
\* MERGEFORMAT
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
                                                           POLLUTION PREVENTION


MEMORANDUM

Date:		15-MAY-2013

SUBJECT:	Propamocarb Hydrochloride (Propamocarb-HCl).  Section 3 Request for use on Lima Beans (Succulent).  Human-Health Risk Assessment.  
 
PC Code:  119302 (propamocarb-HCl)
        119301 (propamocarb)
DP Barcode:  D367968
Decision No.:  402658
Registration No.:  264-678
Petition No.:  2E8072
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical Aggregate
Case No.:  3124
TXR No.:  NA
CAS No.:  25606-41-1 (propamocarb-HCl)
       24579-73-5 (propamocarb)
MRID No.:  NA
40 CFR:  §180.499

FROM:	Jennifer R. Tyler, Chemist
		George F. Kramer, Ph.D., Senior Chemist
		Kelly M. Lowe, Senior Environmental Scientist 
		Anwar Y. Dunbar, Ph.D., Pharmacologist
		Risk Assessment Branch 1 (RAB1)/Health Effects Division (HED; 7509P)

THROUGH:	Dana M. Vogel, Acting Branch Chief, RAB1
      Associate Division Director, HED (7509P)

TO:		Barbara Madden, Risk Manager 05
		Registration Division (RD; 7575P)

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides.  The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the following:  1) the proposed Section 3 request for the use of the active ingredient (ai) propamocarb-HCl [propyl N-[3-(dimethylamino)propyl]carbamate hydrochloride] on succulent lima beans; and 2) existing uses on field-grown and greenhouse-grown ornamentals, for which recent revisions have been made to the registered labels to amend issues with application rates.  A summary of the findings and an assessment of human-health risk resulting from all registered and proposed uses are provided in this document.  The risk assessment and dietary exposure assessment were provided by Jennifer Tyler (RAB1); the residue chemistry data review by George Kramer and Jennifer Tyler (RAB1); the hazard characterization and endpoint selection by Anwar Dunbar (RAB1); the occupational and residential exposure assessment by Kelly Lowe (RAB1); and the drinking water exposure assessment by Mohammed A. Ruhman of the Environmental Fate and Effects Division (EFED).
                               TABLE OF CONTENTS
1.0	Executive Summary	3
2.0	HED Recommendations	6
2.1	Data Deficiencies	6
2.2	Tolerance Considerations	7
2.3	Label Recommendations	8
3.0	Introduction	8
3.1	Chemical Identity	8
3.2	Physical/Chemical Characteristics	8
3.3	Pesticide Use Pattern	8
3.4	Anticipated Exposure Pathways	11
3.5	Consideration of Environmental Justice	12
4.0	Hazard Characterization and Dose-Response Assessment	12
4.1	Toxicology Studies Available for Analysis	12
4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)	13
4.3	Summary of Toxicological Effects	13
4.4	Safety Factor for Infants and Children (FQPA SF)	14
4.5	Toxicity Endpoint and Point of Departure Selections	15
5.0	Dietary Exposure and Risk Assessment	17
5.1	Residues of Concern Summary and Rationale	18
5.2	Food Residue Profile	18
5.3	Water Residue Profile	19
5.4	Dietary Risk Assessment	19
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	20
6.1	Residential Handler Exposure	20
6.2	Post-Application Exposure	20
6.3	Residential Risk Estimates for Use in Aggregate Assessment	21
6.4	Residential Bystander Post-application Inhalation Exposure	21
6.5	Spray Drift	21
7.0	Aggregate Exposure/Risk Characterization	22
7.1	Acute Aggregate Risk	22
7.2	Short-Term Aggregate Risk	22
7.3	Chronic Aggregate Risk	23
8.0	Cumulative Exposure/Risk Characterization	23
9.0	Occupational Exposure/Risk Characterization	24
9.1	Occupational Handler Exposure/Risk Estimates	24
9.2	Occupational Post-application Exposure/Risk Estimates	29
10.0	References	30
Appendix A.  Toxicology Profile Tables.	32
Appendix B.  Physical/Chemical Properties	38


1.0	Executive Summary

Propamocarb is a carbamate fungicide that interferes with fungal synthesis of phospholipids and fatty acids.  Bayer CropScience currently has a single end-use product of propamocarb-HCl that is registered for use on food/feed crops in the U.S.  This 6 pounds (lb)/gallon (gal) flowable-concentrate (FlC) formulation (EPA Reg. No. 264-678) is registered for the control of fungal diseases on lettuce, potatoes, fruiting vegetables, and cucurbit vegetables.  It is approved for multiple broadcast foliar applications to the above crops using ground or aerial equipment at 0.45-1.5 lb active ingredient (ai)/acre (A)/application for a maximum of 4.5-6.0 lb ai/A/season.  Preharvest intervals (PHIs) range from 0-14 days.  Permanent tolerances have been established for residues of propamocarb-HCl in/on the above crops at levels ranging from 0.06 ppm in/on potatoes to 90 ppm in/on leaf lettuce [40 CFR §180.499 (a)].  There are no proposed residential uses at this time; however, there are registered uses for golf course turf which may result in residential post-application exposure.

The Interregional Research Project No. 4 (IR-4) has submitted a petition proposing the use of the above 6 lb/gal FlC formulation of propamocarb-HCl on succulent lima beans grown east of the Rocky Mountains.  The proposed use is for up to four broadcast foliar applications at 1.5 lb ai/A/application, with a minimum 7-day retreatment interval (RTI), for a maximum of 6.0 lb ai/A/season.  The minimum PHI is 12 hours after application (0-day).  Applications can be made using aerial or ground equipment, or by chemigation.  In conjunction with this use, IR-4 is proposing a 2.0 ppm permanent tolerance with a geographical restriction for residues of propamocarb in/on bean, lima, succulent.

In addition to the proposed new use on succulent lima beans, this risk assessment includes a reassessment of occupational exposure resulting from existing uses on field-grown and greenhouse-grown ornamentals.  Recent revisions have been made to the registered labels to amend issues with application rates.

Hazard Assessment:  The hazard database for propamocarb-HCl is complete.  Since the last risk assessment, HED's Hazard Assessment and Policy Committee (HASPOC) evaluated all existing hazard and exposure data, and current use patterns for propamocarb-HCl, and used a weight-of-evidence approach to waive the requirement for a subchronic inhalation toxicity study.

Propamocarb-HCl is categorized as having low acute toxicity via the oral, dermal, and inhalation routes (Toxicity Categories III-IV).  It is not a dermal irritant or a dermal sensitizer.  It is considered a slight eye irritant.

In all species, decreased body weights, body-weight gains, and food consumption were observed for subchronic and chronic durations.  Effects throughout the database are indicative of toxicity to the digestive and gastrointestinal (GI) tracts, specific regions of the nervous system, the eye, and to a lesser degree the respiratory tract.  In mice, decreased absolute body weights and body-weight gains were the only effect observed.  In rats, there were also signs of neurotoxicity in addition to decreased body weights.  Decreased motor activities in females occurred following acute exposure.  Vacuolization of the choroid plexus (ventricles of the brain that produce cerebral spinal fluid) was observed for both subchronic and chronic durations.  Ocular effects in the rat occurred as well, including opacity of the eye and yellow colored eyes in females following chronic dietary exposure.  In dogs, there were notable effects in the digestive and GI tracts, in addition to decreased body weights, evidenced by chronic erosive gastritis, and vacuolization of the salivary glands, stomach, and duodenum.  There were also respiratory effects including vacuolization of the cells of the trachea and lung.  There were ocular effects including vacuolization of the lacrimal gland, retinal degeneration, and hyporeflectivity of the fundus (inner eye tissue below the lens).  Dermal toxicity in rats and rabbits consisted of local effects including scabs, erythema maculate, focal erythema, necrosis, and ulcerative inflammation in the treated skin of females.  No systemic effects were observed.

There was no increased quantitative pre-natal sensitivity due to propamocarb-HCl treatment.  There were however fetal effects at doses which caused maternal toxicity.  Effects in the rat included increased fetal death and post-implantation loss, increases in minor skeletal anomalies, and increased incidences of small fetus.  There was also inter-atrial septal defects, and hemorrhage in the ears, upper GI tract, and nasopharynx/sinuses.  Maternal effects consisted of decreased absolute body weights, body-weight gains and food consumption, and mortality.  In rabbits, the only developmental effect was an increase in post-implantation loss.  Maternal effects consisted of increased abortions, and body-weight decrements.  

In the rat two-generation reproduction studies, parental and offspring effects occurred at the same dose.  Parental effects were similar to the effects observed in the rat subchronic and chronic studies in addition to clinical signs including salivation, reddish material around the mouth, and urine staining.  Offspring effects consisted of pup deaths, decreased viability and lactation indices and litter size, and decreased pup body weights and body-weight gains.  Reproductive effects consisted of increased vacuolization and decreased weight of the epididymides, decreased sperm counts and motility, and abnormal sperm morphology.  In the guideline immunotoxicity study, effects at the high dose included decreased body-weight gain and decreased food consumption.  

In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the Hazard Identification Assessment Review Committee (HIARC) classified propamocarb-HCl as "not likely to be carcinogenic to humans" by all routes of exposure based upon lack of evidence of carcinogenicity in rats and mice. 

Food Quality Protection Act (FQPA) Decision:  The RAB1 risk assessment team recommends that the FQPA Safety Factor (SF) be reduced to 1X for all exposure scenarios.  This decision was based on the following (see Section 4.2 for more detail):
   * The existing toxicology database for propamocarb-HCl is adequate for FQPA SF evaluation.  The following acceptable studies are available:  developmental toxicity studies in rats and rabbits (4); two-generation reproduction studies in rats (2); and acute (2) and subchronic (2) neurotoxicity studies.
   * There are two guideline acute neurotoxicity studies and two subchronic neurotoxicity studies for propamocarb-HCl and the effects are well characterized.  The endpoints selected are protective of these effects.
   * There is no evidence of increased quantitative susceptibility of rat and rabbit fetuses to in utero exposure to propamocarb-HCl.  There are qualitative effects observed however in both studies.  In one of the two-generation reproduction studies, there is an increase in pup mortality at doses that cause parental toxicity.  The level of concern (LOC) for all of these effects is low because:  (1) the effects are well-characterized, (2) clear no-observed-adverse-effect levels (NOAELs) were established, and (3) the developmental rabbit and rat two-generation reproduction studies are being used in endpoint selection.
   * There are no residual uncertainties in the exposure database.

Residue Chemistry and Drinking Water Assessments:  The residue chemistry and drinking water databases are adequate to assess potential human exposure to propamocarb.  Adequate residue chemistry data have been submitted to support the proposed use on succulent lima beans.  EFED provided estimated drinking water concentrations (EDWCs) for surface water [using Tier II Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS)] and groundwater [using Screening Concentration in Ground Water (SCI-GROW)] for propamocarb.

Dietary (Food and Drinking Water) Exposure Assessment:  Acute and chronic dietary (food and drinking water) exposure and risk analyses were conducted for the general U.S. population and various population subgroups using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID; Ver. 3.16).  For acute and chronic dietary risk estimates, HED's LOC is for estimates that exceed 100% of the acute population-adjusted dose (aPAD) or chronic population-adjusted dose (cPAD), respectively.  The acute and chronic dietary exposure assessments were unrefined [assuming tolerance-level residues and assuming 100% crop treated (CT) for all registered and proposed commodities].  The results indicate that the acute (95[th] percentile) and chronic dietary exposure estimates are below HED's LOC for the general U.S. population and all other population subgroups.  For both acute and chronic assessments, the most highly exposed population subgroup is all infants <1 year old at 75% of the aPAD and 50% of the cPAD, respectively.  

