UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: June 26, 2006 MEMORANDUM SUBJECT: Boric Acid/ Sodium Borate Salts: HED Chapter of the Tolerance Reassessment Eligibility Decision Document ( TRED). PC Codes: 011001 ( boric acid), 011102 ( sodium tetraborate decahydrate), 011110 ( sodium tetraborate pentahydrate), 011112 ( sodium tetraborate anhydrous), 011103 ( disodium octaborate tetrahydrate), 011107 ( disodium octaborate anhydrous), 011104 ( sodium metaborate). Case # 0024, DP Barcode D320894.

Regulatory Action: Tolerance Reassessment Progress and Interim Risk Management Decision FROM: Linnea J. Hansen, Biologist Toxicology Branch Health Effects Division ( 7509C)

AND Jeff Evans, Senior Biologist Chemistry and Exposure Branch Health Effects Division ( 7509C)

THROUGH: Louis Scarano, Branch Chief Toxicology Branch Health Effects Division ( 7509C)

TO: Laura Parsons, PM/ Nathan Mottl, CRM Reregistration Branch I Special Review and Reregistration Division ( 7505C) ii Table of Contents 1.0 Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 1 of 82 2.0 Ingredient Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 5 of 82 2.1 Summary of Registered Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 7 of 82 2.2 Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 8 of 82 2.3 Physical and Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . Page 9 of 82 3.0 Metabolism Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 11 of 82 3.1 Comparative Metabolic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 11 of 82 3.2 Nature of the Residue in Foods and in Drinking Water . . . . . . . . . Page 11 of 82 3.3 Environmental Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 12 of 82 4.0 Hazard Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 13 of 82 4.1 Hazard and Dose Response Characterization . . . . . . . . . . . . . . . . Page 13 of 82 4.1.1 Database Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 13 of 82 <IP_ADDRESS> Studies Available and Considered . . . . . . . . . . . . . Page 13 of 82 <IP_ADDRESS>. Mode of Action, Metabolism, Toxicokinetic Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 13 of 82 <IP_ADDRESS> Sufficiency of Studies/ Data . . . . . . . . . . . . . . . . . . Page 14 of 82 <IP_ADDRESS> Toxicological Effects Data Summary and Toxicity Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 14 of 82 4.1.2 Dose response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 21 of 82 4.2 FQPA Hazard Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 22 of 82 4.2.1 Adequacy of the Toxicity Data Base . . . . . . . . . . . . . . . . . Page 22 of 82 4.2.2 Evidence of Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . Page 22 of 82 4.2.3 Developmental Toxicity Studies . . . . . . . . . . . . . . . . . . . . Page 23 of 82 4.2.4 Reproductive Toxicity Study . . . . . . . . . . . . . . . . . . . . . . . Page 26 of 82 4.2.5 Additional Information from Literature Sources . . . . . . . . Page 30 of 82 4.2.6 Pre and/ or Postnatal Toxicity . . . . . . . . . . . . . . . . . . . . . . . Page 30 of 82 <IP_ADDRESS> Determination of Susceptibility . . . . . . . . . Page 30 of 82 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility . . . . . . Page 31 of 82 4.3 Recommendation for a Developmental Neurotoxicity Study . . . . . Page 31 of 82 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 31 of 82 4.3.2 Evidence that supports not requiring a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 31 of 82 4.3.3 Rationale for the UF DB ( when a DNT is recommended) . . . Page 31 of 82 4.4 Hazard Identification and Toxicity Endpoint Selection . . . . . . . . . Page 31 of 82 4.4.1 Acute and Chronic Reference Doses ( aRfD and cRfD) . . . Page 32 of 82 4.4.2 Incidental Oral, Short and Intermediate Term Exposures ( All Populations) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 32 of 82 4.4.3 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 35 of 82 4.4.4 Dermal Exposure ( Short, Intermediate and Long Term) . . Page 35 of 82 iii 4.4.5 Inhalation Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 35 of 82 4.4.6 Margins of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 36 of 82 4.4.7 Recommendation for Aggregate Exposure Risk Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 37 of 82 4.4.8 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . Page 37 of 82 <IP_ADDRESS> Two Year Dietary Study in the Rat . . . . . . . . . . . . Page 37 of 82 <IP_ADDRESS> Two year dietary study in the mouse . . . . . . . . . . . Page 39 of 82 4.5 Special FQPA Safety Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 41 of 82 4.6 Endocrine disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 41 of 82 5.0 Public Health Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 42 of 82 5.1 Incident Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 42 of 82 5.2 Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 44 of 82 6.0 Exposure Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 45 of 82 6.1 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . Page 45 of 82 6.2 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 45 of 82 6.3.2 Other ( Spray Drift, etc.) . . . . . . . . . . . . . . . . . . . . . . . . . . Page 45 of 82 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway . . . . . . . Page 46 of 82 6.3.1 Home Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 46 of 82 <IP_ADDRESS> Residential Handler Exposure Scenarios . . . Page 46 of 82 <IP_ADDRESS> Residential Postapplication Exposure Scenarios  Swimming Pool Incidental Oral . . . . . . . . . . . . . . . . . . Page 50 of 82 <IP_ADDRESS> Residential Postapplication Exposure Scenarios  Children Handto Mouth Transfer . . . . . . . . . . . . . . . . . . . . . . . . . Page 51 of 82 <IP_ADDRESS> Residential Handler Exposure Inerts . . . . . . . . . . . Page 53 of 82 <IP_ADDRESS> Residential Risk Characterization Uncertainties Associated With Residential Postapplication Exposures . . . . . . . . . . Page 54 of 82 6.3.2 Other ( Spray Drift, etc.) . . . . . . . . . . . . . . . . . . . . . . . . . . Page 55 of 82 7.0 Aggregate Risk Assessments and Risk Characterization . . . . . . . . . . . Page 55 of 82 8.0 Cumulative Risk Characterization/ Assessment . . . . . . . . . . . . . . . . . . Page 57 of 82 9.0 Occupational Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . Page 57 of 82 10.0 Data Needs and Label Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . Page 57 of 82 10.1 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 57 of 82 10.2 Residue Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 58 of 82 10.3 Occupational and Residential Exposure . . . . . . . . . . . . . . . . . . . . Page 58 of 82 References: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 58 of 82 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 66 of 82 Page 1 of 84 1.0 Executive Summary Boric acid and its sodium salts ( sodium tetraborate decahydrate, sodium tetraborate pentahydrate, sodium tetraborate anhydrous, disodium octaborate tetrahydrate, disodium octaborate anhydrous and sodium metaborate) are inorganic compounds used as insecticides, acaricides, herbicides, algaecides, fungicides and wood preservatives. There are numerous types of products for these compounds: product formulations include wettable or water soluble powder, dust, liquid concentrate, paste, pellet, bait, granule, soluble concentrate and solid. The percentage of active ingredient ranges from less than 1% ( e. g., agricultural food/ feed products) to 100% ( e. g., crack/ crevice treatments). Multiple types of use sites have registered uses, including agricultural application to numerous food/ feed crops, indoor residential areas including pet quarters and wood preservation, aquatic nonfood residential, indoor food handling/ storage sites and non food sites, outdoor residential, forestry, terrestrial non food crops, medical/ veterinary areas and aquatic non food industrial ( sewer systems) sites. The use sites, formulation types, target organisms and application methods/ rates for each of the above active ingredients of this Reregistration Case are discussed in greater detail in the 1993 Registration Eligibility Decision ( RED) Document for boric acid and its sodium salts ( US EPA, 1993).

In August, 1993, EPA established an exemption from the requirement for a tolerance for residues of boric acid and its sodium salts when used as active ingredients in products applied to all raw commodities. In September, 1993, a RED document was issued for boric acid and its sodium salts and a tolerance exemption was granted for its use as an inert ingredient as a sequestrant or buffering agent in pesticide formulations. The purpose of this Tolerance Reassessment Eligibility Decision ( TRED) document is to reassess the exemption from the requirement of a tolerance for residues of this chemical when used as an active ingredient and an inert ingredient in pesticide formulations. Since the original boric acid RED was issued in September 1993, prior to the development of the Food Quality Protection Act ( FQPA) in August, 1996, tolerances also need to be reassessed to meet the FQPA standard. The Agency has considered any new data generated after the tolerance exemption was issued, new Agency guidance or other federal regulations, as well as previously available information in this assessment.

The toxicology database for boric acid is considered complete at this time. Both boric acid and sodium tetraborate decahydrate show low acute oral, dermal and inhalation toxicity ( Toxicity Category III for oral and dermal routes and Category II for the inhalation route), cause minimal or no primary dermal irritation ( Category III or IV), and boric acid does not cause eye irritation. Sodium tetraborate decahydrate is corrosive to the eye ( Toxicity Category I) and sodium metaborate is moderately dermally irritating. The major target organ is the testes, with testicular atrophy and reduction in sperm production observed in multiple species. This effect results in reduced fertility, as demonstrated in rat and mouse reproductive toxicity studies. The female reproductive tract does not appear to be as sensitive as males, but reduction in the number of ovulating ovaries and fertility in crossover mating protocols using treated females and untreated males indicate that both sexes are susceptible. Other treatment related findings seen in the available animal studies include body weight decreases, slight hematological effects and clinical signs of toxicity at higher dose levels. Page 2 of 84 The fetus is also affected by exposure to boric acid or sodium borate salts. Developmental toxicity studies in the rat show increased fetal susceptibility, with effects on skeletal development and pup weight being the most sensitive and observed at doses that did not cause maternal toxicity. Skeletal abnormalities and reduced fetal weight were also observed in mice at maternally toxic doses. At higher dose levels in the rat and rabbit, visceral abnormalities of the heart and/ or great vessels were observed and in the rat, enlarged lateral ventricles of the brain were observed, with the fetal effects in rabbits observed at maternally toxic doses. Reduced survival was also reported in developmental and reproductive toxicity studies at higher dose levels, with all species tested ( rat, rabbit, mouse) affected.

Boric acid/ sodium borate salts are classified as " not likely to be carcinogenic to humans" under the current ( 2005) Agency Guidelines for Carcinogen Risk Assessment. Long term dietary studies in the rat and the mouse did not show evidence of treatment related increases in tumors and the available genotoxicity data do not indicate mutagenic potential.

Although boric acid/ sodium borate salts are registered for use on numerous food/ feed crops, no dietary or drinking water risk assessments were performed. Boron is a naturally occurring component of both food and water and is believed to be an essential dietary trace nutrient, though a minimum daily requirement has not been established. The contribution of boron residues from agricultural food/ feed applications is expected to be less than the total dietary background intake of boron, based on limited available residue data and the relatively low application rate for agricultural uses. Similarly, although these products are expected to be mobile in the soil and readily dissolve in water ( present as undissociated acid), the low application rate of agricultural products is not expected to add significantly to the background levels naturally occurring in drinking water.

Incident report data indicate that although exposures to boric acid related products in general result in fewer and less severe outcomes relative to other pesticides, significant toxicity may occur from either oral or inhalation exposure with misuse, particularly over application. Common symptoms reported include vomiting, eye irritation, nausea, skin rash, oral irritation and respiratory effects.

Exposure assessments for this tolerance reassessment were performed for ( 1) residential handler inhalation exposure from application of pesticide products and non pesticidal consumer products containing boric acid or borax, ( 2) postapplication incidental oral ingestion in young children from hand to mouth transfer from carpet and crack/ crevice treatment products; ( 3) postapplication incidental oral ingestion in young children from pressure treated wood and in situ deck spray treatments; and ( 4) postapplication incidental oral exposure in children and adults from swallowing treated swimming pool water.

The following endpoints pertinent to the preliminary risk assessment for this tolerance reassessment were selected: Page 3 of 84 ° An incidental oral endpoint for all populations and exposure durations ( one day through six months) was selected from dog subchronic and chronic dietary toxicity studies in the rat, based on testicular atrophy and slight hematological changes;

° An inhalation endpoint for all populations and exposure durations ( one day through long term or lifetime) for residential handler exposure ( adults) was selected from subchronic and chronic dietary toxicity studies in the dog, based on testicular atrophy and slight decreases in hematocrit/ hemoglobin;

° Dermal exposure scenarios for residential handlers were not included in this assessment because boric acid and it sodium salts are not well absorbed across intact skin and are not anticipated to be a significant source of internal dosing.

An uncertainty factor ( UF) of 100 ( using the default values of 10 for interspecies extrapolation and 10 for intraspecies variation) was selected; a Margin of Exposure ( MOE) of 100 is required for all residential exposure risk assessment scenarios. The Food Quality Protection Act ( FQPA) safety factor was reduced to 1X: although increased sensitivity of fetuses was observed, based on decreased fetal weight and skeletal effects in the rat developmental toxicity studies, the database of four developmental toxicity studies in three species, plus two reproductive toxicity studies in two species, is considered sufficient to characterize hazard and no residual uncertainties remain. The endpoint selected for risk assessment ( testicular atrophy) is comparable to the most sensitive developmental endpoint. In addition, the UF of 100 is considered a conservative value because boric acid/ sodium salts are not metabolized, thereby reducing the intra and interspecies variability from individual variations in metabolic enzyme activities, and because pharmacokinetics ( absorption, tissue distribution, lack of significant soft tissue retention) in humans and other species are expected to be somewhat similar. The endpoint was used for exposure scenarios for children, in addition to adults, because there is at present insufficient information to rule out the possibility that boron may cause toxicity to the immature reproductive system of either males or females. It was used for all exposure durations due to uncertainty of the time to onset of this effect. The endpoint did not include the background dietary boron consumption; actual total boron consumption per day would therefore be higher but this information was not provided in the study. Individuals with impaired renal clearance are anticipated to be a more sensitive subpopulation.

The results of the exposure assessments are as follows:

° The residential handler inhalation risks due to boric acid and its sodium salts as active ingredients are not a risk concern and do not exceed the level of concern ( LOC) of 100 ( handler inhalation MOEs range from 800 to 5,600,000). Residential inhalation exposure to non pesticidal consumer products also do not exceed the LOC of 100 ( MOEs range from 16,000 to 13,000,000).

° MOEs for postapplication exposure scenarios for hand to mouth transfer in children from indoor surfaces ( carpet treated with dust or spray) do not exceed the LOC of 100 ( MOEs $ 170).

° MOEs for postapplication exposure scenarios for hand to mouth transfer in Page 4 of 84 children from pressure treated wood or in situ deck spray treatment do not exceed the LOC of 100 ( MOEs $ 180).

