**MEMORANDUM**

**SU BJECT:** 

**PC Code:**  **1 07**  **801 Decision**  **No .:**  **NA Petition**  **No.: NA**  **UNITED STATES**  **ENVIRONMEN TAL**  **PROTECTION AGENCY**  **WASHINGTON, D.**  **C. 20460** 
**OFFICE OF**  **CHEMICAL SAFETY**  **AND POLLUTION**  **PREVENTION**
**December 10**  **, 20**  **12**

**Revised Summary**  **of Human**  **Health Eff**  **ects Data**  **fo r**  **IPBC Registration**  **Review DP**  **Barcode: D4044** **89**

**Reg istration**  **No .:**  **NA Regulatory**  **Action: Registration**  **Review Risk**  **Assess Type:**  **Si ngle**  **Chemical Case**  **No.: 2725**  **TXR No.:**  **NA MRID**  **No .:**  **NA**

**FROM:**

**THRU:**

**TO: CAS**  **No .:**  **55 406-53-6**  **40 CFR:**  **NA**
**Timothy C. Dole,**  **CIH, Industrial**  **Hygienist** 

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**Risk Asses** **sment and**  **Sci ence**  **Support Branch (R** **ASSB) Antimicro** **bials Divisi** **on (75**  **1 0 P)** 
**Timothy Leighton, Senior**  **Sci entist**  **Risk Assess** **ment and**  **Sci ence**  **Support Branch**  **(R ASSB)**  **Antimicrobials Division**  **(7 51**  **OP) Steve**  **Weiss, Branch**  **Chief Risk**  **Assess ment**  **and Sci** **ence Support**  **Branch (R** **ASSB) Antimicrobials**  **Division (7**  **51 OP)**  **Rebecca von dem**  **Hagen, Chemical**  **Review Manager**  **Lance Wor** 

**mell, Team**  **Leader Regulatory Management**  **Branch II**  **Antimicrobials Divisi** **on (75**  **1 OP)** 

**RAS SB**  **has reviewed**  **the human**  **health ef**  **fects data**  **fo r**  **IPBC to**  **determine if**  **additional risk**  **assessments are**  **needed and**  **if additional**  **toxicologi cal**  **and exposure**  **data would**  **be needed**  **to conduct these**  **risk assessments.**  **This review**  **was original** **ly completed**  **as DP**  **38 2446,**  **dated May 5,**  **20 1 1**  **and has**  **been revised**  **to include**  **uses which**  **were previously**  **omitte d.** 

**Page 1**  **of 41** **EXECUTIVE SUM** **MARY**

**IPBC is registered fo** **r use**  **as a**  **wood preservat** **ive, an**  **industrial preservative**  **and as**  **a dry**  **film mildewcide.**  **The wood**  **preservative uses include**  **dip, spray**  **and pressure**  **treatment app** **lications fo** **r milled**  **fo rest**  **products such**  **as new lumber,**  **millwork and**  **jo inery**  **and brush**  **and spray**  **app lications**  **fo r**  **existing above ground**  **structures such**  **as decks.**  **The industrial**  **preservation uses**  **include metal**  **working fluids, adhe** **sives, caulks,**  **sealants, plastics,**  **textiles, paper coatings, canvas,**  **cordage, and**  **inks. Additional**  **preserva tion**  **uses include**  **household, consumer,**  **indust rial,**  **institutional and**  **ja nitorial**  **products such**  **as air**  **fresheners ,**  **dish detergents,**  **laundry products,**  **surf ac** **e clea** **ners, floor**  **care products**  **and fa**  **bric care**  **produc**

**ts. The**  **RED fo** **r IPBC**  **was completed**  **in 1 9** **97 and**  **most of**  **the above uses**  **were fo** **und to be**  **eligible fo** **r regi**  **strat ion.**  **For the**  **industrial wood**  **treatment use,**  **the HV AC**  **use, the**  **textile use**  **and certain**  **non-industrial wood**  **treatment uses,**  **the Agency**  **was unabl**  **e to**  **make a regi**  **stra tion**  **eligibility decision**  **due to**  **a lack**  **of occupational**  **and residential**  **exposure data**  **and thus determined**  **that the**  **uses were**  **ineligible fo** **r registration**  **at the**  **time of**  **the decision.**  **These uses**  **were inadvertently**  **omitted fr** **om the**  **previous version**  **of this**  **document and**  **the exposure**  **data are**  **anti cipated**  **to be**  **required through**  **this regi stra**  **tion review.**  **There is**  **conflic ting**  **inf**

**orma tion**  **regarding the**  **use of**  **IPBC fo** **r fo** **od contact surf**  **ac es.**  **IPBC does**  **not have**  **any FDA**  **approv als**  **fo r**  **fo od**  **contact uses**  **and most**  **the labels restri** **ct uses**  **in adhesive,**  **paper and**  **paper board**  **products and**  **paper coating**  **to non-f**  **ood ap**  **plications. The**  **labels also**  **have simila** **r state** **ments fo** **r plastics**  **and surf ac** **e cleaners**  **that limit**  **the use to**  **non-f ood**  **ar eas.**  **There are several**  **labels which**  **were appr**  **oved beginning**  **in 2004, however,**  **that allow**  **use in**  **dish detergent,**  **which is**  **considered to**  **be a**  **fo od**  **contact surf**  **ac e.**  **Although the**  **toxicologica l**  **database fo** **r IPBC is**  **fa irly**  **extensive, the**  **fo llowing**  **additional studies**  **are needed**  **fo r regi** **strati on**  **review:**
**• Comparative**  **Chol inesterase**  **Assa y**  **with Thyro** **id Measurements** 
**• Dermal**  **Sens itization**  **Thre shold**  **Quantification Although**  **some occupational**  **and residential**  **(ORE) exposures**  **were assessed**  **in the**  **RED, they**  **will need**  **to be**  **reassessed duri** **ng registration**  **review to**  **account fo** **r new**  **data. The fo** **llowing exposure**  **data will**  **also be**  **needed to assess**  **these exposures:**  **• Indoor**  **exposure studi** **es (dermal and inhalation)**  **during open**  **pouring of**  **liquids, open**  **pouring of**  **powders, sapstain**  **treatment, pressure**  **treatment of**  **wood, use**  **of metal**  **working fluids,**  **use of**  **sponges and**  **wipes, ap**  **plic ation**  **of fungicidal protective**  **coatings to HV** **AC systems, and**  **brush/ro ller**  **application of**  **preserved paints.** 
**• Outdoor**  **exposure studi** **es (dermal**  **and inhalation)**  **during airless**  **sprayer application**  **of wood**  **preservative sta** 

**ins.**
**• Leaching**  **studies on**  **plastics, leather and**  **textiles preserved with**  **IPBC**
**• Surf**  **ace residue**  **diss ipation studies**  **on household**  **floors cleaned**  **with IPBC**  **preserved floor**  **cleaners.**
**• Surf**  **ace residue**  **diss ipation**  **studies on**  **IPBC treated**  **wood.**
**• Product**  **use inf** 

**orma tion** 

**Page 2**  **of 41** **In additio** **n, it**  **will be**  **necessary to**  **assess dietary**  **exposures from the**  **dish detergent**  **use and** 

**therefore a**  **residue study**  **on dishes**  **will be**  **needed fo** **r registrati** **on review.**  **1.0 BAC** **KGROUND 1.**  **1 Chemical**  **Identity The**  **chemical identity**  **of IPBC**  **listed in**  **Table 1.**  **Table 1**  **- Chemical**  **Identity of**  **IPBC Chemical**  **Name Common**  **Name PC**  **Code CAS**  **Registry Number**  **Case No.**  **Empirical Formula**  **Structure**

**1.2 Chemical**  **and Phy** **sical Properties**  **3-Iodo-2-propynyl butyl**  **carbamate IPBC**  **107 80**  **1 554** **-5 3**  **-6 27**  **25 C**  **s H**  **1zl NO** **z H**  **�**

# NyO�I

**II 0** 

**The physical**  **and chemical**  **propertie s of IPBC**  **that are**  **relevant fo** **r human health risk**  **asses sment**  **are listed**  **in Table 2.**  **It should**  **be noted**  **that IPBC**  **has a**  **very low vapor**  **pressu re**  **.**
**a e**  **- SICa**  **an em1ca**  **T bl**  **2 Ph**  **. I**  **d Ch**  **. I**  **P f**  **roper Ies**  **o Property**  **'!:...; �· ..,,**  **Value 'It'.**  **,, '·**  **" Molecular**  **Weight 28**  **1 Physical**  **State Powder**  **Melting Point**  **66 C**  **Water Solubility**  **1 5 6**  **mg/1 @**  **20 C**  **Octanol/Water Partition**  **Coefficient Log**  **Kow =**  **2 . 4**  **Vapor Pressure**  **<1 . 8**  **X 10** **' (>**  **@ 20**  **c' 5**  **X 10**  **'**

**0 @**  **30 c**  **Henry's Law**  **Constant**

**2. 0**  **USE IN** **FORMATION 8.**  **9 x**  **to·� atm-** **m j** **/mole @**  **25 C** 

**2. 1**  **Formulation Types**  **and Percent**  **Active Ingredient** 

**Page 3**  **of 41**  **L fiPBC**  **Reference**

**' Based**  **on formula**  **EPA, 1 9**  **97 Toxnet**  **HSDB Toxnet**  **HSDB EPI**  **Suite Estimate**  **EPA, 1997**  **EPI Suite**  **Estimate According**  **to OPPIN, as**  **of 03/2**  **1/ 201**  **1, there**  **are 1 0** **6 products that contain IPBC**  **(0.05% to**  **99. 5%** **) as the**  **active ingredient**  **(ai). The**  **products are**  **fo rmulated**  **as powders and**  **liquids.**

**2.2 Summary**  **of Regis**  **tered Uses**  **IPBC is**  **registered fo** **r use as**  **a wood**  **preserva tive,**  **an industrial**  **preserva tive**  **and as a**  **dry film mildewcide.**  **The wood preservative**  **uses include**  **spray, dip**  **and pressure**  **treatment applications**  **fo r**  **milled fo** **rest products**  **such as**  **new lumber,**  **millw ork**  **and jo** **inery and**  **brush and**  **spray app** **lic ations**  **fo r**  **existing above**  **ground structures such**  **as decks.**  **The industrial**  **preservation uses**  **include metal**  **working fluids, adhesives,**  **caul ks,**  **sealants, plastics,**  **textiles, paper**  **coatings, canvas,**  **cordage, and**  **inks. Additional**  **preserva tion**  **uses include**  **househo ld,**  **consumer, industri** **al, institutional**  **and ja** **nitorial products**  **such as**  **air fresheners,**  **dish detergents,**  **laundry products**  **, surf**  **ace cleaners,**  **floor care products**  **and fab** **ric care**  **product s.**  **IPBC is**  **also registered**  **fo r**  **use as**  **a dry film**  **mildewcide in**  **paints and**  **stains and as a fungicidal**  **protective coating**  **fo r**  **Heating, Ventilation and**  **Air Con** **ditioning (HV** **AC) systems.**  **A summary**  **lis ting**  **of the**  **ap plication**  **rates is**  **included in**  **Table 3.**  **Table 3** 
**- App** **lication Rates**  **for IPBC**  **Use Appl** **ication Rate**  **Example Label** **s Adhesives,**  **Caulks, Patching**  **0.0 04**  **to 0.6%**  **1 2 5 8** 
**- 1 2**  **30 Compounds**  **and Sealants**  **Canvas and**  **Cordage 0.0** **23 to**  **1 . 2%**  **53 83-77**  **Decay and Stain**  **Protection 1 .**  **5% (Non** 

**- Pressure**  **Treatment) 0.0** **37 5**  **lb ai/f** **e (Pressure**  **Treatment) 43**  **8 1 3-43**  **Household, Consumer,**  **Industrial and**  **40 to**  **600 ppm**  **1 2 5 8**  **-12 30**  **Janitorial Products**  **HV AC**  **Systems 0.**  **12 and**  **0. 1 6** **% 63836** **-2, 63836-**  **1 Inks**  **0.45 to**  **3 . 0%**  **1 2 5 8**  **-12 22**  **Leather 0.2**  **0% 464-8**  **125 Metal**  **Working Fluids**  **0.03-0.53% 53**  **83-77 Mildew**  **Inhibition for**  **Paints and**  **Stains 0.32**  **to 1 .**  **08% 538**  **3- 1 1**  **4 Paper**  **Coatings 0.23**  **to 0.9%**  **1258 -12**  **30 Plastics**  **and Plastic**  **Coatings 0.45**  **to 1 .**  **2 % 1 2**  **5 8 -12**  **30 Milled**  **Forest Products**  **(i.e. lumber,**  **0.375% (Bulk**  **Dip Tank)**  **43 8 1**  **3-43 millwork**  **and joinery)**  **0.75% (Conventional**  **Spray) Textiles**  **0.23 to**  **0.98% 538**  **3- 91**  **Wood Finish**  **and Preservative-**  **0.5 %**  **69857 -4,**  **1 0 22-540**  **Homeowner Applied**  **Some of the**  **IPBC labels**  **have limit** **ations fo** **r plastics**  **(not to**  **be used**  **in plastics**  **that will**  **be in**  **contact with**  **fo od**  **or medica** **l applicati** **ons), paper**  **coatings (non-f**  **ood contact**  **packag ing**  **and non**  **fo od**  **contact paper ta** 

**pes), textiles**  **(not to be**  **used on**  **fa brics**  **intended fo** **r human**  **wear or**  **direct skin contact)**  **and surf** 

**ac e**  **cleaners (non-f** 

**ood contac** 

**t). In**  **2004, the first**  **label (538**  **3-1 1 7** **) allowing**  **the use**  **of iPBC**  **as a**  **materi als**  **preservative in**  **liquid detergents,**  **soft soaps,**  **and household**  **cleaning products**  **was app**  **roved. In**  **2005, the**  **first**

**Page 4**  **of 41** **label (6707**  **1 -44)**  **allowing the**  **use of**  **iPBC as**  **a material**  **preservative in**  **Household, Consumer,** 

**Industrial ,**  **Insti tutional**  **and Janitorial products**  **was appr** **oved. These**  **products include**  **liquid and**  **solid soaps,**  **cleaners, detergen**  **ts, laundry**  **products and**  **dishwashing detergents.**  **Si nce**  **that time,**  **several other**  **labels have**  **been ap**  **proved fo** **r these**  **uses. In**  **2009, the**  **first label**  **(464-8 12**  **3) allowing**  **the use**  **on lea** 

**ther was**  **appr oved.** 

**2. 3**  **Summary of**  **Use Data**  **According to**  **the Specialty**  **Bi oci** **des North America**  **Report 2004-2005**  **(Kline, 2006),**  **the total U.**  **S. Consumption**  **of iPBC was**  **$48 million**  **in 2004.**  **The areas of**  **consumption included**  **paints and**  **coatings (67%**  **of total**  **IPBC sales**  **by value),**  **wood preservation**  **(2 5%**  **of sales),**  **metal working**  **fluids (6%**  **of sales),**  **adhesives and**  **sealants (2% of**  **sales) and**  **plastics and**  **resins (** **<1 %**  **of sales).**  **The market**  **share s**  **fo r IPBC were**  **56% fo** **r paints and coatings**  **(as a fungicid** **e), 2%**  **fo r**  **wood preservative** **s (water**  **borne), 8%**  **fo r metal**  **working fluids**  **(as a fungicide), 1%**  **fo r plastics,**  **and 4%**  **fo r**  **adhe sives**  **and sealants**  **(fungicides and**  **mildewcide s).** 