Residential (Non-Occupational) Exposure Assessment:  Residential exposures are not anticipated from the proposed use on lima beans.  There is a registered use of propamocarb on golf courses, and residential exposure from that use has been reassessed using the 2012 Residential Standard Operating Procedures (SOPs).  Residential handler exposure is not anticipated, but there is the potential for residential post-application dermal exposure.  Chemical-specific turf-transferable residue (TTR) data are available for propamocarb and were used in the residential post-application exposure assessment.  The residential post-application dermal exposure and risk estimates for golfers indicate that short-term margins of exposure (MOEs) are not of concern to HED (i.e., MOEs >= 100) on the day of application.  Dermal MOEs ranged from 280 for children 6 to <11 years old to 380 for adults.

Aggregate Exposure Scenarios and Risk Conclusions:  For the proposed uses, human-health aggregate risk assessments have been conducted for the following exposure scenarios:  acute aggregate exposure (food + drinking water), short-term aggregate exposure (food + drinking water + residential), and chronic aggregate exposure (food + drinking water).  An intermediate-term assessment was not conducted as intermediate-term residential exposures are not expected based on the current use patterns.  However, as the short- and intermediate-term points of departure (PODs) are the same, the short-term aggregate is protective of any potential intermediate-term exposures.  A cancer aggregate risk assessment was not performed because propamocarb-HCl is not carcinogenic.  All potential exposure pathways were assessed in the aggregate risk assessment as a conservative, health-protective measure.  All aggregate risk estimates are not of concern to HED for the scenarios listed above.  

Occupational Handler and Post-application Exposure Estimates:  Occupational short- and intermediate-term dermal and inhalation handler exposures are expected for individuals involved in applications of propamocarb-HCl to succulent lima beans (proposed use) and commercially-grown field and greenhouse ornamentals (registered use).  For the proposed succulent lima beans use, HED has determined that risk estimates are not of concern (i.e., MOE >100) with baseline attire.  For the existing use on commercially grown field and greenhouse ornamentals, HED has determined that risks are not of concern (i.e., MOE >100) with baseline attire and chemical-resistant gloves (as required on the label).

Occupational short- and intermediate-term dermal post-application exposures are expected for individuals reentering lima bean fields treated with propamocarb.  HED has determined that the risk estimates are not of concern to HED (i.e., MOEs >= 100) on the day of application. The revised labels for the ornamental uses indicate all applications are to be soil/ground-directed; therefore, post-application exposure to residues on foliage is not expected and a quantitative post-application assessment was not conducted.

Based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment was not performed for propamocarb at this time.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for propamocarb.  For the greenhouse ornamental uses, the Worker Protection Standard (WPS) for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)].  The 12-hour restricted entry interval (REI) is adequate for the proposed use patterns.

Review of Human Research:  This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; and Agricultural Reentry Task Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  For certain studies, that review may have included review by the Human Studies Review Board.  Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.


2.0	HED Recommendations

HED concludes that the toxicological, residue chemistry and occupational/residential databases support a Section 3 registration and establishment of the tolerances listed in Section 2.2.2.  HED is recommending for additional data in conjunction with this petition as listed in Section 2.1.

2.1	Data Deficiencies

2.1.1	Residue Chemistry

OPPTS GLN 860.1650:  An analytical standard for propamocarb is not currently available in the EPA National Pesticide Standards Repository [personal communication with T. Cole, Analytical Chemistry Branch (ACB), 9/5/12].  An analytical reference standard of propamocarb should be supplied and replenished as requested by the Repository.  The reference standard should be sent to the Analytical Chemistry Lab, which is located at Fort Meade, to the attention of Theresa Cole at the following address:

	USEPA
	National Pesticide Standards Repository/Analytical Chemistry Branch/OPP
	701 Mapes Road
	Fort George G. Meade, MD  20755-5350
(Note that the mail will be returned if the extended zip code is not used.)

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

An adequate gas chromatography/nitrogen-phosphorus detection (GC/NPD) method (Analytical Method No. XAM-34) is available for enforcing tolerances on plant commodities.  This method has undergone successful independent laboratory validation (ILV) and petition method validation (PMV) trials (Memo, J. Rowell, 3-OCT-2000; D268955).  The method has been sent to the Food and Drug Administration (FDA) and is currently listed in the Pesticide Analytical Method (PAM) Vol. II for determining residues of propamocarb in plant commodities.  The limit of quantitation (LOQ) for this method is 0.05 ppm.

Adequate multiresidue method testing data are available for propamocarb and these data have been forwarded to FDA for evaluation (Memo, J. Rowell, 15-MAY-2000; D266084).  Parent compound was not recovered by any of the FDA multiresidue methods.

2.2.2	Recommended Tolerances

Table 2.2.3.  Tolerance Summary for Propamocarb.
Commodity
                           Proposed Tolerance (ppm)
                        HED-Recommended Tolerance (ppm)
Comments;
Correct Commodity Definition
                            40 CFR §180.499(c)[1]
Bean, lima, succulent
                                      2.0
                                      2.0

[1]	As the proposed tolerance is geographically restricted to regions east of the Rocky Mountains, the tolerance should be listed under 40 CFR §180.499(c).

2.2.3	Revisions to Petitioned-For Tolerances

The residue chemistry data support a tolerance with a geographical restriction for residues of propamocarb in/on beans, lima, succulent at 2.0 ppm.

Note to RD:  HED recommends the following revision to the tolerance expression to (1) clarify that, as provided in FFDCA section 408(a)(3), the tolerance covers metabolites and degradates of propamocarb not specifically mentioned; (2) clarify that compliance with the specified tolerance levels is to be determined by measuring only the specific compounds mentioned in the tolerance expression; and (3) to harmonize with the codex maximum residue limit (MRL) expression:

     "Tolerances are established for residues of propamocarb, including its metabolites and degradates, in or on the commodities listed below resulting from the application of the hydrochloride salt of propamocarb.  Compliance with the following tolerance levels is to be determined by measuring only propamocarb (propyl N-[3-(dimethylamino)propyl]carbamate)."

2.2.4	International Harmonization

There are currently no established Codex, Canadian, or Mexican MRLs for propamocarb on lima beans.  Therefore, harmonization of MRLs and U.S. tolerances is not an issue at this time.  

2.3	Label Recommendations

HED is not recommending for any changes to the proposed Previcur[(R)] Flex Fungicide (EPA Reg. No. 264-678) label.


3.0	Introduction

3.1	Chemical Identity

Table 3.1.  Propamocarb Nomenclature.
Compound

Common name
Propamocarb HCl
Company experimental name
AE B066752
IUPAC name
Propyl 3-(dimethylamino) propylcarbamate hydrochloride
CAS name
Propyl 3-[(dimethylamino) propyl]carbamate monohydrochloride
CAS registry number
25606-41-1 (propamocarb-HCl)
24579-73-5 (propamocarb)
End-use product (EP)
6.0 lb/gal FlC (Previcur[(R)] Flex Fungicide; EPA Reg No. 264-678)
Chemical Class
Carbamate

3.2	Physical/Chemical Characteristics

THE PHYSICAL AND CHEMICAL PROPERTIES, AS WELL AS A SUMMARY OF RELEVANT ENVIRONMENTAL FATE PARAMETERS ARE DETAILED IN APPENDIX B.  Propamocarb-HCl is relatively non-persistent.  It is stable to photodegradation in water and is photodegradable on soil with a half-life of 35 days.  Propamocarb degrades fairly rapidly by microbial-mediated metabolism and is persistent to anaerobic metabolism.  It dissipates rapidly under field conditions, and has variable mobility (from mobile to relatively immobile).  Propamocarb-HCl has a low vapor pressure (10-7 mmHg) and, therefore, is unlikely to volatilize.  The low Henry's law constant (6.5 x 10[-1][3] atm m[3]/mole) also indicates that it has a low potential of volatizing from water (Memo, Olga M. Odiott, 15-JUL-1995).

3.3	Pesticide Use Pattern

Lima Beans (Proposed Use):  IR-4 has proposed the use of propamocarb-HCl for the control of downy mildew and Pythium root rots and seedling diseases on succulent lima beans grown east of the Rocky Mountains.  Propamocarb-HCl, formulated as Previcur[(R)] Flex Fungicide (EPA Reg. No. 264-678), may be applied using aerial, ground or chemigation equipment.  The proposed propamocarb label for the use on succulent lima beans direct applicators and other handlers to wear long-sleeved shirt and long pants, chemical-resistant gloves made of any waterproof material such as polyethylene or polyvinyl chloride, and shoes plus socks.  An example label containing use directions for lima beans was provided, and is summarized below in Table 3.3.1.

Table 3.3.1.  Summary of Directions for Proposed Use of Propamocarb-HCl on Succulent Lima Beans.
                  Application Timing, Type, and Equipment[1]
                                  Formulation
                                [EPA Reg. No.]
                                   App. Rate
                                   (lb ai/A)
                           Max. No. App. per Season
                            Max. Seasonal App. Rate
                                   (lb ai/A)
                                      PHI
                                    (days)
                       Use Directions and Limitations[2]
             Lima beans (For Use East of the Rocky Mountains Only)
Broadcast foliar  applications under favorable disease conditions; ground or aerial equipment
                                6.0 lb/gal FlC
                                   [264-678]
                                      1.5
                                       4
                                      6.0
                                     0[3]
A minimum 7-day RTI is specified.
Apply in a minimum volume of 5 and 15 gal/A using aerial and ground equipment, respectively.
1.  Applications can also be made by irrigation: transplant watering, drip irrigation or sprinklers.
2.  The label lists the following rotational crop restrictions:  Do not rotate to root and leafy vegetables for 30 days, and do not rotate to winter wheat or other non-labeled crops for 120 days.
3.  Do not harvest lima beans within 12 hours of application.  The REI is also 12 hours.

The submitted use directions are sufficient to allow for evaluation of the submitted residue data relative to the proposed use patterns.  The available field trial data support the proposed use directions for succulent lima beans.

Commercially Grown Field and Greenhouse Ornamentals (Existing Use):  In addition to the proposed use on succulent lima beans, an occupational exposure assessment was conducted for an existing use of propamocarb-HCl on field-grown and greenhouse-grown ornamentals to address recent revisions to product labels.  Applications are made using a variety of equipment, including groundboom, backpack sprayer, mechanically pressurized handgun sprayer, and dipping of the bare root plant.  The use directions for the existing uses on ornamentals are summarized in Table 3.3.2.

