2 Introduction

The Antimicrobial Division (AD) Registrati on Review Team has evaluated the status

of the human health assessments for the ac tive ingredients copper naphthenate (PC Code 023102) and zinc naphthenate (P.C. Code 088301). According to the reregistration eligibility decision (R ED) document, copper and zinc naphthenate are formed when copper or zinc reacts with naphthenic acid, which is essentially a mixture of cyclic carboxylic acids, predominantly cyclopentane derivatives with an average molecular weight of 200-300. Copper and zinc naphthenate are currently registered as fungicides, insecticides and miticides. This document examines the hazard and exposure databases for the registered antimicrobial uses which include material and wood preservation. There

are no food use tolerances for the active ingredient, no registered food uses and no indirect food uses. There is however, one tolerance exemption for residues of copper naphthenate when used as an inert ingredient (40 CFR 180.920).

The wood preservative use sites for coppe r and zinc naphthenate include wood for utility poles, mine timbers , bridge timbers, cross-ties and stakes. The material preservation use sites for coppe r and zinc naphthenate include textiles used to make tents, awnings, tarpaulins, canvas products, nets, r opes, cordage, truck and boat covers, nonrubber fabrics, and burlap. Applications fo r both use sites are primarily done via impregnation, dip, brush, roller and spray.

The primary source of information for this assessment are the risk assessments and supporting documents for the reregistration el igibility decision (RED) documents, which were finalized in September, 2007. The purpose of this screen is to determine whether

sufficient data are availabl e to support registration re view, report on whether risk

assessments have been conducted and to re port whether new human health assessments are needed to support the registration review process. According to the RED, the presence of copper or zinc ion does not have a signifi cant influence on the mammalian toxicity of naphthenic acid. Th erefore, the toxicity data for both the copper and zinc naphthenate are considered togeth er for hazard characterization.3 The available data indicates that copper and zinc naphthenate are fatty acid salts which are practically insoluble in water, so luble in commercial solvents, and have low vapor pressures (~1E-5 mm Hg). Table 1 and 2 presents the identity of copper and zinc naphthenate respectively.

Section 1. Chemical Identity

Table 1. Chemical Identity of Copper Naphthenate

Common

Name Copper Naphthenate

CAS name Copper Naphthenate

PC Code 023102 CAS registry

number 1338-02-9

Registration

Review Case

No. 3099

Structure4 Table 2. Chemical Identity of Zinc Naphthenate

Common

Name Zinc Naphthenate

CAS name Zinc Naphthenate

PC Code 088301 CAS registry

number 12001-85-3

Registration

Review Case

No. 3099

Structure

Section 2. Toxicology

The Agency reviewed the toxicity databa se for copper and zinc naphthenate. No new toxicity studies and have been submitted since the RED. The Agency issued the DCI for both copper and zinc naphthenate on June 9, 2010. The existing toxicology data needs can be found in the Agency’s copper and zinc naphthenate RED at http://www.regulations.gov in docket num ber EPA-HQ-OPP-2007-0589. The Agency does not anticipate the need for any other toxi city data for copper and zinc naphthenate through the registration revi ew program. Although there were no reproductive or carcinogenicity data submitted for either c opper or zinc naphthenate, these data requirements are not considered to be nece ssary for reregistration since there are no registered food uses.

Acute Toxicity

The acute toxicity data for both the c opper and zinc naphthenate are considered together for hazard characterization and are considered adequate for reregistation will also not be needed for registration review . According to the existing RED, there are acceptable acute toxicity data available for the technical grade active (60%) of zinc naphthenate. Batteries of tests (acute oral , dermal, inhalation, primary eye, primary skin, and dermal sensitization) were conducted using 60% a.i. zinc naphthenate. With the5 exception of an acute inhalation study, acute oral, acute dermal, skin irritation, eye

irritation and dermal sensitizati on studies were considered acceptable. In an acute oral toxicity study with zinc napht henate (60%), a toxicity cat egory IV was assigned based on

a LC 50 greater than 5000 mg/kg. A toxicity cat egory of III was also assigned for acute dermal toxicity testing of zinc naphthenate with a LD50 for males and females greater than 2000 mg/kg. Acute inhalation toxicity test ing of 60% a.i. zinc naphthenate indicated a toxicity category of IV with a LC50 gr eater than 11.6 mg/L over a 4 hour exposure period, but the study was unacceptable. Skin and eye irritation testing of zinc naphthenate at 60% showed the compound to be moderate to severe and slight irritants respectively, with a toxicity category of (II, sk in) and (III, eye) assigned for skin and eye

irritation effects. In a de rmal sensitization study with zi nc naphthenate (60%), the material appeared to be a primary skin irritant and a possibl e sensitizing agent.

