UN ITED STA T ES EN VIRONM ENTA L PROTECTION AGENCY WASHINGTON , D. C. 20460 OFFI CE OF C HEMI C AL SAFETY AND POLLUTION PREVEN T ION

MEMORANDUM 

### DATE: Ma y 19 , 20 15 SU BJE CT : Diprop y l- i s ocinchomeronate (Di- N -propy l isocinchomeronat e): 

### Sco pin g a nd Pre limin ary Ri sk Assessme nt for Reg i s tration R ev i ew PC Code : 04720 I DP Barco de : 04191 54 Decision No.: 489507 P

etition No.: NA Registration No.: NA Regulatory Actio n : NA Case No .: NA Ri sk Assessme nt Type : NA TXR No.: NA MRIDNo.:NA CAS No.: 1 36 -4 5 -8 , 3737

-22-2 40 CFR: NA F ROM : 

### T hurston G

. Mo rton , Ri s k Asse sso r

# ~#~~ 

# , f_ 

### Kelly O ' Rourke , Occupational/Resident1al Ex p os ure

## A~~esso**~ ~**  YJ, 0

## !&u~ Ab dall a h Khasawinah , Ph

. D ., Tox icologist , 

# t/

.**{'~** RAB IV , Health Effects Division (75 09P ) THROUGH: 

### E li ssa Reaves, Ph.D. , Bran c h Chief

# c::::_**~** fa- rRAB IV , Health E ff ec t s Division (75 09P) T O: 

### Mariann e Manni x , Chemica l Rev iew Mana ge r Patricia Par rott , Branch C hief RM IB III , P esticide R e - Eva luati on Di v i sion (7508P) Attached i s th e Health Effec t Di v i s ion 's ( HED 's) sco pin g a nd hum an hea lth risk assessment for dipropyl- isoc in c homeron at e to s upport Regis tration Rev iew. An 

### evaluati on of the database fo r diprop y l-i soc in c hom ero n ate did not ide n tify the nee d for a dditional data. Furthermo r e, sc re e nin g -le ve l resi den t ial and occupational exp os ure assessme nt s did not identify any potential risks of co n ce rn v ia dermal or i nhalation routes of ex p osure; the m a rgins of expos ure (MO Es) for dermal and inhalation route s did not fa ll below the Age ncy's l eve l of co ncern (LOC). A dietary ri s k assess m e nt is not required b ecause dipropyl-i so cinchomeronate has no r eg i s tered food uses. A drinkin g wa t e r exposu re assessme nt is not requ ired based o n lab e l spec ificati ons that li mit us e t o personal use products and pet h ea lth care products . ln addition , th e Env i ronmenta l Fate and Effects D iv is i on (E FED ) anticip ates that no quantitative drinkin g water expos ure assessme nt w ill be need ed. In conclusion , thi s scoping and preliminar y ri sk assess m e n t ha s not identifi e d the need for ad di tiona l d ata a nd the assessme n t is consistent with current s cientifi c methodo l ogies and therefo re s uffi c ient for Regi s tration Rev iew.

### Mo rp e l R e p e ll e nt 326 (Di

- N -prop y l isoc in c h omero n ate) /047201 Human Health Ri sk Assessment Introduction D419154
Dipropyl-isocinchomeronate is an insect repellent reg istered for i nclusion in persona l use products that are app li ed topically to hum ans , and in health care product s fo r pets (i

. e., dogs, cats, and horses). Repe ll en t s are thought to work by confusing the in sects so they can't locate the target host. Dipropyl-isocinchomeronate is neve r u sed as a so le active in g redient in either personal us e or pet re p e llants. It 

### is always combined with another repellent and/or insecticide in addition to solvents , propellants and other inert ingre dients. In insect repe ll e nt formulations u se d for human application , dipropyl- i socinchomeronate is always combined with N,N

- diethyl

- mtoluamide (DEET). Formulations intended for animal application may contain piperonyl butoxide, pyrethrin s, and DEET. Diprop y l-i soc in chomeronate is used to repe l flies, gnats, and sim il ar pest i nsects and is used in combination with other repe ll e nts which are used to repel other types of insect s (e.g. , mo sq uitos , ticks , etc.). Dipropyl-isocinchomero nate products intended for human use consist mo s tly of pressurized sp rays , i.e. , ae rosol canister products. It 

### can al so be formulated in lotions , towelettes, gels, sticks, creams , and pump sp ra ys . Dipropyl

- isocinchomeronate is primaril y u sed in animal health products such as s pray s for dogs , cats and hor ses. Accord in g to marketing data available at the time the Reregistrati o n E li gibility D ocumen t (RED) for this chemical was iss ued , the total amount of dipropyl i soc inchomeronate sold to customers with pesticide labe ls for use as "personal insect rep e ll ents" was a pprox im ately 15 , 000 to 20 ,000 pounds ( lb s) of active ingredient (a. i)

. Whe reas u se o n dogs/ cats and horses averaged 2,100 and 14 , 000 lbs of a.i ., respectively (US E PA , 2003). However, in a personal commun ication , the sole technical re g istrant , Vertellu s Specialties , Inc. prov ided more recent production data for the years 2010- 20 1 3 for diprop y l i soc inchomeronate. Comparing the more recent production data to the data provided previou s t o the RE D shows that average annual domestic u se prior to the RED (26,000 lbs annually for years 1997-2001) has decreased to just under 7,000 lb s per ye ar. The only available usage data from public or private databases was from USDA's Na ti ona l Agricultural Stat istics Se rvice. The s urvey indicated that usage on catt le declined from 3 , I 

### 00 lb s a.i. on beef cattle in 1999 , to 1 ,9 00 lbs a. i

. in 2001 , and further to 500 lb s a.i. on dairy cattle in 2006

. Note th at the u se on cattle was cancelled in 2009. Ha za rd Identific a tion and Do se Respon se Assess ment The toxicology databa se for dipropyl

- isocinchomeronate is adequate for evaluating and characterizing toxicity and selecting endpoints. The database includes the following studies (s ummarized in Appendix A)

.
• Acute: Oral , dermal , inhalation , eye irritation , dermal irritation , an d skin sensitization • Subchro ni c: 90-day ora l tox ic ity (rat , mou se), 2 1- day derma l toxic i ty (rabbit) , 90-day inhalation in rat s • De velopmental toxicity: developmental toxicity (rat , rabbit) • Reproduction: 2-generation reproduction ( rat) • Chronic: combi ned oral chronic toxicity/ carcinogenicity (rat) , carcinogenicity (mouse), chron ic oral toxicity (dog) • Other: mutag e nicity battery, metaboli s m , 

### in vivo dermal penetration s tudies.
Page 2 of 21Mo rp e l R e p e ll e nt 

### 32 6 ( Di -N- prop y l i soc in c h o m e r o n a te ) / 047201 Human Health Ri sk Assess m e nt D4 1 9154 In 2014 , H E D Hazard a n d Science P o l icy C ounc il (HASPOC) concluded that ba se d on the weight-of-evidence (WOE) an imm unotoxicity st udy , and a neurotoxicity sc reening battery (acute and s ubchronic ne urot ox icity) are n o t req uire d (TXR No. 0056954). The m a in route of exposure from u se of repe ll e nt products containing diprop y lisocinchomero n ate is via the dermal rout e and possibly the inha lation route from personal s pray applicat ions. Dipropyl -i s oc incho m eronate d id n ot cause tox ic effects after s u bc h ronic expo s ure s throu g h inh a lation to 0.324 m g/L (60 m g/ k g/day) for 90 da ys or through d e rmal app l ication of l 00 m g/kg/day for 90 days. Oral exposu re ma y occur from hand to m o uth ac tiv ity, or incidental oral e xpos ure. T he to xic ity datab ase s u gges ts that th e a d ve rse effects res ulting from ora l ex posure to diprop y lisocinchome ronate in experim e nt a l anima l s occ ur s at relativ e ly h igh d oses . Bod y weig ht loss i s characteristic of chron ic ex p os ures. I n m ice , do ses of 500 m g/kg/day in th e di e t for 18 month s cau se d d ec rease d bod y weight and bod y weight gains and increased li ve r / ga ll bladder we i g ht s in both sexes , and increa sed li ver histiocytosis in males . In rats , dos es of 250 m g/kg/day in th e diet for two yea rs caused decrea ses in the ab so lut e and relati ve kid ney weights i n mal es and females. In do gs, di e tary doses of 1 48 m g/kg/day fo r a year i nhibited body we i ght gain. Higher dose s in dogs cau se d a decrease in t he l iver and k idn ey we ights, and l iver hi s to l ogica l changes. Subchronic di e tary exposur es re s ulted in dec rease d body weights a t 1000- 200 0 m g/kg/day. De velopmenta l toxicity also occ urred at hi g h doses (> 1000 m g/kg day i n rat s ; > 100 m g/kg/day in rabbit s) , w hi c h were hi g he r than those ca u s in g maternal toxicity in rats or rabbit s. T here were also no indi cations of d eve lopmental e ffect s i n expe ri menta l an i ma ls. H owev e r , there was quantitative and qual itativ e ev id e nce of increa se d s u sceptibi l ity of t he off s pring during 

