Page 1 of 42 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: 09/ 27/ 2005 MEMORANDUM SUBJECT: Aquashade: Revised HED Chapter of the Reregistration Eligibility Decision Document ( RED). PC Code: 110301, DP Barcode: 321912 Regulatory Action: Phase 1 Reregistration Action FROM: Wade Britton, MPH, Industrial Hygienist and Risk Assessor Reregistration Branch 3 Health Effects Division ( 7509C)

AND Kim Morgan, PhD, Toxicologist Reregistration Branch 3 Health Effects Division ( 7509C)

THROUGH: Catherine Eiden, Branch Chief Reregistration Branch 3 Health Effects Division ( 7509C)

TO: Kendra Tyler, CRM Reregistration Branch 1 SRRD ( 7508C)

The HED Chapter has been revised to reflect a correction made in Section 6.3.2, Recreational Uses. In the original document, the dose and MOE reported for adult and child recreational swimmers were reversed. Page 2 of 42 Table of Contents 1.0 Executive Summary ........................................................................................................ 4 2.0 Ingredient Profile ............................................................................................................ 8 2.1 Summary of Registered/ Proposed Uses.................................................................... 9 2.2 Structure and Nomenclature................................................................................... 10 2.3 Physical and Chemical Properties ......................................................................... 10 3.0 Metabolism Assessment ................................................................................................ 11 3.1 Comparative Metabolic Profile ............................................................................. 11 4.0 Hazard Characterization/ Assessment ................................................................................. 11 4.1 Hazard Characterization........................................................................................ 11 4.1.5. Acute Toxicity ......................................................................................... 12 4.2 FQPA Hazard Considerations ............................................................................... 15 4.2.1 Adequacy of the Toxicity Data Base .......................................................... 15 4.2.2 Evidence of Neurotoxicity.......................................................................... 15 4.2.3 Developmental Toxicity Studies................................................................. 15 4.2.4 Reproductive Toxicity Study...................................................................... 16 4.2.5 Additional Information from Literature Sources . ...................................... 17 4.2.6 Pre and/ or Post natal Toxicity.................................................................... 17 4.3 Recommendation for a Developmental Neurotoxicity Study.................................. 18 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity Study..... 18 4.3.2 Evidence that supports not requiring Developmental Neurotoxicity Study 18 4.4 Hazard Identification and Toxicity Endpoint Selection .......................................... 18 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49.................................... 18 4.4.2 Acute Reference Dose ( aRfD)  General Population................................... 18 4.4.3 Chronic Reference Dose ( cRfD)................................................................. 18 4.4.4 Incidental Oral Exposure ( Short and Intermediate Term) .......................... 20 4.4.5 Dermal Absorption..................................................................................... 20 4.4.6 Dermal Exposure ( Short, Intermediate  Term)............................................ 20 4.4.7 Inhalation Exposure ( Short, Intermediate Term)........................................ 21 4.4.8 Margins of Exposure .................................................................................. 21 4.4.9 Recommendation for Aggregate Exposure Risk Assessments..................... 22 4.4.10 Classification of Carcinogenic Potential.................................................... 22 4.5 Special FQPA Safety Factor ................................................................................. 25 5.0 Public Health Data ............................................................................................................ 25 5.1 Incident Reports .................................................................................................... 25 6.0 Exposure Characterization/ Assessment ............................................................................. 26 6.1 Dietary Exposure/ Risk Pathway............................................................................. 26 6.2 Water Exposure/ Risk Pathway............................................................................... 27 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway...................................... 27 6.3.1 Home Uses................................................................................................. 28 6.3.2 Recreational Uses....................................................................................... 30 6.3.3 Residential Aggregated Exposure and Risk Estimates .............................. 30 6.3.4 Other ( Spray Drift, etc.) ............................................................................. 31 Page 3 of 42 7.0 Aggregate Risk Assessments and Risk Characterization.................................................... 31 7.1 Acute Aggregate Risk........................................................................................... 31 7.2 Short Term Aggregate Risk ................................................................................... 32 7.4 Long Term Aggregate Risk .................................................................................. 32 7.5 Cancer Risk ........................................................................................................... 32 8.0 Cumulative Risk Characterization/ Assessment .................................................................. 32 9.0 Occupational Exposure/ Risk Pathway ............................................................................... 33 9.1 Short/ Intermediate/ Long Term Handler Risk ......................................................... 33 9.2 Short/ Intermediate/ Long Term Postapplication Risk.............................................. 36 10.0 Data Needs and Label Requirements ............................................................................. 37 10.1 Toxicology .......................................................................................................... 37 10.2 Occupational and Residential Exposure ............................................................... 37 1.0 TOXICOLOGY DATA REQUIREMENTS...................................................................... 39 2.0 NON CRITICAL TOXICOLOGY STUDIES ............................................................... 40 3.0 TOLERANCE REASSESSMENT ................................................................................ 42 Page 4 of 42 1.0 Executive Summary The Health Effects Division ( HED) of EPA's Office of Pesticide Programs has evaluated the toxicity and exposure data bases for the aquatic algaecide/ herbicide Aquashade, containing the dyes erioglaucine ( Acid Blue 9 or FD& C Blue No. 1) and tartrazine ( Acid Yellow 23 or FD& C Yellow No. 5); and has conducted a human health risk assessment in support of the Reregistration Eligibility Decision ( RED) for these active ingredients.

Erioglaucine and tartrazine have many non pesticidal uses, including their use as inert ingredients ( dyes) in other pesticide formulations and as approved food coloring additives in a variety of applications. These substances are each Generally Recognized As Safe ( GRAS) for general use as food, drug, and cosmetic color additives by the Food and Drug Administration ( FDA).

This risk assessment considers only the use of erioglaucine and tartrazine as active ingredients in Aquashade and similar products. Human health risks associated with their use as inert ingredients were recently assessed by the Office of Pesticide Programs' Registration Division ( RD) [ Reassessment of the Requirement of a Tolerance for the FDA Certified Color Additives FD& C Blue No. 1, FD& C Red No. 40, and FD& C Yellow No. 5 ( Tartrazine), K. Liefer, December 21, 2004). HED relied heavily on the information presented in RD's inert ingredient risk assessment in this assessment of the human health risks from the pesticidal uses of Aquashade.

Use Information Aquashade is registered for use as an aquatic algaecide/ herbicide. The two dyes erioglaucine and tartrazine work by blocking penetration of the portion of the light spectrum required for photosynthesis, thereby limiting the growth of filamentous algae and submerged aquatic vegetation. Application is recommended early in the growing season while growth is on the bottom of the water body or later in the season after the killing and/ or removal of any existent growth. Repeated applications are allowed to maintain an effective concentration of product in the water body. Aquashade may be used in natural or manmade ponds, lakes, fountains, fish farms and fish hatcheries; and may be applied by both professional applicators and homeowners ( Admiral Liquid; EPA Reg. No. 67064 2   approved 3/ 24/ 05). Water bodies treated with Aquashade may not be used for human consumption. However, treated water may be used for irrigation of crops, livestock watering and fishing.

Toxicology The available toxicity data on the two main ingredients of Aquashade, erioglaucine and tartrazine, are adequate to assess the chemical's hazard potential. A product containing 68% erioglaucine and 4.5% tartrazine was used in the acute studies. It has a low acute toxicity with no deaths occurring near the limit dose in oral studies ( Category IV). It has a moderate acute toxicity in dermal studies ( Category III). Based on the uses, the requirement for the acute inhalation study has been historically waived. There were no clinical signs of systemic toxicity in the acute oral and dermal studies. No significant differences exist between males and females. Page 5 of 42 The tested product caused slight eye irritation ( Category III). It was negative for dermal irritation ( Category IV); however, it is a dermal sensitizer.

Tartrazine and erioglaucine each have very low toxicity potentials. A definitive target organ has not been identified and clinical signs were not observed in any study performed using these dyes. Systemic toxicity was observed in one study in the toxicity database and was limited to a decrease in mean body weight following long term dietary exposure to high doses in rats. There were no adverse effects observed in mice or dogs. All NOAELs were reported to be $ 500 mg/ kg/ day with the exception of a non guideline 21 day dermal study in rats. The NOAEL for this study was 5 mg/ kg/ day; however, this was the highest dose tested.

In both the prenatal developmental toxicity study in rats and the 3 generation reproduction study in rats with tartrazine, adverse effects were not observed at any levels below the limit dose. Given the similar toxicity profiles of the two dyes, erioglaucine is expected to demonstrate a similar developmental and reproductive toxicity profile. No adverse effects have been associated with exposure resulting from the FDA approved uses of either tartrazine or erioglaucine. Based on the lack of evidence of pre and/ or post natal susceptibility following exposure to tartrazine or erioglaucine, and considering the lack of residual uncertainties for pre and/ or post natal toxicity, no special FQPA safety factor is needed ( 1X).

There was no evidence of neurotoxicity reported in any study.

No evidence of carcinogenicity was observed in carcinogenicity studies in mice and rats with erioglaucine, ( Borzelleca and Hallagan, 1988a, 1988b) and tartrazine ( Borzelleca et al, 1990). These substances are not mutagenic in the standard Ames assay with or without metabolic activation ( Brown et al, 1978).

Erioglaucine and tartrazine are rapidly metabolized, and excreted in rats, rabbits, and dogs. Erioglaucine is poorly absorbed; however, this is not the case for tartrazine. The presence of the dyes was found in the bile. The parent compounds are excreted unchanged mainly in the feces with a small amount excreted by the urine.

Residue Chemistry Water bodies treated with Aquashade may not be used for human consumption. However, treated water may be used for irrigation of crops, livestock watering and fishing, which could theoretically result in residues of erioglaucine and/ or tartrazine in human foods. In addition, Aquashade may be used in fish farms/ hatcheries. In 1982, based on Aquashade's low toxicity profile, EPA waived residue chemistry data requirements and established an exemption from the requirement of a tolerance for erioglaucine when used as an aquatic plant control agent under 40 CFR 180.1074. Tartrazine, when used as a dye, had previously been exempted from the requirement of a tolerance as an inert ( or occasionally as an active) ingredient in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest under 40 CFR 180.1001( c) ( currently 40 CFR 180.910). HED has determined that the existing exemption for tartrazine as an inert ingredient is not sufficient to satisfy reregistration requirements for the active ingredient when used as an aquatic plant control agent. Therefore, we are recommending Page 6 of 42 that the exemption for erioglaucine at 40 CFR 180.1074 be revised to include both erioglaucine and tartrazine.

Environmental Fate The color additives erioglaucine and tartrazine are water soluble, are fully dissociated in the environmentally significant pH range of 5 to 9, and are stable towards abiotic hydrolysis. Indirect photolysis in water is a major route of transformation for these and other structurally related dyes. The two dyes are not readily biodegradable under aerobic conditions, but biodegrade under anaerobic conditions. They do not adsorb strongly to soils/ sediments and are predominantly found in the water column. Volatilization from soils and water is not likely to be a transport process in the environment. Both dyes are highly hydrophilic and are not likely to bioaccumulate in fish.

