 Page 1 of 39 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES January 17, 2006 MEMORANDUM SUBJECT: Coppers: Second Revised Human Health Chapter of the Reregistration Eligibility Decision Document ( RED). Reregistration Case Numbers 0636, 0649, 4025, and 4026. DP Barcode D319683.

PC Codes: 023401, 022901, 022702, 022703, 008001, 024405, 023503, 023501, 008101, 024401, 022501, 042401, 025601, 024403, 023104, 024407, 023306, 024409.

Regulatory Action: Phase 2 Reregistration Action. Risk Assessment Type: Multiple chemical/ no aggregate FROM: Christina Jarvis, Risk Assessor Elissa Reaves, Ph. D., Toxicologist Alan Nielsen, Occupational/ Residential Exposure Reregistration Branch 2 Health Effects Division ( 7509C)

AND Tim McMahon, Risk Assessor Michelle Centra, Toxicologist Jonathan Chen, Toxicologist Doreen Aviado, Biologist Antimicrobials Division ( 7510C)

THROUGH: William Hazel, Branch Chief Reregistration Branch 2 Health Effects Division ( 7509C)

AND Mark Hartman, Acting Branch Chief Regulatory Management Branch II Page 2 of 39 Antimicrobials Division ( 7510C)

TO: Rosanna Louie, Chemical Review Manager Special Review and Reregistration Division ( 7508C)

AND Kathryn Jakob, Chemical Review Manager Antimicrobials Division ( 7510C) Page 3 of 39 Executive Summary This document represents the second revised human health risk assessment chapter of the Reregistration Eligibility Decision ( RED) document for coppers, including copper II compounds, copper sulfates, copper and oxides, copper salts, and other unscheduled coppers. Coppercontaining compounds are used in pesticidal products as fungicides, bactericides, algaecides, herbicides, anti foulants, and wood preservatives, and are applied to a wide variety of agricultural, commercial, and residential use sites. Since copper is a naturally occurring metal that is efficiently regulated in the human system, and since there is a lack of systemic toxicity associated with copper exposure, no toxicological endpoints have been identified for risk assessment purposes. Quantitative dietary and occupational/ residential exposure assessments have not been conducted.

This second revised risk assessment document has been updated to reflect comments submitted by the Copper Reregistration Task Force, Adchem Australia Pty Ltd., and by the Copper Sulfate Task Force.

Copper naphthenate, copper 8 quinolinolate, and cuprous thiocyanate will be assessed individually by OPP's Antimicrobials Division at a later date. The purpose of listing all studies ( including copper naphthenate, copper 8 quinolinolate, and cuprous thiocyanate) in the toxicity data summary tables in Appendix A of this document is to present all available data that have been reviewed and considered acceptable, even though the aforementioned three active ingredients are not included in the scope of this risk assessment.

1.0 Introduction 1.1 Scope of Risk Assessment This risk assessment is unique in two aspects: first, it assesses four copper cases ( and other unscheduled coppers) in one comprehensive document, and second, as copper is a naturally occurring metal that is also an essential element in the human body, no toxicological endpoints have been selected for dietary or exposure risk assessment purposes.

The following 18 copper cases are addressed in this document: copper II compounds ( copper hydroxide, copper carbonate, copper ammonia complex, copper ammonium carbonate, basic copper chloride, copper ( metallic) in the form of chelates of copper citrate and copper gluconate, copper oxychloride sulfate, copper oxychloride), copper sulfates ( basic copper sulfate, copper sulfate pentahydrate), copper and oxides ( copper metallic, cupric oxide, cuprous oxide), copper salts ( copper from triethanolamine complex, copper salts of fatty and rosin acids, copper as elemental from copper ethylenediamine complex), and other unscheduled coppers ( copper octanoate, copper ethanolamine complex).

Table 1. Summary of copper cases included in risk assessment. Case Active ingredient PC Code Copper II compounds ( 0649) Copper hydroxide 023401 Page 4 of 39 Case Active ingredient PC Code Copper carbonate 022901 Copper ammonia complex 022702 Copper ammonium carbonate 022703 Basic copper chloride 008001 Copper ( metallic) in the form of chelates of copper citrate and copper gluconate 024405 Copper oxychloride sulfate 023503 Copper oxychloride 023501 Basic copper sulfate 008101 Copper sulfates ( 0636) Copper sulfate pentahydrate 024401 Copper   metallic 022501 Cupric oxide 042401 Copper and oxides ( 4025)

Cuprous oxide 025601 Copper from triethanolamine complex 024403 Copper salts of fatty and rosin acids 023104 Copper salts ( 4026)

Copper as elemental from copper ethylenediamine complex 024407 Copper octanoate 023306 Other unscheduled coppers Copper ethanolamine complex 024409 1.2 Background Copper is a naturally occurring metal that is also an essential nutrient in the human body. The recommended dietary allowance ( RDA) of copper, as established by the National Academy of Science, ranges from 340 micrograms per day ( ug/ d) in young children to 900 ug/ d in adults. The RDA of copper for pregnant and lactating females is slightly higher, with a range of 1000 to 1300 ug/ d. The maximum level of copper that may be consumed with no likely risk of adverse effects ranges from approximately 1000 ug/ d to 10,000 ug/ d. 1 Organ meats ( particularly liver), seafood, nuts, seeds, wheat bran cereals, whole grain products, and cocoa products are all foods rich in copper. A deficiency of copper may lead to a variety of health effects, such as bone abnormalities, severe anemia, a compromised immune function, and growth retardation, while excessive consumption of copper may cause acute gastrointestinal distress, including nausea and/ or vomiting, and/ or chronic liver toxicity.

Copper is also found in drinking water, often as a result of the use of copper in plumbing fixtures and water pipes. Concentrations of copper in drinking water are regulated by the USEPA under 1 Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc ( 2000). Available at: http:// www. nap. edu/ openbook/ 0309072794/ html/ Page 5 of 39 the Safe Drinking Water Act ( SDWA). Under the SDWA, the USEPA sets maximum contaminant level goals ( MCLGs) for chemicals in drinking water that may cause human health problems. The MCLG for copper in drinking water is set at 1.3 parts per million ( ppm).

1.2.1 Regulatory History Guidance documents for the reregistration of copper sulfates and copper II compounds were prepared in March 1986 and September 1986, respectively. In 1990, HED addressed toxicology, product and residue chemistry, dietary exposure, and reentry and non dietary exposure issues for the reregistration of copper sulfate and copper II compounds ( L. Kutney, 8/ 13/ 1990). At that time, product chemistry data gaps were identified for copper sulfate and copper II compounds, and acute toxicity data gaps were identified for copper II compounds, including acute oral and acute dermal toxicity studies, and primary eye and primary dermal irritation studies.

Additionally, foliar dissipation and post application dermal exposure studies were required for copper sulfate. A 24 hour interim reentry interval was recommended for foliar applications for copper sulfate, pending the submission and review of required reentry data. However, with the promulgation of the Worker Protection Standard for Agricultural Pesticide, a restricted entry interval for each copper species is be established based on the acute toxicity of the copper species ( see discussion later in this document).

With regards to tolerances, HED recommended that the established tolerances for potable water ( see section 1.3.1 below) be revoked, as the Office of Pesticide Programs no longer establishes water tolerances. This tolerance, however, is still established at 1 ppm.

In 1993, HED completed the reregistration eligibility decision document on copper ( metallic), cupric oxide, and cuprous oxide ( A. Aikens, 8/ 6/ 1993). Due to eye irritation and the potential for inhalation exposure, protective gear was recommended for mixers, loaders, and applicators, and the following label language was recommended: " May cause skin sensitization in certain individuals." These label requirements should be based on the acute toxicity of the end use products.

1.2.2 Summary of Pesticidal Uses Copper containing compounds are used in pesticidal products as fungicides, bactericides, algaecides, herbicides, anti foulants, and wood preservatives. Products containing copper may be applied to a wide variety of agricultural, commercial, and residential use sites, and are formulated as dusts, wettable powders, liquids ( including ready to use liquids), dry flowables, water soluble packets, and granulars.

Application methods are as varied as the use sites, and include aerial, airblast, groundboom, rights of way equipment, mechanical duster equipment, low and high pressure handwand, handgun sprayer, hose end sprayer, push type spreader, paint sprayer, brushes, sponges, rollers, dips, direct pour, aerosol spray, pressure treatment equipment, or drip system. Page 6 of 39 1.3 Tolerances 1.3.1 Established tolerances A tolerance is established for residues of basic copper carbonate in or on pears at 3 ppm of combined copper from post harvest use ( impregnated paper wrappers) ( 40 CFR § 180.136).

A tolerance is established for residues of copper in potable water at 1 ppm, resulting from the use of basic copper carbonate, copper sulfate, copper monoethanolamine, and copper triethanolamine to control aquatic plans in reservoirs, lakes, ponds, irrigation ditches, and other potential sources of potable water ( 40 CFR § 180.538).

1.3.2 Tolerance exemptions The following copper products are exempt from tolerance requirements when applied as a fungicide to growing crops using good agricultural practices: Bordeaux mixture, basic copper carbonate, copper ethylenediamine complex, copper hydroxide, copper lime mixtures, copper linoleate, copper octanoate, copper oleate, copper oxychloride, copper sulfate ( basic), cupric oxide, and cuprous oxide ( 40 CFR § 180.1021( b)).

The following are exempt from tolerance requirements in meat, milk, poultry, eggs, fish, shellfish, and irrigated crops: copper sulfate, basic copper carbonate, copper triethanolamine and copper monoethanolamine, and cuprous oxide ( 40 CFR § 180.1021( a)).

Copper sulfate pentahydrate is exempt from tolerance requirements when applied as a fungicide to growing crops or raw agricultural commodities after harvest ( 40 CFR § 180.1021( c)).

Copper ( II) hydroxide is exempt from tolerance requirements when applied to growing crops or raw agricultural commodities as an inert ingredient ( for pH control) in pesticide products ( 40 CFR § 180.1021( d)).

2.0 Hazard Characterization and Assessment [ For complete details regarding the hazard characterization and assessment of coppers, see E. Reaves memo, Appendix A].

Acute toxicity studies exist for most copper species, with the exception of copper ammonium carbonate, copper ammonia complex, chelates of copper gluconate, copper oxychloride sulfate, basic copper sulfate, copper sulfate anhydrous, and copper ethanolamine complex. The component of toxicological interest is elemental copper. Copper has moderate to low toxicity ( toxicity category II, II, and IV) based on acute oral, dermal, and inhalation studies in animals, with the exception of cuprous oxide, which has a toxicity category of I for acute inhalation. Information available through the literature, or studies provided by the registrant, warrants the limitation of excessive inhalation of copper. When ingested orally, copper can be a gastric irritant and produce corrosion of the gastric and intestinal epithelium ( IPCS PIM 1991). Page 7 of 39 Most dermal irritation studies indicate copper is a toxicity category III or IV; however, cuprous oxide and naphthenate forms of copper produce toxicity category I and II irritation, respectively. Copper is generally non sensitizing in guinea pigs and rabbits, except for copper naphthenate, which was a skin sensitizer. A human skin sensitization study indicates copper ( as sulfate pentahydrate) was a sensitizer to human skin. Copper in certain forms is a severe eye irritant ( toxicity categories I and II).

The human body appears to have efficient mechanisms in place to regulate total body copper, given the relatively small and constant body pool of copper. In the healthy adult, nearly twothirds of the body copper content is located in the skeleton and muscle ( due to their large tissue masses), with the liver is the primary organ for the maintenance of plasma copper concentrations. The efficiency of copper absorption varies greatly, depending on dietary intake. When dietary copper is high and more copper is absorbed, mainly through the gastrointestinal tract, endogenous excretion of copper increases, protecting against excess accumulation of copper in the body. When copper intake is low, little endogenous copper is excreted, protecting against copper depletion.

