride (98.8% a.i.)
45400504
1988/Acceptable guideline
0, 10, 30, or 60 mg/kg bw/day by
gavage (2.0 mL/kg)
NOAEL: Not established
LOAEL: 10 mg/kg/day (increased incidence (number of
affected animals) and frequency of emesis and diarrhea in
both sexes (LPT)).
870.3700
Developmental toxicity -
rat
(Sanguinaria extract
(33% sanguinarine
chloride and ~68% total
benzophenanthridine
alkaloid))
44525111
1989/Acceptable nonguideline
0, 5, 20, and 60 mg/kg/day by
gavage (10 mL/kg)
From literature
Maternal NOAEL: 20 mg/kg/day
Maternal LOAEL: 60 mg/kg bw/day (reduced weight
gain)
Developmental NOAEL: Greater than 60 mg/kg/day
(HOT)
Developmental LOAEL: Could not be established.
870.3700
Developmental toxicity -
rabbit
(Sanguinaria extract
(33% sanguinarine
chloride and ~68% total
benzophenanthridine
alkaloid))
44525111
1989/Acceptable nonguideline
0, 5, 15, 25, 50, and 75 mg/kg/day
by gavage (4 mL/kg)
From literature
Maternal NOAEL: 15 mg/kg/day
Maternal LOAEL: 25 mg/kg/day (clinical signs of
toxicity and weight loss mg/kg/day).
Developmental NOAEL: 25 mg/kg/day
Developmental LOAEL: 50 mg/kg/day (decreased
number of fetuses/litter and increased postimplantation
loss).
870.3800
1-Generation
Reproduction - rat
(Sanguinaria extract
(33% sanguinarine
chloride and ~68% total
benzophenanthridine
alkaloid))
44525111
1989/Acceptable nonguideline
0, 10, 30, or 100 mg/kg/day by
gavage (10 mL/kg)
From literature
Parental NOAEL: 10 mg/kg/day
Parental LOAEL: 30 mg/kg bw/day (clinical signs
indicative of central nervous system toxicity)
Offspring NOAEL: 30 mg/kg/day
Offspring LOAEL: 100 mg/kg bw/day (decreased body
weight of pups at birth and during lactation)
Reproductive NOAEL: Greater than 100 mg/kg/day
(HOT)
Reproductive LOAEL: Could not be established.
870.4300
Chronic/Carcinogenicity
- rat (Sanguinaria
Extract (purity not
rpnnrfpfH
45400505
1989/Unacceptable guideline
0, 5, 20, or 60 mg/kg/day by
gavage (10 mL/kg)
NOAEL: 20 mg/kg/day
LOAEL: 60 mg/kg/day based on decreased overall body
weight gain in females and increased salivation and rales
in both sexes
Nnt nnmpprnr iinHpr rnnrHtinns
Summary of Toxicology Findings.
The Agency has not selected acute or chronic reference doses (RfDs) because there are no
proposed food uses for macleaya extract. For this same reason, the potential for increased
susceptibility of infants and children from exposure to macleaya extract was not evaluated.
Incidental oral endpoints are not applicable because there are no residential uses. Neither a
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dermal absorption study nor a dermal study was available so a default dermal absorption value of
100% was applied.
Macleaya extract is a botanical extract ofMacleaya spp. In support of registration,
studies conducted with sanguinaria extract, a product closely related to macleaya extract and
sanguinarine chloride, a major component of macleaya extract have been submitted. Macleaya
extract contains approximately 47-53% sanguinarine and 20-26% chelerythrine whereas
sanguinaria extract contains approximately 37-40% sanguinarine, 16-18% chelerythrine, and
other related products ranging from less than 1% to 9% of the total composition.
Acute Toxicity
The data for macleaya extract indicate that the acute oral toxicity and acute dermal
toxicity values are in toxicity category III and that acute inhalation toxicity is in toxicity category
II. The end-use product, Qwel (CTI 13-19B) Liquid Concentrate, containing 1.5% macleaya
extract, is in toxicity category I for primary eye irritation, toxicity category III for acute oral and
acute dermal toxicity, and in toxicity category IV for acute inhalation and primary dermal
irritation. A repeated insult patch test on humans was submitted which indicated that the product
is negative for sensitization. The test was non-guideline but is acceptable for regulatory purposes.
