Page 1 of 40 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM DATE: September 29, 2005 SUBJECT: Para tertiary amylphenol ( 4 t amylphenol) and its sodium and potassium salts: AD Risk Assessment for the Reregistration Eligibility Decision ( RED) Document. Chemical Nos. 064101, 064111, 064112. Case No. 3016. DP Barcode: D316280 FROM: Deborah Smegal, MPH, Toxicologist/ Risk Assessor Myron Ottley, Ph. D., Toxicologist Tim McMahon, Ph. D. Senior Toxicologist Siroos Mostaghimi, Ph. D. Environmental Engineer Najm Shamim, Ph. D. Chemist Srinivas Gowda, Microbiologist/ Chemist David C. Bays Jonathan Chen, PhD., Toxicologist Antimicrobials Division ( 7510C)

THRU: Norm Cook, Chief Risk Assessment and Science Support Branch Antimicrobials Division ( 7510C)

TO: Killian Swift, Risk Manager Reviewer Team 36, Reregistration Antimicrobials Division ( 7510C)

Attached is the Revised Risk Assessment for Para tertiary amylphenol ( 4 t amylphenol) and its sodium and potassium salts for the purpose of issuing a Reregistration Eligibility Decision ( RED). The disciplinary science chapters and other supporting documents for the 4 t amylphenol RED are also included as attachments as follows: Page 2 of 40 4 t Amylphenol: Report of the Antimicrobials Divisions's Toxicology Endpoint Selection Committee ( ADTC), July 2005 Toxicology Science Chapter for the Reregistration Eligibility Decision Document, From M. Ottley/ D. Smegal to K. Swift, September 2005 D316279 Occupational and Residential Exposure Assessment for t Tert Amylphenol and Salts. S. Mostaghimi . September 2005. D316290 Product Chemistry of Para Tertiary Amylphenol, para tertiary amylphenol, sodium salt and para tertiary amylphenol, potassium salt. From A. N. Shamim to T. McMahon. D316275 Revised Environmental Fate Assessment of 4 tert Amylphenol and its Potassium and Sodium salts for the Reregistration Eligibility Decision ( RED) Document. From S. Gowda, Microbiologist to M. Hartman. September 29 2005, D322006 Ecological Hazard and Environmental Risk Assessment for 4 tert amylphenol and salts to be included in the RED. D. Bays to A. Heyward and K. Swift. October 2005, D316278 Incident Reports Associated with 4 tert amylphenol. J. Chen. May 2005, D316276 Dietary Exposure Assessments for the Reregistration Eligibility Decision. R. Quick. September 29, 2005. D316295. Page 3 of 40 1.0 EXECUTIVE SUMMARY.................................................................................................................... 4 2.0 PHYSICAL AND CHEMICAL PROPERTIES.................................................................................. 11 3.0. ENVIRONMENTAL FATE................................................................................................................ 12 4.0 HAZARD CHARACTERIZATION.................................................................................................... 13 4.1 Hazard Profile ........................................................................................................................... 13 4.2 FQPA Considerations.............................................................................................................. 16 4.3 Dose Response Assessment ..................................................................................................... 17 4.4 Endocrine Disruption .............................................................................................................. 18 5.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION............................................................ 19 5.1 Summary of Registered Uses ................................................................................................... 19 5.2 Dietary Exposure and Risk ...................................................................................................... 19 5.3 Drinking Water Exposure and Risk.......................................................................................... 21 5.4 Residential Exposure/ Risk Pathway......................................................................................... 22 5.4.1 Residential Handler........................................................................................................... 22 5.4.2 Postapplication Residential Exposure ................................................................................ 23 6.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION.................................. 26 6.1 Short and Intermediate Term Aggregate Risk ....................................................................... 27 6.2 Long Term Aggregate Risk ................................................................................................... 28 7.0 CUMULATIVE EXPOSURE AND RISK........................................................................................... 28 8.0 OCCUPATIONAL EXPOSURE AND RISK...................................................................................... 28 9.0 INCIDENTS......................................................................................................................................... 30 10.0 ENVIRONMENTAL RISK................................................................................................................. 31 11.0 DEFICIENCIES/ DATA NEEDS......................................................................................................... 36 12.0 REFERENCES .................................................................................................................................... 37 Page 4 of 40 1.0 EXECUTIVE SUMMARY 4 tertiary amylphenol ( 4 t amylphenol), and salts ( potassium and sodium) are active ingredients in disinfectant, food contact sanitizer and deodorizer products used in agricultural, food handling, commercial/ institutional/ industrial, residential and public access, and medical settings, primarily used on hard, non porous surfaces. The majority of the products are virucidal, fungicidal, tuberculocidal, bactericidal, pseudomonacidal, or staphylocidal. Examples of registered uses for 4 t amylphenol and salts include application to hard surfaces ( e. g., walls, floors, tables, fixtures), textiles ( e. g., clothing, diapers, mattresses, bedding), carpets, medical instruments, and agricultural equipment. Additionally, there are registered uses for fogging in occupational settings and air deodorization in both occupational and residential settings. Concentrations of 4 t amylphenol and salts in products range from 0.0027% to 10%. The products are formulated as soluble concentrates, ready to use liquid solutions, pressurized sprays, and impregnated wipes.

A potential outdoor use, wood protection to treat unseasoned forest products, is apparently no longer supported by any registrant. In addition, the registrant is no longer supporting uses in potable human drinking water systems.

Hazard: The toxicology database for 4 t amylphenol, in terms of guideline studies, is largely incomplete. Studies from the open literature provide limited information, and more data are needed to put together a complete profile.

4 t Amylphenol is a primary dermal irritant ( Category I) and is in Category III for acute oral toxicity based on guideline studies. It also appears to be an eye irritant ( Category I), and may be in Category III for acute dermal toxicity according to data from the open literature. However, acceptable guideline acute studies are not available for dermal, inhalation, primary eye irritation or dermal sensitization, and the literature data protocols were inadequate. Literature studies also indicate it is a skin sensitizer and possible depigmentation agent. In short term studies, 4 t amylphenol produced clinical signs along with decreased food consumption and body weight in a developmental toxicity study, but no systemic effects in a 13 week dermal study. The structural abnormalities and developmental delays that occurred in the developmental study, occurred at higher dose levels than the maternal effects, suggesting that increased quantitative susceptibility concerns are not warranted; however, the minimal maternal effects ( reversible clinical signs) seen in the presence of the developmental effects increases concern for qualitative susceptibility. Neither a developmental study in rabbits nor a reproduction study was available to provide confirmation. Available data suggest that 4 t amylphenol has endocrine disrupter capabilities ( uterotrophic and estrogenic effects) and increased bilirubin production in babies. In addition, this chemical is listed on a European list of " Chemicals purported to be endocrine disruptors".

4 t Amylphenol was negative for carcinogenicity in a subchronic skin painting study from the open literature. However, guideline studies for carcinogenicity are not available. All mutagenicity tests were negative.

Toxicity Endpoints: The toxicity endpoints used in this document to assess potential risks Page 5 of 40 include acute and chronic dietary reference doses ( RfDs), and short, intermediate and/ or long term incidental oral, dermal and inhalation doses. The Antimicrobials Division's endpoint selection committee ( ADTC) selected endpoints in April 2005. Since the toxicological endpoints selected for 4 tert amylphenol and 4 tert amylphenol salts are identical, a separate assessment was not conducted for each active ingredient.

Acute and Chronic RfDs: The acute RfD is 0.67 mg/ kg/ day for females ( 13 50 years, based on adverse developmental effects ( skeletal effects and decreased fetal body weight) at 500 mg/ kg/ day in a rat developmental study. The chronic RfD is 0.17 mg/ kg/ day based on clinical signs of toxicity and decreased body weight and food consumption at 200 mg/ kg/ day in a rat developmental study. An uncertainty factor of 300 ( 10X for interspecies extrapolation, 10X for intraspecies variability, and 3X for database uncertainties) was applied to the NOAEL to obtain the acute and chronic RfDs. A database uncertainty factor of 3x is applied to non occupational risk assessments for 4 t amylphenol, due to the number and significance of the data gaps including lack of repeated oral toxicity studies. An additional Food Quality Protection Factor ( FQPA) safety factor is applied, which is discussed below.

Incidental oral endpoints: The short and intermediate term incidental oral NOAEL is 50 mg/ kg/ day from a rat oral developmental toxicity study that noted clinical signs, decreases in body weight and body weight gain, coupled with decreased food consumption at 200 mg/ kg/ day. The target margin of exposure ( MOE) is 3,000 ( includes 10X FQPA factor).

Dermal endpoints: The short and intermediate term dermal NOAEL is 25 mg/ kg/ day, which is based on the lack of systemic effects identified up to and including a dose of 25 mg/ kg/ day in a rat subchronic dermal toxicity study. Uncertainty factors or " target" margins of exposure ( MOE) for 4 t amylphenol dermal exposures are 100 for occupational scenarios and 1,000 for residential scenario ( includes 10X FQPA factor). It should be noted that 4 t amylphenol caused dermal irritant effects following repeated dermal exposure at 10 mg/ kg/ day, and may also be a potential dermal sensitizer.

Inhalation endpoints: The short, intermediate and long term inhalation NOAEL is 50 mg/ kg/ day from a rat oral developmental toxicity study that noted clinical signs, decreases in body weight and body weight gain, coupled with decreased food consumption at 200 mg/ kg/ day. In the absence of data, it was conservatively assumed that inhalation absorption is equivalent to oral absorption ( i. e., 100%). For inhalation exposures, the uncertainty factors are 300 for occupational scenarios and 3,000 for residential scenarios ( includes 10X FQPA factor).

FQPA Safety Factor. The ADTC committee concluded that the hazard based FQPA safety factor should be retained at 10X. The toxicology data base is not complete with respect to assessing the increased susceptibility to infants and children as required by FQPA for 4 t amylphenol. The rat prenatal developmental study showed no quantitative evidence of increased susceptibility ( i. e., developmental NOAELs/ LOAELs were the higher than those for maternal effects). However, there was qualitative evidence of increased susceptibility as the fetal effects ( i. e., skeletal abnormalities, decreased body weight gain) were considered to be more severe than the maternal toxicity ( reversible clinical signs). In addition, there is an absence of developmental toxicity data in the rabbit, and an absence of reproductive toxicity data. Page 6 of 40 Furthermore, studies in the open literature suggest that 4 t amylphenol may be an endocrine disruptor. It increased non pregnant uterine weight in rats and was associated with elevated blood levels of bilirubin in children exposed to 4 t ampyphenol and other phenols in disinfectant. These studies, while not indicative, are suggestive of a basis for increased concern for reproductive and/ or developmental effects due to exposure to 4 t amylphenol. In addition, this chemical is listed on a European list of " Chemicals purported to be endocrine disruptors".

Based on Agency policy, a RfD modified by a FQPA safety factor is a population adjusted dose ( PAD) 1 FQPA Safety Factor. The Agency calculated an acute PAD and a chronic PAD, and uses this value to estimate acute and chronic dietary risk.

Dietary Exposure and Risk: The Agency has conducted a dietary exposure and risk assessment for use of 4 t amylphenol in a ready to use disinfecting solution. A counter top that is treated with this product may come into contact with food, which in turn may be ingested. This is considered to be an indirect food use. 4 t Amylphenol ( also known as phenol, 4 1,1 dimethylpropyl) ( CAS No. 80 46 6) has a tolerance exception in 40CFR 180.940 ( c) as a food contact sanitizer for use in food processing equipment and utensils with a not to exceed limit of 80 ppm. However, the maximum ingredient percentage for 4 t amylphenol in food handling establishments from the various labeled ready to use products is 0.054 % a. i ( 540 ppm), which exceeds the current tolerance exemption limitation. The Agency estimates that use of this product results in 4 t amylphenol food residues of 340 ppb ( µ g/ kg).

When assessing acute and chronic ( non cancer) dietary risk, AD considered potential dietary exposure to the U. S. population including infants and children, as well as to females of childbearing age ( 13 50 years). AD expresses dietary risk estimates as a percentage of the aPAD or chronic PAD. Dietary exposures that are less than 100% of the aPAD or cPAD are below the Agency's level of concern.

