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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 Ross 
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TERMS, ABBREVIATIONS AND SYMBOLS

ACC Acid Copper Chromate

ACZA Ammoniacal Copper Zinc Arsenate

AD Antimicrobials Division

A.I. or a.i. active ingredient

aPAD acute population adjusted dose 

ASRI activated sludge respiration inhibition

atm-m3

/mole atmospheric pressure-cubic meter per mole

ATSDR Agency for Toxic Substances and Disease Registry

BCF bioconcentration factor 

°C degrees Celsius

CAS Chemical Abstracts Service 

CA Chromated Arsenicals

CCA Chromated Copper Arsenate

CFR Code of Federal Regulations 

CHO Chinese hamster ovary

CMA Chemical Manufacturers Association

CO2 carbon dioxide

COC concentration-of-concern

cPAD chronic population adjusted dose 

CPSC Consumer Product Safety Commission

CrII divalent chromium

CrIII trivalent chromium

CrVI hexavalent chromium

DCI data call-in

EC50 median (or 50 percent) effect concentration

EC05 5 percent effect concentration

ECOTOX ECOTOXicology

EDI estimated daily intake

EDSP Endocrine 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 Federal Food, Drug, and Cosmetic Act

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FQPA Food Quality Protection Act 

FWP Final Work Plan

g/mol grams per mole

GLN guideline number

HPV high production volume

HSRB Human Studies Review Board

IDS Incident Data System 

IRIS Integrated Risk Information System

Koc organic carbon normalized soil-water partition coefficient

Kd soil-water partition coefficient

Kow octanol-water partition coefficient

LC50 median (or 50 percent) lethal concentration

LD50 median (or 50 percent) lethal dose
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LOAEC lowest-observed-adverse-effect-concentration 

LOEC lowest-observed-effect-concentration

LOAEL lowest-observed-adverse-effect-level

Log Kow logarithm of the octanol-water partition coefficient

μg microgram

MCL maximum contaminant level

MCLG maximum contaminant level goal

ml/g milliliter per gram

mg/kg milligram per kilogram

mg/kg/day milligram per kilogram per day 

mg/L milligram per liter

mm Hg millimeter of mercury

MOE margin of exposure 

MRID Master Record Identification Number

MRL maximum residue limit 

N/A not applicable 

nm nanometers

NOAEC no-observed-adverse-effect-concentration

NOAEL no-observed-adverse-effect-level

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 population adjusted dose

PAI pure active ingredient

PDM Probabilistic Dilution Model

% percent

PC Code Pesticide Chemical Code

PCF pounds per cubic foot

pH power of hydrogen or power of the concentration of the hydrogen ion

PHED Pesticide Handler’s Exposure Data

PIS primary irritation score

pKa power of the acid dissociation constant or negative base-10 logarithm of the acid 

dissociation constant of a solution

ppb parts per billion 

ppm parts per million

PWP Preliminary Work Plan

QSAR quantitative structure-activity relationship

RCRA Resource Conversation and Recovery Act

RED Reregistration Eligibility Decision

SAB Scientific Advisory Board

SAR structure activity relationship

SF safety factor

TEP typical end-use product

TGAI technical grade active ingredient

TMDL total maximum daily loads

UF uncertainty factor

USDA United States Department of Agriculture

UV/VIS ultraviolet/visible light absorption

% w/w percent weight per weight.
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WP wettable powder

WWTPs wastewater treatment plants
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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 Summary 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 Anticipated Data Needs.........................................................................................................14

3 Human Health Risk Assessment ...........................................................................................16

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

3.2 Dietary Exposure ............................................................................................................18

3.2.1 Food 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 Environmental Justice .............................................................................................27

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

8 Next Steps .............................................................................................................................28
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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 Arsenicals93

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 Arsenicals......................... 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 . 24
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1 Introduction

This document is the United States Environmental Protection Agency’s (USEPA, EPA or “the 

Agency”) Preliminary Work Plan (PWP) for chromated arsenicals. 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 arsenicals. 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 continue 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 reevaluates 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/pesticidereevaluation.

The Agency 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 standard for 

registration. The regulations governing registration review begin at 40 CFR 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 for 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 comments and data received in the docket during this initial comment period, the 

Agency will develop and commit to a Final Work Plan (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-HQ-OPP-2015-0349. Documents associated 
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with this registration review can be viewed in this docket. Tables 1-2 below summarize 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 details)

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 have been submitted)

Occupational Post 

Application Yes 9/18/2008 Updated Inhalation (Sawdust)

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

Residential 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 Preliminary 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) 2020-09

Close Public Comment Period 2020-10

Phase 3: Registration Review Decision and Implementation 

Open 60-Day Public Comment Period for Proposed Decision 2021-03

Close Public Comment Period 2021-05

Issue Final Decision 2021-09

Begin Post-Decision Follow-up 2021
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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 component because under hydrated, 

acidic conditions found in formulated chromated arsenical products, only arsenic acid is expected 

to be present (National 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 these separate registration 

review cases is being done pursuant to 40CFR §155.42(b)(4) which states that “The 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 registration review.” Documents 

associated with dichromic acid registration review case can be viewed in docket number EPA-HQOPP-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 Number 1333-82-0 7778-39-4 1303-28-2

Molecular Formula CrO3 H3AsO4 As2O5

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/
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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 arsenic 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 oC (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-m3/mol = atmosphere cubic meter per mole; oC = degrees Celsius; mg/L = milligrams per liter; mmHg = 

millimeters of mercury;

1.4 Use/Usage Description

1.4.1 Registrations

There are 15 EPA registered products containing one (or a combination of) the active ingredients 

in the chromated arsenicals case: nine registrations for chromic acid (PC code 021101), four

registrations for arsenic acid (PC code 006801), and four registrations for arsenic oxide (PC code 

006802). Of these, nine are manufacturing 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 oxide1 Chromic acid Arsenic 

acid

Arsenic 

pentoxide 

Zn oxide1

K-33 (60 %) 3008-34 10.5 (8.4) 29.9 (13.2) 0 20 (13) 0
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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 

ACZA2

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 

(60%)

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 cases; documents for these cases can be 

found on www.regulations.gov in the following dockets: Copper Oxide docket: EPA-HQ-OPP-2010-0212, and Zinc 

Oxide docket: EPA-HQ-OPP-2009-0011. 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 

RateA

(PCF)

Posts UC4A

UC4B

Ground contact plus fresh water

Ground contact or fresh water

0.40

0.50 

Poles UC4A

UC4B

UC4C

Ground contact plus salt water splash 0.30 to 0.60B

0.30 to 0.60B

0.30 to 0.60B

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

0.60
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UC1

UC2

Interior construction above dry-groundC

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 waterC

Ground plus salt water splash

0.40 ACZAD

A. Except as noted, retentions are for CCA which contains 16.8% CuO, 44% CrO3 and 30% As2O5. 

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 indicates that no more than four billion pounds of pesticidal chromated arsenicals 

are sold per year in the United States.

1.5 Regulatory History

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 since 1970 (2008, EPA).

Chromated arsenicals were 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 received several 

petitions to ban 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 risk of certain 

types of cancers. 

Manufacturers submitted requests to EPA to voluntarily cancel virtually all residential uses of 

chromated arsenical treated wood effective December 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 arsenical 

products (e.g., brush, dips) were also voluntarily withdrawn by registrants.

The voluntary cancellations did not address existing chromated arsenical-wood structures, nor 

does EPA require the removal of structures made with chromated arsenical-treated wood. Wood 

treated with chromated arsenicals is still available primarily 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, and 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).
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The Agency completed a Reregistration Eligibility Decision (RED) for chromated arsenicals in 

2008. The Agency issued the chromated arsenicals post-RED Data Call-Ins (DCIs) on 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 and Cosmetic Act (FFDCA) 

Section 408. There are also no tolerance exemptions for chromated arsenicals under FFDCA 

Section 408. Chromated arsenicals have 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, there are six incident 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 had 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 installing chromated arsenical treated utility poles which involved cutting, 

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, 

neurological effects, heart palpitations and nausea. One lineman had lower lung 

hyperplasia and another had melanoma which were 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 

chromic acid since September, 2008, when the RED was completed, to July 10, 2015 when the 

IDS was queried.