Dermal Exposure
To evaluate potential risks associated with dermal exposure across all durations of
exposure, an endpoint was selected from a 1-generation reproduction and fertility effects study in
rats. In this study, sanguinaria extract was administered by gavage to groups of 10 male and 20
female rats at doses of 0, 10, 30 or 100 mg/kg/day. The parental systemic LOAEL for
sanguinaria extract is 30 mg/kg/day for F0 male and female rats based on clinical signs indicative
of central nervous system toxicity; the corresponding NOAEL is 10 mg/kg/day. Mortality, more
severe clinical signs, and reduced weight gain occurred at 100 mg/kg/day. The offspring LOAEL
for sanguinaria extract in rats is 100 mg/kg/day, based on decreased body weight of pups at birth
and during lactation; the corresponding offspring NOAEL is 30 mg/kg/day. The reproductive
NOAEL is 100 mg/kg/day (HDT). A reproductive LOAEL was not established in the study.
The dose and endpoint selected for risk assessment from dermal exposure is 10 mg/kg/day
based on one or more of the following clinical signs at the parental LOAEL of 30 mg/kg/day:
breathing difficulty, signs of lethargy, reduced motor activity, intermittent head twitching, and
excessive salivation.
Inhalation Exposure
To evaluate the potential risks associated with inhalation exposure across all durations of
exposure, the Agency selected an endpoint from a 90-day oral toxicity study in monkeys. In this
study, sanguinarine chloride was administered to 4 cynomolgus monkeys/sex/dose via gavage at
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dose levels of 0, 10, 30 or 60 mg/kg/day. The LOAEL for this study is 10 mg/kg/day based on
increased incidence (number of affected animals) and frequency of emesis and diarrhea in both
sexes. The NOAEL was not observed.
The dose/endpoint selected for risk assessment for inhalation exposure islO mg/kg/day
based on increased incidence and frequency of emesis and diarrhea in the males and females.
The 90-day monkey study was selected for the inhalation endpoints because of the possibility that
the effects were partially due to the irritating properties of the chemical, which could translate to
irritation effects in the lung. Although this study was conducted with sanguinarine chloride, it is
not likely to underestimate any potential risks observed with macleaya extract because the effects
are observed at a dose where no effects are observed with sanguinaria extract, which is very
similar to macleaya extract. An additional uncertainty factor of 3 will be used for lack of a
NOAEL.
Carcinogenicity
Carcinogenicity studies are generally not required for indoor, non-food uses. The
following data were submitted for informational purposes.
In a combined chronic toxicity/carcinogenicity study, sanguinaria extract (purity not
reported; Lot #: HIS Sept 86-64) in 1% aqueous citric acid was administered daily by gavage for
91/99 weeks (males/females) to 50 rats/sex/dose at doses of 0, 5, 20, or 60 mg/kg/day.
The LOAEL is 60 mg/kg/day based on decreased overall body weight gain in females and
increased salivation and rales in both sexes. The NOAEL for this study was 20 mg/kg/day.
At the doses tested, no treatment-related increase in the incidence in any type of tumor was
observed when compared to the control groups. Dosing was considered minimally adequate
based on decreased overall body weight gain in females and increased salivation and rales in both
sexes. Although the observed effects in the lung and trachea were not significant enough to use
as the basis for the LOAEL, it is likely that these effects were due to a combination of the route of
administration (gavage) and the irritating properties of the chemical. Because of this, higher
doses may have caused more severe problems.
The oncogenicity portion of the study is unacceptable/guideline, not upgradable and does
not satisfy the guideline for a Carcinogenicity study (OPPTS 870.4200; OECD 451) in rats.
Excessive mortality, including in the control groups, prevented the 104 week duration of
observation for the study. In addition, there were a significant number of gavage errors. For the
chronic toxicity portion of the study, a significant number of guideline measurements were not
performed. These included ophthalmology, clinical chemistry, urinalysis, and organ weight
determinations. In addition, the purity of the sanguinaria extract was not reported. This was
indicated for the subchronic oral study. Without the purity, it is difficult to compare the observed
toxicity of the extract in the two studies. The chronic portion of the study is classified as
unacceptable/guideline, not upgradable and does not satisfy the guideline requirement for a
chronic study in rodents (OPPTS 870.4100; OECD 452). However, some of the data may be
useful for regulatory purposes.