Products containing erioglaucine and tartrazine are applied to contained water bodies with little or no outflow, and none of the water bodies treated with the products serves as a source of drinking water. Therefore, no drinking water assessment is needed for these chemicals when used as algaecides/ herbicides according to product labeling.

Residential Exposure Aquashade is labeled for consumer use to control aquatic algae and weeds in ponds and lakes. The anticipated use patterns and current labeling indicate several residential handler scenarios based on the types of equipment and techniques that can potentially be used to make Aquashade applications. Residents or consumers applying Aquashade products to ponds or lakes may be exposed for short term ( 1 to 30 days) duration through skin contact or by inhalation. All residential handler scenarios assessed ( dermal and inhalation) resulted in estimated MOEs greater than 100 and, therefore, are not of concern. Residential short term dermal MOEs range from 1,930 ( Liquids for Pouring Applications) to 16,000 ( Liquids for LCO Handgun), and shortterm inhalation MOEs range from 550,000 ( Liquids for Garden Hose End Sprayer) to 6,600,000 ( Liquids for Pouring Applications).

Postapplication exposures to children and adults that contact Aquashade treated swimming ponds are anticipated. To address the risk of such exposures, a screening tool called the Swimmer Exposure Assessment Model ( SWIMODEL) was applied. The SWIMODEL uses well accepted screening exposure assessment equations to calculate the total worst case exposure for swimmers expressed as a mass based intake value ( mg/ event). Postapplication residential exposure durations are expected to be short and intermediate term ( 1 to 6 months) in duration. All residential postapplication scenarios assessed ( dermal, ingestion, aural, buccal/ sublingual, and nasal/ orbital routes of exposure) resulted in estimated combined MOEs well above 100 and, therefore, are not of concern.

To better quantify residential Aquashade hazard, results from residential handler and residential postapplication ( i. e., swimmer) risk assessments were aggregated. Aggregate calculations of residential exposure were performed using worst case MOEs resulting from each assessment. Page 7 of 42 The residential aggregated exposure resulted in an estimated MOE of 1700 and, therefore, is not a risk of concern.

Aggregate Risk In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: drinking water, food and residential exposures. Since Aquashade is applied to contained water bodies with little or no outflow, and none of the treated water bodies serves as a source of drinking water, no drinking water exposure is expected. Although water treated with Aquashade may potentially be used for irrigation of food crops and livestock watering, and Aquashade is registered for use in fish farms and hatcheries, HED has not quantitatively assessed exposures and risks from food sources for several reasons: ( 1) Aquashade is used primarily in ornamental and/ or recreational lakes and ponds with very little treated water expected to be used for agricultural purposes. ( 2) Erioglaucine and tartrazine are highly water soluble compounds and, as such, not likely to accumulate in livestock or fish tissues. The results of the rat metabolism study with erioglaucine support this determination, since nearly the entire administered dose was excreted unchanged in the feces in less than 2 days. ( 3) Any residues of erioglaucine or tartrazine occurring in foods from the use of Aquashade as an aquatic algaecide/ herbicide would be negligible compared to residues in food from the common use of these dyes as food coloring additives. ( 4) The most significant route of exposure to erioglaucine and tartrazine from the use of Aquashade is residential exposure, including residential handler and postapplication ( swimming) exposure. HED believes that the conservative residential exposure and risk estimates discussed above are more than adequate to cover any food exposures that could potentially occur from the use of Aquashade as an aquatic algaecide/ herbicide.

Occupational Exposure Exposure of pesticide handlers is likely during the occupational use of Aquashade in a variety of occupational environments. Since no chemical specific handler exposure data are available for Aquashade, short and intermediate term dermal and inhalation exposures were assessed using data from the Pesticide Handlers Exposure Database ( PHED) Version 1.1 and from the Outdoor Residential Exposure Task Force ( ORETF). PHED and ORETF data were used with other HED standard values for areas treated per day, body weight and the level of personal protective equipment ( PPE) and engineering controls to assess handler exposures to Aquashade. Using these assumptions, the calculated occupational handler exposures for all scenarios resulted in estimated MOEs greater than 100 and, therefore, are not of concern. Short and intermediateterm dermal MOEs range from 410 ( Liquids for Pouring Applications) to 4,300 ( Liquids for Garden Hose End Sprayer), and short and intermediate term inhalation MOEs range from 120,000 ( Liquids for Garden Hose End Sprayer) to 1,600,000 ( Liquids for Pouring Applications).

Since Aquashade is an algaecide/ herbicide, HED is not aware of any postapplication activities which may result in exposure. No harvesting is required, and while scouting may include identifying any algae or aquatic weed regrowth, these activities should not require contact with the treated water body. For these reasons, occupational postapplication exposure of workers to Page 8 of 42 previously treated water bodies is expected to be negligible and was not assessed. Furthermore, any postapplication activities that could potentially occur would not be expected to exceed those assessed from residential exposures to Aquashade which are not of concern.

Conclusions Aquashade is a low toxicity algaecide/ herbicide whose potential non occupational routes of exposure include residential handler and postapplication ( swimming) exposures. None of the water bodies treated serves as a source of drinking water; and, while treated water may be used to irrigate food crops or for livestock watering, resulting food residues are expected to be negligible. Under the conditions of its current use, human health risks to workers handling the pesticide or to the general population are below HED's level of concern. Aggregate risk estimates from residential handler and postapplication residential exposures are well below HED's level of concern.

2.0 Ingredient Profile Aquashade is an aquatic algaecide/ herbicide which is composed of a combination of the dyes erioglaucine and tartrazine. Application is recommended early in the growing season while growth is on the bottom of the water body or later in the season after the killing and/ or removal of any existent growth. Repeated applications are allowed to maintain an effective concentration of product in the water body. Aquashade works by controlling the portion of the light spectrum required for photosynthesis, thereby inhibiting growth of filamentous algae and submerged aquatic vegetation.

Aquashade is formulated for use in occupational settings as either a liquid or water soluble packet ( WSP) product, and can be applied by pouring or dropping the WSP in water body from the shoreline, or possibly by boat for larger water bodies. It is formulated for residential use as a liquid product only ( 67064 2). While not specified on product labeling, applications could be made by LCO handgun or garden hose end sprayer. The combination of erioglaucine and tartrazine are the active ingredients for 5 registered products. Each product has a different ratio of the dyes, but in all of the product formulations the percent of Acid Blue 9 is higher than that of Acid Yellow 23. Aquashade is applied at a rate of 0.22 to 1.1 pounds of active ingredient per acre foot. Page 9 of 42 2.1 Summary of Registered/ Proposed Uses Table 2.1 Summary of Registered Aquashade Commercial Uses Liquid Formulation Product Crop Max App Rate ( lb ai/ acre foot) Amount of Product for Area To Be Treated Application Methods Aquashade ( 33068 1) Ornamental and Recreational Lakes and Ponds, Fish Rearing and Fish Farming Ponds, Golf Course Ponds 1.1 0.5 gallon/ acre foot ( 2 ppm) Pouring Admiral Liquid ( 67064 2) Fountains, Fish Farms, Fish Hatcheries, Golf Courses, Lakes, Manmade Ponds, Swimming Ponds 0.73 0.5 gallon/ acre foot ( 2ppm) Pouring Algae Blocker ( 8709 6) Garden Ponds, Goldfish Ponds, Koi Ponds, Ornamental Ponds 0.22 120 ml / 1500 gallons Pouring Aquashade OA ( 33068 2) Aquariums, Fountains, Ornamental Ponds, Recirculated or Artificial Waterscapes 0.22 1 ounce/ 1000 gallons Pouring Water Soluble Packets ( WSP)

Admiral WSP ( 67064 1) Fish Farms, Fish Hatcheries, Fountains, Golf Courses, Manmade Ponds, Swimming Ponds 0.73 2 WSPs/ acre foot ( 11 ounces) WSP Page 10 of 42 2.2 Structure and Nomenclature Table 2.2 Aquashade Nomenclature Chemical Structure Empirical Formula C37H34N2Na2 O9 S3 C16H9N4O9S2Na3 Common Name Erioglaucine, Acid Blue 9 Tartrazine, Acid Yellow 23 CAS Name disodium bis[ 4( N ethyl N 3 sulfonatophenylmethyl) aminophenyl] phenyl methylium 4,5 dihydro 5 oxo 1( 4 sulophenyl) 4 [( 4 sulfophenyl) azo] 1H pyrazole 3 carboxylic acid trisodium salt CAS Registry Number 2650 18 2 1934 21 0 End Use Products/ EPs 33068 1 23.63% 2.39% 33068 2 2.36% 0.24% 67064 1 49.72% 3.27% 67064 2 15.31% 1.00% 8709 6 2.36% 0.24%

2.3 Physical and Chemical Properties Table 2.3 Physicochemical Properties of Aquashade Parameter Value Reference Acid Blue 9 Acid Yellow 23 Molecular Weight 792.86 534.37 SRC, 2004 Melting point > 250 ° C > 300 ° C SRC, 2004 Water solubility at 25 ° C 160 g/ L at 25 ° C EPI Suite, 2004 Page 11 of 42 Table 2.3 Physicochemical Properties of Aquashade Parameter Value Reference Acid Blue 9 Acid Yellow 23 Vapor pressure 2.97 x 10 42 mmHg at 25 ° C 7.43 x 10 22 mmHg at 25 ° C EPI Suite, 2004 Octanol/ water partition coefficient ( Kow) Kow = 0.032 Kow = 6.3 x 10 11 SRC, 2004 3.0 Metabolism Assessment 3.1 Comparative Metabolic Profile Erioglaucine was administered orally to rats as a 2% aqueous solution at a level of 200 mg/ rat. Almost the entire amount was excreted unchanged in the feces within 40 h after administration. In a later investigation, the presence of the color in the bile was observed in rats, rabbits and dogs after oral administration. In the case of the dog, the amount did not exceed 5% of the dose administered ( Hess & Fitzhugh, 1953; 1954; 1955). Administration of an aqueous solution of the color by stomach tube resulted in 89 % excretion in the feces; none was found in the urine. After subcutaneous injection of 80 100 mg some 79% was excreted; 77% appeared in the feces and 2.5% in the urine ( Imperial Chemical Industries, 1958).

Metabolism studies for plants and livestock are not available for comparison and have not been required.

4.0 Hazard Characterization/ Assessment 4.1 Hazard Characterization A combination of erioglaucine ( Acid Blue 9 or FD& C Blue No. 1) and tartrazine ( Acid Yellow 23 or FD& C Yellow No. 5) is commonly referred to as Aquashade. Five currently registered pesticide products, which are used as aquatic algaecides/ herbicides, contain a combination of erioglaucine and tartrazine. These substances are each Generally Recognized As Safe ( GRAS) for general use as food, drug, and cosmetic color additives by the Food and Drug Administration ( FDA).

