TOXICOLOGICAL PROFILE FOR
 

FORMALDEHYDE
 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

July 1999 
FORMALDEHYDE 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. 
FORMALDEHYDE iii 

UPDATE STATEMENT
 

Toxicological profiles are revised and republished as necessary, but no less than once every three years. 

For information regarding the update status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology/Toxicology Information Branch
 

1600 Clifton Road NE, E-29
 

Atlanta, Georgia 30333
 



 

 

FORMALDEHYDE 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: Health Effects: Specific health effects of a given hazardous compound are reported by route 

of exposure, by type of health effect (death, systemic, immunologic, reproductive), 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 2.6 Children’s Susceptibility 

Section 5.6 Exposures of Children 

Other Sections of Interest: 

Section 2.7 Biomarkers of Exposure and Effect 

Section 2.10 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-800-447-1544 (to be replaced by 1-888-42-ATSDR in 1999)

 or 404-639-6357 Fax: 404-639-6359 

E-mail: atsdric@cdc.gov Internet: http://atsdr1.atsdr.cdc.gov:8080 

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. 
FORMALDEHYDE 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@dgs.dgsys.com • AOEC Clinic Director: http://occ-envmed.mc.duke.edu/oem/aoec.htm. 

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, 55 West Seegers Road, Arlington Heights, IL 

60005 • Phone: 847-228-6850 • FAX: 847-228-1856. 
FORMALDEHYDE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHORS(S): 

Sharon Wilbur, M.A.
 

ATSDR, Division of Toxicology, Atlanta, GA
 

M. Olivia Harris, M.A.
 

ATSDR, Division of Toxicology, Atlanta, GA
 

Peter R. McClure, Ph.D., DABT 

Syracuse Research Corporation, North Syracuse, NY 

Wayne Spoo, DVM, DABT, DABVT 

Research Triangle Institute, Research Triangle Park, NC 

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 Research Implementation Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

FORMALDEHYDE xi 

PEER REVIEW
 

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

1.	 Carson Conaway, Research Scientist, American Health Foundation, Valhalla, New York 10595; 

2.	 John Egle, Jr., Professor, Department of Pharmacology and Toxicology, Medical College of 

Virginia, Smith Bldg., Room 656, Richmond, VA 23219; and 

3.	 Vincent Garry, Director, Environmental Medicine, University of Minnesota, 421 29th Ave., 

SE Minneapolis, MN 55414. 

These experts collectively have knowledge of formaldehyde'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. A list of databases reviewed and 

a list of unpublished documents cited are also included in the administrative record. 

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. 

FORMALDEHYDE xiii 

CONTENTS
 

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

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

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

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

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

LIST OF TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xx 
 

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

1.1 WHAT IS FORMALDEHYDE? ................................................ 1 
 

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

1.3 HOW MIGHT I BE EXPOSED TO FORMALDEHYDE? ............................ 3 
 

1.4 HOW CAN FORMALDEHYDE ENTER AND LEAVE MY BODY? .................. 4 
 

1.5 HOW CAN FORMALDEHYDE AFFECT MY HEALTH? ........................... 4 
 

1.6	 HOW CAN FORMALDEHYDE AFFECT CHILDREN? ............................. 5 
 

1.7	 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO FORMALDEHYDE? . . 6
 

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

FORMALDEHYDE? ......................................................... 7 
 

1.9	 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
 

PROTECT HUMAN HEALTH? ................................................ 7 
 

1.10 WHERE CAN I GET MORE INFORMATION? ................................... 8 
 

2. HEALTH EFFECTS ............................................................... 9 
 

2.1 INTRODUCTION ........................................................... 9 
 

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE .................. 9 
 

2.2.1 Inhalation Exposure .................................................. 11 
 

2.2.1.1 Death ..................................................... 11 
 

2.2.1.2 Systemic Effects ............................................ 12 
 

2.2.1.3 Immunological and Lymphoreticular Effects ...................... 71 
 

2.2.1.4 Neurological Effects ......................................... 79 
 

2.2.1.5 Reproductive Effects ......................................... 82 
 

2.2.1.6 Developmental Effects ....................................... 84 
 

2.2.1.7 Genotoxic Effects ........................................... 85 
 

2.2.1.8 Cancer .................................................... 89 
 

2.2.2 Oral Exposure ..................................................... 112 
 

2.2.2.1 Death .................................................... 113 
 

2.2.2.2 Systemic Effects ........................................... 134 
 

2.2.2.3 Immunological and Lymphoreticular Effects ..................... 144 
 

2.2.2.4 Neurological Effects ........................................ 145 
 

2.2.2.5 Reproductive Effects ........................................ 146 
 

2.2.2.6 Developmental Effects ...................................... 148 
 

2.2.2.7 Genotoxic Effects .......................................... 149 
 

2.2.2.8 Cancer ................................................... 150 
 

2.2.3 Dermal Exposure ................................................... 153 
 
FORMALDEHYDE xiv 

2.2.3.1 	 Death .................................................... 153 
 

2.2.3.2 	 Systemic Effects ........................................... 154 
 

2.2.3.3	 Immunological and Lymphoreticular Effects ..................... 162 
 

2.2.3.4 	 Neurological Effects ........................................ 163 
 

2.2.3.5	 Reproductive Effects ........................................ 164 
 

2.2.3.6 	 Developmental Effects ...................................... 164 
 

2.2.3.7 	 Genotoxic Effects .......................................... 165 
 

2.2.3.8 	 Cancer ................................................... 165 
 

2.3 TOXICOKINETICS ........................................................ 166 
 

2.3.1 Absorption ........................................................ 166 
 

2.3.1.1	 Inhalation Exposure ......................................... 167 
 

2.3.1.2	 Oral Exposure ............................................. 168 
 

2.3.1.3	 Dermal Exposure ........................................... 170 
 

2.3.2 Distribution ....................................................... 172 
 

2.3.2.1	 Inhalation Exposure ......................................... 172 
 

2.3.2.2	 Oral Exposure ............................................. 174 
 

2.3.2.3	 Dermal Exposure ........................................... 175 
 

2.3.3 Metabolism ........................................................ 176 
 

2.3.3.1	 Inhalation Exposure. ........................................ 177 
 

2.3.3.2	 Oral Exposure. ............................................. 180 
 

2.3.3.3	 Dermal Exposure ........................................... 180 
 

2.3.4 Elimination and Excretion ............................................ 180 
 

2.3.4.1	 Inhalation Exposure ......................................... 180 
 

2.3.4.2	 Oral Exposure ............................................. 180 
 

2.3.4.3	 Dermal Exposure ........................................... 182 
 

2.3.5	 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models
 

................................................................. 182 
 

2.4 MECHANISMS OF ACTION ................................................ 188 
 

2.4.1 Pharmacokinetic Mechanisms ......................................... 188 
 

2.4.2 Mechanisms of Toxicity .............................................. 191 
 

2.4.3 Animal-to-Human Extrapolations ...................................... 195 
 

2.5 RELEVANCE TO PUBLIC HEALTH ......................................... 197 
 

2.6 CHILDREN’S SUSCEPTIBILITY ............................................ 226 
 

2.7 BIOMARKERS OF EXPOSURE AND EFFECT ................................. 229 
 

2.7.1 Biomarkers Used to Identify or Quantify Exposure to Formaldehyde .......... 230 
 

2.7.2 Biomarkers Used to Characterize Effects Caused by Formaldehyde ............ 233 
 

2.8 INTERACTIONS WITH OTHER CHEMICALS ................................. 235 
 

2.9 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ...................... 236 
 

2.10 METHODS FOR REDUCING TOXIC EFFECTS ................................ 237 
 

2.10.1 Reducing Peak Absorption Following Exposure ........................... 238 
 

2.10.2 Reducing Body Burden .............................................. 238 
 

2.10.3 Interfering with the Mechanism of Action for Toxic Effects .................. 239 
 

2.11 ADEQUACY OF THE DATABASE ........................................... 239 
 

2.11.1 Existing Information on Health Effects of Formaldehyde .................... 240 
 

2.11.2 Identification of Data Needs .......................................... 242 
 

2.11.3 Ongoing Studies .................................................... 263 
 

3. CHEMICAL AND PHYSICAL INFORMATION ...................................... 267 
 

3.1 CHEMICAL IDENTITY .................................................... 267 
 

3.2 PHYSICAL AND CHEMICAL PROPERTIES ................................... 267 
 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ............................ 271 
 
FORMALDEHYDE xv 

4.1 PRODUCTION ........................................................... 271 
 

4.2 IMPORT/EXPORT ........................................................ 276 
 

4.3 USE ..................................................................... 276 
 

4.4 DISPOSAL ............................................................... 280 
 

5. POTENTIAL FOR HUMAN EXPOSURE ........................................... 283 
 

5.1 OVERVIEW .............................................................. 283 
 

5.2 RELEASES TO THE ENVIRONMENT ........................................ 287 
 

5.2.1 Air .............................................................. 287 
 

5.2.2 Water ............................................................ 294 
 

5.2.3 Soil .............................................................. 295 
 

5.3 ENVIRONMENTAL FATE .................................................. 295 
 

5.3.1 Transport and Partitioning ............................................ 295 
 

5.3.2 Transformation and Degradation ....................................... 296 
 

5.3.2.1 Air ...................................................... 296 
 

5.3.2.2 Water .................................................... 298 
 

5.3.2.3 Sediment and Soil .......................................... 299 
 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ............... 299 
 

5.4.1 Air .............................................................. 299 
 

5.4.2 Water ............................................................ 304 
 

5.4.3 Sediment and Soil .................................................. 304 
 

5.4.4 Other Environmental Media ........................................... 305 
 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .................. 305 
 

5.6 EXPOSURES OF CHILDREN ............................................... 308 
 

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ...................... 311 
 

5.8 ADEQUACY OF THE DATABASE ........................................... 311 
 

5.8.1 Identification of Data Needs .......................................... 312 
 

5.8.2 Ongoing Studies .................................................... 315 
 

6. ANALYTICAL METHODS ....................................................... 317 
 

6.1 BIOLOGICAL SAMPLES ................................................... 317 
 

6.2 ENVIRONMENTAL SAMPLES .............................................. 320 
 

6.3 ADEQUACY OF THE DATABASE ........................................... 327 
 

6.3.1 Identification of Data Needs .......................................... 327 
 

6.3.2 Ongoing Studies .................................................... 330 
 

7. REGULATIONS AND ADVISORIES .............................................. 333 
 

8. REFERENCES ................................................................. 343 
 

9. GLOSSARY ................................................................... 417 
 

APPENDICES 

A. ATSDR MINIMAL RISK LEVEL ................................................. A-1 
 

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

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

LIST OF FIGURES 

2-1 Levels of Significant Exposure to Formaldehyde—Inhalation ........................ 35 
 

2-2 Levels of Significant Exposure to Formaldehyde—Oral ............................ 129 
 

2-3 Metabolic Pathways of Formaldehyde Biotransformation ........................... 178 
 

2-4 Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) 

Model for A Hypothetical Chemical Substance ................................... 185 
 

2-5 Existing Information on Health Effects of Formaldehyde ........................... 241 
 

5-1 Frequency of NPL Sites with Formaldehyde Contamination ......................... 284 
 

FORMALDEHYDE xviii 

LIST OF TABLES 

2-1 Levels of Significant Exposure to Formaldehyde—Inhalation ........................... 13 
 

2-2 Definitions of Selected Epidemiology Terms ......................................... 91 
 

2-3 Meta-analysis of Epidemiology Studies of Cancer of the Nose and Nasal Sinuses and 

Nasopharyngeal Cancer ......................................................... 94 
 

2-4 Levels of Significant Exposure to Formaldehyde—Oral ............................... 116 
 

2-5 Levels of Significant Exposure to Formaldehyde—Dermal ............................. 155 
 

2-6 Genotoxicity of Formaldehyde In Vivo ............................................ 220 
 

2-7 Genotoxicity of Formaldehyde In Vitro ............................................ 221 
 

2-8 Ongoing Studies on Formaldehyde ................................................ 264 
 

3-1 Chemical Identity of Formaldehyde ............................................... 268 
 

3-2 Physical and Chemical Properties of Formaldehyde .................................. 269 
 

4-1 Facilities That Manufacture or Process Formaldehyde ................................. 273 
 

4-2 U.S. Formaldehyde Capacity and Production ........................................ 275 
 

4-3 Distribution of Formaldehyde Production According to Uses in the United States ........... 277 
 

5-1 Releases to the Environment from Facilities That Manufacture or Process Formaldehyde ..... 288 
 

5-2 Environmental Transformation Products of Formaldehyde by Medium ................... 297 
 

5-3 Indoor Concentrations of Formaldehyde in U.S. Homes ............................... 301 
 

5-4 Ongoing Studies on the Potential for Human Exposure to Formaldehyde .................. 316 
 

6-1 Analytical Methods for Determining Formaldehyde and Metabolites in Biological Samples . . . 318
 

6-2 Analytical Methods for Determining Formaldehyde in Environmental Samples ............. 321 
 

6-3 Ongoing Studies on Formaldehyde ................................................ 331 
 

7-1 Regulations and Guidelines Applicable to Formaldehyde .............................. 334 
 

FORMALDEHYDE 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about formaldehyde and the effects of exposure. 

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

nation. These sites make up the National Priorities List (NPL) and are the sites targeted for long-term 

federal cleanup activities. Formaldehyde has been found in at least 26 of the 1,428 current or former NPL 

sites. However, it’s unknown how many NPL sites have been evaluated for this substance. As more sites 

are evaluated, the sites with formaldehyde may increase. This is important because exposure to this 

substance may harm you and because these sites may be sources of exposure. 

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

drum or bottle, it enters the environment. This release does not always lead to exposure. You are 

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 formaldehyde, many factors determine whether you’ll 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 the other chemicals you’re exposed to and your age, sex, diet, family traits, lifestyle, and 

state of health. 

1.1 WHAT IS FORMALDEHYDE? 

Formaldehyde is a colorless, flammable gas at room temperature. It has a pungent, distinct odor and may 

cause a burning sensation to the eyes, nose, and lungs at high concentrations. Formaldehyde is also 

known as methanal, methylene oxide, oxymethylene, methylaldehyde, and oxomethane. Formaldehyde 

can react with many other chemicals, and it will break down into methanol (wood alcohol) and carbon 

monoxide at very high temperatures. 

Formaldehyde is naturally produced in very small amounts in our bodies as a part of our normal, 

everyday metabolism and causes us no harm. It can also be found in the air that we breathe at home and 

at work, in the food we eat, and in some products that we put on our skin. A major source of 

formaldehyde that we breathe every day is found in smog in the lower atmosphere. Automobile exhaust 
FORMALDEHYDE 2 

1. PUBLIC HEALTH STATEMENT 

from cars without catalytic converters or those using oxygenated gasoline also contain formaldehyde. At 

home, formaldehyde is produced by cigarettes and other tobacco products, gas cookers, and open 

fireplaces. It is also used as a preservative in some foods, such as some types of Italian cheeses, dried 

foods, and fish. Formaldehyde is found in many products used every day around the house, such as 

antiseptics, medicines, cosmetics, dish-washing liquids, fabric softeners, shoe-care agents, carpet cleaners, 

glues and adhesives, lacquers, paper, plastics, and some types of wood products. Some people are 

exposed to higher levels of formaldehyde if they live in a new mobile home, as formaldehyde is given off 

as a gas from the manufactured wood products used in these homes. 

Formaldehyde is used in many industries. It is used in the production of fertilizer, paper, plywood, and 

urea-formaldehyde resins. It is present in the air in iron foundries. It is also used in the production of 

cosmetics and sugar, in well-drilling fluids, in agriculture as a preservative for grains and seed dressings, 

in the rubber industry in the production of latex, in leather tanning, in wood preservation, and in 

photographic film production. Formaldehyde is combined with methanol and buffers to make embalming 

fluid. Formaldehyde is also used in many hospitals and laboratories to preserve tissue specimens. 

1.2	 WHAT HAPPENS TO FORMALDEHYDE WHEN IT ENTERS THE 

ENVIRONMENT? 

Most of the formaldehyde you are exposed to in the environment is in the air. Formaldehyde dissolves 

easily in water, but it does not last a long time in water and is not commonly found in drinking water 

supplies. Most formaldehyde in the air also breaks down during the day. The breakdown products of 

formaldehyde in air include formic acid and carbon monoxide. Formaldehyde does not seem to build up 

in plants and animals, and although formaldehyde is found in some food, it is not found in large amounts. 

You will find more information about where formaldehyde comes from, how it behaves, and how long it 

remains in the environment in Chapter 5. 
FORMALDEHYDE 3 

1. PUBLIC HEALTH STATEMENT 

1.3 HOW MIGHT I BE EXPOSED TO FORMALDEHYDE? 

You are exposed to small amounts of formaldehyde in the air. It occurs from both natural and man made 

sources although combustion is the largest source. If you live in an unpopulated area, you may be 

exposed to about 0.2 parts per billion (ppb) of formaldehyde in the air outdoors. In suburban areas, you 

may be exposed to about 2–6 ppb of formaldehyde. If you live in a heavily populated area or near some 

industries, you may be exposed to 10–20 ppb. You may also be exposed to higher levels of formaldehyde 

during rush hour commutes in highly populated areas because it is formed in automobile and truck 

exhaust. 

There is usually more formaldehyde present indoors than outdoors. Formaldehyde is released to the air 

from many home products and you may breath in formaldehyde while using these products. Latex paint, 

fingernail hardener, and fingernail polish release a large amount of formaldehyde to the air. Plywood and 

particle board, as well as furniture and cabinets made from them, fiberglass products, new carpets, 

decorative laminates, and some permanent press fabrics give off a moderate amount of formaldehyde. 

Some paper products, such as grocery bags and paper towels, give off small amounts of formaldehyde. 

Because these products contain formaldehyde, you may also be exposed on the skin by touching or 

coming in direct contact with them. You may also be exposed to small amounts of formaldehyde in the 

food you eat. You are not likely to be exposed to formaldehyde in the water you drink because it does not 

last a long time in water. 

Many other home products contain and give off formaldehyde although the amount has not been 

carefully measured. These products include household cleaners, carpet cleaners, disinfectants, cosmetics, 

medicines, fabric softeners, glues, lacquers, and antiseptics. You may also breath formaldehyde if you use 

unvented gas or kerosene heaters indoors or if you or someone else smokes a cigar, cigarette, or pipe 

indoors. The amount of formaldehyde in mobile homes is usually higher than it is in conventional homes 

because of their lower air turnover. 

People who work at or near chemical plants that make or use formaldehyde can be exposed to higher than 

normal amounts of formaldehyde. Doctors, nurses, dentists, veterinarians, pathologists, embalmers, 

workers in the clothing industry or in furniture factories, and teachers and students who handle preserved 

specimens in laboratories also might be exposed to higher amounts of formaldehyde. The National 
FORMALDEHYDE 4 

1. PUBLIC HEALTH STATEMENT 

Institute for Occupational Safety and Health (NIOSH) estimates that 1,329,332 individuals in the United 

States have had the potential for occupational exposure to formaldehyde. 

1.4 HOW CAN FORMALDEHYDE ENTER AND LEAVE MY BODY? 

Formaldehyde can enter your body after you breath it in, drink or eat it, or when it comes in contact with 

your skin. Formaldehyde is quickly absorbed from the nose and the upper part of your lungs. When 

formaldehyde is eaten and drunk, it is also very quickly absorbed. Very small amounts are probably 

absorbed from formaldehyde that comes in contact with your skin. Once absorbed, formaldehyde is very 

quickly broken down. Almost every tissue in the body has the ability to break down formaldehyde. It is 

usually converted to a non-toxic chemical called formate, which is excreted in the urine. Formaldehyde 

can also be converted to carbon dioxide and breathed out of the body. It can also be broken down so the 

body can use it to make larger molecules needed in your tissues, or it can attach to deoxyribonucleic acid 

(DNA) or to protein in your body. Formaldehyde is not stored in fat. 

1.5 HOW CAN FORMALDEHYDE AFFECT MY HEALTH? 

Formaldehyde is irritating to tissues when it comes into direct contact with them. Some people are more 

sensitive to the effects of formaldehyde than others. The most common symptoms include irritation of 

the eyes, nose, and throat, along with increased tearing, which occurs at air concentrations of about 

0.4–3 parts per million (ppm). NIOSH states that formaldehyde is immediately dangerous to life and 

health at 20 ppm. One large study of people with asthma found that they may be more sensitive to the 

effects of inhaled formaldehyde than other people; however, many studies show that they are not more 

sensitive. Severe pain, vomiting, coma, and possible death can occur after drinking large amounts of 

formaldehyde. Skin can become irritated if it comes into contact with a strong solution of formaldehyde. 

To protect the public from the harmful effects of toxic chemicals and to find ways to treat people who 

have been harmed, scientists use many tests. 

One way to see if a chemical will hurt people is to learn how the chemical is absorbed, used, and released 

by the body; for some chemicals, animal testing may be necessary. Animal testing may also be used to 

identify health effects such as cancer or birth defects. Without laboratory animals, scientists would lose a 

basic method to get information needed to make wise decisions to protect public health. Scientists have 
FORMALDEHYDE 5 

1. PUBLIC HEALTH STATEMENT 

the responsibility to treat research animals with care and compassion. Laws today protect the welfare of 

research animals, and scientists must comply with strict animal care guidelines. 

Several studies of laboratory rats exposed for life to high amounts of formaldehyde in air found that the 

rats developed nose cancer. Some studies of humans exposed to lower amounts of formaldehyde in 

workplace air found more cases of cancer of the nose and throat (nasopharyngeal cancer) than expected, 

but other studies have not found nasopharyngeal cancer in other groups of workers exposed to 

formaldehyde in air. The Department of Health and Human Services (DHHS) has determined that 

formaldehyde may reasonably be anticipated to be a human carcinogen (NTP). The International Agency 

for Research on Cancer (IARC) has determined that formaldehyde is probably carcinogenic to humans. 

This determination was based on specific judgements that there is limited evidence in humans and 

sufficient evidence in laboratory animals that formaldehyde can cause cancer. The Environmental 

Protection Agency (EPA) has determined that formaldehyde is a probable human carcinogen based on 

limited evidence in humans and sufficient evidence in laboratory animals. More information on the 

health effects of formaldehyde can be found in Chapter 2. 

1.6 HOW CAN FORMALDEHYDE AFFECT CHILDREN? 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans. Potential effects on children resulting from exposures of the 

parents are also considered. 

Children and adults are likely to be exposed to formaldehyde in the same way. The most common way 

for children to be exposed to formaldehyde is by breathing it. Children may also be exposed by wearing 

some types of new clothes or cosmetics. A small number of studies have looked at the health effects of 

formaldehyde in children. It is very likely that breathing formaldehyde will result in nose and eye 

irritation (burning feeling, itchy, tearing, and sore throat). We do not know if the irritation would occur at 

lower concentrations in children than in adults. Studies in animals suggest that formaldehyde will not 

cause birth defects in humans. Inhaled formaldehyde or formaldehyde applied to the skin is not likely to 

be transferred from mother to child in breast milk or to reach the developing fetus. 
FORMALDEHYDE 6 

1. PUBLIC HEALTH STATEMENT 

1.7	 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO 

FORMALDEHYDE? 

If your doctor finds that you have been exposed to significant amounts of formaldehyde, ask if children 

may also be exposed. When necessary your doctor may need to ask your state department of public 

health to investigate. 

Formaldehyde is usually found in the air. Formaldehyde levels are also higher indoors than outdoors. 

Opening windows or using a fan to bring in fresh air is the easiest way to lower formaldehyde levels in 

the home and reduce the risk of exposure to your family. 

Removing formaldehyde sources from the house will also reduce the risk of exposure. Since 

formaldehyde is found in tobacco smoke, not smoking or smoking outside will reduce exposure to 

formaldehyde. Unvented heaters, such as portable kerosene heaters, also produce formaldehyde. If you 

do not use these heaters in your home or shop, you help to prevent the build up of formaldehyde indoors. 

Formaldehyde is found in small amounts in many consumer products including antiseptics, medicines, 

dish-washing liquids, fabric softeners, shoe-care agents, carpet cleaners, glues, adhesives, and lacquers. If 

you or a member of your family uses these products, providing fresh outdoor air when you use them, this 

will reduce your exposure to formaldehyde. Some cosmetics, such as nail hardeners, have very high 

levels of formaldehyde. If you do not use these products in a small room, or if you have plenty of 

ventilation when you use them, you will reduce your exposure to formaldehyde. If your children are not 

in the room when you use these products, you will also reduce their exposure to formaldehyde. 

Formaldehyde is emitted from some wood products such as plywood and particle board, especially when 

they are new. The amount of formaldehyde released from them decreases slowly over a few months. If 

you put these materials in your house, or buy furniture or cabinets made from them, opening a window 

will lower formaldehyde in the house. The amount of formaldehyde emitted to the house will be less if 

the wood product is covered with plastic laminate or coated on all sides. If it is not, sealing the 

unfinished sides will help to lower the amount of formaldehyde that is given off. 

Some permanent press fabrics emit formaldehyde. Washing these new clothes before use will usually 

lower the amount of formaldehyde and reduce your family’s risk of exposure. 
FORMALDEHYDE 7 

1. PUBLIC HEALTH STATEMENT 

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

EXPOSED TO FORMALDEHYDE? 

We have no reliable test to determine how much formaldehyde you have been exposed to or whether you 

will experience any harmful health effects. 

More information about medical tests for formaldehyde can be found in Chapter 2. 

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. Federal agencies that develop regulations for toxic substances include the EPA, 

the Occupational Safety and Health Administration (OSHA), and the Food and Drug Administration 

(FDA). Recommendations provide valuable guidelines to protect public health but cannot be enforced by 

law. Federal organizations that develop recommendations for toxic substances include the Agency for 

Toxic Substances and Disease Registry (ATSDR) and the NIOSH. 

Regulations and recommendations can be expressed in not-to-exceed levels in air, water, soil, or food that 

are usually based on levels that affect animals, then they are adjusted to help protect people. Sometimes 

these not-to-exceed levels differ among federal organizations because of different exposure times (an 8­

hour workday or a 24-hour day), the use of different animal studies, or other factors. 