### in ute ro exposure to dipropy l-i soc inchomeronate at h ig h do s es in a two- ge ne ration reproduction rat s tudy

. Decre ased body we i g ht s of2 1 day pup s were n o ted at 250 m g/kg/da y (l 8-l 2% , p < 0 .05 or 0.01) and at 1 000 mg/kg/day (l50-63%, p<0.05 or 0.0 I ) c ompared to co ntrol s. In parents , body we ight s were s ignificantl y decreased (l12 -47 %, p <0.05 or 0.0 1 ) only at the 1000 m g/kg/day dose durin g gestat ion and lactat ion. Pup m o rtality was also noted at the l imit do se of 1000 mg/k g/da y with no parenta l mortality occurrin g at this dose

. The concern, how eve r , is low s in ce the points of departure are protecti ve of both the quantitati ve and qualitativ e s u sce ptibility in the reproduction study

. The Cancer Assessment Rev iew Committee (C AR C), ba sed o n the available d ata and in acco rdanc e with the 2005 Guide l ines for Cancer Risk Assessment, has re-cla ss ified Dipropy l

isocinc h omeronate (Morpel 32 6) as "Not Like ly to be Carcinoge ni c to Human s " at this time (TX R 00572 19). The CARC ha s determin ed that this classification i s appl icab le o n l y for th e c urrent ly registered u se ( n on-food , minim a l hum a n exposure). T hi s classification wi ll be reevaluated if there are any c h a n ges in the use pattern (e.g ., food use). Dipropyl-i soc inchomeronate was tested for bacte ria l revers e mutation , 

### in v i tro mammalian ce ll gene mutation in C H O ce ll s and mouse lymphoma cells and for unscheduled D NA sy nthes i s in rat primary he patocytes and found negat ive. Di e tary administration of diprop y lisocinchomeronate at do ses r eac hing 15 55 mg/kg/day for 28 days did not produ ce peroxi so m a l proliferation , did not indu ce peroxisomal enzy m es or induce cytoc hrome P-4 50 mi c ro so m a l e nzyme s ( MRID 430 3330 I ).
Page 

### 3 of 21

### Mo rp el R ep ell e nt 326 (D i-N -propy l isoci n chome r on ate )/0 4720 I Human Health Risk Assessment 

### 0419154 Dipropy l- isocinchomeronate has low acute toxicity via the oral (Toxicity Category III) , inhalation (Toxicity Category IV) , and dermal (Toxicity Category III) routes of exposure. Dipropy l-isocinchome ronate 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 to lerances, the special FQPA safety factor is not applicab le to risk assessments for this chem ical. Although FQPA does not apply to th is r isk assessment, HED examined the toxicity and exposure databas es to determine if any special concerns for infants and children ex ist. Based on this examination, HED has d eterm ined that this risk assessment is adequately protective of all population subgroups, including infants and children. 

### Do se R es p onse Assess m ent Occupational and resid e ntial use sites are the onl y re levant settings for exposure to dipropylisocinchomeronate

. There are no registe red us es invo lving direct application of dipropylisocinchomeronate to agr icultural crops or to livestock , and no outdoor area use s of dipropylisocinchomeronate. Therefore , toxicological endpoints for d ietary and drinking water exposure are not requir e d. Incidental oral and derma l endpoints were se l ected based on a two generation reproductive rat study (NOAEL 65/mg/kg/day). The inhalation endpoint was selected on the basi s of a 90 day rat inhalation study (NOAEL60 mg/k g/day). Residentia l and occupational exposure endpo ints used in the risk assessment are provided in Table I. Ta bl e 1. S u mmary of Tox ico logica l D oses and E n dpo in ts for dip ro p y l-isoc in c h o m ero n ate : 0289139 , A pril 7, 2003 , PC Code: 04720 I Ex p osu r e / Poi n t o f U n certa in ty/ F Leve l of Co n ce rn Sce n a ri o Depa r t ure Q P A Fac t ors for Ri sk Stu d y a n d Tox ico log i ca l E ff ec t s Assessme n t Acute Dietary Not applicable. There are no re g i s tered food us es. All populations Chron ic Di etary Not appl icable

. There are no registered food uses. All population s NOAEL= 65 UF A= IOx L OC for MOE = 2-Ge n. Rep r o. S tud y - Rat Incidental Oral mg/kg/day UF11= !0x 100 MRID 4154780 I (ST/ IT) FQPA = NA LO AEL = 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

. Stu d y - Rat (ST/IT) mg/kg/day UFH = IOx 100 MRID 41547801 DAF = 5% FQPA = NA LOAEL = 250 mg/kg/day based on decreased pup bod y weig ht 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 Inh a lati on 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. Cance r (a ll "N ot Likely to be Carci nogenic 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 cla ss ification will be re-evaluated if there are any changes in the use pattern (e.g., food use). (TX R 0057219) NOAEL = no observed a dverse effect leve l LOAEL = lowest observed adverse effect level MOE = marg in of exposure LOC = l evel of concern DAF = dennal absorption factor , UF A= I Ox , UF 11 = I Ox = intraspecies variability 

### Page 4 of 21

### M orp e l Rep e ll e nt 32 6 ( Di- N- propy l i so cinch o m e ro nate) /04720 I Human Health Risk Assessment


### D i e t ary Expos u res D419154

There are no food use s for dipropy l -isocinchomeronate and it is not like ly to occur in drinkin g wate r , so exposure from consumption of food and water is not expecte d. Therefore , there is no concern for dietary risk. 

### Res id e n t i a l Ex p os ur es Based on the registered uses , residential ex posure is expected for product s containing dipropy l

isocinchomeronate. Th e exposure estimates associated with the use of in sect rep elle nts ha ve been updated s ince the 

### 2003 Re reg istrati on Eligibi lity D oc um e nt (RED) based on the revi sed methodology outlined in the Standard Operat ion Procedures for R es i dentia l Pesticid e Exposure Assessment ( http ://www.epa . gov / pesticides/ science / residential-exposure-sop.htrnl). Although treatment of companion animals is an additional registered use s ite, the in sect rep e ll ent u se (with the inte ntional appl i cation to the skin) is considered representative of the hi g hest expos ure scenario and thus, protective of other uses. The res ulting margin s of exposure (MO Es) are summarized in Tab le 2. The a l gorithms used to estimate dermal and incidental ora l (hand-to

- mouth) exposure are presented in Appendix B , w ith the inputs presented in Tables BI and B2. Because the points of departure ( POD ) for both dermal 

### and incid e ntal oral exposure are based on the same study (i.e., there is a com mon effec t by more than one route of expos ure ) th e dermal and incidental oral MOEs for children were combined. Th e level of concern (L O C) for dipropylisocinchomeronate is for an MOE below I 

### 00 (w hi ch takes into accou nt 

### 1 Ox inter- spec ies and 

### 1 Ox intra-species uncertainty factors relative to the POD). As shown in Tab le 2 , depending on th e amount of active ingredient ( a.i.) in the product, the estimat ed MOEs for adult dermal exposure range from 

### 320 to 

### 1 , 600, and fo r children, the co mbin e d dermal and oral MO Es range from 

### 130 to 

### 630. Inhalation exposure resulting from application of insect repellents i s expected to be minimal relative to the dermal and incidental ora l post-application estimates, and therefore estimates are not prese nted in the table s. For comparison purposes , the inhalation MO E for applying product s containing the max imum amount of active ingredi ent (i