The end use products each have a different ratio of the dyes. A product containing 68% erioglaucine and 4.5% tartrazine was used in the acute studies. It has a low acute toxicity with no deaths occurring near the limit dose in oral studies ( Category IV). It has a moderate acute toxicity in dermal studies ( Category III). Based on the uses, the requirement for the acute inhalation study has been historically waived. There were no clinical signs of systemic toxicity Page 12 of 42 in the acute oral and dermal studies. No significant differences exist between males and females. The tested product caused slight eye irritation ( Category III). It was negative for dermal irritation ( Category IV); however, it is a dermal sensitizer.

Tartrazine and erioglaucine each have very low toxicity potentials. A definitive target organ has not been identified and clinical signs were not observed in any study preformed using these dyes. Systemic toxicity was observed in one study in the toxicity database and was limited to a decrease in mean body weight following long term dietary exposure to high doses in rats. There were no adverse effects observed in mice or dogs. All NOAELs were reported to be $ 500 mg/ kg/ day with the exception of a non guideline 21 day dermal study in rats. The NOAEL for this study was 5 mg/ kg/ day; however, this was the highest dose tested.

In both the prenatal developmental toxicity study in rats and the 3 generation reproduction study in rats with tartrazine, adverse effects were not observed at any levels below the limit dose. Given the similar toxicity profiles of the two dyes, erioglaucine is unlikely to demonstrate quantitative or qualitative susceptibility. No adverse effects have been associated with exposure resulting from the FDA approved uses of either tartrazine or erioglaucine.

Based on the lack of evidence of pre and/ or post natal susceptibility following exposure to tartrazine or erioglaucine, and considering the lack of residual uncertainties for pre and/ or postnatal toxicity, no special FQPA safety factor is needed ( 1X).

There was no evidence of neurotoxicity reported in any study.

No evidence of carcinogenicity was observed in carcinogenicity studies in mice and rats with erioglaucine, ( Borzelleca and Hallagan, 1988a, 1988b) and tartrazine ( Borzelleca et al, 1990). These substances are not mutagenic in the standard Ames assay with or without metabolic activation ( Brown et al, 1978).

Erioglaucine and tartrazine are rapidly metabolized, and excreted in rats, rabbits, and dogs. Erioglaucine is poorly absorbed; however, this is not the case for tartrazine. The presence of the dyes was found in the bile. The parent compounds are excreted unchanged mainly in the feces with a small amount excreted by the urine.

4.1.5. Acute Toxicity Table 4.1a Acute Toxicity Profile  Admiral WSP ( Erioglaucine 68.13%; Tartrazine 4.51%)

Guideline No. Study Type MRIDs Results Toxicity Category 870.1100 Acute oral [ rats] 45281101 LD50 > 5000 mg/ kg IV 870.1200 Acute dermal [ rabbit] 45144401 LD50 > 2000 mg/ kg III Page 13 of 42 870.1300 Acute inhalation NA data requirement waived 870.2400 Acute eye irritation [ rabbit] 44902902 No eye irritation III 870.2500 Acute dermal irritation [ rabbit] 45086102 negative IV 870.2600 Skin sensitization [ guinea pig] 44902904 positive Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3200 21/ 28 Day dermal toxicity ( species) 43410101 Acceptable/ Non Guideline 0, 0.5, 5 mg/ kg/ day Systemic NOAEL   5.0 mg/ kg/ day ( HDT) LOAEL = not identified 870.3700a Prenatal developmental ( rats) Tartrazine 434081011 Acceptable/ Guideline 0, 100, 300, 1000 mg/ kg/ day Maternal NOAEL = 1000 mg/ kg/ day ( HDT) LOAEL = not identified Developmental NOAEL = 1000 mg/ kg/ day ( HDT) LOAEL = not identified 870.3700b Prenatal developmental ( rats) Tartrazine No MRID Collins et al 1990 0, 60, 100, 200, 400, 600 or 1000 mg/ kg/ day Maternal NOAEL = 1000 mg/ kg/ day ( HDT) LOAEL = not identified Developmental NOAEL = 1000 mg/ kg/ day ( HDT) LOAEL = not identified 870.3800 Reproduction and fertility effects ( rats) Tartrazine 43410901 Acceptable/ Guideline 0, 7.5, 75, 225 or 750 mg/ kg/ day Parental/ Systemic NOAEL = 750 mg/ kg/ day ( HDT) LOAEL = not identified Reproductive NOAEL = 750 mg/ kg/ day ( HDT) LOAEL = not identified Offspring NOAEL = NOAEL = 750 mg/ kg/ day ( HDT) LOAEL = not identified 870.4100 Chronic toxicity ( dog) Tartrazine No MRID FDA, 1985 NOAEL = 500 mg/ kg/ day LOAEL = not identified Page 14 of 42 Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.4200 Carcinogencity Satisfied by 870.4300a

870.4300a Combined chronic toxicity/ Carcinogenicity ( rat) Erioglaucine No MRID Borzelleca et al, 1990 F: 0, 63, 631, 1262 mg/ kg/ day M: 0, 54, 536, 1072 mg/ kg/ day NOAEL = 631 mg/ kg/ day LOAEL = 1262 mg/ kg/ day based on decreased body weight in females. No evidence of carcinogenicity 870.4300b Combined chronic toxicity/ Carcinogenicity ( rat) Tartrazine No MRID Borzelleca et al, 1988a F: 0, 53, 1056, 2641 mg/ kg/ day M: 0, 67, 1339, 3348 mg/ kg/ day NOAEL = 2641 mg/ kg/ day ( HDT) LOAEL = not identified No evidence of carcinogenicity 870.4300c Combined chronic toxicity/ Carcinogenicity ( mice) Erioglaucine No MRID FDA, 1982 NOAEL = 1200 mg/ kg/ day ( HDT) LOAEL = not identified No evidence of carcinogenicity 870.4300d Combined chronic toxicity/ Carcinogenicity ( mice) Erioglaucine No MRID Borzelleca et al, 1990 F: 0, 897, 2690, 8966 mg/ kg/ day M: 0, 735, 2206, 7354 mg/ kg/ day NOAEL = 7354 mg/ kg/ day ( HDT) LOAEL = not identified No evidence of carcinogenicity 870.4300e Combined chronic toxicity/ Carcinogenicity ( mice) Tartrazine No MRID Borzelleca et al, 1988b F: 0, 974, 2912, 9735 mg/ kg/ day M: 0, 41, 2431, 8103 mg/ kg/ day NOAEL = 8103 mg/ kg/ day ( HDT) LOAEL = not identified No evidence of carcinogenicity 870.5100 Bacterial reverse mutation test Tartrazine No MRID Hansen et al, 1964 as cited in JEFCA, 1969 Negative.

870.6200b Subchronic neurotoxicity screening battery N/ A 870.6300 Developmental neurotoxicity N/ A Page 15 of 42 Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.7485 Metabolism and pharmacokinetics ( species) No MRID Imperial Chemical Industries, 1958 Erioglaucine was administered orally to rats as a 2% aqueous solution at a level of 200 mg/ rat. Almost the entire amount was excreted unchanged in the feces within 40 h after administration.

870.7600 Dermal penetration ( species) N/ A Special studies N/ A 4.2 FQPA Hazard Considerations 4.2.1 Adequacy of the Toxicity Data Base This risk assessment takes a weight of the evidence approach, considering the available data from a variety of sources, including studies submitted and reviewed by the agency, the Food and Drug Administration ( FDA) and the Joint Expert Committee on Food Additives of the Food and Agriculture Organization/ World Health Organization ( JECFA). This information is sufficient to evaluate the toxicity of Aquashade and related compounds. Based on the information available from these sources, the database is complete and there are no data gaps.

4.2.2 Evidence of Neurotoxicity Neurotoxicity studies have not been conducted on either erioglaucine or tartrazine. However, no evidence of neurotoxicity was observed in any study. No clinical signs indicative of neurotoxicity were noted in subchronic and chronic studies in dogs or rats.

4.2.3 Developmental Toxicity Studies In a developmental toxicity study ( MRID 43408101), groups of 22 23 Long Evans female rats were administered tartrazine ( 92%, Lot No. CCIC 7) at dose levels of 0, 100, 300, or 1000 mg/ kg/ day. Included were 3 control groups containing 22 female rats per group and one positive control group in which trypan blue was administered to 22 female rats at 30 mg/ kg/ day from day 7 through day 9 of gestation by subcutaneous injection. All dams were sacrificed on day 20 of gestation. Page 16 of 42 No clinical signs of toxicity and no mortality were observed. There were no treatment related effects on maternal body weight gain, pregnancy rate, early deliveries, fetal resorption, viability, fetal weight or sex ratio. The NOAEL for maternal toxicity was 1000 mg/ kg/ day ( HDT). The LOAEL could not be determined. The NOAEL for developmental toxicity was 1000 mg/ kg/ day ( HDT) and the LOAEL could not be determined.

The study is acceptable/ guideline. It satisfies the requirement for a guideline series 83 3( a) developmental toxicity study in rats. Although the dose levels chosen for this study were insufficient to produce systemic or developmental toxicity, the limit dose was reached and the intent of the guideline requirement was met. The high dose of 1000 mg/ kg/ day is consistent with no effects in rats and is considered to adequately address the issue as to whether or not FD& C Yellow No. 5 causes prenatal developmental toxicity.

In a second cited prenatal developmental study, tartrazine was given to Osborne Mendel rats by gavage at dose levels of 0, 60, 100, 200, 400, 600 or 1000 mg/ kg/ day on days 0 19 of gestation. No maternal or developmental toxicity was observed when the rats were killed on day 20. The mean daily food consumption for the entire period of gestation was significantly greater in the females given 1000 mg/ kg body weight/ day than in the controls, but maternal body weight gain was not affected. No dose related effects were observed in implantations, fetal viability or external fetal development. Fetal skeletal and visceral development was similar among fetuses from all groups. At the doses given, tartrazine was neither toxic nor teratogenic ( Collins et al, 1990).

4.2.4 Reproductive Toxicity Study In a 3 generation reproduction study ( MRID 43410901), groups of 10 male and 20 female Long Evans rats were administered tartrazine ( 92% ai, Lot No. CC1C 7) at dose levels of 0, 7.5, 75, 225, or 750 mg/ kg/ day in the diet. First generation rats produced 2 litters; second generation rats produced 3 litters ( one of which was sacrificed on Day 19 G. D. for embryologic examination), and the third generation produced 2 litters.

There were no adverse treatment related effects on parental survival, body weight, body weight gain, food consumption, efficiency of food utilization, mating, pregnancy or fertility rates, gestation length, offspring viability, weight and sex, Day 19 sacrifice data or necropsy findings. The NOAEL for reproductive/ systemic effects is 750 mg/ kg/ day ( HDT). The LOAEL was not determined.