Recommendations and regulations are also periodically updated 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 formaldehyde include the following: 

Several international, national, and state authorities have established regulations or guidelines for the use 

and production of formaldehyde. OSHA has established the permissible exposure limit (PEL) 8-hour 

time-weighted average (TWA) at 0.75 ppm and the 15-minute Short-Term Exposure Limit (STEL) at 

2 ppm. The EPA sets regulations for reporting quantities used and how much formaldehyde can legally 

be produced from automobile exhaust; the FDA also has regulations about the use of formaldehyde in the 

food you eat. 
FORMALDEHYDE 8 

1. PUBLIC HEALTH STATEMENT 

Non-enforceable guidelines have also been established for formaldehyde. The American Conference of 

Governmental and Industrial Hygienists (ACGIH) has established a ceiling limit for occupational 

exposure (Threshold Limit Value [TLV]) of 0.4 ppm. NIOSH has a recommended exposure limit for 

occupational exposure (8-hour TWA) of 0.016 ppm, and a 15-minute ceiling limit of 0.1 ppm. 

More information about the federal and state regulations and guidelines for formaldehyde can be found in 

Chapter 7. 

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 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology
 

1600 Clifton Road NE, Mailstop E-29
 

Atlanta, GA 30333
 

* Information line and technical assistance 

Phone: (800) 447-1544
 

Fax: (404) 639-6359
 

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

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

substances. 

* To order toxicological profiles, contact 

National Technical Information Service
 

5285 Port Royal Road
 

Springfield, VA 22161
 

Phone: (800) 553-6847 or (703) 487-4650
 
FORMALDEHYDE 9 

2. HEALTH EFFECTS 

2.1 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 formaldehyde. 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. 

2.2 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 

lowest-observed-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 
FORMALDEHYDE 10 

2. HEALTH EFFECTS 

exposure at which major health effects start to appear. LOAELs or NOAELs should also help in 

determining whether or not 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 (LOAEL) 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 formaldehyde 

are indicated in Tables 2-1, 2-4, and 2-5 and Figures 2-1 and 2-2. Because cancer effects could occur at 

lower exposure levels, Figure 2-1 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. 

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been 

made for formaldehyde. 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 1990c), 

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. 
FORMALDEHYDE 11 

2. HEALTH EFFECTS 

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. 

2.2.1 Inhalation Exposure 

Formaldehyde vapors used in controlled-exposure inhalation studies can be generated by heating 

commercial formalin, aqueous solutions containing 30–50% formaldehyde by weight plus methanol or 

other substances to inhibit intrinsic polymerization, or by heating solid paraformaldehyde, a 

formaldehyde polymer. Unless noted otherwise, inhalation studies used in the preparation of this profile 

provided clear evidence that formaldehyde was the only added gas in the experimental atmosphere. 

2.2.1.1 Death 

Reports of deaths in humans from short-term inhalation exposure to formaldehyde were not located. 

Increased rates of cancer-related mortality associated with occupational exposure to formaldehyde have 

been found in some epidemiological studies, but not in others. A more thorough discussion of available 

epidemiological studies is available in Section 2.2.1.8. 

Repeated exposure to formaldehyde vapors at 40 ppm, 6 hours/day, 5 days/week for up to 13 weeks 

produced 80% mortality in B6C3F1 mice, whereas mice exposed with the same protocol to 20 ppm 

showed no mortalities within the exposure period (Maronpot et al. 1986). Deaths occurred predominately 

in the fifth and sixth week of exposure and were associated with ataxia, severe body weight depression, 

and inflammation and metaplasia in the nasal cavity, larynx, trachea, and lungs. Deaths were attributed to 

occlusive tracheal lesions and/or prominent seropurulent rhinitis (Maronpot et al. 1986). 

In other intermediate duration inhalation bioassays, no exposure-related deaths or early mortalities were 

found in Wistar rats exposed to up to 20 ppm, 6 hours/day, 5 days/week for 13 weeks (Woutersen et al. 

1987), in F344 rats, Cynomolgus monkeys, or Golden Syrian hamsters exposed to up to 2.95 ppm, 

22 hours/day, 7 days/week for 26 weeks (Rusch et al. 1983), or in Wistar rats exposed to up to 20 ppm, 

6 hours/day, 5 days/week for 4, 8, or 13 weeks and subsequently observed for 117 weeks without 

exposure (Feron et al. 1988). No exposure-related maternal or fetal deaths occurred in studies that 

exposed pregnant Sprague-Dawley rats to up to 10 ppm formaldehyde, 6 hours/day on gestation days 
FORMALDEHYDE 12 

2. HEALTH EFFECTS 

6 through 15 (Martin 1990) or up to 40 ppm, 6 hours/day on gestation days 6 through 20 (Saillenfait et al. 

1989). 

In chronic inhalation bioassays, increased mortality (compared with controls) was found in 

Sprague-Dawley rats exposed to 14.2 ppm formaldehyde, 6 hours/day, 5 days/week for up to 588 days 

(Albert et al. 1982), in F344 rats exposed to 5.6 or 14.3 ppm (but not 2 ppm), 6 hours/day, 5 days/week 

for up to 24 months (Kerns et al. 1983b; Swenberg et al. 1980), in F344 rats exposed to 15 ppm (but not 

to 0.7, 2, 6, or 10 ppm) 6 hours/day, 5 days/week for 24 months (Monticello et al. 1996), and in F344 rats 

exposed to 15 ppm (but not to 0.3 or 2 ppm), 6 hours/day, 5 days/week for up to 28 months (Kamata et al. 

1997). In general, observations of increased mortality in the rat bioassays occurred after about one year 

of exposure and were associated with the development of nasal squamous cell carcinomas. Golden Syrian 

hamsters exposed to 10 ppm formaldehyde, 5 hours/day, 5 days/week for life showed a small, but 

statistically significant, increase in mortality compared with controls, but no increased incidence of nasal 

tumors and only a minimal (5% versus zero in controls) increased incidence of hyperplasia or metaplasia 

in the nasal epithelium (Dalbey 1982). No exposure-related increased mortality was found in 

B6C3F1 mice exposed to up to 14.3 ppm for 6 hours/day, 5 days/week for 24 months (Kerns et al. 

1983b). 

The LOAEL values from each reliable study for death in each species and duration category are recorded 

in Table 2-1 and plotted in Figure 2-1. 

2.2.1.2 Systemic Effects 

The highest NOAEL values and all LOAEL values from each reliable study for each systemic effect in 

each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 




























 

FORMALDEHYDE 41 

2. HEALTH EFFECTS 

Results from human and animal studies indicate that the critical target organs to airborne formaldehyde 

are the nose and the eyes, with the lungs being a secondary target at high exposure levels. Due to rapid, 

detoxifying metabolism of formaldehyde by most, if not all, cells, tissues, and organs distant from portals 

of entry are spared toxic effects from formaldehyde at concentrations normally expected to be 

encountered in the ambient or workplace atmosphere. 

Respiratory Effects. 

The respiratory tract, especially the upper respiratory tract, is a critical target of the toxicity of airborne 

formaldehyde as shown by acute controlled exposure human studies, by studies of humans exposed 

acutely or repeatedly under occupational or residential conditions, and by studies of animals (including 

primates) exposed by inhalation for acute, intermediate, and chronic durations. 

Acute Controlled Exposure Human Studies. More than 15 published studies of respiratory function 

and/or irritation of the nose, eyes, and throat are available involving acute controlled exposure of 

volunteers, generally at formaldehyde concentrations #3 ppm. Recent reviews of these studies include 

those by ACGIH (1992), Krivanek and Imbus (1992), and Paustenbach et al. (1997). 

Controlled exposure human studies have found that short-term inhalation exposures to concentrations 

ranging from 0.4 to 3 ppm can produce symptoms of mild to moderate irritation of the eyes, nose, and 

throat. The odor threshold for formaldehyde in humans has been reported to be 1 ppm (Leonardos et al. 

1969), but others have noted that it may range as low as 0.05 ppm (ACGIH 1992). Descriptions follow of 

findings for irritation of the eyes, nose, and throat from a sampling of available controlled exposure 

studies of acute irritation, emphasizing studies that examined symptoms of irritation at the lower end of 

this concentration range (Andersen and Molhave 1983; Bender et al. 1983; Day et al. 1984; Gorski et al. 

1992; Krakowiak et al. 1998; Kulle et al. 1987; Pazdrak et al. 1993; Weber-Tschopp et al. 1977). Several 

of these studies reported that the initial severity of irritation lessened to some degree with continued 

exposure (Bender et al. 1983; Day et al. 1984; Green et al. 1987; Weber-Tschopp et al. 1977). 

Weber-Tschopp et al. (1977) exposed a group of 33 healthy subjects for 35 minutes to concentrations of 

formaldehyde that increased during the period from 0.03 to 3.2 ppm; another group of 48 healthy subjects 

was exposed to 0.03, 1.2, 2.1, 2.8, and 4.0 ppm for 1.5 minute intervals. Eye and nose irritation were 

reported on a 1–4 scale (1=none to 4=strong) in both experiments, and eye blinking rate was measured in 
FORMALDEHYDE 42 

2. HEALTH EFFECTS 

the second experiment. Average indices of eye and nose irritation were increased in both experiments to 

a small, but statistically significant, extent at 1.2 ppm compared with indices for nonexposed controlled 

conditions. The published report of this study graphically showed average severity scores of about 

1.3–1.4 for both indices at 1.2 ppm compared with 1.0–1.1 for nonexposed conditions. The average 

severity score was increased to a greater degree at higher concentrations, but was less than about 2.5 at 

the highest exposure concentration, 4 ppm. Average rates of eye blinking were not significantly affected 

at 1.2 ppm, but were statistically significantly increased at 2.1 ppm (about 35 blinks/minute at 2.1 ppm 

versus about 22 blinks/minutes under nonexposed conditions). 

Andersen and Molhave (1983) exposed a group of 16 healthy subjects to 0.3, 0.5, 1.0, and 2.0 mg/m3

 (0.2, 

0.4, 0.8, and 1.6 ppm) for 4-hour periods preceded by a nonexposed period of two hours. Subjects were 

asked to assess “discomfort” on a 0–100 scale ranging from 0=no discomfort to 100=intolerable 

discomfort (scores between 1 and 33 were rated as “slight discomfort”). Average peak discomfort scores 

for the group generally increased with exposure concentration, but the average discomfort score for the 

highest exposure concentration (1.6 ppm) never exceeded 18. Numbers of subjects who reported “No 

discomfort” ratings at the end of exposure periods were 7, 13, 10, and 6, respectively for 0.2, 0.4, 0.8, and 

1.6 ppm; respective numbers of subjects reporting “conjunctival irritation and dryness in the nose and 

throat” were 3, 5, 15, and 15 of the 16 subjects exposed to each respective concentration. A statistical 

analysis of these data was not reported. 

Bender et al. (1983) exposed groups of 5–28 healthy subjects to 0, 0.35, 0.56, 0.7, 0.9, or 1.0 ppm for 

6-minute periods and asked them to note when they experienced eye irritation and to rate eye irritation on 

a 0–3 scale (0=none to 3=severe, with 1=slight). The subjects were selected from a larger group of 

subjects in a preliminary screening test as those who “responded to 1.3 and 2.2 ppm”. Upper respiratory 

tract irritation was not rated in this study. Average initial severity scores for the five exposure 

concentrations in increasing order were 0.71, 0.79, 0.86, 0.80, and 1.56; no irritation was noted with 

“clean air” exposure. The median times to noting eye irritation (response time measured in seconds) 

generally decreased with increasing concentration as follows: 360 (clean air), 268, 217, 72, 119, and 

78 seconds. Numbers of subjects who reported response times that were less than their clean air response 

time were: 5/12 at 0.35 ppm, 14/26 at 0.56 ppm, 4/7 at 0.7 ppm, 3/5 at 0.9 ppm, and 20/27 at 1.0 ppm. 

The elevation in percentage of subjects with shortened response time was only statistically significant at 

the 1 ppm level. 
FORMALDEHYDE 43 

2. HEALTH EFFECTS 

Kulle et al. (1987; Kulle 1993) exposed 19 healthy subjects to 0, 1.0, and 2.0 ppm for 3-hour periods and 

asked them to note symptoms of eye and nose/throat irritation and to rate severity on a 0–3 scale: 0=none; 

1=mild (present but not annoying); 2=moderate (annoying); and 3=severe (debilitating). Ten of the 

subjects were also exposed to 0.5 ppm and nine were exposed to 3 ppm for 3-hour periods. The 

frequencies of subjects reporting eye irritation or nose/throat irritation increased with increasing exposure 

concentration, especially at concentrations $1 ppm. Under nonexposed conditions, 3/19 subjects noted 

mild nose/throat irritation and 1/19 noted mild eye irritation. At 0.5 ppm, 1/10 subjects noted mild 

nose/throat irritation, but none reported eye irritation. Frequencies for subjects with mild or moderate eye 

irritation were 4/19 at 1 ppm (1 was moderate), 10/19 at 2 ppm (4 were moderate), and 9/9 at 3 ppm 

(4 were moderate). The increased frequency for eye irritation (compared with controls) was statistically 

significant at $2 ppm. Frequencies for mild nose/throat irritation were 1/19 at 1 ppm, 7/19 at 2 ppm, and 

2/9 at 3 ppm. Compared with control frequency for nose/throat irritation, only the response at 2 ppm was 

significantly elevated. 

In a study of volunteers exposed to 1 ppm for 90 minutes, seven subjects reported eye irritation and three 

reported nasal congestion among nine subjects who had previously complained of health effects from 

exposure to urea-formaldehyde insulation in their homes (Day et al. 1984). A similar response to 1 ppm 

formaldehyde was noted among the other nine subjects in this study who had no previous complaints: 

eight reported eye irritation and four reported nasal congestion from the 90-minute exposure. 

In groups of 15 healthy subjects and 15 asthmatics exposed to 2 ppm for 40 minutes while exercising, 

“mild” eye irritation (average severity scores of 1.1 and 1.6 on a 5-point scale ranging from 0=none to 

4=incapacitating, with 1=mild) was reported by eight healthy and five asthmatic subjects (Schachter et al. 

1986; Witek et al. 1986, 1987). Nasal irritation was reported by 5/15 healthy and 5/15 asthmatics 

subjects with average severity scores of 1.2 and 1.8, respectively. 

Gorski and colleagues have reported that symptoms of upper respiratory tract irritation occurred in three 

studies comparing respiratory responses to 2-hour exposures to placebo or 0.5 mg formaldehyde/m3 

(0.4 ppm) in healthy, nonexposed subjects, in subjects with formaldehyde-sensitive contact dermatitis 

(Gorski et al. 1992; Pazdrak et al. 1993), and in formaldehyde-exposed workers with bronchial asthma 

(Krakowiak et al. 1998). Krakowiak et al. (1998) noted that, for these studies, formaldehyde vapors were 

generated by evaporating 10 μL of a 10% aqueous solution of formaldehyde in a 12-m, temperature- and 

humidity-controlled, exposure chamber. Measured airborne concentrations of formaldehyde ranged from 
FORMALDEHYDE 44 

2. HEALTH EFFECTS 

0.2 to 0.7 mg/m3 with a mean of 0.5 mg/m3 (0.4 ppm). Gorski et al. (1992) reported that, after exposure 

to 0.4 ppm, 1/5 healthy subjects and 3/13 subjects with formaldehyde-sensitive contact dermatitis 

experienced nose irritation, sneezing, or eye irritation. Similar exposure produced statistically significant 

increases in the average number and proportion of eosinophils and the concentration of albumin and total 

protein in nasal lavage fluid, both in groups of 9 sensitized subjects and in groups of 11 nonexposed 

subjects; the responses in the two groups were not significantly different (Pazdrak et al. 1993). Pazdrak et 

al. (1993) reported that exposure “caused itching, sneezing, and congestion”, but did not indicate the 

number of subjects reporting these symptoms. In another experiment, exposure to 0.4 ppm also produced 

similar statistically significant increases in eosinophils and protein in nasal lavage fluid in other groups of 

10 nonexposed subjects and 10 formaldehyde-exposed workers with bronchial asthma, and “caused 

sneezing, itching and congestion in all subjects” (Krakowiak et al. 1998). Pulmonary functions were also 

measured in each of these studies, but no exposure-related effects were found in any of the groups (see 

below). An acute inhalation MRL of 0.04 ppm was calculated as described in the footnote in Table 2-1 

and in Appendix A based on the LOAEL (0.4 ppm) from the study by Pazdrak et al. (1993). 

Formaldehyde-induced effects on human pulmonary function variables including forced vital capacity 

(FVC), forced expiratory volume in 1.0 seconds (FEV1.0), peak expiratory flow rate (PEFR), and forced 

expiratory flowrate between 25 and 75% FVC (FEFR25–75), have not been found as consistently as 

symptoms of eye and nose irritation at acute exposure levels in the range of 0.4–3 ppm. In controlled 

exposure studies, no statistically significant exposure-related effects on lung function measurements were 

found in 10 healthy subjects exposed to up to 2 ppm for 3 hours (Kulle et al. 1987; Kulle 1993), 

15 healthy subjects exposed to 0 or 2 ppm for 40 minutes with or without exercise (Schachter et al. 1986; 

Witek et al. 1986), 15 formaldehyde-exposed laboratory workers exposed to 0 or 2 ppm for 40 minutes 

with or without exercise (Schachter et al. 1987), 15 asthmatic volunteers exposed to 0 or 2 ppm for 

40 minutes with or without exercise (Witek et al. 1986, 1987), 18 subjects, 9 of whom had complaints of 

health effects from exposure to urea-formaldehyde foam insulation in their homes, exposed to 1 ppm for 

90 minutes (Day et al. 1984), 16 healthy student volunteers exposed to up to 1.7 ppm for 4 hours 

(Andersen and Molhave 1983), 13 subjects with allergic dermal sensitivity to formaldehyde and 5 

healthy subjects exposed to 0.4 ppm for 2 hours (Gorski et al. 1992), 10 formaldehyde-exposed textile 

or shoe manufacturing workers with purported bronchial asthma and 10 nonexposed healthy subjects 

exposed to 0.4 ppm for 2 hours (Krakowiak et al. 1998), 13 formaldehyde-exposed subjects, who 

previously reported symptoms of chest tightness, coughing, or wheezing, exposed to placebo or up 

to 3 ppm for 20 minutes (Reed and Frigas 1984), or 15 patients with documented severe bronchial 
FORMALDEHYDE 45 

2. HEALTH EFFECTS 

hyperresponsiveness (to histamine) exposed to room air and up to 0.7 ppm for 90 minutes (Harving et al. 

1986, 1990). 

A few controlled exposure studies have found only subtle or infrequent effects of acute exposure to low 

concentrations of formaldehyde on pulmonary function variables (Green et al. 1987; Nordman et al. 1985; 

Sauder et al. 1986). Nordman et al. (1985) measured PEFR, FVC, and FEV1 during and after a 30-minute 

“challenge” exposure to placebo, 1 or 2 ppm in a group of 230 patients who had been occupationally 

exposed to formaldehyde and had reported respiratory symptoms consistent with asthma during a 6-year 

period. Patients were first challenged with 1 ppm; if no response was found, a second challenge of 2 ppm 

was given. Exposure-related drops in PEFR of 15% or greater in response to 2 ppm formaldehyde were 

found in 12/230 of the patients; one of these 12 subjects showed a response to 1 ppm. Formaldehyde 

concentrations were not measured during each test, but periodic checks of exposure concentrations 

indicated that challenge concentrations ranged from 0.8 to 0.9 ppm for the 1 ppm target and 1.7–2.0 ppm 

for the 2 ppm target. Nordman et al. (1985) concluded that pulmonary function sensitivity to 

formaldehyde, at concentrations of 1 to 2 ppm, is rare. Sauder et al. (1986) measured small, but 

statistically significant, decreases in FEV1 (2% decrease) and FEFR25–75 (7% decrease) after 30 minutes of 

exposure to 3 ppm, but not after 1 or 3 hours of exposure, in a group of nine healthy subjects who 

performed intermittent exercise during exposure and who served as their own controls. Green et al. 

(1987) measured statistically significant, but small, average deficits (2–3%) in FEV1, FVC, and FEV3 (but 

no change in FEFR25–75) in a group of 22 exercising healthy subjects during and after 1 hour of exposure 

to 3 ppm, but found no significant deficits in a group of 16 asthmatic subjects similarly exposed. Among 

the 38 subjects in this study, five (13%; 2 normal and 3 asthmatic ) displayed exposure-related percentage 

deficits in FEV1 greater than 10%, but generally less than 15%. 

Acute Occupational Exposure Human Studies. Numerous assessments of pulmonary function variables 

in formaldehyde-exposed workers during workday shifts have found, similar to findings from controlled 

exposure studies, either no effects or only small and subtle effects from formaldehyde exposure during a 

work period. Bracken et al. (1985) measured no significant changes in pulmonary function variables 

(FVC, FEV1, and FEFR25–75) during a workshift in which 10 laboratory technicians were exposed to 

estimated average formaldehyde concentrations ranging from 0.106±0.02 to 0.269±0.05 ppm. No 

significant differences in changes in pulmonary function variables across a workshift were found in 

groups of 22 embalmers exposed to an estimated mean concentration of 0.36±0.61 ppm (range 

0.08–0.81 ppm) during a 2- to 3-hour embalming procedure compared with a nonexposed group of 
FORMALDEHYDE 46 

2. HEALTH EFFECTS 

13 subjects (Holness and Nethercott 1989) or in groups of 55 plywood workers exposed to estimated 

concentrations ranging from 0.22 to 3.48 ppm compared with a nonexposed group of 50 subjects (Malaka 

and Kodama 1990). Kilburn et al. (1985a) reported that decreases in FVC, FEV1, and FEFR25–75 occurred 

during a workshift in a group of fiberglass batt workers and not in a group of nonexposed hospital 

workers, but workplace air concentrations of formaldehyde were not assessed for the batt workers. 

Alexandersson and Hedenstierna (1989) reported that small, but statistically significant, declines in 

FEV1/FVC and FEFR25–75 occurred during a workshift in a group of 11 nonsmoking woodworkers, but not 

in 10 smokers, who were exposed to an estimated mean TWA formaldehyde concentration of 

0.4±0.1 ppm. Alexandersson and Hedenstierna (1989) did not compare workshift changes in the exposed 

group to changes in a control group. Horvath et al. (1988) measured small, but statistically significant, 

average declines in FEFR50, FEFR75, and FEFR25–75 during a workshift in a group of 109 particle board 

workers exposed to estimated TWA formaldehyde concentrations ranging from 0.17 to 2.93 ppm 

(mean 0.69 ppm), but no significant workshift change in these variables in a group of 254 nonexposed, 

food-processing workers. Median concentrations of airborne nuisance particulates (i.e., wood dust) in the 

particle board plant were 0.38 and 0.11 mg/m3

 for total and respirable particulates, respectively. 

Akbar-Khanzadeh et al. (1994) found no statistically significant differences in workshift changes in 

pulmonary function variables (FVC, FEV1, FEV3, and FEFR25–75) in a group of 34 students exposed for 2­

to 3-hour periods to an estimated TWA concentration of 1.24±0.61 ppm (range 0.07–2.94 ppm) in a gross 

anatomy laboratory compared with a nonexposed group of 12 subjects, except that the exposed group 

showed an average 1.2% decline in FEV3 during exposure compared with a 1.3% increase in FEV3 for the 

controls during a comparable period. In another group of 50 students exposed to formaldehydecontaining embalming fluid in a 3-hour gross anatomy laboratory and a control group of 36 nonexposed 

students in a 3-hour physiotherapy laboratory, pulmonary function variables increased during the 3-hour 

periods, but the average increases in FEV1 and FEFR25–75 for the exposed group (2.7% and 2.2%, 

respectively) were statistically significantly less than the average increases (5.2% and 9.3%, respectively) 

for the control group (Akbar-Khanzadeh and Mlynek 1997). Estimates of breathing zone formaldehyde 

concentrations in the anatomy laboratory ranged from 0.3 to 4.45 ppm with a mean of 1.88±0.96 ppm. In 

both studies by Akbar-Khanzadeh and colleagues, eye and nose irritation were reported by more than 

70% of exposed subjects. 

Repeated-Exposure Human Studies. Studies of formaldehyde-exposed humans with repeated exposure 

under occupational or residential conditions provide confirmatory evidence that formaldehyde can be 

irritating to the upper respiratory tract (Boysen et al. 1990; Edling et al. 1988; Garry et al. 1980; 
FORMALDEHYDE 47 

2. HEALTH EFFECTS 

Holmstrom et al. 1989c; Holness and Nethercott 1989; Horvath et al. 1988; Ritchie and Lehnen 1987), 

but only limited evidence that pulmonary functions may be adversely affected by repeated exposure to 

formaldehyde (Alexandersson and Hedenstierna 1988, 1989; Bracken et al. 1985; Holness and Nethercott 

1989; Horvath et al. 1988; Khamgaonkar and Fulare 1991; Kriebel et al. 1993; Krzyzanowski et al. 1990; 

Malaka and Kodama 1990). 

Garry et al. (1980) surveyed 275 possible cases of formaldehyde exposure for which health complaints 

were registered during a 5-month period (February through June) in 1979 with the Minnesota Department 

of Health and measured formaldehyde air levels in living rooms and bedrooms of the subjects’ residences. 

Formaldehyde concentrations ranged from approximately 0.1 to 3 ppm; approximate mean values for the 

5 months were 0.65, 0.4, 0.2, 0.6, and 1.0 ppm. Eye, nose, and throat irritation was reported in about 75% 

of adults (age $18 years, n=102), 60% of children (age 3–12 years, n=30), and 60% of infants (n=36). 

Cough and wheeze reporting percentages were about 35% in adults, 70% in children, and 60% in infants. 

This study provided no information on the duration of exposure. 

Ritchie and Lehnen (1987) surveyed approximately 2,000 people living in conventional and mobile 

homes and measured formaldehyde concentrations in air samples taken from two rooms in each residence. 

Subjects were selected from requests made to the Minnesota Department of Health for formaldehyde 

testing. Reporting percentages of subjects with eye irritation, nose/throat irritation, headaches, and skin 

rash were recorded for homes with formaldehyde concentrations classified as "low" (<0.1 ppm), 

"medium" (0.1 ppm– <0.3 ppm), or "high" (>0.3 ppm). In both conventional and mobile homes with air 

concentrations >0.3 ppm, more than 60% of subjects reported eye irritation, nose/throat irritation, or 

headache; with air concentrations between 0.1 and 0.3 ppm, respective reporting percentages ranged 

approximately from 10 to 20%, 15 to 20%, and 20 to 25%, depending on home type. Reporting 

percentages for homes with concentrations <0.1 ppm were less than 10% for each of these three 

symptoms. A major limitation associated with this study is that the participants, in order to be eligible for 

the study, complained about symptoms and were therefore a self-selected group with a potential bias. 