Table 3.3.2.  Summary of Directions for Existing Use of Propamocarb-HCl on Ornamentals.
                    Application Timing, Type, and Equipment
                          Formulation [EPA Reg. No.]
                              App Rate (lb ai/A)
                           Max. No. App. per Season
                             Max Seasonal App Rate
                                   (lb ai/A)
                                  PHI (days)
                        Use Directions and Limitations
Ornamentals (commercially grown in greenhouses and container grown in nurseries)
                        Seeding and Transplanting area
      Groundboom, Mechanically-pressurized handgun, Backpack sprayer, Dip
                                   Banol[(R)]
                                       
                             EPA Reg. No. 432-942 
                                       
                                SC, 6 lb ai/gal
                                0.014 lb ai/gal
                                       
                                  46 lb ai/A
                          no more than 2 apps/season
                                      128
                                      NA
                           RTI = 7 days to 6 months
                                       
                                REI = 24 hours
                                       
Do not apply through any type of irrigation system.  Do not use on field grown ornamentals.  Apply by soil-directed drench only.  Do not apply soil drench to foliage.
                 Cutting bed (transplants; drench application)
            Mechanically-pressurized handgun, Backpack sprayer, Dip
                                       
                                0.009 lb ai/gal
                                       
                                  82 lb ai/A
no more than 2 apps/ season; if 2 apps made, max rate per app = 31.5 fl oz/1000 sq ft = 64 lb ai/A
                                       
                                       
                                       
                 Potting (dip bare root plant and drench pots)
            Mechanically-pressurized handgun, Backpack sprayer, Dip
                                       
                                0.009 lb ai/gal
                                       
                                  64 lb ai/A
                          no more than 2 apps/season
                                       
                                       
                                       
                        Seeding and Transplanting area
      Groundboom, Mechanically-pressurized handgun, Backpack sprayer, Dip
                    Proplant Turf and Ornamental Fungicide
                                       
                             EPA Reg. No. 55260-9
                                       
                                SC, 6 lb ai/gal
                                0.014 lb ai/gal
                                       
                                  46 lb ai/A
no more than 2 apps/ season; if 2 apps made, max rate per app = 31.5 fl oz/1000 sq ft = 64 lb ai/A
                                      128
                                      NA
                           RTI = 7 days to 6 months
                                       
                                REI = 24 hours
                                       
Do not apply through any type of irrigation system.  Apply by soil-directed drench only.  Maximum single application rate must be <82 lb ai/A.  Foliar applications to ornamentals grown for cut flowers are prohibited.
                 Cutting bed (transplants; drench application)
            Mechanically-pressurized handgun, Backpack sprayer, Dip
                                       
                                0.009 lb ai/gal
                                       
                                  82 lb ai/A
                                       
                                       
                                       
                                       
                 Potting (dip bare root plant and drench pots)
            Mechanically-pressurized handgun, Backpack sprayer, Dip
                                       
                                0.009 lb ai/gal
                                       
                                  64 lb ai/A
                                       
                                       
                                       
                                       
                        Seeding and Transplanting area
      Groundboom, Mechanically-pressurized handgun, Backpack sprayer, Dip
                               Advan Propamocarb
                                       
                             EPA Reg. No. 83070-8
                                       
                                SC, 6 lb ai/gal
                                0.014 lb ai/gal
                                       
                                  46 lb ai/A
                             no more than 2 apps/
                                     year
                                      128
                                      NA
                          RTI = 3 - 6 week intervals
                                       
                                REI = 12 hours
                                       
Do not apply through any type of irrigation system.  Drench applications must be limited to soil directed sprays.  Foliar applications to ornamentals grown for cut flowers are prohibited.
                 Cutting bed (transplants; drench application)
            Mechanically-pressurized handgun, Backpack sprayer, Dip
                                       
                                0.009 lb ai/gal
                                       
                                  82 lb ai/A
                                       
                                       
                                       
                                       
                 Potting (dip bare root plant and drench pots)
            Mechanically-pressurized handgun, Backpack sprayer, Dip
                                       
                                0.009 lb ai/gal
                                       
                                  82 lb ai/A*
                                       
                                       
                                       
                                       
                               Woody ornamentals
                              Drench application
              Mechanically-pressurized handgun, Backpack sprayer
                                  Banol[(R)] 
                                       
                             EPA Reg. No. 432-942
                                       
                                SC, 6 lb ai/gal
                                0.012 lb ai/gal
                                       
                                  64 lb ai/A
no more than 2 apps/ season; if 2 apps made, max rate per app = 31.5 fl oz/1000 sq ft = 64 lb ai/A
                                     128 
                                      NA
             432-942: RTI = 7 days to 6 months and REI = 24 hours
                                       
          55260-9 and 83070-8: RTI = 3 - 4 months and REI = 12 hours
                                       
                                       
                    Proplant Turf and Ornamental Fungicide
                                       
                             EPA Reg. No. 55260-9

                                SC, 6 lb ai/gal
                                       
  no more than 2 apps/ season; maximum single app rate must be <82 lb ai/A
                                       
                                      NA
                                       
                                       
                                       
                               Advan Propamocarb
                                       
                             EPA Reg. No. 83070-8
                                       
                                SC, 6 lb ai/gal
                                       
                          no more than 2 apps/season
                                       
                                      NA
                                       

3.4	Anticipated Exposure Pathways
RD HAS REQUESTED AN ASSESSMENT OF HUMAN HEALTH RISK TO SUPPORT THE PROPOSED NEW USE OF propamocarb-HCl on succulent lima beans.  Humans may be exposed to propamocarb in food and drinking water, since it may be applied directly to growing crops and application may result in propamocarb reaching surface and ground water sources of drinking water.  There are no residential uses associated with the proposed use; however, as propamocarb-HCl is currently registered for use on golf courses, human exposure in residential or non-occupational settings may occur.  In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application to lima beans.  In addition, there is a possibility of post-application dermal exposure to occupational workers when reentering field previously treated with propamocarb-HCl.

The current risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of propamocarb-HCl, but also considers the existing uses as well, particularly for the dietary and residential exposure assessments.  The most recent human-health risk assessment was conducted in 2004 in conjunction with a Section 3 request for the use of propamocarb-HCl on lettuce, fruiting vegetables, and cucurbit vegetables (Memo, J. Tyler, et al.; 20-FEB-2004; D284504).  

3.5	Consideration of Environmental Justice

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," (http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf).  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003-2008) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.


4.0	Hazard Characterization and Dose-Response Assessment

4.1	Toxicology Studies Available for Analysis

There are two data sets for propamocarb-HCl (Memo, G. Reddy et al., 12-OCT-2005, TXR #0052538), the second of which was not accounted for in the previous risk assessment (Memo, J. R-Tyler et al., 20-FEB-2004, D284504).  The first set was sponsored by Bayer Crop Sciences/NOR-AM Agricultural Products (Naperville, Ill.).  The second set was sponsored by Chimac-Agriphar s.a. (Ougrée, Belgium) in support of an import tolerance.  This second set of studies did not change the endpoints from the 2004 risk assessment.

Since the last risk assessment, a guideline immunotoxicity study has been submitted and reviewed.  The hazard database for propamocarb hydrochloride is therefore complete.  

Since the last risk assessment, HED's HASPOC evaluated all existing hazard and exposure data, and current use patterns for propamocarb-HCl, and used a weight-of-evidence approach to waive the requirement for a subchronic inhalation toxicity study (Memo, J. Van Alstine, 14-FEB-2013; TXR#0056466).  This weight-of-evidence approach for waiving the inhalation study considered:  1)  there was no evidence of toxicity to the respiratory tract following inhalation exposure in two acute inhalation studies (no lung pathology) to indicate a concern for toxicity via repeated exposure; 2) in a repeated exposure inhalation study with a structural analog (bendiocarb), there were no clinical signs associated with respiratory tract toxicity and alveolar macrophages of the lungs were seen only at the highest concentration tested; 3) there was no target organ toxicity following oral exposures; only generalized toxicity (decreases in body weigh/body-weight gain and food consumptions were seen in mice, rats, and dogs; and 4) the use of an oral POD results in a MOE of 6100 mixing/loading activities for chemigation applications in green houses.

4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)

Greater than 80% of propamocarb was excreted in the urine 24 hours post dosing, suggesting that it was well absorbed from the GI tract.  Excretion was rapid with the majority of the administered doses eliminated and recovered within six hours following single dosing, and 24 hours following repeated dosing.  Pharmacokinetics parameters for both blood and plasma were Cmax = 0.20-0.25 ug equiv./g, Tmax = 0.50-0.88 h, and T(1/2) = 1.7-2.9 h in all animals.  At 6 hours post dosing, propamocarb was detectable in the blood, skin, liver, lungs, kidneys, ovaries, and adrenals.  At 24 hours post dosing, radioactivity was detectable only in the liver and the kidney, and three weeks following the cessation of treatment, it was undetectable in any tissue.  In the low-dose group, the predominant metabolite was carbonyl propamocarb, and in the high-dose group, the major metabolite was 3-hydroxypropyl propamocarb.

4.2.1	Dermal Absorption

There is no dermal-penetration study available for propamocarb-HCl.  Dermal absorption was estimated by comparing the rabbit maternal toxicity lowest-observed-adverse-effect level (LOAEL) (300 mg/kg/day) from the rabbit developmental toxicity study with the LOAEL (525 mg/kg/day) from the 21-day rabbit dermal study.  The dermal-absorption factor is:  300 mg/kg/day  525 mg/kg/day x 100 = 60%.

4.3	Summary of Toxicological Effects

Propamocarb-HCl was categorized as having low acute toxicity via the oral, dermal, and inhalation routes (Toxicity Categories III-IV).  It is not a dermal irritant or a dermal sensitizer.  It is considered a slight eye irritant.

In all species, decreased body weights, body-weight gains, and food consumption were observed for subchronic and chronic durations.  Effects throughout the database are indicative of toxicity to the digestive and GI tracts, specific regions of the nervous system, the eye, and to a lesser degree the respiratory tract.  In mice, decreased absolute body weights and body-weight gains were the only effect observed.  In rats, there were also signs of neurotoxicity in addition to the decreased body weights.  Decreased motor activities in females occurred following acute exposure.  Vacuolization of the choroid plexus (ventricles of the brain that produce cerebral spinal fluid) was observed for both subchronic and chronic durations.  Ocular effects in the rat occurred as well, including opacity of the eye and yellow colored eyes in females following chronic dietary exposure.  In dogs, there were also notable effects in the digestive and GI tracts, in addition to decreased body weights, evidenced by chronic erosive gastritis, and vacuolization of the salivary glands, stomach, and duodenum.  There were also respiratory effects including vacuolization of the cells of the trachea and lung.  There were ocular effects including vacuolization of the lacrimal gland, retinal degeneration, and hyporeflectivity of the fundus (inner eye tissue below the lens).  Dermal toxicity in rats and rabbits consisted of local effects including scabs, erythema maculate, focal erythema, necrosis, and ulcerative inflammation in the treated skin of females.  No systemic effects were observed.

There was no increased quantitative pre-natal sensitivity due to propamocarb-HCl treatment.  There were however fetal effects at doses which caused maternal toxicity.  Effects in the rat included increased fetal death and post-implantation loss, increases in minor skeletal anomalies, and increased incidences of small fetus.  There was also inter-atrial septal defects, and hemorrhage in the ears, upper GI tract, and nasopharynx/sinuses.  Maternal effects consisted of decreased absolute body-weights, body-weight gains and food consumption, and mortality.  In rabbits, the only developmental effect was an increase in post-implantation loss.  Maternal effects consisted of increased abortions, and body-weight decrements similar.  

In the rat two-generation reproduction studies, parental and offspring effects occurred at the same dose.  Parental effects were similar to the effects observed in the rat subchronic and chronic studies in addition to clinical signs including salivation, reddish material around the mouth, and urine staining.  Offspring effects consisted of pup deaths, decreased viability and lactation indices and litter size, and decreased pup body weights and body-weight gains.  Reproductive effects consisted of increased vacuolization and decreased weight of the epididymides, decreased sperm counts and motility, and abnormal sperm morphology.

In the guideline immunotoxicity study, effects at the high dose included decreased body-weight gain and decreased food consumption.  

4.4	Safety Factor for Infants and Children (FQPA SF)

The propamocarb-HCl risk assessment team evaluated the quality of the hazard and exposure data and determined that the FQPA SF should be reduced to 1X for all exposure scenarios for the following reasons: there is a complete toxicological database, there is no evidence of increased quantitative susceptibility in the developing or young animal, and there is no uncertainty in the exposure data.  The details for reducing the FQPA safety factor to 1X are detailed below.