**3. 0**  **TOXICOLOGY The**  **toxicologi cal**  **datab ase**  **fo r**  **the IPBC**  **registra tion**  **review case is**  **comprised of**  **studies that**  **were available**  **to the**  **Agency when the**  **RED was**  **written in**  **19 97**  **and additional**  **studies that were**  **submitted after**  **the RED.**  **The additional**  **studies include**  **the fo** **llowing:**
**• Acute**  **Neurotoxicity Study**  **in Ra** **ts, MRID**  **4550 94-0**  **1**
**• Subchronic**  **Nuerotoxicity in**  **Ra ts,**  **MRID 455**  **094-02**
**• Subchronic Oral**  **toxicity Study**  **in Ra**  **ts, MRID**  **458 1 2** **3- 01** 
**• Subchronic Inhalation**  **Toxicity Study**  **in Rats** **, MRID**  **43 530** **2-03**
**• Tw**  **o-Generation Reproductive**  **Toxicity Study**  **in Ra**  **ts, MRID**  **444 78**  **8-0 1**  **The acute**  **neurotoxicity study**  **is classified**  **as Acceptable**  **(Nonguideline) and**  **does not**  **satisfy the**  **guideline requirement**  **(870. 6200;**  **OECD 424) due**  **to inc** **omplete evaluations**  **of neuropatho** **logy (lack**  **of histopat**  **hology of**  **nervous system**  **tissue and**  **brain weight** **s). The**  **subchronic neurotoxicity**  **study, the**  **subchronic oral**  **study, the**  **subchronic inhalation**  **study and**  **the two**  **generation reproduction**  **study are**  **classified as**  **Acceptable and**  **fulfill the**  **respective guideline**  **requirements (870.6** **200, 82** **-1, 82-4,**  **870.3 800).**  **3.1 Acute**  **Toxicity A**  **complete datab** **ase of**  **acute toxicity**  **data was available to**  **the Agency**  **at the**  **time the**  **RED was**  **wri tten. A**  **summary of**  **the findings,**  **which are**  **detailed in**  **the RED,**  **is included**  **in Table**  **4. IPBC is**  **a severe**  **eye irritant**  **(i.e. Tox**  **I) and**  **is of**  **low to moderate**  **acute toxicity**  **by the**  **other routes**  **of exposure**  **. IPBC**  **is not**  **a dermal**  **sensi tizer**  **at concentra**  **tions that**  **do not**  **exceed 0.32**  **percent**
**. However,**  **incidence data**  **and published**  **li terature**  **suggest that**  **IPBC may**  **be a**  **dermal sensi** **tizer at**  **either higher**  **concentra tions**  **or fo**  **llowing longer**  **term exposure** **s. Dermal**  **exposure is**  **the primary**  **route of**  **exposure fo** **r some**  **residential use**  **scenarios including**  **textiles and**  **treated wood.**  **As suggested**  **in the**  **FIFRA Sc** **ientific Advisory**  **Panel Meeting**  **(SAP, 2004),**  **it is** 

**Page 5**  **of 41** **important to**  **evaluate the**  **dermal sensitization**  **concern if**  **the dermal exposure**  **is the**  **primary**

**concern and**  **there is**  **no appropriate**  **way to**  **label the**  **treated products.**  **In order to**  **conduct a**  **quantita tive risk**  **asses sment**  **fo r dermal sensitization, a**  **dermal sensi** **tization study with**  **di ff**  **erent conc** **entrat ions**  **of the**  **technical grade product will**  **be requi** **red.**

**T able**  **4 - Acute**  **Toxicity Values**  **for IPBC.**  **Test (species)**  **Result 81-**  **1 Oral**  **Toxicity (rat) LD5**  **0 =**  **110 0**  **mglkg (Females)**  **LD5 0**  **= 15**  **00 mg/kg**  **(Males and**  **Females) 81**  **-2 Dermal**  **Toxicity (rabbit)**  **LD5 0**  **> 20**  **00 mglkg**  **81- 3**  **Inhalation Toxicity**  **(rat) LC**  **50 =**  **0 . 68**  **mg/L 81-4**  **Eye Irritation**  **(rabbit) Severely**  **Irritating 81-** **5 Dermal**  **Irritation (rabbit)**  **Slightly Irritating**  **81-6 Dermal**  **sensitization (guinea**  **pig) Non** 
**- sensitizer**  **at 0 .**  **32%**

**3.2 Subchronic**  **and Chronic**  **Toxicity Toxicity**  **Cate g**  **ory III**  **III III**  **I IV**  **N/A**

**The fo** **llow ing**  **is a**  **summary of**  **the current** **ly availa** **ble toxicology**  **studies fo** **r IPBC.** 

**a. Subchronic**  **Toxicity Oral**  **Studies Subchronic**  **Oral Toxicity**  **in Rats,**  **MRID 409474-01.**  **IPBC was administered**  **by gavage**  **fo r**  **13 weeks**  **at doses**  **of O,**  **20, 50,**  **and 1 2**  **5 mg/kg/d** **ay. An**  **addit ional**  **satellite group**  **was dosed**  **at 1 2**  **5 mg/kg/day**  **and held**  **fo r a**  **28- day**  **observation period**  **fo llow** **ing the**  **1 3 -week**  **dosi ng**  **regimen. At**  **1 2 5**  **mg/kg/day, body**  **weight gain**  **was decreased**  **(19 %**  **in males and**  **12% in**  **fe males)**  **and absolute**  **liver weight**  **was increased**  **(20% in**  **males and**  **31% in**  **fe males).**  **Liver to**  **body weight**  **ratio was**  **significa**

**ntly increas**  **ed by ap** **proximately 31%**  **in both**  **males and**  **fe males**  **at 12**  **5 mg/kg/day,**  **while kidney**  **to body**  **weight ratio**  **in fe** **males was**  **increased 1 8**  **% at**  **1 2 5**  **mg/kg/d ay.**  **The systemic**  **NOEL is**  **20 mglkglday,**  **while the**  **systemic LEL**  **is 50**  **mglkglday, based**  **on increased**  **liver to**  **body weight**  **ratio. This**  **study is**  **classified as**  **core supplementary**  **data (guideline**  **82- 1**  **). Although**  **this guideline**  **is not**  **satisfied, acceptable**  **chronic toxicity**  **data are**  **available and**  **theref**

**ore, additional**  **oral subchronic**  **data are**  **not required.**  **Subchronic Oral**  **toxicity Study in**  **Rats, MRID**  **45812 3-01.**  **IPBC was**  **administered by**  **gavage at**  **doses of**  **O, 1 0** **, 20,**  **35 and**  **80 mg/kg**  **fo r**  **90 days.**  **A Functional**  **Observational Battery (FOB)**  **was perf**  **ormed prior**  **to the**  **first exposure**  **and then**  **weekl y.**  **In the**  **last week**  **of the**  **study, assess**  **ment of**  **sensory reactivity**  **to visual**  **stimuli (visual**  **placing) and**  **motor activity**  **was add** **ed. Food**  **consumption for**  **each rat**  **was determined**  **once a**  **week. Hematology**  **and clinical**  **chemistry examina**  **tions were**  **made at**  **week 1 3**  **, bef**  **ore the**  **terminal sacrifice.**  **Ophthal moscopi** **c examina**  **tions were**  **made on**  **all rats**  **prior to**  **the first**  **administra tion**  **of the**  **test substance, in**  **rats of**  **the highest**  **dose and**  **on control**  **rats at the**  **termina tion.**  **A gross**  **necrop sy**  **and pat** **hology examination**  **was perf** 

**ormed at**  **the end**  **of the**  **study.**

**Page 6**  **of 41** **There was no**  **test art** **icle related**  **findings with respect to**  **fo od**  **consumption ra tio,**  **asses sment**  **of hearing**  **, righting**  **reflex, grip**  **strength, visual**  **placing, motor**  **activi ty,**  **ophthal moscopy,**  **urinary parameters**  **or macro** **scopic and**  **microscopic findings.**  **One male**  **rat dosed**  **at 35**  **mg/kg/day died**  **on day**  **87 from a**  **dosing accident** 

**. The**  **most frequent clinical**  **finding, observed during**  **the daily**  **post -treatment**  **FOB observations**  **was breathing**  **sounds (sli** **ght to**  **moderate in**  **degree) seen**  **in a**  **dose- dependent**  **manner. From day**  **19 of**  **the study until**  **the end of**  **the treatment**  **period, the**  **main finding**  **was a**  **dose related**  **inc idence**  **of sl** **ight salivation**  **seen 25 minutes after**  **dose administration.**  **The eff** 

**ect may**  **be due**  **to be**  **a local**  **ef fe** **ct of**  **the dosi** **ng solutions**  **or to non**  **palatab ility.**  **Cli nical**  **observations included**  **statistically signifi** **cant decreases**  **in body**  **weight gain**  **in males**  **at 35**  **mglkg/day (1**  **2% )**  **and 80 mg/kg/day**  **(1 7%).**  **The NOAEL is**  **20 mglkglday**  **based on decreased**  **body weight**  **in males,**  **and salivation**  **and breathing**  **sounds in**  **females with**  **a LOAEL**  **of35 mglkglday. The**  **study is**  **considered to**  **be Acceptable**  **and fulfils the**  **guideline requirements**  **§8 2-1** 

**. Dermal**  **Studies Subchronic**  **Dermal Toxicity**  **Study in**  **Rats, MRID**  **421 68** **2- 01,** 
**- During**  **this study,**  **rats ( 1**  **0/sex/do se)**  **received dermal**  **doses of**  **50, 200,**  **and 500**  **mg/kg/day IPBC**  **to the shaved**  **skin fo** **r five**  **days a week,**  **six hours**  **per day during a**  **91 day**  **period. At**  **500 mg/kg/day,**  **decreased body**  **weight (4-6%) and weight**  **gain (1**  **1 %)**  **were observed**  **in males,**  **but not**  **in fe** **males. In**  **fe males,**  **signifi cant**  **increases in**  **hemoglobin, hematocrit,**  **and eosinophils were**  **observed at 500**  **mg/kg/day. Reti** **culocytes as**  **a percentage**  **of red**  **cells were**  **decreased at**  **50 and**  **200 mg/kg/day,**  **but not**  **at 50** **0 mg/kg** 

**/day. Decreased**  **serum glucose**  **and decreased**  **serum creatinine**  **were observed**  **in males**  **at 500**  **mg/kg/day. Minimal**  **to mild**  **skin irrit** **ation (acant** **hosis and**  **hyperkera**

**tosis) was**  **observed in**  **both males**  **and fe** **mal es.**  **Increased serum**  **gamma-glu tamyl**  **tra nspeptidase**  **(24% increase)**  **was observed**  **in fe** **males. At**  **200 mg/kg/d** **ay, decreased**  **serum glucose**  **was observed**  **in males,**  **as was minimal**  **to mild**  **acant hosis**  **and hyperkerato** **sis in**  **males and**  **fe mal** **es. Females**  **showed inhibition**  **of plasma ChE**  **at 50** **0 mg/kg/day,**  **which may**  **have been**  **the result**  **of either**  **direct liver**  **toxicity or**  **inhibition of**  **ChE it** **self**

**. The**  **systemic NOEL**  **is 200**  **mglkglday and**  **the systemic**  **LEL is**  **500 mglkglday.**  **This study**  **is classified**  **as core**  **minimum data**  **(guideline 82-3)**  **Inhalation Studies**  **In a**  **subchronic in** **halation toxi** **city study**  **(MRID 435**  **30 203**  **), Omacide**  **(>97% ai)**  **was administered**  **to rats**  **(1 5**  **rats/sex/d ose)**  **by whole-body**  **exposure at nomi** **nal concentrations**  **of O,**  **0.25, 1 .**  **25, or**  **6.25 mg/m**  **3 (measured**  **concen tra**  **tions of**  **0, 0.3,**  **1.1 6,**  **and 6.7 mg/m** **3 )**  **fo r 6**  **hours per**  **day, 5**  **days per**  **week, fo** **r 13**  **consec utive**  **wee ks.**  **The 0.25**  **mg/m 3**  **dose group**  **was repeated**  **based on**  **exposure of**  **the original**  **0.25 mg/m** **3 dose**  **group to**  **twice the**  **nominal co** **ncentration during**  **weeks 6-8**  **of the**  **study. In**  **the 6.25**  **mg/m 3**  **treatment group ,**  **plasma cholinesterase (ChE)**  **activity was**  **significantly reduced**  **(appro ximately**  **20% )**  **in males during**  **weeks 2 and**  **1 3 , and**  **eryth rocyte**  **ChE was decreased**  **in fe** **males at**  **study week 2. Brain ChE activity**  **was significantly**  **reduced in**  **males**

**Page 7**  **of 41** **(I7%) and**  **fe males**  **(2 5%** **), and**  **hyper plasia**  **or squamous**  **meta plasia**  **with necrosis**  **of the ventral**  **cartilage of**  **the larynx**  **was seen**  **after I3**  **weeks of**  **treatment. In**  **the I.25**  **mg/ m** **3 treatment**  **group, brain**  **ChE levels**  **were statistically**  **significantly reduced**  **in most**  **of the**  **fe males**  **(25%; p<** **0.05). No ef**  **fects were**  **observed in**  **the repeat**  **0.25 mg/m** **3 treatment**  **group. The**  **LOEL for**  **systemic toxicity**  **is 1.**  **25 mglm** **3 ,**  **based on**  **depressed brain**  **ChE activity**  **in females**  **. The**  **NOEL was**  **0.25 mglm** **3**

**• This**  **study is**  **acceptable and**  **satisfies the**  **guideline requirement**  **fo r a subchronic**  **inhalation study**  **(82- 4)**  **in rats** 
**.**
**b. Chronic**  **Toxicity/Carcinogenicity Chronic**  **Toxicity/Carcinogenicity Study**  **in Rats,**  **MRID 420**  **08 2-** **06. IPBC was**  **administered to**  **Sprague -Dawley**  **rats (50** **/sex/group) at**  **doses of**  **O, 20, 40,**  **and 80**  **mg/kg/day fo** **r two**  **yea rs.**  **There were**  **no statistically**  **signifi cant**  **incre ases**  **in tumor**  **inc idences**  **in males.**  **The incidence**  **of m**  **amm ary**  **gland fibroadenoma**  **and combined**  **fibroadeno ma/carc** **inoma in**  **fe males**  **was significantly**  **inc reased**  **at 20**  **mg/kg/day vs.**  **contro l**  **by pair**  **wise comparison**  **(p < O.**  **OI) ,**  **but there**  **was no dose-** **related trend.**  **Except at**  **20 mg/kg/day,**  **the incidence**  **of this tumor type**  **was within**  **historical control range**  **fo r**  **Sprague**
**- Dawley**  **ra ts.**  **Since the**  **mammary tumor incidence**  **at 80**  **mg/kg/day was**  **almost equal**  **to contr** **ol, the**  **Agency's (OPP)**  **Health Eff**  **ects Division**  **Carcinogenicity Peer**  **Review Commi** **ttee concluded**  **that the**  **m amm** **ary fibroadenomas**  **were not**  **related to**  **treatment with**  **IPB C.**  **At 80**  **mg/kg/day, body**  **weight gain**  **decrements of**  **20% and I5%**  **were observed in**  **males and**  **fe males,**  **respective ly,**  **during the**  **first 13**  **weeks of**  **the study. At study**  **termina**