2 Anticipated 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 registration review of chromated arsenicals. Table 8 outlines the data 

requirements required by the post-RED DCI issued on September 9, 2011. The Agency anticipates 

reviewing any data received in response to the post-RED DCI as well as data requested for this 
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registration review prior to conducting the registration review risk assessments for the chromated 

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

Applicable 

Exposure Scenario

875.25001,2,3 

Outdoor 

Exposure -

Inhalation

Arsenic and 

CrVI

(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 internal 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

Treated wood is the article; once wood is cut – test for arsenic and hexavalent chromium (CrVI). 

Table 8 –Data Needs Required by the September 9, 2011 Data Call-In for the Chromated 

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. 
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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

Inorganic arsenic and inorganic 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 (CrVI) summarized inTable 9 and 

Table 10. Other 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 Endpoints for Assessing Exposures/Risks to Inorganic Arsenic (V)

EXPOSURE

SCENARIO

DOSE ENDPOINT STUDY

Acute Dietary This risk assessment was not required.

Chronic Dietary This risk assessment was not required.

Incidental Short- and 

Intermediate- Term 

Oral 

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 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)-1
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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 used 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% was used. Route-to-route extrapolation was used to estimate the exposed 

dose.

(d). Inhalation unit risk (IUR) was 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 population, 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 was derived from the risk assessment associated with inorganic in drinking water were presented in 2000. The 2001 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 Agency’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 Chromium VI

EXPOSURE

SCENARIO

DOSE ENDPOINT STUDY

Acute Dietary This risk assessment was not required.

Chronic Dietary This risk assessment was 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 route, no toxicological end-point was selected for use in 

assessing dermal exposure risks to chromium.

Dermal Exposure

Dermal Effects

(All Durations)

CCDS(a) = 92 ng Cr(VI)/cm2

MOE = 1

Based on the MET10

(10% response level)

which was determined by 

the FIFRA SAP to be 

adequate and sufficiently 

conservative.

Proctor, D.; Gujral, S.; 

Fowler, J. 2006 

Inhalation Exposure

(All Durations)

LOAEL(a) = 0.002 mg/m3; 

(or 2.3 x 10-4 mg/kg/day)

MOE = 30

based on nose and throat 

symptoms observed at the 

0.002 mg/m3 level

Linberg and 

Hedenstierna, 1983. 
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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 (2007a)

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 contact with chromated arsenical pesticides. (c) The 24 hours inhalation unit risk is 1.16 x 10-2 (μg/m3

)

-1 which can also be expressed as 0.0116 m3

/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 m3

/μg x 

day/20 m3 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 

population, 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 assess 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 lowdose extrapolation approach (Q1*) for estimating the human cancer risk based on the most potent tumor type.

3.2 Dietary Exposure

The Agency 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 indirect dietary (food) exposure. The 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

EPA anticipates the need to revise the occupational handler assessment conducted in support of 

the 2008 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 mitigation 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-assess exposures during registration review. Additional data is not anticipated 
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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 structures 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 marine construction wood if this wood is 

sawn during construction. The Agency anticipates the need to require data to reassess these 

exposures during registration review.

3.3.3 Residential Handler Exposures

Residential handler exposures are not anticipated because chromated arsenicals are 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 risk 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 Agency recognizes that materials such as utility poles may be 

reused or recycled after their original intended use has ended; at that point, the utility poles 

would likely have significantly 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). Contact 

with utility 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 plant workers, EPA will revisit the need for a residential post-application exposure 

assessment.

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

shakes/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.
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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 chromated 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 regarding 

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 determinations 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 an ecological risk assessment for chromated 

arsenicals. The Agency expects to require additional data for use in conducting the registration 

review.

This registration review document addresses only chromium and arsenic because copper was 

addressed in a separate case (see below). The 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 environment. Such sites include treated wood used in fresh and salt water 

environments. Leaching from treated wood can lead to exposure to soils 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 endangered 

species determination for chromated arsenicals. The risk assessment also will allow the Agency

to determine whether each use of the arsenic acid and chromic acid has '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. 
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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 leaching 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 variable 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/sediments 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, these 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 FeF6

3-

, bonded to organic ligands to form metal 

complexes or as organometallics (containing C-Metal bonds). 

4.1.1 Water Quality

Arsenic and chromium 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 (TMDL) have been developed for arsenic and chromium.

3 More information on impaired 

water bodies and TMDLs can be found at EPA’s website.

4

Both arsenic and chromium have maximum contaminant levels (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 Conceptual Models for Environmental Exposure Pathways

Based on the summary of registered uses of chromated arsenicals presented in Table 6, 

physical/chemical properties presented in Table 4, and environmental fate data presented 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/arsenic/index.cfm 6 http://water.epa.gov/drink/contaminants/basicinformation/chromium.cfm
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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. Releases to surface water via wastewater treatment 

following application of preservatives to 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 preservatives 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; Stanley, 1994). Levels of chromated arsenicals reach background concentrations

within a few meters of the treated wood products in contact with soil (Degroot, 1979) and 

generally within 10 meters of the treated wood products 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 mobility in soil and surface water. Exposure 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 environmental exposure which

are included in “Conceptual Models for Environmental Exposure Pathways of Antimicrobial 

Pesticides” (EPA-HQ-OPP-2014-0638-0002), found in the docket at www.regulations.gov, EPAHQ-OPP-2014-0638. 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 arsenicals, 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 aquatic 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 piling, bulkheads, and bracing timbers underneath nonresidential 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 acid 
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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-treated 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 chromated 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 arsenic acid and chromic 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 group were 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 LC50 = 50 mg/L 41950601

Fathead minnow Chronic NOAEC = 1.9 mg/L 41802201 

Freshwater 

invertebrates Daphnia magna

Acute 48-h EC50 = 15 mg/L 41620001

Chronic LOEC = 0.0038 mg/L

NOAEC = 0.002 mg/L 42001601

Estuarine/marine fish Sheepshead minnow Acute 96-h LC50 = 28 mg/L 41620004

Chronic Not requiredA --

Estuarine/marine 

invertebrates Mysid Shrimp Acute 96-hr LC50 = 2 mg/L 41620002

Chronic Not requiredA --

Algae Green alga Nonlisted 96-hr EC50 = 0.38 mg/L 42290902

Aquatic vascular 

plants Duckweed Nonlisted EC50 = >9.8 mg/L 42290901 

Aquatic plants Freshwater diatom Nonlisted EC50 = 1.4 mg/L 42290903 

Marine plants Marine diatom Nonlisted EC50 = 0.0092 mg/L 42278801

Birds

Bobwhite quail Acute LD50 = 28.9 mg/kg 40409013

Bobwhite quail Subacute 

dietary

LC50 = 168.5 mg/kg 00121618

Chronic Not requiredA --

Mammals

Acute

LD50 = 150 mg/kg

LD50 = 141 mg/kg (males)

LD50 = 160 mg/kg (females)

40409001

Chronic LOAEL = 4 mg/kg/day

NOAEL = 1 mg/kg/day

Nemac, 1988a, 

cited in 
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A Not required for this use pattern.

Table 13 – 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 LC50 = 44 mg/L 41621105

Fathead minnow Chronic NOAEC = 8.2 mg/L 41974901 

Freshwater 

invertebrates Daphnia magna

Acute 48-h EC50 = 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 LC50 = 39 mg/L 41703601

Chronic Not requiredA --

Estuarine/marine 

invertebrates Mysid Shrimp Acute 96-hr LC50 = 5.9 mg/L 41703602

Chronic Not requiredA --

Algae Green alga Nonlisted 96-hr EC50 = 0.2 mg/kg Ref# 3690

Marine plants Marine diatom Nonlisted EC50 = 14.7 mg/kg Ref# 2233 

Birds

Bobwhite quail Acute LD50 = 93.5 mg/kg 41621104

Bobwhite quail Subacute 

dietary

LC50 = >5100 mg/kg 41621101

Chronic Not requiredA --

Mammals

Acute

LD50 = 52 mg/kg

LD50 = 56 mg/kg (males)

LD50 = 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 Required 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 Screening Level Down-the-Drain Analysis

Generally, the 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 LD50 = 7.7 ug/bee 40351301
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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 specifically 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-drain 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 arsenicals

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 assessing risks from pesticides.