In contrast for copper naphthenate, there are no acceptable acute toxicity studies for the technical grade (80-89%) ac tive ingredient in the toxi cology database. The highest concentration of active ingredient that was te sted in acceptable acute toxicity studies was 45.4% a.i. In an acute oral toxicity study with copper naphthenate (45.4%), a toxicity category III was assigned based on testi ng of a single dose of 501 mg/kg (MRID 266172). A toxicity category of III was also assigned for acute dermal toxicity testing of copper naphthenate but the submitted study was not acceptable (HED document number 008158). Acute inhalation toxicity testing of 48% and 58% a.i. copper naphthenate) indicated a toxicity category of IV, but the studies were unacceptable. Skin and eye irritation testing of copper naphthenate at 45.4% show ed the compound to be a severe irritant in both cases, with a toxicity categ ory of I assigned for skin and eye irritation

effects. Dermal sensitization studies on c opper naphthenate from the BIBRA Toxicity profile indicate that copper naphthenate is not a dermal se nsitizer; there is no acceptable

dermal sensitization data av ailable to the Agency on the technical grade of the a.i., although the available data also indi cate no sensitization potential

Sub-chronic Toxicity

Dermal Toxicity

In a 90-day dermal toxicity test (MRID 41615001) designed to determine the sub-chronic toxicity effects of repeated dermal exposure to zinc naphthenate (14.5% purity) in New Zealand white ra bbits, rabbits were dermally exposed to 0, 100, 300, or 1000 mg/kg/day of zinc naphthe nate 6 hours a day, 5 days a week for 13 weeks. Animals were observed twice daily for signs of mort ality and moribundity and daily for signs of toxicity. Systemic toxicity was observed in the form of significantly reduced body weight gain in the high dose group throughout the study. In male rabbits, body weight gain decrement was also seen in the mid dose group throughout the study. No treatment related clinical signs of syst emic toxicity were noted (hematology, clinical chemistry or histopathology). In terms of de rmal effects there were appare nt dose related increases in macroscopic and microscopic lesions related to dermal irritation. The systemic toxicity NOAEL is (100 mg/kg/day, M/F). The system ic toxicity LOAEL is (300 mg/kg/day, M/F), based on reductions in body weight gai n. The dermal toxicity NOAEL is less than 100 mg/kg/day and the dermal toxicity LOAEL is less than or equa l to 100 mg/kg/day.6 Note that in the RED, the NOAEL was c onverted to different units when assessing

dermal irritation. The NOAEL is converted to toxic exposure per area of skin, which is measured in μg/cm 2 . The following equation was us ed to convert the dose: (100 mg[a.i.]/kg[rabbit] x 2.0 kg [body weight of rabbit] x 1000 μg/mg ) / 9 cm2 [area of rabbit exposed] =22,222 μg/cm2.

Assumptions involved in this calculation include body weight of the rabbit and area of skin exposed. If it is deci ded during the registration revi ew risk assessment process that the Agency will use irr itation as the endpoint for shor t-term dermal exposure, the Agency will likely need to convert the NOA EL to a dermal endpoint in the units of μg/cm 2 to do the risk assessment.

Inhalation Toxicity

There are no inhalation toxicity studies avai lable. The existing RED recently called in a 90-day inhalation toxicity study (Ser ies 870.3465) for both copper and zinc naphthenate. EPA confirmed that the inhalati on study required in the RED is still needed for registration review in or der to assess the occupationa l inhalation exposures from wood preservatives. The Agency issued the DCI for the copper and zinc naphthenate RED recently on June 9, 2010; therefore, the Agency does not intend to issue another DCI for this study through the registration review program.