° For incidental oral exposure from ingestion of swimming pool water, the MOEs for adults and children older than age 10 exposed to sodium tetraborate pentahydrate at water concentrations of 240 mg/ L, and for children ( all ages) and adults exposed to boric acid, did not exceed the LOC of 100 ( MOE range 110 to 5,600) and are not a risk concern. However, the MOEs for children age 7 to 10 from incidental oral exposure from swimming pool water treated with sodium tetraborate pentahydrate are of concern, with MOEs of 65 to 74 at pool water concentrations of 480 and 240 mg/ L, respectively.

° The use of products containing boric acid and its sodium salts as inert ingredients was also examined, however, many of the scenarios were already examined in terms of products containing these chemicals as active ingredients. For those active ingredient scenarios, the MOEs were greater than the target MOE of 100 and it was assumed that the inert use products, containing a smaller percentage of the chemicals, would also pose no risk. Certain postapplication scenarios with active ingredient uses resulted in MOEs less than 100 and these were reexamined for the inert use products. All of the resulting MOEs were greater than the target MOE of 100 and are not a risk concern.

An aggregate exposure risk assessment was not conducted for boric acid/ sodium borate salts to characterize the risk from dietary intake ( food and drinking water) plus residential uses, including exposure from pesticidal, inert and consumer uses. No tolerances or residue data are available to perform a dietary exposure assessment. The limited available residue data ( citrus, cottonseed), upon which tolerance exemptions were based, suggests that pesticide residues from boric acid/ sodium borate salt agricultural applications do not significantly contribute to the total dietary intake of boron. For residential uses of pesticidal products, the risks for incidental oral exposure to children from swallowing treated swimming pool water at two of three label directed concentrations exceed the level of concern and fill the risk cup. Therefore, although the MOEs for residential handlers/ applicators were not of concern ($ 800 for inhalation exposure; dermal not conducted because dermal absorption is negligible), an aggregate exposure is not conducted when risks ( in this case, from postapplication exposures to children) exceed the level of concern. However, it is noted that the lowest swimming pool water concentration treatment does not show MOEs that exceed the level of concern. The Agency also considered exposures from nonpesticidal sources of boron ( consumer products such as laundry detergent or general purpose cleaners, and pesticidal products containing boric acid or sodium borate salts as inerts). Based on the large MOEs for handler/ applicator inhalation exposure to the consumer products ( MOEs $ 16,000) and postapplication incidental oral exposure to children or adults from swallowing pool water treated with pesticidal products containing boric acid as an inert ( MOEs $ 5,600), these exposure scenarios would not be a significant source of boron internal dosing and would not contribute significantly to total daily boron exposure when compared to the diet. Page 5 of 84 A cumulative risk assessment has not been performed for boric acid and sodium borate salts because at this time there are no known compounds with which they share a common mechanism of toxicity.

Additional data are required for boric acid/ sodium borate salts. In order to confirm the values used for the postapplication exposure assessments for wood treatment uses, crack and crevice application and carpet dust, data in support of these assessments is required. Page 6 of 84 2.0 Ingredient Profile Boric acid and sodium salts of boric acid are inorganic pesticides acting as acaricides, algaecides, fungicides, herbicides and insecticides and are used on a variety of agricultural ( including food/ feed), non agricultural, residential, commercial, medical, industrial and food/ feed handling sites. These compounds act as acaricides and insecticides either as a stomach poison or by abrasion of exoskeletons. When used as an herbicide or algaecide, they act by causing dessication or interruption of photosynthesis. Products classified as fungicides are wood preservatives.

Many different formulations are registered for products containing boric acid or its sodium salts, including liquids, soluble and emulsifiable concentrates, granulars, powders, dusts, pellets, tablets, solids, paste, baits and crystalline rods. The percentage of active ingredients in these products may range from less than 1% to 99 100%. Boric acid and sodium salts may also be used as inerts in the formulations of other pesticide products. Page 7 of 84 Table 2.1 Tolerance Exemptions Being Reassessed in this Document Tolerance Exemption Expression CAS Nos. 40 CFR PC Code Use Pattern List Classification Boric Acid and its Sodium Salts Active ingredient Boric Acid: 10043 35 3 11113 50 1 41685 84 1 180.1121 011001 Acaricide, algaecide, fungicide, herbicide, insecticide NA Sodium tetraborate decahydrate: 1303 96 4 12447 40 4 011102 Fungicide, insecticide, herbicide Sodium tetraborate pentahydrate: 11130 12 04 12178 04 3 011110 Algaecide, herbicide, insecticide Sodium tetraborate anhydrous: 1330 43 4 12007 42 0 011112 Acaricide, herbicide, insecticide Disodium octaborate tetrahydrate: 12008 41 2 12280 03 4 011103 Fungicide, insecticide Disodium octaborate anhydrous: 12008 41 2 12280 03 4 011107 Fungicide Sodium metaborate: 15293 77 3 7775 19 1 011104 Herbicide Inert Ingredient Boric Acid: 10043 35 3 11113 50 1 41685 84 1 180.920a Used in pesticide formulations applied to growing crops; formulation applied to swimming pools; and general purpose cleaners NA Sodium tetraborate: 1330 43 4 12007 42 0 Sodium metaborate: 15293 77 3 7775 19 1 a Residues listed in section ( d) of 40 CFR 180.920 are exempt from a tolerance when used in accordance with good agricultural practice as inert ingredients in pesticide formulations applied to growing crops only. Page 8 of 84 2.1 Summary of Registered Uses Agricultural food/ feed crops for which sodium tetraborate decahydrate is registered are listed below:

Alfalfa Celery Lettuce, leaf Potato, white Almond Cherry Melons Pumpkin Apple Cotton Nectarine Raspberry Apricot Cucumber Onion Spinach Beans ( dried) Eggplant Peach Squash ( all) Beans ( succulent) Garbanzos Peanuts ( unspec.) Strawberry Blackberry Garlic Peas, southern Sugar beet Blueberry Grapes Peas, succulent Tomato Broccoli Grass forage/ hay Pecan Walnut Cabbage Hops Pepper Bermudagrass Carrots Lentils Pistachio Cauliflower Lettuce, head Plum Application rates for these crops range from 0.01637 to 0.06574 lb/ A. All applications are foliar via spray ( sprayer) or low volume spray ( concentrate)( low volume ground sprayer). Application by aircraft or irrigation is not permitted. The minimum retreatment interval is 7 days and the reentry interval is 12 hours for all crop applications. Additional maximal seasonal rates and applications are not specified on the label. Other use limitations may apply.

Other non agricultural food/ feed uses include baits, traps, dusts, liquids, powders, sprays, rods, etc. for control of insects such as ants or roaches by application in eating establishments, food processing plant premises ( non food contact), premises where food is sold, marketed, stored or distributed, households and poultry houses ( egg/ meat).

Nonfood/ nonfeed residential uses pertinent to this tolerance reassessment ( incidental oral exposure to children and adults; inhalation exposure to adults from household residential application) include products for residential carpet treatment, crack/ crevice treatment and swimming pool algae control. Additional details on these applications may be found in the Residential ( Non Occupational) Exposure/ Risk Pathway section ( Section 6.3) of this document.

There are also numerous other commercial, industrial, medical/ veterinary and agricultural non food/ feed use sites for boric acid and its sodium salts. These include animal housing, turf, wood ( preservative), forests, sewage systems, commercial storage/ transportation, medical/ veterinary institutions, uncultivated agricultural/ nonagricultural areas, refuse/ solid waste sites and ornamental lawns and turf, paved areas and aquatic structures.

Boric acid, sodium metaborate, and sodium tetraborate are identified as inert ingredients as a sequestrant, buffering agent/ corrosion inhibitor, and sequestrant, respectively. CFR 180.920 allows these inert ingredients in pesticide formulations applied to growing crops only to be exempt from the requirement for a tolerance. Page 9 of 84 2.2 Nomenclature Nomenclature for boric acid and its sodium salts are presented below in Tables 2.2a through 2.2g ( see Table 2.3 for boric acid structure).

TABLE 2.2a. Boric Acid Nomenclature Empirical Formula H3BO3 Common name boric acid Other names orthoboric acid, boracid acid PC Number 011001 CAS Registry Number 10043 35 3 TABLE 2.2b. Sodium Tetraborate Decahydrate Nomenclature Empirical Formula Na2B4O7 . 10H20 Common name sodium tetraborate decahydrate Other names borax decahydrate, borax 10 mol, disodium tetraborate decahydrate, sodium borate decahydrate, sodium pyroborate 10H20 PC Number 011102 CAS Registry Number 1303 96 4 TABLE 2.2c. Sodium Tetraborate Pentahydrate Nomenclature Empirical Formula Na2B4O7 . 5H20 Common name sodium tetraborate pentahydrate Other names disodium tetraborate pentahydrate, borax pentahydrate, sodium borate pentahydrate, sodium biborate 5H20, sodium pyroborate 5H20 PC Number 011110 CAS Registry Number 11130 12 4 or 12179 04 3 TABLE 2.2d. Sodium Tetraborate Anhydrous Nomenclature Empirical Formula Na2B4O7 Common name sodium tetraborate, anhydrous Other names borax ( anhydrous), sodium borate ( anhydrous), sodium biborate ( anhydrous), sodium pyroborate ( anhydrous)

PC Number 011112 CAS Registry Number 1330 43 4 Page 10 of 84 TABLE 2.2e. Disodium Octaborate Tetrahydrate Nomenclature Empirical Formula Na2B8O13 . 4H20 Common name disodium octaborate ( anhydrous)

Other names

PC Number 011107 CAS Registry Number 12008 41 2 TABLE 2.2f. Disodium Octaborate Anhydrous Nomenclature Empirical Formula Na2B8O13 . 4H20 Common name disodium octaborate ( anhydrous)

Other names

PC Number 011103 CAS Registry Number 12008 41 2 TABLE 2.2g. Sodium Metaborate Nomenclature Empirical Formula NaBO2 Common name Sodium metaborate Other names

PC Number 011104 CAS Registry Number 15293 77 3 2.3 Physical and Chemical Properties The physical and chemical properties of boric acid and its sodium salts are provided in Table 2.3. There are no known impurities of concern in any of these boron compounds. With the exception of sodium metaborate, which will absorb carbon dioxide to form sodium carbonate and borax, these compounds are stable under storage at room temperature. Page 11 of 84 Table 2.3 Physical/ Chemical Properties of Boric acid and its Sodium Salts Chemical Molecular formula Molecular weight Physical state Meltin g point Solubility in water pH Density/ Specific Gravity Vapor Pressure Estimated Octanol/ Water Coefficient Boric Acid H3BO3 61.9 Solid crystalline powder 171oC 5.6 g/ 100mL 5.1 ( 1% solution at 20oC) 1.51 at 20oC < 10 4 torr at 200C 0.175 Sodium tetraborate decahydrate Na2B4O7 .

10H20 381.87 crystalline powder 75oC 4.70 g/ 100 mL at 20oC 9.2 ( 1% solution at 20oC) 1.73 < 10 6 torr 0.175 Sodium tetraborate pentahydrate Na2B4O7 .

5H20 291.35 mild white alkaline salt < 200oC 3.59% at 20oC 9.2 ( 1% solution at 20oC) 1.82 < 10 6 torr No data Sodium tetraborate Na2B4O7 201.27 Solid crystalline or amorphous 742oC 2.56 g/ 100 mL at 20oC No data 2.37 < 10 6 torr No data Disodium octaborate tetrahydrate Na2B8O13 .

4H20 412.31 Powder 815oC 9.5% at 20oC 8.5 ( 1% solution at 23oC) 25 35 lbs/ ft3 ( specific gravity) < 10 6 torr No data Disodium octaborate Na2B8O13 340.31 Solid rods No data No data No data 1.8 g/ mL at 20oC < 10 6 torr No data Sodium metaborate NaBO2 65.82 Solid white pieces or powder Fuses to clear glass at 966oC Soluble in water 11.82 ( 6% aqueous solution of tetrahydrate Bulk density: loose pack ( 51 55 lbs/ ft3) and tight pack ( 55 61 lbs/ ft3) < 10 6 torr No data References: EPA, 1993; NIOSH, 2001. Page 12 of 84 3.0 Metabolism Assessment 3.1 Comparative Metabolic Profile Boric acid and borate salts exist as the undissociated acid in aqueous solution at physiological pH. No further metabolism occurs in either animals or plants. The compounds are therefore considered to be toxicologically similar and comparisons can be made based on boron equivalents ( percentages used for conversion to boron equivalents are shown below in Table 3.1). In animals, boric acid/ borate salts are essentially completely absorbed following oral ingestion. Absorption occurs via inhalation, although quantitative data are unavailable. Limited data indicate that boric acid/ salts are not absorbed through intact skin to any significant extent, although absorption occurs through skin that is severely abraded. It distributes throughout the body and is not retained in tissues, except for bone, and is rapidly excreted in the urine ( US EPA IRIS, 2004).

Table 3.1. Boron Equivalents Chemical Percent boron Boric acid 17.5%

Sodium tetraborate decahydrate 11.34%

Sodium tetraborate pentahydrate 14.85%

Sodium tetraborate 21.49%

Disodium octaborate tetrahydrate 20.96%

Disodium octaborate 25.38%

3.2 Nature of the Residue in Foods and in Drinking Water Boron exists naturally in plants and is present in edible crops. The diet is a major source of natural background exposure to humans. Dietary intake of boron also results from naturally occurring amounts in drinking water.

The natural concentration of boron in plants varies considerably among different crops and variations are also seen in reported levels for a given crop. Levels tend to be highest in fruits ( especially dried fruits), nuts and pulses. For example, analyses of foods from the United States has given levels of boron in peanut butter of about 15 ppm, avocados about 11 ppm, prunes about 22 ppm, grapes about 5 ppm and bananas have levels around 1 ppm; some analyses of foods conducted in other countries showed even higher levels ( Anderson et al., 1994; Naghii et al., 1996). Agricultural application rates of boric acid or borate salt products are very low and available residue data on cottonseed and citrus ( revoked tolerances of 30 and 8 ppm, respectively) indicate low residue levels as well, compared to the naturally occurring food crop boron levels. For lemons ( not currently a registered use), 1 ppm incremental boron was observed due to treatment, compared with an endogenous level of 2.5 ppm. The contribution of these residues to total background dietary boron intake was considered to be relatively small. A tolerance exemption was therefore granted for boric acid and its sodium salts ( CFR 180.1121). Page 13 of 84 Analyses of boron levels in fresh ( surface water and public water systems) and sea water have been published ( summarized in EPA IRIS, 2004 and ATSDR, 1992). Concentrations of boron in fresh water vary, depending upon environmental conditions and local soil levels, but concentrations in fresh water normally range from < 0.01 to 1.5 ppm ( average of 0.1 ppm) but may be higher in areas of very high soil boron levels. A survey of 989 public water supply systems in the United States showed that 90% had concentrations of 0.4 ppm or less and 99% had concentrations less than 1 ppm. On average, sea water contains higher boron concentrations ( range 0.5 to 9.6 ppm; average 4.6 ppm).