Holness and Nethercott (1989) surveyed 84 funeral directors and apprentices exposed to an estimated 

mean concentration of 0.36±0.19 ppm (range 0.08–0.81 ppm) for an average of 8.2 years and 

38 nonexposed control subjects. Embalmers reported that symptoms of irritation of the eyes, upper 

respiratory tract, and skin occurred during work more frequently than controls: chronic bronchitis 
FORMALDEHYDE 48 

2. HEALTH EFFECTS 

(20 versus 3%), shortness of breath (20 versus 3%), and nasal irritation (44 versus 16%) were among the 

most common respiratory complaints. 

Horvath et al. (1988) surveyed 109 workers in a particle board and molded plastics plant for symptoms of 

respiratory tract irritation. The duration of exposure among exposed workers ranged from <1 year to 

20 years, with a mean and median of 10.3 and 10 years, respectively. Estimates of formaldehyde air 

concentrations ranged from 0.17 to 2.93 ppm with a mean of 0.69 ppm. Nuisance particles 

(predominantly softwood dust) were also detected in the particle board area. The percentages of particle 

board workers reporting a number of symptoms of respiratory irritation over a workshift were statistically 

significantly greater than workshift reporting percentages for a nonexposed group of 264 food-processing 

workers: cough (34.9 versus 18.9%), chest pains (9.2 versus 2%), phlegm production (26.6 versus 9.8%), 

burning nose (28.4 versus 2%), stuffy nose (33.9 versus 14.2%), burning or watering eyes (39.5 versus 

9.1%), itchy nose (21.1 versus 7.9%), and sore/burning throat (22 versus 3.9%). 

Several studies have histologically examined nasal biopsy specimens in formaldehyde-exposed workers 

and observed epithelial lesions that are consistent with the irritant and reactive properties of formaldehyde 

(Ballarin et al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c). 

Edling et al. (1988) found histological evidence of epithelial damage in biopsied specimens from the nasal 

mucosa of 75 workers from two particle board processing plants and a laminate plant. From air 

measurements occasionally made during an 8-year period before the study, estimates of TWA 

concentrations were calculated ranging from 0.08 to 0.9 ppm. (A mean TWA concentration was not 

reported, but the midpoint of this range is 0.49 ppm). Peaks of up to 4.07 ppm were measured during the 

8-year period. Air concentrations were qualitatively assessed as being “somewhat higher” during earlier 

periods. Wood dust air concentrations in the particle board plants ranged from 0.6 to 1.1 mg/m3

; air in the 

laminate plant was reported to be without wood dust. Employment durations ranged from 1 to 39 years 

with a mean of 10.5 years. Runny nose, nasal crusting, and runny eyes when at work were reported by

 60 and 75% of the exposed subjects, respectively, but frequencies were not compared in the report with 

frequencies of symptoms for a control group of 25 nonexposed subjects. Little information was given 

about the selection of the control group, except that they were “selected with regard to age and smoking 

habits”, however, 35% of exposed versus 48% of controls were smokers. Gross clinical examination 

showed that 25% of exposed workers had either swollen nasal mucosa or dry nasal mucosa; prevalence 

of this condition in the control group was not reported. Nasal mucosal biopsy sections were 
FORMALDEHYDE 49 

2. HEALTH EFFECTS 

assigned a score as follows: 0 - normal respiratory epithelium; 1 - loss of ciliated epithelium cells; 

2 - mixed cuboid/squamous epithelium, metaplasia; 3 - stratified squamous epithelium; 4 - keratosis; 

5 - keratosis with budding of epithelium; 6 - mild or moderate dysplasia; 7 - severe dysplasia; and 

8 - carcinoma. Normal ciliated epithelium was found only in 3/75 exposed subjects; whereas a loss of 

ciliated cells and goblet cell hyperplasia was noted in 59/75 subjects, and 6/75 exposed subjects showed 

mild dysplasia. No subjects displayed severe dysplasia or carcinoma. Edling et al. (1988) did not report 

incidences of nasal lesions found in the control group, but did report that the average histological score 

for the exposed group (2.8) was statistically significantly greater than the control score (1.8). Histological 

scores did not increase with increasing employment duration in the exposed group. The authors reported 

that there was no difference in average histological scores between the exposed workers from the particle 

board plants, where confounding exposure to wood dust occurred, and those from the laminate plant 

without wood dust exposure. This observation supports the hypothesis that the observed nasal epithelial 

lesions were caused by formaldehyde and not by an interaction between formaldehyde and wood dust. 

Holmstrom et al. (1989c) examined histological changes in nasal tissue specimens from a group of 

70 workers in a chemical plant that produced formaldehyde and formaldehyde resins for impregnation of 

paper, a group of 100 furniture factory workers working with particle board and glue components, and a 

nonexposed, control group of 36 office workers in the same village as the furniture factories. Mean 

durations of employment in the groups were 10.4 years (sd 7.3, range 1–36 years) for the chemical 

workers and 9.0 years (sd 6.3, range 1–30 years) for the furniture workers. Estimates of personal 

breathing zone air concentrations ranged from 0.04 to 0.4 ppm (median 0.24±0.13 ppm) for the chemical 

workers, from 0.16 to 0.4 ppm (median 0.20±0.04 ppm) for the furniture workers, and from 0.07 to 

0.13 ppm in the late summer for the office workers with a year-round office worker median reported as 

0.07 ppm with no standard deviation. The mean wood dust concentration in the furniture factory was 

reported to have been between 1 and 2 mg/m3

. Nasal mucosa specimens were taken from the medial or 

inferior aspect of the middle turbinate. Histology scores were assigned to each specimen based on a 

0–8 scale, identical to the scale used by Edling et al. (1988; described previously). Nasal histology scores 

ranged from 0 to 4 (mean 2.16, n=62) for the chemical workers, from 0 to 6 (mean 2.07, n=89) for the 

furniture workers, and from 0 to 4 (mean 1.46, n=32) for the office workers. The mean histological score 

for the chemical workers, but not the furniture workers, was significantly different from the control 

score, thus supporting the hypothesis that the development of the nasal lesions is formaldehyde-related 

and not obligatorily related to a possible interaction between formaldehyde and wood dust. The most 
FORMALDEHYDE 50 

2. HEALTH EFFECTS 

severe epithelial change found (light or moderate epithelial dysplasia) was found in two furniture 

workers. Among the chemical workers (not exposed to wood dust), loss of cilia, goblet cell hyperplasia, 

and cuboidal and squamous cell metaplasia replacing the columnar epithelium occurred more frequently 

than in the control group of office workers. Within both groups of formaldehyde-exposed workers, no 

evidence was found for associations between histological score and duration of exposure, index of 

accumulated dose, or smoking habit. A chronic inhalation MRL of 0.008 ppm was calculated as 

described in Table 2-1 and in Appendix A based on the minimal LOAEL of 0.24 ppm for mild nasal 

lesions in chemical factory workers in this study using an uncertainty factor of 30 (3 for the use of a 

minimal LOAEL and 10 for human variability). 

Boysen et al. (1990) histologically examined biopsy specimens from the nasal mucosa of 37 workers in a 

chemical plant that produced formaldehyde and formaldehyde resin and 37 age-matched, nonexposed 

controls. Exposed workers had been employed in the plant for more than 5 years (range 3–36 years, 

mean 20 years), had volunteered for the study, and represented about half of the workers in the plant. 

Controls were selected from office staff of two chemical plants, laboratory personnel from a hospital, and 

outpatients at an eye, ear, and nose clinic. Workers were classified into five exposure level groups based 

on “knowledge of the production process, recent measurements, and previous and present subjective 

sensations experienced by the workers”. Exposure measurement data were not reported, but the exposure 

levels during the 1950s and 1960s were reported to have been “high”. Workers in exposure level 1 

(containing zero exposed workers) were defined as having occasional exposure (not daily) up to the level 

of olfactory detection. Twelve exposed workers reported frequent, but not daily, exposure that was 

irritating to the eyes or upper respiratory tract (exposure level 2), 17 workers reported daily exposure up 

to a level of olfactory detection (level 3), 5 reported daily exposure above the level of irritation (level 4), 

and 3 reported daily exposure inducing discomfort (level 5). The investigators surmised that 

concentrations between 0.5 and 2 ppm were associated with exposure levels 1–3, and that levels 4 and 

5 were associated with concentrations >2 ppm. Biopsy samples were taken from the anterior curvature of 

the middle turbinate of the nasal cavity judged to have the best air flow. Specimen sections were assigned 

histology scores for the following findings: 1 for stratified cuboidal epithelium, 2 for mixed stratified 

cuboidal/stratified squamous epithelium, 3 for nonkeratinizing stratified squamous epithelium, 4 for 

keratinizing stratified squamous epithelium, and 5 for dysplasia. Numbers of subjects in the exposed 

group assigned histological scores ranging from 0 to 5 were: 3, 16, 5, 9, 1, and 3; respective numbers 

of subjects for the control group were: 5, 17, 10, 5, 0, and 0. The mean histological score for the 

exposed group (1.9) was statistically significantly greater than the mean for the controls (1.4). Much 
FORMALDEHYDE 51 

2. HEALTH EFFECTS 

of the difference in histological score between the exposed and control groups can be accounted for by 

three cases of dysplasia and one case of keratinizing stratified squamous epithelium in the exposed group; 

these lesions were not found in the nonexposed group. The workers with dysplasia were purported to 

have been exposed to concentrations in the range of 0.5–2.0 ppm and not to concentrations higher than 

2 ppm. 

Ballarin et al. (1992) examined smears of nasal respiratory mucosa cells sampled from the inner turbinate 

of 15 nonsmokers who were exposed to formaldehyde released from a urea-formaldehyde glue used in a 

plywood factory and 15 age- and sex-matched nonexposed clerks from outside of the factory. Estimates 

of formaldehyde air concentrations ranged from: 0.21 to 0.60 ppm (mean 0.39±0.20 ppm) in the 

warehouse where seven subjects worked, 0.08 to 0.14 ppm (mean 0.1±0.02 ppm) in the shearing press 

where six subjects worked, and 0.09 ppm (only one sample taken) in the sawmill area where two subjects 

worked. Mean wood dust concentrations for the three areas were 0.23±0.1 mg/m3

, 0.41±0.21 mg/m3, and 

0.73 mg/m3

, respectively. Exposed subjects worked at the factory for 2–19 years (mean 6.8±5.0 years). 

Nasal mucosal slides were scored as follows: normal cellularity, 1; number of mucus-secreting cells 

greater than ciliated cells, 1.5; hyperplasia, 2; squamous metaplasia, 2.5; mild dysplasia, 3; moderate 

dysplasia, 4; severe dysplasia, 5; and malignant cells, 6. In the exposed group, all subjects had a greater 

number of nonciliated than ciliated cells, 40% had hyperplasia, 67% had squamous metaplasia, and 6% 

slight dysplasia. In controls, 26% had normal cytology, 67% had more ciliated than nonciliated cells, 

33% had hyperplasia, and 6% had squamous metaplasia. The mean cytology score for the exposed group 

(2.3±0.5) was reported to be statistically significantly greater than the control score (1.6±0.5). Also found 

in this study was a statistically significantly higher percentage of micronucleated mucosal cells in the 

exposed group compared with the control group (0.91%±0.47 versus 0.25%±0.22). 

Studies of baseline pulmonary function variables (e.g., FVC, FEV1, FEFR25–75) that have found no 

abnormal average values for groups of workers repeatedly exposed to formaldehyde or no statistically 

significant exposure-related differences compared with referent, nonexposed workers include those of: 

10 laboratory technicians employed for an average 7.7 years in workplaces with estimated mean 

concentrations ranging from 0.106±0.2 to 0.269±0.05 ppm (Bracken et al. 1985), 109 particleboard 

workers employed for an average 10.3 years (range <1–20 years) in a plant with estimated TWA 

concentrations ranging from 0.17 to 2.93 ppm (mean 0.69 ppm) (Horvath et al. 1988), and 64 embalmers 

(embalming for an average of 10 years) and 12 embalming apprentices (employed less than a year) 
FORMALDEHYDE 52 

2. HEALTH EFFECTS 

estimated to have been exposed to formaldehyde concentrations ranging from 0.08 to 0.81 ppm 

(mean 0.36±0.19 ppm) (Holness and Nethercott 1989). 

Other studies have presented evidence for generally small or subtle formaldehyde-induced changes in 

pulmonary function variables with repeated occupational exposure (Alexandersson and Hedenstierna 

1988, 1989; Khamgaonkar and Fulare 1991; Kriebel et al. 1993; Malaka and Kodama 1990). 

Using American Thoracic Society Criteria, Malaka and Kodama (1990) reported that the percentages of 

subjects with abnormal values for a number of pulmonary function variables (e.g., FEV1 and FEFR25–75 ) 

were significantly higher in a group of 93 plywood workers compared with a group of 93 nonexposed 

subjects. The plywood workers were employed for a mean of 6.2±2.4 years in workplaces with estimated 

formaldehyde air concentrations ranging from 0.22 to 3.48 ppm. The mean product of employment 

duration times workplace air formaldehyde concentration was 6.2 ppm/year (sd 2.72 ppm/year) for the 

exposed group of workers; division of this value by the average duration of employment (6.2 years) 

arrives at an estimated average exposure concentration of 1 ppm formaldehyde. Reported average 

respirable and total wood-dust concentrations in workplace air were 0.60 and 1.35 mg/m3

, respectively. 

Mean values of baseline FEV1 and FEFR25–75 , after adjustment for dust exposure, were reportedly 

statistically significantly lower in the exposed group of workers compared with the nonexposed group 

(FEV1 2.78 L [sd 0.41] versus 2.82 L [sd 0.3]; and FEF25–75 3.14 L/second [sd 0.76] versus 

3.44 L/second [sd 0.78]). Malaka and Kodama (1990) noted that although the small differences were 

statistically significant, their clinical significance was unclear. 

Mean baseline measures of FVC and FEV1 were significantly lower (by <10%) than reference values in a 

group of 21 woodworkers employed for an average of 11 years, but mean values of these variables did not 

decline significantly when measured 5 years later (Alexandersson and Hedenstierna 1989). Estimates of 

workplace air concentrations were 0.3±0.2 ppm at the beginning and 0.4±0.1 ppm at the end of the 5-year 

period. 

Mean values for FVC and FEV1 were significantly lower than reference values in a group of 38 workers 

exposed to formaldehyde and other solvents used in lacquer applications, but the difference was small 

(<5–10% change from reference values) (Alexandersson and Hedenstierna 1988). The workers in the 

lacquer-applying workplace were employed for an average of 7.8 years; estimates of formaldehyde 

concentrations in workplace air ranged from 0.2 to 2.1 ppm with a TWA mean of 0.3 ppm. 
FORMALDEHYDE 53 

2. HEALTH EFFECTS 

Mean values of FVC, FEV1/FVC, and maximum mid-expiratory flow rate were significantly lower in a 

group of 37 anatomy and histopathology workers compared with values for a control group of 

37 nonexposed workers from the same college (FVC 2.18 L versus 2.63 L; FEV1/FVC 0.607 

versus 0.787; flow rate 1.55 L/second versus 2.71 L/second) (Khamgaonkar and Fulare 1991). 

Employment durations were not reported in this study, but estimated formaldehyde air concentrations 

ranged from 0.036 to 2.27 ppm (mean 1.0±0.55 ppm) in the anatomy and histopathology workplaces 

compared with 0 to 0.52 ppm (mean 0.1±0.11 ppm) in the control workplaces. The study authors 

suggested that the apparent bronchoconstrictor effect of formaldehyde was due either to a direct effect of 

formaldehyde or a reflex response caused by irritation of the nose and throat. 

Mean baseline PEFR declined by about 2% over a 10-week period in a group of 24 physical therapy 

students who dissected cadavers for 3-hour periods per week (Kriebel et al. 1993). Estimates of breathing 

zone formaldehyde concentrations ranged from 0.49 to 0.93 ppm (geometric mean 0.73±1.22 ppm). 

PEFR, the only pulmonary function variable measured in this study, was measured before and after each 

exposure period. Postexposure PEFR means were 1–3% lower than preexposure PEFR means during the 

first 4 weeks, but this difference was not apparent during the last 6 weeks. Fourteen weeks after the end 

of the 10-week period, the mean PEFR for the group returned to the preexposure baseline value. 

Effect levels associated with formaldehyde-induced changes in pulmonary function variables in workers 

exposed to airborne formaldehyde concentrations generally less than 1 ppm are not included in Table 2-1 

because the observed differences: are not of sufficient magnitude to be of obvious clinical significance, 

have not been observed consistently across studies, and may be confounded, in some cases, by the 

presence of wood dust particulates which may facilitate transport of adsorbed formaldehyde to deeper 

regions of the respiratory tract compared with low-level exposure to formaldehyde alone. In contrast, 

mild nasal epithelial lesions observed in formaldehyde-exposed workers: have been observed consistently 

across four studies (Ballarin et al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c), 

do not appear to be confounded by exposure to wood dust (see Edling et al. 1988; Holmstrom et al. 

1989c), and are consistent with results from animal toxicity, pharmacokinetic, and anatomical airflow 

studies indicating that, at concentrations #1 ppm, inhaled formaldehyde gas does not reach lower regions 

of the respiratory tract (see following review of animal inhalation toxicity studies and Sections 2.3 and 

2.4). 
FORMALDEHYDE 54 

2. HEALTH EFFECTS 

A single study was located providing suggestive, but to date uncorroborated, evidence that elevated levels 

of formaldehyde in residential air may change pulmonary function variables in children, but not adults. 

Krzyzanowski et al. (1990) reported that children who lived in households with formaldehyde air 

concentrations greater than 0.06 ppm had greater prevalence rates of physician-diagnosed bronchitis or 

asthma compared with children who lived in households with concentrations less than 0.06 ppm. A 

statistically significant trend for increasing prevalence rate with increasing formaldehyde air 

concentration was found for households with environmental tobacco smoke, but the trend was not 

significant in households without tobacco smoke. A statistically significant trend was also found for 

decreasing PEFR values in children with increasing household formaldehyde air concentration. The 

clinical significance of these findings is uncertain (see Section 2.6 for more discussion). 

Acute Inhalation Animal Studies. Studies in animals confirm that the upper respiratory tract is a critical 

target for inhaled formaldehyde and describe exposure-response relationships for upper respiratory tract 

irritation and epithelial damage in several species. Acute inhalation animal studies show that inhaled 

formaldehyde, at appropriate exposure concentrations, damages epithelial tissue in specific regions of the 

upper respiratory tract in rats, mice, and monkeys (Chang et al. 1983; Monticello et al. 1989, 1991; 

Morgan et al. 1986a, 1986c), that formaldehyde is a more potent sensory irritant in mice (Chang et al. 

1981, 1983; Kane and Alarie 1977) than in rats (Chang et al. 1981, 1983), that lung damage from inhaled 

formaldehyde occurs at higher concentrations than those only affecting the upper respiratory tract 

(Kamata et al. 1996a, 1996b; Swiecichowski et al. 1993), that mice are less susceptible to formaldehydeinduced upper respiratory tract epithelial damage than rats (Chang et al. 1983), that rats and monkeys may 

be equally susceptible to epithelial damage from formaldehyde but display similar epithelial lesions in 

different regions of the upper respiratory tract (Monticello et al. 1989, 1991), and that formaldehyde 

induces bronchoconstriction and airway hyperreactivity in guinea pigs (Amdur 1960; Swiecichowski et 

al. 1993). 

Formaldehyde-induced epithelial damage in the nasal cavity of rats (e.g., squamous metaplasia and 

hyperplasia) displays regional specificity (anterior regions of the nasal epithelium, posterior to the 

vestibule at the lowest effective concentrations) and occurs with acute exposures to concentrations 

generally greater than 2–6 ppm. Monticello et al. (1991) found no evidence for histological nasal 

epithelial damage in F344 rats exposed to 0.7 or 2 ppm, 6 hours/day for 1, 4, or 9 days, but damage 

was observed at 6, 10, and 15 ppm. Regions of epithelium showing histological lesions also showed 

increased rates of cellular proliferation at concentrations greater than 6 ppm (Monticello et al. 1991). 
FORMALDEHYDE 55 

2. HEALTH EFFECTS 

Site-specific damage to nasal epithelial cells after acute exposure (6 hours/day for 1 to 3 weeks) of 

F344 rats to formaldehyde was correlated with inhibition of mucociliary function (i.e., mucostasis) at 

concentrations of 2, 6, and 15 ppm, but no effects on these end points were found at 0.5 ppm (Morgan et 

al. 1986a, 1986c). Morgan et al. (1986c) reported that mucus flow was stopped after only 1 hour of 

exposure to 15 ppm in regions of the nasal epithelium that later developed lesions, and that this effect was 

still apparent 18 hours after exposure ceased. Other acute inhalation studies with rats (Bhalla et al. 1991; 

Cassee and Feron 1994; Monteiro-Riviere and Popp 1986; Wilmer et al. 1987) provide supporting 

evidence that short-term exposure to concentrations in excess of 2 ppm can damage nasal epithelial 

tissues in this species (see Table 2-1). 

Upper respiratory tract epithelial lesions similar to those observed in rats have been observed in Rhesus 

monkeys exposed to 6 ppm, 6 hours/day, 5 days/week for 1 week; the regional distribution of these 

lesions was not restricted to the nasal cavity, as they were in rats exposed to 6 ppm (Monticello et al. 

1991), but extended to the trachea and major bronchi (Monticello et al. 1989). Lesions were most severe 

in the nasal passages and were minimal in the lower airways (larynx, trachea, and carina). Regions of 

epithelium with lesions corresponded with regions in which high rates of cellular proliferation were 

measured. No evidence for lesions or changes in cell proliferation rates were found in the maxillary 

sinuses. Studies describing exposure-response relationships for upper respiratory tract epithelial damage 

in monkeys acutely exposed to inhaled formaldehyde were not located. 

Inhaled formaldehyde is a more effective sensory irritant (i.e., stimulates trigeminal nerve endings and 

inhibits respiration rate and tidal volume) in mice than in rats (Chang et al. 1981; Kane and Alarie 1977), 

whereas nasal effects such as rhinitis and degeneration of respiratory epithelial cells are more severe in 

rats than in mice, and increased indices of cell proliferation in nasal epithelium are more frequent in rats 

than mice, after exposure to 15 ppm, 6 hours/day for 1 or 5 days (Chang et al. 1983). Measured 

RD50 values for mice (2.2–5.9 ppm; concentrations associated with a 50% decrease in respiratory rate) 

were much lower than RD50 values for rats (22.7–31.7 ppm) (Chang et al. 1981). Kane and Alarie (1977) 

reported a similar RD50 value, 3.1 ppm, for formaldehyde in mice. These results suggest that the lesser 

sensitivity of mice to formaldehyde-induced nasal tissue damage may be due, at least in part, to the 

mouse’s ability to maintain decreased respiration rates and decreased tidal volumes in the presence of 

airborne formaldehyde, whereas the rat does not have this ability and thus sustains a greater degree of 

tissue damage. 
FORMALDEHYDE 56 

2. HEALTH EFFECTS 

Acute inhalation exposure to formaldehyde has been associated with tissue damage in the lungs only at 

much higher exposure concentrations than those affecting the nasal region alone. Histological and 

ultrastructural examination of lung tissue from rats exposed to 10 ppm, 6 hours/day for 4 days found no 

evidence for tissue injury, although these rats showed clinical signs of eye and nose irritations (Dinsdale 

et al. 1993). In addition, activities of alkaline phosphatase and γ-glutamyl transpeptidase in 

bronchoalveolar lavage fluid and lung tissue concentrations of cytochrome P-450 were not significantly 

elevated in exposed rats compared with control rats. These results indicate that very limited amounts of 

formaldehyde reach the lungs with exposure to 10 ppm. In contrast, Kamata et al. (1996a) reported that 

single 6-hour exposures of male F344 rats to 150 ppm formaldehyde induced histological changes 

throughout the nasal turbinates (including hyperkeratosis of the squamous epithelium in the vestibule, 

desquamation of the respiratory epithelium), the trachea (increased secretion and desquamation of 

mucosal cells), and the lung (hyperplasia of the alveolar wall and plasma-like secretions in the lung), 

whereas similar exposure to 15 ppm produced only slight hypersecretion of the nasal and tracheal 

mucosal epithelium. Kamata et al. (1996b) also noted that F344 rats exposed to 128 or 295 ppm 

formaldehyde for 6 hours showed bloody nasal discharge and pulmonary edema, indicating that, at these 

very high concentrations, formaldehyde can reach and damage lung tissue as well as nasal tissue. 

Experiments with guinea pigs provide evidence that acute exposure to inhaled formaldehyde can 

influence lower airway resistance and hyperreactivity of the lungs (Amdur 1960; Swiecichowski et al. 

1993). Amdur (1960) measured significantly increased airway resistance in guinea pigs exposed for 

1 hour to formaldehyde concentrations as low as 0.3 ppm; the average increase in resistance was about 

14, 29, and 43% over control values at 0.3, 1.2, and 3.6 ppm, respectively. Amdur suggested that the 

changes in resistance were due to bronchoconstriction. More recently, Swiecichowski et al. (1993) 

reported that pulmonary resistance was significantly increased in guinea pigs exposed to 9.4 ppm for 

2 hours, but not in guinea pigs exposed to 3.4 ppm or lower for 2 hours. Longer duration exposure 

(8 hours) changed the exposure-response relationship; concentrations as low as 0.3 ppm produced 

significantly increased pulmonary resistance. Pulmonary sensitivity to acetylcholine was significantly 

increased by 2-hour exposures to concentrations $9.4 ppm and by 8-hour exposures to $0.3 ppm. No 

exposure-related epithelial damage or inflammatory response was detected by histological examinations 

of portions of the midtrachea. 
FORMALDEHYDE 57 

2. HEALTH EFFECTS 

Intermediate Inhalation Animal Studies. Results from intermediate-duration inhalation studies with rats 

(Appelman et al. 1988; Feron et al. 1988; Monticello et al. 1991; Rusch et al. 1983; Woutersen et al. 

1987; Zwart et al. 1988), Rhesus monkeys (Monticello et al. 1989), Cynomolgus monkeys (Rusch et al. 

1983), mice (Maronpot et al. 1986), and hamsters (Rusch et al. 1983) indicate that the nasal epithelium is 

the most sensitive target of inhaled formaldehyde. The studies support the hypothesis that mice and 

hamsters are less sensitive than rats and monkeys to formaldehyde-induced nasal damage (Maronpot et al. 

1986; Rusch et al. 1983), show that formaldehyde-induced damage to the upper respiratory tract 

epithelium (hyperplasia and squamous cell metaplasia) has a wider regional distribution in Rhesus 

monkeys than in rats (Monticello et al. 1989, 1991), show that site-specific nasal lesions in both monkeys 

and rats corresponded to regions with high rates of cellular proliferation (Casanova et al. 1994; 

Monticello et al. 1989, 1991), indicate that damage to the respiratory epithelium is more concentrationdependent than duration-dependent (Wilmer et al. 1987, 1989), and show that concentrations of 

DNA-protein cross links are correlated with regional sites of formaldehyde-induced epithelial damage in 

the nose of rats (Casanova et al. 1994). 

