Page 2 of 39 EXECUTIVE SUMMARY

IPBC is registered for use as a wood preservative , an industrial preservati ve and as a dry film mildewcide. The wood preservative uses include dip, spray and pressure treatment applications for new lumber, millwork and joinery and brush and spray applications for existing above ground structures such as decks. The industria l preservation uses include metal working fluids, adhesives, caulks, sealants, pl astics, textiles, paper coatings, canvas, cordage, and inks. Additional preservation uses include household, cons umer, industrial, institutional and janitorial products such as air fresheners, dish detergents , laundry products, surfa ce cleaners, floor care products and fabric care products. The RED fo r IPBC was completed in 1997 and most of the above uses were found to be eligible for regist ration. For the industrial wood treatment use, the HVAC use, the textile use and certain non-indus trial wood treatment uses, the Agency was unable to make a registration eligibility decision due to a lack of exposure data. These data were required to be submitted as part of a generic antimicrobial exposure DCI.

There is conflicting information regarding th e use of IPBC for food contact surfaces. IPBC does not have any FDA approvals for food contact uses and most the labels restrict uses in adhesive, paper and paper board products and paper coating to non-food applications. The labels also have similar statements for plastics and surface cleaners that limit the use to non-food

areas. There are several labels which were a pproved beginning in 2004, how ever, that allow use in dish detergent, which is consid ered to be a food contact surface.

Although the toxicological databa se for IPBC is fairly extensiv e, the following additional

studies are needed for re gistration review:

• Comparative Cholinesterase Assa y with Thyroid Measurements

• Dermal Sensitization Threshold Quantification

Although some occupational and residential (ORE ) exposures were assessed in the RED, they will need to be reassessed during registra tion review to account for the toxicology studies that were submitted after the RED or in response to the registration review needs listed above. The following exposure data will be needed to assess these exposures:

• Indoor exposure studies (dermal and inhala tion) during open pouring of liquids, open pouring of powders, sapstain treatment, pressu re treatment of wood, use of metal working fluids, use of sponges and wipes and brush/ roller application of preserved paints.

• Outdoor exposure studies (dermal and inhala tion) during airless sp rayer application of wood preservative stains.

• Leaching studies on plastics, leathe r and textiles preserved with IPBC

• Surface residue dissipation studies on house hold floors cleaned with IPBC preserved

floor cleaners.

• Surface residue dissipation studies on IPBC treated wood.

• Product use information

In addition, it will be necessary to assess dietary exposures fro m the dish detergent use and therefore a residue study on dishes will be needed for registration review.Page 3 of 39 1.0 BACKGROUND

1.1 Chemical Identity

The chemical identity of IPBC listed in Table 1.

Table 1 - Chemical Identity of IPBC

Chemical Name 3-Iodo-2-propynyl butyl carbamate

Common Name IPBC

PC Code 107801 CAS Registry Number 554-53-6

Case No. 2725 Empirical Formula C 8 H 12 INO 2 Structure

1.2 Chemical and Physical Properties

The physical and chemical properties of IPBC that are relevant for human health risk assessment

are listed in Table 2. It should be noted that IPBC has a very low vapor pressure.

Table 2 - Physical and Chemical Properties of IPBC

Property Value Reference

Molecular Weight 281 Based on formula

Physical State Powder EPA, 1997

Melting Point 66 C Toxnet HSDB

Water Solubility 156 mg/l @ 20 C Toxnet HSDB

Octanol/Water Partition Coefficient Log Kow = 2.4 EPI Suite Estimate

Vapor Pressure <1.8 X 10 -6 @ 20 C , 5 x 10 -6 @ 30 C EPA, 1997

Henry’s Law Constant 8.9 x 10 -9 atm-m 3 /mole @ 25 C EPI Suite Estimate

2.0 USE INFORMATION

2.1 Formulation Types and Percent Active Ingredient

According to OPPIN, as of 03/21/2011, there are 106 products that c ontain IPBC (0.05% to 99.5%) as the active ingredient (a i). The products are formulat ed as powders and liquids.Page 4 of 39 2.2 Summary of Registered Uses

IPBC is registered for use as a wood preservative , an industrial preservati ve and as a dry film mildewcide. The wood preservative uses includ e spray, dip and pressure treatment applications for new lumber, millwork and joinery and brush and spray applications for existing above ground structures such as decks. The industria l preservation uses include metal working fluids, adhesives, caulks, sealants, pl astics, textiles, paper coatings, canvas, cordage, and inks. Additional preservation uses include household, cons umer, industrial, institutional and janitorial products such as air fresheners, dish detergen ts, laundry products, surf ace cleaners, floor care products and fabric care products. IPBC is also re gistered for use as a dry film mildewcide in paints and stains. A summary listing of the application rates is included in Table 3.

Table 3 – Application Rates for IPBC Use Application Rate Example Labels

Sapstain and Mold Control 0.375% (Bulk Dip Tank) 0.75% (Conventional Spray) 43813-43

Decay and Stain Protection 1.5% (Non – Pressure Treatment)

0.0375 lb ai/ft 3 (Pressure Treatment) 43813-43

Wood Finish and Preservative – Homeowner Applied 0.5 % 69857-4, 1022-540

Mildew Inhibition for Paints and Stains 0.32 to 1.08% 5383-114 Metal Working Fluids 0.03 - 0.53% 5383-77 Adhesives, Caulks, Patching Compounds and Sealants 0.004 to 0.6% 1258-1230

Plastics and Plastic Coatings 0.45 to 1.2 % 1258-1230

Textiles 0.23 to 0.98% 5383-91 Paper Coatings 0.23 to 0.9% 1258-1230 Canvas and Cordage 0.023 to 1.2% 5383-77

Leather 0.20% 464-8125

Inks 0.45 to 3.0% 1258-1222

Household, Consumer, Industrial and

Janitorial Products 40 to 600 ppm 1258-1230

Some of the IPBC labels have limitations for plastics (not to be used in plastics that will be in

contact with food or me dical applications), pa per coatings (non-food contact packaging and nonfood contact paper tapes), textiles (not to be us ed on fabrics intended for human wear or direct skin contact) and surface cl eaners (non-food contact).

The RED for IPBC was completed in 1997 and mo st of the above uses were found to be eligible for registration. For th e industrial wood treatment use, the HVAC use, the textile use

and certain non-industrial wood tr eatment uses, the Agency was unable to make a registration eligibility decision due to a lack of exposure data. This data was required to be submitted as part of a generic antimic robial exposure DCI.

In 2004, the first label (5383-117) allowing the us e of IPBC as a materials preservative in liquid detergents, soft soaps, and household clean ing products was approve d. In 2005, the first label (67071-44) allowing the use of IPBC as a materials preservative in Household, Consumer,Page 5 of 39 Industrial, Institutional and Jani torial products was approved. Th ese products include liquid and solid soaps, cleaners, detergents, laundry products and dishwashing detergents. Since that time, several other labels have been approved for these uses. In 2009, th e first label (464-8123) allowing the use on leather was approved.

2.3 Summary of Use Data

According to the Specialty Biocides Nort h 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 valu e), wood preservation (25% of sales), metal working fluids (6% of sales), adhesives and sealan ts (2% of sales) and pl astics and resins (<1% of sales). The market shares for IPBC were 56% for paints and coatings (as a fungicide), 2% for wood preservatives (water borne), 8% for metal wo rking fluids (as a fungic ide), 1% for plastics,

and 4% for adhesives and sealan ts (fungicides and mildewcides).

3.0 TOXICOLOGY

The toxicological database for the IPBC registrati on review case is comprised of studies that were available to the Agency when the RED was written in 1997 and additional studies that were submitted after the RED. The additional studies include the following:

• Acute Neurotoxicity Study in Rats, MRID 455094-01

• Subchronic Nuerotoxicity in Rats, MRID 455094-02

• Subchronic Oral toxicity Study in Rats, MRID 458123-01

• Subchronic Inhalation Toxicity Study in Rats, MRID 435302-03

• Two-Generation Reproductive Toxic ity Study in Rats, MRID 444788-01

The acute neurotoxicity study is classified as Acceptable (Nonguideline) and does not satisfy the guideline requirement (870.6200; OECD 424) due to incomplete evaluations of neuropathology (lack of histopat hology of nervous system tis sue and brain weights). The subchronic neurotoxicity study, th e subchronic oral study, the subc hronic inhalation study and the two generation reproducti on study are classified as Acceptable and fulfill the respective guideline requirements (870.6200, 82-1, 82-4, 870.3800).