. e. , 

### 2 .5 %) is 

### 2 , 300 , 000

. B ecause these estimates do not fall below the LO C of I 

### 00, no ri sks of concern were identified.

Page 5 of 2 1

### Mo rp e l R ep e U e nt 3 2 6 ( Di -N- prop y l i soci n c h omeron a t e)/ 047201 Hum an H ea lth Risk Assess m ent 

### 0 4 1 9 1 54 T a bl e 2

. Res id e n tia l Po s t-a ppli catio n Exp os u re a nd Ri s k Estim a t es for dipro p y l-i socinc h o me r on ate
. P os t -a pp li cati o n Ex p os ure Amo u n t o f Co mbin ed Ro u te s Li f es tage Sc e n ar i o a. i in Dos e MOE3 X in d icates includ ed C ombi ned MO E 4 Ro ut e o f ( m g/kg/d ay) 2 Use Site E x p os ur e Pr od uc t• in Co mbi n ed MO E) Adult Derma l 0.20 320 N I A


## -- Derma l 2.5% 0.47 140 

## x Chi l d I nc i den ta l Oral 0

. 048 1.400 

## x 130 Adult Dermal 0. 16 400 N I A


## -- Dermal 2 % 0

. 37 170 

## x C hild In sect 150 Repellent: Incidental Oral O.Q38 1.700 

## x Adult Aero s ol or Dermal 0.082 800 N I A


## -- Towelette Dermal 1% 0.19 350 

### x Child In cidenta l Oral 3.400 320 0.0 19 

### x Adult D e rmal 0

. 041 1 .600 N I A


## -- Derm a l 0

. 5% 0. 093 700 

### x Child Incidental Oral 0

. 0095 6.800 

### x 6 3 0 I B ased o n r eg is tered diprop y l-i soc in chom eronatelabel s li s ted in O PPIN Summary Rep on (Q ueried : 24 Jan 2 0 14 )

. 2 D ose ( m g/kg/ da y): equation s and inputs provided in Appendix C (s ee Tables Bl and 8 2)

. N o te that the as s umpti on for fraction o f body area expo sed / treated was modified from the s tandard value of0

. 75 (representing swim s ui t attire) ; it was averaged with the value of0

. 3 1 (repres entin g s hon sleeves and shons ) to re fl ect varying clothin g s cenarios , resulting i n an i n put of0

. 53

. 3 MO E = P O D ( mg/k g/day) + D os e ( mg/k g/ day)

. where bo th the demial and incidenta l o ra l POD s = NOAEL of 65 m g/kg/ day

. 4 Co mbined M OE = I + ( l /demial**O~) +**  (I/ incidental o ral MOS). where applicable

. Volat ili zation A quan ti tat ive res id e n t ia l post app li cati o n inha l ati o n expos ure assess m e n t was not p erformed as inh a lat ion ex p os ure i s expecte d to b e n eg li g ib le fr o m th ese ty p es of a ppli cati o n s. H o w eve r , a n inha la t io n exposu re assessme nt was p e r fo rm ed fo r oc cu pati o n a l h a nd le r s (i

. e. , groo m e r s, trea t e r s , etc) and th i s expos ure sce n ari o s h o ul d be cons id e re d protec ti ve of any pote nti a l low- leve l postapplication inhalatio n exposure that co u ld result fro m these types of appl icat ions. S p ray D r ift The reg i s te re d u ses fo r di p ro p y l

- i so cin c h o m e ro n a te ar e l imite d to p e r s on a l in sec t r e p e ll e nt s a n d treatm ent of co mp an io n a nim a ls; th ese u se patte rn s are n ot li ke l y to re s ult in spray d ri ft

. 

### Occ up a ti ona l E xp o s u re A lt h o u g h expos ure m ay occu r durin g occ upati o n a l tre a tme nt of co m panion an i ma l s, a sc reen in g leve l assessme nt b ase d o n m ax imum a pp l icati o n ra tes a nd b ase line attir e ( i. e . , w ith o ut g loves or resp ira to r) i nd icate d n o ri s k of co n ce rn v i a de rm a l and i nh a la ti o n rou tes of expos ure. Furthermore , some current labe ls requ ire h and lers to wear pe r so n a l p ro tective e qui pme nt (i.e., c h em ica l -resistant gloves i n add it io n to base li ne atti r e). Occ u pat ional pos t -application exposure is expected to be min imal because it i s assumed that the a ni mals wou ld be renirned to their res id e nti a l setti n gs afte r treatme n t. Es tim ates o f occ upational h an dl e r expos ure/ risk are s umm a ri ze d in Tabl e 3.

Page 

### 6 o f2 1

### Morpel Repellent 326 

### (Di-N-propyl iso cinchomeronate)/ 047201 Human H ea lth Risk Assess me nt 

### D4191 54

Table 3. Occupational Handler Exposure Est imates and Risks for diprop y l-isocinchomeronat e . Max Unit Exposure2 Amount Absorbed Dose MOE 5 Exposure Applica- (mg/lb ai) Handled (m2'k! / dav) 4 Scenario tion R ate 1 Derm a l lnhala- daily3 Dermal lnhala- Dermal Inhalation tion tion VETERNARY/ GROOMER

- MIXER/LOADER/APPLICATOR Dip application to 54.3 0.0266 5 ga l 0

. 00044 0

. 0000043 1 50

. 00 0 1 4.000. 00 0 ca1 s/ dog s 0.0026 Spo nge lb ai/ ga l application to 844 0.208 5 gal 0.00 69 0. 00 00 34 9,4 00 1,8 00

. 000

ca ts /dogs

Sp ray 0.167 application to lb ai /ga l 544 3.3 I ga l 0

. 057 0.0069 1.1 00 8.700 horses I A ppli ca ti o n rat e bas ed o n m ax imum rate s fro m rcpre s cntauve la bel s fo r d1pro p y l- isocin ch o meronate : 4 % ai dip tr e atment (E PA Reg . No. 2 3 8 2

- 89) and 2% ai ready -to -u se spray (E PA Reg. No

. 2 70-376). 2 Based on I I E D Expo s ure Science Advi sory Co uncil ' s Occupati o nal Pes t i cide Handler U nit Exp os ure Surrogat e Referenc e T able : ass umin g bas elin e anire ( with o ut g l oves o r re s pirato r ). 3 H E D E xpo s ure Science Advi so ry C o un ci l Policy #9

. 1 4 Dail y Absorbed Do se (mg/k g/day ) = unit exp os ure (m g/ lb ai ) x applicati o n r ate ( lb ai/ gal ) x ani o unt handled ( gal/day) x ab so rp tio n ( 5 % fo r denn al) + bod)• weig ht (8 0 kg)

. 5 M OE = NOA E L (dermal = 65 mg/k g/ day : inhalation = 60 m g/k g/ day ) + absorbed dose ( m g/kg/day)

. LOC = I00

. 

### Public Health and Pesticide Epidemiology Data

a. IDS (Incident Data System) OPP ' s ID S includ es r e ports of a ll eged human he a lth in c ident s from various so urc es, includin g mandato ry Fed eral In sec ticid e, Fungicide and R ode nti cide Act (FIFRA) Sec ti o n 6(a)(2) re port s from regi st rants , other federal and state health and e nvironm e ntal age n cies, and indi vi du a l co n s umers. Since 1 992, OPP ha s co mp il e d these r e port s in IDS. IDS conta ins re p o rt s from ac ro ss the U.S

. and mos t incident s ha ve all re le va nt product inform at ion record e d. R e port s s ubmitted to th e ID S represent anec dota l r eports or allegatio n s only , unl ess o th erw i se s tat e d in the re port. ID S reco rd s incid e nt s in one of two mod ul es: Main ID S and Aggrega te ID S:

o M a in ID S co ntain s incidents resu ltin g in high e r seve rit y o utcom es and provide s more d etail with regard to case s pe ci fic s. This sys tem sto res in c iden t data fo r d eath , major a nd mod erat e in c ident s , and it include s informati on a bout the location , date and nature o f th e in c ident. Main ID S incid e nts in vo lvin g only one active in gre di e nt (as o ppo sed to pe s ticide products w ith multi p le acti ve ingredi e nts) are cons id ere d to pro v ide mo re certai n inform ation abo ut the potential effects of expos ure from the p es ti c id e.

o Agg regate ID S contain s incid e nt s res ultin g in less seve re hum an incid e nt s ( min o r , unknown , or no effects o utcomes ). T he se are re ported b y r eg i s trant s o nl y as co un ts in what are agg regat e s ummaries.

