UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES September 3, 2002 MEMORANDUM SUBJECT: Fenarimol. Updated HED Human Health Assessment for the Tolerance Reassessment Eligibility Decision ( TRED) Document. Chemical No. 206600. No MRID #. DP Barcode No. D285162.

FROM: Barry O'Keefe, Residential Exposure Assessor/ Risk Assessor John Doherty, Toxicologist Danette Drew, Chemist Reregistration Branch 3 Health Effects Division ( 7509C)

THRU: Catherine Eiden, Branch Senior Scientist Reregistration Branch 3 Health Effects Division ( 7509C)

TO: Tom Myers, Chemical Review Manager Special Review and Reregistration Division ( 7508C)

This memorandum and attachments are the Amended & Revised Health Effects Division's Tolerance Reassessment Eligibility Decision ( TRED) Document for fenarimol, taking into consideration comments and additional information on the aquatic photodegradates recieved from the registrant, Gowan Company, and requirements of the 1996 Food Quality Protection Act ( FQPA). This additional information prompted the Environmental Fate and Effects Division ( EFED) to reassess the drinking water exposure for fenarimol. The updated drinking water assessment ( July 31, 2002; D284487) was revised to include fenarimol and its aquatic photodegradates. The model inputs were adjusted so that aquatic concentrations were estimated assuming no aqueous photolysis, which appears to be fenarimol's most significant route of dissipation in the environment. The result provided a screening level estimate of combined concentrations of fenarimol and its aquatic degradates that is conservative and that does not underestimate exposure. Although, there is still some uncertainty as to the identity, fate, and behavior of the photolysis degradates of fenarimol, data will be required to address this uncertainty. Subsequently, the HED FQPA Safety Factor Committee ( SFC) met to reevaluate fenarimol. Based on the updated drinking water assessment and the recent HIARC conclusions regarding aromatase, the FQPA SFC recommended that the FQPA safety factor for fenarimol be reduced from 10x to 3x. 2 Additionally, HED has been informed by SRRD that the registrant has agreed to amend their product labels to prohibit residential use and handling ( i. e. mixing, loading or applying) of fenarimol in residential settings. Applications to turf will be limited to golf courses, and stadium fields or professional athletic fields only. Additionally, the minimum re application interval to turf will be increased to 30 days. Therefore, residential handler and residential postapplication exposure scenarios should no longer exist. The only non occupational postapplication exposure scenario remaining to evaluate is short term dermal exposure to adult golfers. Applications to residential turf will not be permitted by product labels until such time as additional toxicity data are submitted and reviewed. Then the Agency will reevaluate the risk assessment for residential uses.

This assessment only discusses the human health risks required for reassessment of tolerances and does not include an occupational risk assessment required for reregistration of products. Fenarimol was registered after 1984, so it is not subject to reregistration under FIFRA 88. However, fenarimol is subject to tolerance reassessment under the FQPA. When fenarimol undergoes product reregistration, SRRD should insure that all product labels are in compliance with the worker protection standard ( WPS). Cumulative risk assessment considering risks from other pesticides which may have a common mechanism of toxicity is also not addressed in this document.

Attachments: Fenarimol  2nd Report of the FQPA Safety Factor Committee ( B. Tarplee, 8/ 13/ 01) Third Report of the Hazard Identification Assessment Review Committee ( J. Doherty, 7/ 29/ 02) Updated Drinking Water Assessment to Support TRED for Fenarimol ( N. Birchfield, 7/ 31/ 02) Fenarimol. Amendment to Revised HED Human Health Assessment for the Tolerance Reassessment Eligibility Decision ( TRED) Document ( B. O'Keefe, 8/ 1/ 02) Hazard Identification Assessment Review Committee Report ( J. Doherty, 9/ 5/ 01) FQPA Committee Report ( B. Tarplee, 9/ 28/ 01) Mechanism of Toxicity Committee ( METARC) report ( J. Doherty, 9/ 17/ 01), Toxicology Chapter ( J. Doherty, D275392, 10/ 12/ 01) Chemistry Chapter ( D. Drew, D277505, 10/ 18/ 01) Dietary Exposure Analysis ( D. Drew, D278898, 11/ 19/ 01) Metabolism Assessment Review Committee report ( D. Drew, D277692, 9/ 17/ 01) Residential Exposure Analysis ( B. O'Keefe, D280935, 2/ 12/ 02) Drinking Water Assessment to Support the TRED for Fenarimol ( L. Libelo, 8/ 6/ 01).

1.0 EXECUTIVE SUMMARY Fenarimol is a member of the pyrimidine class of fungicides, which also includes dimethirimol, bupirimate, and ethirimol. It is the only member of this class registered for use in the U. S. Fenarimol is a localized systemic foliar fungicide used for control of such pests as scab, powdery mildew, rusts, and leaf spot. Fenarimol inhibits fungal growth by adversely affecting the formation of the fungal sterol ergosterol. The chemical name of fenarimol is alpha( 2 chlorophenyl) alpha( 4 chlorophenyl) 5 pyrimidinemethanol. 3 Use Profile Fenarimol is currently registered for use on the following fruit and nut crops: apples, cherries, filberts, grapes, pears, bananas and pecans. It is also registered for use on ornamental plants, trees, grasses, and turf. The registration of fenarimol is being supported by Gowan Company. Fenarimol total domestic usage for years 1990 1999 averaged approximately 61,000 pounds active ingredient. Its largest markets, in terms of total pounds active ingredient ( ai), are allocated to apples ( 33%), outdoor nurseries ( 20%), turf for lawns ( 16%), and turf for golf courses ( 12%). The remaining usage is primarily on raisin and wine grapes, cherries, filberts, and pears. Crops with a high percentage of the total U. S. planted acres treated include apples ( 25%), raisin grapes ( 21%), sweet cherries ( 13%), tart cherries, wine grapes, and filberts ( 9% each), and table grapes ( 8%).

Fenarimol formulations include granular ( 0.78% ai, turf use only), soluble concentrate/ liquid ( 11.6% ai), flowable concentrate ( 2.4% ai) and emulsifiable concentrates ( 11.6% ai and 12% ai). Only applications to lawns and turf are expected to result in residential exposures. Although some end use products have label restrictions and wording indicative of non homeowner use, fenarimol is not a restricted use pesticide and can be purchased and applied by anyone. Only the granular formulation is assumed to be applied by residents. However, HED has been informed by SRRD that the registrants of fenarimol have agreed to amend their product labels to prohibit residential use and handling ( i. e. mixing, loading or applying) of fenarimol in residential settings. Applications to turf will be limited to golf courses, and stadium fields or professional athletic fields only.

Hazard Identification and Dose Response Assessment The toxicity database for fenarimol is substantially complete, with the following data gaps identified: Primary Dermal Irritation Study ( 870.2400); 28 Day Subchronic Inhalation Study ( 870.3465); and Special Developmental Study ( 870.6300).

Fenarimol has moderate acute toxicity via the oral, dermal or inhalation routes ( all Category III). Fenarimol causes corneal opacity in rabbit eyes ( Category II). There are no data on dermal irritation. Fenarimol was not shown to be a contact dermal sensitizer in the guinea pig.

The rat metabolism study indicates that following oral administration, fenarimol is rapidly absorbed and excreted, with the biliary route being the major route of excretion. Subchronic oral dosing in rats demonstrates very little toxicity except for some slight body weight changes and liver pathology of low degree and consistency ( liver weight increase and fatty liver). In dogs, there was little overt toxicity. Dermal absorption was estimated by HIARC ( 9/ 6/ 01) to be 20% based on a weight of the evidence assessment using rabbit and monkey dermal absorption studies along with a comparison of the rabbit oral developmental toxicity and rabbit 21 day dermal toxicity studies. However, based on additional data supplied by the registrant ( Gowan Company), the HIARC ( 5/ 23/ 02) determined that a dermal absorption rate estimate of 5% was more appropriate for risk assessment purposes.

The liver is the most evident target organ for chronic toxicity, aside from the effects of fenarimol on aromatase. Liver toxicity was manifested by liver weight increases and the presence of " fatty liver" in rats. In dogs, liver weight was increased and there were also increases in serum enzymes indicative of liver toxicity. The data base for carcinogenicity is considered complete. Fenarimol has been 4 classified as a " not likely" human carcinogen ( Group E). The mutagenicity/ genetic toxicity data base is considered complete and indicates no mutagenicity concern.

The data base for prenatal developmental and reproductive toxicity is considered complete. The developmental and reproductive toxicity studies showed no evidence of increased sensitivity or susceptibility of young rats or rabbits following pre or postnatal exposure to fenarimol. The studies demonstrated that fenarimol is associated with hydronephrosis that is reversible.

The most prominent aspect of fenarimol toxicity was evident in the rat multi generation reproduction studies and relates to inhibition of aromatase. Aromatase, also known as estrogen synthetase, is the key enzyme for the conversion of androgens to estrogens and is therefore a potentially critical enzyme in maintaining hormone balance in human physiology. Without aromatase, there could potentially be deficits in estrogens which are important for a variety of physiological functions. Estrogens are largely responsible for the changes that take place during puberty in human females and affect secondary sexual characteristics. It is also recognized that aromatase deficient males do not develop normal skeletal characteristics. The Mechanism of Toxicity Assessment Review Committee ( METARC) met to evaluate the data concerning fenarimol's effects on aromatase and their decision memorandum contains a more detailed discussion of aromatase ( J. Doherty, 9/ 16/ 01).

The multi generation reproduction studies indicate that fenarimol causes reduced fertility and dystocia ( difficult labor). Separate cross dosing studies ( dosing males and mating with untreated females and dosing females and mating with untreated males) indicated that the reduced fertility is due to an effect in males and the dystocia is an effect in females. These effects of fenarimol were demonstrated to be attributed to inhibition of aromatase in adult animals. The decrease in fertility in males results from the decreased conversion of testosterone ( an androgen) to estradiol which is essential for male sexual development. The increase in dystocia in rats was also attributed to inhibition of aromatase because in the rat, progesterone is converted to estrogen by aromatase to facilitate parturition ( birth).

The FQPA required the Agency to consider potential special sensitivity to infants and children from exposure to fenarimol. Submitted toxicity studies showed that there is no increased sensitivity or susceptibility to infants and children based mainly on the results of the developmental/ reproductive toxicity studies. However, a special developmental study is required to determine if the potential hormonal effects as elicited by inhibition of aromatase will result in effects in offspring. Additionally, the environmental fate database is incomplete for the aquatic photolytic degradate of fenarimol, 4 chloro 2( 5 pyrimidyl) 2' chlorobenzophenone. Previously, the Environmental Fate and Effects Division ( EFED) determined that a screening level drinking water assessment, including this degradate of potential toxicological concern, was not possible at that time. Therefore, based on residual uncertainties regarding the toxicology database and exposure considerations, the FQPA committee determined that the 10x FQPA factor should be retained for all fenarimol risk assessments. However, EFED has recently received additional information on this aquatic photo degradate of concern, and subsequently revised the drinking water assessment for fenarimol. The updated drinking water assessment ( July 31, 2002; D284487) was revised to include fenarimol and its aquatic photodegradates. The model inputs were adjusted so that aquatic concentrations were estimated assuming no aqueous photolysis, which appears to be fenarimol's most significant route of dissipation in the environment. The result provides a screening level estimate of combined concentrations of fenarimol and its aquatic degradates that is conservative and that does not underestimate exposure. 5 As a result of this reassessment the chronic EECs increased from 59 to 84

g/ L for surface water, and from 14 to 16

g/ L for ground water. Although, there is still some uncertainty as to the identity, fate, and behavior of the photolysis degradates of fenarimol, data will be required to address this uncertainty. Therefore, the FQPA Safety Factor Committee met on July 29, 2002, to reevaluate fenarimol. The committee also reassessed the uncertainty surrounding the potential effects elicited by inhibition of aromatase by fenarimol. The FQPA SFC agreed with the HIARC conclusion that a special developmental toxicity study to assess for hormonal effects is required for fenarimol, and a database uncertainty factor of 3x is required until the data are received and reviewed. Based on the updated drinking water assessment and the recent HIARC conclusions regarding aromatase, the FQPA SFC recommended that the FQPA safety factor for fenarimol be reduced from 10x to 3x.

