formulations of paints, coatings, stucco , stains, and caulks containing 0.03-4% by weight in the final product.

There are 38 end-use products (EP) formula ted from these two MPs. Of the EPs, 30 are antifoulant boat paints containi ng Irgarol at 0.49-2.38% ai and eight, containing Irgarol at 3.5- 32.5%, are used to manufactu re paints (0.03-4% ai), coatings, stucco, stains, caulks, and build ing materials. Many of these treated materials are to be used outdoors only. Ir garol is used to prevent/control the growth of algae, slime, and plants on coated surfaces including fouling on submerged surfaces. To control other pests such as mussels and barnacles, many of the EPs also contain anot her pesticide, most frequently a coppercontaining compound. Some EPs also cont ain a fungicide or a bactericide. Most

labels warn that neither treated materials nor coated surfaces are to come in contact with food, feed, livestock, dairy ani mals, potable water, or living plants. There are no EPA or FDA tolerances or tolerance exemptions associated with the use of Irgarol.

Irgarol has low to moderate acute mammali an toxicity (Toxicity Category III or IV). It is a moderate de rmal sensitizer. In a mini mally-acceptable developmental toxicity study in rats, the maternal NOAEL was 50 mg/kg/day based on reduced mean daily food consumption and clinical signs at the LOAEL of 150 mg/kg/day (MRID 40684914). The developmental NOAEL was >300 mg/kg/day (HDT). It was the maternal NOAEL of 50 mg/kg/day from this study that was selected by

the ADTC on 1/29/03 for use to calculat e short- and intermediate-term oral and inhalation risks in the 5/13/03 occupationa l and residential assessment by D. Aviado (D286523). Note that a 2006 90- day dog oral toxicity study (MRID 47042106) has been deemed to be unacceptabl e because the doses selected (0.8-38 mg/kg/day) were insufficiently high to elicit adverse effects. However, the

maternal NOAEL from a 2006 rabbit dev elopmental toxicity study was 15 mg/kg/day based on decreased body weig ht, decreased body weight gain, and decreased food consumption at the LO AEL of 45 mg/kg/day (MRID 40684914).

Based on a 21-day rat dermal toxici ty study (MRID 40684912), short- and intermediate-term dermal risks are expecte d to be small as no adverse effects were incited by dermal doses up to the highest tested (1000 mg/kg/day).

In the event long-term dermal exposure of workers is possible, e.g. military or professional boat/ship hull pai nters, the 90-day oral toxi city study in rats (MRID 42239401) could be used for risk assessment. In this study, the NOAEL was 8.2 mg/kg/day based on a number of adverse effects observed at the LOAEL of 59 mg/kg/day. These adverse effects included: decreased red blood cells, hemoglobin (males), hematocrit, and b ilirubin and increased MCH, MCHC, and cholesterol. Decreased testicular weigh t, testicle weight/body weight ratio, and ovary weight resulted as did a mammary carcinoma in one female at the LOAEL. Evidence was provided (MRID 42500001) to satisfy the Agency that the single mammary tumor was a spontaneous occurr ence and that there were no Irgarolrelated morphological or histologica l effects on the epididymides (MRID 42500002) (11/30/92 T. McMahon).

2In the minimally-acceptable developmental to xicity study in rats, the maternal NOAEL was 50 mg/kg/day based on reduc ed mean daily food consumption and clinical signs at the LOAEL of 150 mg/kg/day (MRID 40684914). The developmental NOAEL was >300 mg/kg/ day (HDT). In the 2006 rabbit developmental toxicity study, the mate rnal NOAEL was 15 mg/kg/day based on decreased body weight, decreased body weight gain, and decreased food consumption at the LOAEL of 45 mg/kg/day (MRID 40684914). The developmental NOAEL was 15 mg/kg/day based on increased post-implantation loss, decreased fetal body weight, and delayed fetal development occurring at the LOAEL of 45 mg/kg/day. As development al effects were not observed in rats at the HDT and as the developmental effe cts in rabbits were fairly generalized and occurred at the same dose eliciting mate rnal effects, ther e is no evidence of increased sensitivity of the developing fetus relative to adult animals.

A two-generation rat reproductive toxici ty study was conducted in 2006 (MRID 46822901). It was screened 8/28 /06 (S. Malish, D331274) and determined not to necessitate an expedited review under FIFR A 6(a)(2); therefor e, it has not yet been thoroughly reviewed. Irgarol was admin istered to male and female rats in the diet over two generations at 0, 20, 120, and 720 pp m (mean doses of ♂ and ♀ about 1.5, 9, and 55 mg/kg/day) fo r at least 70 days premating and during pairing and gestation. Females were also fed at about 2.8, 17, and 105 mg/kg/day (mean of P and F1 generations) during the lactation period (days 1-14 postpartum). The NOAEL for maternal effects (mean of P and F1) was 9.5 mg/kg/day based on the following adverse effects occurring at the LOAEL of 58 mg/kg/day: reduced food consumption, reduced body weight gain, increased kidney and liver weights, reduced uterus and ovar y weights, and adverse histopathology in the kidney, ovary, ut erus, and vagina. The NOAEL for reproductive effects was 55 mg/kg/day (HDT) due to the absence of adverse effects on any of the reproductive par ameters evaluated. The NOAEL for pup developmental effects was 17 mg/kg/day based on reduced organ weight and decreased body weight of F1 and F2 pups during lactation at the LOAEL of 105 mg/kg/day. The NOAEL for pup behavioral effects was 17 mg/kg/day based on reduced locomotor activity of F1 male pups at the LOAEL of 105 mg/kg/day. In summary, Irgarol induced no adverse effects on fertility/reproductive parameters even though histopathology and reduced organ weights were observed in organs and structures of the reproductive system of P and F1 animals. Any effects on pup behavior or pup development occurred at the same dose level causing maternal toxicity indicating that devel oping and young animals have no increased sensitivity to Irgarol compared to adults.

To comply with FIFRA 6(a)(2) requirement s, CIBA Corp. submi tted two reports in 2008 to address adverse ecological effects potentially due to endocrine disruption. Agency screening (N. Elkass abany, 11/25/08) determined that these studies need not receive an expedit ed review and, to date, have not been reviewed. Expert statements were submitte d to refute the conclusion that Irgarol adversely affects reproduction of a snail and an isopod via an endocrinedisrupting mode of action in a freshwater indoor me socosm study conducted by

the German Federal Environmen t Agency (MRID 47569002). Also, a

3recombinant yeast screening study indi cated that Irgarol did not exhibit estrogenic, androgenic, anti-estrogenic, or anti-androgenic activity (MRID 47569001).

