UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: June 12,2014 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Macleaya Extract: Preliminary Risk Assessment for Registration Review 

PC Code: 069095 

Decision No.: 489178 

Petition No.: Not Applicable (N/ A) 

Risk Assessment Type: Qualitative 

TXRNo.:N/A 

MRID No.: N/A 

DP.Barcode: 418970 

Registration No.: 69876-1 

Regulatory Action: Registration Review 

Case No.: 7024 

CAS No.: 112025-60-2 

40 CFR: N/A 

FROM: Jessica Kidwell, Risk Assessor WVU.<!.W ~ ........ A. 

Kelly O'Rourke, Occupational/Resi~ntial Ex sure A~sessor "f'...L~ v{/, Q .. Abdallah Khasawinah, Ph.D., Toxicologist / {/~ _) 

RAB IV, Health Effects Division (7509P) 

THROUGH: Elissa Reaves, Ph.D., Branch Chief ?"~~ 2c:: ---.. -­ RAB IV, Health Effects Division (7509~ 

TO: Susan Bartow, Chemical Review Manager 

Kevin Costello, Acting Branch Chief 

RMIB IV, Pesticide Re-Evaluation Division (7508P) 

Attached is the Health Effect Division's (HED's) human health risk assessment for macleaya 

extract to support registration review. A screening level occupational assessment did not 

identify any potential risks of concern via dermal or inhalation routes of exposure; the margins 

of exposure (MOEs) for dermal and inhalation route$ did not fall below the Agency's level of 

concern (LOC). A dietary risk assessment is not required because macleaya extract has no 

registered food uses. A drinking water exposure assessment is not required based on label 

specifications that limit use to enclosed commercial greenhouses. In addition, the 

Environmental Fate and Effects Division (EFED) anticipates that no quantitative drinking 

water exposure assessment will be needed. Based on the r:egistered uses, there are no residential 

exposures for macleaya extract, therefore, a residential exposure assessment is not applicable. 
Macleaya Extract/069095 Human Health Risk Assessment D418970 

Introduction 

Macleaya extract is the active ingredient (1.5%) in the product Qwel TM (CTI 13-1 9B). It is an 

ornamental plant fungicide used in enclosed commercial greenhouses to control powdery 

mildews and leaf spots. Macleaya extract is formulated as a liquid concentrate and applied as a 

foliar spray by backpack or high pressure sprayer. The maximum application rate is 5 fl .oz. 

formulation/! 0 gallons water applied to 1 ,25.0 ft2 for roses and other larger plants (i.e., 0.17 

pounds active ingredient per acre (lb ai/A) or 0.0005 lb a.i. per gallon). Foliar applications may 

be made at 8-10 day intervals as needed. The label does not specify the number of applications. 

Macleaya extract has no registered residential uses; residential exposures are, therefore, not 

expected. Usage of macleaya extract was not reported in the National Agricultural Statistics 

Service (NASS) nursery and floriculture usage surveys conducted in 2002, 2004, or 2007 nor 

was it reported in the 2006-2008 California Department of Pesticide Regulation (CALDPR) 

pesticide usage reports (BEAD Memo, Stebbins, K, Yourman, L. and Faulkner, 12/7/2010). 

Hazard Identification and Dose Response Assessment 

Macleaya extract is a fungicide used for the control of foliar fungal diseases, such as powdery 

mildew, alternaria leaf spot and septaria leaf spot on ornamental plants grown in greenhouses. It 

is the extract of perennial plants Macleaya cordata and Macleaya microcarpa (Macleaya spp.). 

Raw macleaya extract is a mixture of alkaloids belonging to the quaternary benzophenathridine 

alkaloid (QBA) Class. The purified product contains two principal QBAs, sanguinarine (47-

53%) and chelerythrine (20-26%). 

The toxicology database for macleaya extract is very limited and is supported by some studies on 

the closely related sanguinaria extract (contains approximately 3 7-40% sanguinarine, 16-18% 

chelerythrine, and other related products ranging from less than 1% to 9% of the total 

composition), and sanguinarine chloride, a major component of macleaya extract. Based on a 

comparison of structural similarities, physical and chemical characteristics and toxicological 

information found in literature studies, HED determined that available toxicity studies on 

sanguinaria extract and sanguinarine chloride are likely to be acceptable for use as surrogate data 

for macleaya extract. The toxicology database for macleaya extract (based on the use of 

surrogate data) is adequate for registration review. The available studies are listed below and in 

Appendix A. 

• Acute: Oral, dermal, inhalation on macleaya extract. Acute oral and dermal on 

sanguinaria extract. Acute oral, inhalation, eye irritation, dermal irritation, and skin 

sensitization on sanguinarine chloride. 