7 Those ecotoxicity values found in the public 

literature to be more sensitive than those currently in Table 12 and Table 13 and which 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 Development, 

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, neurotoxicity, 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 maturation, 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 part 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.htm 
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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 

identified for EDSP screening was published on June 14, 20138 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 amendments 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 Guidance 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 issuing 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 irritant resolution. The Agency

 8 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals. 9 http://www.epa.gov/endo/
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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 water 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 Risk Assessment and Management Process10 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 sub-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 assessments, 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 benefits 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.htm
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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.
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9 References 

Brown, C.J. and R.A. Eaton. 2001. Toxicity of Chromated 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, 2008. Reregistration Eligibility Decision for Chromated 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 Protection 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 Service, 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 DocumentHazard identification and Toxicology Endpoint Selection for Inorganic Arsenic and 

Inorganic Chromium. US Environmental Protection Agency, Office of Pesticide 

Programs, Antimicrobials Division.
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Stanley, J.S. 1994. Task III- CCA-C: Chromated Arsenical Treated Wood Aqueous 

LeachingStudy. Midwest Research Institute. May 27, 1994. MRID 432492-01. 

Unpublished.

Townsend, T., K. Stook, M. Ward, and H. Solo-Gabriele. 2001. Leaching and Toxicity of CCATreated and Alternative-Treated Wood Products (DRAFT). Florida Center for Solid and 

Hazardous Waste Management, State University System of Florida, Gainesville, 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. 

Environmental Impacts of Preservative-treated Wood Conference, Orlando, Florida. Feb. 

http://www.ccaresearch.org/Pre-conference/pdf/Weis.pdf.
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Appendix A Toxicology 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 toxicology studies that are reviewed by the Agency, or 

through citation of scientific studies in the peer-reviewed literature. The following 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 and 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 substantially 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 CrVI 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 primarily 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 chromated 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 pesticide. In 1991, the Agency 

proposed cancellation of the sole remaining agricultural use of arsenic acid (As+5) on cotton. 

 11 Documents associated with the copper registration review PWP can be found on www.regulations.gov in docket 

number EPA-HQ-OPP-2010-0212.
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Subsequently, this registration was voluntarily canceled by the registrant and made immediately 

effective by the Agency (Federal Register, 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 intakes 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 is 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 al., 2007), 

there are no studies reporting death in humans after dermal exposure to inorganic arsenic

aqueous solution. No mortality at dermal doses up to 1000 mg/kg in animal studies. Mortality 

in humans from short-term inhalation exposure to inorganic arsenic has not been observed in 

occupational settings at air levels up to 100 mg/m3. One study in pregnant rats reported lethality 

of inorganic arsenic at a concentration of 20 mg/m3. Arsenic has been shown to result in contact 

dermatitis in humans exposed to arsenic occupationally. Animal 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 skin 

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

LD50 = _ 141 mg/kg 

 = _ 160 mg/kg 

M+F = 150 mg/kg 

II

26356

Rat

LD50 = _ 76 mg/kg 

 = _ 37 mg/kg 

M+F = 52 mg/kg 

I

81-2

(OPPTS 870.1200)

Acute Dermal 26356 Rabbit

LD50 = _ 1750 mg/kg

 = _ 2300 mg/kg 

II
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81-3

(OPPTS 870.1300)

Acute Inhalation 404639-02 Mouse

LC50 = _ 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 hyperkeratosis 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, effects 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 indicated 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 

μg/L] with arsenic (1958 to 1970). There was a decline in late 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 those 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 40μg/L and in Valparaiso is less than 1μg/L. By comparing the pregnancy and birth
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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 al., 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 (Nemec, 1988), pregnant Crl:CD-1(ICR)BR mice (25 per dose 

group) received 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 red 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 

toxicity 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 determined 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), artificially 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-implantation 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 in three repeated oral dose studies carried out under EPA guidelines for assaying 
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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 transplacental carcinoginicity study (Waalkes et al., 2003), pregnant C3H mice were given 

drinking water containing sodium arsenite 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 gestation 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 lasted 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 increase in the incidences of heptatocellular 

carcinoma, and adrenal tumor. In female offspring, dose-related increases in ovarian tumors and 

lung carcinoma incidences 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 progeny. 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 adverse effects of inorganic arsenic on 

human development remain unsubstantiated.” This conclusion is consistent with ATSDR 

(2007), which noted that “Although several studies have reported marginal associations between 

prolonged low-dose human arsenic exposure 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-response 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 susceptibility to arsenicinduced 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 view 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 non-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 “evidence 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 the 
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publication of these NRC Reports, numerous studies on arsenic research continue to become 

available; and in September 2005 EPA scientists presented the information and asked the

Scientific Advisory Board (SAB) to comment on the adequacy of the information on the impact 

of childhood exposure to inorganic 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 effects of arsenics.

Neurotoxicity and Immunotoxicity

Neurotoxicity of inorganic arsenic 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, 

coma, 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 

arsenic 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 inorganic arsenic exposure can induce cell apoptosis in 

the bone marrow cells of goats. Inorganic arsenic inhibited maturation of monocytes into 

macrophages, and induced small, nonadhesive and abnormal macrophage generation from 

monocytes at levels not causing 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 et 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 

activation (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 (10-7mol/litre-10-4mol/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., 1997).
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Methylated 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 gel 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 the 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 prevalence studies, crosssectional 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 association 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 doseresponse 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 arsenic 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 for 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 resulting 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, Japan, India, South America, and North America where associations 

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 animals 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 noted that hyperpigmentation, keratosis and possible vascular 

complications [Blackfoot disease] occurred at a dose of 0.17 mg arsenic per liter of water, 
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equivalent of 0.014 mg/kg/ day. Several follow-up studies of the Taiwanese population exposed 

to inorganic 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, skin, 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 proceeds 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 products. 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, 2007), but the relative proportions of these products 

vary greatly. There is also variation between species and among human populations in the rate 

and extent of methylation of inorganic arsenic. New study finds there are genetic variations in 

genes associated with arsenic metabolism: MMA reductase gene (identified as glutathione stransferase omega 1-1 gene) and purine nucleoside phosphorylase 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 such 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 exists 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 recommends 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

atmosphere originate from ferrochrome production. Ore refining, chemical and refractory

processing, cement-producing plants, automobile brake lining and catalytic converters for
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automobiles, leather tanneries, and chrome pigments also contribute to the atmospheric 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 the 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 exposures to CrVI or administration of CrVI in 

controlled animal experiments is essentially identical to environmental exposures to CrIII or 

administration of CrIII in controlled experiments. For chromium, hazard data show clearly that 

CrVI demonstrates more significant 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 

evaluating risks associated with CrVI.

Acute Toxicity

The acute toxicity summary of the Chromium VI is summarized in Table A2. In acute toxicity animal 

studies, 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 as 0.217 

mg/L, placing chromium VI in Toxicity Category I for acute lethality. Human 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 gastrointestinal effects (hemorrhage, ulceration). 

In contrast to the acute toxicity of chromium VI, acute 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 acute dermal 

exposure to chromium III. However, skin irritation and sensitization have also been observed 

from exposure to chromium III. 

The dermal irritancy and sensitization potential of chromium 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 sensitivity 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 include the wood 

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 can 
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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 LD50 = _ 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 LD50 = _ >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 LC50 = _ 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) 

compounds]

Literature Strong sensitizer
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Non-Acute Toxicity

Oral 

Subchronic toxicity studies in experimental animals have demonstrated hematologic and hepatic 

effects from repeated 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 examined 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 and 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 ppm 

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 noncarcinogenic effects following inhalation.
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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 

septal 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 inhalation 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 unavailable. 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 developmental 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 suggests 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 

Toxicological 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 observed significant increases in preimplantation and postimplantation losses and dosedependent 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.
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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

during 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 dosedependent 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. Significantly 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 animals (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/kg/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 gestation to determine the potential 

teratogenicity of hexavalent chromium. No notable changes in behavior or clinical signs were 

observed in the control or treated dams. Chromium 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 including 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 group.