Dermal absorption was studied in an in vivo rat study (2006; MRID 47042104) in which skin was treated with [ 14 C]-Irgarol at 0.029 mg/cm 2 applied in a ready-touse boat paint. Recovery of the adminis tered radioactivity from skin plus adhered paint was 98.43% (±1.49%) after 10 hr, 94.61% (±2. 02%) after 24 hr, and 87.63% (SD not given) after 72 hr. The maximum dermal absorption was

4.9% which occurred at 72 hr. An in vitro comparison of rat skin and human skin was also conducted as part of this study. The [ 14 C]-Irgarol at 0.029 mg/cm 2 in a ready-to-use boat paint was also applied to 500- μ thick membranes mounted in diffusion cells. The receptor fluid was analyzed every 15-60 min for 24 hr after

which time the membranes were rinsed. The mean absorbed dose was 12% through rat skin and 1.4% through human skin. It was estimated that, in vitro , rat skin is about 9.4 times more permeable to Irgarol than human skin. Although

neither of these studies was deemed to be acceptable (S. Malish, 7/18/07, D338424), they indicate that there is a low rate of derma l absorption of Irgarol by human skin. This is consistent with the lack of adverse effects in the 21-day rat dermal toxicity study (MRID 40684912) at doses up to the highest tested (1000 mg/kg/day).

Irgarol is fairly rapidly metabolized and excreted by rats (MRID 47042103). Within 3-4 days of an oral dose of [ 14 C]-Irgarol at 20 or 100 mg/kg, about 88 or

94% of the administered 14 C, respectively, was excreted. The bulk of this (65% of the low dose and 80% of the high dose) was biliary and thus was excreted in

the feces. A lesser amount of the administered radioacti vity was excreted in the

urine: 23% of the low dose and 14% of the high dose. The principle rat metabolites were sulfur conjugates: M1 is the S-glucuronide, M2 is the Sglutamic acid, and M4 is the S-glycine c onjugate; M4 account ed for 45% of the administered dose (S. Malish, 7/18/07, D338424). Note that all of these mammalian metabolites retain the cyclopr opyl group and are conjugated – most likely to detoxify them and/or to fac ilitate excretion. However, several photodegradates identified in laboratory studies and natural waters (also named M1, M2, and M3) do not re tain the intact cyclopropyl group and have not been conjugated [T. Arai, et al. (eds.) 2009].

Dietary (food) exposure to Irgarol is not expected to occur because all uses are outside and many of the us e sites are inherently nonfood such as boat bottoms, stucco, and building materials. Although ce rtain treated paints, coatings, stains, and caulks could be applied to surfaces having food contact, such as crop harvesting equipment or commodity shipping bins, four of eight EP labels prohibit use that may result in contact with f ood, feed, livestock, dairy animals, potable water, or living plants. The remaini ng four EP labels should be amended to bear this prohibition.

The registered uses of Irgarol could resu lt in contamination of surface water and groundwater because the algaecide is expect ed to slowly leach from antifoulant4painted boats or structures . Also, wastewater containing residues may be discharged from facilities manufacturing pai nts, coatings, stucco, stains, caulks, and building materials formulated with Irgarol. Finally, leaching of residues from outdoor surfaces covered with or compri sed of Irgarol-treated materials may occur. Published literature indicates that abiotic hydrolysis, photolysis, and microbial metabolism will occur slowly in water. There is evidence that the degradates, which are closely related to Irgarol, are persistent in the aquatic environment. In fact, these degradates have been detected in coastal waters. Therefore, there is the potential for drinking water ex posure to Irgarol residues to occur. The need for a drinking water ex posure assessment will be revisited upon

submission and review of the environmental fate data the Agency anticipates needing. These environmental fate data will be useful to determine if Irgarol can pass through wastewater treatm ent facilities into drinking water or migrate into residential groundwater wells as a resu lt of its current use patterns.

Manufactured materials formulated with Irgar ol to protect the dry film (paints, coatings, stucco, stains, caulks, and build ing materials) from algal growth are permitted to be used outdoors only. They may generally be applied (including the boat paint ECs) by homeowners and other nonoccupational individuals thus resulting in residential exposure. Due to the nature of the treated materials and use sites as well as the low volatility of Irgarol, exposure of children is expected

to be minimal. Data are needed to esti mate residential or other nonoccupational exposure associated with application/us e of Irgarol paints and coatings. A

residential risk assessment will be needed. Provided that evidence is submitted to demonstrate that all preserved mate rials are labeled “For outdoor use only,” residential exposure data and risk assessment will be needed only for outdoor exposure scenarios.

As dietary (food) human exposure is not expected to result from the currently registered Irgarol uses, aggregate risk is lik ely to consist of residential exposure and, possibly, drinking water exposure. However, the need for a drinking water exposure assessment (and inclusi on in an aggregate assessment) will be determined upon submission and review of the environmental fate data the Agency anticipates needing.

Occupational exposures fall into several ge neral categories: (i) direct-pouring of Irgarol 1051 (EPA Reg. No. 40810-11) 98.1% MP to formulate antifoulant paint EPA-registered EPs; (ii) direct-pouring of 3.5-32.5% EPs or Irgarol 1071 (EPA Reg. No. 40810-15) 98.1% MP to preserve paints, coatings, stucco, stains, caulks, and building materials; (iii) cons truction workers/roofers/painters working with preserved building materials such as indoor latex paints, vinyl roofing, or elastomeric roofing; and (iv) painting boat hulls and other aquatic surfaces with EPA-registered EPs that serve as antifoul ant coatings/paints. No chemicalspecific or site-specific exposure data are available to estimate Irgarol exposures to occupational handlers except severa l studies addressing residue migration

from dried films of a number of EP antifoulant paints as well as three plastic polymers in association with the pending registration of EPA File No. 40810-RA in 2003 (this product is still pending).

5The primary sources of information for th is assessment were the 6/2/03 Hazard Assessment by J. Chen (D286522) and the 5/13/03 occupational and residential assessment by D. Aviado (D286523). At th at time, the lack of a developmental toxicity study in nonrodents and a reproductive toxicity study were cited as data deficiencies necessitating the applic ation of an additional 10x database uncertainty factor. Six Irgarol toxicity studies were submitted by Ciba Specialty Chemicals Corp. in 2006 (90-day dog oral toxicity, rabbit developmental toxicity, rat two-generation reproductive toxicity, rat in vivo dermal penetration, in vitro comparative rat vs. human skin penetration, and rat metabolism). These studies

have been considered in this Human Heal th Scoping Document. The purpose of

this document is to determine whether sufficient data are available to support registration review and whether new human health assessments are needed to reflect current use patterns, regulations , and policies. The Agency’s rationale for requiring additional data and/or c onducting new risk assessments under the registration review process hav e been provided in Appendix A.