**tion, body**  **weight gain**  **in males**  **at 80**  **mg /kg/day**  **was decreased**  **to 7I%**  **of contr**  **ol, and**  **in fe** **males, to**  **76% of**  **contr ol** 
**. Si** **gnificant changes**  **in serum**  **chemistry were**  **observed in**  **males at**  **80 mg/kg/day,**  **as were**  **significa nt**  **non-neoplastic changes**  **in the**  **stomach in**  **both sexes.**  **The non-neoplastic**  **changes in**  **the stomach**  **were consi** **dered the**  **result of**  **chronic irritat** **ion, and**  **were not**  **consi dered**  **indicative of**  **a neoplastic**  **response. The**  **systemic LEL**  **is 20**  **mglkglday, which**  **is the**  **lowest dose**  **tested, and**  **it is**  **based on decreased**  **body weight**  **gain in**  **male rats.**  **The 80**  **mg/kg/day dose**  **was consi** **dered adequate**  **fo r**  **testing of**  **carcino genic**  **potential of**  **IPBC, based**  **upon decreased**  **body weight**  **gain in male and fe** **male rats** 
**. This**  **study is**  **classified as**  **core minimum**  **data (guideline**  **83- 5).**  **Carcinogenicity Study**  **in Mice,**  **MRID 420**  **0 82-**  **02. CD-I**  **mice (50**  **mice/sex/do se)**  **were administered**  **IPBC in**  **the diet**  **at 0,**  **20, 50, and**  **I 50**  **mg/kg/day fo** **r 78**  **weeks. In**  **males, a**  **statistical ly**  **significant trend**  **was observed**  **fo r**  **hepato cellular**  **adenoma and**  **hepato cellular**  **adenoma/ carcinoma**  **combined (p<**  **O.OI). A**  **statistica lly**  **significant pair-wise**  **comparison was**  **also observed**  **fo r**  **the incidence**  **of hepat**  **ocellula r**  **adenoma and**  **adenoma/carcinoma combined**  **at I** **50 mg/kg/day**  **vs. contro**  **l (p<**  **0.05). At**  **I 50**  **mg/kg/day ,**  **the incidence**  **of hepato** **cellular adenoma**  **(24%) and**  **combined adenoma** **/carc inoma**  **(3 3%** **) exceeded the**  **historical control**  **range fo** **r CD-I**  **mice provided**  **by the**  **regist rant**  **(average benign**  **hepa tocellular**  **tumor incidence**  **II%, mal**  **ignant tumor**  **incidence 7%**  **). There**  **was no**  **increase in**  **hepato cellular**  **tumor incidence**  **in fe** **male mice.**  **There was**  **a significant**  **dose- related**  **posi tive**  **trend in**  **pulmonary carcinoma**  **fo r**  **fe males,**  **but no significant**  **pair-wise comparison**  **at any**  **dose level**  **tested in**  **this study.**  **Si nce**  **the fo** **rmation of**  **pulmonary carcinomas in**  **mice is**  **cons idered**  **part of a continuum**  **fr om**  **pulmonary adenomas, the** 

**Page 8**  **of 4I** **posi tive**  **trend in**  **carcinomas was**  **not considered**  **biologically signi** **ficant**

**. At**  **the highest**  **dose (150** 

**mg!kg/day) ,**  **body weight**  **gain in**  **males was**  **decreased to**  **73% of**  **control fo** **r weeks**  **0-13 of**  **the study**  **, and**  **to 77%**  **of control at study**  **termina tion.**  **In fe** **males, body**  **weight gain**  **fo r**  **weeks 0-1**  **3 at**  **the high**  **dose was**  **decreased to**  **70% of**  **contro l,**  **and to 80%**  **of control**  **at study**  **terminat ion.**  **No significant**  **ef**

**f ects**  **on fo** **od consumption**  **were observed**  **in this**  **study**

**. In**  **addi tion,**  **no statistically**  **signifi cant**  **ef**

**f ects**  **on survival**  **were seen**  **in this**  **study. The**  **systemic LEL**  **is 20**  **mglkglday, which**  **is the**  **lowest dose**  **tested, and**  **is based**  **on the**  **increased incidence of**  **non-neoplastic pathology**  **of the**  **thyroid in**  **both sexes**  **(atrophic vacuolation,**  **follicular coalescence,**  **and general**  **follicular enlargement).**  **This study**  **is classified**  **as core**  **minimum data (guideline**  **83- 2).** 

**c. Developmental**  **Toxicity Developmental**  **Toxicity Study**  **in Rats,**  **MRID 4099** **04-0 1,**  **Rat s**  **were dosed**  **by oral**  **administration of**  **IPBC at**  **0, 20,**  **50, and**  **12 5**  **mg/kg/day on**  **gestation days**  **six through**  **1 5**

**. Maternal**  **toxicity as reduced**  **body weight gain during**  **dosi ng**  **was observed**  **at 12**  **5 mg!kg/day. Developmental**  **toxicity consisted**  **of an**  **increased incidence of**  **skeletal abn** **ormalities at**  **125 mg/kg/day.**  **The maternal**  **toxicity NOEL**  **is 50**  **mg/kg/day, and**  **the maternal**  **toxicity LEL**  **is 125**  **mg/kg/day, based**  **on reduced**  **body weight**  **gain. The**  **developme ntal**  **toxicity NOEL**  **is 50**  **mg/kg/day, and**  **the developmental**  **toxicity LEL**  **is 1 2**  **5 mg/kg/day,**  **based on**  **in completely**  **ossi fied**  **frontal skull**  **bones and**  **pel vic**  **gir dles.**  **This study**  **is classified**  **as core**  **minimum data**  **(guideline 83-** **3). Developmental**  **Toxicity Study**  **in Rabbits,**  **MRID 424** **81 6-04.**  **This study was**  **conducted in**  **fe male**  **New Zealand**  **white rabb**  **it s,**  **which received**  **oral doses**  **of O,**  **2, 20,**  **and 50**  **mg!kg/day IPBC**  **on gestation**  **days 6**  **through 1 9** 

**. At**  **50 mg!kg/day,**  **maternal toxicity**  **in the**  **fo rm**  **of inc** **reased mortality**  **and abortion**  **was observed.**  **Although changes**  **in cesarean**  **section observations**  **were reported**  **at 50 mg/kg/day, these**  **changes are likely**  **a secon** **dary ef**  **f ect**  **of maternal**  **toxicity. The**  **maternal toxicity NOEL**  **is 20**  **mglkglday, and**  **the LEL**  **is 50**  **mglkglday, based**  **on increased**  **mortality, clinical signs,**  **and decreased**  **body weight**  **gain. The**  **developmental toxicity**  **NOEL is**  **50 mglkglday**  **which was**  **the highest**  **dose tested.**  **This study**  **is classified**  **as core**  **minimum data**  **(guideline 83-** **3). d.**  **Mutagenicity Ames**  **Test, MRID**  **41 975** **2- 06.**  **IPBC was tested**  **fo r**  **the ability**  **to cause**  **muta tions**  **in Salmonella**  **typhimurium strains**  **TA 1 5**  **35, TA**  **1 5 37,**  **TA 1 5**  **38, TA**  **98, and**  **TA 1 0** **0. IPBC**  **was fo** **und to be**  **non-mu tagenic**  **in all**  **five strains**  **with and**  **without metabolic activation at all**  **concentra tions**  **tested (1-10**  **00 ug/** 

**plate). Micronucleus**  **Assay in**  **Mice, MRID**  **4099 04-04.**  **IPBC at doses**  **of 200, 600, and 2000**  **mg/kg did**  **not induce**  **any signifi** **cant increase**  **of the**  **PCE containing**  **micron uclei**  **from the**  **treated mice when**  **compared to**  **that of**  **the vehicle**  **control mice.**  **Unscheduled DNA**  **Synthesis Assays,**  **MRID 4099**  **04-03. In**  **primary rat**  **hepa tocytes,**  **eight doses**  **of iP** **BC ranging**  **fr om**  **3 . 0 to**  **1 3 .5**  **ug/ml did**  **not cause**  **an ap**  **preciable increase**  **in mean**  **net**

**Page 9**  **of 41** **nuclear grain**  **counts. Doses**  **> 13.5**  **ug/ml were**  **cytotoxic, supporting**  **the conclusion that**  **IPBC**

**induced cytotoxicity but**  **not genotoxicity**  **in this**  **assay (guideline**  **84-2).**

**e. Metabolism**  **Rat Metabolism**  **Study, MRID**  **#4 09474-04.**  **Disposi tion**  **of C14 IPBC**  **was examined in**  **male and**  **fe male**  **rats at**  **single oral**  **doses of20**  **and 125**  **mglkg, at**  **20 mg/kg**  **x 14**  **days, and**  **as a**  **single intr** **avenous dose**  **of 0.5**  **mglkg. The**  **time course**  **of tissue**  **distribution, conducted**  **in 5**  **rats of**  **each sex**  **administered 7**  **daily doses**  **of20 mglkg/day** **, was**  **also perf**  **ormed. Se** **veral defici**  **encies were**  **noted in**  **the original**  **review of**  **this study** **, including**  **an inadequate**  **number of**  **rats per**  **dose group,**  **inadequate desi** **gn of**  **the repeat**  **dose study,**  **no jus** **tification fo** **r dose**  **levels used**  **in the**  **study, and**  **no identification**  **of ma** 

**jo r**  **metabo lites.**  **In another**  **rat metabolism**  **study (MRID**  **#43 5**  **707- 0**  **1) ,**  **IBPC was administered**  **orally in**  **0.5% carboxymet** **hylcellulose in**  **the fo** **ll owing**  **manner: Groups**  **of 5**  **male and**  **5 fe** **male rats**  **(groups A**  **and B)**  **received either**  **a si** **ngle oral**  **high dose**  **of radiolabelled**  **IPBC (1**  **25m glkg)**  **or a**  **repeated low**  **oral dose**  **of non-radiolabelled**  **IPBC fo** **llowed by**  **a single**  **radio -labeled**  **dose (20**  **mglkg). Se** **parate groups**  **of rats**  **(9/sex/group, groups**  **C and**  **D) received**  **single oral**  **doses (20**  **and 12**  **5 mg/kg)**  **of radio** **labelled IPBC,**  **and 3 rat** **s/sex were**  **sacrificed at**  **2, 4,**  **and 1 2**  **0 hours**  **post-dose fo** **r determ** **ination of**  **tissue distribution**  **of radioactivity** 
**. Urine**  **, fe** **ces and**  **expired air were collected**  **at 24**  **hour inter** **vals fo** **r groups A and**  **B, while**  **urine and fe** **ces were**  **col lected**  **from groups**  **C and**  **D. Absorption**  **of test**  **chemical at**  **the low**  **and high**  **dose was**  **between 80-90%**  **fo r**  **all dose**  **grou ps,**  **as suggested**  **by excretion data**  **showing the**  **ma jo** **rity of**  **a dose**  **eli minated**  **through urine**  **or exhaled**  **air. Excretion**  **of IPBC**  **-derived radioactivity**  **was mainly**  **via the**  **urine ,**  **with between**  **50-70% of**  **an administered**  **dose excreted**  **by this**  **route at**  **1 6 8**  **hours post-do** **se. Feces**  **was a**  **minor route**  **of excretion**  **in all**  **dose groups**  **( 4-7%**  **of the administered**  **dose), whil**  **e radio**  **labelled C02**  **cons tituted**  **between 1 8**  **-24% of**  **the administered**  **dose. Repeated**  **low oral**  **do sing**  **or a**  **single high**  **oral dose**  **ap**

**peared to**  **result in**  **a decrease**  **in the**  **percentage of**  **radioactivity excreted**  **as 14** **-C02 compared**  **to a**  **single low**  **dose (3**  **8 .22%**  **in MRID**  **# 409474**  **-04). Based**  **on the**  **meta**

**boli te**  **identification data,**  **a scheme**  **fo r**  **meta bolism**  **of IPBC**  **was propo** **sed. According**  **to this**  **scheme, IPBC**  **undergo es**  **reductive dehalogenation**  **fo llowed**  **by dealkylation**  **to fo** **rm the URM-9**  **and URM-**  **10 meta**  **boli tes.**  **In addition,**  **de-carboxylation fo**  **llowing reductive**  **dehalogenation yields**  **carbon dioxide.**  **Various other**  **metabolites fo** **rmed fr** **om dehaloge** **nation are**  **glucuronidated and**  **con stitute**  **minor metabo** **lites of**  **IPBC. This**  **study was**  **submitted in**  **order to**  **addre ss**  **defici encies**  **fr om**  **review of**  **a previous**  **meta bolism**  **study (MRID**  **# 4094** **7 4-04**  **). The**  **data provided**  **in this**  **study in**  **con ju** **nction with**  **MRID #409474-04,**  **satisfy the**  **data requirement**  **fo r a**  **meta bolism**  **study in**  **rats under Subdivision**  **F guideline**  **85 -1.**  **f. Reproductive**  **Toxicity Two** **-G eneration**  **Reproductive Toxicity**  **Study in**  **Rats, MRID**  **4099 04-02.**  **This study**  **was conducted**  **in rats**  **where IPBC**  **was administered**  **over two**  **generations at**  **doses ofO**  **, 6,**  **1 5 ,**  **and 37.5**  **mglkg/day**
**. Reduced**  **body weight**  **and fo** **od consumption**  **was observed**  **fo r P**  **and F**  **ma les** 

**Page 10**  **of 41** **during the**  **premating period**  **at 37.5**  **mg/kg/day. A**  **decreased mean**  **live birth index**  **was reported** 

**fo r P**  **and F**  **generations without**  **an ef**  **fe ct**  **on viabil**  **ity and**  **development of**  **pups .**  **No adverse**  **ef fects**  **on reproductive**  **indices or**  **mating perf**  **ormance were**  **observed at**  **any dose**  **level. The**  **parental toxicity**  **NOEL is**  **15 mglkglday,**  **and the**  **parental toxicity**  **LEL is**  **37 .5**  **mglkglday, based**  **on decreased body**  **weight and**  **food consu**  **mption during**  **premating for P**  **and F**  **males, and**  **decreased mean**  **live birth**  **index for**  **the P**  **and F generations.**  **The reproductive**  **toxicity NOEL**  **is 37** **.5 mglkglday**  **which was**  **the highest**  **dose tested.**  **This study**  **is classified**  **as core**  **minimum data**  **(guideline 83-** **4 ). Two-** **Generation Reproductive**  **Toxicity Study**  **in Rats,**  **MRID 44** **4788 -0**  **1. Omacide** **® (>97%**  **IPBC) was**  **administered to**  **groups of**  **25 male**  **and 25**  **fe male**  **rats by**  **gavage at**  **doses of**  **0, 10**  **, 30,**  **or 1 0** **0 mg/kg/day**  **fo r two**  **generati ons.**  **Cli nical**  **signs of**  **toxicity observed**  **in the**  **mid- and**  **high dose**  **levels included**  **salivation, paddling**  **with both**  **fo repa** **ws, and**  **hunched posture.**  **No treatment-** **related gro**  **ss findings**  **were observed**  **at necr** **opsy of**  **the Fo**  **or F1**  **fe males.**  **Microscopic examination**  **of the**  **Fo adults was**  **unremarka ble.**  **In the**  **F1 adult** **s, diffuse**  **acan thosis**  **with hyperkerato** **sis was**  **observed in**  **the stomach**  **of 1 0** **/10 males**  **and 7/**  **10 fe** **males fr** **om the**  **30 mg/kg/day**  **grou**

