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TOXICOLOGICAL PROFILE FOR
 

ACRYLAMIDE
 


 


 


 


 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

September 2009 
 

 

 


 

ACRYLAMIDE ii 

DISCLAIMER

The use of company or product name(s) is for identification only and does not imply endorsement by the 

Agency for Toxic Substances and Disease Registry. 

This information is distributed solely for the purpose of pre dissemination public comment under 

applicable information quality guidelines. It has not been formally disseminated by the Agency for Toxic 

Substances and Disease Registry. It does not represent and should not be construed to represent any 

agency determination or policy. 

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ACRYLAMIDE iii 

UPDATE STATEMENT
 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine/Applied Toxicology Branch
 

1600 Clifton Road NE
 

Mailstop F-62
 

Atlanta, Georgia 30333
 

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ACRYLAMIDE iv 

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v 

FOREWORD 

This toxicological profile is prepared in accordance with guidelines developed by the Agency for 

Toxic Substances and Disease Registry (A TSDR) and the Environmental Protection Agency (EPA). The 

original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necesslll)'. 

The A TSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

information for these toxic substances described therein. Each peer-reviewed profile identifies and reviews 

the key literature that describes a substance's toxicologic properties. Other pertinent literature is also 

presented, but is described in less detail than the key studies. The profile is not intended to be an 

exhaustive document; more comprehensive sources of specialty information are referenced. 

The focus ofthe profiles is on health and toxicologic information. Each toxicological profile begins 

with a public health statement that describes, in nontechnical language, a substance's relevant toxicological 

properties. Following the public health statement is information concerning levels ofsignificant human 

exposure and, where known, significant health effects. The adequacy of information to determine a 

substance's health effects is described in a health effects summlll)'. Data needs that are ofsignificance to 

protection ofpublic health are identified by A TSDR and EPA. 

Each profile includes the following: 

(A) The examination, summlll)', and interpretation ofavailable toxicologic information and 

epidemiologic evaluations on a toxic substance to ascertain the levels ofsignificant human 

exposure for the substance and the associated acute, subacute, and chronic health effects; 

(B) 	A determination ofwhether adequate information on the health effects ofeach substance is 

available or in the process of development to determine levels of exposure that present a 

significant risk to human health ofacute, subacute, and chronic health effects; and 

(C) 	Where appropriate, identification oftoxicologic testing needed to identifY the types or levels of 

exposure that may present significant risk ofadverse health effects in humans. 

The principal audiences for the toxicological profiles are health professionals at the Federal, State, 

and local levels; interested private sector organizations and groups; and members ofthe public. We pIan to 

revise these documents in response to public comments and as additional data become available. 

Therefore, we encourage comments that will make the toxicological profile series ofthe greatest use. 

Comments should be sent to: 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology and Environmental Medicine 

1600 Clifton Road, N.E. 

Mail Stop F-62 

Atlanta, Georgia 30333 
VI 

The toxicological profiles are developed under the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section 

I 04(i)(1) directs the Administrator ofATSDR to " ...effectuate and implement the health related 

authorities" ofthe statute. This inCludes the preparation oftoxicological profiles for hazardous substances 

most commonly found at facilities on the CERCLA National Priorities List and that pose the most 

significant potential threat to human health, as determined by ATSDR and the EPA. Section 104(i)(3) of 

CERCLA, as amended, directs the Administrator ofA TSDR to prepare a toxicological profile for each 

substance on the list. In addition, A TSDR has the authority to prepare toxicological profiles for substances 

not found at sites on the National Priorities List, in an effort to " ...establish and maintain inventory of 

literature, research, and studies on the health effects oftoxic substances" under CERCLA Section 

I 04(i)(1 XB), to respond to requests for consultation under section 104(iX 4), and as otherwise necessary to 

support the site-specific response actions conducted by ATSDR. 

This profile reflects ATSDR's assessment of all relevant toxicologic testing and information that 

has been peer-reviewed. Staffs ofthe Centers for Disease Control and Prevention and other Federal 

scientists have also reviewed the profile. In addition, this profile has been peer-reviewed by a 

nongovernmental panel and is being made available for public review. Final responsibility for the contents 

and views expressed in this toxicological profile resides with ATSDR. 

Howard Frumkin, M.D., Dr. P.H. VThomas R. Frieden, M.D., M.P.H. 

Director, National Center for Environmental Administrator, Agency for Toxic Substances and 

Health/Agency for Toxic Substances and Disease Disease Registry 

Registry 
 

 

 

 

 

 

 

 


 


 


 


 


 


 


 


 

ACRYLAMIDE vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances will find the following information helpful for fast 

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating 

patients about possible exposure to a hazardous substance. It explains a substance’s relevant 

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of 

the general health effects observed following exposure. 

Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, 

and assesses the significance of toxicity data to human health. 

Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type 

of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length 

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are 

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. Please refer to the Public Health Statement to identify general health effects observed 

following exposure. 

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health 

issues: 

Section 1.6 How Can (Chemical X) Affect Children?
 

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)?
 

Section 3.7 Children’s Susceptibility
 

Section 6.6 Exposures of Children
 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) Fax: (770) 488-4178 

E-mail: cdcinfo@cdc.gov Internet: http://www.atsdr.cdc.gov 

The following additional material can be ordered through the ATSDR Information Center: 

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an 

exposure history and how to conduct one are described, and an example of a thorough exposure 

history is provided. Other case studies of interest include Reproductive and Developmental 

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide 

Toxicity; and numerous chemical-specific case studies. 

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ACRYLAMIDE viii 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident. Volumes I and II are planning guides to assist first responders and hospital emergency 

department personnel in planning for incidents that involve hazardous materials. Volume III— 

Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care 

professionals treating patients exposed to hazardous materials. 

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. 

Other Agencies and Organizations 

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, 

GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, 

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, 

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 

• Phone: 800-35-NIOSH. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212. 

Referrals 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk 

Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266. 

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ACRYLAMIDE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Patricia Ruiz, Ph.D.
 

Obaid Faroon, Ph.D.
 

Moiz Mumtaz, Ph.D.
 

ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA
 

David W. Wohlers, Ph.D.
 

Lynn E. Barber, M.S.
 

Peter R. McClure, Ph.D., DABT
 

Christine Carnegie, B.A.
 

SRC, Inc., North Syracuse, NY
 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

1.	 Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and classifying 

end points. 

2.	 Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3.	 Data Needs Review. The Applied Toxicology Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

4.	 Green Border Review. Green Border review assures the consistency with ATSDR policy. 

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ACRYLAMIDE x 

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ACRYLAMIDE xi 

PEER REVIEW
 

A peer review panel was assembled for acrylamide. The panel consisted of the following members: 

1.	 Herman Bolt, M.D., Ph.D., Professor Emeritus, Leibniz Research Centre for Working 

Environment and Human Factors, Dortmund, Germany 

2.	 Timothy Fennell, Ph.D., Senior Research Chemist, RTI International, Drug Metabolism and 

Pharmacokinetics Department, Research Triangle Park, NC 

3.	 James Klaunig, Ph.D., Professor of Public Health, Director, Center for Environmental Health, 

Indiana University School of Medicine, Indianapolis, IN 

These experts collectively have knowledge of acrylamide‘s physical and chemical properties, 

toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and 

quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer 

review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, 

and Liability Act, as amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer 

reviewers' comments and determined which comments will be included in the profile. A listing of the 

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their 

exclusion, exists as part of the administrative record for this compound. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

content. The responsibility for the content of this profile lies with the ATSDR. 

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ACRYLAMIDE xii 

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CONTENTS
 

DISCLAIMER ..............................................................................................................................................ii
 

UPDATE STATEMENT .............................................................................................................................iii
 

FOREWORD ................................................................................................................................................v
 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS....................................................................vii
 

CONTRIBUTORS.......................................................................................................................................ix
 

PEER REVIEW ...........................................................................................................................................xi
 

CONTENTS...............................................................................................................................................xiii
 

LIST OF FIGURES ..................................................................................................................................xvii
 

LIST OF TABLES.....................................................................................................................................xix
 

1. PUBLIC HEALTH STATEMENT..........................................................................................................1
 

1.1 WHAT IS ACRYLAMIDE? ........................................................................................................1
 

1.2 WHAT HAPPENS TO ACRYLAMIDE WHEN IT ENTERS THE ENVIRONMENT? ...........2
 

1.3 HOW MIGHT I BE EXPOSED TO ACRYLAMIDE?................................................................2
 

1.4 HOW CAN ACRYLAMIDE ENTER AND LEAVE MY BODY?.............................................2
 

1.5 HOW CAN ACRYLAMIDE AFFECT MY HEALTH?..............................................................3
 

1.6 HOW CAN ACRYLAMIDE AFFECT CHILDREN?.................................................................3
 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO ACRYLAMIDE?.............3
 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
 

EXPOSED TO ACRYLAMIDE?.................................................................................................4
 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH?..................................................................................................4
 

1.10 WHERE CAN I GET MORE INFORMATION? ........................................................................5
 

2. RELEVANCE TO PUBLIC HEALTH ...................................................................................................7
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO ACRYLAMIDE IN THE
 
 

UNITED STATES........................................................................................................................7
 

2.2 SUMMARY OF HEALTH EFFECTS.........................................................................................8
 

2.3 MINIMAL RISK LEVELS (MRLs) ..........................................................................................10
 

3. HEALTH EFFECTS..............................................................................................................................15
 

3.1 INTRODUCTION......................................................................................................................15
 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE.................................... 15
 

3.2.1 Inhalation Exposure ............................................................................................................16
 

3.2.1.1 Death...............................................................................................................................16
 

3.2.1.2 Systemic Effects..............................................................................................................17
 

3.2.1.3 Immunological and Lymphoreticular Effects.................................................................21
 

3.2.1.4 Neurological Effects .......................................................................................................21
 

3.2.1.5 Reproductive Effects.......................................................................................................27
 

3.2.1.6 Developmental Effects....................................................................................................27
 

3.2.1.7 Cancer.............................................................................................................................27
 

3.2.2 Oral Exposure .....................................................................................................................30
 

3.2.2.1 Death...............................................................................................................................30
 

3.2.2.2 Systemic Effects..............................................................................................................30
 

3.2.2.3 Immunological and Lymphoreticular Effects .................................................................60
 

3.2.2.4 Neurological Effects .......................................................................................................60
 

3.2.2.5 Reproductive Effects.......................................................................................................62
 

3.2.2.6 Developmental Effects....................................................................................................63
 

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3.2.2.7 Cancer.............................................................................................................................65
 

3.2.3 Dermal Exposure.................................................................................................................70
 

3.2.3.1 Death...............................................................................................................................70
 

3.2.3.2 Systemic Effects..............................................................................................................71
 

3.2.3.3 Immunological and Lymphoreticular Effects.................................................................74
 

3.2.3.4 Neurological Effects .......................................................................................................74
 

3.2.3.5 Reproductive Effects....................................................................................................... 74
 

3.2.3.6 Developmental Effects....................................................................................................75
 

3.2.3.7 Cancer.............................................................................................................................75
 

3.3 GENOTOXICITY ......................................................................................................................75
 

3.4 TOXICOKINETICS...................................................................................................................88
 

3.4.1 Absorption...........................................................................................................................88
 

3.4.1.1 Inhalation Exposure ........................................................................................................89
 

3.4.1.2 Oral Exposure .................................................................................................................90
 

3.4.1.3 Dermal Exposure.............................................................................................................93
 

3.4.2 Distribution .........................................................................................................................94
 

3.4.2.1 Inhalation Exposure ........................................................................................................94
 

3.4.2.2 Oral Exposure .................................................................................................................94
 

3.4.2.3 Dermal Exposure.............................................................................................................95
 

3.4.3 Metabolism .........................................................................................................................95
 

3.4.4 Elimination and Excretion ................................................................................................102
 

3.4.4.1 Inhalation Exposure ......................................................................................................102
 

3.4.4.2 Oral Exposure ...............................................................................................................102
 

3.4.4.3 Dermal Exposure........................................................................................................... 104
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD)
 
 

Models................................................................................................................................ 104
 

3.5 MECHANISMS OF ACTION ................................................................................................. 115
 

3.5.1 Pharmacokinetic Mechanisms........................................................................................... 115
 

3.5.2 Mechanisms of Toxicity.................................................................................................... 115
 

3.5.3 Animal-to-Human Extrapolations..................................................................................... 119
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ......................... 119
 

3.7 CHILDREN’S SUSCEPTIBILITY..........................................................................................120
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ...................................................................124
 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Acrylamide..................................125
 

3.8.2 Biomarkers Used to Characterize Effects Caused by Acrylamide....................................125
 

3.9 INTERACTIONS WITH OTHER CHEMICALS ...................................................................125
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE..............................................126
 

3.11 METHODS FOR REDUCING TOXIC EFFECTS..................................................................127
 

3.11.1 Reducing Peak Absorption Following Exposure ..............................................................128
 

3.11.2 Reducing Body Burden.....................................................................................................128
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects............................................128
 

3.12 ADEQUACY OF THE DATABASE.......................................................................................129
 

3.12.1 Existing Information on Health Effects of Acrylamide ....................................................129
 

3.12.2 Identification of Data Needs.............................................................................................131
 

3.12.3 Ongoing Studies................................................................................................................139
 

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................141
 

4.1 CHEMICAL IDENTITY..........................................................................................................141
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES.......................................................................141
 

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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................145
 

5.1 PRODUCTION ........................................................................................................................145
 

5.2 IMPORT/EXPORT ..................................................................................................................149
 

5.3 USE...........................................................................................................................................149
 

5.4 DISPOSAL...............................................................................................................................150
 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................151
 

6.1 OVERVIEW.............................................................................................................................151
 

6.2 RELEASES TO THE ENVIRONMENT .................................................................................153
 

6.2.1 Air .....................................................................................................................................154
 

6.2.2 Water.................................................................................................................................157
 

6.2.3 Soil....................................................................................................................................158
 

6.3 ENVIRONMENTAL FATE.....................................................................................................158
 

6.3.1 Transport and Partitioning ................................................................................................158
 

6.3.2 Transformation and Degradation ......................................................................................159
 

6.3.2.1 Air .................................................................................................................................159
 

6.3.2.2 Water.............................................................................................................................160
 

6.3.2.3 Sediment and Soil .........................................................................................................160
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ................................160
 

6.4.1 Air .....................................................................................................................................161
 

6.4.2 Water.................................................................................................................................161
 

6.4.3 Sediment and Soil .............................................................................................................162
 

6.4.4 Other Environmental Media..............................................................................................162
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ......................................168
 

6.6 EXPOSURES OF CHILDREN................................................................................................170
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ............................................171
 

6.8 ADEQUACY OF THE DATABASE.......................................................................................171
 

6.8.1 Identification of Data Needs .............................................................................................172
 

6.8.2 Ongoing Studies................................................................................................................174
 

7. ANALYTICAL METHODS................................................................................................................177
 

7.1 BIOLOGICAL MATERIALS..................................................................................................177
 

7.2 ENVIRONMENTAL SAMPLES.............................................................................................179
 

7.3 ADEQUACY OF THE DATABASE.......................................................................................182
 

7.3.1 Identification of Data Needs..................................................................................................182
 

7.3.2 Ongoing Studies.....................................................................................................................183
 

8. REGULATIONS, ADVISORIES, AND GUIDELINES.....................................................................185
 

9. REFERENCES ....................................................................................................................................191
 

10. GLOSSARY ......................................................................................................................................241
 

ACRYLAMIDE xv 

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APPENDICES 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS .............................................................A-1
 

B. USER’S GUIDE.................................................................................................................................. B-1
 

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS...................................................................... C-1
 

D. INDEX ................................................................................................................................................D-1
 

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ACRYLAMIDE xvii 

LIST OF FIGURES 

3-1. Levels of Significant Exposure to Acrylamide - Inhalation ............................................................... 20
 

3-2. Levels of Significant Exposure to Acrylamide - Oral ........................................................................ 52 

3-3. Metabolic Scheme for Acrylamide and Its Metabolite Glycidamide ................................................. 97
 

3-4. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance .................................................................................................... 106
 

3-5. Schematic of the Kirman et al. (2003) Physiologically Based Pharmacokinetic (PBPK) Model 

for Acrylamide .................................................................................................................................. 108
 

3-6. Schematic of the Young et al. (2007) Physiologically Based Pharmacokinetic/Toxicodynamic 

(PBPK/TD) Model For Acrylamide and Glycidamide ..................................................................... 113
 

3-7. Existing Information on Health Effects of Acrylamide .................................................................... 130
 

6-1. Frequency of NPL Sites with Acrylamide Contamination ............................................................... 152
 

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ACRYLAMIDE xix 

LIST OF TABLES 

3-1. Levels of Significant Exposure to Acrylamide - Inhalation ............................................................... 18
 

3-2. Self-Reported Neurological Symptoms and Observed Clinical Signs Among Acrylamide 

Workers and Nonexposed Workers .................................................................................................... 23
 

3-3. Prevalence of Symptoms and Signs of Adverse Health Effects in Acrylamide-Exposed 

Workers and Controls ......................................................................................................................... 25
 

3-4. Levels of Significant Exposure to Acrylamide - Oral ........................................................................ 31 

3-5. Incidence of Tumors with Statistically Significant Increases in 2-Year Bioassays with 

F344 Rats Exposed to Acrylamide in Drinking Water ....................................................................... 69
 

3-6. Levels of Significant Exposure to Acrylamide - Dermal ................................................................... 72
 

3-7. Genotoxicity of Acrylamide In Vivo .................................................................................................. 76
 

3-8. Genotoxicity of Acrylamide In Vitro ................................................................................................. 84
 

3-9. Original Model Parameter Values for Rats in the Kirman et al. (2003) Physiologically
 

Based Toxicokinetic (PBTK) Model ................................................................................................ 109
 

4-1. Chemical Identity of Acrylamide ..................................................................................................... 142
 

4-2. Physical and Chemical Properties of Acrylamide ............................................................................ 143
 

5-1. Facilities that Produce, Process, or Use Acrylamide ........................................................................ 146
 

5-2. 2008 Acrylamide Production in the United States ............................................................................ 148
 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use Acrylamide ................. 155
 

6-2. Acrylamide Levels in Different Food and Food Product Groups from Norway, Sweden, 

Switzerland, the United Kingdom, and the United States................................................................. 164
 

6-3. Acrylamide in Potato Products ......................................................................................................... 165
 

6-4. Acrylamide Content of Food ............................................................................................................ 166
 

6-5. Acrylamide Levels in Food Products Sampled for the 2003–2006 Total Diet Studies (TDS) 

Summary ........................................................................................................................................... 167
 

6-6. Ongoing Research Regarding the Environmental Fate and Exposure to Acrylamide ...................... 175
 

7-1. Analytical Methods for Determining Acrylamide in Biological Samples ........................................ 178
 

7-2. Analytical Methods for Determining Acrylamide in Environmental Samples ................................. 180
 

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8-1. Regulations and Guidelines Applicable to Acrylamide....................................................................187

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ACRYLAMIDE 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about acrylamide and the effects of exposure to it. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the 

nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long-term 

federal clean-up activities. Acrylamide has been found in at least 3 of the 1,699 current or former NPL 

sites. Although the total number of NPL sites evaluated for this substance is not known, the possibility 

exists that the number of sites at which acrylamide is found may increase in the future as more sites are 

evaluated. This information is important because these sites may be sources of exposure and exposure to 

this substance may be harmful. 

When a substance is released either from a large area, such as an industrial plant, or from a container, 

such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You 

can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, 

eating, or drinking the substance, or by skin contact. 

If you are exposed to acrylamide, many factors will determine whether you will be harmed. These factors 

include the dose (how much), the duration (how long), and how you come in contact with it. You must 

also consider any other chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, and 

state of health. 

1.1 WHAT IS ACRYLAMIDE? 

White or colorless, 

odorless crystalline 

solid 

Acrylamide can violently react when melting. When heated, acrid 

fumes may be released. 

Used in industry Acrylamide is used to make polyacrylamide, which is mainly used in 

treating effluent from water treatment plants and industrial processes. 

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ACRYLAMIDE 2 

1. PUBLIC HEALTH STATEMENT 

1.2 WHAT HAPPENS TO ACRYLAMIDE WHEN IT ENTERS THE ENVIRONMENT? 

Most commonly found 

in water 

Acrylamide may enter drinking water if polyacrylamide is used in the 

treatment process. It can be found in soils, but is rarely found in air. 

Rapidly broken down 

in soil and water 

If acrylamide enters soil or water, it will be broken down quickly by 

bacteria. 

1.3 HOW MIGHT I BE EXPOSED TO ACRYLAMIDE?
 

Water and soil Drinking water can sometimes contain acrylamide. It can enter drinking 

water from the treatment process of municipal supplies as well as from 

substances used to construct dams and wells. Acrylamide breaks 

down quickly in water and soil, but there is still a chance of exposure if 

you live near a plastics or dye plants. 

Inhalation and dermal 

contact 

If you smoke, or breathe second-hand tobacco smoke, you might be 

exposed to acrylamide. Tobacco smoke is a major source of 

acrylamide exposure within the general population. People involved in 

the production or use of acrylamide and acrylamide-containing products 

are exposed if they breathe in air that contains acrylamide. They may 

also be exposed by coming into skin contact with acrylamide. 

Food Acrylamide is formed in foods that are rich in carbohydrates (particularly 

potatoes) when they are fried, grilled, or baked at normal cooking 

temperatures. Levels of acrylamide in these foods increase with higher 

temperatures and longer cooking times. Protein-based foods (such as 

meats) probably contain low amounts of acrylamide. Ingestion of foods 

that contain acrylamide is a primary source of exposure. 

1.4 HOW CAN ACRYLAMIDE ENTER AND LEAVE MY BODY?
 

May enter your body 

through food, drinking 

water, breathing, and 

skin contact 

Acrylamide can enter your body when you eat foods containing 

acrylamide. Drinking water that contains acrylamide will have a similar 

effect. Breathing tobacco smoke may cause some level of acrylamide 

to enter your lungs. Acrylamide can also enter your body if it comes in 

contact with your skin. Dermal contact with acrylamide can occur if you 

work in the manufacture of acrylamide or polyacrylamide gels. 

Leaves through bodily 

fluids 

Once in your body, acrylamide enters your body fluids. Acrylamide and 

its breakdown products leave your body mostly through urine; small 

amounts may leave through feces, exhaled air, and breast milk. 

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ACRYLAMIDE 3 

1. PUBLIC HEALTH STATEMENT 

1.5 HOW CAN ACRYLAMIDE AFFECT MY HEALTH? 

This section looks at studies concerning potential health effects in animal and human studies. 

Nervous system 

effects 

Nervous system effects such as muscle weakness, numbness in hands 

and feet, sweating, unsteadiness, and clumsiness were reported in 

some acrylamide workers. However, most people are not exposed to 

acrylamide levels high enough to cause these effects. 

Reproductive effects Acrylamide reduces the ability of male animals to produce offspring and 

could cause similar effects in humans, but not likely at exposure levels 

experienced by most people. 

Cancer Acrylamide has caused several types of cancer in animals. We do not 

know whether acrylamide causes cancer in humans. 

1.6 HOW CAN ACRYLAMIDE AFFECT CHILDREN? 

This section discusses potential health effects in humans from exposures during the period from 

conception to maturity at 18 years of age. 

Effects in children Acrylamide is expected to affect children in the same manner as adults. 

It is not known whether children are more susceptible than adults to the 

effects of acrylamide. 

Developmental effects Effects such as decreased body weight, decreased startle responses, 

and decreased levels of some chemicals involved in transmission of 

brain signals were seen in some animals exposed to acrylamide before 

or shortly following birth. There are no reports of acrylamide causing 

developmental effects in humans. 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO ACRYLAMIDE?
 

Limit exposure to 

tobacco and secondhand smoke 

Tobacco smoke contains acrylamide. Avoid smoking or breathing in 

second-hand smoke. 

Reduce consumption 

of foods that contain 

acrylamide 

Avoid eating a lot of carbohydrate-rich foods that are cooked at high 

temperatures (e.g., French fries). Foods with higher protein content 

appear to have lower amounts of acrylamide. Avoid overcooking foods. 

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ACRYLAMIDE	 	 4 

1. PUBLIC HEALTH STATEMENT 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 

ACRYLAMIDE? 

Can be measured in 

blood and urine 

Acrylamide and its breakdown products can be measured in blood and 

urine. These measurements may be useful in estimating how much 

acrylamide has entered the body. 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. Regulations 

can be enforced by law. The EPA, the Occupational Safety and Health Administration (OSHA), and the 

Food and Drug Administration (FDA) are some federal agencies that develop regulations for toxic 

substances. Recommendations provide valuable guidelines to protect public health, but cannot be 

enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the National 

Institute for Occupational Safety and Health (NIOSH) are two federal organizations that develop 

recommendations for toxic substances. 

Regulations and recommendations can be expressed as “not-to-exceed” levels. These are levels of a toxic 

substance in air, water, soil, or food that do not exceed a critical value. This critical value is usually based 

on levels that affect animals; they are then adjusted to levels that will help protect humans. Sometimes 

these not-to-exceed levels differ among federal organizations because they used different exposure times 

(an 8-hour workday or a 24-hour day), different animal studies, or other factors. 

Recommendations and regulations are also updated periodically as more information becomes available. 

For the most current information, check with the federal agency or organization that provides it. 

Some regulations and recommendations for acrylamide include the following: 

Levels in drinking 

water set by EPA 

The EPA has determined that exposure to acrylamide in drinking water 

at concentrations of 1.5 mg/L for one day or 0.3 mg/L for 10 days is not 

expected to cause any adverse effects in a child. 

Levels in workplace 

air set by OSHA 

OSHA set a legal limit of 0.3 mg/m3 for acrylamide in air averaged over 

an 8-hour work day. 

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ACRYLAMIDE 5 

1. PUBLIC HEALTH STATEMENT 

1.10 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department, or contact ATSDR at the address and phone number below. 

ATSDR can also tell you the location of occupational and environmental health clinics. These clinics 

specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous 

substances. 

Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You may 

request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information and technical 

assistance number at 1-800-CDCINFO (1-800-232-4636), by e-mail at cdcinfo@cdc.gov, or by writing 

to: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine
 

1600 Clifton Road NE
 

Mailstop F-62
 

Atlanta, GA 30333
 

Fax: 1-770-488-4178
 

Organizations for-profit may request copies of final Toxicological Profiles from the following: 

National Technical Information Service (NTIS)
 

5285 Port Royal Road
 

Springfield, VA 22161
 

Phone: 1-800-553-6847 or 1-703-605-6000
 

Web site: http://www.ntis.gov/
 

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ACRYLAMIDE 7 

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2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO ACRYLAMIDE IN THE 

UNITED STATES 

Acrylamide is an industrial chemical used mainly in the production of polyacrylamides, which are used 

primarily as flocculants for clarifying drinking and treating municipal and industrial effluents. In the oil 

industry, acrylamide is used as a flow control agent to enhance oil production from wells. Acrylamide 

and polyacrylamides are also used in the production of dyes and organic chemicals, contact lenses, 

cosmetics and toiletries, permanent-press fabrics, textiles, pulp and paper products; also in ore processing, 

sugar refining, and as a chemical grouting agent and soil stabilizer for the construction of tunnels, sewers, 

wells, and reservoirs. In 2008, approximately 141,000 metric tons of acrylamide were produced in the 

United States. 

Acrylamide may be released to the environment during production and use of polyacrylamides, which are 

used as clarifiers in water treatment. Residual monomer in the polyacrylamide is the main source of 

drinking water contamination by acrylamide. It can be released to soil and land from plastics and dye 

industries and from acrylamide-containing grouting agents used in reservoirs and wells. Acrylamide is 

rarely found in the atmosphere. 

Acrylamide is not considered highly persistent in the environment. It is expected to be highly mobile in 

soil and water and is highly susceptible to biodegradation in both media. It can be removed from soils by 

hydrolysis, though it is typically not present in soil or the atmosphere. Acrylamide is not expected to 

significantly bioconcentrate. 

Acrylamide is sometimes present in drinking water due to leaching of monomer during treatment 

processes. Acrylamide was identified in food samples cooked at high temperatures. Concentrations of 

acrylamide in food vary with the type of food, cooking method, temperature, water content, food 

thickness, and length of heating. Carbohydrate-rich foods typically contain the highest levels of 

acrylamide. 

Exposure to acrylamide occurs mainly through ingestion, dermal contact, and inhalation. Ingestion of 

foods containing acrylamide appears to be one of the most common methods of exposure for the general 

public. Average estimated intake of acrylamide from food sources ranged from 0.3 to 0.8 μg/kg bw/day. 

Children may be susceptible to food-borne exposure 2–3 times that of adults on a body weight basis. 

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ACRYLAMIDE 8 

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Ingestion of contaminated drinking water can result in exposure to acrylamide. Inhalation of tobacco 

smoke, including second-hand smoke, can result in inhalation exposure for both adults and children. In 

the body, acrylamide can cross the placenta and result in exposure to unborn children. Breast milk has 

been shown to contain acrylamide in mothers with diets high in acrylamide-containing foods. 

Occupational exposure to acrylamide is primarily due to dermal contact when handling bags and drums of 

the chemical, followed by inhalation of dust or aerosols. 

2.2 SUMMARY OF HEALTH EFFECTS 

Neurological Effects. Ataxia and skeletal muscle weakness are hallmark symptoms of acrylamideinduced central-peripheral neuropathy. Available information in humans includes case reports and crosssectional studies in which reported symptoms of neuropathy were primarily associated with occupational 

exposure potential via both inhalation and dermal contact. Numerous animal studies confirm the 

neurological effects of acrylamide exposure. Available information in animals primarily involves oral 

exposure. Clinical signs can be elicited following single oral dosing in the range of 100–200 mg/kg; 

lower dose levels require repeated dosing to elicit clinical signs. Histopathological evidence of 

acrylamide-induced peripheral neuropathy has been observed in rats receiving oral doses as low as 

1 mg/kg/day for 3 months; the observed degenerative effects in peripheral nerve fibers at such dose levels 

have been shown to be completely reversible within a few months following the cessation of exposure 

(Burek et al. 1980). 

Reproductive Effects. Pre- and postimplantation losses and decreased numbers of live fetuses have 

been observed in rats and mice receiving repeated oral doses of acrylamide in the range of 3– 

60 mg/kg/day. Results of dominant lethality testing and crossover trials indicate that acrylamide-induced 

reproductive effects are male mediated. Other reported effects in acrylamide-treated laboratory animals 

include decreased sperm mobility, degenerative effects in spermatids, and testicular atrophy. 

Cancer. Available cohort mortality studies of occupationally-exposed workers have not found 

associations between acrylamide and mortality from cancer. Available human data on cancer risk from 

acrylamide in food include case-control studies and reports from ongoing prospective studies. These 

studies provide little evidence for acrylamide-induced cancer in humans exposed to acrylamide in the 

diet. 

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ACRYLAMIDE 9 

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Results of two similarly-designed lifetime studies in orally-exposed rats provide clear evidence of 

acrylamide-induced carcinogenicity. Reported effects common to both studies include significantly 

increased incidences of thyroid (follicular cell) tumors, mesotheliomas of the tunica vaginalis testis, and 

mammary gland tumors. Findings of significantly increased incidences of adrenal pheochromocytomas in 

male rats and tumors of the oral cavity, central nervous system (glial origin), pituitary, and clitoris or 

uterus in female rats in the earlier bioassay were not replicated in the second bioassay. 

Acrylamide was reported to initiate skin tumors in female mice administered repeated oral doses of 

acrylamide followed by dermal applications of 12-O-tetradecanoylphorbol-13-acetate (TPA, a tumor 

promoter) to the shaved back. 

EPA assigned the descriptor B2 (probable human carcinogen) to acrylamide based on “inadequate human 

data and sufficient evidence of carcinogenicity in animals; significantly increased incidences of benign 

and/or malignant tumors at multiple sites in both sexes of rats, and carcinogenic effects in a series of oneyear limited bioassays in mice by several routes of exposures.” EPA noted that positive genotoxicity 

data, adduct formation activity, and structure-activity relationships to vinyl carbamate and acrylonitrile 

provide support to the classification. The International Agency for Research on Cancer assigned 

acrylamide to Group 2A (probably carcinogenic to humans) based on similar assessment. The National 

Toxicology Program has determined that acrylamide is reasonably anticipated to be a human carcinogen. 

Body Weight Effects. Depressed body weight, including actual body weight loss, and depressed body 

weight gain were consistently reported in laboratory animals following oral exposure to acrylamide. 

Significantly depressed mean body weight was observed in male prepubertal and adult ddy mice (range of 

6–13% less than control mean body weight) was noted during 3–5 days following single oral dosing at 

150 mg/kg (Sakamoto et al. 1988). Very slight to slight initial weight loss was reported following single 

oral administration of acrylamide at 126 mg/kg in rats and guinea pigs and 63 mg/kg in rabbits. 

Repeated-dose oral exposure of rats to doses as low as 15 mg/kg/day for 5 consecutive days resulted in 

significantly depressed body weight gain (approximately 40% less than controls); higher doses (30– 

60 mg/kg/day) caused actual weight loss. An 8-week dosing period to dogs at 7 mg/kg/day resulted in 

weight loss. Weight loss was reported in cats receiving acrylamide orally for 16 weeks at 15 mg/kg/day. 

A daily dose as low as 7.5 mg/kg/day during gestation days 6–20 resulted in approximately 12% 

depressed maternal weight gain in rats. 

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ACRYLAMIDE 10 

2. RELEVANCE TO PUBLIC HEALTH 

2.3 MINIMAL RISK LEVELS (MRLs) 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for acrylamide. An 

MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an 

appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are 

derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive 

health effect(s) for a specific duration within a given route of exposure. MRLs are based on 

noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for 

acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate 

methodology does not exist to develop MRLs for dermal exposure. 

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), 

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional 

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an 

example, acute inhalation MRLs may not be protective for health effects that are delayed in development 

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic 

bronchitis. As these kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

Inhalation MRLs 

No inhalation MRLs were derived due to the lack of appropriate data on the effects of inhalation exposure 

to acrylamide. 

Numerous accounts of associations between exposure to acrylamide and neurological impairment are 

available (Auld and Bedwell 1967; Bachmann et al. 1992; Calleman et al. 1994; Davenport et al. 1976; 

Donovan and Pearson 1987; Dumitru 1989; Fullerton 1969; Garland and Patterson 1967; Gjerløff et al. 

2001; Hagmar et al. 2001; He et al. 1989; Igisu and Matsuoka 2002; Igisu et al. 1975; Kesson et al. 1977; 

Mapp et al. 1977; Mulloy 1996; Myers and Macun 1991; Takahashi et al. 1971). Most associations were 

made from occupational exposure scenarios that likely included inhalation and dermal (and possibly oral) 

exposure. Acrylamide levels in the workplace air were measured in some instances; however, reliable 

exposure-response data are not available. 

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ACRYLAMIDE 11 

2. RELEVANCE TO PUBLIC HEALTH 

Acrylamide-induced health effects in laboratory animals following inhalation exposure to acrylamide 

were assessed in two studies that did not include multiple exposure levels. Mortalities and central 

nervous system effects were observed in dogs exposed to acrylamide dust at a concentration of 

15.6 mg/m3 for 6 hours/day for up to 16 days (American Cyanamid Company 1953a). There were no 

signs of adverse effects in similarly-exposed guinea pigs. No adverse effects were seen in cats exposed to 

what was described as a “saturated” vapor for 6 hours/day, 5 days/week for 3 months at a mean analytical 

concentration of 1.65 ppm (4.8 mg/m3

) (Dow Chemical Company 1957). 

Oral MRLs 

An MRL of 0.02 mg/kg/day has been derived for acute-duration oral exposure (14 days or less) to 

acrylamide. 

Available human data are limited to case reports that include findings of persistent peripheral neuropathy 

in a subject who intentionally ingested 18 g of acrylamide crystals (Donovan and Pearson 1987) and signs 

of central and peripheral neurological deficits in family members exposed (likely via oral and dermal 

routes) to acrylamide in well water at a concentration of 400 ppm (Igisu and Matsuoka 2002; Igisu et al. 

1975). Epidemiologic studies designed to evaluate noncancer health effects in groups of orally-exposed 

subjects have not been conducted. 

Single oral doses elicit clinical signs of acrylamide-induced neurological effects in laboratory animals at 

lethal or near-lethal doses (American Cyanamid Company 1953c; Fullerton and Barnes 1966; McCollister 

et al. 1964; Tilson and Cabe 1979). Repeated oral dosing elicits clinical signs at lower daily dose levels. 

For example, convulsions and ataxia were noted as early as day 14 in rats administered acrylamide by 

daily gavage at 25 mg/kg/day for 21 days (Dixit et al. 1981). Daily exposure of male mice to acrylamide 

in the drinking water for 12 days at an estimated dose of 25.8 mg/kg/day caused decreased rotarod 

performance and increased hindlimb splay as early as days 6 and 8, respectively (Gilbert and Maurissen 

1982). 

Histopathological evaluations of nervous tissues following acute-duration oral exposure to acrylamide are 

limited to electron microscope results from peripheral nerve preparations in subgroups of control and 

high-dose (20 mg/kg/day) male rats administered acrylamide in the drinking water for up to 93 days 

(Burek et al. 1980). No signs of acrylamide-induced degenerative effects were observed after 7 days of 

treatment, but degeneration in axons and myelin sheath were noted after 33 days of treatment. These 

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ACRYLAMIDE 12 

2. RELEVANCE TO PUBLIC HEALTH 

interim assessments were not performed at lower dose levels and the effect of treatment following 14 days 

(maximum acute-duration exposure period as defined by ATSDR) was not assessed. 

Acrylamide-induced effects on body weight have been reported in rats following acute-duration oral 

exposure to acrylamide. In one study, repeated-dose oral exposure of rats to doses as low as 

15 mg/kg/day for 5 consecutive days resulted in significantly depressed body weight gain (approximately 

40% less than controls); higher doses (30–60 mg/kg/day) caused actual weight loss, whereas no effect on 

body weight was seen at a dose level of 5 mg/kg/day (Tyl et al. 2000b). Another study reported 

significantly lower mean body weight (magnitude 8%) as early as treatment day 13 in male rats 

administered acrylamide in the drinking water at a concentration resulting in an estimated dose level of 

20 mg/kg/day, but no effect on body weight at an estimated dose level of 5 mg/kg/day (Burek et al. 1980). 

Daily oral administration of acrylamide to male rats at 15 mg/kg/day for as little as 5 days followed by 

mating with unexposed female rats resulted in reduced mating, decreased fertility, and male-mediated 

increased pre- and postimplantation losses; these effects were not seen at 5 mg/kg/day (Sublet et al. 1989; 

Tyl et al. 2000b). A similarly-designed study (Tyl et al. 2000b) confirmed the findings of acrylamideinduced increased implantation loss, although, based on pairwise comparisons with controls, statistical 

significance was achieved only at the highest dose level (60 mg/kg/day). Tyl et al. (2000b) also noted 

significantly decreased body weight gain during the 5 days of dosing at 15 mg/kg/day and actual weight 

loss at higher doses, findings not included in the study report of Sublet et al. (1989). Based on the 

reproducible results for male-mediated implantation loss in the studies of Sublet et al. (1989) and Tyl et 

al. (2000b) and the lack of supporting information regarding the body weight effects, the male-mediated 

implantation loss was selected as the critical effect for deriving an acute-duration oral MRL for 

acrylamide. As discussed in detail in Appendix A, benchmark dose (BMD) analysis was applied to 

provide a point of departure (BMCL10) of 1.78 mg/kg/day; an uncertainty factor of 100 (10 for 

extrapolation from animals to humans and 10 for human variability) was applied, resulting in an acuteduration oral MRL of 0.02 mg/kg/day for acrylamide. 

An MRL of 0.002 mg/kg/day has been derived for intermediate-duration oral exposure (15–364 days) 

to acrylamide. 

No human data are available regarding health effects associated with intermediate-duration oral exposure 

to acrylamide. 

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ACRYLAMIDE 13 

2. RELEVANCE TO PUBLIC HEALTH 

Results of available animal studies demonstrate that neurological effects in males and females and 

reproductive effects in males are the most sensitive noncancer effects associated with intermediateduration oral exposure to acrylamide (Burek et al. 1980; Chapin et al. 1995; Johnson et al. 1984, 1985, 

1986; Sakamoto and Hashimoto 1986; Smith et al. 1986; Tyl et al. 2000a, 2000b; Zenick et al. 1986). 

The lowest dose level reported to induce male-mediated implantation losses was 2.8 mg/kg/day in male 

Long-Evans rats receiving acrylamide from the drinking water for 80 days; this study identified a noobserved-adverse effect level (NOAEL) of 1 mg/kg/day (Smith et al. 1986). Ultrastructural degenerative 

peripheral nerve changes were observed at a dose level as low as 1 mg/kg/day in male F344 rats receiving 

acrylamide from the drinking water for up to 93 days; this study identified a NOAEL of 0.2 mg/kg/day 

(Burek et al. 1980). Available data suggest that neurological effects represent a more sensitive point of 

departure than reproductive effects for deriving intermediate- and chronic-duration oral MRLs for 

acrylamide. Therefore, degenerative nerve change was selected as the critical effect for deriving an 

intermediate-duration oral MRL for acrylamide. The study of Burek et al. (1980) was selected as the 

principal study because it identified the lowest lowest-observed-adverse-effect-level (LOAEL) for the 

critical effect. A NOAEL/LOAEL approach was selected because results of the ultrastructural 

evaluations included only 3 of 10 rats/group and were reported only as the total numbers of fields (per 

group) with ultrastructural changes as axolemma invaginations or Schwann cells without axons and/or 

with degenerating myelin. The lack of adequate quantitative data precludes the utilization of BMD 

analysis to derive an intermediate-duration oral MRL for acrylamide. The NOAEL of 0.2 mg/kg/day was 

selected as the point of departure and was divided by an uncertainty factor of 100 (10 for extrapolation 

from animals to humans and 10 for human variability) to yield an intermediate-duration oral MRL of 

0.002 mg/kg/day for acrylamide. 

No chronic-duration oral MRL was derived for acrylamide. 

No human data are available to evaluate neurological effects following chronic-duration oral exposure to 

acrylamide. Two chronic toxicity and carcinogenicity bioassays are available for male and female F344 

rats receiving acrylamide from the drinking water for up to 2 years (Friedman et al. 1995; Johnson et al. 

1984, 1985, 1986). One study included dose levels of 0, 0.01, 0.1, 0.5, and 2.0 mg/kg/day (Johnson et al. 

1984, 1985, 1986); the other study included dose levels of 0, 0.1, 0.5, or 2 mg/kg/day in males and 0, 1.0, 

or 3.0 mg/kg/day in females (Friedman et al. 1995). Both studies identified a NOAEL of 0.5 mg/kg/day 

and a LOAEL of 2 mg/kg/day for histopathological evidence of degenerative nerve changes. These 

values are slightly higher than the NOAEL of 0.2 mg/kg/day and the LOAEL of 1 mg/kg/day for 

degenerative nerve changes in the intermediate-duration oral study used to derive an intermediate-

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ACRYLAMIDE 14 

2. RELEVANCE TO PUBLIC HEALTH 

duration oral MRL for acrylamide. These differences may be solely the result of differences in dose 

spacing. Because the NOAEL of 0.5 mg/kg/day used as a potential point of departure for deriving a 

chronic-duration oral MRL for acrylamide is slightly higher than the NOAEL of 0.2 mg/kg/day that 

serves as the point of departure for the intermediate-duration oral MRL of 0.002 mg/kg/day, the 

intermediate-duration oral MRL of 0.002 mg/kg/day is expected to be protective of chronic-duration oral 

exposure to acrylamide. 

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ACRYLAMIDE 15 

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3.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of acrylamide. It 

contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. 

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

considerable amount of judgment may be required in establishing whether an end point should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these end points. ATSDR 

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between 

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 

considered to be important because it helps the users of the profiles to identify levels of exposure at which 

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not 

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ACRYLAMIDE 16 

3. HEALTH EFFECTS 

the effects vary with dose and/or duration, and place into perspective the possible significance of these 

effects to human health. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and 

figures may differ depending on the user's perspective. Public health officials and others concerned with 

appropriate actions to take at hazardous waste sites may want information on levels of exposure 

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no 

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans 

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. 

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of acrylamide are 

indicated in Table 3-4 and Figure 3-2. Because cancer effects could occur at lower exposure levels, 

Figure 3-2 also shows a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 

10,000 to 1 in 10,000,000 (10-4 to 10-7), as developed by EPA. 

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in 

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 

3.2.1 Inhalation Exposure 

3.2.1.1 Death 

Human data are available from two cohort mortality studies of occupational exposure to acrylamide, one 

by Collins et al. (1989) with most recent follow up by Marsh et al. (2007) and one by Sobel et al. (1986) 

with follow up by Swaen et al. (2007). In these studies, no significant associations were found between 

occupational exposure to acrylamide and incidences of death from all causes. See Section 3.1.2.7 

(Cancer) for more detailed information regarding these cohorts and assessments of death due to cancers. 

Reliable information regarding death in animals following inhalation exposure to acrylamide is limited. 

In a study performed for the American Cyanamid Company (1953a), two dogs, seven rats, and seven 

guinea pigs (sex and strain unspecified) were exposed to acrylamide dust at 15.6 mg/m3 for 6 hours/day, 

5 days/week for up to 12 exposures in a 16-day period. Four of the seven rats died overnight following 

the first exposure period and two of the remaining rats died a few days later. One of the dogs died on 

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ACRYLAMIDE 17 

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study day 15; there were no deaths among the guinea pigs. The study authors stated that >90% of the 

particles were in the respirable range (0.3–1.2 μm). 

Reliable inhalation mortality data for each species are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.2 Systemic Effects 

No human or animal data were located regarding cardiovascular, gastrointestinal, musculoskeletal, 

hepatic, renal, endocrine, or dermal effects following inhalation exposure to acrylamide. 

Respiratory Effects. Available information regarding acrylamide-associated respiratory effects is 

restricted to complaints of nose and throat irritation in a group of tunnel workers who had been 

occupationally exposed to acrylamide and N-methylolacrylamide in a chemical grouting agent for 

2 months (Hagmar et al. 2001). Increasing incidences of complaints were associated with increasing 

levels of hemoglobin adducts of acrylamide. 

Hematological Effects. No data were located regarding hematological effects in humans following 

inhalation of acrylamide. Available information in animals is limited to a study in which four rats were 

exposed to acrylamide as a “saturated” vapor for 6 hours/day, 5 days/week for 3 months at a mean 

analytical concentration of 1.65 ppm (4.8 mg/m3

); the exposures did not affect hematology results 

(American Cyanamid Company 1954). 

Ocular Effects. Available information regarding acrylamide-associated ocular effects is restricted to 

complaints of eye irritation in a group of tunnel workers who had been occupationally exposed to 

acrylamide and N-methylolacrylamide in a chemical grouting agent for 2 months (Hagmar et al. 2001). 

Increasing incidences of complaints were associated with increasing levels of hemoglobin adducts of 

acrylamide. 

Body Weight Effects. No data were located regarding body weight effects in humans following 

inhalation of acrylamide. Available information in animals is limited to a study in which four rats were 

exposed to acrylamide as a “saturated” vapor for 6 hours/day, 5 days/week for 3 months at a mean 

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159

15.6

166

15.6

25

15.6

161

4.84.8

160

15.6

23

15.6

Table 3-1 Levels of Significant Exposure to Acrylamide - Inhalation 

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Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/m3) (mg/m3) (mg/m3) Chemical Form 

ACUTE EXPOSURE Death 

1 Rat 4 d 15.6 (death of 4/7 rats in 1 day American Cyanamid Co

6 hr/d (NS) and 2 others before day 1953a

8)

Neurological 

2 Rat 4 d 15.6 (loss of coordination and American Cyanamid Co

6 hr/d (NS) equilibrium on exposure 1953a 

day 4) 

INTERMEDIATE EXPOSURE Death 

3 Dog 16 d 15.6 (death of 1/2 dogs on day American Cyanamid Co

5 d/wk (NS) 15) 1953a 6 hr/d 

Systemic 

4 Cat 3 mo Hemato 4.8 American Cyanamid Co

5 d/wk 1954 6 hr/d 

Acrylamide 

Bd Wt 4.8 

Neurological 

5 Gn Pig 16 d 15.6 American Cyanamid Co

5 d/wk (NS) 1953a 6 hr/d 

6 Dog 16 d 15.6 (CNS effects including American Cyanamid Co

5 d/wk (NS) loss of equilibrium and 1953a 6 hr/d coordination) 
82

4.8

7 

Table 3-1 Levels of Significant Exposure to Acrylamide - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/m3) (mg/m3) (mg/m3) Chemical Form 

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Cat 3 mo 4.8 American Cyanamid Co

5 d/wk 1954 6 hr/d 

Acrylamide 

a The number corresponds to entries in Figure 3-1. Bd Wt = body weight; d = day(s); Hemato = hematological; hr = hour(s); LOAEL = lowest-observed-adverse-effect level; mo = month(s); NOAEL = no-observed-advNS = not specified; week(s) 
1

10

100

Death

3d

Hematological

4c

Body Weight

4c

Neurological

7c

6d 5g

mg/m3

Figure 3-1 Levels of Significant Exposure to Acrylamide - Inhalation

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

1r 2r

DeathNeurological

Acute (≤ 14 days)

ACRYLAMIDE

3. HEALTH EFFECTS

20

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ACRYLAMIDE 21 

3. HEALTH EFFECTS 

analytical concentration of 1.65 ppm (4.8 mg/m3); the exposures did not affect body weights (American 

Cyanamid Company 1954). 

3.2.1.3 Immunological and Lymphoreticular Effects 

No data were located regarding immunological or lymphoreticular effects in humans or animals following 

inhalation exposure to acrylamide. 

3.2.1.4 Neurological Effects 

Information in humans is available from numerous case reports in which acrylamide exposure has been 

associated with signs of impaired neurological performance in central and peripheral nervous systems that 

include impaired motor function and muscle weakness (Auld and Bedwell 1967; Davenport et al. 1976; 

Dumitru 1989; Fullerton 1969; Garland and Patterson 1967; Gjerløff et al. 2001; Igisu et al. 1975; Kesson 

et al. 1977; Mapp et al. 1977; Mulloy 1996; Takahashi et al. 1971). Human data are also available from 

cross-sectional studies that included self-reported symptoms and neurological evaluations of acrylamideexposed workers with potential for inhalation and dermal (and possibly oral) exposure (Bachmann et al. 