This study is acceptable and satisfies the guideline requirement for a 2 generation reproductive study ( OPPTS 870.3800); OECD 416 in rat. Although the dose levels chosen for this study were insufficient to produce systemic or reproductive toxicity, the intent of the guideline requirement was met as described in § 81 through § 86 of subdivision F of the Pesticide Assessment Guidelines. The high dose of 750 mg/ kg/ day is consistent with no effects in rats and is considered to adequately address the issue as to whether or not FD& C Yellow No. 5 causes reproductive toxicity. Page 17 of 42 4.2.5 Additional Information from Literature Sources It should be noted that the toxicological database for erioglaucine and tartrazine, including all subchronic and chronic studies, was evaluated by the FDA and an international peer review committee, JEFCA ( http:// www. fao. org/ ag/ AGP/ AGPP/ Pesticid/ Default. html.) The FDA and JECFA evaluations of erioglaucine and tartrazine include reviews of numerous animal toxicity studies involving dogs, hamsters, guinea pigs, rabbits, rats, and mice as part of their toxicity endpoint selection process. In permanently listing erioglaucine and tartrazine as color additives for use in foods, drugs and cosmetics, FDA concluded that these colorants were safe and determined a maximum acceptable daily intake for erioglaucine and tartrazine ( FDA 1982, 1985). Similarly, JECFA has evaluated these compounds for the purpose of establishing estimates of acceptable daily intakes ( ADIs) ( JECFA 1964, 1969, 1980). Table 3 lists the respective FDA and JECFA ADIs for these substances.

Table 3. FDA and JECFA Acceptable Daily Intake ( ADI) Values ( in mg/ kg bw/ day)

Color Additive FDA ADI JECFA ADI Erioglaucine 12.0 0  12.5 Tartrazine 5.0 0  7.5 4.2.6 Pre and/ or Post natal Toxicity <IP_ADDRESS> Determination of Susceptibility No quantitative or qualitative evidence supports increased susceptibility of rat or fetuses from in utero exposure to tartrazine in the developmental toxicity studies. There was not a prenatal developmental study in rabbits available in the database. In both the prenatal developmental toxicity study in rats and the 3 generation reproduction study in rats with tartrazine, adverse effects were not observed at any levels below the limit dose. Given the similar toxicity profiles of the two dyes, erioglaucine is unlikely to demonstrate quantitative or qualitative susceptibility. No adverse effects have been associated with exposure resulting from the FDA approved uses of either tartrazine or erioglaucine.

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility There is no degree of concern and there are no residual uncertainties. No quantitative or qualitative sensitivity was observed in the rat and rabbit developmental studies or in the 3 generation reproduction study in the rat when tested with tartrazine. Given the similar toxicity profiles of the two dyes, erioglaucine is unlikely to demonstrate quantitative or qualitative susceptibility. Based on the lack of evidence of pre and/ or post natal susceptibility following exposure to tartrazine or erioglaucine, and considering the lack of residual uncertainties for pre Page 18 of 42 and/ or post natal toxicity, no special FQPA safety factor is needed ( 1X). There is no concern for developmental neurotoxicity resulting from exposure to erioglaucine and tartrazine.

4.3 Recommendation for a Developmental Neurotoxicity Study 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity Study There is no evidence that supports requiring a developmental neurotoxicity study.

4.3.2 Evidence that supports not requiring Developmental Neurotoxicity Study The available data on the toxicity of Erioglaucine and tartrazine do not support the recommendation for a developmental neurotoxicity study. No evidence of neurotoxicity was observed in any study.

4.4 Hazard Identification and Toxicity Endpoint Selection 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 There is no appropriate endpoint for females age 13 49 attributable to a single exposure available from oral studies including the developmental toxicity studies.

4.4.2 Acute Reference Dose ( aRfD)  General Population There is no appropriate endpoint for the general population to a single exposure available from oral studies including the developmental toxicity studies.

4.4.3 Chronic Reference Dose ( cRfD)

Studies Selected: Chronic oral toxicity study in dogs ( tartrazine) and chronic oral toxicity/ carcinogenicity study in rats ( erioglaucine; co critical).

MRID No.: No MRID; listed as reviewed by the FDA Executive Summary: Chronic oral toxicity study in dogs ( tartrazine). The chronic study in dogs was submitted to the FDA and was used to establish their ADI. In Federal Register Vol. 50. No 171, the FDA reported that there were a " large number of animals of both sexes". Furthermore, " pilot studies to determine maximum tolerated dosages and two control groups increased the power of these tests for detecting dose related effects." These Page 19 of 42 studies were designed and conducted in full compliance with good laboratory practice regulations and were subject to FDA inspection while they were being conducted. The study in dogs showed no adverse effects at any level. The NOAEL was 500 mg/ kg/ day and a LOAEL was not established.

Co Critical Study MRID No.: No MRID; listed as cited by Borzelleca et al, 1990 Executive Summary: Combined chronic toxicity/ carcinogenicity study in rats FD & C Blue No. 1 ( erioglaucine) was fed to Charles River CD rats as a dietary mixture in lifetime toxicity/ carcinogenicity studies. The rat study was conducted with an in utero phase in which the compound was administered to the F0 generation rats ( 60/ sex/ group) at dietary concentrations of 0.0%, 0.1%, 1.0% or 2.0% equaling approximately 0, 63, 631 and 1262 mg/ kg/ day and 0, 54, 536, and 1072 mg/ kg/ day in females males, respectively. After randomly selecting the F1 animals, the lifetime phase was initiated at the same levels with 70 rats/ sex/ group, including two control groups. The maximum exposure times were 116 and 111 weeks for males and females, respectively. The no observed adverse effect levels are dietary concentrations of 2.0% for males ( 1072 mg/ kg body weight/ day), and 1.0% for females ( 631 mg/ kg/ day) based on a 15.0% decrease in terminal body weight and decreased survival in the high dose ( 1262 mg/ kg/ day) females compared with the combined control groups ( Borzelleca et al, 1990 ).

Dose and Endpoint: The NOAEL of 500 mg/ kg/ day ( HDT) in the chronic oral toxicity study in dogs with tartrazine. This is supported by a combined chronic toxicity/ carcinogenicity study in rats with erioglaucine, which reported a NOAEL of 631 mg/ kg/ day based on decreased body weight at 1262 mg/ kg/ day in females ( LOAEL).

Uncertainty Factor ( UF): 100; includes 10x for interspecies extrapolation and 10x for intraspecies variations.

Comments About Study/ Endpoint/ UF: In 1985, the FDA used the chronic study in dogs to derive the ADI for tartrazine. The risk assessment team also used this study ( OPPTS number 870.4100a) for the selection of the chronic endpoint. The rat combined chronic toxicity/ carcinogenicity study ( OPPTS number 870.4300a) using erioglaucine is considered supportive of the oral dog study using tartrazine. The NOAEL of 500 mg/ kg/ day demonstrated in the chronic dog study with tartrazine is the most conservative endpoint in the database. Although this study is from the FDA's register, it is fully supported by rat combined chronic toxicity/ carcinogenicity study ( NOAEL = 631 mg/ kg/ day) with erioglaucine and by other chronic studies in the tartrazine/ erioglaucine database which all demonstrate extremely high NOAELs (> 1000 mg/ kg/ day). Since the formulated products used are often a combination of tartrazine and erioglaucine, the selection of an endpoint using these two studies allowed the team to make the most conservative and protective estimation of the chronic reference dose. Page 20 of 42 Chronic RfD = 500 mg/ kg/ day = 5 mg/ kg/ day ( tartrazine)

100 4.4.4 Incidental Oral Exposure ( Short and Intermediate Term)

Studies Selected: Chronic oral toxicity study in dogs ( tartrazine) and chronic oral toxicity/ carcinogenicity study in rats ( erioglaucine; co critical).

MRID No.: No MRIDs; listed as reviewed by the FDA Executive Summary: see section 4.4.3 Dose and Endpoint: The NOAEL of 500 mg/ kg/ day ( HDT) in the chronic oral toxicity study in dogs with tartrazine. This is supported by a combined chronic toxicity/ carcinogenicity study in rats with erioglaucine, which reported a NOAEL of 631 mg/ kg/ day based on decreased body weight at 1262 mg/ kg/ day in females ( LOAEL).

Uncertainty Factor ( UF): 100; includes 10x for interspecies extrapolation and 10x for intraspecies variations.

Comments About Study/ Endpoint/ UF: Prenatal developmental studies using tartrazine in rats are available; however, the NOAELs are 1000 mg/ kg/ day. For this reason, the team selected the aforementioned chronic studies and acknowledges that these endpoints are conservative and should be protective for any potential adverse effects. Therefore, the duration and dosing and the endpoint are appropriate for this scenario.

4.4.5 Dermal Absorption No dermal absorption study was available. Therefore, the default dermal absorption factor of 100% was used. It should be noted that use of the default dermal absorption factor resulted in a highly conservative estimation of risk through this route of exposure.

4.4.6 Dermal Exposure ( Short, Intermediate  Term)

Studies Selected: Chronic oral toxicity study in dogs ( tartrazine) and chronic oral toxicity/ carcinogenicity study in rats ( erioglaucine; co critical).

MRID No.: 43410101 Executive Summary: See section 4.4.3 Page 21 of 42 Dose and Endpoint: The NOAEL of 500 mg/ kg/ day ( HDT) in the chronic oral toxicity study in dogs with tartrazine. This is supported by a combined chronic toxicity/ carcinogenicity study in rats with erioglaucine, which reported a NOAEL of 631 mg/ kg/ day based on decreased body weight at 1262 mg/ kg/ day in females ( LOAEL).

Uncertainty Factor ( UF): 100; includes 10x for interspecies extrapolation and 10x for intraspecies variations.

Comments about Study/ Endpoint/ UF: An appropriate dermal toxicity study was not available for any exposure scenario. There was a non guideline 21 day dermal study in rabbits in the database with a NOAEL of 5 mg/ kg/ day ( HDT). However, given that all other guideline studies had NOAELs   500 mg/ kg/ day and that 5 mg/ kg/ day was the highest dose tested in the dermal study, selection of an endpoint based on this study is likely to give an extremely conservative endpoint and is unlikely to be near the threshold dose. Therefore, we selected the chronic oral toxicity study in dogs, assuming 100% dermal absorption. This selection is supported by the dietary combined chronic toxicity/ carcinogenicity study in rats using erioglaucine which had a NOAEL of 631mg/ kg/ day ( compared with 500 mg/ kg/ day with tartrazine). The magnitude of the effect over this interval is considered appropriate for short and intermediate term exposures. Since the end use products are composed of mainly erioglaucine, this endpoint should be conservative and protective for any potential adverse effects via the dermal route of exposure.

4.4.7 Inhalation Exposure ( Short, Intermediate Term)

Studies Selected: Chronic oral toxicity study in dogs ( tartrazine) and chronic oral toxicity/ carcinogenicity study in rats ( erioglaucine; co critical).

MRID No.: 43410101 Executive Summary: See Section 4.4.3 Dose and Endpoint: The NOAEL of 500 mg/ kg/ day ( HDT) in the chronic oral toxicity study in dogs with tartrazine. This is supported by a combined chronic toxicity/ carcinogenicity study in rats with erioglaucine, which reported a NOAEL of 631 mg/ kg/ day based on decreased body weight at 1262 mg/ kg/ day in females ( LOAEL).