**ps. Therefore,**  **the LOAEL**  **for systemic**  **toxicity is**  **30 mglkglday**  **based on**  **clinical signs**  **of toxicity**  **in the**  **Fo and**  **Ft males and**  **females and**  **on microscopic**  **lesions in**  **the stomach**  **ofFt males**  **and females.**  **The systemic**  **toxicity NOAEL**  **is 10**  **mglkglday. Fertility**  **indic es**  **fo r**  **the 1 0** **0 mg/kg/day**  **Fo males**  **and fe** **males were**  **significantly (p::;**  **0.05) less**  **than the**  **contro ls.**  **No treatment-related ef**  **f ects**  **were observed**  **on copulation**  **or fe** **rtility of**  **the F1**  **rats**
**. The**  **live bi** **rth indic**  **es fo** **r the**  **F 1 litters**  **in the**  **0, 1 0**  **, 30,**  **and 1 0** **0 mg/kg/day**  **groups were**  **98%, 98%,**  **90%, and**  **80% (p::;**  **0.0 01)** 
**. The**  **live bi** **rth index was**  **�98% fo** **r all groups**  **of F2**  **litters. For**  **the F1**  **pups, the**  **viabili ty**  **indi ces**  **on lactation**  **day 4**  **(precul l)**  **were 92%, 96%, 72% (p::; 0.0**  **1 ) ,**  **and 30%**  **(p::; 0.00**  **1) ,**  **respectively, and the cumulative survival**  **indices were 88%** **, 94%,**  **67% (p::;**  **0.0 1 )**  **, and**  **28% (p::;**  **0.0 01)**  **, respecti** **vely. For**  **the F2**  **pups in**  **the 0,**  **10 ,**  **and 30**  **mg/kg/day groups**  **the viability**  **indic es**  **on lactation**  **day 4**  **(pre cull)**  **were 92%,**  **97%, and**  **87%, respecti** **vely, and**  **the cumulative**  **survival ind** **ices were**  **85% ,**  **93% ,**  **and 83%** **, respectively.**  **Whole litter**  **losses occurred**  **fo r**  **three mid-dose**  **and six hig**  **h-dose Fo**  **fe males**  **and fo** **r two mid-dose F1**  **fe males.**  **Cl inical**  **signs of**  **toxicity in**  **the pups**  **assoc iated**  **with who**  **le litter**  **losses were**  **indicative of**  **lack of**  **maternal care**  **. Body**  **weights of**  **the 1 0** **0 mg/kg/day**  **F1 male pups were significantly**  **(79-86% of**  **contro ls)**  **less than the**  **contro ls**  **beginning on**  **lactation day**  **4 (prec** **ull) and**  **continuing throughout**  **lacta tion.**  **Body weights**  **of the**  **1 0 0**  **mg/kg/day F1**  **fe male**  **pups were significantly**  **(8 1**  **-93% of**  **contro ls)**  **less than**  **the contro**  **ls throughout**  **lactati on.**  **Body weight**  **gains by**  **the 1 0** **0 mg lkg/day**  **F1 male**  **and fe** **male pups**  **were 79%**  **and 82%,**  **respective ly, of**  **the control**  **level during**  **lactation days**  **0- 14**  **and were**  **93 %**  **and 91%**  **, respectively,**  **fo r**  **lactation days**  **14**
**- 21.**  **Body weights**  **of the**  **30 mg/kg/day**  **male and**  **fe male F 1**  **pups during**  **lactation were**  **slightly but**  **non-significantly lower**  **than the**  **contro ls.**  **No statistical**  **dif ferences**  **in body**  **weights of**  **the F2**  **male pups**  **were observed**  **between the**  **treated and**  **control groups**  **at any**  **time during**  **lactat ion.**  **F2 fe** **male pups**  **in the**  **30 mg/kg/day**  **group had significantly**  **lower body**  **weights than**  **the contro** **ls on**  **lactation days**  **14 (9**  **3% of**  **contro ls)**  **and 21**  **(9 1%**  **of contro**  **l). Body**  **weight gains by**  **the 30**  **mg/kg/ F2**  **fe male**  **pups fo** **r lactation**  **days 0-**  **14 and**  **1 4 -2**  **1 were 92% and 87%,**  **respecti vely,**  **of the**  **control level.**  **Pup body**  **weights in**  **the low-dose**  **group were similar**  **to the**  **contro ls**  **in both**  **generati ons.**  **Because dosing** 
**Page 11**  **of 41** **of the**  **pups did**  **not begin until**  **after wean** **ing at**  **25 days**  **of age,**  **the only**  **exposure of**  **the pups**  **to**

**the test ar** **ticle was**  **through the milk.**  **Treatment with**  **the test**  **ar ticle**  **resulted in**  **developm ental**  **delays of**  **the of**  **f spring**  **including a**  **si gnificantly**  **(p $;**  **0. 01)**  **greater anogenital**  **distance in the**  **30 mg/kg/day**  **F2 fe** **males as**  **compared to**  **the contro** **ls (1.1**  **mm vs**  **1 . 0**  **mm ),**  **delayed eye opening**  **fo r**  **the 10** **0 mg/kg/day**  **F1 pups (79%**  **vs 85%**  **of the**  **contro ls on**  **day 1 5**  **) and fo** **r the**  **30 mg/kg/day**  **F2 pups**  **(85% vs**  **97% of**  **the controls**  **on day**  **1 5 ).**  **Therefore, the**  **LOAEL for**  **reproductive toxicity**  **is 30**  **mglkg/day based**  **on reduced**  **pup survival,**  **lower pup**  **body weights,**  **and developmental**  **delays during**  **lactation. The**  **reproductive toxicity**  **NOAEL is**  **10 mglkglday.**  **This study is classified**  **as Acceptable**  **(guideline) and**  **satisfies the**  **guideline requirement**  **fo r a**  **repr oduction**  **study (OPPTS**  **870.3 800;**  **1l0 CFR**  **§83- 4)**  **in rats** 
**. g.**  **Neurotoxicity Acute**  **Neurotoxicity Study**  **(MRID 455094**  **-01). Rats**  **were given a**  **single gavage**  **oral dose of**  **IPBC at**  **doses of**  **0, 1 0**  **0, 30** **0, or**  **1 0 00**  **mg/kg/day and**  **observed twice**  **daily fo** **r 15**  **days. Contro**  **l and**  **treatment groups**  **were divided**  **into the**  **fo llowing**  **3 sets**  **fo r**  **neuro behavioral**  **asses sment**  **and ChE**  **activity evaluations:** 

**• Set**  **1 ( 1**  **2/sex/group) was**  **evaluated fo** **r FOB**  **(functional obs** **erva tional**  **batt ery),**  **MA (motor**  **activity), and**  **blood, plasma**  **and brain**  **ChE at**  **pretest and**  **on Day**  **1.**
**• Set**  **2 (12** **/ sex/group)**  **was evaluated**  **fo r**  **FOB, MA,**  **blood, plasma ChE at**  **pret est,**  **Days 1,**  **8; and**  **1 5 ,**  **and brain**  **ChE on Day**  **15.**
**• Set**  **3 (6/sex/group)**  **was evaluated**  **fo r**  **neuropa thology**  **on Day 15**  **at study**  **terminati on,**  **these animals were**  **euthanized and**  **perfused in**  **situ fo** **r neuropatho** **logical exami** **nati on.**  **A stati**  **stically significa** **nt decreased**  **mean body**  **weight gain**  **was observed for**  **males at**  **30 0**  **and 1 0** **00 mg!kg/day** 

**. In**  **the fe** **males, body**  **weight and**  **body weight**  **gain showed**  **no change**  **at any**  **dose level.**  **FOB obs** **ervations (Incidences)**  **included a**  **statistica lly**  **significa nt**  **lower number**  **of rears**  **in fe** **males treated**  **at 1 ,**  **000 mg/kg/** **day. This ef**  **f ect**  **was not seen**  **in males.**  **A dose**  **relationship was**  **seen on**  **Day 1 (Se** **ts 1 and**  **2) and**  **Day 8 (Set 2).**  **Low Locomotor**  **(Open field)**  **activity was**  **seen at**  **1 0 00**  **mg/kg/day on Day**  **1 in Sets**  **1 and**  **2 in both**  **sexes. This**  **effect was still**  **evident to**  **a lesser**  **degree in**  **both sexes**  **on day**  **8. The**  **number of** **app roaches**  **(open field)**  **showed a**  **dose related**  **decrease in**  **sets 1**  **and 2 in**  **males which**  **was stati** **stically significa** **nt at**  **1 0 00**  **mg/kg/day. In**  **fe males**  **decreases were**  **noted at**  **10 00**  **mg/kg/day but**  **they were**  **not stati** **stically significa** **nt. Rats**  **of both**  **sexes in**  **all treatment**  **groups had**  **an overall**  **lower incidence**  **of motor activity**  **than their**  **control counterparts**  **. Females**  **treated with**  **300 and**  **1 , 000**  **mg/kg had**  **decreased plasma**  **ChE activity**  **on Days**  **8 and**  **15. No**  **si gnificant**  **changes were**  **observed in**  **erythro cyte**  **and brain**  **ChE activity**  **in both**  **sexes. Macroscopic**  **evalua tion**  **revealed no**  **evidence of**  **lesion fo** **rmati on**  **due to**  **treatment.**

**Page 12**  **of 41** **Based on**  **the effects**  **seen in**  **this study,**  **the LOAEL**  **was 1 0**  **0 mglkg**  **bw (LDT)**  **based on** 

**changes in**  **motor activity.**  **A NOAEL**  **could not**  **be determined.**  **This study**  **is classified**  **as Acceptable**  **(Nonguideline) and**  **does not**  **satisfy the**  **guideline requirement**  **fo r**  **an acute**  **neur otoxicity**  **study in**  **rats (870.6200;**  **OECD 424)**  **due to**  **incomplete evaluations**  **of neuropatho** **logy (lack**  **of histopatho** **logy of**  **nervous system tissue**  **and brain**  **weigh ts).**  **It should**  **be noted;**  **however, that**  **no changes**  **were seen**  **in a**  **companion subchronic**  **neurotoxicity study**  **MRID 455**  **094-02. Subchronic**  **Neurotoxicity Study**  **(MRID 455**  **094 02** **) IPBC**  **was administered**  **to rats**  **at dose**  **levels of**  **O, 1 0**  **, 50,**  **or 12**  **0 mg/kg/day**  **fo r**  **13 weeks.**  **Con tro**  **l and**  **treatment groups**  **were divided**  **into 4**  **sets fo** **i: neurobehavioral**  **assessm ent**  **(FOB, MA),**  **ChE act** **ivity ,**  **and neuropatho logy**  **evalua tions.**  **Neuro behavioral**  **asses sment**  **was performed**  **in animal**  **s (1**  **2/sex/ dose)**  **before the**  **initiat ion**  **of the study**  **and at**  **Weeks 4, 8,**  **and 13.**  **ChE activity**  **was determined**  **by a**  **spectrophotometeric assay**  **in plasma**  **and erythro** **cytes prestudy**  **and at**  **Weeks 4,**  **8, and 13,**  **and in 3**  **regions of**  **the brain during**  **Weeks 4,**  **8, and**  **1 7**

**. At**  **study termination**  **(week 1 3**  **) and at**  **recovery (week**  **1 7 ),**  **6/sex/dose were**  **euthanized and**  **perfused fo** **r neuropatho** **logical examinat** **ion. There were**  **no treatm** **ent-related ef**  **fects on**  **mortal it** **y, clinical**  **signs, neurobehavioral**  **activity, and**  **erythro cyte**  **and brain ChE activ** **i ty.**  **Treatment-related eff**  **ects included**  **lower mean**  **body weight/**  **body weight**  **gain and**  **decreased fo** **od consumption**  **at 50-**  **and 1 2** **0 -mg/kg/**  **day. Decreased**  **fo od**  **efficiency at 12**  **0 mg/kg/day**  **correlated with**  **the decrease**  **in fo** **od consumption,**  **contribu ting**  **to the**  **lower body**  **weights of**  **treated animal**  **s. Plasma**  **ChE inhibition**  **was observed**  **at 50** 
**- and**  **12 0** **-mg/kg/day in**  **fe males**  **only. Erythro** **cyte and**  **brain ChE**  **activity was not**  **affected in**  **either sex**  **at any**  **dose or**  **time point.**  **Macro scopic**  **examination indicated**  **tha t**  **the cervical**  **and lumbar dorsal**  **root ganglion**  **might be**  **potential target**  **tissues of**  **the test**  **ar**

**ticle. Microscopic**  **examina tion**  **reported neuronal**  **vacuolation, satellite**  **cell hypertrophy/** **hyper plasia,**  **and neuronal degeneration**  **in these tissues; however, these**  **ef f**  **ects were**  **determined not to**  **be treatment-** **related. No other**  **gross, histo-pat** **hological, or**  **neuro -path** **ological ef**  **fects were observed. All**  **the noted**  **ef f**  **ects in**  **body weight,**  **fo od**  **consumption, fo** **od ef**  **ficiency, and**  **plasma ChE**  **activity were reversed**  **during the**  **recovery period,**  **indicating that the**  **ef f**  **ects of**  **the test**  **art icle**  **were not permanent.**  **No frank**  **neurotoxicity was observed.**  **Based on**  **the effects**  **seen in**  **this study,**  **the LOAEL**  **is 50**  **mglkg/day (based**  **on body**  **weight, food**  **consumption, and**  **ChE activity**  **data), with**  **a NOAEL**  **of 10**  **mglkg!day. The study**  **is classified as**  **Acceptable-Guideline and**  **sa tisfies**  **the guideline**  **requirement fo** **r a subchronic**  **neur otoxicity**  **study in**  **rats (870.6** **200).**

**3.3 Toxicology**  **Endpoints The**  **most recent**  **hazard asses** **sment fo** **r IPBC**  **is included**  **in D3**  **54908 (EPA,**  **2009) which**  **was prepared**  **to evaluate**  **a proposed**  **new use of iPBC**  **on leather.**  **This asse** **ssment included**  **a selection**  **of endpoints to**  **be used**  **fo r**  **risk assessment;**  **however, these endpoints**  **will need**  **to be** 

**Page 13**  **of 41** **reevaluated duri** **ng regi** **stra tion**  **review because**  **additional toxicology studi** **es have**  **subsequently become**  **ava ilable.** 

**4. 0**  **DIETARY ASS** **ES SMENT**  **Dietary Exposure**  **There is**  **conflic ting**  **inf**

**ormati on**  **regarding the**  **use of**  **IPBC fo** **r fo** **od contact**  **surf ac** **es. IPBC**  **does not**  **have any FDA**  **approval s**  **fo r**  **fo od**  **contact uses**  **and most**  **the labels restrict**  **uses in**  **adhesive, paper and**  **paper board products and paper coating**  **to non-f**  **ood ap**  **plicati ons.**  **The labels**  **also have**  **simila r**  **statements fo** **r plastics**  **and surf**  **ac e**  **cleaners that**  **limit the**  **use to**  **non-f ood**  **are as.**  **There are several**  **labels such**  **as #12**  **58-1 230,**  **#1 529-5**  **1, #6707**  **1 -44,**  **however, that**  **allow use in**  **dish detergent,**  **which is**  **considered to**  **be a**  **fo od**  **contact surf**  **ac e.**  **If it**  **is dete** **rmined that**  **the regi** **strants intend**  **to support**  **the dish**  **detergent use,**  **then dietary**  **exposures from**  **this use**  **will need**  **to be**  **assessed during**  **regi stration**  **review. Drinking**  **Water Exposure**  **There is**  **a potential**  **fo r**  **drinking water**  **exposure from**  **the material**  **preservative uses.**  **The Agency**  **expects that**  **the environmental**  **fa te**  **data that are**  **being required**  **will be**  **useful to**  **evaluate this**  **potential**

**. Theref** 

**ore, the**  **need fo** **r a drin** **king water**  **asse ssment**  **will be**  **determined after**  **the environmental**  **fa te**  **data are**  **received and**  **reviewed.**

**5. 0**  **OCCUPA TIONAL/RESIDENTIAL**  **EXPOSURE Occupati** **onal Exposures**  **Assessed in**  **the RED Occupa** **tional handler**  **exposures were assessed**  **in the**  **RED fo** **r the**  **mixing and**  **loading fo** **r the**  **fo llowing**  **uses: general**  **preserva tives,**  **the metal working**  **fluids, oil**  **produ ction**  **and pulp and paper.**  **The MOEs**  **were calcula**  **ted fo** **r "total**  **exposures" based**  **on the**  **addition of the dermal and**  **inhalation exposures**  **and were**  **assessed using**  **the dermal**  **endpoint of**  **200 mg/kg/day**  **fo r**  **short/inter**