The METARC recommended, and the HIARC confirmed, that the reduced male fertility and dystocia effects of fenarimol should be endpoints for human health risk assessment. It is noted that the endpoint from the multi generation reproduction study is based on decreased litter size. This decrease in litter size may be a reflection of the maternal toxicity ( dystocia) or the potential for fenarimol to inhibit aromatase in males ( reduced fertility). Because both males and females are affected, the toxicological endpoint from the multi generation reproduction study is applicable to all populations.

After examining all of the available toxicity data, the HIARC concluded that an acute toxicity endpoint and dose for risk assessment could not be identified. That is, no appropriate endpoint was available to quantitate risk to the general population or females 13 50 years old from a single dose administration of fenarimol. Although hydronephrosis seen in the rat developmental and multigeneration reproductive toxicity studies had been identified as an acute adverse toxic effect ( endpoint) in earlier fenarimol risk assessments, the HIARC concluded that it is not appropriate because: 1) the hydronephrosis is not severe ( its is considered an effect of low degree or magnitude); 2) the hydronephrosis was shown to be reversible; 3) the hydronephrosis developed after multiple exposures and there is no indication that it would develop following a single exposure; and, 4) the hydronephrosis may be related to a developmental delay and not a target specific effect of fenarimol.

For risks associated with chronic dietary exposures, the HIARC identified a reference dose for chronic exposure ( cRfD) of 0.006 mg/ kg/ day from the multi generation reproduction study based on a no observed adverse effect level ( NOAEL) of 0.6 mg/ kg/ day, and a 10X uncertainty factor for interspecies extrapolation and a 10X uncertainty factor for intraspecies variation. The NOAEL of 0.6 mg/ kg/ day is based on decreased live born litter size in the F 1 and F 2 generations at a lowest observed adverse effect level ( LOAEL) of 1.2 mg/ kg/ day. HED calculated a chronic Population Adjusted Dose ( cPAD) of 0.002 mg/ kg/ day. The cPAD is the RfD divided by the FQPA safety factor ( 3X). Chronic dietary exposure estimates greater than 100% of the cPAD would exceed HED's level of concern.

For risks associated with intermediate term residential exposures ( 1 6 months), the same endpoint ( NOAEL of 0.6 mg/ kg/ day) was used for incidental oral, dermal, and inhalation risk assessments. A Margin of Exposure or MOE, which is the ratio of the NOAEL to the exposure estimate, of greater than or equal to 300 does not exceed HED's level of concern for intermediate term risk assessments. A MOE of greater than or equal to 300 is required for these intermediate term exposure scenarios because of the 10x interspecies factor, the 10x intraspecies factor and the 10x 3X FQPA factor. Because the same endpoint was used for all intermediate term exposure assessments, the risk 6 estimates for the various routes of exposure may be aggregated.

For the short term ( 1 30 day) incidental oral, dermal, and inhalation risk assessments, a LOAEL of 35 mg/ kg/ day was selected. This endpoint is based on decreased fertility and dystocia, an indicator of hormonal effects, observed in a special non guideline cross breeding reproduction/ developmental toxicity study in rats. Because a NOAEL could not be identified in the study, and effects were seen at the lowest dose tested, a LOAEL was used, and an additional 3x uncertainty factor was applied. Therefore, a MOE greater than 900 does not exceed HED's level of concern for short term risk assessments. Because the same endpoint was used for all short term exposure assessments, the risk estimates for the various routes of exposure may be aggregated.

Exposure and Risk Assessment Dietary Exposure and Risk Estimates The residue chemistry database for fenarimol is substantially complete and is adequate for tolerance reassessment. The Metabolism Assessment Review Committee ( MARC) has determined that for enforcement purposes, the tolerance for plant commodities should be expressed as parent only. However the dietary assessment for grapes and bananas should include the metabolites [ alpha( 2 chlorophenyl) alpha( 4 chlorophenyl) 1,4 dihydro 5 pyrimidinemethanol] and ( 5[ 2 chlorophenyl) ( 4 chlorophenyl) methyl] 3,4 dihydro 4 pyrimidinol]), because of their structural similarity to fenarimol. The residue of concern in livestock commodities is fenarimol per se. Tolerances for fenarimol are generally low, ranging from 0.01 to 1.0 ppm Because an acute toxicity endpoint was not identified, an acute dietary exposure assessment was neither required nor conducted. The chronic dietary exposure assessment for fenarimol is highly refined using anticipated residues based on Food and Drug Administration ( FDA) monitoring data for apples, bananas, cherries, grapes and pears. There were no USDA Pesticide Data Program ( PDP) monitoring data available for fenarimol. The FDA monitoring data indicated no detectable residues for apples, bananas, grapes and pears. Field trial residue data were used for pecans and filberts. Percent crop treated (% CT) information and processing factors, where available, were used in the assessment. Anticipated residues were calculated for cattle meat, fat, and meat by products. Wet apple pomace is the only animal feed item associated with the registered uses of fenarimol. There are no poultry or hog feedstuffs. Milk was classified as Category 3 of 40 CFR 180.6( a)  that is, there is no reasonable expectation of finite residues.

Chronic dietary risk estimates are provided for the general U. S. population and various population subgroups. This assessment concludes that for all supported registered commodities, the chronic risk estimates are below the HED's level of concern (< 100% of the chronic population adjusted dose, cPAD) for the general U. S. population and all population subgroups. Dietary ( food) exposure estimates were all very low ( all < 1% of the cPAD). This is not surprising based on: the lack of detectable residues for many commodities in the FDA monitoring data; no residues expected in milk, poultry and hogs; and, low anticipated residues for cattle meat, fat, and meat by products.

Environmental fate data show that fenarimol is persistent and mobile in the environment. In field studies, fenarimol dissipated with half lives of 3 months to several years from soil and turf surfaces. Fenarimol is stable to hydrolysis, anaerobic microbial degradation and photolysis on soil. It is degraded very slowly, if at all, by aerobic microbial processes with reported mean aerobic soil 7 metabolism half life of about 4 years. It is degraded by photolysis in aqueous solution. The primary photolysis product was 4 chloro 2( 5 pyrimidyl) 2' clorobenzophenone. The MARC elected not to exclude this degradate in the drinking water exposure assessment because: 1) its potential to occur in surface water; and 2) the lack of data to determine whether it is of toxicological concern.

The environmental fate studies were conducted in the 1970s and early 1980s. The quality of the data provided by these studies is significantly lower then currently required. By current standards most of these studies would not be considered acceptable and the results would not be considered of sufficient quality to allow a reasonably accurate assessment of the environmental fate of this compound. Therefore, the estimated environmental concentrations ( EECs) presented here are somewhat uncertain, and may change substantially when better data become available. It is not possible, using the existing data, to provide a more refined assessment.

To estimate risks from exposure to fenarimol residues potentially present in drinking water, HED has compared EECs for fenarimol in surface water and ground water to calculated drinking water levels of comparison ( DWLOCs). The DWLOC chronic is the concentration in drinking water as a part of the aggregate chronic exposure that occupies no more than 100% of the cPAD when considered together with other sources of exposure. If the EECs are greater than the DWLOCs, there is a potential drinking water concern. Screening level assessments, using conservative modeling to estimate highend average concentrations ( EECs) of fenarimol in surface water and ground water, were conducted by the Environmental Fate and Effects Division ( EFED). Tier I modeling was performed for both surface water ( FIRST model) and groundwater ( SCI GROW model). EFED modeled the turf application use scenario in both cases. A Tier II model is not available for turf.

Initially, the drinking water assessment did not include the water degradate of concern, because the environmental fate database is incomplete for the aquatic photo degradate of fenarimol, 4 chloro 2 ( 5 pyrimidyl) 2' chlorobenzophenone. Consequently, there was some residual uncertainty thatthe drinking water assessment may underestimate exposure. However, recently, the Environmental Fate and Effects Division ( EFED) received additional information on the aquatic photo degradate and revised the drinking water assessment. The updated drinking water assessment ( July 31, 2002; D284487) includes fenarimol and its aquatic photodegradates. The model inputs were adjusted so that aquatic concentrations were estimated assuming no aqueous photolysis, which appears to be fenarimol's most significant route of dissipation in the environment. Minor model input corrections were also made to the application rate and interval. The result provides a screening level estimate of combined concentrations of fenarimol and its aquatic degradates that is conservative and that does not underestimate exposure. As a result of this reassessment the chronic EECs increased from 59 to 84

g/ L for surface water, and from 14 to 16

g/ L for ground water. Although, there is still some uncertainty as to the identity, fate, and behavior of the photolysis degradates of fenarimol, data will be required to address this uncertainty.

The EEC for ground water is less than all DWLOCs; therefore, there is no concern for aggregate chronic exposure to fenarimol and its degradates from food and ground water. The EEC for surface water is greater than all DWLOCs; therefore, there is a potential concern for aggregate chronic exposures to fenarimol from food and surface water. However, the estimated EEC for surface water is a very conservative estimate. It represents the 1 in 10 year mean yearly surface water concentration. EFED's surface water modeling for drinking water uses a default percent cropped area factor ( PCA) for turf, which represents the fraction of the watershed that is cropped and treated with the pesticide being modeled. In the absence of a crop specific PCA factor, a default PCA of 8 0.87 is used. The 0.87 factor represents the maximum fraction of a watershed in the US that is agriculturally cropped. This default PCA was used for fenarimol modeling on turf. EFED is currently attempting to develop PCA factors specific for turf scenarios, and recognizes that it is unlikely that 87% of a watershed used for drinking water would be grown to turf and treated with fenarimol at the maximum rate allowed only for turf applications.

The default PCA factor assumed and used in fenarimol modeling is most likely overestimated and adds to the conservatism of the assessment. Given the relatively low usage of fenarimol across the country it is highly unlikely that the amount applied to the watershed in the model will be concentrated in any real watershed used to derive drinking water.

In summary, the surface water EEC is not likely to underestimate exposure to fenarimol and its degradates based on the conservative inputs to the model ( i. e., default PCA, no decay via the major degradation pathway, and the concentrated application scenario modeled is unlikely to occur in a real watershed where drinking water is derived). The uncertainties related to the aqueous photoproducts would likely be addressed through completion of a satisfactory guideline aqueous photolysis study. Other uncertainties would likely be addressed through the satisfactory completion of other outstanding guideline studies, as detailed by EFED.

Residential Exposure and Risk Estimates Potential residential exposures may occur as a result of applications of fenarimol to residential lawns or turf by residents and by professional lawn care operators ( LCOs). However, HED has been informed by SRRD that the registrants have agreed to amend their product labels to prohibit residential use and handling ( i. e. mixing, loading or applying) of fenarimol in residential settings. Applications to turf will be limited to golf courses, and stadium fields or professional athletic fields only. Therefore, residential handler and residential postapplication exposure scenarios should no longer exist. The only non occupational postapplication exposure scenario remaining to evaluate is short term dermal exposure to adult golfers. Applications to residential turf will not be permitted by products labels until such time as additional toxicity data are submitted and reviewed. Then the Agency will reevaluate the risk assessment for residential uses.

