UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

DATE: May 19, 2015 

SUBJECT: Dipropyl-isocinchomeronate (Di-N-propyl isocinchomeronate): Scoping and 

Preliminary Risk Assessment for Registration Review 

PC Code: 04720 I DP Barcode: 04191 54 

Decision No.: 489507 

Petition No.: NA 

Registration No.: NA 

Regulatory Action: NA 

Risk Assessment Type: NA Case No.: NA 

TXR No.: NA 

MRIDNo.:NA 

CAS No.: 136-45-8, 3737-22-2 

40 CFR: NA 

FROM: Thurston G. Morton, Risk Assessor ~#~~ , f_ 

Kelly O'Rourke, Occupational/Resident1al Exposure A~~esso ~ ~ YJ, 0 !&u~ Abdallah Khasawinah, Ph.D., Toxicologist , t/. {'~ 

RAB IV, Health Effects Division (7509P) 

THROUGH: Elissa Reaves, Ph.D., Branch Chief c::::_~ fa-rRAB IV, Health Effects Division (7509P) 

TO: Marianne Mannix, Chemical Review Manager 

Patricia Parrott, Branch Chief 

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

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

dipropyl-isocinchomeronate to support Registration Review. An evaluation of the database for 

dipropyl-isocinchomeronate did not identify the need for additional data. Furthermore, 

screening-level residential and occupational exposure assessments did not identify any potential 

risks of concern via dermal or inhalation routes of exposure; the margins of exposure (MO Es) 

for dermal and inhalation routes did not fall below the Agency's level of concern (LOC). A 

dietary risk assessment is not required because dipropyl-isocinchomeronate has no registered 

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

that limit use to personal use products and pet health care products. ln addition, the 

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

water exposure assessment will be needed. In conclusion, this scoping and preliminary risk 

assessment has not identified the need for additional data and the assessment is consistent with 

current scientific methodologies and therefore sufficient for Registration Review. 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/047201 

Human Health Risk Assessment 

Introduction 

D419154 

Dipropyl-isocinchomeronate is an insect repellent registered for inclusion in personal use 

products that are applied topically to humans, and in health care products for pets (i.e., dogs, 

cats, and horses). Repellents are thought to work by confusing the insects so they can't locate 

the target host. Dipropyl-isocinchomeronate is never used as a sole active ingredient in either 

personal use or pet repellants. It is always combined with another repellent and/or insecticide in 

addition to solvents, propellants and other inert ingredients. In insect repellent formulations used 

for human application, dipropyl-isocinchomeronate is always combined with N,N-diethyl-mtoluamide (DEET). Formulations intended for animal application may contain piperonyl 

butoxide, pyrethrins, and DEET. Dipropyl-isocinchomeronate is used to repel flies, gnats, and 

similar pest insects and is used in combination with other repell ents which are used to repel other 

types of insects (e.g., mosquitos, ticks, etc.). 

Dipropyl-isocinchomeronate products intended for human use consist mostly of pressurized 

sprays, i.e., aerosol canister products. It can also be formulated in lotions, towelettes, gels, sticks, 

creams, and pump sprays. Dipropyl-isocinchomeronate is primarily used in animal health 

products such as sprays for dogs, cats and horses. According to marketing data available at the 

time the Reregistration Eligibility Document (RED) for this chemical was issued, the total 

amount of dipropyl isocinchomeronate sold to customers with pesticide labels for use as 

"personal insect repellents" was approximately 15,000 to 20,000 pounds (lbs) of active 

ingredient (a.i). Whereas use on dogs/cats and horses averaged 2,100 and 14,000 lbs of a.i., 

respectively (US EPA, 2003). However, in a personal communication, the sole technical 

registrant, Vertellus Specialties, Inc. provided more recent production data for the years 2010-

2013 for dipropyl isocinchomeronate. Comparing the more recent production data to the data 

provided previous to the RED shows that average annual domestic use prior to the RED (26,000 

lbs annually for years 1997-2001) has decreased to just under 7,000 lbs per year. The only 

available usage data from public or private databases was from USDA's National Agricultural 

Statistics Service. The survey indicated that usage on cattle declined from 3, I 00 lbs a.i. on beef 

cattle in 1999, to 1,900 lbs a.i. in 2001 , and further to 500 lbs a.i. on dairy cattle in 2006. Note 

that the use on cattle was cancelled in 2009. 

Hazard Identification and Dose Response Assessment 

The toxicology database for dipropyl-isocinchomeronate is adequate for evaluating and 

characterizing toxicity and selecting endpoints. The database includes the following studies 

(summarized in Appendix A). 

• Acute: Oral, dermal, inhalation, eye irritation, dermal irritation, and skin sensitization 

• Subchronic: 90-day oral toxicity (rat, mouse), 21-day dermal toxicity (rabbit), 90-day 

inhalation in rats 

• Developmental toxicity: developmental toxicity (rat , rabbit) 

• Reproduction: 2-generation reproduction (rat) 

• Chronic: combined oral chronic toxicity/carcinogenicity (rat), carcinogenicity (mouse), 

chronic oral toxicity (dog) 

• Other: mutagenicity battery, metabolism, in vivo dermal penetration studies. 

Page 2 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomer ona te)/047201 

Human Health Risk Assessment D419154 

In 2014, HED Hazard and Science Policy Council (HASPOC) concluded that based on the 

weight-of-evidence (WOE) an immunotoxicity study, and a neurotoxicity screening battery 

(acute and subchronic neurotoxicity) are not required (TXR No. 0056954). 

The main route of exposure from use of repellent products containing dipropylisocinchomeronate is via the dermal route and possibly the inhalation route from personal spray 

applications. Dipropyl-isocinchomeronate did not cause toxic effects after subchronic exposures 

through inhalation to 0.324 mg/L (60 mg/kg/day) for 90 days or through dermal application of 

l 00 mg/kg/day for 90 days. 

Oral exposure may occur from hand to mouth activity, or incidental oral exposure. The toxicity 

database suggests that the adverse effects resulting from oral exposure to dipropylisocinchomeronate in experimental animals occurs at relatively high doses. Body weight loss is 

characteristic of chronic exposures. In mice, doses of 500 mg/kg/day in the diet for 18 months 

caused decreased body weight and body weight gains and increased liver/gall bladder weights in 

both sexes, and increased liver histiocytosis in males. In rats, doses of 250 mg/kg/day in the diet 

for two years caused decreases in the absolute and relative kidney weights in males and females. 

In dogs, dietary doses of 148 mg/kg/day for a year inhibited body weight gain. Higher doses in 

dogs caused a decrease in the liver and kidney weights, and liver histological changes. 

Subchronic dietary exposures resulted in decreased body weights at 1000-2000 mg/kg/day. 

Developmental toxicity also occurred at high doses (> 1000 mg/kg day in rats; > 100 mg/kg/day 

in rabbits), which were higher than those causing maternal toxicity in rats or rabbits. There were 

also no indications of developmental effects in experimental animals. However, there was 

quantitative and qualitative evidence of increased susceptibility of the offspring during in utero 

exposure to dipropyl-isocinchomeronate at high doses in a two-generation reproduction rat study. 