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Mutagenicity
No actual mutagenicity studies are available but there is a literature review. The summary
from the literature review states: "Sanguinaria extract and sanguinarine chloride were tested for
mutagenic potential in a series of assays using bacterial, mammalian cell culture, and mouse DNA
systems. Sanguinaria extract and sanguinarine chloride elicited weak positive responses only in
the bacterial assay using Salmonella typhimurium (Ames assay) in the presence of metabolic
activation. Studies of Sanguinaria extract were negative in the bacterial assay with E. coli, in an
unscheduled DNA synthesis assay in rat primary hepatocytes and in a micronucleus cytogenetic
assay in mice. An Ames test for metabolites of Sanguinaria extract in rat urine using S.
typhimurium was negative. Studies of sanguinarine chloride were negative in a second Ames
assay with S. typhimurium and Saccharomyces cerevisiae with and without metabolic activation.
Two mammalian cell assays with sanguinarine chloride, including a Chinese hamster ovary
(CHO) - HGPRT forward gene mutation assay and unscheduled DNA synthesis assay in rat
primary hepatocytes, provided results that were equivocal or uninterpretable; neither study,
however, gave a positive mutagenic response. The Panel noted that the CHO assay is historically
difficult to conduct and interpret."
Occupational Exposure and Risk Characterization
Handlers (Commercial)
Macleaya extract is the active ingredient (1.5%) in the product Qwel ™ (CTI13-19B). It
is an ornamental plant fungicide to be used in enclosed commercial greenhouses to control
powdery mildews and leafspot. Macleaya will be applied as a foliar spray by backpack or high
pressure sprayer. The application rate is 0.0005 Ib a.i. per gallon. Foliar applications may be
made at 8-10 day intervals as needed. The formulation is a liquid concentrate.
Workers may be exposed to macleaya extract during mixing, loading, and application
activities. Based on the proposed application rates and use scenarios, short-, intermediate- and
long-term dermal and inhalation exposure is expected. The exposure scenarios assessed are:
mixing/loading and applying liquid for backpack and mixing/loading and applying liquid for high
pressure sprayer.
Chemical-specific data for assessing human exposures during pesticide handling activities
were not submitted to the Agency in support of this application. It is the policy of the Agency to
use data from the Pesticide Handler Exposure Database (PHED) Version 1.1 to assess handler
exposures for regulatory actions when chemical-specific monitoring data are not available (HED
Science Advisory Council for Exposure, Policy 007, "Use of Values from the Pesticide
Programs," January 1999).
The unit exposure values calculated by PHED generally range from the geometric mean to
the median of the selected data set. To add consistency and quality control to the values produced
from this system, the PHED Task Force has evaluated all data within the system and has
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developed a set of grading criteria to characterize the quality of the original study data. The
assessment of data quality is based on the number of observations and the available quality
control data. While data from PHED provide the best available information on handler
exposures, it should be noted that some aspects of the included studies (e.g., duration, acres
treated, pounds of active ingredient handled) may not accurately represent labeled uses in all
cases. The Agency has developed a series of tables of standard unit exposure values for many
occupational scenarios that can be utilized to ensure consistency in exposure assessments.
The MOEs calculated for liquid application with high pressure handwand are 400 for
dermal with baseline PPE, 560 for dermal with minimum PPE and 12,000 for inhalation with
baseline PPE. Liquid applications with backpack sprayer had MOEs of 14,000 for dermal with
minimum PPE and 1,200,000 for inhalation with baseline PPE. The handler MOEs for dermal
exposure were greater than 100 and the inhalation exposures were greater than 300 and therefore
did not exceed the Agency's level of concern. The baseline clothing/PPE level scenario for
occupational exposure scenarios is generally an individual wearing long pants, a long-sleeved
shirt, no chemical-resistant gloves and no respirator.
The handler exposure estimates in this assessment are based on using maximum
application rate, and are assumed to be representative of high-end exposures. The uncertainties
associated with this assessment stem from the use of surrogate exposure data (e.g., differences in
use scenario and data confidence) and assumptions regarding the amount of chemical handled.
The estimated exposures are believed to be reasonable high-end estimates based on 100% dermal
absorption and professional experience and judgement.
Post-Application Exposure
Due to the fact that greenhouse workers are exposed to this fungicide on a continuous
basis during post-application activities (cut/harvest, prune, sort and pack), chronic (6 or more
months of continuous exposure) post-application dermal and inhalation exposure is expected.
Since no post-application data were submitted in support of this registration action, exposures
during post-application activities were estimated using dermal transfer coefficients from the
Science Advisory Council For Exposure Policy Number 3.1: Agricultural Transfer Coefficients,
August 2000.
The MOEs calculated for post-application activities are: 110 for hand harvest and pruning,
pinching, and thinning; 2,000 for just harvesting and 4,500 for hand pinching. The post-
application MOEs were greater than 100 and did not exceed the Agency's level of concern. Input
parameters such as the dissipation rate and transfer coefficients are considered to be high-end,
while estimates of the exposure duration and body weight are central tendency estimates.