Systemic effects from oral exposures to copper are rare. In an acceptable non guideline, 12 day dermal toxicity study in the rat, there is a dose related increase in dermal irritation but no systemic toxicity at 1000 mg/ kg/ day ( HDT). Short term feeding studies with rats and mice indicate decreased food and water intake with increasing oral concentrations of copper, with irritation of the stomach at higher copper concentrations. High levels of excess copper administered in the drinking water of mice at 50, 100, 200, or 300 ppm for 3 or 8 weeks suggested an altered immune response; however, the inhibition of immune responses is not unusual since other trace elements have been linked with immuno suppression. In addition, cations like zinc, mercury, and lead have also been reported to alter immune responses. The mechanism by which copper may be exerting a response in the immune system has not been fully determined.

As observed in the short term feeding studies, longer feeding studies indicate decreased feed intake with reductions in body weight gains, and increased copper concentration of the liver. There is no suggestion or evidence that copper or its salts are carcinogenic in animals having normal copper homeostasis. Copper ( metallic) is currently Group D, not classifiable as to human carcinogenicity. Chronic inhalation of copper may become cancerous since available studies from the literature indicate an increased incidence of lung cancer among professional vineyard workers exposed chronically to Bordeaux mixture ( Viller, 1974; Santic et al. 2005); however, this information is not definitive since no information is available on the level of exposure to workers, to either Bordeaux mixture or any other substances with which they might have come into contact. Mutagenicity studies from the literature indicate copper is not mutagenic. There is no indication of endocrine disruption.

Reproductive and developmental studies available by the oral ( gavage or diet) route of exposure indicate that, in general, the main concern in animals for reproductive and teratogenic effects of copper has usually been associated with the deficiency of the element rather than the excess. Page 8 of 39 Reproductive effects such as fetal death, resorptions, and infertility resulting from copper deficiency have been reported in rats and guinea pigs. In a developmental toxicity study in rabbits, the maternal LOAEL is 9 mg Cu/ kg/ day, based on decreased body weight gains and decreased food consumption. The maternal NOAEL is 6 mg Cu/ kg/ day. The developmental LOAEL is 18 mg Cu/ kg/ day ( HDT), based on incidences of hemi vertebra, a malformation, and slight increases in minor variations ( supernumerary ribs and retarded ossification of the mandible, skull, and pelvis). The developmental NOAEL is 9 mg Cu/ kg/ day.

There is no evidence to suggest susceptibility in infants and children. Since copper is a natural essential trace element, with copper deficiency more common in humans than toxicity from excess, and since the dietary contribution of copper to the total diet is low, the additional tenfold FQPA safety factor for the protection of infants and children is unnecessary.

No endpoints of toxicological concern have been identified for risk assessment purposes. Therefore, dietary, residential, and occupational risk assessments have not been conducted.

3.0 Incident Report [ M. Hawkins. Review of Copper Incident Reports. D319175. 8/ 22/ 2005].

An incident report prepared for copper reflects data from the following sources: OPP Incident Data System ( IDS); Poison Control Center; California Department of Pesticide Regulation; National Pesticide Information Center ( NPIC); and the National Institute of Occupational Safety and Health's Sentinel Event Notification System for Occupational Risks ( NIOSH SENSOR).

The IDS has seven recorded pesticide incidents for copper; five involve copper hydroxide and two involve copper sulfate pentahydrate. The majority of the noted effects involved skin and eye irritation, nausea, vomiting, and headaches.

The principle types of copper fungicides included in the Poison Control Center data ( 1993   2003) are copper sulfate and copper hydroxide. Of the 82 copper exposures identified in the Poison Control Center data, only 20 were seen in a health care facility, and just three cases had a moderate medical outcome. The leading symptoms included ocular irritation, vomiting, nausea, and dermal irritation.

Data from the California Department of Pesticide Regulation ( 1982   2003) show that 156 cases ( out of 494) were due to copper compounds. The majority of these cases show eye effects, skin effects, or systemic effects ( including skin, eye, or respiratory effects).

Of the top 200 chemicals for which the NPIC received calls from ( 1984 1991), copper hydroxide was ranked 167th and copper sulfate was ranked 179th, with 15 and 13 reports of illness to humans, respectively.

NIOSH SENSOR data reveal that out of 5899 reported cases between 1998   2003, only 34 cases were documented as involving copper ( copper sulfate pentahydrate, copper hydroxide, and copper ammonia complex). Twenty five of the 34 documented cases were from California, and Page 9 of 39 most likely overlap the cases discussed above from the California Department of Pesticide Regulation.

According to a review of the scientific literature, copper compounds formulated as dusts and as powders are irritating to the skin, respiratory tract, and the eyes. Most copper compounds have low systemic toxicity, due mainly to their limited solubility and absorption. Occupational exposure to copper containing compounds frequently results in irritation effects. These findings from the scientific literature reflect the reported incidents from the above referenced databases.

4.0 Exposure Assessment 4.1 Dietary Exposure ( food and drinking water)

An exposure assessment considers the different pathways ( food, water, occupational, and residential) through which exposure to copper may occur. Copper occurs naturally in foods such as potatoes, vegetables, organ meats ( especially liver), poultry, seafood, beans, nuts, and wholegrains The National Academy of Science establishes recommended daily allowances ( RDAs) of vitamins and minerals for the diet. The RDA for copper ranges from approximately 400 micrograms per day ( ug/ d) in young children to 900 ug/ d in adults. Additionally, over thecounter dietary supplements containing copper at levels ranging from 0.33 mg to 3 mg are available for individuals with low levels of copper. The maximum level of copper that may be consumed with no likely risk of adverse effects ranges from approximately 1000 ug/ d to 10,000 ug/ d ( 1 10 mg/ d). The estimated total daily oral intake of copper ( food plus drinking water) is between 1 and 2 mg/ d, although oral intake may occasionally exceed 5 mg/ d.

In addition to exposure from naturally occurring levels of copper in food, dietary exposure to copper may also occur as a result of the use of copper as a pesticidal product on a variety of food commodities, including fruit, vegetable, and nut crops. However, as noted in Section 1.3.2, the use of various copper products on growing crops and/ or raw agricultural commodities, as well as on meat, milk, poultry, eggs, fish, shellfish, and irrigated crops, is exempt from tolerance requirements. This is due in part to the difficulty in distinguishing naturally occurring, background levels of copper from levels resulting from the application of copper as an active ingredient in pesticide formulations.

Copper may also be found in drinking water, commonly due to the use of copper in plumbing fixtures and water pipes. Copper may also enter drinking water systems via contamination from mining operations, incineration, industrial discharges, and from sewage treatment plants. Residues of copper in drinking water are regulated under the SDWA. A MCLG of 1.3 ppm has been set by the Agency for copper. According to the National Research Council's Committee on Copper in Drinking Water, this level is " set at a concentration at which no known or expected adverse health effects occur and for which there is an adequate margin of safety." 2 2 Copper in Drinking Water. Committee on Copper in Drinking Water, Board on Environmental Studies and Toxicology, Commission on Life Sciences, National Research Council. 2000. Page 10 of 39 Given the role copper plays as an essential element to the human body, its ubiquitous nature in food and drinking water, and the long standing tolerance exemptions for the pesticidal use of copper on growing crops, as well as on meat, milk, poultry, eggs, fish, shellfish, and irrigated crops, a dietary risk assessment is not required. Acute and chronic dietary endpoints have not been selected.

4.1.1 Tolerance Reassessment The 1 ppm tolerance for copper residues in potable water ( 40 CFR § 180.538) should be revoked, as OPP no longer establishes water tolerances. This tolerance revocation was originally recommended by HED in 1990 ( see L. Kutney memo, 8/ 13/ 1990): " The tolerance for potable water should be revoked because OPP no longer establishes water tolerances. The Office of Drinking Water should be advised to consider a 1 ppm Acceptable Residue Level in Drinking Water ( ARLDW) for residues of copper sulfate." The Office of Ground Water and Drinking Water currently has a 1.3 ppm MCLG and a 1.3 ppm Action Level3 in place for copper.

The 3 ppm tolerance for residues of basic copper carbonate in or on pears at 3 ppm of combined copper from post harvest use ( 40 CFR § 180.136) should be revoked. This tolerance is not necessary for human health protection, as many food commodities not treated with coppercontaining products have naturally occurring levels of copper that are higher than those found in or on pears, as a result of the use of treated paper wrappers. In addition, toxicological studies support the view that residues from the use of copper carbonate on impregnated pear wrappers do not pose a significant risk to human health.

The coppers are currently exempt from tolerance requirements on all raw agricultural commodities [ 40 CFR § 180.1021]. As part of the reregistration process for copper, the Agency concludes that all food use copper formulations are still exempt from the requirement of a tolerance. Should any additional copper active ingredients be registered for new food uses in the future, the need for a tolerance for these formulations will be evaluated at that time.

The following list represents all food use copper formulations that are exempt from tolerance requirements on raw agricultural commodities.

  copper hydroxide ( 023401)   copper carbonate ( 022901)   copper ammonia complex ( 022702)   basic copper chloride ( 008001)   copper ( metallic) in the form of chelates of copper citrate and copper gluconate ( 024405)   copper oxychloride sulfate ( 023503)   copper oxychloride ( 023501)   basic copper sulfate ( 008101)   copper sulfate pentahydrate ( 024401)

3 An Action Level is defined by the EPA as " the level of lead or copper which, if exceeded, triggers treatment or other requirements that a water system must follow." Page 11 of 39   cuprous oxide ( 025601)   copper from triethanolamine complex ( 024403)   copper salts of fatty and rosin acids ( 023104)   copper as elemental from copper ethylenediamine complex ( 024407)   copper octanoate ( 023306)   copper ethanolamine complex ( 024409)

4.2 Occupational and Residential Exposure [ For complete agricultural, commercial, and residential use tables for all registered copper products, see A. Nielsen memo, D319173, 9/ 1/ 2005].

Copper formulations are used on a variety of agricultural, commercial, and residential use sites as fungicides, bactericides, algaecides, herbicides, wood preservatives, and anti fouling agents. There is potential for exposure to occupational mixers, loaders, and applicators of copper formulations, as well as to residential homeowners who may apply copper containing products in and around their homes; however, no dermal, oral, or inhalation endpoints of toxicological concern have been identified for copper. Therefore, an occupational/ residential exposure assessment is not required.

Some copper species may cause dermal and eye irritation ( Toxicity Category I/ II) in occupationally or non occupationally exposed individuals. Since no toxicological endpoints of concern were identified for dermal exposures to copper species, no post application dermal risk was assessed. For uses within the scope of the Worker Protection Standard for Agricultural Pesticides ( 40 CFR 170), a restricted entry interval ( REI) must be established. For each copper species, the REI should be based on the category assigned to the acute dermal toxicity, skin irritation potential, and eye irritation potential of the active ingredient. The appropriate REI is 48 hours if any of the three categories is classified as a category one; the appropriate REI is 24 hours if any of the three categories is classified as category two. If all three categories are classified as category three or four, the appropriate REI is 12 hours. If no data are available on the acute dermal toxicity, skin irritation potential, and eye irritation potential of the active ingredient, then a default REI of 48 hours is appropriate.

For commercial uses of copper containing products, dermal, eye, and respiratory irritation effects are addressed through precautionary labeling requirements for use of Personal Protective Equipment ( PPE). In addition, protection is provided with the use of engineering controls for industrial applications. For airborne concentrations in industrial workplace settings, OSHA has set a permissible exposure limit ( PEL) ( 8 hour time weighted average, or TWA) of 1.0 mg/ m3 for dusts and mists ( as Cu).