Acute Dietary Risk. AD has determined that, based on the assumptions and models used, the acute dietary risk from exposure to 4 t amylphenol does not exceed the Agency's level of concern for females of childbearing age, the only subpopulation examined. The dietary risk estimate is 2.7% of the acute PAD.

Chronic Dietary Risk. In the absence of data, screening level estimates used for the acute dietary risk analysis are used to assess potential chronic dietary exposure. The risk analysis assumes daily exposure from the hard surface disinfection of counter tops. The chronic non cancer dietary analysis indicates all risk estimates are below the Agency's level of concern for all population subgroups. The highest dietary risk estimate is 42% of the chronic PAD, for infants and children, assuming 10% of the residues are transferred to food. The Agency requires confirmatory data for this transfer rate because 100% residue transfer indicates risks of concern.

Water Exposure and Risk: There are no currently registered outdoor uses of 4 t amylphenol and its salts that are being supported by the registrant. The potential outdoor uses,

1 PAD = Population Adjusted Dose = Acute or Chronic RfD FQPA Safety Factor Page 7 of 40 wood protection to treat unseasoned forest products, and use in potable human drinking water systems are apparently no longer supported by any registrant. 4 t Amylphenol's use as a general disinfectant allows for the possibility of surface water contamination. However, the estimated value for biodegradation indicates it may biodegrade linearly within days in the aquatic environment, although ultimate biodegradation ( mineralization) may take months. The sodium and potassium salts of 4 t amylphenol are estimated to biodegrade within days to weeks. Because of the possibility of biodegradation in water and soils, 4 t amylphenol and its salts are not likely to contaminate surface and ground waters. Thus, a quantitative drinking water assessment was not conducted for these chemicals.

Residential ( Non Occupational) Exposure and Risk: Some products containing 4 t amylphenol are labeled for residential use as disinfectants and deodorizers. These products are for use on hard surfaces ( e. g., floors, walls, bathroom fixtures, trash cans, household contents), textiles ( e. g., clothing, diapers, and bedding), and carpets. Additionally, there are products which can be used to deodorize air in the home. There are no residential uses for products containing sodium 4 tert amylphenate or potassium 4 tert amylphenate. The following scenarios were considered for residential handlers: application of hard surface disinfectants via ( 1) mopping; ( 2) wiping; ( 3) trigger pump spray; and ( 4) aerosol spray.

The Agency also evaluated potential postapplication exposures to products that contain 4 t amylphenol. Postapplication scenarios evaluated, which were considered to be representative of all possible exposure scenarios, included: contact with treated hard surfaces/ flooring by children ( incidental oral and dermal exposure), dermal contact with treated textiles and diapers, incidental ingestion of treated textiles, and postapplication/ bystander inhalation exposure from use of disinfecting/ deodorizing products. Duration of exposure is short term ( 1 30 days) and intermediate term ( 1 6 months) for all residential scenarios assessed, except for the diaper use, which is also considered to be a long term scenario (> 6 months). The scenarios were evaluated based on the Residential Exposure Assessment Standard Operating Procedures ( SOPs), product label maximum application rates, related use information, Agency standard assumptions, inhalation and dermal unit exposure data from the proprietary Chemical Manufactures Association ( EPA 1999, CMA, 1992), and Pesticide Handlers Exposure Database ( PHED). In addition, the Multi Chamber Concentration and Exposure Model ( MCCEM) was used to estimate postapplication inhalation exposure to air deodorizer. At this time, EPA does not have available chemical specific handler or postapplication exposure studies that meet Agency guidelines.

Residential Handler Risk Summary. For the residential handler dermal and inhalation risk assessment, short and intermediate term risks for all scenarios evaluated are above the respective target MOEs for all scenarios ( i. e., dermal MOEs were > 1,000 and inhalation MOEs were > 3,000), and thus are not of concern.

Postapplication Residential Risk Summary. For the residential postapplication scenarios assessed in this document, risk estimates that exceed the Agency's level of concern ( i. e., dermal MOEs < 1,000, inhalation MOEs < 3,000, and oral MOEs < 3,000) are:

° Incidental oral exposure from children mouthing treated textiles ( oral MOE= 650); Page 8 of 40 ° Dermal exposure from children wearing treated clothing ( Dermal MOE = 0.86 with a 100% transfer factor and Dermal MOE = 17 with a 5% transfer factor); ° Dermal exposure from children wearing a treated diaper ( Dermal MOE = 59 with a 100% transfer factor and Dermal MOE = 1,200 with a 5% transfer factor, which is above the target MOE); ° Dermal exposure from children playing on a treated hard surface in a daycare center ( Dermal MOE = 940); ° Dermal exposure from adults wearing treated clothing ( Dermal MOE = 140 with a 100% transfer factor; however, with a 5% transfer factor the Dermal MOE = 2,700, which is above the target MOE). The Agency will require confirmatory data to support a 5% transfer factor.

As noted previously, 4 t amylphenol also caused dermal irritant effects following repeated dermal exposure at 10 mg/ kg/ day, and may also be a potential dermal sensitizer. Since the MOEs are based on systemic effects at 25 mg/ kg/ day, the Agency intends to consider the potential for irritation and sensitization in recommended labeling language of pesticide products containing 4 t amylphenol, and additional dermal toxicity data on a diluted end use formulation.

Aggregate Exposure and Risk: In order for a pesticide registration to continue, it must be shown that the use does not result in " unreasonable adverse effects on the environment". Section 2 ( bb) of FIFRA defines this term to include " a human dietary risk from residues that result from a use of a pesticide in or on any food inconsistent with standard under section 408..." of FFDCA. As mandated by the FQPA amendments to FIFRA and the Federal Food, Drug and Cosmetic Act ( FFDCA), the Agency must consider total aggregate exposure from food, drinking water and residential sources of exposure to 4 t amylphenol.

Oral and inhalation exposure and risk estimates were combined for the aggregate risk assessment because the toxicity endpoint is identical for both routes of exposure. Dermal residential exposures were not aggregated with the oral or inhalation exposures due to different toxicological endpoints for oral ( clinical signs and body weight changes), and dermal ( no systemic effects at the highest dose tested). Acute and chronic aggregate assessments were not conducted because there are no significant impacts to drinking water sources from the indoor uses of 4 t amylphenol, nor are there long term residential uses. Thus, only short and intermediate term aggregate assessments were conducted.

Short and Intermediate Term. Short and intermediate term aggregate risks are considered together since the exposure and toxicity endpoints are identical for both durations. For children, the short and intermediate term aggregate assessment includes average dietary exposure ( food) and estimated incidental oral exposures from residential uses such as hard surface disinfection. In addition, inhalation exposures from the postapplication of an air deodorizer use were aggregated with the oral exposures since the toxicity endpoint is the same and it is possible that the scenarios could co occur. For adults, the aggregate assessment includes dietary ( oral) and residential inhalation exposures from wiping a hard surface disinfectant, in addition to postapplication inhalation exposure from the air deodorizer.

The aggregate oral and inhalation risks are not of concern for adults, as the total aggregate Page 9 of 40 MOE is 13,000 which is greater than the target of 3,000. For children, the aggregate risk estimates are also above the target MOE of 3000 ( MOE= 3,200), and thus are not of concern. As noted previously, incidental oral exposure to treated textiles are not included in the aggregate assessment because oral MOE is already of concern ( MOE= 650 versus target > 3000). It should be noted that several conservative assumptions were used in this assessment.

A dermal aggregate assessment was not conducted. However, as noted previously, shortand intermediate dermal risks are already of concern for residents for the treated textile and diaper use, and dermal contact with residues from hard surface disinfectant use. The Agency will request confirmatory data to verify these risk estimates.

Long Term Aggregate. A long term aggregate assessment was not conducted because the only long term residential use ( diaper use) results in dermal exposure, which has a different toxicological effect than the chronic dietary oral exposure.

Occupational Exposure and Risk. Based on examination of product labels describing uses for the product, it has been determined that exposure to handlers can occur in a variety of occupational environments. Additionally, postapplication exposures are likely to occur in these settings. The representative scenarios selected by AD for assessment were evaluated using maximum application rates as recommended on the product labels for 4 t amylphenol.

To assess the handler risks, AD used surrogate unit exposure data from both the proprietary Chemical Manufacturers Association ( CMA) antimicrobial exposure study and the Pesticide Handlers Exposure Database ( PHED). Additionally, the MCCEM ( Multi Chamber Concentration and Exposure Model) was used to estimate postapplication/ bystander exposures.

For the occupational handler dermal and inhalation risk assessment, the short and intermediate and long term risks calculated at baseline exposure ( no gloves and no respirators) were above target MOEs for all scenarios ( i. e., dermal MOEs were > 100 and inhalation MOEs were > 300). Note, however, that the high pressure spray application method in the agricultural use site category was assessed using gloved data.

For most of the occupational scenarios, postapplication dermal exposure is not expected to occur or is expected to be negligible based on the application rates and chemical properties of the chemical. Postapplication/ bystander inhalation exposures, however, were assessed for entry into a building after a fogging application. The representative building selected was a poultry barn. The calculated inhalation MOEs were above the target MOE of 300 for all fogging postapplication scenarios.

Other Food Quality Protection Act ( FQPA) Considerations Cumulative Effects. Section 408 of the FFDCA stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effects to human health that may result from dietary, residential, or other non occupational exposure to other substances that have a common mechanism of toxicity. The reason for consideration of other substances is due to Page 10 of 40 the possibility that low level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the other substances individually. A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a common toxic effect by a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe. EPA does not have, at this time, available data to determine whether 4 t amylphenol and its salts have a common mechanism of toxicity with other substances.

Endocrine Disruption. Available data for 4 t amylphenol suggest is has endocrine disruptor capabilities in mammals ( uterotrophic and estrogenic effects) and increased bilirubin production in babies. It has been shown to affect the reproductive process of carp. The Food Quality Protection Act ( FQPA; 1996) requires that EPA develop a screening program to determine whether certain substances ( including all pesticides and inerts) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other endocrine effect...." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP).

When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed and validated, 4 t amylphenol and its potassium and sodium salts may be subjected to additional screening and/ or testing to better characterize effects related to endocrine disruption.

Environmental Hazard and Risk. The registrant has not submitted any ecological effects data to support this RED for 4 tert amylphenol and its salts. The only data that was available was found in the peer reviewed literature. None of these studies met current guideline requirements and therefore, could not be used in a risk assessment. There is a concern about the possibility of endocrine disruption in fish, since 4 t amylphenol is considered an ecoestrogen. This was documented in several studies on carp ( Cyprinus carpio), whose findings were included in the ecotoxicity chapter. However, since this chemical is restricted to indoor uses only, the possibility for exposure of fish to 4 t amylphenol would be limited. The registrant does have to submit three ecological effects studies on the acute toxicity of this chemical. These include an avian acute oral toxicity test, preferably using the bobwhite quail, ( 850.2100/ 71 1), a freshwater fish acute toxicity test, preferably using the rainbow trout, ( 850.1075/ 72 1), and an acute freshwater invertebrate test ( 850.1010/ 72 2). These tests are required in order to document potential acute toxicity to these organisms in the unlikely event that exposure to 4 t amylphenol and its salts does occur. Page 11 of 40 2.0 PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of 4 t amylphenol and its sodium and potassium salts are provided in Table 1.