Decreased body weights of2 1 day pups were noted at 250 mg/kg/day (l8-l 2%, p<0.05 or 0.01) 

and at 1000 mg/kg/day (l50-63%, p<0.05 or 0.0 I) compared to controls. In parents, body 

weights were significantly decreased (l12-47%, p<0.05 or 0.0 1) only at the 1000 mg/kg/day 

dose during gestation and lactation. Pup mortality was also noted at the limit dose of 1000 

mg/kg/day with no parental mortality occurring at this dose. The concern, however, is low since 

the points of departure are protective of both the quantitative and qualitative susceptibility in the 

reproduction study. 

The Cancer Assessment Review Committee (CARC), based on the available data and in 

accordance with the 2005 Guidelines for Cancer Risk Assessment, has re-classified Dipropylisocinchomeronate (Morpel 326) as "Not Likely to be Carcinogenic to Humans" at this time 

(TXR 00572 19). The CARC has determined that this classification is applicable only for the 

currently registered use (non-food, minimal human exposure). This classification will be reevaluated if there are any changes in the use pattern (e.g., food use). 

Dipropyl-isocinchomeronate was tested for bacterial reverse mutation, in vitro mammalian cell 

gene mutation in CHO cells and mouse lymphoma cells and for unscheduled DNA synthesis in 

rat primary hepatocytes and found negative. Dietary administration of dipropylisocinchomeronate at doses reaching 1555 mg/kg/day for 28 days did not produce peroxisomal 

proliferation, did not induce peroxisomal enzymes or induce cytochrome P-450 microsomal 

enzymes (MRID 4303330 I). 

Page 3 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate )/04 720 I 

Human Health Risk Assessment 0419154 

Dipropyl-isocinchomeronate has low acute toxicity via the oral (Toxicity Category III), 

inhalation (Toxicity Category IV), and dermal (Toxicity Category III) routes of exposure. 

Dipropyl-isocinchomeronate is not a skin irritant (Toxicity Category IV) or eye irritant (Toxicity 

Category III). It is not a dennal sensitizer. 

Dipropyl-isocinchomeronate is not registered for use in/on foods and has no supported or 

proposed new tolerances, the special FQPA safety factor is not applicable to risk assessments for 

this chemical. Although FQP A does not apply to this risk assessment, HED examined the 

toxicity and exposure databases to determine if any special concerns for infants and children 

exist. Based on this examination, HED has determined that this risk assessment is adequately 

protective of all population subgroups, including infants and children. 

Dose Response Assessment 

Occupational and residential use sites are the only relevant settings for exposure to dipropylisocinchomeronate. There are no registered uses involving direct application of dipropylisocinchomeronate to agricultural crops or to livestock, and no outdoor area uses of dipropylisocinchomeronate. Therefore, toxicological endpoints for dietary and drinking water exposure 

are not required. Incidental oral and dermal endpoints were selected based on a two generation 

reproductive rat study (NOAEL 65/mg/kg/day). The inhalation endpoint was selected on the 

basis of a 90 day rat inhalation study (NOAEL60 mg/kg/day). Residential and occupational 

exposure endpoints used in the risk assessment are provided in Table I. 

Table 1. Summary of Toxicological Doses and Endpoints for dipropyl-isocinchomeronate: 0289139, April 7, 2003, PC 

Code: 04720 I 

Exposur e/ Point of Uncertainty/F Level of Concern 

Scena rio Departure Q PA Factors for Risk Study a nd Toxicological Effects 

Assessment 

Acute Dietary Not applicable. There are no registered food uses. All populations 

Chron ic Dietary Not appl icable. There are no registered food uses. All populations 

NOAEL= 65 UFA= IOx LOC for MOE = 2-Gen. Repro. Study - Rat 

Incidental Oral mg/kg/day UF11= !0x 100 MRID 4154780 I 

(ST/IT) FQPA = NA LOAEL = 250 mg/kg/day based on decreased 

pup body weight on lactation day 2 1. 

Demrnl NOAEL= 65 UFA= !Ox LOC for MOE = 2-Gen. Repro. Study - Rat 

(ST/IT) mg/kg/day UFH= IOx 100 MRID 41547801 

DAF = 5% FQPA = NA LOAEL = 250 mg/kg/day based on decreased 

pup body weight on lactation day 2 1. 

NOAEL= 60 UFA= IOx LOC for MOE = 90-day inhalation - rat 

mg/kg/day UF11=!0x 100 MRJD 4299020 I 

Inhalation FQPA = NA LOAEL = > 0.324 mg/L (60 mg/kg/day. No 

(ST/IT) toxicity was seen at the highest dose tested 

(NOAEL). However, this dose is protective of all 

toxicity seen with this chemical. 

Cancer (all "Not Likely to be Carcinogenic to Humans" at this time. The CARC has determined that this 

routes) classification is applicable only for the currently registered use (non-food, minimal human exposure). 

This classification will be re-evaluated if there are any changes in the use pattern (e.g., food use). (TXR 

0057219) 

NOAEL = no observed adverse effect level LOAEL = lowest observed adverse effect level MOE = margin of exposure 

LOC = level of concern DAF = dennal absorption factor, UFA= I Ox, UF11 = I Ox = intraspecies variability 

Page 4 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate )/04 720 I 

Human Health Risk Assessment 

Dietary Exposu res 

D419154 

There are no food uses for dipropyl-isocinchomeronate and it is not likely to occur in drinking 

water, so exposure from consumption of food and water is not expected. Therefore, there is no 

concern for dietary risk. 

Residential Exposures 

Based on the registered uses, residential exposure is expected for products containing dipropylisocinchomeronate. The exposure estimates associated with the use of insect repellents have 

been updated since the 2003 Reregistration Eligibility Document (RED) based on the revised 

methodology outlined in the Standard Operation Procedures for Residential Pesticide Exposure 

Assessment (http://www.epa.gov/pesticides/science/residential-exposure-sop.htrnl). Although 

treatment of companion animals is an additional registered use site, the insect repellent use 

(with the intentional application to the skin) is considered representative of the highest 

exposure scenario and thus, protective of other uses. 

The resulting margins of exposure (MO Es) are summarized in Table 2. The algorithms used to 

estimate dermal and incidental oral (hand-to-mouth) exposure are presented in Appendix B, with 

the inputs presented in Tables BI and B2. 

Because the points of departure (POD) for both dermal and incidental oral exposure are based on 

the same study (i.e., there is a common effect by more than one route of exposure) the dermal 

and incidental oral MOEs for children were combined. The level of concern (LOC) for dipropylisocinchomeronate is for an MOE below I 00 (which takes into account 1 Ox inter-species and 1 Ox 

intra-species uncertainty factors relative to the POD). 

As shown in Table 2, depending on the amount of active ingredient (a.i.) in the product, the 

estimated MOEs for adult dermal exposure range from 320 to 1,600, and for children, the 

combined dermal and oral MOEs range from 130 to 630. Inhalation exposure resulting from 

application of insect repellents is expected to be minimal relative to the dermal and incidental 

oral post-application estimates, and therefore estimates are not presented in the tables. For 

comparison purposes, the inhalation MOE for applying products containing the max imum 

amount of active ingredient (i.e., 2.5%) is 2,300,000. Because these estimates do not fall below 

the LOC of I 00, no risks of concern were identified. 

Page 5 of 21 
Morpel RepeUent 326 (Di-N-propyl isocinchomeronate)/047201 

Human Health Risk Assessment 0 4 19154 

Table 2. Residential Post-application Exposure and Risk Estimates for dipropyl-isocinchomeronate. 