Estimates of human daily dietary boron intake ( food plus drinking water) in the United States range from 0.26 to 7.1 mg/ day with a mean of 1.9 mg/ day ( equivalent to about 0.03 mg/ kg/ day for adults; Moore, 1997). Other survey data indicate average daily dietary boron intakes of 0.5 to 3.1 mg/ day ( 0.007 to 0.044 mg/ kg/ day)( Nielsen, 1991). The FDA determined an average U. S. adult male dietary boron intake of 1.52 mg/ day ( 0.025 mg/ kg/ day)( Iyengar et al., 1988).

Rainey et al. ( 1999) also estimated daily boron intake in the diet using a boron nutrient database from the US Department of Agriculture and individual food consumption patterns. Populations included school age children, adult males and females ( non vegetarian and vegetarian) and pregnant females. Values were presented as mean, 5th to 95th percentile and high values. Adult males ranged from 0.43 to 2.42 mg/ day, with a high of 9.64 and mean of 1.17 mg/ day ( about 0.017 mg/ kg/ day). Adult females ranged from 0.33 to 1.94 mg/ day with a high of 8.5 mg/ day and a mean of 0.96 mg/ day ( approximately 0.016 mg/ kg/ day). Values for pregnant females were slightly higher. Intakes of vegetarian males and females were on average 20 27% above non vegetarians and boron intakes in females in the 95th percentile were about twice those of 95th percentile nonvegetarians, but high values were lower than non vegetarians. School age children showed a range of 0.32 to 1.95 mg/ day and high of 3.83 mg/ day, with means of approximately 0.90 mg/ day for all age ranges ( approximately 0.016 to 0.03 mg/ kg/ day for older and younger children, respectively).

3.3 Environmental Degradation Boron exists in nature chemically bound to oxygen, either as boric acid or as alkali or alkaline earth borates, and is present in water and soil. It is not transformed or degraded in the environment, although the exact form may change depending upon physical conditions such as moisture or pH. In nature, it enters water and soil largely through weathering. The environmental fate of boric acid and its sodium salts from agricultural applications is the same as for naturally occurring boron compounds. Page 14 of 84 4.0 Hazard Characterization/ Assessment 4.1 Hazard and Dose Response Characterization 4.1.1 Database Summary <IP_ADDRESS> Studies Available and Considered Acute LD50 ( oral, dermal and inhalation), rat; primary dermal irritation, primary eye irritation; Subchronic oral toxicity, rat ( 2); oral toxicity, dog; Chronic and/ or carcinogenicity oral toxicity, rat ( 2 year dietary); oral carcinogenicity, mouse ( 2 year dietary), oral chronic dog ( 2 year dietary and 38 week dietary); Reproductive/ developmental oral developmental toxicity, rat ( 2); oral developmental toxicity, rabbit; oral developmental toxicity, mouse; oral multigeneration reproductive toxicity, rat; oral multigeneration reproductive toxicity, mouse; Other genotoxicity screening studies, all categories.

<IP_ADDRESS>. Mode of Action, Metabolism, Toxicokinetic Data Boric acid and its sodium salts exist as undissociated boric acid in aqueous solution at physiological pH. For this reason, they are considered together as a group for purposes of hazard and risk characterization and individual toxicology studies on each active ingredient are not required. The moiety of toxicological concern is boron. Dose comparisons are normalized by conversion to boron equivalents, allowing comparison of studies on boric acid or borax ( see Table 3.1). They are well absorbed via the gastrointestinal tract and via inhalation, but not via intact skin. Absorption across severely abraded skin does occur. Boric acid/ borates distribute evenly throughout the body and do not bioaccumulate in soft tissues, but some accumulation may occur in bone. Excretion is rapid and primarily urinary. Metabolism of boric acid and its salts does not occur in vivo, but it may bind and form complexes with some macromolecules.

Limited mode of action data are available for boric acid/ borate salts. The primary mechanistic investigations published in the literature to date are on testicular toxicity ( decreased spermiation and testicular atrophy) and developmental effects to the skeleton. In the testes, the mechanism of toxicity is unknown, but it is suspected that boron affects the Sertoli cells, resulting in alterations in the control of sperm maturation and release. Data indicate that boron causes a slight reduction in plasma testosterone in rats and that the inhibition of spermiation may be CNSmediated as suggested by a lack of direct effect on steroidogenesis in Leydig cells in in vitro studies ( Ku and Chapin, 1994). Co cultures of Sertoli cells/ germ cells in these studies indicate in vitro effects on DNA synthesis of mitotic/ meiotic germ cells and on Sertoli cell energy metabolism. However, additional data are needed to characterize the mechanism of toxicity of boron to the testes. Page 15 of 84 The exact mechanisms causing skeletal abnormalities and growth retardation in the developing fetus are also not definitively identified. There are some data in the rat to suggest that boron may alter expression of the hox gene, a homeotic gene regulating vertebral and rib development, an effect that may occur after a single maternal exposure ( Narotsky et al., 2003; Wery et al., 2003). However, this effect was only examined at a high dose level ( 500 mg/ kg, twice daily) and there are no studies examining dose response at doses relevant to human exposure. Other data suggest effects of boron on ribs by binding to bone tissue and a reduction of fetal growth by a general inhibition of mitosis ( Fail et al., 1998).

<IP_ADDRESS> Sufficiency of Studies/ Data The toxicology database for boric acid and its sodium salts is considered complete at this time. No additional toxicology studies are required to support this tolerance reassessment.

It is noted that a number of the studies used to evaluate boric acid/ borates were conducted prior to current Agency study conduct guidelines and do not meet current standards, but that when taken together, they are considered adequate to provide a hazard characterization. The same studies have been used for boron hazard characterizations by several other reviewing groups and Agencies ( for example, WHO, ATSDR, US EPA IRIS, ECETOC).

<IP_ADDRESS> Toxicological Effects Data Summary and Toxicity Profile The database for acute toxicity for boric acid and sodium tetraborate decahydrate ( borax) is shown below in Tables 4.1a and 4.1b. Boric acid and borate salts have low toxicity by the oral and dermal route ( Toxicity Category III) and are not dermal irritants ( Toxicity Category III or IV), except for sodium metaborate, which is moderately irritating to the skin. In addition to rats, acute oral studies were conducted in dogs but vomiting was noted shortly after dosing, indicating a limited ability to test in this species. Boric acid is classified as Toxicity Category II by the inhalation route but only a single dose was tested and an LC 50 was not determined. Although boric acid is not very irritating to the eyes ( Toxicity Category III), sodium tetraborate decahydrate ( borax) is corrosive ( Toxicity Category I). Human lethal doses for oral ingestion have been estimated from accidental poisonings: in adults, the minimum lethal oral dose is estimated at 15 20 g, in children at 5 6 g and in infants 2 3 g ( Stokinger, 1981; Litovitz, 1988; see also Section 5.0, Public Health Data). Page 16 of 84 Table 4.1a Acute Toxicity Profile  Boric Acid Guideline No. Study Type MRID( s) Results Toxicity Category 870.1100 Acute oral rat 00006719 LD50 males = 3450 mg/ kg ( 2950 4040 mg/ kg) females = 4080 mg/ kg ( 3640 4560 mg/ kg) III 870.1100 Acute oral beagle dog 00064208 LD50 > 631 mg/ kg III 870.1200 Acute dermal rabbit 00106011 LD50 > 2 g/ kg III 870.1300 Acute inhalation rat 00005592 LC50> 0.16 mg/ L ( no deaths) II 870.2400 Acute eye irritation rabbit 00064209 Conjunctival irritation clearing by Day 4 III 870.2500 Acute dermal irritation rabbit 00106011 PIS = 0.1; 1/ 6 erythema at 72 hrs III 870.2600 Skin sensitization guinea pig  Not required

Table 4.1b Acute Toxicity Profile  Sodium tetraborate decahydrate ( Borax)

Guideline No. Study Type MRID( s) Results Toxicity Category 870.1100 Acute oral rat 40692303 LD50 males = 4550 mg/ kg ( 4140 5010 mg/ kg); females = 4980 mg/ kg ( 4310 5760 mg/ kg) III 870.1100 Acute oral dog 40692304 LD50 > 974 mg/ kg III 870.1200 Acute dermal rabbit 43553201 LD50 > 2000 mg/ kg III 870.1300 Acute inhalation rat  Not required

870.2400 Acute eye irritation rabbit 43553203 Corrosive I 870.2500 Acute dermal irritation rabbit 43553202 Non irritating IV 870.2600 Skin sensitization  Not required

The subchronic, chronic and other guideline studies submitted to support registration of boric acid and its sodium salts are summarized below in Table 4.1c.

Boron is a ubiquitous element that is naturally occurring in plants and water. Humans ingest boron in the diet and there is some data to suggest that trace levels are required. This has not been proven at this time and the FDA has not determined a minimum daily requirement ( MDR) for boron. At higher exposure levels, boron causes toxicity. A major target organ of Page 17 of 84 boric acid/ borate salts is the testes and males appear somewhat more sensitive to boric acid/ borate salts than females. The mechanism for testicular atrophy is not known at this time, but seminiferous tubule degeneration, atrophy, reduction in sperm count and reduced testicular weights are observed across species. Dogs appear to be more sensitive to this effect than rats or mice. The ovaries are also a target organ and a reduction in the number of corpora lutea were observed in female rats in a reproductive toxicity study. Crossover matings in rat reproductive toxicity studies demonstrate that fertility is lower in both treated males and females, but the effect on fertility in females is considerably less severe than in males. The red blood cell may be a potential target at higher dose levels, based on slight hematological changes reported in some studies in the rat and the dog.

The developing fetus is also sensitive to boric acid and its sodium salts at doses that do not produce direct maternal toxicity ( e. g., maternal reductions in gravid weight or weight gains are secondary to fetal toxicity). Effects on the fetus include skeletal variations/ malformations, visceral malformations, increased mortality and reduced pup weight. Visceral fetal abnormalities were also reported: enlarged lateral ventricles of the brain were observed in the rat and defects of the great vessels and the heart were observed in the rabbit.

Clinical signs of neurotoxicity have been reported at higher dose levels. Seizures, convulsions, headaches, tremors and in some cases, coma and death have been observed in human infants accidentally poisoned by boric acid or borax in medical case reports. In the guideline studies submitted to the Agency for review, significant clinical signs of toxicity were observed in the rat at higher dose levels; symptoms included hunched posture, rapid respiration and abnormal gait. Other symptoms included swollen paws and penis, ocular inflammation, bloody nasal discharge and coarse fur/ desquamation.

Under the current Agency Cancer Guidelines ( US EPA, 2005), boric acid/ sodium salts are classified as " not likely to be carcinogenic to humans." Tumor incidence did not show a clear treatment related increase in mice or rats administered boric acid or sodium tetraborate decahydrate for two years. Mutagenicity studies in several test systems are negative. Epidemiological data do not indicate any exposure related cancers in humans ( US EPA IRIS, 2004). Page 18 of 84 Table 4.1c Subchronic, Chronic and Other Toxicity Profiles for Boric Acid and Borate Salts Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results ( Note: all dose levels for NOAELs and LOAELS in this table are expressed as mg/ kg/ day of boron equivalents)

870.3100 90 Day oral toxicity ( rat) 00068025 ( 1962) Acceptable/ nonguideline together with 00068883 0, 0.03, 0.1, 0.3, 1.0 or 3.0% boric acid in diet for 90 days. Equivalent to 0, 3.9, 13, 38, 124 or 500 mg/ kg/ day boron NOAEL = 38 mg/ kg/ day LOAEL = 124 mg/ kg/ day, based on clinical signs of toxicity, decreased body weight, testicular atrophy/ reduced testicular weights, reduced ovarian weights.

870.3100 90 Day oral toxicity ( rat) 40692305 ( 1963) Acceptable/ nonguideline together with 40692306 0, 0.0463, 0.154, 0.463, 1.54 or 4.63% sodium tetraborate decahydrate in diet for 90 days. Equivalent to 0, 4.0, 14, 42, 125 or 455 mg/ kg/ day boron NOAEL = 42 mg/ kg/ day LOAEL = 125 mg/ kg/ day based on decr. weight gain and food consumption, decr. testes and ovarian weights, testicular atrophy.

870.3100 90 Day oral toxicity ( rat, male rat only) 40692306 ( 1963) Acceptable/ nonguideline together w/ 40692305 0, 0.015, 0.0463, 0.154 or 0.463% sodium tetraborate decahydrate in diet for 90 days. Equivalent to 0, 1.3, 4.3, 13.1 or 41 mg/ g/ day boron NOAEL = 41mg/ kg/ day ( males only tested) LOAEL > 41 mg/ kg/ day ( HDT).