Additional Toxicity Data Requirements
The data requirements for Macleaya Extract will follow the requirements for a non-food
use chemical (40 CFR 158.340) as follows:
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Primary eye irritation (870.2400). primary dermal irritation (870.2500) and dermal
sensitization (870.2600) studies: data are available on the formulation but not on the technical
material. These data are required in order to evaluate the requested re-entry interval of 4 hours.
In the interim, a 12-hour REI will be required.
90-Day Dermal Study in the Rabbit (§870.3250): There are concerns for toxicity to
workers from dermal exposure. Long-term dermal exposure is anticipated. Based on an
examination of the data, the rabbit appears to be the most sensitive species. Therefore, a dermal
study on the rabbit is required using macleaya extract. No dermal studies are currently available
for macleaya extract. An oral study on sanguinaria extract has been selected to provide a
preliminary estimate for the dermal risk assessment. This oral study is considered to be sufficient
for a preliminary risk estimate because the default assumption of 100% dermal absorption is
considered to be very conservative and is anticipated not to underestimate any potential risk via
the dermal route.
90-Day Inhalation Study in Rats (§870.3465): There are concerns for toxicity to workers
from inhalation exposure. Long-term inhalation exposure is anticipated. Since this chemical
appears to be an irritant via the oral route, toxic effects are anticipated via inhalation exposure.
Therefore, in order to more fully characterize these effects, an inhalation study is required.
Developmental study in the rabbit (§870.3700): A literature article summarizing
developmental studies in the rat and rabbit and a 1-generation reproduction study in the rat is
available for sanguinaria extract. The article indicates that the rabbit is likely to be the most
sensitive species for macleaya extract. The literature article does not provide sufficient data to
fully assess developmental toxicity, particularly as it relates to the disposition of the does in the
rabbit study (i.e. deaths, pregnancy rates, etc.). Individual animal data are needed. Since these
data are not available, the literature study is classified as Non-guideline. Insufficient litters were
available in the rabbit study for a complete assessment. Therefore, we are requesting the rabbit as
the choice of species to satisfy the requirement for a developmental toxicity study in one species.
Mutagenicity battery (gene mutation in bacteria (Ames: 870.5265)) and mammalian cells
(870.5300) and an in vivo cvtogenetics assay (870.5380. .5385. or .5395)): Although
mutagenicity studies have been previously conducted with sanguinarine chloride, the data for
these studies are not available to the Agency for review. Summaries of the data are published but
the data upon which the summaries are based were destroyed in a fire. Mutagenicity studies are
required for a non-food use chemical.
Ecological Effects and Environmental Fate Characteristics
Ecological Toxicity Data. The following toxicity data are available and fulfill the ecological
effects data requirements for an indoor use:
1. In an acute oral study on rats using the technical grade active ingredient (TGAI), the acute
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oral LD50 was 845 and 1216 mg/kg/day which is considered slightly toxic.
2. In a test with the TGAI fed to bobwhite quail, the dietary LC50 was >3946 ppm. The
maximum concentration did not yield an LC50 and did not go up to 5000 ppm so the
toxicity category could not be determined but was no worse than slightly toxic.
3. In a test on rainbow trout using the TGAI, the 96-hour LC50 was 89 ppb which is
considered to be very highly toxic.
4. In a test with Daphnia magna using TGAI, the 48-hour EC50 was 20 ppb which is
considered to be very highly toxic.
Environmental Fate Data
The registrant did not submit environmental fate data for this product. Indoor use
products usually require hydrolysis, aerobic soil metabolism and leaching and
adsorption/desorption studies. Based on the use pattern for this product, these studies are waived
since it is assumed that this chemical will not get outdoors while being used and there is little
likelihood that the mobility, persistence and degradate information obtained from these studies
would be used to characterize exposure or risk.
Contact person at USEPA
Mailing address
Mary L. Waller
Product Manager (21)
Environmental Protection Agency
Office of Pesticide Programs
Registration Division (7505C)
Fungicide Branch
1200 Pennsylvania Avenue NW
Washington, D.C. 20460
Office location and telephone number:
Room 249, Crystal Mall #2
1921 Jefferson Davis Highway
Arlington, VA 22202
10
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703-308-9354
DISCLAIMER: The information in this Pesticide Fact Sheet is for information only and is not to
be used to satisfy data requirements for pesticide registration. The information is believed to be
accurate as of the date on the document.
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