Document ID: EPA-HQ-OPP-2013-0286-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-07-19T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: PV Shah, 703-308-1846

OhSo Clean, Inc.

2E8116

	EPA has received a petition (2E8116) from OhSo Clean, Inc.,  315 Pacific Avenue, San Francisco, CA 94111 requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.940(a) to establish an exemption from the requirement of a tolerance for copper sulfate pentahydrate (CAS Reg. No. 7758-99-8) for use as an inert ingredient in antimicrobial pesticide formulations applied to food-contact surfaces in public eating places, dairy processing equipment and food processing equipment and utensils.  EPA has determined that the petition contains data and information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition.  Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. NA-Remove

	2. Analytical method. An analytical method is not required for enforcement purposes since the Agency is establishing an exemption from the requirement of a tolerance without any numerical limitation. 

	3. Magnitude of residues. Copper is ubiquitous in nature and is a necessary nutritional element for both animals (including humans) and plants.  Copper is found naturally in the food we eat including fruits, vegetables, meats and seafood.  It is found in the water we drink, the air we breathe and in our bodies themselves.  Some of the environmental copper is due to direct modification of the environment by man such as mining and smelting of the natural ore.  It is one of the elements found essential to life.  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-the-counter dietary supplements containing copper at levels ranging from 0.33 milligram (mg) to 3 mg are available for individuals with low levels of copper.  
	The proposed use of copper sulfate pentahydrate as an inert ingredient in the formulation in antimicrobial products used on food contact surfaces is not likely to result in significant copper residues in food.  Potential exposure from this use is negligible, particularly when compared to consumption of supplements and natural dietary sources of copper. It is important to note that the proposed use as an inert ingredient in antimicrobial pesticide formulations (<0.01% w/w) is very small in comparison to currently approved uses as an active ingredient in pesticide formulations (up to 99% w/w) which are exempt from the requirement of a tolerance under 40 CFR § 180.1021.

B. Toxicological Profile

	EPA reviewed the available scientific data and other relevant information in support of an exemption from tolerance for a new pesticidal use of copper sulfate pentahydrate and considered its validity, completeness and reliability and the relationship of this information to human risk (Fed. Reg. 71:46106-46110, August 11, 2006). As part of the review, EPA considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children.  The nature of the toxic effects caused by copper sulfate pentahydrate are summarized below.  
	There is adequate information available to characterize the toxicity of the copper ion. The copper ion is present in the adult human body with nearly two-thirds of the body copper content located in the skeleton and muscle. The liver is the primary organ for the maintenance of plasma copper concentrations.
    Oral ingestion of excessive amounts of the copper ion is unlikely. Copper compounds are irritating to the gastric mucosa. Ingestion of large amounts of copper results in prompt emesis. This protective reflex reduces the amount of copper ion available for absorption into the human body. Additionally, at high levels humans are also sensitive to the taste of copper. Because of this organoleptic property, oral ingestions would also serve to limit high doses.
    Only a small percentage of ingested copper is absorbed, and most of the absorbed copper is excreted. The human body appears to have efficient mechanisms in place to regulate total body copper. The copper ion occurs naturally in food and the metabolism of copper is well understood. The Agency has conducted a risk assessment in connection with the development and issuance of the Reregistration Eligibility Decision Document for Copper (EPA-HQ-OPP-2005-0558; Human Health Chapter). No endpoints of toxicology concern were identified for risk assessment purposes for a number of reasons. One of the foremost of these is the fact that copper is a required nutritional element for both plants and animals. Current available data and literature studies indicate that there is a greater risk from the deficiency of copper intake than from excess intake. Copper also occurs naturally in a number of food items including fruits, vegetables, meats and seafood. 
	Although there is little known about the minimum levels of dietary copper necessary to cause evidence of adverse effect, this situation is likely due to the existence of an effective homeostatic mechanism that is involved in the dietary intake of copper and that protects man from excess body copper. Given that copper is ubiquitous and is routinely consumed as part of the daily diet, it is unlikely that the addition of use as an inert ingredient at <0.01% w/w in antimicrobial pesticides will result in any long term adverse effects.    Finally, sulfate has little toxic effect and is routinely used in medicine as a cathartic when combined with magnesium or sodium, the only adverse manifestation from this use being dehydration if water intake is concurrently limited.

