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Page 2 of 94 Chromated Arsenicals Registration Review Team

Human Health & Environmental Effects Pat Jennings Jim Breithaupt David Bays Tim Dole Jonathan Chen Kristin Rury

Risk Management Sandra O’Neill Tom Luminello Rose Kyprianou

Office of General Counsel Philip RossDocket Number EPA

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Page 3 of 9 4 TERMS, ABBREVIATIONS AND SYMBOLS

ACC Acid Copper Chromate ACZA A mmoniacal C opper Z inc A rsenate AD Antimicrobials Division A.I. or a.i. active ingredient aPAD a cute p opulation a djusted d ose ASRI a ctivated sludge r espiration i nhibition
atm

- m 3 /mole a tmospheric pressure

- cubic meter per mole ATSDR Agency for Toxic Substances and Disease Registry BCF b ioconcentration f actor °C d egrees Celsius CAS Chemical Abstracts Service CA Chromated Arsenicals CCA Chromated Copper Arsenate CFR Code of Federal Regulations CHO Chinese h amster o vary CMA Chemical Manufacturers Association CO 2 c arbon dioxide COC c oncentration

- of

- c oncern cPAD c hronic p opulation a djusted d ose CPSC Consumer Product Safety Commission CrII divalent chromium C r III trivalent chromium C r V I hexavalent chromium DCI data call

- in EC 50 m edian (or 50 percent) e ffect c oncentration EC 05 5 p ercent e ffect c oncentration ECOTOX ECOTOXicology EDI e stimated daily i ntake EDSP E ndocrine Disruptor Screening Program EEC estimated environmental concentration E

- FAST Exposure and Fate Assessment Screening Tool EPI Suite Estimation Program Interface Suite EPA Environmental Protection Agency FDA Food and Drug Administration FFDCA Feder al Food, Drug, and Cosmetic Act FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality Protection Act FWP Final Work Plan g/mol g rams per mole GLN guideline number HPV h igh production v olume HSRB Human Studies Review Board IDS Incident Data System IRIS Integrated Risk Information System Koc o rganic carbon normalized s oil

- water partition coefficient Kd s oil

- water partition coefficient Kow o ctanol

- water partition coefficient LC 50 m edian (or 50 percent) l ethal c oncentration LD 50 m edian (or 50 percent) l ethal d oseDocket Number EPA

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Page 4 of 94 LOAEC l owest

- o bserved

- a dverse

- e ffect

- c oncentration LOEC l owest

- o bserved

- e ffect

- c oncentration LOAEL lowest

- observed

- adverse

- e ffect

- l evel Log K ow l ogarithm of the octanol

- water partition coefficient
μg m icrogram MCL maximum contaminant level MCLG maximum contaminant level goal ml/g m illiliter p er g ram mg/kg m illigram p er k ilogram mg/kg/day m illigram p er k ilogram p er d ay mg/L m illigram p er l iter mm Hg m illimeter of mercury MOE m argin of e xposure MRID Master Record Identification Number MRL m aximum r esidue l imit N/A n ot a pplicable

nm n anometers NOAE C no

- observed

- adverse

- effect

- c oncentration NOAEL n o

- o bserved

- a dverse

- e ffect

- l evel NRC National Research Council OCSPP Office of Chemical Safety and Pollution Prevention OECD Organization for Economic Co

- operation and Development OPP Office of Pesticide Programs RQ risk quotient PAD p opulation a djusted d ose PAI p ure active i ngredient PDM Probabilistic Dilution Model % p ercent PC Code Pesticide Chemical Code PCF p ounds p er c ubic foot pH power of h ydrogen or power of the con centration of the hydrogen ion PHED Pesticide Handler’s Exposure Data PIS primary i rritation s core pKa p ower of the acid dissociation constant or negative base

- 10 logarithm of the acid dissociation constant of a solution ppb p arts p er b illion
ppm p arts p er m illion PWP Preliminary Work Plan QSAR q uantitative s tructure

- a ctivity r elationship RCRA Resource Conversation and Recovery Act RED Rere gistration Eligibility Decision SAB Scientific Advisory Board SAR s tructure a ctivity r elationship SF s afety f actor TEP t y pical e nd

- u se p roduct TGAI t echnical grade active i ngredient TMDL total maximum daily l oads UF uncertainty factor USDA United States Department of Agriculture UV/VIS ultraviolet/v isible light a bsorption % w / w p ercent weight per weight.Docket Number EPA

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Page 5 of 94 WP w ettable p owder WWTPs w astewater treatment plantsDocket Number EPA

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Page 6 of 94 

### Table of Contents 1 Introduction

................................ ................................ ................................ ............................. 8 1.1 Statutory and Regulatory Authority

................................ ................................ ................. 8 1.2 Case Overview

................................ ................................ ................................ .................. 8 1.3 Chemical Identification and Properties

................................ ................................ .......... 10 1.4 Use/Usage Description

................................ ................................ ................................ ... 11 1.4.1 Registrations

................................ ................................ ................................ ............ 11 1.4.2 Su mmary of Registered Uses

................................ ................................ .................. 11 1.4.3 Usage Information

................................ ................................ ................................ ... 13 1.5 Regulatory History

................................ ................................ ................................ ......... 13 1.5.1 Tolerance Information

................................ ................................ ............................. 14 1.6 Incidents

................................ ................................ ................................ .......................... 14 1.6.1 Human Health

................................ ................................ ................................ ......... 14 1.6.2 Ecological

................................ ................................ ................................ ................ 14 2 Anticipate d Data Needs

................................ ................................ ................................ ......... 14 3 Human Health Risk Assessment

................................ ................................ ........................... 16 3.1 Existing Toxicological Endpoints

................................ ................................ .................. 16 3.2 Dietary Exposure

................................ ................................ ................................ ............ 18 3.2.1 Fo od and Drinking Water

................................ ................................ ........................ 18 3.3 Occupational and Residential Exposures

................................ ................................ ....... 18 3.3.1 Occupational Handler Exposure

................................ ................................ .............. 18 3.3.2 Occupational Post Application Exposure

................................ ................................ 19 3.3.3 Residential Handler Exposures

................................ ................................ ............... 19 3.3.4 Residential Post

- Application Exposures

................................ ................................ . 19 3.4 Aggregate and Cumulative Exposure

................................ ................................ ............. 20 3.4.1 Aggregate Exposures

................................ ................................ ............................... 20 3.4.2 Cumulative Exposures

................................ ................................ ............................. 20 4 Environmental Risk Assessment

................................ ................................ ........................... 20 4.1 Environmental Fate Assessment

................................ ................................ ..................... 21 4.1.1 Water Quality

................................ ................................ ................................ .......... 21 4.2 Conceptual Models for Environmental Exposure Pathways

................................ .......... 21 4.3 Ecological Effects Assessment

................................ ................................ ....................... 22 4.3.1 Measures of Effect (Ecotoxicology Endpoints)

................................ ...................... 23 4.4 Exposure Analysis Plan

................................ ................................ ................................ .. 24 4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

................................ ............. 24 4.4.2 Screening Level Down

- the

- Drain Analysis

................................ ............................ 24 4.5 Effects Analysis Plan

................................ ................................ ................................ ...... 25 5 Endocrine Disruptor Screening Program (EDSP)

................................ ................................ . 25 6 Optional Label Changes

................................ ................................ ................................ ........ 26 7 Guidance for Commenters

................................ ................................ ................................ .... 26 7. 1 Preliminary Work Plan

................................ ................................ ................................ ... 26 7.1.1 Trade Irritants

................................ ................................ ................................ .......... 26 7.1.2 Water Quality

................................ ................................ ................................ .......... 27 7.1.3 En vironmental Justice

................................ ................................ ............................. 27 7.1.4 Additional Information

................................ ................................ ............................ 27 8 Next Steps

................................ ................................ ................................ ............................. 28Docket Number EPA

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Page 7 of 94 9 References

................................ ................................ ................................ ............................. 29

Appendix A Toxicology Profile

................................ ................................ ............................... 31 Appendix B Environmental Fate

................................ ................................ .............................. 61 Appendix C Ecotoxicology Profile

................................ ................................ .......................... 65 Appendix D Screening Level Down

- the

- Drain Analysis

................................ ......................... 90 Appendix E Product Chemistry

................................ ................................ ............................... 91 Appendix F Categories of Forest Products That May be Treated with Chromated Arsenicals 93

List of Tables Table 1

– Summary of Anticipated Risk Assessments and Data Needs for Registration Review: Chromated Arsenicals

................................ ................................ ................................ ....................... 9 Table 2

– Anticipated Registration Review Schedule

................................ ................................ ....... 9 Table 3

– Chemical Identification of Chromated Arsenicals

................................ .......................... 10 Table 4

– Physical

- Chemical and Environmental Fate Properties for Active Ingredients in Chromated Arsenicals

................................ ................................ ................................ ..................... 11 Table 5

– Chromated Arsenical End Use Products with Active Registrations

............................... 11 Table 6

– Chromated Arsenical

- Treated Wood Use Table

................................ ............................. 12 Table 7

– Studies Anticipated as Needed for the Registration Review of Chromated Arsenicals

. 15 Table 8

– Data Needs Required by the September 9, 2011 Data Call

- In for the Chromated Arsenicals RED

................................ ................................ ................................ ............................... 15 Table 9

– Toxicological Endpoints for Assessing Exposures/Risks to Inorganic Arsenic (V)

....... 16 Table 10

– Toxicological Endpoints for Assessing Exposures/Risks to Chromium VI

................. 17 Table 11

– Occupational Handler Exposure Scenarios for Chromated Arsenic als

......................... 19 Table 12

– Ecological Effects Endpoints Selected for Assessing Risks from Arsenic Acid Use

... 23 Table 13

– Ecological Effects Endpoints Selected for Assessing Risks from Chromic Acid Use

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Page 8 of 94 

## 1 Introduction

This document is the United States Environmental Protection Agency ’s ( USEPA, EPA or “the Agency ”) Preliminary Work Plan (PWP) for c hromated a rsenicals . The PWP document explains what EPA's Office of Pesticide Programs (OPP) knows about chromated arsenicals , highlighting anticipated data and assessment needs, identifying the types of information that would be especially useful to the Agency in conducting the review, and providing an anticipated timeline for completing chromated arsenicals ’ review.

The registration review process was designed to include a public participation component to solicit input from interested stakeholders. The Agency intends, by sharing this information in the docket, to inform the public of what it knows about chromated arsenicals and what types of new data or other information would be helpful for the Agency to receive as it moves toward a decision on chromated arse nicals

. The Agency encourages all interested stakeholders to review the PWP and to provide comments and additional information that will help the Agency ’s decision

- making process for this chemical.



## 1.1 Statutory and Regulatory Authority
The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All pesticides distributed or sold in the United States generally must be registered by the USEPA based on scientific data showing that they will not cause unreasonable risks to human health or the environment when used as directed on product labeling. The registration review program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continu e to meet the statutory standard of no unreasonable adverse effects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review program, the Agency periodically re evaluates pesticides to make sure that as change occurs, products in the marketplace can be used safely. Information on this program is provided at http://www2.epa.gov/pesticide

reevaluation

.
The A gency is implementing the registration review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA s tandard for registration. The regulations governing registration review begin at 40 CF R 155.40. The Agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened fo r each case. The docket is the Agency ’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a registration review decision. After reviewing and responding to commen ts and data received in the docket during this initial comment period, the Agency will develop and commit to a F inal W ork P lan (FWP) and anticipated schedule for the chromated arsenicals case

.



## 1.2 Case Overview

The docket for the chromated arsenicals ( case 0132 ) has been established
at http://www.regulations.gov in docket number EPA

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. Documents associatedDocket Number EPA

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Page 9 of 94 with this registration review can be viewed in this docket. Tables 1

- 2 b elow summar ize the issues relevant to this registration review case and the anticipated registration review schedule

.

Table 1

– Summary of Anticipated Risk Assessments and Data Needs for Registration Review : Chromated Arsenicals

Risk Assessment Assessment Necessary to

Support Registration Review Date of Most Recent Assessment Type of Assessment

Required (New/Updated) Data Anticipated as Needed ( See Table 7 for detail s )

Dietary (food) No (see 3.2.1 ) N/A None None Dietary (drinking water) No (see 3.2.1 ) N/A None None Occupational Handler Yes 9/18/2008 Updated None (Data ha ve been submitted) Occupational Post Application Yes 9/18/2008 Updated Inhalation (Sawdust)

Residential Handler No (see 3.3.3 ) N/A None None

Resident i al Post Application No (see 3.3.4 ) N/A None None

Aggregate No (see 3.4.1 ) N/A None None

Cumulative No (see 3.4.2 ) N/A None None

Tolerance Review No (see 1.5.1 ) N/A None None Ecological Yes 3/10/2008 Updated Honeybee acute contact N/A = Not applicable

Table 2

– Anticipated Registration Review Schedule
Anticipated Activity Target Date * Completion Date Phase 1: Opening the Docket Open Docket and 60

- Day Comment Period for Preli minary Work Plan 2015

- 09 2015

- 09 Close Public Comment Period 2015

- 11 2015

- 11 Phase 2: Case Development

Issue Final Work Plan 2016

- 03

Issue Data Call

- In (DCI) 2017

- 03

Receive Data to be Considered in Risk Assessment 2019

- 03

Open 30

- Day Public Comment Period for Preliminary Risk Assessment(s) 20 20

- 09

Close Public Comment Period 20 20

- 10
Phase 3: Registration Review Decision and Implementation
Open 60

- Day Public Comment Period for Pro posed Decision 202 1

- 03

Close Public Comment Period 202 1

- 05

Issue Final Decision 202 1

- 09
Begin Post

- Decision Follow

- up 202 1Docket Number EPA

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Page 10 of 94 Total (years) 6

* The anticipated schedule will be revised as necessary ( e.g ., need arising under the Endocrine Disruptor Screening Program with respect to the active ingredients in this case).



## 1.3 Chemical Identification and Properties

Table 3 presents the active ingredient(s) to be assessed in case 0132: arsenic acid (PC Code 006801); chromic acid ( PC Code 021101); and arsenic pentoxide (PC Code 006802). Table 4 presents the chemical and physical properties of the chromic acid and arsenic acid components of chromated arsenicals , but does not include arsenic pentoxide compone nt because under hydrated, acidic conditions found in formulated chromated arsenical products, only arsenic acid is expected to be present (N ational Research Council, 1977)

. 1 Additionally, the dichromic acid registration review case (case 5012, PC code 068306, CAS # 7789

- 12

- 0) will be assessed with the chromated arsenicals case during the risk assessment phase. The combining of th e s e separate registration review case s is being done pursuant to 40CFR §155.42(b)(4) which states that “Th e Agency may... merge two or more registration review cases into a single registration review case. For example, new data or information might suggest that the active ingredients in two or more registration review cases should be grouped together for registr ation review .” Documents associated with dichromic acid registration review case can be viewed in docket number EPA

- HQ

OPP

- 2010

- 0243 at www. regulations.gov.

Table 3

– Chemical Identification of Chromated Arsenicals

Chemical Name Chromic acid Arsenic acid Arsenic pentoxide
PC Code 021101 006801 006802
CAS N umber 1333

- 82

- 0 7778

- 39

- 4 1303

- 28

- 2 Molecular Formula CrO 3 H 3 AsO 4 As 2 O 5 Molecular Weight (grams/mole) 118.01 141.94 229.84 Smiles code O[Cr](O)(=O)=O O=[As](O)(O)O O=[As](=O)O[As](=O)=O

Molecular Structure

The chromated arsenicals product chemistry information relevant to risk assessment is summarized in Table 4 and the details of the product chemistry information are discussed in Appendix E

.

1 NIH, http://www.ncbi.nlm.nih.gov/books/NBK231019/Docket Number EPA

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Page 11 of 94 Table 4

– Physical

- Chemical and Environmental Fate Properties for Active Ingredients in Chromated Arsenicals

Guideline No. Parameter Chromic acid Arsenic acid Arsenic pentoxide Reference

830.7000 pH 1.1 (25 o C)

- 0.33

Not applicable because under hydrated, acidic conditions found in

final chromated arsenical products only ar s enic acid is formed See Appendix E 830.7050 UV/Visible Absorption Sorption from 290

- 500 nm No sorption from 290

- 800

nm 830.7200 Melting point ( o C) 197 N/A

830.7370 Dissociation constant (pKa) 0.74 and 6.5 2.25, 6.77, and 11.6
830.7550 Octanol

- water partition coefficient at 25 o C (Log Kow) N/A N/A

830.7840 Solubility in water (mg/L) 630,000 Miscible

830.7950 Vapor pressure (mmHg) N/A N/A

None Henry's law constant at 25 oC (atm

- m3/mol) N/A N/A

atm

- m 3 /mol = atmosphere cubic meter per mole; o C = degrees Celsius; mg/L = milligrams per liter; mmHg = millimeters of mercury;



## 1.4 Use/Usage Description

1.4.1 Registrations

There are 1 5 EPA registered product s containing one (or a combination of) the active ingredients in the chromated arsenicals case: nine registrations for chromic ac id (PC code 021101), four registrations for arsenic acid (PC code 006801), and four registrations for arsenic oxide (PC code 006802)

. Of these, nine are manufactur ing use products used to formulate end use products and six are end use products.



### 1.4.2 Summary of Registered Uses

Table 5 presents the registered end use chromated arsenical products and the percent active ingredients that will be addressed in this registration review document

.

Table 5

– Chromated Arsenical End Use Products with Active Registrations

Percent Active Ingredient (metal equivalent)

Product EPA Reg. No. Copper oxide 1 Chromic acid Arsenic acid Arsenic pentoxide Zn oxide 1

K

- 33 (60 %) 3008

- 34 10.5 (8.4) 29.9 (13.2) 0 20 (13) 0Docket Number EPA

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Osmose ACC 50 % Wood Preservative 3008

- 60 14.07 (11.3) 35.46 (15.6) 0 0 0

Wolmanac® ACC 50 % Concentrate 62190

- 23 14.07 (11.3) 35.46 (15.6) 0 0 0

Chemonite ACZA 2 62190

- 34 11 (8.8) 0 0 5.5 (3.6) 5.5 (4.4)

Wolmanac® concentrate 60 % 62190

- 14 11.1 (8.9) 28.5 (12.7) 0 20.4 (13.2) 0

CCA TYPE

- C wood preservative (6 0% )
concentrate 10465

- 28 10.52 (8.4) 28.47(12.5) 0 21.01 (13.7) 0

1 Copper Oxide and Zinc Oxide are addressed in other registration review case s ; documents for these cases can be found on www.regulations.gov in the following dockets: Copper Oxide docket : EPA

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- 0212 , and Zinc Oxide docket : EPA

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2 ACZA contains arsenic, copper and zinc.

Table 6 provides information on the chromated arsenicals use profile

. Chromated arsenicals can only be applied by pressure treatment

. Additional information for the categories of forest products that may be treated with chromated arsenicals , including the few remaining treated commodities that may be found in residential settings (e.g. shakes, shingles, and structural members other than decks ), is provided in Appendix F

.

Table 6

– Chromated Arsenical

- Treated Wood Use Table

Use AWPA Use Category Type of Contact Retention Rate A (PCF)

Posts UC4A UC4B Ground contact plus fresh water Ground contact or f resh w ater 0.40 0.50 Poles UC4A UC4B UC4C Ground contact plus salt water splash 0.30 to 0.60 B 0.30 to 0.60 B 0.30 to 0.60 B Round timber piling UC4C Ground contact plus fresh water 0.80 to 1.0

Sawn products UC3B UC4A UC4B UC4C Above ground, exterior, exposed or poor water run

- off Ground contact or fresh water 0.25 0.40

Wood composites UC3B UC4A UC4B UC4C Ground plus fresh water Ground plus salt water splash 0.25 0.40 0.60 0.60Docket Number EPA

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Page 13 of 94 UC1 UC2 Interior construction above dry

- ground C Interior construction above ground

- damp 0.25 0.25 Marine construction wood UC5A UC5B UC5C Continuous salt water exposure (northern, central, and southern waters) 1.5 to 2.5 2.5

Railroad ties UC4A UC4B UC4C Ground plus fresh water C Ground plus salt water splash 0.40 ACZA D

A. Except as noted

, retentions are for CCA which contains 16.8% CuO, 44% CrO 3 and 30% As 2 O 5
. B. Retention for all species is 0.60 pcf except for the inner zone of coastal douglas fir which is 0.30 pcf. C

. Only one label (62190

- 34) has this use. D. ACZA contains arsenic, copper and zinc.



### 1.4.3 Usage Information

EPA’s database indicate s that no more than four billion pounds of pesticidal chromated arsenicals are sold per year in the United States.



## 1.5 Regulatory Histor y Formulated wood preservative products containing arsenic and/or chromium compounds have been registered since the 1940's when pesticides were under the regulatory purview of the United States Department of Agriculture (USDA) and subsequently have been regulated by EPA under FIFRA sinc e 1970 ( 2008, EPA )

.

Chromated arsenicals w ere a major source of treated

- wood for decks, playgrounds, and other outdoor residential structures until 2004.

In 2001, the U.S. Consumer Product Safety Commission (CPSC) and EPA rece ived several petitions to ba n chromated arsenicals use in playground equipment because of potential human health concerns about exposure to chemical residues from contact with the wood and surrounding soil. Exposure concerns centered around arsenic, an element that can increase the r isk of certain types of cancers.

Manufacturers submitted requests to EPA to voluntarily cancel virtually all residential uses of chromated arsenical treated wood effective Decembe r 31, 2003. Although a ban on chromated arsenical

- treated wood was never imposed, the voluntary cancellations prohibited chromated arsenical treatment on wood intended for outdoor residential structures such as decks and playgrounds. In addition, effective May 28, 2003, all non

- pressure treatments for ar senical products (e.g., brush, dips) were also voluntarily withdrawn by registrants.