870.3150 90 Day oral toxicity ( dog) 00064203 ( 1963) Acceptable/ nonguideline together with 40692308 and 00005622 0, 0.01, 0.1 or 1.0% boric acid in diet for 90 days. Equivalent to 0, 0.46, 4.2 or 35 mg/ kg/ day boron NOAEL = 4.2 mg/ kg/ day LOAEL = 35 mg/ kg/ day, based on testicular atrophy 870.3150 90 Day oral toxicity ( dog) 40692307 ( 1963) Acceptable/ nonguideline 0, 0.0154, 0.154, 1.54% sodium tetraborate decahydrate in diet for 90 days. Equivalent to 0, 0.34/ 0.25, 4.1/ 2.6 or 32/ 23 [ M/ F] mg/ kg/ day boron NOAEL = 4.1mg/ kg/ day M/ 2.6 mg/ kg/ day F LOAEL = 32 mg/ kg/ day M/ 23 mg/ kg/ day F, based on decr. HCT/ Hgb, testicular atrophy, decr. testes weight and incr. hemosiderin pigment in spleen, liver, kidneys. Table 4.1c Subchronic, Chronic and Other Toxicity Profiles for Boric Acid and Borate Salts Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results ( Note: all dose levels for NOAELs and LOAELS in this table are expressed as mg/ kg/ day of boron equivalents)

Page 19 of 84 870.3700a Prenatal developmental ( rat) 41725401 ( 1990) Acceptable/ nonguideline 0, 0.1, 0.2, 0.4% GD 0 20 and 0.8% GD 6 15 boric acid in diet. equivalent to 0, 14, 29 or 58 mg/ kg/ day boron and 94 mg/ kg/ day boron Maternal NOAEL = 58 mg/ kg/ day Developmental NOAEL < 14 mg/ kg/ day LOAEL = 14 mg/ kg/ day based on slightly decr. fetal body weight. At 29 mg/ kg/ day, skeletal abnormalities observed and at 58 and 94 mg/ kg/ day, high incidence skeletal and visceral abnormalities, and mortality 870.3700a Prenatal developmental ( rat) 43340101 ( 1994) Acceptable/ nonguideline 0, 0.025%, 0.050%, 0.075%, 0.10% or 0.20% boric acid. Equivalent to 0, 3.3, 6.3, 9.6, 13.3 or 25 mg/ kg/ day boron Maternal NOAEL = 25 mg/ kg/ day LOAEL = not determined ( slightly decreased gravid uterine weight considered secondary to fetal toxicity) Developmental NOAEL = 9.6 mg/ kg/ day LOAEL = 13.3 mg/ kg/ day based on slightly decr. fetal body weight, rib XIII abnormalities 870.3700a Prenatal developmental ( mouse) 41725402 ( 1990) Acceptable/ nonguideline 0, 0.1, 0.2, 0.4% boric acid in diet equivalent to 0, 43, 79 or 176 mg/ kg/ day boron Maternal NOAEL not established < 43 mg/ kg/ day LOAEL = 43 mg/ kg/ day based on renal tubular dilatation/ regeneration. Developmental NOAEL = 43 mg/ kg/ day LOAEL = 79 mg/ kg/ day based on decr. fetal wt, incr. resorptions, incr. malformations ( short rib XIII, fused rib).

870.3700b Prenatal developmental ( rabbit) 42164201, 42164202 ( 1991) Acceptable/ guideline 0, 62.5, 125 or 250 mg/ kg/ day boric acid by gavage. Equivalent to 0, 11, 22 or 44 mg/ kg/ day boron Maternal NOAEL = 22 mg/ kg/ day LOAEL = 44 mg/ kg/ day based on incr. intrauterine bleeding, decreased unadjusted weight gain during treatment ( due to decr. gravid uterine weight). Developmental NOAEL = 22 mg/ kg/ day LOAEL = 44 mg/ kg/ day based on incr. mortality ( resorptions, postimplantation loss), decr. fetal weight, intraventricular septal defect, enlarged aorta.

870.3800 Reproduction and fertility effects ( rat) 00068882 ( 1966) Acceptable/ nonguideline 0, 0.067, 0.20 or 0.67% boric acid in the diet. Equivalent to 0, 8.5/ 9.7, 27/ 29 or 85/ 92 mg/ kg/ day [ M/ F] boron Parental/ Systemic NOAEL = 27 mg/ kg/ day LOAEL = 85 mg/ kg/ day based on clinical signs, decr. body weight, testicular atrophy, decr. testes weight, decr. corpora lutea. Reproductive NOAEL = 27 mg/ kg/ day LOAEL = 85 mg/ kg/ day based on decr. fertility. Offspring NOAEL = 27 mg/ kg/ day LOAEL = 85 mg/ kg/ day based on decr. pup survival. Table 4.1c Subchronic, Chronic and Other Toxicity Profiles for Boric Acid and Borate Salts Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results ( Note: all dose levels for NOAELs and LOAELS in this table are expressed as mg/ kg/ day of boron equivalents)

Page 20 of 84 870.3800 Reproduction and fertility effects ( rat) 40692311( 1966) Acceptable/ nonguideline 0, 0.103, 0.308 or 1.03% sodium tetraborate decahydrate in the diet. Equivalent to 0, 8.1/ 9.2, 25/ 27 or 82/ 92 [ M/ F] mg/ kg/ day boron Parental/ Systemic NOAEL = 25 mg/ kg/ day LOAEL = 82 mg/ kg/ day based on decr. body weight, testicular atrophy, decr. testes weight, decr. corpora lutea. Reproductive NOAEL = 25 mg/ kg/ day LOAEL = 82 mg/ kg/ day based on decr. fertility. Offspring NOAEL = 25 mg/ kg/ day LOAEL = 82 mg/ kg/ day based on decr. pup survival.

870.3800 Reproduction and fertility effects ( mouse) 41589101 ( 1990) Acceptable/ nonguideline 0, 1000, 4500 or 9000 ppm boric acid in diet ( for P1 matings only 0 and 1000 ppm groups). Equivalent to 0, 27, 111 or 221 mg/ kg/ day boron Parental/ Systemic NOAEL = 27 mg/ kg/ day LOAEL = 111 mg/ kg/ day based on decr. testicular weight, atrophy and degeneration of seminiferous tubules. Reproductive NOAEL = 27 mg/ kg/ day LOAEL = 111 mg/ kg/ day based on decr. fertility. Offspring NOAEL = 27 mg/ kg/ day LOAEL = 111 mg/ kg/ day based on decr. pup wt., decreased survival 870.4100a Chronic toxicity ( rat) see 870.4200, below 870.4100b Chronic toxicity ( dog) 00005624 ( 1967) Acceptable/ nonguideline when considered together with 00005622 and 4366910. 0 or 0.67% boric acid decahydrate in diet for 38 weeks. Equivalent to 0 or 40 mg/ kg/ day boron NOAEL not established ($ 40 mg/ kg/ day) LOAEL = 40 mg/ kg/ day, based on testicular atrophy,

870.4100b Chronic toxicity ( dog) 40692308 ( 1967) Acceptable/ nonguideline when considered together with 40692307,  09. 0 or 1.03% sodium tetraborate decahydrate in diet for 38 weeks. Equivalent to 0 or 40 mg/ kg/ day boron NOAEL not established (< 40 mg/ kg/ day) LOAEL = 40 mg/ kg/ day based on decr. body wt. gain, testicular atrophy. Table 4.1c Subchronic, Chronic and Other Toxicity Profiles for Boric Acid and Borate Salts Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results ( Note: all dose levels for NOAELs and LOAELS in this table are expressed as mg/ kg/ day of boron equivalents)

Page 21 of 84 870.4100b Chronic toxicity ( dog) 00005622 ( 1966) Acceptable/ nonguideline when considered together with 00005624 and 00064203 0, 0.033, 0.067 or 0.20% boric acid in diet for two years. Equivalent to 0, 1.6, 3.6 or 10.2 mg/ kg/ day boron, males and 0, 1.8, 4.0 or 11.6 mg/ kg/ day boron, females NOAEL = 10.2 mg/ kg/ day LOAEL not established ($ 10.2 mg/ kg/ day)

870.4100b Chronic toxicity ( dog) 40692310 ( 1967) Acceptable/ nonguideline when considered together with 40692308. 0, 0.051, 0.103 or 0.309% sodium tetraborate decahydrate in the diet for two years . Equivalent to 0, 1.5, 2.9 or 8.8 mg/ kg/ day boron NOAEL = 8.8 mg/ kg/ day LOAEL not established (> 8.8 mg/ kg/ day)

870.4200 Carcinogenicity ( rat) 00068883 ( 1966) Acceptable/ nonguideline 0, 0.01, 0.1 or 1.0% boric acid in the diet for two years. Equivalent to 0, 5.2, 16 or 58 mg/ kg/ day boron, males; 0, 6.3, 19 or 70 mg/ kg/ day boron, females NOAEL = 16 mg/ kg/ day LOAEL = 58 mg/ kg/ day, based on clinical signs, decreased body weight, decreased testicular weight, testicular atrophy, increased anovulatory/ involuted ovaries, decreases in RBC parameters. no evidence of carcinogenicity 870.4200 Carcinogenicity ( rat) 40692309 ( 1966) Acceptable/ nonguideline 0, 0.130, 0.308, 1.030% sodium tetraborate decahydrate in diet for two years. Equivalent to 0, 7.3, 17 or 58 mg/ kg/ day boron NOAEL = 17 mg/ kg/ day LOAEL = 58 mg/ kg/ day based on decr. body weight ( observed by 3 4 weeks), testicular atrophy, slightly decreased hematocrit/ hemoglobin. no evidence of carcinogenicity 870.4300 Carcinogenicity ( mouse) 41861301 ( 1991) Acceptable/ nonguideline 0, 2500 or 5000 ppm boric acid. Equivalent to 0, 78 or 201 mg/ kg/ day boron NOAEL = not established < 78 mg/ kg/ day LOAEL = 201 mg/ kg/ day based on splenic lymphoid depletion in males and pulmonary hemorrhage. Decr. body weights in males and females; testicular atrophy, interstitial cell atrophy at 5000 ppm ( 201 mg/ kg/ day). no evidence of carcinogenicity Table 4.1c Subchronic, Chronic and Other Toxicity Profiles for Boric Acid and Borate Salts Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results ( Note: all dose levels for NOAELs and LOAELS in this table are expressed as mg/ kg/ day of boron equivalents)

Page 22 of 84 Gene Mutation 870. Mouse in vitro lymphoma forward gene mutation assay 42038902 ( 1991) Acceptable/ guideline 1200 5000 µ g/ mL boric acid +/ S9 Negative for induction of mutagenic response in two independently performed mouse L5178Y cell lymphoma forward mutation assays. Marginal cytotoxicity at 3500 5000 µ g/ mL.

Gene Mutation 870. S. typhimurium reverse gene mutation assay 42038901 ( 1991) Acceptable/ guideline 10 2500 µ g/ plate boric acid Negative for induction of mutagenic response in S. typhimurium strains TA1535, TA1537, TA1538, TA98 or TA100 in the presence or absence of S9 up to 2500 µ g/ plate. No cytotoxicity was observed.

Cytogenetics 870. Mouse in vivo micronucleus assay 42038904 ( 1991) Acceptable/ guideline 900, 1800 or 3500 mg/ kg boric acid Negative for induction of clastogenic response to the bone marrow of Swiss mice. No systemic toxicity or target cytotoxicity observed up to 3500 mg/ kg.

Other Effects 870. Rat liver in vitro unscheduled DNA synthesis 42038903 ( 1991) Acceptable/ guideline 5 5000 µ g/ mL boric acid Negative for increased unscheduled DNA synthesis in cultured rat hepatocytes. Slightly increased percent cells in repair at $ 2500 µ g/ mL in repeat assay were secondary to increased cytotoxicity at those dose levels.

4.1.2 Dose response Appropriate endpoints protective for the most sensitive effects were identified for all potential exposure scenarios for boric acid and its sodium salts. The primary effects of concern for the endpoints selected were testicular atrophy and developmental toxicity, including skeletal abnormalities and decreased fetal body weight.

This risk assessment was conducted for a tolerance reassessment for boric acid and sodium borate salt products, which includes residential uses as well as food/ feed uses. However, boric acid and sodium salts are exempt from tolerances due to low levels of residues relative to endogenous levels of boron found in food/ feed crops and drinking water, and lack of significant retention in animal products. Acute and chronic dietary exposure assessments were not conducted as part of this reassessment because of the minor contribution to total dietary boron intake anticipated from crop residues. Background dietary intake was not included in the risk assessment because it was assumed that the test animals from the studies evaluated to derive endpoints ingested background levels of boron in food and drinking water that would approximate an average intake by humans.

Incidental oral postapplication exposure is anticipated to occur to children and adults from swallowing treated swimming pool water. Various household uses including carpet treatment and other residential scenarios would also result in postapplication incidental oral exposure to young Page 23 of 84 children from hand to mouth ingestion. The endpoint selected for exposure to both children and adults is testicular atrophy in the dog for short and intermediate term exposure durations. This endpoint was used for children under twelve because at present it is not known if the mechanism of testicular toxicity is also relevant to the immature testes or testicular development ( or to the developing female reproductive system).

Boric acid/ sodium borate salts are not absorbed across intact skin, based on the available data. Dermal exposure is not expected to be of concern and no endpoints were selected for residential dermal exposure risk assessment.

Since there are no inhalation studies for boric acid and its sodium salts, oral studies were selected for inhalation risk assessment. The systemic toxicity NOAEL from the dog two year dietary study and LOAEL from the dog subchronic dietary study were combined and used to select an endpoint that was protective for testicular atrophy at all exposure durations.

A quantification of cancer risk is not required since boric acid/ borate salts are classified as " not likely to be carcinogenic to humans" under the current ( 2005) Agency Guidelines for Carcinogen Risk Assessment.

For all exposure scenarios, uncertainty factors of 10x for interspecies and 10x for intraspecies variation ( total UF of 100x) were used. However, this is considered a conservative UF because boric acid/ sodium salts are expected to show similar absorption and tissue distribution among different species. There is also no known metabolism of boric acid/ sodium salts that could cause variability among species or individuals due to differing levels of metabolic enzymes.

4.2 FQPA Hazard Considerations 4.2.1 Adequacy of the Toxicity Data Base The toxicology database for boric acid and borate salts is considered adequate for assessment of FQPA hazard considerations at this time. Several developmental toxicity and reproductive toxicity studies in multiple species are available for evaluation. Effects have also been characterized in standard subchronic and chronic dietary studies in several species.

4.2.2 Evidence of Neurotoxicity Rat neurobehavioral screening studies on boric acid/ borate salts have not been conducted and are not a requirement for reregistration. The available experimental and case report data indicate the potential for neurotoxicity at higher exposure levels ( see Section 5.0, Public Health Data). Case reports in humans indicate that neurological symptoms may occur at higher exposure levels. Reports of infant accidental poisonings note CNS symptoms such as convulsions, headaches, tremors and restlessness. Degenerative changes in brain neurons, congestion and brain edema and meninges were reported in infants that died of boron poisoning, although it is not Page 24 of 84 known whether these changes represent primary neurotoxicity or are secondary to acute systemic toxicity. Other symptoms of boron poisoning reported in human case studies and incident reports include lethargy, headache, vomiting, abdominal pain and diarrhea.

Possible neurobehavioral symptoms were reported in the rat in subchronic and chronic dietary studies submitted to the Agency but only at high dose levels. Symptoms included hunched posture, abnormal gait and rapid respiration, although it is noted that these occurred in the presence of numerous other symptoms ( swollen paws and penis, inflamed eyes, bloody nasal discharge, emaciation, coarse fur/ desquamation and shrunken scrotum) and could also have been secondary to systemic effects. In one of the rat developmental toxicity studies, enlarged lateral ventricles of the brain of fetuses was observed at a maternally toxic dose level. The dose at which this was reported ( 58 mg/ kg/ day) was significantly higher than the lowest NOAEL for developmental toxicity ( 9.6 mg/ kg/ day), with the effect also not observed in the rat at 14 or 29 mg/ kg/ day.