1992; Calleman et al. 1994; Hagmar et al. 2001; He et al. 1989; Myers and Macun 1991). Although the 

case reports and cross-sectional studies provide supportive evidence of acrylamide-induced neurotoxicity, 

they lack information regarding relative contributions of natural exposure routes (inhalation, oral, 

dermal), exposure-response relationships, and other confounding exposures. They are therefore 

unsuitable for meaningful quantitative risk analysis. 

He et al. (1989) evaluated health end points in workers employed for 1–18 months at a factory in China 

that began producing acrylamide and polyacrylamide in 1984. A referent group consisted of unexposed 

workers from the same town. Concentrations of acrylamide in the workplace air (determined by gas 

chromatography) reached 5.56–9.02 mg/m3 between March and June 1985 during polymerization when 

there was an exceptional increase in production, and decreased to an average of 0.0324 mg/m3 (range not 

specified) after July 1985. The workers were evaluated in October 1985. The study authors reported that 

heavy skin contamination by aqueous acrylamide monomer was common among the workers. An 

acrylamide level of 410 mg/L was measured in the water in which three of the workers washed their 

hands. Personal interviews were conducted to obtain information on demographic factors, occupational 

history, symptoms, past illnesses, and family history. Physical and neurological examinations, visual 

acuity and visual field testing, skin temperature measurements, electrocardiography, and 

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ACRYLAMIDE 22 

3. HEALTH EFFECTS 

electroencephalography were performed. Sixty-nine of the exposed workers and 48 of the referent 

workers were subjected to electroneuromyographic examinations. 

As shown in Table 3-2, significantly greater percentages of the acrylamide-exposed group reported skin 

peeling from the hands, anorexia, numbness and coldness in hands and feet, lassitude, sleepiness, muscle 

weakness, clumsiness of the hands, unsteady gait, difficulty in grasping, and stumbling and falling. The 

authors stated that initial symptoms of skin peeling were the result of dermal exposure to aqueous 

acrylamide and that other symptoms appeared following 3–10 months of occupational exposure. Greater 

percentages of acrylamide-exposed workers exhibited erythema of the hands, sensory impairments 

(vibration, pain, and touch sensation), diminished reflexes, and intention tremor (Table 3-2). Electrical 

activity, monitored in both the abductor pollicis brevis and abductor digiti minimi muscles of the hand, 

revealed electromyographic abnormalities in the acrylamide-exposed workers that included denervation 

potentials (3/69 exposed workers), prolonged duration of motor units (40/69), increased polyphasic 

potentials (29/69), and discrete pattern of recruitment (9/69). These abnormalities were not seen in 

referent workers, with the exception of prolonged duration of motor units (4/48 referents). Significantly 

increased mean duration and mean amplitude of motor unit potentials and significantly decreased mean 

amplitude of sensory unit potentials were seen in the acrylamide-exposed group compared to the referent 

group. Assessment of visual acuity and visual field, nerve conduction velocity, electrocardiography, and 

electroencephalography revealed no significant exposure-related effects. 

Calleman et al. (1994) performed a cross-sectional analysis of hemoglobin adduct formation and 

neurological effects in a group of 41 factory workers who were exposed to acrylamide (and acrylonitrile, 

from which acrylamide is formed) for 1 month to 11.5 years (mean 3 years) during the production of 

acrylamide and polyacrylamide at a factory in China. As determined by station sampling and gas 

chromatography, mean acrylamide air concentrations were 1.07 and 3.27 mg/m3 in the synthesis and 

polymerization rooms, respectively, during the summer of 1991. Mean exposure concentrations during 

the time of collection of biomarker data (September 1991) were lower, averaging 0.61 and 0.58 mg/m3 in 

synthesis and polymerization rooms, respectively. Information regarding demographic factors, smoking 

and drinking habits, height and weight, occupational history, past illnesses, current symptoms, and 

reproductive history were collected by questionnaire. Neurological examinations were performed 

approximately 1 hour after a work shift. Vibration sensitivity thresholds were measured in fingers and 

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ACRYLAMIDE 23 

3. HEALTH EFFECTS 

Table 3-2. Self-Reported Neurological Symptoms and Observed Clinical Signs
 

Among Acrylamide Workers and Nonexposed Workers
 

Symptom 

Acrylamide 

Number 

group (n=71) 

Percent 

Reference 

Number 

group (n=51) 

Percent 

Skin peeling from the hands 38 53.5a 2 3.9 

Numbness in the hands and feet 15 21.1b 2 3.9 

Lassitude 14 19.7b 1 1.9 

Sleepiness 12 16.9b 0 0 

Muscle weakness 11 15.4b 0 0 

Clumsiness of the hands 8 11.2a 0 0 

Anorexia 8 11.2a 1 1.9 

Unsteady gait 6 8.4a 0 0 

Coldness of the hands and feet 6 8.4a 0 0 

Difficulty in grasping 5 7.0a 0 0 

Stumbling and falling 5 7.0a 0 0 

Sweating 27 38.0 14 27.4 

Dizziness 7 9.8 2 3.9 

Cramping pain 6 8.4 5 9.8 

Sign 

Erythema of hands 16 22.5b 0 0 

Skin peeling from the hands 16 22.5b 1 1.9 

Sensory impairments 

Vibration sensation 12 16.9b 0 0 

Pain sensation 7 9.8a 0 0 

Touch sensation 6 8.4a 0 0 

Position sensation 1 1.4 0 0 

Muscle atrophy in hands 4 5.6 0 0 

Diminished reflexes 

Biceps 12 16.9b 0 0 

Triceps 10 14.0 4 7.8 

Knee 11 15.4a 1 1.9 

Ankle 8 11.2a 1 1.9 

Loss of reflexes 

Biceps 3 4.2 0 0 

Triceps 5 7.0 1 1.9 

Knee 5 7.0a 0 0 

Ankle 17 23.9b 0 0 

Intention tremor 13 18.3a 2 3.9 

Positive Romberg’s sign 15 21.1 3 5.8 

a

p <0.05

b

p <0.01 (χ2 test) 

Source: He et al. 1989 

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ACRYLAMIDE 24 

3. HEALTH EFFECTS 

toes. Physical and neurological examinations and electroneuromyographic (ENMG) testing were 

performed. For each test, a nonexposed referent group was included. Quantitative assessment of 

contributions of dermal and inhalation exposure were not made, although in the synthesis area of the 

factory where neurological symptoms were most severe, dermal contact was considered to have been the 

major exposure route. 

As shown in Table 3-3, a variety of symptoms and signs of adverse health effects were noted in 

acrylamide-exposed workers (Calleman et al. 1994). Other significant (p<0.01) effects in the exposed 

workers included increased (magnitude ≥60%) vibration threshold, decreased (10–20%) conduction 

velocity in the peroneal and sural nerves, and increased (25–36%) latency in median, ulnar, and peroneal 

nerves. Neurotoxicity index scores, a quantitative expression of the severity of peripheral neuropathy, 

decreased with physical distance from the synthesis room where the monomer itself was handled. This 

relationship was not reflected by results of hand or foot vibration sensitivity measurements. 

Hagmar et al. (2001) performed a health examination on a group of 210 tunnel construction workers who 

had been occupationally exposed for 2 months to a chemical grouting agent containing acrylamide and 

N-methylolacrylamide. Workers were expected to have experienced dermal exposure as well as 

inhalation exposure. Venous blood samples were drawn and questionnaires and physical examinations 

were administered 1–5 weeks after exposure was stopped. Quantitative exposure data were limited to two 

personal air samples showing concentrations of 0.27 and 0.34 mg/m3 for the sum of acrylamide and 

N-methylolacrylamide; further analysis suggested that the air contained a 50:50 mixture of these 

compounds. The health examination included an extensive questionnaire and a physical examination that 

included unspecified tests of peripheral nerve function. Blood samples for the analysis of adducts of 

acrylamide with N-terminal valines in hemoglobin were drawn within a month after construction work 

was completed. A group of 50 subjects who claimed recently developed or deteriorated peripheral 

nervous function at the initial physical examination was subjected to more detailed neurophysiologic 

examinations and 6-month follow-up clinical (n=29) and neurophysiological (n=26) examinations. Those 

with remaining symptoms were examined for up to 18 months postexposure. 

Hemoglobin adduct levels for 18 nonsmoking unexposed referents varied between 0.02 and 0.07 nmol/g 

globin. Adduct levels in 47 of the 210 tunnel workers did not exceed the highest level of the referents. 

The remaining workers were divided into three categories according to adduct levels as follows: 89 with 

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ACRYLAMIDE 25 

3. HEALTH EFFECTS 

Table 3-3. Prevalence of Symptoms and Signs of Adverse Health Effects in
 

Acrylamide-Exposed Workers and Controls
 

Symptom or sign Exposed (percent) Controls (n=10) 

Numbness of extremities 29/41 (71)a 0 

Fatigue 29/41 (71)a 0 

Sweating of hands and feet 28/41 (71)a 0 

Skin peeling 24/41 (59)a 0 

Menstruation disorders 4/7 (57) NA 

Loss of pain sensation 22/41 (54)a 0 

Loss of touch sensation 19/41 (46)b 0 

Dizziness 18/41 (44)b 0 

Anorexia 17/41 (41)b 0 

Loss of vibration sensation 17/41 (41)b 0 

Nausea 16/41 (39)b 0 

Loss of ankle reflexes 12/41 (29) 0 

Headache 11/41 (27) 0 

Unsteady gait 9/41 (22) 0 

Loss of knee jerk 8/41 (20) 0 

Unsteady Romberg sign 8/41 (20) 0 

Loss of triceps reflexes 4/41 (10) 0 

Loss of biceps reflexes 4/41 (10) 0 

a

p <0.01 (χ2 test) b

p <0.05 

Source: Calleman et al. 1994 

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ACRYLAMIDE 26 

3. HEALTH EFFECTS 

0.08–0.29 nmol/g globin, 36 with 0.3–1.0 nmol/g globin, and 38 with 1.0–17.7 nmol/g globin. The study 

authors noted a significant (p<0.05) association between self-reported exposure categories and adduct 

levels. Significant positive correlations (p<0.05) between prevalence of self-reported peripheral nervous 

symptoms, irritant symptoms, and symptoms of general discomfort with adduct levels were found. For 

example, in the groups with adduct levels <0.08 nmol/g globin, 0.08–0.29 nmol/g globin, 0.3–1.0 nmol/g 

globin, and >1.0 nmol/g globin, incidences of reported numbness or tingling in the feet or legs were 

2/47 (4%), 10/89 (11%), 9/36 (25%), and 14/38 (37%), respectively. Irritant symptoms and symptoms of 

general discomfort typically disappeared following the end of a workday, whereas peripheral nervous 

symptoms persisted. Follow-up examinations revealed that 58% of the subjects with early signs of 

impaired peripheral nervous function improved, while only 4% showed signs of deterioration. 

Myers and Macun (1991) investigated peripheral neuropathy in a cohort of 66 workers in a South African 

factory that produced polyacrylamide. The investigation followed clinical diagnosis of peripheral 

neuropathy in five workers at the factory. The workforce was divided into a number of exposure 

categories, based on environmental sampling and discussions with workers. Exposure levels for the 

various tasks ranged from 0.07 to 2.5 times the National Institute of Occupational Safety and Health 

(NIOSH) recommended exposure limit (REL) of 0.3 mg/m3

. Workers were then classified as being 

exposed to airborne acrylamide when exposure levels exceeded the REL (n=22), and unexposed when 

exposure levels were below the REL (n=41). Workers completed a questionnaire that was designed to 

capture social, medical, and occupational history. A standard blind neurological examination was also 

performed. 

The exposed group showed higher prevalences of abnormalities for all symptoms (weakness, sensation, 

balance, fatigue, visual, loss of weight, urogenital, and fingertip skin), most signs (fingertip effects, light 

touch, tactile discrimination, pain), and reflexes, coordination, motor weakness, gait, and Rombergism. 

Statistically significant differences between exposed and unexposed groups for individual effects were 

seen only for abnormal sensation symptoms and signs in fingertip skin (including color, peeling, and 

sweating). The overall prevalence of acrylamide-related abnormalities among the exposed was 66.7%, 

which was statistically significantly higher (p<0.05) than that of the unexposed group (prevalence of 

14.3%). The authors stated that most workers observed to have abnormalities (number not reported) were 

employed in areas where exposures were highest (1.6–2.5 times the REL). 

Bachmann et al. (1992) performed a follow-up investigation in July 1990 at the same South African 

factory that had been examined in 1986 by Myers and Macun (1991). The study design was similar to 

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ACRYLAMIDE 27 

3. HEALTH EFFECTS 

that of Myers and Macun (1991), but included measurements of vibration sensation threshold. Among 

82 workers employed at follow-up, increased prevalences of symptoms of tingling and numbness in hands 

and feet, weakness and pain in arms and legs, peeling hand skin, and sweating hands were reported by 

exposed workers, compared with those classified as being unexposed. The symptoms of numbness, limb 

pain, and peeling and sweating of hands were statistically significantly increased in exposed workers. 

Results of clinical examinations provided supporting evidence for the reported increased symptoms of 

peeling and sweating of the hands. No gross neurological abnormalities were found. Mean vibration 

sensation thresholds were similar among unexposed and exposed groups, even when adjusting for age, 

and no association was found between vibration thresholds and any symptoms. 

Information regarding neurological effects in animals exposed to acrylamide by the inhalation route is 

limited to a single study report in which seven rats, seven guinea pigs, and two dogs were exposed to dust 

of acrylamide at an analytical concentration of 15.6 mg/m3 for 6 hours/day, 5 days/week for up to 

12 exposures in a 16-day period (American Cyanamid Company 1953a). Reported signs of neurological 

effects in the three rats that survived to exposure termination on day 4 included loss of equilibrium and 

coordination. There was no mention of neurological signs in the exposed dogs, although one of the dogs 

lost weight and died on day 15. No toxic signs were seen in the guinea pigs. 

3.2.1.5 Reproductive Effects 

No data were located regarding reproductive effects in humans or animals following inhalation exposure 

to acrylamide. 

3.2.1.6 Developmental Effects 

No data were located regarding developmental effects in humans or animals following inhalation 

exposure to acrylamide. 

3.2.1.7 Cancer 

Human data are available from two cohort mortality studies of occupational exposure to acrylamide, one 

by Collins et al. (1989) with most recent follow up by Marsh et al. (2007) and one by Sobel et al. (1986) 

with follow up by Swaen et al. (2007). Exposure to acrylamide was considered to have occurred 

primarily via inhalation and dermal exposure. 

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ACRYLAMIDE 28 

3. HEALTH EFFECTS 

Collins et al. (1989) conducted a cohort mortality study of all male workers (8,854, of which 2,293 were 

exposed to acrylamide) who had been hired between January 1, 1925 and January 31, 1973 at four 

American Cyanamid factories, three in the United States (Fortier, Louisiana [1295 workers]; Warners, 

New Jersey [7,153 workers]; and Kalamazoo, Michigan [60 workers]) and one in the Netherlands (Botlek 

[346 workers]). Estimations of acrylamide exposure were based on available monitoring data and worker 

knowledge of past jobs and processes. Mortality rates among the factory workers were compared with 

the expected number of deaths among men of the United States from 1925 to 1980 or the Netherlands 

from 1950 to 1982 to derive standardized mortality ratios (SMRs) as a measure of relative risk for each 

cohort. No statistically significantly elevated all cause or cause-specific SMRs were found among 

acrylamide-exposed workers (including cancer of the digestive or respiratory systems, bone, skin, 

reproductive organs, bladder, kidney, eye, central nervous system, thyroid, or lymphatic system). Trend 

tests showed no increased risk of mortality due to cancer at several sites (digestive tract, respiratory 

system, prostate, central nervous system, or lymphopoietic system) with increasing level of exposure to 

acrylamide. 

The most recent update report of the cohort of Collins et al. (1989) includes study periods of 1925–2002 

for the 8,508 workers in the three facilities in the United States and 1965–2004 for the 344 workers at the 

Botlek plant in the Netherlands (the original cohort of 346 people included 2 females who were excluded 

in the follow up) (Marsh et al. 2007). Among the workers at the three facilities in the United States 

(during which 4,650 deaths occurred among the 8,508 workers in the period of 1925–2002), excess and 

deficit overall mortality risks were observed for cancer sites implicated in oral studies in experimental 

animals: brain and other central nervous system (SMR 0.67, 95% confidence interval [CI] 0.40–1.05), 

thyroid gland (SMR 1.38, 95% CI 0.28–4.02), and testis and other male genital organs (SMR 0.64, 95% 

CI 0.08–2.30); and for sites selected in the original report (Collins et al. 1989) of this cohort: respiratory 

system cancer (SMR 1.17, 95% CI 1.06–1.27), esophagus (SMR 1.20, 95% CI 0.86–1.63), rectum (SMR 

1.25, 95% CI 0.84–1.78), pancreas (SMR 0.94, 95% CI 0.70–1.22), and kidney (SMR 1.01, 95% CI 0.66– 

1.46). None of the mortality excesses were statistically significant, except for respiratory system cancer, 

which Collins et al. (1989) attributed to muriatic acid (hydrochloric acid) exposure. No significantly 

elevated SMRs were found for rectal, pancreatic, or kidney cancers in exploratory exposure-response 

analyses conducted according to the following exposure parameters and categories: duration of 

employment (<1, 1–, and 15+ years), time since first employment (<20, 20–, and 30+ years), duration of 

exposure (unexposed, 0.001–, 5–, and 20+ years), cumulative exposure (<0.001, 0.001–, 0.03–, and 0.30+ 

mg/m3

-years), and estimated mean exposure concentrations (unexposed, 0.001–, 0.02–, and 0.3+ mg/m3). 

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ACRYLAMIDE 29 

3. HEALTH EFFECTS 

Sobel et al. (1986) conducted a mortality study on a cohort of 371 workers assigned to acrylamide and 

polymerization operations at a Dow Chemical facility in the United States between 1955 and 1979. 

Analysis and review of air monitoring data and job classifications resulted in estimates of personal 8-hour 

time-weighted average acrylamide concentrations of 0.1–1.0 mg/m3 before 1957, 0.1–0.6 mg/m3 from 

1957 to 1970, and 0.1 mg/m3 thereafter. SMRs, calculated for categories in which at least two deaths 

were observed, were based on mortality of white males in the United States. No significantly increased 

incidences of cancer-related deaths were observed within the cohort. 

Followup to the Sobel et al. (1986) study cohort was expanded to include employees hired through 2001 

(Swaen et al. 2007). Exposure to acrylamide was retrospectively assessed based on personal samples 

from the 1970s onwards and area samples from the entire study period. Fewer acrylamide workers died 

(n=141) than expected (n=172.1). No cause-specific SMR for any of the investigated types of cancer was 

exposure related. The authors reported more total pancreatic cancer deaths (n=5) than expected (n=2.3) 

(SMR 222.2, 95% CI 72.1–518.5); however, three of the five were in the low-dose group, with no 

apparent dose-response relationship with acrylamide exposure. 

No data were located regarding cancer in animals following inhalation exposure to acrylamide. EPA 

(IRIS 2009) calculated an inhalation unit risk of 1.3x10-3 (mg/m3

)

-1 for acrylamide based on results of a 

2-year cancer bioassay in orally-exposed male and female F344 rats (Johnson et al. 1986) and route-toroute extrapolation (see Section 3.2.2.7 for details of the oral study). The air concentrations associated 

with risk of 1x10-4, 1x10-5, and 1x10-6 are 0.08, 0.008, and 0.0008 mg/m3

, respectively. 

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ACRYLAMIDE 30 

3. HEALTH EFFECTS 

3.2.2 Oral Exposure 

3.2.2.1 Death 

There are no reports of human deaths associated with oral exposure to acrylamide. 

Acrylamide has been demonstrated to be lethal to laboratory animals following a single oral dose. 

Reported oral LD50 values in rats range from 150 to 413 mg/kg (American Cyanamid Company 1973, 

1977; Dow Chemical Company 1957; Fullerton and Barnes 1966; McCollister et al. 1964; Tilson and 

Cabe 1979; Union Carbide Corporation 1947). Reported LD50 values in mice, guinea pigs, and rabbits 

range from 107 to 195 mg/kg (American Cyanamid Company 1951; Dow Chemical Company 1957; 

Hashimoto et al. 1981; McCollister et al. 1964). 

Repeated oral exposure to acrylamide has also been associated with death in laboratory animals. In one 

rat study, a single 100 mg/kg dose was not lethal, but two 100 mg/kg doses administered 24 hours apart 

resulted in mortalities (Fullerton and Barnes 1966). Sublet et al. (1989) reported death in a group of male 

Long-Evans hooded rats administered acrylamide by daily gavage for 5 days at a dose of 75 mg/kg/day. 

Longer repeated-dose exposure periods to lower daily doses are lethal as well. For example, a dose level 

of 50 mg/kg was lethal to rats receiving 12 daily gavage doses of 50 mg/kg in a 15-day period; the deaths 

occurred within a few days following the cessation of dosing (Fullerton and Barnes 1966). An 

acrylamide gavage dose of 30 mg/kg/day resulted in the death of 4/10 male and 2/10 female rats during 

the third week of daily dosing (Schulze and Boysen 1991). During the last 4 months of a 2-year study in 

which male and female rats received acrylamide from the drinking water at an estimated dose level of 

2 mg/kg/day, decreased survival of both sexes was noted; the increased mortality was statistically 

significant by study termination (Johnson et al. 1984, 1986). 

Reliable acute oral LD50 values for death and other mortality data for each species are recorded in 

Table 3-4 and plotted in Figure 3-2. 

3.2.2.2 Systemic Effects 

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each 

species and duration category are recorded in Table 3-4 and plotted in Figure 3-2. 

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14

294

12

413

1

180

119

203

149

100

125

175

21

316

18

195

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral 

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Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

ACUTE EXPOSURE Death 

1 Rat Once 294 M (LD50) (Wistar) (GW) 

2 Rat Once 413 M (LD50) (Sprague- (GW)

Dawley)

3 Rat Once 180 (LD50) (NS) (GW) 

4 Rat Once 203 F (LD50) (albino) (GW) 5 Rat 2 d 100 (most rats died within 3 1 x/d (albino) days following 2 days of (GW) dosing) 

6 Rat Once 175 M (LD50) (Fischer- 344) (GW) 

7 Rat Once 316 M (LD50) (albino) (GW) 8 Mouse Once 195 M (LD50) (albino) (G) 

Reference Chemical Form 

American Cyanamid Co1973 American Cyanamid Co1977 Dow Chemical CompanMcCollister et al. 1964 Fullerton and Barnes 19Acrylamide Fullerton and Barnes 19Acrylamide Tilson and Cabe 1979 Acrylamide Union Carbide Corporat1947 American Cyanamid Co1951 
135

107

4

180

5

150

167

5

20

95

5

15

117

20

98

100

150

3

126

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

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Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

9 Mouse Once 107 M (LD50) Hashimoto et al. 1981 (NS) Acrylamide 

10 Gn Pig Once 180 (LD50) Dow Chemical Compan

(NS) (GW) McCollister et al. 1964

11 Rabbit Once 150 (LD50) Dow Chemical Compan

(NS) (GW) McCollister et al. 1964

Systemic 

12 Rat 13 d Bd Wt 5 M 20 M (8% decreased mean Burek et al. 1980 (Fischer- 344) (W) body weight) Acrylamide 

13 Rat 5 d Bd Wt 5 M 15 M (significantly depressed Tyl et al. 2000b 1 x/d (Long- Evans) body weight gain during Acrylamide (GW) 5 days of acrylamide 

administration) 

14 Rat Gd 6-17 Walden et al. 1981 

Bd Wt 20 F (Fischer- 344) (GW) Acrylamide 

15 Mouse Once Bd Wt 100 M 150 M (significantly depressed Sakamoto et al. 1988 ddY (NS) body weight) Acrylamide 16 Gn Pig Once Bd Wt 126 (very slight initial body Dow Chemical Compan

(NS) (GW) weight loss) McCollister et al. 1964
6

63

168

20

157

25

120

203

146

100

148

100

47

126

126

100

200

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

17 Rabbit Once Bd Wt 63 (slight initial weight loss) Dow Chemical Compan

(NS) (GW) McCollister et al. 1964

Neurological 

18 Rat 7 d 20 M Burek et al. 1980 (Fischer- 344) (W) Acrylamide 

19 Rat Up to 21 d 25 M (convulsions and ataxia Dixit et al. 1981 1 x/d (Wistar) as early as treatment day Acrylamide (G) 14) 

20 Rat Once 203 F (fine tremors) Fullerton and Barnes 19

(albino) (GW) Acrylamide 

21 Rat Once 100 (fine tremors) Fullerton and Barnes 19

(albino) (GW) Acrylamide 

22 Rat 2 d 100 (generalized weakness) Fullerton and Barnes 19

1 x/d (albino) Acrylamide (GW) 

23 Rat Once 126 F (lethargy) McCollister et al. 1964 (NS) (GW) Acrylamide 

24 Rat Once 100 M 200 M (decreases in hindlimb Tilson and Cabe 1979 (Fischer- 344) (GW) grip strength and Acrylamide locomotory performance) 
94

30

45

118

20

134

25.8

37

100

50

126

92

5

15

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

25 Rat 5 d 30 M 45 M (clinical signs of Tyl et al. 2000b 1 x/d (Long- Evans) neurotoxicity) Acrylamide (GW) 

26 Rat Gd 6-17 20 F Walden et al. 1981 (Fischer- 344) (GW) Acrylamide 

27 Mouse 12 d 25.8 F (decreased rotarod Gilbert and Maurissen 1

(BALB/c) (W) performance, increased Acrylamide hindlimb splay as early 

as days 6-8) 

28 Dog Once 100 (severe neurological American Cyanamid Co

(Mongrel) (C) impairment of the limbs) 1953c 

29 Rabbit Once 126 (tremors) McCollister et al. 1964 (NS) (GW) Acrylamide 

Reproductive 

30 Rat 5 d b5 M 15 M (depressed fertility, Sublet et al. 1989 1 x/d (Long- Evans) increased Acrylamide (GW) preimplantation loss) 
93

30

45

87

30

97

100

32

47

28

2524

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

31 Rat 5 d 30 M 45 M (significantly increased 1 x/d (Long- Evans) postimplantation losses) (GW) 

32 Rat 5 d 30 M (significantly elevated 1 x/d (Fischer- 344) pre- and (GW) post-implantation losses) 

33 Mouse Once 100 M (histologic abnormalities ddY (NS) in spermatids) 

INTERMEDIATE EXPOSURE Death 

34 Rat 21 d 47 M (4/10 deaths during 21 (albino) (F) days of exposure) 

35 Rat 28 d 25 M (death of 8/10 male rats (Fischer- 344) (W) during exposure week 4) 

24 F (death of 5/10 female 

rats during exposure week 4) 

Reference Chemical Form 

Tyl et al. 2000b 

Acrylamide 

Working et al. 1987 

Acrylamide Sakamoto et al. 1988 Acrylamide American Cyanamid Co1953b American Cyanamid Co1991 
122

50

141

30

34

47

114

3.82

30

12

19

129

19

165

1

5

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

36 Rat 12 doses in 50 (death within a few days 15 d (albino) posttreatment) (GW) 

37 Rat 5 wk 30 (death of 4/10 males and 7 d/wk (Sprague- 2/10 females during Dawley) 1 x/d treatment week 3) (GW) 

Systemic 

38 Rat 21 d Bd Wt 47 M (severely depressed (albino) (F) body weight gain) 

39 Rat 2 wk premating Bd Wt 3.82 F and (SpragueDawley) Gd 0-19

(F) 

40 Rat 28 d Endocr 12 M 19 M (decreased serum (Fischer- 344) (W) testosterone, 73% less 

than controls) 

Bd Wt 12 M 19 (emaciation) 

9 F 

41 Rat up to 93 d Hemato 1 F 5 F (decreases in packed cell (Fischer- 344) (W) volume, erythrocytes, 

hemoglobin) 

Reference Chemical Form 

Fullerton and Barnes 19Acrylamide Schulze and Boysen 19Acrylamide American Cyanamid Co1953b American Cyanamid Co1979 Acrylamide American Cyanamid Co1991 Burek et al. 1980 Acrylamide 
100

2.5

7.5

110

25

140

30

138

23.7

106

5

10

104

45

143

90.8

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

42 Rat Gd 6-20 Field et al. 1990 

Bd Wt 2.5 F 7.5 F (12% decreased (Sprague- 1 x/d maternal weight gain) 

Acrylamide Dawley) (GW) 

43 Rat 21 d lactation Bd Wt 25 F (net maternal weight loss Friedman et al. 1999 period (Wistar) 1 x/d during 21-day lactation Acrylamide treatment period) (G) 

44 Rat 5 wk Bd Wt 30 (decreased mean body Schulze and Boysen 19

7 d/wk (Sprague- weight, 27% lower than 1x/d Acrylamide Dawley) controls) (GW) 

45 Rat 90 d Bd Wt 23.7 M Tanii and Hashimoto 19

(Wistar) (W) Acrylamide 

46 Rat Gd 6- Ld 10 Bd Wt 5 F 10 F (approximately 33% Wise et al. 1995 1 x/d (Sprague- depressed maternal body Acrylamide Dawley) (GW) weight gain during 10 

days of postpartum exposure) 

47 Mouse Gd 6-20 Bd Wt 45 F Field et al. 1990 1 x/d (CD-1) Acrylamide (GW) 

48 Mouse Up to 38 d Bd Wt 90.8 M (body weight loss) Ko et al. 1999 (ICR) (W) Acrylamide 
131

7

133

15

39

10

129

10

45

30

52

3

10

43

10

33

47

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

49 Dog 8 wk Bd Wt 7 (up to 12% weight loss) Satchell and McLeod 19

(F) Acrylamide 

50 Cat Up to 16 wk Bd Wt 15 (body weight loss, Post and McLeod 1977a (F) magnitude unspecified) Acrylamide 

Neurological 

51 Monkey 44-61 d 10 F (clinical signs of Dow Chemical Compan

5 d/wk 

peripheral neuropathy) Maurissen et al. 1983 1 x/d 

Acrylamide 

52 Monkey 6-10 wk 10 (degenerative changes in Eskin et al. 1985 5 d/wk 

1 x/d visual nerve fibers) Acrylamide 

53 Monkey NS 30 (peripheral neuropathy) Leswing and Ribelin 19

1 x/d 

Acrylamide 

54 Monkey up to 363 d 3 F 10 F (clinical signs of McCollister et al. 1964 

5 d/wk (NS) 

peripheral neuropathy) Acrylamide (F) 

55 Monkey 33-47 d 10 F (ataxia, adverse visual Merigan et al. 1985 5 d/wk 

1 x/d effects) Acrylamide 

56 Rat 21 d 47 M (paralysis of hind limbs) American Cyanamid Co

(albino) (F) 1953b 
26

25

115

3.82

27

129

19

74

0.2

1

20

153

25

109

25

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

57 Rat NS 25 M (clinical signs of 5 d/wk (albino) peripheral neuropathy) (G) 

58 Rat 2 wk premating 3.82 F and (SpragueDawley) Gd 0-19

(F) 

59 Rat 28 d 12 M 19 (clinical signs of (Fischer- 344) (W) peripheral neuropathy)

9 F 

60 Rat up to 93 d c 0.2 M 1 M (reversible ultrastructural 20 (progressive signs of (Fischer- 344) (W) degeneration in sciatic peripheral neuropathy) 

nerve fibers) 

61 Rat Up to 21 d 25 M (complete hindlimb 1 x/d (Wistar) paralysis by treatment (G) day 21) 

62 Rat 21 d lactation 25 F (progressive clinical period (Wistar) signs of neuropathy 1 x/d beginning as early as (G) treatment day 4) 

Reference Chemical Form 

American Cyanamid Co1959 American Cyanamid Co1979 Acrylamide American Cyanamid Co1991 Burek et al. 1980 Acrylamide Dixit et al. 1981 Acrylamide 

Friedman et al. 1999 

Acrylamide 
121

50

123

6

124

25

150

25

151

10

152

100

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

63 Rat 12 doses in 50 (severe weakness) Fullerton and Barnes 19

15 d (albino) Acrylamide (GW) 

64 Rat variable 6 (slight leg weakness after Fullerton and Barnes 19

(albino) (F) 40 weeks of exposure) Acrylamide 

65 Rat 38 d 25 (severe leg weakness) Fullerton and Barnes 19

(albino) (F) Acrylamide 

66 Rat Variable 25 (severe leg weakness by Fullerton and Barnes 19

5 d/wk (albino) 1 x/d 28 days of treatment) Acrylamide 

(GW) 

67 Rat 55 doses 10 F Fullerton and Barnes 19

5 d/wk (albino) 

1 x/d Acrylamide (GW) 

68 Rat Variable 100 (signs of severe Fullerton and Barnes 19

(albino) 1 d/wk 

1 x/d neuropathy by the third Acrylamide 

dose) (GW) 
31

310

1030

81

0.5

2

139

10

173

3.72 7.89

137

8.8

14.5

127

10

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

69 Rat 21 d 3 M 10 M (clinical and Gorzinski et al. 1979 (Fischer- 344) (W) histopathologic evidence

10 F of peripheral neuropathy) 

30 F (clinical and 

histopathologic evidence of peripheral neuropathy) 

70 Rat 3 mo 0.5 M 2 M (electron microscopic Johnson et al. 1984, 19

6 mo (Fischer- 344) degenerative effects in Acrylamide (W) sciatic nerve fibers) 

71 Rat 5 wk 10 (degenerative effects in Schulze and Boysen 19

7 d/wk (Sprague- nerve fibers) 1x/d Acrylamide Dawley)

(GW)

72 Rat GD6-PD21 3.72 F 7.89 F (abnormal gait) Takahashi et al. 2009 (Sprague- (W) Acrylamide Dawley) 

73 Rat 90 d 

8.8 M 14.5 M (decreased rotarod Tanii and Hashimoto 19

(Wistar) (W) 

performance) Acrylamide 

74 Rat 4 wk 10 M (hindlimb dysfunction) Tilson and Cabe 1979 5 d/wk (Fischer- 344) Acrylamide (GW) 
156

5

5

107

10

15

89

7.914.6

103

15

45

136

36

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

***DRAFT FOR PUBLIC COMMENT***

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

75 Rat 16 wk 5 F 5 M (slight axonal (Fischer- 344) (W) fragmentation in 

peripheral nerves of 6/6 males assessed) 

76 Rat Gd 6- Ld 10 10 F 15 F (hindlimb splay in 100% 1 x/d (Sprague- of dams during the first Dawley) (GW) few days of postpartum 

exposure) 

77 Rat 10 wk 7.9 M (increased incidences of (Long- Evans) (W) hindlimb splay) 

14.6 F (increased incidences of 

foot splay) 

78 Mouse Gd 6-20 15 F 45 F (up to 48% incidence of 1 x/d (CD-1) hindlimb splay) (GW) 

79 Mouse 8 wk 36 M (clinical signs of 2 x/wk peripheral neuropathy, (NS) testicular atrophy) 

Reference Chemical Form 

Tyl et al. 2000a 

Acrylamide 

Wise et al. 1995 

Acrylamide 

Zenick et al. 1986 

Acrylamide Field et al. 1990 Acrylamide Hashimoto et al. 1981 Acrylamide 
142

90.8

144

91.8

36

1

8

38

10

145

5.7

130

7

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

***DRAFT FOR PUBLIC COMMENT***

a 

Key to 

Figure 

80 81 82 83 84 85 

Species 

(Strain) 

Mouse (ICR) Mouse (ICR) Dog (Mongrel) Dog (Mongrel) Dog Dog 

Frequency NOAEL Less Serious Serious (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

Up to 38 d 90.8 M (clinically and (W) histopathologically 

confirmed peripheral neuropathy) 

NS 91.8 M (clinical signs of (W) peripheral neuropathy; 

ultrastructural degeneration in cutaneous nerve terminals) 

19 wk 1 8 (loss of coordination in 6 d/wk the rear extremities) 1 x/day (C) 29 d 10 F (incoordination and 7 d/wk weakness of the hind 1 x/day legs) (C) 6-7 wk 5.7 (clinical evidence of (C) neuropathy) 8 wk 7 (clinical signs of (F) peripheral neuropathy) 

Reference Chemical Form 

Ko et al. 1999 Acrylamide Ko et al. 2000; Ko et al. Acrylamide American Cyanamid Co1953c American Cyanamid Co1953c Hersch et al. 1989a Acrylamide Satchell and McLeod 19Acrylamide 
44

20

158

1

3

132

15

53

10

29

12

19

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

86 Cat NS 20 (peripheral neuropathy) 1 x/d 

87 Cat up to 367 d 1 3 (twitching motion in 5 d/wk (NS) hindquarters at 26 days, (F) slightly unsteady gait at 

47 days, definite weakness in the hindquarters at 68 days) 

88 Cat Up to 16 wk 15 (initial weakness of (F) hindlimbs and 

subsequent paralysis of fore- and hind-limbs) 

89 Baboon up to 137 d 10 (peripheral neuropathy) 1 x/d 

(F) 

Reproductive 

90 Rat 28 d 12 M 19 M (atrophy of the testes (Fischer- 344) (W) and/or seminal vesicles) 

Reference Chemical Form 

Leswing and Ribelin 19Acrylamide 

McCollister et al. 1964 

Acrylamide Post and McLeod 1977a Acrylamide Hopkins 1970 Acrylamide American Cyanamid Co1991 
85

1.5

2.8

83

2

55

88

5.1

7.9

8.8

84

3.1

7.5

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

91 Rat 80 d 1.5 M 2.8 M (male-mediated (Long- Evans) (W) increased 

postimplantation loss) 

92 Rat 16 wk 2 5 M (dominant lethal mutation (Fischer- 344) (W) effects) 

5 (decreases in 

implantations and number of live pups) 

93 Rat 10 wk 5.1 F 7.9 F (decreased pup body 8.8 M (male-mediated (Long- Evans) (W) weight) reproductive effects 

including decreased percentage impregnation of nonexposed females and increased postimplantation loss) 

94 Mouse 16-22 wk 3.1 M 7.5 M (increased early (CD-1) (W) resorptions, total 

postimplantation loss, decreased numbers of live fetuses, decreased numbers of live pups; apparently male mediated) 

Reference Chemical Form 

Smith et al. 1986 Acrylamide Tyl et al. 2000a Acrylamide Zenick et al. 1986 Acrylamide Chapin et al. 1995 Acrylamide 
96

918.7

13.3

113

3.82

99

15

112

1.3

6

108

25

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

95 Mouse 4 wk 9 M 13.3 M (decreased number of Sakamoto and Hashimo

ddY (W) fetuses/dam) 1986

18.7 F Acrylamide 

Developmental 

96 Rat 2 wk premating 

and 3.82 American Cyanamid Co

(Sprague- 1979 

Dawley) Gd 0-19 

Acrylamide (F) 

97 Rat Gd 6-20 15 Field et al. 1990 

(Sprague- 1 x/d 

Acrylamide Dawley) (GW) 

98 Rat 15 wk 1.3 6 (effects on measures of Garey and Paule 2007 Gd 1-21 (Fischer- 344) cognitive motivation) Ppd 1-84 Acrylamide 

(GW) 

99 Rat Throughout 25 M (neurochemical changes Husain et al. 1987 lactation via (Wistar) mothers or in brain regions) Acrylamide

5 d1 x/d(G) 
174

7.89

14.56

105

515

101

15

45

77

2

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

100 Rat GD6-PD21 7.89 14.56 (>40% decreased mean Takahashi et al. 2009 (Sprague- (W) pup body weight) Acrylamide Dawley) 

101 Rat Gd 6- Ld 10 5 F (significantly decreased Wise et al. 1995 1 x/d (Sprague- pup body weight during Acrylamide Dawley) (GW) the preweaning period, 

as much as 9% lower than controls) 

15 (increased overall 

horizontal activity and decreased auditory startle response) 

102 Mouse Gd 6-20 

15 45 (decreased mean fetal Field et al. 1990 1 x/d (CD-1) 

body weight; 15% lower Acrylamide (GW) 

than controls) 

CHRONIC EXPOSURE Death 

103 Rat 2 yr 2 (significantly decreased Johnson et al. 1984, 19

(Fischer- 344) (W) survival after 24 months Acrylamide of treatment) 
164

2323232323232323

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Systemic 

104 Rat 2 yr Resp 2 M Friedman et al. 1995 (Fischer- 344) (W) d Acrylamide 3 F 

Cardio 2 M 

d

3 F 

Gastro 2 M 

d

3 F 

Hemato 2 M 

d

3 F 

Musc/skel 2 M 

d

3 F 

Hepatic 2 M 

d

3 F 

Renal 2 M 

d

3 F 

Endocr 2 M 

d

3 F 
163

22222222

80

0.5

2

75

0.5

2

51

1

3

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

105 Rat 2 yr 

(Fischer- 344) (W) 

Neurological 

106 Rat 2 yr 

(Fischer- 344) (W) 

107 Rat 2 yr 

(Fischer- 344) (W) 

108 Cat up to 367 d 

5 d/wk (NS) (F) 

System 

Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr 

LOAEL 

NOAEL Less Serious Serious Reference

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

2 Johnson et al. 1984, 19

Acrylamide

2

2

2

2

222

0.5 M 2 M (light microscopic Friedman et al. 1995 

evidence of peripheral Acrylamide nerve degeneration) 

0.5 2 (light microscopic Johnson et al. 1984, 19

evidence of moderate to Acrylamide severe degeneration in 

sciatic nerve fibers) 

1 3 (clinical signs of McCollister et al. 1964

peripheral neuropathy) Acrylamide 
155

2

154

2

79

1

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Reproductive 

109 Rat 2 yr 2 Friedman et al. 1995 

(Fischer- 344) (W) 

Acrylamide 

110 Rat 2 yr 2 Johnson et al. 1984, 19

(Fischer- 344) (W) 

Acrylamide 

Cancer 

111 Rat 2 yr 1 F (CEL: mammary gland Friedman et al. 1995 

(Fischer- 344) (W) 

fibroadenomas and Acrylamide adenomas or carcinomas combined) 
76

0.5

Table 3-4 Levels of Significant Exposure to Acrylamide - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

112 Rat 2 yr 0.5 M (CEL: testicular sac Johnson et al. 1984, 19

(Fischer- 344) (W) mesotheliomas) 

Acrylamide 

***DRAFT FOR PUBLIC COMMENT***

a The number corresponds to entries in Figure 3-2. b Study results used to derive an acute-duration oral minimal risk level (MRL) of 0.02 mg/kg/day for acrylamide, as described in detail in Appendix A. Benchmark danalysis was performed on male-mediated implantation loss data to identify a point of departure (BMDL10 of 1.78 mg/kg/day) which was divided by an uncertainty ffor extrapolation from animals to humans and 10 for human variability). c Used to derive an intermediate-duration oral minimal risk level (MRL) of 0.002 mg/kg/day for acrylamide. The NOAEL of 0.2 mg/kg/day was divided by an uncerta(10 for extrapolation from animals to humans and 10 for human variability). d Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-2. Where such differences exist, only the levels most sensitive gender are presented. Bd Wt = body weight; (C) = capsule; Cardio = cardiovascular; CEL = cancer effect level; d = day(s);; Endocr = endocrine; (F) = feed; F = Female; (G) = gavage; Gagastrointestinal; Gd = gestation day; Gn Pig = guinea pig; (GW) = gavage in water; Hemato = hematological; Ld = lactation day; LD50 = lethal dose, 50% kill; LOAElowest-observed-adverse-effect level; M = male; mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; ppd day; Resp = respiratory; (W) = drinking water; wk = week(s); x = time(s); yr = year(s) 
0.01

0.1

1

10

100

1000

Death

10g 8m

9m

1r

2r

3r 4r

5r

6r

7r

11h

Body Weight

16g

15m

15m

12r

12r

13r

13r

14r

17h

Neurological

28d

27m

18r

19r

20r

21r 22r

23r

24r

24r

25r

25r

26r

29h

Reproductive

33m

30r

30r

31r

31r

32r

mg/kg/day

Figure 3-2 Levels of Significant Exposure to Acrylamide - Oral 

Acute (≤14 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

ACRYLAMIDE

3. HEALTH EFFECTS

52

***DRAFT FOR PUBLIC COMMENT***
0.001

0.01

0.1

1

10

100

1000

Death

34r

35r 35r

36r

37r

Hematological

41r

41r

Endocrine

40r

40r

Body Weight

50c

49d

47m

48m

38r

39r

40r

40r

40r

42r

42r

43r 44r

45r

46r

46r

Neurological

86c

87c

87c

88c

89c 82d

82d

83d

84d 85d

51k 52k

53k

54k

54k

55k

78m

78m

79m

80m 81m

56r

57r

58r

59r

59r

59r

60r

60r

60r

61r 62r

63r

64r

65r 66r

67r

68r

mg/kg/day

Figure 3-2 Levels of Significant Exposure to Acrylamide - Oral (Continued)

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

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0.001

0.01

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1

10

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1000

Neurological

69r

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Reproductive

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Developmental

102m

102m

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100r 101r

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mg/kg/day

Figure 3-2 Levels of Significant Exposure to Acrylamide - Oral (Continued)

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

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0.1

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103r

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104r

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104r

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108c108c106r106r 107r

107r

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109r

mg/kg/day

Figure 3-2 Levels of Significant Exposure to Acrylamide - Oral (Continued)

Chronic (≥ 365 days)

c-Catd-Dog r-Ratp-Pig q-Cow

 -Humansk-Monkey m-Mouseh-Rabbita-Sheep

f-Ferretj-Pigeon e-Gerbils-Hamsterg-Guinea Pig

n-Minko-Other

 Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals

 Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans

Systemic

110r

Cancer *

111r112r

*Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer endpoint. 

0.

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Respiratory Effects. No data were located regarding respiratory effects in humans following oral 

exposure to acrylamide. 

No clinical signs or gross or histopathological evidence of respiratory effects were observed in male or 

female F344 rats administered acrylamide in the drinking water for up to 93 days at concentrations 

resulting in doses up to 20 mg/kg/day (Burek et al. 1980) or for up to 2 years at concentrations resulting 

in doses up to 2 or 3 mg/kg/day (Friedman et al. 1995; Johnson et al. 1984, 1986). 

Cardiovascular Effects. No data were located regarding cardiovascular effects in humans following 

oral exposure to acrylamide. 

No clinical signs or gross or histopathological evidence of cardiovascular effects were observed in male 

or female F344 rats administered acrylamide in the drinking water for up to 93 days at concentrations 

resulting in doses up to 20 mg/kg/day (Burek et al. 1980) or up to 2 years at concentrations resulting in 

doses up to 2 or 3 mg/kg/day (Friedman et al. 1995; Johnson et al. 1984, 1986). 

Gastrointestinal Effects. No data were located regarding gastrointestinal effects in humans following 

oral exposure to acrylamide. 

No clinical signs or gross or histopathological evidence of gastrointestinal effects were observed in male 

or female F344 rats administered acrylamide in the drinking water for up to 93 days at concentrations 

resulting in doses up to 20 mg/kg/day (Burek et al. 1980) or up to 2 years at concentrations resulting in 

doses up to 2 or 3 mg/kg/day (Friedman et al. 1995; Johnson et al. 1984, 1986). 

Hematological Effects. No data were located regarding hematological effects in humans following 

oral exposure to acrylamide. 

Burek et al. (1980) reported significant decreases in packed cell volume (PCV), erythrocyte counts, and 

hemoglobin in male and female F344 rats at day 76 during administration of acrylamide in their drinking 

water at a dose level of 20 mg/kg/day. These effects were also noted in females (but not males) dosed at 

5 mg/kg/day for 93 days. Hematological evaluations at 3, 6, 12, 18, and 24 months on male and female 

F344 rats receiving acrylamide doses as high as 2 mg/kg/day from the drinking water for up to 2 years 

revealed no evidence of treatment-related effects (Johnson et al. 1984, 1986). 

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Musculoskeletal Effects. No data were located regarding musculoskeletal effects in humans 

following oral exposure to acrylamide. 

Atrophy of skeletal muscles in the posterior area was noted in F344 rats receiving acrylamide at a dose 

level of 20 mg/kg/day from the drinking water for up to 93 days; however, this effect was considered the 

likely result of acrylamide-induced peripheral neuropathy (Burek et al. 1980). 

Renal Effects. No data were located regarding renal effects in humans following oral exposure to 

acrylamide. 

Urinalysis and gross and histopathological evaluations revealed no evidence of renal effects in male or 

female F344 rats administered acrylamide in the drinking water for up to 93 days at concentrations 

resulting in doses up to 20 mg/kg/day (Burek et al. 1980) or up to 2 years at concentrations resulting in 

doses up to 2 or 3 mg/kg/day (Friedman et al. 1995; Johnson et al. 1984, 1986). Although distended 

bladders were occasionally observed in laboratory animals following repeated-dose oral exposure, this 

effect may be the result of acrylamide-induced effects on nerve fibers that innervate the bladder (Fullerton 

and Barnes 1966). 

Endocrine Effects. No data were located regarding endocrine effects in humans following oral 

exposure to acrylamide. 

Significantly decreased mean serum testosterone levels (27 and 9% of the control mean) were noted in 

adult male F344 rats administered acrylamide in the drinking water for 28 days at concentrations resulting 

in estimated acrylamide doses of 19 and 25 mg/kg/day, respectively; there were no statistically significant 

effects on serum testosterone levels at 14-day interim assessment (American Cyanamid Company 1991). 

In the same study, serum levels of the thyroid hormones thyroxin (T4) and triiodothyronine (T3) and 

serum prolactin were assessed in both male and female F344 rats receiving acrylamide from the drinking 

water at estimated doses up to 24–25 mg/kg/day. High-dose males exhibited significantly increased mean 

T4 concentration compared to controls at 14-day interim assessment and significantly decreased mean T3 

and T4 concentrations at study termination. Terminal (28-day) mean T3 level was significantly decreased 

in 19 mg/kg/day males as well. Mean T3 and T4 levels in treated female rats were not significantly 

different from controls at either time point. Serum prolactin levels were significantly decreased in 19 and 

25 mg/kg/day males at the 14-day interim assessment, but not at terminal assessment. No significant 

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effects on serum prolactin levels were seen in treated female rats. At terminal sacrifice, no significant 

treatment-related effects on thyroid weights were seen in males or females at any dose level. 

Gross and histopathological assessments revealed no evidence of endocrine effects in male or female 

F344 rats administered acrylamide in the drinking water for up to 93 days at concentrations resulting in 

doses up to 20 mg/kg/day (Burek et al. 1980) or up to 2 years at concentrations resulting in doses up to 2 

or 3 mg/kg/day (Friedman et al. 1995; Johnson et al. 1984, 1986). 

Dermal Effects. No data were located regarding dermal effects in humans or animals following oral 

exposure to acrylamide. 