For copper species used in residential settings, dermal and eye irritation effects will be addressed through end use product labeling language.

The following is a summary of the various agricultural, commercial, and residential uses of copper formulations: Page 12 of 39 Agricultural Uses: Twelve species of copper are registered for use on agricultural crops. In agricultural settings, copper formulations are most commonly used as fungicides, but may also be used as bactericides, herbicides, and algaecides. Formulation types include dusts, liquid concentrates, dry flowables, wettable powders, and wettable powders in water soluble packets. Application methods include aerial, airblast, groundboom, rights of way equipment and mechanical duster equipment, low and high pressure handwand sprayers, and handgun sprayers. Agricultural use sites include:

  Virtually all food, feed, fiber, and specialty crops,   All ornamental crops grown in greenhouses and nurseries, and   Turfgrass ( i. e., sod farms).

Commercial Uses: Sixteen species of copper are registered for commercial use, typically as fungicides, bactericides, herbicides, algaecides, and insecticides. Formulation types include wettable powders, wettable powders in water soluble packets, liquid concentrates, granules, water dispersible granules, powders, and ready to use liquids, aerosols, and solids. Application methods include groundboom, low pressure handwand, handgun sprayer, push type spreader, paint sprayer, brushes, sponges, rollers, dips, direct pour, industrial coating equipment, pressure treatment equipment, drip system or pump metering, and other specialty equipment. Commercial use sites include:

  Planter, seed handling equipment, nursery containers, and similar agricultural equipment,   Industrial use fabrics,   Aquatic sites ( swimming pools, ornamental ponds and fountains, potable water, lakes, rivers, irrigation systems, stock watering tanks, troughs),   Household sewers, feedlot lagoons, animal confinement pits, other organic sludges, storm drains, sewers, sewer pumps, and force mains,   Turfgrass ( golf courses, cemeteries, home lawns, industrial and municipal turf areas,   Industrial recirculating cooling systems,   Wood and wood products,   Boats and other marine equipment,   Textiles,   Materials such as paints, adhesives, plastics, fibers, coatings, sealants, clay, china, ceramic, sand, and grout ( incorporated during manufacturing processes),   Paper products, and   Environmental surfaces ( paint, varnish, concrete, brick, glass, tile, metals, plastics, wood, paper, leather, textiles, asphalt shingle).

Residential ( Homeowner) Uses: There are seventeen species of copper that have registered residential ( homeowner) uses. In residential settings, copper formulations are used as fungicides, bactericides, herbicides, and algaecides. Formulations include dusts, liquid concentrates, dry flowables, wettable powders, Page 13 of 39 granules, and ready to use solids, aerosols, and liquids. Application methods include lowpressure handwand, hose end sprayer, brush, roller, paint sprayer, automatic metering systems, dipping, direct pour, or aerosol spray. Residential use sites are as follows:

  Virtually all food and specialty garden crops,   All ornamental crops,   Turfgrass,   Aquatic sites ( aquariums, swimming pools, ornamental ponds and fountains),   Household sewer systems,   Wood and wood products,   Boats,   Environmental surfaces ( paint, varnish, concrete, brick, glass, tile, metals, plastics, wood, paper, leather, textiles, asphalt shingles),   Residential outdoor surfaces ( roofs, decks, patios, sidewalks, driveways),   Textiles, and   Compost.

5.0 Summary Copper is an ubiquitous, naturally occurring metal that is essential to human health. It is found at low levels in a variety of food products, as well as in drinking water. Copper may also be used on a wide variety of agricultural, commercial, and residential use sites as a fungicide, bactericide, algaecide, herbicide, wood preservative, and anti fouling agent. Copper has moderate to low toxicity ( toxicity category II, II, and IV) based on acute oral, dermal, and inhalation studies in animals, with the exception of cuprous oxide, which has a toxicity category of I for acute inhalation. In some forms, it is a severe eye irritant, and copper sulfate pentahydrate may be a dermal sensitizer to human skin.

Acute toxicity data gaps ( acute oral, dermal, and inhalation; primary eye irritation; dermal irritation; and dermal sensitization studies) exist for the following copper species: chelates of copper gluconate, copper ammonium carbonate, copper ammonia complex, copper oxychloride sulfate, basic copper sulfate, and copper ethanolamine complex.

Due to its ubiquitous nature, and because naturally occurring levels of copper on raw agricultural commodities cannot be distinguished from levels that are the result of pesticidal use, many copper species are exempt from tolerance requirements for use on most raw agricultural commodities. A tolerance ( 3 ppm) exists for the use of copper carbonate in/ on pears, and a 1 ppm tolerance exists for residues of copper in potable water.

With respect to dietary issues, HED recommends that the tolerance exemption be expanded to include all existing food use copper formulations, with the exception of three species that do not currently have registered food uses. HED also recommends the tolerance in/ on pears be revoked, as well as the tolerance in potable water. Residues of copper in drinking water are currently addressed by the Agency's Office of Ground Water and Drinking Water. Page 14 of 39 In order to address potential post application exposure from agricultural uses of copper species, HED recommends the establishment of a REI of 12, 24, or 48 hours, depending on the availability and adequacy of acute toxicity studies. If no data are available on the acute dermal toxicity, skin irritation potential, and eye irritation potential of the active ingredient, then a default REI of 48 hours is appropriate. Commercial uses of copper based pesticides will be adequately protected through label specified PPE ( based on the toxicity categories of the end use product), industrial workplace safety standards, and engineering controls. For formulations with residential uses, dermal and eye irritation effects will be addressed via end use product labeling language.

In summary, humans have a unique ability to maintain appropriate copper stores in the body. Exposure is primarily through food that is consumed with established Recommended Daily Allowances ( RDAs) for adults, children, and infants. Copper may be irritating to the skin, eyes, and lung. Copper residues from the use as a pesticidal active ingredient are not expected to significantly contribute to the naturally occurring levels of copper in foods; therefore, toxicological endpoints have not been established and dietary, occupational, and residential risk assessments are not required. Page 15 of 39 Appendix A Hazard Assessment of Copper The hazard profile and characterization for this risk assessment is unique since four copper cases ( 0649, 0636, 4025, 4026) as well as other unscheduled coppers will be assessed in a single document. The copper cases include the copper compounds ( PC Codes: 008001, 024405, 022703, 022901, 023401, 022702, 023501, 023503), copper sulfates ( 008101, 024408, 024401), copper and oxides ( 022501, 042401, 025601), copper salts ( 024403, 024407, 023104), and other unscheduled coppers ( 023306, 024409).

Copper naphthenate, copper 8 quinolinolate, and cuprous thiocyanate will be assessed individually by OPP's Antimicrobials Division at a later date. The purpose of listing all studies ( including copper naphthenate, copper 8 quinolinolate, and cuprous thiocyanate) in the toxicity data summary tables in Appendix A is to present all available data that have been reviewed and considered acceptable, even though the aforementioned three active ingredients are not included in the scope of this risk assessment.

A. Hazard Profile:

The following hazard presentation will describe the toxicology of copper, with the component of toxicological interest as elemental copper. The available toxicity studies submitted for reregistration for each of the coppers differs and are difficult to separate since many of the toxicity studies are old and do not specify the percent of elemental copper used in the studies. However, studies have been separated by their respective PC Code for ease of documentation. Please see the toxicity profile tables in Section K for the available toxicity studies for the different copper cases. The following hazard section also includes review type articles or published studies. Information from the WHO Guidelines, ATSDR ( 2004), Food and Agriculture Organization ( FAO), IOM ( 2001), National Research Council ( 2000), International Programme on Chemical Safety ( IPCS), and National Toxicology Program ( NTP) have also been included in this assessment.

Copper is a naturally occurring element that is essential for the homeostasis of life. The role of copper in maintaining normal health both in animals and humans has been recognized for many years. Sources of human and environmental copper include windblown dust, volcanoes, decaying vegetation, forest fires and sea spray. Copper is also found naturally in various foods, including organ meats ( liver), seafood, beans, nuts, and whole grains. It has been estimated that approximately 40% of dietary copper is consumed from yeast breads, white potatoes, tomatoes, cereals, beef and dried beans and lentils ( Subar et al., 1998). In most foods, copper is present bound to macromolecules rather than as a free ion ( IOM, 2001). Additional copper also may be consumed from drinking water from copper pipes, and using copper cookware. Anthropogenic emissions include smelters, iron foundries, power stations and combustion sources such as municipal incinerators. An estimate for the agricultural use of copper products was approximately 2% of copper released to soil. ( IPCS, 1998). Page 16 of 39 The mechanisms that regulate the metabolism of copper in humans are not yet well understood. However, the mechanisms regulating total body copper seem efficient, given the relatively small and constant body pool of copper. In fact, an estimate of 80 to 150 mg may be found in the body at any given point ( FAO/ WHO, 1970; Turnlund, 1998). In the healthy adult, nearly twothirds of the body copper content is located in the skeleton and muscle ( due to their large tissue masses), with the liver as the primary organ for the maintenance of plasma copper concentrations ( FAO/ WHO 1970; WHO 1974). In newborns it is reported that the liver contains the majority ( 50 60%) of the body copper ( Luza and Speisky, 1996).

The efficiency of copper absorption varies greatly, depending on dietary intake. Changes in efficiency of absorption help to regulate the amount of copper retained by the body. In fact, when dietary copper is high and more copper is absorbed, mainly through the gastrointestinal tract, excretion of endogenous copper increases, protecting against excess accumulation of copper in the body. Depending on the copper status in the body at the time, approximately 20 to 60% of dietary copper may be absorbed ( JECFA # 551). Copper absorption is also affected by other factors such as species, age, chemical form, physiological status ( e. g. pregnancy) and various dietary components. When copper intake is low, little endogenous copper is excreted, protecting against copper depletion.

The proper regulation of copper in humans involves both the carrying protein ceruloplasmin and the excretion of copper mainly in the bile. Dietary copper absorbed through the intestinal mucosa is transported via the portal blood to the liver. Copper that is taken up by the liver is then incorporated into ceruloplasmin, released into the blood, and delivered to tissues ( Turnlund, 1998, WHO Guidelines, 2004). Approximately 60% to 95% of the copper in systemic circulation is bound by ceruloplasmin ( IOM 2001, NRC 2000, IPCS 1998, Luza and Speisky, 1996). It has been reported that humans generally have more of these ceruloplasmin proteins than animals, thereby enhancing copper efficiency in humans ( IPCS PIM, 1991). Most endogenous copper is excreted in the bile, another component in the regulation of the total body level of copper. Very little copper is lost in the urine and sweat. The biological half life of copper in humans has been estimated to be about 4 weeks ( Strickland et al., 1972; Dekaban et al., 1975).

The amount of copper that is retained in the body from the diet and drinking water typically depend on the copper status of the individual at the time. A positive copper balance for humans is generally maintained if the dietary intake is approximately 2 mg/ day. As copper intake increases there is generally an increase in the amount retained, up to an intake of about 8 mg/ day. Copper intake beyond this rate generally results in no significant increase in the amount of copper retained ( Schroeder et al., 1966; Evans, 1973).

In pregnant women, it is hypothesized that increased levels of plasma copper are not due to a greater efficiency of intestinal absorption of copper, but rather to increased biosynthesis of ceruloplasmin and mobilization of liver copper stores ( Markowitz et al., 1955). Page 17 of 39 Improper Metabolism of Copper in Humans:

Copper is an essential cofactor for approximately a dozen copper binding proteins for the proper regulation of copper homeostasis. A deficiency of copper or a defect in copper carrying proteins may result in symptoms such as anemia, defective blood vessel development, copper toxicity, or connective tissue symptoms ( Danks, 1988; Pena et al., 1999; Prohaska and Gybina, 2004).