4.2.3 Developmental Toxicity Studies ( 1) Rat: In a developmental toxicity study ( MRIDs 41725401, main report and 42377101, supplement), 29 pregnant Crl CD( BR) VAF/ Plus outbred Sprague Dawley rats/ dose group were administered boric acid ( technical, 98 99% a. i.) in the diet at concentrations of 0, 0.1, 0.2 or 0.4% ( equivalent to an average daily dose of 0, 78, 163 or 330 mg/ kg/ day boric acid and 0, 14, 29 or 58 mg/ kg/ day of boron equivalents) from gestation days 0 through 20 ( dosing schedule designed to allow plasma boron levels to reach steady state prior to implantation to mimic low dose exposure from food). Additional control and high dose groups of 14 pregnant rats each were administered the test diet at 0% or 0.8% from gestation days 6 through 15 ( equivalent to an average daily dose of 539 mg/ kg/ day boric acid and 94 mg/ kg/ day boron equivalents).

Maternal toxicity: At 0.2%, statistically significantly increased relative kidney weight ( right and left) was observed ( about + 10% above controls), with a similar but nonsignificant increase in absolute right and left kidney weight; relative liver weight was also increased (+ 5%, p< 0.05); however, these marginal changes were not considered to be adverse. At 0.4%, a statistically significant reduction in body weight gain ( 10% below controls) and gravid uterine weight ( 30% below controls) were observed. Statistically significantly increased left kidney weight (+ 8%; right similar increase but not significant) was also seen. At 0.8%, ( treatment only GD 6 15), mean body weight gain and gravid uterine weight during treatment were about  58 to  59% lower than controls. No treatment related effects on survival or clinical signs were reported. The maternal toxicity NOAEL is 0.4% ( 330 mg/ kg/ day boric acid; 58 mg/ kg/ day boron equivalents). A LOAEL was not determined in this study.

Developmental toxicity: At 0.1%, mean fetal body weight was marginally but statistically significantly reduced ( 6% less than controls); this was considered a threshold effect. At 0.2%, decreased mean fetal weight ( 13% below controls), and increased incidences of the litter incidence of short rib XIII ( 28% vs 1%, controls), and cleft sternum ( 4% vs 0%, controls) were Page 25 of 84 reported. At 0.4%, increased fetal resorptions, rib XIII agenesis ( 24 fetuses vs. 0 in controls), enlarged lateral ventricles in the brain ( 21 vs. 0 fetuses in controls; fetal incidence 0.5%) were observed ( fetal weight  37% below controls). At the high dose of 0.8%, prenatal mortality ( live fetuses per litter mean 9.71 vs. 15.39 15.69 in other groups) was observed. Numerous gross malformations ( short and curly tail, anophthalmia, microphthalmia), visceral malformations ( cardiovascular defects, convoluted retina, enlarged lateral ventricles) were observed along with rib XIII agenesis, short rib XIII and cleft sternum. At 0.4% and 0.8%, 100% of the litters were affected with skeletal malformations or other defects; visceral malformations were reported in 36% and 86% of litters, respectively. The developmental toxicity LOAEL ( threshold effect level) is 0.1% ( 78 mg/ kg/ day boric acid; 14 mg/ kg/ day boron equivalents), based on marginally decreased fetal weight and increased incidence of skeletal variations. A developmental toxicity NOAEL was not determined in this study.

The developmental toxicity study in the rat is classified acceptable ( nonguideline) and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in the rat. The test material was administered via the diet instead of gavage to mimic human dietary exposure.

( 2) Rat: In an oral developmental toxicity study ( MRID 43340101), boric acid ( technical, 99% a. i.) was administered to 28 32 pregnant Sprague Dawley rats/ dose/ phase group in the diet at dose levels of 0, 0.025%, 0.050%, 0.075%, 0.10% or 0.20% ( equivalent to average daily intakes of 0, 19, 36, 55, 76 or 143 mg/ kg bw/ day boric acid; 0, 3.3, 6.3, 9.6, 13.3 or 25 mg/ kg/ day boron equivalents) from days 0 through 20 of gestation. The study was conducted in two phases: in phase I, developmental toxicity was examined in fetuses from dams sacrificed on GD 20. In Phase II, dams were allowed to deliver and dams and pups sacrificed on postnatal day 21 for evaluation of persistence of developmental effects.

Maternal toxicity: At 0.2%, slightly reduced gravid uterine weight was observed ( 10%, not significant); uncorrected and corrected body weight gains were not affected. The decrease was considered secondary to decreased fetal weights. There were no treatment related effects on survival, clinical signs or cesarean parameters. The maternal NOAEL is 143 mg/ kg bw/ day boric acid ( 25 mg/ kg/ day boron equivalents; HDT)( slightly reduced gravid uterine weight was considered secondary to reduced fetal weight and not a maternally toxic effect). A maternal LOAEL was not determined in this study.

Developmental toxicity ( Study Phase I): At 0.1%, decreased fetal body weight ( 6.1%, male pups and  7.1%, female pups, both p< 0.05) and increased incidence of short rib XIII ( fetal 17% vs. 9%, controls) and wavy rib ( fetal 10% and litter 6% vs 0%, controls; all p< 0.05) were observed. The developmental LOAEL is 76 mg/ kg bw/ day boric acid ( 13.3 mg/ kg/ day boron equivalents), based on decreased fetal weight and increased incidence ( fetal and litter) of short rib XIII and wavy rib. The developmental NOAEL is 55 mg/ kg bw/ day boric acid ( 9.6 mg/ kg/ day boron equivalents). Page 26 of 84 Phase II ( postnatal evaluation) At 0.1% ( 13 mg/ kg/ day boron), no effects on pup weight or skeletal abnormalities were observed at the Day 21 postnatal sacrifice. At 0.2% ( 25 mg/ kg/ day boron), an increased incidence of short rib XIII was observed; pup weights were unaffected.

This developmental toxicity study in the rat is classified acceptable ( nonguideline) and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in the rat. The test material was administered via the dietary route instead of by gavage and beginning on GD 0 instead of GD6 to imitate human dietary exposure but is considered acceptable for regulatory purposes.

( 3) Rabbit: In a developmental toxicity study ( MRID 42164201 and  02), boric acid ( technical, 99% a. i.) was administered to 30 pregnant ( artificially inseminated) New Zealand White rabbits/ dose by gavage ( 5 mL/ kg dose volume) at dose levels of 0, 62.5, 125 or 250 mg/ kg/ day from days 6 through 19 of gestation, inclusive ( equivalent to 0, 11, 22 or 44 mg/ kg/ day of boron equivalents).

Maternal toxicity: At 250 mg/ kg/ day, does showed weight loss during treatment ( 137 g vs. gain of + 93 g, controls due primarily to decreased gravid uterine weight, based on corrected weight gain and fetal loss), an increased incidence of vaginal bleeding ( GD 19 30; 15 does with bleeding had no live fetuses), and increased relative kidney weights. The maternal weight effects are considered secondary to reduced fetal survival. Although the vaginal bleeding was also associated with reduced fetal survival, it was considered a possible maternally toxic effect because it could have resulted from a direct maternal effect. It is noted that several animals were removed from the study for technical reasons: 6 controls and 3 from each of the other dose groups due to food access problems ( leaky water bottles, feeder knocked off cage), and 3 mid dose animals due to dosing trauma. The maternal LOAEL is 250 mg/ kg bw/ day ( 44 mg/ kg/ day boron equivalents), based on an increased incidence of vaginal bleeding. The maternal NOAEL is 125 mg/ kg bw/ day ( 22 mg/ kg/ day boron equivalents).

Developmental Toxicity: At 250 mg/ kg/ day, the number of resorptions/ dam was increased ( 7.8 vs. 0.72, controls); most were early ( total 140 compared to 4, controls, but late also showed an increase of 16 vs. 9, controls), mean fetal weight was decreased by  8.3% ( not significant) and live fetuses/ dam was decreased to 2.3 vs. 8.8, controls. Postimplantation loss was 92.6% compared to 7%, controls. The percentage of male fetuses was greater at 69% vs. 50%, controls ( not significant). Visceral abnormalities included enlarged aorta, intraventricular septal defect and abnormal position of pulmonary vein. The incidence of agenesis of the gallbladder was also increased. [ Note: at 125 mg/ kg/ day a low incidence of agenesis of the gallbladder was observed, 3/ 153 pups, which is noted but was not used to establish the LOAEL for developmental toxicity due to low incidence and lack of other abnormalities. However, it is a relatively rare malformation]. The developmental LOAEL is 250 mg/ kg bw/ day ( 44 mg/ kg/ day boron equivalents), based on increased fetal resorptions and mortality and increased incidence of visceral abnormalities. The developmental NOAEL is 125 mg/ kg/ day ( 22 mg/ kg/ day boron equivalents). Page 27 of 84 The developmental toxicity study in the rabbit is classified acceptable ( guideline) and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in the rabbit.

( 4) Mouse: In a developmental toxicity study ( MRID 41725402), boric acid ( 98 99% a. i.) was administered to 28 29 pregnant Crl: CD 1( ICR) VAF/ Plus outbred Swiss albino mice/ dose in the diet at dose levels of 0, 0.1%, 0.2% or 0.4% from gestation days 0 through 17 ( equivalent to an average daily dose of 0, 248, 452 or 1003 mg/ kg/ day boric acid; 0, 43, 79 or 176 mg/ kg/ day boron equivalents). Microscopic evaluation of the kidneys was performed on 10 dams/ dose group.

Maternal toxicity: At 0.1%, an increased incidence of renal tubular dilatation was reported ( from control to high dose, 0/ 10, 2/ 10, 8/ 10 and 10/ 10, respectively). At 0.4%, maternal body weight gain was significantly reduced ( 21% below controls), although corrected weight gains were unaffected. Relative kidney weights ( left and right individually) were significantly increased by about 30% ( left kidney absolute weights also increased by 15%), with pale kidneys observed grossly. A transient increase in food and water consumption ( both + 15%) was reported on Days 15 17. There were no treatment related effects on clinical signs or mortality. The maternal LOAEL is 0.1% ( 248 mg/ kg bw/ day boric acid; 43 mg/ kg/ day boron equivalents), based on renal pathology. A maternal NOAEL was not established in this study.

Developmental toxicity: At 0.2%, mean fetal weight was significantly reduced ( about  10% below controls) and the percent with short rib XIII per litter was increased ( 7.5% increasing to 20% at 0.4%, compared to 0% in controls). At 0.4%, the percent of litters with resorptions and % resorptions per litter were increased (+ 65% and + 216%, respectively). The developmental LOAEL is 0.2% ( 452 mg/ kg bw/ day boric acid; 79 mg/ kg/ day boron equivalents), based on decreased fetal weight and increased incidence of short rib XIII. The developmental NOAEL is 0.1% ( 248 mg/ kg/ day boric acid; 43 mg/ kg bw/ day boron equivalents).

This developmental toxicity study in the mouse is classified acceptable ( nonguideline) and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in the rodent. The test material was administered in the diet instead of by gavage to mimic human dietary exposure. The study is considered acceptable for regulatory purposes.

4.2.4 Reproductive Toxicity Study ( 1) In an oral three generation reproduction study ( MRID 40692311), sodium decaborate tetrahydrate ( borax tech., analyzed at 103 105% of theoretical boron content) was administered to 8 male and 16 female Charles River CD rats/ dose in the diet at continuous dose levels of 0, 0.103%, 0.308% or 1.03% ( in males, equivalent to 0, 0, 72, 218 or 729 mg/ kg/ day test material and 0, 8.1, 25 or 82 mg/ kg/ day boron equivalents; in females, equivalent to 0, 81, 241 or 814 Page 28 of 84 mg/ kg/ day test material and 0, 9.2, 27 or 92 mg/ kg/ day boron equivalents). After a 14 week premating period, one male and two females were mated for up to 21 days. Two matings per generation were performed to produce two litters. An exception to the protocol was taken for the 1.03% P1 repeat matings due to no conceptions in the first mating: untreated males were used with the treated females for the subsequent P1 matings. The high dosing group was not continued for P2 and P3 generations due to insufficient successful matings from either attempted P1 mating.

Parental toxicity: At 1.03%, clinical signs ( coarse fur, scaly tails, hunched posture) and decreased premating body weight gain were observed in P1 males ( 14% below controls) and females ( 15%) ( but not in later parental generations). Testicular atrophy with severely decreased testes abs/ rel weights was observed in all P1 males. In females, the number of functioning ovaries was lower than normal ( 4/ 15), although the controls were not examined for comparison. No subsequent generations were tested at this dose level. The parental toxicity LOAEL is 1.03% ( males/ females 729/ 814 mg/ kg/ day test material; 82/ 92 mg/ kg/ day boron equivalents), based on clinical signs, decreased weight and testicular atrophy/ reduced ovarian function. The NOAEL is 0.308% ( males/ females 218/ 241 mg/ kg/ day test material; 25/ 27 mg/ kg/ day boron equivalents).

Offspring toxicity: At 1.03%, no litters were born. In the second mating with untreated males, there were only 2 litters and 1 abortion; no pups survived past Day 3 postpartum ( died or cannibalized). The offspring toxicity LOAEL is 1.03% ( males/ females 729/ 814 mg/ kg/ day test material; 82/ 92 mg/ kg/ day boron equivalents), based on mortality. The NOAEL is 0.308% ( males/ females 218/ 241 mg/ kg/ day test material; 25/ 27 mg/ kg/ day boron equivalents).

Reproductive toxicity: At 1.03%, no litters were produced in the first P1 mating. The second P1 mating with untreated males resulted in 2 litters and 1 abortion out of 16 matings. All pups were either cannibalized or died by Day 3 postpartum. Testes of parental P1 males showed complete atrophy and P1 females had a lower than normal number of functioning ovaries ( 4/ 15 with corpora lutea; however controls were not examined); the study authors concluded that the latter finding was insufficient to completely account for the low fertility observed with untreated males and that some other effect on ovarian function or implantation was occurring. The reproductive toxicity LOAEL is 1.03% ( males/ females 729/ 814 mg/ kg/ day test material; 82/ 92 mg/ kg/ day boron equivalents), based on reduced fertility. The NOAEL is 0.308% ( males/ females 218/ 241 mg/ kg/ day test material; 25/ 27 mg/ kg/ day boron equivalents).