4.4.1	Completeness of the Toxicology Database

The toxicology database is adequate for characterizing propamocarb-HCl toxicity and quantification of hazard for dietary and occupational/residential exposures.  

4.4.2	Evidence of Neurotoxicity

There are two guideline acute neurotoxicity studies and two subchronic neurotoxicity studies for propamocarb-HCl and the effects are well characterized.  The endpoints selected are protective of these effects.

4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased quantitative susceptibility of rat and rabbit fetuses to in utero exposure to propamocarb-HCl.  There are qualitative effects observed however in both developmental studies.  In one of the two-generation reproduction studies, there is an increase in pup mortality at doses that cause parental toxicity.  The LOC for all of these effects is low because:  (1) the effects are well characterized, (2) clear NOAELs were established, and (3) the developmental rabbit and rat two-generation reproduction studies are being used in endpoint selection.

4.4.4	Residual Uncertainty in the Exposure Database

The acute and chronic dietary food exposure assessment utilizes existing and proposed tolerance-level residues and 100% CT information for all commodities.  By using these screening-level assessments, actual exposures/risks will not be underestimated.

The dietary drinking water assessment utilizes water concentration values generated by models and associated modeling parameters, which are designed to provide conservative, health-protective, high-end estimates of water concentrations that will not likely be exceeded.

The residential exposure assessment is based upon the residential SOPs, which are based upon reasonable worst-case assumptions and are not expected to underestimate risk.  

4.5	Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

Acute Dietary Endpoint (females 13-49 years of age):  The rabbit developmental toxicity study (MRID #000072574) was used to select the endpoint for the acute reference dose (aRfD) of 1.5 mg/kg/day for females 13-49 years of age.  The NOAEL is 150 mg/kg/day (developmental).  The LOAEL of 300 mg/kg/day was based on increased post-implantation loss in rabbits.  This endpoint is considered appropriate for females of childbearing age (13-49 years old) since the effects could occur due to a single in utero exposure.  An uncertainty factor of 100 was applied to the NOAEL to derive the aRfD for females 13-49 years of age.  The FQPA SF of 1X is applicable for the acute dietary risk assessment.  Thus, the aPAD for females 13-49 years old is 1.5 mg/kg/day.  

Acute Dietary Endpoint (general population):  The rat acute oral neurotoxicity study (MRID #43062301) was used to select the endpoint for the aRfD of 2.0 mg/kg/day for the general U.S. population (including infants and children).  The NOAEL is 200 mg/kg/day.  The LOAEL of 2000 mg/kg/day is based on decreased body-weight gain and decreased motor activity 8 hrs post-dosing in females.  These effects occurred following a single dose and therefore are appropriate for use in the acute dietary risk assessment.  An uncertainty factor of 100 was applied to the NOAEL to derive the aRfD for the general U.S. population.  The FQPA SF of 1X is applicable for the acute dietary risk assessment.  Thus, the aPAD for the general U.S. population (including infants and children) is 2.0 mg/kg/day.

Chronic Dietary Endpoint:  The mouse carcinogenicity study (MRID #44693801) was used to select the endpoint for establishing the chronic reference dose (cRfD) of 0.12 mg/kg/day.  The NOAEL is 12 mg/kg/day.  The LOAEL of 95 mg/kg/day was based on decreased absolute body-weight and body-weight gain in females.  An uncertainty factor of 100 was applied to the NOAEL to derive the cRfD.  The FQPA safety factor of 1X is applicable for chronic dietary risk assessment.  Thus, the cPAD is 0.12 mg/kg/day.  This POD is protective of the effects in the other species tested observed at higher doses.  This study is further protective for the general U.S. population for exposure for the chronic duration.

Short- and Intermediate-Term Incidental Oral Endpoint:  Short- and intermediate-term incidental oral endpoints were selected from the two-generation rat reproduction study.  The NOAEL is 65.41 mg/kg/day.  The LOAEL is 406.7 mg/kg/day based upon significant reduction in body weights of F0 and F1 pups during days 14 - 21 of lactation.  This study and endpoint are appropriate for the population of concern (infants and children) and the route and durations of exposure.

Short- and Intermediate-Term Dermal Endpoints:  Short- and intermediate-term dermal endpoints were selected from the rabbit 21-day dermal toxicity study (MRID #00071526).  The NOAEL is 150 mg/kg/day and the LOAEL of 525 mg/kg/day is based on decreased body-weight gain in females.  This study was selected because the route of exposure is appropriate for the exposure scenario as well as the expected durations of exposure in occupational settings.  It is also protective of the developmental effects in rabbits.

Short- and Intermediate-term Inhalation Endpoint:  Short- and intermediate-term inhalation endpoints were selected from the two-generation rat reproduction study (MRID #44730103).  The NOAEL is 65.41 mg/kg/day.  The parental LOAEL of 406.7 mg/kg/day is based upon significant reduction in body weights in the parental generation.  This dose/endpoint is appropriate for short- and intermediate-term inhalation exposure for adults in occupational settings.

4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment

Exposures (dermal, oral, and inhalation) can be combined if the toxicological effects are the same.  Decreased body weight was the endpoint of concern for the incidental oral, dermal and inhalation routes for propamocarb.  In the two-generation reproduction study used for the incidental oral route, body-weight changes were observed in both adults and offspring.  Therefore, for propamocarb, the dermal, inhalation, and incidental oral routes can be combined for risk assessment since a common endpoint was observed. 

4.5.3	Cancer Classification and Risk Assessment Recommendation

In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the HIARC classified propamocarb-HCl as "not likely to be carcinogenic to humans" by all routes of exposure based upon lack of evidence of carcinogenicity in rats and mice, therefore, a cancer risk assessment is not required. 

4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table 4.5.4.1.  Summary of Toxicological Doses and Endpoints for Propamocarb-HCl for Use in Dietary and Non-Occupational Human-Health Risk Assessments.
                              Exposure/ Scenario
                                      POD
                        Uncertainty/FQPA Safety Factors
                       RfD, PAD, LOC for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary (Females 13-49 years of age)
NOAEL = 150 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X
Acute RfD = 1.5 mg/kg/day
aPAD = 1.5 mg/kg/day
Developmental Toxicity Study - Rabbit
Developmental LOAEL = 300 mg/kg/day based on increased post-implantation loss.
Acute Dietary
(General U.S. population, including Infants and Children)
NOAEL = 200 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X
Acute RfD = 2 mg/kg/day
aPAD = 2 mg/kg/day
Acute Neurotoxicity Screening Battery - Rat
LOAEL = 2000 mg/kg/day, based on decreased body-weight gain and decreased motor activity.
Chronic Dietary (All Populations)
NOAEL = 12 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X
Chronic RfD = 0.12 mg/kg/day
cPAD = 0.12 mg/kg/day
Carcinogenicity Study - Mouse
LOAEL = 95 mg/kg/day, based on decreased body-weight and body-weight gain in females.
Incidental Oral
Short-l (1-30 days) and Intermediate- Term (1-6 months) 
NOAEL = 65.41 mg/kg/day

UFA = 10X
UFH = 10X
FQPA SF = 1X
Residential LOC for MOE = 100
2-generation Reproduction Toxicity Study - Rat
Offspring LOAEL = 406.7 mg/kg/day, based on reduced pup weights in F0 & F1 during Day 14 - 21 of lactation.
Cancer (oral, dermal, inhalation)
Classification:  "not likely to be carcinogenic to humans."
Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response 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).  FQPA SF = FQPA Safety Factor.  PAD = population-adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  

Table 4.5.4.2.  Summary of Toxicological Doses and Endpoints for Propamocarb-HCl for Use in Occupational Human Health Risk Assessments.
                              Exposure/ Scenario
                                      POD
                              Uncertainty Factors
                            LOC for Risk Assessment
                        Study and Toxicological Effects
Dermal   
Short- (1-30 days) and Intermediate-Term (1-6 months)
NOAEL = 150 mg/kg/day
UFA = 10X
UFH = 10X
Occupational LOC for MOE = 100
21-day Dermal Toxicity Study - Rabbit
LOAEL = 525 mg/kg/day, based on decreased body-weight gain in females.
Inhalation 
Short- (1-30 days) and Intermediate-Term (1-6 months)
NOAEL = 65.41 mg/kg/day
UFA = 10X
UFH = 10X
Occupational LOC for MOE = 100
Two-generation Reproduction Toxicity Study  -  Rat
Parental LOAEL = 406.69 mg/kg/day for males and 467.13 mg/kg/day for females based on decreased body weights.
Cancer (oral, dermal, inhalation)
Classification:  "not likely to be carcinogenic to humans"
Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response 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).  MOE = margin of exposure.  LOC = level of concern.  

5.0	Dietary Exposure and Risk Assessment 

The residue chemistry data submitted in support of the proposed Section 3 use on succulent lima beans were reviewed by HED in a memo dated 15-MAY-2013 (Memo, J. Tyler; D359104).  The EDWCs were provided by EFED (Memo, M. Ruhman; 11-DEC-2012).  The acute and chronic dietary exposure assessment was completed in a HED memorandum dated 15-MAY-2013 (Memo, J. Tyler; D367969).

5.1	Residues of Concern Summary and Rationale

The nature of propamocarb residues in vegetable crops is adequately understood based on the available potato, cucumber, and spinach metabolism studies.  The residue of concern for both risk assessment and tolerance enforcement is propamocarb per se (Memo, J. Rowell, 03-MAY-2000; D264293).  The nature of the residue in ruminants is adequately understood based on acceptable metabolism and feeding studies on dairy cattle, which were submitted as propamocarb-HCl is currently registered for use on ruminant feed items.  The residues of concern in livestock for tolerance and risk assessment purposes are the parent propamocarb and the 2-hydroxy propamocarb and propamocarb glucuronide metabolites (Memos, J. Rowell, 03-MAY-2000, D264293; and J. Tyler, 10-MAR-2005; D304509).  No poultry metabolism study has been submitted.  Propamocarb-HCl is currently not registered for use on any poultry feed items.  However, the results of a poultry feeding study will be required to support any future uses that are classified as poultry feed items.

5.2	Food Residue Profile

Adequate residue chemistry data are available for risk assessment and tolerance assessment.  As the proposed use on succulent lima beans does not include any regulated livestock feedstuffs or processed commodities, data requirements for livestock commodities and processed food and feed are not required. 

The results of the field trials are adequate.  Following 4 or 5 broadcast foliar applications totaling 5.84-7.42 lb ai/A (~1X the proposed maximum seasonal rate of 6.0 lb ai/A), residues of propamocarb were 0.21-0.65 ppm in/on 8 samples of succulent seeds harvested at 0 days after treatment (DAT).  Following eight applications totaling 11.83 lb ai/A (NC trial), the highest residue was 1.01 ppm in/on succulent seeds.  Overall, the highest-average field trial (HAFT) residue in succulent seeds was 0.99 ppm.  No residue-decline data were submitted.  

Although eight field trials are typically required to support a use on lima beans, only five field trials [1 trial in North America Free Trade Agreement (NAFTA) Growing Zone 5 and 4 trials in Zone 2] are required to support a use on lima beans restricted to east of the Rocky Mountains.  Therefore, the geographic representation of the four acceptable trials is adequate.

The residue data for lima beans were analyzed using the Organization for Economic Co-operation and Development (OECD) tolerance calculation procedures.  The recommended tolerance is as follows:

Tolerances are established for residues of propamocarb, including its metabolites and degradates, in or on the commodities listed below resulting from the application of the hydrochloride salt of propamocarb.  Compliance with the following tolerance levels is to be determined by measuring only propamocarb (propyl N-[3-(dimethylamino)propyl]carbamate).