In a study designed to detect potential effects on tissues and organs distant from the nose and to describe 

exposure-response relationships for nasal lesions in rats exposed to between 1 and 20 ppm formaldehyde 

for intermediate durations, Woutersen et al. (1987) exposed groups of 10 male and 10 female Wistar rats 

to 0, 1, 10, or 20 ppm 6 hours/day, 5 days/week for 13 weeks. Sections of the lungs, trachea, larynx, and 

nose were microscopically examined in all rats; all other major organs and tissues were also examined 

microscopically in control and high-exposure groups. Exposure to 20 ppm produced severe and extensive 

keratinized squamous metaplasia of the nasal respiratory epithelium, focal degeneration and squamous 

metaplasia of the olfactory epithelium, and squamous metaplasia of the laryngeal epithelium (males only). 

No exposure-related lesions were found in other tissues or organs. Respiratory effects at 10 ppm were 

restricted to moderate squamous metaplasia of the nasal respiratory epithelium. Effects noted in the 

1-ppm group were restricted to minimal focal hyperplasia and squamous metaplasia of the nasal 

respiratory epithelium found in three rats. 

Zwart et al. (1988) exposed groups of male and female Wistar rats to formaldehyde at concentrations of 0, 

0.3, 1, or 3 ppm, 6 hours/day, 5 days a week for 13 weeks to study details of formaldehyde-induced nasal 

tissue damage. Exposure-related nasal tissue histological changes were restricted to a small area of the 

anterior region of the nose normally covered with respiratory epithelium and were found only in the highexposure group. Lesions were described as ranging from epithelial disarrangement to epithelial 
FORMALDEHYDE 58 

2. HEALTH EFFECTS 

hyperplasia and squamous metaplasia. After 3 days of exposure, increased rates of cellular proliferation, 

compared with controls, were found in the 1- and 3-ppm groups in epithelial regions where lesions were 

found after 13 weeks in the 3-ppm group. After 13 weeks of exposure, cellular proliferation rates were 

not increased in the lesion-laden regions of exposed rats, but were increased in more posterior regions of 

the nasal epithelium, most notably in rats exposed to 3 ppm. These results are consistent with the 

hypothesis that the change of mucus-covered respiratory epithelial cells to squamous epithelial cells is 

adaptive. 

Appelman et al. (1988) exposed groups of male SPF Wistar rats to 0, 0.1, 1, or 10 ppm formaldehyde 

6 hours/day, 5 days/week for 13 or 52 weeks. Within each exposure group, half of the animals had their 

nasal mucosa damaged by acute electrocoagulation prior to formaldehyde exposure. In groups without 

predamaged nasal mucosa, exposure-related effects were restricted to rhinitis and hyperplasia and 

metaplasia of the nasal respiratory epithelium in the 10-ppm group. Comprehensive histological 

examination of major tissues and organs in the control and 10-ppm groups revealed no other exposurerelated lesions. Microscopic examination of nose sections from the 1- and 0.1-ppm groups without 

electrocoagulation revealed no exposure-related effects. Rats with predamaged nasal mucosa were more 

susceptible to the cytotoxic action of formaldehyde; at 52 weeks, focal squamous metaplasia of the nasal 

respiratory epithelium was found in rats exposed to 0.1 or 1 ppm formaldehyde. 

Monticello et al. (1991) exposed groups of 36 male F344 rats to 0, 0.7, 2, 6, 10, or 15 ppm, 6 hours/day, 

5 days/week for up to 6 weeks and labeled with tritiated thymidine prior to scheduled termination to 

determine rates of cellular proliferation in specific regions of the nasal epithelium. After 6 weeks of 

exposure to 10 or 15 ppm, epithelial hyperplasia and squamous metaplasia of the respiratory epithelium 

were located primarily in the nasoturbinates, just posterior to the nasal vestibule, with milder lesions 

extending into more posterior regions including the nasopharynx. Exposure to 6 ppm produced mild 

epithelial hyperplasia and squamous metaplasia that was restricted to the most anterior regions of the 

respiratory epithelium in the nasoturbinates. Statistically significant increases in cellular proliferation 

rates were measured in the groups exposed to 6 ppm or higher. Exposure-related effects on nasal 

epithelium were not found in the 2- or 0.7-ppm groups. Sites of cellular injury were well-correlated with 

sites of increased rates of cellular proliferation. 

Casanova et al. (1994) exposed groups of male F344 rats to 0, 0.7, 2, 6, or 15 ppm 6 hours/day, 

5 days/week for 81 days to examine the effect of preexposure to formaldehyde on the concentrations of 
FORMALDEHYDE 59 

2. HEALTH EFFECTS 

DNA-protein cross links formed in specific regions of nasal cavity epithelium in response to acute 

exposure to radiolabeled formaldehyde. DNA-protein cross link concentrations were approximately 

6-fold higher in the mucosal lining of the lateral meatus (where formaldehyde-induced lesions develop) 

than in the mucosal lining of the medial and posterior meatus (where lesion development is less strong). 

Preexposure to formaldehyde at concentrations #2 ppm did not affect the formation of DNA-protein cross 

links, but at higher concentrations, pre-exposed rats showed decreased acute formation of DNA-protein 

cross links compared with rats without prior exposure to formaldehyde. 

Monticello et al. (1989) exposed groups of three male Rhesus monkeys to 0 or 6 ppm formaldehyde, 

6 hours/day, 5 days/week to compare respiratory responses to formaldehyde in primates with those in 

rodents. Comprehensive histological examination of respiratory tract tissues (and also extra-respiratory 

tissues) was conducted. Exposure-related lesions were confined to the epithelium of the upper respiratory 

tract and were described as mild hyperplasia and squamous metaplasia confined to particular regions of 

the transitional and respiratory epithelium of the nasal passages and the respiratory epithelium of the 

trachea and carina. Cellular proliferation rates were significantly elevated in damaged regions of the 

nasal epithelium. Nasal lesions seen in monkeys were similar to those reported in rats exposed to 6 ppm 

by a similar exposure protocol and duration in a companion study (Monticello et al. 1991) except that the 

lesions extended into the trachea in the monkeys. The lesions in the larynx, trachea, and carina of the 

formaldehyde-exposed primates included multifocal loss of cilia and goblet cells, mild epithelial 

hyperplasia, and early squamous metaplasia. Cell proliferation rates in the trachea and carina were 

increased as well. In both species, regions where lesions were found were well-correlated with regions in 

which high rates of cellular proliferation were measured (Monticello et al. 1989, 1991). The investigators 

suggested that the difference in the location of the lesions was due to different breathing patterns in the rat 

and monkey and differences in the anatomic structure of their respective nasal passages. 

Rusch et al. (1983) histologically examined the lungs, trachea, and nasal turbinates of groups of 6 or 

12 male Cynomolgus monkeys, 20 male and 20 female Fischer 344 rats, and 10 male and 10 female 

Golden Syrian hamsters exposed to 0, 0.2, 0.98, or 2.95 ppm for 22 hours/day, 7 days/week for 26 weeks. 

Examination of other organs and tissues at necropsy for gross lesions revealed no exposure-related 

effects, but these tissues were not microscopically examined. Monkeys exposed to 2.95 ppm showed an 

increased incidence of hoarseness, congestion, and nasal discharge. Monkeys in the lower exposure 

groups showed a greater incidence of nasal discharge than control monkeys, but the discharge was “only a 
FORMALDEHYDE 60 

2. HEALTH EFFECTS 

minimal grade” and was noted sporadically throughout the study. The study authors judged that the nasal 

discharge at the two lowest exposure levels was not of biological significance. Body weights of exposed 

monkeys were not significantly different from body weights of controls. Monkeys and rats exposed to 

2.95 ppm, but not the lower concentrations, showed a significantly increased incidence of squamous 

metaplasia and/or basal cell hyperplasia of the nasal cavity epithelium; the response was reported to be 

most clearly seen in both species in the mid-region of the nasoturbinates. No lesions were found in the 

most anterior sections of the nose or in the ethmoturbinates. Incidences of monkeys with squamous 

metaplasia/hyperplasia in nasal turbinate epithelium were 0/12, 0/6, 1/6, or 6/6 at 0, 0.2, 0.98, and 

2.95 ppm, respectively. Respective incidences of rats with squamous metaplasia/hyperplasia were 5/77, 

1/38, 3/36, and 23/37. The investigators made no mention of any difference in the regional distribution of 

the nasal lesions in rats and monkeys or of any histological changes in the trachea or lungs of the exposed 

monkeys or rats. Ultrastructural examinations were made of the nasal turbinates, trachea, and lungs from 

rats in the control and 0.98-ppm group; no exposure-related changes were found. No histological changes 

were found in the nasoturbinates, trachea, or lungs of the exposed hamsters compared with controls. An 

intermediate inhalation MRL of 0.03 ppm was calculated as described in Table 2-1 and in Appendix A 

based on the NOAEL of 0.98 ppm for nasopharyngeal irritation in Cynomolgus monkeys using an 

uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human variability). 

Wilmer et al. (1987) investigated whether varying the exposure to formaldehyde (i.e., continuous versus 

intermittent) affected formaldehyde cytotoxicity to upper respiratory tract epithelium. Groups of male 

albino Wistar rats were exposed to 0, 5, or 10 ppm formaldehyde, 8 hours/day continuously, or to 10 or 

20 ppm formaldehyde, 8 hours/day intermittently (30-minute exposure periods separated by 30-minute 

periods of nonexposure). Eighteen hours after the third day or fourth week of exposure, three rats from 

each group were injected with 3

H-thymidine, sacrificed, and their nasal cavities were processed and 

examined for cell turnover. After 4 weeks of exposure, cell turnover rates in nasal epithelium were 

significantly elevated in the rats exposed to 10 and 20 ppm intermittently, but not in rats exposed to 5 and 

10 ppm continuously. The majority of cell labeling occurred in the naso- and maxillary turbinates. Focal 

thinning and disarrangement of the respiratory epithelium lining were noted in some of the 10-ppm and 

all of the 20-ppm rats. Squamous metaplasia with cellular hyperplasia was noted in some of the rats 

exposed to 5 ppm and in most of the rats exposed to 10 or 20 ppm. Minimum to moderate rhinitis was 

seen in each of the treatment groups. In a similar study, Wilmer et al. (1989) studied the same 

toxicological end points in male albino Wistar rats using lower concentrations of 0, 1, or 2 ppm 
 

FORMALDEHYDE 61 

2. HEALTH EFFECTS 

formaldehyde, 8 hours/day continuously, or 2 or 4 ppm formaldehyde, 8 hours/day intermittently 

(30-minute exposure periods separated by 30-minute periods of nonexposure), all groups were treated for 

5 days/week for 13 weeks. After 13 weeks of exposure, there were no statistically significant differences 

between the 1 and 2 ppm (continuously dosed), the 2 ppm (intermittently dosed) groups, and the controls 

in cell turnover rates, however, the mean cell turnover rate after 13 weeks of exposure in the 4-ppm rats 

was 2.9-fold greater than that of control rats. Treatment-related histological changes were noted only in 

the 4-ppm intermittent exposure group. The changes consisted of increased disarrangement, hyperplasia, 

and squamous metaplasia with or without keratinization of the respiratory epithelium lining of the septum 

and nasoturbinates. The group continuously exposed to 2 ppm formaldehyde (i.e., the same total daily 

exposure as the 4-ppm intermittent group) did not exhibit an increased incidence of these lesions. These 

data suggest that the concentration of formaldehyde is more important in determining epithelial damage 

than the duration of exposure. 

Maronpot et al. (1986) exposed groups of 10 male and 10 female B6C3F1 mice to formaldehyde 

6 hours/day, 5 days/week for 13 weeks at concentrations of 0, 2, 4, 10, 20, or 40 ppm. Comprehensive 

histological examinations of major tissues and organs were conducted. Significant mortality and severe 

weight loss occurred in the 40-ppm group. Exposure-related lesions were restricted to the respiratory 

tract, except for hypoplasia of the uterus and ovaries in the 40-ppm group which were interpreted to be 

due to severe body weight loss. In the 40-ppm groups, squamous metaplasia, keratinization, suppurative 

inflammatory exudate, serous exudate, and mild degeneration of the epithelium were noted in nasal 

sections. Similar lesions were noted in the 20- and 10-ppm groups, although the severity declined with 

decreasing concentrations. Similar lesions were seen in only one male mouse at 4 ppm, and in none of 

the 4-ppm females; no such lesions were noted in either sex at exposures of 2 ppm. Squamous 

metaplasia, suppurative inflammation, and fibrosis was also noted in the trachea and larynx of most mice 

in the 40-ppm group; similar, though less severe, lesions were noted in the 20-ppm group. Lung lesions 

consisting of epithelial hyperplasia, suppurative inflammation, squamous metaplasia, and fibrosis were 

seen in some of the mice exposed to 40 ppm, but were not found in mice exposed to lesser concentrations. 

Studies of pulmonary function variables in rats after intermediate-duration exposure to inhaled 

formaldehyde have not found marked, exposure-related effects (Dallas et al. 1985, 1986; Saldiva et al. 

1985). Dallas and colleagues measured the change in minute volume produced by acute challenges with 

formaldehyde administered either intratracheally (Dallas et al. 1986) or by nosepiece (Dallas et al. 1985) 
FORMALDEHYDE 62 

2. HEALTH EFFECTS 

in rats exposed to 0, 0.5, 3 (nose-piece experiment only), or 15 ppm formaldehyde, 6 hours/day 

5 days/week for 8 or 16 weeks. Responses to the acute challenge were compared with responses in agematched, nonexposed rats. A slightly diminished minute volume response to the formaldehyde challenge 

was observed in the exposed rats (from the 15-ppm groups only) compared with the response in 

nonexposed rats with both types of challenge administration, but this was statistically significant only 

with nosepiece administration. Saldiva et al. (1985) found no statistically significant differences between 

a group of rats exposed to 5.7 ppm formaldehyde, 8 hours/day, 5 days/week for 5 weeks and a group of 

nonexposed rats in mean values for numerous pulmonary function variables including FEV in 1/4 second 

and several measures of forced expiratory flow rates. 

Chronic Inhalation Animal Studies. Chronic-duration exposures to inhaled formaldehyde have also 

been studied in rats, mice, and hamsters. In rats exposed to concentrations #15 ppm, formaldehydeinduced effects were restricted to nonneoplastic and neoplastic lesions found primarily in anterior regions 

of the nasal epithelium, posterior to the vestibule (Kamata et al. 1997; Kerns et al. 1983b; Monticello et 

al. 1996; Swenberg et al. 1980; Woutersen et al. 1989). Nonneoplastic damage to rat nasal epithelium 

occurred at concentrations as low as 2 ppm, 6 hours/day, 5 days/week (Kamata et al. 1997), whereas 

significantly increased incidences of neoplastic lesions (squamous cell carcinomas, squamous cell 

papillomas or polyploid adenomas) were found in rats generally at concentrations greater than 6 ppm 

(Kamata et al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Woutersen et al. 1989). Nonneoplastic 

damage to upper respiratory tract epithelium has also been observed in mice exposed to $5.6 ppm, 

6 hours/day, 5 days/week for 2 years (Kerns et al. 1983b) and in hamsters exposed to 10 ppm, 

5 hours/day, 5 days/week for life (Dalbey 1982). Nasal tumors similar to those found in formaldehydeexposed rats were found in mice exposed to 14.3 ppm for 2 years (Kerns et al. 1983b), but were not found 

in formaldehyde-exposed hamsters (Dalbey 1982). See Section 2.2.1.8 for more details of neoplastic 

findings from these studies. 

Male and female Fischer 344 rats were exposed to 0, 2, 5.6, or 14.3 ppm formaldehyde for 6 hours/day, 

5 days/week for 24 months (Kerns et al. 1983b; Swenberg et al. 1980). The exposure period was 

followed by a 6-month observation period. Interim sacrifices were performed at 6, 12, 18, 24, 

27 (3 months postexposure), and 30 months (6 months postexposure). In the 14.3-ppm treatment group, 

early mortalities occurred, rats tended to be dyspneic and emaciated, and many had facial swellings which 

were subsequently determined to be nasal cavity carcinomas. Microscopic lesions were limited to the 

nasal cavity and trachea, however, lesions were initially seen only in the ventral portion of the nasal 
FORMALDEHYDE 63 

2. HEALTH EFFECTS 

septum. As the study progressed, the lesions spread and became progressively more severe. In the lowand mid-dose groups, rhinitis, epithelial dysplasia, and squamous metaplasia developed over the course of 

the study. Occasionally, animals in the high-dose group exhibited minimal-to-mild epithelial hyperplasia 

or dysplasia or squamous metaplasia of the tracheal mucosa; these effects were not seen in the lower-dose 

groups and disappeared in the high-dose group during the postexposure periods. Malignant nasal tumors 

were found in 5.6- and 14.3-ppm rats (see Section 2.2.1.8). Neoplastic lesions were not found in other 

regions of the respiratory tract or in other organ systems. 

Woutersen et al. (1989) investigated the effects of damage to the nasal mucosa on the induction of nonneoplastic tissue changes and tumors from long-term exposure to formaldehyde. Male and female Wistar 

rats were used, with 67% of all rats undergoing electrocoagulation of the nasal mucosa. Half of the 

animals were exposed to formaldehyde for 28 months and the other half for 3 months, all at doses of 0, 

0.1, 1, or 10 ppm for 6 hours/day, 5 days/week. In undamaged noses in the 28-month study, 

histopathological changes were not seen in the 0.1 or 1 ppm groups; exposure to 10 ppm resulted in an 

increased incidence of squamous metaplasia and basal cell/pseudoepithelial hyperplasia of the respiratory 

epithelium, thinning and disarrangement of the olfactory epithelium, and rhinitis. In damaged nasal 

mucosa in the long-term study, exposure to all levels of formaldehyde resulted in squamous metaplasia. 

Rats exposed to formaldehyde vapors for 3 months (without electrocoagulation pretreatment) were 

sacrificed following a 25-month recovery period. Non-neoplastic nasal lesions with statistically 

significant increased incidences, compared with controls, were found only in the most anterior regions of 

the nasal cavity in 10-ppm rats: squamous metaplasia of the respiratory epithelium (17/26 compared with 

3/26 in controls; p<0.01, Fisher exact test performed by Syracuse Research Corporation), and rhinitis 

(13/26 compared with 5/26; p<0.05, Fisher exact test performed by Syracuse Research Corporation). 

Nasal tumors were found only in the 10-ppm, 3-month-exposure group; one rat had a squamous cell 

carcinoma and one had a polypoid adenoma (see Section 2.2.1.8 for more details on neoplastic responses 

in this study). 

Monticello et al. (1996) assessed the role of regional increases in nasal epithelial cell proliferation in the 

formation of formaldehyde-induced nasal neoplastic and non-neoplastic tissue damage in male 

Fischer 344 rats. Rats were exposed to 0, 0.7, 2, 6, 10, or 15 ppm formaldehyde, 6 hours/day, 

5 days/week for 24 months. During the last 5 days of exposure prior to each interim sacrifice period 

(3, 6, 12, and 18 months), 6 rats per dose group were labeled with 3

H-thymidine via osmotic pumps to 

measure regional rates of cell proliferation in nasal cavity epithelium. No formaldehyde-induced non­
FORMALDEHYDE 64 

2. HEALTH EFFECTS 

neoplastic lesions were found in the nasal cavities of rats from the 0.7- or 2-ppm groups. Nonneoplastic lesions in the 6-ppm group were limited to focal squamous metaplasia in the anterior region of 

the nasal cavity. In the 10- and 15-ppm groups, lesions seen included epithelial hypertrophy and 

hyperplasia, squamous metaplasia, inflammatory cell infiltration, nasal turbinate adhesions, and olfactory 

degeneration. These lesions occurred more frequently and with greatest severity in the 15-ppm group. 

Cell proliferation in nasal epithelium was not affected by formaldehyde exposures of 6 ppm or less; 

increases in the cell labeling index were significant at the 10- and 15-ppm exposure levels. Nasal tumors 

were found in the 6-, 10-, and 15-ppm groups (see Section 2.1.1.8). 

Kamata et al. (1997) exposed groups of 32 male F344 rats by inhalation to formaldehyde concentrations 

of 0.3, 2, or 15 ppm, 6 hours/day, 5 days/week for up to 28 months. Two control groups of 32 rats were 

included: an inhalation chamber group (“0 ppm”) inhaling 4.2 ppm methanol and a “room control, noexposure group”. Significantly increased mortality (after 9 months) and decreased body weights (after 

4 months) were restricted to the 15-ppm group compared with the control groups. No exposure-related 

effects on hematological parameters were found. Comprehensive autopsies and histological examination 

of the pituitary, thyroid, nasal region, trachea, esophagus, stomach, intestine, prostate gland, spinal cord, 

and mesenteric lymph nodes found exposure-related effects only in the nasal cavities. Epithelial cell 

hyperplasia, hyperkeratosis, and squamous metaplasia were apparent in all exposure groups and were 

predominately restricted to the respiratory epithelium of nasal turbinates and maxilloturbinates, just 

posterior to the nasal vestibule. Incidences for epithelial cell hyperplasia with squamous cell metaplasia 

were 0/32, 0/32, 4/32, 7/32, and 29/32 in the 0-, room control-, 0.3-, 2-, and 15-ppm groups respectively; 

incidences for squamous cell metaplasia without epithelial cell hyperplasia were 0/32, 0/32, 1/32, and 

5/32, respectively (this combination of lesions did not occur in the 15-ppm group). Nasal tumors 

squamous cell carcinomas and papillomas were found only in the 15-ppm group (see Section 2.2.1.8). 

Kamata et al. (1997) concluded that the study did not identify a NOAEL for nonneoplastic nasal lesions 

due to the finding of epithelial cell hyperplasia with squamous cell metaplasia in the 0.3-ppm group, but 

the incidences for nonneoplastic nasal lesions in the 0.3-ppm group were not statistically significantly 

different compared with the controls. In Table 2-1, 0.3 ppm is noted as a NOAEL for non-neoplastic 

lesions in the nasal epithelium. 

Kerns et al. (1983b) exposed male and female B6C3F1 mice to 0, 2, 5.6, or 14.3 ppm formaldehyde for 

6 hours/day, 5 days/week for 24 months, followed by a 6-month observation period. Interim sacrifices 

were performed at 6, 12, 18, 24, 27, and 30 months. Major tissues from each organ system in control and 
 

FORMALDEHYDE 65 

2. HEALTH EFFECTS 

high-exposure mice were examined histologically. Non-neoplastic nasal lesions were found in the 5.6­

and 14.3-ppm groups of mice, most notably inflammatory, dysplastic, and squamous metaplastic changes 

in the respiratory epithelium. Minimal to moderate hyperplasia of the squamous epithelium lining the 

nasolacrimal duct and atrophy of the olfactory epithelium of the ethmoturbinates also were observed in 

the 5.6- and 14.3-ppm groups. At the end of exposure (24 months), nasal lesions were found in >90% of 

14.3-ppm mice and “in a few” 5.6-ppm mice (incidence was not specified). Mice sacrificed 3 months 

postexposure showed regression of the formaldehyde-induced nasal epithelial lesions. At 24 months, 

mice in the 2-ppm group were “free of significant nasal lesions”, but a few mice had serous rhinitis and 

minimal hyperplasia of the squamous epithelium lining the nasolacrimal duct. Two male mice in the 

14.3-ppm group sacrificed at 24 months displayed squamous cell carcinomas in the nasal cavity similar to 

those found in rats. The number of mice sacrificed at 24 months was not specified in the published 

report, but the incidence was indicated to be significantly increased compared with controls. No other 

tumors were reported in exposed or control mice. 

Dalbey (1982) exposed groups of male Golden Syrian hamsters to 0 (n=132) or 10 (n=88) ppm 

formaldehyde, 5 hours/day, 5 days/week for life (up to about 110 weeks). Exposed hamsters showed 

reduced survival time compared with controls. End points in this study were restricted to 

histopathological examinations of respiratory tract tissues. There was no evidence of rhinitis in treated 

animals, and no tumors were found in the respiratory tract of treated or control animals. Hyperplastic and 

metaplastic areas were seen in the nasal epithelium of 5% of the treated hamsters but were not seen in 

controls. Dalbey (1982) also exposed groups of 50 male hamsters to 0 or 30 ppm formaldehyde, 

5 hours/day, 1 day/week for life. No respiratory tract tumors were reported to have been found in control 

or exposed animals, but Dalbey (1982) did not mention if the nasal epithelium was examined for nonneoplastic changes in these two groups of hamsters. 

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after 

inhalation exposure to formaldehyde. 

No histological evidence for formaldehyde effects on cardiovascular tissues was found in intermediateduration inhalation studies, using a 6 hour/day, 5 day/week exposure protocol, with mice exposed to 

up to 40 ppm for 13 weeks (Maronpot et al. 1986), Rhesus monkeys exposed to 6 ppm for 6 weeks 

(Monticello et al. 1989), rats exposed to up to 20 ppm for 13 weeks (Woutersen et al. 1987), or rats 

exposed to up to 10 ppm for 13 or 52 weeks (Appelman et al. 1988). Similarly, no evidence for 
 

 

FORMALDEHYDE 66 

2. HEALTH EFFECTS 

formaldehyde effects on cardiovascular tissues were found in chronic inhalation studies with rats or mice 

exposed to up to 14.3 ppm, 6 hours/day, 5 days/week for 2 years (Kerns et al. 1983b). The only study 

located that examined cardiovascular function in animals exposed to airborne formaldehyde was a report 

that concluded that blood pressure and heart rate were not affected in anesthetized rats exposed for 

1 minute to 1,628 ppm formaldehyde (Egle and Hudgins 1974). 

Gastrointestinal Effects. Few studies regarding gastrointestinal effects after inhalation exposure 

were located. In humans, Kilburn (1994) describes vague gastrointestinal effects in four patients who had 

been occupationally exposed to formaldehyde for 14–30 years. Three of the patients were anatomists and 

were exposed to formalin; the fourth was a railroad worker who worked next to a wood-products factory 

that used large quantities of phenol-formaldehyde resins. Intestinal cramps with flatus and bloody stools 

was one of many nonspecific effects noted in this small population. 