Structure for 4 t amylphenol:

OH C CH 3 CH 3 C H H CH 3 O  Na + CH 3 CH 3 CH 3 Paratertiaryamyl P hen o l, S o d ium S alt O  K + CH 3 CH 3 CH 3 P a rate rtia ry P h en o l, Po tas sium S alt Table 1 Physical and Chemical Properties Property 4 t amylphenol Sodium 4 tert amylphenate Potassium 4 tert amylphenate PC Chemical Code 064101 064111 064112 Cas Number 80 46 6 31366 95 7 53404 18 5 Molecular Formula C11H16O C11H15NaO C11H15KO Page 12 of 40 Table 1 Physical and Chemical Properties Property 4 t amylphenol Sodium 4 tert amylphenate Potassium 4 tert amylphenate Synonyms Para tert amylphenol, 1 hydroxy 4( 2 methyl 2 butyl)

benzene; p( 1,1 dimethylpropyl) phenol; p( alpha, alpha dimethylpropyl)

phenol Molecular Weight 164.25 186.23 202.34 Melting Point 95 o C 205 o C ( estimated) 206 o C Boiling Point 263 o C 485 o C ( estimated) 486 o C Vapor Pressure 1.16 x 10 3 mm Hg at 25 o C 7.7 x10 10 ( estimated) at 25 o C 7.7 x10 10 mm Hg at 25 o C ( estimated)

Solubility ( water) 113.4 mg/ L 4595 mg/ L ( estimated) 3811 mg/ L at 25 o C ( estimated)

Henry Law Constant ( HLC) 2.03 x 10 6 atm m3/ mol ( estimated) 4.10 x 10 14 atm m3 / mole ( estimated) 5.38 x 10 14 atm m3 / mole ( estimated)

Log Koc 3.57 ( estimated) 3.57 3.57 ( estimated)

Log Kow 3.91 1.23 1.23 ( estimated)

Physical State White Solid Solid Solid Persistence in Air ( t ½

in Air) 3.073 hours ( measured against hydroxy radical) 4.67 hours ( measured against hydroxy radical 4.67 hours ( measured against hydroxy radical)

3.0. ENVIRONMENTAL FATE Detailed information on environmental fate is presented in the attached memo from S. Gowda ( September 2005). A brief summary is provided below.

The environmental fate assessment for 4 t amylphenol and its potassium and sodium salts is based on US EPA =

s Estimation Programs Interface ( EPI) Suite. EPI Suite provides estimations of physical/ chemical properties and environmental fate properties.

4 t Amylphenol may be bioaccumlative ( log KOW 3.91) and is likely to pose a concern for aquatic organisms. It is expected to have moderate to slight mobility in soils based upon the estimated Koc value of 3799. Estimated value for biodegradation probability indicates that it may biodegrade linearly within days in aquatic medium. However, ultimate biodegradation ( mineralization) may take months. It is volatile and may vaporize into the atmosphere. The estimated half life in the air for 4 t Amylphenol is about three hours which indicates that it is not persistent in air. Because of the possibility of biodegradation in water and soils, it is not likely to contaminate surface and ground waters. Page 13 of 40 4 t Amylphenol, potassium salt, is not likely to be bioaccumlative ( log KOW 1.23) and may not pose a concern for bioconcentration in aquatic organisms. It may be expected to have moderate to slight mobility in soils as its estimated Koc value is 3799. Estimated probability of biodegradation of 4 t Amylphenol, potassium salt, in soils and water indicates that it is likely to biodegrade within days to weeks. Therefore, it may be unlikely that soil and water contamination would take place. It has low volatility and its estimated half life in air is about 4.68 hours and is not likely to be persistent in air.

4 t Amylphenol, sodium salt, is not likely to be bioaccumlative ( log KOW is 1.23) and may not pose a concern for bioconcentration in aquatic organisms. It may be expected to have moderate to slight mobility in soils as its estimated Koc value is the same as the parent molecule, 4 t Amylphenol. Probability for sodium 4 tert amylphenate biodegradation is the same as the parent molecule, 4 t amylphenol. Hence, it is not likely to persist in soils and water, and surface and ground water contamination is not likely to occur. It has low volatility and its estimated half life in air is about 4.68 hours and is not likely to be persistent in air.

4.0 HAZARD CHARACTERIZATION 4.1 Hazard Profile The toxicology database for 4 t amylphenol, in terms of guideline studies, is largely incomplete. Studies from the open literature provide useful information, but more data are needed to put together a complete profile.

A detailed hazard assessment for 4 t amylphenol and its salts is presented in the attached memorandum ( memo from M. Ottley/ D. Smegal, September 2005). 4 t Amylphenol is a primary dermal irritant ( Category I) and is in Category III for acute oral toxicity based on guideline studies. It also appears to be an eye irritant ( Category I), and may be in Category III for acute dermal toxicity according to data from the open literature. However, acceptable guideline acute studies are not available for dermal, inhalation, primary eye irritation or dermal sensitization, and the literature data protocols were inadequate.

In short term studies, 4 t amylphenol produced clinical signs along with decreased food consumption and body weight in a developmental toxicity study, but no systemic effects in a 13 week dermal study. The structural abnormalities and developmental delays that occurred in the developmental study, occurred at higher dose levels than the maternal effects, suggesting that increased quantitative susceptibility concerns are not warranted; however, the minimal maternal effects ( reversible clinical signs) seen in the presence of the developmental effects increases concern for qualitative susceptibility. Neither a developmental study in rabbits nor a reproduction study was available to provide confirmation.

Available data suggest that 4 t amylphenol has endocrine disrupter capabilities ( uterotrophic and estrogenic effects) and increased bilirubin production in babies. In addition, this chemical is listed on a European list of " Chemicals purported to be endocrine disruptors" ( IEH 2005). When taken with the lack of available developmental and reproductive toxicity data, Page 14 of 40 concerns for FQPA issues are heightened.

No dermal penetration studies were available for 4 t amylphenol, and an extrapolation between the 13 week dermal study and the oral developmental study does not seem possible, for the purposes of estimating dermal absorption.

4 t Amylphenol was negative for carcinogenicity in a subchronic skin painting study from the open literature. However, guideline studies for carcinogenicity are not available. All mutagenicity tests were negative. Tables 2 and 3 highlight key toxicological studies for 4 t amylphenol.

Table 2 Acute Toxicity Studies for 4 t Amylphenol Technical Guideline No./ Study Type MRID No. Results Toxicity Category 870.1100 Acute oral toxicity 46616601 LD50 > 2000 mg/ kg for males and females III 870.1200 Acute dermal toxicity NA [ ]

870.1300 Acute inhalation toxicity NA [ ]

870.2400 Acute eye irritation NA No adequate acute toxicity studies were provided or identified in the open literature.

[ ]

870.2500 Acute dermal irritation 46616602 Corrosive following 4 hour application; scar tissue noted 14 days after treatment I 870.2600 Skin sensitization NA Table 3 Toxicity Profile of 4 t Amylphenol Technical Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3250 90 Day dermal toxicity MRID 42470301 ( 1993) 0, 2.5, 10, 25 mg/ kg/ day not acceptable, no systemic toxicity demonstrated NOAEL = 2.5 mg/ kg/ day LOAEL = 10 mg/ kg/ day based on dermal effects 870.3700a Prenatal developmental in rodents 41920002 ( 1991) Acceptable 0, 50, 200, 500 mg/ kg/ day Maternal NOAEL = 50 mg/ kg/ day LOAEL = 200 mg/ kg/ day based on clinical signs and decreased body weight, weight gain, and food consumption Developmental NOAEL = 200 mg/ kg/ day LOAEL = 500 mg/ kg/ day based on decreased fetal body weight and increased incidence of bent ribs Page 15 of 40 Table 3 Toxicity Profile of 4 t Amylphenol Technical Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Gene Mutation 870.5265 Salmonella typhimurium reverse mutation assay 414384 01 ( 1990) Acceptable 1, 3.2, 10, 31.6, and 100

ug/ plate Negative, with or without activation Gene Mutation 870.5300 In vitro mammalian cell gene mutation test 415727 01 ( 1990) Acceptable non activated conditions  5, 10, 20, 30, and 40

g/ ml; activated conditions  2, 4, 6, 8, and 10 ug/ ml Negative with and without metabolic activation. The few positive results in control plates are consistent with historical control data for the laboratory and test system.

Cytogenetics 870.5395 Mammalian erythrocyte micro nucleus test 417108 ( 1990) Acceptable 62.5 ( M), 250 ( M+ F), 1000 ( M+ F), and 4000 mg/ kg ( F) Negative Skin Sensitization. P tert amylphenol has been reported to be a skin sensitizer and depigmenting agent ( BIBRA Working Group, 1990). Stevenson ( 1984), however, reported p t amylphenol to have a " low depigmenting potential" because none of 129 men who had been exposed to the compound during its manufacture exhibited depigmentation.

Developmental Toxicity. The data base for developmental toxicity is adequate only for non food uses of 4 t amylphenol. Additional data are required for indirect food use. The one study provided, a prenatal developmental toxicity study in rats, indicated a lower NOAEL and LOAEL for maternal toxicity ( i. e., 50 and 200 mg/ kg day) than for developmental toxicity ( i. e., 200 and 500 mg/ kg day), and the developmental effects were not frankly teratogenic. Thus, there is no quantitative indication that the fetus is more susceptible than the pregnant female.

Mutagenicity. The data base for mutagenicity is considered adequate based on EPA's 1991 mutagenicity guidelines and indicates that p tert amylphenol is not mutagenic or genotoxic. In a submitted bacterial study ( MRID No. 414384 01) and a study identified in the published literature ( Zeiger et al. 1988), p t amylphenol was not mutagenic to the bacteria in the presence or absence of mammalian metabolic activation. An assay using cultured mouse lymphoma cells also proved negative ( MRID No. 415727 01). Finally, a mouse micronucleus test using male and female CD 1 mice also was negative ( MRID No. 417108).

Endocrine Disruption. 4 t Amylphenol is listed on a European list of " Chemicals purported to be endocrine disruptors" ( IEH 2005). In the open literature ( Yamasaki et al. 2003), an increase in non pregnant uterine weight was observed in rats following 4 t amylphenol exposure. Another study ( Soto et al. 1995) suggested that 4 t amylphenol may have estrogenic effect. Wysowski et Page 16 of 40 at. ( 1978) reported elevated blood levels of bilirubin in children exposed to 4 t amylphenol and other phenols in disinfectant. These studies, while not indicative, are suggestive of a basis for increased concern for reproductive and/ or developmental effects due to exposure to 4 t amylphenol.

Soto et al. ( 1995) have found p t amylphenol to be estrogenic in the E SCREEN assay, which assesses the estrogenicity of a compound by measuring its proliferative effect on estrogen sensitive cells. The cell number achieved by similar inocula of MCF 7 cells ( estrogen sensitive human breast cancer cells) in the absence of estrogens ( negative control) and in the presence of 17 estradiol ( positive control) is compared with the number of cells achieved with a range of concentrations of the test chemical. For 4 t pentylphenol, a concentration of 10 M was the lowest concentration needed for maximal cell yield. For the positive control 17 estradiol, the lowest concentration needed was 30 pM. The relative proliferative effect ( RPE) is calculated as 100 x ( PE 1) of the test compound divided by ( PE 1) of 17 estradiol. A value of 100 indicates that the compound tested is a full agonist of the estradiol; a value of 0 indicates that the compound lacks estroenicity at the doses tested. Intermediate values suggest that the compound is a partial agonist of 17 estradiol. For 4 t pentylphenol, and RPE of 105 was estimated.

Routledge and Sumpter ( 1997) demonstrated estrogenic activity of 4 tert amylphenol using an estrogen inducible strain of yeast ( Saccharomyces cerevisiae) that expresses the human estrogen receptor. Using the natural estrogen 17    estradiol for comparison, the data indicated that both the position ( para > meta > ortho) and branching ( tertiary > secondary = normal) of the alkyl group affect estrogenicity. In this assay, 4 t amylphenol was found to be 100,000 fold less potent than17 estradiol.

4.2 FQPA Considerations Under the Food Quality Protection Act ( FQPA), P. L. 104 170, which was promulgated in 1996 as an amendment to the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) and the Federal Food, Drug and Cosmetic Act ( FFDCA), the Agency was directed to " ensure that there is a reasonable certainty that no harm will result to infants and children" from aggregate exposure to a pesticide chemical residue. The law further states that in the case of threshold effects, for purposes of providing this reasonable certainty of no harm, " an additional tenfold margin of safety for the pesticide chemical residue and other sources of exposure shall be applied for infants and children to take into account potential pre and post natal toxicity and completeness of the data with respect to exposure and toxicity to infants and children. Notwithstanding such requirement for an additional margin of safety, the Administrator may use a different margin of safety for the pesticide residue only if, on the basis of reliable data, such margin will be safe for infants and children."