Some genetic conditions in humans may produce abnormal copper metabolism, thus resulting in either copper toxicity or deficiency. Autosomal recessive disorders such as Wilson's Disease, OHS ( Occipital Horn Syndrome), TIC ( Tyrolean Infantile Cirrhosis), ICC ( Indian Childhood Cirrhosis), ICT ( Idiopathic Copper Toxicosis), and aceruloplasminanemia, result in copper toxicity. For example, Wilson's disease is due to the inability for biliary excretion of copper which leads to the gradual accumulation of copper predominately in the liver and brain. In contrast, Menkes disease is an X linked neurodegenerative disorder in infants characterized by poor growth and unusual " kinky" hair texture. In Menkes disease, clinical effects include low ceruloplasmin concentrations and decreased concentrations of copper in the liver and brain ( Danks, 1995). The major cause of this copper deficiency is minimal copper absorption by the intestinal mucosa and transport of copper across the blood brain barrier, independent of copper intake ( Danks et al., 1972).

B. Mode of Action:

Copper salts such as copper sulfate are gastric irritants and produce corrosion of the gastric and intestinal epithelium. Copper ion may oxidize oxyhemoglobin from the ferrous to the ferric form. In the ferric form, hemoglobin loses its oxygen binding capacity resulting in methemoglobinemia and cyanosis ( IPCS PIM, 1991).

C. Available In House Studies and Literature Database Description:

Acute Studies: ( Please see Section J for Acute Toxicity Tables)

Acute toxicity studies for the routes of exposure, namely, oral, dermal, and inhalation, exist for almost all copper species. However, none of the acute toxicity studies are available for copper ammonium carbonate, copper ammonia complex, chelates of copper gluconate, copper oxychloride sulfate, basic copper sulfate, copper sulfate anhydrous, and copper ethanolamine complex. Copper has moderate to low toxicity ( toxicity category II, II, and IV) based on acute oral, dermal, and inhalation studies in animals, with the exception of cuprous oxide, which has a toxicity category of I for acute inhalation. However, copper may be a severe eye irritant. Most dermal irritation studies indicate Toxicity Category III or IV, however, cuprous oxide and copper naphthenate produced Toxicity Category I irritation. Copper was generally non sensitizing in guinea pigs and rabbits, except for copper naphthenate which was a skin sensitizer. An available human skin sensitization study indicated copper ( as sulfate pentahydrate) was a sensitizer to human skin and warrants the avoidance of dermal exposure to copper. Page 18 of 39 Subchronic Studies:

Copper is generally less toxic when administered in the diet than when administered in drinkingwater or by gavage. Orally, copper is irritative to the gastrointestinal tract, with few systemic effects reported.

Short term feeding studies with rats and mice indicate decreased food and water intake with increasing oral concentrations of copper with irritation of the stomach at higher copper concentrations. The irritating effects of copper were demonstrated in an NTP study ( Hebert et al., 1993). The study was designed to examine the effects, if any, of cupric sulfate pentahydrate when administered in the drinking water for 2 weeks only ( 300 to 10,000 ppm estimated at 41/ 58 to 524/ 683 M/ F mg/ kg/ day mice and 41/ 39 to 140/ 120 M/ F mg/ kg/ day rats) or diet for 2 weeks ( 1,000 to 16,000 ppm estimated at 168/ 210 to 2817/ 3068 M/ F mg/ kg/ day mice and 92/ 89 to 1275/ 1121 M/ F mg/ kg/ day rats) and 13 weeks ( 500 to 16,000 ppm estimated at 173/ 205 ( 1,000 ppm) to 3201/ 4157 M/ F mg/ kg/ day mice and 32/ 34 to 551/ 528 ( 8,000 ppm) M/ F mg/ kg/ day rats) in B6C3F1 mice and F344/ N rats. Dehydration accounted for the deaths of rats and mice in the high dose groups in the drinking water study. Decreased body weight and food consumption was also observed in the two highest dose groups of rats and mice in the feeding study. In summary, cupric sulfate administered to rats in feed or drinking water resulted in gastric changes ( hyperplasia and hyperkeratosis of the squamous epithelium on the limiting ridge of the forestomach) and hepatic ( inflammation), and renal ( increased number and size of protein droplets in epithelium of the renal cortical tubules) damage. Alterations consistent with microcytic anemia were observed in rats, but not in mice, in the 13 week study. Cupric sulfate produced no effects on any of the reproductive parameters ( sperm morphology, vaginal cytology) measured in rats or mice of either sex.

The role of trace metals such as copper in the regulation of the immune system is not understood. A short term drinking water study examined the influence of excess copper on the immune response of mice ( Pocino et al., 1991). Mice receiving 50, 100, 200, or 300 ppm of copper in the drinking water for 3 to 10 weeks had the same general health as controls with no changes in food ingestion or in mean body weight. Immune response was reported  " to be altered in a fashion related to the dose and duration of treatment". However, administration of copper in the drinking water resulted in diminished water consumption, " which was lower as the concentration of copper increased". The amount of water that was consumed by the mice was not reported. In addition, zinc was not measured in this study and since zinc and copper have antagonistic interactions, a zinc deficiency simultaneously with excess copper could also produce inhibited immune responses observed in mice receiving excess copper. Therefore, it is not known whether the dehydration of the animal and a possible zinc deficiency contributed significantly to any immune response detected in this study.

An older report of a rabbit inhalation study with copper sulfate indicated lung lesions were observed in rabbits kept in compartments continuously saturated with a fine spray of Bordeaux mixture ( copper sulfate neutralized with hydrated lime), generated from a Flit spray gun, over a period of 5.5 months ( MRID 00078547, 00062081). However, any possible contamination with arsenic was not reported in this dated report. Although this report is old and not up to current Page 19 of 39 standard guidelines, the reports do provide some insight into potential inhalation hazards of copper. This study was conducted in animals to substantiate the lesions observed in workers who chronically sprayed vineyards with Bordeaux mixture. In addition, results of a 12 day dermal toxicity study in the rat indicated a dose related increase in dermal irritation but with no systemic toxicity at 1000 mg/ kg/ day ( MRID 44127507).

Long Term/ Chronic Studies:

As observed in the short term feeding studies, longer feeding studies indicate decreased feed intake with reductions in body weight gains, and increased copper concentration of the liver. Wistar rats were given either a standard diet with 10 20 mg copper/ kg feed or diets supplemented with 3000, 4000, or 5000 mg of copper/ kg feed for 15 weeks. Dietary copper concentrations were approximately 0.5 1.0, 150, 200, or 250 mg copper/ kg bw/ day. Copper concentrations increased in the livers of the rats on supplemental copper at 3 4 weeks, decreased significantly at 6 weeks, but were still elevated at 15 weeks. Hepatocellular necrosis was observed in all supplemental groups from weeks 1 6, with regeneration beginning after 3 5 weeks. Adaptation of the liver indicated by decreased liver copper concentration, regeneration, growth, and then tolerance was observed in livers of rats on 3000 to 5000 mg copper supplement for 52 weeks. Rats on 6,000 mg/ kg copper maintained hepatic overload and did not recover ( Haywood and Loughran, 1985).

A number of older studies with various copper compounds have examined the carcinogenicity in laboratory animals, but all these studies are considered inadequate by current methodologies ( NRC, 2000). Regardless of the age of the studies, there is no suggestion or evidence that copper or its salts are carcinogenic in animals having normal copper homeostasis. Copper ( metallic) is currently Group D, not classifiable as to human carcinogenicity.

Reproductive and Developmental studies:

Reproductive and developmental studies available by the oral ( gavage or diet) route of exposure indicate that in general, the main concern in animals for reproductive and teratogenic effects of copper has usually been associated with the deficiency of the element rather than excess. Copper is a nutritionally required trace element that is necessary for maintaining the health of embryos, fetus, newborn, and infant. Reproductive effects such as fetal death, resorptions, and infertility resulting from copper deficiency have been reported in rats and guinea pigs ( Oster and Salgo, 1977).

Reproductive parameters measured in rats and mice from exposure to administered ( water or diet) cupric sulfate ( 2 to 13 weeks) at doses ranging from 500 ppm to 8000 ppm ( Hebert et al., 1993) indicated no significant differences from control values for any of the following reproductive parameters: testis, epididymis and cauda epididymis weights, spermatid count, spermatid number per testis or per gram testis, spermatozoal motility and concentration, estrous cycle length or relative length of time spent in the various estrous stages. Page 20 of 39 As with any substance, high concentrations of copper ( CuSO4) may result in the toxicity of the developing organism. Sexually mature mice ( 2 strains) were fed 0.5, 1.0, 1.5, 2.0, 3.0, or 4.0 g copper per kg food until day 19 of gestation ( Lecyk, 1980). Copper at doses of 0.5 to 1.0 g/ kg had no harmful effect on embryonic growth or development. Copper at doses of 3 and 4 g/ kg resulted in increased mortality and malformations. Mortality in C57BL mice at 3 and 4 g/ kg doses was 21.4% ( 15/ 70) and 28.6% ( 10/ 45), respectively compared to 14.5% ( 11/ 76) in controls. Mortality in DBA mice at 3 and 4 g/ kg doses was 20% ( 14/ 70) and 26.2% ( 16/ 60), respectively, compared to 13.6% ( 12/ 88) in controls. In C57BL mice at the 3 and 4 g/ kg doses, 1.8% ( 1/ 55) and 8.5% ( 3/ 35) of living fetuses had a malformation, respectively. In DBA mice, 3.7% ( 2/ 56) and 7.4% ( 4/ 45) of living fetuses had a malformation, respectively. Malformations were not observed in any lower dose of copper or in control groups. Malformations observed were likely due to the toxic effects of copper.

In a developmental toxicity study ( MRID 46377502), copper hydroxide technical ( 61.14% Cu, Lot # 021121/ 1) in 0.5% aqueous methylcellulose was administered daily via oral gavage to 22 time mated New Zealand White rabbits/ group at dose levels of 0, 6, 9, or 18 mg Cu/ kg/ day at a dose volume of 1 mL/ kg from gestation day ( GD) 7 through 28. At 18 mg Cu/ kg/ day, three rabbits were found dead prior to scheduled termination. Diarrhea, red cageboard staining, weakness, and irregular respiration preceded death on GD 10 in one of these animals. The other two animals were found dead on GD 9 and 16 and appeared normal prior to death; however, dark colored spots or dark mottling were observed in the lungs in these animals at necropsy. In addition, two does in this dose group aborted on GD 22. Staining of the fur, tail, and/ or cage board was noted in animals in this group and corresponded to the diarrhea and/ or abortions. Ulceration and/ or hemorrhage in the stomach was observed in 4/ 21 does at this dose compared to 0/ 22 controls. There were no other treatment related mortalities, abortions, or clinical signs of toxicity.

Body weight gains were decreased during GD 7 10 at 9 mg Cu/ kg/ day ( 125.4 g) and 18 mg Cu/ kg/ day ( 259.2 g) compared to controls ( 2.2 g). Additionally at 18 mg Cu/ kg/ day, body weight gains for the overall ( GD 7 29) treatment period were decreased ( p# 0.05), when the gravid uterine weight was included ( 972%) or when correcting for the gravid uterine weight ( 9101%). Body weights were decreased ( p# 0.05) by 5% at this dose compared to controls on GD 10 and 11. There were no other treatment related effects on body weights or body weight gains. Individual gravid uterine weights were not reported.