• Subchronic: Sanguinaria extract/sanguinaria chloride, 90-day oral toxi city (rat, monkey). 

• Developmental toxicity: Sanguinaria extract, developmental toxicity (rat and rabbit) 

• Reproduction: Sanguinaria extract, !-generation reproduction (rat) 

• Chronic: Sanguinaria extract, combined oral chronic toxicity/carcinogenicity (rat). 

• Other: Sanguinaria extract/sanguinaria chloride, mutagenicity battery. 

Although the 201 1 scoping document (D384098) had previously recommended multiple studies 

be submitted (90-Day Inhalation Toxicity Study, 90-Day Dermal Toxicity Study, Developmental 

Page 2 of 17 
Macleaya Extract/069095 Human Health Risk Assessment D418970

Page 3 of 17

Toxicity Study in Rabbits, Developmental Toxicity Study in Rats, 2-Generation Reproduction 

Toxicity in Rats, Acute Neurotoxicity Study in Rats, Subchronic Neurotoxicity Study in Rats),

HED’s Hazard and Science Policy Council (HASPOC) waived the requirements for these studies 

in 2013 (TXR 0056588). The HASPOC used the Weight of Evidence (WOE) in waiving the

requirements for these studies based on the following: 1) the limited exposure profile of 

macleaya extract; 2) there are no registered food uses of macleaya extract at this time; 3) no 

exposure to macleaya extract is expected through drinking water; 4) the use of an oral point of 

departure (POD) results in dermal MOEs that do not fall below HED’s level of concern (target 

LOC is for MOEs <300) for highest occupational exposures (i.e., MOEs are greater than 3,600 

and 440 for handlers and post-application workers, respectively); 5) the use of an oral POD 

results in inhalation MOEs that do not fall below HED’s level of concern for workers (MOE 

greater than 13,000); and 6) the low vapor pressure (3.92 x10-11 mm Hg at 25C) and physical 

chemical properties of sanguinarine, a major component of macleaya extract. HASPOC also 

waived the immunotoxicity study data requirement (TXR No. 0056719). 

Sanginaria is available commercially in various over-the-counter products. Sanginaria extract is 

used in Viadent® oral rinse and toothpaste products (Frankos et al. 1990). Sanguinaria extract 

also is known to treat gum disease (removes plaque), athlete’s foot, chronic cough, asthma, 

ringworm, rashes, and fungus on the skin when applied topically. 

Macleaya extract exhibits low acute toxicity via oral and dermal routes of exposure. It is not a 

dermal irritant. Primary eye irritation and dermal sensitization studies are available on the 

formulation but not on the technical material. 

Available chronic, subchronic, developmental, and reproductive studies on surrogate sanguinaria 

compounds are available primarily from the published literature. Original reports of the 

published studies have been submitted, but not yet reviewed. A preliminary screen of the study 

reports indicates concordance with the conclusions of the published studies. The test material in 

all these studies (developmental, subchronic, chronic, reproduction) was administered by gavage.

These studies indicate that macleaya extract is likely to be irritating to the stomach and 

lungs. Subchronic and chronic oral studies in monkeys and rats, respectively, showed 

gastrointestinal tract effects indicative of irritation. The subchronic study in rats reported lung 

abnormalities indicative of inflammation. Clinical signs of rales, breathing difficulty, excessive 

salivation, lethargy, reduced motor activity were observed in parental animals in developmental 

and reproductive toxicity studies in rats. No developmental effects were observed in a 

developmental rat study at maternally toxic doses. In the developmental rabbit study, fetal effects 

(e.g., decreased number of fetus/litter) were observed at maternally toxic doses. No reproductive 

effects were observed in the rat reproduction study.

Sanguinarine chloride showed equivocal positive response in mammalian cell forward mutation 

assay in the presence of microsomal activation system, was negative in in vitro mammalian 

cytogenic test system, equivocal response in a DNA repair system. Sanguinaria extract was 

negative in the E. coli mutation test, but produced positive response in Salmonella strains TA98, 

TA100, TA1537, TA1538 (+S9). Sanguinaria extract was not mutagenic in Salmonella strains 

TA98, TA100, TA1535, TA1537, TA1538 (-S9) and TA1535 (+S9). Sanguinaria extract was 

negative in a chromosomal aberration assay and a DNA repair system. Macleaya extract, 
Macleaya Extract/069095 Human Health Risk Assessment D418970

Page 4 of 17

sanguinaria extract, and sanguinarine chloride have not been evaluated for carcinogenicity. A 

published article demonstrated that Macleaya Cordata extract administered as a dietary 

admixture to rats at 600 mg/kg feed induced no DNA damage to rat lymphocytes or hepatocytes 

after 90-days of oral administration (Stiborova, M. et al., 2008)

At the time the scoping document was prepared in 2011, there were no macleaya extract cases in 

the main or aggregate Incident Data System (IDS) databases; therefore, there did not appear to be 

a concern at that time that would warrant further investigation (Recore, 11/30/10, D384109). An

updated IDS query for macleaya extract also indicated there were no incidents reported to either 

Main or Aggregate IDS (Email correspondence, S. Recore, 4/29/14).