The voluntary cancellations did not address existing chromated arsenical

- wood struct ures, nor does EPA require the removal of structures made with chromated arsenical

- trea ted wood. Wood treated with chromated arsenicals is still available prim arily for industrial use, and chromated arsenicals are also still registered with EPA for the treatment of wood products that may be found in residential settings (shakes, shingles, an d structural members other than decks) as well as products found in agricultural/ commercial settings (posts or sawn timbers for fence posts or structural supports) (2009, EPA)

.Docket Number EPA

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Page 14 of 94 Th e A gency completed a Reregist r ation Eligibility Decis ion (RED) for chromated arsenicals in 2008. The A gency issued the chromated arsenicals post

- RED Data Call

- Ins (DCIs) o n September 9 , 2011. Since the 2008 RED, EPA approved requests from manufactures for all chromated arsenical product labels to adopt the label changes specified in the RED to mitigate exposure to treatment workers and the environment.



### 1.5.1 Tolerance Information EPA has not established tolerances in raw agricultural commodities or processed food and feed products for chromated arsenicals under the Federal Food, Drug an d Cos metic Act (FFDCA) Section 408. There are also no tolerance exemptions fo r chromated arsenicals under FFDCA Section 408. Chromated arsenicals ha ve not been cleared as a food additive by the US Food and Drug Administration (US FDA) under FFDCA Section 409.



## 1.6 Incidents

1.6.1 Human Health

Based on a search conducted on July 17, 2015 , covering the period from October 1, 2008 to July 17, 2015

, t here are six in cident reports listed in the OPP Incident Data Systems that involve two incidents that occurred after the RED was completed in September 2008. These two incidents are described below:

• A plant formulation worker who worked for four years in a facility that formulated chromated arsenical wood preservative products ha d cancer which was alleged to have been caused by opening drums of bulk chromated arsenicals

.

• Four lineman alleged in a lawsuit that they were exposed to chromated arsenicals while repairing and i nstalling chromated arsenical treated utility poles which involved c utting, sanding, and drilling. They also alleged that they were exposed to chromated arsenicals while putting out utility pole fires. Their alleged symptoms included respiratory effects,

n eurological effects, heart palpitations and nausea. One lineman had lower lung hyperplasia and another had melanoma which wer e alleged to be caused by chromated arsenicals

. The lawsuit was dismissed in Federal District Court.



### 1.6.2 Ecological

No incidents have been reported in the OPP Incident Data System (IDS) for arsenic acid or

c hromic acid since September

, 200 8 , when the RED was completed

, to July 10, 20 15 when the I DS was queried.


## 2 A nticipated Data Needs

Several studies were required from the assessment of chromated arsenicals in the 2008 RED. In addition to the already

- required RED DCI data, the following studies listed in Table 7 are expected to be needed for the regis tration review of chromated arsenicals

. Table 8 outlines the data requirements required by the post

- RED DCI issued on September 9, 2011

. The Agency anticipates reviewi ng any data received in response to the post

- RED DCI as well as data requested for thisDocket Number EPA

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Page 15 of 94 registration review prior to conducting the registration review risk assessments for the chr o mated arsenicals case

.

Table 7

– Studies Anticipated as Needed for the Registration Review of Chromated Arsenicals

GLN Study Name Test Substance Time Frame (Measured in months from DCI Receipt) Risk Assessment(s) Data Will Support Use Site(s) Triggering Anticipated Data

Requirement Applic able Exposure Scenario

875. 2 5 00 1 ,2 ,3 Outdoor Exposure

- Inhalation Arsenic and C r VI (treated wood) 4 24 Occupational Post Application Wood that is sawn or sanded after

treatment Sawing and sanding treated wood.

850

. 3020 Honeybee
acute contact Chromic acid 12 Ecological Wood treatment Treated wood

1 Prior to initiation of the study, protocols involving intentional exposure of human subjects must be submitted for review by EPA and then the Human Studies Review Board (HSRB) according to 40 CFR 26.1125. Examples of proposed human study research can be found in various reviews provided by the Human Studies Review Board (HSRB) ( http://www.epa.gov/osa/hsrb/index.htm ).

2 Biological monitoring data may be submitted in addition to, or in lieu of, dermal and inhalation passive dosimetry exposure data provided the human pharmacokinetics of the pesticide or metabolite/analog compounds ( i.e., whichever method is selected as an indicator of body burden or interna l dose) allow for a back

- calculation to the total internal dose.

3 The sawing and sanding exposure scenario was not assessed in the 2008 RED and is anticipated to be required for registration review.

4 T reated wood is the article ; once wood is cut

– test fo r arsenic and hexavalent chromium (C r VI )

.
Table 8

– Data Needs Required by the September 9, 2011 Data Call

- In for the Chr o mated Arsenicals RED

GLN Study Name Status of DCI

850.1735 Sediment toxicity

– freshwater

Waiver requests granted

. 850.1740 Sediment toxicity

– marine invertebrate
850.2300 Avian reproduction
850.4225 Terrestrial plant toxicity

– seedling
850.4250 Terrestrial plant toxicity

– vegetative
850.4400 Aquatic plant toxicity
850.5400 Algal toxicity
875.1100 Dermal exposure (outdoor)

Data in review. 875.1200 Dermal exposure (indoor)
875.1300 Inhalation exposure (outdoor)
875.1400 Inhalation exposure (indoor)
875.1600 Applicator exposure monitoring data
875.1700 Product use information Data in review.Docket Number EPA

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Page 16 of 94 

## 3 Human Health Risk Assessment

The Agency anticipates the need to conduct a human health risk assessment for chromated arsenicals . The Agency expects to require additional data for use in conducting the registration review.



## 3.1 Existing Toxicological Endpoints

I norganic arsenic and inorgani c chromium are the compounds of toxicological concern with respect to exposure to chromated arsenical

- treated wood . In the EPA RED for chromated arsenicals (2008 , EPA)

, the Agency selected end

- points for both inorganic arsenic and hexavalent chromium (C r VI ) summarized in Table 9 and

Table 10

. O ther EPA program offices are in the process of re

- evaluating the existing oral carcinogenicity toxicity information for inorganic arsenic and hexavalent chromium including the Integrated Risk Information System (IRIS) which is re

- evaluating hexavalent chromium (Federal Register

, Volume 72, Number 245, pp 72715

- 72719). OPP will update the toxicological endpoints to be consistent with other EPA program offices in preparing the final risk assessment for this case.

Table 9

– Toxicological End points for Assessing Exposures/Risks to Inorganic Arsenic (V)

EXPOSURE SCENARIO DOSE ENDPOINT STUDY

Acute Dietary This risk assessment wa s not required.
Chronic Dietary This risk assessment wa s not required.

Incidental Short

- and Intermediate

- Term Oral L OAEL (a) = 0.05 mg/kg/day

MOE = 30 Based on edema of the face, gastrointestinal, upper respiratory, skin, peripheral and neuropathy symptoms Franzblau et al.(1989) and Mizuta et al. (1956)

Dermal Short

- and Intermediate

- Term (a)(b) LOAEL (a) = 0.05 mg/kg/day

MOE = 30 Based on edema of the face, gastrointestinal, upper respiratory, skin, peripheral and neuropathy symptoms Franzblau et al.(1989) and Mizuta et al. (1956)

Dermal Long

- Term (a)(b) NOAEL (a) = 0.0008 mg/kg/day

MOE = 3 Based on hyperpigmentation, keratosis and possible vascular complications. Tseng et al. (1968) and Tseng (1977)

Inhalation Short

- and Intermediate

- Term (c) LOAEL (a) = 0.05 mg/kg/day

MOE = 30 Based on edema of the face, gastrointestinal, upper respiratory, skin, peripheral and neuropathy symptoms Franzblau et al.(1989) and Mizuta et al. (1956)

Inhalation, Long

- Term NOAEL (a) = 0.0008 mg/kg/day

MOE = 3 Based on hyperpigmentation, keratosis and possible vascular complications. Tseng et al. (1968) and Tseng (1977)

Carcinogenicity

- Inhalation (Inhalation Risk) CSF= 15.1 (d) (mg/kg/day)

- 1 (For general Population) Lung cancer Chronic epidemiological inhalation study on humans

CSF= 5.0 (e) (mg/kg/day)

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Page 17 of 94 EXPOSURE SCENARIO DOSE ENDPOINT STUDY

(For 8 hour working day)
Carcinogenicity

-

Oral Ingestion (Oral and Dermal Risks) CSF = 3.67 (f) (mg/kg/day)

- 1 Internal organ cancer (liver, kidney, lung and bladder) and skin cancer Chronic epidemiological oral study on humans

Note: (a). MOE = Margin of Exposure; NOAEL = No observed adverse effect level; and LOAEL = Lowest observed adverse effect level. (b). The dermal absorption factor = 6.4%. (Note: The FIFRA Scientific Advisory Panel recommended use of a lower value of 2

- 3%. The occupational assessment in the risk assessment use d 6.4 percent dermal absorption because the handlers and workers are exposed to the arsenic residue from the aqueous solution during mixing, loading, and handling or are exposed to newly treated, or “wet’ wood which has arsenic residues on the surface of the wood). (c). For inhalation exposure, a default absorption factor of 100% wa s use d. Route

- to

- route extrapolation wa s used to estimate the exposed dose. ( d). Inhalation unit risk (IUR) wa s derived from a 24 hour exposure inhalation unit risk with a value of 4.3 x 10

- 3 (μg/m3)

- 1. To convert the IUR to a cancer slope factor in units of ( mg/kg/day)

- 1 for the general population = IUR (μg/m3)

- 1 x 1/70 kg x 20 m3/day x 1 mg/1,000 μg (EPA, 1989). (e). For workers working 8 hour per day, the inhalation cancer slope factor (CSF) derived from the 24 hour IUR for general populat ion, is adjusted for an 8 hour work day. CSF for 8

- hr work day = general population CSF of 15.1 (mg/kg/day)

- 1 x (8hrs/24 hrs) = 5.0 (mg/kg/day)

- 1. (f). CSF wa s derived from the risk assessment associated wi th inorganic in drinking water we re presented in 2000. The 200 1 National Research Council (NRC) update made specific recommendation with respect to the overall cancer risk estimates. The Agency is currently considering these recommendations and their potential impact on the cancer potency estimate. Based on the Age ncy’s considerations of these recommendations, the current proposed cancer potency number may change in the risk assessment anticipated for registration review

.

Table 10

– Toxicological Endpoints for Assessing Exposures/Risks to Ch romium VI

EXPOSURE SCENARIO DOSE ENDPOINT STUDY

Acute Dietary This risk assessment wa s not required.
Chronic Dietary This risk assessment wa s not required.

Incidental Short

- and Intermediate

- Term Oral NOAEL (a) = 0.5 mg/kg/day of chromic acid [0.12 mg/kg/day of Cr(VI)]

MOE = 100 based on the increased incidence of maternal mortality and decreased body weight gain at LOAEL of 2.0 [0.48 mg/kg/day of CrVI] Developmental/Rabbit Tyl, 1991

Dermal Exposure (b) Systemic Effects (All Durations) Because dermal irritation and dermal sensitization are the primary concern through the dermal exposure rou te, no toxicological end

- point wa s selected for use in assessing dermal exposure risks to chromium.
Dermal Exposure Dermal Effects (All Durations) CCDS (a ) = 92 ng Cr(VI)/cm 2

MOE = 1 Based on the MET 10 (10% response level ) which was determined by the FIFRA SAP to be adequate and sufficiently conservative. Proct or, D.; Gujral, S.; Fowler, J. 2006

Inhalation Exposure (All Durations) L OAEL (a) = 0.002 mg/m 3 ; (or 2.3 x 10

- 4 mg/kg/day) MOE = 30 based on nose and throat symptoms observed at the 0.002 mg/m 3 level Linberg and Hedenstierna, 1983.Docket Number EPA

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Page 18 of 94 EXPOSURE SCENARIO DOSE ENDPOINT STUDY

Carcinogenicity

- Inhalation (Inhalation Risk) CSF = 40.6 (c) (mg/kg/day)

- 1 (For general Population) Lung tumors IRIS CSF = 13.5 (d) (mg/kg/day)

- 1 (For 8 hour working day)

Carcinogenicity

- Oral Ingestion (Oral and Dermal Risks) CSF = 0.79 (e) (mg/kg/day)

- 1 With age dependent adjustments factors (ADAFs) applied. Female Mice

- Small Intestine (Duodenum, Jejunum or Ileum) adenomas and/or carcinomas combined NTP (2007 a )

Note: ( a). MOE = Margin of Exposure; NOAEL = No observed adverse effect level; and LOAEL = Lowest observed adverse effect level. CCDS = Concentration of Concern for Dermal Sensitization. (b). The dermal absorption factor for CrVI = 1.3% for handler dermal contac t with chromated arsenical pesticides. (c) The 24 hours inhalation unit risk is 1.16 x 10

- 2 (μg/m 3 )

- 1 which can also be expressed as 0.0116 m 3 /μg. To convert the air concentration to a dose to yield units of kg

- day/mg or (mg/kg/day)

- 1 the unit risk is expressed mathematically as 0.0116 m 3 /μg x day/20 m 3 x 1000 μg/mg x 70 kg = 40.6 (mg/kg/day)

- 1 (EPA, 1989). (d) For workers working 8 hour per day, the inhalation cancer slope factor (CSF) derived from the 24 hour CSF for the general
p opulation, is adjusted for an 8 hour work day. CSF for 8

- hr work day = general population CSF of 40.6 (mg/kg/day)

- 1 x (8hrs/24 hrs) = 13.5 (mg/kg/day)

- 1

. (e) CARC (2008) classified hexavalent chromium as “Likely to be Carcinogenic to Humans” based on the presence of oral and tongue tumors and/or carcinomas for rats in both sexes, and the presences of adenoma and carcinoma in both sexes of mice at doses that were adequate but not excessive to asses s the carcinogenicity. There is clear evidence that CrVI is mutagenic. The decision is also qualitatively supported by the human epidemiological study. The Committee recommended using a linear low

dose extrapolation approach (Q1*) for estimating the human cancer risk based on the most potent tumor type.


## 3.2 Dietary Exposure

The A gency does not anticipate the need to conduct a dietary exposure assessment to support this registration review.



### 3.2.1 Food and Drinking Water A dietary (food and drinking water) exposure assessment is not required for chromated arsenicals at this time. The only FIFRA

- registered uses of chromated arsenicals are as a wood preservative. These uses are not expected to result in direct or ind irect dietary (food) exposure. T he use of chromated arsenicals as a wood preservative is also not expected to result in exposure in drinking
water from surface water or ground water

. 

## 3.3 Occupational and Residential Exposures

3.3.1 Occupational Handler Exposure

EP A anticipates the need to revise the occupational handler assessment conducted in support of the 200 8 RED. Occupational handler dermal and inhalation exposures to chromated arsenicals were assessed in the RED for pressure treatment applications and based on these assessments the RED specified certain mitigatio n actions ( including label changes) to reduce exposures. All labels have been amended to reflect the mitigation changes. A follow

- up exposure study has been performed to evaluate the effectiveness of these mitigation actions

, and this exposure study will be used to re

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Page 19 of 94 to be expected to assess occupational handler exposure, the scenarios to be assessed are presented in Table 11

.

Table 11

– Occupational Handler Exposure Scenarios for Chromated Arsenicals

Scenario Exposure Route(s) Duration
Pressure Treatment Dermal Inhalation Short, Intermediate, and Long Term


### 3.3.2 Occupational Post Application Exposure Occupational post application exposure may occur during construction of st ructures using chromated arsenical treated wood if this construction involves sawing and sanding. Because chromated arsenicals are no longer registered for treatment of wood to be used as decks and playground equipment, which required extensive sawing

, the potential for construction worker
exposure has been reduced. There is still some potential for exposure for some of the remaining uses, such as sawn products, wood composites and m arine construction wood if this woo d is sawn during construction. The Agency anticipates the need to require data to reassess t hese exposures during registration review.



### 3.3.3 Residential Handler Exposures Residential handler exposures are not anticipated becau se chromated arsenicals a re a restricted use pesticide that can only be applied using pressure treatment in commercial facilities

. Therefore, residential exposure is not expected from the wood preservative uses of chromated arsenicals and a residential ris k assessment is not anticipated to be needed for this registration review

.


### 3.3.4 Residential Post

- Application Exposures As restricted use pesticides that all also require highly specialized application equipment, chromated arsenicals are neither permitted to be purchased nor expected to be applied by potential residential users. The A gency recognizes that materials such as utility poles may be

reuse d or recycled after their original intended use has ended ; a t that point, the utility poles would likely have signif icantly less transferrable chromated arsenicals than freshly treated wood. EPA recommends that chromated arsenical

- treated utility poles only be reused in a way that EPA has evaluated and determined to pose no unreasonable adverse effects (i.e., poles should only be reused for uses that have been approved by EPA as indicated on the pesticide labeling). C ontact with ut ility poles is expected to be episodic in nature and significantly lower than any occupational exposure to chromated arsenicals . If the Agency identifies risks of concern to treatment plan t workers, EPA will revisit the need for a residential post

- applicat ion exposure
assessment

. The few remaining treated commodities that may be found in residential settings (e.g.,

s hakes/shingles, permanent wood foundations) are not expected to result in any measurable residential exposure. Therefore, residential exposure is not expected from the wood preservative uses of chromated arsenicals and a residential risk assessment is not anticipated to be performed.Docket Number EPA

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Page 20 of 94 

## 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures

The Agency did not conduct an aggregate assessment for the 2008 RED

, and the Agency does not plan to conduct an aggregate risk assessment for registration review. This is because the exposures that are normally included in an aggregate assessment ( residential, dietary and drinking water ) are not anticipated for c hromated arsenicals

.


### 3.4.2 Cumulative Exposures

With respect to cumulative exposure, unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for chromated arsenicals . For information re garding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinat ions and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.


## 4 Environmental Risk Assessment

The Agency anticipates the need to conduct a n ecological risk assessme nt for chromated arsenicals . The Agency expects to require additional data for use in conducting the registration review.

T his registration review document addresses only chromium and arsenic because copper was addressed in a separate case (see below)

. Th e ecological risk assessment planned during registration review will allow the Agency to determine potential acute and chronic risks to aquatic organisms exposed to arsenic acid and chromic acid that are transported from treatment sites into the aquatic en vironment. Such sites include treated wood used in fresh and salt water environments

. Leaching from treated wood can lead to exposure to soil s and sediments , and for chromium ions, potential bioaccumulation in the aquatic and benthic organisms. Exposure to drinking water not expected because of extensive sorption to soil and sediment, and the tendency of these metals to complex with other ions in the environment. The terrestrial risk assessment will also include potential acute risks to bees from treated wood.

The Agency has not previously conducted a risk assessment that supports a complete endange red species determination for chromated arsenicals

. T he risk assessment also will allow the Agency to determine whether each use of the arsenic acid a nd chromic acid ha s 'no effect' or 'may affect' federally listed threatened or endangered species (listed species) or their designated critical habitats. When an assessment concludes that a pesticide’s use 'may affect' a listed species or its designated critical habitat, the Agency will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Services (the Services), as appropriate.Docket Number EPA

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## 4.1 Environmental Fate Assessment
Field and laboratory studies have demonstrated that under certain circumstances, arsenic and chromium can leach from treated wood into the surrounding soil or water. In general, most leaching takes place in the first few days and the extent and rate of lea ching being higher for arsenic than for chromium. Chromium is released into water and soil as trivalent chromium

, and arsenic is leached into soil as pentavalent arsenic. Available field and laboratory studies suggest that leaching of metals is highly vari able and is dependent on environmental conditions. For aquatic uses, these environmental conditions include pH, salinity (fresh water, sea water, estuaries, natural and synthetic, sterile buffered water), temperature, moisture content of the treated wood, wood type, and wood texture. For terrestrial uses, these include soil pH, type, texture, and organic content.

Based on extrapolation from studies on sorption into soils from utility poles, data have indicated that the release of metals into soils/sediment s from the base of treated wood, decks or utility poles or from the pressure treatment facilities do not show a high degree of migration, either to groundwater or to the surface. In most cases, after migration of the metals a few meters down into soil, the se metals attain the background level concentration of soil.

Chromium and arsenic in water exist as: hydrated species (coordinated with water), hydroxy species, bound to inorganic anions like FeF 6 3

- , bonded to organic ligands to form metal complexes or as organometallics (containing C

- Metal bonds).



### 4.1.1 Water Quality

Arsenic and c hromium are not identified as a cause of impairment for any water bodies listed as impaired under section 303(d) of the Clean Water Act

. 2 In addition, no Total Maximum Daily Loads (T MDL) have been developed for arsenic and chromium

. 3 More information on impaired water bodies and TMDLs can be found at EPA’s website

. 4

B oth arsenic and chromium have maximum contaminant level s (MCLs) in drinking water. For arsenic, the MCL and MCLG (maximum contaminant level goal) are 0.010 ppm and 0.0 ppm, respectively

. 5 For chromium, both the MCL and the MCLG are 0.1 ppm for the total of trivalent chromium and hexavalent chromium

. 6



## 4.2 Conceptua l Model s for Environmental Exposure Pathways
Based on the summary of registered uses of chromated arsenicals presented in Table 6
, physical/chemical properties present ed in Table 4 , and environmental fate data p resented in Section 4 and Appendix B, the Agency has developed conceptual model diagrams for exposure

2 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885

3 http ://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant_ group_name=PESTICIDES

4 http://www.epa.gov/owow/tmdl/

5 http://water.epa.gov/lawsregs/rulesregs/sdwa/ars enic/index.cfm

6 http://water.epa.gov/drink/contaminants/basicinformation/chromium.cfmDocket Number EPA

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Page 22 of 94 of ecological organisms to chromated arsenicals

. Potential exposure pathways from wood products treated with wood preservatives include leaching to soil and water from direct contact of wood products during in

- service use. R eleases to surface water via wastewater treatment following application of preservatives t o wood products are not considered to be potential exposure pathways because they are subject to hazardous waste regulations under the Resource Conservation and Recovery Act (RCRA) that apply specifically to waste generated at facilities where wood preserv atives are used to treat wood.