	1. Acute toxicity. Acute toxicity studies for the oral, dermal, and inhalation routes of exposure exist for almost all copper species.  In general, copper has moderate to low toxicity (toxicity category II, III, and IV) based on acute oral, dermal, and inhalation studies in animals.  However, copper may be a severe eye irritant.  Most dermal irritation studies indicate Toxicity Copper is generally non-sensitizing in guinea pigs and rabbits.  Several acute toxicity studies specific to copper sulfate pentahydrate are available.  Copper sulfate pentahydrate has an acute oral LD50 of 790 mg/kg for males and 450 mk/kg for females, and has a Tox Category II classification for acute oral toxicity.  The acute dermal LD50 is >2,000 mg/kg, resulting in a Tox Category IV classification for acute dermal toxicity.  An acute inhalation study specifically for copper sulfate pentahydrate is not available; however, the other copper compounds have classifications of Tox Category II or III, with the exception of cuprous oxide, which is a Tox Category I. (MRID 43396201)

	2. Genotoxicity. Mutagenicity studies available from registrants indicate copper as cuprous oxide or copper sulfate pentahydrate are negative.  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).

	3. Reproductive and developmental toxicity. 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). 

	4. Subchronic toxicity. Copper is generally less toxic when administered in the diet than when administered in drinking-water or by gavage.  Orally, copper is irritative to the gastrointestinal tract, with no 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.  An NTP study (Hebert et al., 1993) has been conducted to examine the effects of cupric sulfate pentahydrate when administered in the drinking water for 2 weeks only, or diet for 2 weeks and 13 weeks.  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.
	A short-term drinking water study examined the influence of excess copper on the immune response of mice (Pocino et al., 1991).  Although immune response appeared to be related to the dose and duration of treatment, 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.  Consumption of drinking water was lower when copper concentrations were increased, and zinc was not measured, therefore, it was not known whether dehydration and/or zinc deficiency affected the immune response of animals.

	5. Chronic toxicity.   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).
	Copper (metallic) is currently Group D, not classifiable as to human carcinogenicity.  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).

	6. Animal metabolism. Copper is a naturally occurring element that is essential for the homeostasis of life.  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. 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).

	7. Metabolite toxicology. NA-Remove 

     	8. Endocrine disruption. Based on the available toxicology studies and literature for copper, there is currently no indication of endocrine disruption.  

C. Aggregate Exposure

	In examining aggregate exposure, FFDCA section 408 directs EPA to consider available information concerning exposures from the pesticide residue in food and all other non-occupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor uses).
	 EPA establishes exemptions from the requirement of a tolerance only in those cases where it can be clearly demonstrated that the risks from aggregate exposure to pesticide chemical residues under reasonably foreseeable circumstances will pose no appreciable risks to human health. In order to determine the risks from aggregate exposure to pesticide chemicals, the Agency considers the toxicity of the chemical in conjunction with possible exposure to residues of the chemical through food, drinking water, and through other exposures that occur as a result of pesticide use in residential settings. If EPA is able to determine that a finite tolerance is not necessary to ensure that there is a reasonable certainty that no harm will result from aggregate exposure, an exemption from the requirement of a tolerance may be established.
	Dietary endpoints are not appropriate at this time for the copper risk assessment since copper is an essential element, the lack of systemic toxicity, and the exemption from a requirement of a tolerance (list CFR notices or see section of risk assessment).  