Section 1. Chemical Identity

Table 1.1 Chemical Identity

Common Name Irgarol, cybutryn

Chemical Name 1,3,5-Triazine-2, 4-diamine, N-cyclopropyl-N’-(1,1- dimethylethyl )-6-(methylthio)- Synonyms s-Triazine, 2-(tert-but ylamino)-4-(cyclopropylamino)-6- (methylthio)-

Molecular Formula C 11 H 19 N 5 S Molecular Weight 253.4

PC Code 128996 CAS Registry Number 28159-98-0 Registration Review Case No. 5031

Chemical Structure

Irgarol is an odorless, whitish-yellow solid at room temperature (25 C) that melts at 127-130 °C. It has low solubility in water (7 ppm) and an octanol/water partition coefficient (log K O/W ) of 3.95 at 25 °C. Irgarol does not dissociate and has very low tendency to volatilize (vapor pressure = 6.6 x 10 -7 mmHg at 25 °C). Irgarol is fairly stable to hydrolysis (a t pHs of 5-9), microbial metabolism, and photodegradation.

6Section 2. Toxicology

The Irgarol toxicology database is consi dered adequate to permit the registration review process to continue. Summari zed below are the toxicology studies available at the time of the 5/13/03 assessment as well as the six toxicity studies

submitted since that time.

a. Acute Toxicity

Irgarol poses mild acute toxicity to rats (Toxicity Category III) via the oral route (LD 50 ≥ 200 mg/kg), the dermal route (LD 50 ≥ 200 mg/kg), and the inhalation route (LC 50 ≥ 4.09 mg/L) and is a slight eye irritant to rabbit (Toxicity Category III). It is a moderate skin sensitizer to guinea pigs and does not induce dermal irritation in the rabbit (Toxicity Category IV). [MRIDs 00160084, 40684907-40684909, 41099401, and 41891405]

b. Subchronic Toxicity

In a 21-day rat dermal study (MRID 40684912 ), five albino rats, Tif:RAIF (SPF) per sex per group received repeated dermal dosing of test compound at 0, 10, 100, or 1000 mg/kg/day for 6 hours/day, 5 days/week for 3 weeks. All rats survived during the course of this study. No signs or symptoms were observed in any of the dose groups. No erythema or edema reactions occurred either in the

animals of the control or the treated groups. The systemic NOAEL is greater than 1000 mg/kg/day (highest dose tested).

In a subchronic (90-day) rat toxicity st udy, Irgarol (99% ai) was administered to groups of male and female albino rats (20/sex/dose) by dietary admix (MRID 42239401). Doses were 0 ppm, 20 ppm (0 .89 and 0.90 mg/kg/day [M/F]), 150 ppm (8.37 and 8.20 mg/kg/day [M /F]), and 1000 ppm (58.63 and 59.32 mg/kg/day [M/F]). Toxicity was obser ved at the 1000-ppm LOAEL in male and female rats. Decreases in red cell count, hemoglobin, and hematocrit were observed, as were decreases in total bilirubin. Increased mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and increased

cholesterol were observed at the LO AEL. Decreased testicular weight and testicular/body weight ratio was observ ed in male rats at the LOAEL as was decreased ovarian weight in female s. A spermatocele and a mammary

carcinoma were observed at the LOAEL in one of 20 males and one of 20 females, respectively. Evidence was provided (MRID 42500001) to satisfy the Agency that the mammary tumor in the female at the LOAEL was a spontaneous occurrence and that there were no Irgarol-re lated morphological or histological effects on the epididymides (MRID 42500 002) (11/30/92 T. McMahon). Based on the results of this study, the sy stemic NOAEL was determined to be 8.2 mg/kg/day, and the systemic LOAEL wa s 59 mg/kg/day for both sexes.

In the 2006 90-day dog oral toxicity study (MRID 47042106), Irgar ol (98% ai) was administered to four groups of beagle dogs/sex /dose in the diet at dose levels of 0, 25, 100, 250, or 1000 ppm (equivalent in the male to 0, 0.8, 3, 8, or 32 mg/kg/

7day and in the female to 0, 0.9, 4, 9, or 38 mg/kg/day). A satellite recovery group

of four animals/sex/dose was maintain ed for 4 weeks on an Irgarol-free diet following dosing at 0, 250, or 1000 ppm. No treatment-related effects were seen including survival, body weight, food consumption, appearance and behavior, hematology, urinalysis, gr oss pathology, organ weight (absolute and relative), and histopathology. Increased cholesterol values were seen at the mid- and high-dose levels. Cholesterol values in the recovery group were still mildly elevated at the mid- and high-dose leve ls vs. the control group. Neither a NOAEL nor a LOAEL could be calculated. This 90-day oral toxicity study in the dog was considered not to be an accept able study (OPPTS GLN 870.3150) due to the lack of overt toxicity at any dose (S. Malish, 7/18/07, D338424). Higher

doses should have been used.

The subchronic inhalation toxicity of Irgarol is not understood. Although this chemical is only mildly irritating via t he inhalation route of exposure and it has a low vapor pressure (6.6 x 10 -7 mmHg at 25 °C), expos ure of residential and occupational antifoulant painters is likely via inhalation of aerosols. The Agency

is concerned that one of t he available oral-dosing to xicity studies will not be protective of the toxicity incited via the inhalation route of ex posure. Therefore, an inhalation toxicity study is expect ed to be needed at this time to assess the risks associated with this major route of exposure. The Agency also anticipates that a quantitative assessment of inhal ation risks posed by Irgarol should be conducted, especially reflecting application of Irgarol-preserved paint/antifoulant coatings.

c. Developmental Toxicity

In a developmental toxicity study in rats (MRIDs 40684913 and 40684914), naturally inseminated female Sprague- Dawley rats (25-31/group) were

administered Irgarol (97.6% a.i.) by arachis o il gavage at doses of 0, 50, 150, and 300 mg/kg/day on gestation days 6 through 15. Pushing of the nose through the sawdust bedding after dosing and decreased body weight gain on days 6-15 were observed at the 300 mg/kg/day dos e level. Reduced food consumption was also observed at the high dose on days 6-10. There were no significant Cesarean section observations at any dos e level in this study. The increased post-implantation loss observed at the high dose (two-fold higher than control)

was not treatment-related as the data were derived from only one dam. No

abnormal external or skeletal observati ons were noted in this study from

examination of fetuses. The Maternal toxicity LOAEL was determined to be 150 mg/kg/day (decreased body weight gain and clinical signs) and the Maternal toxicity NOAEL was determined to be 50 mg /kg/day. The Developmental toxicity

NOAEL was determined to be >300 mg/kg/da y (HDT), and the Developmental toxicity LOAEL was not established. The ADTC considered this study to be minimally acceptable, and recommended t hat the study be repeated using a higher top dose. The animals could have tolerated higher doses and the effects observed at 300 mg/kg/day were not toxicologically significant.