There are no registered food, feed or residential uses for macleaya extract. Therefore, toxicity 

PODs were not selected for dietary or residential exposures. PODs were selected for 

occupational exposures via dermal and inhalation pathways for use in the 2002 occupational 

exposure and risk assessment based on registered uses. The 2002 occupational exposure 

assessment relied on the use of endpoints of toxicity derived from the one-generation 

reproduction study in rats and the subchronic oral toxicity study in monkeys. During its 

deliberations on waiving various studies, the HASPOC recommended that the endpoint of 

toxicity derived from the subchronic oral toxicity study in monkey be used for assessing both the 

dermal and inhalation exposures (short- and intermediate-term durations). In this study, monkeys 

were orally gavaged with sanguinarine chloride at 0, 10, 30 or 60 mg/kg/day. The LOAEL was

10 mg/kg/day (lowest dose tested) based on diarrhea and emesis. The default 10X factor for 

extrapolation from a LOAEL to NOAEL was reduced from 10X to 3X since the test animal was 

a monkey. The total uncertainty factor is 300X (10X for intraspecies variation, 10X for 

interspecies extrapolation, and 3X for use of a LOAEL). Since no inhalation absorption data are 

available, toxicity by the inhalation route is considered to be equivalent to the estimated toxicity 

by the oral route of exposure (100% absorption factor). 

There are no dermal absorption studies or ADME available for this product. Raw macleaya 

extract is a mixture of alkaloids belonging to the quaternary benzophenathridine alkaloid (QBA) 

Class. The purified product contains two principal QBAs, sanguinarine (47-53%) and 

chelerythrine (20-26%). These are charged molecules and are not expected to be absorbed 

through the skin. Experimental data in humans have demonstrated that the quaternary chemical 

diquat (with chemical structure resembling the macleaya extract components) was minimally 

absorbed with only 0.3% absorbed and excreted over a 5 day period (Feldman and Maibach, 

1974, MRID 43736616). This human study was subjected to the appropriate ethical evaluation 

by the Agency (Memo from John Carley to Anne Overstreet, July 27, 2006). Thus for macleaya 

extract, the dermal absorption is expected to be low and to allow for lack of a dermal absorption 

study, therefore, a 10% dermal absorption factor is proposed for this risk assessment and is 

considered to be a conservative assumption. See Appendix B for Endpoint Selection.

Sanguinarine Chelerythrine Diquat
Macleaya Extract/069095 Human Health Risk Assessment D418970

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Dietary Exposures

There are no food uses for macleaya extract, so exposure from consumption of food is not 

expected. Therefore, there is no dietary risk. 

Occupational and Residential Exposures 

Based on the registered uses, there are no residential exposures for macleaya extract, therefore, 

there is no residential risk.

Although exposure may occur during occupational handling and post-application activities, a 

screening level assessment based on maximum application rates and baseline attire (additional 

PPE [i.e., gloves] are required on the label) indicated no risk of concern via dermal and 

inhalation routes of exposure. Estimates of occupational handler and post-application 

exposure/risk are summarized in Tables 1 and 2, respectively. Furthermore, the current label 

requires all handlers to wear personal protective equipment (i.e., chemical-resistant gloves in 

addition to baseline attire) and specifies a restricted entry interval of 12 hours, which is 

considered to be adequately protective.
Macleaya Extract/069095 Human Health Risk Assessment D418970

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Table 1. Summary of Short-/Intermediate-Term Handler Exposures/Risks for Macleaya Extract

Exposure 

Scenario

Max 

Application Rate1

Unit Exposure2

(mg/lb ai)

Area

Treated

or 

Amount 

Handled 

daily3

Absorbed Dose

(mg/kg/day)4 MOE5

Total

MOE6

Dermal Inhalation Dermal Inhalation Dermal Inhalation

GREENHOUSE ORNAMENTALS - MIXER/LOADER (single layer, no gloves)

Groundboom 0.17

lb ai/A 0.22 0.00022 60 A 0.00048 0.000028 3,600 360,000 3,600

GREENHOUSE ORNAMENTALS - APPLICATOR (single layer, no gloves)

Groundboom 0.17

lb ai/A 0.0786 0.00034 60 A 0.00021 0.000043 10,000 230,000 9,600

GREENHOUSE ORNAMENTALS - MIXER/LOADER/APPLICATOR (single layer, no gloves)

Backpack

0.0005

lb ai/gal

13.2 0.14 40 gal 0.00028 0.000035 30,000 290,000 27,000

Manuallypressurized 

Handwand

100 0.030 40 gal 0.000011 0.0000075 4,000 1,300,000 4,000

Mechanicallypressurized 

Handgun

3.5 0.12 1,000 gal 0.0016 0.00075 4,600 13,000 3,400

1 Application rate based on label for macleaya extract (EPA Reg. No. 69876-1).

2 Based on HED Exposure Science Advisory Council’s Occupational Pesticide Handler Unit Exposure Surrogate Reference Table.