3.1 Acute Toxicity

A complete database of acute toxicity data was available to the Agency at the time the RED was written. A summary of the fi ndings, 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 sens itizer at concentrations that do not exceed 0.32 percent. However, incidence data and publishe d literature suggest that IPBC may be a dermal sensitizer at either higher con centrations or following longer te rm exposures. Dermal exposure is the primary route of exposure for some reside ntial use scenarios including textiles and treated wood. As suggested in the FIFRA Scientif ic Advisory Panel Meeting (SAP, 2004), it is important to evaluate the dermal sensitization concern if the dermal exposure is the primaryPage 6 of 39 concern and there is no appropriate way to labe l the treated products. In order to conduct a quantitative risk assessment for de rmal sensitization, a dermal se nsitization study with different

concentrations of the technical grade product will be required.

Table 4 - Acute Toxicity Values for IPBC. Test (species) Result Toxicity Category

81-1 Oral Toxicity (rat) LD50 = 1100 mg/kg (Females) LD50 = 1500 mg/kg (Males and Females) III

81-2 Dermal Toxicity (rabbit) LD50 > 2000 mg/kg III 81-3 Inhalation Toxicity (rat) LC50 = 0.68 mg/L III 81-4 Eye Irritation (rabbit) Severely Irritating I 81-5 Dermal Irritation (rabbit) Slightly Irritating IV 81-6 Dermal sensitization (guinea pig) Non-sensitizer at 0.32% N/A

3.2 Subchronic and Chronic Toxicity

The following is a summary of the currently available toxicology studies for IPBC.

a. Subchronic Toxicity

Oral Studies

Subchronic Oral Toxicity in Rats, MRID 409474-01. IPBC was administered by gavage for 13 weeks at doses of 0, 20, 50, and 125 mg/kg/day. An additional satellite group was dosed at 125 mg/kg/day and held for a 28- day observation period following the 13-week dosing regimen. At 125 mg/kg/day, body weight gain was decreased (19% in male s and 12% in females) and absolute liver weight was increased (20% in ma les and 31% in females). Liver to body weight ratio was significantly increased by approximate ly 31% in both males and females at 125 mg/kg/day, while kidney to body wei ght ratio in females was incr eased 18% at 125 mg/kg/day. The systemic NOEL is 20 mg/kg/day, while th e systemic LEL is 50 mg/kg/day, based on increased liver to body weight ratio. This study is classified as core supplementary data (guideline 82-1). Although this gu ideline is not satisfied, accepta ble chronic toxicity data are available and therefore, additional oral subchronic data are not required.

Subchronic Oral toxicity Study in Rats, MRID 458123-01. IPBC was administered by gavage at doses of 0, 10, 20, 35 and 80 mg/kg for 90 days . A Functional Observational Battery (FOB) was performed prior to the first exposure and then weekly. In the last we ek of the study, assessment of sensory reactivity to visual stimuli (v isual placing) and motor activity was added. Food consumption for each rat was determined once a week. Hematology and clinical chemistry examinations were made at week 13, before the terminal sacrifice. Ophthalmoscopic examinations were made on all rats prior to the fi rst administration of the te st substance, in rats of the highest dose and on contro l rats at the termination. A gross necropsy and pathology examination was performed at the end of the study.Page 7 of 39 There was no test article relate d findings with respect to food consumption ratio, assessment of hearing, righting reflex, grip strength, visual pl acing, motor activity, ophthalmoscopy, urinary parameters or macroscopic and microscopic findi ngs. One male rat dosed at 35 mg/kg/day died on day 87 from a dosing accident. The most freq uent clinical finding, observed during the daily post-treatment FOB observations wa s breathing sounds (slight to mode rate 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 inci dence of slight salivation seen 25 minutes after dose administration. The effect may be due to be a local effect of the dosing solutions or to nonpalatability. Clinical observati ons included statistically significan t decreases in body weight gain in males at 35 mg/kg/day ( 12%) and 80 mg/kg/day (17%).

The NOAEL is 20 mg/kg/day based on decreased body weight in males, and salivation and breathing sounds in females with a LOAEL of 35 mg/kg/day.

The study is considered to be Acceptable and fulfils the gu ideline requirements § 82-1.

Dermal Studies

Subchronic Dermal Toxicity Study in Rats, MRID 421682-01, - During this study, rats (10/sex/dose) received dermal doses of 50, 200, and 500 mg/kg/day IPBC to the shaved skin for 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 females. In females, significant increases in hemoglobin, hematocrit, and eosinophils were observed at 500 mg/kg/day. Reticulocytes as a pe rcentage of red cells were decreased at 50 and 200 mg/kg/day, but not at 500 mg/kg/day. D ecreased serum glucose and decreased serum creatinine were observed in males at 500 mg/kg/day. Minimal to mild skin irritation (acanthosis and hyperkeratosis) was observed in both males a nd females. Increased serum gamma-glutamyl transpeptidase (24% increase) wa s observed in females. At 200 mg/kg/day, decreased serum glucose was observed in males, as was minimal to mild acanthosis and hyperkeratosis in males and females. Females showed inhibition of plas ma ChE at 500 mg/kg/day, which may have been

the result of either direct liver toxi city or inhibition of ChE itself. The systemic NOEL is 200 mg/kg/day and the system ic LEL is 500 mg/kg/day. This study is classified as core minimum data (guideline 82-3)

Inhalation Studies

In a subchronic inhalation toxicity study (MRID 43530203), Omacide (>97% ai) was administered to rats (15 rats /sex/dose) by whole-body exposure at nominal concentrations of 0, 0.25, 1.25, or 6.25 mg/m 3 (measured concentrations of 0, 0.3, 1.16, and 6.7 mg/m 3 ) for 6 hours per day, 5 days per week, for 13 consecutive weeks. The 0.25 mg/m 3 dose group was repeated based on exposure of th e original 0.25 mg/m 3 dose group to twice the nominal concentration during weeks 6-8 of the study.

In the 6.25 mg/m 3 treatment group, plasma cholinestera se (ChE) activity was significantly reduced (approximately 20%) in males duri ng weeks 2 and 13, and erythrocyte ChE was decreased in females at study week 2. Brain ChE activity was significan tly reduced in malesPage 8 of 39 (17%) and females (25%), and hyperplasia or squa mous metaplasia with necrosis of the ventral cartilage of the larynx was seen after 13 weeks of treatment. In the 1.25 mg/m 3 treatment group,

brain ChE levels were statistica lly significantly reduced in most of the females (25%; p<0.05). No effects were observed in the repeat 0.25 mg/m 3 treatment group. The LOEL for systemic toxicity is 1.25 mg/m 3 , based on depressed brain ChE acti vity in females. The NOEL was 0.25 mg/m 3

.