Under conditions of direct contact of chromated arsenicals with soil and surface water , terrestrial and aquatic exposures to chromium and arsenic can occur from treated wood. As metals, chromium and arsenic in water react to form various chemical species but do not degrade. Arsenic and chromium in treated wood leach most quickly when in direct contact with soil and
water during in

- service use

, but the leaching rate rapidly declines within 30 days (Chen and Walters, 1979 ; Stanl ey, 1994) . Levels of chromated arsenicals reach background concentrations within a few meters of the treated wood product s in contact with soil (Degroot, 1979) and generally within 10 meters of the treated wood product s in contact with surface water ( Weis, 1992; Cooper, 1991). So, while leaching from treated wood can occur from direct contact with both soil and water , the area of contamination is very limited due to strong sorption of chromated arsenicals to soils and sediments which limits its mobili ty in soil and surface water. E xposure to drinking water from surface water or ground water sources from treated wood is not expected to

occur because of metal sorption and speciation

.
The Agency has created conceptual models for potential routes of envi ronmental exposure which are included in “Conceptual Models for Environmental Exposure Pathways of Antimicrobial Pesticides” (EPA

- HQ

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- 0638

- 0002), found in the docket at www.regulations.gov , EPA

HQ

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- 0638. For the wood preservative use, refer to slide 29

. All relevant pathways of exposure will be considered when the Agency performs a risk assessment for chromated arsenicals

. 

## 4.3 Ecological Effects Assessment

Ecological data are available for the components of chromated arsenicals in the form of studies that have been submitted to the Agency and studies found in the open literature. This document contains data from two of the three components of chromated arse nicals , chromic acid and arsenic acid. The third component, copper, is covered separately with the other copper containing pesticides.

The previous environmental risk assessment (2008, EPA) addressed hazard to birds, mammals, plants, insects, fish, and aq uatic invertebrates from two components of inorganic arsenical wood preservatives; arsenic acid and chromic acid. In December of 2003, some uses were voluntarily cancelled ; however, chromated arsenicals can still be used to treat freshwater or marine pilin g, bulkheads, and bracing timbers underneath non

residential docks, decks, and walkways. See Table 6 and Appendix F for use sites.

The results of the terrestrial risk assessment indicated that the potential for adverse acute effects to birds and mammals from exposure to average concentrations of arsenic acid or chromic acidDocket Number EPA

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Page 23 of 94 in soil is low. Average residue levels are not expected to result in chronic impacts to birds. A quantitative assessment of the risks to birds and mammals to arsenic acid or chromic acid from direct contact (feet, feathers, oral) with chromated arsenical

- t reated lumber was not conducted because exposure is considered to be minimal. Due to increased concern for pollinator exposures to treated wood, the Agency anticipates requiring an acute contact toxicity study for honeybees which may be exposed to chromate d arsenical treated wood. Adequate data are available for arsenic acid. Data are anticipated to be needed for chromic acid.



### 4.3.1 Measures of Effect (Ecotoxicology Endpoints)

Ecotoxicity endpoint data are used as measures of effects to aquatic and terrestrial organisms. All available ecotoxicity endpoints in the Agency ’s files from a rsenic acid and c hromic acid studies submitted by registrants or other interested parties, federal laboratory data, or from the public literature are tabulated in Appendix C along with the anticipated data requirements and data
gaps. The most sensitive values for each receptor gr oup we re used for the risk assessment in the RED ( Table 12 and Table 13 ). These selected endpoints will be updated during the risk assessment phase of registration review based on any additional submitted data or data found in the public literature.

Table 12

– Ecological Effects Endpoints Selected for Assessing Risks from Arsenic Acid Use

Receptor Group Surrogate Species Risk Scenario Toxicity Endpoint Reference (MRID unless

specified)

Freshwater fish Bluegill sunfish Acute 96

- h LC 50 = 50 mg/L 41950601
Fathead minnow Chronic NOAEC = 1.9 mg/L 41802201

Freshwater invertebrates Daphnia magna Acute 48

- h EC 50 = 15 mg/L 41620001

Chronic LOEC = 0.0038 mg/L NOAEC = 0.002 mg/L 42001601

Estuarine/marine fish Sheepshead minnow Acute 96

- h LC 50 = 28 mg/L 41620004 Chronic Not required A

-- E stuarine/marine

invertebrates Mysid Shrimp Acute 96

- hr LC 50 = 2 mg/L 41620002 Chronic Not required A

-- Algae Green alga Nonlisted 96

- hr EC 50 = 0.38 mg/L 42290902 Aquatic vascular plants Duckweed Nonlisted EC 50 = >9.8 mg/L 42290901

Aquatic plants Freshwater diatom Nonlisted EC 50 = 1.4 mg/L 42290903
Marine plants Marine diatom Nonlisted EC 50 = 0.0092 mg/L 42278801

Birds Bobwhite quail Acute LD 50 = 28.9 mg/kg 40409013

Bobwhite quail Subacute dietary LC 50 = 168.5 mg/kg 00121618

Chronic Not required A

--

Mammals Acute LD 50 = 150 mg/kg LD 50 = 141 mg/kg (males) LD 50 = 160 mg/kg (females) 40409001

Chronic LOAEL = 4 mg/kg/day NOAEL = 1 mg/kg/day Nemac, 1988a, cited inDocket Number EPA

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– Ecological Effects Endpoints Selected for Assessing Risks from Chromic Acid Use

Receptor Group Surrogate Species Risk Scenario Toxicity Endpoint Reference (MRID unless

specified)

Freshwater fish Rainbow trout Acute 96

- h LC 50 = 44 mg/L 41621105
Fathead minnow Chronic NOAEC = 8.2 mg/L 41974901

Freshwater invertebrates Daphnia magna Acute 48

- h EC 50 = 0.76 mg/L 41621103

Chronic LOEC = <0.0086 mg/L NOAEC = <0.0026 mg/L 41881501

Estuarine/marine fish Sheepshead minnow Acute 96

- h LC 50 = 39 mg/L 41703601 Chronic Not required A

-- Estuarine/marine

invertebrates Mysid Shrimp Acute 96

- hr LC 50 = 5.9 mg/L 41703602 Chronic Not required A

-- Algae Green alga Nonlisted 96

- hr EC 50 = 0.2 mg/kg Ref# 3690

Marine plants Marine diatom Nonlisted EC 50 = 14.7 mg/kg Ref# 2233

Birds Bobwhite quail Acute LD 50 = 93.5 mg/kg 41621104

Bobwhite quail Subacute dietary LC 50 = >5100 mg/kg 41621101

Chronic Not required A

--

Mammals Acute LD 50 = 52 mg/kg LD 50 = 56 mg/kg (males) LD 50 = 48 mg/kg (females) 43429401

Chronic LOAEL = 0.48 mg/kg/day NOAEL = 0.12 mg/kg/day Tyl, 1919. Cited in McMahon and Chen, 2001
Nontarget insects Honey bee Acute R equired Data Gap

A Not required for this use pattern.



## 4.4 Exposure Analysis Plan

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

Available OPP models will be used to determine the estimated environmental concentration (EECs) in the aquatic environment. Resulting exposure estimates will be compared to the toxicity endpoints to determine if levels of concern are exceeded for each receptor group.



### 4.4.2 S creening Level Down

- the

- Drain Analysis Generally, t he primary pathway of exposure of aquatic organisms to wood preservatives is from in

- service use of treated wood products in direct contact with surface water. A down

- the

- drain analysis for this exposure pathway is not applicable. McMahon and Chen 2001
Nontarget insects Honey bee Acute LD 50 = 7.7 ug/bee 40351301Docket Number EPA

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Page 25 of 94 Release of wood preservatives from application to treated wood products is a secondary exposure pathway. In the case of chromated arsenicals , such releases would be subject to hazardous waste regulations under RCRA that apply sp ecifically to waste generated at facilities where wood preservatives are used to treat wood. Since chromated arsenicals are a listed hazardous waste, releases to wastewater treatment plants would be expected to be precluded. Consequently, a down

- the

- drai n analysis for chromated arsenicals will not be conducted. In addition, in the event of an unintentional release to a wastewater treatment plant, strong sorption to suspended solids in a wastewater treatment plant would limit releases of chromated arsenic als to surface water. Furthermore, limited transport potential from any contaminated location immediately downstream of a wastewater treatment plant would limit exposure of aquatic organisms to chromated arsenicals

. A complete discussion of the relevance of hazardous waste regulations to chromated arsenical wastes generated at wood treatment facilities is discussed in the RED Document for Chromated Arsenicals (EPA 739

- R

- 08

- 006, September 2008).



## 4.5 Effects Analysis Plan

Additional open literature studies will be identified through EPA’s ECOTOXicology (ECOTOX) database. The ECOTOX database will be searched during the risk assessment phase of chromated arsenicals and the data reviewed following the Agency ’s policy for reviewing public literature for use in asses sing risks from pesticide s

. 7 Those ecotoxicity values found in the public literature to be more sensitive than those currently in Table 12 and T able 13 and w hich satisfy an existing data gap(s) will be used during the risk assessment phase of chromated arsenicals

. ECOTOX was created and is maintained by the USEPA, Office of Research and Deve lopment, and the National Health and Environmental Effects Research Laboratory's Mid

- Continent Ecology Division.


## 5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicit y, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As par t of its reregistration decision , for chromated arsenicals , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), chromated arsenicals are subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

7 http://www.epa.gov/pesticides/science/efed/policy_guidance/team_authors/endangered_species_ reregistration_wor kgroup/esa_evaluation_open_literature.htmDocket Number EPA

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Page 26 of 94 EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP 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 substance 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 interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals ident ified for EDSP screening was published on June 14, 2013 8 and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website. 9



## 6 Optional Label Changes

The Agency invites comment on any label amend ments that could be considered to eliminate the anticipated need for EPA to require certain data, reduce the possibility that EPA’s planned risk assessments overestimate risk due to reliance on conservative assumptions, and/or improve label clarity.


## 7 Guidan ce for Commenters

7.1 Preliminary Work Plan
The public is invited to comment on EPA’s Preliminary Work Plan and rationale. The Agency will carefully consider all comments as well as any additional information or data provided in a timely manner prior to issuin g a final work plan for the chromated arsenicals registration review

case.



### 7.1.1 Trade Irritants Through the registration review process, the Agency intends to solicit information on trade irritants and, to the extent feasible, take steps toward facilitating ir ritant resolution. The Agency

8 See http://www.regulations.gov/#!documentDetail;D=EPA

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- 2009

- 0477

- 0074 for the final second list of

chemicals.

9 http://www.epa.gov/endo/Docket Number EPA

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Page 27 of 94 will work to harmonize tolerances and international maximum residue limits (MRLs) and may modify tolerance levels to do so, when possible. Stakeholders are asked to comment on any trade irritant issues resulting from lack of MRLs or disparities between U.S. tolerances and MRLs in key export markets, providing as much specificity as possible regarding the nature of the concern.



### 7.1.2 Water Quality

The Agency invites submission of w ater quality data for this pesticide. To the extent possible, data should conform to the quality standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s Registration Review Ris k Assessment and Management Process 10 in order to ensure they can be used quantitatively or qualitatively in pesticide risk assessments.



### 7.1.3 Environmental Justice EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all people, regardless of race, color, national origin, or income, in the development, implementation, and enforcement of environmental laws, regulations, and policies. To help address potential environmental justice issues, the Agency seeks information on any groups or segments of the population who, as a result of their location, cultural practices, or other factors, may have atypical, unusually high exposure to chromated arsenicals compared to the general population. Please comment if you are aware of any su b

- populations that may have atypical, unusually high exposure compared to the general population.



### 7.1.4 Additional Information Stakeholders are also specifically asked to provide available information and data that will assist the Agency in refining its risk as sessments, including any species

- specific ecological effects determinations. In registration review, EPA plans to update the benefits and alternatives assessments for chromated arsenicals . Stakeholders are encouraged to provide updated information on benef its and alternatives during the PWP comment period.

The Agency is interested in receiving the following information:

1. Confirmation on the following label information: A. Sites of application B. Geographic limitations on use 2. Use or potential use distribution 3. State or local use restrictions 4. Ecological incidents (non

- target plant damage and avian, fish, reptilian, amphibian and mammalian mortalities) not already reported to the Agency 5. Monitoring data

10 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htmDocket Number EPA

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## 8 Next Steps

After the 60

- day comment period closes in November 2015 , the Agency will review and respond to any comments received in a timely manner, and then issue a Final Work Plan for the chromated arsenicals case.Docket Number EPA

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## 9 References

Brown, C.J. and R.A. Eaton. 2001. Toxicity of Ch romated Copper Arsenate (CCA)

- treated Wood to Non

- target Marine Fouling Communities in Langstone Harbour, Portsmouth, UK. Mar. Pol. Bull. 42:310

- 318.

Chen Abraham Shou

- chien and C.S. Walters, 1979. The Fate of Arsenic in Pressure

- Treated Southern Pine Plywood Subjected to Heavy Artificial Rainfall. American Wood Preservers’ Association: 188

- 232.

Cooper, P.A. 1991 Leaching of CCA from Treated Wood: pH Effects. Forest Products Journal. 41(1): 30

- 32

DeGroot, R.C., Popham, T.W., Gjovik, L.R., and Forehand , T. 1979. Distribution Gradients of Arsenic, Copper, and Chromium Around Preservative

- Treated Wooden Stakes. Journal of Environmental Quality. 8(1): 39

- 41.

EPA 1979. Water

- Related Environmental Fate of 129 Priority Pollutants, EPA

- 440/4

- 79

- 029a.

EPA, 20 08. Reregistration Eligibility Decision for Chromat ed Arsenicals. September, 2008, Antimicrobials Division, Office of Pesticide Programs, Washington, DC.

EPA, 2009. CCA

- Pressure Treated Wood, Guidance for Outdoor Wooden Structures. N.p. Environmental Prot ection Agency. Print

Hobden, B. R. 2000. Proposed Acceptability for Continued Registration Document (PACR) for Chromated Copper Arsenate. PMRA Environmental Assessment Component of the NAFTA Joint Re

- Evaluation of Chromated Copper Arsenate. April 28, revision.

Lebow, S.T., P.K. Lebow, D.O. Foster, and K.M. Brooks. 2000. Environmental Impact of Preservative

- Treated Wood in a Wetland Boardwalk. Forest Products Laboratory. Res. Pap. FPL

- RP

- 582. Madison, WI: U.S. Department of Agriculture, Forest Ser vice, Forest Products Laboratory. 126p.

Lebow, S.T. 2004. Alternatives to Chromated Copper Arsenate (CCA) for Residential Construction. Porceedings of the Environmental Impacts of Preservative

- Treated Wood Conference, Orlando, FL. Febuary 8

- 10, 2004. U.S. Department of Agriculture, Forest Service, Forest Products Laboratory. 12p.

McMahon, T. and Chen J., 2001. FIFRA Scientific Advisory Panel Background Document

Hazard identification and Toxicology Endpoint Selection for Inorganic Arsenic and Inorgani c Chromium. US Environmental Protection Agency, Office of Pesticide Programs, Antimicrobials Division.Docket Number EPA

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Page 30 of 94 Stanley, J.S. 1994. Task III

- CCA

- C: Chromated Arsenical Treated Wood Aqueous LeachingStudy. Midwest Research Institute. May 27, 1994. MRID 432492

- 01. Un published.

Townsend, T., K. Stook, M. Ward, and H. Solo

- Gabriele. 2001. Leaching and Toxicity of CCA

Treated and Alternative

- Treated Wood Products (DRAFT). Florida Center for Solid and Hazardous Waste Management, State University System of Florida, Gain esville, FL

USEPA, IRIS, Chromium (VI), 1998; CASRN 18540

- 29

- 9, 9/3/1998

. Weis, P., J.S. Weis, and L.M. Coohill. 1991. Toxicity to Estuarine Organisms of Leachates from Chromated Copper Arsenate Treated Wood. Arch. Environ. Contam. Toxicol. 20: 188

- 124.

Weis, J.S., and Weis, P. 1992. Transfer of Contaminants From CCA

- Treated Lumber to Aquatic Biota. Journal of Experimental Marine Biology and Ecology. 161:189

- 199

Weis, J., and P. Weis. 1995. Effects of Chromated Copper Arsenate (CCA) Pressure

- Treated Wood in the Aquatic Environment. Ambio 24(5): 269

- 274.

Weis, J.S., and P. Weis. 1996. The Effects of Using Wood Treated with Chromated Copper Arsenate in Shallow

- Water Environments: A Review. Estuaries 19(2A): 306

- 310.

Weis, J.S. and P. Weis. 2002. Contamination of Saltmarsh Sediments and Biota by CCA Treated Wood Walkways. Mar. Pol. Bull 44: 504

- 10.

Weis, J.S. and P. Weis. 2004. Effects of CCA Wood on Non

- target Aquatic Biota. E nvironmental Impacts of Preservative

- treated Wood Conference, Orlando, Florida. Feb. http://www.ccaresearch.org/Pre

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# Appendix A T oxico logy Profile

Toxicology Profile for Chromated Arsenicals

The Agency recognizes that inorganic arsenic and inorganic chromium are the compounds of toxicological concern with respect to exposure to chromated arsenical

- treated wood. In any risk assessment, the toxicity of the primary chemicals of concern must be adequately described, either through submission of guideline toxicolo gy studies that are reviewed by the Agency, or through citation of scientific studies in the peer

- reviewed literature. The follow ing sections characterize the hazards of inorganic arsenic and inorganic chromium. Information was summarized from submitted toxicology studies, the open scientific literature, and from published documents by the USEPA and the Agency for Toxic Substances a nd Disease Registry (ATSDR). It is noted for inorganic arsenic that in most cases, human data (in the form of epidemiology studies and case reports) provide the basis for the hazard identification, as most laboratory animal models appear to be substantiall y less susceptible to arsenic toxicity than humans.

For chromium, hazard data show clearly that CrVI demonstrates more significant toxicity than chromium III ( CrIII ) or trivalent chromium . The Agency has not identified any endpoints of concern for CrIII . For exposure to CrVI, the Agency has identified toxicological endpoints of concern and has used these endpoints in conjunction with exposure to CrV I for evaluating risks associated with CrVI.

Copper as a component of chromated arsenical

- treated wood was addressed separately in the copper 2009 RED and in the copper registration review PWP

. 11

HAZARD CHARACTERIZATION

Hazard Characterization

- Arsenic

Arsenic is a naturally occurring element present in soil, water, and food. In the environment, arsenic exists in many different forms. In water, for example, arsenic exists primarily as the inorganic forms As +3 (arsenite) and As +5 (arsenate), while in food, arsenic exists pr imarily in organic forms (seafood, for example, contains arsenic as arsenobetaine, a form which is absorbed but rapidly excreted unchanged). Human activities also result in the release of arsenic into the environment, such as residual arsenic from former pesticidal use, smelter emissions, and the historical use of c hromated arsenicals in the pressure

- treatment of wood for construction of decks, fences, playgrounds, and other structural uses.

Inorganic arsenic, prior to 1991, was used as an agricultural p esticide. In 1991, the Agency proposed cancellation of the sole remaining agricultural use of arsenic acid (As+5) on cotton.

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Page 32 of 94 Subsequently, this registration was voluntarily canceled by the registrant and made immediately effective by the Agency (Federal Re gister, 1993).



## Acute Toxicity

The acute toxicity summary of inorganic arsenic (arsenic acid 7.5%) is summarized in Table A1

. Humans are very sensitive to arsenic toxicity when compared with other experimental animals. Inorganic arsenic is acutely toxic, and ingestion of large doses leads to gastrointestinal symptoms, disturbances of cardiovascular and nervous system functions, and eventually death. The effects seen after short

- term arsenic exposure (appearance of edema, gastrointestinal or upper respiratory symptoms) differ from those after longer exposure (symptoms of skin and neuropathy). Some of the effects after short

- term exposure tended to subside gradually from the 5th day of the illness, despite continuous intak es of the poison. In contrast, symptoms of peripheral neuropathy appeared in some individuals even after the cessation of arsenical intakes

. The acute oral toxicity of inorganic arsenic in humans shows lethal effects in the range of 22

- 121 mg/kg, which i s consistent with results of animal studies showing LD50 in the range of 15

- 175 mg/kg (ATSDR, 2000a , 2007 ). Although there are incidents with reported fatalities following skin exposure to isopropyl alcohol solution containing 30% arsenic (Cheraghali et a l., 2007),
t here are no studies reporting death in humans after dermal exposure to inorganic arsenic aqueous solution. N o mortality at dermal doses up to 1000 mg/kg in animal studies. Mortality in humans from short

- term inhalation exposure to inorganic a rsenic has not been observed in occupational settings at air levels up to 100 mg/m 3 . One study in pregnant rats reported lethality of inorganic arsenic at a concentration of 20 mg/m 3 . Arsenic has been shown to result in contact dermatitis in humans expose d to arsenic occupationally

. A nimal studies are also suggestive of mild to severe dermal irritation after application of arsenic to skin. Severe ocular irritation was observed in an acute eye irritation study (MRID # 00026356). Arsenic does not produce sk in sensitization in a guinea pig model (MRID # 40646201).

Table A1 . Acute Toxicity Summary of Arsenic Acid (75%)

Guideline Reference No. Study Type MRID/ Data Accession No. Results Toxicity Category

81

- 1

(OPPTS 870.1100) Acute Oral 404090

- 01 Mouse LD 50 =

_ 141 mg/kg

=

_ 160 mg/kg M+F = 150 mg/kg II

26356 Rat LD 50 =

_ 76 mg/kg

=

_ 37 mg/kg M+F = 52 mg/kg I

81

- 2

(OPPTS 870.1200) Acute Dermal 26356 Rabbit LD 50 =

_ 1750 mg/kg

=

_ 2300 mg/kg IIDocket Number EPA

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Page 33 of 94 81

- 3

(OPPTS 870.1300) Acute Inhalation 404639

- 02 Mouse LC 50 =

_ 1.153 mg/L

=

_ 0.79 mg/L M+F = 1.040 mg/L II

81

- 4

(OPPTS 870.2400) Primary Eye Irritation 26356 Rabbit 3/6 animals died by day 7. The 3 surviving animals were sacrificed on day 9 because of severe ocular irritation and corrosion. I

81

- 5

(OPPTS 870.2500) Primary Skin Irritation 26356 Rabbit At 30 minutes, all animals showed moderate to severe erythema and slight to severe edema. All animals died prior to the 24 hour observation. I

81

- 6

(OPPTS 870.2600) Dermal Sensitization 406462

- 01 Guinea Pig Not a Sensitizer



## Subchronic Toxicity

Subchronic studies with arsenic in experimental animal models have produced only generalized toxicity, i.e., weight loss, and decreased survival, while data from human exposures have shown more specific toxic effects, such as neurotoxicity and hyperkeratos is of the skin of the hands and feet (ATSDR, 2000a).