	Bean, lima, succulent							2.0 ppm

The available storage stability data adequately support the storage conditions and durations for samples from the lima bean field trials.

Adequate confined and field rotational crop studies are available, and the data from these studies support the rotational crop restrictions currently specified on the proposed label.

5.3	Water Residue Profile

EFED provided EDWCs for surface water (using Tier II PRZM/EXAMS) and groundwater (using SCI-GROW) for propamocarb-HCl (see Table 5.3).  The EDWCs were calculated based on the maximum application rate for current ornamental labels (2 x 64.3 lbs ai/A).  The acute and chronic EDWCs in surface water are 8,762 ppb and 1,067 ppb, respectively.  The groundwater EDWC is 15.6 ppb.  

Table 5.3  Summary of Estimated Surface Water and Groundwater Concentrations for Propamocarb-HCl.[1]
                                   Scenario
                         Surface Water Conc. (ppb)[2]
                          Groundwater Conc. (ppb)[3]
Acute
8,762
15.6
Chronic (non-cancer)
1,067

1.  Memo, M. Ruhman, 11-DEC-2013, 368070.
2.  From Tier II PRZM/EXAMS.  Input parameters are based on the maximum application rate for ornamental labels (2 x 64.3 lbs ai/A).
3.  From the SCI-GROW model.  Input parameters are based on the maximum application rate for ornamental labels (2 x 64.3 lbs ai/A).

5.4	Dietary Risk Assessment

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the DEEM-FCID (Ver. 3.16), which uses food consumption data from the USDA's NHANES/WWEIA.  This dietary survey was conducted from 2003 to 2008. 

5.4.1	Description of Residue Data Used in Dietary Assessment

 The acute and chronic dietary exposure assessments were unrefined, using tolerance-level residues and assuming 100% CT for all registered and proposed commodities.  Exposure to drinking water was incorporated directly in the acute and chronic dietary assessments using the acute (peak) and chronic (annual average) concentrations for surface water generated by the PRZM-EXAMS model, respectively.

5.4.2	Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary exposure assessments assumed 100% CT for all registered and proposed uses.

5.4.3	Acute Dietary Risk Assessment

The results of the unrefined acute dietary assessment indicates that the acute dietary exposure estimates are below HED's LOC (<100% aPAD) at the 95[th] exposure percentile for the general U.S. population and all other population subgroups.  The acute dietary exposure is estimated at 34% of the aPAD for females 13-49 years old, and 25% of the aPAD for the general U.S. population.  The most highly exposed population subgroup is all infants (<1 year old) at 75% of the aPAD.

The acute assessments were highly conservative, using several upper-end assumptions.  Additional refinements, such as inclusion of anticipated residues (ARs) and %CT data could be made in order to refine the future assessments.  HED is confident that the assessment does not underestimate risk to the general U.S. population or any population subgroup.
5.4.4	Chronic Dietary Risk Assessment

The results of the unrefined chronic dietary assessment indicate that the chronic dietary exposure estimates are below HED's LOC (<100% cPAD) for the general U.S. population and all population subgroups.  The chronic dietary exposure is estimated for the general U.S. population at 31% of the cPAD, and the most highly exposed population subgroup, all infants (<1 years old), at 50% of the cPAD.

 The chronic assessment was highly conservative, using several upper-end assumptions.  Additional refinements, such as inclusion of ARs and %CT data could be made in order to refine the future assessments.  HED is confident that the assessment does not underestimate risk to the general U.S. population or any population subgroup.

5.4.5	Summary Table

 Table 5.4.5.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Propamocarb-HCl.
                              Population Subgroup
                                 Acute Dietary
                              (95[th] Percentile)
                                Chronic Dietary
                                        
                          Dietary Exposure (mg/kg/day)
                                    % aPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
                            General U.S. Population
                                    0.507723
                                       25
                                    0.037228
                                       31
                          All Infants (<1 year old)
                                    1.496493
                                      75*
                                    0.060367
                                      50*
                             Children 1-2 years old
                                    0.762741
                                       38
                                    0.045611
                                       38
                             Children 3-5 years old
                                    0.633181
                                       32
                                    0.044067
                                       37
                            Children 6-12 years old
                                    0.473593
                                       24
                                    0.032129
                                       27
                             Youth 13-19 years old
                                    0.416725
                                       21
                                    0.028399
                                       24
                             Adults 20-49 years old
                                    0.501031
                                       25
                                    0.038290
                                       32
                              Adults 50+ years old
                                    0.449098
                                       22
                                    0.037513
                                       31
                            Females 13-49 years old
                                    0.510324
                                       34
                                    0.039067
                                       33
*The subpopulation(s) with the highest risk estimates.


6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed residential uses at this time; however, there are registered residential uses for golf course turf (at a maximum application rate of 8.2 lb ai/A) that have been reassessed in this document to reflect updates to HED's 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html) along with policy changes for body-weight assumptions.  The revision of residential exposures will impact the human-health aggregate risk assessment for propamocarb-HCl.

6.1	Residential Handler Exposure

It is not anticipated that there will be residential handler exposure from the use on golf courses; therefore, an exposure assessment for residential handlers was not conducted.

6.2	Post-Application Exposure

Post-application dermal exposure was reassessed for adults and children based on the 2012 Residential SOPs.  Table 6.2 provides a summary of the residential post-application risk estimates from the registered use on golf course turf.  There are no MOEs of concern (i.e., all MOEs >=100).
Table 6.2.  Residential Post-application Non-cancer Exposure and Risk Estimates for Propamocarb-HCl.
                                   Lifestage
                      Post-application Exposure Scenario
                               TTR (ug/cm[2])[1]
                                    Dose[2]
                                    MOE[3]
                                     Adult
                               Golf course turf
                                    Dermal
                                     1.50
                                     0.397
                                      380
                         Child (11 < 16 years old)
                                       
                                       
                                       
                                     0.463
                                      320
                          Child (6 < 11 years old)
                                       
                                       
                                       
                                     0.543
                                      280
1.  TTR = chemical-specific data from MRID 45894314 for the PA site adjusted for differences in application rates.  Study application rate = 8.1 lb ai/A, and label maximum application rate = 8.2 lb ai/A.  See Appendix B for more information regarding the available data.
2.  Dose = TTR * CF1 * TC * ET / BW.  See Appendix A of D377624 for inputs.
3.  MOE = Dermal NOAEL (150 mg/kg/day) / Dose (mg/kg/day).

6.3	Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3 reflects the residential risk estimates that are recommended for use in the aggregate assessment for propamocarb-HCl:

   * The recommended residential exposure for use in the adult and child aggregate assessment reflects dermal post-application exposure from golfing.

Table 6.3.  Recommendations for the Residential Exposures for the Propamocarb Aggregate Assessment.[1]
                                   Lifestage
                   Post-application Exposure (mg/kg/day)[2]
            Residential Post-application Total Exposure (mg/kg/day)
                       Residential Post-application MOE
                                       
                                    Dermal
                                  Inhalation
                                     Oral
                                       
                                       
                                  Short-term
                                  Adult Male
                                     0.397
                                      N/A
                                      N/A
                                     0.397
                                      380
                         Child (11 < 16 years old)
                                     0.463
                                      N/A
                                      N/A
                                     0.463
                                      320
                          Child (6 < 11 years old)
                                     0.543
                                      N/A
                                      N/A
                                     0.543
                                      280
1.  Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 
2.  Residential post-application exposure = exposure to treated turf while golfing in previously treated areas (see table 5.2.1).

6.4	Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for propamocarb at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and the vapor pressure (6.1 x 10[-7] mm Hg at 25ºC).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for propamocarb.

6.5	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for propamocarb.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray-drift-management practices (see the Agency's Spray Drift website for more information (http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  On a chemical-by-chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT[(R)] computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray-drift-management practices to reduce off-target drift with specific products with significant risk estimates associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers.  This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post-application inhalation exposure scenarios.   


7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate 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.  In the case of propamocarb-HCl, aggregate risk assessments were performed for acute aggregate exposure (food + drinking water), short-term aggregate exposure (food + drinking water + residential), and chronic aggregate exposure (food + drinking water).  An intermediate-term assessment was not conducted as intermediate-term residential exposures are not expected based on the current use patterns.  However, as the short- and intermediate-term PODs are the same, the short-term aggregate is protective of any potential intermediate-term exposures.  A cancer aggregate risk assessment was not performed because propamocarb-HCl is not carcinogenic.  All potential exposure pathways were assessed in the aggregate risk assessment. 

7.1	Acute Aggregate Risk

The acute aggregate risk assessment takes into account exposure estimates from dietary consumption of propamocarb-HCl (food + drinking water).  The acute dietary exposure is estimated at 34% of the aPAD for females 13-49 years old, and 25% of the aPAD for the U.S. population (see Table 5.4.5).  The most highly exposed population subgroup is all infants (<1 year old) at 75% of the aPAD.  Therefore, the acute aggregate risk associated with the proposed use of propamocarb-HCl does not exceed HED's LOC for the general U.S. population or any population subgroup.

57.2 Short-Term Aggregate Risk

The short-term aggregate risk assessment estimates risks likely to result from 1- to 30-day exposures to propamocarb residues from food, drinking water, and residential pesticide uses.  High-end estimates of residential exposure are used, and average values are used for food and drinking water exposures.

Short-term aggregate risk assessments are necessary for both adults and children as there is potential for short-term post-application dermal exposure from the registered golf course use of propamocarb-HCl.  For adult males, children (6 < 11 years old), and children (11 < 16 years old), the dermal post-application exposures estimates from contacting treated golf courses (see Table 6.3) were aggregated with the chronic dietary exposures (food + drinking water; see Table 5.4.5) to provide a worst-case estimate of short-term aggregate risk for these population subgroups.  

For the short-term aggregate, the chronic dietary exposures were compared to the short-term incidental oral POD, which was based on decreased body weights observed in a two-generation reproduction study in both adults and offspring.  Since the effects were observed in adults, the dietary exposures can be combined with the residential dermal exposures, which are also based on decreased body weights in adults.  The 1/MOE approach was used since the toxicological effects for these exposures are similar (body-weight changes), and the LOCs are the same; however, different PODs were selected for the different routes of exposure.  For the oral route, a NOAEL of 65.41 mg/kg/day was selected from the two-generation reproduction study to be protective of both parents and offspring.  For the dermal route, a NOAEL of 150 mg/kg/day was selected from the dermal study.  As the short-term aggregate MOEs are greater than 100, risks are not of concern.

Table 7.2.  Short-Term Aggregate Risk Calculations.
                                  Population
                           LOC for Aggregate Risk[1]
                   Dietary (Food and Drinking Water) MOE[2] 
                           Residential Dermal MOE[3]
                  Aggregate MOE (Dietary and Residential)[4]
Adult Male
                                      100
                                     1800
                                      380
                                      310
Adult Female

                                     2300
                                      320
                                      280
Child

                                     2000
                                      280
                                      240
1.  The LOC (target MOE) includes 10X for interspecies extrapolation and 10X for intraspecies variation.
2.  MOE dietary = [Short-term oral NOAEL (mg/kg/day)/Chronic dietary exposure (mg/kg/day)].  Short-term oral NOAEL = 65.41 mg/kg/day.  See Table 5.4.4 for chronic dietary exposures.
3.  MOE dermal = [Short-term dermal NOAEL (mg/kg/day)/high-end dermal residential exposure (mg/kg/day)].  Short-term derma NOAEL = 150 mg/kg/day.  See Table 6.4 for residential dermal exposures. 
4.  MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE dermal)].