Residential exposures have been estimated based on label application rates and frequency, and the persistence of fenarimol. Several post application exposure scenarios following application to turf are anticipated; however, if registrants amend their product labels to prohibit residential use and handling of fenarimol in residential settings, as they have agreed to do, then the only non occupational postapplication exposure scenario remaining to evaluate is short term dermal exposure to adult golfers. The updated Residential SOPs were used to address the exposures of adult golfers contacting treated turf. The SOPs for turf use transfer coefficients based on mowing studies. Chemical specific data from a turf transferable residue ( TTR) study were available; however, these TTR data were unacceptable for use in postapplication exposure assessment. Therefore, default assumptions from the SOPs were used. Risk estimates for short term dermal contact with treated turf during the low contact activity of golfing resulted in a margin of exposure ( MOE) of 14,000, which does not exceed the level of concern, a MOE of 900. 9 N N OH Cl Cl Based upon the slow dissipation rate of fenarimol and the possibility of multiple applications to turf, intermediate term exposures of adult golfers are possible. However, if registrants amend their product labels to increase the minimum re application interval to turf to 30 days, as they have agreed to do, then intermediate term exposures should no longer exist.

Mitigating circumstances for exposure to fenarimol residues may include watering in after application to turf. This instruction, however, does not prevent contact with treated turf prior to watering in. The current granular label ( EPA Reg. No. 228 298) recommends, but does not require watering in. The soluble concentrate label ( EPA Reg. No. 62719 142) does not mention watering in. Therefore, label language should be strengthened to ensure that watering in occurs immediately after application. When fenarimol is applied to stadium or professional athletic fields, applicators should water in product immediately after application, or do not enter or allow others to enter treated area for 24 hours after application. If product is watered in after treatment, do not enter or allow other persons to enter until area has dried.

Aggregate Exposure and Risk Estimates Because no acute toxicity endpoint was identified for risk assessment, an aggregate acute risk assessment was not conducted. Short term dermal postapplication exposures for adults golfing were combined with average dietary ( food & water) exposures in a short term aggregate risk assessment. This aggregate risk estimate did not exceed the Agency's level of concern. The exposure from food is insignificant (< 1% cPAD) for adults; therefore, the aggregate risk estimates include only dermal and water exposures. The short term DWLOCs for adults are well above the estimated EECs for ground and surface water, and indicate that combined short term dietary ( food & water) and dermal exposures do not exceed the Agency's level of concern. Risk estimates for chronic aggregate exposures to fenarimol in food and water do not exceed levels of concern.

2.0 PHYSICAL CHEMICAL PROPERTIES CHARACTERIZATION The chemical name for fenarimol is alpha( 2 chlorophenyl) alpha( 4 chlorophenyl) 5 pyridinemethanol. The structure is as follows:

Empirical Formula: C 17 H 12 Cl 2 N 2 O 10 Molecular Weight: 331.2 CAS Registry No.: 60168 88 9 PC Code: 206600 Fenarimol is a white to buff crystalline solid with a melting point of 117 119  C, bulk density of 0.66 0.81 g/ cc ( packed), octanol/ water partition coefficient ( log K ow) of 3.69, and vapor pressure of 2.2 x 10 7 Torr at 25  C. Fenarimol is practically insoluble in water ( 13.7 ppm at pH 7 and 25  C) and is soluble in most organic solvents: hexane ( 1.1 mg/ mL); acetonitrile, heavy aromatic naphtha, and xylene (  50 mg/ mL); benzene and methanol ( 100 125 mg/ mL); acetone (> 250 mg/ mL); and chloroform and cyclohexanone (> 500 mg/ mL).

3.0 HAZARD CHARACTERIZATION 3.1 Hazard Profile Toxicology data are used by HED to assess the potential hazards to humans. The data are derived from a variety of acute, subchronic, and chronic toxicity tests; developmental/ reproductive tests; and tests to assess mutagenicity and pesticide metabolism. The database for fenarimol is adequate to support this TRED.

Acute toxicity values and toxicity categories for fenarimol are summarized in Table 1. The data indicate that fenarimol has low acute oral, dermal, and inhalation toxicity ( category III). Fenarimol is category II with respect to ocular irritation. It is not a dermal sensitizer. A primary dermal irritation study is not available. 11 Table 1. Acute Toxicity of Fenarimol.

Study Type MRID No.: Result 870.1100 Acute Oral Toxicity  rat. Elanco, Study No.: R O 289 82, December 30, 1982 00125392 LD50 > 599 mg/ kg. Toxicity Category III Classification: Guideline 870.1200 Acute Dermal Toxicity  rabbit. Elanco Study No.: B D 27 82, February 17, 1983 00125392 LD50 > 1998 mg/ kg. Toxicity Category III Classification: Minimum 870.1300. Acute Inhalation Toxicity  rat. Elanco, Study No.: R H 102 82, November 16, 1982. 00125292 LC50 > 5.20 mg/ L for males. LC50 between 2.87 and 5.2 mg/ L for females. Toxicity Category III Classification: Guideline 870.2400 Primary Ocular Irritation  Rabbit. Elanco, Study No.: B E 32 82, February 1, 1982 00125392 Day 1: 6/ 6 corneal opacity ( score of 5); 5/ 6 iris irritation ( score 5); 6/ 6 conjunctival irritation ( score of 1 2). Day 7: 3/ 6 corneal opacity and conjunctival irritation. Day 14 all irritation cleared. Toxicity Category II Classification: Minimum 870.2500 Primary Dermal Irritation  rabbit.  No study available.

870.2600 Dermal Sensitization  guinea pig. Elanco, Study No.; GP 9538, January 1, 1980. 00084966 No evidence of sensitization in the Guinea Pig Maximization test of Magnusson and Kligman. Classification: Minimum.

Table 2 presents a summary of subchronic and chronic toxicity studies for fenarimol. Subchronic oral dosing in rats demonstrates very little toxicity except for some slight body weight changes and liver pathology of low degree and inconsistency. In dogs there was also little overt toxicity with there being some effects in the liver. A 28 day subchronic inhalation study is required. The Gowan Company requested that the Agency rescind the data requirement for the 28 day inhalation study. They disagree on its need and cite that this issue was addressed recently by CropLife America, an industrial organization. They also stated that the sprays that will typically result from fenarimol use will have droplets that will be tens or thousands of micrometers in diameter or much larger than the respirable droplets of a few micrometers in diameter. These larger droplets will not reach the alveoli and will become trapped in the upper respiratory tract and eventually swallowed. Thus, they contended that the endpoint from an oral toxicity study is a more appropriate endpoint. In a written response to comments ( 5/ 8/ 02), the HED stated there have been some recent changes in HED policy regarding the need for subchronic inhalation toxicity studies. The comments of the CropLife America organization have been taken into consideration at a recent presentation to the Agency. As a result of these recent changes, the Gowan Company may submit a waiver for the 28 day inhalation study. This waiver must contain sufficient data on the particle size of the sprays and other preparations that may result in inhalation exposure. It also must contain sufficient other information regarding the potential inhalation exposure such as duration of exposure in terms of hours per day, per week, etc. The 12 completed waiver request will be presented to a peer review committee that will determine the need for the subchronic inhalation toxicity study. This peer review group will consist of toxicologists with expertise in inhalation toxicology as well as occupational and residential exposure representatives. The decision on the need for the subchronic inhalation toxicity study will be based on all relevant factors. The more complete the information in the waiver request is, the better the chance for the waiver to be granted. The limited information provided in the April 10, 2002 letter is not sufficient to bring to a peer review committee to consider a waiver for an inhalation toxicity study. Lastly, the HED is already using an oral toxicity endpoint for the inhalation exposure scenarios. However, the subchronic inhalation toxicity study is considered more appropriate for risk assessment based on inhalation exposures.

Adequate data are available to assess the chronic toxicity and carcinogenic potential of fenarimol. The liver appears to be the most evident target organ for chronic toxicity aside from the effects of fenarimol on aromatase. Liver toxicity was manifested by liver weight increases and the presence of " fatty liver" in rats. In dogs, liver weight was increased and there was also associated increases in serum enzymes to indicate liver toxicity. p Nitroanisole o demethylase was also increased indicating stimulation of liver enzymes. Fenarimol has been classified as a Group E " not likely" carcinogen ( no evidence of carcinogenicity for humans). Similarly, the genetic toxicity data indicate there is no mutagenicity concern.

Developmental studies in rats and rabbits, designed to identify possible adverse effects on the developing organism which may result from the in utero exposure to the pesticide were also conducted. The data base for prenatal developmental toxicity is considered complete. The initial guideline study was classified as unacceptable, but this study together with a special study to assess for the reversibility of hydronephrosis are combined with another special study to assess for reproductive performance. All of these studies combine to make an acceptable study and to satisfy the guideline requirement. The rat studies revealed that fenarimol is associated with hydronephrosis that is reversible.

The developmental toxicity studies showed no evidence of increased sensitivity or susceptibility of young rats or rabbits following pre or postnatal exposure to fenarimol. The data base for reproductive toxicity is considered complete. The multi generation reproduction studies indicate that fenarimol causes reduced fertility and dystocia. Separate cross dosing studies ( dosing males and mating with untreated females and dosing females and mating with untreated males) indicated that the reduced fertility is due to an effect in males and the dystocia is an effect in females. These effects of fenarimol were attributed to inhibition of aromatase or the enzyme that converts androgens to estrogens. In addition to the guideline multi generation reproduction study in rats, there are nonguideline studies that assess for the reproductive performance in mice ( MRID No.: 45502307), guinea pigs ( MRID No.: 00126525, 00133474 and 00137159) and rabbits ( MRID No.: 00084967). The mouse study indicated that mice are similar to rats in that there is a decrease in the reproductive performance in the males. However, neither the guinea pig or rabbit studies demonstrated a decrease in reproductive performance indicating that the effect of fenarimol on male reproductive performance is not seen in all species tested. 13 There is no Guideline 870.7600 dermal absorption study available with rats. The upper bound limit for dermal absorption was estimated by HIARC ( J. Doherty, 9/ 6/ 01) to be 20% based on an assessment of the rabbit and monkey dermal absorption studies along with a comparison of the rabbit developmental toxicity and rabbit 21 day dermal toxicity studies. Subsequently, Gowan Company responded by submitting additional information regarding the dermal absorption study in monkeys, as well as other background information. This information was evaluated during a special HIARC revisit, on 5/ 23/ 02. The HIARC decided that a 5% dermal absorption factor is appropriate to use for risk assessment purposes. The 5% dermal absorption factor was derived primarily from the monkey dermal absorption study ( MRID No.: 00162538, 1985) using the Feldman Maibach model. Dermal absorption rates of 1.36%, 2.32%, 3.12% and 4.12% ( mean 2.73% ± 1.17%) were observed for the four individual monkeys in the study. However, from 8 to 29% of the dermally applied radioactivity was not accounted for. Since there was variation in the dermal absorption in the four monkeys and there was unaccounted for radioactivity, a dermal absorption value of 5% from this study was considered appropriate for risk assessment. In addition, the result of a dermal absorption study with rabbits ( MRID No.: 00046639, 1980), using three formulations, indicated up to approximately 15% dermal absorption. By comparison the rabbit developmental toxicity study ( MRID No.: 47716001) and the rabbit 21 day dermal toxicity study ( MRID No.: 00153312) also indicated approximately 15% dermal absorption. However, the rabbit is recognized as being a poor model for estimating dermal absorption in humans, since rabbit skin is more permeable; therefore, the 5% value based primarily on the monkey study is considered appropriate. Refer to the Third Report of the HIARC ( J. Doherty, 7/ 29/ 02) for a more detailed discussion of dermal absorption.