**mediate term**  **exposures and**  **the oral**  **endpoint of**  **20 mg/kg/day**  **fo r long term**  **exposures (in**  **con ju** **nction with**  **a dermal**  **absorption fa**  **ctor of**  **10 percen** 

**t). All**  **of the**  **MOEs exceeded**  **the target MOE of**  **1 0 0**  **and were**  **not conside** **red to**  **be of**  **concern. Occupational**  **handler risks**  **were also**  **assessed fo** **r the**  **app li** **cation of paints**  **or stains**  **using brushes**  **or air**  **less sprayers**  **and one**  **of these**  **MOEs (airless**  **sprayer ap**  **plication of**  **wood preserving**  **sta in,**  **MOE =**  **71) was of**  **concern. Based**  **on these**  **asses sments,**  **the RED**  **required that products intended prima**  **rily fo** **r occu** 

**pational use**  **specify that**  **app lica** **tors and**  **other handlers must**  **wear long-sleeve**  **short and**  **long pants, chemical**  **resi stant**  **gloves and**  **shoe plus socks.**  **The RED did**  **not require**  **respi ratory**  **protec tion.**  **Occupati onal**  **Exposures That**  **Need to**  **be Assessed**  **Occupa tional**  **exposures were**  **not assessed**  **in the**  **RED fo** **r the**  **handlers app** **lying wood**  **preserva tives**  **to lumber using**  **the dip**  **or spray**  **treatment, ha**  **ndlers ap**  **plying HVAC**  **coatings and** 

**Page 14**  **of 41** **machinists using**  **IPBC preserved metal working fluids. In addition, the inhalation**  **exposures for** 

**all of**  **the scenari** **os were**  **not assessed**  **separat ely,**  **nor were**  **they compared**  **to an inhalation**  **specific endpoint.**  **Given these**  **deficiencies, it**  **will be**  **necessary to**  **reassess all**  **of the**  **exposure scenari** **os duri** **ng regis** **tra tion**  **review. In**  **many cases,**  **Series 875**  **indoor exposure studies will be**  **needed to**  **generate the**  **exposure data**  **that will be**  **needed to**  **conduct these**  **assessments. These**  **studies are listed**  **in Table**  **6 of**  **Section 1 0** 
**. Residential**  **Exposures Assessed**  **in the**  **RED Residential**  **handler exposures**  **were assessed**  **in the**  **RED fo** **r home**  **owner app** **lication of paints**  **and stains containing**  **IPBC using**  **brushes and**  **rollers. The**  **MOEs were**  **calcula ted**  **as discussed**  **ab ove**  **fo r**  **occupational exposures**  **and they**  **exceeded the**  **ta rget**  **MOE of**  **1 0 0**  **and were**  **not considered**  **to be**  **of concern.**  **Based on**  **these asses** **sments the**  **RED did not require**  **any label**  **changes. No other**  **residential exposures**  **were assessed.**  **Residential Exposures**  **That Need**  **to be**  **Assessed As is**  **the case**  **fo r**  **occupational app** **licators, the**  **inhalati on**  **exposures fo** **r resi** **dential app** **licators of**  **paints or**  **stains containing**  **IPBC will**  **need to**  **be re-a** **ssessed separa** **tely using**  **an inhalation**  **specific endpoint. It**  **will also**  **be necessary**  **to assess**  **incidental oral**  **exposures to**  **household items**  **and toys**  **made of plastics**  **preserved with**  **IPBC, incidental**  **oral and**  **dermal exposures**  **to floors**  **cleaned with**  **IPBC treated**  **household cleaners**  **and incidental**  **oral and**  **dermal exposures**  **to textile**  **and leather**  **products treated**  **with IPBC.**  **Although the**  **RED stated**  **that exposure**  **data was**  **needed fo** **r assessing**  **inhalati on**  **exposures fo** **llow ing**  **the ap** 

**plication of**  **HV AC**  **coatings, it**  **has been**  **subsequently determi**  **ned that**  **these exposures**  **do not**  **need to**  **be assessed**  **during regis** **trati on**  **review. This**  **is because**  **IPBC is**  **of very**  **low volatility**  **( <1.8**  **x 1 o-6**  **mm hg**  

### @ **20 C) which**  **precludes the**  **release of**  **IPBC as**  **a vapor,**  **and the**  **coating dries**  **to a**  **flexible matrix**  **that does not**  **release parti** **culates A**  **li sting**  **of the**  **exposure studies that**  **will be**  **needed fo** **r registra**  **tion review is included**  **in Table**  **6 of Section**  **1 0**
**.**
**6. 0**  **AGGREGATE AND**  **CUMU LATIVE**  **EX POSU** **RE In**  **examining aggrega** 

**te exposure,**  **EPA takes into**  **account the**  **avai lable**  **and reliable**  **inf ormation**  **concerning exposures**  **to pesticide**  **residues in**  **fo od**  **and drinking**  **water, as**  **well as**  **non-o ccupational**  **(i.e. residential)**  **pesticide exposures.**  **An aggregate**  **risk asse** **ssment may**  **be needed**  **fo r**  **IPBC if it**  **is determined**  **that a**  **drinking water**  **exposure could**  **occur based**  **on the**  **environmental fate**  **data. This**  **assess ment**  **might also**  **need to include**  **dietary exposures**  **fr om**  **the dishwashing**  **detergent use**  **and residential**  **exposures fr** **om the wood**  **treat ment,**  **floor clea** **ners ,**  **plastics, paints,**  **leathers and**  **textile uses.**  **Section 408(** **b)(2)(D)(v) of**  **F FDCA**  **requires that,**  **when considering**  **whether to**  **esta blish,**  **modify, or**  **revoke a**  **tolerance, the Agency consider**  **"avai lable inf**  **orm ati** **on" concerning**  **the**

**Page 15**  **of 41** **cumulative ef**  **f ects**  **of a**  **part icular**  **pesticide's residues**  **and "other**  **substa nces**  **that have a common**  **mechani sm of**  **toxicity." IPBC**  **(3-Iodo-2- propynyl**  **butyl carbamate)**  **is an iodo-carbamate.**  **Iodo-carbamates are**  **not part**  **of theN-methyl carbamate (NMC)**  **class of**  **pesticides and**  **should not**  **be included**  **as part**  **of the**  **NMC cumulative**  **risk assessment**  **as supported**  **by the**  **SAP (2004).** 

**7.0 INCIDE** **NTS In**  **addition to**  **the incidents**  **that occurred**  **prior to**  **1 9 97**  **that were**  **reported in**  **the RED,**  **23 incidents**  **have been**  **reported since**  **1 9 97.**  **A listing**  **of these**  **incidents sorted**  **by product**  **number is**  **given in**  **Table 5.** 
**Table 5**  **-I ncidents**  **Reported for**  **IPBC (1998-Present)**  **Pr oduct**  **Type Number of**  **Years Incident**  **Type Incidents**  **Material Preservative**  **2 199**  **8- 1999**  **Worker exposure**  **during use**  **in manufacturing**  **Material Preservative**  **1 19**  **98 Worker**  **exposure during**  **use in**  **manufacturing Waterproofing**  **Wood Stain**  **11 20**  **0 2 - 2** **004 Consumer**  **exposure during**  **and after**  **applicati on**  **. Surface**  **Disinfectant Used**  **1 20**  **00 Alleged**  **consumer exposure**  **from drift.**  **with Bleach**  **Waterproofing Wood**  **Stain 1**  **20 12**  **Sapstain treatment**  **plant workers**  **applying product**  **to fresh**  **cut lumber.**  **HV AC**  **Coating 7**  **20 0 1** 
**- 20**  **12 Consumer exposures**  **following application**  **to HV**  **AC systems.**  **Both local**  **skin irritation**  **and systemic**  **effects were reported**  **in these**  **incidents. Skin**  **irritat ion**  **and skin**  **sensitizat ion-like**  **symptoms are the primary**  **eff ects**  **that have**  **been reporte** **d, and**  **these ef**  **f ects**  **include rash, swelling,**  **itching, burning**  **and/or tingling**  **sensation, bli**  **ster, erythema/fl** **ushing, and**  **hives. In**  **some cases,**  **chest tight**  **ness and**  **resp iratory**  **problems were repor**  **ted. Other**  **reported systemic**  **ef f**  **ects include**  **nausea/v omit,**  **headache, fa**  **tigue, ver** 

**tigo, and**  **fe ver.**  **There are**  **also reports of skin sensitization**  **in the**  **literat ure**  **. The**  **most recent**  **of these**  **is a**  **report by**  **the North**  **American American Contact**  **Derma titis**  **Group of**  **the results**  **of IPBC**  **patch testing**  **(Warshaw, 201**  **0). This**  **testing was**  **done on**  **25,3 21**  **patients between**  **19 98**  **and 2008**  **using 0.1**  **or 0.5**  **percent IPBC**  **in petrolatum** 

**. There**  **were 226**  **weak reactors**  **and 67**  **strong reacto**  **rs. The**  **ma**

**jo rity**  **of the**  **reactions were**  **to personal**  **care products**  **and most**  **reacti ons**  **were not**  **related to**  **occupa**

**ti on.**  **Only fo** **ur of**  **the strong**  **reactors had**  **definite clin** **ical relevance**  **with a**  **positive use-test**  **reacti on**  **or positive patch-test**  **reaction to**  **a product**  **containing IPBC.**  **The fr** **equency of**  **positive reactions**  **increased fr** **om 0.2 percent**  **to 1 .**  **5 percent**  **when the**  **higher concen**  **tra tion**  **of iPBC**  **was utilized,**  **but most were weak reactions**  **of which**  **some were**  **likely irritant.**  **Based on**  **a prelimin** **ary review**  **of the**  **incident reports**  **, it**  **appears that**  **the ma**  **jo rity**  **of ef** 

**f ects**  **that can**  **be at** **tributed to**  **IPBC are**  **due to**  **dermal exposure**  **during tasks**  **such as**  **paint or stain** 

**Page 16**  **of 41** **app lication**  **when gloves are**  **not used.**  **Although there are several**  **incidents that**  **allege various** 

**ef f**  **ects due**  **to inhala** 

**tion exposure**  **fo llowing**  **the app** **lication of**  **HV AC**  **coa ting,**  **it is**  **not likely**  **that IPBC**  **is the**  **cause of**  **these ef**  **f ects**  **because IPBC**  **is of low**  **volatility and**  **the coating**  **dries to**  **a flexible**  **matr ix.**  **8. 0**  **TOLERANCES There**  **are no**  **tolerances or**  **exemptions from**  **tole ranc** **es fo** **r IPBC.**  **As mentioned**  **in Section**  **4.0, IPBC**  **is not**  **app**

**roved fo** **r use**  **as an**  **indirect fo**  **od additive.**  **9.0 ENDOCRINE**  **DISRUPTION EF** **FEC TS**  **As required**  **under FFDCA**  **section 408(p** **), EPA**  **has developed**  **the Endocrine**  **Di sruptor**  **Screening Program**  **(EDSP) to**  **determine whether**  **certain substanc** **es (including**  **pesticide active**  **and other**  **ingredients) may**  **have an**  **ef f**  **ect in**  **humans or**  **wildlif e**  **simila r**  **to an**  **ef**

**f ect**  **produced by**  **a "natu** **rally occurr** **ing estrogen,**  **or other**  **such endocrine**  **eff ects**  **as the Adminis** **trator may**  **designa te."**  **The EDSP**  **employs a**  **two -tiered**  **ap proach to**  **making the**  **statu torily**  **required determina** 

**tions. Tier 1**  **consists of**  **a battery**  **of 11**  **screening assays**  **to identify**  **the potential**  **of a**  **chemical substance**  **to interact**  **with the**  **estro gen,**  **andr ogen,**  **or thyroid (E,**  **A, or T)**  **hormonal system**  **s. Chemicals**  **that go**  **through Tier 1**  **screening and**  **are fo** **und 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**  **ava ilable**  **data. Tier 2**  **testing is**  **designed to**  **identify any**  **adverse endocrine**  **related ef**  **f ects**  **caused by**  **the substance,**  **and esta** **blish a**  **dose-response relati** **onship between**  **the dose**  **and the**  **E, A,**  **or T ef**  **f ect.**  **Between October**  **2009 and**  **Feb ruary**  **20 1 0**  **, EPA**  **issued test**  **orders/data call-ins**  **fo r**  **the first**  **group of**  **67 chemicals,**  **which contains 58**  **pesticide active**  **ingredients and**  **9 inert**  **ingredients**

**. IPBC**  **is not among**  **this group**  **of chemicals.**  **This list**  **of chemicals**  **was selected**  **based on**  **the potential**  **fo r**  **human exposure**  **through pathways such**  **as fo** **od and water,**  **residential act** **ivity, and**  **certain post-a** 

**pp lication**  **agricultural scenari** **os. This**  **list should**  **not be construed**  **as a list**  **of known**  **or likely**  **endocrine disr**  **upt ors.**  **For further**  **inf**

**ormati on on**  **the status**  **of the**  **EDSP, the**  **policies and**  **procedur es,**  **the list**  **of 67**  **chemical s,**  **the test**  **guidelines and**  **the Tier 1**  **screening battery,**  **please visit**  **our website:**  **http:// www** **.epa.gov /endo/.**  **Endocrine related**  **ef**

**f ects**  **were observed**  **fo r**  **IPBC in**  **some of the**  **available toxicity**  **stu dies.**  **For exam** **ple, in**  **the carcinogenici** **ty study**  **(MRID 420082-02),**  **thyroid gland**  **at rophic**  **vacuola tion,**  **fo lli** **cular coalescence,**  **and general fo**  **llicular enlargement were noticed**  **in both**  **sexes. In**  **the rat**  **reproduc tive**  **study, the**  **F2 fe** **males had**  **a greater**  **anogenital distance**  **as compared**  **to the contro ls.** 

**Page 17**  **of 41** **1 0 .0**  **AN TICIPATED**  **DATA NEEDS** 

**1 0 .1**  **Toxicology Studies**  **1. Com**  **parative Cholin** **esterase As**  **sa y**  **with Thy** 

**roid Measurements**  **Toxicity stu** **dies with**  **IPBC suggest**  **it is**  **an acetyl**  **cholinesterase (AChE) inhibitor.**  **AChE inhibition**  **is observed**  **in toxicity**  **stu dies**  **of dif**  **fe rent**  **routes of**  **admini stra**  **tion from**  **the acute**  **oral neur** **otoxicity study**  **(MRID 455**  **094-0 1 )**  **, subchron** **ic inhalation**  **study (MRID**  **435 302-03),**  **subchronic dermal**  **toxicity study**  **(MRID 42**  **1 682-0**  **1) ,**  **and subchr** **onic oral**  **neurotoxicity study**  **(MRID 455**  **094-02). These**  **various toxic** **ity studies**  **support the finding**  **that IPBC**  **inhibits AChE.**  **According to the**  **stu dies**  **submitted to the**  **agency for**  **the n-methyl**  **carbama tes**  **(N MCs),**  **the Compa**  **rati ve**  **Cholin esterase**  **Assay (CCA)**  **study results have**  **shown ju** **veniles to**  **be more**  **sensitive to**  **AChE inhibition**  **than adult**  **s. Theref**  **ore, a**  **CCA, which**  **includes both**  **adult and**  **PN D 1**  **1 ju** **venile rat** **s is**  **needed, to**  **addre ss**  **potential lif**  **e stage**  **sensitivity. In**  **addi tion,**  **the existing**  **datab ase**  **fo r**  **IPBC does**  **not addre** **ss the**  **time to**  **peak ACHE**  **inhibition, which**  **might under**  **predict the**  **true AChE**  **inhibition. Theref**  **ore, the**  **CCA study**  **fo r**  **IPBC should**  **include suf**  **ficient measurements**  **so that the**  **time to**  **peak inhibition**  **can be**  **dete rmined.**  **Current toxicity**  **studies have**  **also demonst**  **rated that**  **IPBC aff** 