Food consumption was decreased at 9 mg Cu/ kg/ day during GD 7 10 ( 952%) and GD 10 13 ( 932%), resulting in decreased ( p# 0.05) food consumption for the overall ( GD 7 29) treatment period ( 917%). At 18 mg Cu/ kg/ day, food consumption was decreased throughout the treatment period ( 911 89%; p# 0.05, except not significant for GD 25 29). The only finding at 6 mg Cu/ kg/ day was a transient decrease ( 914%; p# 0.05) in food consumption during GD 7 10. The maternal LOAEL is 9 mg Cu/ kg/ day based on decreased body weight gains and food consumption. The maternal NOAEL is 6 mg Cu/ kg/ day.

There were no premature deliveries or dead fetuses. There were no effects of treatment on the numbers of litters, live fetuses, dead fetuses, resorptions ( early, late, total, or complete litter), or Page 21 of 39 on sex ratio or post implantation loss. There were no treatment related effects on fetal body weights. The following incidences of retarded ossification were noted at 18 mg Cu/ kg/ day ( vs 0 controls) and were considered treatment related: ( i) mandible ( 0.8% fetuses; 6.7% litters); ( ii) pelvis ( 1.6% fetuses; 6.7% litters); and ( iii) skull ( 4.0% fetuses; 13.3% litters), resulting in a significant positive trend for this finding. There were no treatment related external or visceral variations. A dose dependent increase in the fetal incidences of supernumerary ribs, a variation, was noted in all treated groups ( 67.1 87.3% fetuses) compared to controls ( 63.6% fetuses), resulting in a significant ( p< 0.05) positive trend. However, because the fetal incidence was only minimally increased over controls at 6 and 9 mg Cu/ kg/ day ( 67.1 79.9% fetuses) compared to controls ( 63.6% fetuses), only the incidence at 18 mg Cu/ kg/ day ( 87.3%) is considered adverse. All litters, with the exception of one litter at 9 mg Cu/ kg/ day ( 95.2 100% litters), had fetuses with supernumerary ribs. There were no treatment related external or visceral malformations. Hemi vertebra, a malformation, was noted in 2 fetuses ( 1.6%) in 2 litters ( 13.3%) at 18 mg Cu/ kg/ day ( vs 0 controls), resulting in a significant ( p< 0.05) positive trend. In the absence of historical control data, this finding is considered treatment related. The developmental LOAEL is 18 mg Cu/ kg/ day based on incidences of hemi vertebra, a malformation, and on slight increases in minor variations ( supernumerary ribs and retarded ossification of the mandible, skull, and pelvis). The developmental NOAEL is 9 mg Cu/ kg/ day.

Excess dietary copper in young Fischer 344 rats caused increased hepatic copper concentration associated with morphologic and biochemical indicators of liver injury ( Fuentealba et al., 2000). Adult ( N= 5/ 11 male/ female rats, respectively) and young ( N= 8/ 8 male/ female) female and male rats were fed a diet containing 1500 ppm copper ( CuSO4) for 18 weeks, or from birth until 16 weeks of age. Control rats ( N= 4/ sex/ age group) of similar ages received less than 10 ppm copper. All rats receiving copper loaded diets had significantly increased hepatic copper concentrations compared to controls. Young copper loaded rats accumulated more hepatic copper, had more severe liver changes, and higher serum liver enzyme activities than adult rats. Hemolysis was not observed in rats with excess dietary copper. Measurement of zinc accumulation between copper loaded and control adult rats were similar. A sex dependent statistical significance was not achieved in this study. However, 2 of 8 young female rats died during the experiment and young female rats accumulated almost 100 ppm more copper than young male rats. Discussion of the results of the study indicated that copper absorption may not be saturable in suckling and weanling rats. The authors also suggested that a combination of factors including immaturity of the biliary system in young rats and high efficiency of copper absorption may result in hepatic accumulation of copper culminating with liver injury. Since the metabolism and saturation point of the young rat versus the young human are not known, but likely different, it is difficult to extrapolate to the human. It should also be noted that the copper concentration in human newborn liver is reportedly 10 times higher than that of adult liver.

A review was undertaken by the Advisory Committee on Pesticides in 1999 to evaluate the use of copper compounds in antifouling products. A mammalian toxicology chapter presented similar data as that discussed here in. Overall the Advisory Committee on Pesticides concluded copper is absorbed readily by rats and humans with the acute oral toxicity of copper compounds variable. The potential for dermal and eye irritation is dependent on the form of copper with skin sensitization studies in the guinea pig negative. Feeding studies in rats and mice are variable Page 22 of 39 depending on the dose and duration. Overall, copper was an irritant to the gastrointestinal tract with higher doses causing protein droplets in the cytoplasm and lumen of the renal cortical tubules, liver inflammation, depletion of haematopoietic cells, and reduced weight gain and food intake. Additionally, studies presented for the potential genotoxicity of copper compounds were equivocal or negative. Overall the conclusion was that no evidence indicated copper or its compounds are carcinogenic with the unlikelihood that copper is a carcinogenic hazard.

Reports on single generation and teratogenicity studies presented by the Committee were not to recognized guidelines. The effects reported in each of the studies were thought to be associated with fetal toxicity and therefore not directly attributable to any teratogenic properties of copper. In addition, no teratogenic effects were noted as a result of implantation of copper wire or rings into the uteri of rats, rabbits or hamsters. Similarly no malformations in human embryos were observed after the presence of approximately 70 ug/ day copper from intrauterine devices. Overall the Advisory Committee on Pesticides concluded that..." the intrinsic hazards posed by copper and those of its compounds were low...".

Genotoxicity:

Mutagenicity studies available from registrants indicate copper as cuprous oxide or copper sulfate pentahydrate are negative. ( Section J, Tables 8 & 9) Literature studies report mixed results depending on the strain/ cell type, concentrations, and type of copper compound. The majority of the genotoxicity studies reported have been conducted using copper sulfate, presumably because of its solubility. From the available data it is difficult to draw firm conclusions on the potential genotoxicity of copper compounds. A number of the apparently positive results may be considered equivocal or negative when the data are examined more closely.

Available human data ( literature):

The metabolism and sensitivity to the effects of copper vary among animal species and are therefore inappropriate for extrapolation to humans. Information from the published literature are provided below for characterization of the nutritional requirement of copper and sensitivity of copper in humans.

Effects on humans:

Copper is an essential element and adverse health effects are related to deficiency as well as excess. Copper deficiency is associated with anemia, neutropenia, and bone abnormalities but clinically evident deficiency is relatively infrequent in humans. At least 12 major proteins require copper as an integral part of their structure. Copper is essential for the utilization of iron in the formation of hemoglobin. The IP EHC set the lower limit of the acceptable range of oral intake at 20 Fg/ kg body weight/ day ( IPCS, 1998). The figure was based on the adult basal requirement with an allowance for variations in copper absorption, retention and storage ( WHO, 1996). In infancy, this figure is 50 ug/ kg body weight/ day. The IP EHC determined the " available data on toxicity in animals were considered unhelpful in establishing the upper limit Page 23 of 39 of the acceptable range of oral intake, owing to uncertainty about an appropriate model for humans. Moreover, traditional methodology for safety assessment, based on application of uncertainty factors to data in animals, does not adequately address the special attributes of essential elements such as copper.... there is greater risk of health effects from deficiency of copper intake than from excess copper intake."

Clinical signs of acute poisoning from ingestion of copper salts ( 10 to 15 mg) may include: metallic taste, abdominal pain, nausea, vomiting, epigastric burning and diarrhea, and in severe cases gastrointestinal bleeding and ulceration. Lethargy, headache, muscular weakness and dizziness, hypotension and shock may precede coma and death ( IPCS PIM 1991). The estimated mean lethal dose is approximately 10 grams ( 10,000 mg), or approximately 140 mg/ kg ( IPCS PIM 1991). A recent review by ATSDR ( 2004) indicates deaths due to copper poisoning were due to ingestion of large doses of copper sulfate ( 6 to 637 mg/ kg Cu). However, the amount was self reported and therefore, doses likely inaccurate. In addition, no studies were reported by the ATSDR for systemic effects regarding endocrine, dermal, ocular, or metabolic effects following oral exposure to copper.

Copper Deficiency in Humans:

Adverse health effects associated with copper deficiency include anemia, neutropenia and bone abnormalities. Clinically evident copper deficiency is relatively infrequent in humans. ( IPCS 1998).

Excessive Copper in Humans:

An acute exposure to a large concentration of copper may produce a metallic taste, abdominal pain, nausea and vomiting, or diarrhea, especially if copper is taken on an empty stomach, taken with acidic foods or beverages, or with other supplements. These effects are largely due to the irritating effects of copper. More severe cases may involve lethargy, headache, muscular weakness and dizziness, with hypotension and shock possibly proceeding coma and death.

Chronic exposure to higher amounts of copper may lead to adverse effects on the liver. Jaundice, elevation of serum transaminase and serum bilirubin levels, enlargement and tenderness of the liver, centriblobular necrosis and biliary stasis of the liver may occur from chronic exposure to high levels of copper. Haemoglobinemia, haemolysis, haemoglobinuria and haematuria, cyanosis may also occur from chronic exposure to copper. ( IPCS PIM, 1991).

Inhalation Exposure in Humans:

The inhalation of copper as dusts or mists are likely irritating to the respiratory system similar to the irritating effects of copper when ingested ( ATSDR 2004). Acute LC50 data from animal studies are available in Section J. The acute toxicity of the different copper compounds differs but is mainly Toxicity Category III. Cuprous oxide was more toxic with a Toxicity Category I study. Chronic inhalation of copper may become cancerous since available studies from the literature indicate an increased incidence of lung cancer among professional vineyard workers Page 24 of 39 exposed chronically to Bordeaux mixture ( Viller, 1974; Santic et al. 2005); however, this information is not definitive since no information is available on the level of exposure to these workers, to either the Bordeaux mixture or any other substances with which they might have come into contact. Copper is considered the etiologic agent in the occupational disease referred to as " vineyards sprayer's lung" and is reviewed in ATSDR 2004. A recent review by ATSDR ( 2004) indicated no studies were available for systemic effects regarding cardiovacular, musculoskeletal, renal, dermal, or body weight effects in humans or animals following inhalation exposure to copper.

Guinea pigs exposed to copper oxide aerosol for 60 minutes displayed few effects on pulmonary parameters with no long lasting effects ( Chen et al., 1991). Male guinea pigs were exposed to ultrafine particles of copper oxide produced from a furnace system designed to mimic primary emissions from smelters ( Hartley, N= 10) at 1.6 ± 0.10 mg/ m3 for 60 minutes to determine the effect on pulmonary parameters ( intrapleural pressure, tidal volume, flow rate). Animals were also monitored for 60 minutes after exposure to the copper aerosol. Slight changes in pulmonary parameters included decreased resistance values ( 5%), compliance ( 17%), and tidal volume ( 5% to 9.5%). No other effects of the aerosol on the pulmonary system were reported.

Information available either through the literature or studies provided by the registrant warrant the limitation of the inhalation of copper.

D. Dietary: Acceptable Daily Intakes:

Estimated and Acceptable Intake Levels for Humans: See Table 1 below.

Copper is a naturally occurring element that is essential for the homeostasis of life. Sources of human and environmental copper include windblown dust, volcanoes, decaying vegetation, forest fires and sea spray. Copper is also found naturally in various foods, including organ meats ( liver), seafood, beans, nuts, and whole grains. It has been estimated that approximately 40% of dietary copper comes from yeast breads, white potatoes, tomatoes, cereals, beef and dried beans and lentils ( WHO, 2004). It has been estimated that approximately 3.2 mg of copper is consumed daily in food with water providing an additional 40 500 picograms ( pg) of copper ( WHO, 1974). In most foods, copper is present bound to macromolecules rather than as a free ion ( IOM, 2001). Additional copper may come from drinking water from copper pipes, and using copper cookware. Anthropogenic emissions include smelters, iron foundries, power stations and combustion sources such as municipal incinerators. An estimate for the agricultural use of copper products was approximately 2% of copper released to soil. ( IPCS, 1998).