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 developmental 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 

predominately in the 2.0 and 5.0 mg/kg/day groups. However, these signs did not show a doseresponse 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/day 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 maternal mortality and decreased body weight gain). The Developmental 
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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 

development 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 gestation period had normal 

fertility, gestational length, and litter size (Ivankovic and Preussman, 1975). Elbetieha and AlHamood (1997) examined fertility following chromium chloride exposures in mice. Sexually 

mature male and female mice were exposed to 1,000, 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 and 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 chloride. 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-part study to investigate oral ingestion of 

hexavalent chromium in experimental animals (NTP, 1996, 1997a). The study included a 

determination of the potential reproductive toxicity of potassium dichromate in Sprague-Dawley 

rats, a repeat of the study of Zahid 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 spermatocyte 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/erythroid 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 their 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 the
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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, decreased 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 the 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, Boscolo 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 

carcinogenesis. 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 generate 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 decrease 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 are 
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generated during the reduction of CrVI to CrIII, including DNA strand breaks, alkali-labile sites, 

DNA-protein and DNA-DNA crosslinks, and oxidative DNA damage, such as 8-oxodeoxyguanosine. 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 results 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 mutagenic (IRIS, 2000). Chromium III has 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 pups 

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 concentration 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 hexavalent 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 engaged 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 which 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 sores 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 increased, 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, exposure durations, and confounding factors 

cannot be established. 
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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) (equivalent 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 mean body weight 

gains of the 1,000 mg/L F 344/N rats at the end of the study were 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 than 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 urine 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 values, 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 observed 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 

concentrations 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 lesions 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 increased 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, regenerative 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. 

The effect of sodium dichromate dihydrate was also examined in three strains of mice: B6C3F1, 

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 B6C3F1 mice; 0, 9, 14, and 24 mg/kg/day, respectively for BALB/c 
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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 

histiocytic infiltration of the small intestines; and increased incidence of pancreatic secretory 

depletion. An increased incidence of glycogen depletion in the liver was observed in B6C3F1

and am3-C57BL/6 mice but not in the BALB/c mice and is attributed to 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 response) earlier observed in BALB/c 

mice. Based on the findings, treatment-related effects were observed 8 mg/kg/day CrVI for 

B6C3F1 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 female 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 those 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. Concentrationrelated 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). Increased 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), groups 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). The 

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 those 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 significantly 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 incidences 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 and 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 incidences 
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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 carcinogenicity 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 

results 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 injection, or intrabronchial 

implantation (Baetjer et al., 1959; Hueper and Payne, 1962; Levy and Venitt, 1975; Levy and 

Martin, 1983). 

The data from oral and inhalation exposures of animals to trivalent chromium do not support 

determination of the carcinogenicity 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 dermal 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 chromium, 

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 experiment, 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 received CrVI 

revealed that the liver and spleen had the highest levels of chromium, although some chromium 
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accumulation was observed in all tissues. In mice that received CrIII, the liver was the only 

organ with detectable amounts of chromium, and at levels 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 drinking 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 

diffusion, 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 Surgenor, 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 of 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). 

Exclusion 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 CrVI 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 

interacts 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 resulted 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 or 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 excretion 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 of 
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chromium, administered 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 urinary 

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. (1984), reported that excretion of 

CrIII and creatinine clearance were almost equal suggesting that tubular absorption or 

reabsorption of chromium in the kidneys was minimal.
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Toxicology References for Appendix A

Aiyar J, Borges K, Floyd RA, et al. 1989. Role of chromium(V), glutathione thiyl radical and 

hydroxyl radical intermediates in chromium(VI)-induced DNA damage. Toxicol Environ 

Chem 22:135-148.

Aruldhas, M.M., Subramanian. S; Sekhar, P.; Vengatesh, G.; Chandrahasan, G.; Govindarajulu,

P. et al. 2005. Chronic chromium exposure-induced changes in testicular 

histoarchitecture are associated with oxidative stress: study in non-human primate 

(Macaca radiata Geoffroy). Hum Reprod 2005;20:2801–13. 

Aruldhas, M.M.; Subramanian, S.; Sekhar, P.; Chandrahasan, G.; Govindarajulu, P.; and 

Akbarsha, M.A. 2004 Microcanalizaiton in the epididymis to overcome ductal 

obstruction caused by chronic exposure to chromium—a study in the mature bonnet 

monkey (Macaca radiata Geoffroy). Reproduction 128:127–37. 

Aruldhas, M.M.; Subramanian, S.; Sekhar, P.; Chandrahasan, G.; Govindarajulu, P.; and 

Akbarsha, M.A. 2006. In vivo spermatotoxic effect of chromium as reflected in the 

epididymal epithelial principal cells, basal cells, and intraepithelial macrophages of a 

nonhuman primate (Macaca radiata Geoffroy). Fertility and Sterility. 86: 1097-1105

ATSDR (2000a). Toxicological Profile for Arsenic.: U.S. Department of Health and Human 

Services, Public Health Service.

ATSDR (2000b): Toxicological Profile for Chromium. U.S. Department of Health and Human 

Services, Public Health Service. 

ATSDR (2007). Toxicological Profile for Arsenic.: U.S. Department of Health and Human 

Services, Public Health Service.

ATSDR (2012). Toxicological Profile for Chromium. U.S. Department of Health and Human 

Services, Public Health Service.

Baetjer, AM; Lowney, JF; Steffee, H; et al. 1959. Effect of chromium on incidence of lung 

tumors in mice and rats. Arch Ind Health 20:124-135.

Bagdon, R.E. and Hazen, R.E. 1991. Skin Permeation and Cutaneous Hypersensitivity as a Basis 

for Making Risk Assessments of Chromium As a Soil Contaminant. Env. Hlth. Perspec. 

92: 111-119. 

Beaumont JJ, Sedman RM, Reynolds SD, et al. 2008. Cancer Mortality in a Chinese population 

exposed to hexavalent chromium in drinking water.Epidemiology. 19:12–23.

Bertolero F, Pozzi G, Sabbioni E, et al. 1987. Cellular uptake and metabolic reduction of 

pentavalent to trivalent arsenic as determinants of cytotoxicity and morphological 

transformation. Carcinogenesis 8:803-808.
Docket Number EPA-HQ-OPP-2015-0349

www.regulations.gov

Page 53 of 94

Bishop, C and Surgenor, M, eds. 1964. The red blood cell: a comprehensive treatise. New York: 

Academic Press.

Boscolo, P., M. Di Gioacchino, P. Bavazzano, M. White and E. Sabbioni, 1997. Effects of 

chromium on lymphocyte subsets and immunoglobulins from normal population and 

exposed workers. Life Sci., 60: 1319-1325.

Bryson WG and Goodall CM. 1983. Differential toxicity and clearance kinetics of chromium(III) 

or (VI) in mice. Carcinogenesis 4(12):1535-1539.

Brunsman, L.L. 2008. Memorandum. Cr(VI) Quantitative Risk Assessment (Q*) based on 

F344/N Rat and B6C3F1 Mouse Carcinogenicity Studies with 3⁄4’s Interspecies Scaling 

Factor. February 5, 2008 TXR No. 0054815

Burrow D 1983. Adverse chromate reactions on the skin. In Burrows D er. Chromium: 

Metabolism and toxicology. Boca raton FL.: CRC Press Inc, 137-163,

Cheraghali, A.M.; Haghqoo, S.; Shalviri, G.; Shariati, Y.R.; and Ghassemi, M. 2007. Fatalities 

following skin exposure to arsenic. Clinical Toxicology 45: 965-967 

Chowdhury AR, Mitra C. 1995. Spermatogenic and steroidogenic impairment after chromium 

treatment in rats. Indian J Exp Biol 33:480-484.

Cohen, Y., Winer, A.M., Creelman, L., and Mabuni, C. 1999.A Critical Assessment of 

Chromium in the Environment. Critical Rev. in Environmental Science and Technology 

29(1): 1-46. 

CPSC, 2003. Briefing Package. Petition to Ban Chromated Copper Arsenate (CCA)-Treated 

Wood in Playground Equipment (Petition HP 01-3). February 2003.

Dangleben NL, Skibola, CF, and Smith MT. 2013. Arsenic Immunotoxicity: a 

review. Environmental Health 12:73-87.

DeFlora S, Badolati GS, Serra D, et al. 1987a. Circadian reduction of chromium in the gastric 

environment. Mutat Res 192:169-174.

DeSesso, JM, Jacobson, CF, Scialli, AR, Farr CH, and Holson JF 1998: An assessment of the

developmental toxicology of inorganic arsenic. Reprod.Toxicol. 12: 385-433

Donaldson DL, Smith CC, and Yunice AA. 1984. Renal excretion of chromium-51 chloride in 

the dog. Am J Physiol 246:F870-F878.

Donaldson RM and Barreras RF. 1966. Intestinal absorption of trace quantities of chromium. J 

Lab Clin Med 68:484-493.
Docket Number EPA-HQ-OPP-2015-0349

www.regulations.gov

Page 54 of 94

Elbetieha A and Al-Hamood MH. 1997. Long-term exposure of male and female mice to 

trivalent and hexavalent chromium compounds: effect on fertility. Toxicology. 15;116(1-

3):39-47.