This study is acceptable and satisfies the guideline requireme nt for a subchronic inhalation study (82-4) in rats.

b. Chronic Toxicity/Carcinogenicity

Chronic Toxicity/Carcinogenicity Study in Rats, MRID 420082-06. IPBC was administered to Sprague-Dawley rats (50/sex/ group) at doses of 0, 20, 40, and 80 mg/kg/day for two years. There were no statistically signifi cant increases in tumor incidences in males. The incidence of mammary gland fibroadenoma and combined fibroadenoma/carcinoma in females was significantly increased at 20 mg/ kg/day vs. control by pair wise comparison (p < 0.01), but there was no dose-related trend. Except at 20 mg/kg/day, th e incidence of this tumor type was within historical control range for Sprague-Dawley ra ts. Since the mammary tumor incidence at 80 mg/kg/day was almost equal to control, th e Agency’s (OPP) Health Effects Division Carcinogenicity Peer Review Committee concluded that the ma mmary fibroadenomas were not related to treatment with IPBC. At 80 mg/kg/ day, body weight gain decrements of 20% and 15% were observed in males and females, respectivel y, during the first 13 weeks of the study. At study termination, body weight gain in males at 80 mg/kg/day was decreased to 71% of control, and in females, to 76% of control. Significan t changes in serum chemistry were observed in males at 80 mg/kg/day, as were significant non-ne oplastic changes in the stomach in both sexes. The non-neoplastic changes in the stomach were c onsidered the result of chronic irritation, and

were not considered indicativ e of a neoplastic response. The systemic LEL is 20 mg/kg/day, 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 considered adequate for testing of carcinoge nic potential of IPBC, based upon decreased body weight gain in male and female rats. This study is classified as core minimum data (guideline 83-5).

Carcinogenicity Study in Mice, MRID 420082-02. CD-1 mice (50 mice/sex/dose) were administered IPBC in the diet at 0, 20, 50, and 150 mg/kg/day for 78 weeks. In males, a statistically significant trend was observed for hepatocellular adenoma and hepatocellular adenoma/ carcinoma combined (p< 0.01). A statis tically significant pa ir-wise comparison was also observed for the incidence of hepatocellu lar adenoma and adenoma/carcinoma combined at 150 mg/kg/day vs. control (p< 0.05) . At 150 mg/kg/day, the inciden ce of hepatocellular adenoma (24%) and combined adenoma/carci noma (33%) exceeded the histor ical control range for CD-1 mice provided by the registrant (a verage benign hepatocellular tu mor incidence 11%, malignant tumor incidence 7%). There was no increase in he patocellular tumor incidence in female mice. There was a significant dose-related positive trend in pulmonary carcinoma for females, but no significant pair-wise comparison at any dose level tested in this study. Since the formation of pulmonary carcinomas in mice is considered part of a continuum from pulmonary adenomas, thePage 9 of 39 positive trend in carcinomas was not considered bi ologically significant. At the highest dose (150 mg/kg/day), body weight gain in males was decrea sed to 73% of control for weeks 0-13 of the study, and to 77% of control at study termination. In females, body weight gain for weeks 0-13 at the high dose was decreased to 70% of control, and to 80% of control at study termination. No significant effects on food consumption were obser ved in this study. In addition, no statistically significant effects on survival were seen in this study. The systemic LEL is 20 mg/kg/day, which is the lowest dose tested, and is base d 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 409904-01, Rats were dosed by oral administration of IPBC at 0, 20, 50, and 125 mg/ kg/day on gestation days six through 15. Maternal toxicity as reduced body weight ga in during dosing was observed at 125 mg/kg/day. Developmental toxicity consisted of an increa sed incidence of skeletal abnormalities at 125 mg/kg/day. The maternal toxicity NOEL is 50 mg/kg/day, and the matern al toxicity LEL is 125 mg/kg/day, based on reduced body weight gai n. The developmental toxicity NOEL is 50 mg/kg/day, and the developmental toxicity LEL is 125 mg/kg/day, based on incompletely

ossified frontal skull bones and pelvic girdles. This study is cl assified as core minimum data (guideline 83-3).

Developmental Toxicity Study in Rabbits, MRID 424816-04. This study was conducted in female New Zealand white rabbits, which recei ved oral doses of 0, 2, 20, and 50 mg/kg/day IPBC on gestation days 6 through 19. At 50 mg/ kg/day, maternal toxicity in the form of increased mortality and abortion was obser ved. Although changes in cesarean section observations were reported at 50 mg/kg/day, thes e changes are likely a secondary effect of maternal toxicity. The maternal toxicity NOEL is 20mg/kg/day, and the LEL is 50 mg/kg/day, based on increased mortality, clinical signs, and decreased body weight gain. The developmental toxicity NOEL is 50 mg/kg/ day which was the highest dose tested. This study is classified as core mi nimum data (guideline 83-3).

d. Mutagenicity

Ames Test, MRID 419752-06. IPBC was tested for the ability to cause mutations in Salmonella typhimurium strains TA 1535, TA 1537, TA 1538, TA 98, and TA 100. IPBC was found to be non-mutagenic in all five strains with and with out metabolic activation at all concentrations tested (1-1000 ug/plate).

Micronucleus Assay in Mice, MRID 409904-04. IPBC at doses of 200, 600, and 2000 mg/kg did not induce any significant in crease of the PCE containing micr onuclei from the treated mice when compared to that of the vehicle control mice.

Unscheduled DNA Synthesis Assays, MRID 409904-03. In primary rat hepatocytes, eight doses of IPBC ranging from 3.0 to 13.5 ug/ml did not cause an appreciable increase in mean netPage 10 of 39 nuclear grain counts. Doses >13.5 ug/ml were cytotoxic, supporting the conclusion that IPBC induced cytotoxicity but not genotoxic ity in this assay (guideline 84-2).

e. Metabolism

Rat Metabolism Study, MRID #409474-04 . Disposition of C 14 IPBC was examined in male and female rats at single oral doses of 20 and 125 mg/kg, at 20 mg/kg x 14 days, and as a single intravenous dose of 0.5 mg/kg. The time course of tissue distribution, conducted in 5 rats of each sex administered 7 daily doses of 20 mg/kg/day, was also performed. Several deficiencies were noted in the original review of this study, including an inadequa te number of rats per dose group, inadequate design of the repeat dose study, no jus tification for dose levels used in the study, and no identification of major metabolites.

In another rat metabolism study (MRID #435707-01), IBPC was administered orally in 0.5% carboxymethylcellulose in the following manner: Groups of 5 male and 5 female rats (groups A and B) received either a singl e oral high dose of radiolabelle d IPBC (125mg/kg) or a repeated

low oral dose of non-radiolabelled IPBC followe d by a single radio-labeled dose (20 mg/kg). Separate groups of rats (9/sex/group, groups C and D) received single oral doses (20 and 125 mg/kg) of radiolabelled IPBC, and 3 rats/sex we re sacrificed at 2, 4, and 120 hours post-dose for

determination of tissue distribution of radioactiv ity. Urine, feces and expired air were collected at 24 hour intervals for groups A and B, while ur ine and feces were collected from groups C and D. Absorption of test chemical at the low and high dose was between 80-90% for all dose groups, as suggested by excretion data showing th e majority of a dose eliminated through urine

or exhaled air.

Excretion of IPBC-derived radioactivity was mainly via the urine, with between 50-70%

of an administered dose excret ed by this route at 168 hours post -dose. Feces was a minor route of excretion in all dose groups (4-7% of th e administered dose), while radiolabelled CO 2 constituted between 18-24% of the administered dose. Repeated lo w oral dosing or a single high oral dose appeared to result in a decrease in the percentage of radioactivity excreted as 14-CO 2 compared to a single low dose (38.22% in MRID # 409474-04).

Based on the metabolite identification data, a scheme for metabolism of IPBC was proposed. According to this scheme, IPBC undergoes reductiv e dehalogenation followed by dealkylation to

form the URM-9 and URM-10 metabolites. In addition, de-carboxylation following reductive dehalogenation yields carbon dioxide . Various other metabolites formed from dehalogenation are glucuronidated and constitute minor metabolites of IPBC. This study was submitted in order to address deficiencies from review of a prev ious metabolism study (MRID # 409474-04). The data provided in this study in conjunction with MR ID #409474-04, satisfy the data requirement for a metabolism study in rats under Subdivision F guideline 85-1.

f. Reproductive Toxicity

Two-Generation Reproductive Toxicity Study in Rats, MRID 409904-02. This study was

conducted in rats where IPBC wa s administered over two genera tions at doses of 0, 6, 15, and 37.5 mg/kg/day. Reduced body weight and food c onsumption was observed for P and F malesPage 11 of 39 during the premating period at 37.5 mg/kg/day. A decreased mean live birth index was reported for P and F generations without an effect on vi ability and development of pups. No adverse effects on reproductive indices or mating perfor mance were observed at any dose level. The parental toxicity NOEL is 15 mg/kg/day, and the parental toxicity LEL is 37.5 mg/kg/day, based on decreased body weight and food consumption during premating for P and F males, and decreased mean live birth index fo r the P and F generations. The reproductive toxicity NOEL is 37.5 mg/kg/day whic h was the highest dose tested. This study is classified as core minimum data (guideline 83-4).