The database for metabolism is considered to be complete. The biliary route is the predominant route of elimination in the rat but the urinary route is the most prominent route of elimination in the rabbit. In rats, fenarimol is rapidly absorbed from the gastro intestinal tract and the half life of the plasma level was determined to be 11.8 to 16.8 hours. Most of the radiolabeled material was recovered in the urine ( 5 to 15%) or feces (~ 80% of the recovered isotope) by day 7. Biliary excretion was the major route of elimination. Fenarimol is extensively metabolized in the rat; less than one percent of the parent is recovered, while more than 30 metabolites are recovered. Metabolism of fenarimol occurs by the oxidation of the carbinol phenyl ring and pyrimidine ring and some qualitative and quantitative differences in sexes and dose level were noted.

There are no acute, subchronic or developmental neurotoxicity studies available. The HIARC ( July 10, 2001) determined that a special developmental study with special inclusions to assess for hormonal effects in adults and post weaning pups, and in vivo inhibition of aromatase should be required. Acute and subchronic neurotoxicity studies are not required. The toxicology profile of fenarimol is shown in Table 2 of this document. 14 Table 2. Toxicology Profile for Fenarimol.

Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3100 ( 12 and 18 month oral toxicity rodents fulfill this guideline) 00235175, 45502302 and 45502304 ( 1978)/ Acceptable/ Non Guideline 0, 2.5, 6.5 or 17.5 both sexes. NOAEL = 6.5 mg/ kg/ day LOAEL = 17.5 mg/ kg/ day based on increased relative liver weight and increased severity of fatty liver.

870.3150 90 Day oral toxicity in nonrodents 00056090 ( 1975)/ Acceptable/ Guideline 0, 1.25, 5 or 20 mg/ kg/ day. NOAEL and LOAEL > 20 mg/ kg/ day ( HDT). A one year study ( MRID 00146959 satisfies this guideline).

870.3200 21/ 28 Day dermal toxicity ( rat) 00153312 ( 1985) Acceptable/ Guideline 0, 500 or 1000 mg/ kg/ day for RUBIGAN ( emulsifiable) formulation and 1000 mg/ kg/ day for technical fenarimol. NOAEL < 1000 mg/ kg/ day LOAEL = 1000 mg/ kg/ day based on slight liver weight effects. Although this study is acceptable, it is of limited usefulness for risk assessment because it did no assess for reproductive effects or possible effects on aromatase.

870.3250 90 Day dermal toxicity No study. No study.

870.3465 90 Day inhalation toxicity No study. No study 870.3700a Prenatal developmental in rodents 00042543/( 1979) Unacceptable/ Guideline but acceptable with other studies ( see below). 0, 5, 13, 35 mg/ kg/ day Maternal NOAEL > 35 mg/ kg/ day ( HDT) LOAEL not established Developmental NOEL = 13 mg/ kg/ day LOAEL = 35 mg/ kg/ day based on hydronephrosis ( this effect was shown to be reversible and is not considered adverse).

Special study to assess for reversibility of hydronephrosis. 00132988/( 1983) Acceptable/ Non Guideline. 0 and 35 mg/ kg/ day. Maternal NOAEL = not established LOAEL = 35 mg/ kg/ day based on sporadic dystocia. Developmental NOEL < 35 mg/ kg/ day. LOAEL = 35 mg/ kg/ day based on kidney effects ( hydronephrosis, this effect was shown to be reversible and is not considered adverse)

Above two studies combine to satisfy the guideline requirement for a developmental toxicity study in rats.

870.3700b Prenatal developmental in rabbits 44716001/ 1990/ Acceptable/ Guideline 0, 15, 50 or 150 mg/ kg/ day. Maternal NOAEL = 50 mg/ kg/ day LOAEL = 150 mg/ kg/ day based on increased abortions and decreased body weights and gain and food consumption. Developmental NOAEL = > 150 mg/ kg/ day Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 15 870.3800 Reproduction and fertility effects 00235175, 45502301 ( 1977) Unacceptable/ Not upgradeable 0, 2.9, 7.9 or 20 mg/ kg/ day in males; 0, 3.4, 9 or 23.5 mg/ kg/ day in females. Parental/ Systemic NOAEL > 23.5 mg/ kg/ day ( HDT) LOAEL not established Reproductive LOAEL < 2.9 mg/ kg/ day based on decreased fertility in the F1 generation second mating. Offspring NOAEL and LOAEL could not be established due to anti fertility effects in the parental generations, which prevented valid assessment of the pup generations.

Second study 00235175, 45502302 ( 1978) Acceptable/ Guideline 0, 0.6, 1.2, 2.5 mg/ kg/ day in males and 0, 0.8, 1.7 or 3.2 mg/ kg/ day in females. Parental/ Systemic NOAEL > 2.5 mg/ kg/ day in males and 3.2 mg/ kg/ day in females ( HDT) LOAEL not established Parental Reproductive NOAEL = 0.6 mg/ kg/ day LOAEL = 1.2 mg/ kg/ day based on decreased liveborn litter size in the F1 and F2 generations. Offspring. NOAEL = 1.2 mg/ kg/ day. LOAEL = 2.5 mg/ kg/ day based on decreased survival indices and possible presence of hydronephrosis Above two studies combine to satisfy the guideline requirement for a multi generation reproduction study in rats.

870.3800 Reproduction and fertility effects ( Special Study) 00084968 Acceptable/ Non Guideline 0, 35 mg/ kg/ day LOAEL for males and females > 35 mg/ kg/ d ( males decreased mating and epididymal weight, females dystocia and related parameters) NOAEL not established 870.4100a Chronic toxicity rodents See combined chronic feeding and carcinogenicity study.

870.4100b Chronic toxicity dogs 00146959/ 1985/ Acceptable/ Guideline 0, 1.25, 12.5 or 125 mg/ kg/ day. NOAEL = 12.5 mg/ kg/ day LOAEL = 125 mg/ kg/ day based on reversible increase in liver weight and increase in alkaline phosphatase.

870.4200 Combined Chronic Feeding and Carcinogenicity rats 00235175/ 1978/ Acceptable/ Guideline 0,2, 5.3, or 14.6 mg/ kg/ day for male and 0, 2.8, 7.6 or 21.55 mg/ kg/ day for females. NOAEL = 5.3 mg/ kg/ day. LOAEL = 14.6 mg/ kg/ day based on hormonal changes ( prolactin and luteinizing hormone) and possibly fatty liver change and decreased WBC count in females.

870.4200 Combined Chronic Feeding and Carcinogenicity rats 00153313/ 1985/ Acceptable/ Guideline 0.5, 1, 2 mg/ kg/ day for males and 0, 0.6, 1.2 or 2.3 mg/ kg/ day for females. NOAEL = 1 mg/ kg/ day in males and > 2.3 mg/ kg/ day in females. LOAEL = 2 mg/ kg/ day in males based on minimal gross and microscopic changes in liver and possibly testis. There was no evidence of carcinogenicity or increase in liver tumors. Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 16 The above two studies combine to satisfy the guideline requirement for carcinogenicity testing in rats. It should be noted that the potential for fenarimol to cause decreased fertility and dystocia at the dose levels tested in the rat studies contributed to the weight of evidence that the rat was assessed at adequate dose levels.

870.4300 Carcinogenicity mice 0071920/ 1978/ Acceptable/ Guideline 0, 7, 24 and 86 mg/ kg/ day for both sexes. NOAEL = > 86 mg/ kg/ day ( HDT). The HIARC and CARC concluded that there was no evidence of carcinogenicity although liver tumors were highest in the high dose group but incidence was considered too low to be meaningful.

Mutagenticity 870. See Table2. a. below.

870.6200a Acute neurotoxicity screening battery No study. No study. Not required.

870.6200b Subchronic neurotoxicity screening battery No study. No study. Not required.

870.6300 Developmental neurotoxicity Study is being required and special inclusions to assess for possible effects due to hormonal disruption required.

870.7485 Metabolism and pharmacokinetics 00261349 and 00261350 ( 1985) A series of studies with radioactive label in different positions established that fenarimol is readily absorbed and excreted with the biliary route being most important in rats but the urinary route being important in rabbits. Metabolism was extensive with 30 or more metabolites noted. Little radioactivity remained in the tissue. Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 17 870.7600 Dermal absorption  monkeys 00162538 ( 1985) A 5% dermal absorption factor is appropriate to use for risk assessment purposes. It was derived primarily from the monkey study ( 00162538) using the Feldman Maibach model. Dermal absorption rates of 1.36%, 2.32%, 3.12% and 4.12% ( mean 2.73% ± 1.17%) were observed for the four individual monkeys. However, from 8 to 29% of the dermally applied radioactivity was not accounted for. Since there was variation in the dermal absorption in the four monkeys and there was unaccounted for radioactivity, a value of 5% was considered appropriate. In addition, the result of a dermal absorption study with rabbits ( 00046639), using three formulations, indicated up to approximately 15% dermal absorption. By comparison the rabbit developmental toxicity study ( 47716001) and the rabbit 21 day dermal toxicity study ( 00153312) also indicated approximately 15% dermal absorption. However, the rabbit is recognized as being a poor model for estimating dermal absorption in humans, since rabbit skin is more permeable; therefore, the 5% value based primarily on the monkey study is considered appropriate.

Special studies Several special studies were presented to investigate the mechanism of the decreased fertility and dystocia. These are listed above in this table under the heading for the study type which they most closely resemble ( i. e. reproduction or developmental)

Table 2. a. Mutagenticity/ Genotoxicity Studies Study Results Bacterial mutagenicity ( Ames test)  Salmonella typhimurium and Escherichia coli. Elanco, 1976. MRID No.: 243372 ( Acc. No.:). Not mutagenic with and without metabolic activation at doses up to 100

g/ plate. Classification: " Minimum" ( Acceptable)

Forward mutation assay in TK ± mouse lymphoma assay. Elanco, August 1, 1979. MRID No.: 00042538 No evidence of mutagenicity when tested at 0, 3, 6, 12, 50 or 100

g/ mL. The 100

g/ mL dose level was toxic. Classification: " minimum" ( acceptable).

DNA repair synthesis. Elanco, Study No.: 790503 1, June 1979. MRID No.: 00042541 No evidence of induction of DNA repair at dose levels of 0, 0.05, 0.1, 0.5, 10, 50 or 100 nanomoles/ mL for five hours incubation. Cytotoxicity resulted at 50 and 100 nano moles/ mL. Classification: " minimum" ( acceptable).

In vivo cytogenetics in hamsters. Cabinet d'Etudes et de Recherches en Tox. Study No.: 658, May 10, 1982. MRID No.: 00144051 Negative for mutagenic effects at does of 250 mg/ kg ( times 2 doses) in bone marrow cells. Classification: Acceptable. Study Results 18 micronucleus assay  mouse Cabinet d'Etudes et de Recherches en Tox. Study No.: 650, May 1, 1982. MRID No.: 00144050 Positive for clastogenic effects in male mice at 1 gm/ kg at 24 hours. Assessments at 48 and 72 hours were considered confounded since there were no positive controls. Classification: UNACCEPTABLE for 48 and 72 hours. ACCEPTABLE for 24 hours.

Evaluation of carcinogenicity in the mouse C3H/ 10T ½ embryonic mouse fibroblast culture system. Elanco, August 1, 1980. MRID No.: 00046637. No malignant transformations were observed in fenarimol treated cultures between 4 and 256 nanomoles/ mL.

Classification: " minimum" ( acceptable).

Dominant lethal  rat. Lilly, Study No.: R 346 January, 1977 MRID No.: 00042542 A single dose of 350 mg/ kg fenarimol ( in acacia solution) did not result in symptoms of toxicity to the males and did not indicate a dominant lethal effect when the rats were mated 4 days after treatment. Classification: " minimum" ( acceptable).