The toxicology data base is not complete with respect to assessing the increased susceptibility to infants and children as required by FQPA for 4 t amylphenol. The rat prenatal developmental study showed no quantitative evidence of increased susceptibility ( i. e., developmental NOAELs/ LOAELs were the higher than those for maternal effects). However, there was qualitative evidence of increased susceptibility ( i. e., fetal effects ( skeletal abnormalities, decreased body weight gain) were considered to be more severe than the maternal toxicity Page 17 of 40 ( reversible clinical signs) observed at the same dose level). In addition, there is an absence of developmental toxicity data in the rabbit, and an absence of reproductive toxicity data.

In the open literature ( Yamasaki et al. 2003), an increase in non pregnant uterine weight was observed in rats following 4 t amylphenol exposure. Another study ( Soto et al. 1995) suggested that 4 t amylphenol may have estrogenic effect. Wysowski et at. ( 1978) reported elevated blood levels of bilirubin in children exposed to 4 t ampyphenol and other phenols in disinfectant. These studies, while not indicative, are suggestive of a basis for increased concern for reproductive and/ or developmental effects due to exposure to 4 t amylphenol.

On the basis of a lack of guideline studies, qualitative evidence of sensitivity in the developmental toxicity study, and the suggestive evidence in the open literature of possible endocrine effects, the ADTC has determined that the FQPA Safety Factor should be retained ( 10x) at this time.

4.3 Dose Response Assessment The doses and toxicological endpoints selected for various exposure scenarios are summarized below.

Table 4. Toxicological Endpoints Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and Endpoint for Risk Assessment Study and Toxicological Effects Acute Dietary ( Females 13  50 years) NOAEL = 200 mg/ kg/ day UF = 100 DB= 3x Acute RfD= 0.67 mg/ kg/ day FQPA SF = 10x aPAD= acute RfD FQPA SF = 0.067 mg/ kg/ day Developmental Toxicity Study in Rats LOAEL = 500 mg/ kg/ day, based on skeletal effects and decreased fetal body weight Chronic Dietary ( all populations) NOAEL = 50 mg/ kg/ day UF = 100 DB= 3x Chronic RfD= 0.17 mg/ kg/ day FQPA SF = 10x cPAD= chronic RfD FQPA SF = 0.017 mg/ kg/ day Developmental toxicity study in the rat LOAEL = 200 mg/ kg/ day based on clinical signs of toxicity, decreased body weight and body weight gain, and decreased food consumption Incidental Oral, Short and Intermediate Term Maternal Oral NOAEL = 50 mg/ kg/ day Target MOE = 3000 ( residential) ( 10x inter and intra species extrapolation, 10X FQPA, 3x database uncertainty) Developmental toxicity study in the rat LOAEL = 200 mg/ kg/ day based on clinical signs of toxicity, decreased body weight and body weight gain, and decreased food consumption Page 18 of 40 Short, and Intermediate  Term Dermal Dermal NOAEL = 25 mg/ kg/ day for systemic effects Target MOE = 1000 ( residential) ( 10x inter and intraspecies factors and 10x FQPA) 100 ( occupational) Subchronic dermal toxicity study in Rats Systemic LOAEL = not identified. No systemic effects identified up to and including 25 mg/ kg/ day ( HDT).

Dermal LOAEL= 10 mg/ kg/ day for dermal effects and irritation. Dermal NOAEL= 2.5 mg/ kg/ day Short, Intermediate, and Long Term Inhalation Oral NOAEL = 50 mg/ kg/ day Target MOE = 300 ( occupational) 3000 ( residential) ( 10x inter and intraspecies extrapolation, 10x FQPA, 3x database uncertainty, and route specific extrapolation factor) Developmental toxicity study in the rat LOAEL = 200 mg/ kg/ day based on clinical signs of toxicity, decreased body weight and body weight gain, and decreased food consumption.

Cancer No cancer data available for 4 t amylphenol Database Uncertainty Factor. For oral and inhalation risk assessments, the ADTC applied an additional uncertainty factor of 3x at this time, due to the number and significance of the data gaps for conduct of these risk assessments. A 3x factor was not needed for the dermal route as an acceptable route specific study was available.

4.4 Endocrine Disruption The Food Quality Protection Act ( FQPA; 1996) requires that EPA develop a screening program to determine whether certain substances ( including all pesticides and inerts) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other endocrine effect...." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP).

When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, 4 t amylphenol and its potassium and sodium salts may be subjected to additional screening and/ or testing to better characterize effects related to endocrine disruption. Page 19 of 40 As noted previously, the available data suggest that 4 t amylphenol has endocrine disrupter capabilities ( uterotrophic and estrogenic effects) and increased bilirubin production in babies.

5.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION Dietary exposure to 4 t amylphenol can occur from use as a disinfectant and food contact sanitizer. Residential exposure can occur from 4 t amylphenol containing products, such as hard surface disinfectants. Postapplication exposure can occur in adults and children from dermal contact with treated textiles and diapers, as well as in children from hand to mouth incidental oral exposure from treated surfaces. Occupational exposure to 4 t amylphenol can occur from mixing/ loading/ application activities in various use sites, including agricultural premises, food handling, commercial/ institutional/ industrial premises and medical premises.

5.1 Summary of Registered Uses 4 t Amylphenol, and salts ( potassium and sodium) are active ingredients in disinfectant, food contact sanitizer and deodorizer products used in agricultural, food handling, commercial/ institutional/ industrial, residential and public access, and medical settings, primarily used on hard, non porous surfaces. Examples of registered uses for 4 tert amylphenol and salts include application to hard surfaces ( e. g., walls, floors, tables, fixtures), textiles ( e. g., clothing, diapers, mattresses, bedding), carpets, medical instruments, and agricultural equipment. Additionally, there are registered uses for fogging in occupational settings and air deodorization in both occupational and residential settings. Concentrations of 4 tert amylphenol and salts in products range from 0.0027% to 10%. The products are formulated as soluble concentrates, ready to use liquid solutions, pressurized sprays, and impregnated wipes. The application rates used in this assessment were the maximum application rates as recommended on the product labels.

5.2 Dietary Exposure and Risk Estimates of dietary risk are based upon the detailed analysis in the Dietary Exposure Assessment memorandum ( memo from R. Quick to K. Swift, September 2005, D316295) and are summarized here for completeness. 4 t Amylphenol and its potassium salt are antimicrobials that can be used as disinfectants or sanitizers on counter tops, tables, refrigerators, on animal premises; and in mushroom premises. There are other registered uses for these chemicals that include but are not limited to odor elimination in rooms, beauty parlors and medical premises. There are 32 registered products that contain 4 t amylphenol or its potassium and sodium salts as active ingredients that may result in dietary exposure. 4 t Amylphenol ( also known as phenol, 4 1,1 dimethylpropyl) ( CAS No. 80 46 6) has a tolerance exception in 40CFR 180.940 ( c) as a food contact sanitizer for use in food processing equipment and utensils with a not to exceed limit of 80 ppm.

The use of antimicrobial chemicals on food or feed contact surfaces, agricultural commodities, in animal premises and poultry premises including hatcheries and application to Page 20 of 40 food grade eggs may result in pesticide residues in human food. The Agency must determine the risk to human health that may occur from exposure to these chemicals.

Refrigerators counter tops, sinks and stoves are use sites on registered labels. These surfaces that have been treated with the 4 t amylphenol products may bear small residues of the 4 t amylphenol products after rinsing with potable water; i. e., rinsing with potable water may not remove all residues deposited on the treated surfaces from the proposed uses. Residues from treated surfaces can migrate to food coming into contact with the treated and rinsed surfaces and can be ingested by humans.

In the absence of residue data for residues of 4 t amyphenol on treated food contact surfaces, the Agency estimated residue levels that may occur in food from the application rates on food contact surfaces. To estimate the Estimated Daily Intake ( EDI), the Agency has used an FDA model. The maximum ingredient percentage for 4 t amylphenol in food handling establishments from the various labeled ready to use products is 0.054 % a. i ( 540 ppm). The Agency estimates that use of this product results in 4 t amylphenol food residues of 340 ppb ( µ g/ kg). The Agency assumed that food can contact 2000 cm2 of treated surfaces, and that 10% of the pesticide migrates to food based on the Agency Residential SOPs. The use of the 10% transfer rate instead of the use of a 100% transfer rate that is used in the FDA Sanitizer Solution Guidelines requires the submission of confirmatory data to establish the reliability of the use of the10% transfer rate. These daily estimates were conservatively used to assess both acute and chronic dietary risks, which are shown below in Table 5.

Table 5. Summary of Dietary Exposure and Risk for 4 t amylphenol Acute Dietary Chronic Dietary Population Subgroup Dietary Exposure ( mg/ kg/ day) a % aPAD b Dietary Exposure ( mg/ kg/ day) a % cPAD b adult male 0.0015 NA 0.0015 9 females ( 13 50 years) 0.0018 2.7 0.0018 10.6 infants/ children 0.0072 NA 0.0072 42 NA= not applicable a acute and chronic exposure analysis based on body weights of 70 kg, 60 kg, and 15 kg for adult males, females and children, respectively. b % PAD = dietary exposure ( mg/ kg/ day) / aPAD or cPAD, where aPAD= 0.067 mg/ kg/ day for females of child bearing age; and cPAD= 0.017 mg/ kg/ day for all populations Dietary exposures from general agricultural premise use, poultry hatcheries, mushroom houses and greenhouse and hydroponic uses are expected to be much lower than the dietary exposures resulting from the surface disinfectant and sanitizing uses.

Agricultural premise uses involve the application of a pesticide chemical to the hard surface interior surfaces of the interior of barns and poultry houses. These uses involve application Page 21 of 40 to the physical structure of the premises ( including floors and walls) and also include, but not limited to, watering troughs, feed troughs, animal halters, ropes and forks.

Poultry hatcheries are not used in the production of eggs for food grade eggs for human consumption. Hatchery eggs are used for the production of chicks. Sanitizer chemicals could penetrate the egg shell and become a residue in the developing chick. Any residues that did penetrate the egg shell and occur in the chick would not be expected to be detectable in birds that are ready for consumption because of growth dilution in the growing birds. The use of p tertiary amylphenol products in poultry hatcheries appears to be a non food use.

4 t Amylphenol is used for cleaning and sanitizing non food contact surfaces between crops in mushrooms. Surfaces that are treated include tanks, air conditioners, air ducts, fans and breezeways, compost wharf, concreted surfaces, inside and outside walls of mushroom houses, lofts, floors, spawning machines, tampers, casing rings, storage sheds and track alleys before spawning. Thus, the use of 4 t amylphenol products in mushroom houses appears to be a non food use.

Food commodities can be grown in greenhouses and on hydroponic farms. The food commodities can be grown in a growing media or hydroponically in water. There is a label restriction against application to crop, soil or growing media in which a crop grows or will be grown. There is also a label instruction that requires a potable water rinse before treated surfaces contact the crop or the substrate in which the crop is or will be grown. A potable water rinse for treated surfaces will likely remove a part, but not all of the residues from treated surfaces. The growing structures could be made of wood, plastic, concrete or metal. The greatest potential for residues adhering to treated surfaces would be expected to be from the use of wood structures. Wood is porous and residues would likely be absorbed into the treated surfaces. This would also be true to a lesser extent on concrete surfaces. Metal surfaces would not be porous and rinsing well or scrubbing would likely remove most or all pesticide residues.