3 HED Exposure Science Advisory Council Policy #9.1

4 Daily Absorbed Dose (mg/kg/day) = daily unit exposure (mg/lb ai) × application rate (lb ai/A or gal) × area treated (A or gal/day) × absorption 

(10% for dermal) ÷ body weight (80 kg).

5 MOE = LOAEL (dermal = 10 mg/kg/day for short-/intermediate-term exposure; inhalation = 10 mg/kg/day for short-/intermediate-term) ÷

absorbed dose (mg/kg/day). LOC = 300.

6 Total MOE = 1 ÷ [(1 ÷ Dermal MOE) + (1 ÷ Inhalation MOE)]

Table 2. Post-application Exposure and Risk for Macleaya Extract

Crop

Applicatio

n Rate

(lb ai/acre)

Activity

Exposure 

Time 

(hrs/day)

Transfer 

Coefficient1

(cm2/hr)

Day 0 

DFR2

(ug/cm2)

Daily 

Dermal 

Dose3

(mg/kg-day)

MOE4

Greenhouse

Crop

(Ornamentals,

Non-bearing 

Plants) 0.17

Harvesting, Hand; Pruning, 

Hand; Scouting; Container 

Moving; Weeding, Hand; 

Transplanting; Grafting; 

Propagating; Pinching; 

Tying/Training

8

230

0.48

0.0011 9,100

Cut Flowers Hand Harvesting 4,800 0.023 440

1 Transfer coefficient from HED Exposure Science Advisory Council Policy #3

2 Dislodgeable Foliar Residue (DFR) on the day of application (i.e., “day 0”) = application rate × percent of residue available for transfer 

(25%)× 4.54E8 μg/lb × 2.47E-8 acre/cm2

3 Daily Dermal Dose = [DFR (μg/cm2) × transfer coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (10%)]  BW (80 kg).

4 MOE = LOAEL (10 mg/kg/day) / daily dermal dose. LOC = 300.
Macleaya Extract/069095 Human Health Risk Assessment D418970

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Volatilization

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for macleaya extract at this time primarily because of the very 

low vapor pressure (3.92 x10-11 mm Hg at 25C)). Although a quantitative post-application 

inhalation exposure assessment was not performed, a screening-level inhalation exposure 

assessment was performed for handlers. This exposure scenario is representative of a worse case 

inhalation exposure and should be considered protective of most post-application inhalation 

exposure scenarios.

Spray Drift

The registered use for macleaya extract is limited to ornamentals in greenhouses, therefore, this 

use pattern will not result in spray drift outdoors.

Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental,

reproductive, and general or systemic toxicity. These studies include endpoints which may be

susceptible to endocrine influence, including effects on endocrine target organ histopathology,

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss,

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and

chronic studies that assess growth, developmental and reproductive effects in different

taxonomic groups. As part of its preliminary risk assessment for registration review of macleaya 

extract, EPA reviewed the available data and selected the most sensitive endpoints for relevant 

risk assessment scenarios from the existing hazard database. However, as required by FFDCA 

section 408(p), macleaya extract is subject to the endocrine screening part of the Endocrine 

Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide

active and other ingredients) may have an effect in humans or wildlife similar to an effect

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator

may designate.” The EDSP employs a two-tiered approach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal

systems. Chemicals that go through Tier 1 screening and are found to have the potential to

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2

testing is designed to identify any adverse endocrine-related effects caused by the substance, and

establish a dose-response relationship between the dose and the E, A, or T effect. Under FFDCA 

section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and 

February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which 

contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals 

identified for EDSP screening was published on June 14, 2013

(http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074) and 

includes some pesticides scheduled for registration review and chemicals found in water. Neither 
Macleaya Extract/069095 Human Health Risk Assessment D418970

Page 8 of 17

of these lists should be construed as a list of known or likely endocrine disruptors. For further 

information on the status of the EDSP, the policies and procedures, the lists of chemicals, future 

lists, the test guidelines and the Tier 1 screening battery, please visit our website

(http://www.epa.gov/endo/).

Data Requirements

None. The studies required as part of the 2011 HED scoping document were waived by 

HASPOC in 2013 (TXR Nos. 0056588 and 0056719).