Uncertainty Factor ( UF): 100; includes 10x for interspecies extrapolation and 10x for intraspecies variations.

Comments about Study/ Endpoint/ UF: Appropriate inhalation toxicity studies were not available for any exposure scenario. The magnitude of the effect over this interval is considered appropriate for short and intermediate term exposures. 100% inhalation absorption is assumed.

4.4.8 Margins of Exposure The Margins of Exposure ( MOEs) of concern for occupational exposure risk assessments are as follows: Page 22 of 42 Duration of Exposure Route of Exposure Short Term ( 1 30 Days) Intermediate Term ( 1 6 Months) Long Term (> 6 Months)

Occupational ( Worker) Exposure Dermal 100 100 NA Inhalation 100 100 NA Residential ( Non Dietary) Exposure Oral 100 100 NA Dermal 100 100 NA Inhalation 100 100 NA N/ A = Not applicable For occupational short and intermediate term dermal and inhalation exposure risk assessments, a MOE of 100 is required. In addition, an MOE of 100 is required for residential short and intermediate term oral, dermal and inhalation exposure risk assessments. All MOEs are based on the conventional uncertainty factor of 100X ( 10X for intraspecies variation and 10X for interspecies extrapolation).

4.4.9 Recommendation for Aggregate Exposure Risk Assessments As per 1996 FQPA, when there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. All routes of exposure for all durations of exposure can be aggregated. A cancer aggregate risk assessment is not required because there is no evidence of carcinogenicity ( see cancer weight of evidence below).

4.4.10 Classification of Carcinogenic Potential No evidence for carcinogenicity was seen in rats. Administration of tartrazine or erioglaucine to rats for two years did not result in an increase in overall tumor incidence or increase the incidence of any specific type of tumor at doses approaching the limit dose. The chemical was negative for gene mutation in Salmonella typhimurium. Page 23 of 42 Table 4.4. Summary of Toxicological Doses and Endpoints for Chemical for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary ( females 13 49) NA No appropriate endpoint for females age 13 49 attributable to a single exposure.

Acute Dietary ( general population) NA No appropriate endpoint for the general population attributable to a single exposure.

Chronic Dietary ( all populations) NOAEL = 500 mg/ kg/ day ( HDT) ( Tartrazine)

Co critical: NOAEL = 631 mg/ kg/ day ( Erioglaucine)

UF = 100X Chronic RfD = 5 mg/ kg/ day FQPA SF = 1X cPAD = chronic RfD FQPA SF = 5 mg/ kg/ day Chronic oral toxicity in dogs LOAEL = not identified ( Tartrazine)

Co critical:

Combined chronic toxicity/ carcinogenicity study in rats ( Erioglaucine)

LOAEL = 1262 mg/ kg/ day based on decreased body weight in females.

Incidental Oral Short ( 1  30 days)

and Intermediate

Term ( 1   6 months) NOAEL = 500 mg/ kg/ day ( HDT) ( Tartrazine)

Co critical: NOAEL = 631 mg/ kg/ day ( Erioglaucine) Residential MOE = 100 Occupational MOE= NA Chronic oral toxicity in dogs LOAEL = not identified ( Tartrazine)

Co critical:

Combined chronic toxicity/ carcinogenicity study in rats ( Erioglaucine)

LOAEL = 1262 mg/ kg/ day based on decreased body weight in females. Page 24 of 42 Table 4.4. Summary of Toxicological Doses and Endpoints for Chemical for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Dermal Short( 1 30 days)

and Intermediate

Term ( 1   6 months) NOAEL = 500 mg/ kg/ day ( HDT) ( Tartrazine)

Co critical: NOAEL = 631mg/ kg/ day ( Erioglaucine)

UF = 100X ( dermal absorption rate = 100%) Residential MOE = 100 Occupational MOE = 100 Chronic oral toxicity in dogs LOAEL = not identified ( Tartrazine)

Co critical Combined chronic toxicity/ carcinogenicity study in rats ( Erioglaucine)

LOAEL = 1262 mg/ kg/ day based on decreased body weight in females.

Dermal Long Term (> 6 months) NA NA Inhalation Short

( 1  30 days) and Intermediate Term ( 1   6 months) NOAEL = 500 mg/ kg/ day ( HDT) ( Tartrazine)

Co critical: NOAEL = 631 mg/ kg/ day ( Erioglaucine)

UF = 100X ( inhalation absorption rate = 100%) Residential MOE = 100 Occupational MOE = 100 Chronic oral toxicity in dogs LOAEL = not identified ( Tartrazine)

Co critical Combined chronic toxicity/ carcinogenicity study in rats ( Erioglaucine)

LOAEL = 1262 mg/ kg/ day based on decreased body weight in females.

Inhalation Long Term (> 6 months) NA NA Cancer ( oral, dermal, inhalation) Classification: No evidence or carcinogenicity Page 25 of 42 4.5 Special FQPA Safety Factor Based on the hazard data, the risk assessment team recommended the special FQPA SF be reduced to 1x because there are no concerns and no residual uncertainties with regard to preand or post natal toxicity. The erioglaucine and tartrazine risk assessment team evaluated the quality of the exposure data; and, based on these data, recommended that the special FQPA SF be reduced to 1x. The recommendation is based on the following:

° No dietary food exposure assessment required.

° The dietary drinking water assessment is not required.

° The SWIMODEL, an assessment tool employed to address the potential for postapplication residential exposures/ risks ( i. e., swimming ponds), uses screening exposure assessment equations to calculate the total worst case exposure for swimmers. The SWIMODEL was developed based upon reliable data and is unlikely to underestimate exposure/ risk.

4.6 Endocrine disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following recommendations of its Endocrine Disruptor and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP). In the available toxicity studies on erioglaucine and tartrazine, there was no estrogen, androgen, and/ or thyroid mediated toxicity.

When additional appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, erioglaucine and tartrazine may be subjected to further screening and/ or testing to better characterize effects related to endocrine disruption.

5.0 Public Health Data 5.1 Incident Reports Reference: Review of Aquashade Incident Reports, Chemicals # 110303, # 110301, and # 110302, DP Barcode: D302184, Jerome Blondell, 08/ 22/ 05. Page 26 of 42 There were almost no reports of ill effects from exposure to Aquashade in the available data bases. The lack of incidents further supports HED's characterization of Aquashade as a low toxicity pesticide with little potential for acute effects.

One report was found in the OPP Incident Data System ( IDS) in which blue water was observed in a government office building in Ohio in 1989. An investigation found that Acid Blue 9 ( a component of Aquashade) had backflowed into the building's potable water system apparently causing 12 illnesses. Ultimately, it was determined that this incident is too poorly documented and not a basis for conclusions about the human toxicity of the product in question.

Reports from scientific literature suggest that there was concern that Aquashade could cloud water to the point of reducing visibility and disorient divers into lakes treated with Aquashade and possibly lead to drowning. However, further studies were conducted and it was concluded that " The results of this study suggest that the drownings reported in North Carolina could not have been solely or primarily due to the addition of Aquashade to the lake water. It appears more likely that a high volume of plant material may have remained in the lake and may have been more responsible for the disorientation of swimmers and divers who drowned. Under the conditions of this experiment, Aquashade does not appear to reduce the visibility of water significantly in a manner that would create unsafe swimming hazards."

There are no incidents reported by the Poison Control Center ( PCC), the California Department of Pesticide Regulation ( CDPR), the National Pesticide Information Center ( NPIC), or the National Institute of Occupational Safety and Health's Sentinel Event Notification System for Occupational Risks ( NIOSH SENSOR).

6.0 Exposure Characterization/ Assessment 6.1 Dietary Exposure/ Risk Pathway Since Aquashade is applied to contained water bodies with little or no outflow, and none of the treated water bodies serves as a source of drinking water, no drinking water exposure is expected. Although water treated with Aquashade may potentially be used for irrigation of food crops and livestock watering, and Aquashade is registered for use in fish farms and hatcheries, HED has not quantitatively assessed exposures and risks from food sources for several reasons: ( 1) Aquashade is used primarily in ornamental and/ or recreational lakes and ponds with very little treated water expected to be used for agricultural purposes. ( 2) Erioglaucine and tartrazine are highly water soluble compounds and, as such, not likely to accumulate in livestock or fish tissues. The results of the rat metabolism study with erioglaucine support this determination, since nearly the entire administered dose was excreted unchanged in the feces in less than 2 days. ( 3) Any residues of erioglaucine or tartrazine occurring in foods from the use of Aquashade as an aquatic algaecide/ herbicide would be negligible compared to residues in food from the common use of these dyes as food coloring additives. Page 27 of 42 6.2 Water Exposure/ Risk Pathway Reference: Ecological Risk Assessment for the Re registration of Tartrazine (" Acid Yellow 23") and Erioglaucine (" Acid Blue 9") Dyes in the End use Products Aquashade, Admiral, and Algae Blocker, James Goodyear and Silvia Termes, 09/ XX/ 05.

The color additives erioglaucine and tartrazine are water soluble, are fully dissociated in the environmentally significant pH range of 5 to 9, and are stable towards abiotic hydrolysis. Indirect photolysis in water is a major route of transformation for these and other structurally related dyes. The two dyes are not readily biodegradable under aerobic conditions, but biodegrade under anaerobic conditions. They do not adsorb strongly to soils/ sediments and are predominantly found in the water column. Volatilization from soils and water is not likely to be a transport process in the environment. Both dyes are highly hydrophilic and are not likely to bioaccumulate in fish.

Products containing erioglaucine and tartrazine are applied to contained water bodies with little or no outflow, and none of the water bodies treated with the products serves as a source of drinking water. Therefore, no drinking water assessment is needed for these chemicals when used as algaecides/ herbicides according to product labeling.

6.3 Residential ( Non Occupational) Exposure/ Risk Pathway References: Aquashade: Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document; DP Barcode: D302180; W. Britton; 09/ 13/ 05.

Aquashade: Revised Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document; DP Barcode: D321915; W. Britton; 09/ 27/ 05.

Aquashade is labeled for consumer use to control aquatic algae and weeds in ponds and lakes. The anticipated use patterns and current labeling indicate several residential handler scenarios based on the types of equipment and techniques that can potentially be used to make Aquashade applications. Residents or consumers applying Aquashade products to ponds or lakes may be exposed for short term ( 1 to 30 days) duration through skin contact or by inhalation. While the potential for inhalation exposure exists, risks are assumed to be negligible based upon very low vapor pressure values corresponding to the dyes erioglaucine and tartrazine; 2.97 x 10 42 mmHg and 7.43 x 10 22 mmHg at 25 ° C, respectively.