The estimated mean daily dietary intake of copper in non occupationally exposed humans ( adults) ranges between 0.9 and 2.2 mg. The estimated contribution of daily intake of copper, particularly in homes without copper piping, seldom exceeds 0.1 mg/ day. The estimated total daily oral intake of copper ( food plus drinking water) is between 1 and 2 mg/ day, although may occasionally exceed 5 mg/ day. Page 25 of 39 Copper supplements are available as over the counter for individuals that are lower in status of copper in order to prevent or treat copper deficiency. Supplements range from 0.33 mg to 3 mg and are recommended from once to two or three times a day. Surveys in the USA indicate that approximately 15% of the population uses a nutritional supplement containing copper ( IOM, 2001).

Acceptable daily intake is 2 to 5 mg Cu/ day. Almost none of the copper is retained and the body content of copper in adults is constant at 100 to 150 mg ( Scheinberg, 1983).

Average daily dietary requirement for copper ( cupric sulphate) in the adult human was estimated at 2 mg and for infants and children at 0.05 mg/ kg bw. NRC ( 1980) reported " estimated safe and adequate" daily dietary intakes of copper ranging from 0.5 to 0.7 mg/ day for infants 6 months of age or less up to 2 3 mg/ day for adults. The recommended daily allowance ( RDA) for adult men and women is 900 Fg/ day ( 0.9 mg/ day). ( IOM, 2001).

In adults, it is generally agreed that average daily intake of copper is between 1 3 mg, or about 15 45 Fg/ kg bw. From the WHO report, FDA ( 1978) data indicated the average adult intake of copper in the US was estimated to equal 1.6 mg/ day from a 3000 calorie diet and 2.1 mg/ day from a 3900 calorie diet.

According to the National Academy of Sciences ( IOM 2001), an NHANES III assessment indicated the highest median intake of copper from the diet and supplements for any gender and life stage group was approximately 1,700 Fg/ day ( 1.7 mg/ day) for men ( 19 50 years) and approximately 1,900 Fg/ day ( 1.9 mg/ day) for lactating women. However, the highest reported copper intake from food and supplements at the 99th percentile was 4,700 Fg/ day ( 4.7 mg/ day) in lactating women. The Tolerable Upper Intake Level ( UL) for adults is 10,000 Fg/ day ( 10 mg/ kg), which was based on protection from liver damage as the critical adverse effect. Page 26 of 39 Table 1. Average, Estimate, and Mean Daily Intake Values for Copper Source Estimate Value Age Notes IPCS 1998 mean daily intake 0.9 to 2.2 mg nonoccupationally exposed adults 0.1 mg/ day Contribution of daily intake w/ out Cu pipping IPCS 1998 estimated total daily oral intake ( food + water) 1 and 2 mg/ day adults IPCS PIM 1991 Acceptable Daily Intake ( ADI) 2 to 5 mg/ day adults JECFA No. 551 Average daily dietary requirement ( Cupric Sulfate) 2 mg 0.05 mg/ kg bw adults infants & children JECFA No. 551 estimated safe and adequate daily dietary intake 0.5 to 0.7 mg/ day to 2 3 mg/ day infants < 6 mos adults WHO 2004, FDA 1978 average adult intake 1.6 mg/ day 2.1 mg/ day 3000 calorie diet 3900 calorie diet IOM 2001 highest median intake from diet and supplements 1.7 mg/ day 1.9 mg/ day men ( 19 50 yrs) lactating women 99th percentile 4.7 for lactating women IOM 2001 Tolerable Upper Intake Level ( UL) 10 mg/ day adults based on protection from liver damage WHO 2004, IOM 2001 RDA, recommended dietary allowance 900 ug/ day ( 0.9 mg/ day) adult men and women ( 19 to > 70 yrs)

IOM 2001 RDA Children 0.34 mg/ day 0.44 mg/ day 1 3 years 4 8 years IOM 2001 RDA Boys & Girls 0.70 mg/ day 0.89 mg/ day 9 13 years 14 18 years IOM 2001 RDA for Pregnancy RDA for Lactation 1.0 mg/ day 1.3 mg/ day 14 50 years 14 50 years Page 27 of 39 Dietary Endpoints Dietary endpoints are not appropriate at this time for the copper risk assessment since copper is an essential element and is exempt from a requirement of a tolerance ( list CFR notices or see section of risk assessment). Copper carbonate ( 022901) has a 3 ppm tolerance as copper impregnated paper wrap for pears.

E. Classification of Carcinogenic Potential:

Copper ( metallic) is currently Group D, not classifiable as to human carcinogenicity. However, the only evidence of carcinogenicity is in workers exposed chronically to inhalation of Bordeaux mixture in the vineyard developing lung tumors. However, the compound causing lung lesions in workers is still under evaluation since arsenic is also present in the Bordeaux mixture. A review by ATSDR ( 2004) failed to locate studies regarding carcinogenic effects in humans following oral exposure to copper. Mutagenicity studies from the literature indicate copper is not mutagenic. Copper chloride at 0.001 10M concentrations was negative in the rec assay with Bacillus subtilis and negative in the reverse mutation assay with E. coli and Salmonella strains ( Kanematsu et al., 1980).

F. Uncertainty Factors:

The application of uncertainty factors is not warranted for this assessment. Dietary endpoints are not required for this assessment and therefore application of uncertainty factors is not required.

G. Endocrine Disruption:

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 endocrine disruption screening 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).

It is notable that based on the available toxicology studies and literature for copper, there is currently no indication of endocrine disruption.

H. FQPA and Special Considerations for Infants and Children:

In humans there does not appear to be any reports in the literature of teratogenesis induced by excess copper ( IPCS PIM, 1991). The only teratogenic effects observed in Page 28 of 39 available animal studies occurred after exposure with copper salts at high doses, in which doses were likely at maternally toxic concentrations. Likewise, based on the available toxicity information from available studies and published literature, there is no evidence to suggest susceptibility in infants and children. The current RDA ( Recommended Daily Allowance) for copper in infants and children is 340 Fg/ day compared to 900 Fg/ day in adults. Since copper is a natural essential trace element, with deficiency more common in humans than toxicity from excess, and the dietary contribution of copper to the total diet is low, then endpoints are not required and therefore not subject to the FQPA Uncertainty Factor. The additional tenfold safety factor for the protection of infants and children is currently not required.

I. Conclusions:

Copper is a natural trace element required for the homeostasis of life with humans having a unique ability to maintain appropriate copper stores in the body. As such, it is inappropriate to compare the toxicity of copper in laboratory animals for extrapolation to human toxicity. Humans are exposed primarily through the food that is consumed with RDAs established for adults, infants, and children. The irritating properties of copper to the gastrointestinal tract are a mechanism by which excess orally absorbed copper is prevented. Copper may be irritating, however, to the skin, eyes, and lungs and should therefore be avoided by these routes of exposure. Copper residues from the use as a pesticidal active ingredient are not expected to significantly contribute to the naturally occurring levels of copper in foods, therefore, toxicological endpoints have not been established for copper.

J. References:

Advisory Committee on Pesticides ( 1999). Evaluation on : Copper compounds, 1st review of their use in antifouling products. Food and Environment Protection Act 1985, Part III. Control of Pesticides Regulations 1986. January Issue No 183. 148 pp.

ATSDR ( 2004). Toxicological profile for copper. US Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry.

Chen LC, Peoples SM, and Amdur MO ( 1991). Pulmonary effects of sulfur oxides on the surface of copper oxide aerosol. Am Ind. Hyg. Assoc. J. 52( 5): 187 191.

Danks BM, Campbell PE, Stevens BJ, Mayne V., and Cartwright E ( 1972). Menke's kinky hair syndrome. An inherited defect in copper absorption with widespread effects. Pediatrics 50 ( 2): 188 201.

Danks DM ( 1988). Copper deficiency in humans. Ann Rev Nutr. 8: 235 257.

Danks DM ( 1995). Disorders of copper transport. In: The metabolic and molecular basis of inherited disease, 7th Ed., CR Scriver, AL Beaudet, WM Sly, and D Valle, eds. New York: McGraw Hill. pp 2211 2235. Page 29 of 39 Dekaban et al. ( 1975). Kinky hair disease: a study of copper metabolism with use of 67Cu. Arch. Neurol. 32: 672 675.

Evans GW ( 1973). Copper homeostasis and metabolism in the mammalian system. Physiological Reviews. 53: 535 569.

FAO/ WHO ( 1970). FAO Nutrition Meetings. Report Series No. 48A. WHO/ Food ADD/ 70.39. Copper and Cupric Sulphate. World Health Organization.

FDA ( 1978). FY' 76 Selected minerals in foods survey Adults, infants and toddlers. Food and Drug Administration. Compliance Program Evaluation Nos. 7320.59 and 7320.63 Washington DC 20204.

Fuentaeloba CI, Mullins JE, Aburto EM, Lau JC, and Cherian GM ( 2000). Effect of age and sex on liver damage due to excess dietary copper in Fischer 344 rats. Clinical Toxicology. 38( 7): 709 717.

Haywood S. and Loughran M. ( 1985). Copper toxicosis and tolerance in the rat. II. Tolerance a liver protective adaptation. Liver. 5: 267 275.

Hebert CD, Elwell MR, Travlos GS, Fitz CJ, and Bucher JR ( 1993). Subchronic toxicity of cupric sulfate administered in drinking water and feed to rats and mice. Fund and Appl Tox 21: 461 475.

IOM ( 2001) Dietary reference intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. http:// www. nap. edu/ catalog/ 10026. html. A report of the panel of micronutrients, subcommittees on upper reference levels of nutrients and of interpretation and use of dietary reference intakes, and the standing committee on the scientific evaluation of dietary reference intakes. Food and Nutrition Board, Institute of Medicine. Washington DC, National Academy Press.

IPCS ( 1998). Copper. Geneva, World Health Organization, International Programme on Chemical Safety ( Environmental Health Criteria 200).

IPCS PIM ( 1991). Poison Information Monograph. G002. Copper and Copper Salts. Http:// www. inchem. org/ documents/ pims/ chemical/ pimg002. htm JECFA # 551. Joint WHO/ FAO Expert Committee on Food Additives JECFA. Copper. WHO Food Additives Series 17. Copper. http:// www. inchem. org/ documents/ jecfa/ jecmono/ v17je31. html Kanematsu N, Hara M, and Kada T ( 1980). Rec assay and mutagenicity studies on metal compounds. Mutation Research 77: 109 116. Page 30 of 39 Luza CS and Speisky HC ( 1996). Liver copper storage and transport during development: implications for cytotoxicity. 63: 812S 820S.

Lecyk M ( 1980). Toxicity of CuSO4 in mice embryonic development. Zoologica Poloniae. 28( 2): 101 105.

Markowitz H et al. ( 1955). Studies on copper metabolism. XIV. Copper , ceruloplasmin and oxidase activity in sera of normal human subjects, pregnant women, and patients with infection, hepatolenticular degeneration and the nephrotic syndrome. J. Clin. Invest. 34: 1498 1508.

National Toxicology Program ( 1993). NTP Technical Report on Toxicity Studies of Cupric Sulfate Administered in Drinking Water and Feed to F344/ N Rats and B6C3F1 Mice. Toxicity Report Series Number 29. NIH Publication 93 3352.

NRC ( National Research Council) ( 1980). Recommended dietary allowances. Food and Nutrition Board, National Research Council and National Academy of Sciences, Washington, DC.