Conclusions

A screening-level exposure assessment did not identify potential risks via dermal or inhalation 

routes resulting from occupational exposure scenarios. The conservative dermal and inhalation 

MOEs are not of concern. A dietary risk assessment is not required because macleaya extract

has no registered food uses and drinking water exposure is not anticipated based on label

specifications that limit use to commercial greenhouses. There is also no residential exposure 

based on the label uses. Therefore, based on the lack of exposure, there are no dietary or 

residential risks for macleaya extract.

References

Collantes, M. 8/9/2002. D284631. Occupational and Residential Exposure and Risk for the 

Proposed Use of Macleaya Extract in Enclosed Commercial Greenhouses.

Daiss, B. 1/5/2011. D384098. Macleaya Extract: Human Health Risk Scoping Document in 

Support of Registration Review.

Feldman and Maibach, 1974. Percutaneous penetration of some pesticides and herbicides in man. 

Toxicology and Applied Pharmacology 28: 126-132; MRID 43736616.

Frankos, V. et al. 1990. Safety of sanguinaria extract as used in commercial toothpaste and oral 

rinse products. J. Can. Dent. Assn. 56:41-47.

Habiba, U. 7/18/2013. TXR No. 0056719. Macleaya Extract: Summary of Hazard and Science 

Policy Council (HASPOC) Meeting of July 18, 2013: Recommendation on the Need for 

Immunotoxicity Study (870.7800).

Hurley, P. 7/30/2002. TXR No. 0050979. Macleaya Extract – 1

st Report of the Hazard 

Identification Assessment Review Committee. 

Recore, S. 11/30/2010. D384109. Macleaya Extract: Review of Human Incidents.

Recore, S. 4/29/2014. Email correspondence from S. Recore to J. Kidwell.
Macleaya Extract/069095 Human Health Risk Assessment D418970

Page 9 of 17

Rury, K. 3/5/2013. TXR No. 0056588. Macleaya Extract: Summary of Hazard and Science 

Policy Council (HASPOC) Meeting of February 14, 2013: Recommendations on the Need for 

Multiple Studies.

Stebbins, K. Yourman, L. Faulkner, J. 12/7/ 2010. BEAD Chemical Profile for Registration 

Review: Macleaya Extract.

Stiborova, M. et al. 2008. Macleaya Cordata Extract and Sangrovit Genotoxicity Assessment In 

Vivo. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 152:35-39.
Macleaya Extract/069095 Human Health Risk Assessment D418970

Page 10 of 17

APPENDIX A

A. TOXICOLOGY DATA SUMMARY

A.1. Macleaya Extract Guideline Toxicology Data Requirements: The toxicology data 

requirements (40 CFR 158.500) for non-food use are presented in Table A.1.1. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1.1. Macleaya Extract Guideline Data Requirements

Study

Technical

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 ....................................................................

870.3465 21/90-Day Inhalation................................................................

yes (CR)

yes (CR)

yes* (CR)

yes* (CR)

-

-

-

-

870.3700a Developmental Toxicity (rodent)..............................................

870.3700b Developmental Toxicity (nonrodent)........................................

870.3800 Reproduction ............................................................................

Yes*

Yes*

Yes*

-

-

-

870.4100a Chronic Toxicity (rodent) .........................................................

870.4200a Carcinogenicity (rat).................................................................

870.4200b Carcinogenicity (mouse)...........................................................

870.4300 Chronic/ Carcinogenicity..........................................................

yes (CR)

yes (CR)

yes (CR)

yes (CR)

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial ................................

870.5300 Mutagenicity—Gene Mutation - mammalian ...........................

870.5375 Mutagenicity—Structural Chromosomal Aberrations ..............

870.5900 Mutagenicity—Other Genotoxic Effects..................................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen) ................................................

870.6100b 90-Day Neurotoxicity (hen)......................................................

870.6200a Acute Neurotox. Screening Battery (rat)...................................

870.6200b 90-Day Neuro. Screening Battery (rat).....................................

870.6300 Develop. Neuro.........................................................................

no

no

yes*

yes*

no

-

-

-

-

yes

870.7485 General Metabolism .................................................................

870.7600 Dermal Penetration ...................................................................

870.7800 Immunotoxicity ........................................................................

no

no

yes**

yes

yes

-

* Waived (HASPOC report TXR # 0056588)

**Waived (HASPOX report TXR #0056719)

CR: CONDITIONALLY REQUIRED
Macleaya Extract/069095 Human Health Risk Assessment D418970

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A.2 Toxicity Profiles

Table A.2.1: Acute Toxicity Profile of Macleaya Extract

GDLN Study Type MRID Results Tox 

Category

81-1 Acute Oral 44525106

Males:= 1016 mg/kg in corn oil);