## Developmental Toxicity and Reproductive Toxicity

Data on the developmental and reproductive toxicity of inorganic arsenic in humans are not extensive. One study conducted in Sweden among copper smelter workers showed significantly reduced live birth weights in offspring of women employed at the copper smelter and increased incidence of spontaneous abortion among those who worked at the smelter or lived in proximity to it. However, e ffects from exposure to lead or copper in this study could not be ruled out. Hopenhayn

- Rich (2000) conducted a retrospective study of late fetal, neonatal and postnatal mortality in Antofagasta, Chile for the years 1950 to 1996. The data from this study i ndicated an elevation in late fetal, neonatal and postnatal mortality compared to a comparison group in Valparaiso, Chile during the period when drinking water in Antofagasta was contaminated [860
μ g/L] with arsenic (1958 to 1970). There was a decline in l ate fetal, neonatal and postnatal mortality when the concentration of arsenic in the drinking water declined due to installation of a water treatment plant. After installation of the plant, the mortality rates in Antofagasta were indistinguishable from tho se in Valparaiso. It was noted that the mothers involved in this incident had characteristic arsenic

- induced skin lesions. A prospective cohort study was conducted in these two cities during the period when drinking water arsenic levels in Antofagasta is 4 0μg/L and in Valparaiso is less than 1μg/L. By comparing the pregnancy and birthDocket Number EPA

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Page 34 of 94 information form these two cities, the results suggests that moderate arsenic exposure (<50μg/L) during pregnancy may associated with reduction in birth weight (Hopenhayn et a l., 2003).

In laboratory animals, the major teratogenic effect induced by inorganic arsenic is neural tube defect, characterized by exencephaly and encephalocele. However, this effect has not been observed in humans (IPCS, 2001). In addition, data on the developmental and reproductive toxicity of inorganic arsenic submitted to the Agency show effects on offspring only at doses that are maternally toxic.

In a developmental toxicity study ( Nem e c , 19 8 8), pregnant Crl:CD

- 1(ICR)BR mice (25 per dose group) re ceived a single daily gavage of aqueous Arsenic Acid (75%) from day 6 through 15 of gestation. Doses were 0, 10, 32 and 64 mg/kg/day. Controls received deionized water. Body weights were recorded at six hour periods. Cesarean section was on day 18. Fetuses were weighed, sexed and examined for external skeletal and soft tissue malformations and variations. At the high dose, two dams died. Signs included lethargy, decreased urination and defecation, soft stool or mucoid feces. Brown urogenital matting, and re d material around the eyes. Necropsy showed bilateral reddening of cortico

- medullary junction (kidneys) and a red areas in the stomach. At mid and (especially) top dose, the dams showed weight loss and an elevated incidence of total litter resorption. An increase in exencephaly occurred in both the low (1/231 fetuses per 1 litter) and the high (2/146 fetuses per 1 litter) doses, but statistical significance was not seen. The Maternal Toxicity NOAEL was determined to be 32 mg/kg/day, and the Maternal toxici ty LOAEL was determined to be 64 mg/kg/day, based on increased total litter resorption, reduced body weight, and increased maternal mortality. The Developmental Toxicity NOAEL was determined to be 32 mg/kg/day and the Developmental Toxicity LOAEL was deter mined to be 64 mg/kg/day, based on reduced mean viable fetuses, reduced fetal weights, increased post implantation loss and increased incidence of exencephaly (not statistically significant).

In a prenatal developmental toxicity study (Nemec, 1988), artif icially inseminated New Zealand White rabbits (20/dose) received aqueous arsenic acid (75%) by gavage from days 6 through 18 of gestation inclusive at doses of 0, 0.25, 1, and 4 mg/kg/ day. At the 4 mg/kg/day dose level, seven dams died or were sacrificed in extremis. Reduced body weight gain, clinical signs of toxicity (prostration, ataxia, decreased defacation and urination, mucoid feces), and histo

- logical alterations in dams sacrificed or dead at the high dose (pale, soft, or mottled kidneys; pale and soft liver; dark red areas of the stomach; dark red lungs) were observed. Fetal data showed increased post

- implantation loss at the 4 mg/kg/day dose (1.8 vs. 0.5 in control) and reduced mean viable fetuses (4.9 vs. 6.7 in control). There was no evidence from the data of increased incidence of fetal alterations (variations, malformations) related to treatment with test article. The Maternal NOAEL was determined to be 1 mg/kg/day, and the Maternal LOAEL was determined to be 4 mg/kg/day, based on increased mortality, decreased body weight gain, clinical signs, and histological alterations of the kidney and liver. The Developmental NOAEL was determined to be 1 mg/kg/day, and the Developmental LOAEL was determined to be 4 mg/kg/day, based on increased post

- im plantation loss and decreased viable fetuses.

With regard to the susceptibility of offspring to the toxicity of inorganic arsenic, DeSesso, (1998) in a review paper exploring the reproductive and developmental toxicity of arsenic acid (As+5) noted that i n three repeated oral dose studies carried out under EPA guidelines for assayingDocket Number EPA

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Page 35 of 94 developmental toxicity, arsenic acid was not teratogenic in: mice by oral gavage (10 to 64 mg/kg/day), rabbits by oral gavage (1 to 4 mg/kg/day)

, and in a mouse two

- generation feeding study (20 to 500 ppm). Other animal developmental and reproductive toxicity data based on the published literature also showed no increased sensitivity to arsenic (+5) when given orally by repeated doses.

In a tran s placental carcinoginicity study (Waalkes et al., 2003), pregnant C3H mice were given drinking water containing sodium arseni te at 0, 42,5 and 85 ppm ad libitum from day 8 to 18 of gestation. These dosages were well tolerated and did not decrease the body weight of the dams during gesta tion and the birth weight of the offspring after birth. However, after weaning at 4 weeks, the offsprings were put into separate gender

- base groups according to maternal exposure level. The offspring received no additional arsenic treatment. The study la sted 74 weeks in males and 90 weeks in females. A complete necropsy was performed on all mice tissues were examined. In male, there was a dose

- related incr ease in the incidences of hepta tocellular carcinoma, and adrenal tumor. In female offsprin g , dose

- re lated increases in ovarian tumors and lung carcinoma incidence s were observed (Waalkes et al., 2003)

. The same authors note that “there is a paucity of human data regarding inorganic arsenic exposure during pregnancy and potential adverse effects on proge ny. The available epidemiological studies were neither rigorously designed nor well controlled. These studies failed to find a definitive or consistent association between arsenic exposure and adverse pregnancy outcome. Consequently, claims of potential ad verse effects of inorganic arsenic on human development remain unsubstantiated.” This conclusion is consistent with ATSDR (200 7 ), which noted that “Although several studies have reported marginal associations between prolonged low

- dose human arsenic expos ure and adverse reproductive outcomes, including spontaneous abortion, stillbirth, developmental impairment, and congenital malformation

... none of these studies have provided convincing evidence for such effects or information concerning possible dose

- respo nse relationships

. ”


## Other Toxicological Effects

The January 22, 2001 Federal Register Notice (Vol. 66, No. 14, pages 7027

- 7028), in which the arsenic drinking water standard was discussed in relation to susceptibility of certain human subpopulations including infants and children also supports the view that inorganic arsenic does not pose a special sensitivity to children. In that notice, the Agency agreed with a report by the National Research Council noting “that there is a marked variation in susc eptibility to arsenic

induced toxic effects which may be influenced by factors such as genetic polymorphisms, life stage at which exposures occur, sex, nutritional status, and concurrent exposures to other agents or environmental factors.” However, the vie w was also shared between EPA and NRC that “there is insufficient scientific information to permit separate cancer risk estimates for potential subpopulations...and that factors that influence sensitivity to or expression of arsenic

- associated cancer and n on

- cancer effects need to be better characterized. EPA agrees with the NRC that there is not enough information to make risk conclusions regarding any specific subpopulations.” In the latest update to this issue (NRC, 2001), it is noted that while “eviden ce from human studies suggests the potential for adverse effects on several reproductive endpoints... “there are no reliable data that indicate heightened susceptibility of children to arsenic.” Since theDocket Number EPA

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Page 36 of 94 publication of these NRC Reports, numerous studies on arsenic research continue to become available; and in September 2005 EPA scientists presented the information and ask ed the Scientific Advisory Board (SAB) to comment on the adequacy of the information on the impact of childhood exposure to inorgan ic arsenics. The SAB concluded , based on available data, it is still not clear whether children differ from adults with regard to their sensitivity to the carcinogenic effect s of arsenics.



## Neurotoxic ity and Immunotoxicity

Neurotoxicity of inorganic arse nic is not evident in studies with experimental animals. However, there is a large body of epidemiology studies and case reports which describe neurotoxicity in humans after both acute and chronic exposures, characterized by headache, lethargy, seizures,

c oma, encephalopathy (after acute exposures of 2 mg/kg/day and above), and peripheral neuropathy (after repeated exposures to 0.03

- 0.1 mg/kg/day) (ATSDR, 2000a).

Evidence, including epidemiological, animal, in vivo and in vitro studies, suggest inorganic

a rsenic exposure may impair immune responses which could lead to increased risk of infections and chronic diseases, including various cancers (Dangleben et al, 2013). Inorganic arsenic exposure increased opportunistic infections including tuberculosis and fungal and respiratory tract infections [26,29,35]. Studies in rats [86

- 88] and mice [89] show that arsenic can suppress the weight, index and/or cellularity of major immunocompetent organs, including spleen and thymus. Patra et al. (2013) demonstrated in organic arsenic exposure can induce cell apoptosis in the bone marrow cells of goat s

. Inorganic arsenic inhibited maturation of monocytes into macrophages

, and induced small, nonadhesive and abnormal macrophage generation from monocytes at level s not caus ing cell death (Sakurai et al., 2006)

. 

## Mutagenicity

Mutagenicity studies using inorganic arsenic have shown mixed results. Sodium arsenite is not genotoxic to Chinese hamster ovary (CHO) cells (Rossman et al., 1980) or Syrian hamster embryo cells (Lee e t al., 1985) when selecting for ouabain

- (ATPase) or thioguanine

- resistant (hypoxanthine phosphoribosyl transferase, HPRT) mutants. In the L5178Y mouse lymphoma assay, sodium arsenite is weakly genotoxic at the thymidine kinase locus without metabolic
act ivation (Oberly et al., 1982; Moore et al., 1997). Sodium arsenate is even a weaker mutagen with (Oberly et al., 1982) and without metabolic activation (Moore et al., 1997). The type of effects reported by Moore et al. (1997) were chromosomal aberrations, micronuclei (arsenite only) polyploidy and endoreduplication.

Sodium arsenate and sodium arsenite induce sister chromatid exchanges and chromosomal aberrations in hamster embryo cells (10

- 7 mol/litre

- 10

- 4 mol/litre) (Larramendy et al., 1981; Lee et al., 1985; Kochhar et al., 1996). The aberrations are characterized by chromatid gaps, breaks, and fragmentation, endoreduplication and chromosomal breaks. These clastogenic effects are observed at lower doses of arsenite than arsenate. The difference may be due to greater in vitro cellular uptake of arsenite than arsenate (Lerman et al., 1983; Bertolero et al., 1987). GaAs (2.5

- 10 μg/ml) did not induce micronuclei in Syrian hamster embryo cells (Gibson et al., 19 97).Docket Number EPA

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Page 37 of 94 M ethylated trivalent forms of arsenic have been shown to nick and/or completely degrade φX174 DNA in vitro (Mass et al., 2001), while sodium arsenite, arsenate, and the pentavalent methylated forms of arsenic were without effect. In the single

- cell g el assay (COMET assay) using human lymphocytes, inorganic arsenite and arsenate produced concentration

- dependent linear increases in DNA damage, but the methylated trivalent forms of arsenic were observed to be 54

- 77 times more potent in this assay than th e non

- methylated forms. DNA damage occurred in the absence of metabolic activation in both assays.


## Chronic Toxicity and Carcinogenicity

There are numerous epidemiologic investigations that have examined the association between arsenic exposure and non

- cancerous and cancer health effects (NRC, 1998 and 2001) . These epidemiologic investigations include many different designs including preva lence studies, cross

sectional studies, case

- control, cohort, nested case

- control, and ecological studies. Each of these types of investigations has certain specific inherent limitations, but the majority of the investigations found some level of associat ion between arsenic and non

- cancerous health effects, and arsenic and cancer.

In humans, arsenic is known to cause cancer of the skin and cancer of the lung, bladder, liver, kidney, and prostate. Prevalence studies of skin cancer in Taiwan indicate some degree of dose

response activity between amount of arsenic exposure and skin cancer and other manifestations including keratosis and hyperpigmentation. They found that ascending rates for skin cancer, keratosis and hyperpigmentation corresponded with arse nic content of well water and identified a dose

- response relationship between arsenic concentration and blackfoot disease.

The Taiwanese population has been extensively studied due to the switch from surface water wells to artesian (ground water) wells f or drinking water more than 80 years ago in an attempt to improve the sanitation and salt content of their drinking water. However, in certain areas of Taiwan these artesian wells have been discovered to be contaminated with naturally occurring arsenic re sulting in widespread exposure to extensive populations in Taiwan. There have also been a number of investigations performed on populations in other regions of the world including Bangladesh, Jap a n, India, South America, and North America where associatio ns between arsenic and cancer have been investigated. A significant dose

- related increase in mortality for both males and females was identified in Cordoba, Argentina for low

- , medium

- , and high

- exposure groups.

Inorganic arsenic in experimental animal s all show a lack of specific toxic effects, whereas the scientific literature that describes chronic human exposure shows a clear relationship between chronic exposure to inorganic arsenic and the development of skin cancer as well as cancers of the lung, liver, and bladder (ATSDR, 2007; NRC, 1999).

The most notable example of this is the data of Tseng, (1968, 1977) who conducted epidemiological studies of chronic oral exposure of humans to arsenic contained in food and water. From these studies it was n oted that hyperpigmentation, keratosis and possible vascular complications [Blackfoot disease] occurred at a dose of 0.17 mg arsenic per liter of water,Docket Number EPA

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Page 38 of 94 equivalent of 0.014 mg/kg/ day. Several follow

- up studies of the Taiwanese population exposed to inorga nic arsenic in drinking water showed an increase in fatal internal organ cancers as well as an increase in skin cancer. Other investigators found that the standard mortality ratios (SMR) and cumulative mortality rates for cancers of the bladder, kidney, sk in, lung, and liver were significantly greater in the Blackfoot disease endemic area of Taiwan when compared with the age adjusted rates for the general population of Taiwan.



## Metabolism

Metabolism of inorganic arsenic first proc eeds through non

- enzymatic reduction of arsenate to arsenite, which can then undergo enzymatic methylation to the products monomethylarsinic acid and dimethylarsinic acid. These products are then reduced to the monomethylarsinous acid and dimethylarsinous acid produ c ts. The major site of methylation appears to be liver, where the methylation reaction is mediated by methyltransferase enzymes using S

- adenylmethionine as a cosubstrate. The products of inorganic arsenic metabolism in urine have been identified as As(+3), As(+5), monomethylarsinous acid, and dimethylarsinous acid

. Urinary products appear similar among species studied (ATSDR, 200 7 ), but the relative proportions of these products vary greatly. There is also variation between species and among human populati ons in the rate and extent of methylation of inorganic arsenic. New study finds there are g enetic variations in genes associated with arsenic metabolism: MMA reductase gene (identified as glutathione s

transferase omega 1

- 1 gene ) and purine nucleoside phos phorylase gene (polymorphism) (NRC, 2001).



## Hazard Characterization

- Chromium

Chromium is a naturally occurring element found in animals, plants, rocks, in soil, and in volcanic dust and gases. In the trivalent (+3) state, chromium compounds are stable and occur in nature in this state in ores s uch as ferrochromite. Chromium VI is second

- most stable relative to the (+3) form, but rarely occurs naturally and is usually produced from anthropogenic sources (ATSDR, 2000b). The general population is exposed to chromium by inhalation of ambient air, ingestion of food, and drinking of water. Dermal contact with chromium can also occur from skin contact with products containing chromium or from soils containing chromium.

In humans and animals, chromium III is an essential nutrient that plays a role in glucose, fat, and protein metabolism. The biologically active form of chromium e xists as a complex of chromium III, nicotinic acid, and possibly the amino acids glycine, cysteine, and glutamic acid to form glucose tolerance factor. GTF is believed to function by facilitating the interaction of insulin with its cellular receptor sites although the exact mechanism is not known. The National Research Council recom mends a dietary intake of 50

- 200 micrograms per day for chromium III.

Chromium in the ambient air occurs from natural sources, industrial and product uses, and burning of fossil fuels and wood. The most important industrial sources of chromium in the
atm osphere originate from ferrochrome production. Ore refining, chemical and refractory processing, cement

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Page 39 of 94 automobiles, leather tanneries, and chrome pigments also contribute to the atmosp heric burden of chromium (Fishbein, 1981).

Surface runoff, deposition from air, and release of municipal and industrial waste waters are sources of chromium in surface waters.

Ingested hexavalent chromium is efficiently reduced to the trivalent form in t he gastrointestinal tract (DeFlora et al., 1987). In the lungs, hexavalent chromium can be reduced to the trivalent form by acerbate and glutathione. Given the rapid reduction of CrVI to CrIII in vivo, it is relevant to consider whether environmental expos ures to CrVI or administration of CrVI in controlled animal experiments is essentially identical to environmental exposures to CrIII or administration of CrII I in controlled experiments. For chromium, hazard data show clearly that CrVI demonstrates more s ignificant toxicity than CrIII. The Agency has not identified any endpoints of concern for CrIII. For exposure to CrVI, the Agency has identified toxicological endpoints of concern and has used these endpoints in conjunction with exposure to CrVI for eval uating risks associated with CrVI.


## Acute Toxicity

The acute to xicity summary of the Chromium VI is summarized in Table A2

. In acute toxicity animal studi es, administration of chromium VI (as chromic acid) by the oral, dermal, and inhalation
routes resulted in significant acute toxicity as measured by lethality. The measured oral LD50 in rats was reported as 52 mg/kg, the dermal LD50 as 57 mg/kg, and the inhalation LC50 a s 0.217 mg/L, placing chromium VI in Toxicity Category I for acute lethality. H uman reports of death after ingestion of chromium show lethality at similar dose levels (ATSDR, 2012 ). Chromium VI is a significant eye and skin irritant, and severe allergic reactions consisting of redness and swelling of the skin have also been noted in exposed animals and humans. Case reports of humans who have intentionally or accidentally ingested chromium have also shown severe respiratory effects (pulmonary edema, bronchitis, and bronchopneumonia), cardiovascular effects (cardiac arrest), and gastroi ntestinal effects (hemorrhage, ulceration).

In contrast to the acute toxicity of chromium VI, ac ute toxicity data for chromium III show less severe acute toxicity, with oral LD50 values in rats reported as 183

- 200 mg/kg or 2365 mg/kg. There are no reports of lethality in experimental animals after acute inhalation or acu te dermal exposure to chromium III. However, skin irritation and sensitization have also been obse rved from exposure to chromium III.

The dermal irritancy and sensitization potential of c hromium compounds are worthy of note. The potent skin allergenicity of chromium has been well documented in the literature, and chromium compounds have been reported to be the most frequent sensitizing agents in man (IRIS, 2000). The prevalence of CrVI se nsitivity among the general U.S. population is estimated to be 0.08%, based on studies conducted by Proctor et al (1998). Most of the occurrences of contact dermatitis and sensitization cited are from the result of occupational exposures, but includ e the w ood preserving industry (Burrows, 1983). For previously sensitized individuals, very low dosage of CrVI can elicit allergic contact dermatitis. Several studies document the sensitization reactions observed in humans previously exposed dismally to chromium VI compounds. Sensitization canDocket Number EPA

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Page 40 of 94 also be observed in humans with chromium III if exposure concentration is high enough (ATSDR, 2000b). Bagdon (1991) collected skin hypersensitivity data for trivalent chromium compounds in human subjects and concluded that the threshold level for evoking hypersensitivity reactions from trivalent chromium compounds is approximately 50

- fold higher than for hexavalent chromium compounds.

Experimental animal models also show that sensitization to chromium compounds can occur, and in some cases, the sensitization response observed is similar using an equivalent dose of either chromium VI or chromium III (ATSDR, 2000b).

Table A2 : Acute Toxicity Summary of Chromium VI

Guideline Study Type [Substance] MRID/Literature Results Toxicity Category

81

- 1 (OPPTS 870.1100) Acute Oral/Rat [Chromic Acid, 100% a.i.] 434294

- 01 LD 50 =

_ 56 mg/kg

=

_ 48 mg/kg M+F = 52 mg/kg I

81

- 2 (OPPTS 870.1200) Acute Dermal/Rabbit [Chromic Acid, 100% a.i.] 434294

- 02 LD 50 =

_ >48 mg/kg

=

_ 48 mg/kg M+F = 57 mg/kg I

81

- 3

(OPPTS 870.1300) Acute Inhalation/Rat [Chromic Acid, 100% a.i.] 434294

- 03 LC 50 =

_ 0.263 mg/L

=

_ 0.167 mg/L M+F = 0.217 mg/L I

81

- 4

(OPPTS 870.2400) Primary Eye Irritation [Various Cr(VI)

compounds] Literature Waiver

Corrosive I

81

- 5 (OPPTS 870.2500) Primary Dermal Irritation [Various Cr(VI)

compounds] Literature Waiver

Corrosive I

81

- 6 (OPPTS 870.2600) Dermal Sensitization /Guinea Pig [Various Cr(VI)

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Page 41 of 94 

## Non

- Acute Toxicity

Oral

Subchronic toxicity studies in experimental animals have demonstrated hematologic and hepatic effects from repe ated oral exposure to chromium VI. In a 9 week study in which male and female Sprague

- Dawley rats were fed diets containing potassium dichromate at dose levels of 0, 15, 50, 100, or 400 ppm potassium dichromate [NTP, 1996], there were no treatment related findings noted in mean body weights, water and feed consumption, organ weights or microscopic pathology of the liver, kidneys and ovaries. Hematology findings consisted of decreases in mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) at the high dose (8.4 and 9.8 mg/kg/day in male and female rats respectively). There were no reported hepatic effects in this study. However, Kumar and Rana (1992) reported increased accumulation of hepatic lipids after gavage treatment of rats with 13.5 mg /kg chromium VI (as potassium chromate) after 20 days of treatment.