NRC ( National Research Council) ( 2000). Copper in Drinking Water. Committee on Copper in Drinking Water. Board on Environmental Studies and Toxicology, Commission on Life Sciences. National Academy Press.

Oster, O and Salgo, MP ( 1977). Copper in mammalian reproduction. Avd. Pharmacol. Chemother. 14: 327.

Pena MO, Lee J, and Thiele DJ ( 1999). A delicate balance: Homeostatic control of copper uptake and distribution. J Nutr 129: 1251 1260.

Pocino M., Baute L., and Malave I ( 1991). Influence of the oral administration of excess copper on the immune response. Fund. and Appl. Tox. 16: 249 256.

Prohaska JR and Gybina AA ( 2004). Intracellular copper transport in mammals. J Nutr 134: 1003 1006.

Schienberg HI ( 1983). Copper, alloys and compounds. In: Parmeggiani, ed. Encyclopedia of occupational health and safety, Geneva, International Labor Organization Publications, pp 546 548.

Schroeder HA, Nason AP, Tipton IH, and Balassa JJ ( 1966). Essential trace elements in man: copper. J. Chonic. Dis. 19: 1007 1034.

Strickland GT, Bechner WM, and Leu ML ( 1972). Absorption of copper in homozygotes and heterozygotes for Wilson's disease and controls: isotope tracer studies with 67Cu and 64Cu. Clin. Sci. 43: 617 625. Page 31 of 39 Subar AF et al. ( 1998) Dietary sources of nutrients among US adults, 1989 to 1991. Journal of the American Dietetic Association, 98: 537 547.

Turnlund, J ( 1998) Human whole body copper metabolism. Am J Clin Nutr 67 ( Suppl): 960S 4S.

Viller JC ( 1974). Vineyard Sprayers Lung. Clinical Aspects. Am. Rev. Respiratory Disease. 110, pg 545.

WHO ( 1974). Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers, and thickening agents: Cupric sulfate. WHO Food Additive Series No. 5.

WHO ( 1996). Trace elements in human nutrition and health. Geneva, World Health Organization.

WHO ( 2004) Copper in Drinking water. Background document for development of WHO guidelines for drinking water quality. Geneva, World Health Organization. 23pp.

K. Toxicity Profile Tables for the Cases of Copper:

A. Acute Toxicity Studies:

I. Acute Studies for Copper Compounds Table 2. Available Acute Toxicity Studies for the Copper Compounds Copper Type PC Code Acute Oral LD50 ( mg/ kg) Acute Dermal LD50 ( mg/ kg) Acute Inhalation ( mg/ L) Primary Eye Irritation Dermal Irritation Dermal Sensitization Acute Studies Copper Chloride ( 57.7% Cu) 008001 M= 1796 F= 2006 Tox Cat. III 43769501 > 2000 ( M & F) Tox Cat III 43769502 NA Corneal opacity cleared by 21 days Tox Cat. II 43769503 Non irritating Tox Cat. IV 43769504 NA Chelates of Copper Gluconate 024405 None Available Copper Ammonium Carbonate 022703 None Available Copper Carbonate ( 96%) 022901 > 2000 Tox Cat III 41889302 NA NA Corrosive, opacity at 21 days Tox Cat I 41889301 Non irritating Tox Cat IV 41889302 NA Page 32 of 39 Table 2. Available Acute Toxicity Studies for the Copper Compounds Copper Hydroxide ( 77%) 023401 M = 2253 F= 2160 Tox Cat. III 41421602 > 2000 Tox Cat III 00159371 00259424 77% M= 1.53 mg/ L F = 1.04 mg/ L 00160580 88% F = 0.5 mg/ L Tox Cat. III Irritative Corneal opacity, iris irritation, chemosis, invasion of cornea by blood vessels Tox. Cat. I At 72 hrs, very slight erythema Tox Cat. IV Non sensitizing Guinea Pig Copper Ammonia Complex 022702 None Available Copper oxychloride ( 94.1%) 023501 M= 1537 F= 1370 Tox Cat. III 00155931 M& F= 710 ( 281 1791) Tox Cat II > 1.7 mg/ L Tox Cat. III 00155932 Corneal opacity redness and vascularization Tox Cat. I 00155934 Non irritating Tox Cat IV 00155935 Nonsensitizing 00155936 Copper oxychloride sulfate 023503 None Available II. Acute Studies for Copper Sulfates Table 3. Available Acute Toxicity Studies for the Copper Sulfates Copper Type PC Code Acute Oral LD50 ( mg/ kg) Acute Dermal LD50 ( mg/ kg) Acute Inhalation ( mg/ L) Primary Eye Irritation Dermal Irritation Dermal Sensitization Acute Studies Basic Copper sulfate 008101 None Available Copper sulfate anhydrous 024408 None Available Copper sulfate pentahydrate ( 99%) 024401 M= 790 F= 450 Tox Cat II 43396201 > 2000 Tox Cat IV 43452201 Severe eye irritation day 1 to day 21 Tox Cat. I 43396201 Non irritating Tox Cat IV 43396201 Human Study produced sensitization 00099581 TXR 004457 Page 33 of 39 III. Acute Studies for Copper and Oxides Table 4. Available Acute Toxicity Studies for the Copper and Oxides ( mg/ kg)

Copper Type PC Code Acute Oral LD50 ( mg/ kg) Acute Dermal LD50 ( mg/ kg) Acute Inhalation ( mg/ L) Primary Eye Irritation Dermal Irritation Dermal Sensitization Acute Studies Copper metallic 022501 50% copper M= 1414 F= 1625 Tox Cat. III 00162424 8.5% elemental > 2000 Tox Cat. III 00150641 23% metallic > 0.1 but < 0.59 Tox Cat III 00156396 50% metallic opacity, irritation, redness, chemosis, cleared by day 21 Tox Cat. II 00126194 50% metallic erythema, edema, irritation, cleared day 14 Tox Cat. IV 00126194 26% metallic nonsensitizing guinea pig 00144555 8.5% elemental nonsensitizing rabbit 00152166 cupric oxide ( 97.6%) 042401 > 5050 ( M& F) Tox Cat IV 41502401 > 2020 ( M& F) Tox Cat III 41502402 > 2.08 ( M& F)

Tox Cat III 41502403 Irritation cleared in 7 days Tox Cat III 41502404 Irritation cleared day 21 PI Index= 1.49 Tox Cat III 41502405 Non sensitizing ( guinea pig) 41502406 cuprous oxide ( 57%) 025601 > 5000 Tox Cat IV 00078971 > 2000 slight erythema, edema Tox Cat III 00245650 40.9% ai 0.1 to 0.59 Tox Cat I 42240303 Opacity, iris irritation, redness, and chemosis clearing by day 14 Tox Cat II 00078974 Severe erythema, edema PIS= 6.1/ 8 Tox Cat I 00078970 Non sensitizing ( guinea pig)

00078970 IV. Acute Studies for Copper Salts Table 5. Available Acute Toxicity Studies for the Copper Salts ( mg/ kg)

Copper Type PC Code Acute Oral LD50 ( Mg/ kG) Acute Dermal LD50 ( mg/ kg) Acute Inhalation ( mg/ L) Primary Eye Irritation Dermal Irritation Dermal Sensitization Acute Studies Copper from triethanolamine complex [ K TEA] 024403 99% M= 1170 F= 1312 Tox Cat. III 41759301 99% > 2000 mg/ kg No deaths Tox Cat. III 41759302 NA 99% moderate irritation of cornea, iris, conjunctive cleared by day 7. Tox Cat. III 41759303 99% mild irritation cleared by day 3 Tox Cat. IV 41759304 NA Copper 8 quinolinolate 024002 99.5% > 5000 M& F Tox Cat. IV 99.5% > 2000 M& F Tox Cat. III 43558501 96% 0.09 M& 0.03 F Tox Cat. II 43611901 98% corneal opacity, redness to day 21 Tox Cat. I 99.7% Non irritating Tox Cat. IV 99.7%

Nonsensitizing guinea pig Page 34 of 39 Table 5. Available Acute Toxicity Studies for the Copper Salts ( mg/ kg)

Copper Type PC Code Acute Oral LD50 ( Mg/ kG) Acute Dermal LD50 ( mg/ kg) Acute Inhalation ( mg/ L) Primary Eye Irritation Dermal Irritation Dermal Sensitization Acute Studies elemental copper ( ethyenediam ine) 024407 KOMEEN 96%, K Tea 99% M= 527 F= 462 Tox Cat. II 41759201 KOMEEN & K Tea > 2000 Tox Cat. III 41759202 KOMEEN & KTea M= 1.36 F= 0.56 Tox Cat. III 42130001 KOMEEN & K Tea moderate irritation Tox Cat. III 41759203 KOMEEN & KTea redness, edema, cleared by day 3 41759204 KOMEEN & K Tea non sensitizing guinea pig 42130002 Copper naphthenate 023102 8% Cu M= > 5050 F= > 5050 Tox Cat. IV 43643701 8% Cu M= > 2020 F= > 2020 Tox Cat. III 43643702 9.5% Cu M& F=> 2.96 Tox Cat. III 1. 8% Cu irritation, chemosis, cleared by 48 hrs, Tox Cat. III 43643703 2. 45% Cu opacity, redness, chemosis & discharge at 72 hrs Tox Cat. I 00266172 8% Cu erythema/ eschar slight edema PIS= 1.1 Tox Cat. III 43642704 2. 80% Cu 72 hrs severe erythema, edema Tox Cat. II 00260891 9.5% Cu sensitizer Copper octanoate, 10% fatty acids 023306 > 2000 M& F Tox Cat. III 43947504 > 2000 M& F Tox Cat. III 43947505 > 0.38 M& F Tox Cat. III 43970201 irritation, cleared by 48 hrs. Tox Cat. IV 43937506 slight erythema, edema, cleared by 72 hrs. Tox Cat. IV 43947507 Nonsensitizing guinea pig 44116101 Copper salts of fatty and rosin acids ( Cu & zinc neoisoate 35%) 023104 > 7000 Tox Cat. IV > 2000 Tox Cat. III NA no irritation Tox Cat. IV Edema, erythema, PIS= 1.0 Tox Cat III NA Page 35 of 39 V. Acute Studies for Other Unscheduled Coppers Table 6. Available Acute Toxicity Studies for the other Unscheduled Coppers ( mg/ kg)

Copper Type PC Code Acute Oral LD50 Acute Dermal LD50 Acute Inhalation Primary Eye Irritation Dermal Irritation Dermal Sensitization Acute Studies Cuprous thiocyanate ( 99%) 025602 > 5000 Tox Cat IV 40834601 > 2000 Tox Cat III 40834601 > 0.5 mg/ L Tox Cat. II 40834605 non irritant 40834605 non irritant 40834604 non sensitizing 40834603 Copper ethanolamine complex 024409 None Available B. Tables of Other Toxicity Studies by Case of Copper.

BI. Other Studies for Copper Compounds Table 7. Other Available Toxicity Studies for Copper Compounds ( mg/ kg)

Copper Type PC Code Guideline Study MRID Results Copper hydroxide, technical 61.14% 023401 83 3b 46377502 46377501 0, 6, 9, or 18 mg Cu/ kg/ day at 1 mL/ kg from GD 7 to GD 28. Maternal LOAEL 9 mg/ kg/ day, based on decreased body weight gains and food consumption. NOAEL 6 mg/ kg/ day. Developmental LOAEL 18 mg/ kg/ day, based on incidences of hemvertebra and slight increased in minor variations ( supernumerary ribs, retarded ossification of the mandible, skull, and pelvis). NOAEL 9 mg/ kg/ day. Acceptable/ Guideline No other studies available for any of the copper compounds ( PC Codes: 008001, 024405, 022703, 022901, 022702, 023501, 023503).