Ocular Effects. No data were located regarding ocular effects in humans following oral exposure to 

acrylamide. 

Ophthalmological evaluations revealed no evidence of ocular effects in male or female F344 rats 

administered acrylamide in the drinking water for up to 93 days at concentrations resulting in doses up to 

20 mg/kg/day (Burek et al. 1980) or up to 2 years at concentrations resulting in doses up to 2 or 

3 mg/kg/day (Friedman et al. 1995; Johnson et al. 1984, 1986). 

Acrylamide-induced neurological effects on the visual system of orally-exposed primates are discussed in 

Section 3.2.2.4 (Neurological Effects). 

Body Weight Effects. No data were located regarding body weight effects in humans following oral 

exposure to acrylamide. 

Depressed body weight, including actual body weight loss, was consistently reported in laboratory 

animals following single or repeated oral exposure to acrylamide. 

Slight initial weight loss (magnitude not specified) was reported following a single oral dose of 126 mg 

acrylamide/kg in rats and guinea pigs and 63 mg/kg in rabbits (Dow Chemical Company 1957). 

Significantly depressed body weight was observed for several days in mice dosed once at 150 mg/kg 

(lethal dose), but not at 100 mg/kg (sublethal dose) (Sakamoto et al. 1988). 

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Depressed body weight or actual body weight loss was observed in repeat-dosing studies as well. Weight 

loss was noted in 3- and 6-week-old mice receiving a high daily dose (90.8 mg/kg) of acrylamide for 20 

and 38 days, respectively (Ko et al. 1999). Most repeated-dose oral studies, however, identified much 

lower body weight effect levels. At treatment day 13 of a 3-month study, significantly decreased mean 

body weights (8% lower than controls) were observed in male and female rats receiving acrylamide at 

20 mg/kg/day from the drinking water (Burek et al. 1980). Significantly depressed body weight gain 

(approximately 40% less than controls) was noted in male Long-Evans rats receiving 15 mg/kg/day of 

acrylamide for 5 consecutive days; there were no apparent acrylamide-induced effects at 5 mg/kg/day 

(Tyl et al. 2000b). Severely depressed body weight gain (approximately 50% that of controls) was 

observed during 21 days of exposure of male albino rats to acrylamide in the food at a concentration 

resulting in an estimated daily acrylamide dose of 47 mg/kg/day (American Cyanamid Company 1953b). 

This dose level resulted in the death of 3/10 of the rats by the end of the treatment period; three surviving 

rats exhibited somewhat greater weight gain than controls during a 10-week recovery period. Severely 

depressed body weight and emaciation were reported in studies of rats administered acrylamide for 

periods of 3–5 weeks at doses in the range of 19–30 mg/kg/day (American Cyanamid Company 1953b, 

1991; Schulze and Boysen 1991). Tanii and Hashimoto (1983), however, reported no significant effects 

on body weight in male Wistar rats administered acrylamide in the drinking water for 90 days at 

concentrations resulting in estimated doses as high as 23.7 mg/kg/day. Dogs and cats are also susceptible 

to the body weight effects of orally-administered acrylamide. An 8-week dosing period to dogs at 

7 mg/kg/day resulted in weight loss (Satchell and McLeod 1981). Cats dosed for 12–16 weeks at 

15 mg/kg/day exhibited weight loss of unspecified magnitude (Post and McLeod 1977a). 

Several groups of investigators assessed effects of maternal body weight on rat or mouse dams receiving 

oral acrylamide during gestation and/or lactation. A daily dose as low as 7.5 mg/kg/day during gestation 

days 6–20 resulted in approximately 12% depressed maternal weight gain in rats, but a NOAEL of 

45 mg/kg/day was identified in similarly-treated mouse dams (Field et al. 1990). Net maternal weight 

loss was observed in rat dams administered acrylamide at 25 mg/kg/day during 21 days of lactation 

(Friedman et al. 1999). Wise et al. (1995) treated rat dams with 5 or 15 mg/kg/day from gestation day 6 

through lactation day 10; no body weight effects were seen at the 5 mg/kg/day dose level, but 

approximately 33% depressed maternal weight gain was noted during the 10-day lactation period in the 

15 mg/kg/day group. 

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3.2.2.3 Immunological and Lymphoreticular Effects 

No data were located regarding immunological or lymphoreticular effects in humans or animals following 

oral exposure to acrylamide. 

3.2.2.4 Neurological Effects 

Neurological deficits are a hallmark of acrylamide toxicity. Most evidence in humans derives from 

occupational exposures that predominantly involved inhalation and dermal routes (see Section 3.2.1.4). 

Available information regarding the neurological effects of oral exposure in humans is limited to a case 

report of persistent peripheral neuropathy in a subject who intentionally ingested 18 g of acrylamide 

crystals (Donovan and Pearson 1987) and signs of central and peripheral neurological deficits in family 

members exposed (likely via oral and dermal routes) to acrylamide in well water at a concentration of 

400 ppm (Igisu and Matsuoka 2002; Igisu et al. 1975). Epidemiologic studies designed to evaluate 

noncancer health effects in groups of orally-exposed subjects have not been conducted. 

Neurological effects associated with oral exposure to acrylamide have been well characterized in 

laboratory animals and include clinical signs such as twitching, loss of balance, tremors, lethargy, and 

general weakness and more subtle indicators of functional deficits such as decreased rotarod performance 

and increased limb or foot splay. Evidence of degenerative lesions in peripheral nerve fibers, as observed 

by light and electron microscopy, have been detected at oral doses lower than those eliciting clinical signs 

and other overt indications of functional deficit. 

Clinical signs have been elicited following single oral exposure of rats, rabbits, and dogs to doses in the 

range of 100–200 mg/kg (American Cyanamid Company 1953c; Fullerton and Barnes 1966; McCollister 

et al. 1964; Tilson and Cabe 1979). Five daily doses to rats at 45 mg/kg (Tyl et al. 2000b) or 75 mg/kg 

(Sublet et al. 1989) elicited typical clinical signs of peripheral neuropathy. Ko et al. (1999) noted the 

onset of altered gait as early as treatment day 5 in 3- and 8-week-old mice receiving acrylamide from the 

drinking water at approximately 90 mg/kg/day. Friedman et al. (1999) and Dixit et al. (1981) observed 

clinical signs of neurological effects as early as treatment days 4 and 14, respectively, in rats receiving 

acrylamide at 25 mg/kg/day. Gilbert and Maurissen (1982) reported decreased rotarod performance and 

increased hindlimb splay as early as days 6–8 of a 12-day exposure of mice receiving acrylamide from the 

drinking water at an estimated dose of 25.8 mg/kg/day. 

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Clinical signs and other indicators of acrylamide-induced functional neurological deficit, such as 

increased hindlimb splay and decreased rotarod performance, during intermediate-duration (15–364 days) 

exposure have been observed in several animal species. In rats and cats, dose levels in the range of 8– 

25 mg/kg/day elicited overt signs of neurological deficit as early as 3–8 weeks following the initiation of 

treatment (American Cyanamid Company 1991; Burek et al. 1980; Fullerton and Barnes 1966; Gorzinski 

et al. 1979; Leswing and Ribelin 1969; McCollister et al. 1964; Post and McLeod 1977a; Takahashi et al. 

2009; Tanii and Hashimoto 1983; Tilson and Cabe 1979; Wise et al. 1995; Zenick et al. 1986). Slight leg 

weakness was reported after 40 weeks of oral dosing at 6 mg/kg/day in one rat study (Fullerton and 

Barnes 1966). In dogs, dose levels of 5.7–10 mg/kg/day elicited clinical signs within 3–4 weeks 

(American Cyanamid Company 1953c; Hersch et al. 1989a; Satchell and McLeod 1981). Hashimoto et 

al. (1981) noted typical signs of peripheral neuropathy and diminished rotarod performance in male mice 

treated at 36 mg/kg/day, 2 days/week for 8 weeks. In primates (monkeys, baboons), clinical signs were 

elicited by doses of 10–30 mg/kg/day for periods of 42–61 days (Eskin et al. 1985; Hopkins 1970; 

Leswing and Ribelin 1969; Maurissen et al. 1983; Merigan et al. 1985). Higher levels of oral dosing 

typically result in earlier onset of clinical signs and more severe effects with continued dosing. 

Histopathological assessment of acrylamide-induced neurological effects includes studies in which light 

and electron microscope evaluations were performed on peripheral nerve fibers of rats administered 

acrylamide in the drinking water (Burek et al. 1980; Johnson et al. 1984, 1985, 1986). In the study of 

Burek et al. (1980), the rats received estimated doses of 0.05–20 mg/kg/day for up to 93 days. This study 

identified a NOAEL of 0.2 mg/kg/day and a LOAEL of 1 mg/kg/day for increased incidences of 

ultrastructural degeneration (axolemma invaginations with cell organelles and/or dense bodies) in the 

sciatic nerve; higher doses elicited more pronounced degenerative effects that could also be detected by 

light microscopy. Clinical signs of peripheral neuropathy were elicited at the 20 mg/kg/day dose level. 

The study of Johnson et al. (1984, 1985, 1986) employed estimated dose levels of 0.01, 0.1, 0.5, and 

2.0 mg/kg/day for up to 2 years. Interim evaluations of peripheral nerve fibers were performed at 3, 6, 12, 

and 18 months; however electron microscope evaluations at interims >12 months were inconclusive due 

to high incidences of degenerative results attributed in part to aging. The studies of Johnson et al. (1984, 

1985, 1986) identified a NOAEL of 0.5 mg/kg/day and a LOAEL of 2 mg/kg/day for increased incidences 

of ultrastructural degeneration (axolemma invaginations) in the sciatic nerve at 3, 6, and 12 months and 

for light microscopy evidence of degenerative effects in peripheral nerve fibers at 12–24 months; there 

were no clinical signs of neurological effects at any dose level . Friedman et al. (1995) duplicated the 

study design of Johnson et al. (1986), but excluded electron microscopy in histopathological evaluations 

of peripheral nerve fibers. The study of Friedman et al. (1995) also identified a NOAEL of 0.5 mg/kg/day 

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and a LOAEL of 2 mg/kg/day for peripheral nerve degeneration as revealed by light microscopy in the 

absence of clinical signs of neurological effects. Histopathological evidence (light microscope) of 

degenerative effects was also noted in fibers from cervical and lumbar spinal cord, gasserian and dorsal 

root ganglia, and sciatic, tibial, and sural nerves of male and female Sprague-Dawley rats that had 

received acrylamide by gavage for 5 weeks at doses of 10 and 30 mg/kg/day (Schulze and Boysen 1991). 

The most severe changes were observed in the large fibers of the tibial and sural nerves of high-dose rats. 

In a 2-generation study of F-344 rats, Tyl et al. (2000a) reported degenerative effects in peripheral nerve 

fibers of F0 (but not female or F1 male or female) rats that had received acrylamide from the drinking 

water at 5 mg/kg/day for 16 weeks. 

Information regarding the neurodevelopmental toxicity of acrylamide is discussed in Section 3.2.2.6. 

The highest NOAEL values and all LOAEL values from each reliable study for neurological effects in 

each species and duration category are recorded in Table 3-4 and plotted in Figure 3-2. 

3.2.2.5 Reproductive Effects 

No studies were located regarding acrylamide-induced reproductive effects in humans. 

Animal studies designed to assess the reproductive toxicity of orally-administered acrylamide revealed 

pre- and postimplantation losses and decreased numbers of live fetuses in rats and mice at repeated doses 

in the range of 3–60 mg/kg/day (Chapin et al. 1995; Sakamoto and Hashimoto 1986; Smith et al. 1986; 

Sublet et al. 1989; Tyl et al. 2000a, 2000b; Working et al. 1987; Zenick et al. 1986). 

Results of dominant lethality testing (Chapin et al. 1995; Smith et al. 1986; Tyl et al. 2000a, 2000b) and 

crossover trials (Chapin et al. 1995; Sakamoto and Hashimoto 1986; Zenick et al. 1986) indicate that 

acrylamide induces male-mediated reproductive effects at repeated oral doses in the range of 2.8– 

19 mg/kg/day. Sublet et al. (1989) reported statistically significant moderately decreased sperm mobility 

in Long-Evans rats administered acrylamide at a gavage dose of 45 mg/kg/day for 5 days, but suggested 

that this effect was not solely responsible for poorer reproductive performance. In apparent contrast, Tyl 

et al. (2000b) found no significant effects on sperm parameters in Long-Evans hooded rats following 

repeated oral dosing at levels as high as 60 mg/kg/day and suggested that indicators of acrylamideinduced reproductive toxicity such as pre-and post-implantation loss and decreased numbers of live 

fetuses may be at least partly the result of impaired mating performance due to acrylamide neurotoxicity. 

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Histologic indicators of degenerative effects were reported in spermatids of ddY mice administered 

acrylamide by daily gavage for 5 days at dose levels of 100 or 150 mg/kg/day (Sakamoto et al. 1988). 

Other investigators reported evidence of acrylamide-induced testicular atrophy in F344 rats receiving 

acrylamide in the drinking water for 28 or 90 days at concentrations resulting in estimated acrylamide 

doses of 19 or 5 mg/kg/day, respectively (American Cyanamid Company 1991; Burek et al. 1980). Gross 

and histopathologic examinations of reproductive organs and tissues from male rats receiving acrylamide 

from the drinking water for up to 2 years at estimated doses as high as 2 mg/kg/day revealed no signs of 

acrylamide-induced effects (Friedman et al. 1995; Johnson et al. 1984, 1986). 

Prebreeding exposure of female mice to acrylamide at 18.7 mg/kg/day (Sakamoto and Hashimoto 1986) 

or female Long-Evans rats to doses up to 14.6 mg/kg/day (Zenick et al. 1986) did not adversely affect 

reproductive performance variables such as fertility or implantation when the animals were bred with 

nonexposed males. Gross and histopathologic examinations of reproductive organs and tissues from 

female rats receiving acrylamide from the drinking water for up to 2 years at estimated doses as high as 

2–3 mg/kg/day revealed no signs of acrylamide-induced effects (Friedman et al. 1995; Johnson et al. 

1984, 1986). 

Atrophy of the testes and/or seminal vesicles was reported in F-344 rats receiving acrylamide at 19 or 

25 mg/kg/day from the drinking water for 28 days; this effect was not seen at 12 mg/kg/day (American 

Cyanamid Company 1991). 

The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects in 

each species and duration category are recorded in Table 3-4 and plotted in Figure 3-2. 

3.2.2.6 Developmental Effects 

No studies were located regarding acrylamide-induced developmental effects in humans. 

Several reports are available in which developmental toxicity was assessed in the offspring of rat or 

mouse dams administered acrylamide via daily gavage during gestation and/or lactation (American 

Cyanamid Company 1979; Field et al. 1990; Friedman et al. 1999; Garey and Paule 2007; Husain et al. 

1987; Takahashi et al. 2009; Walden et al. 1981; Wise et al. 1995). 

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Body weight decreases and decreased auditory startle response were noted in offspring of female 

Sprague-Dawley rats exposed to 5 and 15 mg/kg-day, respectively, on gestation days 6–10 (Wise et al. 

1995). No exposure-related fetal malformations or variations (gross, visceral, or skeletal) were found in 

offspring of Sprague-Dawley rats administered acrylamide at doses of 2.5, 7.5, or 15 mg/kg/day on 

gestation days 6–20 or in CD-1 mice at doses of 3, 15, or 45 mg/kg/day on gestation days 6–17 (Field et 

al. 1990). The highest dose in each species was maternally toxic, as evidenced by depressed maternal 

weight gain in the rats and mice and increased hindlimb splay in the mice. There were no indications of 

treatment-related developmental effects in the offspring of Sprague-Dawley rat dams administered 

acrylamide at doses up to nearly 4 mg/kg/day for 2 weeks premating and throughout gestation (American 

Cyanamid Company 1979). Decreased mean fetal body weight (approximately 15% lower than controls) 

was noted in the offspring of CD-1 mouse dams administered acrylamide by gavage at 45 mg/kg/day 

during gestation days 6–20; a NOAEL for this effect was 15 mg/kg/day (Field et al. 1990). Significantly 

depressed mean body weights were reported in offspring of Sprague-Dawley rat dams administered 

acrylamide in the drinking water at 100 ppm (mean acrylamide intake 14.56 mg/kg/day) from gestation 

day 6 through postnatal day 21; the male and female pups exhibited approximately 42 and 46% lower 

mean body weights, respectively, than unexposed control pups (Takahashi et al. 2009). At lower mean 

maternal exposure levels doses (25 and 50 ppm; mean doses of 3.72 and 7.89 mg/kg/day, respectively), 

pup body weights did not differ significantly from those of controls. There were no signs of acrylamideinduced neurotoxicity or testicular toxicity in pups of any exposure group. The 100 ppm dams exhibited 

increasing severity of gait abnormalities from postnatal day 2 onward; abnormal gait was observed in 

50 ppm dams from postnatal day 18 onward. 

Periodic significantly decreased brain levels of selected catecholamines (noradrenaline, dopamine, 

5-hydroxytryptamine) were noted in pups of rat dams administered acrylamide at 25 mg/kg/day during 

lactation only (Husain et al. 1987). Similar effects on brain catecholamines were observed in rat pups 12– 

21 days of age at the beginning of a 5-day period in which they were administered acrylamide by gavage 

at 25 mg/kg/day; these effects were not seen in rat pups that were 60 days of age at the initiation of dosing 

(Husain et al. 1987). Decreased performance in an operant test of cognitive motivation was reported in 

adolescent F344 rats exposed during gestation and lactation and extending through 12 weeks of age at an 

average dose of 6 mg/kg/day, but not at 1.3 mg/kg/day (Garey and Paule 2007). Significant decreases in 

whole brain levels of noradrenaline, dopamine, and 5-hydroxytryptamine were observed in pups of rat 

dams administered acrylamide at 25 mg/kg/day during lactation. Walden et al. (1981) found significant 

alterations in intestine enzyme levels in young Sprague-Dawley rat pups whose mothers had received 

acrylamide via gavage on gestation days 6–17 at 20 mg/kg/day; the toxicological significance of these 

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findings is uncertain. Friedman et al. (1999) reported increased mortality and reduced body weights in 

pups of rat dams dosed at 25 mg/kg/day during lactation; however, serious maternal toxicity was noted as 

well. 

The highest NOAEL values and all LOAEL values from each reliable study for developmental effects in 

each species and duration category are recorded in Table 3-4 and plotted in Figure 3-2. 

3.2.2.7 Cancer 

Available epidemiology studies on increased risk of cancer from acrylamide in food include case-control 

studies (Michels et al. 2006; Mucci et al. 2003, 2004, 2005; Pelucchi et al. 2006, 2007; Wilson et al. 

2009a) and reports from ongoing prospective studies (Hogervorst et al. 2007, 2008a, 2008b; Larsson et al. 

2009a, 2009b, 2009c, 2009d; Mucci et al. 2006; Wilson et al. 2009b). These studies provide little 

evidence for acrylamide-induced cancer in humans exposed to acrylamide in the diet. See Section 3.2.1.7 

(Cancer) for information regarding cancer among acrylamide workers primarily exposed via inhalation 

and dermal routes. 

Case-control Studies. No statistically significant associations were found between self-reported 

consumption of foods with high (300–1,200 μg/kg) or moderate (30–299 μg/kg) acrylamide 

concentrations and increased risk of large bowel, kidney, or bladder cancer in a population-based casecontrol study (692 controls and 875, 391, and 186 large bowel, kidney, and bladder cancer cases, 

respectively) (Augustsson et al. 1999; Mucci et al. 2003). Information on intake of various foods and 

nutrients was assessed by questionnaire. Cancer cases were born in Sweden between 1918 and 1942 and 

resided in Stockholm for at least 1 month between November 1992 and December 1994. Controls were 

selected from a Swedish national population registry and matched to cases by age and gender. 

Mucci et al. (2005) assessed acrylamide intake of >43,000 women, including 667 breast cancer cases, 

who were enrolled in the Swedish Women’s Lifestyle and Health Cohort. The estimated average daily 

acrylamide intake among the participants was 25.9 μg/day and was based on results of food frequency 

questionnaires (FFQs) and the Swedish National Food Administration database of information on 

acrylamide content of selected food items. After ranking the women into quintiles of estimated 

acrylamide intake (means of 12, 20, 25, 31, and 44 μg/day), there was no significant increased risk of 

breast cancer in the higher quintiles compared to the lowest quintile. 

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Within an integrated network of Italian and Swiss hospital-based case-control studies to investigate the 

relation between dietary acrylamide intake and cancers at several sites, no significant associations were 

found between estimated dietary acrylamide intake and cancers of the oral cavity and pharynx, esophagus, 

large bowel, larynx, breast, ovary, or prostate (Pelucchi et al. 2006). Dietary acrylamide intake was 

estimated based on results of FFQs and average content of acrylamide in foods from resources of the 

World Health Organization and Swiss Federal Office of Public Health. In another case-control study that 

included four areas of Italy, no significant association was found between total dietary acrylamide intake 

and renal cell cancer (Pelucchi et al. 2007). In this study, statistically significantly elevated odds ratios 

(ORs: 1.49, 95% CI 1.18–1.87; 1.70, 95% CI 1.25–2.30) were noted for weekly white bread portions of 

7–<21 and ≥21, respectively; however, the study authors indicated that the relationship between white 

bread consumption and renal cell cancer might be explained by a high glycemic content and consequent 

effect on levels of insulin-like growth factors. 

Wilson et al. (2009a) conducted a case-control study to assess possible associations between acrylamide 

and prostate cancer risk using two measures of acrylamide exposure: intake from FFQs and acrylamidehemoglobin adduct levels in blood samples. Dietary data were available for 1,499 prostate cancer cases 

and 1,118 controls from a Cancer of the Prostate in Sweden (CAPS) population-based case-control study. 

Acrylamide-hemoglobin adduct levels were measured in blood samples from a subset of 170 prostate 

cancer cases and 161 controls. Controls were randomly selected from the Swedish Population Registry 

and were frequency matched to cases by 5-year age groups and region of residence. No significant 

association was found between acrylamide exposure (as measured by FFQ or acrylamide-hemoglobin 

adduct levels) and risk of prostate cancer. 

Michels et al. (2006) conducted a case-control study to evaluate whether diet during preschool age 

affected a woman’s risk of breast cancer later in life. Cases and controls were selected from participants 

in two prospective cohort studies, the Nurses’ Health Study and the Nurses’ Health Study II. Information 

concerning childhood diet of the nurses at ages 3–5 years was obtained from FFQs filled out by the 

mothers of the participants. The median year of birth of the mothers was 1914 for case mothers and 1913 

for control mothers. The results indicated an increased risk of breast cancer among woman who had 

frequently consumed French fries at preschool age. For one additional serving of French fries per week, 

the OR for breast cancer adjusted for adult life breast cancer risk factors was 1.27 (95% CI=1.12–1.44). 

Consumption of whole milk was associated with a slightly decreased risk of breast cancer (covariateadjusted OR for every additional glass of milk per day=0.90; 95% CI=0.82–0.99). Intake of none of the 

nutrients calculated was related to the breast cancer risk in this study. The authors noted that they did not 

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ACRYLAMIDE 67 

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observe a similar association of breast cancer with frequent consumption of hot dogs or ground beef, 

suggesting that French fry consumption was not a marker of “fast food” habits. The study results suggest 

a possible association between diet before puberty and the subsequent risk of breast cancer, but the 

conclusions and the study are of limited use. No information is available on cooking methods or 

acrylamide content in the foods being evaluated, and the ability of mothers to accurately recall preschool 

diets of their daughters is questionable. 

No significant associations were found between acrylamide-hemoglobin or glycidamide-hemoglobin 

adduct levels and total breast cancer in a Danish nested case-control study that examined breast cancer 

and acrylamide exposure using acrylamide-hemoglobin and glycidamide-hemoglobin adduct levels in red 

blood cells as presumed biomarkers for oral exposure to acrylamide (Olesen et al. 2008). After adjusting 

for confounding factors including smoking behavior, the study authors noted that a 10-fold increase in 

acrylamide-hemoglobin adduct levels was associated with a 1.9 (95% CI 0.9–4.0) times higher risk of 

breast cancer and a 5-fold increase (which corresponds to the range in acrylamide-hemoglobin adduct 

levels among nonsmokers) was associated with a 1.6 (95% CI 0.9–2.6) times higher risk. A significant 

positive association was observed between acrylamide-hemoglobin adduct level and ER+ breast cancer; a 

10-fold increase in adduct level was associated with a 4.9 (95% CI 1.2–20) times increased risk in 

smokers and 2.7 (95% CI 1.1–6.6) times increased risk after adjustment for smoking. However, this 

study is limited by the relatively small number of subjects (374 cases and 374 controls) and uncertainty 

regarding extrapolation of acrylamide exposure as assessed by a few months of acrylamide-hemoglobin 

adduct measurements to a lifetime of exposure. 

Mucci et al. (2004) analyzed data from a large population-based Swedish case-control study of renal cell 

cancer. FFQs were used to collect information on intake of 11 food items with elevated acrylamide levels 

as ascertained through extensive food databases in Sweden and the United States and quartiles of daily 

food and acrylamide intake were created. This study found no evidence that food items with elevated 

acrylamide were associated with a higher risk of renal cell cancer risk. 

Prospective Studies. Recent and ongoing prospective studies designed to evaluate possible associations 

between acrylamide in food and risk of cancers at various sites include cohorts from Sweden (Larsen et 

al. 2009a, 2009b, 2009c, 2009d; Mucci et al. 2006), the United States (Wilson et al. 2009b), and the 

Netherlands (Hogervorst et al. 2007, 2008a, 2008b). Most studies found no statistically significant 

associations between acrylamide in food and risks of cancers of the esophagus, stomach, or pancreas 

(Hogervorst et al. 2008b); colon or rectum (Hogervorst et al. 2008b; Larsen et al. 2009c; Mucci et al. 

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ACRYLAMIDE 68 

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2006); bladder or prostate (Hogervorst et al. 2008a); breast (Hogervorst et al. 2007; Larsson et al. 2009d; 

Wilson et al. 2009b); endometrium (Hogervorst et al. 2007; Larsson et al. 2009a), or ovarian epithelium 

(Larsson et al. 2009b). Exceptions include increased risks of postmenopausal endometrial and ovarian 

cancer (Hogervorst et al. 2007) and renal cell cancer (Hogervorst et al. 2008a) with increasing dietary 

acrylamide in prospective studies of a Dutch population, but in these studies, estimations of dietary 

acrylamide levels in foods on the market at baseline in 1986 were based on food samples analyzed since 

2001 and questionnaires did not include details regarding specifics of food preparation. Some of the 

tumor sites observed in animal studies (thyroid, testis, central nervous system) have not been evaluated in 

humans, and there are limitations in some of the study methods and cohort sizes in the prospective 

studies. 

Information regarding the carcinogenicity of acrylamide in orally-exposed animals is available from two 

similarly-designed 2-year bioassays (Friedman et al. 1995; Johnson et al. 1984, 1985, 1986) in which 

groups of male and female F344 rats were administered acrylamide in the drinking water at 

concentrations calculated to provide doses up to 2 mg/kg/day (3 mg/kg/day for high-dose female rats of 

the Friedman et al. 1995 study). Selected tumor types with significantly increased incidences in 

acrylamide-treated rats from both studies are summarized in Table 3-5. Significantly increased 

incidences of mesotheliomas of the tunica vaginalis testis were observed by Johnson et al. (1984, 1986) in 

male rats at the two highest dose levels (0.5 and 2 mg/kg/day). Additional findings included significantly 

increased incidences of thyroid (follicular cell) adenomas (no carcinomas), mesotheliomas of the tunica 

vaginalis testis, and benign adrenal pheochromocytoma in high-dose males and mammary gland benign 

tumors (adenoma, fibroadenomas, or fibroma), central nervous system tumors of glial origin, thyroid 

(follicular cell) adenomas or adenocarcinomas, squamous papillomas of the oral cavity, uterine 

adenocarcinomas, benign clitoral gland adenomas, and pituitary gland adenomas in high-dose females. 

The study of Friedman et al. (1995) noted increased incidences of tunica vaginalis mesothelioma and 

thyroid gland (follicular cell) adenoma (and adenoma or carcinoma) in high-dose males and thyroid gland 

follicular cell neoplasms (adenomas and carcinomas combined) in high-dose females and mammary gland 

tumors (fibroadenomas or combined fibroadenomas and carcinomas) in low- and high-dose (1 and 

3 mg/kg/day) females. The findings of statistically significant increased incidences of adrenal 

pheochromocytomas in male rats, oral cavity tumors in female rats, central nervous system tumors of glial 

origin, and clitoral or uterine tumors in female rats in the earlier bioassay (Johnson et al. 1986) were not 

replicated in the second bioassay (Friedman et al. 1995); however, Rice (2005) reported that the study of 

Friedman et al. (1995) did not include examination of all the brains or spinal cords in the treatment groups 

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ACRYLAMIDE 69 

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Table 3-5. Incidence of Tumors with Statistically Significant Increases in 2-Year
 

Bioassays with F344 Rats Exposed to Acrylamide in Drinking Water
 

Dose (mg/kg/day) 

Reference/tumor type 0 0 0.01 0.1 0.5 1.0 2.0 3.0 

Johnson et al. 1986; males 

Follicular cell adenoma 1/60 – 0/58 2/59 1/59 – 7/59a – 

Tunica vaginalis mesothelioma 3/60 – 0/60 7/60 11/60a – 10/60a – 

Adrenal pheochromocytoma 3/60 – 7/59 7/60 5/60 – 10/60a – 

Johnson et al. 1986; females 

Follicular cell adenoma/ 1/58 – 0/59 1/59 1/58 – 5/60b – 

carcinoma 

Mammary adenocarcinoma 2/60 – 1/60 1/60 2/58 – 6/61 – 

Mammary benign 10/60 – 11/60 9/60 19/58 – 23/61a – 

Mammary benign + malignantc 12/60 – 12/60 10/60 21/58 – 29/61a – 

Central nervous system 1/60 – 2/59 1/60 1/60 – 9/61a – 

tumors of glial origin 

Oral cavity malignant + benign 0/60 – 3/60 2/60 3/60 – 8/60a – 

Uterus adenocarcinoma 1/60 – 2/60 1/60 0/59 – 5/60b – 

Clitoral adenoma, benign 0/2 – 1/3 3/4 2/4 – 5/5b – 

Pituitary gland adenoma 25/59 – 30/60 32/60 27/60 – 32/60b – 

Friedman et al. 1995; malesd 

Follicular cell 2/102f – 12/203 5/101 – 17/75a – 

adenoma/carcinoma 

Tunica vaginalis mesotheliomae 4/102 4/102 – 9/204 8/102 – 13/75a – 

Friedman et al. 1995; femalesd 

Follicular cell adenoma/ 

carcinoma 

1/50 

7/46 

1/50 

4/50 

– 

– 

– 

– 

– 

– 

10/100 

21/94a – – 

23/100a 

30/95a 

Mammary benign + malignant 

a

Statistically significantly (p<0.05) different from control, Fisher’s Exact test. b

Statistically significantly (p<0.05) different from control, after Mantel-Haenszel mortality adjustment.
 c

Incidences of benign and adenocarcinoma were added herein, based on an assumption that rats assessed with 

adenocarcinoma were not also assessed with benign mammary gland tumors.

d

Two control groups were included in the study design to assess variability in background tumor responses.

e

Incidences reported herein are those originally reported by Friedman et al. (1995) and not those reported in the 

reevaluation study by Iatropoulos et al. (1998).

f

The data reported in Table 4 in Friedman et al. (1995) noted one follicular cell adenoma in the second control group;
 

however, the raw data obtained in the Tegeris Laboratories (1989) report (and used in the time-to-tumor analysis)
 

listed no follicular cell adenomas in this group. The corrected number for adenomas (0) and the total number (2) of
 

combined adenomas and carcinomas in the second control group are used in the tables of this assessment.
 

Sources: Friedman et al. 1995; Johnson et al. 1986 

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ACRYLAMIDE 70 

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and that seven reported cases of a morphologically distinctive category of primary brain tumor described 

as “malignant reticulosis” were excluded from the analysis. 

The cancer effect levels (CELs) from the rat cancer bioassays of Johnson et al. (1984, 1986) and 

Friedman et al. (1995) are recorded in Table 3-4 and plotted in Figure 3-2. 

The potential for acrylamide to initiate skin tumors was examined in two studies of female mice 

administered acrylamide at oral dose levels of 0, 12.5, 25, or 50 mg/kg/day, 6 times during a 2-week 

period, followed 2 weeks later by dermal applications of 12-O-tetradecanoylphorbol-13-acetate (TPA, a 

tumor promoter) to the shaved back 3 times/week for 20 weeks (Bull et al. 1984a, 1984b). Incidences of 

skin papillomas and skin carcinomas were significantly elevated in the mice receiving acrylamide at oral 

dose levels of 25 and/or 50 mg/kg/day, indicating that acrylamide initiated skin tumors under the 

conditions of the studies. 

EPA, IARC, and the Department of Health and Human Services have concluded that acrylamide is likely 

to be carcinogenic to humans. This conclusion is based on lack of adequate human data and sufficient 

evidence of carcinogenicity in the animal studies summarized above. The Department of Health and 

Human Services (NTP 2005) assigned the cancer descriptor “reasonably anticipated to be a human 

carcinogen”. IARC (1994) assigned acrylamide to Group 2A (probably carcinogenic to humans). EPA 

(IRIS 2009) assigned the classification of B2; probable human carcinogen. Based on the results of 

Johnson et al. (1986), EPA derived an oral slope factor of 4.5 (mg/kg/day)-1 for acrylamide. For cancer 

risks of 1x10-4–1x10-6, the corresponding dose levels range from 2.2x10-5 to 2.2x10-7 mg/kg/day. These 

risk levels are presented in Figure 3-2. 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

There are no reports of human deaths associated with dermal exposure to acrylamide. 

Acrylamide has been demonstrated to be lethal to laboratory animals following a single dermal dose. 

Reported dermal LD50 values are 252 mg/kg in rats (American Cyanamid Company 1973) and 941 mg/kg 

in rabbits (American Cyanamid Company 1977). Dow Chemical Company (1957) reported that one of 

two rabbits administered a single 24-hour dermal dose of 1,000 mg/kg died 2 days following dosing. 

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ACRYLAMIDE 71 

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Reliable acute dermal LD50 values for death and other mortality data for each species are recorded in 

Table 3-6. 

3.2.3.2 Systemic Effects 

No human or animal data were located regarding respiratory, cardiovascular, gastrointestinal, 

hematological, musculoskeletal, hepatic, renal, or endocrine effects following dermal exposure to 

acrylamide. 

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each 

species and duration category are recorded in Table 3-6. 

Dermal Effects. Peeling of the skin was a common complaint among workers in factories with 

measurable acrylamide levels in the air and probable dermal exposure as well (Bachmann et al. 1992; 

Calleman et al. 1994; He et al. 1989; Myers and Macun 1991). Available information in animals is 

limited. Slight dermal irritation was reported in rats and rabbits following single dermal application of 

acrylamide in the range of 200–1,120 mg/kg (American Cyanamid Company 1951, 1973, 1977; Dow 

Chemical Company 1957). There was no evidence of dermal irritation in male mice receiving dermal 

applications of acrylamide for 5 days at doses ranging from 25 to 125 mg/kg/day (Gutierrez-Espeleta et 

al. 1992). 

Ocular Effects. No data were located regarding ocular effects in humans following dermal exposure to 

acrylamide. Mild to moderate irritation was noted in the eyes of rabbits following ocular instillation of 

acrylamide (in water); irritation resolved during the ensuing 24 hours (American Cyanamid Company 

1951; Dow Chemical Company 1957). 

Body Weight Effects. No data were located regarding body weight effects in humans following 

dermal exposure to acrylamide. Available information in animals is restricted to a report of very slight 

initial weight loss (magnitude not specified) among a group of two rabbits administered a single 

500 mg/kg dermal dose of acrylamide (Dow Chemical Company 1957) and another report of weight loss 

Table 3-6 in rabbits administered acrylamide dermally at 50 mg/kg/day for 5 weeks (Rohm and Haas 

Company 1975). 

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15

mg/kg

170

mg/kg/day

13 mg/kg7

mg/kg

171 mg/kg/day19

mg/kg

Table 3-6 Levels of Significant Exposure to Acrylamide - Dermal 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

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ACUTE EXPOSURE 

Death 

Rat Once American Cyanamid Co

252 M (LD50) (albino) 1973 mg/kg 

Mouse 5 d Gutierrez-Espeleta et a

1 x/d 200 M (4/8 died during 30 days

mg/kg/day following cessation of Acrylamide dosing)

Rabbit Once American Cyanamid Co

941 M (LD50) (New 1977 

Zealand) mg/kg Rabbit Once Dow Chemical Compan

1000 (death of 1/2 rabbits) (NS) McCollister et al. 1964 mg/kg 

Systemic 

Mouse 5 d Dermal Gutierrez-Espeleta et a

125 M 1 x/d 

mg/kg/day Acrylamide 

Rabbit Once Dermal American Cyanamid Co

18 h 1120 M (slight dermal irritation (albino) 1951 mg/kg in 1/3 rabbits) 
16

mg/kg

169 mg/kg

mg/kg

41 mg/kg/day

Table 3-6 Levels of Significant Exposure to Acrylamide - Dermal (continued) 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

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Neurological 

Rat Once American Cyanamid Co

200 M (unspecified CNS (albino) 1973 mg/kg symptoms) 

Reproductive 

Mouse 5 d Gutierrez-Espeleta et a

1 x/d 25 M 50 M (significantly increased 

mg/kg mg/kg number of dead Acrylamide implants) 

INTERMEDIATE EXPOSURE 

Neurological 

Rabbit 5 wk Rohm and Haas Compa

(New 3 x/d 50 (clinical signs of peripheral neuropathy) Zealand) mg/kg/day Acrylamide 

d = day(s); hr = hour(s); LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effect level; wk = w
 

 

 

 

 

 

 

ACRYLAMIDE 74 

3. HEALTH EFFECTS 

3.2.3.3 Immunological and Lymphoreticular Effects 

No human or animal data were located regarding immunological or lymphoreticular effects following 

dermal exposure to acrylamide. 

3.2.3.4 Neurological Effects 

Available human data consist of occupational exposure scenarios with suspected inhalation and dermal 

exposure. See Section 3.2.1.4 for information regarding neurological effects in occupationally-exposed 

workers. Unspecified clinical signs of central nervous system effects were reported in rats that died 

following single dermal application of acrylamide at doses in the range of 200–800 mg/kg (American 

Cyanamid Company 1973). Clinical signs that included shaking and loss of coordination were reported 

in rabbits following single dermal application at doses in the range of 784–1,568 mg/kg (American 

Cyanamid Company 1977). Clinical signs of hindlimb neuropathy became apparent during treatment 

week 4 in a study of rabbits administered acrylamide dermally for 5 weeks at 50 mg/kg/day (Rohm and 

Haas Company 1975). 

The highest NOAEL values and all LOAEL values from each reliable study for neurological effects in 

each species and duration category are recorded in Table 3-6. 

3.2.3.5 Reproductive Effects 

No data were located regarding reproductive effects in humans following dermal exposure to acrylamide. 

Dermal applications of acrylamide to male mice for 5 days at doses ranging from 25 to 125 mg/kg/day 

followed by matings to unexposed female mice resulted in significantly increased numbers of dead 

implants (Gutierrez-Espeleta et al. 1992). At doses ≥50 mg/kg/day, significantly decreased numbers of 

living embryos were noted as well; this effect is indicative of dominant lethality. 

The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects in 

each species and duration category are recorded in Table 3-6. 

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ACRYLAMIDE 75 

3. HEALTH EFFECTS 

3.2.3.6 Developmental Effects 

No data were located regarding developmental effects in humans or animals following dermal exposure to 

acrylamide. 

3.2.3.7 Cancer 

No data were located regarding cancer associated with dermal exposure to acrylamide in humans. 

The potential for acrylamide to initiate skin tumors was examined in a study of female mice administered 

acrylamide at dermal dose levels of 0, 12.5, 25, or 50 mg/kg/day, 6 times during a 2-week period, 

followed 2 weeks later by dermal applications of 12-O-tetradecanoylphorbol-13-acetate (TPA, a tumor 

promoter) to the shaved back 3 times/week for 20 weeks (Bull et al. 1984a). Incidences of skin 

papillomas and skin carcinomas were not significantly elevated at any acrylamide dose level. It was 

concluded that acrylamide did not act as a skin tumor initiator under the conditions of the study. 

3.3 GENOTOXICITY 

The genotoxicity of acrylamide has been studied both in vivo and in vitro. Studies are limited almost 

exclusively to laboratory rodents and nonmammalian species with the exception of a few in vitro assays 

of human cells. Results indicate that acrylamide is genotoxic and most potent in its ability to induce 

clastogenic effects (including heritable translocations in offspring of acrylamide-exposed male rodents 

mated with untreated females), deoxyribonucleic acid (DNA) damage, and gene mutations (including 

male-germ-cell-mediated dominant lethal mutations and heritable specific-locus mutations). 

Table 3-7 summarizes the results of in vivo assays for acrylamide. Numerous assays have been 

performed in rodents. Dominant lethal mutations were induced consistently following administration of 

acrylamide via oral, dermal, or intraperitoneal injection in rodents (Adler et al. 2000; Chapin et al. 1995; 

Gutierrez-Espeleta et al. 1992; Sakamoto and Hashimoto 1986; Shelby et al. 1987; Smith et al. 1986; 

Sublet et al. 1989; Tyl et al. 2000a, 2000b; Working et al. 1987; Zenick et al. 1986). Exposure via 

intraperitoneal injection was also associated with specific locus mutations in offspring of male mice 

exposed to 50–125 mg/kg acrylamide before mating to untreated females (Ehling and Neuhäuser-Klaus 

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ACRYLAMIDE 76 

3. HEALTH EFFECTS 

Table 3-7. Genotoxicity of Acrylamide In Vivo 

Species (test system) End point Result Test conditions Reference 

Mammalian gene mutation 

Mouse Dominant lethal 

mutation 

Mouse	 Dominant lethal 

mutation 

Mouse	 Dominant lethal 

mutation 

Mouse	 Dominant lethal 

mutation 

Rat	 Dominant lethal 

mutation 

Rat	 Dominant lethal 

mutation 

Rat	 Dominant lethal 

mutation 

Rat	 Dominant lethal 

mutation 

Rat	 Dominant lethal 

mutation 

Mouse	 Dominant lethal 

mutation 

Mouse (spleen Gene mutation 

lymphocytes, tk and 

HPRT loci) 

+	 1x125 mg/kg, intraperitoneal 

injection of males before 

mating with untreated 

females 

+	 5x40 or 50 mg/kg, 

intraperitoneal injection of 

males before mating with 

untreated females 

+	 6 weeks; 0.81, 3.19, or 

7.22 mg/kg/day, drinking 

water of males before mating 

with untreated females 

+	 4 weeks; 3.3–16.3 mg/kg/day 

estimated drinking water 

doses of males before 

mating with untreated 

females 

+	 64 days; 0.5,5.0 mg/kg/day 

drinking water of males 

before mating with untreated 

females 

+	 5 days; 5, 15, 30, 45, or 

60 mg/kg drinking water of 

males before mating with 

untreated females 

+	 5 days; 30 mg/kg gavage of 

males before mating with 

untreated females 

+	 80 days; 1.5, 2.8, or 

5.8 mg/kg/day, drinking 

water of males before mating 

with untreated females 

+	 10 weeks; 4.65, 7.86, or 

11.53 mg/kg/day estimated 

drinking water doses of 

males before mating with 

untreated females 

+	 5 days 25–125 mg/kg/day, 

dermal exposure of males 

before mating with untreated 

females 

–	 0, 0.14, or 0.70 mmol/kg, 

intraperitoneal injection on 

postnatal days 1, 8, or 15 

Adler et al. 2000 

Shelby et al. 1987 

Chapin et al. 1995 

Sakamoto and 

Hashimoto 1986 

Tyl et al. 2000a, 

2000b 

Sublet et al. 1989 

Working et al. 1987 

Smith et al. 1986 

Zenick et al. 1986 

Gutierrez-Espeleta 

et al. 1992 

Von Tungeln et al. 

2009 

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ACRYLAMIDE 77 

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Table 3-7. Genotoxicity of Acrylamide In Vivo 

Species (test system) End point Result Test conditions Reference 

Mouse (spleen Gene mutation + 0, 0.14, or 0.70 mmol/kg, Von Tungeln et al.
 

lymphocytes, tk and intraperitoneal injection on 2009
 

HPRT loci) postnatal days 1–8
 

Mouse (liver ceIIs, Gene mutation + 3–4 weeks; 100 or 500 mg/L Manjanatha et al.
 

lymphocyte HPRT drinking water 2006
 

locus)
 

Muta® Mouse (lac z Gene mutation + 5x50 mg/kg intraperitoneal Hoorn et al. 1993
 

loci) injection 

Muta® Mouse (lac z Gene mutation – 1x50–100 mg/kg, Krebs and Favor
 

loci) intraperitoneal injection 1997
 

Mouse (offspring coat Gene mutation + 1x50 or 75 mg/kg, Neuhäuser-Klaus
 

color loci) intraperitoneal injection of and Schmahl 1989
 

pregnant females 

Mouse (offspring coat Gene mutation + 3x50 or 75 mg/kg, Neuhäuser-Klaus 

color loci) intraperitoneal injection of and Schmahl 1989 

pregnant females 

Mouse (offspring coat Gene mutation + 5x50 mg/kg, intraperitoneal Russell et al. 1991 

color loci) injection of males before 

mating with untreated 

females 

Mouse (offspring coat Gene mutation + 1x100–125 mg/kg, Ehling and 

color loci) intraperitoneal injection of Neuhäuser-Klaus 

males before mating with 1992 

untreated females 

Chromosomal alterations in mammalian cells 

Mouse (bone Chromosomal + 1x50–150 mg/kg, Adler et al. 1988 

marrow) aberration intraperitoneal injection 

Mouse (bone Chromosomal + 1x100 mg/kg, intraperitoneal Čihák and 

marrow) aberration injection Vontorková 1988 

Mouse (bone Chromosomal – 1x100–200 mg/kg, Shiraishi 1978
 

marrow) aberration intraperitoneal injection
 

Mouse (bone Chromosomal – 7–21 days 78 mg/kg-day diet Shiraishi 1978
 

marrow) aberration 

Rat (bone marrow) Chromosomal – 1x100 mg/kg, intraperitoneal Krishna and Theiss 

aberration injection 1995 

Mouse (spleen Chromosomal – 1x50–125 mg/kg, Backer et al. 1989 

lymphocyte) aberration intraperitoneal injection 

Mouse (splenocyte) Chromosomal – 1x100 mg/kg, intraperitoneal Kligerman et al. 

aberration injection 1991 

Mouse Chromosomal – 1x50–150 mg/kg, Adler et al. 1988 

(spermatogonia) aberration intraperitoneal injection 

Mouse Chromosomal – 1x50–125 mg/kg, Backer et al. 1989 

(spermatogonia) aberration intraperitoneal injection
 

Mouse Chromosomal – 5x50 mg/kg/day, Adler 1990
 

(spermatogonia) aberration intraperitoneal injection
 

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ACRYLAMIDE 78 

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Table 3-7. Genotoxicity of Acrylamide In Vivo 

Species (test system) End point Result Test conditions Reference 

Mouse Chromosomal + 1x100 mg/kg, intraperitoneal Adler 1990 

(spermatocyte) aberration injection 

Mouse (first cleavage Chromosomal + 1x75 or 125 mg/kg or Pacchierotti et al. 

one-cell zygote) aberration 5x50 mg/kg/day, 1994 

intraperitoneal injection of 

males before mating with 

untreated females 

Mouse (first cleavage Chromosomal + 5x50 mg/kg/day, Marchetti et al. 1997 

zygote) aberration intraperitoneal injection of 

males before mating with 

untreated females 

Mouse (offspring Heritable + 5x40–50 mg/kg/day, Shelby et al. 1987 spermatocyte) translocation intraperitoneal injection of 

males before mating with 

untreated females 

Mouse (offspring Heritable + 1x50–100 mg/kg, Adler et al. 1994 

spermatid) translocation intraperitoneal injection of 

males before mating with 

untreated females 

Mouse (offspring Heritable + 5x50 mg/kg/day, dermal Adler et al. 2004 

spermatocyte) translocation exposure of males before 

mating with untreated 

females 

Mouse (offspring Heritable + 5x50 mg/kg/day, Adler 1990 

spermatocyte) translocation intraperitoneal injection 

Mouse (bone Polyploidy or + 1x100–200 mg/kg, Shiraishi 1978 

marrow) aneuploid intraperitoneal injection 

Mouse (bone Polyploidy or + 7–21 days 78 mg/kg/day, Shiraishi 1978 

marrow) aneuploid diet 

Mouse (bone Spindle disturbance – 1x120 mg/kg, intraperitoneal Adler et al. 1993 

marrow) injection 

Mouse (bone Micronucleus + 1x50–125 mg/kg, Adler et al. 1988 

marrow) intraperitoneal injection 

Mouse (bone Micronucleus + 1x100 mg/kg, intraperitoneal Čihák and 

marrow) injection Vontorková 1988 

Mouse (bone Micronucleus + 2 days 25–100 mg/kg/day, Čihák and 

marrow) intraperitoneal injection Vontorková 1988 

Mouse (bone Micronucleus + 1x136 mg/kg, intraperitoneal Knaap et al. 1988 

marrow) injection 

Mouse (bone Micronucleus + 1, 2, or 3 days 42.5– Čihák and 

marrow) 100 mg/kg/day, Vontorková 1990 

intraperitoneal injection 

Sprague-Dawley Rat Micronucleus – 1x100 mg/kg, intraperitoneal Paulsson et al. 2002 

(bone marrow) injection 

Rat (bone marrow) Micronucleus – 1x100 mg/kg, intraperitoneal Krishna and Theiss 

injection 1995 

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ACRYLAMIDE 79 

3. HEALTH EFFECTS 

Table 3-7. Genotoxicity of Acrylamide In Vivo 

Species (test system) End point Result Test conditions Reference 

Mouse (reticulocyte) Micronucleus + 1x50–100 mg/kg, Russo et al. 1994 

intraperitoneal injection 

Mouse (reticulocyte) Micronucleus + 1x25–100 mg/kg, Paulsson et al. 2002 

intraperitoneal injection 

Mouse (reticulocyte Micronucleus – 0, 0.14, 0.70 mmol/kg, Von Tungeln et al. and nonchromatic postnatal day 1, 8, 15, 2009
 erythrocyte)
 intraperitoneal injection 

Mouse (reticulocyte Micronucleus –
 0, 0.14, 0.70 mmol/kg, Von Tungeln et al. and nonchromatic postnatal day 1–8, 2009
 erythrocyte)
 intraperitoneal injection 

Mouse (reticulocyte) Micronucleus + 28 days 0–24 mg/kg/day, Zeiger et al. 2009 

gavage 

Mouse Micronucleus + 28 days 0–24 mg/kg/day, Zeiger et al. 2009 (normochromatic gavage
 erythrocyte)
 

Mouse (erythrocyte) Micronucleus + 5 days 0, 25, 50 mg/kg/day, Ghanayem et al. 

intraperitoneal injection 2005b 

Mouse (spleen Micronucleus + 1x50–125 mg/kg, Backer et al. 1989 

lymphocyte) intraperitoneal injection
 

Mouse (splenocyte) Micronucleus +
 1x100 mg/kg, intraperitoneal Kligerman et al. 

injection 1991 

Mouse (spermatid) Micronucleus + 1x10–100 mg/kg, Collins et al. 1992 

intraperitoneal injection 

Mouse (spermatid) Micronucleus + 1x50–100 mg/kg or Russo et al. 1994 

4x50 mg/kg/day, 

intraperitoneal injection 

Lewis Rat (spermatid) Micronucleus + 1x50–100 mg/kg or Xiao and Tates 

4x50 mg/kg/day, 1994 

intraperitoneal injection 

Sprague-Dawley rat Micronucleus + Lähdetie et al. 1994 1x50–100 mg/kg or
 (spermatid)
 4x50 mg/kg/day,
 

intraperitoneal injection
 

Mouse (germ cell) Synaptonemal –
 1x50–150 mg/kg Backer et al. 1989 

complex aberration intraperitoneal injection
 

Mouse (germ cell) Synaptonemal +
 1x50–150 mg/kg, Backer et al. 1989 

complex asynapsis intraperitoneal injection 

Asynapsis in meiotic 

prophase 

Sister chromatid exchange 

Mouse (spleen Chromatid + 1x50–125 mg/kg, Backer et al. 1989 

lymphocytes) exchange intraperitoneal injection 

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ACRYLAMIDE 80 

3. HEALTH EFFECTS 

Table 3-7. Genotoxicity of Acrylamide In Vivo 

Species (test system) End point Result Test conditions Reference 

Mouse (splenocytes) 

DNA damage 

Mouse 

(spermatocytes and 

early spermatids) 

Mouse (bone marrow, 

spleen, liver, kidney, 

lungs, testes) 

Mouse (leukocytes, 

liver, lung) 

Rat (hepatocyte) 

Rat (spermatocyte) 

Mouse (germ cell) 

Mouse (testis) 

Mouse (liver) 

Sprague-Dawley rat 

(liver, lung, kidney, 

brain, testis) 

Mouse (liver, kidney, 

brain) 

Neonatal mouse 

(whole body)
 

Mouse (liver, lung, 

kidney) 

Mouse (liver, lung) 

Mouse (lung, liver, 

spleen, bone marrow) 

Chromatid 

exchange 

DNA breakage 

DNA breakage 

DNA breakage 

Unscheduled DNA 

synthesis 

Unscheduled DNA 

synthesis 

Unscheduled DNA 

synthesis 

DNA adduct 

(Alkylation) 

DNA adduct 

(Alkylation) 

DNA adduct (N7­

GA-Gua) 

DNA adduct (N7­

GA-Gua) 

DNA adduct (N7-

GA-Gua, N3-GAAde) 

DNA adduct (N7-

GA-Gua, N3-GAAde) 

DNA adduct (N7-

GA-Gua, N3-GAAde) 

DNA adduct (N7-

GA-Gua, N3-GAAde) 

+	 1x100 mg/kg, intraperitoneal 

injection 

+	 1x0–125 mg/kg, 

intraperitoneal injection 

+	 1x0–125 mg/kg, 

intraperitoneal injection 

+	 5 day 0, 25, 50 mg/kg/day, 

intraperitoneal injection (wild 

type mice) 

– 1x100 mg/kg or 

5x30 mg/kg/day, gavage 

+	 1x100 mg/kg or 

5x30 mg/kg/day, gavage 

+	 1x7.8–125 mg/kg, 

intraperitoneal injection 

+	 1x46 mg/kg, intraperitoneal 

injection 

+	 1x46 mg/kg, intraperitoneal 

injection 

+	 1x46 mg/kg, intraperitoneal 

injection 

+	 1x53 mg/kg, intraperitoneal 

injection 

+	 1x50 mg/kg, intraperitoneal 

injection 

+	 1x50 mg/kg, intraperitoneal 

injection 

+	 1x1–10 mg/kg, 

intraperitoneal injection 

+	 0, 0.14, 0.70 mmol/kg 

intraperitoneal injection, 

postnatal day 1, 8, 15 

Kligerman et al. 