No histological evidence for formaldehyde effects on the gastrointestinal tract was found in intermediateduration inhalation studies using a 6 hour/day, 5 days/week exposure protocol with mice exposed to up to 

40 ppm for 13 weeks (Maronpot et al. 1986), Rhesus monkeys exposed to 6 ppm for 6 weeks (Monticello 

et al. 1989), rats exposed to up to 20 ppm for 13 weeks (Woutersen et al. 1987), or rats exposed to up to 

10 ppm for 13 or 52 weeks (Appelman et al. 1988). Similarly, no evidence for formaldehyde effects on 

gastrointestinal tissues were found in chronic inhalation studies with rats exposed to up to 15 ppm, 

6 hours/day, 5 days/week for 2 years or more (Kamata et al. 1997; Kerns et al. 1983b), or in mice exposed 

similarly (Kerns et al. 1983b). 

Hematological Effects. Pross et al. (1987) evaluated the immunologic response of asthmatic 

subjects exposed to urea-formaldehyde foam insulation (UFFI) off-gas products. Subjects consisted of 

23 individuals with a history of asthmatic symptoms attributed to UFFI and 4 individuals (controls) with 

asthma unrelated to UFFI by-products. Subjects were exposed to one of the following: room air (placebo) 

for 30 minutes; 1 ppm formaldehyde gas for 3 hours; UFFI particles (4 μm, 0.5 particles/mL) for 3 hours, 

commencing 48 hours after formaldehyde gas exposure; and UFFI off-gas products for 3 hours, 

commencing 48 hours after UFFI particle exposure. There were no significant alterations in any of the 

white blood cell populations when the four unexposed controls were compared to the subjects (who also 

lived in a home where UFFI is present) before or after being exposed to UFFI in the chamber. 

However, there was a significant increase in the percentage and absolute number of eosinophils and 
 

 

FORMALDEHYDE 67 

2. HEALTH EFFECTS 

basophils in the subjects (who also lived in UFFI-homes) after exposure to UFFI in the exposure chamber 

when compared to the white blood cell values obtained before chamber exposure to UFFI. 

No exposure-related effects on hematological variables were found in rats exposed to up to 20 ppm 

formaldehyde 6 hours/day, 5 days/week for 13 weeks (Woutersen et al. 1987), in rats exposed to up to 

10 ppm, 6 hours/day, 5 days/week for up to 52 weeks (Appelman et al. 1988), in rats or mice exposed to 

up to 14.3 ppm, 6 hours/day, 5 days/week for up to 24 months (Kerns et al. 1983b), or rats exposed to up 

to 15 ppm for 28 months (Kamata et al. 1997). Dean et al. (1984) reported that female mice exposed to 

up to 15 ppm for 6 hours/day, 5 days/week for 3 weeks showed a statistically significant decrease in 

absolute number of monocytes compared with control values, but no other hematological variable was 

affected by exposure in this study. 

Musculoskeletal Effects. Few studies were located that described musculoskeletal effects of 

formaldehyde after inhalation exposure. Holness and Nethercott (1989) reported that muscle or joint 

stiffness was reported more frequently by a surveyed group of funeral directors and embalmers than in a 

referent nonexposed group (23 versus 5%), but reporting of similar symptoms has not been frequently 

encountered in other health surveys of formaldehyde-exposed groups of workers. 

With 6-hours/day, 5-days/week exposure protocols, no formaldehyde-induced histological changes in 

muscle or skeletal tissue were found in mice exposed to up to 40 ppm for 13 weeks (Maronpot et al. 

1986), in monkeys (bone marrow of sternum) exposed to 6 ppm for 6 weeks (Monticello et al. 1989), in 

rats (femur and muscle tissue) exposed to up to 15 ppm for 28 months (Kamata et al. 1997), or in rats or 

mice exposed to up to 14.3 ppm for 24 months (Kerns et al. 1983b). 

Hepatic Effects. No studies were located that reported hepatic effects in humans following exposure 

to airborne formaldehyde. 

Murphy et al. (1964) found increased activities of alkaline phosphatase in livers of rats exposed to 

35 ppm formaldehyde for 18 hours and suggested that formaldehyde may be hepatotoxic. More recent 

animal studies, however, have found no consistent evidence for formaldehyde-induced hepatotoxicity. 

Woutersen et al. (1987) found statistically significant increased levels of aspartate amino transferase, 

alanine amino transferase, and alkaline phosphatase in plasma of rats exposed to 20 ppm, (but not to 

10 or 1 ppm) 6 hours/day, 5 days/week for 13 weeks, but found no exposure-related microscopic lesions 
 

FORMALDEHYDE 68 

2. HEALTH EFFECTS 

in the livers of these rats. In another experiment from the same laboratory, Appelman et al. (1988) found 

no exposure-related changes in serum aspartate amino transferase, alanine amino transferase, or alkaline 

phosphatase in plasma, no changes in liver concentrations of total protein or reduced glutathione, and no 

hepatic histological changes in rats exposed to up to 10 ppm by the same protocol for 13 or 52 weeks. 

Kamata et al. (1997) also reported that no exposure-related changes were found, at several sampling 

dates, in activities of serum alkaline phosphatase, aspartate amino transferase, or alanine amino 

transferase in rats exposed to up to 15 ppm, 6 hours/day, 5 days/week for up to 28 months. In 15-ppm 

rats, absolute, but not relative, liver weights were statistically significantly decreased compared with 

controls. This effect appears to have been a secondary effect from decreased food consumption at this 

exposure level rather than a direct effect of formaldehyde on the liver. No histological liver changes were 

found in Rhesus monkeys exposed to 6 ppm formaldehyde, 6 hours/day, 5 days/week for 6 weeks 

(Monticello et al. 1989), in mice exposed to up to 40 ppm by a similar protocol for 13 weeks (Maronpot 

et al. 1986), or in rats or mice exposed to up to 14.3 ppm for 24 months (Kerns et al. 1983b). The weight 

of available evidence suggests that airborne formaldehyde may produce toxic effects on the liver only at 

high concentrations that may exceed metabolic and binding capacities in the respiratory tract. 

Renal Effects. In the only report located regarding renal effects in humans after inhalation exposure 

to formaldehyde, Freestone and Bentley (1989) noted that renal failure occurred in a 68-year-old man 

who inhaled and/or ingested an undetermined amount of formaldehyde. He stated that he had inhaled 

formaldehyde for a sore throat, however, the medical staff believed that he may have gargled with the 

formaldehyde as well. Dopamine was administered until renal function improved and the man was 

released. 

No evidence from histological examinations or blood chemistry monitoring for formaldehyde-induced 

kidney effects has been found in intermediate-duration inhalation studies with rats, Rhesus monkeys, or 

mice (Appelman et al. 1988; Maronpot et al. 1986; Monticello et al. 1989; Woutersen et al. 1987), or in 

chronic inhalation studies with rats and mice (Kamata et al. 1997; Kerns et al. 1983b). Appelman et al. 

(1988) noted that rats exposed to 10 ppm, 6 hours/day, 5 days/week for 52 weeks had “frequent oliguria”. 

Kerns et al. (1983b) also measured urinalytic variables in rats and mice exposed to up to 14.3 ppm by a 

similar protocol for 24 months, but did not report a similar finding. 
 

 

FORMALDEHYDE 69 

2. HEALTH EFFECTS 

Endocrine Effects. No studies were located regarding endocrine effects in humans exposed to 

inhaled formaldehyde. No evidence from histological examinations or organ weight measurements for 

formaldehyde-induced effects on endocrine organs (e.g., pancreas, pituitary, adrenals, thyroid) has been 

found in intermediate-duration inhalation studies with rats, mice or Rhesus monkeys (Appelman et al. 

1988; Maronpot et al. 1986; Monticello et al. 1989; Woutersen et al. 1987), or in chronic inhalation 

studies with rats or mice (Kamata et al. 1997; Kerns et al. 1983b). 

Dermal Effects. Occupational exposures to formaldehyde have been associated with dermal irritation 

and the diagnosis of allergic contact dermatitis by patch testing. Reported historical percentages of 

subjects with skin problems showing positive responses to formaldehyde in patch tests performed by 

dermatologists using aqueous solutions with 1 or 2% formaldehyde include 7.8% in North America 

between 1992 and 1994 (Marks et al. 1995), 1.6% in a 1983–1984 Swedish study (Meding and Swanbeck 

1990), 2.6% in a 1988–1989 European study (Menné et al. 1991), and 3.7% in a 1990–1994 Polish study 

(Kiec-Swierczynska 1996). Lack of case-specific exposure information for these patients precludes the 

determination of the degree to which sensitization may have been caused by direct dermal contact to 

formaldehyde in liquids or by contact with formaldehyde gas in air, but the widespread use of 

formaldehyde or formaldehyde-releasing chemicals in cosmetics and cleaning agents (Flyvholm 1991; 

Rastogi 1992) suggest that the dermal route of exposure may be the more important sensitizing route. 

Dermal effects in humans from exposure to formaldehyde are further discussed in Sections 2.2.3.2 and 

2.2.3.3. 

Acute controlled exposure studies of volunteers exposed to airborne formaldehyde at concentrations 

ranging from 0.4 to 3 ppm have not found increased reporting of skin irritation symptoms (Andersen and 

Molhave 1983; Bender et al. 1983; Day et al. 1984; Gorski et al. 1992; Krakowiak et al. 1998; Kulle et al. 

1987; Pazdrak et al. 1993; Weber-Tschopp et al. 1977). Eberlein-Konig et al. (1998), however, found 

subtle skin effects in seven subjects described as having formaldehyde atopic eczema compared with 

seven nonsensitized subjects. Exposure to 0.08 ppm formaldehyde for 4 hours in an exposure chamber 

induced increased transepidermal water loss, but not skin roughness, on the uncovered lower arms of 

subjects with atopic eczema; neither transepidermal water loss nor skin roughness were increased by 

similar exposure in a group of seven subjects without atopic eczema. Serum levels of eosinophil cationic 

protein and soluble interleukin-2 receptor were not increased by exposure in either group. 
 

 

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No evidence for formaldehyde-induced effects on the skin has been reported in intermediate-duration 

inhalation studies with rats, hamsters, Rhesus monkeys, or mice (Appelman et al. 1988; Maronpot et al. 

1986; Monticello et al. 1989; Woutersen et al. 1987), or in chronic inhalation studies with rats or mice 

(Kamata et al. 1997; Kerns et al. 1983b), except that the highest concentration used in these studies 

(40 ppm used in the 13-week mouse study by Maronpot et al. 1986) produced severe clinical signs of 

toxicity in mice including mouth breathing, ataxia, and “loss of skin elasticity”. 

Ocular Effects. From occupational exposure experience and results in controlled acute inhalation 

exposure studies in humans, airborne formaldehyde is well-known as an eye irritant. Because 

formaldehyde-induced eye irritation and upper respiratory tract irritation have often been noted at similar 

exposure concentrations, results from survey studies of occupationally-exposed workers and controlled 

acute exposure studies in which subjects reported symptoms of eye irritation were discussed earlier in the 

Respiratory Effects part of this section. 

Studies of animals exposed to airborne formaldehyde for intermediate and chronic durations have not 

found increased incidences of histological changes in the eyes of mice exposed to up to 40 ppm (Kerns et 

al. 1983b; Maronpot et al. 1986), rats exposed to up to 20 ppm (Appelman et al. 1988; Kerns et al. 1983b; 

Swenberg et al. 1980; Woutersen et al. 1987), or monkeys exposed to 6 ppm (Monticello et al. 1989). 

Kerns et al. (1983b) reported that ophthalmoscopic examinations revealed no exposure-related changes in 

rats or mice examined at several intervals during a 2-year period of exposure to concentrations as high as 

14.3 ppm. Clinical signs of eye irritation during exposure, however, have been reported in monkeys 

(“mild lacrimation and conjunctival hyperemia”) exposed to 6 ppm for up to 6 weeks (Monticello et al. 

1989), in rats exposed to 10 ppm for up to 4 days (Dinsdale et al. 1993), and in rats (“ocular discharge”) 

exposed to 2 to 15 ppm, but not to 0.5 ppm, for up to 3 weeks (Morgan et al. 1986c). Swenberg et al. 

(1980) described the development of a “unilateral ocular discharge” that was associated with the 

subsequent development of nasal tumors in rats exposed to 14.3 ppm; this discharge is likely distinct from 

the clinical signs of eye irritation noted in the other animal studies and in the human studies. 

Body Weight Effects. Body weight effects have not been associated with formaldehdye exposure in 

humans, but exposure-response relationships have been described in animal studies. 
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Body weight decreases $10% of control values were observed in male rats exposed to 10 ppm, but not to 

1 ppm, 6 hours/day, 5 days/week for 13 or 52 weeks (Appelman et al. 1988); in male rats exposed to 

2.95 ppm, but not to 0.98 ppm, 22 hours/day, 7 days/week for 26 weeks (Rusch et al. 1983); in male rats 

exposed to 20 ppm, but not to 10 ppm, 6 hours/day, 5 days/week for 13 weeks (Woutersen et al. 1987); in 

male mice exposed to $20 ppm, and female mice exposed to 40 ppm, 6 hours/day, 5 days/week for 

13 weeks (Maronpot et al. 1986); in male and female rats exposed to 14.3 ppm, but not to 5.6 ppm, 

6 hours/day, 5 days/week for 2 years (Kerns et al. 1983b); in male rats exposed to 15 ppm, but not to 

2 ppm, 6 hours, 5 days/week for 4 to 28 months (Kamata et al. 1997); and in male rats exposed to 

10 ppm, but not to 1 ppm, 6 hours/day, 5 days/week for 28 months (Woutersen et al. 1989). 

No body weight effects were observed in Rhesus monkeys exposed to 6 ppm, 6 hours/day, for 5 days or 

5 days/week for 6 weeks (Monticello et al. 1989), in female rats, Cynomolgus monkeys, or hamsters 

exposed to up to 2.95 ppm, 22 hours/day, 7 days/week for 26 weeks (Rusch et al. 1983), in female rats 

exposed to up to 20 ppm, 6 hours/day, 5 days/week for 13 weeks (Woutersen et al. 1987), or in mice 

exposed to up to 14.3 ppm, 6 hours/day, 5 days/week for 24 months (Kerns et al. 1983b). 

2.2.1.3 Immunological and Lymphoreticular Effects 

As discussed previously in Section 2.2.1.2 (dermal effects from inhalation exposure), formaldehyde is 

commonly diagnosed as a dermal allergen worldwide. Lack of case-specific exposure information 

precludes determining the degree to which sensitization may have been caused by direct dermal contact to 

formaldehyde in liquids or by contact with formaldehyde gas in air, but the widespread use of 

formaldehyde or formaldehyde-releasing chemicals in cosmetics and cleaning agents (Flyvholm 1991; 

Rastogi 1992) suggest that the dermal route of exposure may be the more important sensitizing route. 

Dermal effects in humans from exposure to formaldehyde, including formaldehyde allergic contact 

dermatitis, are further discussed in Section 2.2.3.2 and 2.2.3.3. 

Investigations into the possibility of immunologically-mediated respiratory responses in formaldehydeexposed individuals reporting respiratory problems such as bronchial asthma have provided very limited 

positive evidence. 

There are only a few available case reports of bronchial asthma suggestive of respiratory tract 

sensitization to formaldehyde gas including two renal dialysis nurses (Hendrick and Lane 1975, 1977; 
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2. HEALTH EFFECTS 

Hendrick et al. 1982), a plastic moulder (Burge et al. 1985), a printer (Burge et al. 1985), a worker in a 

phenol formaldehyde manufacturing plant (Burge et al. 1985), and a carpenter (Lemiere et al. 1995). 

These cases of formaldehyde-exposed workers all displayed marked changes in FEV1 or airflow rates in 

response to acute challenges with formaldehyde gas at exposure levels <3 ppm. Nordman et al. (1985) 

provided acute formaldehyde (2 ppm) challenges to 230 patients who had been occupationally exposed to 

formaldehyde and who had reported respiratory symptoms consistent with asthma, but found challengeinduced decreases in PEFR >15% in only 12 subjects. Although an immunologic-mediated response may 

be consistent with the observed airway responses, the mechanism of sensitization in these subjects is 

uncertain. Challenge-induced deficits in FEV1 or airflow rates indicative of lower airway sensitization 

were not found in studies of: 9 subjects complaining of respiratory problems from urea-formaldehyde 

foam insulation in their homes who were challenged with 1–1.2 ppm formaldehyde for 90 minutes (Day 

et al. 1984); 10 formaldehyde-exposed textile or shoe manufacturing workers with purported bronchial 

asthma who were challenged with 0.41 ppm for 2 hours (Krakowiak et al. 1998); and 13 formaldehydeexposed subjects who had previously reported asthma-like symptoms who were challenged with 0.1, 1, or 

3 ppm for 20 minutes (Reed and Frigas 1984). 

Several studies have examined serum for formaldehyde-specific IgE antibodies in groups of 

formaldehyde-exposed humans (Dykewicz et al. 1991; Grammar et al. 1990; Kramps et al. 1989; Wantke 

et al. 1996a, 1996b). In general, the studies do not provide consistent evidence for a formaldehydeinduced allergic respiratory syndrome, but provide suggestive evidence that children may have an 

increased tendency to develop specific antibodies after exposure to low levels of formaldehyde in indoor 

air (Wantke et al. 1996a). 

Formaldehyde-specific IgE antibodies could be detected in only 1/86 serum samples from four groups of 

formaldehyde-exposed subjects (Kramps et al. 1989). The groups included 28 subjects living or working 

in places with formaldehyde-containing construction materials (e.g., chipboard) and estimated 

formaldehyde concentrations ranging from 0.08 to 0.37 ppm, 18 occupationally exposed subjects from an 

anatomy laboratory and in other unspecified industries where air concentrations were not measured, 

12 hospital attendants who worked with formaldehyde-sterilized hemodialysis equipment, and 

28 hemodialysis patients treated with formaldehyde-sterilized equipment. Variable symptoms such as 

headache, eye irritation, and respiratory complaints were reported by 24/28 subjects in the constructionmaterial group. The group of 18 occupationally exposed subjects reported nonspecific irritation of eyes 

and airways associated with their work; the subject with detected formaldehyde-specific IgE displayed no 
FORMALDEHYDE 73 

2. HEALTH EFFECTS 

allergic symptoms. The hospital attendants and hemodialysis patients reported no exposure-related 

symptoms. Durations of exposure or employment were not reported for the subjects in this study. 

Grammer et al. (1990) studied the immunologic nature of formaldehyde sensitivity in 37 workers who 

complained of formaldehyde-related illness and were examined by a group of physicians. Blood samples 

were collected and assayed for IgE and IgG activity against formaldehyde and formaldehyde-human 

serum albumin (f-HSA). Fourteen workers had symptoms consistent with an irritant syndrome, another 

14 had symptoms consistent with a possible irritant, and 9 had no work-related symptoms. Four workers 

also had symptoms consistent with formaldehyde allergy. None of the workers had IgG activity against 

formaldehyde. Five workers had antiformaldehyde IgE activity, but further testing revealed that the IgE 

lacked formaldehyde specificity. The authors concluded that in this group of workers, there was no 

evidence of an immunologically mediated response to formaldehyde. 

Dykewicz et al. (1991) sought to determine whether IgE or IgG antibodies to formaldehyde were related 

to formaldehyde exposure or respiratory symptoms arising from such an exposure. The authors studied 

55 hospital histology technicians, internal medicine residents, pathology residents, current smokers, 

subjects with known workplace exposure to formaldehyde, and controls with no history of formaldehyde 

exposure. Reported workplace formaldehyde concentrations were 0.2–0.64 ppm for pathology residents, 

0.64 ppm for histology technicians, and 0.6–11 ppm for miscellaneous formaldehyde exposure scenarios. 

No workplace air concentrations were measured for the other occupations. Average years of occupational 

exposure to formaldehyde were 12.45 years for histology technicians, 0.38 years for medical residents, 

3.21 years for pathology residents, and 18.34 years for 5 subjects exposed to miscellaneous workplaces 

with formaldehyde. Each subject was evaluated by questionnaire for the presence of upper- and lowerrespiratory tract and ocular symptoms and formaldehyde-related illnesses. Blood samples were drawn 

from each subject and were analyzed for IgE and IgG reactivity with f-HSA. Three subjects had IgE 

against f-HSA; these three and two others had low levels of anti-f-HSA IgG. The presence of IgG and 

IgE antibodies to formaldehyde was not clearly related to formaldehyde exposure or pack-years of 

smoking. One subject had both IgE and IgG antibodies and also suffered from eye and respiratory 

symptoms when exposed to formaldehyde at his workplace. The authors concluded that they could 

not establish a relationship of IgE and IgG to formaldehyde exposure. They further concluded that 

if immunologically mediated rhinitis or conjunctivitis existed, it must occur at extremely low 

frequencies. Several limitations of this study should be noted. First, the investigators recruited 

volunteers who may have systematically differed from the general populations from which they were 
FORMALDEHYDE 74 

2. HEALTH EFFECTS 

sampled. One of the exposure groups comprised cigarette smokers, who have exposures to many 

chemicals in addition to their formaldehyde exposures. Although the study focuses on formaldehyde 

antibodies, which would be unaffected by the other chemicals, respiratory symptoms among smokers 

would reflect exposures to the other smoke constituents. 

Wantke et al. (1996a) measured elevated levels of formaldehyde-specific IgE in 24/62 8-year-old children 

who were students in three particle board-paneled classrooms with estimated formaldehyde air 

concentrations of 0.075, 0.069, and 0.043 ppm. In a health survey, the children reported headaches 

(29/62), fatigue (21/62), dry nasal mucosa (9/62), rhinitis (23/62), cough (15/62), and nosebleeds (14/62). 

Sums of numbers of children with each of nine symptoms for each classroom decreased with decreasing 

formaldehyde concentration (49, 47, and 24, respectively, for the 0.075-, 0.069-, and 0.043-ppm 

classrooms), but the investigators reported that elevated levels of specific IgE did not correlate with the 

number and severity of symptoms. The children were moved to a new school without particle board 

paneling and were evaluated again, 3 months after moving. Estimated formaldehyde concentrations in the 

new classrooms were 0.029, 0.023, and 0.026 ppm. The numbers of children reporting symptoms 

decreased significantly compared with premoving reporting figures, and mean serum levels of 

formaldehyde-specific IgE, measured in 20 of the children, declined significantly compared with 

premoving mean levels. 

Formaldehyde-specific IgE was not detected in a group of 45 medical students, before or after the 

students attended a 4-week anatomy dissecting course (Wantke et al. 1996b). Estimates of laboratory air 

concentrations of formaldehyde ranged from 0.059 to 0.219 ppm (mean 0.124±0.05 ppm). Surveys 

revealed frequencies of irritation symptoms consistent with other studies (e.g., itching of the skin in 

33/45 students, headache in 15/45, and burning eyes in 13/45). 

Thrasher et al. (1987) assessed the effects of formaldehyde exposure on cellular immunity and antibody 

formation in eight symptomatic and eight unexposed individuals. The exposed group was comprised of 

three males and five females. Seven of the exposed individuals resided in mobile homes for periods 

ranging from 2 to 7 years; the eighth exposed subject was a laboratory worker who resided in a newly 

decorated, energy-efficient apartment. Air monitoring in four of the homes revealed formaldehyde vapor 

concentrations ranging from 0.07 to 0.55 ppm. Venous blood samples were collected from all subjects 

and lymphocytes were used for T- and B-cell enumeration and blastogenesis; serum samples were used to 

determine IgG and IgE antibodies to formaldehyde. IgE antibodies to formaldehyde were not detected in 
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2. HEALTH EFFECTS 

exposed or control subjects; IgG antibodies in exposed subjects ranged from 1:8 to 1:256, but were 

undetected (1:4) in 7 of the controls. T- and B-cell numbers were significantly lower (p<0.05) in mobile 

home residents (48 and 12.6%, respectively) compared to control subjects (65.9 and 14.75%, 

respectively). Phytohemagglutinin-stimulated T- and B-cell blastogenesis was significantly depressed 

(p<0.01) in mobile home residents compared to control subjects (17,882 versus 28,576 counts per minute, 

respectively). 

In a later study, Thrasher et al. (1990) evaluated four groups of patients with varying levels and durations 

of formaldehyde exposure. The groups consisted of asymptomatic chiropractic students exposed during 

anatomy classes (controls), mobile home residents, office workers, patients with multiple symptoms who 

had been removed from the source of formaldehyde for at least a year, and occupationally exposed 

patients. All groups were assessed for immunologic function via white cell, lymphocyte and T-cell 

counts, T-helper/suppressor ratios, B cell counts, and production of antibodies against f-HSA. When 

compared to controls (students), the patient groups had significant elevations in formaldehyde antibody 

titers and B-cell titers. The level of autoantibodies was also significantly elevated in patients exposed 

long-term to formaldehyde. 

Gorski et al. (1992) investigated the correlation between formaldehyde-induced contact dermatitis and 

granulocyte chemiluminescence resulting from free-radical release in healthy and formaldehyde-sensitive 

patients. Thirteen patients with contact dermatitis who were occupationally exposed to formaldehyde and 

five healthy volunteers participated in the study. All subjects underwent skin-prick tests for common 

allergens as well as a histamine inhalation provocation test. Subjects were exposed to 0.5 mg/m3 

(0.41 ppm) formaldehyde for 2 hours, and peak expiratory flow was measured immediately before 

exposure, at 60 and 120 minutes of exposure, and at 6 and 21 hours after completion of exposure. In 

formaldehyde-sensitive patients, skin-prick tests and total serum IgE were normal; no antiformaldehyde 

IgE was detected. In formaldehyde-sensitive patients, peripheral blood granulocyte chemiluminescence 

significantly increased within 30 minutes of exposure commencement, and remained elevated 24 hours 

later, compared to initial values. Granulocyte chemiluminescence did not increase in healthy patients. 

Pross et al. (1987) evaluated the immunologic response of asthmatic subjects exposed to UFFI off-gas 

products. Subjects consisted of 23 individuals with a history of asthmatic symptoms attributed to UFFI 

and 4 individuals with asthma unrelated to UFFI byproducts. All subjects were exposed to the following 

in an environmental chamber: room air (placebo) for 30 minutes; 1 ppm formaldehyde gas for 3 hours; 
FORMALDEHYDE 76 

2. HEALTH EFFECTS 

UFFI particles (4 μm, 0.5 particles/mL) for 3 hours, commencing 48 hours after formaldehyde gas 

exposure; and UFFI off-gas products for 3 hours, commencing 48 hours after UFFI particle exposure. 