Post-application Exposure Amount of Combined Routes 

Lifestage 

Scenario a.i in Dose MOE3 X indicates included Combined MOE4 

Route of (mg/kg/day)2 

Use Site Exposure Prod uct• in Combined MOE) 

Adult Dermal 0.20 320 NIA -- Dermal 2.5% 0.47 140 x Child 

Incidental Oral 0.048 1.400 x 130 

Adult Dermal 0. 16 400 NIA -- Dermal 2% 0.37 170 x Child Insect 150 

Repellent: Incidental Oral O.Q38 1.700 x 

Adult Aerosol or Dermal 0.082 800 NIA -- Towelette Dermal 1% 0.19 350 x Child 

Incidental Oral 3.400 

320 0.019 x 

Adult Dermal 0.041 1.600 NIA --

Dermal 0.5% 0.093 700 x Child Incidental Oral 0.0095 6.800 x 630 

I Based on registered dipropyl-isocinchomeronatelabels listed in OPPIN Summary Repon (Queried: 24 Jan 2014). 

2 Dose (mg/kg/day): equations and inputs provided in Appendix C (see Tables Bl and 8 2). Note that the assumption for fraction of body area 

exposed/treated was modified from the standard value of0.75 (representing swimsuit attire); it was averaged with the value of0.31 

(representing shon sleeves and shons) to refl ect varying clothing scenarios, resulting in an input of0.53. 

3 MOE = POD (mg/kg/day) + Dose (mg/kg/day). where both the demial and incidental oral PODs = NOAEL of 65 mg/kg/day. 

4 Combined MOE = I + (l/demial O~) + (I/incidental oral MOS). where applicable. 

Volatilization 

A quantitative residential post application inhalation exposure assessment was not performed as 

inhalation exposure is expected to be negligible from these types of applications. However, an 

inhalation exposure assessment was performed for occupational handlers (i.e., groomers, treaters, 

etc) and this exposure scenario should be considered protecti ve of any potential low-level 

postapplication inhalation exposure that could result from these types of applications. 

Spray Drift 

The registered uses for di propyl-isocinchomeronate are limited to personal insect repellents and 

treatment of companion animals; these use patterns are not likely to result in spray drift. 

Occupational Exposure 

Although exposure may occur during occupational treatment of companion animals, a screening 

level assessment based on maximum application rates and baseline attire (i.e., without gloves or 

respirator) indicated no risk of concern via dermal and inhalation routes of exposure. 

Furthermore, some current labels require handlers to wear personal protective equi pment (i.e., 

chemical-resistant gloves in addition to baseline attire). Occupational post-application exposure 

is expected to be minimal because it is assumed that the animals would be renirned to their 

residential settings after treatment. Estimates of occupational handler exposure/risk are 

summari zed in Table 3. 

Page 6 of21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/047201 

Human Health Risk Assessment D4191 54 

Table 3. Occupational Handler Exposure Estimates and Risks for dipropyl-isocinchomeronate. 

Max Unit Exposure2 Amount Absorbed Dose MOE5 

Exposure Applica- (mg/lb ai) Handled (m2'k!/dav)4 

Scenario tion Rate1 Dermal lnhala- daily3 Dermal lnhala- Dermal Inhalation tion tion 

VETERNARY/GROOMER - MIXER/LOADER/APPLICATOR 

Dip 

application to 54.3 0.0266 5 gal 0.00044 0.0000043 150.000 14.000.000 

ca1s/dogs 0.0026 

Sponge lb ai/gal 

application to 844 0.208 5 gal 0.0069 0.000034 9,400 1,800.000 

cats/dogs 

Spray 0.167 application to lb ai/gal 544 3.3 I gal 0.057 0.0069 1.1 00 8.700 

horses 

I Application rate based on maximum rates from rcprescntauve labels for d1propyl-isocinchomeronate: 4% ai dip treatment (EPA Reg. No. 

2382-89) and 2% ai ready-to-use spray (EPA Reg. No. 270-376). 

2 Based on I IED Exposure Science Advisory Council's Occupational Pesticide Handler Unit Exposure Surrogate Reference Table: assuming 

baseline anire (without gloves or respirator). 

3 HED Exposure Science Advisory Council Policy #9.1 

4 Daily Absorbed Dose (mg/kg/day) = unit exposure (mg/lb ai) x application rate (lb ai/gal) x aniount handled (gal/day) x absorption (5% for 

dennal) + bod)• weight (80 kg). 

5 MOE = NOA EL (dermal = 65 mg/kg/day: inhalation = 60 mg/kg/day) + absorbed dose (mg/kg/day). LOC = I 00. 

Public Health and Pesticide Epidemiology Data 

a. IDS (Incident Data System) 

OPP's IDS includes reports of alleged human health incidents from various sources, including 

mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports 

from registrants, other federal and state health and environmental agencies, and individual 

consumers. Since 1992, OPP has compiled these reports in IDS. IDS contains reports from 

across the U.S. and most incidents have all relevant product information recorded. Reports 

submitted to the IDS represent anecdotal reports or allegations only, unless otherwise stated in 

the report. 

IDS records incidents in one of two modules: Main IDS and Aggregate IDS: 

o Main IDS contains incidents resulting in higher severity outcomes and provides 

more detail with regard to case specifics. This system stores incident data for 

death, major and moderate incidents, and it includes information about the 

location, date and nature of the incident. Main IDS incidents involving only one 

active ingredient (as opposed to pesticide products with multiple active 

ingredients) are considered to provide more certain information about the 

potential effects of exposure from the pesti cide. 

o Aggregate IDS contains incidents resulting in less severe human incidents (minor, 

unknown, or no effects outcomes). These are reported by registrants only as 

counts in what are aggregate summaries. 

Page 7 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/04720 1 

Human Health Risk Assessment D419154 

As previously stated, dipropyl isocinchomeronate is never used as the sole active ingredient and 

is always co-formulated in pesticide products. As expected, for the Main IDS, from January 1, 

2009 to March 5, 20 14, there were no incidents reported for single chemical only in the database. 

There were 26 incidents reported involving more than one chemical. Twenty five incidents were 

classified as moderate severity. Of these, two incidents were suicide attempts and one incident 

was a duplication. One incident was classified as major severity. A 54 year old female got less 

than I tsp. of the product on her hand while transferring the product from a refill bottle into a 

spray bottle. She experienced an allergic reaction. The remaining narratives are summarized in 

Appendix 1. 

In Aggregate IDS, from January 1, 2009 to March 5, 2014, there were 449 incidents reported 

involving dipropyl isocinchomeronate. One hundred seventy nine incidents were classified as 

unknown or no effects and 270 incidents were classified as minor severity. 

Most (95%) of the incidents reported to IDS involving dipropyl isocinchomeronate were either 

minor severity (n=270) or no or unknown effects (n= l 79). For the minor incidents, this means 

that a person alleged or exhibited some symptoms, but they were minimally traumatic, the 

symptoms resolved rapidly and usually involved skin, eye or respiratory irritation. For the 

no/unknown effects, this mean that symptoms are unknown, unspecified or are alleged to be of 

delayed or chronic nature that may appear in the future. 