P age 7 of 21Morp e l Rep e llent 326 (Di-N- propy l i soc inchomeronate)/04720 1 Human Health Risk Assessment D419154 As prev ious ly stated , dipropy l isoc in chomeronate i s never used as the so le active ingredi ent 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 incid e nt s report ed involving more than one chemical. Twenty fiv e incid ents were classified as moderate severity. Of these, two incidents were su icide attempts and one in c id e nt was a duplication. O ne incident was classified as major severity. A 54 year old female got less than 

### I tsp. of the product on he r hand while transferring the product from a refill bottle into a spray bottle. She experienced an allergic reaction. The remaini n g narratives are summarized in Appendix 1.
In Aggregate IDS, from January 1 , 2009 to March 5, 2014 , there were 449 incidents reported involving dipropyl i socinchomeronate. One hundred seventy nine incidents were classified as unkn own o r no effects and 270 incid e nt s were class ifi ed as minor seve rit y . Most (95%) of the in c id ents re ported to IDS in vo lvin g dipropyl isocinchomeronate were either minor severity (n= 270) or no or unknown effects (n = l 79). For the minor incidents, this m eans that a person alleged or exhibited some symptoms , but they were minimally traumatic , the sy mptom s resolved rapid ly and usually involved skin, eye or respiratory irritati o n. For the no/ unknown effects , this mean that symptoms are unknown, unspecified or are alleged to be of delayed or ch ronic n ature that may appear in the future. The most often implicated product in both Main and Aggregate IDS is Reg. No. 270 -34 3 (Adams Flea and Tick Mist). ln addition to containing 0.5 % dipropyl isocinchomeronate , this product also con tain s pyrethrins (0

. 15%), piperonyl butoxide ( 1.50%) and n-octyl bicycloheptene dicarboximide (0.5%). It was implic ated in 73% of the dipropyl i socinc hom ero nate incid ents reported to ID S. This may be potentially attributable to high use of this product by consumers. Obtaining add itional information on current usage data for dipropyl isocinchomeronate would improve future assessments. Adams Flea and Tick Mist is used by homeowners on hor ses , dogs , puppies , cats , and kittens to kill fleas , ticks, and l ice and to repel flies , gnat , and mosquitoes. This product label in structs users to rub the product in to pets' fur with their hands leading to dermal exposure. 

### b. SENSOR-P esticid es The SENSOR- P esticides 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 worke rs ' compe n sation claims when reported by physicians, reports from State Departments of Agriculture , and p h ys ic ian reports to state D epart m ents of H ealth. Although both occupational and non-occupational incidents are includ ed in the database, SENSO R-P est icides focuses on occupational pesticide incidents, and i s of particular value in providing that information. The state coord inator at eac h of the 11 respective s tate Dep art ment s of Health conducts case fo ll owup activities such as obtaining medical records to verify symptoms and severity. Using standardized protocol and case definitions derived from poison center reporting, the state SENSO R -Pest icid e coo rdin ator enters the incid e nt information into the state

- based system which is sent to N T OS H annually to be aggregated.
Page 8 of 21

### Morpel Repellent 32 6 ( Di-N-prop y l is ocinchomeron a tc)/04720 I Human Health Risk Assessment 0419154 A query of SENSOR-Pesticides from 1998-20 1 0 identi fies 73 cases in volv ing d ipropy l 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-re lated. Cases involved eit h e r insect repe ll ents or flea/t ick pet products. Thirty two cases involved children under age 12. Twe nty 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 in vo l ved app l icati on to ope n wounds. T he hi g h and m oderate severity cases are summarized in Table 1.

Table 1. S EN S OR-Pes ticid es 1 9 98-2010 Hi2h & Moderate Dioroovl lsoiochomeronat e Ca s e Descriotion s ID 

# I S everity 

# I Y e ar 

# 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 in secticide. Comp lainant had tire ant bites on his legs when he applied product. Open wounds provided d irect route of entry to b loodstream Case licked arms that had insect spray on them. Later mother noticed case had twitching of eye and neck muscles

. C losed container over press ur ized in a ircraft result i ng in exposure to pilot Case reported that he was sprayed with fly-foil sp ray 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 de r ma l (n = 26). The symptoms reported reflects this as well w i th ocu la r sy m ptoms (s uch as redness and irritation) being the mo s t common (n = 44) followed by dermal symptoms (n = 22). A summary of symptoms reported is provided in Table 2.

Table 2. SENSOR- Pest ic ides 1998-2010: Reported Hea l th Effects for Dip ropy l l so i ncho m e ronate 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 effect s


### Page 9 of 21

### Morpe l Repe ll en t 326 (D i-N-pro p y l isocinchomeronate) / 047201 Human Health Ri sk Assessme nt
c . Agricultura l Health Stud y (AHS) D 4 19 1 54

The AH S is a high quality , prospective e pid em i o log y study eva l u ating the link between pesticid e use and various health outco mes including cance r . The AHS include s private and co mm erc ial pesticide app li cat o r s and th e ir spo us es. I f there are AHS findin gs re levant to a particular pesticide go in g throu g h r eg i stration rev iew , the Agency w ill e n s ure the y are co n s idered in the problem fo rmulation/ sco pin g phase o f th e process and , if appropriate, fully rev iewe d in th e ri sk assessment phase of th e pro cess. The AHS includes infonn a tio n on use of 50 different pesti c id e active in g redie nt s commonly u se d in agriculture. Diprop y l isocinc hom ero n ate is n o t includ ed in the AHS, and therefore thi s study does not provide in fonnat ion for this report. Co nclu s ion: Based o n the low seve rity of in c id e nt cases r eporte d for diprop y l isocinchome ronate in both ID S an d SENSOR- Pestic id es, ther e does not appear to b e a con ce rn a t thi s time th at wo uld warran t further in vesti gati on. The Agency w ill continu e to monitor the incident in fo rmation and if a co ncern is triggered , additional an alys i s will b e included in the ri s k assessme nt. Endocrine Di s ruptor Sc r eening Pr ogra m As re quir ed by 

### FIFRA and FFD CA, E P A reviews num ero u s s tudie s to assess potential a dv erse o ut comes from exposure to chemica ls. Co ll ectively, these stud ies includ e acute , subchroni c and chronic toxicity, includin g assessments of carcinogenici ty , neurotoxicity , d evelo pm ental , reproductive , an d general or syste mic tox icity. These s tudi es include endpoints which may be s u sce ptibl e to e ndocrin e influenc e, includin g effects o n e nd oc rin e target organ hi s topath o lo gy , organ we ig ht s, estru s cyclic i t y, sex ual maturation , fert ili ty , preg nancy rat es, re productive loss , and sex ra ti os in offspring. For eco lo gical hazard assess me nt s, E PA eva l u ates ac ut e tests and chron i c s tudie s that assess growt h , developmental and reproductive effects in different taxonomic gro up s . As part of it s reregistration decision fo r dipropyl-isoc inchomeronate , EPA reviewed these data and se lec t ed the m os t se n si ti ve endpoints for relevant ri sk assessment scenario s from the exi s tin g h azard d ataba se. Howev er , as re quir e d by FFD CA sec tion 408(p ) , dipropy l -isoc in chomeronate i s s ubject to th e e ndocrin e sc ree nin g part o f th e E ndocrine Di s rupt o r Screeni ng Program (E D S P)

. E P A has developed the E D S P to detennine whe ther certain substances ( includin g pesticide act ive and ot h er ingred ie nt s) m ay hav e an effec t in human s o r w ildlife sim i lar to an effec t produc e d by a " naturall y occ urring estrogen , or o ther such e ndocrine eff ects as th e A dmini s tr ato r ma y d es ig n ate." Th e E D S P e mploys a two-tie re d approac h to making the statutorily required determinations. Tier 1 

### co n s is t s of a batt ery of 11 

### s cre enin g assays to identi fy th e p ote ntial of a chemica l s ub stance to interact with the estrogen , androgen , or thyroid (E , A , or T ) honnonal sys t ems. C hemicals that go through Tier 1 