Two-Generation Reproductive Toxicity Study in Rats, MRID 444788-01. Omacide ® (>97% IPBC) was administered to groups of 25 male and 25 female rats by gavage at doses of 0, 10, 30, or 100 mg/kg/day for two generations. Clinical si gns of toxicity observed in the mid- and high dose levels included salivation, paddling with both forepaws, and hunched posture. No treatment-related gross findings we re observed at necropsy of the F 0 or F 1 females. Microscopic

examination of the F 0 adults was unremarkable. In the F 1 adults, diffuse acanthosis with hyperkeratosis was observed in the stomach of 10/10 males and 7/10 females from the 30 mg/kg/day groups. Therefore, the LOAEL for systemic to xicity is 30 mg/kg/day based on clinical signs of toxicity in the F 0 and F 1 males and females and on microscopic lesions in

the stomach of F 1 males and females. The systemic toxicity NOAEL is 10 mg/kg/day.

Fertility indices for the 100 mg/kg/day F 0 males and females were significantly (p ≤ 0.05) less

than the controls. No treatment-related effects were observed on copulation or fertility of the F 1 rats. The live birth indices for the F 1 litters in the 0, 10, 30, a nd 100 mg/kg/day groups were 98%, 98%, 90%, and 80% (p ≤ 0.001). The live birth index was ≥ 98% for all groups of F 2 litters.

For the F 1 pups, the viability indices on lactation day 4 (precull) were 92%, 96%, 72% (p ≤ 0.01), and 30% (p ≤ 0.001), respectively, and the cumulative survival indices were 88%, 94%, 67% (p ≤ 0.01), and 28% (p ≤ 0.001), respectively. For the F 2 pups in the 0, 10, and 30 mg/kg/day groups the viability indices on lact ation day 4 (precull) were 92%, 97%, and 87%, respectively, and the cumulative survival indice s were 85%, 93%, and 83%, respectively. Whole

litter losses occurred for thr ee mid-dose and six high-dose F 0 females and for two mid-dose F 1 females. Clinical signs of toxi city in the pups associated with whole litter losses were indicative

of lack of maternal care.

Body weights of the 100 mg/kg/day F 1 male pups were significantl y (79-86% of controls) less than the controls beginning on lactation day 4 (precull) and continui ng throughout lactation. Body weights of the 100 mg/kg/day F 1 female pups were significantly (81-93% of controls) less than the controls throughout lactation. Body weight gains by the 100 mg/kg/day F 1 male and female pups were 79% and 82%, respectively, of th e control level during lactation days 0-14 and were 93% and 91%, respectively, for lactation days 14-21. Body weight s of the 30 mg/kg/day

male and female F 1 pups during lactation were slightly but non-significantly lower than the

controls. No statistical diffe rences in body weights of the F 2 male pups were observed between the treated and control groups at any time during lactation. F 2 female pups in the 30 mg/kg/day group had significantly lower body weights than th e controls on lactation days 14 (93% of controls) and 21 (91% of control). Body weight gains by the 30 mg/kg/ F 2 female pups for lactation days 0-14 and 14-21 were 92% and 87%, respectively, of the control level. Pup body weights in the low-dose group were similar to the cont rols in both generati ons. Because dosingPage 12 of 39 of the pups did not begin until after weaning at 25 days of age, the only exposure of the pups to the test article was through the milk.

Treatment with the test article resulted in de velopmental delays of the offspring including a significantly (p ≤ 0.01) greater anogenital dist ance in the 30 mg/kg/day F 2 females as compared to the controls (1.1 mm vs 1.0 mm), delayed eye opening for the 100 mg/kg/day F 1 pups (79% vs 85% of the controls on day 15) and for the 30 mg/kg/day F 2 pups (85% vs 97% of the controls on day 15).

Therefore, the LOAEL for reproductive toxici ty is 30 mg/kg/day based on reduced pup survival, lower pup body weights, and deve lopmental delays during lactation. The reproductive toxicity NOAEL is 10 mg/kg/day.

This study is classified as Acceptable (guideline) and satisfies the guideline requirement for a reproduction study (OPPTS 870.3800; 40 CFR §83-4) in rats.

g. Neurotoxicity

Acute Neurotoxicity Study (MRID 455094-01 ). Rats were given a si ngle gavage oral dose of IPBC at doses of 0, 100, 300, or 1000 mg/kg/day and observed twice daily for 15 days. Control and treatment groups were divided into the follo wing 3 sets for neurobehavioral assessment and ChE activity evaluations:

• Set 1 (12/sex/group) was evaluated for FOB (functional observati onal battery), MA (motor activity), and blood, plasma and brain ChE at pretest and on Day 1.

• Set 2 (12/sex/group) was evaluated for FOB, MA , blood, plasma ChE at pretest, Days 1, 8, and 15, and brain ChE on Day 15.

• Set 3 (6/sex/group) was evaluated for neur opathology on Day 15 at study termination, these animals were euthanized and perfused in situ for neuropathological examination.

A statistically significant decr eased mean body weight gain wa s observed for males at 300 and 1000 mg/kg/day. In the females, body weight an d body weight gain showed no change at any dose level. FOB observations (In cidences) included a statistica lly significant lower number of

rears in females treated at 1,000 mg/kg/day. This effect was not seen in males. A dose relationship was seen on Day 1 (S ets 1 and 2) and Day 8 (Set 2) . Low Locomotor (Open field) activity was seen at 1000 mg/kg/da y on Day 1 in Sets 1 and 2 in bot h sexes. This effect was still evident to a lesser degree in both sexes on day 8.

The number of approaches (open field) showed a dose related decrease in sets 1 and 2 in males which was statistically significan t at 1000 mg/kg/day. In female s decreases were noted at 1000 mg/kg/day but they were not sta tistically significant. Rats of both sexes in all treatment groups

had an overall lower incidence of motor activity than th eir control counterpart s. Females treated with 300 and 1,000 mg/kg had decreased plasma Ch E activity on Days 8 and 15. No significant changes were observed in eryt hrocyte and brain ChE activity in both sexes. Macroscopic

evaluation revealed no evidence of lesi on formation due to treatment.Page 13 of 39 Based on the effects seen in this study, the LOAEL was 100 mg/kg 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 for an acute neurotoxicity study in rats (870.6200; OECD 424 ) due to incomplete evaluations of neuropathology (l ack of histopathology of ner vous system tissue and brain weights). It should be noted; however, that no changes were seen in a companion subchronic neurotoxicity study MRID 455094-02.

Subchronic Neurotoxicity Study (MRID 45509402) IPBC was administered to rats at dose levels of 0, 10, 50, or 120 mg/kg/day for 13 weeks. Control and treatment groups were divided

into 4 sets for neurobehavioral assessment (FOB, MA), ChE activity, and neuropathology

evaluations. Neurobehavioral a ssessment was performed in animals (12/sex/dose) before the initiation of the study and at Weeks 4, 8, and 13. ChE activity was determined by a spectrophotometeric assay in plas ma and erythrocytes prestudy and at Weeks 4, 8, and 13, and in

3 regions of the brain during Weeks 4, 8, and 17. At study termination (week 13) and at recovery (week 17), 6/sex/dose were euthanized and perfused for neuropa thological examination.

There were no treatment-related effects on morta lity, clinical signs, neur obehavioral activity, and erythrocyte and brain ChE activ ity. Treatment-related effect s included lower mean body weight/body weight gain and decreased f ood consumption at 50- and 120-mg/kg/day. Decreased food efficiency at 120 mg/kg/day corr elated with the decrease in food consumption, contributing to the lower body we ights of treated animals.