5.3 Drinking Water Exposure and Risk There are no currently registered outdoor uses of 4 t amylphenol and its salts that are being supported by the registrant. The potential outdoor uses, wood protection to treat unseasoned forest products, and use in potable human drinking water systems are apparently no longer supported by any registrant. 4 t Amylphenol's use as a general disinfectant allows for the possibility of ground and surface water contamination. It has been found in an effluent sample from a municipal waste water treatment plant. However, the estimated value for biodegradation indicates it may biodegrade linearly within days in the aquatic environment, although ultimate biodegradation ( mineralization) may take months. It is also volatile based on its vapor pressure of 0.00116 mmHg, and has a moderate to slight mobility in soils based on its estimated Koc value of 3799. The sodium and potassium salts of 4 t amylphenol are also slightly to moderately mobile in soils, and are estimated to biodegrade within days to weeks. Because of the possibility of biodegradation in water and soils, 4 t amylphenol and its salts are not likely to contaminate surface and ground waters. Thus, a drinking water assessment was not conducted for these chemicals. Page 22 of 40 5.4 Residential Exposure/ Risk Pathway Details of the residential exposure assessment can be found within the companion memorandum ( memorandum from S. Mostaghimi, September 2005). A summary of the residential assessment is presented below.

5.4.1 Residential Handler Exposure Scenarios 4 t Amylphenol is a disinfectant, sanitizer and deodorizer, that is used in agricultural, food handling, commercial/ institutional/ industrial, residential and medical settings. It is used as a hard surface disinfectant ( e. g., walls, floors, tables, fixtures), textiles ( e. g., clothing, diapers, mattresses, bedding), carpets, medical instruments and agricultural equipment. The following representative residential handler scenarios were evaluated:

( 1) mopping hard surfaces, ( 2) wiping hard surfaces, ( 3) using trigger pump equipment to treat hard surfaces and/ or textiles, and ( 4) application to air using an aerosol spray can 4 t amylphenol and salt products are widely used disinfectants and have a large number of use patterns that are difficult to completely capture in this assessment. As such, AD has selected representative scenarios for each use site that are believed to be representative of the vast majority of 4 t amylphenol and salt uses, based on end use product application methods and use amounts.

Exposure Data and Assumptions There are no chemical specific exposure data to assess paint applications with a brush, roller, airless sprayer or aerosol can. However, surrogate data are available for mopping, wiping, trigger pump spray and aerosol can application methods. Dermal and inhalation exposures were assessed for mopping and wiping using proprietary Chemical Manufacturers Association ( CMA) data ( CMA 1992, USEPA 1999). These data are based on individuals mopping floors and receiving exposure via contact with the mop or with the bucket, or using a finger pump sprayer to apply the product and then wipe the surfaces with a paper towel. Dermal and inhalation exposures were assessed for trigger pump spray and aerosol application methods using PHED Version 1.1 values found in the Residential Exposure SOPs ( U. S. EPA, 1997a, 2001). The surrogate exposure data in PHED are based on test subjects applying an aerosol insecticide to baseboards in kitchens. The dermal and inhalation exposures from these techniques have been normalized by the amount of active ingredient handled and reported as unit exposures ( UE) expressed as mg/ lb ai handled.

In addition, product label maximum application rates, related use information, and Agency standard values were used to assess residential handler exposures. For example, it was assumed that one gallon of diluted solution is used for mopping floors, while 0.5 liters ( 0.13 gallons) are used in the wiping and trigger pump spray scenario. For aerosol can spray, it was assumed that Page 23 of 40 one 16 oz can of product is used in a day. The residential handler scenarios are assumed to be of short and intermediate term duration ( 1 30 days and 1 6 months)

Risk Characterization A summary of the residential handler exposures and risk are presented on Table 6. The non cancer risk estimates are expressed in terms of the MOE. For residential handlers that handle products containing 4 t amylphenol and its salts, short term, and intermediate term MOEs were above the target MOEs ( i. e.,   > 1000 for dermal and > 3000 for inhalation) and thus, do not exceed the Agency's level of concern for any of the residential handler scenarios evaluated.

Table 6 Estimates of Exposures and Risks to Residential Handlers of 4 t Amylphenol and salts ( Short and Intermediate Duration)

Scenario Dermal Dose ( mg/ kg/ day) a Inhalation Dose ( mg/ kg/ day) b Dermal MOEc ( Target MOE> 1000) Inhalation MOEd ( Target MOE> 3000)

( 1) Mopping 0.00128 4.25x10 5 20,000 1,200,000 ( 2) Wiping 0.00666 1.56x10 4 3,800 320,000 ( 3) Trigger Pump Spray 0.00198 2.16x10 5 13,000 2,300,000 ( 4) Aerosol Spray 0.00233 2.54x10 5 11,000 2,000,000 a Dermal Dose ( mg/ kg/ day) = [ Unit Dermal Exposure ( mg/ lb ai) * Use Rate ( lb ai/ lb product or lb ai/ gal product) * Amount Handled per Day ( lb product/ day)] / Body Weight ( kg). b Inhalation Dose ( mg/ kg/ day) = [ Unit Inhalation Exposure ( mg/ lb ai) * Use Rate ( lb ai/ lb product or lb ai/ gal product) * Amount Handled per Day ( lb product/ day)* inhalation absorption ( 1.0)] / Body Weight ( kg) c Dermal MOE = Dermal NOAEL ( mg/ kg/ day) / Dermal Dose ( mg/ kg/ day). Where the NOAEL is 25 mg/ kg/ day from the subchronic rat dermal toxicity study. d Inhalation MOE = Inhalation NOAEL ( mg/ kg/ day) / Inhalation Dose ( mg/ kg/ day). Where the inhalation NOAEL of 50 mg/ kg/ day is from an oral rat developmental study. In the absence of data, inhalation absorption is assumed to be equivalent to oral absorption 5.4.2 Postapplication Residential Exposure Residential postapplication exposures result when bystanders ( adults and children) come in contact with 4 t amylphenol and its salts in areas where pesticide treated end use products have recently been applied ( e. g., treated hard surfaces/ floors), or when children incidentally ingest the pesticide residues through mouthing the treated end products/ treated articles ( i. e., hand to mouth or object to mouth contact).

For the purposes of this screening level assessment, postapplication scenarios have been developed that encompass multiple products, but still represent a high end exposure scenario for all products represented. Representative postapplication scenarios assessed include: Page 24 of 40 ° contacting treated hard surfaces/ floors ( dermal and incidental oral exposure to children), ° wearing treated clothing ( dermal exposure to adults and children), ° wearing diapers treated with a trigger pump spray ( dermal exposure to children), ° mouthing treated textiles such as clothing and blankets ( incidental oral exposure to children), and ° postapplication/ bystander inhalation exposures from use of disinfecting/ deodorizing products ( vapor exposure to adults and children).

Exposure Data and Assumptions Typically, most products used in a residential setting result in exposures occurring over a short term time duration ( 1   30 days). If the products are used on a routine basis ( i. e., once a week) and the active ingredient has a long indoor half life, exposures may occur over an intermediate term time duration ( 30 days   6 months). At this time, AD does not have residue dissipation data or reliable use pattern data, including the frequency and duration of use of antimicrobial products in the residential setting. Even though AD does not believe that the use patterns of many residential products result in intermediate term exposure, they are assessed to provide an upper bound estimate of exposure. AD does believe, however, that intermediate term exposure to children may occur in day care centers where disinfecting products are used more frequently.

A number of conservative assumptions were used in assessing postapplication risks including maximum application rate from the label. In addition quantities handled/ treated were estimated based on information from various sources, including the Draft Standard Operating Procedures ( SOPs) for Residential Exposure Assessments ( USEPA 2000, 2001) and the AD Draft Residential SOP use table. In certain cases, no standard values were available for some scenarios. Assumptions for these scenarios were based on AD estimates and could be further refined from input from affected sectors. In the absence of data, for both the textile and diaper scenarios, it was assumed that either 100% or 5% of 4 t amylphenol could transfer and be available for dermal contact. The Agency will require data to confirm the actual transfer factor of 4 t amylphenol No postapplication air concentration data have been submitted for 4 t amylphenol to determine potential vapor inhalation risk. Therefore, the Multi Chamber Concentration and Exposure Model ( MCCEM v1.2) was used to present a screening level estimate of the potential inhalation risk to adults and children for the air deodorizer use. MCCEM estimates average and peak indoor air concentrations of chemicals released from products or materials in houses, apartments, townhouses, or other residences. The data libraries in MCCEM contain information about residential settings. MCCEM estimates inhalation exposures to chemicals, calculated as single day doses, chronic average daily doses, or lifetime average daily doses. ( All dose estimates are potential doses; they do not account for actual absorption into the body.)

Risk Characterization A summary of the residential postapplication exposures and risks are presented on Table 7. The non cancer risk estimates are expressed in terms of the MOE. The target MOEs are > 1000 Page 25 of 40 for dermal exposures, and > 3000 for incidental oral and inhalation exposures.

Dermal Risks. The child short and intermediate term dermal MOEs for contact following hard surface disinfection is above the target MOE of 1,000 for residential settings ( MOE = 3,700) and slightly below the MOE for daycare centers ( MOE = 940). The short and intermediate term MOEs for dermal contact with treated clothing is of concern for young children ( MOEs are < 1 assuming a 100% transfer factor; MOE= 17 assuming a 5% transfer factor). For adults, the dermal MOE is below the target MOE of 1,000 using a 100% transfer factor ( MOE = 140) and above the MOE using the 5% transfer factor ( MOE = 2,700). The dermal MOE for a children wearing treated diapers is only of concern ( MOE= 59) using a transfer factor of 100%, but it not of concern when using a transfer factor of 5%. The Agency requires confirmatory data for a 4 t amylphenol transfer factor from clothing and diapers. In addition, it should be noted that 4 t amylphenol caused dermal irritant effects following repeated dermal exposure, and may also be a potential dermal sensitizer. The Agency intends to consider these effects in the labeling of pesticide products containing 4 t amylphenol, and request additional dermal toxicity data on the diluted end use formulated product.

Incidental Oral Risks. The short and intermediate term incidental oral MOEs following hard surface disinfection are above the target MOE of 3,000 for residential settings ( MOE = 61,000) and daycare centers ( MOE = 15,000), and thus are not of concern. However, the oral MOE for children mouthing treated textiles exceeds the Agency's level of concern ( MOE= 650 compared to target MOE> 3000).

Inhalation Risks. For both adults and children, the calculated inhalation MOEs are greater than the target MOE of 3,000 ( MOE= 27,000 and 7,500, respectively), for inhalation exposures following use of an air deodorizer.

Table 7 Summary of Short and Intermediate Term Residential Postapplication Exposures and Risks Scenario Dose a ( mg/ kg/ day) MOEb ( Target MOE> 1000 dermal; > 3000 oral and inhalation) Dermal Exposure Residential Setting 0.0067 3,700 Hard surface Disinfection Daycare center 0.0267 940 Adults 0.0092 ( 5% transfer) 0.185 ( 100% transfer) 2,700 140 Treated clothing Children 1.45 ( 5% transfer) 28.9 ( 100% transfer) 17 < 1 Treated Diapers Children 0.0212 ( 5% transfer) 0.424 ( 100% transfer) 1,200 59 Incidental Oral Exposure Residential Setting 0.000817 61,000 Hard surface Disinfection Daycare center 0.00155 32,000 Treated clothing Children 650 Inhalation Exposure Page 26 of 40 Table 7 Summary of Short and Intermediate Term Residential Postapplication Exposures and Risks Scenario Dose a ( mg/ kg/ day) MOEb ( Target MOE> 1000 dermal; > 3000 oral and inhalation) Adults 0.00186 27,000 Air Deodorizer Children 0.00666 7,500 a Dose calculations for each scenario above are outlined in the attached Occupational/ Residential Assessment ( memo from S. Mostaghimi, May 2005). b MOE= NOAEL ( mg/ kg/ day) / PDR ( mg/ kg/ day). Oral and inhalation NOAEL is 50 mg/ kg/ day; dermal NOAEL is 25 mg/ kg/ day 6.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION In order for a pesticide registration to continue, it must be shown that the use does not result in " unreasonable adverse effects on the environment". Section 2 ( bb) of FIFRA defines this term to include " a human dietary risk from residues that result from a use of a pesticide in or on any food inconsistent with standard under section 408..." of FFDCA. As mandated by the FQPA amendments to FIFRA and the Federal Food, Drug and Cosmetic Act ( FFDCA), the Agency must consider total aggregate exposure from food, drinking water and residential sources of exposure to 4 t amylphenol. Aggregate exposure is the total exposure to a single chemical ( or its residues) that may occur from dietary ( i. e., food and drinking water), residential, and other non occupational sources, and from plausible exposure routes ( oral, dermal, and inhalation).