The most often implicated product in both Main and Aggregate IDS is Reg. No. 270-343 (Adams 

Flea and Tick Mist). ln addition to containing 0.5 % dipropyl isocinchomeronate, this product 

also contains pyrethrins (0.15%), piperonyl butoxide ( 1.50%) and n-octyl bicycloheptene 

dicarboximide (0.5%). It was implicated in 73% of the dipropyl isocinchomeronate incidents 

reported to IDS. This may be potentially attributable to high use of this product by consumers. 

Obtaining additional information on current usage data for dipropyl isocinchomeronate would 

improve future assessments. Adams Flea and Tick Mist is used by homeowners on horses, dogs, 

puppies, cats, and kittens to kill fleas, ticks, and lice and to repel flies, gnat, and mosquitoes. 

This product label instructs users to rub the product in to pets' fur with their hands leading to 

dermal exposure. 

b. SENSOR-Pesticides 

The SENSOR-Pesticides database covers 11 states from 1998-20 l 0, although reporting varies 

from state to state. Cases of pesticide-related illnesses are ascertained from a variety of sources, 

including: reports from local Poison Control Centers, state Department of Labor workers' 

compensation claims when reported by physicians, reports from State Departments of 

Agriculture, and physician reports to state Departments of Health. Although both occupational 

and non-occupational incidents are included in the database, SENSOR-Pesticides focuses on 

occupational pesticide incidents, and is of particular value in providing that information. The 

state coordinator at each of the 11 respective state Departments of Health conducts case fo llowup activities such as obtaining medical records to verify symptoms and severity. Using 

standardized protocol and case definitions derived from poison center reporting, the state 

SENSOR-Pesticide coordinator enters the incident information into the state-based system which 

is sent to NTOSH annually to be aggregated. 

Page 8 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomerona tc)/04720 I 

Human Health Risk Assessment 0419154 

A query of SENSOR-Pesticides from 1998-2010 identifies 73 cases involving dipropyl 

isocinchomeronate (PC code 047201). All cases involve multiple active ingredients. Only 8 

cases were work-related, 40 cases were not work-related and 25 cases were unknown with 

regards to whether or not it was work-related. Cases involved either insect repellents or flea/tick 

pet products. Thirty two cases involved children under age 12. Twenty of these cases involved 

the child getting the product sprayed in their face/eye. 

Two cases were high in severity, three cases were moderate in severity, and 68 cases were low in 

severity. One high severity case involved intentional ingestion of the product and the second 

high severity incident involved application to open wounds. The high and moderate severity 

cases are summarized in Table 1. 

Table 1. SENSOR-Pesticides 1998-2010 

Hi2h & Moderate Dioroovl lsoiochomeronate Case Descriotions 

ID I Severity I Year I Case Description 

NY00695 

FL00261 

TXOl609 

OROI 115 

NM00022 

High 

High 

Moderate 

Moderate 

Moderate 

2003 

1998 

1999 

2004 

2005 

According to chart, mother reports patient ingested unknown amount of 

Wellbutrin and Wipe On for horses insecticide. 

Complainant had tire ant bites on his legs when he applied product. Open 

wounds provided direct route of entry to bloodstream 

Case licked arms that had insect spray on them. Later mother noticed case had 

twitching of eye and neck muscles. 

Closed container over pressurized in aircraft resulting in exposure to pilot 

Case reported that he was sprayed with fly-foil spray when fly-foil spray was 

being applied to a truck full of onions. 

Route of Exposure and Symptoms 

The most common route of exposure reported was ocular (n=4 l ); followed by dermal (n=26). 

The symptoms reported reflects this as well with ocular symptoms (such as redness and 

irritation) being the most common (n=44) followed by dermal symptoms (n=22). A summary of 

symptoms reported is provided in Table 2. 

Table 2. SENSOR-Pesticides 1998-2010: Reported 

Health Effects for Dipropyl lsoinchomeronate 

N=73 

Health Effect # of Times Reported 

Dermal 22 

Ocular 44 

Respiratory 13 

Gastrointestinal 10 

Renal 0 

Nervous System 13 

Cardiovascular I 

• Cases may report multiple health effects 

Page 9 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/047201 

Human Health Risk Assessment 

c. Agricultural Health Study (AHS) 

D4 19 154 

The AHS is a high quality, prospective epidemiology study evaluating the link between pesticide 

use and various health outcomes including cancer. The AHS includes private and commercial 

pesticide applicators and their spouses. If there are AHS findings relevant to a particular 

pesticide going through registration review, the Agency will ensure they are considered in the 

problem formulation/scoping phase of the process and, if appropriate, fully reviewed in the risk 

assessment phase of the process. The AHS includes infonnation on use of 50 different pesticide 

active ingredients commonly used in agriculture. Dipropyl isocinchomeronate is not included in 

the AHS, and therefore this study does not provide infonnation for this report. 

Conclusion: Based on the low severity of incident cases reported for dipropyl 

isocinchomeronate in both IDS and SENSOR-Pesticides, there does not appear to be a concern at 

this time that would warrant further investigation. The Agency will continue to monitor the 

incident information and if a concern is triggered, additional analysis will be included in the risk 

assessment. 

Endocrine Disruptor Scr eening Program 

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

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

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

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

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

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

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

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

taxonomic groups. As part of its reregistration decision for dipropyl-isocinchomeronate, EPA 

reviewed these data and selected the most sensitive endpoints for relevant risk assessment 

scenarios from the existing hazard database. However, as required by FFDCA section 408(p), 

dipropyl-isocinchomeronate is subject to the endocrine screening part of the Endocrine Disruptor 

Screening Program (EDSP). 

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

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

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

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

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

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

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

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

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

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

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

Page 10 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/04 720 I 

Human Health Risk Assessment D419 154 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 20 I 0, EPA issued test orders/data call-ins for the first group of 67 

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

chemicals identified for EDSP screening was published on June 14, 20131 and includes some 

pesticides scheduled for registration review and chemicals found in water. Neither of these lists 

should be construed as a list of known or likely endocrine disruptors. 

For further information on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier I screening battery, please visit our 

website.2 

1 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals. 

2 http://www.epa.gov/endo/ 

Data Requirements 

None. HED Hazard and Science Policy Council (HASPOC) concluded that based on the weightof-evidence (WOE) an immunotoxicity study, and a neurotoxicity screening battery are not 

required (TXR No. 0056954). 

Conclusions 

A dietary risk assessment is not applicable because dipropyl-isocinchomeronate has no 

registered food uses and drinking water exposure is not anti cipated based on use sites. The 

exposure assessment did not identify potential risks via dermal or inhalation routes resulting 

from residential or occupational exposure scenarios. The conservative dermal and inhalation 

MOEs are not of concern. 

References 

Recore, S. 4/9/2014. D4 l 9225. Dipropyl lsocinchomeronate (MGK-326): Tier I Review of 

Human Incidents 

MGK ®Repellent 326 (Di-N-propyl isocinchomeronate): Summary of Hazard and Science 

Policy Counci l (HASPOC) Meeting of: Recommendations on the requirement of neurotoxicity 

(acute and subchronic), and immunotoxicity studies. TXR# 0056954. August 19, 2014. 

U.S. EPA. 2003; revised 3/ 11 /2005. Reregistration Eligibility Decision (RED): Di-n-propyl 

isocinchomeronate (MGK ® Repellent 326) 

Nako, S. 8/14/2003. DP 292906. MGK ® Repellent 326 Homeowner Use of MGK® 326 based 

on Residential Exposure Joint Venture, National Pesticide Use Survey (REJV). 