Federal Register, May 6, 1993, Vol 58, p. 26975, [as cited in Federal Register, Vol 58, No 

234/Wednesday, Dec. 8, 1993/Notices, p. 64580-64582]

Fishbein L. 1981. Sources, transport and alterations of metal compounds: An overview. I. 

Arsenic,beryllium, cadmium, chromium and nickel. Environ Health Perspect 40:43-64.

Franzblau, A. and Lilis, R. 1989. Acute Arsenic Intoxication from Environmental Arsenic 

Exposure. Archives of Envir. Health 44(6). 385-390. 

Freeman, G.B., Schoof, R.A., Ruby, M.V., Davis, A.O., Dill, J.A., Liao, S.C., Lapin, C.A., and 

Bergstrom, P.D. 1995. Bioavailability of Arsenic in Soil and House Dust Impacted by 

Smelter Activities Following Oral Administration in Cynomologus Monkeys. 

Fundamental and Applied Toxicology 28:215-222

Freeman, GB., Johnson, J.D., Killinger, J.M., Liao, S.C., Davis, A.O., Ruby, M.V., Chaney, 

R.L., Lovre, S.C., and Bergstrom, P.D. 1993. Bioavailability of Arsenic in Soil Impacted 

by Smelter Activities Following Oral Administration in Rabbits. Fundamental and 

Applied Toxicology 21:83-88

Gibson DP, Brauninger R, Shaffi HS, et al. 1997. Induction of micronuclei in Syrian hamster 

embryocells: comparison of results in the SHE cell transformation assay for national 

toxicology program test chemicals. Mutat Res 392(1-2):61-70.

Groen, K., Vaesen, H.A.G., Klest, J.I.G. deBar, J.L.M., von Ooik, T. Timmerman, A. and Vlug, 

R.G. 1993. Bioavailability of Inorganic Arsenic from Bog Ore-Containing Soil in the 

Dog. Environmental Health Perspective 102: 182-184.

Henderson RF, Rebar AH, Pickrell JA, et al. 1979. Early damage indicators in the lung. III. 

Biochemical and cytological response of the lung to inhaled metal salts. Toxicol Appl 

Pharmacol 50:123-136.

Hopenhayn, C, Ferreccio, C, Browning, SR, Huang, B. et al. 2003. Arsenic Exposure from 

Drinking Water and Birth Weight. Epidemiology 14:593-602.

Hopenhayn-Rich et al., 1998: Lung and Kidney Cancer Mortality Associated with Arsenic in 

Drinking Water in Cordoba, Argentina. Epidemiology 27: 561-569.

Hopenhayn-Rich et al., 2000: Chronic Arsenic Exposure and Risk of Infant Mortality in Two 

Areas of Chile. Env. Hlth. Perspec. 108: 667-673, July 2000. 

Hueper, WC and Payne, WW. 1962. Experimental studies in metal carcinogenesis--Chromium,

nickel, iron, arsenic. Arch Environ Health 5:445-462.
Docket Number EPA-HQ-OPP-2015-0349

www.regulations.gov

Page 55 of 94

International Agency for Research on Cancer (IARC). 1990. IARC monographs on the 

evaluation of the carcinogenic risk of chemicals to humans. Vol. 49. Some metals and 

metallic compounds. Lyon, France: World Health Organization.

IPCS, 2001. Environmental health criteria on arsenic and arsenic compounds. Environmental 

Health Criteria Series, No. 224. Arsenic and arsenic compounds, second, WHO, Geneva, 

521

IRIS. 2000. Chromium VI. Integrated Risk Information System. U.S. Environmental Protection

Agency, Office of Health and Environmental Assessment, Environmental Criteria and 

Assessment Office, Cincinnati, OH.

Ivankovic, S; Preussman, R. 1975. Absence of toxic and carcinogenic effects after 

administrations of high doses of chronic oxide pigment in subacute and long term feeding 

experiments in rats. Food Cosmet Toxicol 13:347-351.

Jennette KW. 1982. Microsomal reduction of the carcinogen chromate produced chromium(V). J 

Am Chem Soc 104:874-875.

Junaid M, Murthy RC and Saxena DK. 1996. Embryo- and fetotoxicity of chromium in 

pregestationally exposed mice. Bull Environ Contam Toxicol 57:327-334.

Kanojia RK, Junaid M and Murthy RC. 1996. Chromium induced teratogenicity in female rat. 

ToxicolLett 89:207-213.

Kenyon, E.M. and Hughes, M.F. 2001.: A concise review of the toxicity and carcinogenicity of 

dimethylarsinic acid. Toxicology 160: 227-236. 

Kidwell, J. 2008. Inorganic Hexavalent Chromium (Cr(VI)): Report of the Cancer Assessment 

Review Committee. Cancer Assessment Review Committee (CARC) Health Effects 

Division (HED), Office of Pesticide Programs. March 12. 2008 TXR:0054811

Kirpnick-Sobol, Z., Reliene, R. and Schiestl R.H. 2006. Carcinogenic Cr(VI) and the Nutritional 

Supplement Cr(III) Induce DNA Deletions in Yeast and Mice. Cancer Res 66: (7). 3480-

3484.

Kochhar TS, Howard W, Hoffman S, et al. 1996. Effect of trivalent and pentavalent arsenic in 

causing chromosome alterations in cultured Chinese hamster ovary (CHO) cells. Toxicol 

Lett 84(1):37-42.

Kumar A. and Rana SVS. 1982. Lipid accumulation in chromium-poisoned rats. Int J Tissue 

React. 4(4): 291-295
Docket Number EPA-HQ-OPP-2015-0349

www.regulations.gov

Page 56 of 94

Larramendy ML, Popescu NC and DiPaolo J. 1981. Induction by inorganic metal salts of sister 

chromatid exchanges and chromosome aberrations in human and Syrian hamster strains. 

Environ Mutagen 3:597-606.

Lebow, S. 1996. Leaching of Wood Preservative Components and their Mobility in the 

Environment- Summary of Pertinent Literature. Gen. Tech. Rep. FPL-GTR-93. Madison, 

WI: U.S. Department of Agriculture, Forest Service, Forest Products Laboratory, 36 p.

Lee, T-C, et al. 1985. Comparison of arsenic-induced cell transformation, cytotoxicity, mutation, 

and cytogenetic effects in Syrian hamster embryo cells in culture. Carcinogenesis 6(10): 

1421-1426. 

Lerman S, Clarkson TW and Gerson RJ. 1983. Arsenic uptake and metabolism by liver cells is 

dependent on arsenic oxidation state. Chem Biol Interact 45:401-406.

Levy, LS and Martin, PA. 1983. The effects of a range of chromium-containing materials on rat 

lung. Dye Color Manufacturers Association.

Levy, LS and Venitt, S. 1975. Carcinogenic and mutagenic activity of chromium-containing 

materials. Br J Cancer 32:254-255.

Mazumder, D.N.G.; Haque, R.; Ghosh, N.; De, B.K.; Santra, A.; Chakraborty, D. and Smith, 

A.H. 1998. Arsenic levels in drinking water and the prevalence of skin lesions in West 

Bengal, India. International Journal of Epidemiology 27:871-877.

MacKenzie, RD; Byerrum, RU; Decker, CF; et al. 1958. Chronic toxicity studies. II. Hexavalent 

and trivalent chromium administered in drinking water to rats. Am Med Assoc Arch Ind 

Health 18:232-234.

Maruyama, Y.1982: The health effect of mice given oral administration of trivalent and 

hexavalent chromium over a long term. Acta Scholae Medicinalis Universitatis in Gifu 

31:24-36. 

Mass, M.J. et al. 2001.: Methylated Trivalent Arsenic Species are Genotoxic. Chem. Res. 

Toxicol. 14: 355-361. 

Mizuta, N, Mizuta, et al. 1956. An Outbreak of Acute Arsenic Poisoning Caused by ArsenicContaining Soy-Sauce (Shoyu). A Clinical Report of 220 Cases. Bull Yamaguchi Med 

Sch 4(2-3):131-149.

Moore MM, Harrington-Brock K and Doerr CL. 1997. Relative genotoxic potency of arsenic and 

its methylated metabolites. Mutat Res 386(3):279-290.