This study is classified as acceptable ( nonguideline) and satisfies the guideline requirement for a multi generation reproductive study ( OPPTS 870.3800; OECD 416) in the rodent ( rat). Although the study had several deficiencies ( incomplete histopathology evaluation, 2: 1 matings, less than 20 pregnant females/ group, lack of gestation period data and low lactation indices in control animals), the data are considered acceptable for regulatory purposes and a new study is not required at this time, based on consideration of this data together with other studies on reproductive/ developmental toxicity and systemic toxicity in the rat. Page 29 of 84 ( 2) In an oral three generation reproductive toxicity study ( MRID 00068882), boric acid ( technical grade, $ 98.7% a. i.) was administered continuously in the diet to 8 male and 16 female Sprague Dawley rats/ dose at concentrations of 0, 0.067%, 0.20% or 0.67% ( equivalent to average daily boron intakes of 0, 8.5, 26.6 or 85 mg/ kg/ day, males and 0, 9.7, 29 or 91.6 mg/ kg/ day, females). Matings ( 2 females per male) were conducted over three generations, with two matings performed per generation. The high dosing group was not continued for P2 and P3 generations due to lack of litters.

Parental toxicity: At 0.67%, clinical signs of toxicity were reported, body weights of males and females were decreased and at autopsy, testes of males were visibly atrophied ( not examined microscopically but confirmed by lack of spermiation in other feeding studies). About half of the females showed evidence of reduced ovulation. The parental toxicity LOAEL is 0.67% ( 85/ 92 mg/ kg/ day boron equivalents), based on clinical signs of toxicity, decreased body weights, testicular atrophy and reduced ovulation. The NOAEL is 0.20% ( 27/ 29 mg/ kg/ day boron equivalents).

Reproductive toxicity: At 0.67%, no litters were produced. As noted for parental toxicity, testes were atrophied and ovaries showed signs of reduced ovulation. A cross mating of the treated females with males administered untreated diet was unsuccessful, indicating effects on the female reproductive system as well as the male ( the authors did not consider the reduced ovulation sufficient to explain the complete lack of fertility, indicating a more pronounced effect on males). The reproductive toxicity LOAEL is 0.67% ( 85/ 92 mg/ kg/ day boron equivalents), based sharply reduced fertility related to testicular atrophy, reduced ovulation and probably other effects. The NOAEL is 0.20% ( 27/ 29 mg/ kg/ day boron equivalents).

Offspring toxicity: At 0.67%, no litters were produced. A cross mating of treated females with untreated males resulted in reduced numbers of P1 litters and pup survival. The offspring toxicity LOAEL is 0.67% ( 85/ 97 mg/ kg/ day boron equivalents), based on reduced pup survival from a treated female/ untreated male mating. The NOAEL is 0.20% ( 27/ 29 mg/ kg/ day boron equivalents).

This study is classified acceptable ( nonguideline) and satisfies the guideline requirement for a multi generation reproductive study ( OPPTS 870.3800; OECD 416) in the rodent ( rat). Although the study had several deficiencies ( incomplete histopathology evaluation, 2: 1 matings, less than 20 pregnant females/ group, lack of gestation period data and low lactation indices in control animals), the data are considered acceptable for regulatory purposes and a new study is not required at this time, based on consideration of this data together with other studies on reproductive/ developmental toxicity and systemic toxicity of boron in the rat.

( 3) In a two generation oral reproduction study ( MRID 41589101), boric acid ( 99% a. i., batch/ lot # 872703) was administered in the diet to 38 CD 1 Swiss mice/ sex at 0 mg/ kg/ day and to 19 20 CD 1 Swiss mice/ sex/ dose at continuous dose levels of 0, 1000, 4500 or 9000 ppm Page 30 of 84 ( equivalent to 0, 152, 636 or 1262 mg/ kg/ day test material and 0, 27, 111 or 221 mg/ kg/ day boron equivalents). For the F1 generation, only 0 and 1000 ppm doses were administered due to reduced fertility at the higher doses. The study was performed by NTP according to the reproductive assessment by continuous breeding ( RACB) protocol. Animals were given a one week premating period and a 14 week cohabitation period, followed by a holding period. Litters born during cohabitation were removed by 24 hr postpartum; those born later remained with the dams for 21 days. In addition, a cross over mating period between 20/ sex/ dose of control and mid dose males and females to determine the affected sex and an offspring assessment, in which F1 offspring from the continuous F0 mating litters were selected, were performed.

Parental toxicity: At 4500 ppm ( F0 parental animals only), decreased body weight in females ( at week 18,  23%; considered largely secondary to lower fertility rather than direct toxicity) and sharply decreased abs/ rel testes weight ( 40 to 50% of controls) and degeneration of seminiferous tubules ( 17/ 20 males) were observed; a decrease in cauda epididymides and prostate weights were also noted. Sperm showed a significantly lower concentration per mg caudal tissue ( 72%), motility (  32%) and a higher percentage of abnormal sperm ( 61% vs. 11%, controls). A slight but statistically significant reduction in adrenal/ kidney weight was also observed in females ( 9%). At 9000 ppm, mean body weight gain was significantly decreased in males and females. In addition to severe reduction in testicular weights and seminiferous tubule atrophy, 12/ 15 males produced no sperm and those that did had only 50% of sperm being motile. Lacrimation, exophthalmos and cloudiness of the eyes were observed. A parental systemic LOAEL is 4500 ppm ( 636 mg/ kg/ day test material; 111 mg/ kg/ day boron equivalents), based on decreased testicular weight in males and possibly adrenal/ kidney weight decrease in females. The parental systemic NOAEL is 1000 ppm ( 152 mg/ kg bw/ day test material; 27 mg/ kg/ day boron equivalents).

Offspring toxicity: At 4500 ppm ( F1 pups only), mean pup weight was decreased ( 14% below controls) and reductions in the average number of litters per pair ( 2.3 vs. 4.7, controls), number of live pups per litter ( 8.67 vs. 13.52, controls) and % alive ( 11%) were observed. The offspring LOAEL is 4500 ppm ( 636 mg/ kg/ day test material; 111 mg/ kg/ day boron equivalents), based on reduced pup weight and lower survival. The offspring NOAEL is 1000 ppm ( 152 mg/ kg bw/ day test material; 27 mg/ kg/ day boron equivalents).

Reproductive toxicity: At 4500 ppm ( F0 mating only), fertility was sharply reduced ( 44% vs. 94%, controls). The number of days to litter in the F0 continuous breeding portion increased after the second litter, with the number of dams producing litters and live pups per litter also decreasing with each litter. In the crossover mating evaluation, mating/ fertility indices were sharply reduced in matings of treated males with control females ( 30%/ 5% vs. 79%/ 74%, controls) but also slightly affected in matings of treated females with control males ( 70%/ 64%), thereby indicating that although effects were greater on males, some effect on females was also present. Testicular effects are described under parental toxicity, above. At 9000 ppm, no litters were produced and males showed decreased sperm concentration and motility, as described above under parental toxicity. The reproductive LOAEL is 4500 ppm ( 636 mg/ kg/ day test material; Page 31 of 84 111 mg/ kg/ day boron equivalents), based on reduced fertility and reduced sperm concentration. The reproductive NOAEL is 1000 ppm ( 152 mg/ kg bw/ day test material; 27 mg/ kg/ day boron equivalents).

This study is classified as acceptable ( nonguideline) and satisfies the guideline requirement for a multi generation reproductive study ( OPPTS 870.3800; OECD 416) in the rodent ( mouse). The study was not conducted according to Agency guidelines and some deficiencies are noted ( including only one dose level in the P1 mating, incomplete histopathology, nonguideline mating protocol). However, this study, conducted by the NTP, provides sufficient information to characterize the reproductive toxicity of boric acid and is considered acceptable for regulatory purposes.

4.2.5 Additional Information from Literature Sources Several studies have investigated the mechanism of axial skeletal defect formation in the developing rat. Narotsky et al. ( 2003) dosed rat dams with 500 mg/ kg boric acid twice/ day on single days of gestation ( 6 through 11). Using in situ hybridization, it was demonstrated that exposure on GD 9 caused alterations in the expression of homeotic genes hoxc6 and hoxa6 that occurred along with increased elevation of rudimentary cervical ribs. Single exposures on GD 8, 9 or 10 all caused axial skeletal defects. Reduction of fetal weight but not skeletal effects was observed with dosing on GD 7 and 11. The role of hox genes in developmental of axial skeletal defects and confirmation of GD9 as a sensitive window of development was supported by a second study by Wery et al. ( 2003), who found alterations in expression of hoxd4, hoxa4, hoxc5 and hoxc6 in the somites responsible for cranial caudal axial skeletal development. These studies would appear to support the conclusion that a single exposure at a critical developmental stage could cause developmental defects. However, effects on hox genes have not been evaluated at lower dose levels and therefore the significance of this finding at doses relevant to human exposure is not known at this time.

The mechanism of testicular toxicity ( reduced spermiation, atrophy) is also not well understood. Studies have been conducted to evaluate the effects of boron on the testes of the rat ( Ku and Chapin, 1994). In the rat, boron causes a slight inhibition of plasma testosterone that is not considered sufficient to result in atrophy. The data suggest a possible CNS mediated effect of boron on the testes, based on lack of effect on steroidogenic function of Leydig cells in in vitro studies. The most sensitive in vitro endpoint was DNA synthesis of mitotic/ meiotic germ cells in Sertoli cell/ germ cell cultures, with energy metabolism of Sertoli cells also affected. Further work is needed to fully characterize the mechanism of toxicity.

4.2.6 Pre and/ or Postnatal Toxicity <IP_ADDRESS> Determination of Susceptibility There is evidence of increased developmental susceptibility to boric acid and its sodium Page 32 of 84 salts, based on fetal toxicity ( reduced fetal body weight and skeletal developmental abnormalities) observed in the rat at doses below maternally toxic levels. In the rabbit and mouse developmental toxicity studies, developmental toxicity was observed at doses causing maternal effects.

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility Although fetal toxicity is observed at doses below maternally toxic levels in the rat, developmental toxicity has been well characterized in four developmental toxicity studies in three species. Rabbits and mice did not demonstrate clearly increased fetal sensitivity, although developmental toxicity, including skeletal or visceral abnormalities and reduced fetal survival, was observed. Reproductive toxicity studies in two species are also available. The mechanism of testicular effects ( inhibited spermiation, testicular atrophy) has not been characterized, but the lack of effects on male reproductive function in the rat and mouse reproductive toxicity studies at doses greater than the endpoint used for this risk assessment suggests that there is not increased sensitivity of the developing testes. At this time, there are no residual uncertainties, based on sufficient data to characterize the developmental effects. The NOAEL used for risk assessments is lower than the rat developmental toxicity NOAEL that is the most sensitive developmental endpoint and is the most sensitive endpoint identified from the available data.

4.3 Recommendation for a Developmental Neurotoxicity Study 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study Enlarged lateral ventricles of the brain were reported in a rat developmental toxicity study. Acute exposure to higher doses of boron compounds may induce neurological symptoms. Case reports of infants poisoned with boric acid/ borax show convulsions and other neurological signs of toxicity and in the case of some that died, brain pathology.

4.3.2 Evidence that supports not requiring a Developmental Neurotoxicity study Evidence of clinical signs of neurotoxicity occurs at high dose levels that are above the exposure levels causing other signs of toxicity. There was no clear evidence of unequivocal neurotoxicity in adult animals in the available studies. Developmental effects on the brain ( enlarged lateral ventricles) were observed in the rat at doses above those causing the most sensitive effects ( skeletal variations and malformations).

4.3.3 Rationale for the UFDB ( when a DNT is recommended)

At this time a DNT study is not recommended and a database uncertainty factor is not required. Page 33 of 84 4.4 Hazard Identification and Toxicity Endpoint Selection Boric acid and its sodium salts are exempt from tolerances because boron is present at endogenous levels in plants that are higher than the contribution from pesticidal products applied to crops. Boron does not accumulate in animal tissues. A dietary risk assessment is therefore not required at this time ( see Sections 6.1 and 6.2, below for additional discussion).

4.4.1 Acute and Chronic Reference Doses ( aRfD and cRfD)

Reference doses for acute and chronic exposure were not selected for this risk assessment because dietary ( food plus drinking water) risk assessments were not performed.

It is noted that chronic dietary or drinking water reference doses have been selected by several reviewing groups. For example, the U. S. EPA IRIS ( 2004) selected an RfD of 0.2 mg/ kg/ day, based on a benchmark dose lower limit of the 95th percentile confidence interval for a 5% decrease in fetal body weight ( BMDL 05 ) of 10.3 mg/ kg/ day from the two rat developmental toxicity studies and a combined uncertainty factor ( UF) of 66. ECETOC ( 1994) and the National Academy of Sciences Food and Nutrition Board ( 2001) both determined a tolerable daily intake ( TDI) of 0.32 mg/ kg/ day using the developmental toxicity NOAEL of 9.6 mg/ kg/ day from the rat developmental toxicity study of Price et al. ( MRID 43340101) and a combined UF of 30. WHO ( 1998) selected a TDI of 0.4 mg/ kg/ day, based on the developmental toxicity NOAEL of 9.6 mg/ kg/ day and a combined UF of 25.

4.4.2 Incidental Oral, Short and Intermediate Term Exposures ( All Populations)

Studies selected: 90 day, 38 week and 2 year dietary studies in the dog MRID Nos.: 40692307, 40692308, 40692310 Executive Summaries:

( 1) In a chronic toxicity study ( MRID 40692310), sodium tetraborate decahydrate ( technical borax, purity 100% a. i.) was administered to four beagle dogs/ sex/ dose in the diet at dose levels of 0, 0.051%, 0.103% or 0.309% ( equivalent to average daily intakes of 0, 13, 26 or 77 mg/ kg/ day test material; 0, 1.5, 2.9 or 8.8 mg/ kg/ day boron equivalents) for 104 weeks. One male and one female/ group were sacrificed at week 52 for interim evaluation; one male and one female from the control and high dose groups were sacrificed at week 117 for a recovery assessment, with removal of test diet at week 104. Only limited clinical chemistry parameters were evaluated and ophthalmologic examinations were not performed.