	1. Dietary exposure. Copper is ubiquitous in nature and is a necessary nutritional element for both animals (including humans) and plants. It is one of several elements found essential to life. The human body must have copper to stay healthy. A variety of biochemical processes in the body to operate normally, copper must be part of our daily diet. 
	Copper is needed for certain critical enzymes to function in the body. Copper deficiency can lead to disease.

	i. Food. The main source of copper for infants, children, and adults, regardless of age, is the diet. Copper is typically present in mineral rich foods like vegetables (potato, legumes (beans and peas), nuts (peanuts and pecans), grains (wheat and rye), fruits (peaches and raisins), and chocolate in levels that range from 0.3 to 3.9 ppm. A single day's diet may contain 10 mg or more of copper. The daily recommended allowance of copper for adult nutritional needs is 2 mg. It is not likely that the approval of this tolerance exemption petition would significantly increase exposure over that of the existing levels of copper.

	ii. Drinking water. Copper is a natural element found in the earth's crust. As a result, most of the world's surface water and ground water that is used for drinking purposes contains copper. The actual amount varies from region to region, depending on how much is present in the earth, but in almost all cases the amount of copper in water is extremely low. Naturally occurring copper in drinking water is safe for human consumption, even in rare instances where it is at levels high enough to impart a metallic taste to the water. Residues of copper in drinking water are regulated under the Safe Drinking Water Act. A Maximum Contaminant Level Goal 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.'' The Agency believes that this level of protection would not cause any potential health problems, i.e. stomach and intestinal distress, liver and kidney damage and anemia. It is not likely that the approval of this petition would significantly increase exposure over that of the existing levels of copper. 

	2. Non-dietary exposure. Copper compounds have many uses on crops (food as well as non-food) and ornamentals as a fungicide.

Dermal exposure. Given the prevalence of copper in the environment, no significant dermal exposure increase above current levels would be expected from the non-occupational use of copper sulfate pentahydrate.

Inhalation exposure. Air concentrations of copper are relatively low. A study based on several thousand samples assembled by EPA's Environmental Monitoring Systems Laboratory showed copper levels ranging from 0.003 to 7.32 micrograms per cubic meter. Other studies indicated that air levels of copper are much lower. The Agency does not expect the air concentrations of copper to be significantly affected by the use of copper sulfate pentahydrate.

D. Cumulative Effects

	The Agency believes that copper has no significant toxicity to humans and that no cumulative adverse effects are expected from long-term exposure to copper salts including copper sulfate pentahydrate.  For the purposes of this tolerance action, EPA has not assumed that copper compounds have a common mechanism of toxicity with other substances.

E. Safety Determination

    Copper sulfate pentahydrate is considered as Generally Recognized as Safe (GRAS) by the Food and Drug Administration (FDA). EPA has also exempted various copper compounds from the requirement of a tolerance when used as aquatic herbicides (40 CFR 180.1021). Copper compounds, including copper sulfate pentahydrate, are also exempt from the requirements of a tolerance when applied to growing crops when used as a plant fungicide in accordance with good agricultural practices (40 CFR 180.1021).  All of these uses represent much higher potential for residues in food than use as an inert ingredient (<0.01% w/w) in antimicrobial pesticides.
	1. U.S. population. Copper is a component of the human diet and an essential element. In addition, no acute or chronic dietary end points were selected because no endpoints of toxicological concerns have been identified for risk assessment purposes. Use of copper sulfate pentahydrate is not expected to increase the amount of copper in the diet as a result of its use on growing crops and post harvest use.
	2. Infants and children. Copper is also a component of the diet of infants and children and also an essential element of their diet. Since no endpoints of concern have been identified, EPA has not conducted a quantitative risk assessment for copper sulfate pentahydrate. The Agency has also determined that the special FQPA safety factor to protect infants and children was not needed since there are no toxicity endpoints or uncertainty surrounding exposure.
    Based on the information available for copper sulfate pentahydrate, EPA concludes that there is a reasonable certainty of no harm to the general population, including infants and children, from aggregate exposure to copper sulfate pentahydrate residues.

F. International Tolerances

	The Agency is not aware of any country requiring a tolerance for copper sulfate pentahydrate nor have any CODEX Maximum Residue Levels (MRLs) been established for any food crops at this time. 

References

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

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.

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.

Luza CS and Speisky HC (1996). Liver copper storage and transport during development: implications for cytotoxicity. 63:812S-820S.
 
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.
 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. 

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.
 
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.

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

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