BII. Other Studies for Copper Sulfates Table 8. Other Available Toxicity Studies for Copper Sulfates ( mg/ kg)

Copper Type PC Code Guideline Study MRID Results Cu sulfate, pentahydrate 024401 82 1 subchronic rat 00058020 00075116 NOEL not determined Cu sulfate, pentahydrate 024401 83 4 1 Gen Repro 0, 500, 1000, 1500, 2000, 3000, & 4000 ppm Page 36 of 39 Cu sulfate, pentahydrate 024401 Mutagenic Ames 84 2 00085218 Negative in S. typhimurium LT 2 and for gene mutation o S. cerevisiase D 7 Cu sulfate, pentahydrate 024401 Metabolism 85 1 00062085 Intraperitoneal doses of 0.625 3.75 mg/ kg daily with sacrifice at 24 hrs, 1, 2, 6, 12, and 18 weeks. Cu accumulated in all tissues at the high level. As little as 0.3 mg/ kg of i. p. Cu for 18 wks. will elevate hepatic Cu.

BIII. Other Studies for Copper and Oxides Table 9. Other Available Toxicity Studies for Copper and Oxides ( mg/ kg)

Copper Type PC Code Guideline Study MRID Results Cuprous oxide 025601 84 2 NA No significant mutagenic activity with/ without metabolic ( S 9) activation. Strains tested: Salmonella TA1535, TA 1537, TA 98, TA 100; E. coli WP2 uvrA. Doses tested: 0, 20, 100, 500, 2500, 5000 ug.

Cupric oxide 042401 None Available Copper metallic 022501 None Available BIV. Other Studies for Copper Salts A. Cu 8 Quinolinolate Table 10. Other Available Toxicity Studies for Copper 8 Quinolinolate ( mg/ kg)

Copper Type PC Code Guideline Study MRID Results Cu 8 quinolinolate 024002 82 1a subchronic dog 42986802 99.5%, capsule for 13 weeks at 0, 5, 50, or 250 mg/ kg/ day. NOAEL is 5 mg/ kg/ day LOAEL = 50 mg/ kg/ day, based on vomiting, reduced total plasma protein and albumin, reddened mucosa and hyperemia in stomach or small intestine. Acceptable/ Guideline Cu 8 quinolinolate 024002 82 1a subchronic rat 42986801 99.5%, dietary intake for 13 weeks to 0, 30, 100, 300, and 1000/ 700 mg/ kg/ day; high dose decreased to 700 due to toxicity; NOAEL= 30 mg/ kg/ day, LOAEL = 100 mg/ kg/ day is based on statistically significant ALT, AST and billirubin in males, increased spleen weights in females, increased incidence of diffuse degeneration, focal necrosis, extramedullary hematopoieses in liver. Acceptable/ Guideline Cu 8 quinolinolate 024002 82 1a subchronic mouse 43572401 97%, dietary intake of 0, 300, 1000, 3000, or 6000 ppm ( 0, 50, 148, 438, and 979 M and 0, 67, 200, 578, and 1066 mg/ kg/ day F) for 13 weeks.

NOAEL 979 M and 1066 F mg/ kg/ day ( HDT)

LOAEL not established.

Acceptable/ Guideline Page 37 of 39 Table 10. Other Available Toxicity Studies for Copper 8 Quinolinolate ( mg/ kg)

Cu 8 quinolinolate 024002 82 1a subchronic mouse 42937301 99.9%, dietary intake of 0, 100, 300, or 476 mg/ kg/ day for 6 to 13 weeks. No toxicity at highest dose. Supplemental/ Not Upgradeable Cu 8 quinolinolate 024002 82 1a subchronic mouse 42957801 Oxine Cu dietary exposure 13 weeks of 0, 300, 1000, 3000, or 6000 ppm ( conversion of 42.8, 142.8, 428.6, 857.1 mg/ kg/ day). NOAEL = 142.8 mg/ kg/ day LOAEL= 428.6 mg/ kg/ day, based on abnormal coloring and thickening of glandular mucosa of stomach, high dose effects of cysts on ovaries and slightly decreased absolute and relative spleen weight.

Cu 8 quinolinolate 024002 82 2 28 dermal 42957802 99.7% moistened and applied to gauze patches on intact skin at doses of 0, 50, 200, or 1000 mg/ kg/ day for 6 hrs./ day for 4 weeks. High dosed produced necrosis of the thymic lymphocytes in males. dermal NOAEL = 1000 mg/ kg/ day, systemic NOAEL = 200 mg/ kg/ day, systemic LOAEL = 1000 mg/ kg/ day based on necrosis of thymic lymphocytes.

Cu 8 quinolinolate 024002 83 2 carcinogen. Mice 43267201 80 week onco feeding study at 0, 100, 400, 1500, or 6000 ppm corresponding to 0, 14.5, 57.1, 207.7, and 855.8 mg/ kg/ day for males, 0, 16.1, 66.2, 246.2, and 855.8 mg/ kg/ day for females. NOAEL = 57.1 M and 66.2 F LOAEL = 207.7 M and 246.2 F, based on increased incidence of stomach ulcers in males; mild anemia and adverse liver effects in females. No dose related increase in individual neoplastic lesions was observed. Acceptable/ Guideline Cu 8 quinolinolate 024002 83 3a develop. Rat 42986803 oxine Cu by gavage on Gds 6 15 inclusive at 0, 50, 200, or 800 mg/ kg/ day. maternal NOAEL = 200 mg/ kg/ day maternal LOAEL = 800 mg/ kg/ day, based on increased clinical signs ( piloerection, poor general condition, encrustation of nose and mouth), and decreased body weight and gain. developmental NOAEL = 800 mg/ kg/ day, no developmental toxicity was observed. developmental LOAEL > 800 mg/ kg/ day. Acceptable/ Guideline Cu 8 quinolinolate 024002 83 4 reproduct. Rat 43267202 Diet at 0, 25, 250, or 2500 ppm ( 0, 1.8/ 2, 18.2/ 20.8, 181/ 203 mg/ kg/ day M/ F F0 and 2/ 2.2, 19.8/ 22.8, 196/ 218 mg/ kg/ day M/ F F1). Parental NOAEL = 250 ppm, LOAEL = 2500 ppm based on increase liver weight in F1 males. reproductive NAOEL = 250 ppm, LOAEL = 2500 ppm, based on decreased mean number of live pups at birth ( 85% of controls) and decreased litter weights at day 0 and during lactation in F1 generation. Acceptable/ Guideline Cu 8 quinolinolate 024002 84 2 muta Ames 00248746 Doses tested: 0.001,  0.3 ul/ plate ( 0.2 and 0.3 ul were toxic). Induced increases in histidine revertants in one strain TA100, possibly also TA1538 and TA98 with metabolic activation ( weak mutagen). Acceptable/ Guideline Cu 8 quinolinolate 024002 84 4 muta 00248746 no induced increases in tryptophan revertants at mutagenic conducted with and without metabolic activation. Doses tested: 0.0005  1.0 ul/ plate ( 1.0 said to be toxic no survival data). Acceptable/ Guideline Page 38 of 39 Table 10. Other Available Toxicity Studies for Copper 8 Quinolinolate ( mg/ kg)

Cu 8 quinolinolate 024002 85 1 42962304 42962305 14C labeled oxine copper at oral doses of 30 or 1000 mg/ kg, repeated oral doses ( 14 daily) unlabeled oxine copper at 30 mg/ kg followed by single oral labeled oxine copper at 30 mg/ kg. Major route of excretion via urine ( 62 86%) and feces ( 8 26%) within 48 hrs. Rapid absorption inferred by rapid excretion of metabolites in urine. radioactivity in tissue residues very low in all tissues including blood (< 0.05%). Bioaccumulation minimal. Radioactivity in urine associated with parent ( 5 16%) and sulfate ( 12 18%) and glucuronide conjugates ( 36 66%) of the parent. In feces, radioactivity associated with parent ( 4 23%) and glucuronide conjugate of the parent ( 0.1 4%). Acceptable/ Guideline B. Studies available for the other copper salts Table 11. Other Available Toxicity Studies for Copper Salts ( mg/ kg)

Copper Type PC Code Guideline Study MRID Results Cu octanoate 023306 None available Cu salts of fatty and rosin acids 023104 None available Cu triehanolamine complex 024403 82 2 12 day dermal rat 44127507 K TEA applied at 100 or 1000 mg/ kg/ day for 6 hrs/ day for 12 days. Volume dosage of 0.09 and 0.86 ml/ kg bw. Dose related increase in dermal irritation ( erythema, edema, fissuring, desquamation and eschar were noted at 100 while exfoliaion and clear exudate limited to 1,000 mg/ kg group. No evidence of systemic toxicity. systemic LOAEL > 1000 mg/ kg and systemic NOAEL > 1000 dermal LOAEL = 100 mg/ kg M& F; dermal NOAEL < 100 mg/ kg Acceptable/ Non guideline Elemental Cu 024407 82 2 12 day dermal rat 44127507 8% a. i., rats treated topically at 100 or 1000 mg/ kg/ day hrs/ day for 12 days. dose related increase in dermal irritation. no systemic toxicity noted. systemic LOAEL > 1000 mg/ kg/ day, systemic NOAEL > 1000 dermal LOAEL = 100 M & F, dermal NOAEL < 100 mg/ kg/ day Acceptable/ Non guideline Cu naphthenate 023102 82 3 9.5% Cu, Crl: CD ( BR) albino rats dermally exposed to 0, 100, 300, or 1000 mg/ kg/ day hrs/ day/ 5 days/ week for 13 weeks. slight systemic toxicity as reduced body weight gain & food efficiency in high dose males along with increase in kidney weight and decrease in testes weight. No other signs. systemic NOAEL = 300 mg/ kg/ day, systemic LOAEL = > 1000 mg/ kg/ day, based on reduced food efficiency and body wt. gain/ dermal NOAEL = 100 mg/ kg/ day, dermal LOAEL = 300 mg/ kg/ day. Acceptable/ Guideline Cu naphthenate 023102 83 3 develop, 0, 30, 100, or 300 mg/ kg, GD 6 15 inclusive maternal NOAEL= 30 mg/ kg maternal LOAEL= 100 mg/ kg, based on decreased body weight, food consumption, increase early resorptions, losses at HDT. developmental NOAEL > 300 mg/ kg, Page 39 of 39 Table 11. Other Available Toxicity Studies for Copper Salts ( mg/ kg)

Elemental Cu 024407 83 3a develop rat 44127507 Komeen ( 8% Cu) gavage at 0, 100, or 500 mg/ kg/ day GD 6 15. Maternal toxicity at 500 mg/ kg/ day by decrease body weight and food consumption, no frank toxicity. Maternal LOAEL= 500 mg/ kg/ day Maternal NOAEL= 100 mg/ kg/ day No developmental toxicity developmental NOAEL= 500 mg/ kg/ day developmental LOAEL not established UNACCEPTABLE: limit dose not reached, a detailed fetal exam should be conducted to investigate developmental potential Cu triehanolamine complex 024403 83 3 develop rat 44127506 8 Cu ( a. i.) In water ( 5 ml/ kg) at 0, 100, or 700 mg/ kg/ day from GD 6 15 inclusive. 1 F at 700 d ied GD10. Transient weight loss and food consumption during first two days of dosing in high group. maternal NOAEL = 100 mg/ kg/ day maternal LOAEL = 700 mg/ kg/ day, based on weight loss and food consumption. No developmental toxicity, increased post implantation loss at high dose. developmental NOAEL = 100 mg/ kg/ day, developmental LOAEL = 700 mg/ kg/ day, based on increased post implantation loss. Acceptable/ Non guideline BV. Other Studies for the Other Unscheduled Coppers No data available.