Developmental Toxicity

In a prenatal developmental toxic ity study (MRID 41615101), copper naphthenate was administered by gastric intubation to 4 gr oups of 25 rats/dose by gastric intubation at dose levels of 0, 30, 100, or 300 mg/kg/day, resp ectively, from gestation days (GD) 6 to 15. Maternal toxicity was noted in the 100 mg/kg/day and 300 mg/kg/day groups in the form of decreases in body weight and food c onsumption. Maternal toxicity was noted in the 100 and 300 mg/kg/day groups in the form of decreases in body weight and food consumption. Evaluation of developmental t oxicity revealed an increase in the mean number of early resorptions only, however the mean litter size of the treated and control groups was comparable. Therefore, these increas es were considered to be of no biological significance. The maternal NOAEL is 30 mg /kg/day and the maternal LOAEL is 100 mg/kg/day. The developmental toxicity NOAEL was determined to be greater than or equal to 300 mg/kg/day and the developmen tal toxicity LOAEL was greater than 300 mg/kg/day.

In another prenatal developmental toxi city study (MRID 41615002), zinc naphthenate was administered orally at 0, 50, 250, or 500 mg/kg/day from days 6-15 of gestation. The NOAEL of 500 mg/kg/day derived is the highest dose tested. This study was reviewed as an unacceptable guideline study.

Mutagenicity

The Agency identified several mutagenicity studies in the RED. These studies included two gene mutation assays submitted to satisfy guideline 870.5300, two chromosome aberration assays submitt ed to satisfy guideline 870.5385, and two7 unscheduled DNA synthesis (UDS) studies. Th e RED DCI did not specify the need for any other mutagenicity studies and no new mutagenicity studies were submitted since the RED. The Agency does not anticipate the n eed for additional mutagenicity studies for registration review.

870.5300 In vitro mammalian cell gene mutation test

There were two gene mutation assays . In the first study, MRID 41402502, copper naphthenate was evaluated for mutagenic potential using the L5178Y TK+/- mouse lymphoma mutagenesis assay. A repeat test confirmed the increase of mutant frequencies with copper naphthenate in th e presence of metabolic activa tion (+S9). In another mouse lymphoma assay (MRID 41400701), zinc naphthen ate was tested with mouse lymphoma

L5178Y TK +/- cells without and with ra t liver activation (m ale Sprague-Dawley, Aroclor 1254 induced). There was a possible ad verse effect since the mutation frequency was increased in a concentration-dependent response both without and with activation. There was also a greater increase in small col onies versus large colonies with exposure to zinc naphthenate as opposed to copper naphthenate exposure

. Although the Office of Pesticide Programs reported these two studies to be unacceptable, California Department of Pesticide Regulation (CAL EPA) found the studies to be acceptable.

870.5385 Mammalian bone marrow chromosomal aberration test

There were two chromosome aberration test s submitted to the Agency. In the first study (MRID 41402503), copper naphthenate was tested in the first trial in a chromosome aberration assay using Chinese hamster ovary (CHO) cells. No effect on the mitotic index was seen at any concentrati on with activation. There were no significant reproducible

increases in CHO cells with aberrations for any of the copper naphthenate doses

.

In the other study (MRID 41400702), zinc napht henate was tested in two trials without metabolic activation and in the pres ence of metabolic activ ation. With activation, in the first trial, positive results were f ound at 80 ug/ml in the repeat +S9 trial and positive results were reported at 60, 80 and 100 ug/ml. In both repeat trials, there was a concentration dependent increase. There was a possible adverse effect of an increase in chromosomal aberrations with increasing con centrations of zinc naphthenate. Although the Agency reported these two studies to be unacceptable, the California Department of Pesticide Regulation (CAL EPA) fo und the studies to be acceptable

.