There were no effects observed on mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights or gross/ microscopic pathology that were considered to be clearly associated with treatment. At 0.304%, reduced sperm counts were Page 34 of 84 reported and one male at the 52 week sacrifice showed signs of testicular atrophy and reduced testicular weight. The study pathologist reported that the finding appeared to be of recent origin and probably unrelated to treatment. The NOAEL is 0.304% ( 77 mg/ kg/ day test material; 8.8 mg/ kg/ day boron equivalents) ( HDT). A LOAEL was not determined in this study.

This chronic study in the dog is classified as acceptable ( nonguideline) and satisfies the guideline requirement for a chronic oral study [ OPPTS 870.4100, OECD 452] in the dog when considered together with MRID 40692308, a 38 week dietary dog study ( HED TXR # 009301), which establishes a clear effect level. Although this two year dietary study in the dog was originally classified as " Supplementary" due to lack of effects, the HED RfD Committee determined that taken together with the 38 week study and the 90 day study, there are sufficient data to adequately characterize the chronic toxicity of borate to the dog ( memoranda dated November 24, 1993 and June 12, 1995).

( 2) In a chronic toxicity study ( MRID 40692308), sodium tetraborate decahydrate ( borax technical) was administered to 4 beagle dogs/ sex/ dose in the diet at dose levels of 0 or 1.03% ( for males/ females, equivalent to 0 or 348/ 400 mg/ kg/ day test material; 0 or 40/ 46 mg/ kg/ day boron equivalents) for up to 38 weeks. Two animals/ dose/ sex were sacrificed at week 26, one treated male and female and two controls/ sex at week 38 and one treated animal/ sex was maintained on basal diet for a three week recovery phase and sacrificed at week 41.

At 1.03%, decreased body weight gain was observed in males and females ( 10 to  11% below controls). In males, testicular atrophy and decreased testicular weight were observed. At 26 weeks, 2/ 2 males showed generalized spermatogenic arrest at the spermatocyte stage, progressing to complete atrophy of the seminiferous epithelium in some tubules, whereas ½ controls showed scattered atrophy. At 38 weeks, 1 control male showed severe degeneration of the seminiferous tubules and 1 showed 10 15% of tubules undergoing degenerative changes; 1 treated male showed 5 10% of the tubules undergoing degenerative changes. At 41 weeks, 1 treated male showed a moderate tubular degeneration and evidence of complete cessation of spermatogenesis. Absolute and relative testicular weights of treated animals were also reduced ( 35% to  45%). No increases in boron levels were reported in blood, brain, liver, fat, kidney or muscle in dogs sacrificed at 26 or 38 weeks, but an increase in urinary boron was observed. Excretion was complete before 4 days after cessation of treatment. There were no treatmentrelated effects on survival, clinical signs of toxicity. The LOAEL is 1.03% ( 40/ 46 mg/ kg/ day, males/ females), based on decreased body weight gain in males and females and testicular atrophy in males. A NOAEL was not determined in this study.

This chronic study in the dog is classified acceptable ( nonguideline) when considered together with the findings of a two year dietary study in the dog ( MRID 40692310); by itself it does not satisfy the guideline requirement for a chronic oral study [ OPPTS 870.4100, OECD 452] in the dog. Only a single dose was tested, a small number of animals were available for each time point evaluation and only limited clinical chemistry parameters were evaluated. At this time, the data requirement for a chronic oral toxicity study in the dog is considered to be satisfied and Page 35 of 84 no additional data are required.

( 3) In a subchronic oral toxicity study ( MRID 40692307), sodium tetraborate decahydrate ( technical borax, analyzed at 105% of theoretical) was administered for 13 weeks to 5 beagle dogs/ sex/ dose in the diet at dose levels of 0, 0.0154, 0.154 or 1.54% ( in males, equivalent to average daily intakes of 0, 2.9, 35 or 268 mg/ kg/ day test material and 0, 0.34, 4.1 or 32 mg/ kg/ day boron equivalents; in females, to 0, 2.1, 22 or 192 mg/ kg/ day test material; 0, 0.25, 2.6 or 23 mg/ kg/ day boron equivalents). Clinical chemistry evaluations were limited to blood urea nitrogen and non fasting glucose, and urinalysis.

At 1.54%, testicular atrophy and reduced testes weight in males, slightly but statistically significantly decreased hematocrit/ hemoglobin at 13 weeks ( 15%/ 11% males and  6%/ 11% females) and increased hemosiderin pigment in spleen, liver and kidneys were observed. An increase in the width of the adrenal cortex in females and a slight increase in epithelial nests of the thyroid in males were reported; slightly widened adrenal cortex in females and slightly increased proportion of epithelial nests in males were also reported at 0.154% but were of uncertain toxicological significance and were not used to establish the LOAEL for this study. There were no treatment related changes in mortality, clinical signs of toxicity, body weight, food consumption or clinical chemistries. The LOAEL is 1.54% ( in males, 268 mg/ kg/ day test material and 32 mg/ kg/ day boron equivalents; in females, 192 mg/ kg/ day test material and 23 mg/ kg/ day boron equivalents), based on decreased body weight gain, testicular histopathology and slightly decreased hematocrit/ hemoglobin. The NOAEL is 0.154% ( in males, 35 mg/ kg/ day test material and 4.1 mg/ kg/ day boron equivalents; in females, 22 mg/ kg/ day test material and 2.6 mg/ kg/ day boron equivalents).

This 90 day oral toxicity study in the dog is classified as acceptable ( nonguideline) and satisfies the guideline requirement for a 90 day oral toxicity study ( OPPTS 870.3150; OECD 409) in the dog when considered together with 38 week and 2 year dietary dog studies. This study was not conducted according to standard guideline procedures several clinical chemistry parameters were not examined and histopathological examination was missing some tissues. However, the study is considered to be acceptable for regulatory purposes.

Dose and Endpoint for Risk Assessment: 8.8 mg/ kg/ day ( 2 year study), based on testicular atrophy and slightly decreased hematocrit/ hemoglobin at 32 mg/ kg/ day ( 90 day study)

Comments about Study/ Endpoint: The endpoint of concern was derived by consideration of three dietary studies in the dog: a 90 day, a 38 week and a 2 year study. A NOAEL of 8.8 mg/ kg/ day was identified in the 2 year study ( HDT). Clear effects on the testes were seen at the subchronic LOAEL of 32 mg/ kg/ day and the 38 week LOAEL of 40 mg/ kg/ day; slight decreases in hematocrit/ hemoglobin was also reported at 32 mg/ kg/ day at 90 days of treatment. The endpoint is considered appropriate for the route ( oral) and durations ( up to one month for short term exposure and one to six months for intermediate term exposure). Although the exact onset of the testicular effects is not Page 36 of 84 known from the available studies, it is clearly evident by 90 days. It was selected for the short term incidental oral endpoint as well as the intermediate term endpoint to ensure a protective exposure level due to the uncertainty regarding time of onset of testicular atrophy.

4.4.3 Dermal Absorption Dermal absorption data were not submitted to the Agency. However, the available data in experimental animals indicate that boric acid and sodium borate salts are not absorbed across intact or slightly abraded skin, although absorption is significant across severely damaged skin. A number of dermal absorption studies have been cited and reviewed in reviews on boron and compounds prepared by EPA IRIS ( 2004), ATSDR ( 1992) and WHO ( 1998). Nielsen ( 1970, as cited in IRIS, 2004) demonstrated no absorption in rats with intact skin treated with 3% boric acid as aqueous jelly or ointment and absorption of 1% of dose from oleaginous ointment exposure. In contrast, rats with severely damaged skin absorbed up to 23% of the applied dose of aqueous boric acid. In another study, urinary boron was not increased in rabbits exposed dermally ( intact or mildly abraded skin) to boric acid as undiluted powder, 5% in talc or 5% aqueous solution ( 1.5 hr/ day, 4 days, exposure under occlusion to 10 15% of body surface area).

Data in humans showing lack of absorption of boric acid across intact skin are also available. A number of studies are reviewed in the IRIS Toxicological Review of Boron and Compounds ( US EPA IRIS, 2004). One study ( Draize and Kelly, 1959, MRID 46852201) showed no increase in urinary excretion of boron in one human volunteer exposed to topically applied powdered boric acid to the forearm for four hours.

4.4.4 Dermal Exposure ( Short, Intermediate and Long Term)

Boric acid and borate salts are not absorbed through the intact skin to a significant extent. A dermal exposure risk assessment is not required at this time.

4.4.5 Inhalation Exposure ( Short, Intermediate and Long Term)

Study Selected: Chronic and subchronic toxicity in the dog ( oral) three studies were considered together to derive an appropriate endpoint.

MRID Nos.: 40692307, 40692308, 40692310 Executive Summaries: See Incidental Oral, above ( 4.4.2)

Dose and Endpoint for Risk Assessment: Systemic toxicity NOAEL = 8.8 mg/ kg/ day ( two year dog dietary study, MRID 40692310), based on testicular atrophy and slight decreases in hematocrit/ hemoglobin at 32 mg/ kg/ day ( 90 day dog dietary study). Page 37 of 84 Comments about Study/ Endpoint: See Incidental Oral, above ( 4.4.2). Oral studies were selected because there was no inhalation study of appropriate duration. The effects observed at the selected endpoint ( testicular atrophy) were clearly identified by exposure durations of 90 days and longer, but the time of onset following initiation of exposure is not known. The NOAEL was selected to ensure adequate protection at all durations of inhalation exposure, based on the uncertainty of time to onset of testicular atrophy. For route to route extrapolation, absorption via the inhalation route is assumed to be equivalent to oral absorption.

4.4.6 Margins of Exposure The target Margins of Exposure ( MOEs) for residential and occupational exposure and risk assessment are as follows:

Route of Exposure Duration of Exposure Short Term ( 1 30 Days) Intermediate Term ( 1 6 Months) Long Term (> 6 Months)

Occupational Exposure Dermal 100 100 100 Inhalation 100 100 100 Residential Exposure Incidental Oral 100 100 NR Dermal NR NR NR Inhalation 100 100 100 NR not required.

The default MOE of 100 was retained but is considered a conservative value. Actual intraspecies/ interspecies variations are likely to be somewhat lower, due to lack of metabolism of boric acid/ sodium borate salts, lack of significant accumulation in soft tissues and similarities in absorption and renal clearance of boron among species. However, individuals with impaired renal clearance may be more sensitive to effects of boric acid/ sodium borate salts. Other reviews of boron or boric acid and its salts by various groups or Agencies have selected lower uncertainty factors, based on toxicokinetic and toxicodynamic considerations. For example, the US EPA IRIS ( 2004) selected a combined uncertainty factor of 66, WHO ( 1998) selected a combined uncertainty factor of 25, and both the National Academy of Sciences Food and Nutrition Board ( 2001) and the European Centre for Ecotoxicology and Toxicology of Chemicals ( ECETOC, 1995) selected a combined uncertainty factor of 30. A published risk assessment for drinking water exposure to humans proposed a combined uncertainty factor of 32 ( Murray, 1995). Page 38 of 84 4.4.7 Recommendation for Aggregate Exposure Risk Assessments As per FQPA ( 1996), when there are potential residential exposures to a pesticide, an aggregate risk assessment must consider exposures from the three major routes: oral, dermal and inhalation. Boric acid and its sodium salts are currently exempted from tolerances, based on what is anticipated to be a relatively smaller contribution anticipated from crop residues and drinking water runoff than the naturally occurring background boron levels. Dietary ( food plus drinking water) risk assessment was therefore not performed. An aggregate exposure risk assessment was not performed for the reasons outlined in Section 7.0 of this document ( Aggregate Risk Assessments and Risk Characterization).

4.4.8 Classification of Carcinogenic Potential <IP_ADDRESS> Two Year Dietary Study in the Rat ( 1) In an oral carcinogenicity study ( MRID 40692309), borax ( sodium tetraborate decahydrate tech., 103.2 105.4% of theoretical value) was administered to 70 control and 35 treated Sprague Dawley Charles River cesarean derived rats/ sex/ dose in the diet at dose levels of 0 ( control), 0.103%, 0.308% or 1.03% ( equivalent to 0, 65, 154 or 515 mg/ kg/ day test material; 0, 7.3, 17 or 58 mg/ kg bw/ day for elemental boron) for two years. Interim sacrifices of 5 animals/ sex/ dose were performed at weeks 28 and 56.

At 1.030%, clinical signs attributed to treatment included dry scaly tails, rough fur, hunched appearance, wheezing, bloody nasal and ocular discharge, drooping, inflamed eyelids, swollen paw pads, abnormally long claws and shrunken scrotum. Mean body weight/ weight gain were reduced in both males ( 16%/ 19% below controls) and females( 33%/ 41% below controls), with decreases observed beginning in the first weeks of treatment. Significant reductions in absolute and relative testes weight at 6, 12 and 24 months' sacrifice were observed. The latter correlated with grossly visible small testes, testicular tubular atrophy ( primarily severeobserved in all animals examined at 6, 12 and 24 months) and a possible increase in testicular calcific arteriosclerosis. Hematocrit and hemoglobin were slightly decreased in both sexes at several time points, beginning at month 2 ( Hct  5% to  13% and Hgb  10 to  14%; sporadic statistically significant changes seen). There were no treatment related effects on survival ( control to high dose males 58%, 76%, 64% and 72%; females 67%, 68%, 58% and 80%), clinical chemistry or urinalysis parameters. The systemic toxicity LOAEL is 1.03% ( 515 mg/ kg/ day test material and 58 mg/ kg/ day elemental boron), based on decreased body weight, clinical signs of toxicity, decreased rbc parameters and testicular pathology. The NOAEL is 0.308% ( 154 mg/ kg/ day test material and 17 mg/ kg/ day elemental boron).

At the doses tested, there was not a treatment related increase in tumor incidence when compared to controls. Dosing was considered adequate based on observations of clinical signs, decreased body weight, slight hematological changes and testicular atrophy. Page 39 of 84 This carcinogenicity study in the rat is classified as acceptable ( nonguideline) and satisfies the guideline requirement for a chronic toxicity/ carcinogenicity study [ OPPTS 870.4200; OECD 451] in rats. It is noted that some clinical chemistry parameters were not evaluated and that ophthalmologic examinations and microscopic examination of the eyes were not performed. In addition, the percent survival of mid dose males as presented in the study report ( 76.9%) differed from calculation from the individual animal survival data ( 64%); however, this discrepancy has been clarified by the registrant and 64% is the correct value.