Armoatase inhibition assay in stimulated rat ovarian microsomal system. Elanco, January 1, 1982. MRID No.: 00093876 Fenarimol is a moderately weak inhibitor of aromatase activity in the stimulated rat ovarian microsomal system Classification: Supplementary.

3.2 FQPA Considerations The FQPA Safety Factor committee addressed the potential enhanced sensitivity of infants and children from exposure to fenarimol as required by the FQPA of 1996. The HIARC examined the prenatal developmental toxicity studies in rats and rabbits and the two generation reproduction study in rats, and concluded that the database does not show evidence of increased susceptibility to fetuses and young ( HIARC, 9/ 5/ 01). The HIARC determined that a special developmental toxicity study should be required based on the need to determine if the potential hormonal effects as elicited by inhibition of aromatase will result in effects in the rat pups. The HIARC confirmed this decision on May 23, 2002 during a revisit of the issue in response to comments received on 4/ 11/ 02, Gowan Company requesting that the HED re evaluate the need for a developmental neurotoxicity ( DNT) study. In accordance with the 2002, OPP Guidance Document on Determination of the Appropriate FQPA Safety Factor( s) in Tolerance Assessment, this data requirement is considered to be " for cause" and therefore the HIARC concluded ( July 29,2002; TXR No. 0050977) that a Database Uncertainty Factor of 3X is required until the data are received and evaluated. Evidence suggesting a special developmental toxicity study to assess hormonal effects is needed is given below.

 The NOAEL and LOAEL for risk assessments are based on reduced fertility in males and dystocia in females associated with fenarimol's potential to affect hormones in adult rats. The potential for fenarimol to affect the hormonal system in developing rats needs to be assessed to determine if the developing fetus and neonate may also be affected as can be judged by the special developmental toxicity study that will have special emphasis on potential 19 disruption of the hormonal system by biochemical methods and include special provisions to assess for physiological manifestations of hormonal disruption. The LOAEL on which risk assessments are based is related to potential hormonal effects.

This study should follow the same dosing regimen as a developmental neurotoxicity study, but does not need to include all of the functional observational battery ( FOB) assessments. The protocol for this study should be submitted to HED for review prior to initiating the study.

Based on the HIARC determinations, the FQPA Safety Factor Committee ( SFC) initially recommended that the 10x Safety Factor should be retained at 10x for all populations and all fenarimol risk assessments fenarimol due to the following data gaps ( B. Tarplee, 9/ 28/ 01):

 a special developmental toxicity study with fenarimol is required to determine if the potential hormonal effects elicited by inhibition of aromatase will result in effects in the rat pups; and  the environmental fate database is incomplete for the aquatic photolytic degradate of fenarimol, 4 chloro 2( 5 pyrimidyl) 2' chlorobenzophenone. Consequently, the photolytic degradate was not included in the assessment and there was residual uncertainty that the drinking water assessment may underestimate exposure.

In a revisit meeting on July 29, 2002, the FQPA SFC reevaluated fenarimol because the Environmental Fate and Effects Division ( EFED) received additional information on the aquatic photo degradate of concern, and subsequently revised the drinking water assessment for fenarimol. The updated drinking water assessment ( July 31, 2002; D284487) was revised to include fenarimol and its aquatic photodegradates. The model inputs were adjusted so that aquatic concentrations were estimated assuming no aqueous photolysis, which appears to be fenarimol's most significant route of dissipation in the environment. Minor model input corrections were also made to the application rate and interval. The result provides a screening level estimate of combined concentrations of fenarimol and its aquatic degradates that is conservative and that does not underestimate exposure. As a result of this reassessment the chronic EECs increased from 59 to 84

g/ L for surface water, and from 14 to 16

g/ L for ground water. Although, there is still some uncertainty as to the identity, fate, and behavior of the photolysis degradates of fenarimol, data will be required to address this uncertainty.

The FQPA SFC also reassessed the uncertainty surrounding the potential effects elicited by inhibition of aromatase by fenarimol. The FQPA SFC agreed with the HIARC conclusion that a special developmental toxicity study to assess for hormonal effects is required for fenarimol, and a database uncertainty factor of 3x is required until the data are received and reviewed. Based on the updated drinking water assessment and the recent HIARC conclusions regarding aromatase, the FQPA SFC recommended that the FQPA safety factor for fenarimol be reduced from 10x to 3x.

3.3 Dose Response Assessment and Hazard Endpoint Selection The strengths and weaknesses of the fenarimol toxicology database were considered during the process of toxicity endpoint and dose selection. In general, most of the required guideline studies on fenarimol were available and provided reasonable confidence when the toxicity endpoints and doses for risk assessment were selected. Based on the evaluation of the above summarized studies, the Hazard Identification Assessment Review Committee ( HIARC) identified the toxicity endpoints and 20 the dose levels for use in risk assessment ( HIARC document of 9/ 5/ 01). The recently updated HIARC report ( July 29,2002; TXR No. 0050977) did not change any toxicity endpoints or dose levels for use in risk assessment. The selected toxicity endpoints are summarized in Table 3.

The METARC recommended ( J. Doherty, 9/ 17/ 01), and the HIARC confirmed, that the reduced male fertility and dystocia effects of fenarimol should be endpoints for human health risk assessment. It is noted that the endpoint from the multi generation reproduction study is based on decreased litter size. This decrease in litter size may be a reflection of the maternal toxicity or the potential for fenarimol to inhibit aromatase. In this regard, it is a meaningful endpoint for all populations, males and females.

Consequently, HED identified a reference dose for chronic exposure ( cRfD) of 0.006 mg/ kg/ day from the multi generation reproduction study based on a no observed adverse effect level ( NOAEL) of 0.6 mg/ kg/ day, and a 10X uncertainty factor for interspecies extrapolation and a 10X uncertainty factor for intraspecies variation. The NOAEL of 0.6 mg/ kg/ day is based on decreased live born litter size in the F 1 and F 2 generations at a lowest observed adverse effect level ( LOAEL) of 1.2 mg/ kg/ day. The HED calculated a chronic Population Adjusted Dose ( cPAD) of 0.002 mg/ kg/ day. The cPAD is the RfD divided by the FQPA safety factor ( 3X). Chronic dietary exposure estimates greater than 100% of the cPAD would exceed HED's level of concern.

For risks associated with intermediate term ( IT) exposures ( 1 6 months), the same endpoint ( NOAEL of 0.6 mg/ kg/ day) was used for incidental oral, dermal, and inhalation risk assessments. A Margin of Exposure or MOE, which is the ratio of the NOAEL to the exposure estimate, of greater than 300 does not exceed HED's level of concern for IT risk assessments. An MOE of greater than 300 is required because of the 10x interspecies factor, the 10x intraspecies factor and the 3x FQPA factor. However, HED has been informed by SRRD that the registrant has agreed to amend their product labels to extend the re application interval to turf to 30 days; thereby eliminating any residential intermediate term exposure scenarios. Given these label changes, intermediate term scenarios and risks should no longer exist. Refer to the previous HED TRED chapter for risk estimates involving such scenarios ( i. e., " Fenarimol. Revised HED Human Health Assessment for the Tolerance Reassessment Eligibility Decision ( TRED) Document. Chemical No. 206600. No MRID #. DP Barcode No. D283429", dated June 7, 2002).

For the short term ( 1 30 day) incidental oral, dermal, and inhalation risk assessments, a LOAEL of 35 mg/ kg/ day was selected. This endpoint is based on decreased fertility and dystocia, an indicator of hormonal effects, observed in a special non guideline cross breeding reproduction/ developmental toxicity study in rats. Because a NOAEL could not be identified, and effects seen at the lowest dose tested, a LOAEL was used, and an additional 3x uncertainty factor was applied. Therefore, a MOE greater than 900 does not exceed HED's level of concern for short term risk assessments. Dermal absorption was estimated to be 5% based on data from a monkey dermal absorption study ( see section 3.1 for details). An acute dietary toxicity endpoint was not identified by HIARC, and consequently, no acute risk assessment was required. 21 Table 3. Summary of Toxicity Endpoints and Doses for Risk Assessment.

EXPOSURE SCENARIO DOSE ( mg/ kg/ day) ENDPOINT STUDY Acute Dietary No appropriate study for a single dose risk assessment.

Chronic Dietary NOAEL = 0.6 UF = 100X FQPA = 3X Decreased liveborn litter size in rat reproduction study. LOAEL = 1.2 mg/ kg/ day Rat reproduction MRID # 00235175 Chronic RfD = 0.006 mg/ kg/ day Chronic PAD = 0.002 mg/ kg/ day Incidental Oral, Short Term LOAEL= 35 UF = 300X FQPA = 3X Decreased fertility and dystocia an indication of hormonal effects. Special reproduction study MRID # 0084968 Incidental Oral, Intermediate Term NOAEL= 0.6 UF = 100X FQPA = 3X Decreased liveborn litter size. LOAEL = 1.2 mg/ kg/ day Rat reproduction MRID # 00235175 Dermal, Short Term Oral LOAEL= 35 UF = 300X FQPA = 3X Decreased fertility and dystocia an indication of hormonal effects. Special reproduction study MRID # 0084968 Dermal, Intermediate Term Oral NOAEL= 0.6 UF = 100X FQPA = 3X Decreased liveborn litter size. LOAEL = 1.2 mg/ kg/ day Rat reproduction MRID # 00235175 Dermal, Long Term Oral NOAEL= 0.6 UF = 100X FQPA = 3X Decreased liveborn litter size. LOAEL = 1.2 mg/ kg/ day Rat reproduction MRID # 00235175 Inhalation, Short Term Oral LOAEL = 35 UF = 300X FQPA = 3X Decreased fertility and dystocia an indication of hormonal effects Special reproduction study MRID # 0084968 Inhalation, Intermediate Term Oral NOAEL= 0.6 UF = 100X FQPA = 3X Decreased liveborn litter size. LOAEL = 1.2 mg/ kg/ day Rat reproduction MRID # 00235175 Inhalation, Long Term Oral NOAEL= 0.6 UF = 100X FQPA = 3X Decreased liveborn litter size. LOAEL = 1.2 mg/ kg/ day Rat reproduction MRID # 00235175 Because a toxicity endpoint from an oral study was selected for dermal and inhalation endpoints, a dermal absorption factor of 5% must be used for oral to dermal route to route exposures and a 100% inhalation absorption factor must be used for inhalation exposures.

3.4 Endocrine Disruption The Agency 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 bases 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 22 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).

Fenarimol has demonstrated effects on hormonal systems. When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, fenarimol may be subjected to additional screening and/ or testing to better characterize effects related to endocrine disruption.

4.0 EXPOSURE ASSESSMENT 4.1 Summary of Registered Uses Fenarimol is currently registered for use on fruit and nut crops such as apples, cherries, filberts, grapes, pears, and pecans as well as on ornamental plants, trees, grasses, and turf. Fenarimol is also used on imported bananas. The registration of fenarimol is being supported by Gowan Company. The sole fenarimol formulation class which is registered for use on fruit and nut crops is an emulsifiable concentrate sold under the trade name RubiganJ, and this formulation is typically applied using ground equipment. HED has been informed by SRRD that the registrant has agreed to amend their product labels to limit applications to turf to golf courses and professional playing fields only. Applications to residential turf will not be permitted on products labels until such time as additional data are submitted, reviewed, found acceptable, and warrant these uses to be reinstated on product labels.