Brassard, D. 4/28/2014. BEAD Chemical Profile (BCP) for Registration Review: Dipropyl 

isocinchomeronate (PC Code 04 720 l ). 

Report of the Cancer Assessment Review Committee: Morpel 326 ® Repellent. 5/12/2015. 

TXR# 0057219. 

Page 11 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/047201 

Hwnan Health Risk Assessment 

APPENDIX A 

A. TOXICOLOGY DATA SUMMARY 

D419154 

A.1. Dipropyl-isocinchomeronateGuideline Toxicology Data Requirements: The toxicology 

data requirements (40 CFR 158.340) are presented in Table A.1.1. Use of the new guideline 

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

Guideline Data Requirements for dioroovl-isocinchomeronate 

Test Technical 

Required 

870.1100 Acute Oral Toxicity yes 

870.1200 Acute Dermal Toxicity yes 

870.1300 Acute Inhalation Toxicity yes 

870.2400 Primary Eye Irritation yes 

870.2500 Primary Dermal Irritation yes 

870.2600 Dermal Sensitization yes 

870.3100 Oral Subchronic (rodent) yes 

870.3150 Oral Subchronic (non-rodent) yes 

870.3200 21-Day Dermal yes 

870.3250 90-Day Dermal yes 

870.3465 28/90-Day Inhalation yes 

870.3700a Developmental Toxicity (rodent) yes 

870.3700b Developmental Toxicity (non-rodent) yes 

870.3800 Reproduction yes 

870.41 OOa Chronic Toxicity (rodent) yes 

870.41 OOb Chronic Toxicity (non-rodent) yes 

870.4200a Oncogenicity (rat) yes 

870.4200b Oncogenicity (mouse) yes 

870.4300 Chronic/Onco.genicity yes 

870.5100 Mutagenicity-Gene Mutation - bacterial yes 

870.5300 Mutagenicity-Gene Mutation - mammalian yes 

870.5375 Mutagenicity- Structural Chromosomal yes 

Aberrations yes 

870.5500 Mutagenicity- Other Genotoxic Effects 

870.6 IOOa Acute Delayed Neurotox. (hen) no 

870.6100b 90-Day Neurotoxicity (hen) no 

870.6200a Acute Neurotox. Screening Battery (rat) no** 

870.6200b 90-Day Neuro. Screening Battery (rat) no** 

870.6300 Develop. Neuro no 

870.7485 General Metabolism yes 

870.7600 Dermal Penetration yes 

870.7800 lmmunotoxicity no** 

xxxxxxx Developmental thyroid study no 

* The requirement of a subchronic study is satisfied by the chronic study in dogs 

** waived (HASPOC TXR# 0056954:) 

Page 12 of 21 

Satisfied 

yes 

yes 

yes 

yes 

yes 

yes 

no 

yes* 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

-

-

-

-

-

yes 

yes 

yes 

-
Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/047201 

Human Health Risk Assessment 0419154 

A.2 Toxicity Profiles 

Table A.2: Acute Toxicity Data on dioroovl-isocinchomeronate (Tecbnicaf 

Guideline Study Type MRID # Results Toxicity Category 

No. 

870.1100 Acute Oral Toxicity- rat 00155068 ( 1985) LDso =5850 mg/kg ~ Ill based on female 

LDso =4270 mg/kg ~ toxicity 

LDso =5120 mg/kg ~+9 

870.1200 Acute Dermal Toxicity-rabbit 4164860 I (1990) LDso = >2000 mg/kg Ill 

870.1300 Acute Inhalation Toxicity- rat 41571501 ( 1990) LCso>6.09 mg/L IV 

870.2400 Acute Eye Irritation 41800501 ( 1990) Non-irritating Ill 

870.2500 Acute Dermal Irritation* 41826505 (1991) Non-irritating IV 

870.2600 Skin Sensitization 41648602 ( 1990) Non sensitizer NA 

* Liquid m aerosol material tested. 

Table A.3 Subchronic, Chronic and Other Toxicit" Profile: diproovl-isocinchomeronate 

Guideline No./ Study MRID No. (year)/ Results 

Type Classification /Doses 

870.3100 42942801 (199 1) LOA EL = I 000 mg/kg/day, based on the reduction in body weights 

3- month oral toxicity Acceptable/G uideline in both sexes. and organ weight decreases in males. 

study - rats 0, 125, 250, 500, 1000 or NOA EL = 500 mg/kg/day 

2000 mg/kg/day 

870.3100 42942802 ( 199 1) LOA EL = 2000 mg/kg/day based on decreased body weights and 

3- month oral toxicity Acceptable/Guideline body weight gains and increased food consumption and liver (mild 

range finding study - (when considered with tan foci-multi-lobular) and kidney (mild white focus-unilateral) 

mice MRJD 42100102) efTects observed in males. 

0, 125, 250,500, 1000, or NOA EL = I 000 mg/kg/day 

2000 mg/kg/day 

870.3150 

3-month dog 

870.3200 42427202 ( 1992) LOAEL for systemic toxicity = > 100 mg/kg/day 

21 - Day dem1al Acceptable/Guideline NOAEL for systemic toxicity = 100 mg/kg/day 

toxicity - rabbits 0, I 0, 30 or I 00 mg/kg/day, LOA EL for dermal toxicity = I 00 mg/kg/day effects based on 

6 hours/day, 7 days/week. fissuring and moderate skin reactions 

LOA EL for systemic toxicity = 30 mg/kg/day 

870-3465 4299020 I (I 993) LOA EL = >0.324 mg/L (60 mg/kg/day) for systemic effects based 

90-Day Inhalation Acceptable/Gu ideline on the lack of toxic effects. 

Toxicity Study - Rat. 0, 0.0 I 05, 0.028, 0.095, or NOA EL = 0.324 mg/L (60 mg/kg/day). 

0.324 mg/L for 6 

hours/day, 5 days/week 

870.3700a 4 1987802 ( 1991) Maternal LOA EL = I 000 mg/kg/day based on reduced body 

Developmental Acceptable/Gu idelinc weight gain ( 14.5% decrease; p<O.O I) during GD 6-15. 

Tox ic ity- Rat 0, I 00, 300 or I 000 Materna l NOA EL = 300 mg/kg/day. 

gavage mg/kg/day Developmental LOA EL => I 000 mg/kg/day (the highest dose 

Range Finding 0, JOO, tested. 

200, 400, or8001ng/kg/day Developmenta l NOA EL = I 000 mg/kg/day. 

Page 13 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/047201 

Human Health Risk Assessment 0419154 

Table A.3 Subchronic Chronic and Other Toxicit 1 Profile: dipropyl-isocinchomeronate 

Guideline No./ Study MRID No. (year)/ Results 

Type Classification /Doses 

870.3700b 4043330 I ( 1987) Maternal LOA EL == 350 mg/kg/day, based on mortality preceded 

Developmental Acceptable/Guideline by decreased body weight gain. Low incidence of clinical signs: 

Toxicity- Rabbit 0, 35, I 00, or 350 leaning to the left, labored breathing, involuntary eye movement, 

mg/kg/day dry white material in nasal area, decreased motor activity, and no 

righting reflex. Several animals that died or were sacrificed in 

extremis displayed no clinical signs of toxicity. 