( 2) In an oral chronic toxicity/ carcinogenicity study ( MRID 00068883), boric acid ( technical,

$ 98.7% a. i.) was administered in the diet to 35 Sprague Dawley rats/ sex/ dose at 0.067, 0.20 or 0.67% ( equivalent to average daily intakes of 0, 5.2, 16 or 58 mg/ kg/ day, males and 0, 6.3, 19 or 70 mg/ kg/ day, respectively, females). In addition, control groups of 70/ sex were administered untreated diet. Interim sacrifice groups ( 5/ sex/ dose) were evaluated at 26 and 52 weeks. Samples of blood, urine and feces were collected at 26, 52 and 104 weeks for boron balance analyses; select tissue samples were also collected from 5 animals/ sex at sacrifice times for boron analyses.

At 0.67%, clinical signs of toxicity beginning at 4 6 weeks ( hunched posture, desquamation of tail and paws, swollen paws, inflamed eyes, respiratory effects and shrunken scrotum), decreased mean body weights, low red blood cell volume and hemoglobin in males and decreased abs/ rel testes weight and severe testicular atrophy ( by 26 weeks, progressing in severity with time). In females, anovulatory ovaries were observed. At 104 weeks control, low and mid dose males also showed signs of atrophy. The incidence was not increased but severity showed a slight increase; however, given the advanced age of the rats, this was not considered clearly treatment related. Boron balance studies showed that there was no significant accumulation in tissues, although levels of treated animals were higher than controls. Boron blood levels increased with dose. The LOAEL is 0.67% ( 58 mg/ kg/ day boron equivalents), based on clinical signs, decreased body weight, hematological changes in males, testicular atrophy and possibly increased anovulatory ovaries. The NOAEL is 0.20% ( 16 mg/ kg/ day boron equivalents).

There was no evidence of a treatment related increase in tumors. Dosing was considered adequate based on significant toxicity at the highest dose tested.

This carcinogenicity study in the rat is classified as acceptable ( nonguideline) and satisfies the guideline requirement for a chronic toxicity/ carcinogenicity study [ OPPTS 870.4200; OECD 451] in rats. It is noted that some clinical chemistry parameters were not evaluated, ophthalmologic examinations were not performed and some tissues were not examined microscopically. However, it is considered an acceptable study for regulatory purposes. Page 40 of 84 <IP_ADDRESS> Two year dietary study in the mouse In an oral carcinogenicity study ( MRID 41863101), boric acid ( technical, 99.7% a. i., lot no. 051479) was administered to 50 B6C3F1 mice/ sex/ dose in the diet at dose levels of 0, 2500 or 5000 ppm ( equivalent to 0, 275 or 549 mg/ kg/ day test material; 0, 78 or 201 mg/ kg/ day for boron equivalents) for two years.

At 2500 ppm, slightly reduced survival of males was seen in the last weeks of the study ( 60% vs. 82%, controls); female survival was unaffected ( control to high dose 66%, 66% and 74%). Splenic lymphoid depletion in males ( controls to high dose 5/ 48, 11/ 49 and 25/ 48, respectively) was considered secondary to stress. At 5000 ppm, survival of males was reduced compared to controls during the second year of treatment ( at termination, 44% at high dose vs. 82%, controls), although it was noted that 5 high dose males died accidentally. Mean body weights were decreased in males ( 17% at termination) and females ( 20% at termination) beginning during months 6 8. Increases in the incidence of testicular atrophy ( control to high dose 3/ 49, 6/ 50 and 27/ 47) and interstitial cell hyperplasia ( 0/ 49, 0/ 50 and 7/ 47) were seen in males. No treatment related effects on clinical signs of toxicity were reported. Clinical pathology, hematology, ophthalmologic and organ weight data were not collected in this study. The LOAEL in males is 2500 ppm ( 275 mg/ kg/ day test material; 78 mg/ kg/ day boron equivalents), based on increased mortality and splenic lymphoid depletion. A NOAEL in males was not determined (< 275 mg/ kg/ day test material; 78 mg/ kg/ day boron equivalents). The LOAEL in females is 5000 ppm ( 549 mg/ kg/ day test material; 201 mg/ kg/ day boron equivalents), based on decreased body weight. The NOAEL in females is 2500 ppm ( 275 mg/ kg/ day test material; 98 mg/ kg/ day boron equivalents).

At the doses tested, there was not a treatment related increase in tumor incidence when compared to controls. A marginal increase in the incidence of hepatocellular carcinomas in low dose males ( control to high dose overall rates 5/ 50, 12/ 50 and 8/ 49) and combined hepatocellular adenomas and carcinomas ( control to high dose overall rates 14/ 50, 19/ 59 and 15/ 49) in low dose males were not considered treatment related because they were within historical control range and not significant when analyzed by the incidental tumor test. An increase in the combined incidence of subcutaneous tumors ( fibromas, sarcomas, fibrosarcomas, neurofibrosarcomas) in mid dose males 2/ 50, 10/ 50 and 2/ 50) was not considered treatment related because of the variability in spontaneous occurrence of these tumors in historical controls and lack of a dose response. Dosing was considered adequate in males and females based on findings of reduced survival of males at mid and high dose, testicular atrophy in males at the high dose and reduced body weights in males and females at the high dose of 5000 ppm. The study report noted that sensitivity of the cancer assessment in males may have been reduced due to reduced survival at the high dose.

This carcinogenicity study in mice is classified as acceptable ( nonguideline) and satisfies the guideline requirement for a carcinogenicity study [ OPPTS 870.4200; OECD 451] in mice. Several study deficiencies are noted for this report, including lack of clinical pathology and organ weights ( liver, kidney, tested, brain). However, MTDs were achieved for both sexes and the Page 41 of 84 study is considered adequate for purposes of assessing the carcinogenicity of boric acid in the mouse.

Cancer classification: Boric acid and borate salts may be classified under the current carcinogen assessment guidelines ( US EPA, 2005) as " not likely to be carcinogenic to humans." The HED RfD Committee previously classified boric acid/ borate salts as Group E not carcinogenic to humans using the 1986 Agency cancer guidelines ( RfD/ Peer Review Report of Boric Acid/ Borax, HED Memorandum dated 11/ 24/ 93 from G. Ghali to R. Forrest and L. Rossi, dated November 24, 1993). Available genotoxicity studies do not indicate mutagenic potential. Two year dietary studies in the rat and a mouse carcinogenicity study did not show clear evidence of increased cancer incidence.

Table 4.4. Summary of Toxicological Doses and Endpoints for Chemical for Use in Human Risk Assessments expressed in boron equivalents Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute and Chronic Dietary ( all populations) The contribution of boron residues from food/ feed crop application of boric acid/ sodium borate salts to the total naturally occurring background dietary boron intake from food and water is not considered to be significant. Endpoints for acute and chronic dietary exposure were not selected for this risk assessment because it was determined that a dietary risk assessment ( food plus drinking water exposure) was not necessary at this time.

Incidental Oral  all populations, all exposure durations ( short and intermediate term) NOAEL 8.8 mg/ kg/ day Residential LOC for MOE = 100 Occupational LOC for MOE = 100 Chronic and subchronic oral toxicity in dogs ( several studies considered together)

LOAEL = 32 mg/ kg/ day, based on testicular atrophy, slight hematological changes in subchronic study Dermal  all exposure durations ( short, intermediate and long term) Boric acid and its sodium salts are not absorbed across intact skin and a dermal exposure assessment is not required.

Inhalation all exposure durations ( short, intermediate and long term) NOAEL = 8.8 mg/ kg/ day ( Assume inhalation absorption = oral absorption) Residential LOC for MOE = 100 Occupational LOC for MOE = 100 Chronic and subchronic oral toxicity in dogs ( several studies considered together)

LOAEL = 32 mg/ kg/ day, based on testicular atrophy, slight hematological changes in subchronic study Cancer ( oral, dermal, inhalation) Classification: Not carcinogenic to humans UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level. * Refer to Section 4.5 Page 42 of 84 4.5 Special FQPA Safety Factor Based upon the hazard data presented above, it is recommended that the special FQPA SF be reduced to 1x because there are no residual uncertainties with regard to pre and/ or postnatal toxicity. The pre and post natal toxicity of boric acid and its sodium salts has been adequately characterized. Increased fetal sensitivity was observed in the rat in developmental toxicity studies, as evidenced by decreased fetal body weight and increased incidence of skeletal abnormalities below maternally toxic doses. Rabbits and mice did not demonstrate increased fetal sensitivity. Reproductive toxicity studies in two species are also available. The mechanism of testicular effects ( inhibited spermiation, testicular atrophy) has not been characterized, but the lack of effects on male reproductive function in the rat and mouse reproductive toxicity studies at doses ( NOAELS 25 26 mg/ kg/ day) greater than the endpoint used for this risk assessment ( NOAEL 8.8 mg/ kg/ day) suggests that there is not increased sensitivity of the developing testes.

Clinical effects on the nervous system in animal studies are observed only at high dose levels. The increased incidence of enlarged fetal lateral ventricles seen in the rat developmental toxicity study ( MRID 41725401, 42377101) was also observed at a much higher dose level ( 58 mg/ kg/ day, no increase observed at 14 or 29 mg/ kg/ day) than the most sensitive available LOAEL for developmental toxicity ( 13.3 mg/ kg/ day, with a NOAEL of 9.6 mg/ kg/ day in the rat, MRID 43340101). The CNS effect observed in the rat study was not observed in developmental toxicity studies in two other species ( mouse and rabbit) at comparable or higher doses. The endpoint selected for the various exposure scenarios in this risk assessment is the most sensitive NOAEL ( 8.8 mg/ kg/ day based on testicular atrophy) and is therefore considered adequately protective of the fetus for developmental effects on the nervous system.

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).

The potential for disruption of the endocrine system by boric acid/ sodium borate salts is Page 43 of 84 not known at this time. Boric acid and sodium borate salts are known to inhibit spermiation in multiple species. Studies indicate that at high dose levels, boric acid causes a mild reduction in basal serum testosterone levels in male rats and that this effect may be CNS mediated, based on lack of apparent effects on steroidogenic function on isolated Leydig cells ( Ku and Chapin, 1994a). At this time, Fail et al. ( 1998) have noted that boron is unlikely to act as an endocrine disruptor because the hormonal changes appear to be secondary to testicular cytotoxicity. However, the mechanism by which inhibition of spermiation, as well as effects on the ovary, occur in vivo have not been fully characterized. When the appropriate screening and/ or testing protocols being considered under the EDSP have been developed, boric acid/ sodium borate salts may be subject to additional screening and/ or testing.

5.0 Public Health Data 5.1 Incident Reports Incident reporting data and case reports of human toxicity have been reviewed by HED ( memorandum from Monica Hawkins and Hans Allender to Linnea Hansen, DP Barcode DP320914). The following databases were reviewed and findings are summarized for each:

1) OPP Incident Data System ( IDS)  reports of incidents from various sources, including registrants, other federal and state health and environmental agencies and individual consumers, submitted to OPP since 1992. Reports submitted to the Incident Data System represent anecdotal reports or allegations only, unless otherwise stated. Typically no conclusions can be drawn implicating the pesticide as a cause of any of the reported health effects. Nevertheless, sometimes with enough cases and/ or documentation risk mitigation measures may be suggested.

Findings: Twenty incident cases for boric acid or sodium borate salts were reported to OPP since 1992. Of these, about one half were reportedly due to inhalation exposure either during application or postapplication. Some cases appeared to be due to misapplication of products; other reports did not contain sufficient information to make that determination. Symptoms commonly reported included headache, nausea, vomiting, rash, respiratory irritation/ shortness of breath, coughing, chest pain, ocular irritation and diarrhea.

2) Poison Control Centers  as the result of a data purchase by EPA, OPP received Poison Control Center data covering the years 1993 through 1998 for all pesticides. Most of the national Poison Control Centers ( PCCs) participate in a national data collection system, the Toxic Exposure Surveillance System which obtains data from about 65 70 centers at hospitals and universities. PCCs provide telephone consultation for individuals and health care providers on suspected poisonings, involving drugs, household products, pesticides, etc.

Findings: Comparisons were made between boric acid related products and all pesticides cases reported for percent cases with symptomatic outcomes and degree of severity of the outcome, and the percent resulting in a visit to a health care facility and of those, the percentage Page 44 of 84 resulting in hospitalization or requiring intensive care. Separate comparisons were made for occupational cases, non occupational cases for adults and older children and non occupational cases for children under six years of age. The largest number of exposures was reported in children under six ( total 26,993), followed by non occupational adult/ older child ( 4,231) and occupational exposures to adults ( 93). Comparisons of the data indicated that relative to all pesticides, boric acid related products were in general less likely to result in symptomatic outcomes of any severities, or to require medical care. Occupational cases for boric acid related products were more likely than the non occupational cases to result in a symptomatic outcome, or an outcome with moderate to severe effects. The incidence of moderate to severe outcomes was relatively low for all groups ( 9.8%, occupational, 4.11%, non occupational adult/ older child and 0.26%, children under six) and outcomes that were life threatening or fatal were rare ( one reported among children under six). The most common findings reported among the symptomatic outcomes were vomiting, eye irritation, nausea and oral irritation; these symptoms were observed among a relatively small percentage of the total exposures.

3) California Department of Pesticide Regulation  California has collected uniform data on suspected pesticide poisonings since 1982. Physicians are required by statute to report to their local health officer all occurrences of illness suspected of being related to exposure to pesticides. The majority of the incidents involve workers. Information on exposure ( worker activity), type of illness ( systemic, eye, skin, eye/ skin and respiratory), likelihood of a causal relationship, and number of days off work and in the hospital are provided.

Findings: Since 1982, 80 cases of illness judged as definitely, probably or possibly related to boric acid compounds alone were identified. The majority reported systemic effects, but respiratory, skin and eye effects were also commonly seen. Usually there were from one to five incidents per year, but in a few years more were observed. These were due to two separate incidents of multiple persons being exposed at a workplace following misapplication of boric acid. Exposures of applicators to excessive amounts of boric acid accounted for 21% of the reported incidents. Systemic effects reported included headache, difficulty breathing, sore throat, chemical pneumonitis and diarrhea.

4) National Pesticide Information Center ( NPIC)  NPIC is a toll free information service supported by OPP. A ranking of the top 200 active ingredients for which telephone calls were received during calendar years 1984 1991, inclusive has been prepared. The total number of calls was tabulated for the categories human incidents, animal incidents, calls for information, and others.

Findings: On the list of the top 200 chemicals for which NPIC received calls from 1984 1991 inclusively, boric acid was ranked 25th with 142 incidents in humans reported and 48 in animals ( mostly pets).