Postapplication exposures to children and adults that contact Aquashade treated swimming ponds are anticipated. To address the risk of such exposures, a screening tool called the Swimmer Exposure Assessment Model ( SWIMODEL) was applied. The SWIMODEL uses well accepted screening exposure assessment equations to calculate the total worst case exposure for swimmers expressed as a mass based intake value ( mg/ event). Postapplication residential exposure durations are expected to be short and intermediate term ( 1 to 6 months) in duration. Page 28 of 42 To better quantify residential Aquashade hazard, results from residential handler and residential postapplication risk assessments were aggregated. Aggregate calculations of residential exposure were performed using worst case MOEs resulting from each assessment.

6.3.1 Home Uses Aquashade Residential Handler Exposure Scenarios: Aquashade is labeled for consumer use to control aquatic algae and weeds in ponds and lakes; therefore, pesticide handler exposure to Aquashade is likely to occur during its use. The anticipated use patterns and current labeling indicate several residential handler exposure scenarios based on the types of equipment and techniques that can be potentially used for consumer Aquashade applications. The quantitative exposure/ risk assessment developed for residential handlers is based on the following scenarios.

Mixer/ Loader/ Applicators: ( 1) Liquids for Pouring Applications ( using PHED mixer/ loader data) ( 2) Liquids for Garden Hose End Sprayer ( ORETF) ( 3) Liquids for LCO Handgun ( ORETF)

Data and Assumptions for Handler Exposure Scenarios: A series of assumptions served as the basis for completing the residential handler risk assessments. Each assumption and factor is detailed below. In addition to these factors, unit exposure values were used to calculate risk estimates. Mostly, these unit exposure values were taken from the Pesticide Handlers Exposure Database ( PHED) and the Outdoor Residential Exposure Task Force ( ORETF) studies. Both PHED and the individual studies are presented below. [ Note: Several of the assumptions and factors used for the assessment are similar to those used in the occupational assessment presented in Section 9.1. As such, only factors that are unique to the residential scenarios are presented below.]

C HED has developed standard unit exposure values for many occupational scenarios to ensure consistency in exposure assessments. These standard values were used to calculate handler exposures for the associated scenarios. For those scenarios where standard values have not been developed, surrogate values based on a similar scenario were used.

C HED always considers the maximum application rates allowed by labels in its risk assessments. If additional information such as average or typical rates are available, these values also may be used to allow risk managers to make a more informed risk management decision.

Risk Summary: A summary of the short term risks ( dermal and inhalation) for each exposure scenario is presented below in Table 6.3.1. All residential handler scenarios assessed resulted in estimated MOEs greater than 100 and, therefore, are not of concern. Short and intermediateterm MOEs do not differ because they share the same toxicological endpoint. Residential shortterm dermal MOEs range from 1,930 ( Liquids for Pouring Applications) to 16,000 ( Liquids for LCO Handgun), and short term inhalation MOEs range from 550,000 ( Liquids for Garden Hose End Sprayer) to 6,600,000 ( Liquids for Pouring Applications). Page 29 of 42 Table 6.3.1 Short term Exposures and Risks for Residential Handlers of Aquashade Exposure Scenario ( Scenario #) Crop1 Dermal Unit Exposure ( mg/ lb ai)

2 Inhalation Unit Exposure ( Ug/ lb ai) 3 Application Rate3 ( lb ai / acre foot) 4 Area Treated Daily ( acrefeet 5 Surface Area ( acres) Depth of Water Body ( feet) Baseline Dermal MOE 6 Baseline Inhalation MOE7 Mixer/ Loader/ Applicator Liquids for Pouring Applications ( 1) Fountains, Fish Farms,

Fish Hatcheries, Golf Courses, Lakes, Manmade Ponds, Swimming Ponds 3.1 1.2 0.73 8 8 1 1930 5000000 Liquids for Pouring Applications ( 1) Ornamental and Recreational Lakes and Ponds 3.1 1.2 1.1 4 1 4 2600 6600000 Liquids for Garden Hose End Sprayer ( ORETF) ( 2) Fountains, Fish Farms,

Fish Hatcheries, Golf Courses, Lakes, Manmade Ponds, Swimming Ponds 2.6 11 0.73 8 8 1 2300 550000 Liquids for Garden Hose End Sprayer ( ORETF) ( 2) Ornamental and Recreational Lakes and Ponds 2.6 11 1.1 4 1 4 3100 720000 Liquids for LCO Handgun ( ORETF) ( 3) Fountains, Fish Farms,

Fish Hatcheries, Golf Courses, Lakes, Manmade Ponds, Swimming Ponds 0.50 1.9 0.73 8 8 1 12000 3100000 Liquids for LCO Handgun ( ORETF) ( 3) Ornamental and Recreational Lakes and Ponds 0.50 1.9 1.1 4 1 4 16000 4200000 Page 30 of 42 1Crops and use patterns are from product labeling. 2Baseline dermal unit exposures represent short pants and short sleeved shirt. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 or are from data submitted by the Outdoor Residential Exposure Task Force dated May 2000. 3Baseline inhalation unit exposures represent no respirator. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 or are from data submitted by the Outdoor Residential Exposure Task Force dated May 2000. 4Application rates are based on maximum values found in various sources including LUIS and various labels. In most scenarios, a range of maximum application rates is used to represent the range of rates for different crops/ sites/ uses. Most application rates upon which the analysis is based are presented as lb ai/ acre foot. 5Amount treated is based on the area or gallons that can be reasonably applied in a single day for each exposure scenario of concern based on the application method and formulation/ packaging type. ( Standard EPA/ OPP/ HED values). 6 Dermal MOE = NOAEL ( 500 mg/ kg/ day) / Daily dermal dose ( mg/ kg/ day). MOEs are reported to 2 significant figures. 7Inhalation MOE = NOAEL ( 500 mg/ kg/ day) / Daily inhalation dose ( mg/ kg/ day). MOEs are reported to 2 significant figures.

6.3.2 Recreational Uses Aquashade can be used in areas that can be frequented by the general population including residential areas ( i. e., swimming ponds). There is potential for dermal, ingestion, aural, buccal/ sublingual, and nasal/ orbital routes of exposure to adults and children following its residential application. The potential for incidental exposures of short term duration exist from the day of application to the water body. Intermediate term exposures could also occur and were considered as well.

Risks were calculated for residential handler and postapplication exposures using the Margin of Exposure ( MOE) approach; the MOE is a ratio of the body burden to the toxicological endpoint of concern. All short and intermediate term residential postapplication scenarios assessed ( dermal, ingestion, aural, buccal/ sublingual, and nasal/ orbital routes of exposure) resulted in estimated combined MOEs greater than 100 and, therefore, are not of concern. A summary of these MOEs is presented in Table 6.3.2.

Table 6.3.2 Recreational Swimmer Aquashade MOEs Exposed Person Exposure Duration Water Concentration ( µ g/ L) Dose ( mg/ kg/ day) NOAEL ( mg/ kg/ day) MOE Child   22 kg 2000 0.10 500 4900 Adult   70 kg Short/

Intermediateterm 2000 0.032 500 15600 6.3.3 Residential Aggregated Exposure and Risk Estimates To better quantify residential Aquashade hazard, results from residential handler and residential postapplication risk assessments were aggregated. Aggregate calculations of residential exposure were performed using worst case MOEs resulting from each assessment.

The residential aggregated exposure resulted in an estimated MOE of 1700 and, therefore, is not a risk of concern. Page 31 of 42 6.3.4 Other ( Spray Drift, etc.)

Spray drift is always a potential source of exposure of residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application methods employed for Aquashade. 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. On a chemical by chemical basis, 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 with specific products with significant risks associated with drift.

7.0 Aggregate Risk Assessments and Risk Characterization In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: drinking water, food and residential exposures. Since Aquashade is applied to contained water bodies with little or no outflow, and none of the treated water bodies serves as a source of drinking water, no drinking water exposure is expected. Although water treated with Aquashade may potentially be used for irrigation of food crops and livestock watering, and Aquashade is registered for use in fish farms and hatcheries, HED has not quantitatively assessed exposures and risks from food sources for several reasons: ( 1) Aquashade is used primarily in ornamental and/ or recreational lakes and ponds with very little treated water expected to be used for agricultural purposes. ( 2) Erioglaucine and tartrazine are highly water soluble compounds and, as such, not likely to accumulate in livestock or fish tissues. The results of the rat metabolism study with erioglaucine support this determination, since nearly the entire administered dose was excreted unchanged in the feces in less than 2 days. ( 3) Any residues of erioglaucine or tartrazine occurring in foods from the use of Aquashade as an aquatic algaecide/ herbicide would be negligible compared to residues in food from the common use of these dyes as food coloring additives. ( 4) The most significant route of exposure to erioglaucine and tartrazine from the use of Aquashade is residential exposure, including residential handler and postapplication ( swimming) exposure. HED believes that the conservative residential exposure and risk estimates discussed above are more than adequate to cover any food exposures that could potentially occur from the use of Aquashade as an aquatic algaecide/ herbicide.

7.1 Acute Aggregate Risk A toxicological endpoint of concern attributable to a single dose has not been identified for Aquashade. Therefore, an acute aggregate risk assessment has not been conducted. Page 32 of 42 7.2 Short Term Aggregate Risk The short term aggregate risk assessment considered residential handler and postapplication ( swimming) exposures to Aquashade only, as there are no sources of drinking water treated with Aquashade and food exposures are expected to be negligible. Short term residential handler exposure may result when Aquashade is used to control aquatic algae and weeds in ponds and lakes. Short term residential postapplication exposures may result when children and adults contact Aquashade treated swimming ponds. Short term risks were calculated for residential handler and postapplication exposures using the Margin of Exposure ( MOE) approach; the MOE is a ratio of the body burden to the toxicological endpoint of concern.

To better quantify residential Aquashade hazard, results from residential handler and postapplication risk assessments were aggregated. Calculations of aggregate residential exposures were performed using worst case MOEs from each assessment.

The estimated aggregate residential exposure resulted in an MOE of 1700 and, therefore, is not of concern.

7.3 Intermediate Term Aggregate Risk The use of Aquashade as an algaecide/ herbicide is not expected to result in dietary exposure to erioglaucine or tartrazine, either from drinking water or food; and residential handler exposures are expected to be short term only. Therefore, only intermediate term postapplication ( swimming) exposures are expected and an intermediate term aggregate risk assessment is not necessary.

7.4 Long Term Aggregate Risk Long term exposures are not expected based on current uses; therefore, a long term aggregate assessment was not conducted.

7.5 Cancer Risk A cancer aggregate risk assessment is not required, since there was no evidence of carcinogenicity in the toxicology studies submitted for Aquashade.

8.0 Cumulative Risk Characterization/ Assessment Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to erioglaucine and tartrazine and any other substances and Aquashade does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that Aquashade has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, Page 33 of 42 see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ pesticides/ cumulative/.

9.0 Occupational Exposure/ Risk Pathway Reference: Aquashade: Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document; DP Barcode: D302180; W. Britton; 09/ 13/ 05.