8In a second developmental toxicity study (MRID 47042105) TK 13079, Irgarol (98% a.i., Batch No. 34076FC4) was administered to 20 female Himalayan rabbits/dose by gavage at dose levels of 0, 5, 15, or 45 mg/kg/day (in 0.5% aqueous methyl-cellulose) from days 6 throu gh 27 of gestation. Maternal toxicity was observed at 45 mg/kg/day and inclu ded decreased body weight, decreased body weight gain, and decreased food consum ption. There were no treatmentrelated effects on maternal survival or c linical signs. The maternal NOAEL is 15 mg/kg/day based on decreased body weigh t, decreased body weight gain, and decreased food consumption at the ma ternal LOAEL of 45 mg/kg/day. Treatment-related effects on developm ental parameters observed at 45 mg/kg/day included increased post-impl antation loss, decreased fetal body weights, and increased incidences of del ayed ossification. The decreased fetal body weights were attributed to maternal toxicity. The delayed ossification was attributed to delayed fetal development, as evidenced by decreased fetal body weight in this group. The developm ental LOAEL is 45 mg/kg/day, based on increased post-implantation loss, decreas ed fetal body weight, and delayed fetal development. The developmental NOAEL is 15 mg/kg/day.

As developmental effects were not obser ved in rats at the HDT and as the developmental effects in rabbits were fairly generalized and occurred only at the same dose eliciting maternal effects, ther e is no evidence of increased sensitivity of the developing fetus relative to adult animals.

d. Reproductive Toxicity

A two-generation rat reproductive toxici ty study was conducted in 2006 (MRID 46822901). It was screened 8/28 /06 (S. Malish, D331274) and determined not to necessitate an expedited review under FIFR A 6(a)(2); therefor e, it has not yet been thoroughly reviewed. Irgarol was admin istered to male and female rats in the diet over two generations at 0, 20, 120, and 720 pp m (mean doses of ♂ and ♀ about 1.5, 9, and 55 mg/kg/day) fo r at least 70 days premating and during pairing and gestation. Females were also fed at about 2.8, 17, and 105 mg/kg/day (mean of P and F1 generations) during the lactation period (days 1-14 postpartum). The NOAEL for maternal effects (mean of P and F1) was 9.5 mg/kg/day based on the following adverse effects occurring at the LOAEL of 58 mg/kg/day: reduced food consumption, reduced body weight gain, increased kidney and liver weights, reduced uterus and ovar y weights, and adverse histopathology in the kidney, ovary, ut erus, and vagina. The NOAEL for reproductive effects was 55 mg/kg/day (HDT) due to the absence of adverse effects on any of the reproductive par ameters evaluated. The NOAEL for pup developmental effects was 17 mg/kg/day based on reduced organ weight and decreased body weight of F1 and F2 pups during lactation at the LOAEL of 105 mg/kg/day. The NOAEL for pup behavioral effects was 17 mg/kg/day based on reduced locomotor activity of F1 male pups at the LOAEL of 105 mg/kg/day. In summary, Irgarol induced no adverse effects on fertility/reproductive parameters even though histopathology and reduced organ weights were observed in organs and structures of the reproductive system of P and F1 animals. Any effects on pup behavior or pup development occurred at the same dose level causing

9maternal toxicity indicating that devel oping and young animals have no increased sensitivity to Irgarol compared to adults.

e. Chronic Toxicity

A chronic toxicity study is not availabl e for Irgarol. In the 6/2/03 Toxicology Review (J. Chen, D286522) and the 5/13/03 risk assessment (D. Aviado, D286523), this antimicrobial was cons idered to be a nonfood chemical; the registered uses are still considered to be nonfood. Upon receipt and review of the environmental fate data considered to be needed, a determination of the extent of Irgarol exposure via drinki ng water will be made. Drinking water risks and long-term dermal and inhalation risks ma y be calculated using the 90-day rat oral subchronic toxicity endpoint. As a result, a chronic toxicity study has been

determined not to be needed at this time. The available toxicity database is adequate for the conduct of any needed human health risk assessments.

f. Carcinogenicity

A carcinogenicity study for Irgarol is not available. The absence of positive results in the available mutagenicity studi es (below) provide some evidence that Irgarol is not a mutagen with the potential to be a mammalian carcinogen. The available toxicity database is adequat e for the conduct of any needed human

health risk assessments.

g. Mutagenicity

In the Ames Salmonella test (MRID # 40684915), Irgarol was nonmutagenic to TA 98, TA100, TA100, TA102, TA1535 and TA1537 strains of Salmonella typhimurium either with or without metabolic activation at tested concentrations of 20, 78, 313, 1250, & 5000 μ g/plate (0.1ml). Irgarol was nonmutagenic in the in

vitro Chinese hamster (CCL61) forward mutation assay and Chinese Hamster (V79) with or without metabolic activati on at the tested concentrations (MRID 40684916 and 41578303). Irgarol did not cause DNA damage or inducible repair in rat hepatocytes in the DNA repair assay (MRID 40684918). The tested concentrations were 0.3, 3, 5, 15, 20, and 30 μ g/ml. Irgarol had a negative effect

in the in vivo Chinese hamster micronucleus test (MRID 40684917) at all the three sampling times (16, 24, & 48 hrs posttreatment) at the dose level tested (3334 mg/kg). The results of these tests i ndicate that Irgarol is not likely to be mutagenic.

h. Potential Endocrine Effects

To comply with FIFRA 6(a)(2) requirement s, CIBA Corp. submi tted two reports in 2008 to address adverse ecological effects potentially due to endocrine disruption. Agency screening (N. Elkass abany, 11/25/08) determined that these studies need not receive an expedit ed review and, to date, have not been reviewed. Expert statements were submitted to refute the conclusion that Irgarol adversely affects reproduction of a snail and an isopod via an endocrine10disrupting mode of action in a freshwater indoor me socosm study conducted by

the German Federal Environmen t Agency (MRID 47569002). Also, a recombinant yeast screening study indi cated that Irgarol did not exhibit estrogenic, androgenic, anti-estrogenic, or anti-androgenic activity (MRID 47569001).

Irgarol is a member of a class of pestici des collectively referred to as “triazine” pesticides. The triazines are derivatives of the s-triazine moiety, manufactured by the reaction of trichlorocyanuric acid with appropriate intermediates. Several classes of compounds result from thes e reactions, and include the s-triazine herbicides, the sulfonyl urea herbici des with an s-triazine moiety, and

miscellaneous s-triazines.