1991 

Sega and Generoso 

1990 

Dobrzynska 2007 

Ghanayem et al. 

2005b 

Butterworth et al. 

1992 

Butterworth et al. 

1992 

Sega et al. 1990 

Sega et al. 1990 

Sega et al. 1990 

Segerbäck et al. 

1995 

Segerbäck et al. 

1995 

Gamboa da Costa 

et al. 2003 

Gamboa da Costa 

et al. 2003 

Gamboa da Costa 

et al. 2003 

Von Tungeln et al. 

2009 

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ACRYLAMIDE 81 

3. HEALTH EFFECTS 

Table 3-7. Genotoxicity of Acrylamide In Vivo 

Species (test system) End point Result Test conditions Reference 

Mouse (lung, liver, 

spleen) 

Mouse (liver) 

Mouse (liver, lung, 

kidney, leukocyte, 

testis) 

Mouse (liver) 

Rat (liver, brain, 

thyroid, leukocyte, 

mammary gland, 

testis) 

Rat (liver) 

DNA adduct (N7-

GA-Gua, N3-GAAde) 

DNA adduct (GAGua)
 

DNA adduct (N7-

GA-Gua, N3-GAAde)
 

DNA adduct (N7-

GA-Gua, N3-GAAde)
 

DNA adduct (N7-

GA-Gua, N3-GAAde)
 

DNA adduct (N7-

GA-Gua) 

Nonmammalian gene mutation 

Drosophila 

melanogaster 

D. melanogaster 

D. melanogaster 

D. melanogaster 

D. melanogaster 

Sex-linked recessive 

lethal 

Sex-linked recessive 

lethal 

Somatic mutation 

and recombination 

Somatic mutation 

and recombination 

Somatic mutation 

and recombination 

+	 0, 0.14, 0.70 mmol/kg 

postnatal day 1–8, 

intraperitoneal injection 

+	 28 days 0–24 mg/kg/day, 

gavage 

+	 1x50 mg/kg, intraperitoneal 

injection 

+	 14 days 1 mg/kg/day, 

drinking water 

+	 1x50 mg/kg, intraperitoneal 

injection 

+	 14 days 1 mg/kg/day, 

drinking water 

–	 1x40–50 mM, abdominal 

injection 

+	 48 hour 0.25–5 mM, larvae 

feeding 

+	 1–1.5 mM, larvae feeding 

until pupation 

+	 10–30 mM, larvae feeding 

until pupation 

+	 48 hour 0.25–5 mM, larvae 

feeding 

Von Tungeln et al. 

2009 

Zeiger et al. 2009 

Doerge et al. 2005a 

Doerge et al. 2005a 

Doerge et al. 2005a 

Doerge et al. 2005a 

Knaap et al. 1988 

Tripathy et al. 1991 

Knaap et al. 1988 

Batiste-Alentorn et 

al. 1991 

Tripathy et al. 1991 

– = negative result; + = positive result; DNA = deoxyribonucleic acid 

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ACRYLAMIDE 82 

3. HEALTH EFFECTS 

1992; Russell et al. 1991) and in offspring of pregnant female mice exposed to 50 or 75 mg/kg 

(Neuhäuser-Klaus and Schmahl 1989). Heritable or reciprocal translocations were noted in offspring of 

male mice exposed to 50–100 mg/kg acrylamide via intraperitoneal injection or dermal application before 

mating to untreated females (Adler 1990; Adler et al. 1994, 2004; Shelby et al. 1987). Intraperitoneal 

exposure to acrylamide also increased mutations at the tk and HPRT loci in lymphocytes of mice 

(Majanatha et al. 2006; von Tungeln et al. 2009) and at lac z loci in transgenic mice (Hoorn et al. 1993; 

Krebs and Favor 1997). 

Prominent clastogenic effects consistently associated with in vivo exposure include sister chromatid 

exchanges (Backer et al. 1989; Kligerman et al. 1991), micronucleus formation (Backer et al. 1989; Čihák 

and Vontorková 1988, 1990; Collins et al. 1992; Ghanayem et al. 2005b; Kligerman et al. 1991; Knaap et 

al. 1988; Lähdetie et al. 1994; Paulsson et al. 2002; Russo et al. 1994; Xiao and Tates 1994; Zeiger et al. 

2009), and aneuploidy or polyploidy (Shiraishi 1978). Acrylamide induced DNA damage in various 

rodent tissues (including testes and male germ cells), evidenced as DNA breakage (Dobrzynska 2007; 

Ghanayem et al. 2005b; Sega and Generoso 1990), unscheduled DNA synthesis (Butterworth et al. 1992; 

Sega et al. 1990), and DNA adduct formation (Doerge et al. 2005a; Gamboa da Costa et al. 2003; Sega et 

al. 1990; Segerbäck et al. 1995; Von Tungeln et al. 2009; Zeiger et al. 2009). Increases in chromosomal 

aberrations were observed in the first cleavage zygote of acrylamide-treated male mice mated with 

untreated females (Marchetti et al. 1997; Pacchierotti et al. 1994). 

Assays for acrylamide-induced chromosomal aberrations in bone marrow, spleen, or spermatogonia of 

acrylamide-treated rodents produced both positive (Adler 1990; Adler et al. 1988; Čihák and Vontorková 

1988) and negative (Adler 1990; Adler et al. 1988; Backer et al. 1989; Kligerman et al. 1991; Krishna and 

Theiss 1995; Shiraishi 1978) results. Acrylamide did not induce micronuclei in a small number of rat and 

mouse assays (Krishna and Theiss 1995; Paulsson et al. 2002; Von Tungeln et al. 2009). Results for 

synaptonemal complex aberrations in male mouse germ cells were negative or only weakly positive 

(Backer et al. 1989). Acrylamide did not induce spindle disturbances in the bone marrow of 

intraperitoneally-injected mice (Adler et al. 1993). 

Somatic mutations and recombination (Batiste-Alentorn et al. 1991; Knaap et al. 1988; Tripathy et al. 

1991) and sex-linked recessive lethal mutations (Tripathy et al. 1991) were induced in drosophila larval 

feeding assays. Negative results were obtained for sex-linked recessive lethal mutations in another assay 

that employed abdominal injection (Knaap et al. 1988). 

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ACRYLAMIDE 83 

3. HEALTH EFFECTS 

Table 3-8 summarizes the results of in vitro assays. Acrylamide induced mutations at the tk and HPRT 

loci in several assays with mammalian cells including mouse lymphoma L5178Y cells (Barfknecht et al. 

1988; Knaap et al. 1988; Mei et al. 2008b; Moore et al. 1987) and human promyelocytic leukemia HL-60 

and NB4 cells (Ao et al. 2008). In Chinese hamster V79H3 cells (which do not express genes for CYP 

enzymes), acrylamide did not induce mutations at the HPRT locus (Tsuda et al. 1993). Acrylamide did 

not induce reverse mutations in multiple strains of Salmonella typhimurium or in Escherichia coli WP2 

uvrAwith or without metabolic activation (Hashimoto and Tanii 1985; Jung et al. 1992; Knaap et al. 

1988; Lijinsky and Andrews 1980; Müller et al. 1993; Tsuda et al. 1993; Zeiger et al. 1987). One 

exception was a weakly positive result in a few trials of TA98 and TA100, but only with S9 activation 

(Zeiger et al. 1987). 

Clastogenic effects associated with in vitro exposure to acrylamide include: chromosomal aberrations in 

mammalian cells (Knaap et al. 1988; Moore et al. 1987; Tsuda et al. 1993); polyploidy, sister chromatid 

exchanges, and spindle disturbances in Chinese hamster cells (Adler et al. 1993; Knaap et al. 1988; 

Martins et al. 2007; Tsuda et al. 1993; Warr et al. 1990); and micronuclei in human hepatoma G2 cells 

(Jiang et al. 2007). Although acrylamide did not induce micronuclei in one in vitro assay using 

seminiferous tubule segments from rats (Lähdetie et al. 1994), micronuclei were induced in spermatids of 

rodents exposed to acrylamide in vivo (Collins et al. 1992; Lähdetie et al. 1994; Russo et al. 1994; Xiao 

and Tates 1994). 

DNA damage associated with in vitro exposure to acrylamide includes DNA damage in Bacillus subtilis 

(Tsuda et al. 1993); DNA breakage and oxidative DNA damage in human hepatoma G2 cells (Jiang et al. 

2007); unscheduled DNA synthesis in human mammary epithelial cells (Butterworth et al. 1992); and 

glycidamide-DNA adducts in Chinese hamster V79 cells (Martins et al. 2007), mouse embryonic 

fibroblasts (Besaratinia and Pfeifer 2004), and human bronchial epithelial cells (Besaratinia and Pfeifer 

2004). DNA adducts were not detected when mouse lymphoma cells were incubated with up to 20 mM 

acrylamide, but glycidamide concentrations in the range of 0.5–4 mM induced DNA adducts in these cells 

(Mei et al. 2008b). Acrylamide in vitro exposure also caused cell morphological transformations in 

several mouse cell lines and Syrian hamster embryo cells (Abernethy and Boreiko 1987; Banerjee and 

Segal 1986; Park et al. 2002; Tsuda et al. 1993). 

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ACRYLAMIDE 84 

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Table 3-8. Genotoxicity of Acrylamide In Vitro 

Result 

Activation 

WithSpecies (test system) End point With out Test conditions Reference 

Prokaryotic 

Bacterial gene mutation 

Salmonella. Reverse – – 10–10,000 μg/plate Zeiger et al. 1987 

typhimurium TA98, mutation +/- S9 activation 

TA100, TA1535, Weakly positive in TA98 

TA1537 and TA100 in only a few 

trials with activation; all 

other strains negative 

S. typhimurium TA97, Reverse – – 100–10,000 μg/plate Zeiger et al. 1987 

TA98, TA100, mutation +/- S9 activation 

TA1535 

S. typhimurium TA98, Reverse – – 1–100 mg/plate Knaap et al. 1988 

TA100, TA102, mutation +/- S9 activation 

TA1535, TA1537 

S. typhimurium TA98, Reverse – – 0.5–50 mg/plate Tsuda et al. 1993 

TA100, TA1535, mutation +/- S9 activation 

TA1537 

S. typhimurium Reverse – – Up to 5 mg/plate Müller et al. 1993 ; 

TA1535 mutation +/- S9 activation Jung et al. 1992 

S. typhimurium TA98, Reverse – – Up to 1 mg/plate Lijinsky and Andrews 

TA100, TA1535, mutation +/- S9 activation 1980 

TA1537, TA1538 

S. typhimurium TA98, Reverse – – 0.5–5,000 μg/plate Hashimoto and Tanii 

TA100, TA 1535, mutation +/- S9 activation 1985 

TA1537, TA1538 

Escherichia coli WP2 Reverse – – 0.5–50 mg/plate Tsuda et al. 1993 

uvrA- mutation +/- S9 activation 

Klebsiella. Fluctuation No – 2–10 mg/L Knaap et al. 1988 

pneumoniae ur -pro - data 

DNA damage and repair and DNA adduct formation 

Bacillus subtilis DNA damage + + 1–50 mg/ disk Tsuda et al. 1993 

+/- S9 activation 

Mammalian gene mutation assays 

Mouse lymphoma Gene + + 10 mM Barfknecht et al. 1988 

L5178Y TK+/-, tk locus mutation 

Mouse lymphoma Gene No + 0–0.85 mg/mL Moore et al. 1987 

L5178Y TK+/-, tk locus mutation data No activation 

Clastogenic response
 

Mouse lymphoma Gene No + 0–18 mM Mei et al. 1988
 

L5178Y TK+/-, tk locus mutation data No activation
 

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ACRYLAMIDE 85 

3. HEALTH EFFECTS 

Table 3-8. Genotoxicity of Acrylamide In Vitro 

Result 

Activation 

WithSpecies (test system) End point With out Test conditions Reference 

Mouse lymphoma Gene – – 0.5–7.5 mg/mL Knaap et al. 1988 

L5178Y TK+/-, tk and mutation +/- S9 activation 

HPRT loci Mutation only at cytotoxic 

concentrations 

Mouse lymphoma Gene + + 0.1–0.5 mg/mL Knaap et al. 1988 

L5178Y TK+/-, HPRT mutation Cocultivated activation 

locus 

Chinese hamster Gene No – 1–7 mM Tsuda et al. 1993 

V79H3, HPRT locus mutation data No activation 

Human promyelocytic Gene No + 0–700 mg/L Ao et al. 2008 

leukemia HL-60 and mutation data 

NB4, HPRT locus 

Chromosomal alteration in mammalian cells 

Chinese hamster Chromoso- No + 0.5–5 mM Tsuda et al. 1993 

V79H3 mal data No activation 

aberration 

Chinese hamster V79 Chromoso- + + 0.1–3 mg/mL Knaap et al. 1988 

mal +/- S9 activation 

aberration 

Chinese hamster V79 Chromoso- No – 0–2,000 μM Martins et al. 2007 

mal data No activation 

aberration 

Mouse lymphoma Chromoso- No + 0.65–0.85 mg/mL Moore et al. 1987 

L5178Y TK+/- mal data No activation 

aberration 

Chinese hamster Polyploidy No + 0.5–5 mM Tsuda et al. 1993 

V79H3 data 

Chinese hamster Polyploidy No + 0.0125–0.5 mg/mL Warr et al. 1990 

LUC2 p5 data 

Chinese hamster V79 Spindle No + 0.01–1 mg/mL Adler et al. 1993 

disturbance data 

Chinese hamster Spindle No + 0.2–2 mg/mL Warr et al. 1990 

DON:Wg3h disturbance data 

Chinese hamster Spindle No + 0.01–1 mg/mL Warr et al. 1990 

LUC2 p5 disturbance data 

Rat seminiferous Micronucleus No _ 5–50 μg/mL Lähdetie et al. 

tubular segments data 1994 

Human hepatoma G2 Micronucleus No + 0–2.5 mM Jiang et al. 2007 

data 

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ACRYLAMIDE 86 

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Table 3-8. Genotoxicity of Acrylamide In Vitro 

Result 

Activation 

WithSpecies (test system) End point With out Test conditions Reference 

Sister chromatid exchange 

Chinese hamster V79 Chromatid + + 0.1–1 mg/mL Knaap et al. 1988 

exchange 

Chinese hamster V79 Chromatid No + 0.5–2.5 mg/mL Tsuda et al. 1993 

exchange data 

Chinese hamster V79 Chromatid No + 0–2,000 μM Martins et al. 2007 

exchange data 

DNA damage and repair and DNA adduct formation 

Human hepatoma G2 DNA No + 0–20 mM Jiang et al. 2007 

breakage data 

Human hepatoma G2 Oxidative No + 0–20 mM Jiang et al. 2007 

DNA damage data 

F344 Rat primary Unscheduled No – 0.01–1 mM Butterworth et al. 

hepatocytes DNA data 1992 

synthesis 

Human mammary Unscheduled No + 1–10 mM Butterworth et al. 

epithelial DNA data 1992 

synthesis 

Chinese hamster V79 DNA adducts No + 0–2,000 μM Martins et al. 2007 

(N7-GA-Gua, data 

N3-GA-Ade) 

Mouse lymphoma DNA adducts No – 0–20 mM Mei et al. 2008b 

L5178Y TK+/- (N7-GA-Gua, data 

N3-GA-Ade) 

Big Blue mouse DNA adducts No + 0, 0.0032, 0.320. and Besaratinia and 

embryonic fibroblasts	 (N7-GA-Gua, data 16 mM Pfeifer 2004
 

N1-GA-Ade,
 

N3-GA-Ade)
 

Human bronchial DNA adducts No + 0, 0.320 and 3.2 mM Besaratinia and 

epithelial (N7-GA-Gua, data Pfeifer 2004 

N1-GA-Ade, 

N3-GA-Ade) 

Cell transformation 

Mouse C3H/10T1/2 Morphologi- No + 25–200 μg/mL Banerjee and Segal 

cal data 1986 

transformation 

Mouse NIH/3T3 Morphologi- No + 2–200 μg/mL Banerjee and Segal 

cal data 1986 

transformation 

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ACRYLAMIDE 87 

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Table 3-8. Genotoxicity of Acrylamide In Vitro 

Result 

Activation 

WithSpecies (test system) End point With out Test conditions Reference 

Mouse C3H/10T1/2	 Morphologi- No – 10–300 μg/mL Abernethy and 

cal data Boreiko 1987 

transformation 

Mouse BALB/c 3T3	 Morphologi- No + 0.5–2 mM Tsuda et al. 1993 

cal data 

transformation 

Syrian hamster	 Morphologi- No + 0.1–0.7 mM Park et al. 2002 

embryo	 cal data 

transformation 

Syrian hamster	 Morphologi- No – 0.001–10 mM Kaster et al. 1998 

embryo	 cal data 

transformation 

– = negative result; + = positive result; DNA = deoxyribonucleic acid 

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ACRYLAMIDE 88 

3. HEALTH EFFECTS 

3.4 TOXICOKINETICS 

Acrylamide and its principal and toxicologically significant (epoxide) metabolite, glycidamide, react with 

various biologically significant targets. The chemical basis for these interactions is strongly associated 

with the degree of electrophilicity (electron deficiency) with nucleophilic centers (i.e., unshared 

electrons). Electrophiles and nucleophiles are generally characterized as being either “hard” or “soft” 

corresponding to a spectral range of high or low charge densities or electronegativity for reactivity 

(Pearson and Songstad 1967). Due to its ά,β-unsaturated structure and ready capacity to undergo 

Michael-type additions, acrylamide may be classified as a “soft” electrophile. Soft electrophiles like 

acrylamide react readily with soft nucleophiles such as the thiol groups of proteins or glutathione. 

Glycidamide, on the other hand, has a relatively high positive charge density, and acts as a hard 

electrophile, more capable of reacting with centers of high electronegativity (i.e., hard nucleophiles) such 

as the purine and pyrimidine bases in DNA (Dearfield et al. 1995; Lopachin and DeCaprio 2005;). 

Hemoglobin adducts have been used as biomarkers of exposure to acrylamide and are based on the 

assumption that a measured adduct level represents a steady-state level from a continuous exposure to 

acrylamide over the previous 120 days, which is the average life span of a red blood cell. Hemoglobin 

adduct levels provide a direct measure of the total amount of acrylamide and its reactive metabolite, 

glycidamide, in the blood over a given time period, which is quantified as the area under the curve (AUC 

in amount-unit time/volume). AUC is the integral of “concentration” (e.g., mg or mmol/L) × “time” (e.g., 

minutes or hours). Under the reasonable assumption that the amount of parent or reactive toxicant in 

blood indicates the amount available to bind to tissue macromolecules or DNA, hemoglobin adducts 

provide a relevant internal metric for use in estimating the risk of acrylamide toxicity. 

3.4.1 Absorption 

Detection of hemoglobin adducts of acrylamide in exposed workers and volunteers provides qualitative 

evidence of absorption. Controlled human studies of the formation of hemoglobin adducts of acrylamide 

following oral and dermal exposure provide some information regarding the extent of absorption via these 

exposure routes. Available animal data indicate that acrylamide is readily and rapidly absorbed following 

inhalation and oral exposure, and somewhat less readily absorbed following dermal exposure. 

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ACRYLAMIDE 89 

3. HEALTH EFFECTS 

3.4.1.1 Inhalation Exposure 

Hagmar et al. (2001) measured hemoglobin adducts of acrylamide in a group of 210 tunnel construction 

workers who were occupationally exposed for 2 months to a chemical grouting agent containing 

acrylamide and N-methylolacrylamide. Within 1 month after construction work was completed, blood 

samples were drawn for the analysis of adducts of acrylamide with N-terminal valines (acrylamideVal) in 

hemoglobin. Workers were expected to have experienced both inhalation and dermal exposure. 

Quantitative exposure data were limited to two personal air samples showing concentrations of 0.27 and 

0.34 mg/m3 for the sum of acrylamide and N-methylolacrylamide; further analysis suggested that the air 

contained a 50:50 mixture of these compounds. Hemoglobin adduct levels for 18 nonsmoking unexposed 

reference subjects varied between 0.02 and 0.07 nmol/g globin. The frequency distribution of adduct 

levels in the 210 tunnel workers was as follows: 47 with <0.08 nmol/g globin; 89 with 0.08–0.29 nmol/g; 

36 with 0.3–1.0 nmol/g; and 38 with 1.0–17.7 nmol/g. Adduct levels were determined in blood samples 

collected at intervals up to 5 months after cessation of exposure from five workers with initial levels 

ranging from about 2.2 to 4.4 nmol/g. Adduct levels decreased to background levels within 120 days, 

consistent with the approximate 120-day life of red blood cells. 

Hemoglobin adduct levels were measured in 41 Chinese workers who were exposed to acrylamide for 

0.1–8 years (Bergmark et al. 1993). AcrylamideVal hemoglobin levels were measured. Workers were 

involved in the production of acrylamide (via the hydration of acrylonitrile) and polyacrylamide. The 

adduct levels in exposed workers ranged from 0.3 to 34 nmol acrylamide/g hemoglobin. AcrylamideVal 

levels were not detected in blood samples of 10 control workers from the same city who had not been 

occupationally exposed to acrylamide (or acrylonitrile). Blood samples from 5 of the 41 exposed workers 

were also analyzed for hemoglobin adducts of glycidamide (glycidamideVal), a principal metabolite of 

acrylamide in animals (see also Section 3.4.3, Metabolism). A statistically significant linear relationship 

was observed between levels of acrylamideVal and glycidamideVal in these five workers; the ratio 

between acrylamideVal and glycidamideVal was approximately 3:10. Average levels of acrylamide in air 

samples were 1.52 and 0.73 mg/m3 for workplaces involved with polymerization and synthesis processes, 

respectively. Workers involved in these processes showed average acrylamideVal levels of 7.3±3.4 

(n=12, polymerization) and 14.7±10.6 nmol/g hemoglobin (n=14, synthesis). 

Bergmark et al. (1993) made the following assumptions based on a central assumption that these workers 

may have experienced only inhalation exposure: (1) adducts are stable during the life of erythrocytes; 

(2) the lifespan of human erythrocytes is about 120 days (17 weeks); (3) the second-order reaction rate 

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ACRYLAMIDE 90 

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constant for the reaction of acrylamideVal in human hemoglobin is 4.4x10-6 [L (g Hb)

-1hour -1] (based on 

in vitro experiments); (4) the human ventilation rate is 0.2 L minute-1 kg bw-1; and (5) inhaled acrylamide 

is 100% absorbed. Using these assumptions, the predicted levels of acrylamideVal were only 0.93 and 

0.44 nmol/g hemoglobin, respectively. The large disparity between the observed and predicted adduct 

levels resulted in the conclusion that dermal contact may have been the predominant source of absorption 

in these workers. 

Animal studies indicate that inhaled acrylamide is readily absorbed (Sumner et al. 2003). Male F344 rats 

and B6C3F1 mice were exposed to approximately 3 ppm of a mixture of [13C]-labeled acrylamide and 

[

14C]-labeled acrylamide vapor via nose-only inhalation for 6 hours. Selected rats and mice were 

sacrificed immediately following the exposure period for determination of [14C] content in tissues, an 

indicator of the extent of absorption of inhaled acrylamide. The remaining rats and mice were monitored 

for 24-hour elimination of acrylamide and metabolites via urine, feces, and expired air. Immediately 

following the 6-hour exposure period, approximately 18 and 8 μmol of [14C]-equivalents were recovered 

from tissues and carcasses of the rats and mice, respectively. At the end of the 24-hour postexposure 

period, 42% of the total recovered radioactivity was in urine, feces, and nose-tube and cage washes of 

rats; <3% was in exhaled air; and 56% remained in the body. In mice, 51% was recovered in urine, feces, 

and nose-tube and cage washes; <3% was in exhaled air, and 46% remained in the body. Fractional 

absorption could not be determined from the presented data because ventilation rates were apparently not 

measured. 

3.4.1.2 Oral Exposure 

Fennell and coworkers evaluated metabolism and hemoglobin adduct formation (Fennell et al. 2005b) and 

kinetics of elimination of urinary metabolites of acrylamide (Fennell et al. 2006) following oral 

administration of [1,2,3-13C3]-acrylamide to 24 adult male volunteers exposed under controlled 

conditions. All volunteers were aspermic (i.e., clinically sterile because of the potential for adverse 

effects of acrylamide on sperm), and had not used tobacco products for the prior 6 months. The health of 

the volunteers was continually monitored. Acrylamide was administered in an aqueous solution (single 

dose of 0.5, 1, or 3 mg/kg) to the volunteers. For the 3 mg/kg dose group, approximately 40% of the 

administered dose was recovered as urinary metabolites in the 24-hour urine. Approximately 86% of the 

urinary metabolites were derived from GSH conjugation and excreted as N-acetyl-S-(3-amino-3-

oxopropyl)cysteine and its S-oxide; the remainder included glycidamide, glyceramide, and low levels of 

N-acetyl-S-(3-amino-2-hydroxy-3-oxopropyl)cysteine. Mean levels of hemoglobin adducts of acrylamide 

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(

13C3-acrylamideVal) and glycidamide (13C3-glycidamideVal) in the 3 mg/kg group at 24 hours 

postadministration were 2,479 and 1,076 fmol/mg globin, respectively. These findings demonstrate that 

orally-administered acrylamide is rapidly and readily absorbed by the gastrointestinal tract. 

Fuhr et al. (2006) evaluated the toxicokinetics of acrylamide in six young healthy volunteers after the 

consumption of a meal containing 0.94 mg of acrylamide. Urine was collected up to 72 hours thereafter. 

Unchanged acrylamide; its mercapturic acid metabolite, N-acetyl-S-(2-carbamoylethyl)cysteine (AAMA), 

its epoxy derivative, glycidamide; and the respective metabolite of glycidamide, N-acetyl-S-(2-hydroxy2-carbamoylethyl)cysteine (GAMA), were quantified in the urine by liquid chromatography-mass 

spectrometry. Toxicokinetic variables were obtained by noncompartmental methods. Overall, 

approximately 60% of the dose was recovered in the urine. Although no glycidamide was found, 

unchanged acrylamide, AAMA, and GAMA accounted for urinary excretion of approximately 4.5, 50, 

and 6% of the dose, respectively. These results indicate that most of the acrylamide ingested with food is 

absorbed in humans. 

Boettcher et al. (2006a) investigated the human metabolism of acrylamide to AAMA and GAMA in a 

healthy male volunteer who received a single dose of about 1 mg deuterium-labeled (d(3)) acrylamide, 

representing 13 μg/kg body weight, in drinking water. Urine samples before dosing and within 46 hours 

after the dose were analyzed for d(3)-AAMA and d(3)-GAMA. Total recovery of AAMA and GAMA in 

the 24-hour urine was about 51% of the administered dose, which provides additional demonstration of 

the rapid and extensive absorption of ingested acrylamide. 

Boettcher et al. (2006b) reported the influence of an acrylamide-free diet on the excretion of urinary 

mercapturic acid metabolites derived from acrylamide in three healthy volunteers who fasted for 

48 hours. Urinary acrylamide mercapturic acid metabolites were considerably reduced after 48 hours of 

fasting, with levels even well below the median level in nonsmokers. These results indicate that the 

acrylamide in the diet is the main source of environmental acrylamide exposure in humans, apart from 

smoking. 

Bjellaas et al. (2007a) reported urinary mercapturic acid derivatives of acrylamide in a clinical study 

comprised of 53 subjects. Median intakes (range) of acrylamide were estimated based on 24-hour dietary 

recall as 21 (13–178) μg for nonsmokers and 26 (12–67) μg for smokers. The median dietary exposure to 

acrylamide was estimated to be 0.47 (range 0.17–1.16) μg/kg body weight per day. The median (range) 

total excretion of acrylamide in urine during 24 hours was 16 (7–47) μg for nonsmokers and 74 (38–106) 

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μg for smokers. In a multiple linear regression analysis, a statistically significant correlation was found 

between the urinary excretion of acrylamide metabolites and intake of aspartic acid, protein, starch, and 

coffee. 

Studies in rats indicate that orally administered acrylamide is rapidly and extensively absorbed by the 

gastrointestinal tract (Dixit et al. 1982; Doerge et al. 2005b; Fennell et al. 2005a; Kadry et al. 1999; Miller 

et al. 1982; Ramsey et al. 1984). The time course of urinary elimination of radioactivity from male F344 

rats during a 7-day period following single oral doses of 10 mg/kg [2,3-14C]-acrylamide was essentially 

the same as that observed with male F344 rats following single intravenous dosing at 10 mg/kg 

[2,3-14C]-acrylamide (Miller et al. 1982). This observation suggests that 100% of the oral dose was 

absorbed. The time courses of urinary elimination of radioactivity were similar for groups of rats given 

single 1, 10, or 100 mg/kg oral doses of radiolabeled acrylamide, suggesting that the extent of absorption 

was not affected by dose level in the tested range. The rapidity of absorption was demonstrated by 

observations that peak plasma levels of radioactivity were attained by 1 hour after administration and that 

53–67% of administered radioactivity was detected in the urine collected within 24 hours of 

administration (Miller et al. 1982). Similar results indicating rapid and extensive oral absorption were 

reported for studies in which male Sprague-Dawley rats were given single 50 mg/kg oral doses of 

[1-

14C]-acrylamide (Kadry et al. 1999). Radioactivity was detected in blood 5 minutes after 

administration, and peak plasma levels of radioactivity occurred at 38 minutes after administration. 

Approximately 51% of administered radioactivity was detected in urine collected within 24 hours of 

administration (Kadry et al. 1999). Fennell et al. (2005a) administered 3 mg/kg of 

[1,2,3-13C3]-acrylamide by gavage to male F344 rats. The total amount of acrylamide metabolites 

recovered in urine by 24 hours after dosing was 50%, which is similar to that reported by Miller et al. 

(1982) and Kadry et al. (1999). 

Doerge et al. (2005c) compared the toxicokinetics of acrylamide and glycidamide in serum and tissues of 

male and female B6C3F1 mice following a single 0.1 mg/kg acrylamide dose by intravenous injection or 

gavage or a comparable dose of acrylamide from a feeding exposure for 30 minutes. Study groups also 

received an equimolar amount of glycidamide from either intravenous injection or gavage dosing. 

Following oral dosing, acrylamide was rapidly absorbed, widely distributed to tissues, and efficiently 

converted to glycidamide. Liver levels of glycidamide-DNA adducts were increased at 8 hours 

postdosing when acrylamide had been eliminated from the serum. Oral glycidamide dosing also resulted 

in rapid absorption, wide distribution to tissues, and liver DNA adduct levels that were approximately 

40% higher than those from an equimolar dose of orally-administered acrylamide. Based on the kinetics 

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of acrylamide following intravenous injection, oral administration from the diet attenuated acrylamide 

bioavailability to 23% of the intravenous dose, and aqueous gavage attenuated acrylamide bioavailability 

to 32–52%. In contrast, oral exposure resulted in higher relative internal glycidamide levels compared 

with levels following an intravenous injection, likely due to a first-pass effect but possibly the result of 

some other kinetic change. 

3.4.1.3 Dermal Exposure 

Fennell and coworkers evaluated metabolism and hemoglobin adduct formation (Fennell et al. 2005b) and 

kinetics of elimination of urinary metabolites of acrylamide (Fennell et al. 2006) following dermal 

administration of [1,2,3-13C3]-acrylamide to 24 adult male volunteers exposed under controlled 

conditions. All volunteers were aspermic (i.e., clinically sterile because of the potential for adverse 

effects of acrylamide on sperm) and had not used tobacco products for the prior 6 months. The health of 

the volunteers was continually monitored. Acrylamide was administered as three daily 24-hour occluded 

dermal doses of 3 mg/kg. Mean levels of hemoglobin adducts of acrylamide (13C3-acrylamideVal) and 

glycidamide (13C3-glycidamideVal) increased from 116 and 55 fmol/mg globin, respectively, following 

the first exposure period to 464 and 316 fmol/mg globin, respectively, following the last exposure period. 

Based on total amount administered, formation of acrylamideVal after dermal exposure was much lower 

than after oral administration (4.9 vs. 74.7 nmol/g globin/mmol acrylamide/kg). Approximately 4.5% of 

the administered dose was recovered as urinary metabolites through day 4. Dermal exposure also resulted 

in much lower formation of glycidamideVal (9.7% of that formed following oral exposure). 

Animal studies confirm that acrylamide is readily absorbed following dermal exposure (Ramsey et al. 

1984; Sumner et al. 2003). In male F344 rats, an average of 22% of an occluded dermal dose of 

162 mg/kg [2,3-14C]-labeled acrylamide was absorbed during a 24-hour exposure period (Sumner et al. 

2003). Following dermal administration of [1,3-14C]-labeled acrylamide to other F344 rats, peak plasma 

concentrations of acrylamide occurred at approximately 2 and 5 hours postadministration, respectively 

(Ramsey et al. 1984). The peak concentration at the high dose was about 20-fold higher than that of the 

low dose. 

Results of an in vitro study describe dermal absorption of acrylamide. Marty and Vincent (1998) applied 

[

14C]-labeled acrylamide (in an aqueous gel of 2% polyacrylamide) to biopsied human abdominal skin for 

24 hours at acrylamide concentrations of 1.28 or 2 ppm. Approximately 28 and 21% of the applied doses, 

respectively, was recovered in the receptor fluid. Between 1.6 and 3.4% of applied doses was recovered 

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in dermis and epidermis. The authors estimated total absorption of acrylamide to be 33.2 and 26.7% at 

low and high concentration, respectively, based on radioactivity recovered from the receptor phase, 

epidermis, and dermis. 

3.4.2 Distribution 

Results from several animal studies indicate that, following absorption, radioactivity from radiolabeled 

acrylamide is widely distributed with no specific accumulation in any tissues other than red blood cells 

(Barber et al. 2001a; Crofton et al. 1996; Edwards 1975; Hashimoto and Aldridge 1970; Ikeda et al. 1985; 

Kadry et al. 1999; Marlowe et al. 1986; Miller et al. 1982; Ramsey et al. 1984) and late-staged spermatids 

(Sega et al. 1989). Results of intravenous injection studies in pregnant animals indicate that acrylamide 

and/or its metabolites readily cross the placenta and are distributed within the developing fetus in a 

manner similar to that of the pregnant mother (Ikeda et al. 1983, 1985; Marlowe et al. 1986). In a recent 

study designed to assess hemoglobin adduct levels of acrylamide in blood samples of pregnant mothers 

and umbilical cord blood of neonates, the concentration in umbilical cord blood was approximately 50% 

of that found in the blood of the mother, indicating that acrylamide readily passes from mother to 

developing fetus (Schettgen et al. 2004a). 

3.4.2.1 Inhalation Exposure 

Immediately following a 6-hour inhalation exposure of male F344 rats to 3 ppm of [14C]/[13C]-acrylamide 

vapor, the rank of acrylamide equivalent concentrations was: blood cells (~7 μg/g) > testes, skin, liver, 

and kidneys (~6 μg/g) > brain, spleen, lung, and epididymis (~4 μg/g) (Sumner et al. 2003). Acrylamide 

equivalent concentrations in similarly-treated male B6C3F1 mice were: testes (~14 μg/g) > skin and liver 

(~11 μg/g) > epididymis (~8 μg/g) > brain (~7 μg/g) > lung and blood (~6 μg/g) > fat (~5 μg/g) (Sumner 

et al. 2003). 

3.4.2.2 Oral Exposure 

Following 13 daily oral doses of [1,3-

14C]-labeled acrylamide at 0.05 or 30 mg/kg/day, tissue 

concentrations of acrylamide in male F344 rats were similar among tissues with the exception of red 

blood cells, which showed higher concentrations, presumably due to the formation of acrylamideVal 

and/or glycidamideVal hemoglobin adducts (Ramsey et al. 1984). Mean concentrations (μg equivalents 

[

14C]-acrylamide per gram of tissue) at the high dose were 383.7 μg/g in red blood cells, 87.74 μg/g in 

liver, 70.43 μg/g in kidneys, 70.60 μg/g in epididymis, 67.14 μg/g in testis, 54.00 μg/g in sciatic nerve, 

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53.52 μg/g in brain, 47.56 μg/g in carcass, 39.11 μg/g in skin, and 16.45 μg/g in plasma. At the low dose, 

the mean concentration in red blood cells was 1.26 μg/g (approximately 61% of the total recovered dose) 

compared with a range of 0.07–0.13 μg/g in other tissues. 

In Sprague-Dawley rats given single 50 mg/kg oral doses of [1-

14C]-labeled acrylamide, tissue 

concentrations of radioactivity at 28 and 144 hours postadministration were indicative of wide 

distribution of acrylamide metabolites among tissues with no evidence for accumulation in toxicity targets 

(Kadry et al. 1999). These results suggest the binding of acrylamide in the absence of its accumulation in 

erythrocytes or neural tissue. At 28 hours, brain, thyroid, testes, adrenal, pancreas, thymus, liver, kidney, 

heart, and spleen showed a narrow range of mean concentrations, approximately 0.05–0.10% of the initial 

dose/g. Higher concentrations were noted in the skin, bone marrow, stomach, and lung (0.15–0.18% of 

the initial dose/g); only the gastric contents showed a markedly higher concentration (1.37% of the initial 

dose/g. At 144 hours after administration, tissue concentrations were uniformly low for tissues including 

the gastric contents, ranging from 0.01 to 0.05% of the initial dose/g, with the exception of skin, bone 

marrow, and lung, which exhibited mean concentrations of 0.06, 0.08, and 0.19% of the initial dose/g, 

respectively. 

3.4.2.3 Dermal Exposure 

Following 24-hour dermal exposure of male F344 rats to 162 mg/kg [14C]-labeled acrylamide, the highest 

concentration of acrylamide equivalents (excluding skin at the application site) was found in blood cells 

(71 μg/g), followed by skin at nondosing sites (~28 μg/g); liver, spleen, testes, and kidneys (~21 μg/g); 

lungs, thymus, brain, and epididymis (~14 μg/g); and fat (<4 μg/g) (Sumner et al. 2003). 

3.4.3 Metabolism 

Results from rat and mouse studies indicate that acrylamide is rapidly metabolized and excreted 

predominantly in the urine as metabolites (Dixit et al. 1982; Edwards 1975; Miller et al. 1982; Ramsey et 

al. 1984; Sumner et al. 1992, 1999, 2003; Twaddle et al. 2004). Figure 3-3 depicts a metabolic scheme 

for acrylamide adapted from reports of Calleman (1996), IARC (1994), and Sumner et al. (1992, 1999). 

According to the metabolic scheme, acrylamide reacts readily with glutathione to form a glutathione 

conjugate, which is further metabolized to N-acetyl-S-(3-amino-3-oxopropyl)cysteine or S-(3-amino3-oxopropyl)cysteine. Another initial step, catalyzed by CYP2E1, involves oxidation of acrylamide to the 

epoxide derivative, glycidamide. Glycidamide can react with glutathione to form conjugates that are 

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ACRYLAMIDE 96 

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further metabolized to N-acetyl-S-(3-amino-2-hydroxy-3-oxopropyl)cysteine or N-acetyl-S-(1-

carbamoyl-2-hydroxyethyl)cysteine. Glycidamide may also undergo hydrolysis, perhaps catalyzed by 

epoxide hydrolases, leading to the formation of 2,3-dihydroxypropionamide and 2,3-dihydroxypropionic 

acid. 

Both acrylamide and glycidamide react with nucleophilic sites in macromolecules (including hemoglobin 

and DNA) in Michael-type additions (Bergmark et al. 1991, 1993; Segerbäck et al. 1995; Solomon et al. 

1985). In rats, the binding index of acrylamide to cysteine in hemoglobin was extremely high 

(6,400 pmol/g Hb/μmol acrylamide/kg); the binding index of glycidamide to cysteine was 1,820 pmol/g 

Hb/μmol glycidamide/kg. The lower binding index for glycidamide may be the result of lower reactivity 

toward hemoglobin-cysteine and shorter half-life in blood. Rate constants of 0.0054 and 0.021 M-1s

-1 for 

reactions of acrylamide with human serum albumin and glutathione, respectively, were reported by Tong 

et al. (2004), suggesting that these reactions account for most of the elimination of absorbed acrylamide. 

Doerge et al. (2005a) measured DNA adducts following a single intraperitoneal administration of 

acrylamide to adult B6C3F1 mice and F344 rats at 50 mg/kg. Glycidamide-derived DNA adducts of 

adenine and guanine formed in all tissues examined, including target tissues identified in rodent 

carcinogenicity bioassays and nontarget tissues. Dosing rats and mice with an equimolar amount of 

glycidamide (61 mg/kg) typically produced higher levels of DNA adducts than those observed from the 

acrylamide dose. Gamboa da Costa et al. (2003) measured DNA adduct formation in selected tissues of 

adult and whole body DNA of 3-day-old neonatal mice treated with acrylamide and glycidamide. In adult 

mice, DNA adduct formation was observed in liver, lung, and kidney; glycidamide treatment produced 

modestly higher adduct levels than acrylamide treatment. However, glycidamide-treated neonates 

exhibited 5–7-fold higher whole-body DNA adduct levels than the acrylamide-treated neonates. 

Results from studies of CYP2E1 null and wild-type mice demonstrate the importance of 

CYP2E1 in catalyzing the oxidative formation of glycidamide from acrylamide. Following oral 

administration of single 50 mg/kg doses of [1,2,3-13C]-acrylamide to wild-type mice, 

considerable amounts of metabolites derived from glycidamide were found in the 24-hour urine 

(Sumner et al. 1999). Approximately 22% of the excreted metabolites were derived from 

glutathione conjugation with glycidamide (N-acetyl-S-[3-amino-2-hydroxy-3-oxopropyl]cysteine 

and N-acetyl-S-[1-carbamoyl-2-hydroxyethyl]cysteine) and 28% were derived from glycidamide 

and its hydrolysis products (2,3-dihydroxypropionamide and 2,3-dihydroxypropionic acid). In 

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CYP2E1 

acrylamide 

GSH 

HOCH2 CHOH-COOH 

2,3-dihydroxpropionic acid 

GS-CH2 CHOH-CONH2 

N-AcCys-S CH2 CHOH-CONH2 

N acetyl S (3-amino-2-hydroxy 3-oxopropyl)cysteine 

 

 

ACRYLAMIDE 97 

3. HEALTH EFFECTS 

Figure 3-3. Metabolic Scheme for Acrylamide and Its Metabolite Glycidamide* 

acrylamide Hb adducts glycidamide Hb adducts 

Hb Hb DNA adducts 

O O 

HOCH -CHOH-CONH H2C C C NH2 H2C C CONH 2 2 

H H 2 2,3-dihydroxypropionamide 

glycidamide 

GSH GSH 

-

GS-CH2-CH2-CONH2 -

CH2OH 

N-AcCys-S-CH2-CH2-CONH2 GS C CONH2 

N-acetyl-S-(3-amino-3-oxypropyl)cysteine H 

Cys-S-CH2-CH2-CONH2 - - S-(3-amino-3-oxypropyl)cysteine - - - - CH2OH 

N-AcCys-S-CH2-CH2-CONH2-sulfoxide N-AcCys S C CONH 2 N-acetyl-S-(3-amino-3-oxypropyl)cysteine-sulfoxide H 

N-acetyl-S-(1-carbamoyl-2-hydroxyethyl)cysteine) 

*Processes involving several steps are represented with broken arrows. 

GSH = reduced glutathione; Hb = hemoglobin; N-AcCys = N-acetylcysteine 

Sources: Calleman 1996; Fennell et al. 2006; IARC 1994a; Sumner et al. 1992, 1999 

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contrast, no evidence was found for the formation of these metabolites in the 24-hour urine of CYP2E1 

null mice or wild-type mice treated with the CYP2E1 inhibitor, aminobenzotriazole. The wild-type and 

CYP2E1-null mice excreted a similar percentage of the administered dose in the urine within 24 hours 

(about 30%), suggesting that the CYP2E1-null mice compensated for the CYP2E1 deficiency by 

metabolizing more of the administered acrylamide via direct conjugation with glutathione. 

Ghanayem et al. (2005c) investigated the formation of hemoglobin adducts of acrylamide and 

glycidamide and DNA adducts of glycidamide in wild-type and CYP2E1-null mice following the 

administration of a single 50 mg/kg dose of acrylamide via intraperitoneal injection. At 6 hours 

posttreatment, mean plasma levels of acrylamide and glycidamide were 0.84 and 33.0 μM, respectively, 

in the wild-type mice and 115 and 1.7 μM, respectively, in the CYP2E1-null mice. Levels of hemoglobin 

adducts of acrylamide were approximately 2-fold higher in the CYP2E1-null mice compared to the wildtype mice. Although only traces of DNA adducts of glycidamide were seen in the CYP2E1-null mice, 

levels were 52–66 times higher in the wild type mice. These results demonstrate the importance of 

CYP2E1 in the epoxidation of acrylamide to glycidamde and the formation of hemoglobin adducts and 

glycidamide-DNA adducts. 

N-Acetyl-S-(3-amino-3-oxopropyl)cysteine has been identified as the major urinary metabolite of 

acrylamide in male F344 rats exposed to oral doses of 1–100 mg/kg [2,3-14C]-labeled acrylamide (Miller 

et al. 1982) and in male F344 rats and B6C3F1 mice exposed to oral doses of 50 mg/kg 

[1,2,3-13C]-acrylamide (Sumner et al. 1992). 

Following oral administration of [1,2,3-13C]-acrylamide (50 mg/kg) to rats and mice, glycidamide and 

glycidamide-derived metabolites accounted for about 33% (rats) and 59% (mice) of the total metabolites 

excreted in the urine within 24 hours, indicating that acrylamide is transformed to glycidamide to a 

greater extent in mice than in rats (Sumner et al. 1992). Similar results were reported in a study of 

metabolites in urine collected for 24 hours after 6-hour inhalation exposure (nose only) of rats and mice to 

3 ppm [14C]/[13C]-acrylamide where glycidamide and glycidamide-derived metabolites accounted for 36% 

(rats) and 73% (mice) of total metabolites excreted in the urine within 24 hours (Sumner et al. 2003). 