Typically, aggregate risk assessment are conducted for acute ( 1 day), short term ( 1 30 days), intermediate term ( 1 6 months) and chronic ( 6 months to lifetime) exposures. However, acute and chronic aggregate assessments were not conducted because there are no significant impacts to drinking water sources, nor are there long term residential uses. Thus, only short and intermediate term aggregate assessments were conducted. Oral and inhalation exposure and risk estimates were combined for the aggregate risk assessment because these endpoints are based on the same toxicity study ( oral developmental study) and effects of concern ( clinical signs and changes in body weight and food consumption). Dermal exposures were not aggregated with the oral or inhalation exposures due to different toxicological endpoints for oral ( clinical signs and body weight changes), and dermal ( no systemic effects at the highest dose tested).

In performing aggregate exposure and risk assessments, the Office of Pesticide Programs has published guidance outlining the necessary steps to perform such assessments ( General Principles for Performing Aggregate Exposure and Risk Assessments, November 28, 2001; available at http:// www. epa. gov/ pesticides/ trac/ science/ aggregate. pdf ). Steps for deciding whether to perform aggregate exposure and risk assessments are listed, which include: identification of toxicological endpoints for each exposure route and duration; identification of potential exposures for each pathway ( food, water, and/ or residential); reconciliation of durations and pathways of exposure with durations and pathways of health effects; determination of which possible residential exposure scenarios are likely to occur together within a given time frame; Page 27 of 40 determination of magnitude and duration of exposure for all exposure combinations; determination of the appropriate technique ( deterministic or probabilistic) for exposure assessment; and determination of the appropriate risk metric to estimate aggregate risk.

6.1 Short and Intermediate Term Aggregate Risk Aggregate short and intermediate term risk assessments are designed to provide estimates of risk likely to result from exposures to the pesticide or pesticide residues in food, water, and from residential ( or other non occupational) pesticide uses. Short and intermediate term aggregate risks are considered together because the exposure and toxicity endpoints are identical for incidental oral, and inhalation residential exposures for both durations. For children, the short and intermediate term aggregate assessment includes average dietary exposure ( food) and estimated incidental oral exposures to children from residential uses such as hard surface disinfection. In addition, inhalation exposure from the postapplication of an air deodorizer use was aggregated with the oral exposures since the toxicity endpoint is the same. For adults, the aggregate assessment includes dietary ( oral) and residential inhalation exposures from wiping a hard surface disinfectant, in addition to postapplication inhalation exposure from the air deodorizer.

Aggregate risks were calculated using the total MOE approach outlined in OPP guidance for aggregate risk assessment ( August 1, 1999, Updated " Interim Guidance for Incorporating Drinking Water Exposure into Aggregate Risk Assessments"). The assumptions and equations are presented in the footnotes on Table 8.

Oral and Inhalation Aggregate Risks. Table 8 presents a summary of the short and intermediate term aggregate risk MOEs. The aggregate oral and inhalation risks are not of concern for adults, as the total aggregate MOE is 13,000 which is greater than the target of 3,000. For children, the aggregate risk estimates are also above the target MOE of 3000 ( MOE= 3,200) and thus are not of concern. It should be noted that several conservative assumptions were used in this assessment. As noted previously, incidental oral exposure to treated textiles are not included in the aggregate assessment because the oral MOE is already of concern ( MOE= 650 vs target > 3000).

Dermal Risk Results. A dermal aggregate assessment was not conducted because the toxicity effects for the dermal exposure route are not the same as the oral/ inhalation exposure route. However, as shown previously on Table 7, short and intermediate dermal risks are already of concern for residents for the treated textile and diaper use.

Table 8 Summary of Short and Intermediate Term Aggregate Risk Estimates Dose a ( mg/ kg/ day) Total MOEb ( Target MOE> 3000) Exposure Scenario Child Adult Child Adult Oral Exposure Dietary Exposure 0.0072 0.0018 ( a) 6940 ( c) 28,000 ( c) Hard surface Disinfection  Daycare center 0.00155 NA 32,000 NA Page 28 of 40 Table 8 Summary of Short and Intermediate Term Aggregate Risk Estimates Dose a ( mg/ kg/ day) Total MOEb ( Target MOE> 3000) Exposure Scenario Child Adult Child Adult Inhalation Exposure Handler of hard surface disinfectant wiping NA 0.000156 NA 320,000 Air Deodorizer 0.00666 0.00186 7,500 27,000 Total Aggregate Dose and MOE 0.0154 0.00316 3,240 13,000 NA= Not applicable ( a) Chronic dietary exposure for females 13 50 years. ( b) MOE = NOAEL ( mg/ kg/ day) / potential dose rate ( mg/ kg/ day) [ Where short and intermediate term oral NOAEL = 50 mg/ kg/ day]. Target MOE = 3,000. ( c) Risk estimates are equivalent to percent of the PAD of 42% for child and 10.6% for adults.

6.2 Long Term Aggregate Risk A long term aggregate assessment was not conducted because the only long term residential use ( diaper use) results in dermal exposure, which has a different toxicological effect than the chronic dietary oral exposure.

7.0 CUMULATIVE EXPOSURE AND RISK Another standard of section 408 of the FFDCA which must be considered in making an unreasonable adverse effect determination is that the Agency considers " available information" concerning the cumulative effects of a particular pesticide's residues and " other substances that have a common mechanism of toxicity."

For the purposes of this tolerance action, therefore, EPA has not assumed that 4 t amylphenol and its potassium and sodium salts have a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ pesticides/ cumulative/.

8.0 OCCUPATIONAL EXPOSURE AND RISK AD has assessed the exposures and risks to occupational workers that handle 4 t amylphenol ( memorandum from S. Mostaghimi, September 2005). This section summarizes the results of the occupational exposure assessment.

Based on examination of product labels describing uses for the product, it has been determined that exposure to handlers can occur in a variety of occupational settings. Additionally, Page 29 of 40 postapplication exposures are likely to occur in these settings. The representative scenarios selected by AD for assessment were evaluated using maximum application rates as recommended on the product labels for 4 t amylphenol.

Occupational Handlers. The Agency has determined that there is potential for dermal and inhalation worker exposure to 4 t amylphenol at various use sites including agricultural premises, food handling, commercial/ institutional/ industrial premises, and medical premises. The occupational exposure scenarios, and estimated risks are presented on Table 9.

To assess the handler risks, AD used surrogate unit exposure data from both the proprietary Chemical Manufacturers Association ( CMA) antimicrobial exposure study and the Pesticide Handlers Exposure Database ( PHED).

For the occupational handler dermal and inhalation risk assessment, the short and intermediate term risks calculated at baseline exposure ( no gloves and no respirators) were above target MOEs for all scenarios ( i. e., dermal MOEs were > 100 and inhalation MOEs were > 300). Note, however, that the high pressure spray application method in the agricultural use site category was assessed using gloved data.

Table 9 Short, Intermediate Term Risks for Occupational Handlers MOE c Exposure Scenario Method of Application Application Rate ( lb ai/ gallon) Quantity Handled/ Treated per day ( gallons) Baseline Dermal ( a) ( Target MOE> 100) PPE Gloves Dermal ( b) ( Target MOE> 100) Baseline Inhalation ( Target MOE> 100) Agricultural Premises and Equipment Low Pressure Handwand 10 270 No Data 150,000 High Pressure Handwand 40 No Data 5,100 210,000 Mopping 2 3,600 No Data 220,000 Wiping 0.26 690 No Data 59,000 Application to hard surfaces Trigger Pump Spray 0.0034 0.26 10,000 24,000 3,000,000 Fogger Liquid Pour of soluble concentrate 0.163 lb ai/ gal/ 6,000 ft2 15,000 ft2 120 No Data 4,500 Food Handling Low Pressure Handwand 2 1,800 No Data 1,000,000 Mopping 2 4,900 No Data 290,000 Wiping 0.26 940 No Data 80,000 Application to indoor hard surfaces Trigger Pump Spray 0.0025 0.26 7,300 17,000 2,100,000 Commercial/ Institutional Premises Application to indoor Low Pressure Handwand 0.005 2 920 No Data 510,000 Page 30 of 40 Table 9 Short, Intermediate Term Risks for Occupational Handlers MOE c Mopping 2 2,400 No Data 150,000 Wiping 0.26 470 No Data 40,000 hard surfaces Trigger Pump Spray 0.26 7,100 17,000 2,100,000 Air Deodorization Aerosol Spray 0.074% ai by weight 3 16 oz cans 4,100 9,700 1.200,000 Medical Premises and Equipment Low Pressure Handwand 2 920 No Data 510,000 Mopping 45 110 No Data 6,500 Wiping 0.26 470 No Data 40,000 Application to indoor hard surfaces Trigger Pump Spray 0.005 0.26 7,100 17,000 2,100,000 Air Deodorization Aerosol Spray 0.074% ai by weight 3 16 oz cans 4,100 9,700 1,200,000 ( a) Baseline Dermal: Long sleeve shirt, long pants, no gloves. ( b) PPE Dermal with gloves: baseline dermal plus chemical resistant gloves. c MOE = NOAEL ( mg/ kg/ day) / Daily Dose [ Where short and intermediate term NOAEL = 25 mg/ kg/ day for dermal exposure and short, and intermediate term inhalation NOAEL = 50 mg/ kg/ day for inhalation exposure]. Target MOE is 100 for dermal exposure and 300 for inhalation exposure.

Postapplication Exposure and Risk. For most of the occupational scenarios, postapplication dermal exposure is not expected to occur or is expected to be negligible based on the application rates and chemical properties of the chemical. Postapplication/ bystander inhalation exposures, however, were assessed for entry into a building after a fogging application. The representative building selected was a poultry barn. The Agency used the MCCEM ( Multi Chamber Concentration and Exposure Model) to estimate postapplication/ bystander exposures. The calculated inhalation MOEs were above the target MOE of 300 for all fogging postapplication scenarios.

9.0 INCIDENTS A detailed summary of the human incident data is presented in the memorandum from J. Chen D316276, July 2005. Below is a brief summary of this information. The Agency consulted the following databases for poisoning incident data for 4 t amylphenol and its salts, and other similar phenolic disinfectant compounds:

( 1) OPP Incident Data System ( IDS)  The Incident Data System of The Office of Pesticide Programs ( OPP) of the Environmental Protection Agency ( EPA) contains reports of incidents from various sources, including registrants, other federal and state health and environmental agencies and individual consumers, submitted to OPP since 1992. Reports submitted to the Incident Data System represent anecdotal reports or Page 31 of 40 allegations only, unless otherwise stated. Typically no conclusions can be drawn implicating the pesticide as a cause of any of the reported health effects. Nevertheless, sometimes with enough cases and/ or enough documentation risk mitigation measures may be suggested. ( 2) Poison Control Centers  as the result of a data purchase by EPA, OPP received Poison Control Center data covering the years 1993 through 1998 for all pesticides. Most of the national Poison Control Centers ( PCCs) participate in a national data collection system, the Toxic Exposure Surveillance System, which obtains data from about 65 70 centers at hospitals and universities. PCCs provide telephone consultation for individuals and health care providers on suspected poisonings, involving drugs, household products, pesticides, etc. ( 3) California Department of Pesticide Regulation  California has collected uniform data on suspected pesticide poisonings since 1982. Physicians are required, by statute, to report to their local health officer all occurrences of illness suspected of being related to exposure to pesticides. The majority of the incidents involve workers. Information on exposure ( worker activity), type of illness ( systemic, eye, skin, eye/ skin and respiratory), likelihood of a causal relationship, and number of days off work and in the hospital are provided. ( 4) National Pesticide Telecommunications Network ( NPTN)  NPTN is a toll free information service supported by OPP. A ranking of the top 200 active ingredients for which telephone calls were received during calendar years 1984 1991, inclusive, has been prepared. The total number of calls was tabulated for the categories human incidents, animal incidents, calls for information, and others.