870.5550 Unscheduled DNA synthesis in mammalian cells in culture

Two Unscheduled DNA Synthesis (UDS) studies were also reviewed by OPP. In the first study (MRID 41402504), copper naphthenate was evaluated in the unscheduled DNA synthesis test using rat primary he patocytes and autoradiography. The mean number of net nuclear grains did not increase significan tly at any dose level over the

solvent control. It was concl uded, therefore, that copper na phthenate was tested over 12 an appropriate range of concentrations and failed to induce a genotoxic response. In the other UDS study (MRID 41400703), primary rat hepa tocytes, isolated from male livers, were treated with zinc naphthenate at c oncentrations. There was no evidence for the induction of UDS by zinc naphthenate to to xic doses. Toxicity was also evaluated8 microscopically by cellular morphology. Th ere was no adverse effect under the conditions of the assay. It was concluded, theref ore, that zinc naphthe nate was tested over an appropriate range of concentrations and failed to induce a genotoxic response.

Section 3. Dietary Assessment

Dietary

Dietary (food) exposures ar e not anticipated as a concern. Copper and zinc naphthenate residues are not e xpected to be introduced in to the food. There are no food

use tolerances for the active i ngredient, no registered food us es and no indirect food uses. There is however, one tolerance exemption fo r residues of copper naphthenate when used in accordance with good agricultural practices as an inert ingred ient in pesticide formulations applied to growing crops onl y (40 CFR 180.920). This exemption from the requirement of a tolerance was reassessed sepa rately as an inert tolerance assessment and

is not reconsidered in this document. For th e inert ingredient, no mo re than 2.5% copper naphthenate can be present, and products containing copper naphthenate can only be applied before the edible portions of the plant begin to form.

Drinking Water

According to the product chemistry chapter of the RED, copper and zinc naphthenate are highly to moderately imm obile in soil and only slightly soluble in water. Copper and zinc naphthenate leached from treated wood poles would likely remain immobile in soil

and break down and not migrate to groundwater.

Copper and zinc naphthenate products are re gistered for the use in treated wood to construct docks and piers and the Agency will model environmental concentrations of copper and zinc naphthenate in the surface water during the registration review risk assessment process and will also develop a drinking water assessment.

Section 4. Occupational/Residential Exposure

An occupational and/or residential exposur e assessment is required for an active ingredient if (1) cert ain toxicological criteria are triggered and (2) there is potential exposure to handlers (mixers, loaders, applicat ors, etc.) during use or to persons entering treated sites after application is complete. For copper and zinc naphthenate, the Agency needs to select toxicological endpoints befo re a risk assessment can be conducted. The Agency also anticipates n eeding to conduct occupational and residential dermal and

inhalation risk assessments once the needed exposure data from the RED has been submitted, reviewed, and accepted by the Agency.

Based on the available use information, AD c oncludes that there is potential exposure to occupational handlers (i.e., from applications of wood pr eservatives and textiles) and residential handlers (e.g., homeowner wood tr eatment applications). In addition, the Agency expects there also will be exposure from occupational post-application exposures (i.e., workers exposed to wood treatment f acilities) and residential post-application exposure concerns for children (i.e., contac t with treated wood playsets and decks).9 Hander Exposure

Occupational Handlers

The Agency identified potential occupati onal handler exposures for copper and zinc naphthenate previously in the RED. No ot her new uses were identified during the registration review process. The potential occupational hand ler risk assessments (both short-term (1-30 days) and intermediate-ter m (>30 days)) by scenario that the Agency expects to conduct during re gistration review include:

• Incorporation into Textiles Du ring Industrial Manufacturing;

• Handler Exposure to Workers at Non-pre ssure Treatment Facilities (i.e., diptank operator, blender/spray operat or, and chemical operator);

• Handler Exposure to Workers at Pressu re Treatment Facilities (i.e., treatment operator and treatment assistant);

• Handler Exposure to Workers at Commercial Wood/Lumber Facilities; and

• Application to In-service Utility Poles, Pilings, Posts, and Other Standing

Timbers.

The methods of direct app lication include liquid pour a nd liquid pump, low pressure spray, brush/roller, non-pressure treatment, pr essure treatment, brush, trowel or grease gun, and pre-manufactured bandage.

Residential Handlers

Residential handler exposure can occur th rough the application of copper and zinc naphthenate preservative coa tings via paintbrush or spra yer application. The Agency expects to conduct residential handler risk assessments for these scenarios and the Agency is likely to conduct risk assessmen t only of short-term duration (1-30 days).