Maternal NOA EL = I 00 mg/kg/day. 

Developmental LOAEL = was not observed. Due to high 

mortality in the 350 mg/kg/day does, fetal toxicity at this dose could 

not be evaluated. No fetal toxicity was observed at 35 or I 00 

mg/kg/day. 

Developmental NOA EL = I 00 mg/kg/day. 

Norn-Guideline 4568290 I ( 1986) Mortality occurred at the 500, I 000, and 2000 mg/kg/day group 

Developmental Acceptable/Non- (60%, 100%, 100%, respectively). The surviving animals were 

Toxicity Range Guideline comparable to control animals in behavior and appearance. The 

Finding - Rabbit 0, 125, 250, 500, I 000 or mean number of viable fetuses, post-implantation loss, total 

Gavage 2000 mg/kg/day (5 implantations and corpora lutea of the 125 and 250 mg/kg /day 

females/group) on groups were comparable to those of the controls. Doses of 35, I 00. 

gestation days 7 through 19 and 350 mg/kg/day were selected (MRID 4043330 I) for 

developmental toxicity study. 

870.3800 4 1547801 (1990) Parental Toxicity 

2-Generation Acceptable/Guideline LOA EL == 1000 mg/kg/day based on decreased body weights, body 

reproduction- Rat dietary dose levels ofO. 65, weight gains, and food consumption and histopathological liver 

Dietary 250 or I 000 mg/kg/day changes in the males and females (trace to mild biliary stasis and 

portal bile duct proliferation in Fo females. Trace to mi ld portal bile 

duct proliferation and trace portal mononuclear cell infiltrates in the 

F1 males and females) 

NOA EL == 250 mg/kg/day 

Offspring Toxicity 

LOAEL == 250 mg/kg/day based on decreased pup body weight. At 

I 000 mg/kg, increased deaths in F 1 pups relative to controls during 

PND 0-4 and PND 4 through 21 and the F2 pups during PND 4 

through 2 1 were noted. 

NOA EL == 65 mg/kg/day. 

870.4100 42320602 ( 1989) Main Study 

12-Month Chronic Acceptable/Guideline LOAEL == 4,000 ppm (148.0 mg/kg/day) based on the inhibition of 

Oral Toxicity 0, 250, 1,000 or 4,000 ppm body weight gain 

(dietary) - Dogs (0, 8.27, 34.3, or 148.0 NOA EL = 1,000 ppm (34.3) mg/kg/day. 

mg/kg/day for males; 0, Range Finding Study 

8.12, 34.1or117.5 At ~ 7500 ppm: marked decrease in body weights and food 

mg/kg/day for females) consumption, a decrease in the liver and kidney weights, liver 

2-month Range Find ing histological changes (centrilobular hypertrophy, bile duct 

Study: 0, 4,000, 7 ,500, proliferation and portal fibrosis). At 15,000/ 10,000 ppm: marked 

15,00011 0,000: increase in alanine transferase activity in both sexes, a slight 

30,000/1,000 or decrease in the testicular weights of males and in the ovarian 

60,000/2,000 ppm weights of fema les. 

870.4100 42093902 ( 1991) LOA EL = 250 mg/kg/day based on decreases in the absolute and 

24-Month 42973501 relative kidney weights in males and females 

Chronic/Carcinogenic Acceptable/Guideline NOAEL == 65 mg/kg/day. 

ity -Rats 0, 0, 65, 250 or l 000 At I 000 mg/kg/day (upper limit dose), the test compound produced 

Dietary mg/kg/day increases in the incidence of liver and renal cell tumors. Body 

weights. food consumption and food efficiency were significantly 

decreased in males and females at this dose. 

Page 14 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/047201 

Human Health Risk Assessment D419 154 

Table A.3 Subchronic, Chronic and Other Toxicit , Profile: dipropyl-isocinchomeronate 

Guideline Nol Study MRID No. (year)/ Results 

Type Classification /Doses 

870.4200 42100102 ( 1991) LOA EL = 500 mg/kg/day based on decreased body weights and 

18-Month Acceptable/Guideline body weight gains in both sexes, increased liver/gall bladder 

Carcinogenicity in 0,0, 125, 500,or2000 weights in both sexes, and increased liver histiocytosis in males. 

Mice. Dietary mg/kg/day (2 x limit dose). NOA EL = 125 mg/kg/day 

At 2000 mg/kg/day, the test compound increased incidences of liver 

adenomas in females and alveolar bronchiolar adenomas in males. 

870.6200 Waived (HASPOC TXR# 0056954 ) 

Acute neurotoxicity 

in rats 

870.6200 Waived (HASPOC TXR# 0056954 ) 

Subchronic 

neurotoxicity in rats 

870-5100 4038210 I ( 1986) No mutagenic effect was noted with or without microsomal 

Bacterial reverse Acceptable/Guideline activation at concentrations up to the toxic range of 5000 

mutation I 00-5000 μg/plate micrograms of MGK 326/plate in the initial tests or in the 

Salmonella tested up to cytotoxic dose confinnatory assay. 

tvohimurium strains 

870.5300 40382102 (1987) MGK repellent 326 was negative for the induction of structural 

In Vitro mammalian Acceptable/Guideline chromosome aberrations in the duplicate assays in the presence and 

cell Gene Mutation 0.0001 - 1.0 μUml ± S-9 absence of S9 activation up to toxic dose levels (0.2 μL/mL without 

assay in CHO cells activated system S9; 0.5 and 1.0 μL/mL with S9) 

870.5300 40382104 ( 1986) MGK Repellent 326 was tested up to cytotoxic levels (>0. 18 

In Vitro mammalian Acceptable/Guideline μL/mL, -S9 and >0.24 μL/mL, +S9). Increases in mean mutant 

cell gene mutation - 0.13-1.2 or 0.024-0.32 frequency of at least 2x background with > I 0% gr0\\1h were 

L5 l 78Y TK +/- μL/mL ± S-9, respectively observed in the absence (0.18 μLlmL, trial 4) and presence ( 1.0 

Mouse Lymphoma μL/mL, trial I; 0.9 and 1.2 μL/mL, trial 2) ofS9-activation; 

Mutagenesis Assay however, because the results were not reproducible (-S9) and there 

was no clear dose-response observed in any trial(+ or -S9), the 

results of the study are considered equivocal 

870-5550 40382103 ( 1987) MGK Repellent 326 was tested up to cytotoxic levels (0.06 μL/mL) 

Unscheduled DNA Acceptable/Guideline as determined by increased levels of lactic acid dehydrogenase 

synthesis in Rat 0.001 - 0.2 μL/mL tested (LOH) activity. No significant increases in mean net nuclear grains 

Primary Hepatocytes (NNG) or percent cells in repair were observed compared to 

controls. The positive control, dimethylbenz(a)anthracene 

(OMBA). induced the appropriate response. 

870.7485 4230570 I ( 1990) Pyridine-4- ~C- dipropyl-isoeinchomeronate, administered orally, 

Metabolism and Acceptable/Guideline was absorbed rapidly and reached a peak blood level at 30 minutes 

pharmacokinetics Pyridine-4- 14

C- dipropyl- and 45 minutes after dosing in male and female rats, respectively. 