Morales, K. H.; Ryan, L.; Kuo, T.; Wu, M.; and Chen, C. 2000. Risk of Internal Cancers from 

Arsenic in Drinking Water. Environ. Health Perspect 108:655-661. National Research 
Docket Number EPA-HQ-OPP-2015-0349

www.regulations.gov

Page 57 of 94

Council (US) committee on Medical and Biological Effects of Environmental Pollutants. 

Arsenic: Medical and Biological Effects of Environmental Pollutants. Washington (DC): 

National Academies Press (US); 1977. 2, Chemistry of 

Arsenic. http://www.ncbi.nlm.nih.gov/books/NBK231019/

National Research Council (NRC). 1999. Arsenic in Drinking Water. National Academy Press, 

Washington, D.C.

National Research Council (NRC): Arsenic in Drinking Water: 2001 Update. September, 2001, 

National Academy Press, Washington, D.C. 

National Toxicology Program (NTP). 1996. Final report on the reproductive toxicity of 

potassium dichromate (hexavalent)(CAS No. 7778-50-9) administered in diet to SD rats. 

Dec. 16, 1996. U.S. Department of Commerce, National Technical Information Service, 

PB97125355.

National Toxicology Program (NTP). 1997a. Final report on the reproductive toxicity of 

potassium dichromate (hexavalent) (CAS No. 7778-50-9) administered in diet to 

BALB/C mice. Jan 10, 1997. U.S. Department of Commerce, National Technical 

Information Service, PB97125363.

National Toxicology Program (NTP) 2007a. NTP Draft Technical Report on the Toxicology and 

Carcinogenesis Studies of Sodium Dichromate Dihydrate (CAS No. 7789-12-0) in F344

Rats and B6C3F1 Mice (Drinking Water Studies). Southern Research Institute, Birmingham, 

AL. NTP TR 546 (NIH Publication No. 07-5887), 2007. Published by the National Institutes 

of Health, U.S. Department of Health and Human Services. MRID No. 47325703.

National Toxicology Program (NTP) 2007b. NTP Technical Report on the Toxicity Studies of 

Sodium Dichromate Dihydrate (CAS No. 7789-12-0) Administered in Drinking Water to 

Male and Female F344/N Rats and B6C3F1 Mice and Male BALB/c and am3-C57BL/6 

Mice. Southern Research Institute, Birmingham, AL. NTP TR 72 (NIH Publication No. 07-

5964), January, 2007. Published by the National Institutes of Health, U.S. Department of 

Health and Human Services. MRID 47325704.

Nemec MD, Holson JF, Farr CH, and Hood RD 1988. Developmental toxicity assessment of 

arsenic acid in mice and rabbits. Reprod. Toxicol. 12(6):647-658.

Oberly TJ, Piper CE, McDonald DS. 1982. Mutagenicity of metal salts in the L5178Y mouse 

lymphoma assay. J Toxicol Environ Health 9:367-376.

Patra PH, Bandyopadhyay S, Bandyopadhyay MC, and Mandal TK. 2013 Immunotoxic and 

Genotoxic Potential of Arsenic and its Chemical Species in Goat. Toxicol Int. 20(1): 6–

10.

Proctor, D.; Gujral, S. and Fowler, J. 2006. Repeated Open Application Test for Allergic Contact 

Dermatitis due to Hexavalent Chromium [Cr(VI)] as CopperShield®: Risk Assessment 

for Dermal Contact with Cr(VI). Unpublished study conducted by Dermatology 
Docket Number EPA-HQ-OPP-2015-0349

www.regulations.gov

Page 58 of 94

Specialists, PSC, and Exponent under Project No. FPRL #012506. 324 p. MRID 

46884001.

Proctor, D.; Gujral, S.and Fowler, J. 2006. Supplemental Information to the Final Report Titled 

“Repeated Open Application Test for Allergic Contact Dermatitis due to Hexavalent 

Chromium [Cr(VI)] as CopperShield®: Risk Assessment for Dermal Contact with 

Cr(VI).” Unpublished document dated August 24, 2006. Project No. FPRL #012506. 347 

p. MRID 46922901.

Proctor, D.; Gujral, S.; Su, S. and Fowler, J. 2006. Repeated Open Application Test for Allergic 

Contact Dermatitis due to Hexavalent Chromium [Cr(VI)] as Potassium Dichromate: 

Risk Assessment for Dermal Contact with Cr(VI). Unpublished study conducted by 

Dermatology Specialists, PSC, and Exponent under Project No. FPRL #012406. Includes 

Supplemental Information documenting ethical conduct of the research. 664 p. MRID 

46930701.

Rossman, T.G. et al. 1980: Absence of arsenite mutagenicity in E. coli and Chinese hamster 

cells. Environ. Mut. 2: 371-379.

Sakurai T, Ohta T, Tomita N, Kojima C, Hariya Y, Mizukami A and Fujiwara K. 2006. 

Evaluation of immunotoxic and immunodisruptive effects of inorganic arsenite on human 

monocytes/macrophages. International Immunopharmacology 6: 304– 315

Sayato Y, Nakamuro K, Matsui S, et al. 1980. Metabolic fate of chromium compounds. I. 

Comparative behavior of chromium in rat administered with Na2

51CrO4 and 51CrCl3. J 

Pharm Dyn 3:17-23.

Schroeder, HA; Balassa, JJ and Vinton, WH, Jr. 1965. Chromium, cadmium and lead in rats:

effects on lifespan, tumors, and tissue levels. J Nutr 86:51-66.

Sedman RM, Beaumont J, McDonald TA, Reynolds S, Krowech G, and Howd R. 2006. Review 

of the evidence regarding the carcinogenicity of hexavalent chromium in drinking water. 

J Environ Sci Health C. 24:155–182. [PubMed]

Suzuki Y and Fukuda K. 1990. Reduction of hexavalent chromium by ascorbic acid and 

glutathione with special reference to the rat lung. Arch Toxicol 64:169-176.

Towill, LE; Shriner, CR; Drury, JS; et al. 1978. Reviews of the environmental effects of 

pollutants. III. Chromium. Prepared by the Health Effects Research Laboratory, Office 

ofResearch and Development, U.S. Environmental Protection Agency, Cincinnati, OH. 

Report No. ORNL/EIS-80. EPA 600/1-78-023. NTIS PB 282796. 

Trivedi B, Saxena DK, Murthy RC, et al. 1989. Embryotoxicity and fetotoxicity of orally 

administered hexavalent chromium in mice. Reprod Toxicol 3:275-278.
Docket Number EPA-HQ-OPP-2015-0349

www.regulations.gov

Page 59 of 94

Tseng W-P. 1977. Effects and dose-response relationships of skin cancer and Blackfoot disease 

with arsenic. Environ Health Perspect 19:109-119.

Tseng, W.P., H.M. Chu, S.W. How, J.M. Fong, C.S. Lin, and S. Yeh. 1968. Prevalence of skin 

cancer in an endemic area of chronic arsenicism in Taiwan. J. Natl. Cancer Inst. 

40:453-463.

USEPA Region 8, 2001: Derivation of Acute and Subchronic Oral Reference Doses for 

Inorganic Arsenic. 

USEPA, IRIS, Chromium (VI), 1998; CASRN 18540-29-9, 9/3/1998.

USEPA. 2001. National Primary Drinking Water Regulation; Arsenic and Clarifications to 

Compliance and New Source Contaminants Monitoring; Final Rule. Federal Register. 

Vol. 66, No. 14. p. 6975, January 22, 2001.

USEPA. 2005. Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure 

to Carcinogens. EPA/630/R-03/003F. 

USEPA. Bioavailability of Arsenic and Lead in Environmental Substrates. 1. Results of an Oral 

Dosing Study of Immature Swine. Superfund/Office of Environmental Assessment, 

Region 10, EPA 910/R-96-002, 1996.

Waalkes, MP; Ward, JM; Liu, J. and Diawan, BA. 2003. Transplacental carcinogenicity of 

Inorganic Arsenic in the Drinking Water: Induction of Hepatic, Ovarian, Pulmary, and 

Adrenal Tumors in Mice. Toxicology and Applied Pharmacology: 186:7-17.

Wester, R.C., Maibach, H.I., Sedik, L. Melendres, J., and Wader, M. 1993. In Vivo and in Vitro 

Percutaneous Absorption and Skin Decontamination of Arsenic From Water and Soil. 