Following dermal application of 138 mg/kg [1,2,3-13C]-acrylamide, male F344 rats excreted 

approximately 2% of the applied dose in the 24-hour urine as GSH-acrylamide derived metabolites 

(~50% of the urinary metabolites), glycidamide (~17%), and GSH-glycidamide derived metabolites 

(~31%) (Sumner et al. 2003). 

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Figure 3-3 does not include a possible minor pathway in which CO2 may be released from the hydrolysis 

products of glycidamide, because of conflicting results from several studies. Following intravenous 

administration of 100 mg/kg [1-

14C]-labeled acrylamide to male albino Porton rats, about 6% of the 

injected dose of radioactivity was exhaled as CO2 in 8 hours (Hashimoto and Aldridge 1970), but 

following administration of [2,3-14C]-labeled acrylamide to male Fischer 344 rats, no radioactivity was 

detected in exhaled breath (Miller et al. 1982). Sumner et al. (1992) hypothesized that these results may 

be consistent with the existence of a minor pathway involving metabolism of 2,3-dihydroxypropionamide 

to glycerate and hydroxypyruvate with the subsequent release of CO2 and production of glycoaldehyde, 

but they did not detect two-carbon metabolites in urine of mice exposed to [1,2,3-13C]-acrylamide. In 

other experiments, no exhaled 14CO2 was detected following 50 mg/kg oral dosing of [1-

14C]-labeled 

acrylamide to male Sprague-Dawley rats (Kadry et al. 1999), whereas 3–4% of intravenously injected 

[1,3-14C]-acrylamide (2 or 100 mg/kg) was detected as 14CO2 in exhaled breath of male Fischer 344 rats 

(Ramsey et al. 1984). 

Species differences in acrylamide metabolism are apparent. Twaddle et al. (2004) administered 

acrylamide at approximately 50 mg/kg via gavage to adult male and female B6C3F1 mice. Serum 

concentrations of acrylamide and glycidamide were taken at 0.5, 1, 2, 4, and 8 hours postdosing. Livers 

were removed from control and acrylamide-treated mice and analyzed for glycidamide-derived DNA 

adducts. The results indicated no systematic sex differences in acrylamide or glycidamide serum levels at 

each time point. Twaddle et al. (2004) estimated an acrylamide half-life of elimination from plasma at 

0.73 hours. This value in mice can be compared to an estimate of 2 hours in F344 rats following a 

subchronic oral administration of 2.8 mM acrylamide in drinking water for 34 days or subacute 

intraperitoneal doses at 50 mg/kg/day for 11 days (Barber et al. 2001). Miller et al. (1982) estimated a 

1.7-hour half-life for acrylamide in rat blood following a 10 mg/kg intravenous dose. Twaddle et al. 

(2004) reported an elimination half-life of 1.9 hours for the acrylamide-treated mice, which is identical to 

that measured by Barber et al. (2001) in rats. Barber et al. (2001) also reported a 

glycidamide/acrylamide-areas under the curve (AUC) ratio of 0.18 for Sprague-Dawley rats treated with 

20 mg/kg acrylamide by gavage. This contrasts to the observation of equal AUCs for glycidamide and 

acrylamide in B6C3F1 mice (Twaddle et al. 2004). Since rats and mice had a comparable glycidamide 

elimination half-life, this approximately 5-fold difference in internal exposure to glycidamide for mice 

compared with rats is considered to be the result of an increased rate of glycidamide formation in the 

mouse. 

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The metabolism of acrylamide has also been investigated in controlled human studies (Boettcher et al. 

2006a; Fennell et al. 2005b, 2006; Fuhr et al. 2006). 

Fennell and coworkers evaluated metabolism and hemoglobin adduct formation (Fennell et al. 2005b) and 

kinetics of elimination of urinary metabolites (Fennell et al. 2006) following oral and dermal 

administration of [1,2,3-13C3)-acrylamide and/or [2,3-14C]-acrylamide to 24 adult male volunteers. 

Metabolism of the administered acrylamide was investigated by 13C nuclear magnetic resonance (NMR) 

spectroscopy (Fennell et al. 2005b) and by liquid chromatography-tandem mass spectroscopy (Fennell et 

al. 2006). Urinary metabolites accounted for approximately 40% of a 3 mg/kg oral dose of acrylamide 

and 4.5% of a 3 mg/kg/day repeated (3 consecutive days) dermal dose (Fennell et al. 2006). 

Approximately 86% of the recovered urinary metabolites were derived from glutathione conjugation and 

excreted as N-acetyl-S-(3-amino-3-oxopropyl)cysteine and its S-oxide. Glycidamide, glyceramide 

(2,3-dihydroxypropionamide), and low levels of N-acetyl-S-(3-amino-2-hydroxy-3-oxopropyl)cysteine 

were also detected in urine (Fennell et al. 2005b). On oral administration, a linear dose response was 

observed for acrylamideVal and glycidamideVal in hemoglobin. The main pathway of metabolism in 

humans was via direct glutathione conjugation, forming N-acetyl-S-(3-amino-3-oxopropyl)cysteine and 

its S-oxide, which has not been reported previously (Fennell et al. 2006). Epoxidation to glycidamide 

was the other important pathway, with glyceramide formed as a major metabolite in humans. 

Glycidamide was detected in low amounts. The glutathione conjugation of glycidamide, which is a major 

pathway in rodents, appeared to occur at very low levels in humans. Metabolism via glycidamide in 

humans was approximately 12% of the total urinary metabolites. This is considerably lower than the 

amount of glycidamide-derived metabolites reported for oral administration of acrylamide in rats (28% at 

50 mg/kg, [Sumner et al. 2003]) and in mice (59% at 50 mg/kg [Sumner et al. 1992]). It should be noted 

that glyceramide has only been quantitated in human urine by NMR spectroscopy in combination with 

administration of [1,2,3-

13C3]-acrylamide. 

The Fennell et al. (2005b) study also provided data on the amount of hemoglobin adducts derived from 

acrylamide and glycidamide following administration of a defined dose of acrylamide to adult male 

volunteers. Both acrylamideVal and glycidamideVal increased linearly with increasing dose of 

acrylamide administered orally, suggesting that saturation of the conversion of acrylamide to glycidamide 

is not reached in the dosing range of 0.5–3.0 mg/kg. The ratio of glycidamideVal:acrylamideVal 

produced by administration of acrylamide was similar to the ratio of the background adducts prior to 

exposure. Compared with the equivalent oral administration in rats (3 mg/kg), the ratio of 

glycidamideVal:acrylamideVal was lower in humans (0.44 compared to 0.84 for the rat), and the absolute 

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amounts of acrylamideVal and glycidamideVal formed were approximately 2.7- and 1.4-fold higher, 

respectively, in humans compared to rats. 

Fennell et al. (2005b) calculated the expected amount of adduct that would accumulate in men from 

continuous exposure based on the amount of adduct formed/day of exposure, and from the lifespan of the 

erythrocyte. Oral intake of 1 μg/kg acrylamide/day (1.05 fmol acrylamideVal/mg globin/day) for the 

lifespan of the erythrocyte (120 days) was estimated to result in the accumulation of adducts to 

63 fmol/mg globin. Daily dermal exposure to 1 μg/kg acrylamide (0.18 fmol acrylamideVal/mg 

globin/day) for the lifespan of the erythrocyte (120 days) would result in the accumulation of adducts to 

10.8 fmol acrylamideVal/mg globin. With workplace exposure of 5 days/week, this would decrease to 

approximately 7.8 fmol acrylamideVal/mg globin. 

Boettcher et al. (2006a) investigated the human metabolism of acrylamide to AAMA and GAMA in a 

healthy male volunteer who received a single dose of about 1 mg deuterium-labeled (d(3)) acrylamide, 

representing 13 μg/kg body weight, in drinking water. Urine samples before dosing and within 46 hours 

after the dose were analyzed for d(3)-AAMA and d(3)-GAMA using liquid chromatography-mass 

spectrometry (LC-MS). Total recovery in urine after 24 hours was about 51% as the sum of AAMA and 

GAMA and was similar to recoveries in rats (53–66%) given a gavage dose of 0.1 mg/kg (Doerge et al. 

2007). After 2 days, AAMA accounted for 52% of the total acrylamide dose, and was the major 

metabolite of acrylamide in humans. GAMA accounted for 5%, and appeared as a minor metabolite of 

acrylamide. A urinary ratio of 0.1 was observed for GAMA/AAMA compared to previously reported 

values of 0.2 for rats and 0.5 for mice (Doerge et al. 2005b, 2005c). The authors concluded that the 

metabolic fate of acrylamide in humans was more similar to that in rats than in mice as previously 

demonstrated in terms of hemoglobin adducts. 

Fuhr et al. (2006) evaluated the urinary levels of acrylamide, AAMA, glycidamide, and GAMA (using 

LC-MS) in six young healthy volunteers after the consumption of a meal containing 0.94 mg of 

acrylamide. Urine was collected up to 72 hours thereafter. No glycidamide was found. Unchanged 

acrylamide, AAMA, and GAMA accounted for urinary excretion of approximately 4.5, 50, and 6% of the 

dose, respectively. Conjugation with glutathione exceeded the formation of the reactive metabolite 

glycidamide. The data suggest 2- and 4-fold lower relative internal exposures for glycidamide from 

dietary acrylamide in humans compared with rats and mice, respectively. 

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Hemoglobin adducts of acrylamide and glycidamide and urinary metabolites have been used as 

biomarkers of exposure to acrylamide (Bergmark 1997; Bergmark et al. 1993; Boettcher et al. 2005; 

Calleman et al. 1994). Refer to Section 3.8. for detailed information regarding biomarkers of exposure to 

acrylamide. 

3.4.4 Elimination and Excretion 

Available human and animal data indicate that urinary excretion of acrylamide metabolites is the primary 

route of elimination of absorbed acrylamide (Barber et al. 2001a; Boettcher et al. 2006a; Doerge et al. 

2007; Fennell et al. 2005b, 2006; Fuhr et al. 2006; Hashimoto and Aldridge 1970; Kadry et al. 1999; 

Miller et al. 1982; Ramsey et al. 1984; Sumner et al. 1992, 1999, 2003). 

3.4.4.1 Inhalation Exposure 

No human data were located regarding excretion and elimination following inhalation exposure to 

acrylamide. Sumner et al. (2003) exposed male F344 rats and B6C3F1 mice nose-only to a mixture of 

[1,2,3-13C]-acrylamide (90%) and [2,3-14C]-acrylamide (10%) vapors at an average analytical 

concentration of 1.17 ppm for 6 hours. During a 24-hour postexposure period, the distribution of the 

inhaled dose in the rats was: 31% in the urine, 56% retained in the body, 3% in the feces, and 2% as 

exhaled organic volatiles and 14CO2. The distribution of the inhaled dose in the mice was: 27% in the 

urine, 46% in tissues, 5% in feces, 2% as organic volatiles, and 1% as14CO2. 

3.4.4.2 Oral Exposure 

Approximately 34% of an orally-administered 3 mg/kg dose of acrylamide to adult male volunteers was 

recovered in the total urinary metabolites within 24 hours of administration (Fennell et al. 2005b). In a 

male volunteer who received a single dose of about 1 mg deuterium-labeled acrylamide (representing 

13 μg/kg body weight) in drinking water, elimination via urinary AAMA and GAMA followed a 

two-phase pattern (Boettcher et al. 2006a). Elimination half-lives of both AAMA and GAMA were 

estimated to be approximately 3.5 hours for the first phase and >10 hours up to few days for the second 

phase. After 2 days, urinary AAMA and GAMA accounted for 52 and 5%, respectively, of the total 

acrylamide dose. The ratio GAMA/AAMA was approximately 0.2. 

Fuhr et al. (2006) measured acrylamide and metabolite levels in a 72-hour urine collection from six young 

healthy volunteers after the consumption of a meal containing 0.94 mg of acrylamide. Unchanged 

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acrylamide, AAMA, and GAMA accounted for urinary excretion of approximately 4, 50, and 10%, 

respectively, of the administered dose; glycidamide was not detected. Estimated elimination half-lives for 

the unchanged acrylamide, AAMA, and GAMA were 2.4, 17.4, and 25.1 hours, respectively. 

Heudorf et al. (2009) reported median levels of 36 μg AAMA/L and 13 μg GAMA/L in the urine of 

110 children (63 boys and 47 girls; 5–6 years of age). Children who reported higher regular consumption 

of French fries had significantly higher urinary levels of acrylamide metabolites. Based on the urinary 

levels of AAMA and GAMA, mean estimated acrylamide dietary intakes were 1.13 μg/kg/day (creatinine 

excretion based model) and 0.81 μg/kg/day (volume based model). The ratio GAMA/AAMA was 

approximately 0.4, which is 2-fold higher than that observed by Boettcher et al. (2006a) in adults. Based 

on this finding, Heudorf et al. (2009) suggest that acrylamide may undergo oxidative metabolism to a 

greater extent in children than adults. 

In male Fischer 344 rats given oral (1, 10, or 100 mg/kg) doses of [2,3-14C]-acrylamide, about 60 and 

70% of the administered radioactivity was excreted in urine collected within 24 hours and 7 days, 

respectively (Miller et al. 1982). Less than 2% of radioactivity in the urine was accounted for by 

acrylamide. Elimination of radioactivity from tissues was biphasic with half-lives of about 5 and 8 hours, 

respectively. The elimination time course of parent compound from tissues exhibited single phase 

exponential elimination with a half-life of about 2 hours. Fecal excretion accounted for 4.8 and 6% of 

administered radioactivity at 24 hours and 7 days, respectively. Bile-duct cannulated rats given single 

intravenous 10 mg/kg doses of [2,3-

14C]-acrylamide excreted about 15% of the administered radioactivity 

as metabolites within about 6 hours; <1% of radioactivity in the bile was in the form of acrylamide 

(Miller at al. 1982). These results are consistent with the existence of enterohepatic circulation of 

metabolites. 

Doerge et al. (2007) administered acrylamide to male and female rats and mice at 0.1 mg/kg by oral 

gavage or via the diet and measured the percentages of parent compound and metabolites in the 24-hour 

urine. For rats and mice combined, the percentage of total dose excreted as the sum of acrylamide and its 

metabolites (glycidamide, AAMA, and GAMA) averaged 49%. Excretion of glycidamide and 

glycidamide-derived species was typically greater in mice than rats. 

No radiolabeled CO2 was captured from rats given [2,3-

14C]-acrylamide orally (Kadry et al. 1999; Miller 

et al. 1982). However, intravenous injection of rats with a 100 mg/kg dose of [1-

14C]-labeled acrylamide 

(Hashimoto and Aldridge 1970) or a 2 mg/kg dose of [1,3-14C]-labeled acrylamide (Ramsey et al. 1984) 

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ACRYLAMIDE 104 

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resulted in the capture of about 6 and 4%, respectively, of the radioactivity as CO2 in the expired air 

during the subsequent 6–8 hours. 

3.4.4.3 Dermal Exposure 

Fennell et al. (2006) exposed 24 adult male volunteers to dermal applications of [1,2,3-13C3]-acrylamide 

under controlled conditions. Acrylamide was administered as three daily 24-hour occluded dermal doses 

of 3 mg/kg. Approximately 4.5% of the administered dose (12.35% of the absorbed dose) was recovered 

as urinary metabolites through day 4. Urinary recovery included 13C3-acrylamide (~4% of total urinary 

recovery) and metabolites 13C3-cysteine-S-propionamide (13C3-CP; ~0.8%), 13C3-N-acetyl cysteine-Spropionamide (13C3-NACP; ~70%), 13C3-NACP sulfoxide (~22.5%), 13C3-GAMA3 (~2.6%), and 

13C3-GAMA2 (~0.4%). Glycidamide was not detected in the majority of the urine samples. 

13C3- 13C3-Acrylamide and 13C3-CP were detected in 2–4 hour urine samples collected on the first day. 

NACP and its sulfoxide were first detectable in the urine between 4 and 8 hours posttreatment. The 

mercapturic acids of glycidamide (13C3-GAMA2 and 13C3-GAMA2) were first detectable in the urine 

between 8 and 16 hours posttreatment. The metabolite, glycidamide, was not detectable in the majority of 

the urine samples collected over the 4-day period. 

Sumner et al. (2003) exposed male F344 rats to [2,3-14C]-labeled acrylamide under occluded dermal 

conditions for 24 hours. During a 24-hour postexposure period, approximately 8% of the applied dose 

(36% of the absorbed dose) was excreted in the urine, 3% as volatiles and 14CO2 in exhaled air, <1% in 

feces, and53% remained in tissues. 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

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PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-4 shows a conceptualized representation of a PBPK model. 

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ACRYLAMIDE 106 

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Figure 3-4. Conceptual Representation of a Physiologically Based 

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance
 

Inhaled chemical Exhaled chemical 

Ingestion 

Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax 

Km GI 

Tract 

Feces 

Urine

 Chemicals 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

contacting skin 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: adapted from Krishnan and Andersen 1994 

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If PBPK models for acrylamide exist, the overall results and individual models are discussed in this 

section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species 

extrapolations. 

Physiologically based pharmacokinetic (PBPK) models for acrylamide are available (Calleman et al. 

1992, 1993; Kirman et al. 2003; Walker et al. 2007; Young et al. 2007). 

Calleman et al. (1992, 1993) Model 

Calleman et al. (1992, 1993) developed a nonlinear dosimetric model to simultaneously determine 

hemoglobin adduct formation by acrylamide and its genotoxic metabolite, glycidamide, in rats. The 

model is not useful for human health risk assessment. 

Kirman et al. (2003) Model 

Kirman et al. (2003) developed a PBPK model (Figure 3-5) to predict the behavior of acrylamide and its 

epoxide metabolite, glycidamide, in the rat for intravenously-, intraperitoneally-, or orally-administered 

acrylamide. The model includes components for both acrylamide and glycidamide, each consisting of 

five compartments (arterial blood, venous blood, liver, lung, and all other tissues). The acrylamide 

component is linked to the glycidamide portion of the model via metabolism in the liver. Model 

parameters are listed in Table 3-9. Rat physiological parameters were selected from measured data 

(Brown et al. 1997; Kedderis et al. 1996). Partition coefficients for acrylamide were estimated based on 

an algorithm derived by Poulin and Krishnan (1995, 1996a, 1996b) using specific chemical properties. 

Partition coefficients for glycidamide were derived by application of a proportionality constant of 3.2 to 

the values calculated for acrylamide (Kedderis et al. 1996). Metabolism of acrylamide and glycidamide 

are represented only in the liver. Estimated values for metabolism and tissue binding were based on 

fitting of the model to metabolism and urinary elimination data from Miller et al. (1982), Ramsey et al. 

(1984), Raymer et al. (1993), and Sumner at al. (1992). Depletion and resynthesis of glutathione were 

included in the model structure (D’Souza et al. 1988). 

The PBPK model of Kirman et al. (2003) was developed to predict the behavior of acrylamide and 

glycidamide in the rat. The model has only been partially validated in rats and is not useful for human 

risk assessment. 

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Figure 3-5. Schematic of the Kirman et al. (2003) Physiologically Based
 

Pharmacokinetic (PBPK) Model for Acrylamide
 

Acrylamide Glycidamide 

Tissues 

Liver 

Tissues 

Liver 

Arterial Blood

Arterial Blood

Venous Blood

Venous Blood 

Lung Lung 

Oral dose 

P450 

GST GST EH 

i.v/i.p. 

dose 

EH = epoxide hydrolase; GST = glutathione S-transferase; i.p. = intraperitoneal injection; i.v. = intravenous 

injection; 

Source: Kirman et al. 2003 

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ACRYLAMIDE 109 

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Table 3-9. Original Model Parameter Values for Rats in the Kirman et al. (2003)
 

Physiologically Based Toxicokinetic (PBTK) Model
 

Parameter 

group Parameter Symbol (units) Value Reference/source 

Rat physiology 

Absorption 

Body weight 

Cardiac output 

Alveolar ventilation 

Liver blood flow 

Fraction arterial 

Fraction venous 

Liver volume 

Tissue volume 

Tissue blood flow 

Volume blood 

Hemoglobin 

concentration 

Fraction blood cells 

Fraction blood serum 

Absorption rate from 

gastrointestinal tract 

(oral dose) or 

intraperitoneal cavity 

(intraperitoneal dose) 

Infusion time 

(intravenous dose) 

BW (kg)
 

QCC (L/hourkg)
 

QPC (L/hourkg)
 

QLC (fraction 

QCC)
 

FABC (fraction
 

VB)
 

FVBC (fraction
 

VB)
 

VLC (fraction 

BW)
 

VTC (fraction 

BW)
 

QTC (fraction 

QCC)
 

VBC (fraction 

BW)
 

HGB (g/L)
 

FBC (fraction 

VB)
 

FBS (fraction 

VB)
 

KA (/hour)
 

TINF (hour)
 

Study specific 

14 

14 

0.25 

0.35 

0.65 

0.04 

0.87 

0.75 

0.06 

1.5 

0.44 

0.56 

5 

0.003 

Study specific 

Kedderis et al. 1996 

Kedderis et al. 1996 

Kedderis et al. 1996 

Kedderis et al. 1996 

Kedderis et al. 1996 

Brown et al. 1997 

Calculated (0.91-VLC) 

Calculated (1-QLC) 

Brown et al. 1997 

Kedderis et al. 1996 

Kedderis et al. 1996 

Kedderis et al. 1996 

Model simulations fit to 

Miller et al. 1982; 

Ramsey et al. 1984; 

Raymer et al. 1993 

Model simulations fit to 

Miller et al. 1982; 

Ramsey et al. 1984; 

Raymer et al. 1993 

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Table 3-9. Original Model Parameter Values for Rats in the Kirman et al. (2003)
 

Physiologically Based Toxicokinetic (PBTK) Model
 

Parameter 

group Parameter Symbol (units) Value Reference/source 

Partition 

coefficients 

Metabolism 

Blood:air, AA 

Liver:blood, AA 

Tissue:blood, AA 

Blood:air, GA 

Liver:blood, GA 

Tissue:blood, GA 

Cytochrome P-450 

oxidation rate, AA 

Cytochrome P-450, 

Michaelis-Menten 

constant, AA 

Epoxide hydrolase 

hydrolysis rate, GA 

Epoxide hydrolase, 

Michaelis-Menten 

constant, GA 

Reaction with 

glutathione, AA 

Reaction with 

glutathione, GA 

PB1 (unitless)
 

PL1 (unitless)
 

PL1
 

PB2 (unitless)
 

PL2 (unitless)
 

PT2 (unitless)
 

VMAXC1
 

(mg/hour-kg)
 

KMC1 (mg/L)
 

VMAXC2 

(mg/hour-kg) 

KMC2 (mg/L) 

KGSTC1 

(L/mmol GSHhr) 

KGSTC2 

(L/mmol GSHhour) 

31,000,000 

0.83 

0.95 

98,000,000 

2.7 

3.0 

1.6 

10 

1.9 

100 

0.55 

0.8 

Estimated 

Poulin and Krishnan 

1995, 1996a, 1996b 

Poulin and Krishnan 

1995, 1996a, 1996b 

Poulin and Krishnan 

1995, 1996a, 1996b 

Poulin and Krishnan 

1995, 1996a, 1996b 

Poulin and Krishnan 

1995, 1996a, 1996b 

Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993; Sumner et al. 

1992 

Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993; Sumner et al. 

1992 

Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993; Sumner et al. 

1992 

Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993; Sumner et al. 

1992 

Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993; Sumner et al. 

1992 

Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993; Sumner et al. 

1992 

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Table 3-9. Original Model Parameter Values for Rats in the Kirman et al. (2003)
 

Physiologically Based Toxicokinetic (PBTK) Model
 

Parameter 

group Parameter Symbol (units) Value Reference/source 

Tissue binding Binding to hemoglobin, 

AA 

KHGB1 

(L/gHGB) 

0.5 Model simulations fit to 

Miller et al. 1982, Raymer 

et al. 1993 

Binding to hemoglobin, 

GA 

KHGB2 

(L/gHGB-hour) 

0.25 Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993 

Binding to liver 

macromolecules, 

acrylamide 

KFEEL1 (/hour) 0.2 Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993 

Binding to liver 

macromolecules, GA 

KFEEL2 (/hour) 0.1 Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993 

Binding to tissue 

macromolecules, AA 

KFEET1 (/hour) 0.08 Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993 

Binding to tissue 

macromolecules, GA 

KFEET1 (/hour) 0.04 Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993 

Binding to blood 

macromolecules, AA 

KFEEB1 (/hour) 0.01 Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993 

Binding to blood 

macromolecules, GA 

KFEEB2 (/hour) 0.005 Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993 

Protein turnover KPT (/hour) 0.008 Model simulations fit to 

Miller et al. 1982; Raymer 

et al. 1993 

Glutathione GSH production rate KGSHP 

(mmol/hour) 

0.025 D’Souza et al. 1988 

GSH loss rate KGSHL (/hour) 0.35 D’Souza et al. 1988 

Initial GSH GSHL0 7.0 D’Souza et al. 1988 

concentration in liver (mmol/L) 

AA = acrylamide; GA = glycidamide; GSH = glutathione 

Source: Kirman et al. 2003 

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Young et al. (2007) Model 

Young et al. (2007) produced a PBPK/toxicodynamic (TD) model to predict the behavior of acrylamide, 

glycidamide, and their respective glutathione conjugates in rats, mice, and humans (Figure 3-6). The 

model was developed using PostNatal, a windows-based program from the U.S. FDA’s National Center 

for Toxicological Research (NCTR). The program controls up to four PBPK model units (depicted as 

PBPK 1–4 in Figure 3-6) under one shell with multiple input and output options. Each PBPK unit is 

comprised of 28 organ/tissue/fluid components maintained independently or connected through metabolic 

pathways. Pharmacodynamic components for liver glycidamide-DNA adducts and hemoglobin adducts 

with acrylamide and glycidamide are included in the model as well. Dose administration can be either 

acrylamide or glycidamide. All metabolism and urinary elimination are considered first order. 

Physiological parameters were assigned values from within the PostNatal program based on animal 

species, gender, and total body weight. Serum acrylamide and glycidamide concentrations and urinary 

elimination levels for male and female rats and mice were simulated from intravenous and oral 

administration of 0.1 or 0.12 mg/kg glycidamide. Adduct formation and decay rates were determined 

from a 6-week exposure to 1 mg/kg acrylamide in the drinking water followed by 6 weeks of 

nontreatment. 

The data used to calibrate the Young et al. (2007) model for rats and mice include acrylamide serum 

levels in rats following intraperitoneal administration (Raymer et al. 1993); plasma acrylamide and 

glycidamide levels, and acrylamide and glycidamide hemoglobin adduct levels following relatively high 

(50 mg/kg bw) repeat intraperitoneal dosing in rats for 11 days or 2.8 mM of acrylamide in drinking 

water for 47 days (Barber et al. 2001); urinary excretion profile and acrylamide and glycidamide 

hemoglobin adduct levels following dosing via intraperitoneal injection (50 mg/kg), gavage (50 mg/kg), 

dermal application (150 mg/kg), or inhalation (3 ppm for 6 hours) (Sumner et al. 2003); and serum and 

tissue levels of acrylamide and glycidamide, and liver glycidamide-DNA adduct data in rats and mice 

following relatively low-dose administration via intravenous injection (acrylamide and glycidamide at 

0.1–0.12 mg/kg), gavage (acrylamide and glycidamide at 0.12 and 50 mg/kg), diet (~0.1 mg/kg over 

30 minutes), and drinking water (~1 mg/kg acrylamide over 42 days) (Doerge et al. 2005a, 2005b, 

2005c). The single and multiple oral data from Barber et al. (2001) were combined with the urinary 

elimination data of Sumner et al. (1992, 2003) and simulated with the model. The Raymer et al. (1993) 

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Input Input 

PBPK-1 PBPK-2 1st order 

Acrylamide Glycidamide metabolism (AA) (GA) 

PD 

Hemoglobin 

Adducts 

DNA 

Adducts 

urine urine 

1st order 

metabolism 

1st order 

metabolism 

Kf Kf Kf 

Kd Kd

turn over 

repair 

PBPK-3 PBPK-4 

Acrylamide metabolite Gylcidamide metabolites 

(AA-GS) (GA-GS) 

urine urine 


 


 


 

ACRYLAMIDE 113 

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Figure 3-6. Schematic of the Young et al. (2007) Physiologically Based
 

Pharmacokinetic/Toxicodynamic (PBPK/TD) Model For
 

Acrylamide and Glycidamide*
 

*Block diagram for the metabolism of AA to GA and further metabolism of both to their glutathione 

conjugates. All pharmacokinetic and pharmacodynamic (PD) processes are first order. 

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ACRYLAMIDE 114 

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data were also combined with the urinary elimination data of Sumner et al. (1992, 2003) and simulated in 

a similar manner. The NCTR tissue data (Doerge et al. 2005a, 2005b, 2005c) were used to develop 

partition coefficients. Only those tissues specifically analyzed for acrylamide or glycidamide were 

partitioned differently from the blood compartment. Values for the human parameters were calibrated 

against urinary excretion data (Fennell et al. 2005b; Fuhr et al. 2006) and hemoglobin adduct data from a 

dietary exposure (Boettcher et al. 2005). 

Values for the metabolism and elimination of acrylamide or glycidamide, for acrylamide or glycidamide 

binding to hemoglobin, and for glycidamide-DNA adduct formation were derived by optimizing the fit of 

the simulation results to individual animal data. All rate constants for the metabolic and elimination 

processes, the binding and decay of acrylamide or glycidamide to hemoglobin, and the binding of 

glycidamide to liver macromolecule are represented as first order. Although Young et al. (2007) 

calibrated their model parameter values in a logical sequence against the data identified in the paper, a 

number of sensitive parameters were allowed to vary when fitting the individual animal data so as to 

optimize the model fit to each set of data. The authors evaluated the resulting differences among the 

model parameter values relative to gender and study conditions for insights into the toxicokinetics of 

acrylamide and glycidamide, and to assess the uncertainty in the model parameter values. Although there 

are statistically significant differences in some cases in the fitted model parameter values for basic 

physiological functions such as excretion of acrylamide-GSH conjugates in urine (which varies as much 

as 4–6 for model fits to different studies), the authors argued that the ranges of values are not exceedingly 

wide considering that different routes of administration for different chemicals are all being compared, 

and that there is very little difference for each metabolic rate constant when comparing across gender, 

dose, and route. 

For the purpose of quantitative risk assessment, a PBPK model is generally developed to produce a single 

set of parameter values that fits at least the most relevant data for a particular application. Evaluating the 

importance of uncertainty in parameter values also depends upon the choice of the dose metric and its 

sensitivity to parameters of interest. For useful application of the PBPK model of Young et al. (2007) to 

human health risk, additional studies are needed to identify a single set of parameters, and to evaluate the 

sensitivity of various dose metrics to the parameters that are the most uncertain. 

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Walker et al. (2007) Model 

Walker et al. (2007) described an adaptation of the PBPK model of Kirman et al. (2003) to account for: 

(1) hemoglobin adduct data for rats (Fennell et al. 2003) and (2) extrapolation to adult humans using 

human adduct data (Fennell et al. 2004, 2005b). The Walker et al. (2007) model incorporates available 

information regarding children’s changing physiology and metabolic capacity for selected processes 

involved in acrylamide disposition (i.e., CYP2E1, glutathione conjugation, epoxide hydrolase). However, 

this model has not been calibrated or validated with respect to acrylamide dosimetry in children. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Acrylamide is readily absorbed via all natural routes of exposure (inhalation, oral, dermal) and is 

distributed throughout the body via the blood. No studies were located regarding mechanisms for 

acrylamide absorption across lung, gut, or skin; processes may include passive and/or facilitative 

mechanisms. Acrylamide and its reactive metabolite, glycidamide, readily bind to hemoglobin, but do not 

accumulate appreciably in any tissues. Acrylamide metabolism is relatively rapid; both parent compound 

and the epoxide, glycidamide, appear to be involved in acrylamide toxicity. Animal data demonstrate the 

importance of CYP2E1 in acrylamide metabolism. Metabolism is assumed to take place primarily in the 

liver. Urinary excretion of conjugated acrylamide derivatives represents the major excretory pathway for 

acrylamide. 

3.5.2 Mechanisms of Toxicity 

Neurotoxic Effects. The neurotoxicity of acrylamide has been assessed since the 1950s in numerous 

animal studies; notable signs and symptoms include hindfoot splay, decreased grip strength, and 

increasingly impaired mobility with continued exposure (see Sections 3.2.1.4, 3.2.2.4, and 3.2.3.4 for 

detailed information regarding neurological effects in animals administered acrylamide by inhalation, 

oral, and dermal exposure routes, respectively). Observations of neurological effects in acrylamideexposed humans include muscle weakness and other signs of functional impairments (Calleman et al. 

1994; Hagmar et al. 2001; He et al. 1989). Early histopathologic investigations performed on acrylamideintoxicated animals revealed degenerative effects in distal portions of large peripheral nerve fibers and 

associated myelin sheath (Spencer and Schaumberg 1974, 1977). The degeneration was observed to 

progress proximally in a process termed “dying back”. Early hypotheses to explain this “dying back” 

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effect involved damage to axonal neurofilaments, impairment of cellular metabolism, effects on axonal 

transport mechanisms, and disruption of axon cytoskeleton (Cavanaugh 1964; Harris et al. 1994; Harry 

1992; Lapadula et al. 1989; LoPachin and Lehning 1994; Padilla et al. 1993; Pleasure et al. 1969; Sickles 

1991; Spencer et al. 1979). 

Specific mechanisms of acrylamide neurotoxicity have not been clearly elucidated. However, results of 

numerous studies designed to assess mechanisms of acrylamide-induced neurological effects have led to 

two major hypotheses: (1) acrylamide-induced disruption of fast axonal transport (Sickles et al. 2002a) 

and (2) acrylamide-induced disruption of nitric oxide signaling at nerve terminals (LoPachin and Barber 

2006; LoPachin et al. 2008). In addition, recent work by Zhu et al. (2008) provides some support to a 

hypothetical mode of action whereby acrylamide exposure results in increases in reactive oxygen species, 

damage to cellular macromolecules, and subsequent degeneration of neural tissues. 

Disruption of Fast Axonal Transport. The hypothesis that acrylamide induces peripheral neuropathy via 

disruption of fast axonal transport proposes the binding of acrylamide to kinesin, which leads to 

impairment of the fast axonal transport system responsible for the distal delivery of macromolecules. 

This would result in deficiencies in proteins responsible for maintaining axonal structure and function. 

The particular vulnerability of distal axons and nerve terminals is based on the large axonal volume and 

transport distance from cell body to distal regions. Kinesin, which plays an integral role in intracellular 

transport along microtubules, is inhibited by neurotoxic doses of acrylamide. Evidence was provided 

from results of a microtubule motility assay in which preincubation of purified kinesin with acrylamide 

produced a dose-dependent loss of numbers of microtubules moving over a bed of kinesin and less-steady 

locomotory activity (Sickles et al. 1996). These effects were proposed to result from covalent adduction 

through sulfhydryl alkylation by acrylamide. Comparable effects were produced by glycidamide. 

Disruption of Nitric Oxide Signaling at Nerve Terminals. The hypothesis that acrylamide induces 

peripheral neuropathy via disruption of nitric oxide signaling at nerve terminals was proposed by 

LoPachin and coworkers (LoPachin and Barber 2006; LoPachin et al. 2008) based on critical review of 

available data for conjugated α,β-unsaturated carbonyl derivatives, a group of type-2 alkenes that includes 

acrylamide. The hypothesis is based on evidence that: (1) acrylamide inhibits neurotransmission in 

peripheral and central synapses and (2) soft electrophiles such as acrylamide form Michael-type adducts 

with soft nucleophilic sulfhydryl groups on protein cysteine residues. 

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According to the review of LoPachin and Barber (2006), the functional status of many synaptic processes 

is determined by proteins whose activity is regulated by the redox state of highly nucleophilic sulfhydryl 

groups within corresponding catalytic triads. Acrylamide (a soft electrophile) forms adducts with soft 

nucleophilic sulfhydryl groups on cysteine residues (reviewed in LoPachin and DeCaprio 2005). Results 

of early electrophysiological studies demonstrated acrylamide-induced neurotransmitter inhibition at 

peripheral and central synapses (reviewed in LoPachin et al. 2002, 2003). Results of subsequent 

mechanistic studies indicate that acrylamide causes decreases in neurotransmitter release, uptake, and 

storage (Barber and LoPachin 2004; LoPachin et al. 2004, 2006) and that these effects may be mediated 

by acrylamide-sulfhydryl adduction of specific cysteine residues on functionally critical proteins (Barber 

and LoPachin 2004). Because the cysteine-acrylamide adduction sites are also sites of nitric oxide 

nitrosylation (Jaffrey et al. 2001; Stamler et al. 2001), it has been suggested that acrylamide inhibits 

synaptic activity by disrupting nitric oxide signaling (LoPachin and Barber 2006). LoPachin and 

coworkers suggest that acrylamide itself, and not its major electrophilic metabolite glycidamide, is 

responsible for the neurotoxicity because glycidamide is a hard electrophile that forms adducts with hard 

nucleophiles (nitrogen, carbon, oxygen) consistent with glycidamide adducts on adenine and guanine 

bases. 

Reactive Oxygen Species Hypothesis. Results of Zhu et al. (2008) provide some indication that 

acrylamide-induced neurotoxicity may involve enhancement of lipid peroxidation and decreased 

antioxidative capacity, depletion of neural glutathione levels and antioxidant enzyme activities, leading to 

increased levels of reactive oxygen species, damage to cellular macromolecules, and subsequent 

degeneration of neural tissues. Time-dependent decreased glutathione levels and anti-reactive oxygen 

species activities and increased malondialdehyde levels in sciatic nerve preparations were highly 

correlated with changes in electrophysiological indices of acrylamide-induced neurotoxicity in rats 

receiving repeated intraperitoneally-injected doses of 40 mg/kg acrylamide. 

Reproductive Effects. Mechanisms of acrylamide-induced reproductive toxicity are poorly 

understood. There is some indication that mutagenic effects on male germ cells may play a significant 

role (see Section 3.3 Genotoxic Effects). Available data provide suggestions that acrylamide-induced 

male dominant lethal mutations may involve clastogenic events from binding of acrylamide and/or 

glycidamide to spermatid protamines or spindle fiber proteins and/or direct alkylation of DNA by 

glycidamide (Adler et al. 2000; Perrault 2003; Sega et al. 1989; Tyl and Friedman 2003; Tyl et al. 2000b). 

Tyl and Friedman (2003) also suggested that adverse effects on mounting, sperm motility, and 

intromission could be related to distal axonopathy resulting from binding of acrylamide to motor proteins. 

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Results of one study using male CYP2E1-null and wild-type mice demonstrate the importance of 

metabolism in acrylamide-induced germ cell mutations (Ghanayem et al. 2005a). The male mice were 

administered acrylamide via intraperitoneal injection for 5 consecutive days at dose levels of 0, 12.5, 24, 

or 50 mg/kg/day and subsequently mated with untreated B6C3F1 female mice. Dose-related increased 

incidences of dominant lethal mutations and decreases in numbers of pregnant females and proportion of 

living fetuses were observed in females mated to wild-type male mice. No significant changes in any 

fertility parameters were seen in females mated to CYP2E1-null male mice. These results demonstrate 

the importance of CYP2E1-mediated epoxidation to acrylamide-induced germ cell mutations in male 

mice. 

Genotoxic/Carcinogenic Effects. Specific mechanisms whereby acrylamide induces tumors in 

laboratory animals are not understood at present. However, the weight of evidence supports a mutagenic 

mode of action (Besaratinia and Pfeiffer 2005, 2007; Dearfield et al. 1995; Moore et al. 1987; Segerbäck 

et al. 1995). Evidence for a mutagenic mode of action includes findings that: (1) acrylamide is 

metabolized by CYP2E1 to DNA-reactive glycidamide; (2) acrylamide and glycidamide induce mutations 

in lymphocyte HPRT and liver cII cells; (3) DNA adducts of glycidamide have been detected in tissues of 

all relevant tumor targets of acrylamide-and glycidamide-exposed male and female rats and mice; 

(4) glycidamide is mutagenic to bacteria and male mouse germ cells and male and female mouse somatic 

cells in vivo; (5) acrylamide induces heritable translocations and specific locus mutations in germ cells of 

exposed male mice; (6) acrylamide induces clastogenic effects in mouse lymphoma assays; and 

(7) dominant lethal effects in rodents occur at subchronic oral exposure levels comparable to those 

associated with carcinogenic effects in chronically-exposed rats. These findings support a proposed mode 

of action whereby acrylamide is metabolized to the relatively long-lived epoxide, glycidamide, which 

reacts with proteins and DNA, causing mutations that persist in viable somatic cells, resulting in tumor 

formation. Ghanayem et al. (2005b) observed significant dose-related increases in micronucleated 

erythrocytes and DNA damage in somatic cells (leukocytes, liver, lung) of acrylamide-treated wild-type 

mice, but not in CYP2E1-null mice, indicating that genetic damage in somatic cells is dependent on 

metabolism of acrylamide by CYP2E1. Allen et al. (2005) investigated dose-response relationships from 

in vivo genotoxicity data (chromosomal damage, gene mutations, and recombinations in somatic and 

germ cells) for acrylamide using three different mathematical models according to end point; the 

investigation included benchmark dose calculations. The results were not consistent with a genotoxic 

mode of action for the thyroid tumors reported in 2-year cancer bioassays in rats (Friedman et al. 1995; 

Johnson et al. 1984, 1986). Based on these results, Allen et al. (2005) suggested that a nongenotoxic 

mode of action may be primarily responsible for acrylamide-induced thyroid tumors in rats. 

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Another hypothetical mode of action involves disruption of hormone levels or hormone signaling for 

acrylamide-induced tumors in hormonally-sensitive tissues including mammary gland and thyroid or 

tissues adjacent to hormonally sensitive tissue, such as tunica vaginalis mesothelium (DFG 2009, 

Dourson et al. 2008; Environ 2002; Haber et al. 2009; Klaunig 2008; Shipp et al. 2006). In support of 

this hypothetical mode of action, American Cyanamid Company (1991) reported decreases in serum 

testosterone and thyroid hormone (T3 and T4) levels in rats following oral exposure to acrylamide. 

The induction of cellular proliferation is yet another proposed mode of action for acrylamide 

carcinogenicity in selected target tissues, although limited supporting data are available. Lafferty et al. 

(2004) demonstrated that tumorigenic doses of acrylamide administered to male rats induced cell 

proliferation in thyroid, tunica vaginalis, and adrenal medulla (tumor target tissues), but not in liver or 

adrenal cortex (nontarget tissues). 

3.5.3 Animal-to-Human Extrapolations 

Available data from rats and mice indicate that acrylamide is transformed to glycidamide to a greater 

extent in mice than rats. Following oral administration of radiolabeled acrylamide (50 mg/kg), 

glycidamide and glycidamide-derived metabolites accounted for about 33% (rats) and 59% (mice) of the 

total metabolites excreted in the urine within 24 hours (Sumner et al. 1992). Similar results were reported 

in a study of metabolites in urine collected for 24 hours after 6-hour inhalation exposure (nose only) of 

rats and mice to 3 ppm acrylamide where glycidamide and glycidamide-derived metabolites accounted for 

36 % (rats) and 73 % (mice) of total metabolites excreted in the urine within 24 hours (Sumner et al. 

2003). 

Available PBPK models for acrylamide (Kirman et al. 2003; Walker et al. 2009; Young et al. 2007) have 

not been adequately calibrated and validated for useful extrapolation from animals to humans. 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 

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naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 

similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought 

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; 

Giwercman et al. 1993; Hoel et al. 1992). 

No studies were located regarding endocrine disruption in humans after exposure to acrylamide. 

One repeated-dose oral study in rats reported acrylamide-induced decreases in serum testosterone levels, 

thyroid hormone (T3 and T4) levels, and prolactin (American Cyanamid Company 1991). 

No in vitro studies were located regarding endocrine disruption of acrylamide. 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

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effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

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Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

Specific information regarding acrylamide-induced health effects in children was not located. 

Neurotoxic end points have been examined in acrylamide-exposed mature and immature animals; 

however, with respect to possible age-related differences in susceptibility to acrylamide neurotoxicity, 

results are conflicting. Some reports indicate that young animals may be less susceptible than older ones 

(Fullerton and Barnes 1966; Kaplan et al. 1973), whereas other reports present evidence that young 

animals may be more sensitive (Ko et al. 1999; Suzuki and Pfaff 1973). In rats administered acrylamide 

orally at 100 mg/kg/day, Fullerton and Barnes (1966) noted that 26-week-old rats experienced earlier and 

more severe neurotoxic effects than 5-week-old rats. In contrast, Ko et al. (1999) reported that oral 

administration of acrylamide at 91 mg/kg/day resulted in earlier onset and more rapid progression of 

neuropathy in 3-week-old mice compared to 8-week-old mice. Studies that employed intraperitoneal 

injection of acrylamide also yielded conflicting results (Kaplan et al. 1973; Suzuki and Pfaff 1973). In 

rats repeatedly injected with 50 mg/kg acrylamide, earlier and more prominent degenerative 

histopathologic changes were noted in peripheral nerves of 1-day-old pups compared to adults. Kaplan et 

al. (1973) found the opposite in rats repeatedly injected with the same dose; 14-week-old rats experienced 

impaired rotarod performance earlier than 5-week-old rats (although the younger rats recovered more 

slowly). 

Cancer is also a possible human health effect based on evidence that carcinogenic responses in rats 

chronically exposed to acrylamide throughout adulthood are likely mediated through a mutagenic mode 

of action that could occur in humans. In the absence of direct evidence that early-life exposure leads to 

increased risk for cancer, EPA (2005b) assumes that increased risk occurs with early-life exposure to 

agents that act through a mutagenic mode of action. For acrylamide, no human or animal studies were 

located that examined whether early-life exposure to acrylamide increased the risk for cancer, compared 

with exposure during adulthood alone; however, there is evidence that acrylamide acts through a 

mutagenic carcinogenic mode of action. CYP2E1, which catalyzes acrylamide to its DNA-reactive 

metabolite glycidamide, is not expressed in the developing fetus, but attains levels of expression during 

early postnatal periods that are similar to levels in adults (Johnsrud et al. 2003). 

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There is no information regarding developmental health effects as a result of acrylamide exposure in 

humans. Developmental effects observed in acrylamide-exposed rats include decreased brain levels of 

catecholamines, decreased auditory startle response, decreased performance in an operant test of cognitive 

motivation, and decreased body weight (Field et al. 1990; Garey and Paule 2007; Husain et al. 1987; Wise 

et al. 1995). Decreased brain levels of catecholamine resulted from various lengths of exposure via 

lactation or gavage (Husain et al. 1987). Decreased auditory startle response followed exposure during 

gestation (Wise et al. 1995), and decreased performance in an operant test of cognitive motivation 

followed either exposure during gestation, lactation, or through 12 weeks of age (Garey and Paule 2007). 

Acrylamide has been shown to distribute across the placenta in exposed pregnant animals. Two hours 

following intravenous administration of acrylamide to pregnant beagle dogs, concentrations of 

radioactivity in blood, brain, heart, and lung were similar in both maternal and fetal tissues (Ikeda et al. 

1983, 1985; Marlowe et al. 1986). Humans are unlikely to be exposed by intravenous routes, but these 

results show that acrylamide could cross the placenta if exposure was great enough to achieve comparable 

maternal blood levels. 

Sörgel et al. (2002) reported the detection of low levels of acrylamide (3.17–18.8 ng/mL) in breast milk 

samples taken from mothers (n=2) during 8 hours following the ingestion of potato chips (estimated 

acrylamide dose of 0.8–1 mg); predose acrylamide in the breast milk was below the level of 

quantification (5 ng/mL). 

In studies of offspring of nursing rat dams receiving acrylamide orally at 25 mg/kg/day throughout 

lactation, the dams exhibited severe toxic effects (some mortalities, body weight loss, and hindlimb splay 

in 90% of the dams) (Friedman et al. 1999). Starting at lactation day 4, offspring showed progressively 

decreased body weight, compared with control offspring (at lactation day 21, mean body weight of 

exposed pups was about 43% of the control pup weight); many of the pups died or became moribund 

during the lactational period without exhibiting signs of peripheral neuropathy (Friedman et al. 1999). In 

surviving acrylamide-exposed male pups, grip strength was decreased at postnatal day (PND) 30, 

compared with controls, but was not significantly different from control values at PNDs 60 and 90 

(Friedman et al. 1999). The absence of milk in the stomachs of exposed pups that died or became 

moribund during lactation suggests that inadequate milk supply caused these effects in the offspring. An 

earlier study by Husain et al. (1987) reported complete hindlimb paralysis in male offspring of 

comparably-exposed rat dams of the same strain, but neither of the studies examined breast milk for the 

presence of acrylamide. Free acrylamide was not detected in the serum of Sprague-Dawley rat dams 

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receiving acrylamide from the drinking water from gestation day 6 through postnatal day 21 at 

concentrations resulting in mean daily acrylamide doses as high as 14.56 mg/kg (Takahashi et al. 2009). 

No free acrylamide was detected in stomach contents and serum of the pups at postnatal day 14. 

However, dose-related increases in acrylamide-Hb adduct levels of both dams and their pups were noted; 

the levels in the pups were ≥10-fold lower than those of their respective dams. 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 

A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction 

between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment 

of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance 

itself, substance-specific metabolites in readily obtainable body fluid(s), or excreta. However, several 

factors can confound the use and interpretation of biomarkers of exposure. The body burden of a 

substance may be the result of exposures from more than one source. The substance being measured may 

be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from 

exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., 

biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and 

all of its metabolites may have left the body by the time samples can be taken. It may be difficult to 

identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids 

(e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to 

acrylamide are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by acrylamide are discussed in Section 3.8.2. 

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A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.10, Populations That Are Unusually Susceptible. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Acrylamide 

Several biomarkers of exposure to acrylamide have been reported in the literature. Unchanged 

acrylamide, its mercapturic acid metabolite, AAMA, its epoxy derivative, glycidamide, and the respective 

metabolite of glycidamide, GAMA, were quantified in the urine of six volunteers after the consumption 

of a meal containing 0.94 mg of acrylamide (Fuhr et al. 2006). Urinary mercapturic acid derivatives of 

acrylamide and/or glycidamide were quantified in other human studies as well (Bjellaas et al. 2007a; 

Boettcher et al. 2005, 2006a, 2006b). Results of epidemiological studies support the use of hemoglobin 

adducts of acrylamide and/or glycidamide as biomarkers of exposure to acrylamide (Bergmark et al. 