(Rat) isocinchomeronate used. Its blood half-life was 1.5 hours. About 89 - 99% of the 

I) Single oral I 00 mg/kg administered dose was eliminated within 12 hours of dosing, mainly 

for blood collection over in the urine. Fecal excretion was minimal and accounted for 1-3% 

14 hour period. of the administered dose (occurred after the first 12 hours of 

2) Single oral I 00 or I 000 dosing). Residual radioactivity in the tissues was nil to 

mg/kg/day or single iv insignificant. There were no differences between males and 

dose of I mg/kg and held females or between single oral and multiple dosing regarding the 

168 h. elimination panem of the radioactiviry. In the single high dose 

3) Daily oral dosing 100 group, the elimination of the radioactivity appeared to be slower 

mg/kg of unlabeled than the other groups. In the iv dosing, the elimination of the 

compound for 14 days radioactivity was much faster; 87- 89% of the administered dose 

followed by a single oral was eliminated during the first 4 hours. The feca l excretion was 

dose of labeled I 00 mg/kg less than 1.3% of the administered iv dose. 

and held for 168 h. 

Page 15 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate )/047201 

Human Health Risk Assessment 0 419154 

Table A.3 Subchronic, Chronic and Other Toxicit Profile: dioroovl-isocinchomeronate 

Guideline No./ Study MRID No. (year)/ Results 

Type Classification /Doses 

870-7485 42246502 () HPLC metabolic profiles of male and female rat urine were similar. 

Metabolism - Acceptable/Guideline HPLC analysis revealed a major peak (Metabolite A: 95-99% of the 

Identification of Addendum to MRID urinary radioactivity) and a minor peak (Unknown I; up to 4.5%). 

Metabolites - Rat 4230570 1 The parent compound was not detected in the urine samples. 

Metabolite A fraction was further purified, concentrated and 

analyzed with mass spectrometry (MS) and identified as the 

dicarboxylic acid derivative of MGK Repellent 326. Based upon 

these results, it was postulated that the parent compound was 

hydrolyzed at the two ester sites to form the dicarboxylic acid 

derivative of MGK Repellent 326. 

870-7485 4224650 I ( 1990) None to a negligible amount (<0.04%) of the 14C in the pyridine 

Metabolism - Acceptable/Guideline ring of the parent compound was metabolized to 14C02. 

detennination of Pyridine-4-14C- dipropylexpired C02 - Rat isocinchomeronate used. 

Single oral dose I 05 mg/kg 

Non-Guideline 4309940 I ( 1993) Peak radioactivity blood levels were attained at 2 - 4 hours with a 

Metabolism Study - Acceptable/non-guideline plasma half-life of 5.3-8.0 hours. The test compound was rapidly 

Humans Pyridine-4- 1

'

1

C- dipropyl- absorbed from the gastrointestinal system and eliminated in the 

isocinchomeronate used urine ( 4 1.5% - 54% during the first 8 hours; 81 .9-85. I% of the AD 

6.1-6.8 mg/kg; 95. I μCi during the first 36 hours). Total urinary excretion of the 

2 adult healthy males radioactivity amounted to 82.3-85.8% of the AD by 128 hours after 

dosing. Excretion of the radioactivity in the feces was minimal and 

occurred mostly within the first 6 hours after dosing ( 1.87% -

2.61 % of the AD). The balance of the AD was not accounted for. 

The HPLC analysis of the 0-24 hour composited urine of the two 

volunteers revealed three metabolites with no parent compound 

present. These were identified by mass spectrometric (MS) analysis 

as the hydrolysis products of the parent material: Metabolite A: the 

diacid of MGK 326 (39.8% of the urinary radioactivity), Metabolite 

B; 5-carboxy un-esterified (3.9% of the urinary radioactivity) and 

Metabolite C: 2-carboxy un-esterified (40.3% of the urinary 

radioactivity). Metabolites B and C were converted to Metabolite 

A by acid hydrolysis. 

Non-Guideline 4297460 I (I 992) Plasma radioactivity levels indicated that 14C-MGK® 326 was 

Dennal Absorption & steadily absorbed through the human skin, and a peak plasma 

Mass Balance- Pyridine-4-14C- dipropyl- concentration was reached when the exposure was terminated at 8 

Humans isocinchomeronate. hours. Mean dermal absorption of radiolabeled MGK-326 (sum 

41. 7 ug/cm2 in isopropanol of radioactivity in urine and feces) from an 8 hr exposure was 

4 healthy human volunteers 24.9% (cumulative total measured over 128 hrs). Absorbed 

radioactivity was eliminated mainly in the urine (24.7% of the 

applied dose) and only negligible amounts were eliminated in the 

feces. The majority of unabsorbed dose was found in the 

isopropanol wash (48.5%). Mean total recovery of applied dose 

was 95.5%. 

Page 16 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomcronate)/04720 1 

Human Health Risk Assessment 0 419154 

Table A.3 Subcbronic, Chronic and Other ox it: ~ Profil e: dipropyl-isocincbomeronate 

Guideline No./ Study MRID No. (year)/ Results 

Type Classification /Doses 

Non-Guideline 42732101 (1993) 

Dcm1al Absorption & 

Mass BalanceHumans - Multiple 

Dosing 

Non-Guideline 

Dermal Absorption & 

Mass BalanceHumans 

870.7600 

Dermal Absorption -

Rats 

Fomiulated Pyridine-4-14Cdipropylisocinchomeronate ( 1.0% 

w/w) with DEET ( 17 .5% 

w/w) and MGK 264 (5% 

w/w). 

4.2 ug/cm2 daily for 14 

days followed by 4.2 

ug/cm2 of the labeled 

material (37.9 μC) on day 

15. 

42974602 ( 1992) 

Formulated Pyrid ine-4- ~Cdipropylisocinchomeronate (I. I% 

w/w) with DEET ( 17.5% 

w/w) and MGK® Repellent 

264 (5% w/w). 

46.6 ug/cm2 in isopropanol. 

3 healthy human volunteers 

42246503 ( 1990) 

Pyridine-4-14

C- dipropylisocinchomeronate. 

Group 1: Five male rats 80 

ug/cm2 in isopropanol. 

Blood collected over 168 h. 

Groups 2-5: Five 

males/group 60 μg/cm2

, 

sacrificed at I, I 0, 19 or 

168 hours. 

Plasma radioactivity levels indicated that the formulated 14 C-MGK~ 

326 was continuously absorbed through the human skin, and peaked 

when the exposure was terminated. The plasma radioactivity levels 

as a function of time were ana logous to those obtained with single 

dose dermal application of the pure material (MRID 42974601) and 

the formulated material (MRJD 42974602). 

Mean dermal absorption of radiolabeled MGK® Repellent 326 

(sum of radioactivity in urine and feces) from an 8 hr exposure 

was 4.75% (cumulative total measured over 128 hrs). Absorbed 

radioactivity was eliminated mainly in the urine and only negligible 

amounts were eliminated in the feces. The majority of unabsorbed 

dose was found in the isopropyl alcohol swabs (79%). Mean total 

recovery of applied dose was 99.28. 

Plasma radioactivity levels indicated that the formulated 14C-MGKii 

326 was continuously absorbed through the human skin, and a peak 

plasma concentration was reached when the exposure was 

terminated. Plasma radioactivity levels dipped after isopropanol 

wash. Mean dermal absorption of radiolabelcd MGK-326 (sum 

of radioactivity in urine and feces) from a n 8 hr exposure was 

3.4% (cumulative total measured over 128 hrs). Absorbed 

radioactivity was eliminated mainly in the urine and only negligible 

amounts were eliminated in the feces. The majority of unabsorbed 

dose was found in the isopropyl alcohol swabs (78%). Mean total 

recovery ofaoolied dose was 102. 17%. 