4.2 Dietary Exposure and Risk Assessment 4.2.1 Residue Profile The established permanent and time limited tolerances for fenarimol are published in 40 CFR § 180.421 and are expressed in two different ways. Tolerances listed under 40 CFR § 180.421( a)( 1) and § 180.421( b) are expressed in terms of residues of fenarimol per se. Tolerances listed under 40 CFR § 180.421( a)( 2) are expressed in terms of the combined residues of fenarimol and its metabolites [ alpha( 2 chlorophenyl) alpha( 4 chlorophenyl) 1,4 dihydro 5 pyrimidinemethanol( Metabolite B) and 5[ 2 chlorophenyl)( 4 chlorophenyl) methyl] 3,4 dihydro 4 pyrimidinol] ( Metabolite C) measured as the total of fenarimol and 5[ 2 chlorophenyl)( 4 chlorophenyl) methyl] pyrimidine ( calculated as fenarimol).

The registration requirements for plant metabolism are fulfilled. Acceptable studies depicting the metabolism of [ 14C] fenarimol in apples, cherries, and grapes are available. The apple and cherry metabolism studies indicate that the parent fenarimol is the major residue component whereas the grape metabolism study identified the parent plus Metabolites B and C as the principal residue components. The Metabolism Assessment Review Committee ( MARC) has determined that for enforcement purposes, the tolerance should be expressed as parent only. However, the dietary assessment for grapes and bananas should include the Metabolites B and C, because of their structural similarity to parent fenarimol and because there are existing residue data for the metabolites on those commodities ( D277692, 9/ 17/ 01, D. DREW). Combined residues of Metabolites B and C occur on banana pulp samples at a range of 0.24x to 1.7x that of parent fenarimol, and on grapes at a range of 23 N N OH Cl Cl NH N OH Cl Cl N NH Cl Cl OH 0.59x to 3.3x that of parent fenarimol. Analytical methods exist for determining residues of Metabolites B and C ( measured as deshydroxyfenarimol) in plants. The chemical names and structures of fenarimol and Metabolites B and C are depicted below in Figure 1.

Figure 1. Chemical Names and Structures of Fenarimol and Metabolites B and C.

Common Name Chemical Structure Chemical Name Common Name Chemical Structure Chemical Name Common Name Chemical Structure Chemical Name Fenarimol Metabolite B ( Compound 212746) Metabolite C ( Compound 210302)

[ alpha( 2 chlorophenyl) alpha( 4 chlorophenyl) 5 pyrimidinemethanol] [ alpha( 2 chlorophenyl) alpha( 4 chlorophenyl) 1,4 dihydro 5 pyrimidinemethanol] [ 5[ 2 chlorophenyl)( 4 chlorophenyl methyl] 3,4 dihydro 4 pyrimidinol]

The qualitative nature of the residue in milk and ruminant tissues is adequately understood. For the purpose of registration, the terminal residue of concern in milk and ruminant and hog tissues is fenarimol per se. Wet apple pomace is the only animal feed item associated with the registered uses of fenarimol. There are no hog or poultry feed items.

The registration requirements for residue analytical methods are fulfilled. Adequate methods are available for data collection and enforcement of tolerances for residues of fenarimol per se in/ on plants and livestock. Adequate methods are also available for determination of residues of fenarimol and Metabolites B and C in plants [ Pesticide Analytical Manual ( PAM) Volume II, Methods I ( AMAA CA R039 AB 755), II ( AM AA CA R072 AA 755), and III ( AM AA CA R124 AA 755].

The requirements for data depicting magnitude of the residue in/ on plants are fulfilled for the following raw agricultural commodities ( RACs): apples, cherries, filberts, grapes, pears, and imported bananas. Overall, a sufficient number of field trials were conducted, and the trials were conducted using representative fenarimol formulations at the maximum registered application rates. In some cases, residue data were translated from closely related plant groups with identical use patterns. Adequate processing data are also available. Studies indicate that fenarimol per se concentrate in wet apple pomace ( 3.7x) but not in apple juice ( 0.05x). Grape processing studies indicate that the combined residues of fenarimol and its metabolites concentrate in grape juice ( 1.6x) and raisins ( 1.2x). The concentration factors for grape products are of such small magnitude that tolerances will not have to be established for grape juice or raisins. 24 4.2.2 Dietary Exposure Risk from Food Sources HED conducts dietary risk assessments using the Dietary Exposure Evaluation Model ( DEEMJ Version 7.075), which incorporates consumption data generated in USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII), 1989 1992. For chronic dietary risk assessments, the three day average of consumption for each sub population is combined with average residues in commodities to determine average exposures in mg/ kg/ day.

The chronic dietary exposure assessment for fenarimol is highly refined using anticipated residues based on 1996 1999 Food and Drug Administration ( FDA) monitoring data for apples, bananas, cherries, grapes and pears. Field trial residue data were used for pecans and filberts. Percent crop treated (% CT) information and processing factors, where available, were used in the assessment. There were no PDP monitoring data available for fenarimol.

Residues of fenarimol per se were nondetectable ( below the method limit of detection, or LOD) in all 1996 1999 FDA monitoring samples of apples, bananas, grapes, and pears ( a total of more than 3,000 samples). Out of 214 cherry samples, three had detectable residues. Residues of fenarimol per se were nondetectable (< LOD) in/ on all but one pecan nut meat sample from seven trials. There were no detectable residues in filbert samples from four field trials.

FDA results for bananas and grapes were adjusted to account for potential residues of Metabolites B and C. Banana and grape field trial data indicate that total metabolites of fenarimol occur in banana pulp at a maximum 2X of fenarimol per se, and in grape at a maximum of 3x.

The anticipated secondary residues of fenarimol in ruminant tissues ( meat, fat and meat byproducts) are derived from a cattle feeding study ( MRID 40098605, PP# 4F3108, F. Boyd, 9/ 20/ 84). Wet apple pomace is the only feedstuff associated with registered uses of fenarimol. Anticipated residues were all very low ( all less than 0.003 ppm). Milk, eggs, poultry tissue and hog tissue were not included in the dietary assessment because the Agency has determined that there is no reasonable expectation of finite residues of fenarimol in these animal commodities, and is recommending that established tolerances for milk, hog tissues, poultry tissues, and eggs be revoked as per Category 3 of 40 CFR § 180.6( a). There are no poultry or hog feed items associated with the registered uses of fenarimol.

This assessment concludes that for all supported registered commodities, the chronic risk estimates are below the Agency's level of concern (< 100% of the chronic population adjusted dose, cPAD) for the general U. S. population and all population subgroups (< 1% of the cPAD); see Table 4.

Table 4. Results of Chronic Dietary Exposure Analysis Population Subgroup Exposure ( mg/ kg/ day) % cPAD1 U. S. Population ( total) 0.000000 < 1 All Infants (< 1 year) 0.000001 < 1 Children 1 6 years 0.000002 < 1 Children 7 12 years 0.000001 < 1 Females 13 50 0.000000 < 1 Males 13 19 0.000000 < 1 Population Subgroup Exposure ( mg/ kg/ day) % cPAD1 25 Males 20+ years 0.000000 < 1 Seniors 55+ 0.000000 < 1 1 cPAD = 0.0006 mg/ kg/ day 4.3 Water Exposure Pathway This assessment is based on environmental fate studies conducted in the 1970s and early 1980s. The quality of the data provided by these studies is significantly lower than currently required. By current standards most of these studies would not be considered acceptable and the results would not be considered of sufficient quality to allow a reasonably accurate assessment of the environmental fate of this compound.

Fenarimol is persistent and moderately mobile in the environment. In field studies, fenarimol reportedly dissipated with half lives of three months to several years from soil and turf surfaces and much slower when incorporated into soil. Based on fenarimol's chemical properties it is likely that this chemical will move to surface water and groundwater, and it may accumulate in the environment. It is believed to be stable to hydrolysis, anaerobic microbial degradation and photolysis on soil. It is degraded very slowly, if at all, by aerobic microbial processes with reported mean aerobic soil metabolism half life of about 4 years. It is degraded by photolysis in aqueous solution. The primary photolysis product is 4 chloro 2( 5 pyrimidyl) 2' clorobenzophenone. The MARC elected not to exclude this aquatic photolysis degradate in the drinking water exposure assessment because: 1) its potential to occur in surface water; and, 2) the lack of data to determine whether or not it is of toxicological concern.

Tier I surface water and ground water Estimated Environmental Concentrations ( EECs) for fenarimol were calculated using FIRST ( surface water) and SCI GROW ( groundwater) modeling of application to turf. FIRST is a first tier screening model designed as a coarse screen to estimate the pesticide concentrations found in an ` Index Reservoir' located in Shipman, Illinois for use in environmental risk assessments for drinking water. As such, it provides high end estimates of the concentrations of a pesticide in drinking water that might be derived from surface water. This first level tier is designed as a coarse screen and estimates concentrations from only a few basic chemical parameters and pesticide label application information. The FIRST program is designed to mimic a more complex simulation such as using the linked PRZM and EXAMS models, but requires less time and effort to complete. If a risk assessment performed using FIRST output does not exceed the level of concern, then one can be reasonably confident that the acute risk will not be exceeded. However, for stable chemicals with long environmental half lives FIRST may significantly underestimate long term EECs.

SCI GROW provides a ground water screening exposure value to be used in determining the potential risk to human health from drinking water contaminated with the pesticide. SCI GROW estimates EEC values in shallow ground water for only a single season and so is much less useful in estimating EEC values for stable compounds that may persist in the environment. The EEC value calculated using SCI GROW should therefore be used with caution since it probably underestimates possible ground water concentrations.

Since the last version of this HED TRED ( June 7, 2002), the Environmental Fate and Effects Division ( EFED) received additional information on the aquatic photo degradate ( i. e. 4 chloro 2( 5 pyrimidyl) 2' clorobenzophenone) and has subsequently revised the drinking water assessment. The 26 updated drinking water assessment ( N. Birchfield; July 31, 2002; D284487) was revised to include fenarimol and its aquatic photodegradates. The previous drinking water assessment ( L. Liebelo, August 6, 2001; D276622) did not attempt to account for possible photo degradates of concern. In the new updated drinking water assessment, the model inputs were adjusted so that aquatic concentrations were estimated assuming no aqueous photolysis, which appears to be fenarimol's most significant route of dissipation in the environment. Minor model input corrections were also made to the application rate and interval. The result provides a screening level estimate of combined concentrations of fenarimol and its aquatic degradates that is conservative and that does not underestimate exposure. The EECs for surface and ground water are summarized in Table 5. As a result of this reassessment, the surface water acute EEC increased from 242 to 261

g/ L, and the chronic EECs increased from 59 to 84

g/ L for surface water, and from 14 to 16

g/ L for ground water. These surface water EEC values represent the maximum surface water concentration ( acute EEC), and the mean yearly concentration ( chronic EEC), respectively, resulting from fenarimol use on turf. The ground water screening concentration, calculated using SCI GROW, represents a 90 day average concentration value. This value should be used for both chronic and acute ground water estimates. Although, there is still some uncertainty as to the identity, fate, and behavior of the photolysis degradates of fenarimol, data will be required to address this uncertainty.

Table 5. Modeling Results ( Estimated Environmental Concentrations ( EECs)) for Application of Fenarimol to Turf.

Model Concentrationa FIRST Peak Day ( Acute) Surface Water 261

g/ L FIRST Annual Average ( Chronic) Surface Water 84

g/ L SCI GROW Ground Water Value 16

g/ L a EECs are for parent fenarimol and the aqueous photolytic degradate.

4.4 Residential Exposure Potential residential exposures were possible as a result of applications of fenarimol to residential lawns or turf by residents and by professional lawn care operators ( LCOs). However, as mentioned above, HED has been informed by SRRD that the registrant has agreed to amend their product labels to limit applications to turf to golf courses and professional playing fields only. Applications to residential turf will not be permitted on products labels until such time as additional data are submitted, reviewed, found acceptable, and warrant these uses to be reinstated on product labels. Therefore, the only residential/ recreational exposure scenario to evaluate is adult golfers. These residential/ recreational exposures have been estimated based on label application frequency, and the persistence of fenarimol. Most assumptions for risk estimation were based on the Residential SOPs. Chemical specific data from a turf transferable residue ( TTR) study were available, but were not used to estimate the short term postapplication risk to golfers, because of several limitations of the day zero TTR data. As a result of uses on golf courses and professional playing fields, the HED has concerns for potential exposures to adults.