### sc reening and are found to have the p o t ential to interact with E , A, or T hormonal sys te m s wi ll proce ed to the n ex t s tage of th e EDSP where EPA will determine which , i f any, of the Tier 2 

### t ests a re nec essary based on the availab le data. Tier 2 

### te s tin g i s de s ig ne d to id e ntif y any adverse e nd oc rine - rel a ted effects caused b y the s ubstan ce , a nd estab li sh a d ose -respo n se re lations hip betwe e n the do se a nd the 

### E, A , or T effec t.

Pa ge 10 of 21Morpel Repellent 326 (Di-N-propyl isocinchomeronate)/ 04 

### 720 I Human Health Risk Assessment D 419 1 54 U nd er FFD CA sec tion 408(p) , the Agency must sc reen a ll p es ti cide chemicals. Between October 2009 and F eb ru ary 20 I 0 , E P A i ss ue d test orde rs/data ca ll-in s for the fir s t g roup of 67 chemical s , which contains 58 pesticide active ingredients and 9 in ert ingredient s . A seco nd l ist of chemicals id e ntified for EDS P sc reening was published on Jun e 14, 20 1 31 and includes some pesticide s sc heduled for r eg i stration review and chemicals found in wate r. Ne ith er of these lists shou ld be co n s trued as a li s t of known o r li kely endocrine di s rupt o rs . For furth er in fo rmation on th e status of the E D S P , th e po li cies and pro ce dures, the l ists of chemical s , future li sts, th e te s t guidelines an d the Tier I 

### sc reening battery , plea se v isit our website. 2

1 See http: //www.regulations.gov/# !documentDetail ; D= EPA-HQ-OP PT-2009-0477-0074 for th e final second li s t of chemicals. 2 http: //www.epa.go v /endo/ Data Requirements 

### None. HE D Hazard and Science P o licy Co un cil ( HAS PO C) conclu ded that b ased on the weightof -e vide n ce (WOE) an immunoto x ici ty st ud y , and a neurotoxic i ty sc ree nin g battery are no t requ ired (TXR No

. 005 6954). Conclusions 

### A dietary risk assessment is not ap plic ab l e becau se dipropyl-isocinchomeronate ha s no registered food u ses and drinki ng water expos ure is not anti c ip ate d based o n u se s ite s . Th e expos ure assessment did not id e ntify pote nti a l ri s ks vi a de rmal o r inhalati on routes re s ulting from re s idential or occ up ati o n a l exposure sce narios. The co n servati ve d e rm a l and inhalation MOEs are not of concern. Reference s 

### Reco re, S. 4 /9/2 014

. D4 l 

### 9225. Dipropyl l soc in c homeronat e ( MGK- 326): Ti e r I 

### R ev i ew of Hum an Incidents MGK ®Repe ll ent 326 (Di-N -propyl isocinchomeronate): Summary of Hazard and Science Policy Counci l (HAS PO C) Meeting of: Reco mmendation s o n th e requirement of ne uroto x icity (ac u te and s ubchro ni c), a nd immunotoxicity st udi es. TXR # 0056954. A ug u s t 1 9, 2 014. U.S. EPA. 2003; revised 3 / 11 / 2005. R e regist ration Eligibility D ecis ion (RE D ): Di-n-prop y l isocinchomero n ate (MG K ® Repellent 326) Nako, S. 8/14/2003. DP 292906. MGK ® Repellent 326 Ho meowner Use of M GK ® 326 b ased o n Residential Ex p os ure J o int Venture , Natio n al Pesticid e Use S urvey (REJV). Bras sard, D. 4/28 / 20 1 4. B EA D C h emical Profi le ( BCP ) for Reg i s tration Revi ew: Dipropyl isoci nchomeronate (PC Code 04 720 l )

. 

### Report of th e Cance r Assess m e nt Rev ie w Co mmittee: Morpe l 326 ® Rep e ll ent. 5/12/2015. TXR # 0057219. Pag e 11 of 21

### Morpel Repe ll ent 326 (D i- N - propyl isocinchomeronate)/ 047201 Hwnan H ea lth Ri s k Assessment
APPENDIX A A. TOXICOLOGY DATA SUMMARY D419154

A.1. Dipropy l-isocinchomeronateGuideline Toxicology Data Requirements: The toxicology data requ i rements (40 CFR 158.340) are presented in Table A.1.1. Use of the new guide li ne numbers does not imply that the new (1998) guideline protoco l s were used.
Guideline Dat a Requi rements for dioro ov l-isoc i nchomeronat e T est Technica l R e quired 870.1100 Acute Oral Toxicity yes 870.1200 Acute D e rm a l Tox ic ity yes 870.1300 Acute Inhalation Toxicity yes 870.2400 Prim ary Eye Irr itation yes 870.2500 Prim ary Dermal Irritation yes 870.2600 D erma l Se n s itization yes 870.3100 Ora l Subchro ni c ( rode nt) yes 870.3150 Oral Subchronic ( no n-rod e nt) yes 870.3200 21- D ay Dermal yes 870.3250 90-Day Dermal yes 870.3465 28/ 90

- Day I nhalation yes 870.3700a Developmental Toxicity (rodent) yes 870.3700b Developmental Tox ici ty (non -rod ent) yes 870.3800 Reproduction yes 870.41 OOa Chronic T oxic i ty (ro de nt) yes 870.41 OOb Ch ronic Tox ic ity (no n-rodent) yes 870.4200a Oncogenicity (rat) yes 870.4200b O ncoge ni city (mouse) yes 870.4300 C hronic/ Onco.genic ity yes 870.5100 Mutagen ic ity-Gene Mutation

- bacterial yes 870.5300 Mutagenicity-Gene Mutation

- mammalian yes 870.5375 Mutagenicity

- Structural Chromosoma l yes Aberrations yes 870.5500 Mutagenicity

- Other Genotoxic Effects 870.6 I OOa Acute Delayed Neuro tox. (hen) no 870.6100b 90-Day Neurotox icity (hen) no 870.6200a Acute Neu rotox. Screening Battery (rat) no** 870.6200b 90-Day Neu ro. Scree nin g B attery (rat) no** 870.6300 Develop. Neuro no 870.7485 General Metaboli s m yes 870.7600 D e rmal Penetr ation yes 870.7800 lmmunotoxi c ity no ** xxxxxxx Developmental thyroid study no * The requirement of a subc hroni c study is sat i sfied by the c hronic stu d y in dogs ** waived ( H ASPOC 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



### -

### Morpe l Repe ll ent 326 (Di-N-propy l isocinchome r onate)/047201 Human Health Ri s k Assessme nt 

### 0419154 A.2 

### Toxicity Profiles
Tab l e A.2: Ac u te Toxic ity Data on dioroovl-i socinchomeronate (Tecbn ica f Gu i de li ne Study Type MRID # Res ult s Tox ic i ty Category No. 870.1100 Acute Oral Toxicity

- rat 00155068 ( 1985 ) LD so = 5850**mg/kg ~**  Ill based on femal e LD so = 4270 mg/kg**~** toxicity LD so = 5120 m g/ kg**~+9** 870.1200 Acute Derm al Toxicity-rabbit 4164 860 I (1990) LD so = > 2000 mg/kg Ill 870.1300 Acute Inhalation T oxici t y - rat 41571501 ( 199 0) LC so> 6.09 mg/L IV 870.2400 Acute Eye Irritati on 41800501 ( 1990) Non

- irritating Ill 870.2500 Acute Dermal Irritati o n * 41826505 (1991) Non-irri t ating I V 870.2600 Skin Sensitization 41648602 ( 1990) Non sen s itizer NA * Liquid m aerosol material t ested

. Tab le A.3 Subchro n ic, Chronic and Other Toxicit" Profile: diproovl- i soc in chome r onate Guideline No ./ Study MRID No. (year)/ Results Type C las sification /D ose s 870.3100 42942801 (199 1) LOA EL = I000 mg/kg/day, based on the red uction in bod y weights 3- month oral toxicity Acceptable/G u ide l ine in both sexes. and organ weight decreases in males. s tud y - rats 0 , 125 , 250 , 500 , 1000 or N OAEL = 500 mg/k g/ day 2000 mg/kg/day 870

. 3100 42942802 ( 199 1) LOA EL = 2000 mg/k g/ day based on decrea s ed body weigh t s and 3