1993; Boettcher et al. 2005; Calleman et al. 1994; Fennell et al. 2005b, 2006; Hagmer et al. 2001; Olesen 

et al. 2008). Results of animal studies indicate similar biomarkers of exposure to acrylamide. 

Metabolites can be measured for assessment of recent exposure. Hemoglobin adducts provide a 

biomarker of exposure for longer periods. See the introductory paragraph in Section 3.4 (Toxicokinetics) 

for a more detailed discussion of hemoglobin adduct levels as biomarkers of exposure. 

It should be noted that hemoglobin adducts of N-methylolacrylamide are indistinguishable from 

hemoglobin adducts of acrylamide. 

3.8.2 Biomarkers Used to Characterize Effects Caused by Acrylamide 

Glycidamide-derived DNA adduct formation has been quantified in rats and mice exposed to acrylamide 

(Doerge et al. 2005a; Gamboa da Costa et al. 2003). There are no other known biomarkers of effect that 

are considered to be specific to acrylamide exposure. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

Nesterova et al. (1999) demonstrated an enhanced effect of acrylamide-induced clastogenicity in male 

mice administered acrylamide in combination with Verapamil (a calcium antagonist). No other 

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information was located regarding health effects attributed to interactions between acrylamide and other 

substances. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to acrylamide than will most 

persons exposed to the same level of acrylamide in the environment. Reasons may include genetic 

makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters result in reduced detoxification or excretion of acrylamide, or compromised function of 

organs affected by acrylamide. Populations who are at greater risk due to their unusually high exposure 

to acrylamide are discussed in Section 6.7, Populations with Potentially High Exposures. 

No human data were located regarding populations that would be particularly sensitive to acrylamide 

toxicity. 

Available animal data demonstrate increased susceptibility of males to acrylamide-induced reproductive 

effects expressed as male-mediated implantation loss, reduced number of fetuses, and testicular atrophy. 

The dominant lethal effects observed in male, but not female, rodents may be caused by acrylamideinduced alkylation of sperm protamine during spermiogenesis (Adler et al. 2000; Generoso et al. 1996; 

Perrault 2003; Sega et al. 1989; Sublet et al. 1989). Key determinants of male reproductive performance 

such as copulatory behavior (Zenick et al. 1986) and sperm motility (Sublet et al. 1989; Tyl et al. 2000b) 

may also be adversely affected by acrylamide. 

Available animal data do not suggest gender-related differences in susceptibility to acrylamide 

neurotoxicity. Male and female rats experience similar neurological effects at comparable dose levels 

(Burek et al. 1980; Friedman et al. 1995; Fullerton and Barnes 1996; Johnson et al. 1984, 1986). Results 

of animal cancer bioassays do not indicate any gender-related differences in susceptibility to acrylamide 

carcinogenicity. Chronic exposure of F344 rats to acrylamide in drinking water induced increased 

incidences of thyroid follicular cell tumors in both genders, scrotal sac mesotheliomas in males, and 

mammary gland fibroadenomas in females (Friedman et al. 1995; Johnson et al. 1986). 

No human data were located regarding age-related differences in susceptibility to acrylamide toxicity in 

humans. Conflicting reports are available from animal studies. Some reports indicate that young animals 

may be more susceptible than older ones (Ko et al. 1999; Suzuki and Pfaff 1973), whereas other reports 

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suggest decreased susceptibility in young animals (Fullerton and Barnes 1966; Kaplan et al. 1973). It 

should be noted that CYP2E1, which catalyzes acrylamide to its DNA-reactive metabolite glycidamide, is 

not expressed in the developing fetus, but attains levels of expression during early postnatal periods that 

are similar to levels in adults (Johnsrud et al. 2003); however, the toxicological significance of this 

finding has not been demonstrated. Refer to Section 3.7 (Children’s Susceptibility) for a detailed 

discussion of children’s susceptibility to acrylamide toxicity. 

Genetic polymorphisms in the acrylamide metabolizing P-450 enzyme CYP2E1 have been identified in 

humans (Hanioka et al. 2003). Polymorphisms in CYP2E1 could conceivably confer a differential risk to 

acrylamide toxicity and carcinogenicity. There is currently no quantitative estimate of differences in 

acrylamide or glycidamide tissue or blood levels that might result from CYP2E1 polymorphisms at high 

or low levels of acrylamide exposure. It is also noted that, since both acrylamide and glycidamide can 

exert toxic effects, different catalytic activities of CYP2E1 may result in different spectra of adverse 

effects. 

Because the acrylamide metabolite, glycidamide, is DNA reactive, individual differences in DNA repair 

and detoxification mechanisms might influence susceptibility to acrylamide toxicity. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to acrylamide. However, because some of the treatments discussed may be experimental and 

unproven, this section should not be used as a guide for treatment of exposures to acrylamide. When 

specific exposures have occurred, poison control centers and medical toxicologists should be consulted 

for medical advice. The following texts provide specific information about treatment following exposures 

to acrylamide: 

Currance PL, Clements B, Bronstein AC. 2007. Tri-ortho-cresyl phosphate (TOCP) and related 

compounds. In: Emergency care for hazardous materials exposure. 3rd ed. St. Louis, MO: MosbyJems, 

482-484. 

Goldfrank LR, Flomenbaum NE, Lewin NA, et al. 1998. Goldfrank's toxicologic emergencies. 

Stamford, CT: Appleton & Lange, 322-324, 475. 

Leikin JB, Paloucek FP. 2002. Leikin & Paloucek's poisoning & toxicology handbook. 3rd ed. Hudson, 

OH: Lexi-Comp, Inc., 193-194. 

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Palmer RB. 2004. Acrylic acid and derivatives. In: Dart RC, ed. Medical toxicology. 3rd ed. 

Philadelphia, PA: Lippincott Williams & Wilkins, 1358-1368. 

The following methods for reducing the toxic effects of acrylamide are applicable to numerous organic 

chemicals; they are not unique to acrylamide. 

3.11.1 Reducing Peak Absorption Following Exposure 

Rapid absorption of acrylamide can occur following exposure via inhalation, oral, and dermal routes. In 

the case of inhalation exposure, recommendations include removal from the site of exposure, 

establishment of a patent airway in the patient, and accompaniment by suction, ventilation, or 

administration of oxygen by a nonbreathing mask, if necessary (Currance et al. 2007). In the presence of 

airborne acrylamide, an impervious body protector may shield from absorption via dermal exposure 

(Leikin and Paloucek 2002). To reduce percutaneous absorption, immediate decontamination with mild 

liquid soap and large quantities of water has been recommended (Currance et al. 2007; Goldfrank et al. 

1998). To reduce absorption resulting from oral exposure, administration of activated charcoal (Leikin 

and Paloucek 2002; Palmer 2004), particularly within 1 hour of ingestion (Leikin and Paloucek 2002) has 

been recommended. Because of its potential for central nervous system depression and seizures, ipecacinduced emesis has been discouraged for treatment of acrylamide ingestion (Currance et al. 2007). Use of 

gastric lavage has not been proven helpful and is not recommended (Palmer 2004). 

3.11.2 Reducing Body Burden 

No data were located regarding methods for reducing the body burden of absorbed acrylamide. 

Animal studies indicate that acrylamide and its metabolites do not accumulate in any tissue other than red 

blood cells (Barber et al. 2001a; Crofton et al. 1996; Edwards 1975; Hashimoto and Aldridge 1970; Ikeda 

et al. 1985; Kadry et al. 1999; Marlowe et al. 1986; Miller et al. 1982; Ramsey et al. 1984) and late staged 

spermatids (Sega et al. 1989) and that elimination of acrylamide and its metabolites is relatively rapid 

(Fuhr et al. 2006; Leikin and Paloucek 2002). 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

The peripheral nervous system is the primary target of acrylamide toxicity in humans and animals. 

Neurotoxic effects have been observed following inhalation, oral, and dermal exposures. Administration 

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of pyridoxine has been suggested as a possible treatment to delay the onset of neurotoxic effects (Leikin 

and Paloucek 2002). N-Acetylcysteine has also been utilized, but is of unproven benefit (Leikin and 

Paloucek 2002). 

Administration of 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo[D] imidazole to acrylamideexposed rodents reduced acrylamide-induced behavioral deficits. This effect is suggestive of a 

therapeutic potential for peripheral neuropathy (Nakagawa-Yagi et al. 2001). 

3.12 ADEQUACY OF THE DATABASE 

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of acrylamide is available. Where adequate information is not 

available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the 

initiation of a program of research designed to determine the health effects (and techniques for developing 

methods to determine such health effects) of acrylamide. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

3.12.1 Existing Information on Health Effects of Acrylamide 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

acrylamide are summarized in Figure 3-7. The purpose of this figure is to illustrate the existing 

information concerning the health effects of acrylamide. Each dot in the figure indicates that one or more 

studies provide information associated with that particular effect. The dot does not necessarily imply 

anything about the quality of the study or studies, nor should missing information in this figure be 

interpreted as a “data need”. A data need, as defined in ATSDR’s Decision Guide for Identifying 

Substance-Specific Data Needs Related to Toxicological Profiles (Agency for Toxic Substances and 

Disease Registry 1989), is substance-specific information necessary to conduct comprehensive public 

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Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Figure 3-7. Existing Information on Health Effects of Acrylamide 

Inhalation 

Oral 

Dermal 

Systemic 

Human 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Systemic 

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Inhalation 

Oral 

Dermal 

Animal 

Existing Studies 

ACRYLAMIDE 130 

3. HEALTH EFFECTS 

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health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific 

information missing from the scientific literature. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. Available human information is limited to a single case in which 

intentional ingestion of 18 g of acrylamide resulted in clinical signs of peripheral neuropathy (Donovan 

and Pearson 1987). Limited acute-duration animal data are available for inhalation and dermal exposure 

routes. Clinical signs of neurological effects were observed in laboratory animals exposed to acrylamide 

dust at 15.6 mg/m3

, a lethal or near-lethal concentration (American Cyanamid Company 1953a). Acuteduration dermal exposure elicited indications of male-mediated decreased fertility in rabbits at 

50 mg/kg/day (Gutierrez-Espeleta et al. 1992), clinical signs of neurological effects in rats at doses 

≥200 mg/kg (American Cyanamid Company 1973), and slight initial weight loss and slight dermal 

irritation in rabbits at doses ≥500 mg/kg (American Cyanamid Company 1951; Dow Chemical Company 

1957). 

Numerous reports are available regarding the effects of acute-duration oral exposure in animals. Acute 

oral LD50 values range from 107 to 413 mg/kg (American Cyanamid Company 1951, 1973, 1977; Dow 

Chemical Company 1957; Fullerton and Barnes 1966; Hashimoto et al. 1981; McCollister et al. 1964; 

Tilson and Cabe 1979; Union Carbide Corporation 1947). Symptoms of acrylamide-induced 

neurotoxicity were elicited by single oral doses at lethal or near-lethal levels (100–200 mg/kg) (American 

Cyanamid Company 1953c; Fullerton and Barnes 1966; McCollister et al. 1964; Tilson and Cabe 1979) 

and at lower dose levels (25–45 mg/kg/day) during repeated oral dosing for ≥14 days (Dixit et al. 1981; 

Gilbert and Maurissen 1982; Tyl et al. 2000b). Single oral dosing at 63–150 mg/kg resulted in depressed 

body weight gain or actual weight loss (Dow Chemical Company 1957; Sakamoto et al. 1988); similar 

effects on body weight were elicited during repeated oral dosing at lower dose levels (15–20 mg/kg/day) 

(Burek et al. 1980; Tyl et al. 2000b). Male-mediated implantation losses were noted following acuteduration repeated oral dosing of rats at levels as low as 15–45 mg/kg/day (Sublet et al. 1989; Tyl et al. 

2000b; Working et al. 1987). 

Additional acute-duration studies of animals exposed by inhalation could be designed to assess exposure 

concentration-response relationships and provide a basis for an acute-duration inhalation MRL for 

acrylamide, although the general population is not likely to encounter acutely hazardous airborne 

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concentrations of acrylamide. Additional dermal studies using multiple dose levels could be designed to 

more extensively characterize the hazards of dermal exposure to acrylamide. 

Intermediate-Duration Exposure. Information in humans is available from numerous case reports in 

which acrylamide exposure was associated with signs of impaired neurological performance in central 

and peripheral nervous systems that include impaired motor function and muscle weakness (Auld and 

Bedwell 1967; Davenport et al. 1976; Dumitru 1989; Fullerton 1969; Garland and Patterson 1967; 

Gjerløff et al. 2001; Igisu et al. 1975; Kesson et al. 1977; Mapp et al. 1977; Mulloy 1996; Takahashi et al. 

1971). Human data are also available from cross-sectional studies that included self-reported symptoms 

and neurological evaluations of acrylamide-exposed workers with potential for inhalation and dermal (and 

possibly oral) exposure (Bachmann et al. 1992; Calleman et al. 1994; Hagmar et al. 2001; He et al. 1989; 

Myers and Macun 1991). In the cross-sectional studies, workers were exposed for time periods as short 

as 1 month (but predominantly for more than 1 year); typical signs and symptoms of acrylamide-induced 

neuropathy were reported. However, the human studies do not include meaningful exposure-response 

data, and relative contributions of inhalation, dermal, and oral exposure routes could not be determined. 

Most available intermediate-duration animal studies employed the oral exposure route. Treatment-related 

deaths were noted at repeated doses in the range of 25–50 mg/kg/day (American Cyanamid Company 

1953b, 1991; Fullerton and Barnes 1966; Schulze and Boysen 1991). Several studies reported 

acrylamide-induced adverse effects on body weight (American Cyanamid Company 1953b, 1979, 1991; 

Field et al. 1990; Friedman et al. 1999; Ko et al. 1999; Post and McLeod 1977a; Satchell and McLeod 

1981; Schulze and Boysen 1991; Tanii and Hashimoto 1983; Wise et al. 1995). One study reported 12% 

decreased maternal weight gain in rats administered acrylamide at a dose as low as 7.5 mg/kg/day during 

gestation days 6–20 (Field et al. 1990). A 28-day drinking water study reported acrylamide-associated 

decreases in serum testosterone and thyroid hormones T3 and T4 in male rats (American Cyanamid 

Company 1991). Male-mediated implantation losses were noted following intermediate-duration 

repeated oral dosing of rats or mice at levels as low as 2.8–13.3 mg/kg/day (Chapin et al. 1995; Sakamoto 

and Hashimoto 1986; Smith et al. 1986; Tyl et al. 2000a; Zenick et al. 1986). The developmental toxicity 

of acrylamide has been assessed to some extent (American Cyanamid Company 1979; Field et al. 1990; 

Garey and Paule 2007; Husain et al. 1987; Sakamoto and Hashimoto 1986; Wise et al. 1995); reported 

effects include neurochemical changes in the neonatal rat brain (Husain et al. 1987), decreased fetal body 

weight (Field et al. 1990), increased activity and decreased startle response (Wise et al. 1995), and subtle 

effects on measures of cognitive motivation (Gary and Paule 2007). 

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Numerous studies reported clinical signs and other indicators (e.g., hindlimb splay) of neurological effects 

associated with intermediate-duration oral exposure in laboratory animals at doses in the range of 5.7– 

100 mg/kg/day (American Cyanamid Company 1953b, 1953c, 1959, 1991; Burek et al. 1980; Dixit et al. 

1981; Dow Chemical Company 1981; Field et al. 1990; Friedman et al. 1999; Fullerton and Barnes 1966; 

Gorzinski et al. 1979; Hashimoto et al. 1981; Hersch et al. 1989a, 1989b; Hopkins 1970; Ko et al. 1999, 

2000, 2002; Leswing and Ribelin 1969; Maurissen et al. 1983; McCollister et al. 1964; Merigan et al. 

1985; Post and McLeod 1977a; Satchell and McLeod 1981; Tanii and Hashimoto 1983; Tilson and Cabe 

1979; Wise et al. 1995; Zenick et al. 1986). In general, the higher the dose level, the earlier the 

appearance of neurological signs. Some studies included histopathological evaluation of peripheral nerve 

fibers in acrylamide-treated animals (Burek et al. 1980; Eskin et al. 1985; Gorzinski et al. 1979; Johnson 

et al. 1985, 1986; Schulze and Boysen 1991). One study reported ultrastructural evidence of degenerative 

effects in sciatic nerve fibers from male F344 rats that had received acrylamide from the drinking water at 

1 mg/kg/day for up to 93 days and served as the basis for deriving an intermediate-duration oral MRL for 

acrylamide (Burek et al. 1980). 

Available intermediate-duration animal data for inhalation and dermal exposure are limited. Death and 

clinical signs of neurotoxicity were reported in dogs repeatedly exposed to acrylamide dust at 

15.6 mg/m3

, for up to 16 days (American Cyanamid Company 1953a) and rabbits administered 

acrylamide dermally at 50 mg/kg/day for 5 weeks (Rohm and Haas 1975). No adverse effects were 

observed in cats repeatedly exposed to acrylamide dust at 4.8 mg/m3 for up to 3 months (American 

Cyanamid Company 1954). 

Additional intermediate-duration studies of animals exposed by inhalation designed to assess exposure 

concentration-response relationships could serve as the basis for deriving an intermediate-duration 

inhalation MRL for acrylamide. Additional dermal studies using multiple dose levels could be designed 

to better characterize the hazards of intermediate-duration dermal exposure to acrylamide. 

Chronic-Duration Exposure and Cancer. Reports of chronic occupational exposure in humans 

describe a spectrum of neurological effects resulting from inhalation (Calleman et al. 1994; Myers and 

Macun 1991) and dermal effects such as peeling of skin as a result of dermal exposure (Bachmann et al. 

1992; Calleman et al. 1994; He et al. 1989; Myers and Macun 1991). Questionnaires, physical 

examinations, neurological examinations, and ENMG tests provide support from a cross-sectional 

analysis on factory workers in China (Calleman et al. 1994). This study also utilized hemoglobin adduct 

levels as a biomarker (Calleman et al. 1994). Neurological effects in rats from chronic oral exposures to 

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acrylamide are documented and provide NOAEL and LOAEL for increased incidence of ultrastructural 

degeneration in the sciatic nerve and degenerative effects in peripheral nerve fibers (Johnson et al. 1984, 

1985, 1986). 

One case-control human study suggests a possible association between diet before puberty and 

subsequent risk of breast cancer; this particular study, however, is of limited use due to lacking 

documentation of significant factors such as cooking methods and accurate recall (Michels et al. 2006). 

Olesen et al. (2008) discovered a significant positive correlation between acrylamide-hemoglobin adduct 

levels and ER+ breast cancer, but the conclusions are also only of limited use due to the small study size 

and uncertainty regarding extrapolation of exposure. Most prospective studies found no statistically 

significant associations between acrylamide in food and risks of cancers of the esophagus, stomach, or 

pancreas (Hogervorst et al. 2008b); colon or rectum (Hogervorst et al. 2008b; Larsen et al. 2009c; Mucci 

et al. 2006); bladder or prostate (Hogervorst et al. 2008a); breast (Hogervorst et al. 2007; Larsson et al. 

2009d; Wilson et al. 2009b); endometrium (Hogervorst et al. 2007; Larsson et al. 2009a); or ovarian 

epithelium (Larsson et al. 2009b). Exceptions include increased risks of postmenopausal endometrial and 

ovarian cancer (Hogervorst et al. 2007) and renal cell cancer (Hogervorst et al. 2008a) with increasing 

dietary acrylamide. The conclusions of these studies are only somewhat reliable as the estimations of 

dietary acrylamide levels in food on the market at baseline in 1986 are based on food samples analyzed in 

2001 and details regarding the specifics of food preparation are lacking. 

Conclusions of a 2-year bioassay of male and female F344 rats include significant increases in thyroid 

(follicular cell) adenomas (no carcinomas), mesotheliomas of the tunica vaginalis testis, mammary gland 

benign tumors (adenoma, fibroadenomas, or fibroma), and pituitary gland adenomas in high dose females 

(Johnson et al. 1984, 1986). 

The NCTR (2009) recently performed cancer bioassays on Fischer 344 rats and B6C3F1 mice 

administered acrylamide or glycidamide in the drinking water for 2 years. The carcinogenicity of 

acrylamide and glycidamide has also been assessed in neonatally-exposed B6C3F1 mice. Post-public 

comment drafts of this ATSDR Toxicological Profile for Acrylamide will include available results from 

these carcinogenicity bioassays. 

Genotoxicity. The genotoxicity of acrylamide has been studied both in vivo and in vitro. Studies are 

limited almost exclusively to laboratory rodents and nonmammalian species with the exception of a few 

in vitro assays of human cells. Results indicate that acrylamide is genotoxic and most potent in its ability 

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to induce clastogenic effects (including heritable translocations in offspring of acrylamide-exposed male 

rodents mated with untreated females), DNA damage, and gene mutations (including male-germ-cellmediated dominant lethal mutations and heritable specific-locus mutations). 

Genotoxicity assessments for acrylamide and its metabolite, glycidamide, in rats and mice are currently 

underway at NTCR (2009). Post-public comment drafts of this ATSDR Toxicological Profile for 

Acrylamide will include available results from these assessments. 

Reproductive Toxicity. The reproductive toxicity of acrylamide has been studied almost exclusively 

in orally-exposed rats and mice. Pre- and postimplantation losses and decreased numbers of live fetuses 

were noted at repeated doses in the range of 3–60 mg/kg/day (Chapin et al. 1995; Sakamoto and 

Hashimoto 1986; Smith et al. 1986; Sublet et al. 1989; Tyl et al. 2000a, 2000b; Working et al. 1987; 

Zenick et al. 1986). 

Results of dominant lethality testing and crossover trials indicate that acrylamide induces male-mediated 

reproductive effects at repeated oral doses in the range of 2.8–19 mg/kg/day (Chapin et al. 1995; 

Sakamoto and Hashimoto 1986; Smith et al. 1986; Tyl et al. 2000a, 2000b; Zenick et al. 1986). Other 

reported effects include decreased sperm mobility in Long-Evans rats receiving acrylamide at 

45 mg/kg/day for 5 days (Sublet et al. 1989), degenerative effects in spermatids of ddY mice dosed at 

100 or 150 mg/kg/day for 5 days (Sakamoto et al. 1988), and testicular atrophy in F344 rats at doses as 

low as 5 mg/kg/day for 90 days (American Cyanamid Company 1991; Burek et al. 1980). In apparent 

contrast, Tyl et al. (2000b) found no significant effects on sperm parameters in Long-Evans hooded rats 

following repeated oral dosing at dose levels as high as 60 mg/kg/day. Gross and histopathologic 

examinations of reproductive organs and tissues from male and female rats receiving acrylamide from the 

drinking water for up to 2 years at estimated doses as high as 2 mg/kg/day revealed no signs of 

acrylamide-induced effects (Friedman et al. 1995; Johnson et al. 1984, 1986). Prebreeding exposure of 

female rats and mice to acrylamide at doses of approximately 14 and 19 mg/kg/day did not adversely 

affect reproductive performance (Sakamoto and Hashimoto 1986; Zenick et al. 1986). 

The reproductive toxicity of acrylamide appears to have been adequately characterized in laboratory 

animals. Continued assessment of possible reproductive effects in humans with potential for significant 

exposure to acrylamide is recommended. 

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Developmental Toxicity. The developmental toxicity of acrylamide has been assessed only in oral 

studies of rats and mice. Effects include body weight decreases and decreased auditory startle response in 

offspring of female Sprague-Dawley rats exposed to 5 and 15 mg/kg-day, respectively, on gestation days 

6–10 (Wise et al. 1995), decreased mean fetal body weight in offspring of CD-1 mouse dams 

administered acrylamide by gavage at 45 mg/kg/day during gestation days 6–20 (Field et al. 1990), 

decreased mean fetal body weight in offspring of Sprague-Dawley rat dams receiving acrylamide from 

the drinking water (estimated acrylamide intake as high as 14.56 mg/kg/day) from gestation day 6 

throughout lactation (Takahashi et al. 2009), decreased brain levels of selected catecholamines 

(noradrenaline, dopamine, 5-hydroxytryptamine) in pups of rat dams administered acrylamide at 

25 mg/kg/day during lactation only or in young pups receiving the same dose for 5 days (Husain et al. 

1987), and decreased cognitive motivation in adolescent F344 rats exposed during gestation and lactation 

and extending through 12 weeks postpartum (Garey and Paule 2007). No exposure-related fetal 

malformations or variations (gross, visceral, or skeletal) were found in offspring of Sprague-Dawley rats 

administered acrylamide at doses of 2.5, 7.5, or 15 mg/kg/day on gestation days 6–20 or in CD-1 mice at 

doses of 3, 15, or 45 mg/kg/day on gestation days 6–17 (Field et al. 1990). 

Section 3.12.3 (Ongoing Studies) lists information regarding an ongoing developmental neurotoxicity 

study in rats. The results of this study should be evaluated prior to assessing a need for additional 

developmental toxicity studies of acrylamide. 

Immunotoxicity. No human or animal data were located in which acrylamide was considered to be a 

potential immunological concern. Immunotoxicity studies do not appear necessary at this time. 

Neurotoxicity. Information in humans is available from numerous case reports in which acrylamide 

exposure has been associated with signs of impaired neurological performance in central and peripheral 

nervous systems that include impaired motor function and muscle weakness (Auld and Bedwell 1967; 

Davenport et al. 1976; Dumitru 1989; Fullerton 1969; Garland and Patterson 1967; Gjerløff et al. 2001; 

Igisu et al. 1975; Kesson et al. 1977; Mapp et al. 1977; Mulloy 1996; Takahashi et al. 1971). Human data 

are also available from cross-sectional studies that included self-reported symptoms and neurological 

evaluations of acrylamide-exposed workers with potential for inhalation and dermal (and possibly oral) 

exposure (Bachmann et al. 1992; Calleman et al. 1994; Hagmar et al. 2001; He et al. 1989; Myers and 

Macun 1991). 

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Neurological effects associated with oral exposure to acrylamide have been well characterized in 

laboratory animals and include clinical signs such as twitching, loss of balance, tremors, lethargy, and 

general weakness and more subtle indicators of functional deficits such as decreased rotarod performance 

and increased limb or foot splay. Evidence of degenerative lesions in peripheral nerve fibers, as observed 

by light and electron microscopy, have been detected at oral doses lower than those eliciting clinical signs 

and other overt indications of functional deficit. See Sections 3.2.1.4, 3.2.2.4, and 3.2.3.4 for detailed 

information regarding neurological effects in acrylamide-exposed animals. Available animal data appear 

to adequately characterize acrylamide neurotoxicity; additional neurotoxicity studies do not appear 

necessary at this time. 

Refer to Section 3.12.2 (Developmental Effects) for a summary of information regarding acrylamideinduced neurodevelopmental effects. 

Epidemiological and Human Dosimetry Studies. Early epidemiological studies focused on 

neurological signs and symptoms in workers employed in the manufacture and/or use of acrylamide 

(Bachmann et al. 1992; Calleman et al. 1994; Hagmar et al. 2001; He et al. 1989; Myers and Macun 

1991). Although these studies, as well as available case reports, provide supportive evidence of 

acrylamide-induced neurotoxicity, they lack information regarding relative contributions of natural 

exposure routes (inhalation, oral, dermal), exposure-response relationships, and other confounding 

exposures. 

More recent investigations have focused on examining possible associations between acrylamide dietary 

intake and various cancer end points (Hogervorst et al. 2007, 2008a, 2008b; Larsson et al. 2009a, 2009b, 

2009c, 2009d; Michels et al. 2006; Mucci et al. 2003, 2004, 2005, 2006; Pelucchi et al. 2006, 2007; 

Wilson et al. 2009a, 2009b). These studies provide little evidence of acrylamide-induced carcinogenicity 

from estimated intakes through the diet. However, a major deficiency of these studies is the use of 

questionnaires to estimate prior dietary intake of acrylamide. 

Continued epidemiological research should focus on improving methods for estimating acrylamide intake. 

Additional information regarding biomarkers of exposure to acrylamide and improved PBPK modeling 

could be beneficial. 

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Biomarkers of Exposure and Effect. 

Exposure. Biomarkers of exposure to acrylamide include unchanged acrylamide, its mercapturic acid 

metabolite, AAMA, its epoxy derivative, glycidamide, and the respective metabolite of glycidamide, 

GAMA in urine (Bjellaas et al. 2007a; Boettcher et al. 2005, 2006a, 2006b; Fuhr et al. 2006) and 

hemoglobin adducts of acrylamide and glycidamide (Bergmark et al. 1993; Boettcher et al. 2005; 

Calleman et al. 1994; Fennell et al. 2005b; Hagmer et al. 2001; Olesen et al. 2008). However, 

N-methylolacrylamide forms hemoglobin adducts that are indistinguishable from hemoglobin adducts of 

acrylamide. The development of a method to measure levels of the metabolite, glyceramide, in urine 

could help to determine the relative importance of glycidamide via glutathione conjugation versus 

hydrolysis. 

See Section 3.12.3 (Ongoing Studies) for information regarding assessments currently underway to assess 

biomarkers of exposure to acrylamide. 

Effect. Glycidamide-DNA adducts may be considered a biomarker of effect from exposure to acrylamide 

(Doerge et al. 2005a; Gamboa da Costa et al. 2003). It is not likely that additional biomarkers of effect 

specific to acrylamide would be identified. 

Absorption, Distribution, Metabolism, and Excretion. Available human data indicate that 

acrylamide is readily absorbed following oral or dermal exposure; significant absorption of inhaled 

acrylamide is expected. In animals, acrylamide is readily absorbed following inhalation, oral, or dermal 

exposure. Absorbed acrylamide is widely distributed (accumulates only in red blood cells), rapidly 

metabolized in the liver, and excreted in the urine mainly as acrylamide-derived conjugates. Existing 

PBPK models for acrylamide are not adequate for human health risk assessment. However, as described 

in Section 3.12.3 (Ongoing Studies) a new PBPK model for acrylamide is presently being developed. 

Additional pharmacokinetic studies may be necessary to assist in calibration and validation of PBPK 

models for acrylamide. 

Comparative Toxicokinetics. Available data in rats and mice indicate species differences in 

acrylamide metabolism. Additional comparative toxicokinetic studies may be warranted pending the 

outcome of the new PBPK model being developed for acrylamide. 

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Methods for Reducing Toxic Effects. Suggested methods for reducing absorption of acrylamide 

include removal from exposure source, decontamination of exposed skin with soap and water, and 

administration of activated charcoal within 1 hour following ingestion. There are no known methods for 

reducing the body burden following absorption of acrylamide and no proven methods for interfering with 

the mechanism of action for toxic effects. 

Children’s Susceptibility. No specific data were located regarding acrylamide-induced health effects 

in children. The database of information in animals provides conflicting results. Children are not 

expected to be less susceptible than adults to acrylamide toxicity. 

Data needs relating to both prenatal and childhood exposures, and developmental effects expressed either 

prenatally or during childhood, are discussed in detail in the Developmental Toxicity subsection above. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

3.12.3 Ongoing Studies 

Search of the NCTR website revealed the following (NCTR 2009): 

Dr. Frederick Beland (principal investigator), Division of Biochemical Toxicology, is comparing the 

carcinogenicity of acrylamide and its metabolite glycidamide in B6C3F1 mice treated neonatally and in 

B6C3F1 mice and Fischer 344 rats treated for 2 years. The 2-year study is funded by the National 

Toxicology Program (NTP). 

Dr. Daniel Doerge (principal investigator), Division of Biochemical Toxicology, in collaboration with the 

Division of Genetic and Reproductive Toxicology and Division of Personalized Nutrition and Medicine 

and funding from the University of Maryland, is working to (1) develop a PBPK/PD model for 

acrylamide and glycidamide and (2) determine mutagenicity of acrylamide and glycidamide in Big Blue® 

rats. Dr. Doerge, in collaboration with the Department of genetic and Reproductive Toxicology and 

funding from NTP, is studying genotoxicity, mutagenicity, and biomarkers of exposure for acrylamide 

and glycidamide in rodents. 

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ACRYLAMIDE 140 

3. HEALTH EFFECTS 

Dr. Merle Paule (principal investigator), Division of Neurotoxicology, in collaboration with the Division 

of Biochemical Toxicology and funding from NTP, is assessing developmental neurotoxicity of 

acrylamide in rats. 

Dr. Eden Tareke (principal investigator), Division of Neurotoxicology, is investigating the effects of 

acrylamide on normal human brain cortical neuronal (HCN-1), PC12, and HepG2 cells in vitro. 

Search of the Federal Research in Progress database (FEDRIP 2009) revealed the following: 

Dr. John Essigmann (principal investigator), Massachusetts Institute of Technology, Cambridge, 

Massachusetts, is investigating the genotoxic effects of several compounds, including acrylamide, with 

the goal of developing new biomarkers. The sponsoring organization is the National Institute of 

Environmental Health Sciences. 

Dr. Richard LoPachin (principal investigator), Montefiore Medical Center, Bronx, New York, is 

performing ongoing research to elucidate specific mechanisms responsible for acrylamide toxicity. 

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ACRYLAMIDE 141 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Acrylamide is an unsaturated amide that is produced mainly for use as an intermediate in the production 

of polyacrylamide (Abdelmagic 1982; Haberman 2002). Information regarding the chemical identity of 

acrylamide is located in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Acrylamide is a white or colorless, odorless crystalline solid. Information regarding the physical and 

chemical properties of acrylamide is located in Table 4-2. Acrylamide is stable at room temperature but 

can violently polymerize at its melting point or under UV light (Lewis 2000, 2007; O’Neil et al. 2006). 

Acrid fumes, as well as NOx, may be released when it is heated to decomposition (Lewis 2000). 

Acrylamide is soluble in water, alcohol, and acetone, and is insoluble in benzene and heptanes (Lewis 

2007). 

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ACRYLAMIDE 142 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Acrylamide 

Characteristic Information Reference 

Chemical name Acrylamide 

Synonym(s) AAM; acrylagel; acrylic acid amide; HSDB 2009; Lewis 2000 

acrylic amide; akrylamid (Czech); 

amresco acryl-40; amid kyseliny 

akrylove; ethylenecarboxamide; 

optimum; propenamide; 2-propenamide; propereamide; propenoic 

acid amide; vinyl amide 

Registered trade name(s) No data 

Chemical formula C3H5NO HSDB 2009; WHO 2003 

Chemical structure 

Identification numbers: 

CAS registry 79-06-1 

NIOSH RTECS NIOSH/AS3325000 NIOSH 2005 

EPA hazardous waste U007 HSDB 2009; Lewis 2000 

OHM/TADS No data 

DOT/UN/NA/IMDG shipping UN 2074; IMO 6.1 HSDB 2009; Lewis 2000 

HSDB 191 HSDB 2009 

NCI No data 

STCC 49 091 83 HSDB 2009 

49 131 87 HSDB 2009 

CAS = Chemical Abstracts Service; DOT/UN/NA/IMDG = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for 

Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; 

RTECS = Registry of Toxic Effects of Chemical Substances; STCC = Standard Transport Commodity Code 

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ACRYLAMIDE 143 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Acrylamide 

Property Information Reference 

Molecular weight 71.08 Haberman 2002; HSDB 2009 

Color White HSDB 2009; Lewis 2000 

Colorless Lewis 2007; WHO 2003 

Physical state Crystalline solid HSDB 2009; Lewis 2000 

Lewis 2007; WHO 2003 

Melting point 84.5 °C Lewis 2007 

Boiling point 192.6 °C Lide 2008 

87 °C (2 mm) O’Neil et al. 2006 

103 °C (5 mm) O’Neil et al. 2006 

125 oC (25 mm) Lewis 2007; O’Neil et al. 2006 

Density at 30 °C/4 °C 1.122 HSDB 2009; Lewis 2007 

Odor Odorless Lewis 2007 

Odor threshold: 

Water No data 

Air No data 

Solubility: 

Water at 0 °C No data 

at 20 °C 3.711x105 mg/L HSDB 2009 

at 30 °C 4.048x105 mg/L HSDB 2009 

Organic solvents Soluble in water, alcohol, acetone Lewis 2007 

Insoluble in benzene and heptanes Lewis 2007 

Partition coefficients: 

Log Kow -0.67 HSDB 2009 

Log Koc No data 

Vapor pressure 

at 25 °C 0.9 Pa (7x10-3 mm Hg) Haberman 2002; HSDB 2009 

at 40 °C 4.4 Pa (3.3x10-2 mm Hg) Haberman 2002 

at 50 °C 9.3 Pa (7.0x10-2 mm Hg) Haberman 2002 

Henry's law constant: 

at 25 °C 1.7x10-9 atm-m3/mol (estimated) HSDB 2009 

Autoignition temperature 424 °C HSDB 2009 

Flash point 138 °C (closed cup) HSDB 2009 

Flammability limits No data 

Conversion factors 1 mg/m3

=0.34 ppm HSDB 2009 

(25 °C, 1 atm) 1 ppm=2.95 mg/m3 

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4. CHEMICAL AND PHYSICAL INFORMATION 

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ACRYLAMIDE 145 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.1 PRODUCTION 

No information is available in the TRI database on facilities that manufacture or process acrylamide 

because this chemical is not required to be reported under Section 313 of the Emergency Planning and 

Community Right-to-Know Act (Title III of the Superfund Amendments and Reauthorization Act of 

1986) (EPA 1998). 

Acrylamide can be produced from acrylonitrile treated with sulfuric acid or hydrochloric acid, followed 

by base neutralization or use of an ion exclusion column to separate the chemical from its sulfate salt 

(Haberman 2002; HSDB 2009; Lewis 2007; O’Neil et al. 2006). Although historically the primary 

method of acrylamide production, this method results in sulfate byproducts and significant waste streams, 

and thus, commercial acrylamide producers no longer use this process (Haberman 2002). A newer 

process was developed in which a solution of acrylonitrile is passed over a fixed bed copper catalyst at 

85 °C, resulting in an acrylamide solution. This method has been modified by various companies since its 

development. A Raney copper catalyst can also be used in both slurry and fixed-bed reactors (Haberman 

2002). American Cyanamid uses a proprietary catalytic direct hydration process to produce acrylamide 

from acrylonitrile, using a reaction of water of solid surfaces of metal, metallic salts, or metallic oxides, 

which avoids the formation of unwanted byproducts (HSDB 2009). 

Numerous other methods of acrylamide production have been developed. Acryloyl chloride or acrylic 

anhydride can be reacted with ammonia to yield acrylamide. Microorganisms can also be used to convert 

acrylonitrile to acrylamide via an enzymatic hydration process (Haberman 2002). 

Table 5-1 lists the facilities in each state that manufacture, process, or use acrylamide as well as the 

intended use and the range of amounts of acrylamide that are stored on site. There are currently 

216 facilities that produce, process, or use acrylamide in the United States. The data listed in Table 5-1 

are derived from the Toxics Release Inventory (TRI 07 2009). These data should be used with caution, 

however, since only certain types of facilities are required to report. Therefore, this is not an exhaustive 

list. Commercial production of acrylamide in 1983 was reported as 86,233 pounds (HSDB 2009). 

Currently, there are four major producers of acrylamide in the United States, with a combined production 

capacity of approximately 141,000 metric tons (311 million pounds) (SRI 2008). These producers and 

their respective plant locations are provided in Table 5-2. 

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ACRYLAMIDE 146 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Facilities that Produce, Process, or Use Acrylamide 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 4 10,000 9,999,999 6, 14 

AR 5 0 99,999 6, 7, 12 

CA 15 0 9,999,999 1, 2, 3, 4, 6, 7, 8, 9, 10 

CO 2 0 99,999 6 

CT 6 10,000 9,999,999 2, 3, 4, 6 

DE 1 0 0 0 

FL 3 100,000 999,999 2, 3, 6 

GA 8 0 9,999,999 1, 4, 6, 7 

IL 14 0 9,999,999 2, 3, 6, 7, 12 

IN 1 10,000 99,999 12 

KY 4 10,000 999,999 6, 12 

LA 13 0 9,999,999 1, 2, 3, 4, 6, 9, 10, 12, 13 

MA 4 1,000 99,999 6, 7 

MD 4 0 999,999 6, 7 

MI 21 0 49,999,999 1, 2, 3, 4, 6, 7, 8, 10, 11, 12 

MO 5 100 99,999 1, 2, 3, 6, 7, 8 

NC 7 100 999,999 6, 7 

NE 4 0 99,999 3, 7, 8, 11, 12 

NJ 8 0 999,999 1, 6, 10, 12, 13 

NY 11 100 99,999 6, 7, 9, 10, 12 

OH 10 0 999,999 1, 6, 7, 12, 13 

OR 1 1,000 9,999 6 

PA 6 0 499,999,999 6 

SC 12 0 999,999 6, 7, 12 

TN 8 0 9,999,999 6, 12 

TX 18 0 9,999,999 1, 5, 6, 7, 12, 13 

UT 1 1,000 9,999 12 

VA 7 100,000 49,999,999 1, 2, 3, 4, 6 

WA 2 100,000 999,999 6, 12 

WI 5 0 99,999 2, 3, 6, 7 

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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Facilities that Produce, Process, or Use Acrylamide 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

WV 5 0 499,999,999 1, 5, 6, 12 

WY 1 1,000,000 9,999,999 9 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 

Source: TRI07 2009 (Data are from 2007) 

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ACRYLAMIDE 148 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-2. 2008 Acrylamide Production in the United States 

Company Location 

Annual capacity 

(metric tonsa) Remarks 

Chemtall, Inc. Riceboro, Georgia 65,000 From purchased 

acrylonitrile; captive 

consumption for 

polyacrylamide 

Ciba Specialty Chemicals 

Corporation Water & Paper 

Treatment Business 

Segment 

Suffolk, Virginia 15,000 From purchased 

acrylonitrile; primarily 

captive consumption for 

polyacrylamide 

Kemira Water Solutions, Inc. Waggaman, 

Louisiana 

41,000 From captive acrylonitrile; 

captive consumption for 

polyacrylamide 

Nalco Company Garyville, Louisiana 20,000 From purchased 

acrylonitrile; primarily 

captive consumption for 

polyacrylamide 

Total 141,000 

a

All production is as solution. 

Source: SRI 2008; SRI Consulting estimates as of February 1, 2008. 

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ACRYLAMIDE 149 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Acrylamide is produced as a byproduct when foods are cooked at high temperatures, such as by frying, 

roasting, and baking (Muttucumaru et al. 2008). This occurs by the Maillard reaction, where thermal 

degradation of amino acids occurs in the presence of reducing sugars at temperatures above 120 °C. The 

major precursors for acrylamide formation by the Maillard reaction are free asparagines and reducing 

sugars (Arisseto et al. 2007; Mottram 2002; Muttucumaru et al. 2008; Stadler et al. 2002). Acrylamide 

concentrations in the foods rise with temperature and length of heating, and appear to be affected by water 

content, food composition, and processing conditions (WHO 2002). 

5.2 IMPORT/EXPORT 

The demand for acrylamide in the United States was reported as 245 and 253 million pounds in 2006 and 

2007, respectively. U.S. imports were 61 and 55 million pounds in 2006 and 2007, respectively, while 

U.S. exports were 57 and 53 million pounds in 2006 and 2007, respectively (CMR 2008). 

5.3 USE 

Commercially-produced acrylamide is used mainly as an intermediate in the production of 

polyacrylamides (EU 2002; Haberman 2002; O’Neil et al. 2006; WHO 2003). This accounts for 94% of 

manufactured acrylamide (Haberman 2002). Polyacrylamides are then primarily used as flocculants for 

clarifying drinking and treating municipal and industrial effluents (Abdelmagid 1982; EPA 2006c; EU 

2002; Haberman 2002; WHO 2003;). They aid in dewatering sludge from sewage treatment plant 

effluent as well as industrial waste water from pulp and paper plants (Abdelmagid 1982; Haberman 

2002). Polyacrylamides are also found in cosmetics and toiletries and are used to prepare polyacrylamide 

gels for use in biotechnology laboratories (EU 2002; Lewis 2007). In the oil industry, acrylamide is used 

as a flow control agent to enhance oil production from wells. Acrylamide and polyacrylamides are also 

used in the production of dyes and organic chemicals such as N-methylacrylamide, in copolymers for 

contact lenses, in permanent-press fabrics, for sizing paper and textiles, as a binder and retention aid for 

pulp and paper production, in the processing of ore, in sugar refining, and as a chemical grouting agent 

and soil stabilizer for the construction of tunnels, sewers, wells, and reservoirs (Abdelmagid 1982; EPA 

2006c; EU 2002; Haberman 2002; Lewis 2007; O’Neil et al. 2006; WHO 2003). 

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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.4 DISPOSAL 

Acrylamide is typically produced as an intermediate for the production of polyacrylamides (Haberman 

2002; O’Neil et al. 2006), and is therefore consumed in the process. No information was found regarding 

the disposal of acrylamide. 

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ACRYLAMIDE 151 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Acrylamide has been identified in at least 3 of the 1,699 hazardous waste sites that have been proposed 

for inclusion on the EPA National Priorities List (NPL) (HazDat 2007). However, the number of sites 

evaluated for acrylamide is not known. The frequency of these sites can be seen in Figure 6-1. 

Acrylamide is an industrial chemical used mainly in the production of polyacrylamides, which are 

primarily used as flocculants for clarifying drinking and treating municipal and industrial effluents 

(Abdelmagid 1982; EPA 2006c; EU 2002; Haberman 2002; O’Neil et al. 2006; WHO 2003). Acrylamide 

may be released to the environment during production and use of polyacrylamides, which are used as 

clarifiers in water treatment. Residual monomer released from the polyacrylamide coagulants is the main 

source of acrylamide contamination of drinking water (Abdelmagid 1982; Cavalli et al. 2004; EPA 

2006c; WHO 2003), though it can also be released from plastics and dye industries and from acrylamidecontaining grouting agents used in reservoirs and wells (Cavalli et al. 2004; EPA 2006c). Acrylamide can 

be released to the environment during formulation of cosmetics or other consumer products and in the 

laboratory while gel chromatography is being performed (Boettcher and Angerer 2005; EU 2002). Due to 

its low vapor pressure and high water solubility, acrylamide is rarely identified in atmospheric samples 

(WHO 2003). 

Acrylamide is expected to be highly mobile in soil and water (EPA 2006c; HSDB 2009; WHO 2003). It 

is highly susceptible to biodegradation in both soils and surface water (Abdelmagid 1982; EPA 2006c; 

Haberman 2002; WHO 2003). It is not typically present in the atmosphere (HSDB 2009; Pratt 2000). 

Acrylamide is not expected to significantly bioconcentrate (EPA 2006c; Haberman 2002; WHO 2003). 

Acrylamide is sometimes present in drinking water due to leaching of monomer during treatment 

processes (Abdelmagid 1982; Cavalli et al. 2004; EPA 2006c; van Dijk-Looijaard and van Genderen 

2000; WHO 2003), as well as release from grouting agents in wells and dams and releases from plastics 

and dye industries (Cavalli et al. 2004). It is rarely found in soil samples (HSDB 2009). Acrylamide is 

not a common air pollutant, due to its low vapor pressure and high water solubility. It is rarely identified 

in atmospheric samples (HSDB 2009; Pratt 2000; WHO 2003). 

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ACRYLAMIDE 152 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with Acrylamide Contamination 

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ACRYLAMIDE 153 

6. POTENTIAL FOR HUMAN EXPOSURE 

In 2002, acrylamide was first identified in samples of food cooked at high temperatures (Tareke et al. 

2002). Concentrations of acrylamide in food vary with the type of food and method of cooking, and 

typically increase with temperature and length of heating (Sorgel et al. 2002; WHO 2002, 2003). 

Carbohydrate-rich foods typically contain the highest levels of acrylamide (Muttucumaru et al. 2008; 

Tareke et al. 2002; WHO 2003), whereas protein-based foods contain smaller amounts (Tareke et al. 

2002). As acrylamide content in food appears to be affected by temperature, water content, food 

thickness, and length of heating, various steps can be taken to minimize the exposure of acrylamide from 

food sources (Sorgel et al. 2002; WHO 2002, 2003). 

Acrylamide is a carcinogen with the potential to cause nervous system damage (Arisetto et al. 2007; EPA 

2006c; Lewis 2000). Exposure occurs mainly via ingestion, dermal contact, and inhalation routes (Lewis 

2000; Sorgel et al. 2002). Ingestion of foodstuffs containing acrylamide appears to be one of the most 

common methods of exposure for the general public. Average estimated intake of acrylamide from food 

sources ranged from 0.8 to 6.0 μg/kg bw/day for short-term exposure and 0.3 to 0.8 μg/kg bw/day for 

long-term exposure (WHO 2002, 2003). Children may be susceptible to food-borne exposure 2–3 times 

that of adults on a body weight basis (WHO 2002, 2003). 

Ingestion of polyacrylamide-treated drinking water containing residual monomer as well as water in 

contact with acrylamide-containing products, such as grouting agents, can result in exposure to 

acrylamide (EPA 2006c; EU 2002; WHO 2003). The presence of acrylamide in tobacco smoke can result 

in inhalation exposure for both adults and children (EU 2002; Moreno Navarro et al. 2007). Dermal 

exposure can result from contact with cosmetics and toiletries containing polyacrylamides (EU 2002). 

Once in the body, acrylamide is widely dispersed by body fluids, and can also cross the placental barrier 

(WHO 2003), resulting in exposure to unborn children. Breast milk of mothers with diets high in 

acrylamide-containing foods can contain high amounts of acrylamide (Sorgel et al. 2002). Occupational 

exposure to acrylamide is primarily due to dermal contact when handling bags and drums of the chemical 

or preparing polyacrylamide gels, followed by inhalation of dust or aerosols (EU 2002; Lewis 2000). 

6.2 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005a). This is not an exhaustive list. Manufacturing and 

processing facilities are required to report information to the TRI only if they employ 10 or more full-time 

employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 

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6. POTENTIAL FOR HUMAN EXPOSURE 

1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the 

purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust 

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities 

primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces, 

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI 

chemical in a calendar year (EPA 2005a). 

6.2.1 Air 

Estimated releases of 11,791 pounds (~5.3 metric tons) of acrylamide to the atmosphere from 81 domestic 

manufacturing and processing facilities in 2007, accounted for about 0.2% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI07 2009). These releases are 

summarized in Table 6-1. 