Plasma ChE inhibition was observed at 50- and 1 20-mg/kg/day in females only. Erythrocyte and brain ChE activity was not affected in either sex at any dose or time point. Macroscopic

examination indicated that the cervical and lumbar dorsal root ganglion might be potential target tissues of the test article. Microscopic examin ation reported neuronal va cuolation, satellite cell hypertrophy/hyperplasia, and neuron al degeneration in these tissues ; however, these effects were

determined not to be treatment-related. No other gross, histo-pathological, or neuro-pathological

effects were observed. All the noted effects in body weight, food consumption, food efficiency, and plasma ChE activity were reversed during the recovery period, indicati ng that the effects of the test article were not permanent. No frank neurotoxicity was observed.

Based on the effects seen in this study, the LOAEL is 50 mg/kg/day ( based on body weight, food consumption, and ChE activity data ) , with a NOAEL of 10 mg/kg/day

.

The study is classified as Acceptable-Guideline and satisfies the guideline requirement for a subchronic neurotoxicity study in rats (870.6200).

3.3 Toxicology Endpoints

The most recent hazard assessment for IP BC is included in D354908 (EPA, 2009) which was prepared to evaluate a proposed new use of IPBC on leather. This assessment included a selection of endpoints to be used for risk assessment; however, thes e endpoints will need to bePage 14 of 39 reevaluated during registration review because a dditional toxicology studies have subsequently

become available.

4.0 DIETARY ASSESSMENT

Dietary Exposure

There is conflicting information regarding th e use of IPBC for food contact surfaces. IPBC does not have any FDA approvals for food contact uses and most the labels restrict uses in adhesive, paper and paper board products and paper coating to non-food applications. The labels also have similar statements for plastics and surface cleaners that limit the use to non-food

areas. There are several labels such as #1258-1230, #1529-51, #67071-44, however, that allow use in dish detergent, which is c onsidered to be a food contact surf ace. If it is determined that the registrants intend to support the dish detergent use, then dietary exposures from this use will need to be assessed during registration review.

Drinking Water Exposure

There is a potential for drinking water exposur e from the material preservative uses. The Agency expects that the environmental fate data th at are being required will be useful to evaluate this potential. Therefore, the need for a drinking water assessment will be determined after the

environmental fate data ar e received and reviewed.

5.0 OCCUPATIONAL/RESIDENTIAL EXPOSURE

Occupational Exposures Assessed in the RED

Occupational handler exposures were assessed in the RED for the mixing and loading for the following uses: general preservatives, the meta l working fluids, oil production and pulp and paper. The MOEs were calculated for “total ex posures” based on the add ition of the dermal and inhalation exposures and were assessed usi ng the dermal endpoint of 200 mg/kg/day for short/intermediate term exposures and the oral endpoint of 20 mg/kg/day for long term exposures (in conjunction with a dermal absorption factor of 10 percent). All of the MOEs exceeded the target MOE of 100 and were not considered to be of concern. Occupational handler risks were also assessed for the application of paints or stai ns using brushes or air less sprayers and one of these MOEs (airless sprayer appl ication of wood preserving stai n, MOE = 71) was of concern. Based on these assessments, the RED required that products inte nded primarily for occupational use specify that applicators and other handlers must wear long-sleeve short and long pants, chemical resistant gloves and shoe plus socks. The RED did not require respiratory protection.

Occupational Exposures That Need to be Assessed

Occupational exposures were not assessed in the RED for the handlers applying wood preservatives to lumber using the dip or sp ray treatment nor were exposures assessed forPage 15 of 39 machinists using IPBC preserved metal working fl uids. In addition, the inhalation exposures for all of the scenarios were not assessed separate ly, nor were they compared to an inhalation specific endpoint. Given these deficiencies, it wi ll be necessary to reasse ss all of the exposure scenarios during registration review.

Residential Exposures Assessed in the RED

Residential handler exposures were assessed in the RED for home owner application of paints and stains containing IP BC using brushes and rollers. The MOEs were calculated as discussed above for occupational exposures they exceeded the target MOE of 100 and were not

considered to be of concern. Based on these assessments 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 for occupational applicator s, the inhalation exposures for residential applicators of paints or stains containing IPBC w ill need to be re-assessed separately using an inhalation specific endpoint. It will also be necessary to asse ss incidental oral exposures to household items and toys made of plastics pres erved with IPBC, incidental oral and dermal exposures to floors cleaned with IPBC treated household cleaners a nd incidental oral and dermal exposures to textile and leathe r products treated with IPDB.

A listing of the exposure studies that will be needed for registration review is included in Section 10 and detailed justifica tions are included in Appendix A.

6.0 AGGREGATE AND CUMULATIVE EXPOSURE

In examining aggregate exposure, EPA take s into account the available and reliable information concerning exposures to pesticide re sidues in food and drinking water, as well as non-occupational (i.e. residential) pesticide exposures. An aggr egate risk assessment may be

needed for IPBC if it is determined that a dr inking water exposure could occur based on the environmental fate data. This assessment might al so need to include dietary exposures from the dishwashing detergent use and residential expos ures from the wood treatment, floor cleaners, plastics, paints, leathe rs and textile uses.

Section 408(b)(2)(D)(v) of FFD CA requires that, when consid ering whether to establish, modify, or revoke a tolerance, the Agency consider "available information” concerning the cumulative effects of a particular pesticide's re sidues and "other substances that have a common mechanism of toxicity.” IPBC (3 -Iodo-2-propynyl butyl carbamate) it an iodo -carbamate.

Iodo -carbamates are not part of the N -methyl carbamate (NMC) cla ss of pesticides and should not be included as part of the NMC cumulative risk assessment as supported by the SAP (2004).Page 16 of 39 7.0 INCIDENTS

There are 27 human incidents repo rted in the OPP incident database that are associated with IPBC exposure. Both local skin ir ritation and systemic effects were reported in these incidents. Skin irritation and skin sensitization-like symptoms are the primary effects that have been reported, and these effects include rash, swe lling, itching, burning and/ or tingling sensation, blister, erythema/flushing, and hives. In some cases, chest tightness and respiratory problems were reported. Other reported systemic effects include nausea/vomit, headache, fatigue, vertigo,

and fever.

There are also reports of skin se nsitization in the literature. The most recent of these is a report by the North American American Contact Dermatitis Group of the results of IPBC patch testing (Warshaw, 2010). This testing was done on 25,321 patients between 1998 and 2008 using 0.1 or 0.5 percent IPBC in petrolatum. There were 226 weak r eactors and 67 strong reactors. The majority of the r eactions were to personal care pr oducts and most reactions were not related to occupation. Only four of the stro ng reactors had definite clinical relevance with a positive use-test reaction or pos itive patch-test reaction to a product containing IPBC. The frequency of positive reactions increased from 0.2 percent to 1.5 percent when the higher

concentration of IPBC was utiliz ed, but most were weak reactions of which some were likely

irritant.

8.0 TOLERANCES

There are no tolerances or exemptions from to lerances for IPBC. As mentioned in Section 4.0, IPBC is not approved for use as an indirect food additive.

9.0 ENDOCRINE DISRUPTION EFFECTS

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide active and other ingredients) may have an effect in humans or wildlife si milar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered ap proach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticid e active ingredients and 9 inert ingredients. IPBC is not among this group of chemicals. This list of chemicals was selected based on the potential for human exposure thr ough pathways such as food and water, residential activity, and certain post-application agricultural scenarios. Th is list should not be construed as a list of known or likely endocrine disruptors. For furthe r information on the stat us of the EDSP, thePage 17 of 39 policies and procedures, the list of 67 chemicals, the test guide lines and the Tier 1 screening battery, please visit our webs ite: http://www.epa.gov/endo/.

Endocrine related effects were observed for IPBC in some of the available toxicity studies. For example, in the carcinogenicity st udy (MRID 420082-02), thyroid gland atrophic vacuolation, follicular coalescence, and genera l follicular enlargement were noticed in both sexes. In the rat reproduc tive study, the F2 females had a greater anogenital distance as compared to the controls.