- month oral toxicity Acceptab l e / Guideline body weight ga in s and increased food co n sumpt ion and li ver (m ild range finding s tud y - (w hen co n si d e r e d with t an foci-multi- lob ular) and kidn ey (m ild white foc u s-un ilateral ) mice MRJD 42100102) efTects observed in males. 0 , 125 , 250,500 , 1000 , or NOA EL = I000 m g/kg/day 2000 mg/kg/day 8 7 0.3150 3-mo nth dog 870.3200 42427202 ( 1 992) LOAEL for s ys temic toxicit y = > 100 mg/k g/ da y 21

- Day dem1al Acceptab le/ Guideline NOAEL for syste mi c toxicity = 100 m g/kg/d ay toxicity

- rabbit s 0 , I0 , 30 o r I00 m g/kg/day , LOA EL for derma l toxicity = I00 m g/ kg/day effec t s based on 6 hours/day , 7 day s/ week. fissuring and modera te ski n reactions LOA EL for sys te mic toxicity = 30 mg/ kg/ da y 870-3465 4299020 I (I 993) LOA EL = > 0.324 m g/L (60 mg/k g/day) fo r sy s temic effects based 9 0 -Da y Inh alation Acceptable / Gu ide lin e on th e lack of toxic effects

. Tox icit y St ud y - Rat. 0, 0.0 I 05, 0 .028 , 0.095, or NOA EL = 0.324 mg/L (60 mg/kg/day). 0.324 m g/ L fo r 6 hours/ day, 5 days/ week 870.3700a 4 198 7802 ( 1991) Maternal LOA EL = I 000 mg/kg/da y based on red uced bod y Developmental Acceptable/Gu idelinc weight gain ( 14.5% decrease ; p <O.O I) during G D 6-15. Tox i c ity- Rat 0 , I 00 , 30 0 or I000 Mate rn a l NOA EL = 30 0 mg/kg/day. g a vage mg/k g/day Deve l opmental LOA EL => I000 mg/ kg/ da y ( the highest do s e Range Findin g 0, JOO, t es ted

. 200 , 400 , or8001ng/k g/ day Deve lopmenta l NOA EL = I000 mg/k g/ day

.



### Pa ge 13 of 21

### Morpe l Repe ll ent 326 (Di

- N

- propy l isoc inchom e ronate )/0472 01 Human Hea lth Ri sk Assessment 

### 0419154 Tab l e A.3 S u bchronic C hron ic a nd Other T ox ic i t 1 Pro file : dipr o py l-isoc in cho me r o n ate Guideline No./ Study MRID No. (year)/ R esults Type C lassification / Dose s 870.3700b 4043330 I ( 1987) M a t erna l LOA E L == 350 mg/kg/day , based on mortality preceded Developmental Acceptab l e/G u id eline by decreased body weight gain. Low incidence of clinical signs: Tox ici ty- Rabbit 0, 35, I00 , or 350 leanin g to the left, labored breathing, involuntary eye movement, mg/kg/day dry white mate rial in nasa l area, decreased motor activity, and no righting reflex. Several animals that died or were sacrificed in extremis displayed no clinical signs of toxicity. Mat er nal NOA EL = I00 mg/kg/day. D

eve lo p me n ta l LOAEL = was not observed. Du e to high mortality in th e 350 mg/kg/day does , fetal toxicity at this dose could not be evaluated. No fetal toxicity was observed at 35 or I00 mg/kg/day. Dev e lo pm e n t a l NOA EL = I 00 mg/kg/day. Norn-Guideline 4568290 I ( 1986) Mortality occurred at th e 500 , I000, and 2000 mg/kg/day group Developmental Acceptab le/No n - (60 % , 1 00% , 100%, respectively). The surviving animals were Toxicity Range G u id eli n e comparable to control animals in behavior and appearance. The Findin g - Rabbit 0 , 125 , 250, 500, I 000 or mean number of viable fetuses, post-implantation loss, total Gavage 2000 mg/kg/day (5 imp lantat ion s and corpora lutea of the 125 a nd 250 mg/kg / day females /group) on groups were comparable to those of the controls. Doses of 35, I00. gestation days 7 through 19 and 350 mg/kg/day were selec ted (MRID 4043330 I) for developmental toxicity study. 870.3800 4 1547801 (1990) P arenta l To xicity 2-Generati on Acce p table/G u i d e line 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 bi le duct proliferation in F o 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 Off s prin g Toxicity LOA EL == 250 mg/kg/day based on decreased pup body weight. At I000 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 E L == 65 mg/kg/day. 870.4100 42320602 ( 1989) M a in St ud y 12-Month Chronic Acce pt a bl e/G u id e line 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 ga in (die ta ry)

- 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, Rang e Fin d in g S tudy 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 hi sto logical changes (centrilobular hyp ertrophy, bile duct Study: 0 , 4 , 000 , 7 , 500 , proliferation and portal fibrosis). At 15 , 000/ 10 , 000 ppm: marked 15,000 11 0 , 000: increase in alanine transferase activity in both sexe s, a s light 30,000/1,000 or decrease in th e testicular weights of males and in the ovarian 60 , 000 /2 , 000 ppm weights of fema les . 870.4100 42093902 ( 1991) LOA E L = 250 mg/kg/day based on decreases in the absolute and 24-Month 42973501 relative kidney weight s in males and females Chronic/ Carcinogenic Acceptab l e / Gu id elin e NOAEL == 65 mg/ kg/day. ity -Rats 0, 0, 65, 250 o r l 000 At I000 mg/kg/day (upper limit dose) , the test compound produced Dietary mg/kg/day increases in the incidence of liv er and renal cell tumors. Body weights. food consumption and food efficiency were s ignificantly decreased in males and females at this do se. 

### Page 14 of 21

### Mo rp el R epell e nt 326 (Di-N-propy l i soc inchomeronat e)/ 047201 Human Health Risk Assessment 

### D4 19 1 54 Tab le A.3 S ubchr o ni c, C hroni c and Oth e r Toxicit , Profil e: dipr o p y l-i s ocinchomeronate Guide lin e No l Study MRID No. (year) / Re s ul ts Type Classification /Doses 870.4200 42100102 ( 1991) LOA EL = 500 mg/kg/day based on decreased body weights and 18-Month Acceptab le / Guide lin e body weight gains in both sexes, increased li ver / gall bladder Carcinogenic ity 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). N OA EL = 125 mg/kg/day At 2000 mg/kg/day , the test compound increased incidences of liver adenomas in females and a lveo lar bronchiolar adenomas in males. 870.6 200 Waived ( HA S POC TXR# 0056954 ) Acute neurotoxicity in rats 870.6200 Waived (HASPOC TXR# 0056954 ) Subchronic ne urotoxicity in rat s 870-5100 4038210 I ( 1986) No mutagenic effect was noted with or without microsomal Bacterial reverse Acceptab le/G u ide lin e activation at concentrations up to the toxic range of 5000 mutation I00

- 5000 μg/plate micrograms of MGK 326 /plate in the initial tests or in the Salm o n e lla 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 Accept ab l e / Gu id e line chromosome aberration s in the duplicate a s says 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 wi thout assay in C HO cells act ivated system S9; 0.5 and 1.0 μL/mL with S9) 870.5300 40382104 ( 1986) MGK R epelle nt 326 was t ested up to cytotoxic leve ls (> 0. 1 8 In Vitro mam m alian Acceptab le/G uid el in e μL/m L , -S9 and > 0.24 μL / mL , + S9). I ncreases 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 -acti vation; Mutagenesis Assay however, because the results were not reproducible (-S9) a nd 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 Acceptab l e/G uid eli n e as determined by increased levels of lactic acid dehydrogenase synthesis in Rat 0.001

- 0.2 μL/mL tested (LO H ) activity. No significant increases in mean net nuclear grains Primar y Hepatocytes (NNG) or p ercent ce ll s in repa ir 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-isoeinchomerona te, administered orally, Metabolism and Acceptable/ G uid e lin e was absorbed rapid l y and reached a peak blood level at 30 minutes pharmacokinetics Pyridine-4- 14 C- dipropyl- and 45 min utes afte r dos in g in male and female rats , re spec tive ly. (Rat) isocinchomeronate used. Its blood half-life was 1.5 hours. About 89

- 99% of the I) Single oral I00 mg/kg administered dose was e limin ated 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) S in gle ora l I00 o r I000 dosing). Re s idual radioactivit y in the tissues was nil to mg/kg/day o r s ingle iv insignificant. There were no differences between male s a nd dose of I mg/kg and held females or between single ora l 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 m

g/kg of unlabeled than the othe r g roup s. In the iv dosing, the el imination of the compound for 14 days radioactivi t y was much faster; 87- 89% of the adm ini ste red dose followed by a s in gle oral was eliminated during the first 4 hours. The feca l excretion was dose of labeled I00 mg/kg less than 1.3 % of the administered iv dose. and held for 168 h.