In a 9

- week feeding study in mice conducted by the National Toxicology Program (1996) in which mice were fed diets containing 1.1, 3.5, 7.4, and 32 mg/kg/day chromium (males) or 1.8, 5.6 , 12, and 48 mg/kg/day chromium (females), hepatic cytoplasmic vacuolization was observed to be slightly increased at the high dose in males and females, and the appearance of the vacuoles was suggestive of lipid accumulation. Additional endpoints examine d in this study included body weights, feed and water consumption, organ weights, microscopic evaluation of the liver, kidney and ovaries, hematology, histology of the testis and epididymis for Sertoli nuclei, and preleptotene spermatocyte counts in Stage X or XI tubules and chromatin analysis. Slight decreases in body weight were observed during this study, but there was no significant effect of treatment on clinical signs, necropsy findings, or microscopic histology. Hematologic effects were observed a nd consisted of a 2

- 4% decrease in MCV at weeks 3, 6, and 9 in high dose males and females and at week 6 in the 100 ppm females. The MCV returned to normal in the female mice after the recovery period (week 17); however the MCV increased 2.8% in the 400 pp m males. The MCV changes at weeks 3, 6 and 9 were, in general associated with small decreases in the RBC, and small decreases in the MCH, although only the MCH values from the 400 ppm males (week 9), the 400 ppm females (Weeks 3 and 6), the 15 and 100 ppm females (week 3) were decreased.



## Inhalation

Occupational exposure to chromium by inhalation has been studied in the chromate manufacturing and ferrochromium industries; however, exposures all include mixed exposures to both CrIII and CrVI. The CrVI species is widely considered to be the causative agent in reports of excess cancer risk in chromium workers. However, studies are inadequate to rule out a contribution by CrIII, and CrVI cannot be unequivocally demonstrated to be the causative agent for no ncarcinogenic effects following inhalation.Docket Number EPA

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Page 42 of 94 A number of epidemiologic studies have considered the association between inhalation of chromium and noncarcinogenic endpoints, including upper respiratory irritation and atrophy, lower respiratory effects, and systemic effects. Symptoms reported from inhalation exposure to mists and dusts containing chromium have included nasal tissue damage, perforated septum, ulcerated septum, chrome holes, nosebleed, inflamed mucosa, nasal septal perforation, and nasal septa l ulceration (USEPA IRIS, 1998). Exposure to vapors of chromium salts has also been suspected as a cause of asthma, coughing, wheezing, and other respiratory distress in ferrochromium workers.

Despite the consistency of the reported effects from inhalat ion of chromium contained in dusts and mists, the actual CrIII and CrVI exposure levels in many of the studies attributing respiratory effects to chromium were unknown. In addition, data on other confounding factors such as smoking were frequently unavaila ble. These caveats significantly complicate determination of the potential health effects associated with inhalation exposure to chromium (ATSDR, 2000b).


## Developmental Toxicity and Reproductive Toxicity

Despite the wealth of animal studies on the developm ental and reproductive toxicity of chromium VI, there are too few human data with which to make any reliable conclusion regarding the susceptibility of the developing fetus, infants, or children to the toxic effects of chromium VI. The evidence available s uggests similar toxic effects in adults and children from ingestion of chromium VI (ATSDR, 2000b).


## Developmental Toxicity

Although human data examining developmental endpoints are scarce, animal studies have consistently shown that chromium, particularly chromium VI, is a developmental toxicant. Oral ingestion of chromium VI compounds in experimental animals results in significant developmental toxicity. Studies describing the effects observed have been published in the IRIS Toxicolog ical Reviews for both chromium VI and chromium III as well as from submitted studies to the Agency are summarized here.

Trivedi et al. (1989) exposed mice to 250, 500, and 1,000 ppm potassium dichromate daily through drinking water during the entire gestational period. The authors reported decreased fetal weight, increased resorptions, and increased abnormalities (tail kinking, delayed ossification of the cranium) in exposed mice. The medium

- and high

- dose groups registered significant reductions in body weight gain when compared to controls. The most significant finding of the study was the complete absence of uterine implantation in the high

- dose group. The 250 and 500 ppm dose groups also showed significant incidences of resorption as compared to controls. The authors o bserved significant increases in preimplantation and postimplantation losses and dose

dependent reductions in total weight and crown

- rump length in the lower dose groups. Additional effects included treatment

- related increases in abnormalities in the tail, wrist forelimbs and subdermal hemorrhagic patches in the offspring.Docket Number EPA

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Page 43 of 94 Junaid et al. (1996) exposed female Swiss albino mice to 250, 500, or 750 ppm potassium dichromate in drinking water to determine the potential embryotoxicity of hexavalent chromium duri ng days 6

- 14 of gestation. No notable changes in behavior or clinical signs were observed in the control or treated dams. Chromium levels in blood, placenta, and fetus increased in a dose

dependent fashion over the course of the study. The authors reported retarded fetal development and embryo

- and fetotoxic effects including reduced fetal weight, reduced number of fetuses (live and dead) per dam, and higher incidences of stillbirths and postimplantation loss in the 500 and 750 ppm dosed mothers. Significan tly reduced ossification in nasal, frontal, parietal, interparietal, caudal, and tarsal bones was observed in the high

- dose group, while reduced ossification in only the caudal bones was observed in the 500 ppm dose group. Based on the body weight of the a nimals (30 +/

- 5 g) and the drinking water ingested by the animals in the 250 ppm dose group (8.0 ml/mouse/day), the dose level in the 250 ppm group can be identified as 67 mg/kg

- day. The maternal NOAEL was 63 [22.3] mg/kg/day while the LOAEL was 42.1 mg/k g/day and was based on a decreased gestational body weight. At the lowest dose tested, the incidence of resorptions was increased and a developmental NOAEL was, therefore, not determined.

Kanojia et al. (1996) exposed female Swiss albino rats to 250, 500, or 750 ppm potassium dichromate in drinking water for 20 days 3 months prior to gesta tion to determine the potential
t eratogenicity of hexavalent chromium. No notable changes in behavior or clinical signs were observed in the control or treated dams. Chro mium levels in blood, placenta, and fetus were significantly increased in the dams of the 500 and 750 ppm dose groups. The authors reported a educed number of corpora lutea and implantations, retarded fetal development, and embryo

- and fetotoxic effects i ncluding reduced number of fetuses (live and dead) per dam and higher incidences of stillbirths and postimplantation loss in the 500 and 750 ppm dosed mothers. Significantly reduced parietal and interparietal ossification was observed in the high

- dose grou p. Based on the body weight of the animals (175 +/

- 25 g) and the drinking water ingested by the animals in the 250 ppm dose group (26 ml/mouse/day) the dose level in the 250 ppm group can be identified as 37 mg/kg

- day.

Tyl (1991) examined the development al and maternal effects of daily administration of chromic acid (55.0% a.i.) at dosages of 0, 0.1, 0.5, 2.0 or 5.0 mg/kg/day by gavage in rabbits. Clinical signs of toxicity, including diarrhea, and slow, audible or labored breathing were observed in predo minately in the 2.0 and 5.0 mg/kg/day groups. However, these signs did not show a dose

response and were observed in lesser incidence at 5.0 mg/kg/day vs. 2.0 mg/kg/day. However, the incidence of mortality (at 2.0 mg/kg/day, one doe died on gestation day (GD) 28; at 5.0 mg/kg/day, 5 does died (one each on GD 10, 14, and two on GD 15) and the magnitude of decreased body weight gain during the dosing period (average weight loss of 48 grams at 2.0 mg/kg/day, and average weight loss of 140 grams at 5.0 mg/kg/d ay during gestation days 7

- 19) were observed to occur in a dose

- related fashion at 2.0 and 5.0 mg/kg/day. Food efficiency was also observed to be significantly lower during the dosing period in the 5.0 mg/kg/day dose group. Cesarean section observations were unremarkable in this study at any dose level. No treatment related effects on either fetal malformations or variations were observed.

The Maternal NOAEL = 0.5 [0.12] mg/kg/day and LOAEL = 2.0 [0.48] mg/kg/day (based on the increased incidence of mat ernal mortality and decreased body weight gain). The DevelopmentalDocket Number EPA

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Page 44 of 94 NOAEL = 2.0 [0.48] mg/kg/day and LOAEL > 2.0 [>0.48] mg/kg/day based on the lack of developmental effects at any dose level tested. By contrast to effects of chromium VI, effects on develop ment and reproduction from exposure to CrIII show either negative results or effects only at high doses. For example, male and female rats treated with 1,806 mg CrIII kg/day as CrIII oxide 5 days/week for 60 days before gestation and throughout the gestat ion period had normal fertility, gestational length, and litter size (Ivankovic and Preussman, 1975). Elbetieha and Al

Hamood (1997) examined fertility following chromium chloride exposures in mice. Sexually mature male and female mice were exposed to 1,0 00, 2,000, or 5,000 mg/L chromium chloride in drinking water for 12 weeks. Exposure of male mice to 5,000 ppm trivalent chromium compounds for 12 weeks had adverse impacts on male fertility. Testes weights were increased in the males exposed in the 2,000 a nd 5,000 mg/L dose groups, while seminal vesicle and preputial gland weights were reduced in the 5,000 mg/L exposed males. The number of implantation sites and viable fetuses were significantly reduced in females exposed to 2,000 and 5,000 mg/L chromium ch loride. Water consumption was not reported precluding calculation of the doses received. However it is evident that adverse effects were observed only at a high dose of CrIII.



## Reproductive Toxicity

The National Toxicology Program conducted a three

- par t study to investigate oral ingestion of hexavalent chromium in experimental animals (NTP, 1996, 1997 a ). The study included a determination of the potential reproductive toxicity of potassium dichromate in Sprague

- Dawley rats, a repeat of the study of Zahi d et al. (1990) using BALB/C mice, and a Reproductive Assessment by Continuous Breeding study in BALB/C mice. The study in the Sprague

- Dawley rat (NTP, 1996) was conducted in order to generate data in a species commonly used for regulatory studies. Groups of 24 males and 48 females were exposed to 0, 15, 50, 100, or 400 ppm potassium dichromate daily in the diet for 9 weeks followed by a recovery period of 8 weeks. Six male and 12 female rats were sacrificed after 3, 6 or 9 full weeks of treatment or after the full recovery period. Animals were examined for body weights; feed and water consumption; organ weights; microscopic evaluation of the liver, kidney, and ovaries; hematology; histology of the testis and epididymus for Sertoli nuclei and preleptotene sp ermatocyte counts in Stage X or XI tubules; and chromatin analysis. No treatment

- related hematology findings were reported except for slight decreases in MCV and MCH values in the male and female treatment groups receiving 400 ppm potassium dichromate (24 mg/kg

- day). While the trends in MCV and MCH were not large and were within the reference ranges, they are consistent with the findings of the companion studies in BALB/C mice and were characterized by the authors as suggestive of a potential bone marrow/er ythroid response. The authors considered the 100 ppm (6 mg/kg

- day) dose group to be representative of the NOAEL for the study.

The reproductive study in BALB/C mice (NTP, 1996) was conducted to reproduce the conditions utilized by Zahid et al. (1990) in t heir examination of comparative effects of trivalent and hexavalent chromium on spermatogenesis of the mouse. Groups of 24 male and 48 female BALB/C mice were exposed to 0, 15, 50, 100, or 400 ppm potassium dichromate in the diet for 9 weeks followed by a recovery period of 8 weeks. Six male and 12 female mice were sacrificed after 3, 6, or 9 full weeks of treatment or after the full recovery period. Animals were examined for body weights; feed and water consumption; organ weights; microscopic evaluation of theDocket Number EPA

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Page 45 of 94 liver, kidney, and ovaries; hematology; histology of the testis and epididymus for Sertoli nuclei and preleptotene spermatocyte counts in Stage X or XI tubules; and chromatin analysis. Treatment

- related effects included a slight reduction in the mean body weights in the 400 ppm males and the 100 ppm females, a slight increase in food consumption at all dose levels, a slight decrease in MCV and MCH at 400 ppm, and cytoplasmic vacuolization of the hepatocyte at 50, 100 and 400 ppm. None of the effects on spermatogenesis reported by Zahid et al. (1990) were observed in this study. On the basis of the cytoplasmic vacuolization of the hepatocyte in the 50, 100, and 400 ppm dose groups, the authors selected 15 ppm (4 mg/kg

- day) as the NOAEL.

Increased resorptions and increased post

- implantation loss as well as gross fetal abnormalities were observed in offspring of pregnant mice exposed to potassium dichromate at 57 mg/kg/day in drinking water during gestation (ATSDR, 2000b). At a higher dose of 234 mg/kg/day, no implantations were observed in maternal mice. In a second study in mice, potassium dichromate was administered in the diet for 7 weeks at dose levels of 15.1 and 28 mg/kg/day. Reduced sperm counts and degeneration of the outer layer of the seminiferous tubules was observed at the 15.1 mg/kg/day dose, and morphologically altered sperm was observed at the 28 mg/kg/day dose.

In male rats administered 20 mg/kg/day chromium trioxide for 90 days by gavage, reduced testicular weight, decreas ed testicular testosterone, and reduced Leydig cell number was observed (Chowdhury and Mitra, 1995). In male bonnet monkeys exposed to potassium dichromate in drinking water at level of 100, 200, and 400 ppm hexavalent chromium can bring toxic effects on t he testis and epididymis, including spermatotoxicity (Aruldhas et al., 2004, 2005, and 2006).


## Neurotoxicity and Immunotoxicity

Immunotoxicity and neurotoxicity of CrVI are not evident in studies with experimental animals. In addition, a human study, Bo scolo et al. (1997), found no significant difference in serum immunoglobulin concentrations from exposure of chromium to workers.


## Mutagenicity and Carcinogenicity

In vitro data are suggestive of a potential mode of action for hexavalent chromium carcinog enesis. Hexavalent chromium carcinogenesis may result from the formation of mutagenic oxidatitive DNA lesions following intracellular reduction to the trivalent form. CrVI readily passes through cell membranes and is rapidly reduced intracellularly to ge nerate reactive CrV and CrIV intermediates a reactive oxygen species. A number of potentially mutagenic DNA lesions are formed during the reduction of CrVI. Hexavalent chromium is mutagenic in bacterial assays, yeasts, and V79 cells, and CrVI compounds d ecrease the fidelity of DNA synthesis in vitro and produce unscheduled DNA synthesis as a consequence of DNA damage. Chromate has been shown to transform both primary cells and cell lines (ATSDR, 2000b).

Intracellular reduction of CrVI generates reactive chromium V and chromium IV intermediates as well as hydroxyl free radicals (OH) and singlet oxygen. A variety of DNA lesions areDocket Number EPA

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Page 46 of 94 generated during the reduction of CrVI to CrIII, including DNA strand breaks, alkali

- labile sites, DNA

- protein and DNA

- DNA cros slinks, and oxidative DNA damage, such as 8

- oxo

deoxyguanosine. The relative importance of the different chromium complexes and oxidative DNA damage in the toxicity of CrVI is unknown.

There is clear evidence that CrVI is a mutagen, including positive res ults from in vitro mutagenicity studies and from in vivo animal studies. Hexavalent chromium in the presence of glutathione has been demonstrated to produce genotoxic DNA adducts that inhibit DNA replication and are mut agenic (IRIS, 2000). Chromium III h as also produced positive mutagenic responses in vitro (IRIS, 2000). Evidence indicated CrVI can be absorbed by animal and further pass the placental barrier to the embryo. Kirpnick

- Sobol et al. (2006) reported that exposure of pregnant mice (C57BL/6J pun /pun) to either potassium dichromate (CrVI; 62.5 or 125.0 mg/L) or chromium III chloride (1,875 or 3,750 mg/L) in drinking water during gestational days 10 to 20 resulted in significant increases in the frequencies of large

- scale DNA deletions in their pup s examined at 20 days of age. Kirpnick

- Sobol et al. (2006) reported that in comparing the embryo chromium concentrations to DNA deletion frequency revealed that CrIII exposure lead to induction of DNA deletions at an ~3

- fold lower embryo chromium concentr ation than dose exposure to CrVI.

The International Agency for Research on Cancer ( IARC ) (1990) concluded that there is sufficient evidence of respiratory carcinogenicity in humans occupationally exposed during chromate production. Human exposure to hexav alent chromium by the inhalation route has been linked to increased rates of cancer in several occupational studies. A number of retrospective studies have associated significant increases in respiratory cancer to hexavalent chromium exposure in workers en gaged in chromate production and chromate pigment production. Increased incidence of lung cancer has also been observed in workers employed in the chromium plating industries.

In human population, through oral exposure, only one study was identified in w hich cancer risk was investigated in a population exposed to hexavalent chromium in drinking water. Zhang and Li (1987) studied a population of 155 subjects outside Jinzhou, China who were exposed to drinking water at a concentration of approximately 20 mg /L. The source of the contamination was a chromium ore smelting facility located in a rural area near the city of Jinzhou in Liaoning Province in northeastern China. CrVI contamination was detected in area wells in 1965. Subjects were observed to have sore s in the mouth, diarrhea, stomachache, indigestion, vomiting, elevated white blood cell counts with respect to the controls, and higher per capita rates of cancers, including lung cancer and stomach cancer. Beaumont et al. (2008) reevaluated the available information and confirmed that there is a substantial association between stomach cancer mortality and exposure to CrVI contaminated drinking water compared with nearby uncontaminated area and with Liaoning Province. Lung cancer mortality was also increase d, but only in the comparison with Liaoning Province. Sedman et al. (2006) reviewed and summarized the findings of this study as well as additional reports by the investigators. The limitations of the study are that the precise exposure conditions, exposur e durations, and confounding factors
cannot be established

.Docket Number EPA

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Page 47 of 94 In 2007, the National Toxicology Program (NTP) released the study results for 3

- month toxicity studies in F344/N rats and B6C3F1, BALB/c, and am3

- C57BL/6 mice and the two year cancer studies of male and female F344/N rats and B6C3F1 mice exposed to sodium dichromate dihydrate (greater than 99.7% pure) in drinking water (NTP, 2007a and 2007b).

In a 90

- day subchronic study by the National Toxicology Program (2007b), sodium dichromate dihydrate (> 99.7% a.i., Lot no. 062001) was administered to 10 F344/N rats/sex/dose and 10 B6C3F1 mice/sex/dose (core study animals) via drinking water at dose levels of 0, 62.5, 125, 250, 500, or 1,000 mg sodium dichromate dihydrate/L for 3 months (14 weeks) (equival ent to approximately 0, 1.7, 3.5, 5.9, 11.2, and 20.9 mg hexavalent chromium/kg body weight per day for rats and 0, 3.1, 5.2, 9.1, 15.7, and 27.9 mg/kg per day for mice). The m ean body weight gains of the 1,000 mg/L F 344/N rats at the end of the study we re significantly lower than those of the controls for males and females (89% and 94%, respectively, of the control. Additionally, the mean body weight gain for the 500 mg/L male rats was significantly different from the control group (95% of the control). Final mean body weights and overall body weight gain of the male and female B6C3F1 mice exposed to 125 mg/L of sodium dichromate dihydrate and higher were significantly less th an those of the control animals , as well as the overall body weight gain in the 62.5 mg/L male mice. Water consumption by both male and female rats exposed to at least 250 mg/L and mice exposed to 125 mg/L or higher sodium dichromate dihydrate was generally less than that of the controls. Decreases in urine volume and increases in u rine specific gravity in the clinical pathology rats were also observed and attributed to the reduced water consumption.

Signs of microcytic hypochromic anemia were observed at all dose levels and represented by lower automated and manual hematocrit val ues, hemoglobin concentrations, and erythrocyte counts. These results were considered to be treatment

- related in both rats and mice, with lower severity in mice. Additionally, increased neutrophil lymphocyte, leukocyte, and monocyte counts, mostly observe d at the higher dose levels, were attributed to inflammatory response related to the inflammatory lesions observed during the histopathological examination (e.g., gastric lesions). For the clinical chemistry analyses, serum cholesterol and triglyceride

con centrations were decreased and considered to be related to muscle injury. Increased alanine aminotransferase and sorbitol dehydrogenase activities and bile acid concentrations may have resulted from altered hepatic function. However, the only liver lesion s reported in rats were chronic focal inflammation in females, and this lesion was also observed in the controls.

Only nonneoplastic lesions were found in the animals, with the incidences of histiocytic cellular infiltration generally significantly increa sed in the duodenum of rats and mice, the liver of female rats, and the mesenteric lymph node of mice exposed to levels about 125 mg/L. In male and female rats exposed to 1,000 mg/L of sodium dichromate dihydrate, there was increased focal ulceration, reg enerative epithelial hyperplasia, and squamous epithelia metaplasia in the glandular stomach. Incidences of epithelia hyperplasia was also significantly increased in the duodenum of all exposed groups of mice.

T he effect of sodium dichromate dihydrate w as also examined in three strains of mice: B6C3F 1 , BALB/c, and am3

- C57BL/6 mice. Am3

- C57BL/6 mice at levels of CrVI of 0, 8, 15, and 26 mg/kg/day, respectively, for B6C3F 1 mice; 0, 9, 14, and 24 mg/kg/day, respectively for BALB/cDocket Number EPA

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Page 48 of 94 mice; and 0, 8, 15, and 25 mg/kg/day, respectively for am3

- C57BL/6 mice (NTP, 2007b). All strains showed the following treatment

- related effects: decreased body weight and body weight gains; decreased water consumption; increased erythrocytic microcytosis; increased incidence of h istiocytic infiltration of the small intestines; and increased incidence of pancreatic secretory depletion. An increased incidence of glycogen depletion in the liver was observed in B6C3F 1 and am3

- C57BL/6 mice but not in the BALB/c mice and is attributed t o decreased food consumption. BALB/c and am3

- C57BL/6 mice displayed increased serum alanine aminotransferase levels. Based on these results, this study did not confirm the hepatotoxic effects (with the exception of the minor alanine aminotransferase respon se) earlier observed in BALB/c mice. Based on the findings, treatment

- related effects were observed 8 mg/kg/day CrVI for B6C3F 1 and am3

- C57BL/6 mice and 9 mg/kg/day CrVI for BALB/c mice.