10.0 ANTICIPATED DATA NEEDS

10.1 Toxicology Studies

1. Comparative Cholinesterase Assay with Thyroid Measurements

Toxicity studies with IPBC suggest it is an acet yl cholinesterase (AChE) inhibitor. AChE inhibition is observed in toxicity studies of different routes of ad ministration from the acute oral neurotoxicity study (MRID 455094-01), subchron ic inhalation study (MRID 435302-03), subchronic dermal toxicity study (MRID 421682-01), and subchroni c oral neurotoxicity study (MRID 455094-02). These various toxicity studies s upport the finding that IPBC inhibits AChE. According to the studies submitted to the agency for the n-methyl carbamates (NMCs), the Comparative Cholinesterase A ssay (CCA) study results have s hown juveniles to be more

sensitive to AChE inhibition th an adults. Therefore, a CCA, which includes both adult and PND11 juvenile rats is needed, to address potential life stage sens itivity. In addition, the existing

database for IPBC does not address the time to peak ACHE inhibition, which might under predict the true AChE inhibi tion. Therefore, the CCA study fo r IPBC should include sufficient measurements so that the time to p eak inhibition can be determined.

Current toxicity studies have al so demonstrated that IPBC affect s the thyroid. In the chronic mouse study, IPBC increased the incidence of non- neoplastic pathology of the thyroid in both sexes (atrophic vacuolation, follicular coales cence, and general follicular enlargement). Furthermore, iodine uptake in the developing fe tus is a critical developmental life stage. Therefore, the Agency requires comparative thyr oid measurements in the pregnant females and the developing fetus to determine potential susceptibility.

The AChE and thyroid measurements may be samp led from the same sets of animals in the CCA study. The thyroid paramete rs should include triiodothyroni ne (T3), thyroid stimulating hormone (TSH), and thyroxine (T4) hormone measurements as well as thyroid weight and histopathological examination of both the adult and young animals. This is consistent with Agency policy to reduce the number of animals and to refine the measurements taken in the study. Fetal thyroid evaluations ar e conducted at GD 20 in order to determine whether the test chemical alters fetal hormones or thyroid st ructure during this cri tical period of brain development.Page 18 of 39 The CCA with Thyroid Measurement Study shou ld include the following components:

1) Acute study: measure AChE inhibition in di rect dosing to post -natal day 11 and young

adult rats. The acute study should be acco mpanied by a range-finding and time to peak

effect study;

2) Eleven (11) day repeated, direct dosing to juvenile rats (PND 11-21) and young adult

rats; and

3) Gestational exposures to pr egnant dams followed by sacr ifice at gestational day 20

(measuring brain and blood AChE activ ity in dams and fetuses).

Each component study should include a control gr oup and at least 3 trea tment groups. The

AChE measurements should include both RBC and brain AChE. The studies should be performed in order, since the results of the fi rst study impact the design of subsequent studies. Protocols should be submitted to the Agency for review before onset of testing.

2. Dermal Sensitization Study

In order to conduct a quan titative risk assessment for dermal sensitization, a dermal sensitization study with different concentrations of the technical grade product is needed.

10.2 Exposure Studies

There are 15 exposures studies that are needed to assess diet ary and occupational/residential exposures. These studies are listed in Table 5 with brief rationales as to why they are needed and more detailed justifications are provided in Appendix A.Page 19 of 39 Table 5 –Exposure Studies Needed for IPBC Registration Review

Study Needed Guideline Rationale

Residues from Dish Detergent No Guideline Dishes washed with IPBC preserved dishwashing detergents may become contaminated with IPBC. Indoor Exposure (Open Pour Powders A,B ) 875.1100 (Dermal) 875.1300 (Inhalation) 875.1600 (Data Reporting) Exposure may occur during open pour addition of IPBC powder products during material preservation.

Indoor Exposure (Open Pour Liquids A,B ) 875.1100 (Dermal) 875.1300 (Inhalation) 875.1600 (Data Reporting) Exposure may occur during open pour addition of IPBC liquid products during material preservation.

Indoor Exposure (Spray and Dip Treatment B ) 875.1100 (Dermal) 875.1300 (Inhalation) 875.1600 (Data Reporting) Exposure may occur during in-plant spray and dip treatment of lumber using IPBC.

Indoor Exposure (Pressure Treatment B ) 875.1100 (Dermal) 875.1300 (Inhalation) 875.1600 (Data Reporting) Exposure may occur during pressure treatment of lumber using IPBC.

Indoor Exposure (Brush/Roller Painting B ) 875.1100 (Dermal) 875.1300 (Inhalation) 875.1600 (Data Reporting) Exposures may occur during brush roller application of paints preserved with IPBC.

Indoor Exposure (Metal Working Fluids B ) 875.1100 (Dermal) 875.1300 (Inhalation) 875.1600 (Data Reporting) Exposure may occur during use of metal working fluids preserved with IPBC.

Indoor Exposure (Sponges and Wipes B ) 875.1100 (Dermal) 875.1300 (Inhalation) 875.1600 (Data Reporting) Exposure may occur during use of sponges and wipes preserved with IPBC.

Outdoor Exposure (Airless Sprayer Painting B ) 875.1200 (Dermal) 875.1400 (Inhalation) 875.1600 (Data Reporting) Exposures to paint aerosols containing IPBC.

Leaching Study on Plastics No Guideline Incident al oral exposures may occur from mouthing household items and toys made from IPBC preserved plastics. Leaching Study on Leather No Guideline Dermal a nd incidental oral exposures may occur from leather articles made from IPBC preserved leather. Leaching Study on Textiles No Guideline Dermal a nd incidental oral exposures may occur from clothing made from textiles treated with IPBC preserved spin finish solutions. Surface Residue Dissipation (Household Floors) 875.2300 Dermal and incidental oral exposures may occur from

contact with floors cleaned with IPBC treated household cleaning products. Surface Residue Dissipation (Treated Wood) 875.2300 Dermal and incidental oral exposures may occur from

contact with IPBC treated wood. Product Use Information 875.1700 Use information can be used to evaluate exposures and assist in the planning of exposure studies. A. If the labels are amended to require closed mixing and loading for liquid products and water soluble packaging for powder products, then the exposure studies will not be needed for the open loading/mixing scenarios.

B. It may be possible to use proprietary surrogate exposure data if data compensation issues can be addressed.Page 20 of 39 11.0 REFERENCES

EPA, 1997. Reregistration Eligibility Decisi on (RED) for 3-Iodo-2-propynyl butylcarbamate (IPBC), March 1997, http://www.epa.gov/pesticides/r eregistration/status.htm

EPA, 2009. Toxicology Endpoints for Risk Asse ssment for a Proposed New Use of 3-Iodo-2- propynyl butyl carbamate in/on Leather. D354908, January 5, 2009

Kline, 2006. Specialty Biocides North America 2004-2005, Kline and Company, Inc.