### Page 15 of 21

### Morpe l Repellent 326 (Di-N-propyl isocinchomeronate)/ 047201 Human Health Risk Assess ment 0 4 1 9 1 54 T ab le A.3 Subchronic , Chronic and O t h e r To xic it Profile: dioroovl-isocinch o m e ron ate Gu id eline No./ Study M RID No. (year) / R es ul ts Type C lass i fication /Do ses 870

- 7485 42246502 () HPL C metabolic p rofiles of ma le and fema le rat urine we r e similar. Metabolism

- Acceptab l e/G uidelin e HPL C ana lys is revealed a major peak (Metabol ite A: 95

- 99% of the Identification of Adde ndum to MRID urinary radioactiv ity) and a minor peak (U nknown I; up to 4.5%). Metabolites

- Rat 4230570 1 Th e parent compou nd was not detected in the urine samp le s. M

e tabolite A fract ion was furth e r pu ri fied, concentrated and analyzed with mass s pectrometry (MS ) and identifi ed as the dicarboxylic acid derivative of MGK Repellent 326. Based upon th ese res ults , it was postulated that the parent compound was hydro lyzed at the two ester s ites to fo rm the dicarboxy li c acid derivative of MGK Repellent 326. 870-7485 4224650 I ( 1990) None to a negligible a m o unt (<0

. 04%) of the 14 C in the pyridin e Metaboli sm - Acceptable/ Guideline rin g of the parent co m pound was metabol ized to 14 C02. detenninat ion of P yrid ine-4- 14 C- dipropylexpired C0 2

- Rat isocinchomeronate used. S in gle ora l dose I 05 mg/kg Non-Gu id eline 4309940 I ( 1 993) P eak ra dio activity blood leve l s were attained at 2

- 4 hours with a Metaboli sm Study

- Acceptable/ n o n -g uidelin e p lasma half-life of 5.3-8.0 hours. The t es t compound was rapidl y Human s P y ridin e-4

- 1 ' 1C- dipropyl- absorbed from the gastro in testinal system and eliminated in the isocinchomeronate used ur ine ( 4 1 .5%

- 54% during th e first 8 hours ; 81 .9

- 85. I % of the AD 6.1-6.8 mg/kg; 95. I μCi dur in g the fir s t 36 hours). Tota l urinary excretion of the 2 adult hea lth y ma les rad ioac ti vity amounted to 82.3-85.8 % of the AD by 128 hours after dosing. Excretion of the radioactivity in th e feces was minimal and occurred mostly w ithin the fir s t 6 hours after dosing ( 1 .87%

- 2

. 61 % of the AD)

. The balance of the AD was not accounted for. Th e HPLC ana lys i s of the 0-24 hour compos ited urine of the two vo lunt eers revealed three metabol ites with no paren t compound present. These were identified by mass spectrometric (MS) analysis as the hydrolysis products of th e parent material: Metabolite A: the diacid of MGK 326 (39.8% of the urinary radioactivity) , Metaboli te B ; 5

- carboxy un- este rifi ed (3.9% of the urinary radioacti v ity) and M

e tabolite C: 2

- carboxy un-esterified (40.3% of the urinary radioact iv ity). Metabolite s B and C we re converted to Metabolite A by acid hydrolysis. No n- Guideline 4297460 I (I 992) Pl asma rad io activ ity level s in d icated that 14 C -MGK®326 was Denna l Absorpt ion & stea d i ly absorbed thro ugh th e human skin, and a peak p lasma Mass Balance- P yridine-4- 14 C- diprop y l- co nce ntr ation was reached when the exposure was terminated at 8 Human s isoc inchomeronate. ho urs . Mean dermal absorption of r ad iolab e led MGK- 326 (su m 41. 7 ug/cm2 in iso propanol o f radioacti v ity in urin e a nd feces) from an 8 hr expo s ur e was 4 heal thy human vo l unteers 24 .9 % (cumu lative tota l meas ur ed over 128 hrs)

. Absorbed radioactivity was eliminated ma inl y in the urin e (24.7 % of th e appl ied do se) a nd onl y negligible amounts were eliminated in the feces. The majority of unab so rb ed do se was found in the isopropanol wash (48.5%). M ea n total recovery of applied dose was 95.5%.



### Page 16 of 21

### Morpel Repellent 326 (Di-N-propy l isocinchomcron a te)/04720 1 

### Human H ealth Ri sk Assessment 0 4 1 9 1 54 Table A.3 S ubcbroni c, C hronic and Other**ox it:** **~** Pr o fil e: dipropyl

- isoc incbom e ronate Gu ideline No./ Study MRID No. (year)/ R esu lts Type C lass i ficatio n / D oses Non -Guid eline 42732101 (1993) Dcm1al Absorption & Mass BalanceH

uma n s - Multiple Dosing

Non-Guideline Dermal Absorption & Mass BalanceHumans

870.7600 Dermal Absorption

- Rats Fomiulated P yridine-4- 1 4Cd ip ropyl

isocinchomeronate ( 1.0% w

/ w) with DEET ( 17 .5% w

/ w) and MGK 264 (5% w

/ w). 4.2 ug/cm 2 daily for 1 4 days followed by 4.2 ug/cm 2 of th e labeled material (37.9 μC) on day 15. 42974602 ( 1992) Formulated**Pyrid in** **e-4- ~C** dipropylis ocinchome ronate (I. I % w

/ w) with DEET ( 17.5 % w

/ w) and MGK ® R epelle nt 264 (5% w / w). 46.6 ug/cm 2 in isopropanol. 3 healthy human volunteers 42246503 ( 1990) Pyridine-4- 1 4C- dipropylisocinchomerona te. G r o up 1 : Fi ve mal e rat s 80 ug/cm 2 in isopropanol. Blood collected over 168 h

. G r o u ps 2-5: Five males/group 60 μ g/cm 2
, sac rificed at I, I 0, 1 9 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 ex po sure was term in ated. The plasma radioa ctivi ty levels as a function of tim e we re ana logous to tho se obtained with single dose dermal application of the pure material (M RID 42974601) and the formulated material (MRJD 42974602). Mea n d e rmal absorpt ion of r ad iol a b e led MGK® R epe ll e nt 326 (su m o f radioactivit y in urin e a nd f eces) from a n 8 hr ex po s ur e wa s 4 .75% (cumulative tota l m eas ur ed over 12 8 hr s). Absorbed radioactivity was eliminated mainly in the urine and only negligible amounts we re e liminated in the feces. The majority of unabsorbed do se was found in the isopropyl alcohol swabs (79%). Mea n total recovery of applied dose was 99.28. Pla sma radioactivity levels indicated that the formulated 14 C-MGK ii 326 was continuously absorbed through th e human skin , and a peak pla s ma co ncentrati on was reac hed when the expos ure wa s terminated. Pla sma radioactivity levels dipped after isopropanol wash. M ean derm a l abso rp t ion o f radiolabelcd M G K-3 26 (s um o f r ad i oact iv it y in urin e a nd f eces) from a n 8 hr expo s ure wa s 3.4 % (c umul a ti ve total meas ure d over 128 hrs). Absorbed rad ioactivity was e limin ated ma inl y in the urin e and only neg li g ibl e amounts we re eliminated in the feces. The majority of unabsorbed dose was found in the isopropyl alcohol swabs (78 % ). Mean total reco very ofa oolied dose was 1 02. 1 7%. The t es t material was abso rbed thr o ugh the sk in and rapidly reached a peak blood level ( 13 % of the administered dose) at I hour after dosing and g radu ally declining reaching a plateau level after 24 hours. The study author calculated a first half-life of9 hours and a seco nd ha lf -li fe of 1 9 hours. Mean derma l ab so rpti o n of r a di o labe l ed MGK- 326 (t h e s um o f r a dioacti vity in urin e ( m ajo r a mo unt ), f eces, ti ss u es /ca rc ass , an d cage was h ) a ft e r 10 h o urs of ex p os ur e wa s 45 %
. Mean rec overies of th e t es t mate ri a l ranged from (95 -103 %). The majority of reco vered test material was found in the sk in rinse at the I and 10 hr time intervals (86 and 53% respectively). Mean amounts of test substance found in the skin rinse decrea s ed s ignificant ly at the 19 a nd 168 hr time intervals (3 1 and 7% respective ly) indic ating that materia l remaining inion th e skin continues to be absorbed over time. 8 7 0-7800 lmmunotoxiciry Waived ( H ASPOC TXR# 0056954 ) Non- g uidelin e Special study: Hepatic Enzyme Induction Study