There are some reported incidents associated with exposure to end use products containing 4 tert amylphenol. Dermal, ocular and inhalation are the primary routes of exposure. Dermal exposure is considered as a very important route of exposure. Most of the incidents are related to irritation reaction. The most common symptoms reported for cases of inhalation exposure were respiratory irritation/ burning, irritation to mouth/ throat/ nose, coughing/ choking, shortness of breath, dizziness, flu like symptoms, and headache. Eye pain, burning of eyes, conjunctivitis, blurring vision, and acute inflammation have been reported in ocular exposure incidents. Neurological effects, such as dizziness, headache and blurred vision have also been reported.

10.0 ENVIRONMENTAL RISK A detailed ecological hazard and environmental risk assessment for 4 t amylphenol and its salts is presented in the attached memorandum ( memo from D. Bays, October 2005). A brief summary is presented below.

Environmental Modeling/ Exposure. The limited environmental exposure resulting from indoor uses of 4 t amylphenol and its salts is not anticipated to cause adverse effects to terrestrial or aquatic organisms.

Ecological Hazard and Risk. The registrant has not submitted any ecological effects data to support this RED. The only data that was available was found in the peer reviewed literature. None of these studies met current guideline requirements and therefore, could not be used in a risk Page 32 of 40 assessment. There is a concern about the possibility of endocrine disruption in fish, since 4 t amylphenol is considered an ecoestrogen. This was documented in several studies on carp ( Cyprinus carpio), whose findings were included in the ecotoxicity chapter. However, since this chemical is restricted to indoor uses only, the possibility for exposure of fish to 4 t amylphenol would be limited. The registrant does have to submit three ecological effects studies on the acute toxicity of this chemical. These include an avian acute oral toxicity test, preferably using the bobwhite quail, ( 850.2100/ 71 1), a freshwater fish acute toxicity test, preferably using the rainbow trout, ( 850.1075/ 72 1), and an acute freshwater invertebrate test ( 850.1010/ 72 2). These tests are required in order to document potential acute toxicity to these organisms in the unlikely event that exposure to 4 t amylphenol and its salts does occur.

The acute toxicity data for 4 t amylphenol are summarized on Table 10. As shown in Table 10, acute toxicity for freshwater fish ranged from 2.50 mg/ L to 16 mg/ L in the fathead minnow. The first study was conducted using criteria similar to OPP/ OPPTS guidelines and would have more weight than the second study which did not provide any information on how the study was conducted. Therefore, the data indicates that 4 t amylphenol is moderately toxic to coldwater species, such as the fathead minnow. The fathead minnow is considered to be less sensitive than the bluegill. Also shown in Table 10, acute toxicity to shrimp was LC50 = 1.7 mg/ L. This indicated that 4 t amylphenol was moderately toxic to shrimp. The study does not meet current guideline requirements and could not be used in a risk assessment.

Table 10. Acute Toxicity of 4 t amylphenol and salts Organism Results  LC50 ( mg/ L) ( 95% Confidence Limit) Toxicity Category Comments Reference Freshwater Fish Fathead minnow ( Pimephales promelas) 2.50 ( 1.87  3.34) moderately toxic  96h test duration;  flow through bioassay  caused necrosis in fish Holcombe, G W et al. 1984 Environ Pollut ser A Ecol Biol 35: 367 81 Fathead minnow ( Pimephales promelas) 16 Slightly toxic  No information available on the test parameters Russon, C L et al. 1997 Environ. Toxicol. Chem 16: 948 Marine/ Estuarine Invertebrates Shrimp ( Crangon septemspinosa) 96h LC50 = 1.7 mg/ L Moderately toxic  96h test duration;  aerated gently and changed at 49 hours McLeese, D W 1981 Chemosphere 10( 7): 723 Endocrine Disruption Effects in Fish. EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee ( EDSTAC), EPA determined that there was scientific basis for including, as Page 33 of 40 part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effects in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP). When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, 4 t amylphenol and its salts may be subjected to additional screening and/ or testing to better characterize effects related to endocrine disruption.

4 t Amylphenol was estrogenic in a number of different fish models from the in vitro rainbow trout ER competitive binding assay ( MED) to in vivo medaka full life cycle tests ( Seki et al., 2003) as summarized in the table below. Many types of estrogenic or endocrine disruptive responses were observed such as increased expression of vitellogening ( Vtg) mRNA and protein, sex reversal, and reduction of P450 11   hydoxylase levels. The estrogenic LOEC varied among models, while it took a 4 t amylphenol concentration of  3.7/ 3.3 log M to increase Vtg mRNA expression in trout liver slices in vitro, a concentration of only  6.5 log M increased Vtg protein levels in medaka full life cycle tests. Efficacy of the 4 t amylphenol estrogenic response was nearly equal to the maximum response elicited by exposure to 17    estradiol ( E2). The effect of 4 t amylphenol exposure on cell viability was measured in a number of these studies and was found to occur at concentrations above the estrogenic LOEC, although the toxic concentration of 4 t amylphenol was never more than an order of magnitude greater than the estrogenic LOEC. While there are only a small number of studies of the estrogenic effects 4 t amylphenol the relative estrogenic potency of 4 t amylphenol appeared to be an order of magnitude higher in fish than in mammals. This chemical is also on a European list of " Chemicals purported to be endocrine Disrupters" ( IEH, 2005; page 85 in the Consumer Products table which references Miller et al., 2001 and Schultz et al., 2000, and a priority list produced by an European consulting firm).

Examples of 4 t amylphenol affecting the reproductive processes of carp have been reported in the peer reported literature. Since the use pattern for this chemical is restricted to indoor uses, exposure to fish, such as carp, should be limited. Therefore, no additional testing for endocrine disruption effects on fish is necessary at this time.

Table 11: Examples of 4 t amylphenol Affecting the Endocrine System in Fish Organism Results Toxicity Category Comments Reference Male common carp ( Cyprinus carpio) caused formation of oviducts in male fish and reduced the number of primordial germ cells in gonads identified as an ecoestrogen  test concentration 0.14 mg/ L  exposed embryos and fingerlings at various ages Gimeno et al. 1997 Environ Sci Technol 31( 10): 2884 2890.

Male common carp ( Cyprinus carpio) 30 day EC50 for oviduct formation = 63 ug/ L NOEC for oviduct identified as causing endocrine  120 male carp tested  nominal concentrations of 100, 320, & 1000 ug/ L were tested Gimeno, S. et al. 1998a Aquatic Toxicology ( Amsterdam) Page 34 of 40 Table 11: Examples of 4 t amylphenol Affecting the Endocrine System in Fish Organism Results Toxicity Category Comments Reference formation = < 36 ug/ L primordial germ cells lower in treated fish NOEC for vitellogenin induction = 90 256 ug/ L disruption effects  160 day test duration  intermittent flow through system 43: 77 92.

Cultured hepatocytes from genetically unifor m, all male, F1 hybrid progenies of common carp ( Cyprinus capio) vitellogenin induction in carp hepatocytes with LOEC ranging from 5 50 uM, cytotoxic at 100uM identified as causing endocrine disruption effects  six month old hepatocytes with fully mature testes containing mature sperm Smeets, J. M. et al. 1999. Toxicol. Sci. 50( 2): 206 213.

Trout RTH 149 Recombinant trout ER Estrogenic LOEC=  6 log M; IC50= 7.6x10 7 M Identifid as causing endocring disruption effects  relative potency is 0.036 approximately 75% of maximum E2 Hornung et al. 2003 Partial life cycle carp ( Cyprinus carpio) Estrogenic LOEC=  6.2 log M Identified as causing endocrine disruption effects  oviduct development in male Gimeno et al. 1996 Partial life cycle Medaka ( Oryzias latipes) Estrogenic LOEC= 5.8 log M Identified as causing endocrine disruption effects  sex reversal; Inhibition of P450 11B hydroxylase mRNA levels Yokota et al. 2005 Full life cycle Medaka ( Oryzias latipes) Estrogenic LOEC=  6.5; cytotoxicity =  5.2 F0 and  5.8 F1 Identified as causing endocrine disruption effects  Vtg induction at  6.5 log M Seki et al. 2003 Rainbow trout cytosol ER competitive binding Estrogenic LOEC=  5 log M; IC50= 2.2x10 4 M; RBA 0.004% Identified as causing endocrine disruption effects Tapper et al. 2005 Male rainbow trout liver slice/ Vtg gene expression Estrogenic LOEC=  3.7 log M; IC50= 1.8x10 4 M; cytotoxicity=  3 log M Identified as causing endocrine disruption effects  relative potency = 0.004% approximately 75% of maximum E2 Tapper et al. 2005 Male common carp ( Cyprinus carpio) elevated levels of vitellogenin, inhibition of spermatogenesis, disappearance of spermatozoa and identified as causing endocrine disruption effects and no mortality or  3 month test duration  nominal concentrations of 32, 100, 320 and 1000 ug/ L were tested Gimeno et al. 1998b Aquatic Toxicology ( Amsterdam) 43: 93 109. Page 35 of 40 Table 11: Examples of 4 t amylphenol Affecting the Endocrine System in Fish Organism Results Toxicity Category Comments Reference spermatogenic cysts, reduced diameter of seminiferous lobules, reduced spermatocrit values and early appearance of ovo testes LOAEL= 0.032 mg/ L growth effects E2= 17    estradiol; ; Vtg = vitellogening; RBA = relative binding affinity Vitellogenin, an egg yolk pre cursor protein is produced in female trout liver and transported to the gonad for the production of eggs. Male trout retain ER in the liver and the ability to produce vitellogenin, and can be induced to do so upon exposure to estrogen ( 17    estradiol; E2), or estrogenic chemicals.

Environmental Risk Assessment The indoor uses of 4 tert amylphenol and its salts considered in this RED make it unlikely that any appreciable exposure to terrestrial or aquatic organisms would occur when 4 t amylphenol and its salts are used according to label directions. Even though there is a low potential for risk due to the lack of expected environmental exposure from the registered uses of this product, three acute toxicity studies ( avian acute oral toxicity test [ 850.2100/ 71 1] preferably using the bobwhite quail; freshwater fish acute toxicity test [ 850.1075/ 72 1] preferably using the rainbow trout; and an acute freshwater invertebrate test [ 850.1010/ 72 2]), will need to be submitted by the registrant in order to determine potential toxicity to birds and aquatic organisms in the unlikely event that exposure does occur.

Endangered Species Considerations The Agency has developed the Endangered Species Protection Program to identify pesticides whose use may cause adverse impacts on endangered and threatened species, and to implement mitigation measures that address these impacts. The Endangered Species Act requires federal agencies to ensure that their actions are not likely to jeopardize listed species or adversely modify designated critical habitat. To analyze the potential of registered pesticide uses to affect any particular species, EPA puts basic toxicity and exposure data developed for risk assessments into context for individual listed species and their locations by evaluating important ecological parameters, pesticide use information, the geographic relationship between specific pesticide uses and species locations, and biological requirements and behavioral aspects of the particular species. A determination that there is a likelihood of potential impact to a listed species may result in limitations on use of the pesticide, other measures to mitigate any potential impact, or consultations with the Fish and Wildlife Service and/ or the National Marine Fisheries Service as necessary.

Based on the low likelihood of environmental exposure from the registered indoor uses of 4 t amylphenol and its salts to fish, aquatic invertebrates, and aquatic plants, adverse impacts to endangered species are not expected from the registered uses of 4 t amylphenol and its salts. Page 36 of 40 11.0 DEFICIENCIES/ DATA NEEDS Hazard Data Gaps. There are several data gaps for 4 t amylphenol. The existing acute toxicity data iincomplete and 4 new acute toxicity studies using the technical grade active ingredient must be conducted. The current hazard database is inadequate to support the indirect food use of 4 t amylphenol. The ADTC ( 2005) identified the following data gaps for 4 t amylphenol:

Acute toxicity testing: 870.1200 ( acute dermal), 870.1300 ( acute inhalation), 870.2400 ( primary eye irritation, and 870.2600 ( dermal sensitization) 90 oral subchronic study in the rat, modified to examine endocrine disrupter effects Developmental toxicity study in the rabbit 2 generation reproduction study in the rat or other available information on reproductive toxicity Repeat dose inhalation toxicity study of at least 28 days duration Because 4 t amylphenol appears to cause severe dermal irritation and is a sensitizer following repeated dermal exposure, a dermal toxicity study with the diluted end use formulated product would be helpful to ensure that clothing and diapers containing 4 t amylphenol will not be irritating to skin.