The Agency has examined the triazine class of pesticides with respect to a potential common mechanism of toxicity. This examination may be found at http://www.epa.gov/oppsrrd1/cumulative/triazines/triazinescommonmech.pdf

. Several members of this class have been id entified as causing toxicity through a similar mechanism of action. Specifically, atrazine, simazine, propazine, and certain degradates are considered to ac t through disruption of the hypothalamicpituitary-gonadal axis to attenuate the lutein izing hormone surge. As a result of this attenuation, exposure of the anima l to estrogen is continuous, providing an

environment conducive to the devel opment of mammary gland tumors. Mammary gland tumors have been observed in female rats after administration of these chemicals, and the postulated m ode of action of t he triazine pesticide atrazine has been reviewed by the FIFRA Sc ientific Advisory Panel and has been found to be plausible (U.S. EPA, 2000).

In the case of Irgarol, stru ctural similarity exists wit h at least one member of the triazine class, namely Terbut ryn. In the subchronic toxicity study conducted using Irgarol, the induction of mammary carcinoma at 1000 ppm occurred. This is similar to mammary tumors being induced by the close structural analog Terbutryn at 3000 ppm although other triazine pesticides induce mammary

tumors after chronic administration. T he induction of a mammary tumor in a rat dosed with Irgarol at 1000 ppm for onl y 90 days as opposed to chronic dosing raises concern and suggests that Irgarol shares a similar mechanism of mammary tumor production to other tria zine pesticides. However, there are no mechanistic data specific to Irgarol t hat have been generated to determine if it causes any disruption of the hypothalam ic-pituitary-gonadal axis. Pharmacokinetic data for Irgarol have also not been generat ed to permit comparison with those of other structurally-similar tr iazine pesticides. Without additional data such as the above, neither can it be determined whether Irgarol shares a common mechanism of toxicity with other triazine pesticides nor can it be completely ruled out.

i. Dermal absorption

Dermal absorption was studied in an in vivo rat study (2006; MRID 47042104) in which skin was treated with [ 14 C]-Irgarol at 0.029 mg/cm 2 applied in a ready-to11use boat paint. Recovery of the adminis tered radioactivity from skin plus adhered paint was 98.43% (±1.49%) after 10 hr, 94.61% (±2. 02%) after 24 hr, and 87.63% (SD not given) after 72 hr. The maximum dermal absorption was

4.9% which occurred at 72 hr. An in vitro comparison of rat skin and human skin was also conducted as part of this study. The [ 14 C]-Irgarol at 0.029 mg/cm 2 in a ready-to-use boat paint was also applied to 500- μ thick membranes mounted in diffusion cells. The receptor fluid was analyzed every 15-60 min for 24 hr after

which time the membranes were rinsed. The mean absorbed dose was 12% through rat skin and 1.4% through human skin. It was estimated that, in vitro , rat skin is about 9.4 times more permeable to Irgarol than human skin. Although

neither of these studies was deemed to be acceptable (S. Malish, 7/18/07, D338424), they indicate that there is a low rate of derma l absorption of Irgarol by human skin. This is consistent with the lack of adverse effects in the 21-day rat dermal toxicity study (MRID 40684912) at doses up to the highest dose tested (1000 mg/kg/day).

j. Rat Metabolism

Irgarol is fairly rapidly metabolized and excreted by rats (MRID 47042103). Within 3-4 days of an oral dose of [ 14 C]-Irgarol at 20 or 100 mg/kg, about 88 or

94% of the administered 14 C, respectively, was excreted. The bulk of this (65% of the low dose and 80% of the high dose) was biliary and thus was excreted in

the feces. A lesser amount of the administered radioacti vity was excreted in the

urine: 23% of the low dose and 14% of the high dose. The principle rat metabolites were Sulfur conjugates: M1 is the S-glucuronide, M2 is the Sglutamic acid, and M4 is the S-glycine c onjugate; M4 account ed for 45% of the administered dose (S. Malish, 7/18/07, D338424). Note that all of these mammalian metabolites retain the cyclopropyl group and are conjugated – most likely to detoxify them and/or to fac ilitate excretion. However, several photodegradates identified in laboratory studies and natural waters (also named M1, M2, and M3) do not re tain the intact cyclopropyl group and have not been conjugated [T. Arai, et al. (eds.) 2009].

k. Toxicology Data Needs

The Agency anticipates the need for a 90-day rat inhalation toxicity study testing Irgarol.

Section 3. Dietary Exposure

a. Food Exposure

Dietary (food) exposure to Irgarol is not expected to occur because all uses are outside and many of the us e sites are inherently nonfood such as boat bottoms, stucco, and building materials. Although ce rtain treated paints, coatings, stains, and caulks could be applied to surfaces having food contact, such as picnic tables, crop harvesting equipment, or co mmodity shipping bins, product labels

12prohibit use that may result in contact with food, feed, livestock, dairy animals, potable water, or living plants. The label for the MP (Irgarol 1071; EPA Reg. No. 40810-15) from which these EPs are fo rmulated clearly specifies that manufactured (treated) products are not to be used wher e they can contact food; therefore, all EP labels shoul d clearly limit use of preserved materials to nonfood

areas.

b. Drinking Water Exposure

The registered uses of Irgarol could resu lt in contamination of surface water and groundwater because the algaecide is expect ed to slowly leach from antifoulantpainted boats. Also, wast ewater containing residues may be discharged from facilities manufacturing paints, coatings , stucco, stains, caulks, and building materials formulated with Irgarol. Finally, leaching of residues from outdoor surfaces covered with Irgarol-treated mate rials may occur. Published literature indicates that abiotic hydrolysis, phot olysis, and microbial metabolism will occur slowly in water. There is evidence t hat the degradates, which are closely related to Irgarol, are persistent in the aquatic environment. In fact, these degradates

have been detected in a number of coastal waterways. Therefore, there is the potential for human exposure to Irgarol resid ues in drinking water to occur. The need for a drinking water exposure asse ssment will be revisited upon submission

and review of the environmental fate dat a the Agency anticipates needing.

These environmental fate data will be usef ul to determine if Irgarol can pass through wastewater treatment facilities into drinking water or migrate into residential groundwater wells as a resu lt of its current use patterns.