**ects the**  **thyr**

**oid. In**  **the chroni** **c mouse**  **stu dy,**  **IPBC increased**  **the incidence**  **of non-neoplastic**  **pat hology**  **of the**  **thyroid in**  **both sexes**  **(at rophic**  **vacuola ti** **on, fo** **llic ular**  **coalescence, and general**  **fo llic** **ular enlargemen**  **t)**

**. Furtherm** **ore, iodine**  **uptake in**  **the developing**  **fe tus**  **is a**  **critical developm** **ental lif**  **e sta** **ge. Theref**  **ore, the**  **Agency requires**  **comparative thyro** **id measurements**  **in the**  **pregnant fe** **males and**  **the developing**  **fe tus**  **to determine**  **potential suscept ibility.**  **The AChE**  **and thyroid**  **measurements may**  **be sampled**  **fr om**  **the same**  **sets of**  **animal s**  **in the CCA**  **study: The thyro** **id para**  **meters should**  **include triiodothyronine**  **(T3), thyro** **id stimulating**  **hormone (TSH),**  **and thyroxine (T4) hormone**  **measurements as**  **well as**  **thyroid weight**  **and histopa**  **tho logical**  **examination of**  **both the**  **adult and**  **young animal**  **s. This is**  **consi stent**  **with Agency**  **policy to**  **reduce the**  **number of**  **animals and**  **to refine the**  **measurements taken**  **in the**  **study. Fe** **tal thyroid**  **evalua tions**  **are conducted**  **at GD**  **20 in**  **order to determine**  **whether the test**  **chemical alters**  **fe tal**  **hormones or**  **thyroid structure**  **during this**  **critical period of**  **brain development.**  **The CCA**  **with Thyr oid**  **Measurement Study should**  **include the**  **fo llowing**  **components :**  **1) Acute**  **study: measure**  **AChE inhibition**  **in direct**  **dosing to**  **post-natal day**  **11 and**  **young adult**  **ra ts.**  **The acute**  **study should**  **be accompa** **nied by**  **a ra**  **nge-finding and**  **time to peak**  **effect study ;**  **2) Eleven**  **(11) day**  **repea ted,**  **direct dosing to**  **ju venile**  **rats (PND**  **1 1 -2**  **1) and**  **young adult**  **ra ts;**  **and 3)**  **Gestational exposures**  **to pregnant**  **dams fo** **llowed by**  **sacrifice at**  **gestational day**  **20 (measuring**  **brain and blood AChE**  **act ivity**  **in dams**  **and fe** **tu ses).** 
**Page 18**  **of 41** **Each component study should include**  **a contro** **l group and at least**  **3 treatment**  **grou ps**  **. The**  **AChE measurements**  **should include**  **both RBC**  **and brain AChE.**  **The studies**  **should be**  **perf ormed**  **in order,**  **since the**  **results of**  **the first**  **study impact**  **the design**  **of subsequent**  **stud ies.**  **Prot ocols**  **should be**  **submitted to the**  **Agency fo** **r review**  **bef ore**  **onset of**  **testing. 2. Dermal**  **Sensit ization**  **Stud y**  **In order to conduct a**  **quantita tive**  **risk asses** **sment fo** **r dermal sensitiza**  **tion, a dermal**  **sens itizati** **on study**  **with dif** 

**f erent**  **concen tra** **tions of**  **the technical**  **grade product**  **is needed.**  **1 0 .2**  **Exposure Studies**  **(Occupational/Residential and**  **Dietary) The exposure**  **studies that**  **are needed**  **fo r**  **the regi** **stra tion**  **review of**  **IPBC are listed**  **in Table**  **6 with**  **brief rati** **onales as**  **to why**  **they are**  **needed. Detailed**  **ju stifi** **ca tions**  **are provided**  **in Appendix**  **A. These**  **study requirements**  **supersede those**  **listed in**  **the RED**  **and they**  **addr ess**  **the data**  **requirements fo** **r the uses listed**  **in the**  **RED as**  **"ineligible fo** **r reregi** **strati on".** 

**Page 19**  **of 41** **a e -**  **T bl**  **6 E xposure**  **u 1es ee**  **e or**  **e g**  **iS ra**  **IOD St**  **d" N d d �**  **IPBC R . t f R** **ev1ew Study**  **Needed Guideline**  **Rationale Residues**  **from Dish**  **No Guideline**  **Dishes washed**  **with IPBC**  **preserved dishwashing**  **Deterg ent**  **deterg ents**  **may become**  **contaminated with**  **IPBC. Indoor**  **Exposure 875.**  **1 10**  **0 (Dermal)**  **Exposure may**  **occur during**  **open pour**  **addition of**  **IPBC (Open**  **Pour Powders** **A ,**  **s )**  **875. 1 3**  **00 (In** **halation) powder**  **products during**  **material preservation.**  **87 5**  **.16 00**  **(Data Re** 

**porting) Indoor**  **Exposure 875.**  **1 1 00**  **(Dermal) Exposure**  **may occur**  **during open**  **pour addition**  **of IPBC**  **(Open Pour**  **Liquids A** **, s** **) 875.**  **1 3 00**  **(Inh alation)**  **liquid products**  **during material preservation.**  **875. 1**  **600 (Data**  **Re**

**porting) Indoor**  **Exposure 875.**  **1 1 00**  **(Dermal) Exposure**  **may occur**  **during in-** **plant spray**  **and dip**  **(Spray and**  **Dip Treatment** **s )**  **875. 1 3**  **00 (In** **halation) treatment**  **of lumber**  **using IPBC.**  **875. 16** **00 (Data**  **Re**

**porting) Indoor**  **Exposure 87** **5. 11**  **00 (Dermal)**  **Exposure may**  **occur during**  **pressure treatment**  **of lumber**  **(Pressure Treatment** **s )**  **875. 1 3**  **00 (In** **halation) using**  **IPBC. 875.**  **1 600**  **(Data Re** 

**porting) Indoor**  **Exposure 875.**  **1 1 00**  **(Dermal) Exposures**  **may occur**  **during brush roller**  **application of**  **(Brush/Roller Painting** **s )**  **875. 1 3**  **00 (Inh**  **alation) paints**  **preserved with**  **IPBC. 875.**  **1 600**  **(Data Rep** 

**orting )**  **Indoor Exposure**  **875. l l**  **00 (Dermal)**  **Exposures may**  **occur during**  **spray application**  **of products**  **(HV AC**  **Applications**

**c )**  **875. 1 3**  **00 (In** **halation) fo** **r HV**  **AC treatment.** 

**875. 1**  **600 (Data**  **Repo rting**  **) Indoor**  **Exposure 875.**  **1 1 0** **0 (Dermal)**  **Exposure may**  **occur during**  **use of**  **metal working**  **fl uids**  **(Metal Working**  **Fluids s**  **) 875.**  **1 3 00**  **(Inhalation) preserved**  **with IPBC.**  **875. 16**  **00 (D** **ata Re** 

**porting) Indoor**  **Exposure 875.**  **I 10**  **0 (Dermal)**  **Exposure may**  **occur during**  **use of**  **sponges and wipes (Sponges**  **and Wipes**  **s )**  **875. 1 3**  **00 (Inh** **alation) preserved**  **with IPBC.**  **87 5**  **.16 00**  **(D ata**  **Repo rting**  **) Outdoor**  **Exposure 875.**  **1 2 00**  **(Dermal) Exposures**  **to paint**  **aerosols containing**  **IPBC. (Airless**  **Sprayer Painting** **s )**  **875. 1**  **400 (In** **halation) 87** **5 .16**  **00 (Data**  **Re**

**porting) Leaching**  **Study on**  **Plastics No**  **Guideline Incidental**  **oral exposures**  **may occur**  **from mouthing**  **household items**  **and toys made from**  **IPBC preserved**  **plastics. Leaching**  **Study on**  **Leather No**  **Guideline Dermal**  **and incidental**  **oral exposures**  **may occur**  **from leather**  **articles made**  **from IPBC**  **preserved leather.**  **Leaching Study**  **on Textiles**  **No Guideline**  **Dermal and**  **incidental oral**  **exposures may**  **occur from**  **clothing made**  **from textiles**  **treated with**  **IPBC preserved**  **spin finish**  **solutions. Surf**  **ace Residue**  **Dissipation 875.**  **2 300**  **Dermal and**  **incidental oral**  **exposures may**  **occur from**  **(Household Floors)**  **contact with**  **fl oors**  **cleaned with**  **IPBC treated**  **household cleaning** **pr oducts.**  **Surface Residue**  **Dissipation 875.**  **2 300**  **Dermal and**  **incidental oral**  **exposures may**  **occur from**  **(Treated Wood)**  **contact with**  **IPBC treated**  **wood. Product**  **Use Inf** 

**ormation 875.**  **1 700**  **Use inf**  **ormation can**  **be used**  **to evaluate**  **exposures and**  **assist in**  **the planning**  **of ex**  **posure studies.**  **Notes for**  **Table 6**  **A. If**  **the labels**  **are amended**  **to require**  **closed mixing**  **and loading**  **fo r**  **liquid products**  **and water**  **soluble packaging**  **fo r**  **powder products,**  **then the**  **exposure studies will not**  **be needed**  **fo r**  **the open**  **loading/mixing scenarios.**  **B. It**  **may be**  **possible to**  **use proprietary**  **surrogate exposure**  **data if**  **data compensation**  **issues can**  **be addressed.**  **C. The**  **HV AC**  **application scenario**  **is uncommon**  **and there**  **are no**  **proprietary exposure**  **data available.** 

**Page 20**  **of 41** **11.0 RE** **FERENCES**

**EPA, 1 9** **97. Reregistra** 

**tion Eligibility**  **Decision (RED)**  **fo r**  **3-Iodo-2- propynyl**  **butylca rbamate**  **(IPBC), March**  **1 9 97,**  **htt p://**  **www .epa.g** 

**ov/p esticides** **/rereg**

**istration/sta**

**tus.htm EPA,**  **2009. Toxicology**  **Endpoints fo** **r Risk**  **Assessment fo** **r a Proposed**  **New Use**  **of 3-Iodo-2-**  **propynyl butyl**  **carbamate in/on**  **Leather. D354908,**  **January 5,**  **2009 Kline,**  **2006. Specialty**  **Bi ocides**  **North America**  **2004-2 005,**  **Kline and**  **Company, Inc.**  **Warshaw et**  **al., 20**  **1 0 . Po**  **sitive Patch-Test**  **Reac tions**  **to Iodopropynl**  **Butylca rbamate**  **: Retro** **spective Analysis**  **of North**  **American Contact**  **Derma titis**  **Group Data**  **from 1 9** **98 to**  **20 08.**  **Warshaw E.M. et al.,**  **Dermati tis,**  **Volume 21,**  **Issue 6,**  **pp 303**  **-31 0,**  **November**

**- December,**  **20 10.** 

**Page 21**  **of 41** **This page intentionally**  **left blank.** 

**Page 22**  **of 41** 

# Ap **pendi x**  **A - Ju**  **stification fo**  **r the**  **Studies Needed**  **fo r**  **the Human**  **Heal th**  **Registration Review of**  **IPB C** 

**Pa ge**  **23 of**  **41 Guideline** 

**N/A Appendix**  **A, Table**  **1 -**  **Toxicology Study**  **Justifications fo**  **r IPBC**  **Registration Review** 

**Study Title**  **Comparative Cholinesterase**  **Assay (CCA)**  **with Thyroid**  **Measurements Practical**  **Utili ty**  **of the**  **Data 1)**  **What is**  **the value**  **of the**  **study ?**  **The existing**  **toxicity stu** **dies fo** **r IPBC indicate that**  **it inhibits**  **AChE. According**  **to the**  **stu dies**  **submitted fo** **r the**  **NMCs, the**  **Comparative Chol**  **inesterase Assay**  **(CCA) results**  **have also**  **shown ju** **veniles to be more**  **sensitive to**  **AChE inhibition**  **than adu** **lts. Theref**  **ore, a**  **CCA study**  **fo r**  **IPBC is**  **needed to address**  **potential lif**  **e stage**  **sensitivity by**  **including both**  **adult and**  **PND l l**  **juvenile ra**  **ts. It**  **also is**  **not known the**  **time to peak**  **AChE inhibition,**  **such that**  **the existing**  **AChE data**  **fo r**  **IPBC may**  **be under predicting**  **the true**  **AChE inhibition.**  **Theref ore,**  **the CCA**  **study fo** **r IPBC**  **should include**  **suf**

**ficient measurements**  **so that**  **the time to**  **peak inhibition**  **can be**  **determi ned.**  **In add** **ition, current**  **toxicity studies**  **have demon** **strate d**  **that IPBC**  **aff ects**  **the thyr oid. In the**  **chronic mouse**  **stu**

**dy, IPBC**  **increased the**  **incidence of**  **non-neoplastic pat** **hology of**  **the thyro**  **id in**  **both sexes.**  **Furthe rmore** **, iodine**  **uptake in**  **the developing**  **fe tus**  **is critical** 

**. Theref**  **ore, the**  **CCA study should**  **include compara**  **tive thyro** **id measurements**  **in the**  **pregnant fe** **ma les**  **and in**  **the developing**  **fe tus**  **to determine**  **potential suscept** **ibility. 2)**  **How would**  **the data**  **be used?**  **The data**  **would be**  **used to**  **identify endpoints**  **fo r**  **risk assessment**  **to be**  **used fo** **r assessing**  **exposures of**  **adults and children**  **to products**  **preserved with**  **IPBC. 3)**  **How could**  **the data affect**  **the risk**  **assessment? The**  **data might**  **indicate that**  **existing endpoints**  **are not**  **sufficiently prot** **ective for**  **AChE inhibition**  **or thyroid**  **effects. 4)**  **What is**  **triggering the**  **need for**  **this data?**  **The fa**  **ct that**  **IPBC causes**  **AChE inhibition**  **and affects**  **the thyro**  **id.**

**Page 24**  **of 41** **Guideline**

**N/A Appendix**  **A, Table**  **1 - Toxicology**  **Study Justifications**  **fo r**  **IPBC Registration**  **Review**

**Study Title**  **Dermal Sensitization**  **Threshold Quantification**  **·� -**  **Prac tical**  **Utility of**  **the Data**  **1) What**  **is the**  **value of**  **the study**  **? This study**  **is needed**  **to quan**  **tify the dermal sensitization effects**  **that have**  **been reported**  **in the**  **literatu re.**  **2) How**  **would the**  **data be**  **used? The**  **data would**  **be used**  **to identify**  **a threshold**  **fo r**  **the dermal**  **sensitization of**  **IPBC. Specifically**  **the data would be**  **used to**  **identify a**  **saf e**  **thr eshold**  **level fo** **r the**  **elic itati** **on phase**  **of sensitization**  **which is**  **protective of**  **induction as**  **recommended by**  **the FIFRA**  **SAP (See**  **note 1**  **)**

**. This**  **level would**  **then be**  **used to**  **assess the risk**  **of dermal**  **sensitization from**  **exposure to**  **IPBC. 3)**  **How could**  **the data affect**  **the risk**  **assessme nt?**  **Currently it**  **is not**  **possible to**  **assess the**  **risks of**  **sensitization from**  **exposure to IPBC**  **because some**  **of the**  **use rates are**  **higher than**  **the rate**  **tested in**  **the submitted**  **study. 4)**  **What is**  **triggering the**  **need for**  **this data?**  **The need fo** **r this**  **data is**  **triggered by**  **occupational dermal**  **exposures from the**  **metal working**  **fluid use**  **and the**  **residential dermal**  **exposures from**  **the wood**  **and tex** **tiles uses.**  **Note 1 -**  **Transmittal of**  **Min ute** **s of**  **the FI** **FRA Scie** **nti fic**  **Advisory Panel**  **Meeting Held**  **May 4-6,**  **2004: A**  **Consultation on**  **Dermal Sens** **itization Issues**  **fo r**  **Exposures to**  **Pesticides, Memorandum**  **of 1**  **July 2004.** 