7.3	Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of propamocarb (food + drinking water) and long-term residential uses.  However, there are no registered or proposed uses that would result in long-term residential exposure; therefore, the chronic aggregate risk assessment takes into account exposure to food and drinking water only.  The chronic dietary exposure is estimated at 31% of the cPAD for the U.S. population (see Table 5.4.5).  The most highly exposed population subgroup is all infants (<1 year old) at 50% of the cPAD.  Therefore, the chronic aggregate risk associated with the proposed use of propamocarb-HCl does not exceed HED's LOC for the general U.S. population or any population subgroups.


6.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to propamocarb-HCl and any other substances and propamocarb-HCl does not appear to produce a toxic metabolite produced by other substances.  Although a carbamate, propamocarb is not an N-methyl carbamate and does not cause cholinesterase inhibition.  Thus it was not included in the N-methyl carbamate cumulative risk assessment.  For the purposes of this tolerance action, therefore, EPA has not assumed that propamocarb-HCl has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.


7.0 Occupational Exposure/Risk Characterization

Based on the proposed application scenarios and toxicological considerations, non-cancer occupational handler (dermal and inhalation) and post-application (dermal) assessments were conducted for the proposed uses on succulent lima beans.  In addition, because of recent label revisions for the currently registered use on ornamentals, non-cancer occupational handler (dermal and inhalation) and post-application (dermal) assessments were reassessed for ornamentals.  Occupational exposures were evaluated by HED and reviewed by the HED Science Advisory Council for Exposure (ExpoSAC; Memo, K. Lowe, 15-MAY-2013; D377624). 

9.1	Occupational Handler Exposure/Risk Estimates

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 exposures can vary depending on the specifics of each task.  Job requirements (amount of chemical used in each 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.  

Based on the anticipated use patterns and current labeling (see Tables 3.3.1 and 3.3.2), types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed use on lima beans, and the registered uses on ornamentals.  The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: 

Proposed Use on Lima Beans:
   * Mixing/loading Liquids for aerial, chemigation, and groundboom applications,
   * Applying sprays via aerial and groundboom equipment, and,
   * Flagging for aerial sprays applications.

Registered Use on Ornamentals:
   * Mixing/loading liquids for groundboom applications,
   * Applying sprays via groundboom equipment, 
   * Mixing/loading liquids for dip applications,
   * Mixing/loading/applying liquids with a mechanically-pressurized handgun, and,
   * Mixing/loading/applying liquids with a backpack sprayer.

For propamocarb-HCl, based on the proposed use on succulent lima beans, short- and intermediate-term exposures are expected since the product can be applied up to 4X per season at the maximum single application rate, with a RTI of 7 days.  In addition, the short- and intermediate-term PODs are the same for both dermal and inhalation routes; therefore, the short-term exposure and risk estimates are protective of longer-term exposures.

Estimates of dermal and inhalation exposure were calculated for various levels of personal-protective equipment (PPE).  Results are presented for "baseline," defined as a single layer of clothing consisting of a long-sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc.).  The proposed propamocarb-HCl label for the use on lima beans directs applicators and other handlers to wear long-sleeved shirt and long pants, chemical-resistant gloves made of any waterproof material such as polyethylene or polyvinyl chloride, and shoes plus socks.  The registered labels with ornamental uses direct applicators and other handlers to wear long-sleeved shirt and long pants, chemical-resistant gloves made of any waterproof material, shoes plus socks, and a chemical-resistant apron when making dip applications.

It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include PHED 1.1, the AHETF database, the ORETF database, or other registrant-submitted occupational exposure studies.  Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures," are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website (http://www.epa.gov/pesticides/science/handler-exposure-data.html). 

HED has no data to assess exposures to pilots using open cockpits.  The only data available are for exposure to pilots in enclosed cockpits.  Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, and socks); pilots are not required to wear protective gloves.  With this level of protection, there are no risk estimates of concern for applicators.

The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential.  While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades.  According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of the Global Positioning System (GPS) for swath guidance in agricultural aviation has grown steadily from the mid 1990s.  Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990s to only 1% in the most recent (2012) NAAA survey.  The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

The occupational handler exposure and risk estimates indicate that short- and intermediate-term dermal and inhalation combined MOEs are not of concern to HED (i.e., MOEs > 100) with baseline attire or with the addition of gloves (as required on the labels).  For the proposed use on lima beans, the dermal plus inhalation MOEs range from 100 to 4,500 with baseline attire (see Table 9.1.1).  For the registered use on ornamentals, the dermal plus inhalation MOEs range from 120 to 39,000 with baseline attire and/or gloves (see Table 9.1.2).

Table 9.1.1.  Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Proposed Use of Propamocarb on Lima Beans.
                               Exposure Scenario
                            Crop / Target Category
                              Application Rate[1]
                       Amount Handled / Area Treated[2]
                             Dermal Unit Exposures
                                 (ug/lb ai)[3]
                           Inhalation Unit Exposures
                                 (ug/lb ai)[3]
                          Dermal Dose (mg/kg/day)[4]
                                 Dermal MOE[5]
                        Inhalation Dose (mg/kg-day)[6]
                               Inhalation MOE[7]
                                Combined MOE[8]
                            Mixing/Loading Liquids
                              Aerial application
                                  Lima beans
                                  1.5 lb ai/A
                                   350 acres
                                      220
                                     0.219
                                     1.45
                                      100
                                    0.00144
                                    45,000
                                      100
                           Chemigation applications
                                       
                                       
                                       
                                       
                                       
                                     1.45
                                      100
                                    0.00144
                                    45,000
                                      100
                            Groundboom applications
                                       
                                       
                                   80 acres
                                       
                                       
                                     0.33
                                      450
                                   0.000329
                                    200,000
                                      450
                                Applying Sprays
                              Aerial applications
                                  Lima beans
                                  1.5 lb ai/A
                                   350 acres
                                    5 (EC)
                                  0.068 (EC)
                                  0.0329 (EC)
                                  4,600 (EC)
                                 0.000446 (EC)
                                 150,000 (EC)
                                  4,500 (EC)
                            Groundboom applications
                                       
                                       
                                   80 acres
                                     78.6
                                     0.34
                                     0.118
                                     1,300
                                    0.00051
                                    130,000
                                     1,300
                                   Flagging
                              Aerial applications
                                  Lima beans
                                  1.5 lb ai/A
                                   350 acres
                                      11
                                     0.35
                                    0.0723
                                     2,100
                                    0.0023
                                    28,000
                                     2,000
1.  Based on proposed label (Reg. #264-678).
2.  ExpoSAC Policy #9.1.
3.  Based on "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (September 2012); includes data from PHED/ORETF/AHETF.  Level of mitigation: Baseline (single layer of clothing, no gloves, no respirator) for all scenarios except for aerial applicators which is assessed using engineering controls (EC).
4.  Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) / BW (80 kg).
5.  Dermal MOE = Dermal NOAEL (150 mg/kg/day)/Dermal Dose (mg/kg/day).
6.  Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) / BW (80 kg).
7.  Inhalation MOE = Inhalation NOAEL (65.41 mg/kg/day)/ Inhalation Dose (mg/kg/day).
8.  Total MOE = 1/(1/Dermal MOE + 1/Inhalation MOE)


Table 9.1.2.  Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Reassessment of Ornamental Use of Propamocarb.
                               Exposure Scenario
                            Crop / Target Category
                              Application Rate[1]
                       Amount Handled / Area Treated[2]
                             Dermal Unit Exposures
                                 (ug/lb ai)[3]
                           Inhalation Unit Exposures
                                 (ug/lb ai)[3]
                          Dermal Dose (mg/kg/day)[4]
                                 Dermal MOE[5]
                        Inhalation Dose (mg/kg-day)[6]
                               Inhalation MOE[7]
                                Combined MOE[8]
                            Mixing/Loading Liquids
                            Groundboom applications
                        Greenhouse/Nursery ornamentals
                                  46 lb ai/A
                                   60 acres
                                     220 
                                  (baseline)
                                       
                                     37.6 
                                 (with gloves)
                                     0.219
                                     7.59 
                                  (baseline)
                                       
                                     1.3 
                                 (with gloves)
                                      20 
                                  (baseline)
                                       
                                     120 
                                 (with gloves)
                                   0.00755 
                                     8,700
                                      20
                                  (baseline)
                                       
                                     120 
                                 (with gloves)
                               Dip applications
                                       
                              0.014 lb ai/gallon
                                  100 gallons
                                       
                                       
                              0.00385 (baseline)
                                    39,000
                                  (baseline)
                                  0.00000384
                                  17,000,000
                                    39,000
                                       
                                       
                                       
                                 1000 gallons
                                       
                                       
                                    0.0385 
                                  (baseline)
                                     3,900
                                  (baseline)
                                   0.0000384
                                   1,700,000
                                     3,900
                                Applying Sprays
                            Groundboom applications
                        Greenhouse/Nursery ornamentals
                                  46 lb ai/A
                                   60 acres
                                     78.6
                                  (baseline)
                                       
                                     16.1
                                 (with gloves)
                                     0.34
                                     2.71
                                  (baseline)
                                       
                                     0.555
                                 (with gloves)
                                      55
                                  (baseline)
                                       
                                      270
                                 (with gloves)
                                    0.0117
                                     5,600
                                      54
                                  (baseline)
                                       
                                      260
                                 (with gloves)
                        Mixing/Loading/Applying Liquids
                               Backpack sprayer
                    Nursery (ornamentals, container stock)
                              0.014 lb ai/gallon
                                  40 gallons
                                     8,260
                                     2.58
                                    0.0579
                                     2,600
                                   0.000018
                                   3,600,000
                                     2,600
                       Mechanically-pressurized handgun
         Greenhouse (ornamentals, roses, cut flowers, container stock)
                                       
                                 1000 gallons
                                     3,500
                                      120
                                     0.613
                                      240
                                     0.021
                                     3,100
                                      220
                                       
                    Nursery (ornamentals, container stock)
                                       
                                       
                                     1,300
                                      3.9
                                     0.228
                                      660
                                   0.000683
                                    96,000
                                      660
1.  Based on registered labels (Reg. #432-942, #55260-9, and #83070-8).
2.  ExpoSAC Policy #9.1.
3.  Based on "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (September 2012); includes data from PHED/ORETF/AHETF.  Level of mitigation: Baseline (single layer of clothing, no gloves, no respirator), Baseline with gloves, or engineering controls (EC; closed cockpit) for aerial applicators. 
4.  Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) / BW (80 kg).
5.  Dermal MOE = Dermal NOAEL (150 mg/kg/day)/Dermal Dose (mg/kg/day).
6.  Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) / BW (80 kg).
7.  Inhalation MOE = Inhalation NOAEL (65.41 mg/kg/day)/ Inhalation Dose (mg/kg/day).
8.  Total MOE = 1/(1/Dermal MOE + 1/Inhalation MOE).

9.2	Occupational Post-application Exposure/Risk Estimates

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

For the proposed use on lima beans, post-application exposure is anticipated based on the use pattern.  For the registered ornamental use, post-application exposure is not anticipated since the labels indicate applications are to be limited to soil-directed sprays.

9.2.1	Occupational Post-application Dermal Exposure/Risk Estimates

HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months as intermediate-term.  For propamocarb, based on the proposed use, short- and intermediate-term exposures are expected since the product can be applied up to 4X per season at the maximum single application rate, with a RTI of 7 days.  In addition, the short- and intermediate-term PODs are the same for both dermal and inhalation routes; therefore, the short-term exposure and risk estimates are protective of longer-term exposures.