The test material was absorbed through the sk in and rapidly reached 

a peak blood level ( 13% of the administered dose) at I hour after 

dosing and gradually declining reaching a plateau level after 24 

hours. The study author calculated a first half-life of9 hours and a 

second half-life of 19 hours. 

Mean dermal absorption of radiolabeled MGK-326 (the sum of 

radioactivity in urine (major amount), feces, tissues/carcass, 

and cage wash) aft er 10 hours of exposure was 45%. Mean 

recoveries of the test material ranged from (95-103%). The 

majority of recovered test material was found in the skin rinse at the 

I and 10 hr time intervals (86 and 53% respectively). Mean 

amounts of test substance found in the skin rinse decreased 

significantly at the 19 and 168 hr time intervals (3 1 and 7% 

respectively) indicating that material remaining inion the skin 

continues to be absorbed over time. 

870-7800 

lmmunotoxiciry 

Waived (HASPOC TXR# 0056954 ) 

Non- guideline 

Special study: 

Hepatic Enzyme 

Induction Study -

Rats 

4303330 I ( 1992) 

Acceptable/non-guideline 

0, 96.9, 373.4, 783.9 or 

I 554.5 mg/kg/day for 28 

days to males. 

Positive conrrol: Sodium 

phenobarbital: 53.7 

mg/kg/day 

dipropyl-isocinchomeronate did not affect serum chemistries. It did 

not produce peroxisomal proliferation, induce peroxisomal enzymes 

(palmitoyl-CoA oxidation) or induce cytochrome P450 dependent 

mixed function oxidase enzymes including N-ethylmorphine 

N-demethylase, 7-ethoxycoumarin 0-deethylase, 7-ethoxyresorutin 

0-deethylase or gamma-glutamyl-transferase. MGK 326 was not a 

rat liver microsomal enzyme inducer. 

Page 17 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/047201 

Human Health Risk Assessment 0419154 

Table A.3 Subchronic, Chronic and Other Toxicit / Profile: diproovl-isocinchomeronate 

Guideline No./ Study MRID No. (year)/ Results 

Type Classification /Doses 

Non- guideline 42974603 ( 1992) Only copies of the original autoradiograms were submined in the 

Special study: Unacceptable/Non- report and were difficult to evaluate due to their poor quality. No 

Whole Body Guideline quantitative data on the distribution of the radioactivity in the 

Autoradiography Pyridine-4-14C- dipropyl- various tissues and body regions were presented in the report. This 

isocinchomeronate, type of study was not required and HED did not encourage the 

I 00 ml?)kg body weight Registrant to conduct such study. 

Page 18 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/04 720 l 

Human Health Risk Assessment 0419154 

APPENDIX B 

Insect Repellents: Post-application Dermal Exposure Algorithm (inputs provided in Table 

Bl) 

where: 

D 

ARr 

FA! 

ET 

AppF 

SA/BW 

F Body 

AF 

D = ARF * FA1 *ET* AppF * SAIBW *Foody * AF 

= dose (mg/kg-day); 

= formulation-specific application rate (mg product/cm2 skin); 

= product-specific fraction of active ingredient (mg ai/mg product); 

=exposure time (hours/day); 

= application frequency (applications/hour); 

= total body surface area to body weight ratio ( cm2/kg); 

=clothing-dependent fraction of body exposed (fraction exposed/application); 

= absorption factor. 

Table Bl: Insect Repellents - Inputs for Residentia l Post-application Derma l Expos ure 

Algorithm Exposure Factor Point Estimate(s) 

Notation (units) 

Aerosol I. I 

ARF Formulation-specific application rate Pump spray 0.62 (not used) 

(mg product/cm2 skin) Lotion 2.0 (not used) 

Towelette I. I 

FAJ Amount of active ingredient Varies among products 

(%) (0.5, 1.0, 2.0 a nd 2.5%) 

Fraction/area of body exposed per application - based on an 

average of two clothing scenarios: 

F0o<1y 

I. 75% - representing swimsuit attire (shorts for men and 0.53 shons/top for women), and 

2. 31 % - representing short-sleeve shirt, shorts. socks, 

shoes 

Surface Area to Body Weight Ratio Adult 280 

SNBW (cm2

/kg) Children I < 2 

years old 640 

Adult 3.7 

ET Exposure Time (hours/day) Children I < 2 3.5 

years old 

Application Frequency Traditional 0.25 

Appf (applications/hour) With sunscreen 0.5 (not used) 

Insect Repellents: Post-application Incidental Oral (Hand-to-Mouth) Exposure Algorithm 

(inputs provided in Table 82) 

Exposure from hand-to-mouth activity is calculated as follows (based on the algorithm utilized in 

SHEDS-Multimedia): 

Page 19 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate )/047201 

Human Health Risk Assessment 0 4 19154 

E = [HR * (F:11 * SA1-!) * (ET* N_Replen) * (1 - (1 - SEfFreq l-11MIN-Repte11J)j 

where: 

and 

E 

HR 

FM 

SA11 

ET 

N_Replen 

SE 

f-reCL_HtM 

=exposure (mg/day); 

= hand residue loading (mg/cm2

); 

= fraction hand surface area mouthed/event (fraction/event); 

= typical surface area of one hand ( cm2

); 

= exposure time (hours/day); 

= number of replenishment intervals per hour (intervals/hour); 

=saliva extraction factor (i.e., mouthing removal efficiency); and 

= number of hand-to-mouth contacts events per hour (events/hour). 

where: 

HR 

ARF 

F A1 

= hand residue loading (mg/cm2); 

= formulation-specific application rate (mg ai/cm2 skin); 

= product-specific fraction of active ingredient (mg ai/mg product); 

Oral dose, normalized to body weight, are calculated as: 

where: 

D 

E 

BW 

= dose (mg/kg-day); 

= exposure (mg/day); and 

= body weight (kg). 

E D= -

BW 

Table 8 2: Insec t Repellents - Inputs for Residential Post-aoolication Ha nd-to-Mouth Exposure 

Algorithm Exposure Factor Point Estirna te(s) 

Notation (units) 

Aerosol I. I 

Formulation-specifi c application rate Pump spray 0.62 (not used) 

AR" (mg product/cm2 skin) Lotion 2.0 (not used) 

Towelette I. I 

F AI 

Amount of active ingredient Varies among products 

(%) (0.5, 1.0, 2.0 and 2.5% ) 

SA11 Typical surface area of one hand (cm2), children I < 2 years old 150 

FM Fraction hand surface area mouthed 0.127 (fraction/event) 

N_Replen Replenishment intervals 0.25 (intervals/hr) 

ET Exposure Time 3.5 

Page 20 of 21 
Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/047201 

Human Health Risk Assessment 

Table B2: insect Repellents - Inputs for Residential Post-aoplication Hand-to-Mouth Exposure 

(hours/day) 

SE Saliva extraction factor 0.48 (fraction) 

Freq_HtM Hand-to-mouth events per hour 13.9 (events/hr) 

BW Body Weight 11 (kg) 

Page 21 of 21 

041 9 154