**Page 25**  **of 41** **Appendix A-**  **Table 2**  **- Expos**  **ur e Study**  **Justifications fo**  **r IPBC**  **Registration Review** 

**Guideline** 

### I **Stud**

**y Title**  **N/A** 

### I **Residue**

**Dissipation (Dish**  **washing Detergents)** **-- �** **� ...** **. -**

**1) What**  **is the**  **value of**  **the study?**  **Pr actical**  **Utility of**  **the Data**  **Dietary exposures**  **to IPBC are**  **expected duri** **ng the**  **use of**  **dish detergents**  **that are**  **preserved with**  **IPBC. This**  **residue data**  **fr om**  **this study**  **could be**  **used in**  **place of**  **def ault**  **assump**

**tions to**  **quant ify**  **dietary exposures**  **and risks resulting**  **from the**  **dish detergent**  **use. 2)**  **How would**  **the data**  **be used?**  **The data**  **would be**  **used to**  **assess the risks of**  **dietary exposures**  **that result**  **from the**  **use of**  **dish detergents**  **preserved with**  **IPBC. 3)**  **How could the data**  **affect the**  **risk assessme** **nt ?**  **The residue**  **data would**  **be used**  **to assess**  **the dietary**  **risks from**  **the IPBC**  **dish detergent**  **use to**  **determine if**  **mitigation measure** **s, such**  **as rate**  **reductions are**  **needed to reduce**  **these risks.**  **4) What is**  **trigge ring**  **the need**  **for this**  **data? IPBC**  **is labeled**  **fo r use**  **as a**  **preservative in**  **"Household, consumer,**  **industri al,**  **and ja** **nitorial products**  **such as**  **liquid and**  **solid air**  **fr esheners** **, dish**  **detergents, laundry**  **products ,**  **soaps and**  **detergen ts,**  **non fo** **od contact**  **surf**

**ac e**  **cleaners, floor**  **care produc**  **ts, bat** **hroom cleaners** **, window**  **cleaners ,**  **fa bric**  **care produ**  **cts, au** **tomotive care**  **products and**  **furniture care**  **products ".** 

**Page 26 of**  **41 Guidel** **ine**

**87 5.1**  **1 0 0**  **875 . 1**  **300 875**  **. 1 600**  **Appendix A- Table**  **2 -**  **Exposur e**  **Study Justifications**  **fo r**  **IPBC Registration**  **Review**

**Study Title**  **Applicator Indoor**  **Exposure (Open**  **Pour Powders)**  **Dermal Inhalation**  **Data Reportin**  **g .. ,**  **Practical Utility**  **of the**  **Data 1)**  **What is**  **the value**  **of the**  **study? Dermal**  **and inhalati** **on exposures**  **to IPBC are**  **expected du** **ring the**  **open pour addition**  **of powders such as**  **product #**  **1 5 29-40**  **duri ng**  **mat erials**  **preservat**

**ion. In**  **addi tion,**  **dermal and**  **inhalation exposures**  **fr om**  **open pouring**  **of powders**  **are evident**  **in exposure**  **studies in**  **the Pesticide**  **Handlers Exposure Database**  **(PHED). The**  **existing Chemical**  **Man ufac** **turer Assoc** **iation (CMA)**  **data base**  **and PHED**  **fo r**  **these scenar** **ios are**  **limited in scope**  **fo r**  **QA/QC and the number of**  **rep licates**  **(i. e.,**  **number of**  **times a**  **worker is**  **monitored fo** **r a specific**  **acti vity).**  **EPA presented**  **the need**  **fo r**  **additional handler exposure**  **data to the January**  **2007 Science**  **Advisory Panel**  **(SAP) as**  **well as**  **to the April**  **2007 Human**  **Studies Review**  **Bo ard**  **(HSRB) and**  **both groups**  **agreed that**  **additional data are**  **warrante d.**  **2) How**  **would the data**  **be used?**  **The data**  **would be**  **used to**  **assess dermal**  **and inhalation**  **exposures that**  **result from**  **the open pour**  **addi tion**  **of powders**  **duri ng**  **mate rials**  **preservati on.**  **3) How could**  **the data**  **affect the**  **risk assessm**  **ent? The**  **exposure data**  **would be**  **used to assess the**  **risks to occupational**  **workers and**  **determine if**  **mitigation measur**  **es, such**  **as water**  **soluble pack** **aging, are**  **needed to**  **reduce these**  **risks. 5)**  **What is**  **triggering the**  **need for this data?**  **The need**  **fo r**  **the exposure**  **study is**  **based on**  **the potential**  **fo r**  **exposure fr** **om the open**  **pour addition**  **of liquids**  **during the**  **mate rials**  **preservation uses**  **listed on**  **the label.** 

**Page 27**  **of 41** **Guideline**

**87 5.1**  **1 0 0**  **87 5.13**  **00 87**  **5.16 00**  **Appendix A- Table**  **2**
**- Expos**  **ur e**  **Study Justifications**  **fo r**  **IPBC Registration**  **Review**

**Study Title**  **Applicator Indoor Exposur**  **e (Open**  **Pour Liquids)**  **Dermal Inhalation**  **Data Reporting** 

### :...**... �.:�"":"**  **Practical Utility**  **of the**  **Data 1)**  **What is**  **the val** **ue of**  **the study?**  **Dermal and**  **inhalation exposures**  **to IPBC**  **are expected**  **during the open pour**  **addition of**  **liquids during**  **mate rials**  **preservati on.**  **In addition,**  **dermal and**  **inhala tion**  **exposures from**  **open pouring**  **of liquids**  **are evident**  **in exposure**  **studies in**  **the Pesticide**  **Handlers Exposure**  **Database (PHED).**  **The existing**  **Chemical Manuf**  **acturer Associa** 

**tion (CMA)**  **data base**  **and PHED**  **fo r**  **these scenarios**  **are limited**  **in scope**  **fo r**  **QA/QC and**  **the number**  **of repli** **cate s**  **(i.e., number**  **of times a**  **worker is**  **monitored fo** **r a specific**  **activit y).**  **EPA presented**  **the need**  **fo r**  **additional handler exposure data**  **to the**  **January 2007**  **Science Advisory**  **Panel (SAP)**  **as well**  **as to**  **the April**  **2007 Human**  **Studies Review**  **Boa rd**  **(HSRB) and both**  **groups agreed**  **that additional**  **data are warran**  **ted. 2)**  **How would the**  **data be**  **used? The**  **data would be**  **used to**  **assess dermal**  **and inhalation**  **exposures that**  **result from**  **the open**  **pour addition**  **of liquids**  **during materi** **als preserva**  **tion. 3)**  **How could the**  **data affect**  **the risk**  **assessment ?**  **The exposure data would be**  **used to**  **assess the**  **risks to**  **occupational workers**  **and determine**  **if mitigation**  **measur es,**  **such as**  **closed system**  **loading, are**  **needed to**  **reduce these**  **risks. 6) What**  **is triggering**  **the need**  **for this**  **data ?**  **The need**  **for the**  **exposure study**  **is based**  **on the**  **potential for**  **exposure from**  **the open pour**  **addition of**  **liquids during**  **the mate** **rials pre** **serva tion**  **uses listed**  **on the**  **label.**

**Page 28 of**  **41 Appendix**  **A- Exposure**  **Study Justifications**  **fo r**  **IPBC Registration**  **Review**

**Guidel ine**  

### I **Study Title** 

**87 5.1 10**  **0 875**  **. 1 300**  **87 5.1**  **600 Applicator**  **Indoor Exposur**  **e (Spray**  **and Dip**  **Treatment) Dermal**  **Inhalation Data**  **Reporting Practical**  **Utility of**  **the Data**  **1) What**  **is the**  **value of**  **the study**  **? Dermal**  **and inhalation exposures**  **to IPBC are expected**  **dur ing**  **the spray and**  **dip app** **lications IPBC**  **containing sapstain**  **treatments fo** **r treating**  **fr esh**  **cut lumber** 

**. There**  **are no**  **open lit** **erature studi** **es avai**  **lable to**  **assess these**  **exposur es**  ***. 2)**  **How would**  **the data**  **be used?**  **The exposure**  **data would**  **be used to assess IPBC**  **exposures that**  **result from**  **the spray**  **and dip**  **app lications**  **of IPBC**  **Sapstain treat** **ments. 3)**  **How could**  **the data**  **affect the**  **risk assessmen**  **t? Current**  **there are**  **no open**  **lit erature data**  **available to**  **assess the**  **exposure of**  **IPBC from**  **the use**  **of IPBC**  **in Sapstain**  **treatment and**  **therefore the**  **risks fr** **om this**  **use are**  **unknown. The**  **exposure data would**  **be used**  **to assess**  **these risks**  **and determine**  **if mitigation**  **is needed**  **to reduce**  **these risks.**  **4) What**  **is triggering**  **the need**  **for this**  **data ?**  **IPBC is**  **labeled fo** **r use as**  **a sap**  **stain dip**  **and spr** 

**ay treatment**  **in fresh**  **cut lumber.**  ***T here**  **are proprietary stu** **dies, such**  **as the**  **Sapstain Industry**  **Group Study**  **(MRID 476**  **1 8 3-** **01) ,**  **that can**  **be used**  **as surrogate**  **data fo** **r this**  **exposure scenario**  **if data**  **compensation issues**  **can be**  **addr essed.** 

**Page 29 of**  **41 Guideline** 

**87 5.1**  **1 0 0**  **87 5.1**  **300 875**  **. 1 600**  **Appendi x**  **A- Exposur** **e Study**  **Justifications fo**  **r IPBC**  **Regis tration**  **Review**

**Study Title**  **Applicator Indoor**  **Exposure (Pressure Treatment)**  **Dermal Inhalation**  **Data Reporting**  **Practical Utility**  **of the Data**  **1) What**  **is the value**  **of the**  **study ?**  **Dermal and inhalation**  **exposures to**  **IPBC are expected duri** **ng the**  **pressure treatment**  **app lications**  **ofiPBC containing**  **sapstain treatments**  **to fresh**  **cut lumber.**  **There are**  **no open**  **li terature**  **studies avai**  **lable to**  **assess these**  **exposures** ***. 2)**  **How would**  **the data**  **be used?**  **The exposure**  **data would**  **be used**  **to assess**  **IPBC exposures**  **that result**  **from the**  **pressure treatment**  **app lications**  **of IPBC**  **sapstain treatmen**  **ts. 3)**  **How could**  **the data**  **affect the**  **risk assessment?**  **Current there**  **are no**  **open li** **terature data available**  **to assess**  **the exposure**  **of IPBC**  **from the**  **use of**  **IPBC in**  **sapstain pressure**  **tre atment**  **and therefore**  **the risks**  **from this use are unknown.**  **The exposure**  **data would**  **be used to**  **assess these**  **risks and**  **determine if**  **mitigation is**  **needed to reduce**  **these risks.**  **4) What**  **is triggering**  **the need**  **for this**  **data? IPBC**  **is labeled**  **fo r use**  **as a**  **sap stain**  **pr essure**  **treatment in**  **fresh cut lumber.**  ***T here**  **are proprietary**  **stu dies,**  **such as**  **the CCA**  **Pressure Treatment**  **Worker Exposure Stud**  **y (MRID 4550** **21- 01)**  **that can be**  **used as**  **surrogate data**  **fo r**  **this exposure scenario**  **if data**  **compensa tion**  **issues are**  **addre ssed.** 

**Pa ge**  **30 of**  **41 �**  **' Appendix**  **A- Exposur** **e Study Justifications**  **fo r**  **IPBC Registration**  **Review**

**Guideline** 

### I **Study Title** 

**87 5.1**  **1 0 0**  **87 5.1**  **300 87**  **5.16 00**  **Applicator Indoor**  **Exposure**

**(Brush/Roller Painting)**  **Dermal Inhalation**  **Data Report** **ing Practical**  **Uti lity**  **of the**  **Data 1)**  **What is**  **the value**  **of the**  **study? Dermal**  **and inhalation**  **exposures to**  **IPBC are expected**  **during interior**  **brush/ roller**  **ap pli** **cat ion**  **of IPBC preserved**  **pain ts.**  **There are no**  **stu dies**  **available to**  **assess these**  **exposure s.**  **2) How**  **would the**  **data be**  **used? The**  **exposure data**  **would be**  **used to**  **assess IPBC**  **exposures that**  **result from**  **brush/r oller**  **app lication**  **of IPBC**  **preserved paints** 

**. 3)**  **How could**  **the data**  **affect the**  **risk ass** **es smen**  **t? Current**  **there are**  **no data**  **available to**  **assess the**  **exposure of**  **IPBC from the**  **use of**  **IPBC in**  **paints and**  **therefore the risks from this**  **use are unkn** **own. The**  **exposure data**  **would be**  **used to assess**  **these risks and**  **determine if**  **mitigation is**  **needed to**  **reduce these**  **risks. 4) What is triggering**  **the need**  **for this**  **data? IPBC**  **is labeled**  **fo r**  **use as**  **a pr**  **eservative in**  **"Paints".**

**Page 31**  **of 41** **Appendix A-**  **Exposure Study**  **Justifications fo**  **r IPBC**  **Registration Review** 

**Guideline** 

### I **Study Title** 

**875. 1 1**  **00 87**  **5.1 30** **0 87**  **5.1 600**  **Applicator Indoor**  **Exposur e**  **(HV AC**  **Fungicidal Coating)**  **Dermal Inhalation**  **Data Reporting**  **. Practical**  **Utility of**  **the Data**  **r 1)**  **What is**  **the value**  **of the**  **study? Dermal**  **and inhalation**  **exposures to**  **IPBC are**  **expected during**  **the app** **lication of**  **IPBC fungicidal**  **coating to**  **HV AC**  **systems. There**  **are no**  **studies avai** **lable to**  **assess these**  **exposur es.**  **2) How**  **would the**  **data be**  **used ?**  **The exposure data**  **would be used**  **to assess**  **IPBC exposures**  **that result**  **from the**  **app lication**  **of HV AC**  **coatin gs.**  **3) How**  **could the**  **data affect**  **the risk assessmen**  **t? Current**  **there are**  **no data avai**  **lable to**  **assess the**  **exposure of**  **IPBC from**  **the use**  **of IPBC**  **in HV** **AC coatings**  **and therefore**  **the risks from this use**  **are unknown.**  **The exposure**  **data would**  **be used**  **to assess**  **these risks**  **and determine**  **if mitigation**  **is needed**  **to reduce**  **these risks.**  **4) What is**  **triggering the**  **need for**  **this data?**  **IPBC is labeled**  **fo r**  **use as**  **a fungicidal**  **protective coating**  **in products**  **63836-1 and**  **63836**
**- 2.** 

**Page 32**  **of 41** **Guideline**

**87 5.1**  **1 0 0**  **87 5.1**  **300 87**  **5.1 600**  **Appendix A-**  **Exposure Study**  **Justifications fo**  **r IPBC**  **Registration Review** 