It is the policy of HED to use the best available data to assess post-application exposure.  Sources of generic post-application data, used as surrogate data in the absence of chemical-specific data, are derived from ARTF exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting post-application exposure that are used in this assessment, known as "transfer coefficients",  are presented in the ExpoSAC Policy 3 (http://www.epa.gov/pesticides/science/exposac_policy3.pdf)" which, along with additional information about the ARTF data, can be found at the Agency website (http://www.epa.gov/pesticides/science/post-app-exposure-data.html). 

The short- and intermediate-term post-application exposure scenarios associated with the proposed uses for propamocarb are summarized in Table 9.2.1.  All scenarios resulted in MOEs greater than the LOC of 100 (ranging from 190 to 5,100) on day 0 (12 hours after application) and, therefore, are not of concern to HED.

Table 9.2.1.  Summary of Short- and Intermediate-term Post-application Risk Estimates for Propamocarb.
                                   Crop/Site
                                  Activities
                        Transfer Coefficient (cm[2]/hr)
                                  DFR/TTR[1]
                                 Dermal Dose 
                                (mg/kg/day)[2]
                                    MOE[3]
                                  Lima beans
                                 Hand weeding
                                      70
                                     4.21
                                    0.0295
                                     5,100
                                       
                                   Scouting
                                      210
                                       
                                    0.0884
                                     1,700
                                       
                           Scouting, Hand harvesting
                                     1000
                                       
                                     0.463
                                      320
                                       
                             Irrigation (hand set)
                                     1900
                                       
                                      0.8
                                      190
1.  DFR = Application Rate x F x (1-D)[t] x 4.54E8 ug/lb x 2.47E-8 acre/cm[2]; where F = 0.25 and D = 0.10 per day.  
2.  Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 8 hrs/day  BW (80 kg).
3.  MOE = POD (150 mg/kg/day) / Daily Dermal Dose.  

9.2.2	Occupational Post-application Inhalation Exposure/Risk Estimates

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for propamocarb at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and the vapor pressure (6.1 x 10[-7] mm Hg at 25ºC).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for propamocarb.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

For the greenhouse ornamental uses, it should be noted that the WPS for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)].


10.0	References

K. Lowe, 15-MAY-2013, D377624, Propamocarb.  REVISED Occupational and Residential Exposure Assessment for a Proposed Use on Lima Beans and an Assessment for a Registered Use on Ornamentals.

O. Odiott, 15-JULY-1995, The HED Chapter of the Reregistration Eligibility Decision Document (RED) for Propamocarb.

G. Reddy et al., 12-OCT-2005, TXR #0052538, DER Subchronic Neurotoxicity Study in Rats.

J. Rowell, 03-MAY-2000, D264293, Propamocarb HCl.  Results of the Health Effects Division (HED) Metabolism Assessment Review Committee (MARC) Meeting of 4/6/00.

J. Rowell, 15-MAY-2000, D266084,  Propamocarb Hydrochloride in/on Potatoes and Livestock Commodities.  Review of Amendment Submitted in Response to HED's Memo of 10/17/96.

J. Rowell, 3-OCT-2000, D268955, Propamocarb Hydrochloride in or on Potatoes and Tomatoes.  Results of Petition Method Validation (PMV) Request.  
M. Ruhman, 11-DEC-2012, D368070, Propamocarb hydrochloride (Propamocarb-HCl):  Refined Drinking Water Estimated Environmental Concentrations for use in the Human Health Risk Assessment in support of the proposed new use on Lima beans.

J. Tyler, et al., 20-FEB-2004, D284504, Propamocarb Hydrochloride in/on Fruiting Vegetables, Cucurbit Vegetables, and Head and Leaf Lettuce.  Health Effects Division (HED) Risk Assessment.

J. Tyler, 10-MAR-2005, D304509, Propamocarb Hydrochloride on Potatoes.  HED Determination of Appropriate Livestock Tolerances.

J. Tyler, 15-MAY-2013, D359104, Propamocarb Hydrochloride (Propamocarb-HCl):  Petition for Tolerances and Use on Lima Beans (Succulent).  Summary of Analytical Chemistry and Residue Data.

J. Tyler, 15-MAY-2013, D367969, Propamocarb Hydrochloride (Propamocarb-HCl) Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on Lima Beans (Succulent).  

J. Van Alstine, 14-FEB-2013, TXR#0056466, Propamocarb Hydrochloride:  Summary of Hazard and Science Policy Council (HASPOC) Meeting of September 13, 2012:  Recommendations on the Requirement of a Subchronic Inhalation Study for Propamocarb Hydrochloride. 
























cc: J. Tyler, G. Kramer, A. Dunbar, K. Lowe
RDI: RAB1 (2/20/13); G. Kramer (2/27/13)
J. Tyler: S-10943: Potomac Yard 1 (PY1): (703) 305-5564: 7509P: RAB1

Appendix A.  Toxicology Profile Tables.

Table A.2.1.  Acute Toxicity Profile  -  Propamocarb-HCl.
                                 Guideline No.
                                  Study Type
                                    MRID(s)
                                    Results
                               Toxicity Category
                                   870.1100
                               Acute oral [rat]
                                   41278115
LD50 = 2900 mg/kg (M)
LD50 = 2000 mg/kg (F)         
                                      III
                                   870.1200
                              Acute dermal [rat]
                                   41278116
LD50 >3,000 mg/kg          
                                      III
                                   870.1300
                            Acute inhalation [rat]
                                   93193044
LC50 >7.90 mg/L (Limit Test)         
                                      IV
                                   870.2400
                             Acute eye irritation
                                   41278117
Slight irritation, resolved within 72 hrs
                                      III
                                   870.2500
                       Acute dermal irritation [rabbit]
                                   41278118
No erythema after 24 hours
                                      IV
                                   870.2600
                        Skin sensitization [guinea pig]
                                   00083808
Non-sensitizer
                                       -

Table A.2.2.  Subchronic, Chronic, and Other Toxicity Profile.
                                Guideline No. 
                                  Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
870.3100

90-Day oral toxicity (mouse)
44810401 (1998)
Acceptable/guideline
0, 5000, 10,000, or 20,000 ppm
M:  0, 318, 646, or 1363 mg/kg/day 
F:  0, 363, 716, or 1549 mg/kg/day
NOAEL = 363 mg/kg/day in females and 646 mg/kg/day in males.
LOAEL = 716 mg/kg/day in females, based on decreased body weight and body-weight gain and decreased food efficiency.  LOAEL in males is 1363 mg/kg/day based on decreased food efficiency.
870.3100

90-Day oral toxicity (rat)
46145201 (2001)
Acceptable/guideline
0, 375, 1500, or 6000 ppm
0/0, 28/34, 104/130, and 434/540 mg/kg/day [M/F]

NOAEL = 1500 ppm (104/130 mg/kg/day [M/F]).
LOAEL = 6000 ppm (equivalent to 434/540 mg/kg/day [M/F]) based on decreased body-weight gains in females throughout the study, and histopathological effects in the brain (moderate to severe vacuolation of the choroid plexus) and the lacrimal glands (minimal to slight vacuolar alteration).
870.3150

90-Day oral toxicity in dogs
46145202 (2001) 
Acceptable/guideline
0, 1000, 3000, or 10,000 ppm
0/0, 45/51, 131/161, and 433/471 mg/kg/day [M/F] 
NOAEL = 3000 ppm (131/161 mg/kg/day [M/F]).
LOAEL = 10,000 ppm (equivalent to 433/471 mg/kg/day [M/F]) based on vacuolation alterations of the trachea, lungs, salivary glands, stomach, lymph nodes, and lacrimal glands; and retinal degeneration and hyporeflectivity of the fundus.
870.3200

21-Day dermal toxicity (rabbits)
00071526 (1980)
Acceptable/guideline
M & F:  0, 150, 525, or 1500 mg/kg/day
NOAEL = 150 mg/kg/day for both sexes.
LOAEL = 525 mg/kg/day based on dose-related skin irritation and depressed body-weight gain.
870.3200

28-Day dermal toxicity (rats)
45894201 (2002)
Acceptable/guideline
M & F:  0, 75, 300, or 1200 mg/kg bw/day
Systemic NOAEL >1200 mg/kg/day.
Systemic LOAEL was not established.
Dermal NOAEL = 300 mg/kg/day.
Dermal LOAEL = 1200 mg/kg/day based on dermal effects (scabs, erythema maculate, focal erythema, necrosis, and ulcerative inflammation) in the treated skin of the females.
870.3700a

Prenatal developmental in (rat)
00101641 (1981) and 93193042 (1990)
Acceptable/guideline
F:  0, 74, 221, 740, or 2210 mg/kg/day
Maternal NOAEL = 221 mg/kg/day.
LOAEL = 740 mg/kg/day based on mortality.
Developmental NOAEL = 221 mg/kg/day.
LOAEL = 740 mg/kg/day based on GD 20 fetal death and a possible increase in minor skeletal anomalies.
870.3700a

Prenatal developmental in (rat)
46145203 (2001), 46462801 (2005)
Acceptable/guideline
F:   0, 31, 123, and 456 mg/kg/day
Maternal NOAEL = 123 mg/kg/day.
Maternal LOAEL = 456 mg/kg/day based on decreased body weights, body-weight gains, and food consumption.
Developmental NOAEL = 123 mg/kg/day.
Developmental LOAEL = 456 mg/kg/day based on decreased fetal body weights, and increased incidences of small fetus, inter-atrial septal defect, and hemorrhage in the ears, upper GI tract, and nasopharynx/sinuses and post-implantation loss.
870.3700b

Prenatal developmental in (rabbit)
00072574 (1981), 93193043 (date not available) Acceptable/guideline
F:  0, 15, 45, 150, 300, and 600 mg/kg/day
Maternal NOAEL = 150 mg ai/kg/day
LOAEL = 300 mg /kg/day based on decreased body-weight gains for GD 6-18 and possible increased abortions.
Developmental NOAEL = 150 mg/kg/day
LOAEL = 300 mg/kg/day based on increased post-implantation loss.
870.3700b

Prenatal developmental in (rabbit)
46145204 (2002, 2005) 
Acceptable/guideline
F:  0, 20, 76, and 269 mg/kg/day   
Maternal NOAEL = 76 mg/kg/day.
Maternal LOAEL = 269 mg/kg/day based on decreased body-weight gains, and food consumption.
Developmental NOAEL = 269 mg/kg/day.
Developmental LOAEL was not observed.
870.3800

Reproduction and fertility effects
(rat)
44730103 (1998), 44730102 (1998)
Acceptable/guideline
F0 M:  9.95, 65.41, or 406.69 mg/kg/day
F0 F:  12.79, 76.78, or 467.13 mg/kg/day
F1 M:  12.08, 75.36, or 484.90 mg/kg/day 
F1 F:  14.22, 85.32, or 541.78 mg/kg/day
Parental/Systemic NOAEL = 65.41 mg/kg/day for males and 76.78 mg/kg/day for females.
LOAEL = 406.69 mg/kg/day for males and 467.13 mg/kg/day for females based on decreased body weights.
Reproductive/Offspring NOAEL = 65.41 mg/kg/day for males and 76.78 mg/kg/day for females.
LOAEL = 406.69 mg/kg/day for males and 467.13 mg/kg/day for females based on reduced pup weights.
870.3800