Warshaw et al., 2010. Positive Patch-Test Reactions to Iodopropynl Butylcarbamate: Retrospective Analysis of North American Contact Dermatitis Group Data from 1998 to 2008. Warshaw E.M. et al., Dermatitis, Volume 21, Issue 6, pp 303-310, November – December, 2010.Page 21 of 39 This page intentionally left blank.Page 22 of 39Appendix A – Justification for theStudies Needed for the Human HealthRegistration Review of IPBCPage 23 of 39Appendix A, Table 1 - Toxicology Study Justifications forIPBC Registration ReviewGuidelineStudy TitlePractical Utility of the DataN/AComparativeCholinesteraseAssay (CCA) withThyroidMeasurements1) What is the value of the study?The existing toxicity studies for IPBC indicate thatit inhibits AChE. According to the studiessubmitted for the NMCs, the Comparative Cholinesterase Assay (CCA) results have also shownjuveniles to be more sensitive to AChE inhibition than adults. Therefore, a CCA study for IPBCis needed to address potential life stage sensitivity by including both adult and PND11 juvenilerats. It also is not known the time to peak AChEinhibition, such that the existing AChE data forIPBC may be under predicting the true AChE inhibition. Therefore, the CCA study for IPBCshould include sufficient measurements so that thetime to peak inhibition can be determined. Inaddition, current toxicity studieshave demonstrated that IPBC affects the thyroid. In the chronicmouse study, IPBC increased the incidence of non-neoplastic pathology of the thyroid in bothsexes. Furthermore, iodine uptake in the developing fetus is critical. Therefore, the CCA studyshould include comparative thyroid measurementsin the pregnant females and in the developingfetus to determine potentialsusceptibility.2) How would the data be used?The data would be used to identify endpointsfor risk assessment to be used for assessingexposures of adults and childrento products preserved with IPBC.3) How could the data affect the risk assessment?The data might indicate that existing endpoints are not sufficientlyprotective for AChE inhibitionor thyroid effects.4) What is triggering the need for this data?The fact that IPBC causes AChE inhibition and affects the thyroid.Page 24 of 39Appendix A, Table 1 - Toxicology Study Justifications forIPBC Registration ReviewGuidelineStudy TitlePractical Utility of the DataN/ADermalSensitizationThresholdQuantification1) What is the value of the study?This study is needed to quantify the dermal sensitization effects that havebeen reported in theliterature.2) How would the data be used?The data would be used to identify a threshold for the dermal sensitization of IPBC. Specificallythe data would be used to identify a safe threshold level for the elicitation phase of sensitizationwhich is protective of induction as recommendedby the FIFRA SAP (See note 1). This levelwould then be used to assessthe risk of dermal sensitization from exposure to IPBC.3) How could the data affect the risk assessment?Currently it is not possible to assess the risksof sensitization from exposure to IPBC becausesome 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 for this data is triggered by occupational dermal exposures from the metal workingfluid use and the residential dermal exposures from the wood and textiles uses.Note 1 - Transmittal of Minutes of the FIFRA Scientific AdvisoryPanel Meeting Held May 4-6, 2004: A Consultation on DermalSensitization Issues for Exposures toPesticides, Memorandum of 1 July 2004.Page 25 of 39Appendix A- Table 2 - Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the DataN/AResidueDissipation(DishwashingDetergents)1) What is the value of the study?Dietary exposures to IPBC are expected during the useof dish detergents thatare preserved with IPBC.This residue data from this study could be usedin place of default assumptions to quantify dietaryexposures and risks resulting fromthe dish detergent use.2) How would the data be used?The data would be used to assessthe risks of dietary exposures thatresult from the use of dishdetergents preserved with IPBC.3) How could the data affect the risk assessment?The residue data would be usedto assess the dietary risks from the IPBC dish detergent use todetermine if mitigation measures, such as ratereductions are needed to reduce these risks.4)What is triggering the need for this data?IPBC is labeled for use as a preservative in “Household, consumer, industrial,and janitorial productssuch as liquid and solid air fresheners,dish detergents, laundry products, soaps and detergents, nonfood contact surface cleaners, floor care products, bathroom cleaners, window cleaners, fabric careproducts, automotive care products andfurniture care products”.Page 26 of 39Appendix A- Table 2 - Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the Data875.1100875.1300875.1600Applicator Indoor Exposure(Open Pour Powders)DermalInhalationData Reporting1) What is the value of the study?Dermal and inhalation exposures to IPBC areexpected during theopen pour addition ofpowders such as product #1529-40 during materials preservation. In addition, dermal andinhalation exposures from open pouring of powders are evident in exposure studies in thePesticide Handlers Exposure Database (PHED). The existing Chemical ManufacturerAssociation (CMA) data base and PHED for these scenarios are limited in scope forQA/QC and the number of replicates (i.e., number of times a worker is monitored for aspecific activity). EPA presented the need for additional handler exposure data to theJanuary 2007 Science Advisory Panel (SAP) aswell as to the April 2007 Human StudiesReview Board (HSRB) and both groups agreed that additional data are warranted.2) How would the data be used?The data would be used to assess dermal and inhalation exposures that result from theopen pour addition of powders during materials preservation.3) How could the data affect the risk assessment?The exposure data would be used to assess the risks to occupational workers anddetermine if mitigation measures, such as water soluble packaging, are needed to reducethese risks.5)What is triggering the need for this data?The need for the exposure study is based on the potential for exposure from the open pouraddition of liquids during the materialspreservation uses listed on the label.Page 27 of 39Appendix A- Table 2 - Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the Data875.1100875.1300875.1600Applicator Indoor Exposure(Open Pour Liquids)DermalInhalationData Reporting1) What is the value of the study?Dermal and inhalation exposures to IPBC areexpected during theopen pour addition ofliquids during materials preservation. In addition, dermaland inhalation exposures fromopen pouring of liquids are evident in exposure studies in the Pesticide Handlers ExposureDatabase (PHED). The existing ChemicalManufacturer Association (CMA) data baseand PHED for these scenarios are limitedin scope for QA/QC and the number ofreplicates (i.e., number of times a workeris monitored for a specific activity). EPApresented the need for additional handler exposure data to the January 2007 ScienceAdvisory Panel (SAP) as wellas to the April 2007 Human Studies Review Board (HSRB)and both groups agreed that additional data are warranted.2) How would the data be used?The data would be used to assess dermal and inhalation exposures that result from theopen pour addition of liquids during materials preservation.3) How could the data affect the risk assessment?The exposure data would be used to assess the risks to occupational workers anddetermine if mitigation measures, such as closed system loading, are needed to reducethese 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 pouraddition of liquids during the materialspreservation uses listed on the label.Page 28 of 39Appendix A- Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the Data875.1100875.1300875.1600Applicator Indoor Exposure(Spray and Dip Treatment)DermalInhalationData Reporting1) What is the value of the study?Dermal and inhalation exposures to IPBCare expected during the spray and dipapplications IPBC containing sapstain treatmentsfor treating fresh cut lumber. There areno open literature studies available 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 spray anddip applications of IPBC Sapstain treatments.3) How could the data affect the risk assessment?Current there are no open literature data available to assess the exposure of IPBC from theuse of IPBC in Sapstain treatment and therefore the risks from this use are unknown. Theexposure data would be used to assess these risks and determine if mitigation is needed toreduce these risks.4) What is triggering the need for this data?IPBC is labeled for use as a sapstain dipand spray treatment in fresh cut lumber.*There are proprietary studies, such asthe Sapstain Industry Group Study (MRID 476183-01), that can be used as surrogate dataforthis exposure scenario if data compensation issues canbe addressed.Page 29 of 39Appendix A- Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the Data875.1100875.1300875.1600Applicator Indoor Exposure(Pressure Treatment)DermalInhalationData Reporting1) What is the value of the study?Dermal and inhalation exposures to IPBC areexpected during the pressure treatmentapplications of IPBC containing sapstain treatments to fresh cut lumber. There are noopen literature studies available 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 pressuretreatment applications of IPBC sapstain treatments.3) How could the data affect the risk assessment?Current there are no open literature data available to assess the exposure of IPBC from theuse of IPBC in sapstain pressure treatment and therefore the risks from this use areunknown. The exposure data would be usedto assess these risks and determine ifmitigation is needed to reduce these risks.4) What is triggering the need for this data?IPBC is labeled for use as a sapstain pressure treatment in fresh cut lumber.