Fundamental and Applied Toxicology 20:336-340

Wiegand, HJ; Ottenwalder, H and Bolt, HM. 1985. Fast uptake kinetics in vitro of 51 Cr(VI) by 

red blood cells of man and rat. Arch Toxicol 57:31-34.

Williams, T.W. : Rawlins, B.G.; Smith, B.; and Breward, N. 1998. In-Vitro Determination of 

Arsenic Bioavailability in Contaminated Soil and Mineral Benefication Waste from Ron 

Phibun, Southern Thailand: A Basis for Improved Human Risk Assessment. 

Environmental Geochemistry and Health: 20

Witmer CM, Park HS, and Shupack SI. 1989. Mutagenicity and disposition of chromium. Sci 

Total Environ. 1;86(1-2):131-48.

Witmer, C.M, Harris R and Shupack SI. 1991. Oral bioavailability of chromium from a specific 

site. Environ Health Perspect 92:105-110.
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Zahid, Z.R., Al-Hakkak ZS, Kadhim AHH, et al. 1990. Comparative effects of trivalent and 

hexavalent chromium on spermatogenesis of the mouse. Toxicol Environ Chem 25:131-

136.

Zhang, J and Li, X. (1987) Chromium pollution of soil and water in Jinzhou. J Chin Prevent Med 

21:262-264.
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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.

Chromium 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 preservatives which contain these metals. Chromated 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 investigated, 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 wood, wood type, 

and wood texture. Results from a number of studies indicate that most of the leaching takes place 

in the first few days after the application. Most of these studies have shown that both the total 

leaching and rate of leaching is higher for arsenic 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. Leaching 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 within 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 arsenical-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 than 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-column concentrations of these metals in aquatic habitats 
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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 and 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 medium 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 RED 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 chromated 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 construction/maintenance would help reduce the impact of chromated arsenical 

metals in the environment (Lebow et al., 2000, Lebow, 2004).

Chromium

Divalent chromium (CrII) is unstable in water, and trivalent chromium goes through hydrolysis 

and forms various species. The important species of trivalent chromium found in aqueous 

systems are: CrOH2+, Cr(OH)2

+

, Cr(OH)4

1- and ,Cr(OH)3(s). In addition, polymeric species like: 

Cr2(OH)2 and Cr3(OH)4

5+ are also formed in water. All these species are present in aqueous 

systems in the absence of any complexing agents. Similarly, hexavalent chromium also 

hydrolyzes in water and forms CrO4

2-

(at pH > 6.5), and HCrO4

1- and Cr2O72- in acidic medium. 

In fresh water at pH 6, species detected are: HCrO4

1-

, Cr(OH)2

1+, Cr(OH)21+, CrO42-

, trivalent 

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

CrO42-

, Cr(OH)2+, Cr(OH)3, NaCrO4

1-

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

1-

, KCrO4

1-

, and HCrO4

1- . Trivalent 

chromium is kinetically stable and hexavalent chromium 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 water 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, oxidize 
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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, however, adsorption 

of trivalent chromium on iron and manganese oxides increases.

Arsenic

The common and important arsenic ores are: tenantite (Cu6[Cu4(Fe,Zn)2]As4S13), cobaltite 

(CoAsS), arsenopyrite (FeAsS), niccolite (NiAs), and enargite (Cu3AsS4). 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 total 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, the 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 H2AsO4

and HAsO4

2-

. At pH 12 and above, it is predominantly HAsO3

2- and AsO3-3

.
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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 Quality. 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 432492-01. 

Unpublished.

Holm, T.R. 1979. Chemical Modeling in Aqueous systems, E.A. Jenne, Editor, American

Chemical 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.

Wauchope, 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. 161:189-199
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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 - no 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 bird). 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 Birds
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Substance/ % 

Active Ingredient 

(AI)

Organism Endpoints/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 - core study Hobden, 2000 

(T15)
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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 duck (a waterfowl) and bobwhite quail (an 

upland gamebird). The results of avian subacute dietary tests are tabulated below.

Table C4. 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 evaluated 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/kgday. This value was based on the results of a chronic dietary study that evaluated the effects of 

chromium (as CrIII) to black ducks during a ten month study duration. 

Mammals - no additional toxicity data are anticipated to be needed.
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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) substitute 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 identified for arsenic acid in Chen et al. (2001) 

are summarized in the table below.

Table C5. 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 identified in McMahon and 

Chen (2001) for chromic acid is provided in the table below.

Table C6. 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-

01 as cited in 
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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 exposure 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 (HIARC) 

report on arsenic (McMahon and Chen, 2001) included several toxicity endpoints for mammalian 

species. These endpoints have been provided in the following table.

Table C7. 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 

- endpoint was histology 

effects to the liver and anemia 

Byron et al., 

1967, cited in 

ATSDR, 1997
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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. 

Table C8. 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 required 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 C9. 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

(40351301)
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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 - no 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 conditionally 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 et 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 sensitive 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 

considered 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, poorly 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 of 
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30ppm chromium, while 10 ppm chromium had no observed effect. Another study calculated 

EC50 concentrations 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 - no 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 C10. 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, 

1987
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(Lepomis 

macrochirus)

NOEL < 12 - 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 two acute toxicity studies are summarized 

below.

Table C11. 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-stage testing was required 
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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 requirements. Early life-stage testing was submitted to the Agency for 

arsenic acid and chromic acid using freshwater species; that data is summarized below.

Arsenic acid

Table C12. 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 C13. 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

(41974901)
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This result indicates that chromic acid causes larval growth effects at levels above 4.0 ppm. 

Freshwater Invertebrates - no 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 C14. 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 C15. 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 environment. The preferred test species is Daphnia magna. 
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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 C16. 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 C17. 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. 
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Estuarine/Marine Fish - no additional toxicity data are anticipated to be needed.

Estuarine/Marine Fish, Acute

Acute 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 pilings. Results of these tests are tabulated below for arsenic acid 

and chromic acid.

Table C18. 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 C19. 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

The results indicate that chromic acid is moderately toxic to estuarine/marine fish on an acute 

basis. 
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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 lifestage 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/estuarine 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 - no additional toxicity data are anticipated to be needed.

Estuarine/Marine Invertebrates, Acute

Acute toxicity testing with estuarine/marine invertebrates 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 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 this test are provided below.

Table C20. 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 C21. 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 41703602
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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 aquatic 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, and 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 invertebrate 

is not anticipated to be required for arsenic acid or chromic acid.

Aquatic Plants - no 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 arsenicaltreated wood can be used in the aquatic environment. The results of the submitted data for this 

requirement are listed below.

Table C22. 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 EPA2002a
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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 flosaquae)

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 species 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 C23. 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)
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- 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 - no 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 

invertebrates from chromic acid. These data were required in the RED DCI.

Whole Sediment Acute Invertebrate, Marine - no additional toxicity data are anticipated to be 

needed.

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 - no 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 are exposed to very high 

concentrations of the metals. For example, benthic organisms that occur near chromated 
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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 chromated 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).
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Ecotoxicology References for Appendix C

Albuquerque, R.M., and S. M. Cragg. 1995. Fouling Organisms as Indicators of the 

Environmental 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 Service. 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 Laboratory, Doc. No. 5786.

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

296-305.

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/mainpages/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 1991-1992 Site Auditing Program of the Ontario CCA Wood 

Preservation Industry. (unpublished) 
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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-target Marine Fouling Communities in Langstone Harbour, Portsmouth, 

UK. Mar. Pol. Bull. 42:310-318.

Campbell, S., K.A. Hoxter, and G.J. Smith. 1990. Arsenic Acid (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.

Efroymson, 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-85/R2.

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 Desiccant 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-Life Associates for Pennwalt 

Corporation.

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.

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..
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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 International 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 Boardwalk. 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. 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.

Lee, A.W.C.; Grafton, J.C.; F.H. Tainter. 1993. Effect of rapid 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. 

LeLievre, 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 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 Static Acute Toxicity Test with Sheepshead 

Minnow, 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 Laboratories, 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. 
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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.LeLievre, M. 1990. Chromic Acid: Static 48-

hour Acute Toxicity Using Daphnia magna. MRID 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 Springborn 

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 Association. 

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: Toxicity 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 

promelas) Embryos and Larvae. MRID 41974901. Conducted by Springborn 

Laboratories, Inc., for Chemical Manufacturers Association

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

Hazard Identification and Toxicology Endpoint Selection for Inorganic Arsenic and 

Inorganic Chromium. US Environmental Protection Agency, Office of Pesticide 

Programs, Antimicrobials Division.