Reproduction and fertility effects
(rat)
46145205 (2002)
Acceptable/guideline
0, 50, 200, or 1000 mg/kg bw/day
Parental/Systemic NOAEL = 200 mg/kg/day. 
Parental/Systemic LOAEL = 1000 mg/kg bw/day (limit dose), based on clinical signs of toxicity (pre- and post-dose salivation, reddish material around the mouth, and urine staining) and decreased body-weight gains in the females during gestation and lactation and vacuolar changes in choroid plexus of brain in males and females. 
Offspring NOAEL = 200 mg/kg/day.
Offspring LOAEL = 1000 mg/kg/day based upon increased pup deaths, decreased viability and lactation indices and litter size, and decreased pup body weights and body-weight gains.
Reproductive NOAEL = 200 mg/kg/day.
Reproductive LOAEL = 1000 mg/kg/day based upon increased vacuolization and decreased weight of the epididymides and decreased sperm count, motility, and normal morphology in both generations.
870.4100

Chronic toxicity
(mouse)
00101638 (1981)
Acceptable/guideline
M:  0, 1.0, 5.1, or 25.6 mg/kg/day
F:  0, 1.3, 6.5, or 31.9 mg/kg/day
NOAEL = 25.6 mg/kg/day.
LOAEL = >25.6 mg/kg/day.  There were no signs of toxicity attributable to treatment at any dose level.
870.4100

Chronic toxicity (dog)
41278119 (1977) and 43044201 (1985)
Acceptable/guideline
M:  0, 22.75, 70.81, or 243.32 mg ai/kg/day 
F:  0, 22.752, 72.91, or 228.31 mg/kg/day
NOAEL was not achieved.
LOAEL = 22.75 mg/kg/day based upon body-weight gain depression, decreased food efficiency and focal or multi-focal chronic erosivegastritis.
870.4100

Chronic toxicity (dog)
46145207 (2003) 
Acceptable/guideline
0/0, 39/42, 97/116, and 378/404 mg/kg/day [M/F]
NOAEL = 39/42 mg/kg/day.
LOAEL = 97/116 mg/kg/day based upon retinal degeneration and hyporeflectability in males; vacuolar alterations of the duodenum, lungs, pyloric glands of the stomach, and trachea in both sexes, rat testes and testicular blood vessels in males and vagina in females.
870.4200

Carcinogenicity
(mouse)
44693801 (1998)
Acceptable/guideline
M: 0, 11, 84, or 690 mg/kg/day
F: 0, 12, 95, or 883 mg/kg/day
NOAEL = 12 mg/kg/day in females and  690.0 mg /kg/day in males.
LOAEL = 95 mg/kg/day in females based on decreased body weight and body-weight gains.
No evidence of carcinogenicity.
870.4200

Carcinogenicity
(mouse)
46145208 (2003)
Acceptable/guideline
0/0, 15/19, 106/136, and 790/1014 mg/kg/day [M/F
NOAEL = 106/136 mg/kg/day
LOAEL = 790/1014 mg/kg/day based upon decreased body weight and body-weight gains in both sexes and emaciation in females.
No Evidence of carcinogenicity.
870.4200

Carcinogenicity
(rat)
44730101 (1998)
Acceptable/guideline 
M:  0, 10.4, 84, or 682 mg/kg/day
F:  0, 14.0, 112, or 871 mg/kg/day
NOAEL = 84 mg/kg/day in males, 112 mg/kg/day in females.
LOAEL = 682 mg/kg/day in males, 871 mg/kg/day in females based on decreased body weight and body-weight gain, decreased food consumption, and an increased incidence of vacuolization of choroid plexus ependymal cells in the brain in both sexes and decreased water consumption in the females.
No evidence of carcinogenicity.
870.4300

Chronic/ Carcinogenicity
(rat)
46145209 (2001)
Acceptable/guideline 
0/0, 150/155, 368/392, and 989/1022 mg/kg/day in M/F

NOAEL = 150/155 mg/kg bw/day.
LOAEL = 368/392 mg/kg bw/day based on clinical signs in females, and decreased body weights, body-weight gains, and food consumption in both sexes and macroscopic and microscopic lesions in the reproductive system in males eye opacity in females.
No evidence of carcinogenicity.
 870.5100
reverse gene mutation assay in bacteria
41278121 (1987)
Acceptable/guideline
There was no evidence of induced mutant colonies over background.
870.5100
reverse gene mutation assay in bacteria
45894202 (2001)
Acceptable/non-guideline
There was no evidence of induced reverse mutation [increased revertant colonies over background in 4 replicate trials of one bacterial strain (E. Coli WP2 uvrA)].
870.5375
in vitro mammalian cytogenetics assay
41278122 (1987)
Acceptable/guideline
Increases in aberrant metaphases were within the historical control range.
870.5375
in vitro mammalian cytogenetics assay
45894203 (2001)
Acceptable/guideline
There was no evidence of chromosome aberrations induced over background in the presence or absence of S9-activation.
870.5395
bone marrow micronucleus assay
00101642 (1980)
Acceptable/guideline with 00101643
There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow at any dose tested.
870.5395
bone marrow micronucleus assay
 00101643 (1980)
Acceptable/guideline with 00101642
There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time.
870.5575
Saccharomyces cerevisiae, mitotic recombination, gene conversion assay
00101624 (1977)
Acceptable/guideline with 00101645
Under the conditions of the study there was no evidence of gene conversion. 
870.5575
Saccharomyces cerevisiae, mitotic recombination, gene conversion assay
00101645 (1980)
Acceptable/guideline with 41278124
There was no evidence of gene conversion in the tested strains without activation.
870.5575
Saccharomyces cerevisiae, mitotic recombination, gene conversion assay
41278124 (1985)
Acceptable/guideline with 00101645
There was no evidence of gene conversion in the tested strains with activation.
870.6200a

Acute neurotoxicity screening battery (rat)
43062301 (1993) and 43013101 (1993)
Acceptable/guideline
M & F:  0, 20, 200, or 2000 mg/kg/day
NOAEL = 200 mg/kg/day.
LOAEL =2000 mg/kg/day based on soiled fur coat (both sexes) and decreased motor activity 8 hours post-dosing (females only).
870.6200a

Acute neurotoxicity screening battery (rat)
45894205 (2002) and 46598501 (2005)  
Acceptable/guideline
0, 20, 200, or 2000 mg/kg
NOAEL = 200 mg/kg/day.
LOAEL =2000 mg/kg/day based on decreased motor activity (overall session distance moved, number of movements, and mean velocity) on Day 0 in males and females.
870.6200b

Subchronic neurotoxicity screening battery (rat)
43013102 (1993)
Acceptable/guideline
M: 0, 12.9, 134.6, or 1320.8 mg/kg/day
F: 0, 14.2, 148.5, or 1485.6 mg/kg/day
NOAEL = 1320.8 mg/kg/day in males and 1485.6 mg/kg/day in females.
LOAEL = not observed.
870.6200b

Subchronic neurotoxicity screening battery (rat)
45894206 (2002, 2005)
Acceptable/guideline
0, 22.5/24.9, 89.7/99.5, and 352.8/382.8 mg/kg/day [M/F]
NOAEL = 89.7/99.5 mg/kg/day [M/F].
LOAEL = 352.8/382.8 mg/kg/day [M/F] based on decreased body-weight gain, and food consumption in females and intra-epithelial vacuolization of the choroid plexus in the cerebrum and cerebellum in both sexes.
870.7485

Metabolism and pharmacokinetics
(rat)
00101640 (1978)
Unacceptable/guideline
M & F:  0.5 mg/kg
A higher dose (at least equivalent to levels of human exposure) should have been tested, and the metabolites should have been identified.
870.7485

Metabolism and pharmacokinetics
(rat)
45894207 (2000)
acceptable/guideline
M & F:  1 & 100 mg/kg
Overall recovery of the radioactive dose from both sexes was 92-97%.  The majority of the dose was recovered in the urine and cage wash within 6 hours in the 1 or 100 mg/kg single dose groups (56-69% dose) and within 24 hours in the 1 mg/kg repeated group (87-88% dose).  Over the entire study, 87-93% dose was detected in the urine, and minimal radioactivity was detected in the feces (3-6% dose), carcass (0.4-1% dose), and cage debris (<0.3% dose) in all groups.  Pharmacokinetics parameters for both blood and plasma were Cmax = 0.20-0.25 ug equiv./g, Tmax = 0.50-0.88 h, and T(1/2) = 1.7-2.9 h in all animals.  This information indicates that propamocarb is quickly and extensively absorbed, and rapidly excreted.  Sex related differences were not observed, and increasing the dose or number of treatments did not change the excretion profile.  The distribution and concentration of radioactivity in tissues were generally similar over time for both sexes from both the single and repeated 1 mg/kg dose groups.  Excluding the GI tract, concentrations of radioactivity at 0.75 hours post-dose were highest in kidneys, liver, and adrenals (repeated dose males only) at 1.28-4.39 ug equiv./g.  Initial concentrations in heart, lung, spleen, ovaries and adrenals (0.308-0.594 ug equiv./g) were also slightly higher than in whole blood and plasma (0.227-0.336 ug equiv./g), but radioactivity in the remaining tissues were at or below the concentrations in blood.  Radioactivity in tissues declined steadily over time, and by 24 hours post-dose, the maximum concentrations of radioactivity were generally associated with the liver and the GI tract (0.056-0.094 ug equiv./g).  Concentrations of radioactivity were higher in tissues from the 100 mg/kg group, but the increase was not proportional to dose.  The general distribution of radioactivity in this group was similar to the two 1 mg/kg dose groups.  In each dose group, the predominant metabolites were carbonyl propamocarb at 24-27% dose in the 1 mg/kg groups and 13-15% dose in the 100 mg/kg group, and 3-hydroxypropyl propamocarb at 8-12% dose in the 1 mg/kg groups and 19-24% dose in 100 mg/kg animals.
Special studies
00130267 (1981)
Unacceptable/non-guideline
In vitro: Rat and dog plasma incubated for 30 min at 37C
Dose: 0.925 to 74 mg a.i./ml plasma 

In vivo: Dog
Dose: Single oral Previcur N (67.5%) = 674 mg a.i./kg b.w.

1 male & 1 female died within 43 min; exhibited tremors, convulsions, respiratory, standstill, and death.  ChE inhibition dead animals, plasma - no effect; RBC - 19-54%, and brain decrease 10X the controls.  No appreciable decrease in ChE in the surviving dog.

Conclusion:  The cholinesterase inhibition studies were of questionable quality.  The chemical does not cause any appreciable inhibition of cholinesterase.
Special studies
870.7600

Immunotoxicity
(rat)
48752605 (2011)
Acceptable/guideline
0, 1400, 4500, or 15000 ppm
(0, 65.3, 205.6 and 807.7 mg/kg/day [F])
Systemic NOAEL = 4500 ppm (205.6 mg/kg/day)
    
Systemic LOAEL = 15000 ppm (equivalent to 807.7 mg/kg/day) based on decreased body-weight gain and decreased food consumption. 

Immunotoxic NOAEL = 15000 ppm (equivalent to 807.7 mg/kg/day).  

The Immunotoxicity LOAEL was not established.

Appendix B.  Physical/Chemical Properties

Table B.1.  Physicochemical Properties of the Technical Grade Propamocarb-HCl.
Parameter
Value
Reference
Melting range
45-64°C
DP# D267921, J. Tyler, 2/20/04
pH
4.7

Density
1.083 g/mL

Water solubility (20°C)
1005 g/L

Solvent solubility (mg/L 20°C to 25°C)
Dichloromethane > 4.3 x 10[5]
Hexane <100 
Toluene <100
Methanol >7 x 10[5]
Ethyl Acetate 2.3 x 10[4]

Vapor pressure (25°C)
0.87 mPa 

Dissociation constant, pKa
9.29

Octanol/water partition coefficient, log POW (20°C)
-2.6 (pH 4.1)

UV/visible absorption spectrum
Not available