Acrylamide may be released to the atmosphere during production of polymers, formulation of cosmetics 

or other consumer products, and in the laboratory while gel chromatography is being performed 

(Boettcher and Angerer 2005). Release of tobacco smoke, which was shown to contain acrylamide 

(Schumacher et al. 1977), may also contribute to airborne acrylamide in confined spaces. However, 

acrylamide is not anticipated to be a common air contaminant due to its low vapor pressure and high 

water solubility. Acrylamide is not expected to be removed from soils or water by volatilization (WHO 

2003). Limited data indicate that atmospheric acrylamide concentrations are very low, when it is 

identified at all (Pratt 2000; HSDB 2009). 

The total national baseline National Toxics Inventory (NTI) emissions for acrylamide during 1900–1998 

were 35.4 tons/year. Total urban emissions were 33.5 tons/year while total rural emissions were 

1.9 tons/year (EPA 2000). The National Emissions Inventory database, maintained by the EPA, reports 

total U.S. acrylamide emissions of 12.12 tons per year in 2005 from various sources, including 

degreasing, waste disposal, pulp and paper, solvents, oil and gas production, industrial surface coatings, 

and oil and gasoline production among others (EPA 2009f). 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
 

Use Acrylamidea
 

Reported amounts released in pounds per yearb 

Total release 

On- and 

Statec RFd Aire Waterf UI

g Landh Otheri On-sitej Off-sitek off-site 

AL 1 90 0 0 4 4,555 90 4,559 4,649 

AR 3 55 0 0 1 580 55 581 636 

CA 2 1 No data 0 0 0 1 0 1 

CO 1 0 No data 0 0 0 0 0 0 

CT 2 2 7 0 83 0 9 83 92 

DE 1 0 No data 0 0 0 0 0 0 

GA 6 5,629 0 0 798 0 5,629 798 6,427 

IL 6 99 0 0 0 0 99 0 99 

KY 1 0 No data 0 0 0 0 0 0 

LA 5 1,980 216 873,489 2,936 0 876,491 2,130 878,621 

MA 1 0 No data 0 0 5 0 5 5 

MD 2 2 0 0 0 0 2 0 2 

MI 3 6 0 0 0 0 6 0 6 

NC 8 1,860 0 0 0 0 1,860 0 1,860 

NE 1 2 0 0 0 0 2 0 2 

NJ 2 19 0 0 0 0 19 0 19 

OH 6 1,299 0 960,000 10 0 961,299 10 961,309 

PA 5 19 5 0 0 0 24 0 24 

SC 8 500 250 0 0 0 750 0 750 

TN 5 98 No data 0 0 357 98 357 455 

TX 6 26 0 4,303,938 8 0 4,303,971 0 4,303,971 

UT 1 1 0 0 0 0 1 0 1 

VA 1 64 0 0 176 0 64 176 240 

WA 1 21 No data 0 0 0 21 0 21 

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ACRYLAMIDE 156 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
 

Use Acrylamidea
 

Reported amounts released in pounds per yearb 

Total release 

Statec RFd Aire Waterf UI

g Landh Otheri On-sitej Off-sitek 

On- and 

off-site 

WI 3 18 No data 0 0 2,038 18 2,038 2,056 

Total 81 11,791 478 6,137,427 4,016 7,535 6,150,510 10,737 6,161,247 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used.
 d

Number of reporting facilities.
 e

The sum of fugitive and point source releases are included in releases to air by a given facility.
 f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal
 

and metal compounds).
 g

Class I wells, Class II-V wells, and underground injection. h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills.

i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for
 

disposal, unknown

j

The sum of all releases of the chemical to air, land, water, and underground injection wells.

k

Total amount of chemical transferred off-site, including to POTWs.
 

RF = reporting facilities; UI = underground injection 

Source: TRI07 2009 (Data are from 2007) 

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6.2.2 Water 

Estimated releases of 478 pounds (~0.22 metric tons) of acrylamide to surface water from 81 domestic 

manufacturing and processing facilities in 2007, accounted for about 0.01% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI07 2009). These releases are 

summarized in Table 6-1. 

Acrylamide in drinking water is typically a result of the release of residual monomer from polyacrylamide 

coagulants that are used as clarifiers in the treatment of raw water (Abdelmagid 1982; Cavalli et al. 2004; 

EPA 2006c; WHO 2003). The clarifiers served to coagulate and trap suspended solids such that they may 

be removed more easily from the water. Acrylamide that does not coagulate is released into the 

environment as a drinking water contaminant (Abdelmagid 1982; EPA 2006c). Use of polyacrylamides 

as grouting agents in reservoirs and wells can result in release to drinking water supplies. They can also 

be released in water from plastics and dye industries (Cavalli et al. 2004; EPA 2006c). When released to 

land, acrylamide does not bind to soil and will thus move rapidly through the soil column (EPA 2006c), 

which can result in increased risk of surface or groundwater contamination. 

Total release of acrylamide to water between 1987 and 1993 was 36,287 pounds. Major industries found 

to release acrylamide to water include plastics and resins (19,002 pounds), pulp mills (8,000 pounds), 

industrial organics (3,107 pounds), and industrial inorganics (2,510 pounds) (EPA 2006c). According to 

the EPA’s Toxic Chemical Release Inventory, release of acrylamide to land and water from 1987 to 1993 

was over 40,000 pounds. Acrylamide releases were typically from plastics industries, with the largest 

releases occurring in Michigan (EPA 2006c). 

As required by the 1974 Safe Drinking Water Act, EPA developed a maximum contaminant level (MCL) 

for acrylamide, which specifies the concentration at which it is not expected to cause health problems. 

The MCL for acrylamide is zero (EPA 2006c). EPA requires water suppliers to control the amount of 

acrylamide added to water during the treatment process. This can be accomplished by limiting the 

amount of acrylamide in the polyacrylamide flocculants or by limiting the dose of flocculants (WHO 

2003). Uncoagulated acrylamide in drinking water must be <0.5 μg/L (ppb) (Cavalli et al. 2004; EPA 

2006c). This concentration corresponds to a maximum authorized dose of polymer of 1 mg/L (for a 

monomer content of 0.05%), as this corresponds to 0.5 μg/L of monomer in the water (Cavalli et al. 2004; 

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WHO 2003). In European Union countries, the maximum allowable concentration in drinking water is 

0.1 μg/L (Cavalli et al. 2004). 

If acrylamide is found to be present in raw water, the concentration can be decreased through ozonation or 

by treating the water with potassium permanganate. Acrylamide is not removed by conventional water 

treatment processes (WHO 2003). 

6.2.3 Soil 

Estimated releases of 4,016 pounds (~1.8 metric tons) of acrylamide to soils from 81 domestic 

manufacturing and processing facilities in 2007, accounted for about 0.06% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI07 2009). An additional 

6,137,427 pounds (~2,783 metric tons), constituting about 99.6% of the total environmental emissions, 

were released via underground injection (TRI07 2009). These releases are summarized in Table 6-1. 

Polyacrylamides releases to land can occur from plastics and dye industries (Cavalli et al. 2004; EPA 

2006c). When released to land, acrylamide does not bind to soil and will thus move rapidly through the 

soil column (EPA 2006c; WHO 2003). Total release of acrylamide to land between 1987 and 1993 was 

5,818 pounds. Major industries found to release acrylamide to land include plastics and resins 

(2,177 pounds), industrial organics (2,200 pounds), and industrial inorganics (500 pounds) (EPA 2006c). 

According to the EPA’s Toxic Chemical Release Inventory, release of acrylamide to land and water from 

1987 to 1993 was over 40,000 pounds. Acrylamide releases were typically from plastics industries, with 

the largest releases occurring in Michigan (EPA 2006c). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

Acrylamide is expected to be highly mobile in soil and water. When released to land, acrylamide does 

not bind to soil and will thus move rapidly through the soil column and into groundwater, where it is also 

expected to have high mobility (EPA 2006c; HSDB 2009; WHO 2003). Acrylamide has a higher 

mobility in sandy soils than in clay soils, which can result in increased risk of surface or groundwater 

contamination (Abdelmagid 1982; EPA 2006c; WHO 2003). Acrylamide is not expected to be removed 

from soils or water by volatilization (WHO 2003). 

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Acrylamide is not expected to significantly bioconcentrate in aquatic organisms due to its high water 

solubility and its ability to be degraded by microorganisms (EPA 2006c; Haberman 2002; WHO 2003). 

Acrylamide was determined to have a bioconcentration factor (BCF) of around 1 in both the carcass and 

viscera (0.86–1.44 and 1.12–1.65, respectively) of rainbow trout exposed to acrylamide concentrations of 

0.338 and 0.710 mg/L. This indicates that acrylamide did not bioaccumulate significantly in the trout 

(Petersen et al. 1985). 

6.3.2 Transformation and Degradation 

Acrylamide is susceptible to biodegradation in both soils and surface water (Abdelmagid 1982; EPA 

2006c; Haberman 2002; HSDB 2009; WHO 2003). As it does not bind to soil, acrylamide moves rapidly 

through the soil column where it is quickly degraded (EPA 2006c; WHO 2003). 

In sandy soils, acrylamide has a higher mobility and lower rate of degradation than in clay soils 

(Abdelmagid 1982; EPA 2006c; WHO 2003). Acrylamide has been shown to biodegrade in effluent from 

a sludge dewatering process (WHO 2003). 

Enzyme-catalyzed hydrolysis is a dominant mechanism for removal of acrylamide from soils (WHO 

2003). Abdelmagid (1982) showed that acrylamide is readily hydrolyzed in soils under both aerobic and 

anaerobic conditions, resulting in the release of NH4

+

. The rate of decomposition in soil is influenced by 

temperature and incubation time. Soil type did not appear to be a factor, as acrylamide decomposed in 

both sandy and heavy-textured soils (Abdelmagid 1982). 

Acrylamide was shown to degrade by an average of 41.5% by BOD in 14 days at 25 °C and 100 mg/L 

test substance, with 30 mg/L activated sludge (CERI 1999). 

6.3.2.1 Air 

Limited data indicate that acrylamide concentrations in the atmosphere are very low (HSDB 2009; Pratt 

2000). In the atmosphere, acrylamide is susceptible to degradation via photochemically generated 

hydroxyl radicals and ozone. The rate constant for acrylamide’s reaction with hydroxyl radicals has been 

estimated as 1.1x10-11 cm3

/molecule-second, and its reaction with ozone is estimated as 

1.7x10-18 cm3

/molecule-second using a structure estimation method (Meylan and Howard 1993). Using 

an average atmospheric hydroxyl radical concentration of 1.5x106 molecules/cm3 and ozone concentration 

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of 7x1011 molecules/cm3, estimated half-lives of approximately 12 hours (hydroxyl radical reaction) and 

6.5 days (ozone reaction) can be calculated. 

6.3.2.2 Water 

Acrylamide is expected to be quickly degraded in water by biological processes (Abdelmagid 1982; EPA 

2006c; Haberman 2002; WHO 2003). At an initial concentration of 10 ppm, acrylamide was completely 

degraded in about 12 days using water obtained from the Hackensack River (Cherry et al. 1956). 

Acrylamide, at an initial concentration of 8 μg/L, was rapidly degraded following a lag period of 

approximately 9 days in well-aerated, sunlit river water obtained from the Thames River, England (Croll 

et al. 1974). Subsequent re-seeding of the water with acrylamide resulted in rapid degradation with little 

or no lag period. 

6.3.2.3 Sediment and Soil 

When released to land, acrylamide does not bind to soil and will thus move rapidly through the soil 

column, where it is expected to be quickly degraded (EPA 2006c; Haberman 2002; WHO 2003). 

Acrylamide has a higher mobility and lower rate of degradation in sandy soils than in clay soils 

(Abdelmagid 1982; EPA 2006c; WHO 2003). 

Enzyme-catalyzed hydrolysis is a dominant mechanism for removal of acrylamide from soils (WHO 

2003). Abdelmagid (1982) showed that acrylamide is readily hydrolyzed in soils, producing NH4

+

. The 

rate of decomposition in soil is influenced by temperature and incubation time. Soil type did not appear 

to be a factor, as acrylamide decomposed in both sandy and heavy-textured soils. Acrylamide, therefore, 

does not appear to accumulate in soils (Abdelmagid 1982). 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to acrylamide depends in part on the reliability of 

supporting analytical data from environmental samples and biological specimens. Concentrations of 

acrylamide in unpolluted atmospheres and in pristine surface waters are often so low as to be near the 

limits of current analytical methods. In reviewing data on acrylamide levels monitored or estimated in the 

environment, it should also be noted that the amount of chemical identified analytically is not necessarily 

equivalent to the amount that is bioavailable. The analytical methods available for monitoring acrylamide 

in a variety of environmental media are detailed in Chapter 7. 

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6.4.1 Air 

Acrylamide is not anticipated to be a common air contaminant due to its low vapor pressure and high 

water solubility. Limited data indicate that acrylamide concentrations in the atmosphere are very low 

(HSDB 2009; Pratt 2000). Air samples were collected at 25 sites throughout Minnesota over various 

periods of time (up to 8 years) from 1991 to 1998. Acrylamide was not identified in any of the samples 

(Pratt 2000). As of 1978, acrylamide concentrations in the air near six U.S. acrylamide/polyacrylamide 

producers or users averaged <0.2 μg/m3 in vapor or particulate form. Concentrations ranged from <0.1 to 

1.1 μg/m3 (EPA 1978). 

The total national baseline NTI emissions for acrylamide during 1900–1998 were 35.4 tons/year. Total 

urban emissions were 33.5 tons/year, while total rural emissions were 1.9 tons per year (EPA 2000). 

6.4.2 Water 

Acrylamide in drinking water is typically a result of leaching during treatment processes (van DijkLooijaard and van Genderen 2000). Acrylamide results from the release of residual monomer from 

polyacrylamide coagulants that are used as clarifiers in the treatment of raw water (Abdelmagid 1982; 

Cavalli et al. 2004; EPA 2006c; WHO 2003). Polyacrylamides can enter water supplies due to their use 

as grouting agents in reservoirs and wells in addition to being released in water from plastics and dye 

industries (Cavalli et al. 2004; EPA 2006c). 

Acrylamide concentrations of <5 μg/L were found in river and tap water. In the sampling area, 

polyacrylamides were known to be used in treating potable water (WHO 2003). Public drinking water 

supply wells in West Virginia contained acrylamide concentrations of 0.024–0.041 μg/L (WHO 2003). 

One water sample, taken from downstream of the effluent of a producer of polyacrylamide, contained 

acrylamide at 1,500 μg/L, while samples from other industrial sites (acrylamide and polyacrylamide 

production and use locations) contained <0.8 μg/L acrylamide (EPA 1978). 

Various effluents in the United Kingdom have been found to contain acrylamide, including effluent from 

a clay pit (16.0 μg/L), a tailings lagoon (39–42 μg/L), coal washing lagoon (1.8 μg/L), colliery/cooking 

plant, (0.74 μg/L), treated paper mill (0.47–14.4 μg/L), and paper mill process water (45.4 μg/L) (Croll et 

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al. 1974; IPCS 1985). In Devon, England, 17.4 ppb of acrylamide was detected in sewage effluent 

(Brown and Rhead 1979). 

6.4.3 Sediment and Soil 

Soil samples obtained near six U.S. acrylamide and/or polyacrylamide producers contained <0.02 μg/g of 

acrylamide. Concentrations ranged from <0.02 to <0.08 μg/g (EPA 1978). 

6.4.4 Other Environmental Media 

Acrylamide was detected in waste materials and containers at 3 of the 1,699 hazardous waste sites that 

have been proposed for inclusion on the EPA NPL (HazDat 2007). Acrylamide was also identified in 

tobacco smoke samples, obtained from nonfiltered cigarettes smoked under typically conditions. The 

presence of acrylamide was identified in the smoke condensate by infrared (IR), mass spectrometry (MS), 

and nuclear magnetic resonance (NMR) (Schumacher et al. 1977). 

In 2002, acrylamide was first shown to be produced when foods are cooked at high temperatures (Tareke 

et al. 2002). Concentrations of acrylamide in food vary with the type of food and method of processing 

and cooking. Acrylamide concentrations in food typically increase with temperature and length of 

heating (Sorgel et al. 2002; WHO 2002, 2003). Starchy foods, such as potato-based products, typically 

contain the highest levels of acrylamide (Muttucumaru et al. 2008; Tareke et al. 2002; WHO 2003), 

whereas protein-based foods contain smaller amounts (Tareke et al. 2002). 

Tareke et al. (2002) analyzed acrylamide content of various heated foods. Acrylamide concentrations 

were determined by gas chromatography (GC)-MS and liquid chromatography (LC)-MS/MS. In heated 

protein-rich foods, acrylamide concentrations of 5–50 μg/kg were found. Carbohydrate-rich foods, such 

as potato, beetroot, potato products, and crispbread, contained much higher concentrations, ranging from 

150 to 4,000 μg/kg. The median acrylamide concentration in fried foods, including beef, chicken, 

soymeal, grated potatoes, boiled mashed potatoes, and grated beetroot were 17, 28, 16, 447, 172, and 

850 μg/kg, respectively. In microwave-heated grated potatoes, the median acrylamide concentration was 

found to be 551 μg/kg, while microwave-heated cod was less than the detection limit (<5 μg/kg). In 

restaurant-prepared or purchased foods, the median acrylamide concentrations for hamburger, French 

fries, potato crisps, and three types of crispbread were 18, 424, 1,739, and 208, respectively. Unheated 

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controls and boiled foods contained very little acrylamide, with all results being less than the detection 

limits for the methods (<5 μg/kg by GC-MS and <10 μg/kg by LC-MS/MS) (Tareke et al. 2002). 

Acrylamide concentrations were analyzed in food samples in Norway, Sweden, Switzerland, the United 

Kingdom, and the United States in various studies (Table 6-2). Almost all items analyzed contained some 

level of acrylamide. Of the food tested, chips and crisps contained the highest average concentrations, 

ranging from not detectable to 3.5 mg/kg (WHO 2002). 

Acrylamide concentrations were determined for various foods prepared using home cooking methods, 

including the use of a household oven and microwave oven. The data are presented in Tables 6-3 and 

6-4. The authors concluded that longer cooking times and higher temperatures appear to cause increased 

acrylamide concentrations in food (Sorgel et al. 2002). 

The acrylamide content of various carbohydrate-rich Brazilian foods was determined by LC-MS/MS. 

Samples were obtained from grocery stores, restaurants, and fast food restaurants in Campinas, Sao Paulo, 

Brazil between September 2004 and April 2006. The foods sampled included French fries, potato chips, 

bread, crispbread, crackers, breakfast cereals, coffee, beer, and other high carbohydrate foods typically 

processed at high temperatures. Of 111 samples from 19 product categories, acrylamide concentrations 

ranged from <20 to 2,528 mg/kg. Considerable differences in concentration existed between individual 

foods within the same product class. Potato chips, processed at high temperatures, and instant coffee had 

the highest concentrations of acrylamide, while cassava- and maize-based foods, bread, and beer were 

found to have the lowest levels. The detection limit and limit of quantification were 10 and 20 mg/kg, 

respectively (Arisseto et al. 2007). 

An ongoing U.S. Food and Drug Administration (FDA) survey collects acrylamide data on U.S. food 

products under the Total Diet Study (TDS). Data on approximately 280 core foods (or TDS foods) were 

collected to determine the nutrient and contaminant levels in the foods from each of the geographic 

regions in the United States (West, North Central, South, and Northeast). Food samples are collected 

from grocery stores and fast food restaurants from three cities in each region, prepared for consumption, 

and then analyzed (FDA 2009). The summary results for the 2003–2006 TDS data on acrylamide are 

presented in Table 6-5. Foods within certain food groups (i.e., grains/starches/baked goods) have been 

found to have very high levels of acrylamide. It should be noted that the high levels within the vegetable 

group were primarily due to potato chips and French fries. 

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Table 6-2. Acrylamide Levels in Different Food and Food Product Groups from
 

Norway, Sweden, Switzerland, the United Kingdom, and the United States
 

Acrylamide levels (μg/kg)a 

Food/product 

group Meanb Median2 

MinimumMaximum Number of 

Samples 

Crisps, potato/sweet 

potatoc 

1,312 1,343 170–2,287 38 

Chips, potatod 537 330 <50–3,500 39 

Batter based 36 36 <30–42 2 

products 

Bakery products 112 <50 <50–450 19 

Biscuits, crackers, 423 142 <30–3,200 58 

toast, bread crisps 

Breakfast cereals 298 150 <30–1346 29 

Crisps, corn 218 167 34–416 7 

Bread, soft 50 30 <30–162 41 

Fish and seafood 35 35 30–39 4 

products, crumbled, 

battered 

Poultry or game, 52 52 39–64 2 

crumbed, battered 

Instant malt drinks 50 50 <50–70 3 

Chocolate powder 75 75 <50–100 2 

Coffee powder 200 200 170–230 3 

Beer <30 <30 <30 1 

a

The limits of detection and quantification varied among laboratories; values reported as less than a value are below
 

the limit reported by the laboratory.

b

Mean and median values were calculated where individual data were available; sample sizes were extremely small,
 

particularly for some food categories; where the mean and median are different, it reflects the skewed distribution of
 

the underlying data that were collected in different countries and may represent different food items within the larger
 

category.
 c

Products that are thinly sliced and fried (such as potato chips). d

Products that are more thickly sliced (such as French fries).
 

Source: WHO 2002 

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Table 6-3. Acrylamide in Potato Products 

Acrylamide 

Cooking Cooking time concentration 

Sample Size (mm) temperature (°C) (minutes) (μg/kg) 

Potato chips 3 180 2 2,557.9 

3 140 2 36.3 

3 180 4 7,678.3 

3 140 4 53.3 

1 180 1 121.1 

1 140 2 20.0 

1 180 3 9,670.2 

1 140 4 35.3 

French fries 5 180 2 1,716.9 

5 160 2 53.8 

5 140 2 11 

5 180 4 2,687.0 

5 160 4 1,049.5 

5 140 4 77.0 

10 180 2 674.2 

10 160 2 <8 

10 140 2 <8 

10 180 4 1,084.3 

10 160 4 87.3 

10 140 4 10.0 

13 180 4 476.2 

13 140 2 <8 

13 180 6 880.0 

13 140 4 <8 

Source: Sorgel et al. 2002 

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Table 6-4. Acrylamide Content of Food 

Acrylamide 

Cooking time concentration 

Sample Description Cooking method (minutes) (μg/kg) 

Walnuts Roasted <8 

Pine seeds Roasted 16.4 

Candied chestnuts Baked 8.3 

Crème carmel Boiled <8 

Whiskey <8 

Liver of beef Baked <8 

Breaded fish Baked <8 

Goose skin Oven <8 

Goose meat Oven <8 

Gingerbread Lightly baked 200 °C 12.1 

Gingerbread Dark baked 200 °C 113.0 

Gingerbread 180.7 

Gingerbread balls 639.5 

Spiced cookies 143.6 

Popcorn Microwave, 800 W 1 29.7 

Popcorn Microwave, 600 W 2 50.0 

Popcorn Microwave, 800 W 2 132.8 

Popcorn Microwave, 600 W 3 250.3 

Popcorn Microwave, 600 W 4 307.1 

Croquettes 180 °C 2 354.7 

Croquettes 180 °C 4 453.4 

Hash browns 180 °C 2 446.1 

Hash browns 180 °C 4 751.7 

Fried potatoes 543.1 

Croutons Baked 27.9 

Bread crust 370.6 

Toast Toasted 54.1 

Source: Sorgel et al. 2002 

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Table 6-5. Acrylamide Levels in Food Products Sampled for the 2003–2006 Total 

Diet Studies (TDS) Summary
 

TDS food Acrylamide range Acrylamide range Acrylamide range Acrylamide range 

category (ppb) for 2003 (ppb) for 2004 (ppb) for 2005 (ppb) for 2006 

Dairy ND–16 ND ND–16 ND–18 

Eggs ND No data ND No data 

Baby food ND–267 ND–407 ND–442 ND–381 

Meat/poultry/fish ND–26 ND–27 ND–30 ND–19 

Legumes ND–93 ND–93 ND–84 ND–54 

Grains/starches/ ND–647 ND–946 ND–616 ND–470 

baked goods 

Fruits ND–202 109–355a ND–250 326a 

Vegetables ND–536b ND-829b ND–529 ND–393 

Mixtures (e.g., ND–187 ND–210 ND–93 ND–55 

casseroles, 

sandwiches, soups, 

pizza) 

Candy/sweets/ ND–29 ND–42 13–50 17–32 

Sugars/syrups 

Fats/oils ND No data No data No data 

Beverages ND–12 ND–21 ND–28 ND 

a

Only bottle prune juice was included in this category for 2004 and 2006.

b

The highest levels in the vegetable category are for potato chips and French fries; the majority of the vegetables
 

had low or non-detectable levels.
 

ND = Not detected 

Source: U.S. Food and Drug Administration 2006 

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Temperature, water content, food thickness, and length of heating appear to be important factors affecting 

the amount of acrylamide that is formed while cooking foods (Sorgel et al. 2002; WHO 2002, 2003). 

Reversing these factors could help minimize acrylamide formation (e.g., heating to <180 °C, making 

products very thick, etc.) (Sorgel et al. 2002). In many countries, food manufacturers have been 

requested to take steps to decrease the formation of acrylamide in their products, which has become an 

important area of research (Amrein et al. 2007). 

With potato products, controlling reducing sugars, processing temperature, and moisture content can help 

limit formation of acrylamide (Amrein et al. 2007). It is thought that the amount of asparagine is also an 

important factor in acrylamide formation in potatoes (Muttucumaru et al. 2008). With bakery products, 

the amount of free asparagines as well as the type of baking agent can affect acrylamide concentration. 

Replacing the baking agent NH4HCO3, for example, with NaHCO3 in sweet bakery products can help 

reduce acrylamide content. In almonds, temperature and free asparagine content are thought to affect the 

amount of acrylamide formed during roasting. High concentrations of acrylamide can form during 

heating of olives and dried fruit (Amrein et al. 2007). Additional research is needed to determine the 

acrylamide reduction strategies for each type of food. 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Acrylamide is a probable or confirmed carcinogen with the potential to cause nervous system damage, 

weakness, and incoordination of the legs following short-term exposure to high levels. Long-term effects 

of acrylamide include nervous system damage, paralysis, and cancer (Arisetto et al. 2007; EPA 2006c; 

Lewis 2000). Exposure can occur via ingestion, dermal contact, inhalation, and intraperitoneal routes 

(Lewis 2000; Sorgel et al. 2002). Once in the body, acrylamide is widely dispersed by body fluids. It can 

also cross the placental barrier (WHO 2003). 

Exposure to high levels of acrylamide can result from ingestion of various foodstuffs. Acrylamide is 

produced when certain foods are cooked at high temperatures (Tareke et al. 2002). Concentrations of 

acrylamide in food vary with the type of food and method of processing and cooking, and typically 

increase with temperature and length of heating (Sorgel et al. 2002; WHO 2002, 2003). Foodstuffs, 

particularly those rich in carbohydrates, may develop high levels of acrylamide when cooked at high 

temperatures (Moreno Navarro et al. 2007). Potato products, including chips and other potatoes cooked at 

high temperatures, may comprise a large percentage of the total acrylamide intake from food. However, 

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foods with lower acrylamide content but eaten at a higher frequency, such as bread, may contribute 

significantly to the total exposure from foods (WHO 2002). 

Food was found to contribute significantly to the overall exposure of the general population to 

acrylamide. Short-term dietary intake of acrylamide was estimated using Monte Carlo techniques based 

on data from The Netherlands, United States, and Sweden. The short-term exposure estimates ranged 

from 0.8 to 6.0 μg/kg-bw/day for the average consumer to the 98th percentile consumer (WHO 2002). 

Average estimated long-term intake of acrylamide from food sources was determined based on data from 

Australia, Norway, The Netherlands, Sweden, and the United States, as well as data from the International 

Agency for Research on Cancer (IARC). Long-term intake estimates ranged from 0.3 to 0.8 μg/kgbw/day (WHO 2002, 2003). Tareke et al. (2002) concluded that the acrylamide levels found in heated 

foods could result in a daily acrylamide intake of a few tens of micrograms. 

Due to the presence of acrylamide in tobacco smoke (EU 2002; Schumacher et al. 1977), the general 

population can be exposed to acrylamide via inhalation (Moreno Navarro et al. 2007). This may include 

second-hand smoke, and is thought to be a significant source of exposure for the general population 

(WHO 2002). Due to its low vapor pressure and high water solubility, acrylamide is not anticipated to be 

a common air contaminant (WHO 2003), and thus, inhalation exposure is likely limited to tobacco smoke 

exposure. 

Nonfood exposure to acrylamide is thought to be low for nonsmokers. Exposure can result from 

ingestion of polyacrylamide-treated drinking water containing residual monomer (EPA 2006c; EU 2002; 

WHO 2003), and from water in contact with acrylamide-containing products (e.g., grouting agents in 

dams) (Sorgel et al. 2002, van Dijk-Looijaard and van Genderen 2000). The MCL for acrylamide in 

drinking water, which specifies the concentration at which it is not expected to cause health problems, is 

zero (EPA 2006c). Dermal exposure can result from contact with cosmetics and toiletries containing 

polyacrylamides (EU 2002). 

Acrylamide and its metabolite, glycidamide, can react with biomolecules such as hemoglobin. 

Concentrations of adducts in the blood relevant to dietary exposure can be determined, and thus, the 

adducts can be used as biomarkers to determine a time-averaged estimate of acrylamide exposure. 

Urinary biomarker use may also be possible (WHO 2002). 

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Occupational exposure occurs mainly through dermal contact of acrylamide from solution, followed by 

inhalation of dry monomer or aerosols of solution during manufacture of acrylamide and polyacrylamide 

as well as during acrylamide grouting or preparation of polyacrylamide gels in the laboratory. Ingestion 

is a minimal concern in the workplace (EU 2002; Lewis 2000). A unique danger of acrylamide is its 

ability to be absorbed through unbroken skin (Lewis 2000). In the workplace, handling of dry 

acrylamide, such as emptying bags and drums, results in an inhalation and dermal hazard from dust 

(Haberman 2002). 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

Acrylamide exposure to children can occur via ingestion and inhalation. Food was found to contribute 

significantly to the overall exposure of the general population to acrylamide. The short-term exposure 

estimates ranged from 0.8 to 6.0 μg/kg bw/day, while the estimated long-term intake of acrylamide from 

food sources ranged from 0.3 to 0.8 μg/kg bw/day for adults. Exposure in children is expected to be 2– 

3 times that of adults on a body weight basis (WHO 2002, 2003). Children can also be exposed to 

acrylamide via inhalation of second-hand smoke (Moreno Navarro et al. 2007; WHO 2002). 

In the body, acrylamide is widely dispersed by body fluids, and can also cross the placental barrier, 

exposing the fetus to high levels of acrylamide (Sorgel et al. 2002, WHO 2003). Fetuses and newborns 

do not have a fully developed blood-brain barrier, and thus, women who consume large amounts of 

acrylamide-containing foods risk significant acrylamide transfer to the fetus. Postnatally, acrylamide can 

be transferred via breast milk. According to Sorgel et al. (2002), when mothers consume foods with high 

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acrylamide concentrations, daily consumption of 500 mL of breast milk can result in up to 10 μg of 

acrylamide transferred to the baby. Women who eat lesser amounts of acrylamide-containing foods, such 

as potato chips, may still transfer 2 μg of acrylamide to the baby. For these two scenarios, the doses for a 

3 kg infant would be 3.3 and 0.66 μg/kg, respectively (Sorgel et al. 2002). 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

In addition to the individuals who are occupationally exposed to acrylamide (see Section 6.5), there are 

several groups within the general population that may receive potentially high exposures (higher than 

background levels) to acrylamide. These populations include individuals living in proximity to sites 

where acrylamide is produced or used in manufacturing or sites where acrylamide is disposed, and 

includes individuals living near the three NPL hazardous waste sites where acrylamide has been detected 

in some environmental media (HazDat 2007). Smokers and those breathing second-hand smoke are 

subject to high acrylamide exposures (Moreno Navarro et al. 2007). Children of mothers whose diets are 

high in acrylamide-containing foods can be exposed to high amounts of acrylamide through breast milk 

(Sorgel et al. 2002). 

6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of acrylamide is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of acrylamide. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

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6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of acrylamide are well 

understood and have been discussed in Chapter 4 (Table 4-2). There are no data needs. 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency Planning 

and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit 

substance release and off-site transfer information to the EPA. The TRI, which contains this information 

for 2007, became available in February of 2009. This database is updated yearly and should provide a list 

of industrial production facilities and emissions. 

Methods of manufacturing, production volumes, and uses of acrylamide are available and have been 

discussed in Chapter 5. Demand and import/export volumes are also available. No data needs are 

identified. 

Environmental Fate. The environmental fate of acrylamide is reasonably well understood. If released 

to the environment, acrylamide has a low potential to volatilize to air from water or soil surfaces; 

however, its low soil adsorption coefficient suggests that it has potential to leach into groundwater. 

Acrylamide appears to degrade fairly rapidly by biological processes in both soil (Abdelmagid 1982) and 

water (Cherry et al. 1956; Croll et al. 1974). If released to air, acrylamide is expected to degrade through 

reaction with photochemically generated hydroxyl radicals and ozone molecules. No data needs are 

identified. 

Bioavailability from Environmental Media. No data exist regarding acrylamide’s bioavailability 

from environmental media such as soil or drinking water. Acrylamide is produced when certain foods are 

cooked at high temperatures (Tareke et al. 2002). Foodstuffs, particularly those rich in carbohydrates, 

may develop high levels of acrylamide when cooked at high temperatures (Moreno Navarro et al. 2007). 

Food Chain Bioaccumulation. Acrylamide is not expected to significantly bioconcentrate due to its 

high water solubility and its ability to be degraded by microorganisms (EPA 2006c; Haberman 2002; 

WHO 2003). Therefore, bioaccumulation through the food chain is expected to be low. No data needs 

are identified. 

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Exposure Levels in Environmental Media. Reliable monitoring data for the levels of acrylamide in 

contaminated media at hazardous waste sites are needed so that the information obtained on levels of 

acrylamide in the environment can be used in combination with the known body burden of acrylamide to 

assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste 

sites. 

Exposure Levels in Humans. Acrylamide was found to be present in various foods at high 

concentrations (Tareke et al. 2002). In order to better characterize the degree of exposure from food 

sources, further information is necessary to determine the background levels of acrylamide in both the 

environment and in humans. Additional information concerning methods to decrease acrylamide content 

in foods, and thus decrease exposure, is needed. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. Children are exposed to acrylamide by the same routes as adults. Food was 

found to contribute to high levels of exposure in children, possibly 2–3 times that of an adult (WHO 

2002, 2003). Inhalation of second-hand smoke can also result in exposure (Moreno Navarro et al. 2007; 

WHO 2002). Acrylamide has been detected in breast milk, which can result in significant exposure to 

infants (Sorgel et al. 2002). Additional data would be useful to determine the exposures of children to 

acrylamide via these methods. 

Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data 

Needs: Children’s Susceptibility. 

Exposure Registries. No exposure registries for acrylamide were located. This substance is not 

currently one of the compounds for which a sub-registry has been established in the National Exposure 

Registry. The substance will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates 

the epidemiological research needed to assess adverse health outcomes that may be related to exposure to 

this substance. 

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6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2009) database provides additional information obtainable 

from a few ongoing studies that may fill data needs identified in Section 6.8.1. Titles for these studies are 

listed in Table 6-6. 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-6. Ongoing Research Regarding the Environmental Fate and Exposure to 

Acrylamide
 

Investigator Affiliation Description Sponsor 

Lehotay SJ, 

Handel A 

Drexel University Development of new methods to detect and control 

acrylamide formation in deep-fat fried foods 

USDA 

Chen H University of Delaware Improvement of thermal and alternative processes for 

foods 

USDA 

Calder BL, 

Perkins LB, 

Bushway AA, 

et al. 

University of Maine Improving the post-harvest quality of fresh-cut and 

processed Maine potatoes 

USDA 

Daley LS Oregon State University Regulation of photosynthetic processes USDA 

USDA = U.S. Department of Agriculture 

Source: FEDRIP 2009 

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ACRYLAMIDE 177 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring acrylamide, its metabolites, and other biomarkers of exposure and effect to 

acrylamide. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is 

to identify well-established methods that are used as the standard methods of analysis. Many of the 

analytical methods used for environmental samples are the methods approved by federal agencies and 

organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other 

methods presented in this chapter are those that are approved by groups such as the Association of 

Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). 

Additionally, analytical methods are included that modify previously used methods to obtain lower 

detection limits and/or to improve accuracy and precision. 

7.1 BIOLOGICAL MATERIALS 

Methods for the detection of acrylamide in biological materials are summarized in Table 7-1. Acrylamide 

can be detected in biological samples using gas chromatography (GC) with electron-capture detection. 

Acrylamide is converted to its 2,3-dibromopropionamide derivation in aqueous solution, plasma, or tissue 

homogenates by ionic bromination. The limits of detection for this method correspond to 9.5x10-12 g of 

acrylamide on the column or 8.4x10-9 g in the final biological extract of 0.5 mL. Acrylamide recovery by 

this method exceeds 80% at nanogram levels (HSDB 2009). 

A liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay was developed to examine 

unchanged acrylamide concentrations in bodily fluids, specifically urine, breast milk, and placental 

perfusion medium. A bioanalytical method was developed to analyze acrylamide in bodily fluids using 

LC-MS/MS following liquid/liquid extraction of acrylamide and evaporation under a stream of N2 at 

35 °C. A reversed-phase column eluted with an isocratic solvent system consisting of water, acetic acid, 

and an organic modifier was used for chromatographic separation. Method detection limits were 1 ng/mL 

for urine, 2 ng/mL for placenta perfusate, and 5 ng/mL for breast milk (Sorgel et al. 2002). 

GC-MS methods have been used to determine the adducts of acrylamide and its metabolites (such as 

glycidamide) with hemoglobin in blood samples. These methods are sensitive enough to measure adducts 

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Table 7-1. Analytical Methods for Determining Acrylamide in Biological Samples 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection 

limit 

Percent 

recovery Reference 

Urine Liquid/liquid extraction, 

evaporation under N2 

stream at 35 °C 

LC-MS/MS 1 ng/mL Sorgel et al. 2002 

Breast milk Liquid/liquid extraction, 

evaporation under N2 

stream at 35 °C 

LC-MS/MS 5 ng/mL Sorgel et al. 2002 

Placental 

perfusion 

medium 

Liquid/liquid extraction, 

evaporation under N2 

stream at 35 °C 

LC-MS/MS 2 ng/mL Sorgel et al. 2002 

Biological 

samples 

Ionic bromination of 

acrylamide in sample 

GC with 

electroncapture 

device 

Corresponds 

to 9.5x10-12 g 

acrylamide 

(column), 

8.4x10-9 g 

(extract) 

HSDB 2009 

GC = gas chromatography; LC = liquid chromatography; MS = mass spectrometry 

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at blood levels relevant to potential dietary acrylamide exposure, which allows for use of the adducts as 

biomarkers of exposure (WHO 2002, 2003). A more recent method of detection for hemoglobin adducts 

of acrylamide utilizes LC-MS/MS (Fennell et al. 2003). 

Acrylamide and glycidamide were measured in serum and tissues of mice following dosing by 

intravenous, gavage, and dietary routes at 0.1 mg/kg acrylamide and by intravenous and gavage routes at 

equimolar amounts of glycidamide. LC-electrospray (ES)/MS/MS was utilized to measure acrylamide 

and glycidamide in serum and tissues with recoveries of 70% for acrylamide and 63% for glycidamide. 

The limit of detection was below 0.1 pmol/mg tissue for both acrylamide and glycidamide (Doerge et al. 

2005b). Doerge et al. (2005a) detected DNA adducts derived from administration of acrylamide and 

glycidamide to mice and rats. A single intraperitoneal injection containing an aqueous solution of 100 μL 

of 50 mg/kg acrylamide or 61 mg/kg glycamide was given to the mice. Rats were treated with a single 

intraperitoneal injection of the same concentration using a volume of 100 μL per 100 g body weight. Six 

hours after dosing, the tissues were removed following gassing by carbon dioxide. Tissues were frozen 

and stored at -80 °C. DNA adducts were analyzed using a Quattro Ultima triple stage guadrupole mass 

spectrometer with an electrospray source, with an ion source temperature of 120 °C, desolvation gas 

temperature of 400 °C, and constant cone voltage of 35 V. DNA was isolated using a Blood and Cell 

Culture Maxi kit and adducts were quantified using LC-/MS/MS. The limit of quantification ranged from 

1 to 1.5 adducts in 108 nucleotides and the limit of detection was 0.5 adducts in 108 nucleotides (Doerge et 

al. 2005a). 

7.2 ENVIRONMENTAL SAMPLES 

Methods for the detection of acrylamide in environmental samples are summarized in Table 7-2. 

Acrylamide detection in water samples can be achieved using direct injection and a reversed-phase high 

performance liquid chromatography (HPLC)-ultraviolet (UV) absorption procedure, which has a limit of 

detection of 5 μg/L (Cavalli et al. 2004). An HPLC method can be used to determine the amount of 

acrylamide monomer in natural and polluted aqueous environments. Acrylamide undergoes bromination 

and the resulting dibromopropionamide is assayed. The detection limit for the method was found to be 

0.2 μg/L in river, sea, and estuarine waters as well as potable waters, sewage, and china clay works 

effluents (HSDB 2009). 

Solid phase extraction, extraction with activated carbon filter, and GC-MS analyses can also be used 

(Cavalli et al. 2004). A water sample is brominated to form 2,3-dibromopropionamide, which is then 

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Table 7-2. Analytical Methods for Determining Acrylamide in Environmental
 

Samples
 

Sample matrix 

Preparation 

method 

Analytical 

method 

Sample 

detection limit 

Percent 

recovery Reference 

Water Direct injection Reversed-phase 

HPLC-UV 

5 μg/L Cavalli et al. 

2004 

absorption 

Natural and 

polluted water 

Bromination of 

acrylamide in 

sample 

HPLC 0.20 μg/L HSDB 2009 

Organic-free 

reagent water 

HPLC 10 μg/L HSDB 2009 

Aqueous 

matrices 

GC 0.032 μg/L HSDB 2009 

Drinking water Direct injection 

of 500 μL 

Ion-exclusion 

chromatographic 

separation/MS 

0.20 ppb Cavalli et al. 

2004 

Airborne dust, 

vapors 

Differential pulse 

polarographic 

method 

HSDB 2009 

Food Water extract 

food, brominates 

sample 

GC-MS 5–10 μg/kg WHO 2002 

Food Bromination of 

sample 

GC-MS 5 μg/kg Tareke et al. 

2002 

Food Water extract 

food 

LC-MS/MS 20–50 μg/kg WHO 2002 

Food LC-MS/MS 10 μg/kg Tareke et al. 

2002 

Food LC-MS/MS 10 μg/kg 100–115% Arisseto et al. 

2007 

GC = gas chromatography; HPLC = high performance liquid chromatography; LC = liquid chromatography; MS = 

mass spectrometry; SIM = selected ion monitoring; UV = ultraviolet 

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analyzed by GC-MS using methacrylamide as an internal standard (Ahn et al. 2002). Additional methods 

include polarography and electron capture GC (WHO 2003). EPA-OSW 8316 method determines 

acrylamide concentrations by HPLC in organic-free reagent water, with a limit of detection of 10 μg/L. 

The EPA-OSW 8032A method analyzes acrylamide in aqueous matrices using GC, with a detection limit 

of 0.032 μg/L (HSDB 2009). 

Cavalli et al. (2004) utilized a method for detecting acrylamide in drinking water using a combination of 

ion-exclusion chromatographic separation and MS detection. Drinking water samples are injected 

directly into the microbore ICE-AS1 column and are then detected in the selected-ion monitoring mode 

by a single quadrupole system with electrospray ionization. The detection limit for the method was 

determined to be 0.20 ppb with an injection volume of 500 μL (Cavalli et al. 2004). 

Airborne acrylamide vapors and dust can be determined in air by a differential pulse polarographic 

method (HSDB 2009). Two additional methods of detection in air were found (called Method 21 and 

OSHA PV2004), though only very limited details were provided (HSDB 2009). 

Various methods are available to determine the acrylamide content of food. The most common methods 

utilize either GC-MS or LC-MS/MS (Ahn et al. 2002; Arisseto et al. 2007). Water is often used as the 

extraction solvent. Solid-phase extraction (SPE) is typically use to prepare samples. SPE phases that 

have been used for this method include graphitized carbon black, mixed mode anion and cation exchange, 

and polymeric materials (Arisseto et al. 2007) 

The GC-MS method of determining acrylamide content in food is well established. A water extract of the 

food is brominated to form 2,3-dibromopropionamide, a derivative of acrylamide with enhanced GC 

properties. The derivative is then analyzed by GC-MS using methacrylamide as an internal standard (Ahn 

et al. 2002; WHO 2002). Detection limits for the GC-MS method are typically in the 5–10 μg/kg range 

(WHO 2002). Tareke et al. (2002) analyzed food samples for acrylamide using an improved GC-MS 

method involving bromination. A detection limit of 5 μg/kg was achieved. 

The LC-MS/MS method was developed over concerns that artifacts were forming during the bromination 

procedure used with the GC-MS method. LC-MS/MS allows for direct acrylamide analysis without the 

need for a derivative (WHO 2002). In this method, a water extract of food is tested by LC-MS/MS using 

deuterated acrylamide as an internal standard (Ahn et al. 2002). Acrylamide is then identified by its 

retention time and the relative ion intensities. WHO (2002) reports that the detection limits of this 

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method are typically 20–50 μg/kg, although lower detection limits have since been obtained for this 

method. 

Tareke et al. (2002) also utilized the LC-MS/MS method to determine underivitized acrylamide 

concentrations. This method had a detection limit of 10 μg/kg. Sorgel et al. (2002) used a modified LCMS/MS method, similar to that developed for analysis of acrylamide in bodily fluids, to determine 

acrylamide content in food. Brazilian foods were analyzed by LC-MS/MS to determine acrylamide 

content (Arisseto et al. 2007). Detection limits of 10 μg/kg were achieved, along with a limit of 

quantification of 20 μg/kg and mean recoveries ranging from 100 to 115%. 

7.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of acrylamide is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of acrylamide. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. Exposure to acrylamide can be determined directly by LC-MS/MS for biological samples, 

including urine, breast milk, and placental perfusion medium with detection limits of 1, 5, and 2 ng/mL, 

respectively (Sorgel et al. 2002). GC-MS methods are also used to detect the adducts of acrylamide and 

its metabolites in blood and tissue samples (HSDB 2009; WHO 2002, 2003). Methods are described in 

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Table 7-1. Additional methods for the detection of acrylamide and its metabolites in biological samples 

would be helpful. 

Effect. Information on biomarkers of effect for acrylamide would be useful. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. There are several variations on methods for identifying acrylamide in water, air, and food. The 

methods are summarized in Table 7-2. The methods for water, primarily involving the use of HPLC and 

GC are fairly sensitive (e.g., ~0.03-10 μg/L for water (Cavalli et al. 2004; HSDB 2009). In air, a 

differential pulse polarographic method was identified, although limited details were provided (HSDB 

2009). Additional information concerning the detection of acrylamide in air, including detection limits, 

would be useful. Various methods are available to determine acrylamide content of food using primarily 

GC-MS or LC-MS/MS (Ahn et al. 2002; Arisseto et al. 2007). GC-MS involved bromination, while LCMS/MS can determine acrylamide content directly. Detection limits for GC-MS methods typically range 

from 5 to 10 μg/kg, while limits of detection for the LC-MS/MS method are typically in the range of 10– 

50 μg/kg (Tareke et al. 2002; WHO 2002). More sensitive methods for direct determination of 

acrylamide in food via the LC-MS/MS method would use useful. 

7.3.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2009) database contains a study sponsored by the U.S. 

Department of Agriculture in which new methods are being developed for detecting and controlling 

acrylamide formation in deep-fat fried foods. 

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MRLs are substance specific estimates, which are intended to serve as screening levels, are used by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. 

ATSDR has derived an acute-duration oral MRL of 0.02 mg/kg/day for acrylamide based on benchmark 

dose (BMD) analysis of results of fertility testing of male F344 rats administered acrylamide by gavage 

for 5 days prior to 1-week mating sessions with untreated female rats (Sublet et al. 1989). The resulting 

BMDL10 of 1.78 mg/kg/day was divided by an uncertainty factor of 100 (10 for extrapolation from 

animals to humans and 10 for human variability). See Appendix A for details regarding BMD analysis. 

ATSDR has derived an intermediate-duration oral MRL of 0.002 mg/kg/day for acrylamide based on a 

NOAEL of 0.2 mg/kg/day and a LOAEL of 1 mg/kg/day for ultrastructural changes in peripheral nerve 

fibers in male F344 rats receiving acrylamide from the drinking water for up to 93 days (Burek et al. 

1980). The NOAEL of 0.2 was divided by an uncertainty factor of 100 (10 for extrapolation from 

animals to humans and 10 for human variability). 

EPA (IRIS 2009) has established an oral reference dose (RfD) for acrylamide of 2x10-4 mg/kg/day based 

on a no-observed-effect-level (NOEL) of 0.2 mg/kg/day for nerve damage in male and female Fischer 344 

rats exposed to acrylamide in the drinking water for 90 days (Burek et al. 1980). The uncertainty factor 

used in this assessment was 1,000 (10 for interspecies extrapolation, 10 for the protection of sensitive 

human subpopulations, and 10 for the uncertainty in the effect of duration when extrapolating from 

subchronic to chronic exposure). 

EPA (IRIS 2009) has not derived an inhalation reference concentration (RfC) for acrylamide. 

The International Agency for Research on Cancer (IARC) has classified acrylamide as a Group 2A 

carcinogen (probably carcinogenic to humans) (IARC 2009). The National Toxicology Program (NTP) 

has determined that acrylamide is reasonably anticipated to be a human carcinogen (NTP 2005). 

EPA has classified acrylamide as a B2 carcinogen (probable human carcinogen) (IRIS 2009). The 

American Conference of Governmental Industrial Hygienists (ACGIH) has classified acrylamide as an 

A3 carcinogen (confirmed animal carcinogen with unknown relevance to humans) (ACGIH 2008). 

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OSHA has required employers of workers who are occupationally exposed to acrylamide to institute 

engineering controls and work practices to reduce and maintain employee exposure at or below 

permissible exposure limits (PELs) (OSHA 2009). The employer must use engineering and work practice 

controls to reduce exposures to not exceed 0.3 mg/m3 for acrylamide at any time (OSHA 2009). 