1544 mg/kg (CMC)

Females:= 629 mg/kg in corn oil;

960 mg/kg (CMC)

III

81-2 Acute Dermal - rabbit 44525107 

(1997) LD50 > 2000 mg/kg III

81-3 Acute Inhalation 44525108 

(1997)

Males:< 0.22 mg/L

Females:> 0.22 mg/L and < 0.52 mg/L II

81-4

Primary Eye Irritation 

of macleaya end use 

product formulation

44525109 

(1998) Eye irritant I

81-5

Primary Skin Irritation 

end use product 

formulation

44525110 

(1997) Not irritating IV

81-6 Dermal Sensitization - Not conducted N/A

Table A.2.2: Acute Toxicity Profile of Sanguinaria Extract

GDLN Study Type MRID Results Tox 

Category

81-1 Acute Oral

44525111

Literature 

summary

1440 mg/kg in water

1250 mg/kg in corn oil III

81-2 Acute Dermal - rabbit

44525111

Literature 

summary

46273804 

(1983)

LD50 > 200 mg/kg II

81-3 Acute Inhalation -

Not conducted -

81-4 Primary Eye Irritation - Not conducted -

81-5 Primary Skin Irritation - Not conducted -

81-6 Dermal Sensitization - Not conducted N/A
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Table A.2.3: Acute Toxicity Profile of Sanguinarine Chloride

GDLN Study Type MRID Results Tox 

Category

81-1 Acute Oral

44525111

Literature 

summary

LD50 = 1525 mg/kg in CMC

1664 mg/kg in corn oil III

81-2 Acute Dermal - rabbit - Not conducted. -

81-3 Acute Inhalation

44525111

Literature 

summary

Mild pulmonary and ocular irritant

0.16-0.37 mg/mL, LC50 unclear. Conservative 

estimate of 0.16 mg/mL

II?

Acute Inhalation 46273806 

(1983)

Males:< 0.22 mg/L

Females:> 0.22 mg/L II

81-4 Primary Eye Irritation

44525111

Literature 

summary

Mild irritant cannot 

estimate

81-5 Primary Skin Irritation

44525111

Literature 

summary

Slight irritant cannot 

estimate

81-6 Dermal Sensitization 46273803 

(1990) Not a sensitizer -
Macleaya Extract/069095 Human Health Risk Assessment D418970

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Table A.2.4 Subchronic, Chronic and Other Toxicity Profile for Macleaya Extract

Guideline No.

Study Type

MRID No. (year)

Classification

Dose Levels

Results

28-day dietary toxicity study-rat

sanguinaria extract (33.1%, 

sanguinarine chloride and 68.4% 

total alkaloid)

45400501

Unacceptable/nonguideline

0, 5, 15, 45, 135, and 

405 mg/kg/day

NOAEL = 405 mg/kg/day (HDT)

LOAEL was not observed

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 (LDT)).

Blood clotting measurements were not quantified.

The nose, pharynx, larynx, and seminal vesicles were not examined 

histologically.

There was a very high rate of death and gavage error incidences 

which tended to confound the results. Insufficient numbers of 

animals were available in some groups to allow for an adequate 

interpretation of the results.

4-week range finding study

cynomolgus monkey

(sanguinaria extract (purity not 

provided)

45400503 (1987)

Acceptable/nonguideline

O, 50, 100, 150, 200 

mg/kg/day in O.2% 

CMC 2 mL/kg

One monkey/sex/dose

NOAEL: 50

LOAEL: 100 mg/kg/day increased and/or severity of clinical signs 

(emesis, diarrhea, inappetence, and dehydration).

870.3100

13-week cynomolgus monkey 

(sanguinarine chloride (98.8% a.i)

45400504 (1988)

Acceptable guideline

0, 10, 30, or 60 mg/kg 

bw/day by gavage in 

0.1% CMC (2.0 mL/kg) 

4 monkeys/sex/dose

NOAEL: not established

LOAEL: 10 mg/kg/day (increased incidence (number of affected 

animals) and frequency of emesis and diarrhea in both sexes 

(LDT)).

No other clear treatment-related effects were observed in the study. 

Special Study

28-day Subchronic Mucosal 

Irritancy Study of Three 

Sanguinarine Chloride Preparations 

in Dogs

46273802 (1987)

Acceptable/nonguideline

This is a special study and no DER was prepared. However, a 

screening of the study findings did not impact the dermal or 

inhalation endpoints for the qualitative screen.