In the two year rat study (NTP, 2007a), groups of 50 male and 50 fem ale rats were exposed to drinking water containing 0, 14.3, 57.3, 172, or 516 mg/L sodium dichromate dehydrate (equivalent to 0, 5, 20, 60, or 180 mg/L chromium) for 2 years (equivalent to average daily doses of 0, 0.21, 0.77, 2.10, or 5.95 mg CrVI/kg body weight for males and 0, 0.26, 0.95, 2.45 or 7 mg CrVI/kg body weight for females). The incidences of squamous cell papillomas or squamous cell carcinomas in the oral mucosa or tongue of the 516 mg/L male and female rats were significantly greater than tho se in the controls (significant trend and pair

- wise comparisons, both at p<0.01). The incidence in 172 mg/L females and the 516 mg/L males and females exceeded the historical control ranges for drinking water studies and for all routes of administration. Concentration

related non

- neoplastic liver lesions were observed in males and females exposed to 57.3 mg/L or greater. These included histiocytic cellular infiltration, chronic inflammation, fatty change (females), and clear cell focus (females). I ncreased incidences of histiocytic infiltration also occurred in the small intestine (duodenum), mesenteric lymph node, and pancreatic lymph node of males and/or females exposed to 57.3 mg/L or greater.

In this B6C3F1 mouse oncogenicity study (NTP, 2007a), group s of 50 male mice were exposed to drinking water containing 0,14.3, 28.6, 85.7, or 257.4 mg/L sodium dichromate dihydrate for 2 years (equivalent to average daily doses of approximately 0, 0.45, 0.9, 2.4, or 5.7 mg Cr(VI) /kg body weight for males). Groups of 50 female mice were exposed to drinking water containing 0, 14.3, 57.3, 172, or 516 mg/L sodium dichromate dihydrate for 2 years (equivalent to average daily doses of approximately 0, 0.3, 1.2, 3.2 or 8.8 mg CrVI/kg body weight for females). T he incidences of neoplasms of the small intestine (duodenum, jejunum, or ileum combined) were increased in exposed groups of male and female mice. The incidences of adenomas in 257.4 mg/L males and 172 and 516 mg/L females were significantly greater than thos e in the controls. The incidences of carcinomas were significantly increased in the 257.4 mg/L males and 516 mg/L females. The incidences of combined adenomas or carcinomas combined in the 85.7 and 257.4 mg/L males and 172 and 516 mg/L females were signifi cantly increased compared to that in the controls.. The incidences in the ≥85.7 mg/L males and ≥57.3 mg/L females exceeded the historical control ranges for drinking water studies and for all routes of administration. In the small intestine, the incidence s of diffuse epithelial hyperplasia were significantly increased in the duodenum of all exposed groups of male and female mice. The incidences of cellular histiocytic infiltration were significantly increased in the duodenum of 85.7 and 257.4 mg/L males an d in 172 and 516 mg/L females. In the jejunum, the incidences of diffuse epithelial hyperplasia and histiocytic cellular infiltration were significantly increased in 516 mg/L females. The incidencesDocket Number EPA

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Page 49 of 94 of histiocytic cellular infiltration of the liver in all exposed groups of females, of the mesenteric lymph node in all exposed groups of males and females, and of the pancreatic lymph node of 85.7 and 257.4 mg/L males and 172 and 516 mg/L females were significantly increased.

Data addressing human carcinogenic ity from exposures to CrIII alone are not available, and data are inadequate for an evaluation of human carcinogenic potential. Two oral studies located in the available literature (Schroeder et al., 1965; Ivankovic and Preussman, 1975) reported negative

r esults for rats and mice. Several animal studies have been performed to assess the carcinogenic potential of CrIII by inhalation. These studies have not found an increased incidence of lung tumors following exposure either by natural routes, intrapleural i njection, or intrabronchial implantation (Baetjer et al., 1959; Hueper and Payne, 1962; Levy and Venitt, 1975; Levy and Martin, 1983).

T he data from oral and inhalation exposures of animals to trivalent chromium do not support determination of the carcin ogenicity of trivalent chromium. IARC (1990) concluded that animal data are inadequate for the evaluation of the carcinogenicity of CrIII compounds. Furthermore, although there is sufficient evidence of respiratory carcinogenicity associated with exposure to chromium, the relative contributions of CrIII, CrVI, metallic chromium, or soluble versus insoluble chromium to carcinogenicity cannot be elucidated.



## Metabolism

Absorption of chromium by the oral route ranges from essentially zero for the insoluble chromium III compound chromic oxide to 10% for potassium chromate. Absorption through exposure in the diet, in water, or from contaminated soil is consistently low, with values reported in the range of 1

- 5% (ATSDR, 2000b; USEPA, 1998). Hexavalent chromium can be reduced to the trivalent form in the epithelial lining fluid of the lungs by ascorbate and glutathione as well as by gastric juice in the stomach, which contributes to the low oral absorption. Absorption by the der mal route is also low (1.3% after 24 hours as reported by Bagdon et al., 1991)

Once absorbed, chromium compounds are distributed to all organs of the body without any preferential distribution to any one organ. However, exposures to higher levels of chro mium, such as can occur in the chrome plating industry and chrome refining plants, may result in accumulation of chromium in tissues. Witmer et al. (1989, 1991) studied chromium distribution in tissues of rats administered chromium via gavage. In one expe riment, the highest dose of sodium chromate [5.8 mg CrVI/kg/day for 7 days] resulted in concentrations of chromium in the tissues in the following order: liver (22 μg chromium/whole organ) > kidney (7.5 μg) > lung (4.5 μg) > blood (2 μg) > spleen (1 μg). These tissues combined retained about 1.7% of the administered dose; however, some tissues were not analyzed. At the two lower doses administered (1.2 or 2.3 mg/kg/day), very little chromium was detected (<0.5 μg/organ) in the organs analyzed.

Maruyama ( 1982) studied the chromium content in major organs of mice exposed to CrVI or CrIII for 1 year in drinking water. Groups of mice received 4.4, 5.0 or 14.2 mg CrVI/kg/day or 4.8, 6.1 or 12.3 mg CrIII/kg/day. Examination of organs and blood in mice that re ceived CrVI revealed that the liver and spleen had the highest levels of chromium, although some chromiumDocket Number EPA

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Page 50 of 94 accumulation was observed in all tissues. In mice that received CrIII, the liver was the only organ with detectable amounts of chromium, and at level s that were about 40

- 90 times less than in mice that received the CrVI compound. MacKenzie et al. (1958) reported that in rats following the administration of similar concentrations of CrVI as potassium chromate or CrIII as chromium trichloride in drinkin g water for 1 year, tissue levels were approximately 9 times greater in rats that received the CrVI compound, compared to rats that received the CrIII compound.

If hexavalent chromium is absorbed, it can readily enter red blood cells through facilitated d iffusion, where it will be reduced to the trivalent form by glutathione. During reduction to the trivalent form, chromium may interact with cellular macromolecules, including DNA (Wiegand et al., 1985), or may be slowly released from the cell (Bishop and S urgenor, 1964). Chromium III can be cleared rapidly from the blood but more slowly from tissues, which may be related to the formation of trivalent chromium complexes with proteins or amino acids (Bryson and Goodall, 1983).

The liver is a primary site o f chromium metabolism and has been studied in animals. Incubation of CrVI with rat liver microsomes in the presence of the enzyme cofactor nicotinamide adenine dinucleotide phosphate (NADPH) resulted in the reduction of CrVI to CrIII (ATSDR, 2000b). Exclu sion of the co

- factors necessary for the production of NADPH resulted in a large decrease in the reduction of CrVI to CrIII.

Chromium metabolism can result in the formation of species that interact with deoxyribonucleic acid (DNA). The reduction of CrV I to a CrV intermediate involves a single electron transfer from the microsomal electron

- transport cytochrome P

- 450 system (Jennette 1982). These reactive CrV complexes/ intermediates are relatively unstable and persist for approximately 1 hour in vitro

. During this time the CrV complexes/ intermediates can interact with deoxyribonucleic acid (DNA), which may eventually lead to cancer. When CrVI interacts with glutathione, CrV complexes and glutathione thionyl radicals were produced, and when CrVI intera cts with DNA and glutathione, DNA adducts were formed (Aiyar et al. 1989). The formation of CrV was found to correlate with DNA adduct formation. Following reactions of CrVI with hydrogen peroxide, hydroxyl radicals were produced; the addition of DNA res ulted in the formation of an 8

- hydroxy guanine adduct and DNA strand breakage.

The elimination of chromium after oral exposure has been studied in both humans and animals. In one study, human volunteers received an acute oral dose of radiolabeled CrIII o r CrVI (Donaldson and Barreras 1966). Fecal samples were collected for 24 hours, and urine samples were collected for 6 days and analyzed for chromium. Approximately 99.6% of the CrIII compound was recovered in the 6

- day fecal sample, while 89.4% of the CrVI compound was recovered. The results of the analysis of the 24

- hour urine samples indicated that 0.5% and 2.1% of the administered dose of the CrIII and the CrVI compounds, respectively, were recovered in the urine. Other potential routes of excretio n include hair, fingernails and breast milk (ATSDR 2000b).

In several studies in which rats and hamsters were fed CrVI compounds, fecal excretion of chromium varied slightly from 97% to 99% of the administered dose, and urinary excretion ofDocket Number EPA

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Page 51 of 94 chromium, admi nistered as CrIII or CrVI compounds, varied from 0.6% to 1.4% of the dose (Donaldson and Barreras 1966, Henderson et al. 1979, Sayato et al. 1980). Following the gavage administration of 13.92 mg chromium/kg/day as calcium chromate for 8 days, the total u rinary and fecal excretion of chromium on days 1 and 2 of dosing were <0.5% and 1.8%, respectively (Witmer et al. 1991). The total urinary and fecal excretion of chromium on days 7 and 8 of dosing were 0.21% and 12.35%, respectively. Donaldson et al. (19 84), reported that excretion of CrIII and creatinine clearance were almost equal suggesting that tubular absorption or reabsorption of chromium in the kidneys was minimal.Docket Number EPA

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Page 52 of 94 Toxicology References for Appendix A
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# Appendix B Environmental Fate

Environmental Fate and Transport Properties of Chromated Arsenicals

The Agency does not anticipate the need to require environmental fate studies for registration review.

C hromium and arsenic as oxides are the active ingredients of the water

- borne wood preservative of chromated arsenicals that are addressed in this document . There are a number of commercially available wood preservati ves which contain these metals. Chromat ed arsenicals

are primarily used as a pressure treatment wood preservative for utility poles. The major exposure from the use of this wood preservative are in three environmental compartments: soil /sediments, surface and ground water

, and bioaccumulation in the aquatic and benthic organisms. Additional information on the environmental fate of chromated arsenicals may be seen in the 2008 RED.

The leaching of these metals (chromium and arsenic) into water from chromated arsenicals has been widely investig ated, and both the laboratory and field studies generally indicate that leaching of the metals is a function of pH, salinity (fresh water, sea water, estuaries, natural and synthetic, sterile buffered water), temperature, moisture content of the treated wo od, wood type, and wood texture. Results from a number of studies indicate that most of the leaching takes place in the first f ew days after the application. Most of these studies have shown that both the total leaching and rate of leaching is highe r for a rsenic than chromium . Available studies were conducted under different conditions and the exact concentrations of chromated arsenical solution absorbed by wood (e.g. utility poles) are not known. Sorption constants of these metals are high in soil. Leachin g of the metals into soils also depends on the pH of the soil, type and texture of the soils, organic content of the soils; however, studies on sorption into soils from utility poles have shown that the release of metals into soils/sediments from the base of treated wood, decks or utility poles or from the pressure treatment facilities, do not show a high degree of downward or ground level migration. Arsenic and chromium leach most quickly when placed in the environment, but the leaching rate declines withi n 30 days (Chen and Walters, 1979; Stanley, 1994), and reaches background concentrations in soil within a few meters (Degroot, 1979) and generally within 10 meters in water (Weis, 1992; Cooper, 1991).

Published studies on the effects of chromated arsen ical

- treated wood on aquatic organisms indicate that the metals released from the treated wood are localized within sediments, typically within 10 meters of the treated wood. Chromated arsenical metals are released at higher concentrations from new wood t han from old wood, and benthic levels are higher in poorly flushed tidal areas close to the treated wood. Leachates from pilings in well flushed tidal areas do not appear to have adverse effects on the benthic community (Weis et al., 1991; 1995, 1996, 2002 , 2004; Brown et al. 2001). Water

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Page 62 of 94 would likely be much lower than the values obtained in leaching studies conducted in small laboratory vessels due to dispersion in the water body by tidal flow and wave action, and the degree of partitioning into biota and sediment.

Bioaccumulation studies indicate that both chromium and arsenic can bioconcentrate in various aquatic and benthic organisms , but this bioconcentration can be limited by the fixation process in the wood structure an d sorption to soil and sediment

. The bioconcentration factors for chromium were 70

- 440X and for arsenic were 333X (fish and invertebrates) (EPA, 1979)

. In general, these metal ions exist in water and soil as:

(1) A free metal ion, which in aqueous medi um is aquated (solvated or complexed with water molecules); (2) Simple inorganic species like oxides, hydroxides, halides, carbonates etc.; or (3) Complexed with organic and inorganic ligands.

Risk quotients (RQs) were not calculated at the time of the RE D because of the high degree of variability in available data and the inability to predict metals speciation and bioavailability in aquatic environments. The bioavailability of arsenic and chromium is considered to be relatively constant regardless of chr omated arsenical wood contribution due to steady background environmental levels. Some research indicates that making sure that wood is properly conditioned (complete the fixation reaction) prior to installation in water and collection of sawdust during co nstruction/maintenance would help reduce the impact of chromated arsenical metals in the environment (Lebow et al., 2000, Lebow, 2004).

Chromium

Divalent chromium ( Cr II ) is unstable in water, and trivalent chromium goes through hydrolysis and forms variou s species. The important species of trivalent chromium found in aqueous systems are: CrOH 2+ , Cr(OH) 2 + , Cr(OH) 4 1

- and ,Cr(OH) 3 (s). In addition, polymeric species like: Cr 2 (OH) 2 and Cr 3 (OH) 4 5+ are also formed in water. All these species are present in aqueou s systems in the absence of any complexing agents. Similarly, hexavalent chromium also hydrolyzes in water and forms CrO 4 2

- (at pH > 6.5), and HCrO 4 1

- and Cr 2 O 7 2

- in acidic medium.

In fresh water at pH 6, species detected are: HCrO 4 1

- , Cr(OH) 2 1+ , Cr(OH) 2 1+ , CrO 4 2

- , trivalent chromium and Cr(OH) 3 (s). On the other hand, the species detected in sea water at pH 8 are: CrO4 2

- , Cr(OH) 2+ , Cr(OH) 3 , NaCrO 4 1

- , Cr(OH) 2+ , Cr(OH) 4 1

- , KCrO 4 1

- , and HCrO 4 1

-

. Trivalent chromium is kinetically stable and hexavalent chromi um is thermodynamically stable in aqueous medium. Hexavalent chromium is more water

- soluble and more mobile and can easily move through wet soils into ground water and may become more bioavailable (Lebow, S. 1996). The half

- life of trivalent chromium in wa ter has been estimated to be 1

- 20 months which demonstrates persistence of this form of the metal (Pettine, M. and F.J. Millero, 1990).

Chromium goes through oxidation

- reduction reactions when sorbed in soils. Organic matter in soils, which has a high sorption capacity for chromium, reduces hexavalent chromium to trivalent chromium spontaneously. Manganese oxides in the soils, on the other hand, oxidizeDocket Number EPA

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Page 63 of 94 trivalent chromium to hexavalent chromium . Chromate and dichromate ions form soluble salts and increase the mobility of toxic hexavalent chromium in soils. Chromium as hexavalent chromium reduces to trivalent chromium under anoxic conditions. In water at neutral conditions (pH 7), formation of dichromate ions (chromium as hexavalent chromium is minimized). Hexavalent chromium is adsorbed less and less by hydrous metal oxides and soils as the alkalinity of the medium increases. The presence of anions like sulfate and phosphate decrease the sorption phenomenon. At low pH and low concentrations of chromium, ho wever, adsorption of trivalent chromium on iron and manganese oxides increases.

Arsenic

The common and important arsenic ores are: tenantite ( Cu 6 [Cu 4 (Fe,Zn) 2 ]As 4 S 13 ) , cobaltite (CoAsS), arsenopyrite (FeAsS) , niccolite ( NiAs) , and enargite (Cu 3 AsS 4 ) . Arsenic has a strong tendency to sorb to soils and sediments. The sorption capacity of arsenic varies with soil texture, with values of 1

- 252 μg total As/g soil in silty fine sand with low clay, 1

- 80 μg total As/g soil (brown clay sand), and 1.1

- 7.9 μg t otal As/g soil for fine sand. Arsenic sorption is dependent on pH, redox conditions, competing anions, salinity, clay content and hydrous oxide content (aluminum or iron). Arsenic mobility in clay soils is low to moderate. Pentavalent arsenic ( As V) under proper conditions can reduce to trivalent arsenic ( As III) . In aerobic and anaerobic sediments, arsenate is more strongly sorbed than methylarsenic acid (Holm, R.T. 1979; Wauchope, R.D. 1975).

The sorption potential of arsenic decreases with rising pH, t he mobility of arsenic increases. Organoarsenates decrease the sorption of arsenic and increase the arsenic mobility. Organoarsenates are more mobile than arsenic. Arsenic mobility in clay soils is low to moderate. However, in loamy and sandy soils, mobility increases (6

- 10 cm/day for loamy sand). Between pH values of 2 and 11, the common species of arsenic present in aqueous medium are H 2 AsO 4 and HAsO 4 2

- . At pH 12 and above, it is predominantly HAsO 3 2

- and AsO 3 - 3

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Page 64 of 94 Environmental Fate References for Appendix B

Chen Abraham Shou

- chien and C.S. Walters, 1979. The Fate of Arsenic in Pressure

- Treated Southern Pine Plywood Subjected to Heavy Artificial Rainfall. American Wood Preservers’ Association: 188

- 232.

Cooper, P.A. 1991 Leaching of CCA from Treated Wood: pH Effects. Forest Products Journal. 41(1): 30

- 32

DeGroot, R.C., Popham, T.W., Gjovik, L.R., and Forehand, T. 1979. Distribution Gradients of Arsenic, Copper, and Chromium Around Preservative

- Treated Wooden Stakes. Journal of Environmental Q uality. 8(1): 39

- 41.

EPA 1979. Water

- Related Environmental Fate of 129 Priority Pollutants, EPA

- 440/4

- 79

- 029a. Stanley, J.S. 1994. Task III

- CCA

- C: Chromated Arsenical Treated Wood Aqueous Leaching Study. Midwest Research Institute. May 27, 1994. MRID 432 492

- 01. Unpublished.

Holm, T.R. 1979. Chemical Modeling in Aqueous systems, E.A. Jenne, Editor, American C hemical Society Symposium Series 93, Washington, DC, pp 711.
Lebow, S. 1996. USDA Forest Product Lab, General Technical Report., FLP

- GTR

- 93.
Pettine, M. and F.J. Millero. 1990. Limnology Oceanography, volume 35(3), pp 730

- 736.
Stanley, J.S. 1994. Task III

- CCA

- C: Chromated Arsenical Treated Wood Aqueous Leaching Study. Midwest Research Institute. May 27, 1994. MRID 432492

- 01. Unpublished.

Wauc hope, R.D. 1975. J. Environ. Qual. Volume 4, pp 499.

Weis, J.S., and Weis, P. 1992. Transfer of Contaminants From CCA

- Treated Lumber to Aquatic Biota. Journal of Experimental Marine Biology and Ecology. 161:189

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Page 65 of 94 

# Appendix C Ecotoxicology Profile

Toxicity to Terrestrial Receptors

The Agency anticipates the need to require an ecotoxicology study on beneficial insects for registration review.

Birds

- n o additional toxicity data are anticipated to be needed.

Arsenic acid

An acute oral toxicity study using the technical grade of the active ingredient (TGAI) was required to establish the toxicity of arsenic acid to birds. The preferred test species were either mallard duck (a waterfowl) or bobwhite quail (an upland game bir d). The results of two studies are presented in the following table.

Table C1 . Acute Oral Toxicity of Arsenic Acid to Birds

Substance/ % Active Ingredient (AI) Organism Endpoints/Results ( mg/kg) Comments Reference

arsenic acid/ 75% Northern bobwhite ( Colinus virginianus ) LD50 = 28.9

- core study

- organism age: 27 wks

- 21 day test duration Fletcher, 1987 (40409013)

arsenic acid/ 76.1% Northern bobwhite ( Colinus virginianus ) LD50 = 46

NOEL = 12.5 - core study

- organism age: 18 wks

- 14 day test duration

- NOEL effect: weight loss Campbell et al., 1990

(41719201)

These results indicate that arsenic acid is highly toxic to avian species on an acute oral basis.

Two subacute dietary studies using the TGAI were required to establish the toxicity of arsenic acid to birds. The preferred test species were mallard duck (a waterfowl) and bobwhite quail (an upland gamebird). The results of three avian subacute dietary tests are tabulated below.

Table C2 . Subacute Dietary Toxicity of Arsenic Acid to BirdsDocket Number EPA

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Page 66 of 94 Substance/ % Active Ingredient (AI) Organism E ndpoints/Results (mg/kg) Comments Reference

arsenic acid/ 75% Northern bobwhite ( Colinus virginianus ) LC50 = 168.5

- core study

- 8 day test duration EPA 2002a(001216 18)

arsenic acid/ 76% Northern bobwhite ( Colinus virginianus ) LC50 = 432

NOEL = 15.6 - core study

- organism age: 10d

- 8 day test duration

- NOEL effect: pharmacotoxic signs Long et al, 1990

(41719202)

arsenic acid/ 75% Fulvous whistling duck ( Dendrocygna bicolor ) LC50 = 1145

NOEC < 156 - core study

- organism age: 9 days

- 8 day test duration

- NOEL effect: reduced weight gain Fletcher, 1987

(40409012)

These results indicate that arsenic acid is slightly to highly toxic to avian species on a subacute dietary basis.