Application and subsequent exposure in residential settings for the use sites other than turf ( i. e. ornamentals, roses, grapes, apples, pears, cherries, and pecans) is considered unlikely. Dow AgroSciences, the previous registrant, has asserted to HED that product for these use sites is intended for and used only in commercial operations. Product packaging and label language suggest 27 that applications in residential settings would not occur. Label language restrictions include equipment requirements such as personal protective equipment ( PPE) requirements, worker protection standard ( WPS) requirements, restrictions for use by PCOs, and application methods that would never occur in residential settings.

4.4.1 Home Uses <IP_ADDRESS> Handler Exposure Current product labels indicate that residential handler exposure could occur from handling the granular fenarimol product. However, HED has been informed by SRRD that the registrant has agreed to amend their product labels to prohibit handling ( i. e. mixing, loading or applying) of fenarimol by residents. Therefore, residential handler exposure scenarios should no longer exist. Refer to the previous HED TRED chapter for risk estimates involving such scenarios ( i. e., " Fenarimol. Revised HED Human Health Assessment for the Tolerance Reassessment Eligibility Decision ( TRED) Document. Chemical No. 206600. No MRID #. DP Barcode No. D283429", dated June 7, 2002).

<IP_ADDRESS> Postapplication Exposure Current product labels indicate that several post application exposure scenarios following application to turf are anticipated. However, since the registrant has agreed to amend their product labels to prohibit use of fenarimol in residential settings and to increase the re application interval to 30 days, then the only remaining postapplication residential/ recreational exposure scenario to evaluate is shortterm exposure to adult golfers.

The short term postapplication dermal exposure and risk estimates for adult golfers are presented in Table 6. Margins of Exposure ( MOEs) greater than 900 do not exceed HED's level of concern. For adult golfers, a MOE of 14,000 is estimated for short term postapplication dermal exposure, and does not exceed HED's level of concern.

Table 6: Residential Postapplication Activities on Treated Turf: Dermal Exposure and Non Cancer Risk Estimates Short term Risk Estimates at DAT 0 Activity DAT0 TTR (

g/ cm2) ( a) Transfer Coefficient ( cm2/ hr) ( b) Dermal Dose ( mg/ kg/ day) ( c) MOE ( d)

golf course reentry by adults 1.53 500 0.0026 14,000 a TTR source: Standard Operating Procedures ( SOPs) for Residential Exposure Assessments, SOP 2.2: Postapplication dermal potential dose from pesticide residues on turf. DAT 0 residue values were used for the short term assessments at day 0 after application. TTR = AR x F x ( 1 D) t x CF1 x Cf2, where AR = application rate ( lbs a. i./ acre), F = fraction of a. i. retained on foliage ( unitless), D = fraction of residue that dissipates daily ( unitless), t = postapplication day on which exposure is being assessed, CF1 = weight unit conversion factor to convert the lbs a. i. in the application rate to

g for the DFR value ( 4.54E8

g/ lb), and CF2 = area unit conversion factor to convert the surface area units ( ft2) in the application rate to cm2 for the DFR value ( 24.7E 9 acre/ cm2); e. g. TTR at DAT 0 = 2.73 lbs a. i./ acre x 0.05 x 4.54E8

g/ lb x 24.7E 9 acre/ cm2 = 1.53

g/ cm2. b Transfer coefficient from the Residential SOP's ( 02/ 01). c Dermal Dose = TTR (

g/ cm2) x TC ( cm2/ hr) x conversion factor ( 1 mg/ 1,000

g) x exposure time ( 4 hrs golfing) x Dermal Absorption Factor ( 5/ 100)/ body weight ( 60 kg adult). Short term MOEs were calculated using DAT 0 residue values. 28 d MOE = LOAEL ( 35 mg/ kg/ day; based on a oral study) / dermal dose; Note: Target MOE is 3000 or greater, since a NOAEL was not established and a LOAEL is used. TTR = turf transferable residue DAT = days after treatment Uncertainties Residential SOPs were utilized to estimate initial residues ( i. e. DAT 0 residues) based on application rate and to estimate contact rates with turf. Chemical specific data from a turf transferable residue ( TTR) study ( MRID 44690801) were available. However, these TTR data were found to be generally unacceptable for use in postapplication exposure assessment. These data had limitations, as follows: 1) the sampling period was not sufficiently long enough to adequately characterize dissipation; 2) only duplicate samples were collected at each sampling interval, not the Agency recommended triplicate sampling; and 3) the day 0 ( DAT 0) data from the California site were inconsistent with data from the other two sites. Therefore, based on the weight of evidence these data were discounted. A dissipation rate of 8% ( daily) was derived from these data. Also, the data show that 6.1%, 0.85%, and 0.59% ( for CA, IN & MS, respectively) of the applied fenarimol was detected on DAT 0. By comparison, the Agency's SOP uses a transfer efficiency ( percent of application rate) of 5%. Therefore, due to the variability of the study transfer efficiency data, the poor quality of the study itself, and because no transfer coefficient exists for the California roller method that was used in this study, the HED will use the 5% transfer efficiency rate for risk assessment purposes. However, the HED notes that the 6.1% transfer efficiency rate measured from the CA site may be an outlier, since the DAT 1 data ( residues detected one day after application) from the CA site were an order of magnitude lower, and the DAT 0 and DAT 1 data from the IN and MS sites were considerably lower. Therefore, use of the 5% transfer efficiency rate may be a conservative assumption. Better data may indicate a value closer to 1%, which would increase the MOEs by five fold.

The exposure estimates generated for the golfing turf use using the Draft SOPs is based on some upper percentile assumptions ( i. e., duration of exposure and maximum application rate for this shortterm assessment) and is considered to be representative of high end exposures. The uncertainties associated with this assessment stem from the use of an assumed amount of pesticide retained on turf, and assumptions regarding the transfer of fenarimol residues. The turf risk estimate is believed to be a reasonable and protective estimate, that is based on Agency residential SOPs. Therefore, the level of confidence is fairly high, and does not under estimate risk.

HED assumes that the general public's exposure on a golf course will not be mitigated by use of personal protective gear. Therefore, only administrative controls ( e. g., formulation changes or use rate reductions) are feasible methods of risk reduction. Mitigating circumstances for residential exposure to fenarimol residues may include the watering in of the granular formulation to turf. This instruction, however, does not prevent contact with treated turf prior to watering in. The current granular label ( EPA Reg. No. 228 298) recommends, but does not require watering in. The soluble concentrate label ( EPA Reg. No. 62719 142) does not mention watering in. Therefore, label language should be strengthened to ensure that watering in occurs immediately after application. When fenarimol is applied to stadium or professional athletic fields, applicators should water in product immediately after application, or do not enter or allow others to enter treated area for 24 hours after application. If product is watered in after treatment, do not enter or allow other persons to enter until area has dried.

4.4.2 Spray Drift 29 Spray drift is always a potential source of exposure to the public near spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from groundboom application methods. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U. S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off target drift and risks associated with aerial as well as other application types where appropriate.

5.0 AGGREGATE RISK ASSESSMENT AND RISK CHARACTERIZATION 5.1 Acute Aggregate Risk Assessment Because an acute toxicity endpoint was not identified by HIARC, an acute aggregate risk assessment is not required.

5.2 Short and Intermediate Term Aggregate Risk Assessment Based on agreements with the registrant regarding amendments to product labels as described above, HED does not anticipate any intermediate term exposure, nor any residential handler or postapplication exposures, other than those from uses on golf course and professional playing fields. Short term dermal postapplication exposures for adults golfing were combined with average dietary ( food & water) exposures in a short term aggregate risk assessment. This aggregate risk estimate did not exceed the Agency's level of concern. The exposure from food is insignificant for adults; therefore, the aggregate risk estimates include only dermal and water exposures. Table 7 presents the aggregate risk estimates for adult males and females, calculated using HED SOP 99.5. The shortterm DWLOCs for adults are well above the estimated EECs for ground and surface water, and indicate that combined short term dietary ( food & water) and postapplication dermal exposures do not exceed the Agency's level of concern. 30 Table 7. Short Term Aggregate Risk and DWLOC Calculations ( Oral/ Dermal Endpoints and NOAELs the Same)

Population Short Term Scenario NOAEL mg/ kg/ day Target MOE1 Max Exposure2 mg/ kg/ day Average Food Exposure mg/ kg/ day Residential Exposure3 mg/ kg/ day Aggregate MOE ( food and residential) 4 Max Water Exposure5 mg/ kg/ day Ground Water EEC6 (

g/ L) Surface Water EEC6 (

g/ L) Short Term DWLOC7 (

g/ L)

Adult Male 35 900 0.0388 0.0 0.0026 13460 0.0362 16 84 1267 Adult Female 35 900 0.0388 0.0 0.0026 13460 0.0362 16 84 1086 1 Target MOE = 10x uncertainty factor ( UF) for intra species variability, a 10x UF for inter species extrapolation, a 3x UF for lack of a NOAEL in the study used as the basis of the endpoint, and an FQPA Safety Factor of 3x 2 Maximum Exposure ( mg/ kg/ day) = NOAEL/ Target MOE 3 Residential Exposure = Dermal Exposure for Adults Golfing 4 Aggregate MOE = [ NOAEL ÷ ( Avg Food Exposure + Residential Exposure)]

5 Maximum Water Exposure ( mg/ kg/ day) = Target Maximum Exposure  ( Food Exposure + Residential Exposure)

6 The crop producing the highest level was used.

7 DWLOC (

g/ L) = [ maximum water exposure ( mg/ kg/ day) x body weight ( kg)] Male body weight = 70 kg; Female body weight = 60 kg; water consumption = 2 L [ water consumption ( L) x 10 3 mg/

g] 31 5.3 Chronic Aggregate Risk Assessment 5.3.1 Aggregate Chronic Risk Assessment The aggregate chronic risk assessment for fenarimol considers both chronic food and drinking water exposure to fenarimol. Chronic exposure to residues of fenarimol in/ on food does not exceed HED's level of concern. However, the EEC for surface water exceeds the chronic DWLOCs for all population subgroups ( see below), indicating a potential concern for exposure through drinking water. Tier I EECs were calculated for the turf use of fenarimol. A Tier II model is not available for turf.

5.3.2 Chronic DWLOC Calculations HED has calculated drinking water levels of comparison ( DWLOCs) for chronic exposure to fenarimol in surface and ground water which are presented in Table 8. The DWLOC chronic is the concentration in drinking water as a part of the aggregate chronic exposure that occupies no more than 100% of the chronic PAD. To calculate the DWLOC for chronic exposure relative to a chronic toxicity endpoint, the chronic dietary food exposure ( from DEEMJ) was subtracted from the chronic PAD to obtain the acceptable chronic exposure to fenarimol in drinking water. DWLOCs were then calculated using default body weights and drinking water consumption figures. Assumptions used in calculating the DWLOCs include 70 kg body weight for the U. S. population, 60 kg body weight for adult females, 10 kg body weight for children, two liters of water consumption per day for adults, and one liter consumption for children.