**Study Title**  **Applicator Indoor**  **Exposur e**  **(Metal Working**  **Fluids) Dermal**  **Inhalati on**  **Data Reporting**  **Practical Utility**  **of the**  **Data 1)**  **What is**  **the value**  **of the**  **stud y?**  **Dermal and**  **inhalation exposures**  **to IPBC**  **are expected**  **use of**  **metal working**  **fluids preserved**  **with IPBC.**  **There are no**  **studies available**  **to assess**  **the se**  **exposur es.**  **2) How**  **would the**  **data be**  **used ?**  **The exposure data**  **would be**  **used to**  **assess IPBC exposures**  **that result**  **from the**  **use of**  **IPBC preserved metal working fluids.**  **3) How**  **could the**  **data affect**  **the risk**  **ass essmen**  **t? Current**  **there are**  **no data**  **available to**  **assess the**  **exposure of**  **IPBC from**  **the use**  **of IPBC**  **in metal working**  **fluids and**  **theref ore**  **the risks fr** **om this**  **use are**  **unknown. The**  **exposure data**  **would be**  **used to**  **assess these**  **risks and**  **determine if mitigation is needed**  **to reduce**  **these risks.**  **4) What is**  **triggering the**  **need for**  **this data?**  **IPBC is**  **labeled fo** **r use**  **as a**  **pre servative**  **in "Metal**  **Workin g**  **Fluids".**

**Page 33 of**  **41 Appendi** **x A- Exposure**  **Study Justifications**  **fo r**  **IPBC Registration**  **Review**

**Guideline** 

### I **Study Title** 

**87 5.1**  **1 0 0**  **87 5.1**  **30 0**  **875 . 1**  **600 Applicator**  **Indoor Exposur** **e**

**(Sponges and**  **Wipes) Dermal**  **Inhal ation**  **Data Reporting**  **Practical Utility of**  **the Data**  **1) What**  **is the**  **value of**  **the study**  **? Dermal and inhalation exposures**  **to IPBC**  **are expected**  **dur ing**  **the use**  **IPBC preserved**  **sponges and**  **wipes. There**  **are no studi** **es avai** **lable to**  **assess these**  **exposur es** *

**. 2)**  **How would**  **the data**  **be used**  **? The**  **exposure data would**  **be used**  **to assess**  **IPBC exposures that result**  **fr om the use**  **of IPBC**  **preserved sponges**  **and wipes.**  **3) How**  **could the**  **data affect**  **the risk**  **assess ment?**  **Current there**  **are no**  **data available**  **to assess the**  **exposure of**  **IPBC fr** **om the**  **use of IPBC**  **preserved sponges**  **and wipes**  **and therefore**  **the risks from this**  **use are**  **unk nown.**  **The exposure**  **data would**  **be used**  **to assess**  **these risks and**  **determine if**  **mitigation is**  **needed to**  **reduce these**  **risks. 4)**  **What is**  **triggering the need**  **for this**  **data? IPBC**  **is labeled**  **fo r**  **use as**  **a pre** **servative in**  **sp onges**  **and wip** 

**es.** ***T here**  **are proprietary**  **stu dies,**  **such as the**  **AEATF II**  **Wipe Study**  **(MRID 483**  **756 -0**  **1 ) ,**  **that can**  **be used**  **as surrogate**  **data for**  **th1s exposure**  **scenario if**  **data compensation**  **issues are**  **addre ssed** 

**Page 34**  **of 41** **Appendix A-**  **Exposu re**  **Study Justifications**  **fo r**  **IPBC Registration**  **Review**

**Guideline** 

### I **Study Title**

**875 . 1**  **200 87**  **5.14 00**  **875 . 1**  **600 Applicator**  **Outdoor Exposure** 

**(Airless Spr** **ayer Painting)**  **Dennal Inhalation**  **Data Reporting**  **Practi cal**  **Utility of**  **the Data**  **1) What**  **is the**  **value of**  **the study?**  **Dermal and**  **inhalation exposures**  **to IPBC**  **are expected**  **during outdoor**  **air less**  **sprayer app** **lication of**  **IPBC containing**  **wood preserva**  **tives. There are**  **no studi** **es available**  **to assess**  **the se**  **exposure s.**  **2) How**  **would the**  **data be**  **used? The**  **exposure data**  **would be**  **used to**  **assess IPBC**  **exposures that**  **result from**  **air less**  **sprayer app** **lication of**  **IPBC containing**  **wood preserva**  **tives. 3)**  **How coul** **d the**  **data affect**  **the risk**  **assess ment?**  **Current there are**  **no data**  **available to**  **assess the exposure**  **of IPBC**  **from the use of**  **IPBC in**  **air less**  **sprayer ap** 

**plied wood**  **preservatives and**  **therefore the**  **risks from**  **this use are**  **unknown. The**  **exposure data**  **would be**  **used to**  **assess these**  **risks and**  **determine if**  **mitigation is**  **needed to**  **reduce the** **se risks. 4)**  **Wh at**  **is tri** **ggering the**  **need for**  **this data?**  **IPBC is**  **labeled fo** **r use as a water**  **repella nt**  **wood preservative**  **that can**  **be spray**  **ap plied**  **as an**  **exterior coating**  **(see label**  **1 0 22-540**  **which indicates**  **that desirable**  **plants and**  **shrubs should**  **be covered**  **to pr** 

**event in**  **ju ry).** 

**Page 35**  **of 41** **Appendi x**  **A- Exposure**  **Study Justifications**  **fo r**  **IPBC Registration**  **Review**

**Guideline** 

### I **Study Title N/A**  **Plastics Leaching**  **Study Practical**  **Utili ty**  **of the**  **Data**

**I 1)**  **What is**  **the value**  **of the**  **study? Incidental**  **oral exposures**  **to IPBC**  **are expected**  **during use**  **of household**  **items and**  **toys made**  **from plastics**  **that are**  **preserved with**  **IPBC. There**  **are no**  **leaching studies**  **available to**  **assess these**  **exposure s.**  **2) How**  **would the**  **data be**  **used? The**  **leaching data**  **would be**  **used to assess IPBC**  **exposures that**  **result from**  **the use**  **of household**  **items and**  **toys made**  **fr om**  **plastics that**  **have been**  **preserved with**  **IPBC. 3)**  **How could**  **the data affect**  **the risk**  **assessment? The**  **IPBC specific**  **leaching data**  **would refine the risk**  **assessment by**  **elim inating**  **the use of**  **default assumptions**  **of the**  **amount that**  **could be**  **leached. 4)**  **What is**  **triggering the**  **need for**  **this data?**  **IPBC is**  **labeled fo** **r use as**  **a preservative**  **in plas** **tics. Although**  **some labels**  **contain the**  **Discla imer:**  **"Product is**  **not intended**  **fo r use**  **in fo** **od-con tact**  **ar ticles,**  **toys or**  **texti les**  **and other**  **materi als**  **used in**  **prolonged direct**  **dermal contact with the**  **human body"**  **other labels**  **do not**  **have this**  **disclaimer.**

**Page 36**  **of 41** **Appendix A-**  **Exposure Study**  **Justifications fo**  **r IPBC**  **Registration Review** 

**Guideline** 

### I **Study Title**  **NIA Leather**  **Leaching Study**  **Practi cal**  **Utility of**  **the Data** 

**.. 1)**  **Wh at**  **is the**  **value of**  **the study?**  **Dermal and**  **incidental oral**  **exposures to**  **IPBC are**  **expected during**  **use of**  **leather goods**  **made from**  **leather that is processed**  **with leather**  **processing liquors**  **that are preserved**  **with IPBC.**  **There are**  **no leaching**  **stu dies**  **available to**  **assess these**  **exposure s.**  **2) How**  **would the**  **data be**  **used? The**  **leaching data**  **would be**  **used to**  **assess IPBC**  **exposures that**  **result from**  **the use**  **of leather**  **processed with**  **leather pr**  **ocessing liquors**  **that are**  **preserved with**  **IPBC. 3)**  **How could**  **the data**  **aff ect**  **the risk assessmen**  **t? The**  **IPBC specific**  **leaching data**  **would refine**  **the risk**  **assessment by**  **elimin ating**  **the use**  **of default**  **assumpti ons**  **of the**  **amount that**  **could be**  **leached. 4)**  **What is**  **triggering the**  **need for**  **this data?**  **IPBC is**  **labeled fo** **r use as a preservative**  **in "Leather"**  **on label**  **#464-82 14**  **(approved 4/**  **28/1 0)**  **and there**  **are no**  **human contact**  **restri ctions**  **listed on**  **the label**  **fo r**  **this use.** 

**Page 37 of**  **41 Appendix**  **A- Expos**  **ur e Study**  **Justifications fo**  **r IPBC**  **Registration Review** 

**Guideline** 

### I **Study Title**  **N/A Textiles**  **Leaching Study**  **,. Practical**  **Utility of**  **the Data**  **'1 � ._**  **•: 1)**  **What is**  **the value**  **of the**  **study? Dermal**  **and inciden** 

**tal oral**  **exposures to**  **IPBC are**  **expected duri** **ng use of**  **consumer goods**  **such as**  **clothing, towels**  **and blankets made from tex**  **tiles that are**  **treated with**  **spin finishes**  **that are**  **preserved with**  **IPBC. There**  **are no**  **leaching studies**  **avai lable**  **to assess**  **these exposure**  **s. 2)**  **How would**  **the data**  **be used**  **? The**  **leaching data**  **would be**  **used to**  **assess IPBC exposures that**  **result fr**  **om the**  **use of**  **clothing, towels**  **and blankets**  **made from**  **textiles that**  **are treated**  **with spin**  **finishes that**  **are preserved**  **with IPBC.**  **3) How**  **could the**  **data affect**  **the risk**  **assessment? The**  **IPBC specific**  **leaching data**  **would refine the**  **risk assessment**  **by elimi** **na ting**  **the use of**  **def**

**ault assumptions**  **of the**  **amount that**  **could be**  **leached. 4)**  **What is**  **triggering the**  **need for**  **this data?**  **IPBC is**  **labeled fo** **r use as**  **a preservative**  **in "Spin-finish**  **solution in**  **the textile**  **industry" on**  **label #**  **6707 1 -44**  **(approved 3/3**  **1/1 0)**  **and there**  **are no**  **human contact**  **lim ita**  **tions listed**  **on the**  **label fo** **r this**  **use.**

**Page 38**  **of 41** **. Appendix**  **A- Exposur** **e Study Justifications**  **fo r**  **IPBC Registration**  **Review**

**Guideline** 

### I **Study Title**  **875.2 300**  

# I **Surface Residue** 

**Diss ipation**  **(Household Floors)**  **Practical Utility**  **of the**  **Data -**  **1) What is the**  **value of**  **the study?**  **Dermal and incidental**  **oral exposures**  **to IPBC**  **are expected fo** **r toddlers who sit**  **or play**  **on household**  **floors after they**  **are cleaned**  **with floor**  **cleaners that**  **are preserved**  **with IPBC.**  **Sur fa**  **ce residue**  **dissipation data are**  **needed to**  **accura tely**  **assess the** **se exposur**  **es. 2)**  **How would**  **the data**  **be used?**  **The surf**  **ace residue**  **data would**  **be used to assess**  **IPBC exposures**  **that result**  **from the use**  **of floor cleaners**  **preserved with**  **IPBC. 3) How**  **could the**  **data affect**  **the risk**  **assessment? The**  **surf ace**  **residue data**  **will be**  **used dur** **ing registration**  **review to decide**  **if the**  **dermal and**  **incidental oral**  **exposures to**  **toddlers playing**  **on floors**  **treated with**  **IPBC generates**  **a risk**  **of concern**  **that requires**  **mitigati on.**  **This mitigation**  **could include**  **reduction of**  **the app** **lication rate**  **or elim** **ination of**  **the use.**  **If surf**  **ace residue**  **data are**  **not avai**  **lable, then**  **the standard assumption**  **of 10** **0 percent transf**  **erab le**  **surface residue will**  **be used which**  **might overestimate**  **the risk**  **and require**  **excessive miti**  **gati on.**  **4) What**  **is tr** **iggering the**  **need for**  **this data?**  **IPBC is**  **labeled fo** **r use as**  **a preservative**  **in "Household,**  **consumer, indust**  **rial, and**  **ja nitorial**  **products such**  **as liquid**  **and solid**  **air fresheners**  **, dish**  **detergents ,**  **laundry produ**  **cts, soaps**  **and detergents**  **, non-f ood**  **contact surf** 

**ace clea** **ners ,**  **floor care**  **products, bathro** **om cleaners**  **, window**  **cleaners ,**  **fa bric**  **care products,**  **au tomotive**  **care products**  **and furniture**  **care product** **s".**

**Page 39**  **of 41** **Appendix A-**  **Exposure Study**  **Justifications fo**  **r IPBC**  **Registra tion**  **Review**

**Guideline** 

### I **Study Title**  **875.2 300**  

### I **Surface Residue** 

**Dissipation (Treated**  **Wood) Practical Utility**  **of the**  **Data 1)**  **What is**  **the value**  **of the**  **study ?**  **Dermal and**  **inciden**

**tal oral**  **exposures to**  **IPBC are expected fo** **r toddlers who sit**  **or play**  **on IPBC**  **treated wood**  **surfac es.**  **Surf ace**  **residue diss** **ipation data**  **are needed to**  **accurate ly**  **assess these**  **exposur**

**es. 2)**  **How would**  **the data**  **be used? The**  **surface residue**  **data would**  **be used**  **to assess**  **IPBC exposures**  **that result**  **fr om**  **contact with**  **wood treated**  **with IPBC.**  **3) How**  **could the**  **data affect**  **the risk**  **assess ment?**  **The surface**  **residue data**  **will be**  **used during**  **registra tion**  **review to**  **decide if**  **the dermal**  **and incid** **ental oral**  **exposures to**  **toddlers playing**  **on wood**  **surf aces**  **floors treated**  **with IPBC**  **generates a**  **risk of**  **concern that**  **requires mitiga**  **tion. This**  **mitigation could**  **include re** **duction of**  **the app** **lication rate**  **or elimination**  **of the**  **use. If**  **surf ace residue**  **data are not**  **ava ilable,**  **then the**  **standard assump**  **tion of**  **1 . 0**  **ug/cm 2**  **transf erab** **le surface**  **residue will**  **be used**  **wh ich**  **might overestimate**  **the risk**  **and require**  **excessive mitigati** **on. 4)**  **What is**  **triggering the**  **need for**  **this data?**  **IPBC is**  **labeled fo** **r use**  **as a**  **wood preservative**  **app lied**  **to fr** **esh cut**  **lumber.**

**Page 40 of**  **41 Appendix**  **A- Exposur** **e Study Justificat** **ions fo**  **r IPBC**  **Registration Review** 

**Gui deline**  

### I **Study Title**  **875 .17** **00** 

### I **Product Use**  **Information Practical**  **Utility of**  **the Data**  **1) What**  **is the**  **value of**  **the study?**  **Product use**  **inf**

**ormati on is**  **a description**  **of how**  **the product**  **is actual**  **ly app** **lied; it**  **is not**  **a field**  **study . A**  **description of**  **how this**  **product is**  **used would provide**  **fo r a**  **comprehe nsive**  **real istic**  **asses sment**  **of its**  **potential app** **lica tions.**  **2) How**  **woul d**  **the data**  **be used?**  **The product**  **use inf** 

**ormation will**  **be used**  **to define and**  **charac terize**  **the exposure**  **scenari os**  **that will be**  **assessed in**  **the risk**  **assessment. 3)**  **How coul** **d the**  **data affect**  **the risk**  **assessmen t?**  **A complete**  **description of**  **product use**  **would ensure**  **that the**  **risk assessment**  **is inclusive**  **of the**  **types of**  **exposures occurring**  **duri ng use**  **and that these**  **exposure s**  **are accurate** **ly assessed.**  **4) What is**  **triggering the need**  **for this**  **data? The**  **need fo** **r a risk**  **asses sment**  **under Regist** **ra tion**  **Review in**  **turn necess**  **itates that**  **the risk**  **assessor understand**  **how the**  **pr oduct**  **is used.** 

**Page 41**  **of 41**