Dietary Data Gaps. In the absence of chemical specific data, the Agency used a 10% migration factor for the dietary assessment. The Agency requests confirmatory data to support the 10% migration factor.

Confirmatory data are needed to show whether residues would be absorbed into treated surfaces, especially wood surfaces, of feeding devices and not be removed by scrubbing with soap and rinsing with water. If the antimicrobial residues are absorbed into the wood, these residues would be available for livestock ingestion. This finding could entail the need to generate data for large animals including livestock and poultry metabolism studies, analytical methods for livestock and poultry tissues and residue data for livestock and poultry.

Ecological Data Gaps. For indoor uses, an acute oral toxicity study using the technical grade of the active ingredient ( TGAI) is required to establish the toxicity of 4 tert amylphenol and its salts to birds. The preferred test species is either mallard duck ( a waterfowl) or northern bobwhite quail ( an upland game bird). Two avian acute toxicity studies were found in the Agency's files for 4 tert amylphenol or its salts. The tests were conducted in 1974 using the bobwhite quail ( MRID # 240116618) and mallard duck ( MRID # 011504216). The tests were conducted using antiquated procedures and do not meet the current guideline requirements. The results showed moderate toxicity, which makes it important that a test using current guideline requirement be conducted by the registrant. Avian acute oral toxicity testing ( 850.2100/ 71 1), preferably using the bobwhite quail, is required to support the currently registered uses of 4 tert amylphenol and it salts.

Freshwater fish toxicity studies using the TGAI are required to establish the toxicity of 4 tert amylphenol to fish. Data are generally required for only one species. Testing in two fish Page 37 of 40 species is required for stable chemicals with high volume effluents ( e. g., including, but not limited to, egg washing, fruit and vegetable rinses, swimming pools or materials preservatives) and if the LC50 in the first species is greater than (>) 1 ppm. The preferred test species are rainbow trout ( a coldwater fish) and bluegill sunfish ( a warmwater fish), although other test species identified in the OPPTS Guideline ( i. e., OPPTS 850.1075 ( e)( 4)( i)( A)) may also be used. No freshwater fish acute toxicity studies were identified from peer reviewed literature. Two fish studies were found in the agency's files, but no studies have been submitted to support registration of 4 tert amylphenol. The first study ( MRID # 240116619) was conducted in 1974 and tested both rainbow trout and bluegill sunfish in the same study. The second study( MRID # 444742 08) was conducted in 1992 using zebra fish, but only tested one concentration of TGAI. Neither of these studies meets current guideline requirements and cannot be used in a risk assessment. Freshwater fish acute toxicity testing ( 850.1075/ 72 1) on one species preferably the rainbow trout is required to support the currently registered uses of 4 tert amylphenol and its salts.

A freshwater aquatic invertebrate toxicity test using the TGAI is required to establish the toxicity of a pesticide to aquatic invertebrates. The preferred test species is Daphnia magna or Daphnia pulex. No toxicity studies were identified for these species in peer reviewed literature. No studies have been submitted by registrants to support the registered uses of 4 tert amylphenol and its salts. Freshwater invertebrate acute toxicity testing ( 850.1010/ 72 2) is required for the currently registered uses of 4 tert amylphenol and its salts.

Residential/ Occupational Data Gaps. Confirmatory worker exposure data are necessary, due to the significant limitations of the existing exposure data used in this assessment. The Agency is requesting worker exposure studies that evaluate both dermal ( Guideline 875.1200) and inhalation ( Guideline 875.1400) exposure for indoor uses. The Agency also requires confirmation of descriptions of human activity ( 875.2800) associated with the uses assessed in this document. In addition, the Agency requests confirmatory data to support the assumption that only 5% of 4 t amylphenol is transferred from treated textiles/ diapers to skin.

Environmental Fate Data Gaps: 4 t Amylphenol and its potassium and sodium salts are registered as indoor use products and minimum environmental fate data required by EPA for an indoor use product is hydrolysis ( 161 1). However, no hydrolysis data as indicated in the U. S. Environmental Protection Agency's Environmental Fate Data Requirements published in Pesticide Assessment Guidelines, Subdivision N, § 161 1 have been submitted to the Agency for these chemicals.

12.0 REFERENCES BIBRA, Working Group ( 1990): Para tertiary Amylphenol. Toxicity Profile BIBRA Toxicology International. 3 pp.

MRID No. 00417108 Edwards, C. N. 1990. Assessment of Clastogenic Action on Bone Marrow Erythrocytes in the Micronucleus Test. Prepared by Life Science Research Ltd., Suffolk, UK. Study No. 90/ NLL033/ 0533. Submitted by Nipa Laboratories, Inc., Wilmington, DE. Page 38 of 40 Gimeno, S., Gerritsen, A., Bowmer, T., and Komen, H. ( 1996). Feminization of male carp. Nature 384, 221 222.

Gimeno, S., Komen, H., Venderbosch, P. W., and Bowner, T. ( 1997) Disruption of sexual differentiation in genetic male carp ( Cyprinus carpio) exposed to an alkyphenol during different life stages. Environ. Sci. Technol. 31( 10): 2884 2890.

Gimeno, S., Komen, H., Gerritsen, A. G., and Bowner, T. ( 1998a): Feminisation of young males of the common carp, Cyprinus carpio, exposed to 4 tert pentyphenol during sexual differentiation. Aquatic Toxicology ( Amsterdam) 43: 77 92.

Gimeno, S., Komen, H., Jobling, S., Sumpter, J., and Bowner, T. ( 1998b): Demasculinisation of sexually mature male common carp, Cyprinus carpio, exposed to 4 tert amylphenol during spermatogenesis. Aquatic Toxicology ( Amsterdam) 43: 93 109.

Holcombe, G. W., Phipps, G. L., Knuth, M. L., and Felhabert, T. ( 1984) The acute toxicity of selected substituted phenols, benzenes and benzoic acid ester to fathead minnows Pimephales promelas. Environ. Pollut. Ser. A Ecol. Biol. 35( 4): 367 381.

Hornung, M., Ankley GT, and Schmieder, P. ( 2003). Induction of an estrogen responsive reporter gene in rainbow trout hepatoma cells ( RTH 149) at 11 or 18C. Environ Toxicol Chem. 22, 866 871.

MRID No. 41572701 Lloyd, J. M. 1990. Investigation of Mutagenic Activity in the TK+/ Mouse Lymphoma Cell Mutation System. Prepared by Life Science Research Ltd., Suffolk, UK. Study No. 90/ NLL034/ 0395. Submitted by Nipa Laboratories, Inc., Wilmington, DE.

MRID No. 41438401 May, K. 1990. Nipacide PTAP ( para tertiary amylphenol): Assessment of Mutagenic Potential in Histidine Auxotrophs of Salmonella typhimurium. Prepared by Life Science Research Ltd., Suffolk, UK. Study No. 90/ 0109. Submitted by Nipa Laboratories, Inc., Wilmington, DE.

MRID 42470301 Siglin 1992. Ninety One Day Dermal Toxicity Study in Rats with Nipacide PTAP. Springborn Laboratories.

Tapper, M., Sheedy, B., Denny, J., and Schmieder, P. ( 2005) Rainbow trout estrogen ( ER) binding and ER mediated vitellogenin production in a trout liver slice assay. [ Measurements made at the EPA/ ORD/ NHEERL/ Midcontinent Ecology Division ( MED) Duluth, MN]

MRID No. 46616601. Tuffnell, P. P. Phenol, 4( 1,1 dimethylpropyl) Acute Oral Toxicity in the Rat. Safepharm Laboratories Ltd., Derby U. K., Laboratory Test No. 47/ 2097. July 23, 1992. Unpublished. Page 39 of 40 MRID No. 46616602. Tuffnell, P. P. Phenol, 4( 1,1 dimethylpropyl) Acute Dermal Irritation Test in the Rabbit. Safepharm Laboratories Ltd., Derby U. K., Laboratory Test No. 47/ 2098. July 25, 1992. Unpublished.

IEH ( 2005) Chemicals Purported to be Endocrine Disrupters: A Compilation of Published Lists ( Web Report W20), Leicester, UK, MRC Institute for Environment and Health, available at http:// www. le. ac. uk/ ieh/

McLeese, D. W. ( 1981) Lethality and accumulation of alkyphenols in aquatic fauna. Chemosphere 10( 7): 723.

Routledge, E. J. and Sumpter, J. P. ( 1997) Structural features of alkylphenolic chemicals associated with estrogenic activity. J. Biol. Chem. 272( 6): 3280 3288.

Russon, C. L., Bradbury, S. P., Broderius, S. J., Hammermeister, R. A., and Drummond, R. A. ( 1997) [ no title given] environ. Toxicol. Chem. 16: 948.

Seki, M., Yokota, H., Matsubara, H., Maeda, M., Tadokoro, H., Kobayashi, K. ( 2003). Fish full life cycle testing for the weak estrogen 4 t pentylphenol on medaka ( Oryzias latipes). Environ Toxicol Chem 22, 1487 1496.

MRID No. 41920002 Siglin, J. C. 1991. Nipacide PTAP, Teratology Study in Rats. Prepared by Springborn Laboratories, Inc., Spencerville, OH. Study No. 3227.3. Submitted by Nipa Laboratories, Inc., Wilmington, DE.

Smeets, J. M., Van, H. I., Giesy, J. P., Seinen, W., and van den, B. M. ( 1999): Estrogenic potencies of several environmental pollutants, as determined by vitellogenin induction in a carp hepatocyte assay. Toxicol. Sci. 50( 2): 206 213.

Soto, et al. ( 1995) The E SCREEN assay as a tool to identify estrogens: An update on estrogenic environmental pollutants. Environ. Health Perspect. 103 ( Suppl. 7): 113 122.

Stevenson, C. J. ( 1984): Environmentally induced vitiligo ( leukoderma) from depigmenting agents and chemicals. J. Toxicol. Cutaneous Ocul. Toxicol. 3( 3): 299 308.

USEPA. 1999. Evaluation of Chemical Manufacturers Association Antimicrobial Exposure Assessment Study. Memorandum from Siroos Mostaghimi, Ph. D., USEPA, to Julie Fairfax, USEPA. Dated November 4, 1999. DP Barcode D247642.

U. S Environmental Protection Agency ( EPA) 2001. Residential SOPs Policy Update 12, EPA Office of Pesticide Programs  Human Health Division. Dated April 5, 2000.

U. S. Environmental Protection Agency ( EPA). 2002. ECOTOX User Guide: ECOTOXicology Page 40 of 40 Database System. Version 3.0. Available: http:// www. epa. gov/ ecotox/

Wysowski, D. K. et al. ( 1978) Epidemic neonatal hyperbilirubinemia and use of a phenolic disinfectant detergent. Pediatrics 61: 165 170.

Yamasaki, K., et al. ( 2003) Immature rat uterotrophic assay of 18 chemicals and Hershberger assay of 30 chemicals. Toxicology 183: 93 115.

Yokota, H., Abe. T., Nakai, M., Murakami, H., Eto, C., Yakabe, Y. ( 2005) Effects of 4 tert pentylphenol on the gene expression of P450 11  hydroxylase in the gonad of medaka. Aquatic Toxicology 71, 121 132.

Zeiger, E., Anderson, B., Haworth, S., Lawlor, T., and Mortelmans, K. ( 198): Salmonella mutagenicity tests. 4. results from the testing of 300 chemicals. Environ. Mol. Mutagen 11: 1 158.