There was a significant increase in the percentage and absolute number of eosinophils and basophils in 

the subjects that lived in UFFI-homes. There were no differences between exposure groups with respect 

to lymphocyte subpopulations either before or after UFFI exposure. However, when T8 suppressor cell 

count control values for the UFFI-exposed group were compared to T8 (suppressor) cell count values 

collected after UFFI chamber exposure, a small but statistically significant (p<0.01) increase in T8 cell 

count was observed. The significance of this change in T8 cell count is not known. Phytohemagglutinand formalin-treated-red-blood-cell-stimulation studies revealed no differences between treatment groups 

in nonspecific or specific lymphocyte reactivity in response to UFFI exposure. Likewise, UFFI exposure 

had no effect on humoral immunity. Natural killer function was also unaffected by in-home or chamber 

exposure to UFFI, as was the interferon-boosted (IFN) natural killer cell response. Approximately half of 

the subjects from each group were classified as atopic based on skin-prick tests, but there was little 

correlation with NK function. The authors concluded that short-term exposure to formaldehyde was not 

immunosuppressive and did not result in systemic immune reactivity. 

No histopathological effects on lymphoreticular tissues (e.g., spleen, thymus, lymph nodes) were 

observed in Rhesus monkeys exposed to 6 ppm, 6 hours/day, 5 days/week for 6 weeks (Monticello et al. 

1989); in rats exposed to up to 10 ppm, 6 hours/day, 5 days/week for 13 or 52 weeks (Appelman et al. 

1988); in rats exposed to up to 20 ppm, 6 hours/day, 5 days/week for 13 weeks (Woutersen et al. 1987); 

in mice exposed to 40 ppm, 6 hours/day, 5 days/week for 13 weeks (Maronpot et al. 1986); in rats and 

mice exposed to up to 14.3 ppm, 6 hours/day, 5 days/week for 24 months (Kerns et al. 1983b); or in rats 

exposed to up to 15 ppm, 6 hours/day, 5 days/week for 28 months (Kamata et al. 1997). 

In a study by Adams et al. (1987), the effects of exposure to formaldehyde on the maturation of the 

mononuclear phagocyte system in female B6C3F1 mice were investigated. Mice were exposed to a target 

concentration of 15 ppm formaldehyde 6 hours/day, 5 days/week for 3 weeks. Exposure to formaldehyde for 3 weeks did not affect lymphoid organ weights or the number of resident or activated 

macrophages. Formaldehyde exposure resulted in lower peritoneal macrophage leucine aminopeptidase 

concentrations, but did not appear to induce maturation of resident macrophages. Formaldehyde 

treatment did not alter the ability of induced macrophages to bind and lyse tumor cells. In macrophages 

elicited by pyran copolymer MVE-2, the ability to release reactive oxygen intermediates (H2O2) was 

increased almost 2-fold as a result of formaldehyde exposure. The authors concluded that formaldehyde 
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2. HEALTH EFFECTS 

exposure did not disturb the systemic development of tumoricidal macrophages, but did enhance the 

release of reactive oxygen intermediates. 

Dean et al. (1984) studied immune function in female B6C3F1 mice 6–8 weeks of age. Mice were 

exposed by inhalation to 15 ppm formaldehyde for 6 hours/day, 5 days/week for 3 weeks. Several tests 

that evaluated immune function were used: (1) tumor challenge procedure consisting of a subcutaneous 

injection of PYB6 sarcoma cells, (2) tumor resistance assessment consisting of an intravenous injection of 

B16F10 melanoma cells, and (3) an intravenous challenge using Listeria monocytogenes bacteria. Other 

tests that evaluated immune function were cell-mediated immunity (consisting of monitoring the delayed 

hypersensitivity response to keyhole limpet hemocyanin); lymphoproliferative responses to T-cell 

mitogens (phytohemagglutinin) and B-cell mitogens (Escherichia coli lipopolysaccharide); spontaneous 

cytotoxicity (natural killer cell); macrophage function (elicitation, activation, phagocytic); plaque-forming 

cell activity; and spleen and bone marrow cellularity. Thymus and spleen weights were unaffected by 

formaldehyde exposure. A significant decrease in the absolute number of monocytes was observed in the 

formaldehyde-treated mice (4/mm3

 versus 43/mm3 in controls; p<0.05); all other hematological 

parameters in treated mice were similar to those of controls. Spleen and bone marrow cellularity were 

similar in treated and control groups. Formaldehyde-treated animals experienced lower mortality (30%) 

than controls (70%) in response to challenge with Listeria monocytogenes. Formaldehyde-treated mice 

were also less susceptible to tumor transfer or formation compared to controls. No differences were noted 

in treated and control mice for the following parameters: delayed hypersensitivity reaction; natural killer 

cell-mediated tumor cytotoxicity; lymphocyte proliferation; lymphocyte surface markers; macrophage 

function; and plaque-forming cell response. The authors concluded that exposure to 15 ppm 

formaldehyde for 3 weeks was not immunotoxic; they hypothesized that this was due to the highly 

reactive nature of the compound which prevents penetration into the deep lung and tissue penetration in 

general. 

Holmstrom et al. (1989b) evaluated the long-term inhalation effects of formaldehyde exposure to immune 

function in female Sprague-Dawley rats exposed to 12.6 ppm formaldehyde for 6 hours/day, 5 days/week 

for 22 months. After 22 months of formaldehyde exposure, the rats were inoculated subcutaneously with 

Pneumovax (Merck Sharpe and Dohme) and antitetanus vaccine (National Bacteriological Laboratory). 

Animals were sacrificed at 21–25 days after vaccination. Blood samples were collected from each animal 

before vaccination and just prior to sacrifice. The blood was analyzed for response to Pneumovax and 

tetanus vaccination using an enzyme-linked immunosorbant assay technique. The results indicated that 
FORMALDEHYDE 78 

2. HEALTH EFFECTS 

there were no differences between exposed and control animals in IgM production in response to 

Pneumovax. Mean overall IgG production in response to Pneumovax was similar between exposed and 

control rats; however, a 2-fold increase in IgG production in response to the 19F pneumococcal antigen 

was seen in 4 of 8 exposed rats compared to 1 of 6 control rats. The IgM response to tetanus 

immunization was similar in the exposed and control groups; levels increased at least 2-fold in a majority 

of animals in both groups. Likewise, IgG levels increased significantly in response to tetanus toxoid, but 

the response did not differ between treatment groups. The authors concluded that there was no evidence 

of immunosuppression in response to long-term exposure to near-maximal levels of formaldehyde in rats. 

Whereas other animal experiments have not found convincing evidence that repeated inhalation exposure 

to formaldehyde has direct effects on the immune system, there is suggestive evidence that it may have an 

indirect effect by facilitating sensitization of nasal tissue to high-molecular weight allergens in mice 

(Tarkowski and Gorski 1995). The ability of intranasal administration of 25 μg of ovalbumin (once a 

week for 7 weeks) to increase the titer of serum IgE antibodies to ovalbumin (IgE anti-OVA) was 

examined in groups of 10 Balb/c mice preexposed to 0 or 1.6 ppm formaldehyde 6 hours/day for 10 days, 

or to 0 or 1.6 ppm, 6 hours/day once a week for 7 weeks. In a second experiment, groups of mice were 

preexposed to 0 or 1.6 ppm, 6 hours/day for 10 days, injected with up to 4 doses of 1 μg ovalbumin in the 

peritoneum, and examined for serum IgE antiOVA titers. Serum titers of IgE antiOVA were significantly 

higher (after four intranasal doses of OVA) in mice preexposed to formaldehyde 6 hours/day for 10 days 

compared with control titers; mean IgE antiOVA titer at 7 weeks in 10-day preexposed mice 

was >60 units compared with about 15 units for controls. No significant difference in IgE-OVA was 

found between controls and the group preexposed to formaldehyde once a week for 7 weeks. With 

intraperitoneal administration of ovalbumin, preexposure to formaldehyde for 10 consecutive days had no 

effect on serum IgE-OVA titers compared with controls. 

In a similar experiment with guinea pigs, Riedel et al. (1996) observed a greater percentage of allergic 

responses to inhaled ovalbumin in a group of guinea pigs pre-exposed to 0.25 ppm formaldehyde, 

8 hours/day for 5 days than in a control group without preexposure to formaldehyde (10/12 versus 3/12) 

(Riedel et al. 1996). 

The highest NOAEL values and all LOAEL values from each reliable study for immunological/ 

lymphoreticular effects in each species and duration category are recorded in Table 2-1 and plotted in 

Figure 2-1. 
FORMALDEHYDE 79 

2. HEALTH EFFECTS 

2.2.1.4 Neurological Effects 

Bach et al. (1990) sought to determine whether humans reacted acutely to formaldehyde exposure, and if 

previous chronic-duration exposure to formaldehyde altered the responses noted in acute exposure. 

Thirty-two men with at least 5 years of occupational exposure to formaldehyde and 29 matched controls 

were exposed to formaldehyde at concentrations of 0, 0.12, 0.32, or 0.98 ppm for 5.5 hours. During the 

exposure period, subjects underwent a battery of performance tests designed to estimate the subject’s 

distractibility, short-term memory, and capability to understand and perform certain tasks. Controls 

tended to suffer from headaches, "heavy head", and physical tiredness more than the exposed workers. In 

both occupationally exposed subjects and nonexposed subjects, decreased performances in several tests 

were statistically significantly correlated with increasing acute concentration of formaldehyde. 

Occupationally exposed subjects showed significantly decreased performance, compared with 

nonexposed subjects, only in a digit span test, but not in variables for a graphic continuous line test, an 

addition test, or a digit symbol test. The authors noted that the typical dose-related symptoms of 

respiratory irritation were not seen in this study. 

Kilburn and colleagues have presented evidence for neurological impairments in several studies of 

formaldehyde-exposed histology technicians, but confounding exposure to other neurotoxic solvents 

prevents drawing definitive conclusions concerning the neurotoxicity of formaldehyde from these studies 

(Kilburn 1994; Kilburn and Warshaw 1992; Kilburn et al. 1985b, 1987). Kilburn et al. (1985b) reported 

that a group of 76 female histology technicians reported statistically significantly greater frequencies of 

neurobehavioral symptoms such as lack of concentration and loss of memory, disturbed sleep, impaired 

balance, variations in mood, and irritability than did a referent group of 56 non-exposed female clerical 

workers. The technicians had been employed from 2 to 37 years (mean 12.8 years). Analysis of 

workplace air samples indicated concentrations for several solvents ranging from 0.2 to 1.9 ppm for 

formaldehyde, 3.2 to 102 ppm for xylene, 2 to 19.1 ppm for chloroform, and 8.9 to 12.6 ppm for toluene. 

Subsequently, Kilburn et al. (1987) administered a battery of 10 tests that assessed memory, balance, 

coordination, dexterity, motor speed, and aspects of cognitive function to 305 female histology 

technicians and analyzed the results by regression analysis with age, years of smoking, hours per day of 

exposure to formaldehyde and other solvents as explanatory variables. Increased daily hours of exposure 

to formaldehyde were significantly correlated with decreased performance in several tests, whereas hours 

of daily exposure to other solvents were only correlated with decreased perfomance in a single test. 

However, in a later prospective study of performance by 318-494 histology technicians in a battery of 
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2. HEALTH EFFECTS 

neurobehavioral tests, no statistically significant cumulative effects due to occupational exposure to 

formaldehyde (or other solvents) or of aging were found over a 4-year period (Kilburn and Warshaw 

1992). Kilburn (1994) further reported that three anatomists and one railroad worker, who were 

occupationally exposed to airborne formaldehyde for 14-30 years and who were disabled, each showed 

impaired performance on several neurobehavioral tests (e.g., choice reaction time, abnormal balance, digit 

symbol, and tests of perceptual motor speed). 

In laboratory animals, Morgan et al. (1986a) studied male Fischer 344 rats exposed to 15 ppm 

formaldehyde for 10, 20, 45, or 90 minutes, or 6 hours. Some additional rats were also exposed to 2 ppm 

formaldehyde for 90 minutes or 6 hours to establish whether this level was a no-effect concentration. The 

rats exposed to 15 ppm formaldehyde exhibited restless behavior for the first 10–15 minutes of exposure. 

Boja et al. (1985) investigated the effects of low-level formaldehyde exposure on behavior and 

neurochemistry in male Sprague-Dawley rats. Animals were exposed to either air or formaldehyde at 

concentrations of 5, 10, or 20 ppm for 3 hours. The following day the rats were exposed to either the 

same treatment or the opposite treatment (i.e., treatment groups of air-air, air-formaldehyde, 

formaldehyde-air, or formaldehyde-formaldehyde). Behavioral activity was periodically monitored. 

After the second day of exposure, rats were sacrificed, their brains were removed, and samples of 

striatum, nucleus accumbens, frontal cortex, lateral septum, amygdala, hypothalamus, and hippocampus 

were collected and analyzed for norepinephrine, dopamine, and 5-hydroxytryptamine and their major 

metabolites. Exposure to 5 ppm formaldehyde resulted in statistically significant decreased motor activity 

within 15 minutes. At the beginning of day 2, all of the rats exposed to formaldehyde on day 1 displayed 

lower activity levels. Similar effects on motor activity were seen at the 10 ppm formaldehyde exposure 

level, whereas effects seen after 20 ppm exposure were reported to be “not readily interpretable” and were 

not shown. Exposure to 5 ppm formaldehyde statistically significantly increased concentrations of 

5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and dopamine in the hypothalamus, but did 

not affect the concentrations of norepinephrine or 5-hydroxytryptamine. Data for other brain regions or 

exposure concentrations were not reported (Boja et al. 1985). 

Wood and Coleman (1995) assessed the behavioral response to formaldehyde exposure in male Swiss 

mice. Eight mice were trained to terminate exposure to noxious gases, using 1,000 ppm ammonia. All 

animals learned to terminate 100% of the ammonia exposures. After mice consistently terminated 
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2. HEALTH EFFECTS 

ammonia exposures, they were exposed to a series of formaldehyde exposures at concentrations of 0, 1, 

1.8, 3, 5.6, and 10 ppm. Beginning at the lowest formaldehyde concentration (1 ppm), mice terminated 

significantly more exposures compared to air (p<0.0005). The number of terminations increased and the 

time to termination decreased as the concentration of formaldehyde increased. Exposure durations in the 

second series were significantly shorter (p=0.0012) than those experienced in the first series, indicating an 

increased sensitivity to formaldehyde. Wood and Coleman (1995) suggested that a conditioned response 

may have developed in the mice rather than a change in the sensitivity of the sensory epithelium. 

In studies of intermediate-duration exposure, Maronpot et al. (1986) studied the effects of formaldehyde 

exposure in male and female B6C3F1 mice. Animals were exposed to formaldehyde 6 hours/day, 

5 days/week for 13 weeks at target concentrations of 0, 2, 4, 10, 20, or 40 ppm. No obvious gross signs 

of neurotoxicity were seen in mice treated with 2, 4, or 10 ppm formaldehyde, but mice in the 20-ppm 

group exhibited dyspnea, listlessness, and hunched posture. These symptoms were also noted in the 

40-ppm groups with greater severity; in addition, mice in this group exhibited ataxia. 

Appelman et al. (1988) examined the effects of preexisting nasal damage and formaldehyde exposure in 

male SPF Wistar rats. Groups of 40 rats each were exposed to 0, 0.1, 1, and 10 ppm formaldehyde. 

Within each dose group, half of the animals had their nasal mucosa damaged by electrocoagulation. 

Animals were exposed to formaldehyde 6 hours/day, 5 days/week for either 13 or 52 weeks (n=10 per 

dose/nasal damage subgroup). Behavior and appearance were not affected by formaldehyde exposure; 

brain weights and histopathology in all of the formaldehyde-treatment groups were not significantly 

different from the control animals. 

Woutersen et al. (1987) examined the effects of inhalation exposure to formaldehyde in male and female 

Wistar rats. Groups of 10 animals per sex were exposed to target concentrations of 1, 10, or 20 ppm 

formaldehyde 6 hours/day, 5 days/week for 13 weeks. Uncoordinated movement and wall-climbing were 

noted during the first 30 minutes of each exposure period in the 20-ppm group; the rats in the lower-dose 

groups did not exhibit abnormal behavior. In the 20-ppm males, relative organ weights were higher in 

6 of the 11 animals examined (no further data supplied), and in the females of this dose group, only 

relative brain weights were significantly greater than those of controls. No treatment-related gross or 

histopathological lesions of the brain were noted in any sex or dose-group at necropsy. 
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Kerns et al. (1983b) studied the effects of long-term formaldehyde exposure on 120 male and female 

Fischer 344 rats and B6C3F1 mice exposed to 0, 2, 5.6, or 14.3 ppm formaldehyde for 6 hours/day, 

5 days/week for 24 months. The dosing period was followed by a 6-month observation period. Interim 

sacrifices were performed at 6, 12, 18, 24, 27, and 30 months. No dose-related neurofunctional effects 

were noted at any dose or interim sacrifice time-point in either sex or species. 

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 2-1 and plotted in Figure 2-1. 

2.2.1.5 Reproductive Effects 

Ward et al. (1984) investigated whether formaldehyde exposure resulted in altered sperm numbers or 

morphology in male pathologists. Exposed subjects consisted of 11 men; 10 were employed for 

1–11 months (average 4.3 months) and the other was employed for several years. All subjects provided 

three semen samples collected at 2–3 month intervals. Sperm samples were analyzed for sperm count, 

morphology, and F-body frequency. Time-weighted average air concentrations in workplaces ranged 

from 0.61 to 1.32 ppm (midpoint of range 0.97 ppm). The mean sperm count for exposed workers was 

lower than that of controls (62.9x106

/mL versus 87.4x106/mL); however, the difference was not 

statistically significant. The frequency of abnormal sperm was not greater in exposed subjects. The 

frequency of sperm containing 1F- or 2F-bodies was similar between exposed and control subjects. The 

small number of subjects in this study limited its detection power. 

Garry et al. (1980) investigated the health effects associated with formaldehyde exposure in Minnesota 

residents. A total of 275 cases of possible formaldehyde exposure were investigated between February 

and June 1979. Medical histories of the patient and all family members were recorded, and 30-minute air 

samples were collected from the living room and bedroom of each residence. Environmental information 

(age, type of home, type of insulation, type of heat) was also collected. Formaldehyde levels ranged from 

0.1 to 3 ppm. The rate of miscarriages in exposed women in this study (11.6%) did not differ from the 

rate of miscarriages seen in other studies of non-exposed women. There is no information on the duration 

of exposure; therefore, chronic-duration exposure is assumed. 

The possible teratogenic effects of inhaled formaldehyde were investigated in groups of 25 female rats 

exposed to airborne formaldehyde at levels of 0, 2, 5, and 10 ppm, 6 hours/day on gestation days 6–15. 
FORMALDEHYDE 83 

2. HEALTH EFFECTS 

No maternal or fetal deaths occurred, and pregnancy parameters (numbers of corpora lutea, implantation 

sites, pre-implantation losses) were not affected by formaldehyde exposure (Martin 1990). 

Although maternal toxicity, expressed as a statistically significant decrease in bodyweight gain, was 

observed in pregnant Sprague Dawley rats exposed to 40 ppm, but not 20 ppm, 6 hours/day on gestation 

days 6–20 (Saillenfait et al. 1989), other statistically significant changes in reproductive variables (e.g., 

number of implantation sites and number of resorptions), however, were not found. 

Woutersen et al. (1987) examined the effects of inhalation exposure to formaldehyde in male and female 

Wistar rats. Groups of 10 animals per sex were exposed to target concentrations of 1, 10, and 20 ppm 

formaldehyde 6 hours/day, 5 days/week for 13 weeks. No treatment-related gross lesions were noted for 

the ovaries and testes at necropsy. 

Appelman et al. (1988) provided data on the reproductive organs of rats exposed to formaldehyde. Male 

SPF Wistar rats were exposed to 0, 0.1, 1, and 10 ppm formaldehyde. Within each dose group, half of the 

animals (n=20) had their nasal mucosa damaged by electrocoagulation. Animals were exposed to 

formaldehyde 6 hours/day, 5 days/week for either 13 or 52 weeks. No significant changes in testicle 

weights of treated rats were noted when compared to controls. 

Maronpot et al. (1986) examined the effects of formaldehyde exposure on reproductive organs in male 

and female B6C3F1 mice. Animals were exposed to formaldehyde 6 hours/day, 5 days/week for 

13 weeks at concentrations of 2, 4, 10, 20, and 40 ppm. Gross and histopathological examination showed 

ovarian and uterine hypoplasia characterized by decreased prominence of endometrial glands and stroma 

and an associated lack of ovarian luteal tissue in 40-ppm females. Ovarian and uterine hypoplasia were 

not observed in the lower exposure groups. No histopathological effects were noted in male reproductive 

organs. Maronpot et al. (1986) ascribed to the belief that the ovarian and uterine effects reflected “the 

general debility and weight loss rather than a direct target organ effect of formaldehyde”. 

The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects for 

the intermediate duration category are recorded in Table 2-1 and plotted in Figure 2-1. 
FORMALDEHYDE 84 

2. HEALTH EFFECTS 

2.2.1.6 Developmental Effects 

Studies regarding the developmental toxicity of airborne formaldehyde in humans are limited to a 

population-based case-control study of 244 mothers with “low-birth weight” newborns in Lithuania 

compared with 4,089 control mothers with “normal weight” newborns (Grañulevi...iene et al. 1998). 

Questionnaire information was collected from cases and controls for risk factors including place of 

residence. Based on air monitoring data, residential districts were grouped into low (mean concentration 

1.6 ppb), moderate (2.8 ppb), or high (3.8 ppb) formaldehyde-exposure districts. After adjustment for 

other risk factors such as age, occupation, last pregnancy outcome, and smoking habit, the odds ratio 

(OR) for low-birth weight incidence was elevated in those with formaldehyde exposure >2.8 ppb 

compared with those with exposure <2.8 ppb, but not to a statistically significant degree (OR=1.37, 

95% confidence interval [CI] 0.90–2.09). 

Martin (1990) exposed groups of 25 pregnant Sprague-Dawley rats to 0, 2, 5, or 10 ppm in an inhalation 

chamber, 6 hours/day from gestation days 6 to 15. Another nonexposed group of 25 pregnant rats was 

housed outside of the inhalation chamber (“room control”). Dams were sacrificed on day 20 and uterine 

contents were evaluated. Statistically significant decreased food consumption and weight gain occurred 

in the 10-ppm dams. No statistically significant effects from exposure were found on the following 

variables: numbers of corpora lutea, implantation sites, live fetuses, dead fetuses and resorptions, fetal 

weights, fetal sex ratios, and pre- and postimplantation losses. Likewise, no exposure-related effects were 

reported on the incidences of litters and fetuses with major malformations, minor external and visceral 

anomalies, and minor skeletal anomalies. The only statistically significant finding reported was for 

increased incidences of reduced ossification of the pubic and ischial bones in the 5- and 10-ppm groups, 

compared with the 0-ppm groups but not the “room control” group. Martin (1990) did not consider these 

findings to be biologically significant, noting that they were considered to be related to the “slightly 

lower” fetal weights and “slightly larger” litter sizes in the 5- and 10-ppm groups. The published report, 

however, did not provide more details on the quantitative data collected, making assignment of fetal 

effect levels in this study uncertain. 

Saillenfait et al. (1989) assessed the effects of maternal formaldehyde inhalation on embryonic and fetal 

development in Sprague-Dawley rats. Groups of 25 mated females were exposed to 0, 5, 10, 20, and 

40 ppm formaldehyde on gestation days 6–20. The dams were weighed on gestation days 0, 6, and 21. 

All dams survived the experiment. On gestation day 21, the dams were sacrificed and their uteri were 
FORMALDEHYDE 85 

2. HEALTH EFFECTS 

exposed and examined. The following parameters were assessed: maternal weight gain, percentage 

pregnant, litter sex ratio, fetal mortality, fetal weight, cleft palate malformations, and alterations of soft 

and skeletal tissues. Exposure to 40 ppm formaldehyde resulted in a 51% reduction in weight gain in 

dams compared to controls (p<0.01). There were no significant differences between treatment groups in 

the incidences of pregnancies; number of implantations or resorptions; numbers of dead or live fetuses; 

fetal sex ratios; or the incidences of external, visceral, or skeletal abnormalities. Fetal weights were 

significantly lower in male offspring from dams exposed to 20 ppm formaldehyde (p<0.05) and in male 

and female offspring from dams exposed to 40 ppm formaldehyde (p<0.01); the decreases seen in the 

20 ppm group were <5% of control values. At 40 ppm, the differences in weights averaged 21%. The 

authors concluded that maternal exposure to formaldehyde during gestation days 6–20 was not 

teratogenic at levels #40 ppm, but was slightly fetotoxic at 20 ppm. 

The highest NOAEL value and less serious and serious LOAEL values from the Saillenfait (1989) study 

for developmental effects in rats are recorded in Table 2-1 and plotted in Figure 2-1. 

2.2.1.7 Genotoxic Effects 

Several studies were identified that described the genotoxic effects of formaldehyde after inhalation 

exposure. In one study, peripheral lymphocytes from eight anatomy students exposed to formaldehydeembalming solution over a 10-week course were examined for sister chromatid exchange (SCE). Results 

were compared with preexposure values for each student. Breathing-zone monitoring revealed mean 

exposure of 1.2 ppm (range 0.73–1.95 ppm). A small average increase in the incidence of SCE was 

observed in the lymphocytes of the students after exposure (7.2/cell) when compared to values obtained 

before exposure (6.39/cell) (Yager et al. 1986). Conversely, Vasudeva and Anand (1996) examined the 

effects of formaldehyde exposure on the incidence of chromosomal aberrations in peripheral blood 

lymphocytes of 30 medical students exposed to formaldehyde vapors at concentrations of <1 ppm for 

15 months. Questionnaires established that the participants were healthy and had insignificant medical 

histories. There was no difference in the incidences of chromosomal aberrations among the exposed and 

control groups. The mean frequencies of aberrant metaphases in the exposed and control groups were 

1.2 and 0.9%, respectively. There was no correlation between reported irritant effects of formaldehyde 

and the number of aberrant metaphases, and the authors concluded that exposure to formaldehyde at 

concentrations seen in this study does not lead to chromosomal aberrations. 
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Fleig et al. (1982) performed chromosome analyses on 15 exposed and 15 non-exposed employees from 

formaldehyde manufacturing facilities. Exposed workers had an average duration of exposure of 28 years 

(range 23–35 years). Average exposure concentrations did not exceed 5 ppm prior to 1971 and 1 ppm 

after 1971. The formaldehyde exposures of individual workers were classified into one of the three 

following categories: Category 1: exposure #25% of the maximum workplace concentration (MAK); 

Category 2: exposure up to a maximum of 60% MAK; and Category 3: exposure up to 100% of the 

MAK. Peripheral blood samples were collected from each worker and lymphocytes were separated and 

cultured for 70–72 hours at 37 EC. Cells were subsequently fixed and examined for chromatid- and 

chromosome-type aberrations. There were no differences between exposed and control groups in the 

incidence of chromosomal aberrations. The mean frequency of aberrant metaphases among 

formaldehyde-exposed persons was 3.07 versus 3.33% in controls. No correlation was found between 

formaldehyde exposure levels and the number of aberrant metaphases. 