*There are proprietary studies, such as the CCA Pressure Treatment Worker Exposure Study(MRID 455021-01) that can be used assurrogate data for this exposure scenario if data compensation issues are addressed.Page 30 of 39Appendix A- Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the Data875.1100875.1300875.1600Applicator Indoor Exposure(Brush/Roller Painting)DermalInhalationData Reporting1) What is the value of the study?Dermal and inhalation exposures to IPBC areexpected during interior brush/rollerapplication of IPBC preserved paints. There are no studies available to assess theseexposures.2) How would the data be used?The exposure data would be used to assessIPBC exposures that result from brush/rollerapplication of IPBC preserved paints.3) How could the data affect the risk assessment?Current there are no data available to assess the exposure ofIPBC from the use of IPBCin paints and therefore the risks from thisuse are unknown. The exposure data would beused 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 for use as a preservative in “Paints”.Page 31 of 39Appendix A- Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the Data875.1100875.1300875.1600Applicator Indoor Exposure(Metal Working Fluids)DermalInhalationData Reporting1) What is the value of the study?Dermal and inhalation exposures to IPBC are expected use of metal working fluidspreserved with IPBC. There are no studies available to assess these exposures.2) How would the data be used?The exposure data would be used to assessIPBC exposures that result from the use ofIPBC preserved metal working fluids.3) How could the data affect the risk assessment?Current there are no data available to assess the exposure ofIPBC from the use of IPBCin metal working fluids and therefore therisks from this use are unknown. The exposuredata would be used to assess these risks anddetermine if mitigation is needed to reducethese risks.4) What is triggering the need for this data?IPBC is labeled for use as a preservative in “Metal Working Fluids”.Page 32 of 39Appendix A- Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the Data875.1100875.1300875.1600Applicator Indoor Exposure(Sponges and Wipes)DermalInhalationData Reporting1) What is the value of the study?Dermal and inhalation exposures to IPBC are expected during the use IPBC preservedsponges and wipes. There are no studiesavailable to assessthese exposures*.2) How would the data be used?The exposure data would be used to assessIPBC exposures that result from the use ofIPBC preserved sponges and wipes.3) How could the data affect the risk assessment?Current there are no data available to assess the exposure ofIPBC from the use of IPBCpreserved sponges and wipes and therefore the risks from this use are unknown. Theexposure data would be used to assess these risks and determine if mitigation is needed toreduce these risks.4) What is triggering the need for this data?IPBC is labeled for use as a preservative in sponges and wipes.*There are proprietary studies, such asthe AEATF II Wipe Study (MRID 483756-01), that can be used as surrogate data for thisexposure scenario if data compensation issues are addressedPage 33 of 39Appendix A- Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the Data875.1200875.1400875.1600Applicator Outdoor Exposure(Airless Sprayer Painting)DermalInhalationData Reporting1) What is the value of the study?Dermal and inhalation exposures to IPBC are expected during outdoor airless sprayerapplication of IPBC containingwood preservatives. Thereare no studies available toassess these exposures.2) How would the data be used?The exposure data would be used to assess IPBC exposures that resultfrom airless sprayerapplication of IPBC containing wood preservatives.3) How could the data affect the risk assessment?Current there are no data available to assess the exposure ofIPBC from the use of IPBCin airless sprayer applied wood preservativesand therefore the risks from this use areunknown. The exposure data would be usedto assess these risks and determine ifmitigation is needed to reduce these risks.4) What is triggering the need for this data?IPBC is labeled for use as a water repellant wood preservative that can be spray applied asan exterior coating (see label 1022-540 which indicates that desirable plants and shrubsshould be covered to prevent injury).Page 34 of 39Appendix A- Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the DataN/APlastics Leaching Study1) What is the value of the study?Incidental oral exposures to IPBC are expected during use of household items and toysmade from plastics that are preserved with IPBC. There are no leaching studies availableto assess these exposures.2) How would the data be used?The leaching data would be used to assessIPBC exposures that result from the use ofhousehold items and toys made from plasticsthat have been preserved with IPBC.3) How could the data affect the risk assessment?The IPBC specific leaching data would refinethe risk assessment by eliminating the useof default assumptions of the amount that could be leached.4) What is triggering the need for this data?IPBC is labeled for use as a preservative inplastics. Although some labels contain theDisclaimer: “Product is not intended for use infood-contact articles, toys or textiles andother materials used in prolonged direct dermalcontact with the human body” other labelsdo not have this disclaimer.Page 35 of 39Appendix A- Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the DataN/ALeather Leaching Study1) What is the value of the study?Dermal and incidental oral exposures toIPBC are expected during use of leather goodsmade from leather that is processed with leather processing liquors that are preserved withIPBC. There are no leaching studiesavailable to assess these exposures.2) How would the data be used?The leaching data would be used to assessIPBC exposures that result from the use ofleather processed with leather processing liquors that are preserved with IPBC.3) How could the data affect the risk assessment?The IPBC specific leaching data would refinethe risk assessment by eliminating the useof default assumptions of the amount that could be leached.4) What is triggering the need for this data?IPBC is labeled for use as a preservative in “Leather” on label #464-8214 (approved4/28/10) and there are nohuman contact restrictions listedon the label for this use.Page 36 of 39Appendix A- Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the DataN/A Textiles Leaching Study 1) What is the value of the study?Dermal and incidental oral exposures to IPBC are expected during use of consumer goodssuch as clothing, towels and blankets made fromtextiles that are treated with spin finishesthat are preserved with IPBC. There areno leaching studies available to assess theseexposures.2) How would the data be used?The leaching data would be used to assessIPBC exposures that result from the use ofclothing, towels and blankets made from textiles that are treated with spin finishes that arepreserved with IPBC.3) How could the data affect the risk assessment?The IPBC specific leaching datawould refine the risk assessment by eliminating the use of default assumptions of theamount that could be leached.4) What is triggering the need for this data?IPBC is labeled for use as a preservative in“Spin-finish solution inthe textile industry”on label # 67071-44 (approved 3/31/10) and there are no human contact limitations listedon the label for this use.Page 37 of 39Appendix A- Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the Data875.2300 Surface ResidueDissipation (HouseholdFloors)1) What is the value of the study?Dermal and incidental oral exposures to IPBCare expected for toddlers who sit or play onhousehold floors after they are cleaned with floor cleaners that are preserved with IPBC.Surface residue dissipation data are needed to accurately assess these exposures.2) How would the data be used?The surface residue data would be used to assess IPBC exposures that result from the useof floor cleaners preserved with IPBC.3) How could the data affect the risk assessment?The surface residue data will be used during registration review to decide if the dermaland incidental oral exposuresto toddlers playing on floorstreated with IPBC generates arisk of concern that requires mitigation.This mitigation could include reduction of theapplication rate or elimination of the use.If surface residue dataare not available, thenthe standard assumption of 100 percent transferable surface residue will be used whichmight overestimate the risk and require excessive mitigation.4) What is triggering the need for this data?IPBC is labeled for use as a preservativein “Household, consumer, industrial, andjanitorial products such as liquid and solidair fresheners, dish detergents, laundryproducts, soaps and detergents,non-food contact surface cleaners,floor care products,bathroom cleaners, window cleaners, fabriccare products, automotive care products andfurniture care products”.Page 38 of 39Appendix A- Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the Data875.2300 Surface ResidueDissipation (TreatedWood)1) What is the value of the study?Dermal and incidental oral exposures to IPBCare expected for toddlers who sit or play onIPBC treated wood surfaces. Surface residuedissipation data are needed to accuratelyassess these exposures.2) How would the data be used?The surface residue data would be used to assess IPBC exposures that result from contactwith wood treated with IPBC.3) How could the data affect the risk assessment?The surface residue data will be used during registration review to decide if the dermaland incidental oral exposuresto toddlers playing on wood surfaces floors treated withIPBC generates a risk of concern that requires mitigation. This mitigation could includereduction of the application rate or eliminationof the use. If surface residue data are notavailable, then the standard assumption of 1.0 ug/cm2transferable surface residue will beused which might overestimate the risk and require excessive mitigation.4) What is triggering the need for this data?IPBC is labeled for use as a wood preservative applied to fresh cut lumber.Page 39 of 39Appendix A- Exposure Study Justifications for IPBC Registration ReviewGuidelineStudy TitlePractical Utility of the Data875.1700 Product Use Information 1) What is the value of the study?Product use information is a description of howthe product is actuallyapplied; it is not afield study. A description of how this productis used would provide for a comprehensiverealistic assessment of its potential applications.2) How would the data be used?The product use information will be used to define and characterize the exposurescenarios that will be assessed in the risk assessment.3) How could the data affect the risk assessment?A complete description of product use would ensure that the risk assessment is inclusiveof the types of exposures occurring during use and that these exposures are accuratelyassessed.4)What is triggering the need for this data?The need for a risk assessment under Registration Review in turn necessitates that the riskassessor understand how the product is used.