Chromic acid

An acute oral toxicity study using the TGAI was required to establish the toxicity of a chromic acid to birds. The preferred test species were either mallard duck (a waterfowl) or bobwhite quail (an upland gamebird). The results of two studies are presented in the following table.

Table C3 . Acute Oral Toxicity of Chromic Acid to Birds

Substance/ % Active Ingredient (AI) Organism Endpoints/Results (mg/kg) Comments Reference

chromic acid/ 57% Northern bobwhite ( Colinus virginianus ) LD50 = 93.5

- core study Hoxter., 1990

(41621104)

chromic acid/ 57% Northern bobwhite ( Colinus virginianus ) LC50 = 164

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Page 67 of 94 NOEL > 62

- organism age: 38wks

- 14 day test duration

- NOEL effect: weight loss

These results indicate that chromic acid is moderately toxic to avian species on an acute oral basis.

Two subacute dietary studies using the TGAI were required to establish the toxicity of chromic acid to birds. The preferred test species were mallard d uck (a waterfowl) and bobwhite quail (an upland gamebird). The results of avian subacute dietary tests are tabulated below.

Table C 4. Subacute Dietary Toxicity of Chromic Acid to Birds

Substance/ % Active Ingredient (AI) Organism Endpoints/Results (mg/kg) Comments Reference

chromic acid/ 57% Mallard duck (Anas platyrhynchus) LC50 > 5100

- core study

- organism age: 10d

- 8 day test duration Hoxter, 1990(41621102)

chromic acid/ 57% Northern bobwhite ( Colinus virginianus ) LC50 > 5100

- core study

- organism age: 10d

- 8 day test duration Hoxter,1990

(41621101)

These results indicate that chromic acid is practically non

- toxic to avian species on a subacute dietary basis.

Birds, Chronic

Avian reproduction studies using the TGAI were conditionally required for wood preservatives. A study found in the open literature (Sample et al.,1996) identified a chronic avian NOAEL of 5.1 mg/kg

- day for sodium arsenite (As 3+). This value was based on the results of a chronic dietary study that ev aluated the effects of sodium arsenite (As 3+) to mallard ducks over a 128

- day study period. Sample et al. (1996) also identified a chromium avian NOAEL of 1 mg/kg

day. This value was based on the results of a chronic dietary study that evaluated the eff ects of chromium (as CrIII) to black ducks during a ten month study duration.

Mammals

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Page 68 of 94 Wild mammal testing is required on a case

- by

- case basis, depending on the results of lower tier laboratory mammalian studies, intended use pattern and pertinent environmental fate characteristics. In most cases, toxicity values for laboratory animals (e.g., rat, mouse) obtained from the Agency's Health Effects Division (HED) substi tute for wild mammal testing

.
Arsenic acid

No studies on the acute effects of arsenic acid to wild mammals were found in the primary or secondary data sources considered for this assessment; therefore, laboratory mammal acute toxicity endpoints are used. Acute toxicity values ident ified for arsenic acid in Chen et al. (2001) are summarized in the table below.

Table C 5. Mammalian Acute Toxicity of Arsenic Acid

Substance/ % Active Ingredient (AI) Organism Endpoints/Results (mg/kg) Comments Reference

Arsenic acid/ 75% Laboratory mouse ( Mus musculus ) LD50 = 150 LD50 is the mean value for male (141mg/kg) and female mice (160mg/kg) #40409001 as cited in Chen et al,. 2001

Arsenic acid/ 75% Laboratory rat

(Rattus norvegicus) LD50 = 52 LD50 is the mean value for male (76mg/kg) and female rats (37mg/kg) # 26356 as cited in Chen et al,. 2001

These results indicate that arsenic acid is moderately to highly toxic to mammalian species on an acute oral basis.

Chromic acid

No studies on the acute effects of chromic acid to wild mammals were found in the primary or secondary data sources considered for this assessment; therefore, laboratory mammal acute toxicity endpoints are used. The results of one acute toxicity study iden tified in McMahon and Chen (2001) for chromic acid is provided in the table below.

Table C 6. Mammalian Acute Toxicity of Chromic Acid

Substance/ % Active Ingredient (AI) Organism Endpoints/Results (mg/kg) Comments Reference

Chromic acid/ 100% Laboratory rat (Rattus norvegicus) LD50 = 52 LD50 is the mean value for male (56 mg/kg) and female mice (48mg/kg) MRID# 434294

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Page 69 of 94 McMahon and Chen, 2001

This study indicates that chromic acid is highly toxic to mammalian species on an acute oral basis.

Mammals, Chronic

Chronic hazard to wild mammals from chromated arsenicals is of concern due to the potential for repeated or continuous mammalian expos ure to chromated arsenical components from either direct contact with treated structures or exposure to residues in soil and/or water from treated
structures.

Arsenic acid

The Health Effects Division’s Hazard Identification Assessment Review Committee’s (H IARC) report on arsenic (McMahon and Chen, 2001) included several toxicity endpoints for mammalian species. These endpoints have been provided in the following table.

Table C 7. Mammalian Chronic Toxicity of Arsenic Acid

Substance/ % Active Ingredient (AI) Organism Endpoints/Results (mg/kg/day) Comments Reference

arsenic acid/ 75% Laboratory mouse

( Mus musculus ) LOAEL = 64

NOAEL = 32 - gavage administration to pregnant females during day 6

- 15 of gestation

- effects were reduced body weight, increased mortality and increased total litter resorption Nemac 1968b, cited in McMahon and Chen, 2001

arsenic acid/ 75% New Zealand White Rabbit LOAEL = 4

NOAEL = 1 - gavage administration to pregnant females during day 6

- 18 of gestation

- effects were reduced body weight, increased mortality and histological effect to the liver/kidneys Nemac 1988a, cited in McMahon and Chen, 2001

arsenic V/ AI not available Dog

– Beagle LOAEL = 2.4

NOAEL = 1 - study duration

– 2 yrs

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Page 70 of 94 These studies indicate that arsenic acid is moderately toxic to mammalian species on a chronic basis.

Chromic acid

The Health Effects Division’s Hazard Identification Assessment Review Committee’s (HIARC) review of chromium (McMahon and Chen, 2001) included several toxicity endpoints for mammalian species. These endpoints have been provided in the following table.

T able C 8. Mammalian Chronic Toxicity of Chromic Acid

Substance/ % Active Ingredient (AI) Organism Endpoints/Results (mg/kg/day) Comments Reference

Chromic acid/ 55% Laboratory rabbit LOAEL = 0.48

NOAEL = 0.12 - effects included reduced body weight, increased mortality Tyl, 1991, cited in McMahon and Chen, 2001

Potassium dichromate/ AI not available Swiss albino mice LOAEL = 42.1

NOAEL = 22.3 - effects were reduced maternal body weight, retarded fetal development and increased fetal resorption * Junaid et al., 1996, cited in McMahon and Chen, 2001

* The endpoints were based on maternal effects, the fetal effects were seen at every dose tested so a developmental NOAEL could not be determined.

These studies indicate that chromic acid is moderately to highly toxic to mammalian species on a chronic basis.

Beneficial Insects

– the Agency anticipates the need to require additional toxicity data.

A honey bee acute contact study using the TGAI is requi red for the active components of chromated arsenicals because its use as a wood preservative may result in honey bee exposure. Results of this test for arsenic acid are tabulated below.

Table C 9. Nontarget Insect Acute Contact Toxicity of Arsenic Acid

Substance/ % Active Ingredient (AI) Organism Endpoints/Results (ug/bee) Comments Reference

arsenic acid/ 75.1% Honey bee

(Apis mellifera ) LD50 = 7.7

- core study Hoxter, 1987

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Page 71 of 94 The results indicate that arsenic acid is highly toxic to bees on an acute contact basis.

There were no honey bee studies identified for chromic acid in the pesticide database; the guideline requirement (141

- 1/OPPTS 850.3020) is not fulfilled for chromic acid and is anticipated to be required

.
Terrestrial Plants

- n o additional toxicity data are anticipated to be needed.

Terrestrial plant tests, including seedling emergence (123

- 1/OPPTS 850.4225) and vegetative vigor testing (123

- 1/OPPTS 850.4250), are c onditionally required for wood preservatives in cases where the treated wood will be used in the aquatic environment (e.g., bulkheads, piers, pilings). Several studies in the open literature have evaluated the effects of chromated arsenical components to various terrestrial plant species. The results of these studies are summarized below.

Arsenic acid

Arsenic is taken up actively by plant roots, with arsenate being more easily absorbed than arsenite. Because arsenic is chemically similar to phosphorus , it is translocated in the plant in a similar manner and is able to replace phosphorus in many cell reactions. Mechanisms of arsenic (V) toxicity to terrestrial plants include interrupted phosphorylation and adverse effects to enzyme systems (Efroymson e t al. 1997).

In review of the literature, one study evaluated the toxicity of arsenic (V) to corn grown from seed for 4 weeks in a loamy sand with a pH of 7.1. Results of the study indicated that corn fresh weight reductions rose from less than 10% with the addition of 10 ppm arsenic to more than 65% with the addition of 100 ppm arsenic (Efroymson et al. 1997). Another study assessed the toxicity of arsenic (III) and arsenic (V) added to soil on the yield of ryegrass and barley grown from seed for 1 year in a greenhouse. According to the study, there was a significant reduction in the yield of ryegrass (63%) following the addition of 250 ppm arsenic (V) to the soil (Efroymson et al., 1997). It should be noted that rice and legumes appear to be more sensi tive to arsenic than other plants. Symptoms include wilting of new

- cycle leaves, followed by retardation of root and top growth, and leaf necrosis.

Chromium

Chromium VI is more soluble and available to plants than chromium III and is therefore

con sidered to be the more toxic form. Chromium that is taken up by plants generally remains in the roots because of the many binding sites in the cell wall capable of binding chromium ions. Symptoms of chromium toxicity in plants include stunted growth, poor ly developed roots and leaf curling. Chromium may interfere with carbon (C), nitrogen (N), phosphorus (P) and iron (Fe) metabolism and enzyme reactions (Efroymson et al., 1997).

One study investigated the effect of chromium VI on soybean seedlings grown three days in a loam soil. The study found that fresh shoot weight was reduced 30% following the addition ofDocket Number EPA

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Page 72 of 94 30ppm chromium, while 10 ppm chromium had no observed effect. Another study calculated EC50 concentrati ons for effects of chromium VI on lettuce , tomato and oats grown in a growth chamber from seed for 14 days. Test plants grown in a loam soil had EC50 values ranging from 1.8 ppm (in lettuce) to 7.4 ppm (in oats). Test plants grown in a humic sand soil appeared to be relatively less sensitive to chromium VI exposure with EC50 values ranging from > 11 ppm (in lettuce) to 31 ppm (in oats), respectively (Efroymson et al.,1997). 

## Toxicity to Aquatic Receptors

Freshwater Fish

- n o additional toxicity data are anticipated to be needed.

Arsenic acid

Two freshwater fish toxicity studies using the TGAI were required to establish the toxicity of arsenic acid to fish. The preferred test species were rainbow trout (a coldwater fish) and bluegill sunfish (a warm water fish). Several acute toxicity studies were identified for each compound of interest in the pesticide database. The results of these tests are summarized below.

Table C 10. Freshwater Fish Acute Toxicity of Arsenic Acid

Substance/ % Active Ingredient (AI) Organism Endpoints/Results (mg/L) Comments Reference

arsenic acid/ 76.1% Rainbow trout

(Oncorhynchus mykiss) LC50 = 72

NOEL = 3.4 - core study

- static system

- 96

- hr test duration LeLievre, 1990

(41620003)

arsenic acid/ 75% Rainbow trout

(Oncorhynchus mykiss) LC50 = 53

- supplemental study

- static system

- 96

- hr test duration

- test organism weight 0.57g EPA 2002 a (MRID # not reported)

arsenic acid/ 75.8% Bluegill sunfish

(Lepomis macrochirus) LC50 = 50

NOEL = 10 - core study

- flow

- through system

- 96

- hr test duration

- test organism weight 1.1g Machado, 1991

(41950601)

arsenic acid/ 75% Bluegill sunfish LC50 = 54

- supplemental study Suprenant, 1987Docket Number EPA

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- static system

- 96

- hr test duration

- test organism weight 1.8g (40409014)

These results indicate that arsenic acid is slightly toxic to freshwater fish on an acute basis.

Chromic acid

Two freshwater fish toxicity studies using the TGAI were required to establish the toxicity of chromic acid to fish. The preferred test species were rainbow trout (a coldwater fish) and bluegill sunfish (a warmwater fish). The results of t wo acute toxicity studies are summarized below.

Table C 11. Freshwater Fish Acute Toxicity of Chromic Acid

Substance/ % Active Ingredient (AI) Organism Endpoints/Results (mg/L) Comments Reference

Chromic acid/ 57% Rainbow trout

(Oncorhynchus mykiss) LC50 = 28

NOEL = 8.6 - core study

- static system

- 96

- hr test duration

- test organism weight

– 0.5g LeLievre, 1990

(41621105)

Chromic acid/ 57% Bluegill sunfish

(Lepomis macrochirus) LC50 = 44

NOEL = 13 - core study

- static system

- 96

- hr test duration

- test organism weight

– 0.5g LeLievre, 1990

(41658401)

These results indicate that chromic acid is slightly to moderately toxic to freshwater fish on an acute basis.

Freshwater Fish, Chronic

Fish early life stage tests are required if the product is applied directly to water or expected to be transported to water from the intended use site. The preferred test species is fathead minnow ( Pimephales promelas ), but other species may be used. Fish early life

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Page 74 of 94 due to the likelihood of continuous exposure from chromated arsenical

- treated structures in aquatic habitats. Freshwater and marine/estuarine fish are comparably sensitive to arsenic acid and chromic acid on an acute basis, so early life

- stage testing on either type of fish is sufficient to satisfy guideline requir ements. Early life

- stag e testing was submitted to the A gency for arsenic acid and chromic acid using freshwater species; that data is summarized below.

Arsenic acid

Table C 12. Freshwater Fish Early Life Stage Toxicity of Arsenic Acid

Substance/ % Active Ingredient (AI) Organism Endpoints/Results (mg/L) Comments Reference

Arsenic acid/ 76.1% Fathead minnow

(Pimphales promelas) LOAEC = 1.9

NOAEC = 0.97 - core study

- flow

- through system

- 35 day test duration

- endpoint is larval survival Machado, 1991

(41802201)

The results of this study indicate that arsenic acid affects fish larval survival at levels greater than 0.97 ppm.

Chromic acid

Table C 13. Freshwater Fish Early Life Stage Toxicity of Chromic Acid

Substance/ % Active Ingredient (AI) Organism Endpoints/Results (mg/L) Comments Reference

chromic acid/ 57% Fathead minnow

(Pimphales promelas) LOAEC = 8.2

NOAEC = 4.0 - core study

- flow

- through system

- 35 day test duration

- endpoint is larval growth Machado, 1991

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Page 75 of 94 This result indicates that chromic acid causes larval growth effects at levels above 4.0 ppm.

Freshwater Invertebrates

- n o additional toxicity data are anticipated to be needed.

A freshwater aquatic invertebrate toxicity test using the TGAI was required to establish the toxicity of the components of chromated arsenicals to aquatic invertebrates. The preferred test species was Daphnia magna . Results of this test for arsenic acid and chromic acid are provided in the tables below.

Table C 14. Acute Toxicity of Arsenic Acid to Freshwater Invertebrates

Substance/ % Active Ingredient (AI) Organism Endpoints/Results

(mg/L) Comments Reference

arsenic acid/ 76.1% Water flea (Daphnia magna) EC50 = 15

NOEL = 2.6 - core study

- static system

- 48

- hour test duration

- endpoint is immobilization LeLievre, 1990

(41620001)

This study indicates that arsenic acid is slightly toxic to aquatic invertebrates on an acute basis.

Table C 15. Acute Toxicity of Chromic Acid to Freshwater Invertebrates

Substance/ % Active Ingredient (AI) Organism Endpoints/Results

(mg/L ) Comments Reference

chromic acid/ 57% Water flea

(Daphnia magna) EC50 = 0.76

NOEL < 0.35 - core study

- static system

- 48

- hour test duration

- endpoint is immobilization LeLievre, 1990

(41621103)

This study indicates that chromic acid is highly toxic to aquatic invertebrates on an acute basis.

Freshwater Invertebrate, Chronic

A freshwater invertebrate life

- cycle test using the TGAI is required for a pesticide when it is used in the aquatic enviro nment. The preferred test species is Daphnia magna

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Page 76 of 94 Aquatic invertebrate life

- cycle testing was required for the components of chromated arsenicals since chromated arsenical

- treated lumber will be used to construct structures in aquatic environments (e. g., pier, piling, or dock uses). The results of these tests for arsenic acid and chromic acid are provided below.

Table C 16. Freshwater Aquatic Invertebrate Life

- Cycle Toxicity of Arsenic Acid

Substance/ % Active Ingredient (AI) Organism Endpoints/Results

(ug/L ) Comments Reference

arsenic acid/ 76.1% Water flea (Daphnia magna) LOEC = 38

NOAEC = 20 - supplemental study

- flow

- through system

- 21day test duration

- NOAEC effect

- growth McNamara, 1991

(42001601)

These results indicate that arsenic acid impacts the growth of aquatic invertebrates at levels greater than 20 ppb.

Table C 17. Freshwater Aquatic Invertebrate Life

- Cycle Toxicity of Chromic Acid

Substance/ % Active Ingredient (AI) Organism Endpoints/Results

(ug/L ) Comments Reference

Chromic acid/ 57% Water flea (Daphnia magna) LOEC < 8.6

NOAEC < 2.6 - core study

- flow

- through system

- 21day test duration

- NOAEC effect

- reproduction McNamara, 1991

(41881501)

These results indicate that chromic acid impacts the reproduction of aquatic invertebrates at levels greater than 2.6 ppb.Docket Number EPA

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Page 77 of 94 Estuarine/Marine Fish

- n o additional toxicity data are anticipated to be needed.

Estuarine/Marine Fish, Acute

Acut e toxicity testing with estuarine/marine fish using the TGAI is required for a pesticide when the end

- use product is intended for direct application to the marine/estuarine environment or the active ingredient is expected to reach this environment because of its use in coastal counties. The preferred test species is sheepshead minnow. Marine/estuarine acute testing was required for the components of chromated arsenicals due to its use as a wood preservative for lumber used to construct docks, piers and pi lings. Results of these tests are tabulated below for arsenic acid and chromic acid.

Table C 18. Acute Toxicity of Arsenic Acid to Estuarine/Marine Fish

Substance/ % Active Ingredient (AI) Organism Endpoints/Results

(mg/L ) Comments Reference

arsenic acid/ 76.1% Sheepshead minnow

(Cyprinodon variegatus) LC50 = 28

NOEL = 13 - core study

- static system

- 96 hour test duration 41620004

LeLievre, 1990

This study indicates that arsenic acid is moderately toxic to estuarine/marine fish on an acute basis. The guideline requirement (72

- 3a) is fulfilled (MRID #41620004).

Table C 19. Acute Toxicity of Chromic Acid to Estuarine/Marine Fish

Substance/ % Active Ingredient (AI) Organism Endpoints/Results

(mg/L) Comments Reference

chromic acid/ 57% Sheepshead minnow

(Cyprinodon variegatus) LC50 = 39

NOEL = 20 - core study

- static system

- 96 hour test duration 41703601

LeLievre/1990

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Page 78 of 94 Estuarine and Marine Fish, Chronic

Fish early life

- stage testing using the TGAI is required for wood preservatives if the product will be used to treat wood used in an aquatic habitat, such as piers, pilings, and docks. Early life

stage toxicity data are required on the more sensitive type of fish, freshwater or estuarine/marine. Based on review of the acute toxicity data, freshwater and marine/estuari ne fish appear to be comparably sensitive to arsenic acid and chromic acid. Since acceptable fish early life

- stage data were available for the freshwater species fathead minnow, fish early life

- stage testing with a marine/estuarine fish is not anticipated to be required for either arsenic acid or chromic acid.

Estuarine/Marine Invertebrates

- n o additional toxicity data are anticipated to be needed.

Estuarine/Marine Invertebrates, Acute

Acute toxicity testing with estuarine/marine invertebrates using the T GAI is required for a pesticide when the end

- use product is intended for direct application to the marine/estuarine environment or the active ingredient is expected to reach this environment because of its use in coastal counties. The preferred test specie s are mysid shrimp and eastern oyster. Estuarine/marine invertebrate testing was required for the components of chromated arsenicals due to its use as a wood preservative for lumber used to construct docks, piers and pilings in coastal waters. The results of th i s test are provided below.

Table C 20. Acute Toxicity of Arsenic Acid to Estuarine/Marine Invertebrates*

Substance/ % Active Ingredient (AI) Organism Endpoints/Results

(mg/L ) Comments Reference

arsenic acid/ 76.1% Mysid

( Mysidopsis bahia ) LC50 = 2 NOEL < 0.32 - core study

- static system

- 96 hour test duration 41620002

LeLievre/1990

* Note: Oyster testing was waived for arsenic acid

The results indicate that arsenic acid is moderately toxic to the Mysid shrimp on an acute basis.

Table C 21. Acute Toxicity of Chromic Acid to Estuarine/Marine Invertebrates*

Substance/ % Active Ingredient (AI) Organism Endpoints/Results

(mg/L ) Comments Reference

chromic acid/ 57% LC50 = 5.9

NOEL = 2.3 - core study 41703602Docket Number EPA

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Page 79 of 94 Mysid

( Mysidopsis bahia ) - static system

- 96 hour test duration LeLievre, 1990

* Note: Oyster testing was waived for chromic acid

The results indicate that chromic acid is moderately toxic to the Mysid shrimp on an acute basis.

Estuarine/Marine Invertebrate, Chronic

Aquatic invertebrate life

- cycle testing using the TGAI is required for wood preservatives if the product will be used to treat wood used in an aq uatic habitat, such as piers, pilings, and docks. Data are required on the more sensitive type of invertebrate, freshwater or estuarine/marine. Acute data show that freshwater and marine/estuarine invertebrates are comparably sensitive to arsenic acid, a nd that freshwater invertebrates are more sensitive than marine/estuarine invertebrates to chromic acid. Since acceptable aquatic invertebrate life

- cycle data was submitted for the freshwater species Daphnia magna , testing with a marine/estuarine inverteb rate is not anticipated to be required for arsenic acid or chromic acid.