EPA has designated acrylamide as a hazardous air pollutant (HAP) under the Clean Air Act (CAA) (EPA 

2009a). Acrylamide is on the list of chemicals appearing in “Toxic Chemicals Subject to Section 313 of 

the Emergency Planning and Community Right-to-Know Act of 1986" and has been assigned a reportable 

quantity (RQ) limit of 5,000 pounds (EPA 2009b). Acrylamide is also considered to be an extremely 

hazardous substance (EPA 2009c). The RQ represents the amount of a designated hazardous substance 

which, when released to the environment, must be reported to the appropriate authority. 

The international and national regulations, advisories, and guidelines regarding acrylamide in air, water, 

and other media are summarized in Table 8-1. 

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Table 8-1. Regulations and Guidelines Applicable to Acrylamide 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification Group 2Aa IARC 2009 

WHO Air quality guidelines 

Drinking water quality guidelines 

No 

0.0005 mg/Lb 

WHO 2000 

WHO 2006 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA)c,d 0.03 mg/m3 ACGIH 2008 

TLV-basis (critical effect) Central nervous 

system impairment 

AIHA ERPG values No AIHA 2008 

EPA Hazardous air pollutant Yes EPA 2009a 

42 USC 7412 

NIOSH 

Second AEGL Chemical Priority List 

REL (10-hour TWA)f 

IDLH 

Yese 

0.03 mg/m3 

60 mg/m3 

EPA 2008 

NIOSH 2005 

Potential occupational carcinogen Yes 

OSHA 

Target organs 

PEL (8-hour TWA) for general industryf 

Eyes, skin, central 

nervous system, 

peripheral nervous 

system, and 

reproductive system 

0.3 mg/m3 OSHA 2009 

29 CFR 1910.1000, 

Table Z-1 

b. Water 

EPA Drinking water standards and health 

advisories 

EPA 2006a 

1-day health advisory for a 10-kg 

child 

1.5 mg/L 

10-day health advisory for a 10-kg 

child 

0.3 mg/L 

DWEL 0.007 mg/L 

Lifetime No data 

10-4 Cancer risk 0.0008 mg/L 

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Table 8-1. Regulations and Guidelines Applicable to Acrylamide 

Agency Description	 Information Reference 

NATIONAL (cont.) 

EPA National primary drinking water EPA 2003 

standards 

Treatment technique Yesg 

Potential health effects from Nervous system or 

exposure above the MCL blood problems 

Common sources of acrylamide in Added to water during 

drinking water sewage/waste water 

treatment; increased 

risk of cancer 

treatment 

Public health goal Zero 

National recommended water quality No EPA 2006b 

criteria 

c. Food 

FDA EAFUSh No FDA 2008 

d. Other 

ACGIH Carcinogenicity classification A3i ACGIH 2008 

EPA Carcinogenicity classification B2j IRIS 2009 

RfC Value not estimatedk 

RfD 2x10-4 mg/kg/day 

Inhalation unit risk 1.3x10-3 (μg/m3)

-1 

Oral slope factor 4.5 (mg/kg/day)-1 

Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous Yesl EPA 2009b 

substance 40 CFR 302.4 

Reportable quantity 5,000 pounds 

Effective date of toxic chemical 01/01/1987 EPA 2009d 

release reporting 40 CFR 372.65 

Extremely hazardous substances 1,000/10,000 pounds EPA 2009c 

and its threshold planning quantity	 40 CFR 355, 

Appendix A 

TSCA health and safety data reporting EPA 2009e 

Effective date 40 CFR 716.120 10/04/1982 

Sunset date 10/04/1992 

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8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Acrylamide 

Agency Description Information Reference 

NATIONAL (cont.) 

NTP Carcinogenicity classification Reasonably NTP 2005 

anticipated to be a 

human carcinogen 

a

Group 2A: probably carcinogenic to humans b

For substances that are considered to be carcinogenic, the guideline value is the concentration in drinking-water 

associated with an upper-bound excess lifetime cancer risk of 10-5 (one additional cancer per 100,000 of the 

population ingesting drinking-water containing the substance at the guideline value for 70 years) (WHO 2006). c

TWA: inhalable fraction and vapor. Material exerts sufficient vapor pressure such that it may be present in both 

particle and vapor phases.

d

Skin: refers to the potential significant contribution to the overall exposure by the cutaneous route. 

e

Acryalmide is included on the list of 371 priority chemicals that are acutely toxic and represent the selection of 

chemicals for AEGL development by the NAC/AEGL committee during the next several years.

f

Skin designation 

g

Each water system must certify, in writing, to the state (using third-party or manufacturers certification) that when it 

uses acrylamide to treat water, the combination (or product) of dose and monomer level does not exceed 0.05% of 

acrylamide dosed at 1 mg/L (or equivalent).

h

The EAFUS list of substances contains ingredients added directly to food that FDA has either approved as food 

additives or listed or affirmed as GRAS. 

i

A3: confirmed animal carcinogen with unknown relevance to humans. 

j

B2: probable human carcinogen, based on sufficient evidence of carcinogenicity in animals 

k

The health effects data for acrylamide were reviewed by the U.S. EPA RfD/RfC Work Group and determined to be 

inadequate for derivation of an inhalation RfC.

l

Designated CERCLA hazardous substance pursuant to Section 112 of the Clean Air Act and Section 3001 of the 

Resource Conservation and Recovery Act. 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline levels; 

AIHA = American Industrial Hygiene Association; CERCLA = Comprehensive Environmental Response, 

Compensation, and Liability Act; CFR = Code of Federal Regulations; DWEL = drinking water equivalent level; 

EAFUS = Everything Added to Food in the United States; EPA = Environmental Protection Agency; 

ERPG = emergency response planning guidelines; FDA = Food and Drug Administration; GRAS = Generally 

Recognized As Safe; IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or 

health; IRIS = Integrated Risk Information System; MCL = maximum contaminant level; NAC = National Advisory 

Committee; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; 

OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit; REL = recommended 

exposure limit; RfC = inhalation reference concentration; RfD = oral reference dose; TLV = threshold limit values; 

TSCA = Toxic Substances Control Act; TWA = time-weighted average; USC = United States Code; WHO = World 

Health Organization 

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ACRYLAMIDE 191 

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Youssef AF, Santi BW. 1997. Simple neurobehavioral functional observational battery and objective 

gait analysis validation by the use of acrylamide and methanol with a built-in recovery period. Environ 

Res 73(1-2):52-62. 

Youssif MI, Ismail AA, Fayed MA, et al. 1995. Effect of acrylamide on the central nervous system of 

rats histochemical and histopathological studies. J Med Res Inst 16(4):1-17. 

Yu S, Son F, Yu J, et al. 2006. Acrylamide alters cytoskeletal protein level in rat sciatic nerves. 

Neurochem Res 31(10):1197-1204. 

Yuan Y, Chen F, Zhao GH, et al. 2007. A comparative study of acrylamide formation induced by 

microwave and conventional heating methods. J Food Sci 72(4):C212-C216. 

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*Zeiger, E. Anderson, B, Haworth, S, et al. 1987. Salmonella mutagenicity tests. III. Results from the 

testing of 255 chemicals. Environ Mutatagen 9(Suppl 9):1-110. 

*Zeiger E, Recio L, Fennell TR, et al. 2009. Investigation of the low-dose response in the in vivo 

induction of micronuclei and adducts by acrylamide. Toxicol Sci 107(1):247-257. 

+*Zenick H, Hope E, Smith MK. 1986. Reproductive toxicity associated with acrylamide treatment in 

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Zhang X, Jiang L, Geng C, et al. 2008. Inhibition of acrylamide genotoxicity in human liver-derived 

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*Zhu YJ, Zeng T, Zhu YB, et al. 2008. Effects of acrylamide on the nervous tissue antioxidant system 

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*Ziegler EE, Edwards BB, Jensen RL, et al. 1978. Absorption and retention of lead by infants. Pediatr 

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ACRYLAMIDE 241 

10. GLOSSARY
 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 

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ACRYLAMIDE 242 

10. GLOSSARY 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 

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ACRYLAMIDE 243 

10. GLOSSARY 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

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ACRYLAMIDE 244 

10. GLOSSARY 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

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ACRYLAMIDE 245 

10. GLOSSARY 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 

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ACRYLAMIDE 246 

10. GLOSSARY 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 

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ACRYLAMIDE 247 

10. GLOSSARY 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 

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10. GLOSSARY 

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ACRYLAMIDE A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

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ACRYLAMIDE A-2 

APPENDIX A 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency-wide MRL 

Workgroup reviews, with participation from other federal agencies and comments from the public. They 

are subject to change as new information becomes available concomitant with updating the toxicological 

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. 

For additional information regarding MRLs, please contact the Division of Toxicology and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-32, Atlanta, Georgia 30333. 

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ACRYLAMIDE A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Acrylamide 

CAS Numbers: 79-06-1 

Date: August 27, 2009 

Profile Status: Draft for Public Comment 

Route: [ ] Inhalation [x] Oral 

Duration: [x] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 33 

Species: Rat 

Minimal Risk Level: 0.02 [x] mg/kg/day [ ] ppm 

Reference: Sublet VH, Zenick H, Smith MK. 1989. Factors associated with reduced fertility and 

implantation rates in females mated to acrylamide-treated rats. Toxicology 55:53-67. 

Experimental design: Groups of male Long-Evans hooded rats (15/group) were administered acrylamide 

(in distilled water) by oral gavage for 5 days at doses of 0, 30, 45, or 60 mg/kg/day (experiment 1) and 0, 

5, or 15 mg/kg/day (experiment 2). Males were then mated on weeks 1, 2, 3, 4, 7, and 10 to proestrus 

females (weeks 1–4 only for experiment 2). Mating was confirmed by vaginal lavage. Females were 

sacrificed on gestation day 15 and numbers of corpora lutea, implantation sites, and fetuses were 

determined and estimates of pre- and postimplantation losses were calculated. 

Effect noted in study and corresponding doses: Effects of acrylamide exposure on mating, fertility, and 

pre-and postimplantation losses are summarized in Table A-1. There were no significant treatmentrelated effects on mating index (number of sperm positive/number mated) at any dose level and no 

significant effects on any measures of reproductive success at the 5 mg/kg/day dose level. Assessments 

of reproductive indices at week 1 revealed significantly depressed fertility rates and elevated 

preimplantation losses at doses ≥15 mg/kg/day. Increased postimplantation loss was seen at weeks 2 and 

3 at doses ≥15 mg/kg/day. In sperm samples collected from the 45 mg/kg/day group, the percentage of 

motile sperm was modestly (but significantly) decreased (58 vs. 73% in controls) at week 3, but not at 

weeks 2 or 4. This study identified a NOAEL of 5 mg/kg/day and a LOAEL of 15 mg/kg/day for 

significantly decreased fertility and increased preimplantation loss during week 1 posttreatment and 

significantly increased postimplantation loss during weeks 2 and 3 posttreatment. 

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ACRYLAMIDE A-4 

APPENDIX A 

Table A-1. Effects of Acrylamide on Selected Reproductive Indices Following 

Gavage Dosing of Male Long-Evans Rats for 5 Days
 

Posttreatment Mating Fertility Preimplantation Postimplantation 

Treatment 

(mg/kg) 

mating 

week 

index 

(percent)a 

index 

(percent)b 

loss index 

(percent)c 

loss index 

(percent)d 

Controle 1 25/30 (83) 22/25 (88) 19.57 4.20 

2 26/30 (87) 25/26 (96) 11.54 5.70 

3 29/30 (97) 28/29 (97) 11.46 6.80 

4 27/30 (90) 26/27 (96) 9.48 5.00 

5 1 15/15 (100) 12/15 (80) 24.29 8.30 

2 14/15 (93) 11/14 (79) 25.40 10.80 

3 15/15 (100) 14/15 (93) 10.77 5.40 

4 13/15 (87) 11/13 (85) 17.08 7.10 

15 1 

2 

3 

13/15 (87) 

11/15 (73) 

13/15 (87) 

6/13 (46)f 

11/11 (100) 

12/13 (92) 

74.69f 

8.5 

13.42 

10.30 

15.40f 

15.70f 

4 13/15 (87) 12/13 (92) 10.36 5.50 

30 1 

2 

3 

12/15 (80) 

15/15 (100) 

15/15 (100) 

2/12 (17)f 

15/15 (100) 

14/15 (93) 

97.83f 

15.90 

14.51 

0.00 

25.40f 

35.00f 

4 15/15 (100) 15/15 (100) 4.90 17.50 

45 1 

2 

3 

13/15 (87) 

15/15 (100) 

15/15 (100) 

2/13 (15)f 

12/15 (80) 

10/15 (67)f 

85.89f 

33.04f 

59.13f 

26.77 

60.77f 

55.50f 

4 15/15 (100) 15/15 (100) 11.60 7.67 

60 1 

2 

3 

4 

15/15 (100) 

15/15 (100) 

15/15 (100) 

15/15 (100) 

1/15 (7)f 

8/15 (53)f 

1/15 (7)f 

9/15 (60)f 

98.33f 

73.39f 

98.80f 

70.84* 

33.33 

77.87f 

50.00f 

17.11* 

a Mating index = number sperm/positive females/number mated.
 b Fertility index = number pregnant/number sperm-positive females.
 c Preimplantation loss = (number of corpora lutea/female – number of implant sites/female)/(number of corpora 

lutea/female) x 100.

d Postimplantation loss = (number of implant sites/female – number of fetuses/females)/(number of implant
 

sites/female) x 100.
 e Control data from “high” and “low” dose dominant lethal studies are combined for tabular presentation. However
 

statistical differences associated with acrylamide treatment are based upon comparison with appropriate control
 

group.

f

p≤0.05
	

Source: Sublet et al. 1989 

Dose and end point used for MRL derivation: 1.78 mg/kg/day (BMDL10) for decreased fertility in rats (as 

assessed by number of nonpregnant rats/number of sperm-positive females) following oral administration 

of acrylamide to male Long-Evans hooded rats for 5 days and subsequent mating with untreated female 

rats (see Table A-2). 

All dichotomous models in the EPA Benchmark Dose Software (Version 2.1) were fit to the fertility data 

shown in Table A-2. Although the magnitude of the fertility response represents a more serious effect, 

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ACRYLAMIDE A-5 

APPENDIX A 

the group sizes in this study (15 male rats/dose) did not support a benchmark response (BMR) lower than 

10%; thus, an extra risk incidence of 10% above controls was selected as the BMR. Model results for the 

data on fertility are shown in Table A-3. All dichotomous models provided adequate fit to the data 

(p>0.1). Comparing across models, a better fit is generally indicated by a lower Akaike’s Information 

Criteria (AIC). The multistage (1-degree polynomial) and quantal linear models converged on the same 

model providing the best fit (as assessed by AIC) to the fertility data; these models both predicted a 

BMD10 of 2.44 mg/kg/day and a BMDL10 of 1.78 mg/kg/day. Figure A-1 shows the fit of the multistage 

(1-degree polynomial) model to the fertility data. 

Table A-2. Selected Results of Attempted Impregnation by Male Rats 

Administered Acrylamide by Gavage for 5 Days Prior to Mating
 

with Untreated Female Rats During Week 1 Posttreatment
 

Dose (mg/kg/day) 

0 5 15 30 45 60 

Number sperm-positive females 25 15 13 12 13 15 

Number nonpregnant females 3 (12%) 3 (20%) 7 (54%) 10 (83%) 11 (85%) 14 (93%) 

Source: Sublet et al. 1989 

Table A-3. Model Predictions for the Fraction of Unsuccessful Impregnation 

(Number of Nonpregnant Females/Number of Sperm-Positive Females)
 

Among Male Rats Administered Acrylamide by Gavage for 5 Days 

and Mated to Untreated Female Rats During Week 1 Posttreatment
 

Model 

BMD10 

(mg/kg/day) 

BMDL10 

(mg/kg/day) χ2 p-value AIC 

Gammaa 3.51 1.80 0.84 87.48 

Logistic 

Log-logisticb 

Log-probitb 

Multi-stagec 

Probit 

6.02 

4.76 

4.79 

2.44 

6.02 

4.48 

1.55 

3.01 

1.78 

4.67 

0.53 

0.95 

0.94 

0.91 

0.44 

87.71 

86.98 

87.01 

85.69 

88.31 

Weibulla 3.13 1.80 0.83 87.56 

Quantal linear 2.44 1.78 0.91 85.69 

a

Power restricted to ≥1. b

Slope restricted to ≥1. c

Betas restricted to ≥0; lowest degree polynomial with adequate fit is reported; degree of polynomial=1. 

AIC = Akaike’s Information Criteria; BMD = benchmark dose 

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ACRYLAMIDE A-6 

APPENDIX A 

Figure A-1. Predicted and Observed Fractions of Unsuccessful Impregnation 

(Number of Nonpregnant Females/Number of Sperm-Positive Females) by Male 

Rats Administered Acrylamide by Gavage for 5 Days and Mated to Untreated 

Female Rats During Week 1 Posttreatment * 

Multistage Model with 0.95 Confidence Level 

Fraction of Unsuccessful Impregnation 

1 

0.8 

0.6 

0.4 

0.2 

0 

BMDL BMD

Multistage 

0 10 20 30 40 50 60 

dose 

10:57 06/03 2009 

*BMD and BMDL associated with a 10% extra risk increase over control are shown; doses given in units of 

mg/kg/day. 

[ ] NOAEL [ ] LOAEL [x] Benchmark 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[x] 10 for extrapolation from animals to humans 

[x] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable.
 

Was a conversion used from intermittent to continuous exposure? No.
 

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ACRYLAMIDE A-7 

APPENDIX A 

Other additional studies or pertinent information that lend support to this MRL: As demonstrated in 

Table 3-4 (Levels of Significant Exposure to Acrylamide – Oral), male-mediated implantation loss and 

decreased mean body weight gain represent the most sensitive effects of acute-duration oral exposure to 

acrylamide. The lowest dose level reported to induce significantly decreased male-mediated implantation 

loss was 15 mg/kg/day in male Long-Evans rats administered acrylamide by gavage for 5 days followed 

by mating sessions with unexposed female rats (Sublet et al. 1989); this study identified a NOAEL of 

5 mg/kg/day. A similarly-designed study (Tyl et al. 2000b) confirmed the findings of acrylamide-induced 

increased implantation loss, although, based on pairwise comparisons with controls, statistical 

significance was achieved only at the highest dose level (60 mg/kg/day). Tyl et al. (2000b) also noted 

significantly decreased body weight gain (>40% lower than controls) during the 5 days of dosing, a 

finding not included in the study report of Sublet et al. (1989). Based on the reproducible results for 

male-mediated implantation loss in the studies of Sublet et al. (1989) and Tyl et al. (2000b) and the lack 

of supporting information regarding the body weight effects, the male-mediated implantation loss was 

selected as the critical effect for deriving an acute-duration oral MRL for acrylamide. The study of Sublet 

et al. (1989) identified the lowest LOAEL for the critical effect and was therefore selected as the principal 

study 

Results of several other studies corroborate the findings of male-mediated decreases in fertility and 

increases in implantation losses following oral exposure to acrylamide (Chapin et al. 1995; Sakamoto and 

Hashimoto 1986; Smith et al. 1986; Tyl et al. 2000a; Zenick et al. 1986). 

Agency Contacts (Chemical Managers): Patricia Ruiz, Ph.D.; Obaid Faroon, Ph.D.; Moiz Mumtaz, Ph.D. 

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ACRYLAMIDE A-8 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Acrylamide 

CAS Numbers: 79-06-1 

Date: August 27, 2009 

Profile Status: Draft for Public Comment 

Route: [ ] Inhalation [x] Oral 

Duration: [ ] Acute [x] Intermediate [ ] Chronic 

Graph Key: 63 

Species: Rat 

Minimal Risk Level: 0.002 [x] mg/kg/day [ ] ppm 

Reference: Burek JD, Albee RR, Beyer JE, et al. 1980. Subchronic toxicity of acrylamide administered 

to rats in the drinking water followed by up to 144 days of recovery. J Environ Pathol Toxicol 4(5-

6):157-182. 

Experimental design: Groups of 6-week-old male (23–29/group) and female (10/group) F344 rats were 

administered acrylamide in the drinking water for up to 93 days at concentrations designed to result in 

acrylamide intakes of 0, 0.05, 0.2, 1, 5, or 20 mg/kg/day. Ten rats/sex/group were assigned to the basic 

90-day study and were observed for body weight and water consumption (recorded weekly) throughout 

the treatment period. Following 7 and 33 days of treatment, three control and three high-dose male rats 

were sacrificed for interim electron microscopic examination of the sciatic nerve. Ten male (nine in the 

high-dose group, due to one death prior to treatment termination) and all female rats from each treatment 

group were subjected to gross and histopathologic examination of all major organs and tissues at the end 

of the treatment period, at which time, three other male rats from each group were processed for electron 

microscopic examination of the sciatic nerve. The remaining rats (all males) in each group were observed 

for signs of recovery from treatment-related effects for up to 144 days following cessation of treatment. 

Three rats/group were subjected to electron microscopic examination of the sciatic nerve on recovery 

days 25, 111, and 144. Body weights were recorded for two rats/dose level prior to sacrifice on recovery 

day 111. At the end of the 144-day recovery period, the remaining four rats of each dose level were 

weighed and sacrificed for gross and histopathologic examination of all major organs and tissues. 

All rats were observed daily (during the 5-day work week) for general health and clinical signs. Hindlimb 

foot splay was measured weekly in four control and four high-dose (20 mg/kg/day) male and female rats 

until the onset of neuropathy was detected, after which neuropathy in the high-dose group was monitored 

by clinical signs. After neuropathy was detected in high-dose rats, male and female rats in the 

5 mg/kg/day dose groups were also subjected to weekly testing of foot splay (rats in the lower treatment 

groups were not tested due to the lack of response at 5 mg/kg/day). Blood samples collected from seven 

rats/sex in the control and high-dose groups on treatment day 76 and from all rats alive on day 60 of the 

recovery period were examined for packed cell volume, total erythrocyte count, total and differential 

leukocyte counts, and hemoglobin concentration. The study design included urinary sampling from 

10 control and 10 high-dose rats per sex on treatment day 76 and at the end of the treatment period. 

Blood serum was collected from the 10 rats/sex/dose that were sacrificed at the end of treatment and 

from the 4 male rats/group that were maintained throughout the 144-day recovery period. Blood urea 

nitrogen, alkaline phosphatase, serum glutamic pyruvic transaminase, and serum cholinesterase activity 

were determined. 

Light microscopic examinations were performed on brain, spinal cord, and peripheral nerves (including 

brachial plexus, sciatic, and femoral nerves) from selected male and female rats of each dose group. 

Nervous tissues were fixed in glutaraldehyde-paraformaldehyde and stained with hematoxylin eosin. 

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ACRYLAMIDE A-9 

APPENDIX A 

Additional sections of brain, spinal cord, and peripheral nerves were subjected to the luxol fast blueperiodic acid Schiff (LFB/PAS) reaction for myelin staining and to Bodian's stain to elucidate more subtle 

axonal changes. Myelin and axonal degeneration was classified as severe (degeneration in approximately 

50% of the observed fibers), moderate (degeneration in 20–50% of observed fibers), slight (degeneration 

in <20% of observed fibers), very slight (effects restricted to focal or multifocal changes in individual 

nerves), or equivocal (nerves could not be graded as clearly normal). Only sciatic nerve tissues from 

male rats were examined by electron microscopy. Three blocks of sciatic nerve fibers, two longitudinal 

and one transverse, were selected per rat for thin sectioning and ultrastructural analysis. Ultrastructural 

alterations were counted by examining a maximum of 50 fields per block, a field defined as a section 

through any Schwann cell. This resulted in an examined maximum of 150 fields/rat or 

450 fields/treatment group of three rats. 

Hematology, urinary and clinical chemistry parameters, body weights, organ-to-body weight ratio data, 

foot spread results, and water consumption were statistically analyzed by one-way analysis of variance 

followed by Dunnett's test. The level of significance chosen was p<0.05. The study report did not, 

however, include individual or averaged incidences or extent of changes in these parameters, so an 

independent analysis of the results of body and organ weights, water consumption, foot splay, 

hematology, urinalysis, or serum chemistry was not possible. 

Effect noted in study and corresponding doses: Significantly lower body weights were reported in the 

high-dose male and female rats relative to controls: 8% lower (males and females) on treatment days 13 

and 20, and 21 and 24% lower (males and females, respectively) on treatment day 91. No significant 

body weight effect was seen in rats of lower dose groups. High-dose rats also exhibited treatment-related 

effects on organ weights including significantly decreased absolute liver, kidney, and thymus weights in 

males (also testicular) and females, significantly decreased absolute brain and heart weights in females 

(trend for decreased weights in males), increased relative brain, heart, liver, and kidney weights in males 

and females, and decreased relative thymus (females only) and testicular weight in males. Absolute and 

relative liver weight was increased in 5 mg/kg/day males. Marginally statistically significant increases in 

relative heart weight in 0.05 and 0.2 mg/kg/day females were not considered to be of toxicological 

significance due to the lack of a dose response. High-dose female rats exhibited significantly decreased 

water consumption (15–39% decreased) between treatment days 20 and 90. Although decreased water 

consumption was noted in high-dose males, the decrease reached the level of statistical significance in 

only 4 of the 13 intervals recorded. The few instances of significantly increased water consumption in 

low-dose rats did not follow a consistent pattern or trend, and may be of no toxicological significance. By 

day 144 of the posttreatment recovery period, the high-dose group had recovered with higher (but not 

statistically significant) body weights than controls, significantly higher absolute liver and kidney 

weights, and as significantly higher relative brain and liver weights. 

Significantly increased instances of hindlimb foot splay were observed in high-dose male and female rats 

on treatment day 22 (incidences were not reported), which became more pronounced on treatment day 29. 

Foot splay testing was terminated with this treatment group (to prevent injury), but clinical signs of 

neuropathy (including curling of the toes, rear limb splay, incoordination, and posterior weakness) 

progressed in severity throughout the remainder of the treatment period. Beginning on treatment day 29, 

rats of the 5 mg/kg/day dose level were tested, but foot splay was not detected at this treatment level in 

either males or females. No other treatment-related clinical effects were observed in the 5 mg/kg/day 

males or females or any of the lower dose groups. By day 7 of the posttreatment recovery period, the 

high-dose groups showed clear signs of improvements continuing to day 111 with only slight posterior 

weakness and curling of the toes. By day 144, these high-dose rats appeared clinically similar to the 

controls. 

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ACRYLAMIDE A-10 

APPENDIX A 

At the end of the treatment period, serum cholinesterase activity was increased and alkaline phosphatase 

activity was statistically significantly increased in high-dose females. Significant decreases in packed cell 

volume, total erythrocyte count, and hemoglobin concentrations in high-dose males and females and 

5 mg/kg/day females were noted. Results of urinalysis did not reveal any acrylamide-induced 

abnormalities. By day 144 posttreatment, the high-dose group (sex not specified) had statistically 

significant decreased serum cholinesterase levels and no significant differences in other clinical chemistry 

parameters. 

Upon necropsy, gross observations of rats following the 92- or 93-day treatment period revealed 

treatment-related alterations only in the high-dose group, including perineal soiling, decreased adipose 

tissue, decreased liver size, darkened kidneys, foci or mottled appearance of lungs, decreased size or 

flaccid testicles, decreased size of male accessory genitalia, decreased uterus size, altered appearance of 

peripheral nerves, atrophy of skeletal muscle in the posterior portion of the body, bladder distention, and 

diffuse mural thickening of the stomach. The authors did not include incidence data regarding gross 

examination data, however. Histopathologic examination of high-dose rats revealed effects such as 

atrophy of skeletal muscle (2/10 males, 8/10 females), slightly increased hematogenous pigment in the 

spleen (4/9 males), ulcerative gastritis or hyperkeratosis in the nonglandular stomach (4/10 males), 

atrophy of mesenteric fat (8/10 females), vacuolization of the smooth muscle in the bladder wall 

(1/10 males, 2/9 females), inflammation in the lungs (3/10 males, 5/10 females), and testicular effects that 

included atrophy (10/10), mineralization in seminiferous tubules (5/10), and increased cellular debris 

and/or decreased spermatogenic segments in the tubular lamina of the epididymides (9/10). The 

statistical significance of these findings could not be assessed because incidence data for controls were 

not reported. By day 144 posttreatment, only the high-dose rats had persistent gross pathological effects, 

primarily dark testicles and slightly distended bladders. The testicular histological lesions consisted of 

focal or multifocal atrophy to individual seminiferous tubules, some with mineral and cellular debris, and 

indication of partial reversibility of the testicular atrophy. Light microscopic examination of the sciatic 

nerve sections (stained with hematoxylin and eosin) revealed severe degeneration in the high-dose groups 

that was characterized by demyelinization (LFB/PAS-treated sections) and axonal degeneration 

(Bodian's-treated sections) in 10/10 females and similar but less severe effects in males (degeneration 

moderate in 5/10 and severe in the other 5). These lesions were also seen in other peripheral nerve 

sections (brachial plexus and femoral nerve) but varied in severity from equivocal to severe (incidences 

not reported). The authors noted equivocal to very slight degenerative changes in peripheral nerves of 

5 mg/kg/day males (9/10) and females (6/10) but found no light microscopic evidence of peripheral nerve 

lesions in 0.05, 0.2, or 1 mg/kg/day treatment groups. Very slight to slight degenerative changes 

(demyelinization, swollen astrocytes and axons) were seen in spinal cord sections of high-dose male 

(5/10) and female (9/10) rats. No treatment-related lesions were observed at any dose level within brain 

sections examined by light microscopy. After 144 days of posttreatment recovery, no nerve tissue 

alterations were observed in any of the 5 mg/kg/day or lower dose groups. In the high-dose group, 

alterations ranged from very slight to slight in the sciatic nerve and no alterations were noted in sections 

of the brachial nerve. The authors stated that if the recovery period had been extended beyond 144 days, 

the remaining tissue changes would likely have completely reversed. 

Ultrastructural (electron microscope) examinations of sciatic nerve preparations from three male 

rats/group included the examination of fields (defined as a section through any Schwann cell) for signs of 

axolemma invaginations, axonal invaginations with cell organelles and/or dense bodies, and Schwann 

cells without axons and/or with degenerating myelin. After 7 days of treatment, no significant differences 

were seen between control and high-dose rats (other treatment groups were not subjected to 7-day interim 

sacrifice). After 33 days of treatment, high-dose male rats exhibited increased prevalence of fields 

showing axolemma invaginations with cell organelles and/or dense bodies and fields exhibiting Schwann 

cells without axons and/or with degenerating myelin (other groups were not subjected to 33-day interim 

sacrifice). Following 90 days of treatment, severe axonal degeneration and axonal loss were seen in high-

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ACRYLAMIDE A-11 

APPENDIX A 

dose rats. Approximately 55% of the fields examined exhibited alterations in myelinated nerves or 

Schwann cells (compared with 12 and 21% after treatment days 7 and 33, respectively). Similar, but less 

severe, ultrastructural alterations in approximately 34% of the fields examined were seen in the 

5 mg/kg/day dose group. At the 1 mg/kg/day dose level, approximately 24% of the fields examined 

showed axolemma invaginations with cell organelles and/or dense bodies, but not more severe signs of 

ultrastructural alterations. The alterations in the sciatic nerve fields examined in the control, 0.05, and 0.2 

mg/kg-day groups were roughly comparable (15, 9, and 12%, respectively), suggesting that there were no 

adverse effects at the 0.05 and 0.2 mg/kg/day doses. Importantly, the increase in lesions observed via 

electron microscopy in the 1 and 5 mg/kg/day groups appeared to have completely reversed by days 25 

and 111 posttreatment, respectively. The observed lesions in the high-dose group were partially or 

completely reversed by day 144 posttreatment. 

In summary, the study of Burek et al. (1980) identified a NOAEL of 0.2 mg/kg/day and a LOAEL of 

1 mg/kg/day, based on ultrastructural degeneration (axolemma invaginations with cell organelles and/or 

dense bodies) in the sciatic nerve of male rats (as detected by electron microscopic examinations, which 

were limited to males). The increased frequency was characterized by the study authors as "slight" for the 

LOAEL at 1 mg/kg/day, and the lesions were reversible (back to control levels) by day 25 posttreatment 

in all 1 mg/kg/day treated rats. At the resolution of the light microscope, the 5 mg/kg/day dose was the 

lowest dose resulting in degenerative effects in the sciatic nerve of male and female rats. 

Dose and end point used for MRL derivation: 0.2 mg/kg/day 

[x] NOAEL [ ] LOAEL 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[x] 10 for extrapolation from animals to humans 

[x] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? No. 

Other additional studies or pertinent information that lend support to this MRL: As demonstrated in 

Table 3-4 (Levels of Significant Exposure to Acrylamide – Oral), degenerative nerve changes and malemediated implantation losses represent the most sensitive effects of intermediate-duration oral exposure to 

acrylamide. The lowest dose level reported to induce male-mediated implantation losses was 

2.8 mg/kg/day in male Long-Evans rats receiving acrylamide from the drinking water for 80 days; this 

study identified a NOAEL of 1 mg/kg/day (Smith et al. 1986). Ultrastructural degenerative peripheral 

nerve changes were observed at a dose level as low as 1 mg/kg/day in male F344 rats receiving 

acrylamide from the drinking water for up to 93 days; this study identified a NOAEL of 0.2 mg/kg/day 

(Burek et al. 1980). Available data suggest that neurological effects represent a more sensitive point of 

departure than reproductive effects for deriving intermediate- and chronic-duration oral MRLs for 

acrylamide. Therefore, degenerative nerve change was selected as the critical effect for deriving an 

intermediate-duration oral MRL for acrylamide. The study of Burek et al. (1980) was selected as the 

principal study because it identified the lowest LOAEL for the critical effect. A NOAEL/LOAEL 

approach was selected because results of the ultrastructural evaluations included only 3 of 10 rats/group 

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ACRYLAMIDE A-12 

APPENDIX A 

and were reported only as the total numbers of fields (per group) with ultrastructural changes as 

axolemma invaginations or Schwann cells without axons and/or with degenerating myelin. This reporting 

of the electron microscopy data does not support a statistical comparison of the incidence of changes 

between the exposed and control groups because it is unknown within any exposure group how the 

numbers of changes were distributed among the three rats (i.e., whether the apparent increase in incidence 

of fields with changes was due to one, two, or all three rats in the 1, 5, and 20 mg/kg-day groups). 

Therefore, a BMD approach was not feasible. 

Interim data from a chronic toxicity and carcinogenicity bioassay of male and female F344 rats receiving 

acrylamide from the drinking water for up to 2 years (Johnson et al. (1984, 1985, 1986) provide support 

to the findings of Burek et al. (1980). In the 2-year study, interim sacrifices were performed at 3, 6, 12, 

and 18 months on some rats from each exposure group. One aspect of interim sacrifices was to evaluate 

the condition of selected peripheral nerve sections using light and electron microscopy. The most 

significant noncancer effects were increased incidences of axolemma invaginations (observed by electron 

microscopy) in the tibial branch of the sciatic nerve of male rats following 3 and 6 months of treatment 

and increased prevalence of "moderate" to "severe" degeneration (observed by light microscopy) in both 

males and females following 2 years of treatment. This study identified a NOAEL of 0.5 mg/kg/day and 

a LOAEL of 2.0 mg/kg/day for light and electron microscope evidence of peripheral nerve fiber 

degeneration in the male rats. Electron microscope evaluations at interims ≥12 months were not 

considered meaningful due to age-related degenerative effects that could not be distinguished from 

acrylamide-induced effects. 

Agency Contacts (Chemical Managers): Patricia Ruiz, Ph.D.; Obaid Faroon, Ph.D.; Moiz Mumtaz, Ph.D. 

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ACRYLAMIDE B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1.	 What effects are known to occur in humans? 

2.	 What effects observed in animals are likely to be of concern to humans? 

3.	 What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

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ACRYLAMIDE B-2 

APPENDIX B 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

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ACRYLAMIDE B-3 

APPENDIX B 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1)	 Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2)	 Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is reported. For quick 

reference to health effects occurring from a known length of exposure, locate the applicable 

exposure period within the LSE table and figure. 

(3)	 Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4)	 Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5)	 Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6)	 Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

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ACRYLAMIDE B-4 

APPENDIX B 

(7)	 System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8)	 NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 

(9)	 LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10)	 Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11)	 CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12)	 Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13)	 Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14)	 Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)	 Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in 

mg/kg/day. 

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ACRYLAMIDE B-5 

APPENDIX B 

(16)	 NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 

corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17)	 CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 

(18)	 Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19)	 Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 

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1 

2 3 4 

→→→

Key tfigure

INTERSyste

→→

18 CHRO

Cance38 

39 

40 

a The nb Used 

by an u

12 

SAMPLE 

Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalat

Exposure 

o frequency/ 

a Species duration 

MEDIATE EXPOSURE 

5 6 

mic ↓ ↓

NOAEL 

System (ppm) 

7 8 ↓ ↓

LOAEL (effect) Less serious (ppm) 

9 

↓

Serious (ppm) 

Rat 13 wk Resp 3b 10 (hyperplasia) 

5 d/wk 6 hr/d 

NIC EXPOSURE 

r 11 

↓

Rat 18 mo 20 (CEL, multiple 

5 d/wk organs) 7 hr/d 

Rat 89–104 wk 10 (CEL, lung tumors, 

5 d/wk nasal tumors) 6 hr/d 

Mouse 79–103 wk 10 (CEL, lung tumors, 

5 d/wk hemangiosarcomas) 6 hr/d 

umber corresponds to entries in Figure 3-1. 

to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent 

ncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

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ACRYLAMIDE B-8 

APPENDIX B 

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ACRYLAMIDE C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD/C benchmark dose or benchmark concentration 

BMDX dose that produces a X% change in response rate of an adverse effect 

BMDLX 95% lower confidence limit on the BMDX 

BMDS Benchmark Dose Software 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

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ACRYLAMIDE C-2 

APPENDIX C 

DOL 

DOT 

DOT/UN/ 

NA/IMDG 

DWEL 

ECD 

ECG/EKG 

EEG 

EEGL 

EPA 

F 

F1 

FAO 

FDA 

FEMA 

FIFRA 

FPD 

fpm 

FR 

FSH 

g 

GC 

gd 

GLC 

GPC 

HPLC 

HRGC 

HSDB 

IARC 

IDLH 

ILO 

IRIS 

Kd 

kg 

kkg 

Koc 

Kow 

L 

LC 

LC50 

LCLo 

LD50 

LDLo 

LDH 

LH 

LOAEL 

LSE 

LT50 

m 

MA 

MAL 

Department of Labor 

Department of Transportation 

Department of Transportation/United Nations/ 

North America/Intergovernmental Maritime Dangerous Goods Code 

drinking water exposure level 

electron capture detection 

electrocardiogram 

electroencephalogram 

Emergency Exposure Guidance Level 

Environmental Protection Agency 

Fahrenheit 

first-filial generation 

Food and Agricultural Organization of the United Nations 

Food and Drug Administration 

Federal Emergency Management Agency 

Federal Insecticide, Fungicide, and Rodenticide Act 

flame photometric detection 

feet per minute 

Federal Register 

follicle stimulating hormone 

gram 

gas chromatography 

gestational day 

gas liquid chromatography 

gel permeation chromatography 

high-performance liquid chromatography 

high resolution gas chromatography 

Hazardous Substance Data Bank 

International Agency for Research on Cancer 

immediately dangerous to life and health 

International Labor Organization 

Integrated Risk Information System 

adsorption ratio 

kilogram 

metric ton 

organic carbon partition coefficient 

octanol-water partition coefficient 

liter 

liquid chromatography 

lethal concentration, 50% kill 

lethal concentration, low 

lethal dose, 50% kill 

lethal dose, low 

lactic dehydrogenase 

luteinizing hormone 

lowest-observed-adverse-effect level 

Levels of Significant Exposure 

lethal time, 50% kill 

meter 

trans,trans-muconic acid 

maximum allowable level 

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ACRYLAMIDE C-3 

APPENDIX C 

mCi millicurie 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

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ACRYLAMIDE C-4 

APPENDIX C 

OTS 

OW 

OWRS 

PAH 

PBPD 

PBPK 

PCE 

PEL 

pg 

PHS 

PID 

pmol 

PMR 

ppb 

ppm 

ppt 

PSNS 

RBC 

REL 

RfC 

RfD 

RNA 

RQ 

RTECS 

SARA 

SCE 

SGOT 

SGPT 

SIC 

SIM 

SMCL 

SMR 

SNARL 

SPEGL 

STEL 

STORET 

TD50 

TLV 

TOC 

TPQ 

TRI 

TSCA 

TWA 

UF 

U.S. 

USDA 

USGS 

VOC 

WBC 

WHO 

> 

Office of Toxic Substances 

Office of Water 

Office of Water Regulations and Standards, EPA 

polycyclic aromatic hydrocarbon 

physiologically based pharmacodynamic 

physiologically based pharmacokinetic 

polychromatic erythrocytes 

permissible exposure limit 

picogram 

Public Health Service 

photo ionization detector 

picomole 

proportionate mortality ratio 

parts per billion 

parts per million 

parts per trillion 

pretreatment standards for new sources 

red blood cell 

recommended exposure level/limit 

reference concentration 

reference dose 

ribonucleic acid 

reportable quantity 

Registry of Toxic Effects of Chemical Substances 

Superfund Amendments and Reauthorization Act 

sister chromatid exchange 

serum glutamic oxaloacetic transaminase 

serum glutamic pyruvic transaminase 

standard industrial classification 

selected ion monitoring 

secondary maximum contaminant level 

standardized mortality ratio 

suggested no adverse response level 

Short-Term Public Emergency Guidance Level 

short term exposure limit 

Storage and Retrieval 

toxic dose, 50% specific toxic effect 

threshold limit value 

total organic carbon 

threshold planning quantity 

Toxics Release Inventory 

Toxic Substances Control Act 

time-weighted average 

uncertainty factor 

United States 

United States Department of Agriculture 

United States Geological Survey 

volatile organic compound 

white blood cell 

World Health Organization 

greater than 

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ACRYLAMIDE C-5 

APPENDIX C 

≥ greater than or equal to 

= equal to 

< less than 

≤ less than or equal to 

% percent 

α alpha 

β beta 

γ gamma 

δ delta 

μm micrometer 

μg microgram 

q1

* cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 

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ACRYLAMIDE C-6 

APPENDIX C 

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ACRYLAMIDE D-1 

APPENDIX D. INDEX
 

absorbed dose.................................................................................................................................... 104, 125
 

adduct................................................... 9, 24, 26, 66, 67, 80, 81, 82, 83, 84, 86, 88, 89, 90, 92, 96, 98, 100,
 

101, 102, 112, 114, 115, 116, 124, 125, 138, 170, 178, 180, 183
 

adenocarcinoma .................................................................................................................................... 68, 69
 

adsorption..................................................................................................................................................173
 

aerobic.......................................................................................................................................................160
 

anaerobic...................................................................................................................................................160
 

atrophy ........................................................................................................................................................23
 

axolemma.............................................................................................................................................. 13, 61
 

bioaccumulation........................................................................................................................................173
 

bioavailability ..................................................................................................................................... 93, 173
 

bioconcentration factor .............................................................................................................................160
 

biodegradation............................................................................................................................... 7, 152, 160
 

biomarker ................................................ 22, 67, 88, 124, 125, 133, 137, 138, 139, 140, 170, 178, 180, 184
 

body weight.................................................................... 3, 7, 9, 12, 17, 21, 58, 59, 64, 65, 71, 91, 101, 102, 

112, 121, 122, 123, 131, 132, 136, 154, 171, 180
 

body weight effects......................................................................................................... 9, 12, 17, 58, 59, 71
 

breast milk..................................................................................................... 3, 123, 171, 172, 174, 178, 183
 

cancer...........................3, 8, 16, 28, 29, 65, 66, 67, 68, 70, 75, 118, 121, 122, 126, 134, 137, 169, 189, 190
 

carcinogen....................................................................................................... 9, 70, 154, 169, 186, 188, 190
 

carcinogenic .......................................................................................... 9, 10, 15, 16, 70, 118, 122, 186, 190
 

carcinogenicity.............................................................. 9, 13, 68, 70, 96, 119, 126, 127, 134, 137, 139, 190
 

carcinoma.......................................................................................................................... 68, 69, 70, 75, 134
 

cardiovascular ................................................................................................................................. 17, 56, 71
 

cardiovascular effects..................................................................................................................................56
 

chromosomal aberrations...................................................................................................................... 82, 83
 

clastogenic..................................................................................................................... 75, 82, 117, 118, 135
 

death.................................................................................................................................... 15, 16, 30, 59, 71
 

degenerative effects .................................................................................... 8, 11, 61, 63, 115, 133, 134, 135
 

deoxyribonucleic acid (see also DNA) ........................................................................................... 75, 81, 87
 

dermal effects.......................................................................................................................... 17, 58, 71, 133
 

developmental effects ..................................................................................... 3, 27, 63, 64, 65, 74, 137, 139
 

DNA (see also deoxyribonucleic acid) ...................... 75, 80, 81, 82, 83, 84, 86, 87, 88, 92, 96, 98, 99, 112,
 

114, 117, 118, 122, 124, 125, 127, 135, 138, 180
 

DNA adducts......................................................................... 83, 86, 92, 96, 98, 99, 112, 118, 124, 138, 180
 

dominant lethality ..................................................................................................................... 8, 62, 74, 135
 

dopamine............................................................................................................................................. 64, 136
 

endocrine................................................................................................................... 17, 57, 58, 71, 119, 120
 

endocrine effects............................................................................................................................. 57, 58, 71
 

erythema......................................................................................................................................................22
 

fertility .......................................................................................................................... 12, 63, 118, 131, 186
 

fetal tissue .................................................................................................................................................123
 

fetus............................................................................................................................. 94, 121, 122, 127, 171
 

foot splay............................................................................................................................................. 60, 137
 

gait ................................................................................................................................ 22, 23, 25, 26, 60, 64
 

gastrointestinal effects ................................................................................................................................56
 

general population......................................................................................................... 2, 131, 170, 171, 172
 

genotoxic............................................................................................................... 15, 75, 107, 118, 134, 140
 

genotoxicity..................................................................................................................... 9, 75, 118, 134, 139
 

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ACRYLAMIDE D-2 

APPENDIX D 

groundwater .............................................................................................................................. 158, 159, 173
 

half-life.................................................................................................................................. 96, 99, 103, 124
 

hematological effects ............................................................................................................................ 17, 56
 

hemoglobin .................................................. 17, 22, 24, 56, 66, 67, 88, 89, 90, 93, 94, 96, 97, 98, 100, 101,
 

107, 111, 112, 114, 115, 125, 133, 134, 138, 170, 178, 180 

hemoglobin adduct............................................... 17, 22, 66, 67, 88, 89, 90, 93, 94, 98, 100, 101, 107, 112, 

114, 115, 125, 133, 134, 138, 180
 

heritable translocations ............................................................................................................... 75, 118, 135
 

hindlimb splay........................................................................................................... 11, 60, 61, 64, 123, 133
 

hydrolysis.......................................................................................................... 7, 96, 99, 110, 138, 160, 161
 

hydroxyl radical ................................................................................................................................ 160, 173
 

immunological .................................................................................................................. 15, 21, 60, 74, 136
 

implantation loss ..................................................................................................... 12, 13, 62, 126, 131, 132
 

Kow ............................................................................................................................................................143
 

LD50......................................................................................................................................... 30, 70, 71, 131
 

leukemia................................................................................................................................................ 83, 85
 

lymphatic ....................................................................................................................................................28
 

lymphopoietic .............................................................................................................................................28
 

lymphoreticular............................................................................................................................... 21, 60, 74
 

male-mediated......................................................................................................... 12, 13, 62, 126, 131, 135
 

mammary gland tumors .................................................................................................................... 9, 68, 69
 

mass spectroscopy.....................................................................................................................................100
 

mesotheliomas......................................................................................................................... 9, 68, 126, 134
 

micronuclei ........................................................................................................................................... 82, 83
 

milk ................................................................................................................. 8, 66, 123, 154, 172, 178, 179
 

motor function............................................................................................................................. 21, 132, 136
 

musculoskeletal effects...............................................................................................................................57
 

neonatal............................................................................................................................................... 96, 132
 

neurobehavioral.........................................................................................................................................120
 

neurochemical...........................................................................................................................................132
 

neurodevelopmental............................................................................................................................ 62, 137
 

neurological effects........................... 8, 11, 13, 21, 22, 27, 58, 60, 61, 62, 74, 115, 116, 126, 131, 133, 137
 

neurophysiological......................................................................................................................................24
 

neurotransmitter ........................................................................................................................................117
 

nuclear............................................................................................................................................... 100, 163
 

ocular effects................................................................................................................................... 17, 58, 71
 

odds ratio.....................................................................................................................................................66
 

partition coefficients .................................................................................................................................114
 

peripheral neuropathy ............................................................... 8, 11, 24, 26, 57, 60, 61, 116, 123, 129, 131
 

pharmacodynamic............................................................................................................................. 104, 113
 

pharmacokinetic........................................................................................ 104, 105, 106, 107, 113, 121, 138
 

placenta ................................................................................................................................... 8, 94, 123, 178
 

placental barrier ........................................................................................................................ 154, 169, 171
 

rate constant ................................................................................................................................ 90, 114, 160
 

renal effects.................................................................................................................................................57
 

reproductive effects................................................................................. 8, 13, 27, 62, 63, 74, 117, 126, 135
 

respiratory effects.................................................................................................................................. 17, 56
 

retention ............................................................................................................................................ 150, 182
 

rotarod............................................................................................................................. 11, 60, 61, 122, 137
 

solubility ........................................................................................................... 152, 155, 159, 162, 170, 173
 

sperm mobility ................................................................................................................................ 8, 62, 135
 

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ACRYLAMIDE D-3 

APPENDIX D 

spermatogonia....................................................................................................................................... 77, 82
 

systemic effects............................................................................................................................... 17, 30, 71
 

T3 (see also triiodothyronine)............................................................................................. 57, 119, 120, 132
 

T4 (see also thyroxine)........................................................................................................ 57, 119, 120, 132
 

testicular atrophy..................................................................................................................... 8, 63, 126, 135
 

thyroid tumors...........................................................................................................................................118
 

thyroxine (see also T4)................................................................................................................................57
 

toxicokinetic.................................................................................................................... 15, 91, 92, 114, 138
 

tremors ................................................................................................................................................ 60, 137
 

triiodothyronine (see also T3).....................................................................................................................57
 

tumors ................................................................................................... 9, 68, 69, 70, 75, 118, 119, 126, 134
 

tunica vaginalis ....................................................................................................................... 9, 68, 119, 134
 

vapor phase ...............................................................................................................................................190
 

vapor pressure ........................................................................................................... 152, 155, 162, 170, 190
 

volatilization ..................................................................................................................................... 155, 159
 

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