Section 4. Residential Exposure

The dry film of paints, c oatings, stucco, stains, and caulks and finished building materials are protected from algal growth by formulating with one of eight Irgarol EPs. These treated materials may be used in residential and public settings thus resulting in residential and other nonoccupat ional exposures. Three of the eight EPs specifically limit use to outdoor produc ts such as exterior paints, two labels limit a few materials to outdoor use, wher eas three EPs are silent on the final use site of the preserved materials. The l abel for the MP (Irgar ol 1071; EPA Reg. No. 40810-15) from which these EPs are fo rmulated clearly specifies that manufactured (treated) products are to be used outdoors only; therefore, all EP labels should clearly limit use of preserved materials to the outdoors. Residential exposure of children to Ir garol is expected to be mini mal due to the nature of the

treated materials and use sites as well as t he low volatility of Irgarol. Adults in residential settings are expected to be expo sed to Irgarol via both the inhalation and dermal routes while painting or applying coatings or stains. Adult applicator and children’s postapplication exposure studies will be needed to permit the

needed assessment of residential risk. Prov ided that evidence is submitted to demonstrate that all preserved material s are labeled “For outdoor use only,” residential exposure data and risk assessment will be needed only for outdoor exposure scenarios.

13Also, the boat antifouling paint EPs may be applied by homeowners and other private boat-owners. Da ta are needed to estimate residential exposure associated with brush/roller and spray-app lication of Irgarol-treated paints or coatings. A residential risk assessment will be needed reflecting this boat antifoulant paint applic ation scenario.

Section 5. Aggregate Risk

As dietary (food) human exposure is not expected to result from the currently registered Irgarol uses, aggregate risk is lik ely to consist of residential exposure and, possibly, drinking water exposure. However, the need for a drinking water exposure assessment (and inclusi on in an aggregate assessment) will be determined upon submission and review of the environmental fate data the Agency anticipates needing.

Section 6. Occupational Exposure

Occupational exposures fall into several ge neral categories: (i) direct-pouring of Irgarol 1051 (EPA Reg. No. 40810-11) 98.1% MP to formulate EPA-registered antifoulant paint EPs; (ii) direct-pouring of 3.5-32.5% EPs or Irgarol 1071 (EPA Reg. No. 40810-15) 98.1% MP to preserve paints, coatings, stucco, stains, caulks, and building materials; (iii) cons truction workers/roofers/painters using or applying preserved building materials such as latex paints, vinyl roofing, or elastomeric roofing; and (iv) painting boat hulls and other aquatic surfaces, using paint rollers and airless sprayers wit h EPA-registered EPs that serve as antifoulant coatings/paints. No chemical -specific or site-specific exposure data are available to estimate Irgarol expos ures to occupational handlers except a preliminary study of three TBT alternativ e antifoulants includi ng Irgarol which was determined to be insufficient (D. Av iado, 3/31/98, D243433 and D243434); the full spectrum of worker exposure studies were recommended. Studies are also available addressing residue migration from dried films of a number of EP antifoulant paints as well as from th ree plastic polymers (MRID 45753201) in association with the pending registration of EPA File No. 40810-RA in 2003 (this product is still pending). Data are needed to estimate occupational exposures reflecting the four general categories listed above. These exposure estimates will be used to calculate occupational risks which also need to be assessed.

Section 7. Cumulative Risk

EPA does not have, at this ti me, available data to deter mine whether Irgarol has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. At this stage of this Registration Review, EPA has assumed that Irgarol does not have a common mechanism of toxicity with other substances. Duri ng the risk assessment stage, however, the

14Agency will address the possibility that Irgarol shares a common mechanism of toxicity with other substances incl uding members of t he Triazine Common Mechanism Group (CMG). Note that Irgar ol (cybutryn) was neither included in the Triazine Cumulative Assessment Group (CAG) nor a member of the Triazine

CMG associated with the 3/28/06 Triazine Cumulative Risk Assessment.

Section 8. Endocrine Disruption

As required under FFDCA section 408( p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingr edients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or

other such endocrine effects as the Admi nistrator may designate.” The EDSP employs a two-tiered approach to making t he statutorily requi red determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will det ermine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T

effect.

Between October 2009 and February 2010, EPA i ssued test orders/data call-ins for the first group of 67 chem icals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pat hways such as food and water, residential activity, and certain post-applicat ion agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors.

Irgarol is not among the group of 58 pesticide active ingredients on the initial list

to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accord ingly, EPA anticipates issuing future

EDSP test orders/data call-ins for a ll pesticide active ingredients.

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and t he Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/.

Section 9. Human Incident Data

There have been no human incidents repor ted in any of the OPP databases associated with exposure to Irgarol.

15Section 10. Over all Conclusions

There is no reasonable expectation of hum an dietary exposure to residues of Irgarol via food. No EPA or FDA regulati ons (tolerances or tolerance exemption) have been established for Irgarol. There ar e use patterns of Ir garol that could result in contamination of drinking wa ter. However, environmental fate data anticipated to be needed concerning Ir garol passage through wastewater treatment plants will be used to determi ne the likelihood of human drinking water

exposure.

The dry film of paints, coatings, stucco, stains, and caulks and finished building materials are protected from algal growth by formulating with one of eight Irgarol EPs. These treated materials may be used in residential and public settings thus resulting in residential and other nonocc upational exposures. Also, the boat antifouling paint EPs ma y be applied by homeowners and other private boatowners thus resulting in residential exposure. Studies are expected to be needed to estimate exposures reflecting these residential scenarios. A

residential risk assessment is recommended. Aggregate assessment of residential exposure and, possibly, dr inking water exposure, will then need to be

conducted.

Exposure studies are needed for the following scenarios to estimate inhalation and dermal exposures to occupational handler s: (i) direct-pour ing of Irgarol 1051 (98.1% MP) to formulate EPA-registered ant ifoulant paint EPs; (ii) direct-pouring of 3.5-32.5% EPs or Irgar ol 1071 (98.1% MP) to preserve paints, coatings, stucco, stains, caulks, and building material s; (iii) construction workers, roofers, and painters using or applying preserved build ing materials such as latex paints, vinyl roofing, or elastomeri c roofing; and (iv) painting b oat hulls and other aquatic surfaces with EPA-registered EPs that serve as antifoulant coatings/paints. Each

of these scenarios will need to be assess ed to estimate the risks to workers.

a. Data Needs

The Agency anticipates that the following toxicology study (utility and rationale provided in Appendix A) is needed:

Toxicology Data

• 90-day rat inhalation toxicity study (GLN 870.3465)

In addition, the nondietary exposure studi es listed below (utility and rationale provided in Appendix A) are anticipat ed to be needed to permit assessment of several residential and occupational handler scenarios.