Postapplication Exposure

Occupational

The Agency identified potential occupa tional postapplication exposures for copper and zinc naphthenate previously in the RED. No other new uses were identified during the registration review process. The po tential occupational scenarios include:

• Post-application Exposure to Workers at Sawmills/Planer Mills (e.g., grader, trim saw operator, millwright, and clean-up); and,

• Post-application Exposure to Workers at Pr essure Treatment Faci lities (e.g., tram setter, stacker operator, loader operator , supervisor, test borer, and tallyman).

Residential

The Agency expects that it will need to conduct a residential assessment to examine hand-to-mouth and dermal exposures to children from playsets and decks.10 Section 5. Aggregate and Cumulative Exposure

In examining aggregate exposure, EPA take s into account the available and reliable information concerning exposures to pesticid e residues in food and drinking water, and non-occupational pesticide exposures. Food exposur es of concern are not anticipated as a concern based on the fact that copper or zi nc naphthenate are not expected to be introduced into the food, ther e are no food use tolerances, no registered food uses and no

indirect food uses.

The Agency expects that it will need to conduct a residential assessment to examine hand-to-mouth and dermal exposures to childre n from playsets and decks. The aggregate

assessment will include both residen tial and drinking water exposures.

Section 408(b)(2)(D)(v) of FFDCA require s that, when considering whether to establish, modify, or revoke a tolerance, th e Agency consider "available information” concerning the cumulative effects of a part icular pesticide's residues and "other

substances that have a common mechanism of toxicity.” EPA has not yet determined whether copper and zinc naphthenate ha s a common mechanism with other compounds, consequently a cumulative assessment will not be performed.

Section 6. Endocrine Disruption

As required under FFDCA section 408(p) , EPA has developed the Endocrine Disruptor Screening Program (EDSP) to dete rmine whether certain substances (including pesticide active and other ingred ients) may have an effect in humans or wildlife similar to an effect produced by a “natur ally occurring estrogen, or othe r such endocrine effects as the Administrator may designate.” The ED SP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substa nce to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to inte ract with E, A, or T hormonal systems will proceed to the next stage of the EDSP wher e EPA will determine which, if any, of the Tier 2 tests are necessary based on the avai lable data. Tier 2 te sting is designed to identify any adverse endocrine related eff ects caused by the substance, and establish a dose-response relationship between th e dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA i ssued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active i ngredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathways such as food and wa ter, residential activity, and certain postapplication agricultural s cenarios. This list should not be construed as a list of known or likely endocrine disruptors.

Copper and zinc naphthenate are not among the group of 58 pesticide active ingredients on the initi al list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemi cals. Accordingly, EPA anticipates issuing

future EDSP test orders/data call-ins for all pesticide active ingredients.11 For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and th e Tier 1 screening ba ttery, please visit our website: http://www.epa.gov/endo/.

Section 7. Incidents

According to the RED, the Agency review ed available sources of human incident

data for incidents relevant to copper and zinc naphthenate. EPA consulted the following sources of information for human poisoni ng incidents related to copper and zinc naphthenate use: (1) OPP Incident Data Syst em (IDS) - The Office of Pesticide Programs (OPP) Incident Data System contains reports of incidents from vari ous sources, including registrants, other federal a nd state health and environmen tal agencies and individual consumers, submitted to OPP since 1992; (2) California Department of Pesticide Regulation (1982-2004) – The Calif ornia Department of Pes ticide Regulati on pesticide poisoning surveillance program consists of repor ts from physicians of illness suspected of being related to pesticide exposure since 1982; (3) National Pesticide Information Center (NPIC) - NPIC is a toll-free informati on service supported by OPP That provides a ranking of the top 200 active ingredients for which telephone calls were received during calendar years 1984-1991; (4) National Pois on Control Centers (PCC) (1993-1996); and (5) Published Scientific L iterature on Incidents.

The RED also reported that since 1992, only one incident associated with copper or zinc naphthenate alone has been recorded. The incident report noted a strong odor and adverse health effects were reported fo llowing residential application of copper naphthenate containing wood pr eservative. However, no clear symptoms were described in the report.