HED determined that the potential for occupational exposure to Aquashade exists in a variety of occupational environments. The anticipated use patterns and current labeling indicate several occupational exposure scenarios based on the types of equipment and techniques that can potentially be used for Aquashade applications. These include the handling of Aquashade during mixing, loading, and applying processes ( i. e. mixer/ loaders, and mixer/ loader/ applicators). As a result, a risk assessment has been completed for the occupational handler scenario. Short term ( 1 to 30 days) and intermediate term dermal and inhalation exposures ( 1 to 6 months) may occur; however, long term exposures ( greater than 6 months) are not expected.

9.1 Short/ Intermediate/ Long Term Handler Risk Aquashade Handler Exposure Scenarios: The anticipated use patterns and current labeling indicate several occupational exposure scenarios based on the types of equipment and techniques that can be potentially used for Aquashade applications. The quantitative exposure/ risk assessment developed for occupational handlers is based on the following scenarios.

Mixer/ Loaders: ( 1) Liquids for Pouring Applications Mixer/ Loader/ Applicators: ( 2) Liquids for Garden Hose End Sprayer ( ORETF) ( 3) Liquids for LCO Handgun ( ORETF)

Data and Assumptions for Handler Exposure Scenarios: A series of assumptions served as the basis for the occupational handler risk assessments. The assumptions used in the risk assessment calculations are detailed below:

C Occupational handler exposure estimates were based on surrogate data from the Pesticide Handlers Exposure Database ( PHED) and the Outdoor Residential Exposure Task Force ( ORETF).

C HED has developed standard unit exposure values for many occupational scenarios to ensure consistency in exposure assessments. These standard values were used to Page 34 of 42 calculate handler exposures for the associated scenarios. For those scenarios where standard values have not been developed, surrogate values based on a similar scenario were used.

C The adverse effects for the short and intermediate term dermal and inhalation endpoints are based on studies where the effects were observed in males and females, therefore, the body weight of an average adult ( i. e. 70 kg) was used to estimate exposure.

C For non cancer assessments, HED assumes the maximum application rates allowed by labels in its risk assessments.

C The average occupational workday is assumed to be 8 hours.

C The daily areas treated were defined for each handler scenario ( in appropriate units) by determining the amount that can be reasonably treated in a single day ( e. g., acres, square feet, cubic feet, or gallons per day). When possible, the assumptions for daily areas treated are taken from the Health Effects Division Science Advisory Committee on Exposure SOP # 9: Standard Values for Daily Acres Treated in Agriculture, which was completed on July 5, 2000. Since Aquashade is not used in agriculture the above source is not applicable. Therefore, the daily area treated with Aquashade was investigated and was assumed to be 25 acre feet per day [ Personal Communication per Email from Dr. Kurt Getsinger ( USACE) to J. Carter ( OPP, BEAD), 8/ 22/ 05]. This high end estimate is recognized to be conservative; however, the value is assumed to result in risks that represent reasonable worst case estimates of exposure to occupational handlers of Aquashade.

Risk Summary: A summary of the short and intermediate term risks ( dermal and inhalation) for each exposure scenario is presented below in Table 9.1. The calculated occupational handler exposures for all scenarios resulted in estimated MOEs greater than 100 and, therefore, are not of concern. Short and intermediate term MOEs do not differ because they share the same toxicological endpoint. Short and intermediate term dermal MOEs range from 410 ( Liquids for Pouring Applications) to 4,300 ( Liquids for Garden Hose End Sprayer), and short and intermediate term inhalation MOEs range from 120,000 ( Liquids for Garden Hose End Sprayer) to 1,600,000 ( Liquids for Pouring Applications). Page 35 of 42 Table 9.1 Short and Intermediate term Baseline Exposures and Risks for Occupational Handlers of Aquashade Exposure Scenario ( Scenario #) Crop1 Dermal Unit Exposure ( mg/ lb ai) 2 Inhalation Unit Exposure ( Ug/ lb ai) 3 Application Rate ( lb ai / acre foot) 4 Area Treated Daily ( acrefeet 5 Baseline Dermal MOE 6 Baseline Inhalation MOE7 Mixer/ Loader Liquids for Pouring Applications ( 1) Ornamental and Recreational Lakes and Ponds 3.1 1.2 1.1 25 410 1100000 Liquids for Pouring Applications ( 1) Fountains, Fish Farms, Fish Hatcheries, Golf Courses, Lakes, Manmade Ponds, Swimming Ponds 3.1 1.2 0.73 25 620 1600000 Mixer/ Loader/ Applicator Liquids for Garden Hose End Sprayer ( 2) Ornamental and Recreational Lakes and Ponds 0.45 11 1.1 25 2800 120000 Liquids for Garden Hose End Sprayer ( 2) Fountains, Fish Farms, Fish Hatcheries, Golf Courses, Lakes, Manmade Ponds, Swimming Ponds 0.45 11 0.73 25 4300 170000 Liquids for LCO Handgun ( ORETF) ( 3) Ornamental and Recreational Lakes and Ponds 0.50 1.9 1.1 25 2500 670000 Liquids for LCO Handgun ( ORETF) ( 3 Fountains, Fish Farms, Fish Hatcheries, Golf Courses, Lakes, Manmade Ponds, Swimming Ponds 0.50 1.9 0.73 25 3800 100000 Page 36 of 42 1 Crops and use patterns are from product labeling. 2Baseline dermal unit exposures represent long pants, long sleeved shirts, shoes, and socks. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 or are from data submitted by the Outdoor Residential Exposure Task Force dated May 2000. 3Baseline inhalation unit exposures represent no respirator. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 or are from data submitted by the Outdoor Residential Exposure Task Force dated May 2000. 4Application rates are based on maximum values found in various sources including LUIS and various labels. In most scenarios, a range of maximum application rates is used to represent the range of rates for different crops/ sites/ uses. Most application rates upon which the analysis is based are presented as lb ai/ acre foot. 5Amount treated is based on the area or gallons that can be reasonably applied in a single day for each exposure scenario of concern based on the application method and formulation/ packaging type. ( Standard EPA/ OPP/ HED values). 6 Dermal MOE = NOAEL ( 500 mg/ kg/ day) / Daily dermal dose ( mg/ kg/ day). MOEs are reported to 2 significant figures. 7Inhalation MOE = NOAEL ( 500 mg/ kg/ day) / Daily inhalation dose ( mg/ kg/ day). MOEs are reported to 2 significant figures.

HED believes that the risk estimates presented in this occupational assessment represent the best quality results that could be produced given the exposure, use, and toxicology data that are available. HED also believes that the risks represent reasonable worst case estimates of exposure, because maximum application rates are coupled with medium to high end estimates of area treated daily to define risk estimates that likely fall in the upper percentiles of the actual exposure distributions. Using these worst case assumptions, estimated occupational handler MOEs for all exposure scenarios are greater than 100 and are, therefore, not of concern.

9.2 Short/ Intermediate/ Long Term Postapplication Risk HED uses the term A postapplication @

to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide ( also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Postapplication exposure levels vary over time and depend on such things as the type of activity ( scouting, harvesting, etc.), the nature of the crop or target that was treated, the type of pesticide application ( foliar, soil incorporated, banded, etc.) and the chemical =

s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for postapplication exposure.

Aquashade is generally applied prior to or early in the growing season when growth is on the bottom of the water body. Applications can also be made later in the growing season when growth is closer to the surface after the killing and/ or removal of any existent growth. Since Aquashade is an algaecide/ herbicide, HED is not aware of any postapplication activities which may result in exposure. No harvesting is required, and while scouting may include identifying any algae or aquatic weed regrowth, these activities should not require contact with the treated water body. For these reasons, occupational postapplication exposure of workers to previously treated water bodies is expected to be negligible and was not assessed. Furthermore, any postapplication activities that could potentially occur would not be expected to exceed those assessed from residential exposures to Aquashade which are not of concern.

In accordance with the Worker Protection Standard ( WPS), a restricted entry interval ( REI) is established to mitigate contact with a pesticide in treated agricultural areas. However, since Aquashade has no agricultural applications an REI was not required. Page 37 of 42 10.0 Data Needs and Label Requirements 10.1 Toxicology   none required 10.2 Occupational and Residential Exposure  none References:

Review of Aquashade Incident Reports, Chemicals # 110303, # 110301, and # 110302, DP Barcode: D302184, Jerome Blondell, 08/ 22/ 05.

Aquashade: Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document; DP Barcode: 302180, Wade Britton, 09/ 13/ 05.

Aquashade: Revised Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document; DP Barcode: D321915; W. Britton; 09/ 27/ 05.

Toxicity References:

BIBRA. 1999. BIBRA International Ltd. Toxicity profile: Brilliant Blue FCF, 3rd ed. Carshalton, Surrey: BIBRA International Ltd., 11 pp.

Borzelleca, J. F. and J. B. Hallagan. 1988a. Chronic toxicity/ carcinogenicity studies of FD& C Yellow No. 5 ( tartrazine) in rats. Fd. Chem. Toxicol. 26( 3): 179 187.

Borzelleca, J. F. and J. B. Hallagan. 1988b. A chronic toxicity/ carcinogenicity study of FD& C Yellow No. 5 ( tartrazine) in mice. Fd. Chem. Toxicol. 26( 3): 189 194.

Borzelleca, J. F., K. Depukat, and J. B. Hallagan. 1990. Lifetime toxicity/ carcinogenicity studies of FD& C Blue No. 1 ( Brilliant Blue FCF) in rats and mice. Fd. Chem. Toxicol. 28: 221 234.

Brown, J. P., G. W. Roehm, and R. J. Brown. 1978. Mutagenicity testing of certified food colors and related azo, xanthene and triphenylmethane dyes with the Salmonella/ microsome system. Mutat. Res. 56: 249 271.

Collins, T. F. X., T. N. Black, L. H. Brown, et al. 1990. Study of the teratogenic potential of FD& C Yellow No. 5 when given by gavage to rats. Fd. Chem. Toxic. 28( 12): 821 827.

Collins, T. F. X., T. N. Black, M. W. O'Connell, Jr., et al. 1992. Study of the teratogenic potential of FD& C Yellow No. 5 when given in drinking water. Fd. Chem. Toxic. 30( 4): 263 268.

FDA. 1982. FD& C Blue No. 1.; Final Rule. 47 FR 42563; September 28, 1982 FDA. 1985. FD& C Yellow No. 5.; Final Rule; Removal of Stay. 40 FR 35774; September 4, 1985. Page 38 of 42 IACM. 2004. International Association of Color Manufacturers. Test Plan and Robust Summaries for C. I. Acid Yellow 23 ( FD& C Yellow 5). http:// www. epa. gov/ chemrtk/ ciacdylo/ c15133tp. pdf JECFA. 1964. Joint FAO/ WHO Expert Committee on Food Additives. Tartrazine. WHO Food Additive Series. 66.25/ NMRS 38B JECFA 8/ 88. http:// www. inchem. org/ documents/ jecfa/ jeceval/ jec_ 1936. htm JECFA. 1969. Joint FAO/ WHO Expert Committee on Food Additives. Toxicological Evaluation of Some Food Colours, Emulsifiers, Stabilizers, Anti caking Agents and Certain Other Substances. FAO Nutrition Meetings Report Series No. 46A . World Health Organization, Geneva. http:// www. inchem. org/ documents/ jecfa/ jecmono/ v46aje08. htm Leifer, Kerry. 2004. United States Environmental Protection Agency. Reassessment of Exemptions from the requirement of a tolerance for the FDA certified color additives FD& C Blue No. 1, FD& C Red No. 40, and FD& C Yellow No. 5.