Residential/Occupational Exposure Data

• Outdoor Dermal Expo sure (GLN 875.1100)

• Indoor Dermal Exposure (GLN 875.1200)

16• Outdoor Inhalation Ex posure (GLN 875.1300)

• Indoor Inhalation Ex posure (GLN 875.1400)

• Applicator Exposure Monitoring Data Reporting for Dermal and Inhalation Data (GLN 875.1600)

• Product Use Information (GLN 875.1700)

b. Risk Assessments Needed

• A dietary (drinking water) expos ure assessment may be needed to estimate any risk associated with l eaching of Irgarol residues into water from antifoulants, paints, coat ings, stucco, stains, caulks, and building materials formulated wit h Irgarol. The need for this assessment will depend on the outcome of the environmental fate data anticipated to be needed.

• Assessment of residential handle r risks reflecting exposures associated with use of preserv ed materials and antifoulant paint (brush/roller and airless spraye r) are expected to be needed.

• Residential (and possibly drinking water) sources of exposure will be aggregated to estimate aggregate risks.

• Risks to occupational handlers: (i) direct-pouring of Irgarol 1051 (EPA Reg. No. 40810-11) 98.1% MP to fo rmulate EPA-registered antifoulant paint EPs; (ii) direct-pouring of 3.5-32.5% EPs or Irgarol 1071 (EPA Reg. No. 40810-15) 98.1% MP to pres erve paints, coatings, stucco, stains, caulks, and building materials; (iii) using or applying preserved building materials such as latex pain ts, vinyl roofing, or elastomeric roofing (construction workers/roofer s/painters); and (iv) painting boat hulls and other aquatic surfaces with EPA-registered EPs that serve as antifoulant coatings/paints using br ush/roller and airless sprayer.

c. Recommended Label Changes

• Three of the eight EPs specifically limit use to outdoor products such as exterior paints, two labels limit a few materials to outdoor use, whereas

three EPs are silent on the final dis position (indoors vs. outdoors) of the preserved materials. The label fo r the MP (Irgarol 1071; EPA Reg. No. 40810-15) from which these EPs are fo rmulated clearly specifies that manufactured (treated) products are to be used outdoors only; therefore, all EP labels should clearly limit us e of preserved materials to the

outdoors. Confirmation is needed that all preserved materials treated with Irgarol to protect the film from algal growth are l abeled to restrict their use to outdoors only.

• The Irgarol 1071 MP also directs that treated materials may not be used in such a way as to contact food, feed, drinking water, livestock, or living plants. Of the eight EPs, four stat e the same whereas four are silent on this topic. The remaining four EP labels should be amended to also bear this prohibition

17Appendix A. Need for, and Uses of, the Data

Guideline Number: 870.3465 Study Title: 90-Day Inhalation Toxicity (Rat) Rationale for Requiring the Data

This study is required under the updated data requirements at 40 CFR 158.500 because, although Irgarol has very low vapor pressure, inhalable aerosols are created during application of preserved materials (especially airless paint spraying). The length of the study is important

because human handlers of Irgarol -treated materials will often be repeatedly exposed for weeks or months at a stretch. A 90-day inhalati on toxicity study has not been conducted and is required. The inhalation route is expected to be a major route of human exposure to Irgarol for several occupational and residential handler scenarios.

Practical Utility of the Data

1. How did the Agency make its earlier regulatory decisions without these data?

Earlier regulatory decisions were made having only oral toxicity studies and a 21-day dermal toxicity study. Route-to-route extrapolation of both dose and effect cannot be done with any confidence. As a major exposure route for several scenarios is inhalation, there is no toxicity study to demonstrate the types of adverse effects that may be manifested via the inhalation route of exposure or expressed at the lung-specific adverse effect dose. A dose and effect from this 90-day inhalation toxicity study are the most appropriate to be used as the hazard components of a quantitative inhalation risk assessment.

2. How will the data be used?

The data will be used to properly characterize and quantify the hazard and risks to occupational and residential handlers exposed to Irgarol associated with its use in such a way that a spray or aerosol is generated. This study will allow the selection of a dose and endpoint and the conduct of a risk assessment that is duration- and route-appropriate.

3. How could the data impact the Agency’s future decision-making?

In the absence of inhalation toxicity data, the Agency would have to estimate inhalation risks using an oral toxicity study and rely on the assumption that effects, absorption, distribution, and toxicity of Irgarol are the same via the oral and inhalation routes of exposure. The 90-day inhalation toxicity study will allow the Agency to refine its estimates of inhalation risks which allows greater confidence that risks from Irgarol will not be over- or underestimated. This study will permit appropriate label warnings, PPE, and any necessary risk mitigation.

18Guideline Number: 875.1100 Study Title: Outdoor Dermal Exposure

Guideline Number: 875.1200 Study Title: Indoor Dermal Exposure Rationale for Requiring the Data

The dermal exposure route is very important fo r exposure scenarios such as painting with antifoulants, caulking, or applying roofing shingles. However, very limited worker exposure monitoring data are available for antimicrobial pesticides, including materials preservatives used in paint and other consumer products. EPA would be forced to use these limited data to perform screening level risk assessments if it did not now require these studies. The existing data in the Chemical Manufacturers Association (CMA) database and Pesticide Handlers Exposure Database (PHED) for worker exposure scenarios are limited in scope and quality. The CMA data also has QA/QC problems, including the lack of field fortification, laboratory recoveries, and/or storage stability information. In addition, the CMA data have an insufficient number of replicates. EPA presented the need for addition al handler exposure data to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 Human Studies Review Board (HSRB) and both groups agreed that additional data are warranted. To protect workers from dermal exposures to pesticides, EPA requires de rmal exposure monitoring data. Chemicalspecific dermal exposure data are needed to esti mate handler exposures for the occupational

and residential uses.

Practical Utility of the Data

1. How did the Agency make its earlier regulatory decisions without these data?

The Agency conducted a risk assessment in 1998 using limited, preliminary exposure data concerning antifoulant application. No other quantitative assessments of registered uses have been conducted. Significant dermal exposure is associated with registered Irgarol uses. This triggers the need for chemical- and use pattern-specific occupational and residential exposure data upon which to base a quantitative risk assessment.

2. How will the data be used?

The dermal exposure data will be used to quantitatively assess the occupational and residential exposure of handlers applying antifoulant paints using sprayers and brush/rollers, handlers direct-pouring the preservative during the manufacturing of paint, coatings, stains, caulk, stucco, and building materials. These data will be used to assess Irgarol exposure of residential and professional handlers in a chemical- and use pattern-specific way.

3. How could the data impact the Agency’s future decision-making?

The dermal exposure data will be used to quantify dermal risks to occupational and residential handlers using the registered antifoulant paint products and materials preserved with Irgarol

. These data will be used to accurately quantify exposures for the first time.