Shaham et al. (1996a) measured the formation of DNA-protein cross links in peripheral white blood cells 

of occupationally exposed workers (n=12) and unexposed controls (n=8). The average length of 

occupational exposure was 13 years. All subjects completed a questionnaire regarding demographics, 

occupational and medical background, and smoking and hygiene habits. Venous blood samples were 

collected from each worker and were processed to isolate DNA-protein cross links. Personal and room 

concentrations of formaldehyde were collected at various periods during the working day among the 

exposed subjects, with formaldehyde room concentrations ranging from 1.38 to 1.6 ppm. Personal 

monitoring devices indicated formaldehyde concentrations of 2.8–3.1 ppm during peak work and an 

average concentration of 1.46 ppm at times when work was usually completed. Exposure to 

formaldehyde resulted in a significant increase in the incidence of DNA-protein cross links. Mean (±sd) 

incidences in exposed and nonexposed workers were 28±6 and 22±6%, respectively. Within the exposed 

workers group, technicians had significantly greater levels of DNA-protein cross links than physicians 

(32.3±4.3 and 26.3±4.4%, respectively). A linear relationship between years of exposure and 

DNA-protein cross links formation was also detected. When the data were analyzed considering worker 

smoking habits, DNA-protein cross links was consistently elevated among formaldehyde-exposed versus 

corresponding controls (p=0.03). The authors concluded that DNA-protein cross links can be used as a 

biomarker of exposure; however, the assay measures DNA-protein cross links in general, not those 

specific to formaldehyde cross link formation. 
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2. HEALTH EFFECTS 

Chebotarev et al. (1986) examined the lymphocytes sister chromatic exchanges (SCEs) of 40 woodworking employees and 22 control workers for chromosomal aberrations, SCEs, and unscheduled DNA 

repair or synthesis. The level of chromosomal aberrations in formaldehyde-exposed workers was 2.76%, 

which was significantly elevated compared to spontaneous chromosomal aberrations in controls (1.64%, 

p<0.05). The incidence of chromosomal breakage in exposed workers (2.95%) was significantly greater 

than the frequency of spontaneous breakage (1.64%, p<0.05). No differences between exposed and 

control subjects were seen for SCEs either at baseline (8.01 versus 8.24 exchanges per cell) or after 

induction with the genotoxin thiotepa (23.32 versus 25.78 exchanges per cell). There were no differences 

between formaldehyde-exposed and control samples in unscheduled DNA repair rates at baseline 

(335.2 versus 341.9) or after treatment with hydroxyurea (179.8 versus 194.2). However, when treated 

with thiotepa, unscheduled DNA repair rates in lymphocytes from formaldehyde-exposed workers were 

lower than those from control workers (217.2 versus 270.4, p<0.05). Using another measure of 

mutagenicity, Ballarin et al. (1992) evaluated 15 nonsmoking workers (8 males, 7 females) who worked 

in a plywood factory for cytopathologic changes in nasal mucosal cells, and compared the results to 

matched controls. Mean levels of exposure to formaldehyde ranged from 0.07 to 0.08 ppm in the sawmill 

and shearing press departments to 0.32 ppm in the warehouse. The total range of exposure in all areas 

containing formaldehyde vapors was 0.06–0.49 ppm. Workers were also exposed to wood dust. Nasal 

mucosal cells from exposed workers exhibited significantly increased incidence of micronuclei 

(0.9 versus 0.25 for controls), chronic inflammation, and a significantly higher frequency of squamous 

metaplasia cells (histological score: 2.3 versus 1.6) than cells from control workers. Micronuclei were 

found mainly in the ciliated cells. 

In another study, Connor et al. (1985b) tested urine obtained from hospital autopsy service workers 

exposed to formaldehyde and from matched control workers for cellular mutagenicity. Exposed workers 

had worked in the hospital for at least 6 months. Actual exposure to formaldehyde was determined to be 

from 0.1 to 5.8 ppm, using personal breathing zone monitoring; the TWA exposures to formaldehyde in 

work areas were estimated to be 0.61–1.32 ppm. Mutagenicity tests using Salmonella typhimurium 

(S. typhimurium) TA 100 and TA 98 were conducted, with or without rat S9 (microsomes containing 

cytochrome P-450) suspension. No increase was seen in mutagenicity using urine of exposed workers, 

compared to control urine. Addition of S9 had no significant effect on the genotoxicity of the urine. 

Studies in laboratory animals have also demonstrated that formaldehyde can be genotoxic in some cells 

after inhalation exposure. Dallas et al. (1992) exposed male Sprague-Dawley rats to formaldehyde 
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2. HEALTH EFFECTS 

concentrations of 0, 0.5, 3, and 15 ppm, by inhalation for 6 hours/day for 5 days. The rats were 

sacrificed, and their pulmonary macrophages and bone marrow cells were harvested and analyzed by flow 

cytrometry and cytogenetic analysis. Cell division was arrested using colchicine treatment (1 mg/kg) 

2 hours prior to sacrifice. Five days after the beginning of exposure, formaldehyde-exposed groups 

exhibited no more than 4% chromosomal aberrations in the bone marrow cells, which was not 

significantly different from control values. There were no differences with respect to dose group. 

Chromatid breaks, chromosome breaks, and centric fusions were observed in bone marrow cells, but were 

not considered to be associated with formaldehyde exposure. An increase in chromosomal abnormalities 

in pulmonary macrophages, predominantly chromatid breaks, was observed in the 15 ppm group 

(7.5 versus 3.4% for controls) after 5 days of exposure. Small increases were also seen in the 0.5 and 

3 ppm groups, but these were not statistically significant. No chromosome breaks or centric fusions were 

observed in control cells obtained by pulmonary lavage. 

Dallas et al. (1992) also extended the exposure treatment time to 1 or 8 weeks. The rats were sacrificed 

after 1 or 8 weeks of exposure, and pulmonary macrophages and bone marrow cells were harvested and 

analyzed by flow cytrometry and cytogenetic analysis. Formaldehyde-exposed groups exhibited no more 

than 4% chromosomal aberrations in the bone marrow cells, which was not significantly different from 

control values. Chromatid breaks, chromosome breaks, and centric fusions were observed in bone 

marrow cells, and again, were not associated with formaldehyde exposure. With respect to pulmonary 

macrophages, an increase in chromosomal abnormalities was observed in the 15 ppm group (9.2 versus 

4.8% for controls) after 5 days of exposure. Small increases were also seen in the 0.5 and 3 ppm group, 

but these were not statistically significant. The predominant cytogenetic damage was chromatid breaks, 

observed in both control and treated cells. No chromosome breaks or centric fusions were observed in 

control cells obtained by pulmonary lavage. In formaldehyde-treated animals, chromosome breaks and 

centric fusions were noted, but were not dose-related. 

Lam et al. (1985) studied the effects of inhalational co-exposure to acrolein and formaldehyde in male 

Fischer 344 rats. Rats were exposed for 6 hours to room air (controls), 2 ppm acrolein, 6 ppm 

formaldehyde, or a combination of 2 ppm acrolein and 6 ppm formaldehyde. The animals were sacrificed 

immediately after completion of exposure, and their nasal tissues were harvested. The DNA was 

isolated and the aqueous and interfacial portions were collected separately. Exposure to formaldehyde significantly increased the percentage of interfacial DNA (12.5%), the specific portion of the 

DNA which contains the DNA cross linked to proteins, compared to rats exposed to room air only 
FORMALDEHYDE 89 

2. HEALTH EFFECTS 

(8.1%, p<0.05). Co-exposure to acrolein resulted in a further increase in the percentage of interfacial 

DNA (18.6%) which was significantly greater than the effect of formaldehyde alone (p<0.05). The 

authors concluded that simultaneous exposure to acrolein enhanced formaldehyde-induced DNA-protein 

cross linking. 

Other genotoxicity studies are discussed in Section 2.5. More extensive evaluation of the genotoxic 

potential of formaldehyde is available (IARC 1995; WHO 1989). 

2.2.1.8 Cancer 

Human Studies Overview. The finding of nasal tumors in rodents exposed to high levels of airborne 

formaldehyde in the early 1980s (Albert et al. 1982; Kerns et al. 1983b; Swenberg et al. 1980) led to a 

concern for cancer effects in occupationally exposed workers. There are now more than 40 epidemiology 

studies examining the potential for occupational formaldehyde exposure to cause cancer in humans. The 

studies include cohort mortality studies of formaldehyde-exposed industrial workers, cohort mortality 

studies of formaldehyde-exposed professionals or medical specialists, and case-control studies that looked 

for associations between occupational exposure to formaldehyde and cancers of the nose, pharynx, or 

lung. Published reviews and evaluations of the epidemiology studies include early reviews by IARC 

(1987), Purchase and Paddle (1989), and an ad hoc panel convened by Universities Associated for 

Research and Education in Pathology (1988). More recent reviews have been published by Conaway et 

al. (1996), ECETOC (1995), IARC (1995), and McLaughlin (1994). In addition, three meta-analyses of 

the data have been published (Blair et al. 1990a; Collins et al. 1997; Partanen 1993). Although some of 

the epidemiological studies have found some scattered evidence for extra-respiratory site cancers in 

groups of formaldehyde-exposed workers, the data are not consistent across studies and adjustment for 

potential confounding cancer risk factors has not often been possible. Most, if not all reviewers, have 

agreed that cancer of the respiratory tract, particularly the upper respiratory tract, is more biologically 

plausible than formaldehyde-induced cancer at distant sites given the reactivity of formaldehyde, the 

capacity of tissues to metabolize formaldehyde, and the results from chronic rodent inhalation studies 

showing that formaldehyde-induced nonneoplastic and neoplastic effects are restricted to the upper 

respiratory tract with exposures to concentrations below 5–10 ppm. Accordingly, the meta-analyses of 

the human data have focused on the findings for respiratory cancer deaths in occupationally exposed 

humans. 
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2. HEALTH EFFECTS 

Six mortality studies of the following cohorts of formaldehyde-exposed industrial workers are included in 

recent reviews and the meta-analyses: 26,561 U.S. workers involved in formaldehyde production, resin 

making, and several other activities using formaldehyde (Blair et al. 1986, 1990a); 7,660 workers in six 

British plants using formaldehyde (Acheson et al. 1984a; Gardner et al. 1993); 11,030 workers in three 

U.S. garment facilities (Stayner et al. 1988); 1332 Italian workers involved in resin making (Bertazzi et al. 

1986, 1989); 3929 foundry workers exposed to formaldehyde (Andjelkovich et al. 1994b, 1995a); and 

6,039 workers in a Conneticut chemical plant that included some of the workers from the Blair et al. study 

(Marsh et al. 1994, 1996). Data from the Blair et al. (1986) study have been independently analyzed by 

Sterling and Weinkam (1989, 1995). 

In the industrial worker cohort studies, the range of standardized mortality ratios (SMR; see Table 2-2 for 

definitions of selected epidemiological terms) relevant to exposure to airborne formaldehyde were (a zero 

reflects a finding of no deaths from the subject cancer): 

C for lung cancer - 0.9 to 1.4 (lung cancer deaths were reported in each cohort); 

C for nasopharyngeal cancer - 0 to 3.0 (only the Blair et al. [1986, 1990a] study had 

nasopharyngeal cancer deaths: 6 observed versus 2 expected); 

C for nasal cancer - 0 to 0.6 (Andjelkovich et al. 1994b, 1995a; Bertazzi et al. 1986, 1989; Marsh et 

al. 1994, 1996; and Stayner et al. 1988, however, did not report nasal cancer deaths); and 

C for buccal cavity and/or pharynx cancer - 1.1 to 1.69 (only Bertazzi et al. 1986, 1989 did not 

report buccal cavity and/or pharynx cancer). 

Small excess relative risks for buccal cavity and/or pharynx cancer and lung cancer were most 

consistently observed across these studies. The increases in risk were generally not of statistical 

significance with the exception of the Blair et al. (1986) report of an SMR of 3.0 (95% CI, 1.3–6.6) for 

nasopharyngeal cancer. 

Nine mortality studies of the following cohorts of formaldehyde-exposed professionals or medical 

specialists are included in recent reviews and the meta-analyses: 2,079 British pathologists and 

12,944 medical specialists (Harrington and Shannon 1975); 1,263 deceased New York embalmers 

(Walrath and Fraumeni 1983); 1,109 deceased California embalmers (Walrath and Fraumeni 1984); 

1,477 Ontario funeral workers (Levine et al. 1984a); 2,317 U.S. anatomists (Stroup et al. 1986); 

5,810 U.S. pathologists (Matanoski 1991); 5,585 U.S. pathologists (Logue et al. 1986); 4,046 deceased 
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2. HEALTH EFFECTS 

Table 2-2. Definitions of Selected Epidemiology Terms 

Standardized mortality 

ratio (SMR) 

Proportionate mortality 

ratio (PMR) 

Standardized proportionate 

incidence ratio (SPIR) 

Odds Ratio(OR) and 

Relative Risk (RR) 

is the ratio of a cause-specific mortality rate in an exposed cohort during 

a given period to the mortality rate of an unexposed cohort; mortality 

rates are often adjusted for age or other confounding variables. 

is the ratio of a cause-specific mortality proportion in an exposed group 

to the mortality proportion in an unexposed group; mortality proportions 

may be adjusted for confounding variables such as age. Cause-specific 

mortality proportions can be calculated when the cohort (the population 

at risk) cannot be defined due to inadequate records, but the number of 

deaths and the causes of deaths are known. 

is similar to a PMR in that it is a ratio of a proportion of a specific 

disease in an exposed group compared with the proportion in an 

unexposed group. 

are risks expressed as ratios of the incidence of diseased subjects 

exposed to a particular risk factor to the incidence of diseased subjects 

in a nonexposed referent group. 
 

FORMALDEHYDE 92 

2. HEALTH EFFECTS

 members of U.S. funeral directors’ organizations (Hayes et al. 1990); and 4,512 British pathologists (Hall 

et al. 1991). 

In the professional worker cohort studies, the range of SMRs or proportionate mortality ratios (PMRs) for 

respiratory or buccal cavity sites were: 

C for lung cancer - 0.1 to 1.1 (the group of New York State embalmers [Walreth and Fraumeni 

1983] was the only cohort that showed an excess: 72 observed versus 66.8 expected); 

C for nasopharyngeal cancer - 2.1 (the group of deceased U.S. funeral directors was the only 

professional cohort reporting this type: 4 observed versus 1.85 expected [Hayes et al. 1990]); 

C nasal cancer deaths were either reported as zero or not reported among the nine professional 

cohorts; 

C for buccal cavity and/or pharynx cancer - 0.2 to 1.3 (at least one buccal cavity and/or pharyngeal 

cancer death was noted in each of the professional cohorts). 

Case-control studies examining potential associations between occupational exposure to formaldehyde 

and specific types of cancer include those of: 

C lung cancer (Bond et al. 1986; Chiazze et al. 1993; Coggon et al. 1984; Gerin et al. 1989; Jensen 

and Andersen 1982; Partanen et al. 1985, 1990) with relative risks ranging from 0.6 to 1.1; 

C nasal cancer (Brinton et al. 1984, 1985; Hayes et al. 1986; Hernberg et al. 1983a, 1983b; Luce et 

al. 1993b; Olsen et al. 1984; Rousch et al. 1987; Vaughan et al. 1986a, 1986b) with relative risks 

ranging from 0 to 12.6; and 

C nasopharyngeal cancer (Olsen et al. 1984; Rousch et al. 1987; Vaughan et al. 1986a, 1986b; 

West et al. 1993) with relative risks ranging from 0.6 to 5.5. 

The first two meta-analyses of the epidemiology studies (Blair et al. 1990a; Partanen 1993) took similar 

approaches to analyzing the same data, except that Partanen included three case-control studies not 

included in the earlier analysis. Both analyses calculated summary or aggregate relative risks for lung 

cancer, cancer of the nose and nasal sinuses, and nasopharyngeal cancer, and analyzed data from a subset 

of the available studies that were classified into “low/medium” or “substantial” exposure categories based 

on exposure level and/or duration of exposure information. Although different methods to calculate 

aggregate relative risks across studies were used in the two studies, similar results were obtained and 

conclusions reached. 
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2. HEALTH EFFECTS 

In both analyses, aggregate relative risks for lung cancer deaths calculated for formaldehyde-exposed 

medical and nonmedical professionals were at or below those expected. Aggregate relative risks for lung 

cancer in industrial worker studies showed a small excess relative risk (1.1) in both analyses, but no 

evidence for an exposure-related increase in relative risk comparing the “low/medium” relative risks (1.2) 

with those of the “substantial” exposure class (1.0 or 1.1). Small excess aggregate relative risks for 

occupationally-exposed workers in all of the studies existed for cancer of the nose and nasal sinuses 

(1.1 [95% CI, 0.8–1.4] - Blair et al. 1990a; 1.1 [95% CI, 0.8–1.5] - Partanen 1993), and cancer of the 

nasopharynx (1.2 [95% CI, 0.8–1.7] - Blair et al. 1990a) and 2.0 [95% CI, 1.4–2.90] - Partanen 1993). 

Relative risks for both types of cancer increased with increasing exposure intensity in Table 2-3. 

Both Blair et al. (1990a) and Partanen (1993) concluded that a causal role for formaldehyde in the 

induction of the observed cancers of the nasopharynx and nasal cavities was supported by their evidence 

for exposure-response relationships, the portal-of-entry site of these cancers, and the consistency of these 

findings with results from animal studies. 

A third meta-analysis by Collins et al. (1997) arrived at the conflicting conclusion that the available 

studies do not support a causal relationship between formaldehyde exposure and nasopharyngeal cancer. 

This study analyzed data from essentially the same case-control studies, but included a few cohort 

mortality studies that were not available or included in the earlier meta-analyses (e.g., Andjelkovich et al. 

1994b, 1995a; Gardner et al. 1993). Collins et al. (1997) noted that nasopharyngeal cancer rates were 

elevated in a minority of the available studies, that most studies did not find any nasopharyngeal cancers, 

and that many studies did not report on nasopharyngeal cancer. Unlike the calculational techniques used 

in the previous meta-analyses, a calculational technique was used to adjust for underreporting of expected 

mortality rates in the calculation of “weighted meta relative risks”. Meta relative risks (with 95% CIs) for 

nasopharyngeal cancer were 1.0 (0.5–1.8) for the 14 cohort studies included in the analysis, 1.2 (0.4–2.5) 

for the six industrial worker cohort studies, and 1.3 (0.9–2.1) for the seven case-control studies. Collins 

et al. (1997) concluded from their review of the available studies that exposure estimates for the casecontrol studies were both lower and less certain than exposures in the industrial worker cohort studies, 

and that their analysis does not support an exposure-response relationship between formaldehyde and 

nasopharyngeal cancer. 

Recent reviews of the available epidemiology studies arrive at differing conclusions. NTP (1998) notes 

that formaldehyde is reasonably anticipated to be a human carcinogen. IARC (1995) concluded, “Taken 
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Table 2-3. Meta-analysis of Epidemiology Studies of Cancer of 

the Nose and Nasal Sinuses and Nasopharyngeal Cancer 

Cancer site Level or duration of exposure to formaldehyde 

Low/medium Substantial 

O/Ea RRb O/E RR O/E RR O/E RR 

Blair et al. 1990a Partanen 1993 Blair et al. 1990a Partanen 1993 

Nose and 38/46 0.8 (0.6–1.1) 33/30 1.1 (0.7–1.8) 30/28 1.1 (0.7–1.5) 36/21 1.7 (1.0–2.8) 

nasal sinuses 

Nasopharynx 30/27 1.1 (0.7–1.6) 23/16 1.6 (1.0–2.7) 13/6 2.1 (1.1–3.5) 11/4 2.7 (1.4–5.6) 

a

 Observed/Expected cancer deaths
 b

 Relative risk (with 95% CI); CIs for the Blair et al. 1990a entries were calculated by Partanen (1993).
 
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 together, the epidemiological studies suggest a causal relationship between exposure to formaldehyde 

and nasopharyngeal cancer, although the conclusion is tempered by the small numbers of observed and 

expected cases in the cohort studies”. IARC’s overall evaluation that formaldehyde is probably 

carcinogenic to humans (Group 2A) was based on specific evaluations that there is limited evidence in 

humans for the carcinogenicity of formaldehyde and sufficient evidence in experimental animals. EPA 

(1991a) classified formaldehyde in Group B1 - probable human carcinogen, based on an evaluation of 

limited human evidence and sufficient laboratory animal evidence. More recently, in a collaborative 

review and evaluation of the formaldehyde epidemiology studies, EPA and CIIT (CIIT 1998) concluded, 

“It appears that a weak association between nasopharyngeal cancer and formaldehyde exposure cannot be 

completely ruled out.” Adopting another view, McLaughlin (1994) concluded, “Clearly, the causal 

criteria used by epidemiologists to evaluate an association, such as strength of the association, 

consistency, specificity, dose-response, plausibility, and coherence, are not satisfied by the epidemiologic 

studies in the formaldehyde-cancer research domain”. ECETOC (1995) similarly concluded, “After a 

careful review of the cytologic, cytogenic and epidemiological studies there is an absence of evidence to 

support the judgement of an etiologic relationship between formaldehyde and human cancer risk.” 

Selected Cohort Mortality Studies. Blair et al. (1986) performed a historical cohort study to evaluate the 

mortality experience of 26,561 workers in 10 formaldehyde-producing or -using workplaces. TWA 

exposures to formaldehyde were estimated to range from trace amounts to >2 ppm. The mortality 

experience of workers exposed to workplace air concentrations $0.1 ppm was compared with that of 

“nonexposed” workers in the cohort exposed to concentrations <0.1 ppm. Using national rates of 

mortality as reference, greater than expected mortalities for a number of cancer types were noted in the 

exposed group, but the elevated rates of mortality were not statistically significantly different than 

national rates. Types of cancers with elevated SMRs included: Hodgkin’s disease (SMR=1.42); and 

cancers of the liver (SMR=1.02); larynx (SMR=1.42); lung (SMR=1.11); bone (SMR=1.23); prostate 

(SMR=1.15); and kidney (SMR=1.23). The nonexposed group generally showed less than expected 

deaths from these cancers, (i.e., SMRs<1.00) Mortality from selected cancers were also compared among 

several subgroups of the cohort with varying exposure-concentration experiences. Among the 

aforementioned cancers, only deaths due to Hodgkin’s disease exhibited a dose response. No individual 

exposure category SMR, however, was significantly elevated, and comparisons of the SMRs across 

different exposure categories is inappropriate for this indirectly adjusted measure. No unusual cancer 

patterns were noted among white women or black men. Among subsites of the buccal cavity, the 

nasopharynx had a significantly greater than expected incidence (7 cases observed versus 2.2 cases 
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expected) of cancer. This study demonstrated that there was insufficient evidence to firmly associate 

occupational formaldehyde exposure with the observed cancers, even when considering that the SMRs for 

the unexposed workers were small. No consistent correlation was noted between cumulative exposure 

and the risk of any cancer. This study used a cohort study design with a large study population. 

Additional strengths of this study included the fact that experienced nosologists assigned the cause of 

death and in addition to the SMR analysis based on vital statistics data, the study also included analyses 

using internal comparison groups. Industrial hygienists made estimates of the intensity of formaldehyde 

exposures using all available sources of information (most similar studies estimated only the duration). 

Overall, the analysis was very thorough and allowed for different exposure intensity levels and different 

possible “latency” periods between exposure and death. The investigators attempt to rule out 

confounding factors from socioeconomic status, and the follow up was good overall (95%), although it 

was only 83% for women. Weaknesses included the fact that death certificate data can often be 

inaccurate, so some cancers of interest could have been missed. Also, no information about tobacco use 

or other nonoccupational exposures was available. 

In a later study by Blair et al. (1990b), the risk of lung cancer was assessed among 20,714 white male 

workers exposed to formaldehyde in 10 production plants. The estimated average levels of exposure were 

0.1–1.9 ppm formaldehyde. The overall risk of lung cancer did not appear to be correlated with average 

formaldehyde levels in each plant. Among the exposed sample, the SMRs did not increase consistently 

with any measure of exposure. The SMR for those with cumulative exposures of <0.5 ppm-year was 1.3, 

while the SMR for those with >5.5 ppm-year was 1.7. The risk of lung cancer did not increase with the 

time from last exposure; however, the risk did increase based upon the year of entry into the industry. 

Among the >20-year latency group, those beginning employment prior to 1958 had a greater risk of 

cancer than did those beginning work in 1958 or later (SMR=1.4). Those exposed to formaldehyde at or 

after the age of 35 were more likely to have lung cancer than those exposed prior to age 35 (SMR=1.3). 

The interaction of formaldehyde with other noxious substances was investigated and the results suggested 

that those exposed to formaldehyde were not at risk of cancer unless exposed to another substance. The 

authors concluded that no clear exposure-response trends could be identified from the data. Strengths and 

weaknesses of this study were basically the same as those described in the Blair et al. (1986) study. 

Data from the Blair et al. (1986) study were reanalyzed by Sterling and Weinkam (1989, 1995) to 

account for the healthy worker effect. The cohort was composed of all workers employed in 10 selected 
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plants. For lung cancer mortalities, mortality risk increased with cumulative exposure, approaching 

statistical significance in all workers with cumulative exposures of >2 ppm-years. The authors concluded 

that, when comparing workers with high formaldehyde exposures to those with little or no exposure, there 

is an increased risk of lung cancer associated with exposure to formaldehyde. 

Harrington and Shannon (1975) examined a population of 2,079 British pathologists and 12,944 medical 

laboratory technicians or pathologists between January 1, 1955 and December 31, 1973. During that 

period, 154 technologists and 156 pathologists died, and copies of all death entries were obtained. The 

SMR was 60 for pathologists and 67 for medical technologists. Excess deaths from lymphatic and 

hematopoietic neoplasms were noted in male pathologists (observed 8, expected 3.3, p<0.01). No other 

neoplastic diseases were noted as causing excess mortality in either occupational group. It should be 

noted that the study group was too small for any firm conclusions to be drawn about the carcinogenicity 

of formaldehyde exposure in humans. No records were available and no adjustment was made for 

smoking or other possible confounding factors. 