Sasaki, Y. F., S. Kawaguchi, A. Kamaya, et al. 2002. The comet assay with 8 mouse organs: results with 39 currently used food additives. Mutat. Res. 519: 103 119.

SRC. 2004. Syracuse Research Corporation. Interactive Physical Properties ( PHYSPROP) Database Demo. Search terms: FD& C Blue. No. 1, FD& C Red No. 40, FD& C Yellow No. 5. ( November 28, 2004) http:// www. syrres. com/ esc/ physdemo. htm Page 39 of 42 Appendices 1.0 TOXICOLOGY DATA REQUIREMENTS The requirements ( 40 CFR 158.340) for food use for erioglaucine and tartrazine are in Table 1. Use of the new guideline numbers does not imply that the new ( 1998) guideline protocols were used.

Technical Test Required Satisfied 870.1100 Acute Oral Toxicity.................................................... 870.1200 Acute Dermal Toxicity ............................................... 870.1300 Acute Inhalation Toxicity ........................................... 870.2400 Primary Eye Irritation ................................................. 870.2500 Primary Dermal Irritation............................................ 870.2600 Dermal Sensitization................................................... yes yes no yes yes yes yes yes  yes yes yes 870.3100 Oral Subchronic ( rodent) ............................................ 870.3150 Oral Subchronic ( nonrodent)....................................... 870.3200 21 Day Dermal........................................................... 870.3250 90 Day Dermal........................................................... 870.3465 90 Day Inhalation....................................................... yes yes yes no no yes* yes* yes

870.3700a Developmental Toxicity ( rodent) ................................ 870.3700b Developmental Toxicity ( nonrodent)........................... 870.3800 Reproduction.............................................................. yes yes yes yes yes yes 870.4100a Chronic Toxicity ( rodent) ........................................... 870.4100b Chronic Toxicity ( nonrodent)...................................... 870.4200a Oncogenicity ( rat)....................................................... 870.4200b Oncogenicity ( mouse)................................................. 870.4300 Chronic/ Oncogenicity................................................. yes yes yes yes yes yes yes yes** yes** yes 870.5100 Mutagenicity  Gene Mutation  bacterial.................... 870.5300 Mutagenicity  Gene Mutation  mammalian............... 870.5375 Mutagenicity  Structural Chromosomal Aberrations .. 870.5385 Mutagenicity  Other Genotoxic Effects...................... yes no no no yes

870.6100a Acute Delayed Neurotox. ( hen)................................... 870.6100b 90 Day Neurotoxicity ( hen) ........................................ 870.6200a Acute Neurotox. Screening Battery ( rat)...................... 870.6200b 90 Day Neuro. Screening Battery ( rat) ........................ 870.6300 Develop. Neuro .......................................................... no no no no no

870.7485 General Metabolism.................................................... 870.7600 Dermal Penetration..................................................... yes no yes

Special Studies for Ocular Effects Acute Oral ( rat) .......................................................... Subchronic Oral ( rat) .................................................. Six month Oral ( dog).................................................. no no no

* Satisfied by the chronic ( rodent) toxicity study guideline 870.4100a ** Satisfied by the chronic ( nonrodent) toxicity study guideline 870.4100b ** Satisfied by the chronic/ oncogenicity study guideline 870.4300 Page 40 of 42 2.0 NON CRITICAL TOXICOLOGY STUDIES Chronic toxicity/ carcinogenicity studies of FD & C Yellow No. 5 ( tartrazine) in rats ( 870.4300b)

FD & C Yellow No. 5 was fed to Charles River CD rats as a dietary mixture in two long term toxicity/ carcinogenicity studies. The studies were conducted with an in utero phase in which the compound was administered to the F0 generation rats ( 60/ sex/ group) at levels of 0.0, 0.1, 1.0 or 2.0% (' original study') equal to 0, 53, 1056, 2641 mg/ kg/ day and 0, 67, 670, 1339, 3348 mg/ kg/ day, in males and females, respectively. A second study (` high dose study') was conducted with 0.0 or 5.0% tartrazine equal to 2641 or 3348 in males and females, respectively. The concurrent control groups received the basal diet. After random selection of the F1 animals, the long term phase was initiated using the same dietary levels with 70 rats of each sex/ group, including the three control groups. The maximum exposure to the coloring was 113 and 114 wk for males and females, respectively, in the ' original' study and 122 and 125 wk for males and females, respectively, in the ' high dose' study. No compound related effects were noted. The noadverse effect level found in this study was 5.0% in the diet providing an average intake of 2641 and 3348 mg/ kg/ day for male and female rats, respectively ( Borzelleca et al, 1988b).

Chronic toxicity/ carcinogenicity studies of FD & C Blue No. 1 ( erioglaucine) in mice ( 870.4300d) Charles River CD 1 mice ( 60/ sex/ group) were fed FD & C Blue No. 1 as a dietary admixture at levels of 0.0%, 0.5%, 1.5% or 5.0% in a lifetime toxicity/ carcinogenicity study. The maximum exposure time was 104 wk for both males and females. No consistent, significant compoundrelated adverse effects were noted. The no observed adverse effect level established in this study is a dietary concentration of 5.0% ( 7354 mg/ kg/ day and 8966 mg/ kg/ day for male and female mice, respectively ( Borzelleca et al, 1990)

Chronic toxicity/ carcinogenicity study of FD & C Yellow No. 5 ( tartrazine) in mice ( 870.4300e)

Charles River CD 1 mice were fed FD & C Yellow No. 5 in the diet at levels of 0.0, 0.5, 1.5 or 5.0% in a long term toxicity/ carcinogenicity study. Each group consisted of 60 males and 60 females. Maximum exposure was 104 wk for both males and females. No consistent, significant compound related adverse effects were noted. The no observed adverse effect level established in this study was 5.0% ( 8103 mg/ kg/ day and 9735 mg/ kg/ day for male and female mice, respectively ( Borzelleca et al, 1988b).

http:// www. ncbi. nlm. nih. gov/ entrez/ query. fcgi? db= pubmed& cmd= Search& term=% 22Borzelleca + JF% 22% 5BAuthor% 5D 21 Day Dermal ( rabbits) In a subchronic dermal toxic: ( MRID 43410101), 54 female albino rabbits were divided into 6 treatment groups of 9 animals each. Three animals with intact skin and 3 animals with abraded skin per group were given 20 treatments over 2 days. An additional 3 animals with intact skin per group received 65 doses over 28 days. An additional 3 animals with intact skin per group received 65 doses over a 91 day period. Treatments were composed of the following: 1) water, 2) Page 41 of 42 USP White Ointment, 3) 0.1% a. i. ( Acid Blue 9) in water, 4) 1.0% a. i. in water, 5) 0.1% a. i. in USP ointment and 6) 1.0% a. i. in USP White Ointment. Treatments were applied at a rate of 0.5 g or 0.5 ml per kg. of body weight ( representing approximately 0.5 and 5.0 mg/ kg/ day). There were no treatment related effects on survival, clinical signs, body weight, hematology, urinalysis, organ weight or pathology. The NOAEL is > 5.0 mg/ kg/ day females ( HDT). The LOAEL was not determined.

The study is acceptable/ non guideline. It satisfies the requirement for a guideline series 82 2 subchronic dermal toxicity study in rabbits.

Bacterial reverse mutation test ( Ames Test)

Thirty seven azo, xanthene and triphenylmethane dyes including FD& C colors currently approved for use in the U. S. A. and a number of de listed food colors were tested in the Salmonella/ microsome system. In addition to direct plate tests with five tester strains ( TA1535, TA100, TA1537, TA1538, TA98), the azo dyes were also assayed after chemical reduction to their component amines. Also, a selected group of azo dyes was subjected to liquid tests ( both aerobic with microsomes and anaerobic) and to plate tests involving initial 16 h anaerobic incubations to facilitate microbial reduction of the azo bond. None of the presently listed FD and C colors was mutagenic in any of the test modifications. Among formerly listed colors only Butter Yellow ( p dimethylaminoazobenzene), a recognized animal carcinogen, was mutagenic in the aerobic liquid test. Several other azo dyes were either directly mutagenic, viz. Acid Alizarin Yellow R and Alizarin Yellow GG; required microsomal activation, viz. Acid Alizarin Red B and Methyl Red; or required chemical reduction and microsomal activation, viz. Acid Alizarin Violet N and Sudan IV. Of the non azo dyes tested only two xanthene dyes appeared to be mutagenic, viz. 9( 2 sulfophenyl) 6 hydroxy 3 isoxanthenone and its 2,4,5,7 tetrabromo derivative ( Brown et al, 1978).

Metabolism Erioglaucine was administered orally to rats as a 2% aqueous solution at a level of 200 mg/ rat. Almost the entire amount was excreted unchanged in the feces within 40 h after administration. In a later investigation, the presence of the color in the bile was observed in rats, rabbits and dogs after oral administration. In the case of the dog, the amount did not exceed 5% of the dose administered ( Hess & Fitzhugh, 1953; 1954; 1955). Administration of an aqueous solution of the color by stomach tube resulted in 89 % excretion in the feces; none was found in the urine. After subcutaneous injection of 80 100 mg some 79% was excreted; 77% appeared in the feces and 2.5% in the urine ( Imperial Chemical Industries, 1958). Page 42 of 42 3.0 TOLERANCE REASSESSMENT Active ingredient Current Tolerance Tolerance Reassessment Comment Tolerance Exemption Listed Under 40 CFR § 180.1074:

F. D.& C. Blue No. 1 Exempted from the requirement of a tolerance when used as an aquatic plant control agent. Exempted from the requirement of a tolerance when used as an aquatic plant control agent. In 1982, based on Aquashade's low toxicity profile, EPA waived residue chemistry data requirements and established an exemption from the requirement of a tolerance for erioglaucine ( F. D& C. Blue No. 1) when used as an aquatic plant control agent. Tartrazine, when used as a dye, had previously been exempted from the requirement of a tolerance as an inert ( or occasionally as an active) ingredient in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest under 40 CFR 180.1001( c) ( currently 40 CFR 180.910). HED has determined that the existing exemption for tartrazine as an inert ingredient is not sufficient to satisfy reregistration requirements for the active ingredient when used as an aquatic plant control agent.

Therefore, HED recommends that the exemption for erioglaucine at 40 CFR 180.1074 be revised to include both erioglaucine ( F. D.& C. Blue No. 1) and tartrazine ( F. D.& C. Yellow No. 5).