Special Study

Gingival Irritation Study in Dogs: 

10% Sanguinarine Chloride (57% 

NMP), 33% PLA Polymer, 50% 

Sanguinarine Chloride (35% NMP), 

15% PLA Polymer, 100% 

Sanguinarine Chloride

46273805 (1990)

Acceptable/nonguideline

This is a special study and no DER was prepared. However, a 

screening of the study findings did not impact the dermal or 

inhalation endpoints for the qualitative screen.
Macleaya Extract/069095 Human Health Risk Assessment D418970

Page 14 of 17

Table A.2.4 Subchronic, Chronic and Other Toxicity Profile for Macleaya Extract

Guideline No.

Study Type

MRID No. (year)

Classification

Dose Levels

Results

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 in 1% citric acid 

(10 mL/kg)

From literature

46273808 (1988) GD 

15-20

46273810 (1990) GD 6-

15

Maternal NOAEL: 20 mg/kg/day

Maternal LOAEL:60 mg/kg/ reduced body weight gain and 

clinical toxicity (rales).

Developmental NOAEL: Greater than 60 mg/kg/day

(HDT)

Developmental LOAEL: Could not be established.

This study was reported as a scientific investigation (open literature 

study); therefore, many of the elements required under OPPTS 

guidelines were not present. Nevertheless, this study does provide 

some data which may be used for regulatory purposes. The study 

report (MRID 46273810) provided more details with same 

conclusions.

870.3700b

Developmental Toxicity in nonrodents (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 in 

1% citric acid (4 

mL/kg), GD 6-18

From literature 

46273807 (1988)

Maternal NOAEL = 15 mg/kg/day

LOAEL = 25 mg/kg/day based on decreased maternal body weight 

gain.

Developmental NOAEL = 25 mg/kg/day

LOAEL = 50 mg/kg/day based on decreased number of 

fetuses/litter and increased postimplantation loss.

This study was reported as a scientific investigation (open literature 

study); therefore, many of the elements required under OPPTS 

guidelines were not present. Nevertheless, this study does provide 

some data which may be used for regulatory purposes. The most 

significant deficiency in this study is the low number of litters 

available for examination. The study only started with 16 animals 

per group. Without the individual animal data, the pregnancy rate 

cannot be determined. In addition, for some parameters, the 

standard deviations are very high. Again, without the individual 

animal data, it cannot be determined whether or not the high 

standard deviations are due to a few outliers. The study report 

(MRID 46273807) did not provide additional information on these 

questions.

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 in 1% citric acid 

(10 mL/kg)

From literature

46273809 (1988)

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 (HDT)

Reproductive LOAEL: Could not be established.

This study was reported as a scientific investigation (open literature 

study); therefore, many of the elements required under OPPTS 

guidelines were not present. Nevertheless, this study does provide 

some data which may be used for regulatory purposes. Study report 

(MRID 46273809) provides additional detail.
Macleaya Extract/069095 Human Health Risk Assessment D418970

Page 15 of 17

Table A.2.4 Subchronic, Chronic and Other Toxicity Profile for Macleaya Extract

Guideline No.

Study Type

MRID No. (year)

Classification

Dose Levels

Results

870.4300

Chronic toxicity/ carcinogenicity in 

rodents (rat)

Sanguinaria extract (purity not 

reported)

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.

Not oncogenic under conditions of study.

Excessive mortality, including in the control groups, prevented the 

104 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. However, some of the data 

may be useful for regulatory purposes.

870.5300

CHO/HGPRT Mammalian Cell 

Forward Gene Mutation Assay: 

Sanguinarine chloride. 

46273811 (1985)

Acceptable/Guideline

Sanguinarine chloride was cytotoxic at doses of 0.3-8.0 μg/mL (-

S9) and at doses ≥20 μg/mL (+S9).

Sanguinarine chloride was not mutagenic up to toxic dose of 0.3 

μg/mL (-S9).

Sanguinarine chloride produced reproducible statistically 

significant increase in the mutant frequencies of the cultures treated 

with 10 μg/mL (+S9).

870.5375

Mammalian spermatogonial 

chromosomal aberration 

In Vitro Mammalian Cytogenetic 

Test Using Human Peripheral 

Lymphocytes: Sanguinarine chloride

46273812 (1991)

Acceptable/Guideline

Sanguinarine chloride was insoluble at 500 μg/mL and higher.

It was tested at 0.63, 1.25, 5, 10 μg/mL (-S9) and at 1.25, 2.5, 5.0, 

10, 20 μg/mL(+S9). The test material was soluble at these doses. 

Cytotoxicity was noted at the two higher doses.

No statistically significant increase in structural chromosome 

aberrations was observed in the absence or presence of metabolic 

activation, regardless of harvest time (20 or 44 hours harvest).

870.5550

Rat Hepatocyte Primary 

Culture/DNA Repair Test: 

Sanguinarine chloride.