To estimate the potential risks associated with chronic exposure to fenarimol in drinking water, HED compared estimated environmental concentrations ( EECs) of fenarimol in surface and ground water to chronic DWLOCs. If EECs are greater than DWLOCs, then risk estimates exceed HED's levels of concern. The surface water EECs represent annual average concentrations of fenarimol, and the ground water EECs represent 90 day average concentrations of fenarimol. The EECs are based on tier 1 models ( FIRST for surface water; SCI GROW for ground water) for a turf use scenario with maximum application rates. Initially, the drinking water assessment did not include the water degradate of concern, because the environmental fate database is incomplete for the aquatic photodegradate of fenarimol, 4 chloro 2( 5 pyrimidyl) 2' chlorobenzophenone. Consequently, the drinking water assessment may underestimate exposure. Recently, the Environmental Fate and Effects Division ( EFED) received additional information on the aquatic photo degradate and revised the drinking water assessment. The updated drinking water assessment ( July 31, 2002; D284487) was revised to include fenarimol and its aquatic photodegradates. The model inputs were adjusted so that aquatic concentrations were estimated assuming no aqueous photolysis, which appears to be fenarimol's most significant route of dissipation in the environment. Minor model input corrections were also made to the application rate and interval. The result provides a screening level estimate of combined concentrations of fenarimol and its aquatic degradates that is conservative and that does not underestimate exposure. As a result of this reassessment the chronic EECs increased from 59 to 84

g/ L for surface water, and from 14 to 16

g/ L for ground water. Although, there is still some uncertainty as to the identity, fate, and behavior of the photolysis degradates of fenarimol, data will be required to address this uncertainty. 32 Table 8. Fenarimol  Summary of Chronic DWLOC Calculations Population Subgroup cPAD ( mg/ kg/ day ) Food Exposure ( mg/ kg/ day) Available Water Exposure ( mg/ kg/ day) Chronic DWLOC (

g/ L) EFED Generated EECs ( Chronic)

Surface Water ( FIRST) (

g/ L) Ground Water ( SCI GROW) (

g/ L)

U. S. Populationa 0.002 0.000000 0.002 70 84 16 Females 13 50 yrs 0.000000 0.002 60 Children 1 6 yrs b 0.000002 0.000598 20 All Infants 0.000001 0.000599 20 EEC = Estimated Environmental Concentrations for fenarimol and its aquatic photodegradates.

NOAEL ( No Observable Adverse Effect Level) = 0.6 mg/ kg/ day UF ( Uncertainty Factor) = 100 cRfD ( Chronic Reference Dose) = NOAEL = 0.006 mg/ kg/ day UF FQPA SF ( Food Quality Protection Act Safety Factor) = 3 cPAD = Chronic Population Adjusted Dose = cRfD = 0.002 mg/ kg/ day FQPA SF DWLOCchronic = water exposure X body weight ( where water exposure = cPAD  average food exposure) Liters of water/ day X10 3 Body weight = 70 kg for U. S. Population, 60 kg for females, 10 kg for infants and children Consumption = 2L/ day for Adults and 1L/ day for infants and children a Also represents Males 13 19 years, Males 20+ years, and Seniors 55+ b Also represents Children 7 12 years old.

The EEC for ground water is less than all DWLOCs; therefore, there is no concern for aggregate chronic exposure to fenarimol and its degradates from food and ground water. The EEC for surface water is greater than all DWLOCs; therefore, there is a potential concern for aggregate chronic exposures to fenarimol from food and surface water. However, the estimated EEC for surface water is a very conservative estimate. It represents the 1 in 10 year mean yearly surface water concentration. EFED's surface water modeling for drinking water uses a default percent cropped area factor ( PCA) for turf, which represents the fraction of the watershed that is cropped and treated with the pesticide being modeled. In the absence of a crop specific PCA factor, a default PCA of 0.87 is used. The 0.87 factor represents the maximum fraction of a watershed in the US that is agriculturally cropped. This default PCA was used for fenarimol modeling on turf. EFED is currently attempting to develop PCA factors specific for turf scenarios, and recognizes that it is unlikely that 87% of a watershed used for drinking water would be grown to turf and treated with fenarimol at the maximum rate allowed only for turf applications.

The default PCA factor assumed and used in fenarimol modeling is most likely overestimated and adds to the conservatism of the assessment. Given the relatively low usage of fenarimol across the country it is highly unlikely that the amount applied to the watershed in the model will be concentrated in any real watershed used to derive drinking water. 33 In summary, the surface water EEC is not likely to underestimate exposure to fenarimol and its degradates based on the conservative inputs to the model ( i. e., default PCA, no decay via the major degradation pathway, and the concentrated application scenario modeled is unlikely to occur in a real watershed where drinking water is derived). The uncertainties related to the aqueous photoproducts would likely be addressed through completion of a satisfactory guideline aqueous photolysis study ( Guidelines 161 2, 835.2240). Other uncertainties would likely be addressed through the satisfactory completion of other outstanding guideline studies; as detailed by EFED.

6.0 Cumulative Exposure To Substances with Common Mechanism of Toxicity.

The Food Quality Protection Act ( 1996) 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 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.

HED did not perform a cumulative risk assessment as part of this risk assessment for fenarimol because HED has not yet initiated a review to determine if there are any other chemical substances that have a mechanism of toxicity common with that of fenarimol. For purposes of this tolerance reassessment review, EPA has assumed that fenarimol does not have a common mechanism of toxicity with other substances.

7.0 TOLERANCE REASSESSMENT RECOMMENDATIONS 7.1 Tolerance Reassessment Recommendation Table 9 summarizes the tolerance reassessment for fenarimol.

Table 9. Reassessed fenarimol tolerances.

Commodity Established Tolerance ( ppm) Reassessed Tolerance ( ppm) Comment [ Correct Commodity Definition]

Tolerance Listed Under 40 CFR § 180.421( a)( 1)

Apple pomace ( wet and dry) 2.0 0.3 The available data indicate that the tolerance for wet apple pomace should be reduced. Dry apple pomace is no longer considered a significant livestock feed item. [ Apple, wet pomace]

Apples 0.1 0.1 [ Apple]

Cattle, fat 0.1 0.01 Cattle, meat 0.01 0.01 Cattle, mbyp 0.01 0.05 [ Cattle, meat byproducts, except kidney] Commodity Established Tolerance ( ppm) Reassessed Tolerance ( ppm) Comment [ Correct Commodity Definition]

34 Cattle, kidney 0.1 0.01 Cattle, liver 0.1 Revoke [ included in meat byproducts]

Eggs 0.01 Revoke There are no poultry feed items associated with presently registered uses.

Goat, fat 0.1 0.01 Goat, meat 0.01 0.01 Goat, mbyp 0.01 0.05 [ Goat, meat byproducts, except kidney]

Goat, kidney 0.1 0.01 Goat, liver 0.1 Revoke [ included in meat byproducts]

Hog, fat 0.1 Revoke There are no hog feed items associated with presently registered uses. Hog, meat 0.01 Revoke Hog, mbyp 0.01 Revoke Hog, kidney 0.1 Revoke Hog, liver 0.1 Revoke Horse, fat 0.1 0.01 Horse, meat 0.01 0.01 Horse, mbyp 0.01 0.05 [ Horse, meat byproducts, except kidney]

Horse, liver 0.1 Revoke [ included in meat byproducts]

Horse, kidney 0.1 0.01 Milk 0.003 Revoke Category 3 of 40 CFR § 180.6( a)

Pears 0.1 0.1 [ Pear]

Pecans 0.1 0.02 [ Pecan]

Poultry, fat 0.01 Revoke There are no poultry feed items associated with presently registered uses. Poultry, meat 0.01 Revoke Poultry, mbyp 0.01 Revoke Sheep, fat 0.1 0.01 Sheep, meat 0.01 0.01 Sheep, mbyp 0.01 0.05 [ Sheep, meat byproducts, except kidney]

Sheep, kidney 0.1 0.01 Sheep, liver 0.1 Revoke [ included in meat byproducts]

Tolerance Listed Under 40 CFR § 180.421( a)( 2)

Bananas 0.5 ( Not more than 0.25 ppm shall be present in the pulp after peel is removed) 0.25 [ Banana]

Cherries 1.0 1.0 [ Cherry] Commodity Established Tolerance ( ppm) Reassessed Tolerance ( ppm) Comment [ Correct Commodity Definition]

35 Grape juice 0.6 Revoke Not required based on reexamination of available grape processing data.

Grape pomace ( wet and dry) 2.0 Revoke No longer considered a significant livestock feed item.

Grapes 0.2 0.1 [ Grape]

Raisin waste 3.0 Revoke No longer considered a significant livestock feed item.

Raisins 0.6 Revoke Not required based on reexamination of available grape processing data.

Tolerance Listed Under 40 CFR § 180.421( b)

Filberts 0.02 Revoke ( expired) Expiration/ revocation date of 12/ 31/ 98 * Field trial data support a 0.02 ppm tolerance Hops 5 Revoke ( expired) Expiration/ revocation date of 12/ 31/ 98 7.2 Codex/ International Harmonization The Codex Alimentarius Commission has established several maximum residue limits ( MRLs) for residues of fenarimol in/ on various raw agricultural and processed commodities. The Codex MRLs are expressed in terms of fenarimol per se. A numerical comparison of the Codex MRLs and the corresponding reassessed U. S. tolerances is presented in Table 10. Table 10 shows that except for cattle liver, cherries, and pecans, the U. S. tolerances and Codex MRLs are not in harmony with respect to numerical levels.

Table 10. Codex MRLs and applicable U. S. tolerances for fenarimol. Recommendations are based on conclusions following reassessment of U. S. tolerances.

Codex Reassessed U. S. Tolerance, ppm Recommendation And Comments Commodity, As Defined MRL 1 ( mg/ kg)

Apple pomace, dry 5 wet apple pomace = 0.3 Dry apple pomace is no longer considered a significant livestock feed item.

Artichoke globe 0.1

Banana 0.2 0.25 Cattle kidney 0.02 (*) 0.01 (*)

Cattle liver 0.05 Revoke covered by tolerance for meat byproducts Cattle meat 0.02 (*) 0.01 (*)

Cherries 1 1 Dried grapes ( currants, raisins and sultanas) 0.2 Revoke Grapes 0.3 0.1 Codex Reassessed U. S. Tolerance, ppm Recommendation And Comments Commodity, As Defined MRL 1 ( mg/ kg)

36 Hops, dry 5

Melons, except watermelon 0.05

Peach 0.5

Pecan 0.02 (*) 0.02 (*)

Peppers, sweet 0.5

Pome fruits 0.3 apple/ pear = 0.1 Strawberry 1

1 All MRLs are at CXL step. An asterisk (*) signifies that the MRL or US tolerance was established at or about the limit of detection.

8.0 DATA NEEDS Toxicology:

A primary dermal irritation study ( 870.2400); a 28 day subchronic inhalation study ( 870.3465); and a special developmental toxicity study ( 870.6300). The special developmental toxicity study being required must include a special protocol that assesses potential hormonal effects.

Product and Residue Chemistry:

Additional data are required concerning enforcement analytical methods, stability, storage stability, pH, UV/ Visible absorption, density, octanol/ water partition coefficient, and solubility ( OPPTS 830.1800, 6313, 6317, 7000, 7050, 7300, 7550, and 7840) of the T/ TGAI.

Storage stability data for livestock commodities are required to support the storage intervals used in the livestock feeding studies.

Label Language:

Mitigating circumstances for exposure to fenarimol residues may include watering in after application to turf. This instruction, however, does not prevent contact with treated turf prior to watering in. The current granular label ( EPA Reg. No. 228 298) recommends, but does not require watering in. The soluble concentrate label ( EPA Reg. No. 62719 142) does not mention watering in. Therefore, label language should be strengthened to ensure that watering in occurs immediately after application. When fenarimol is applied to stadium or professional athletic fields, applicators should water in product immediately after application, or do not enter or allow others to enter treated area for 24 hours after application. If product is watered in after treatment, do not enter or allow other persons to enter until area has dried.