Aquatic Plants

- n o additional toxicity data are anticipated to be needed.

Aquatic plant testing is required for wood preservatives if they are used to treat wood intended for use in aquatic environments (e.g., pier, piling, or dock uses). Testing is conducted with five aquatic plant species; one species of aquatic floating macrophyte ( Lemna gibba ), one green algae species ( Skeletonema costatum ) , one blue

- green cyanobacteria ( Anabaena flos

- aquae ) , one marine diatom ( Selenastrum capricornutum ), and one freshwater diatom (Navicula pelliculosa ). The components of chromated arsenicals meet the criteria for testing, since chromated arsenical

treated wood can be used in the aquatic environm ent. The results of the submitted data for this requirement are listed below.

Table C 22. Acute Toxicity of Arsenic Acid to Aquatic Plants

Substance/ % Active Ingredient (AI) Organism Endpoints/Results

(mg/L ) Comments Reference

arsenic acid / 75.8% Duckweed (Lemna gibba) EC50 > 9.8 ppm

NOEL < 9.8 ppm - core study

- static system

- 14 day test duration EPA 2002a (42290901)

arsenic acid / 75.8% EC50 = 0.038 ppm

NOEL =0.005 ppm - core study EPA2002aDocket Number EPA

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Page 80 of 94 Green alga (Selenastrum capricornutum) - static system

- 5 day test duration (42290902)

arsenic acid / 75.8% Freshwater diatom ( Navicula pelliculosa ) EC50 = 1.4 ppm

NOEL < 0.66 ppm - supplemental study

- static system

- 5 day test duration EPA2002a

(42290903)

arsenic acid / 75.8% Marine diatom ( Skeletonema
costatum ) EC50 = 0.0092 ppm

NOEL < 0.007 ppm - supplemental study

- static system

- 5 day test duration EPA 2002a (42278801)

arsenic acid / 75.8% Bluegreen alga ( Anabaena flos

aquae ) EC50 > 2.4 ppm

NOEL = 0.28 ppm - supplemental study

- static system

- 5 day test duration EPA2002a

(42278802)

The results indicate that arsenic acid is moderately toxic to very highly toxic to aquatic plants. The guideline 850.5400 is fulfilled. The marine diatom, Skeletonema costatum appears to be substantially more sensitive to arsenic acid than the other spec ies tested.

Aquatic plant toxicity data have not been submitted for chromic acid. Two studies were identified in the ECOTOX database that evaluated the effects of chromic acid to aquatic plants. Results of these studies are summarized below:

Table C 23. Acute Toxicity of Chromic Acid to Aquatic Plants

Substance/ % Active Ingredient (AI) Organism Endpoints/Results

(mg/L ) Comments Reference

chromic acid / AI not available Green alga (Selenastrum capricornutum) EC50 = 0.2 ppm

- supplemental

- static system EPA, 2002b, (ref #3690)Docket Number EPA

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Page 81 of 94 - 120 hour test duration

- endpoint is population growth

chromic acid, dipotassium salt / AI not available Marine diatom ( Skeletonema

costatum ) EC50 = 14.7 ppm

- supplemental

- static system

- 5 day test duration

- endpoint is population growth EPA, 2002b (ref #2233)

The results indicate that chromic acid is moderately to highly toxic to aquatic plants.

Whole Sediment Acute Invertebrate, Freshwater

- n o additional toxicity data are anticipated to be needed.

Chromated arsenical

- treated wood is used in aquatic environments and available data regarding the acute toxicity of the components of chromated arsenicals indicates high toxicity to freshwater inverte brates from chromic acid. These data were required in the RED DCI.

Whole Sediment Acute Invertebrate, Marine

- n o additional toxicity data are anticipated to be

n eeded.

Whole sediment acute invertebrate, marine studies are conditionally required for wood preservatives. Several published studies have evaluated the effects of chromated arsenicals to marine and estuarine sediment

- dwelling organisms. Weis et al. (1998) studied five chromated arsenical

- treated wood bulkheads of different ages in estuaries from New York to South Carolina. These authors concluded that metals leached from the treated wood and accumulated in the fine

- grain fractions of nearby sediments. Benthic community species richness, diversity and biomass were reduced at sample stations one meter from the bulkheads, generally returning to background characteristics at a distance of 10 meters from the bulkheads.

Freshwater Organism Toxicity Data from Published Scientific Literature

- n o additional toxicity data are anticipated to be needed.

Several studies in the open literature have evaluated the effects of chromated arsenical components to aquatic organisms. Scientific literature indicates that aquatic organisms may be adversely affected by the components of chromated arsenicals if they ar e exposed to very high concentrations of the metals. For example, benthic organisms that occur near chromatedDocket Number EPA

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Page 82 of 94 arsenical

- treated structures such as docks and bulkheads are likely to be exposed to very high metal concentrations (Weis et al., 1991). Actual concentrations of arsenic and chromium in surface water and sediment as the result of leaching from chr o mated arsenical

- structures are dependent on many factors such as size of the waterbody, flow patterns (e.g., current, tides), physiochemical properties of the surface water and sediment, and characteristics of the treated structure (e.g., size, wood type, structural age).Docket Number EPA

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Page 83 of 94 Ecotoxicology R eferences for Appendi x C

Albuquerque, R.M., and S. M. Cragg. 1995. Fouling Organisms as Indicators of the Environme ntal Impact of Marine Preservative

- Treated Wood. Presented at The International Research Group on Wood Preservation 26th Annual Meeting, Helsingør, Denmark, 12

- 16 June, 1995.

Agency for Toxic Substances and Disease Registry (ATSDR). U.S. Public Health S ervice. 1997. Toxicological Profiles. CRC Press, Inc.

Baes, C.; Sharp, R.; Sjoreen, A. and R. Shor. 1984. A Review and Analysis of Parameters for Assessing Transport of Environmentally Released Radionuclides through Agriculture. Oak Ridge National La boratory, Doc. No. 5786.

Baldwin, W. J., E. A. Pasek, and P. D. Osborne. 1996. Sediment Toxicity Study of CCA

- C

Treated Marine Piles. Forest Prod. J. 46(3): 42

- 50.

Besser, J., Dwyer, F., Ingersoll, C. and N. Wang. 2001. Early Life

- Stage Toxicity of Copper to Endangered and Surrogate Fish Species. U.S. Environmental Protection Agency, Office of Water. EPA 600/R

- 01/051

. Beyer, W.; Conner, E. and S. Gerould. 1994. Estimates of Soil Ingestion by Wildlife. Journal of Wildlife Management, 58: 375

- 382.

Breslin, V.T., and L. Adler

- Ivanbrook. 1998. Release of Copper, Chromium and Arsenic from CCA

- C Treated Lumber in Estuaries. Estuarine, Coastal and Shelf Science 46( 1): 111

- 125.

Brooks, K.M. 1996. Evaluating the Environmental Risks Associated with the Use of Chromated Copper Arsenate

- Treated Wood Products in Aquatic Environments. Estuaries 19 (2A): 296

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Brooks, K.M. 1997. Literature Review and Assessment of the Environmental Risks Associated with the Use of CCA Treated Wood Products in Aquatic Environments. Prepared for the Western Wood Preservers Institute, Vancouver, WA. ( www.wwpinstitute.org/mainpa ges/thesciencewoodinaquat.shtml)

Brooks, K. M. 2000. Assessment of the Environmental Effects Associated with Wooden Bridges Preserved with Creosote, Pentachlorophenol, or Chromated Copper Arsenate. U.S. Department of Agriculture, Forest Service, Forest Products Laboratory, Research Paper FPL

- RP

- 587.

Brown, P.M., S. Lakhani, J. Moffat and F. Rodrigues. 1994. Summary of Results and Recommendations from the 1991

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Page 84 of 94 Brown, C.J. and R.A. Eaton. 2001. Toxicity of Chromated Copper Arsenate (CCA)

- treated Wood to Non

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- 318.

Campbell, S., K.A. Hoxter, and G.J. Smith. 1990. Arsenic A cid (76.1% ) Encapsulated: An Acute Oral Toxicity Study with the Northern Bobwhite (Colinus virginianus). MRID 41719201. Conducted by Wildlife International for Chemical Manufacturers Association.

Chen, J., Malish, S., and McMathon, T. 2001. Inorganic arsenic

– Report of the Hazard Identification Assessment Review Committee. Memorandum to Cook, N., Risk Assessment and Science Support Branch, Antimicrobial Division, USEPA.

Cox, C. 1991. Chromated Copper Arsenate. J. Pesticide Reform Spring 1991.

Efro ymson, R.; Will, M.; Suter II, G. and A. Wooten. 1997. Toxicological Benchmarks for Screening Potential Contaminants of Concern for Effects on Terrestrial Plants: 1997 Revision. ES/ER/TM

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Eisler, Ronald. 1994. Review of Arsenic Hazards to Plants and Animals with Emphasis on Fishery and Wildlife Resources. in Arsenic in the Environment, Part II: Human Health and Ecosystem Effects , edited by Jerome O. Nriagu. John Wiley, New York, NY.

Fletcher, D.W. 1987. 8

- Day Dietary Study with Arsenic Acid as D esiccant L

- 10 in Mallard ( Anas platyrhynchos ) Ducklings. MRID 40409012. Conducted by Bio

- Life Associates for Pennwalt Corporation.

Fletcher, D.W. 1987. 21

- Day Acute Oral Toxicity Study with Arsenic Acid as Desiccant L

- 10 in Bobwhite Quail. MRID 40409013 . Conducted by Bio

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Hobden, B. R. 2000. Proposed Acceptability for Continued Registration Document (PACR) for Chromated Copper Arsenate. PMRA Environmental Assessment Component of the NAFTA Joint Re

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Hoxter, K.A., and M. Jaber. 1987. Arsenic Acid: An Acute Contact Toxicity Study with the Honey Bee ( Apis mellifera ). MRID 40351301. Conducted by Wildlife International for Pennwalt Corporation.

Hoxter, K.A. 1990. Eight

- Day Dietary Toxicity LC50 Test with Mallard Duck, Anas platyrhynchos. MRID 41621102. Conducted by Wildlife International for Chemical Manufacturers Association.

Hoxter, K.A. 1990. Chromic Acid: Avian Acute Oral Toxicity Using Colinus virginianus

. MRID 41621104. Conducted by Wildlife International for Chemical Manufacturers Association..Docket Number EPA

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Page 85 of 94 Hoxter, K.A. 1990. Eight Day Dietary Toxicity LC50 Test with Bobwhite Quail ( Colinus virginianus ). MRID 41621101. Conducted by Wildlife I nternational for Chemical Manufacturers Association.

Imlay, Mark J., and Parley V. Winger. 1983. Toxicity of Copper to Gastropoda with Notes on the Relation to the Apple Snail: A Review. Malacol. Rev. 16: 11

- 15.

Kalnins, M. A., and B. F. Detroy. 1984. Effect of Wood Preservative Treatment of Beehives on Honey Bees and Hive Products. J. Agric. Food Chem. 32: 1176

- 1180.

Lebow, S.T., P.K. Lebow, D.O. Foster, and K.M. Brooks. 2000. Environmental Impact of Preservative

- Treated Wood in a Wetland Boardwal k. Forest Products Laboratory. Res. Pap. FPL

- RP

- 582. Madison, WI: U.S. Department of Agriculture, Forest Service, Forest Products Laboratory. 126p.

Lebow, S.T. 2004. Alternatives to Chromated Copper Arsenate (CCA) for Residential Construction. Porc eedings of the Environmental Impacts of Preservative

- Treated Wood Conference, Orlando, FL. Febuary 8

- 10, 2004. U.S. Department of Agriculture, Forest Service, Forest Products Laboratory. 12p.

Lee, A.W.C.; Grafton, J.C.; F.H. Tainter. 1993. Effect of ra pid redrying after treatment on leachability of CCA treated Southern Pine. In: Winardy, J.; Barnes, M.; Eds. Chromium

- containing waterbourne wood preservatives: Fixation and environmental issues. Madison, WI: Forest Products Society pp. 52

- 55.

L eLievre, M. 1990. Arsenic Acid: 96

- hour Static Acute Toxicity Test with Rainbow Trout, Oncorhynchus mykiss . MRID 41620003. Conducted by Springborn Laboratories, Inc., for Chemical Manufacturers Association.

LeLievre, M. 1990. Arsenic Acid: 96

- hour St atic Acute Toxicity Test with Rainbow Trout, Oncorhynchus mykiss . MRID 41620003. Conducted by Springborn Laboratories, Inc., for Chemical Manufacturers Association.

LeLievre, M. 1990. Arsenic Acid: 96

- hour Static Acute Toxicity Test with Sheepshead Min now, Cyprinodon variegatus . MRID 41620004. Conducted by Springborn Laboratories, Inc., for Chemical Manufacturers Association.

LeLievre, M. 1990. Arsenic Acid: Static Acute Toxicity Test Using Daphnia magna . MRID 41620001. Conducted by Springborn Laborat ories, Inc. for Chemical Manufacturers Association.

LeLievre, M. 1990. Arsenic Acid: Static Acute Toxicity Test with Mysid Shrimp, Mysidopsis bahia . MRID 41620002. Conducted by Springborn Laboratories, Inc., for Chemical Manufacturers Association.Docket Number EPA

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Page 86 of 94 LeLievre, M. 1990. Chromic Acid: 96

- hour Static Acute Toxicity Using Bluegill Sunfish ( Lepomis macrochirus ). MRID 41658401. Conducted by Springborn Laboratories, Inc., for Chemical Manufacturers Association.

LeLievre, M. 1990. Chromic Acid: 96

- hour Static Acute Toxicity Test Using Rainbow Trout, Oncorhynchus mykiss . MRID 41621105. Conducted by Springborn Laboratories, Inc., for Chemical Manufacturers Association. L eLievre, M. 1990. Chromic Acid: Static 48

- hour Acute Toxicity Using Daphnia magna . M RID 41621103. Conducted by Springborn Laboratories, Inc., for Chemical Manufacturers Association.

LeLievre, M. 1990. Chromic Acid: 96

- hour Static Acute Toxicity Test Using Sheepshead Minnow ( Cyprinodon variegatus ). MRID 41703601. Conducted by Springbo rn Laboratories, Inc., for Chemical Manufacturers Association.

LeLievre, M. 1990. Chromic Acid: Static Acute Toxicity Test Using Mysid shrimp ( Mysidopsis bahia) . MRID 41703602. Conducted by Springborn Laboratories, Inc., for Chemical Manufacturers Assoc iation.

Long, R.D., J. Foster, K.A. Hoxter and G.J. Smith. 1990. Arsenic Acid: A Dietary LC50 Study with the Northern Bobwhite ( Colinus virginianus ). MRID 41719202. Conducted by Wildlife International for Chemical Manufacturers Association.

Machado, M .W. 1991. Arsenic Acid: Acute Toxicity to Bluegill Sunfish ( Lepomis macrochirus ) Under Flow

- Through Conditions. MRID 41950601. Conducted by Springborn Laboratories, Inc., for Chemical Manufacturers Association.

Machado, M.W. 1991. Arsenic Acid: Toxicit y Test with Fathead Minnow ( Pimephales promelas ) Embryos and Larvae. MRID 41802201. Conducted by Springborn Laboratories, Inc., for Chemical Manufacturers Association.

Machado, M.W. 1991. Chromic Acid: Toxicity Test with Fathead Minnow ( Pimephales promela s ) Embryos and Larvae. MRID 41974901. Conducted by Springborn Laboratories, Inc., for Chemical Manufacturers Association

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McNamara, P.C. 1991. Chronic Acid: Chronic Toxicity to Daphnids ( Daphnia magna ) Under Flow

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Salanki, J., and K. V.

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Sheppard, S.C. 1992. Summary of Phytotoxic Levels of Soil Arsenic. Water, Air and Soil Pollution 64: 539

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Solo

- Gabriele, H., and T. Townsend. 1999. Disposal Practices and Management Alternatives for CCA

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- 10) to Bluegill (Lepomis macrochirus). MRID 40409014. Conducted by Springborn Life Sciences, Inc., for Pennwalt Corporation.

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Treated Wood in Recovered Wood. Env. Eng. Sci 17(1): 19

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Townsend, T., K. Stook, M. Ward, and H. Solo

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Treated and Alternative

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- 10.

Weis, J.S. and P.Weis. 2004. Effects of CCA Wood on Non

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Weis, J., P. Weis, and T. Procto r. 1998. The Extent of Benthic Impacts of CCA

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Weis, P., J.S. Weis, and J. Couch. 1993. Histopathology and Bioaccumulation in Oysters Crassostrea virginica Living on Wood Prserved with Chromated Copper Arsenate. Dis. Aquat. Org. 17: 41

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Page 89 of 94 Wendt, P.H., R.F. Van Dolah, M.Y. Bobo, T.D. Mathews, and M.V. Levisen. 1996. Wood Preservative Leachates from Docks in and Estuarine Envir onment. Arch Environ Contam Toxicol 31(1): 24

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Whiticar, D. and D.E. Konasewich. 1992. Lower Mainland Region Antisapstain Facilities: Assessment of Operational Practices and Environmental Discharge Volume Two. Prepared for B.C. Ministry of Environme nt, Lands and Parks, Lower Mainland Regional Office.Docket Number EPA

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Page 90 of 94 

# Appendix D Screening Level Down

- the

Drain Analysis

Because of the limited mobility of chromated arsenical chemicals, the potential for their release to wastewater treatment plants from application of chromated arsenicals to wood products and in

- service use is expected to be negligible. Consequently, the Agency does not expect to assess potential exposures to ecological organisms from wastewater treatment plants downstream of domestic and industrial wastewater t reatment facilities.Docket Number EPA

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# Appendix E Product Chemistry

The chromated arsenicals product chemistry information is summarized in Table F 1 for chromic acid, Table F 2 for arsenic acid, and Table F 3 for arsenic pentoxide. The information sources included EPI

- Suite and guideline studies cited in tables.

Table F1 Physical

- Chemical and Environmental Fate Properties for Chromic Acid

Guideline No. Parameter Value Reference (MRID unless specified) / Comments

830.7000 pH 1.1 (25 o C) 43756904 1 % v/v at 25 o C 830.7050 UV/Visible Absorption Sorption from 290

- 500 nm 49184601 830.7200 Melting point ( o C) 197 43756904

830.7370 Dissociation constant (pKa) 0.74 and 6.5 43756904 25 o C

830.7550 Octanol

- water partition coefficient at 25 o C (Log K ow ) N/A 43756904 Not applicable for non

- organic polar material s

830.7840 Solubility in water (mg/L) 630,000 43756904 25 o C

830.7950 Vapor pressure (mmHg) N/A 43756904 Material is a solid at room temperature and m elting point is 197 o C
None Henry's law constant at 25 o C (atm

- m 3 /mol) N/A Volatility from water is not significant because of lack of
vapor pressure atm

- m 3 /mol = atmosphere cubic meter per mole; o C = degrees Celsius; mg/L = milligrams per liter; mmHg = millimeters of mercury;

Table F 2 Physical

- Chemical and Environmental Fate Properties for Arsenic Acid

Guideline No. Parameter Value Reference (MRID unless specified) / Comments

830.7000 pH

- 0.33 49185701 20 o C 830.7050 UV/Visible Absorption No sorption from 290

- 800 nm 49177501

830.7200 Melting point ( o C) N/A 49185701 Material is liquid at room temperature 830.7370 Dissociation constant (pKa) 2.25, 6.77, and 11.6 49185701

830.7550 Octanol

- water partition coefficient at 25 o C (Log K ow ) N/A 49185701 Not applicable for non

- organic polar materials
830.7840 Solubility in water (mg/L) Miscible 49185701

830.7950 Vapor pressure (mmHg) N/A 49185701 Solid material has melting point above 30 o CDocket Number EPA

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None Henry's law constant at 25 o C (atm

- m 3 /mol) N/A Volatility from water is not significant because of lack of
vapor pressure
atm

- m 3 /mol = atmosphere cubic meter per mole; o C = degrees Celsius; mg/L = milligrams per liter; mmHg = millimeters of mercury;

Table F 3 Physical

- Chemical and Environmental Fate Properties for Arsenic Pentoxide

Guideline No. Parameter Value Reference/ Comments

830.7000 pH

Not applicable because arsenic pentoxide forms arsenic acid under hydrated,

acidic conditions in final chromated arsenical products None 830.7050 UV/Visible Absorption
830.7200 Melting point ( o C) 830.7370 Dissociation constant (pKa)

830.7550 Octanol

- water partition coefficient at 25 o C (Log K ow ) 830.7840 Solubility in water (mg/L) 830.7950 Vapor pressure (mmHg)
None Henry's law constant at 25 o C (atm

- m 3 /mol)

atm

- m 3 /mol = atmosphere cubic meter per mole; o C = degrees Celsius; mg/L = milligrams per liter; mmHg = millimeters of mercury;
Product Chemistry References for Appendix F

MRID 43756904. Saur, J.; Walcheski, P. (1995) Product Chemistry Studies: (Physical and Chemical Characteristics): (Chromic Acid). Unpublished study prepared by Chemical Specialties, Inc. 8 p.

MRID 49177501. Miller, R. (2013) Viscosity and UV/Visible Absorption Arsenic Acid: Final Report. Project Number: ARC/EX/1326. Unpublished study prepared by Analytical & Regulat ory Chemistry, Inc. 41p.

MRID 49184601. Miller, R. (2013) UV/Visible Absorption of Chromic Acid: Final Report. Project Number: ARC/EX/1315, ARC/EX/1315/009/P/1. Unpublished study prepared by Analytical & Regulatory Chemistry, Inc. 41p.

MRID 49185701. Arc her, K. (2013) Product Chemistry of Arsenic Acid Solution. Unpublished study prepared by Viance, LLC. 7p.Docket Number EPA

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# Appendix F Categories of Forest Products That May be Treated with Chromated Arsenicals

Supplemental Labeling for Chromated Arsenical Products.Docket Number EPA

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