The RED stated that the most common sy mptoms reported for cases of ocular exposure were eye irritation/burning. Eye pain and swelling of eyes also have been reported in some cases. No incidents of oral exposure have been reported. No new incidents have been reported to the Agency after the completion of the RED in September

2007.

Section 8. Anticipated Data Needs

The Agency issued the DCI for coppe r and zinc naphthenate on June 9, 2010. The data needs for the DCI for reregistration can be found in the Agency’s copper and zinc naphthenate RED at http://www.regulati ons.gov in docket number EPA-HQ-OPP-2007- 0589. The Agency does not anticipate the need for any other hazard, exposure data for copper and zinc naphthenate for registration re view since the data were already recently called in. The toxicity and exposure data al ready called in from the RED DCI include:

• 90-day inhalation toxi city (Series 870.3465);

• Dermal exposure (Series 875.1100 and 875.1200);

• Inhalation exposure (Series 875.1300 and 875.1400);

• Application exposure mon itoring (Series 875.1600);

• Product use (Series 875.1700); and12 • Wood leaching study (Special Study).

Section 9. Tolerances

There are no tolerances or exemptions from tolerances for the copper and zinc naphthenate active ingredients a nd no registered food uses. Si nce the only registered uses are for non-food uses and no dietary assessmen t is needed, no tolerance or exemption from the requirement of a tolerance will be needed to support the existing active ingredient registered uses of copper and zinc naphthenate.

It should be noted that ther e is also one inert exempti on from the requirement of a tolerance for residues of copper and zinc napht henate when used in accordance with good agricultural practices as an in ert ingredient in pesticide fo rmulations applied to growing crops only (40 CFR 180.920). For this inert tolerance exemption, no more than 2.5% copper naphthenate can be pres ent, and products containing copper naphthenate can only be applied before the edible portions of plants begin to form. This tolerance was reassessed separately as an inert tolerance as sessment and is not reconsidered in this document since it only reassesses the active ingredient.

Section 10. Overall Conclusions

The Agency reviewed the hazard and exposure databases for copper and zinc naphthenate and does not anticipate that additio nal data will be needed since the Agency recently reassessed copper and zinc naphthena te in the RED and also sent out a recent RED DCI for pending data needs. Dependi ng on the outcome of the review and acceptance of the new data from the copper and zinc naphthenate RED DCI, the Agency anticipates the need to conduct new handl er and post-application assessments for registration review. The EPA also anticipat es that occupational, residential, and aggregate assessments will be needed to ensure that copper and zinc naphthenate registration review case meet s the safety standards esta blished by FFDCA, as amended by FQPA. After the Agency conducts the surf ace water modeling, the Agency will then be able to develop a drinking water assessment. No additional label changes are suggested at this time.

Section 11. Recommended Label Changes

The RED, which was finalized in September, 2007, recommended a number of label changes to minimize the dermal risk s of concern. From zinc naphthenate. The Agency noticed in reviewing the labels for registration review that a number of the currently registered labels have not been updated to accommodate the risk mitigation specified in the RED. Among the changes li sted in p46 of the RED were the following:

• Limit application for preservation of outdoor-use textiles for zinc naphthenate products to low-pr essure sprayer and liquid pump applications. Application to outdoor-use textiles using a brush/roller or liquid pour is prohibited.13 • Remove pressure treatment and remedi al treatment of utility poles from all zinc naphthenate labels;

• Limit application for general preserva tion of wood for zinc napththenate products to low-pressure sprayer app lications. Application for general preservation of wood using a brush/ro ller or airless spra yer is prohibited.

• Reduce maximum application rate for use in wood preservative applications by blender spray opera tors to 15% a.i. by weight. Applicators must wear long sleeved shirt, long pants, shoes, socks, chemical resistant gloves, and chemical resistant apron;

• Reduce maximum application rate for use in dip tank operations to 25% a.i.; and,

• Require chemical resistant gloves to be used on all zinc naphthenate products.

Section 12. Reference

• Reregistration Eligibility Decision (RED ) Copper and Zinc Naphthenate Salts, September, 2007. http://www.epa.gov/pesticides/r eregistration/status.htm