McNamara, P.C. 1991. Arsenic Acid: Chronic Toxicity to Daphnids (Daphnia magna) Under 

Flow-Through Conditions. MRID 42001601. Conducted by Springborn Laboratories, 

Inc., for Chemical Manufacturers Association.

McNamara, P.C. 1991. Chronic Acid: Chronic Toxicity to Daphnids (Daphnia magna) Under 

Flow-Through Conditions. MRID 41881501. Conducted by Springborn Laboratories, 

Inc., for Chemical Manufacturers Association. Playle, R.C., R.W. Gensemer, and D. G. 

Dixon. 1992. Copper Accumulation on Gills of Fathead Minnows: Influence of Water 
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Hardness, Complexation and pH of the Gill Micro-Environment. Env. Toxicol. Chem. 

11: 381-391.

R. Faust. 1992. Toxicity Summary for Copper. Oak Ridge National Laboratory, Health and 

Safety Research Division. Oak Ridge, TN.

Salanki, J., and K. V.-Balogh. 1989. Physiological Background for Using Freshwater Mussels 

in Monitoring Copper and Lead Pollution. Hydrobiol. 188/189: 445-454.

Sample, B.E., Opresko, D.M. and G.W. Suter II. 1996. Toxicological Benchmarks for Wildlife: 

1996 Revision. U.S. Department of Energy, Office of Environmental Management, Oak 

Ridge. ES/ER/TM-86/R3.

Sheppard, S.C. 1992. Summary of Phytotoxic Levels of Soil Arsenic. Water, Air and Soil 

Pollution 64: 539-550.

Solo-Gabriele, H., and T. Townsend. 1999. Disposal Practices and Management Alternatives 

for CCA-Treated Wood Waste. Waste Management Res. 17: 378-389.

Stilwell, D.E. and Gorny, K.D. 1997. Contamination of Soil with Copper, Chromium, and 

Arsenic Under Decks Built from Pressure Treated Wood. Bulletin of Environmental 

Contamination and Toxicology, 58: 22-29.

Sunila, I., and R. Lindstom. 1985. Survival, Growth and Shell Deformities of Copper- and 

Cadmium-Exposed Mussels (Mytilus edulis L.) in Brackish Water. Estuarine, Coastal 

and Shelf Science 21: 555-565.

Suprenant, D.C. 1987. Acute Toxicity of Arsenic Acid (Desiccant L-10) to Bluegill (Lepomis 

macrochirus). MRID 40409014. Conducted by Springborn Life Sciences, Inc., for 

Pennwalt Corporation. 

Tolaymat, T. M., T.G. Townsend, and H. Solo-Gabriele. 2000. Chromated Copper AresnateTreated Wood in Recovered Wood. Env. Eng. Sci 17(1): 19-28.

Townsend, T., K. Stook, M. Ward, and H. Solo-Gabriele. 2001. Leaching and Toxicity of CCATreated and Alternative-Treated Wood Products (DRAFT). Florida Center for Solid and 

Hazardous Waste Management, State University System of Florida, Gainesville, FL.

Tyl, R.W., M. Marr and C.B. Meyers, 1991. Developmental toxicity evaluation of chromic acid

administered by gavage to CD-1 mice. Research Triangle Institute, Research Triangle 

Park, NC 27709, Study No. 60C-4808-10/20. November 12. MRID 420998-01.U.S. 

Environmental Protection Agency, ELL-Fate Model (Version 1.2) 1999.U.S. 

Environmental Protection Agency (USEPA). 1989. Risk Assessment Guidance for 

Superfund. Volume II: Environmental Evaluation Manual. Interim Final. EPA/540/1-

89/001. March, 1989. 
Docket Number EPA-HQ-OPP-2015-0349

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Page 88 of 94

U.S. Environmental Protection Agency (USEPA). 1993. Wildlife Exposure Factors Handbook. 

Volume I. Office of Research and Development, Washington, D.C. EPA/630/R-93/187a. 

U.S. Environmental Protection Agency (USEPA). 2001. Generic Estimated Environmental 

Concentration Model (GENEEC) Version 2.0. Environmental Fate and Effects Division, 

Office of Pesticide Programs

U.S. Environmental Protection Agency. 2002a. Office of Prevention, Pesticides and Toxic 

Substances/Office of Pesticide Programs. Pesticide Ecotoxicity Database. 

U.S. Environmental Protection Agency. 2002b. ECOTOX User Guide: ECOTOXicology 

Database System. Version 2.0. Available: http:/www.epa.gov/ecotox, 8/1/2002, 

8/14,2002

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. 

Environmental Impacts of Preservative-treated Wood Conference, Orlando, Florida. Feb. 

http://www.ccaresearch.org/Pre-conference/pdf/Weis.pdf.

Weis, J., P. Weis, and T. Proctor. 1998. The Extent of Benthic Impacts of CCA-Treated Wood 

Structures in Atlantic Coast Estuaries. Arch. Environ. Contam. Toxicol. 34: 313-322.

Weis, P., J.S. Weis, and L.M. Coohill. 1989. Biological Impact of Wood Treated with 

Chromated Copper Arsenate on Selected Estuarine Organisms. In Pesticides in 

Terrestrial and Aquatic Environments: Proceedings of a National Research Conference 

May 11-12, 1989, edited by Diana L. Weigmann. Virginia Polytechnic Institute and 

State University, Blacksburg, VA.

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, R., J.S. Weis, A. Greenberg, and T.J. Nosker. 1992. Toxicity of Construction Materials in 

the Marine Environment: A Comparison of Chromated-Copper-Arsenate-Treated Wood 

and Recycled Plastic. Arch. Environ. Contam. Toxicol. 22(1): 99-106.

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: 41-46.
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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 Environment. Arch Environ 

Contam Toxicol 31(1): 24-37.

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 Environment, Lands and Parks, Lower Mainland Regional 

Office.
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Appendix D Screening Level Down-theDrain 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 treatment facilities.
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Appendix E Product Chemistry

The chromated arsenicals product chemistry information is summarized in Table F1 for chromic 

acid, Table F2 for arsenic acid, and Table F3 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 oC) 43756904

1 % v/v at 25 oC

830.7050 UV/Visible Absorption Sorption from 290-500 nm 49184601

830.7200 Melting point (oC) 197 43756904

830.7370 Dissociation constant (pKa) 0.74 and 6.5 43756904

25 oC

830.7550 Octanol-water partition 

coefficient at 25 o

C (Log Kow) N/A

43756904

Not applicable for non-organic 

polar materials

830.7840 Solubility in water (mg/L) 630,000 43756904

25 oC

830.7950 Vapor pressure (mmHg) N/A

43756904

Material is a solid at room 

temperature and melting point is 

197 oC 

None Henry's law constant at 25 o

C

(atm-m3

/mol) N/A

Volatility from water is not 

significant because of lack of 

vapor pressure

atm-m3/mol = atmosphere cubic meter per mole; oC = degrees Celsius; mg/L = milligrams per liter; mmHg = 

millimeters of mercury;

Table F2 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 oC

830.7050 UV/Visible Absorption No sorption from 290-800 nm 49177501

830.7200 Melting point (oC) 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 Kow) 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 oC
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Guideline 

No. Parameter Value Reference (MRID unless specified) / Comments

None Henry's law constant at 25 o

C 

(atm-m3

/mol) N/A

Volatility from water is not 

significant because of lack of 

vapor pressure

atm-m3/mol = atmosphere cubic meter per mole; oC = degrees Celsius; mg/L = milligrams per liter; mmHg = 

millimeters of mercury;

Table F3 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 (oC)

830.7370 Dissociation constant (pKa)

830.7550 Octanol-water partition 

coefficient at 25 oC (Log Kow)

830.7840 Solubility in water (mg/L)

830.7950 Vapor pressure (mmHg)

None Henry's law constant at 25 oC 

(atm-m3/mol)

atm-m3/mol = atmosphere cubic meter per mole; oC = 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 & 

Regulatory 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. Archer, K. (2013) Product Chemistry of Arsenic Acid Solution. Unpublished 

study prepared by Viance, LLC. 7p.
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Appendix F Categories of Forest Products 

That May be Treated with Chromated 

Arsenicals

Supplemental Labeling for Chromated Arsenical Products.
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