19Guideline Number: 875.1300 Study Title: Outdoor Inhalation Exposure Guideline Number: 875.1400 Study Title: Indoor Inhalation Exposure Rationale for Requiring the Data

The inhalation exposure route is likely to be the most important for exposure scenarios such as application of antifoulant paint using paint rollers/airless sprayers where aerosols will be generated. However, very limited worker exposure monitoring data are available for antimicrobial pesticides, including antifoulants and material preservatives used in paint, caulk, and other building products. EPA would be forced to use these limited data to perform screening

level risk assessments for Irgarol if it did not now require these studies. The existing data in the Chemical Manufacturers Association (CMA) database and Pesticide Handlers Exposure Database (PHED) for worker exposure scenarios are limited in scope and quality. For the CMA data, inhalation concentrations were typically below the detection limits, so the unit exposures for the inhalation exposure could not be accurately calculated. The CMA data also has QA/QC problems, including the lack of field fortification, laboratory recoveries, and/or storage stability information. In addition, the CMA data have an insufficient number of replicates. EPA presented the need for additional handler exposure data to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 Human Studies Review Board (HSRB) and both groups agreed that additional data are warranted. To protect workers from inhalation exposure to pesticides, EPA requires inhalation exposure moni toring data. The data are required to support handler exposures for the industrial and residential uses. Practical Utility of the Data

1. How did the Agency make its earlier regulatory decisions without these data? The Agency conducted a risk assessment in 1998 using limited, preliminary exposure data concerning antifoulant application; there was low confidence in the risk estimates resulting. No quantitative assessments of other registered uses have been conducted. Significant inhalation exposure is associated with registered Irgarol uses. This triggers the need for chemical- and use pattern-specific occupational and residential exposure data upon which to base a quantitative risk assessment.

2. How will the data be used? The inhalation exposure data will be used to quantitatively assess the occupational and residential exposure of handlers applying antifoulant paints using sprayers and brush/rollers, handlers direct-pouring the preservative during the manufacturing of paint, coatings, stains, caulk, stucco, and building materials. These data will be used to assess Irgarol exposure of residential and professional handlers in a chemical- and use pattern-specific way.

3. How could the data impact the Agency’s future decision-making? The inhalation exposure data will be used to reliably estimate inhalation risks to occupational and residential handlers using Irgarol-treated antifoulant paints and building materials. If future risk assessments are performed without these data, the Agency will have to assume a significant degree of uncertainty in its regulatory decision-making process. The lack of these data could

result in underestimation or overestimation of handler risks. The former would result in the Agency not protecting human health whereas the latte r could greatly limit the flexibility of the Agency and registrants with respect to decisions made from high-end screening level assessments. If risks warrant mitigation, the in halation exposure data will provide the types of mitigation necessary, such as closed systems for commercial uses and/or potential removal of

uses from the label.

20Guideline Number: 875.1600 Study Title: Applicator Exposure Monitoring Data Reporting for Dermal and Inhalation

Data Rationale for Requiring the Data

This data requirement is linked to the dermal and inhalation exposure data also being required. The submission of these exposure monitoring data serves as quality assurance and control (QA/QC) for the dermal and inhalation data. These data are intended to ensure that the product manufacturer and registrant conducting the study adhere to a defined set of quality criteria and meet the study requirements of the Agency. These data allow the Agency to determine if the quality of data provided will serve the risk assessment needs of the Agency and support the registrant’s goal for registration review. S ubmission of exposure monitoring data reporting increases the Agency’s confidence in the data submitted.

Practical Utility of the Data

1. How did the Agency make its earlier regulatory decisions without these data?

There are currently only very limited, preliminar y exposure data that permitted an assessment of risk to only one Irgarol use scenario. As the study was unsatisfactory, the reporting data were likewise unsatisfactory. As a result, earlier regulatory decisions were based on an incomplete

and low-confidence assessment of risk.

2. How will the data be used?

These studies will be used to validate the data generated in the indoor and outdoor dermal and inhalation applicator exposure studies. These data are important because it allows EPA to assess the quality of each exposure study and thus the accuracy of the exposure calculations derived from that study. Information that must be submitted includes a description of the purpose of the study and what requirement(s) it is intended to satisfy, a summary of the study, a comprehensive section on materials, methods, and calculations, a section interpreting the scientific results of the study, a discussion of quality assurance, identification of the location of the raw data, and any references, communications, and protocols relevant to the conduct of the study.

3. How could the data impact the Agency’s future decision-making?

If the exposure monitoring data reporting is not submitted in conjunction with the indoor and outdoor dermal and inhalation applicator exposure studies, the Agency may not be able to utilize

the studies to the fullest extent to conduct it s human health exposure and risk assessments. Thelack of such data could cause the Agency to use inadequate surrogate data, resulting in a highend screening level risk assessment and a potential overestimation of exposures.

2122 Guideline Number: 875.1700 Study Title: Product Use Information Rationale for Requiring the Data

Product use information is a narrative description of which, when, and how materials are preserved when the product is actually applied; it is not a field study. A description of how products containing Irgarol are used will provide a comprehensive, realistic assessment of its potential applications and resulting handler exposure. Descriptions are needed of: (i) what specific types of materials are treated; (ii) what stage in the manufacturing process each material is treated; (iii) the conditions to which the Irgarol will be exposed (temperatures, pH’s, etc.); (iv) the rate of degradation of Irgarol ; etc. These will provide a comprehensive, realistic assessment of potential residential and occupational exposures. Therefore, these data are required.

Product use information permits EPA to more accurately assess pesticide exposure to applicators by describing how the pesticide is actually used and applied. EPA requires this information because differences in use can translate to significant differences in exposure and

thus risk.

The guideline for postapplication product use information was presented to the FIFRA Science Advisory Panel (SAP) in March 1998. (The draft guideline is available at http://www.epa.gov/scipoly/sap/meetings/1998/march/contents.htm .). The guideline for applicator product use information should be substantially similar to the one for postapplication. Practical Utility of the Data 1. How did the Agency make its earlier regulatory decisions without these data?

The Agency used its best professional judgment based on its years of experience and general use information from the registered product labels as well as product chemistry data.

2. How will the data be used?

The description of the materials preserved, application techniques, and physicochemical disposition will be used to determine the exposure scenarios for which exposure studies will be required for use in risk assessment and for the Agency to determine how representative the exposure data are of the “real-world” use scenarios.

3. How could the data impact the Agency’s future decision-making?

These data will enable the Agency to understand how the registered products are applied and to

ensure that the risk assessment is inclusive of the types of exposures occurring during pesticide use and from any potential postapplication contact. This information will permit a determination of which use patterns are expected to result in exposures less than the Agency’s level of concern, which ones must be supported by additional data, and which ones are likely to have risks of concern and, therefore, must be mitigated.