- Rats 4303330 I ( 1 992) Acce ptabl e / n o n -g uid e lin e 0 , 96.9, 373.4 , 783.9 or I 554.5 mg/kg/day for 28 d ays to ma les. Positive conrrol: Sodium phenobarbital: 53.7 mg/kg/day d ip ropyl- isoc inchom e ronate did not affect se rum chem ist rie s. It did not produce peroxisomal proliferation, induce peroxisomal enzyme s (palmitoyl-CoA oxidation) or induce cytochrome P 450 dependent mixed function oxidase enzymes including N-et hy lmorphin e N-demethylase, 7-ethoxycoumar in 0-deethy lase, 7-ethoxyresorutin 0-deethylase or gam m a-glutamy l-tran sferas e. MGK 326 was not a rat liver microsomal enzyme inducer.



### P

age 17 of 21

### Morpe l Repe ll ent 326 ( Di-N-prop y l isocinchomeronat e) / 047201 Human Hea l th Ri sk Assessment 

### 0419154 Tab l e A

. 3 Subc hro ni c, C hro nic and Othe r Toxic it / Profile : diproovl

- i s ocinchomeron a te Guideline No ./ Study MRID No. (year)/ Re s u lts Type Class i fication /Doses Non- guideline 42974603 ( 1992) On l y copies of the original autoradiograms were submined in the Special study: U n acce ptabl e/No n - report and were difficult to evaluate due to their poor quality. No Whole Body G uid e l ine quanti t ative dat a on the distribution of the radioactivity in the Autoradiography Pyridine-4- 14 C

- 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 I00 ml?)kg body weight Registrant to conduct such s tud y.



### Page 1 8 of 21

### Morpel Repell e nt 326 ( Di -N -propy l isocinchomeronate)/ 04720 l Human Health Risk Assessment 

### 0419154 

### APPENDIX B

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

### Bl)

wher e: 

### D ARr FA! 

### ET AppF SA/BW F Body 

### AF 

### D 

## = ARF 

## * F A1 *ET* AppF 

## * SA I BW *F oody * AF

= do se (mg/kg -d ay); = formulat ion-specific application rate (mg product/cm 2 

### skin);

= product- s pecific fraction of active ingredient (mg ai / mg product) ; =ex posure time (hours/day);

= applicat ion frequenc y (applications/hour); 

## = total body surface area to body weight ratio (cm2 

### / kg) ; =clothing-dependent fraction of body exposed (fraction exposed / application); = absorption factor.
Tab l e Bl: In sect Repe ll ents

- Inpu ts for R eside nti a l Post-application Derm a l Ex po s ure

Algorithm Ex p os ure Facto r Po int Es timate(s) Notat ion ( uni ts) Aerosol I. I

ARF Formulation-specific appl icati on rate Pump spray 0

. 62 (not used) (mg produ ct/cm 2 skin) Lotion 2.0 (not used) Towelett e I. I F

AJ Amount of active in gred ient Varies among product s (%) (0.5 , 1.0 , 2.0 a nd 2.5%) Fraction / area of body exposed per application

- based on an average of two clo th ing scenarios: F0o<1y I. 75 %

- representing swimsuit attire (shorts for men and 0.53 shons / top for women) , and 2. 31 %

- representin g short-sleeve shirt, shorts. socks, shoes Surface Area to Body Weight Ratio Adult 2 80 SNBW (c m 2 /kg) Children I < 2 years old 640

Adult 3.7 ET Exposure Tim e (hours/day) Children I < 2 3.5 yea rs old Application Frequency Traditional 0.25 Appf (a pplications/ hour) With s unscreen 0.5 (not used)



### Insect Repellents: Post-application Incidenta l Oral (Hand-to-Mouth) Exposure Algorithm (inp u ts provided in Tabl e 82) Exposure from hand-to-mouth activity is calculated as follows (bas e d on the algorithm utili zed in SHEDS -Multimedia):
Pa ge 19 of 21

### M orp e l R e p ell e nt 3 26 (D i- N -prop y l iso cinch om eronate)/ 04 72 01 H um a n Hea lth Ri sk Assess m en t 

### 0 4 1 9 1 5 4


### E = [ HR 

## * (F:11 

## * SA1-!) * (ET* N

_R ep len ) 

## * (1
- (1
- 

### SEf Freq l-11M IN-Rep t e 11J)j whe re:

an d 

### E HR 

## F

M SA11 

### ET N

_ Rep le n 

## SE f- reCL_ H tM =ex p os u re ( m g/day);

= hand r es idue loa d i n g ( m g/c m2 ); = frac ti o n h and surface area mo uth ed/event (fract ion/eve nt) ; = typ i ca l s urface area of o ne h and (cm 2 );
= ex p os ur e tim e ( h o urs/ d ay); = num be r o f r ep le n is hm e nt inte rval s p e r hour ( in t erval s/ h o u r); =sa l iva ex traction facto r ( i .e . , m o uth i ng re m oval effic ie ncy) ; and

= num be r of h a nd-to -m o uth co n tac t s eve nt s p e r h o ur (eve nt s/ho ur).

w he r e: 

### HR A R F F A 1 = h a nd res id u e l o adin g ( m g/c m 2 );
= fo rmulati o n -s pecifi c app l icat io n rat e ( m g ai/cm 2 s kin );

= pro du ct

- s p ec ific frac t io n o f ac ti ve ingred ie nt ( m g a i / m g pro du c t); O ra l d ose, n o rm a l ize d to b o dy w e ight , a r e calc ul ate d as:

w here: 

### D E 

### B W = dose ( m g/kg -d ay) ;
= ex p os ure ( m g/da y); a nd = bo d y we ig ht ( k g). 

### E 

### D=

- BW

T a b le 8 2: In s e c t R ep e ll e nts - I npu ts for R es identi a l P os t-ao o li ca ti o n H a nd-to- M outh Ex p os ure

A lgo rithm E xp os ure Fa ctor Po int Es tirn a t e(s) Notat io n ( uni ts) Aerosol I. I Fo r mul a ti o n- spe c i fi c ap pli cati o n rat e Pu m p s pray 0.62 (not used ) AR " ( mg prod uct/cm 2 ski n) Lot io n 2. 0 ( not used) Towe lette I. I

F AI A m o unt of ac ti ve in g red ie nt Va ri e s a m o n g prod u c t s (%) ( 0 .5, 1. 0 , 2.0 a n d 2.5 % ) SA11 Typical surfac e area of one hand (cm 2 ), children I < 2 years old 150 

### FM Fractio n h and s ur face area mout hed 0.127 (fraction/eve nt) N

_ Replen Rep l en is hmen t intervals 0.25

( interval s/h r ) ET Exposure Time 3.5 Page 20 of 21

### Mo rp e l R e p e ll e n t 3 2 6 ( Di -N- propy l i so cin c h o m er o n a t e) / 047201 Human Health Ri s k Assessment T a ble B2 : in sec t Rep e ll e nts - Inpu ts for R es id enti a l P ost-a opli ca ti o n Ha n d

- t o-M o u t h Ex po s ure (hours/ da y) SE Sa li va ex tra ctio n factor 0.48 (fract ion) Freq_HtM Hand-to-mouth eve nt s per ho ur 1 3.9 (even ts/h r) BW Body W e igh t 11 (kg)



### P age 2 1 of 2 1 

### 041 9 1 54