46273813 (1985)

Acceptable/Guideline

Sanguinarine chloride dissolved in DMSO was tested at 2, 5, 10, 

20, 50, 100, 200, 400, 1000, 2000 μg/well. Dose levels at 200 

μg/well and above produced net nuclear grain counts that were 

substantially greater than the solvent control. A dose related 

increases in net nuclear grains was observed at dose levels of 100, 

200 and 400 /well reaching 3.4 net nuclear grains at the 400 

μg/well dose. In addition, 30% of the cells had ≥ 5 net nuclear 

grains. A mean net nuclear grain of 5 or greater was not observed 

at any concentration. The results were considered to be equivocal.

870.5100

Bacterial reverse mutation test 

Salmonella/Mammalian-Microsome 

Plate Incorporation Mutagenicity 

Assay (Ames Test) And Escherichia 

Coli WP2uvrA Reverse Mutation 

Assay: Sanguinaria extract

46273814 (1986)

Acceptable/Guideline

Sanguinaria extract was not positive in the E. coli Wp2uvrA with 

or without aroclor-induced rat liver microsomal activation.

Sanguinaria extract was positive in the Salmonella strains TA98, 

TA100, TA1537, TA1538 (+S9).

Sanguinaria extract was not mutagenic in Salmonella strains TA98, 

TA100, TA1535, TA1537, TA1538 (-S9) and TA1535 (+S9).

870.5385

Mammalian bone marrow 

chromosomal aberration 

Micronucleus Cytogenetic Assay in 

Mice: Sanguinaria extract

46273815 (1987)

Acceptable/Guideline

IP injection of sanguinaria extract at 1.4, 7.1 or 14.2 mg/kg twice 

with 24 hour interval between dosing, did not induce 

micronucleated polychromatic erythrocytes in male or female CD1 mice. It was considered to be negative in this study. 
Macleaya Extract/069095 Human Health Risk Assessment D418970

Page 16 of 17

Table A.2.4 Subchronic, Chronic and Other Toxicity Profile for Macleaya Extract

Guideline No.

Study Type

MRID No. (year)

Classification

Dose Levels

Results

870.5395

Mammalian erythrocyte 

micronucleus Unscheduled DNA 

Synthesis in Rat Primary 

Hepatocytes: Sanguinaria extract

46273816 (1987)

Acceptable/Guideline

Sanguinaria extract was tested at 11 dose levels ranging from 0.001 

μg/mL to 100 μg/mL and was fully evaluated at 10.0, 3.0, 1.0, 0.3, 

and 0.1 μg/mL. It did not produce a significant increase in the 

mean number of net nuclear grain counts. It was considered to be 

negative in this test.
Macleaya Extract/069095 Human Health Risk Assessment D418970

Page 17 of 17

APPENDIX B

Summary of Points of Departure Used in Risk Assessment

Toxicological doses/endpoints selected for the macleaya extract risk assessment are provided in 

Table B.1.

Table B.1. Summary of Toxicological Doses and Endpoints for Macleaya Extract for Use in Occupational

Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/

FQPA 

Safety 

Factors

RfD, PAD, LOC 

for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary No dietary exposure

Chronic Dietary No dietary exposure

Incidental Oral No dietary exposure

Dermala

Short- (1-30 

days) and 

Intermediate-

(1-6 months) 

Term

LOAEL = 

10 

mg/kg/day 

(LDT)

(NOAEL 

not 

established)

UFA = 10X

UFH = 10X

UFL = 3X

Occupational 

LOC for MOE 

=300

90-day monkey study

(MRID 45400504)

LOAEL = 10 mg/kg/day (LDT)

based on increased incidence 

(number of affected animals) and 

frequency of emesis and diarrhea 

in both sexes 

Inhalationb

Short- (1-30 

days) and 

Intermediate-

(1-6 months) 

Term

LOAEL = 

10 

mg/kg/day 

(LDT)

(NOAEL 

not 

established)

UFA = 10X

UFH = 10X

UFL = 3X

Occupational 

LOC for MOE = 

300

90-day monkey study

(MRID 45400504)

LOAEL = 10 mg/kg/day (LDT)

based on increased incidence 

(number of affected animals) and 

frequency of emesis and diarrhea 

in both sexes 

Cancer (all 

routes)

Carcinogenicity was not evaluated. 

Point of Departure (POD) = A data point or an estimated point that is derived from observed doseresponse data and used to mark the beginning of extrapolation to determine risk associated with lower 

environmentally relevant human exposures. 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). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study for longterm risk assessment. UFDB = to account for the absence of key date (i.e., lack of a critical study). FQPA 

SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference 

dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

a10% default dermal absorption factor is used.

bSince no inhalation absorption data are available, toxicity by the inhalation route is considered to be 

equivalent to the estimated toxicity by the oral route of exposure (100% absorption factor).