Levine et al. (1984a) studied the mortality patterns of 1,477 male undertakers licensed from 1928 to 1957 

(dose not specified). The numbers of deaths due to malignant neoplasms (SMR=0.87) and specific 

cancers (SMR=0.52–1.24) were not significantly elevated. Mortality due to nonmalignant diseases was 

slightly elevated, but could not be clearly related to the inhalation of formaldehyde. Strengths of this 

study include the following: a cohort design with a high rate of success for ascertaining vital status (96%), 

death certificates obtained for most decedents, and underlying cause of death coded by a trained 

nosologist. Several apparent weaknesses should be noted, including the sample size, which was small for 

detecting rare outcomes of disease. Exposure levels to formaldehyde were low, and the undertakers did 

not necessarily engage in embalming work, so the exposures may have been too low to cause mortality 

excesses. Death certificate data are often inaccurate, so some cancers of interest could have been missed. 

Exposure began in the late 1920s, but the 40 deaths that occurred before 1950 (13% of all deaths) were 

excluded from the analysis. These earlier decedents could have had higher exposure levels than those 

who were still alive in 1950, so a potentially important source of information was unavailable due to data 

constraints for the reference population. 

Harrington and Oakes (1984) established a population of 2,307 men and 413 women to study the 

incidence of cancer induction due to formaldehyde exposure in humans. During the study period, 126 of 

these pathologists died; death certificates were obtained for 121 of them. Observed and expected deaths 
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from all causes and from certain specific causes were reported as well as the corresponding SMR for 

observed deaths as a percentage of expected deaths. Excess deaths from brain tumors were found 

(observed 6, expected <2, p<0.02), but no nasal cancers were found. Strengths of this study included the 

use of a cohort design and a very low rate of follow up loss (0.6% for pathologists and 1.5% for medical 

laboratory technicians). The study also achieved some adjustment for possible confounding effects of 

socioeconomic status for one of the analyses by comparing the study cohort mortality experience with 

that of other medical groups, although that analysis could only examine broad categories of death. 

Weaknesses of this study included the fact that specific exposures or their possible levels were not 

identified for the two cohorts (there is no mention of formaldehyde exposure). The follow up period 

(19 years maximum for pathologists and only 11 years for the technicians) was somewhat short, but it is 

unclear whether exposures may have occurred before the beginning of the follow up period. Moreover, 

the modest number of pathologists (n=2,079) results in low statistical power for detecting any excesses of 

rare outcomes. It was also noted that for the primary analysis, there presumably were substantial 

socioeconomic differences between the cohort members and the reference population, so confounding 

could have occurred. Because the SMR is an indirectly standardized measure (i.e., it uses internal 

weights), the comparison of SMRs across occupational groups was considered to be inappropriate. 

Walrath and Fraumeni (1984) performed a proportionate mortality study of 1,007 white male embalmers 

in California from 1916 to 1978 who were known to have died between 1925 and 1980. Total cancer 

mortality was significantly elevated, with PMR of 1.21. Deaths from cancers of the brain and the nervous 

system (PMR=1.94), colon (PMR=1.87), prostate (PMR=1.75), and leukemia (PMR=1.75) were 

significantly higher than expected. The reported types of brain cancer were for glioblastoma (2), 

astrocytoma (3), adenocarcinoma (1), and unspecified cancers (3). No increase in mortality for cancers of 

the respiratory tract, including the nasal passages was noted in this study. A parallel mortality study of 

embalmers from New York State (Walrath and Fraumeni 1983) showed similar findings with significant 

excess of deaths from cancers of the brain and nervous system (PMR=1.56), colon (PMR=1.43), ischemic 

heart disease (PMR=1.12), and nonsignificant excess of cirrhosis of the liver (PMR=1.33), and leukemia 

(PMR=1.40). PMRs were significantly elevated for cancers of the skin, kidney, and brain among those 

who were licensed only as embalmers. Even with these findings, the authors suggested that a more 

thorough investigation was needed to quantify the risks of cancer and other chronic diseases in relation 

to formaldehyde exposure. Strengths and weaknesses for both of these studies are similar. Strengths 

included the fact that formaldehyde was probably the primary chemical exposure for this PMR 

analysis of embalmers, although embalming fluid does include smaller amounts of other chemicals 
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(methanol, diethylene glycol, propylene glycol, phenol, benzoic acid, fragrances, etc.). Exposure 

durations and follow up periods were probably long enough for the study to detect any cancer excesses 

associated with formaldehyde exposure, although details about individual decedents were unavailable. 

For the final analysis, death certificates were available for a large percentage (92%) of the identified 

decedents. A trained nosologist coded the underlying cause of death for all death certificate using the 

coding rules in effect at the time of each death. Therefore, the assignment of the cause of death should 

have been comparable to that used for standard (comparison) population. The analysis controlled for 

potential confounding effects from age, race, sex, and calendar year. Several weaknesses of this study 

were also noted. In general, PMR studies have a relatively weak design compared to other types of 

studies. The analysis included only those deaths reported to the Bureau of Funeral Directing and 

Embalming, and the completeness of this reporting is not known. The authors indicate that deaths at ages 

>65 years were substantially under reported. Consequently, the causes of death in the analysis could have 

differed systematically from the causes found in the total population of deceased embalmers (e.g., for 

chronic conditions that led to death at older ages). The total U.S. population was used as the external 

comparison population, even though rates from New York state would probably be stable enough to 

provide expected values. Possible regional differences in cancer incidence (rather than occupational 

exposures) could have affected the observed pattern of mortality excesses and deficits. Study weaknesses 

included that cancer deaths are often reported inaccurately on death certificates. Exposure levels for 

formaldehyde were unknown, no analyses that combine the white and black decedents (with appropriate 

adjustment) were presented, even though there were similarities in the pattern of excess deaths. A 

combined analysis presumably would have greater statistical power. Lastly, the expected number of 

deaths for nasal cancer, an end point of particular interest, was only 0.7, so the study had low statistical 

power to detect an excess of this cancer. 

Stroup et al. (1986) evaluated the risk of death due to cancers and other causes in 2,317 anatomists in a 

retrospective cohort study. Of the 2,317 in the study population, 33% (n=738) were known to have died. 

SMRs for deaths due to various cancers in anatomists was variable; the only condition with a significantly 

elevated SMR (SMR=2.7, p<2.25) was brain cancer. All of the anatomists that died of brain cancer were 

in either gross anatomy, microanatomy, or a combination of the two, indicating relatively high exposures 

to formaldehyde. The authors concluded that there was a substantial risk of brain cancer among 

anatomists, but since these anatomists were also exposed to a large number of biological stains and 

solvents, in addition to formalin and formaldehyde, the etiologic agent responsible for these results 

was not certain. This study has several strengths and weaknesses. The study of the anatomists used a 
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classic retrospective cohort design with a well defined denominator; follow up was at least 10 years for all 

cohort members. Follow up and death certificate acquisition was good and a trained nosologist coded the 

underlying cause of death for all cohort members. In addition to using national disease rates for the SMR 

analysis, the authors also used mortality rates from a cohort of psychiatrists, who presumably have similar 

demographic and socioeconomic characteristics compared with the anatomists. Subgroups of anatomists 

were studied in an attempt to separate possible effects of formaldehyde from those of other occupational 

chemical exposures. Among the study weaknesses was the fact that exposure levels for formaldehyde 

were unknown and occupational exposures to chemicals other than formaldehyde (or to viruses) could 

have been responsible for the observed cancer excesses. Diagnoses from death certificates are unreliable, 

but the use of the psychiatrist comparison group helps eliminate the possibility of differential disease 

misclassification (i.e., detection bias). The low expected number of deaths (0.5) for cancer of the nasal 

cavity and sinus indicates that the study had low statistical power for detecting an excess of nasal cancer. 

Stayner et al. (1985a, 1985b, 1988) evaluated the carcinogenicity of formaldehyde in garment workers by 

performing a proportionate mortality study of 256 deaths reported from three shirt-manufacturing plants. 

All three plants had processed formaldehyde-treated fabrics since 1958 and the duration of employment 

for the study group averaged 9.4 years. Air monitoring in two of the plants revealed that virtually all 

employees were exposed to 0.1–1 ppm formaldehyde. Statistically significant excesses in mortality were 

detected for cancers of the buccal cavity (PMR=7.50), biliary passages and liver (PMR=3.13), and other 

lymphatic and hematopoietic sites (PMR=4.00). The number of deaths in each organ category was low; 

hence, the degree of confidence in PMRs and in the conclusion that cancers are associated with 

formaldehyde exposure must also be low. Stayner concluded that, based upon factors such as the long 

latency period and lack of exposure to other known carcinogens, the excesses in mortality in garment 

workers due to cancers of the buccal cavity, biliary passages and liver, and other lymphatic and 

hematopoietic sites were likely associated with formaldehyde exposure. There was no attempt to adjust 

the cancer rate for smoking or other confounding factors, and no air sampling records were evaluated. 

Later, Stayner et al. (1988) examined the relationship between formaldehyde exposure and the 

development of upper respiratory cancers in garment factory workers. A total of 2,008 men and 

9,022 women from three garment factories had a formaldehyde concentration exposure geometric mean 

value of 0.15 ppm (range 0.14–0.17 ppm). Across all workers, mortality from all causes was less than 

expected, as was mortality from all malignant neoplasms. However, significantly (p<0.05) greater than 

expected mortalities were detected for the buccal cavity (SMR=3.43) and connective tissue (SMR=3.64). 
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Nonsignificant elevations were also noted for the trachea/bronchus/lung (SMR=1.14), pharynx 

(SMR=1.13), bladder (SMR=1.12), leukemia and aleukemia (SMR=1.14), and other lymphopoietic 

neoplasms (SMR=1.70). When stratified by sex and race, white females had significant excesses of 

buccal cavity cancer (SMR=4.85). When stratified by latency period, cancers of the buccal cavity 

(SMR=7.05) and leukemia (SMR=3.10) were significantly elevated for workers with latencies of 20 years 

or more, while cancers of the trachea/bronchus/lung (SMR=1.71) were significantly elevated among 

workers with latencies of >10 years. When stratified by duration of exposure, mortalities due to cancers 

of the buccal cavity (SMR=7.57) and other lymphopoietic neoplasms (SMR=3.81) were significantly 

elevated for workers with exposure durations of 10 years or more, while mortalities due to connective 

tissue cancers were significantly elevated in workers exposed for 4–9 years (SMR=6.19). Mortalities due 

to cancer of the trachea/bronchus/lung appeared to be inversely related to duration of exposure. In their 

discussion, the authors stressed that, while no excesses in nasal cancer were seen, the power of the study 

was too low to detect an effect for this rare cancer. Also, the authors noted that the patterns seen in 

trachea/bronchus/lung cancers (most prevalent in short duration/latency groups) were inconsistent with 

normal dose-response patterns; this was also attributed to a lack of statistical power. A strength of this 

study is that the cohort study design is more powerful than the PMR design used in the earlier study 

(Stayner et al. 1985a, 1985b) that included some of the same workers. As in the earlier study, 

confounding factors from other occupational exposures were unlikely. Vital status was ascertained for a 

very high proportion of the cohort members (96%). The authors also used various sources to verify the 

employment histories and vital status of the workers and the analyses of mortality by duration of exposure 

add credibility to the observed cancer excesses (i.e., the risk was positively associated with duration of 

exposure). Some of the weaknesses were the same as in the authors’ earlier PMR study: exposures that 

may have been too low to cause a detectable increased risk of mortality and historical exposures that may 

have been higher, but with unknown levels. Because of the small study population, the study had only 

modest statistical power to detect possible excesses of rare outcomes. Death certificate data are often 

inaccurate, so some cancers of interest could have been missed. The authors attempted to rule out 

possible nonoccupational confounding factors with mixed results. For example, at least two of the four 

who died from buccal cancer had a history of tobacco use (one had used snuff, a fairly strong risk factor 

for buccal cancer). The authors concluded that the results of the study should be viewed with caution, 

due to limited statistical power and latency periods and the possibility of other confounding factors. 
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Bertazzi et al. (1986) attempted to correlate occupational exposure to formaldehyde with cancer rates in 

male resin workers using SMR analysis. Based on job descriptions, workers were divided into three 

groups: "exposed to formaldehyde", "exposed to other chemicals", or "exposure unknown". An analysis 

of the death rates revealed a significantly (p<0.05) elevated rate of deaths from all cancers when 

compared to the national rates (SMR=1.54); however, significance declined when the cohort was 

compared to the local population trends (SMR=1.06). Among individual cancer types, significantly 

elevated SMRs were detected for lung cancer against the national and local trends (SMRs=2.36 and 1.86, 

respectively). Deaths from hematologic neoplasms were elevated (SMRs=1.54 and 2.01), but not 

significantly. When the cohort was divided by chemical exposure, the group exposed to formaldehyde 

tended to have elevated SMR values; however, the trends were not significant. The authors concluded 

that, in addition to the significantly elevated lung cancer mortality rate among all workers, the mortality 

rates among formaldehyde-exposed workers for all cancers, and cancers of the alimentary tract, lung and 

blood system were noteworthy, although nonsignificant. Study strengths included a cohort design with 

high rate of follow up (98.6%); formaldehyde exposure levels that were apparently high (although not 

well characterized); and past exposures that were not measured but were presumably higher. It appears 

that most workers with formaldehyde exposure had not been exposed to other chemicals in the plant 

(although this point was not made completely clear by the authors). Subanalyses looked at SMRs with 

regard to duration of employment and by formaldehyde exposure status. Some apparent weaknesses of 

this study were that the cohort was too small (1,332 persons) to detect increases in rare diseases and that 

the follow up period after formaldehyde exposure was somewhat short (as noted by the authors), so that 

exposure-related cancers with long latency periods might not have had time to appear during the course of 

this study. Environmental measurement data were very sparse and detailed work history records were 

unavailable for most cohort members, so “reconstructions” were obtained through interviews of past 

workers and others (few details were provided). No exposure levels were provided for 18% of workers. 

Data for individuals with regard to potential confounding variables were unavailable, and no information 

was provided on the assignment of the cause of death codes used in the SMR analyses. 

Gardner et al. (1993) assessed the risk of disease and cancers among British male chemical workers 

exposed to formaldehyde. The cohort for the study consisted of 7,660 men who began employment prior 

to 1965 and 6,357 men who began employment after 1964. Formaldehyde exposure ranged from 

<0.1 to >2 ppm. There was one death from nasal cancer and no deaths from nasopharyngeal cancer, nor 

were any nonfatal cases of nasopharyngeal reported. Among lung cancer cases, there was no association 

of cancer with formaldehyde exposure. Among men classified as exposed to the higher end of possible 
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exposure levels of formaldehyde, there was no indication of a relationship between cancer and duration of 

employment, and no association between cancer and cumulative dose. In those employed prior to 1965, 

there was a significant excess of lung cancer, with the authors stating that the increase was probably due 

to smoking and other environmental pollution. This appears to be related to one factory in which more 

men were exposed to high levels of formaldehyde. The determination of exposure levels in this study 

was crude and the information on co-exposure to other chemicals was not analyzed. The possibility of 

dermal exposure cannot be ruled out in many of these workers. Strengths of this study included the 

cohort design, with careful checks of member eligibility and systematic assignment of estimated exposure 

levels. SMR analyses use disease rates from local populations to help avoid potential biases due to 

regional differences in disease rates and the long follow up period allows time for the manifestation of 

any exposure-related cancers. Weaknesses of this study included the observation that no actual 

measurements of formaldehyde exposure levels occurred, but the investigators did undertake a detailed 

estimation procedure for classifying expected exposure levels. There were also potential confounding 

factors from other occupational exposures. In addition, the procedure for assigning the underlying cause 

of death for cohort members was not explicitly described, and comparisons of the SMRs across different 

exposure categories is inappropriate for this indirectly adjusted measure. The authors presumably could 

have used a regression modeling approach to explore possible dose-response associations without the 

need for an external referent population. A pronounced “healthy worker effect” is typically expected in 

this type of cohort study for all-causes mortality, but only one of the six factory populations showed an 

SMR <0.95, even for workers who were hired relatively recently. The authors may have overlooked this 

indirect evidence of a health hazard in the factories. 

Andjelkovich et al. (1990) examined mortality in a cohort of 8,147 foundry workers who worked in an 

automobile manufacturing plant for at least 6 months between 1950 and 1979. For the observation period 

of 1950 through 1984, a significant excess was found for lung cancer mortality, but most of the excess of 

lung cancer deaths was accounted for by smoking habits. In a subsequent nested case control study of 

this cohort that examined risk factors for 220 cases of lung cancer mortality that occurred between 1950 

and 1989 compared with 2,200 age- and race-matched controls without lung cancer, cigarette smoking 

was a strong predictor of lung cancer mortality, but exposure to formaldehyde was not significantly 

associated with lung cancer (Andjelkovich et al. 1994b). In a final phase of these studies, 

Andjelkovich et al. (1995a) studied the mortality experience (for the period between 1960 and 1989) 

of a subset of 3,929 members of the cohort who were exposed to formaldehyde in the foundry during 

the period of January 1960 through 1987, and compared it to the experience of a referent, nonexposed 
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population of 2,032 men who worked at the foundry, but not in formaldehyde-exposed jobs. The 

year 1960 was chosen as the starting point of the study because it was the year that formaldehyde was 

introduced into the operations used in the foundry. Exposure to formaldehyde was assessed via work 

histories and was ranked as high, medium, low, or none (but exposure concentration ranges were not 

reported). In the exposed group, elevated SMRs (calculated using national rates for comparison) were 

found for deaths from several cancer types, but the elevation was not statistically significant for any 

cancer type. Cancer types with elevated SMRs were (with SMRs noted in parentheses): buccal cavity and 

pharynx (1.31); stomach (1.64); rectum (1.17); trachea, bronchus, and lung (1.20); and urinary organs 

(1.13). Similar SMRs were found for the nonexposed control group. Because of the findings from 

animal studies of formaldehyde-induced nasal tumors, special attention was given to malignant and nonmalignant diseases of the respiratory system (cancers of the buccal cavity and pharynx, larynx, or trachea, 

bronchus, and lung, and emphysema), but comparison of the cause-specific mortality between the 

exposed and nonexposed groups showed no statistically significant difference, except for a significantly 

elevated SMR for emphysema in the nonexposed group. 

Strengths of the Andjelkovich et al. (1990, 1994b, 1995a) studies included the nested case-control design, 

which provided a high degree of efficiency while ensuring that the controls were selected from the same 

population that gave rise to the cases. Incidence density sampling of controls leads to an unbiased 

estimate of the mortality rate ratio. The use of conditional logistic regression analysis enabled appropriate 

adjustments for covariates and attempts to control for effects of cigarette smoking appeared to be fairly 

successful, although the response rate for collecting the smoking information was less than ideal (about 

70%). In addition, the follow up duration was long enough for exposure-related lung cancer excesses to 

appear, and the data analysis allowed for “latency” periods of different duration. Industrial hygienists 

estimated the exposure levels for formaldehyde as well as for silica, a potential confounder of the 

formaldehyde-cancer association. There was no opportunity for “recall bias” (except for the smoking 

information, which was collected from cohort members or their families). Study weaknesses were related 

to lung cancer information, which came almost exclusively from death certificates, which can be 

inaccurate. Tumor histology information was unavailable. It seemed apparent that no actual 

measurements of formaldehyde exposure levels were available, although some silica measurements were 

available. The study authors point out that a only a modest proportion of the cohort was exposed to 

formaldehyde, so the statistical power of the study was somewhat low. However, the estimated odds 

ratios indicate a lack of association that would presumably be unaffected by an increase in the study’s 

sample size. 
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Selected Case-Control Studies. Luce et al. (1993b) attempted to determine whether occupational 

exposure to formaldehyde was associated with an increased risk of sinonasal cancer in humans. Case 

subjects were patients with primary malignancies of the nasal and paranasal sinuses. Odds ratios for 

squamous cell carcinomas in formaldehyde-exposed workers, when adjusted for wood dust and glue 

exposure, were not significantly elevated. The odds ratio for adenocarcinomas was confounded by the 

frequent co-exposure to wood dust, a known carcinogen. However, in those exposed to wood dust, an 

increased odds ratio was noted in those also exposed to formaldehyde. The authors concluded that the 

data did not support an increased risk of nasal cancers due to formaldehyde alone. 

Partanen et al. (1985), in a case-referent study, attempted to determine whether respiratory cancer was 

associated with formaldehyde exposure in woodworkers. Anatomic sites classified as “respiratory 

cancers” included the tongue, mouth, pharynx, nose, sinuses, larynx, epiglottis, lung, trachea, and “other”. 

Fifty-seven male production workers diagnosed with respiratory cancers were selected, with the average 

level of formaldehyde exposure being 1 ppm and the average duration of exposure being 10 years. The 

odds ratios for respiratory cancers due to formaldehyde, adjusted for latency periods, peak exposures, or 

co-exposures, were statistically significant. The authors concluded that a positive relationship between 

respiratory cancers and formaldehyde exposure could not be substantiated, because 87% of the workers 

exposed to formaldehyde were also exposed to wood dust, a known nasal carcinogen. The strengths of 

this study were that cases and controls were sampled from a large cohort, so the population at risk is well 

defined. Exposure status was determined from a review of work histories (blinded with regard to disease 

status), so recall bias was avoided. Some air measurements were available for assessing exposure levels. 

The investigators used a fairly elaborate exposure matrix approach to classify cases and controls with 

regard to exposure status, and at least some control for potential confounding effects from other 

occupational exposures and cigarette smoking was possible. Study weaknesses included the notation that 

the cohort was too small for studying nasal cancer; there were no reported cases, and the expected number 

of cases in the total cohort was <1. In addition, smoking information was missing for a large proportion 

of cases and controls, and there was high correlation between formaldehyde and wood dust exposures, so 

it was difficult to separate their respective effects. The breaking of the matched case-control pairs in the 

analysis can lead to inflation of the odds ratio even if the analysis stratifies by levels of the matching 

variables. 

In a later study, Partanen et al. (1990) performed a retrospective study that attempted to determine the 

association of respiratory cancer (136 cases, 408 controls) with formaldehyde exposure; this case control 
FORMALDEHYDE 106 

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study was nested in a total cohort of 7,307 woodworkers having had a minimum level of 0.1 ppm and a 

minimum cumulative exposure of 3 ppm months to formaldehyde. The odds ratio for respiratory cancers 

in exposed versus unexposed workers, when corrected for vital status, smoking, and a latency period of 

10 years, was not statistically significant. The strengths were that the study population was an expansion 

of that used in the authors' earlier study (Partanen et al. 1985). Additional industries were added and the 

follow up period was extended, so the number of workers with respiratory cancers was considerably 

larger. The strengths and weaknesses were essentially the same as those in the earlier study. However, 

there were improvements over the initial study. First, the study’s statistical power was greater due to the 

larger sample size. Second, the authors conducted a more proper analysis by using conditional logistic 

regression modeling that preserved the matched sets of cases and controls (the earlier analysis broke the 

matched sets). Lastly, the authors presented some separate analyses for lung cancer cases and upper 

respiratory cancer cases, so that more homogeneous groups of respiratory cancers that might have 

different etiologies were analyzed separately. 

In a study by Roush et al. (1987), the potential for mortality from nasopharyngeal cancer and sinonasal 

cancer associated with occupational exposure to formaldehyde was investigated. Cases of 

nasopharyngeal and sinonasal cancer were identified through the Connecticut Tumor Registry; the list 

was restricted to males with these cancers who died in Connecticut during the period 1935–1975. 

Controls were obtained from men dying in Connecticut during the same time period. Information on the 

death certificate was used to search for information on the subjects' work history. The work history 

information was used by an industrial hygienist to classify each subject into formaldehyde exposure 

categories based on likelihood and level of exposure. For those with probable exposure at some point at 

least 20 years before death, the odds ratio for nasopharyngeal cancer was 2.3. The odds ratio increased to 

4 in the same group when narrowed to those dying at the age of $68. When frequencies of cancers were 

analyzed by occupation, the odds ratio for developing either cancer in the rubber industry was elevated 

(2.2), but not significantly. All four printers developed cancer. The authors concluded that there is an 

increased risk of nasopharyngeal cancer associated with probable exposure to formaldehyde; further, they 

concluded that the association is latency- and age-dependent. The authors suggest that the cause of 

sinonasal cancer in printers may be due to the presence of mineral oil mist, which has previously been 

associated with sinonasal cancer in the metals industry. Strengths of this study included a fairly large 

number of cases and a clinical review of medical records conducted for 75% of cases to confirm the 

diagnosis. Weaknesses included the fact that all cases and controls were deceased, and the possibility 

that risk factors for nasopharyngeal or sinonasal cancer that also increase the risk of death from other 
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causes (e.g., cigarette smoking) could be over represented in the control groups (a conservative bias 

would disguise exposure-disease associations for nasal cancer). Occupational information was 

ascertained from death certificates and city directories, so substantial exposure misclassification was 

likely. Information about possible occupational or nonoccupational confounders was lacking, as persons 

with formaldehyde exposures may also have had other carcinogenic exposures. The low prevalence of 

substantial formaldehyde exposures among study participants leads to low statistical power for detecting 

exposure-disease associations. This study is also limited because it was dependent on indirect 

information in creating the exposure index, nonoccupational exposures to formaldehyde were not 

addressed, and exposure to other potentially causal agents was not addressed. 

Hayes et al. (1986) attempted to determine the environmental factors associated with nasal cancers in 

males from the Netherlands. A total of 91 case and 195 control subjects were included in the study. 

Patients or, if already deceased, close relatives completed interviews concerning work, smoking, and 

drinking histories. Based on these interviews, subjects were classified based on probability and level of 

formaldehyde exposure. The relative risk (measured as the odds ratio) of adenocarcinomas of the nasal 

cavity and sinuses was elevated (11.3) for those working in the wood and paper industries; the relative 

risk for all other cancers was not elevated. The relative risk for squamous cell carcinomas associated with 

formaldehyde exposure was significantly elevated (p<0.05) when the data were adjusted for wood dust 

exposure. Adjustments for smoking did not perceptibly change the relative risk. The authors concluded 

that formaldehyde may be a human carcinogen, but conceded that the study’s limitations (questionable 

exposure conditions) prevented conclusive statements. Although the authors describe this case-control 

study as having low statistical power, they included a substantial number of persons with nasal cancer 

(n=116) given the rarity of this tumor. The study included incident (rather than prevalent) cases. Tumor 

histology information was available and trained industrial hygienists, who were unaware of each 

participant’s case/control status, estimated the potential for formaldehyde and wood dust exposure for 

each reported job. The study collected fairly extensive information about exposures and potential 

confounders. Regarding study weaknesses, no actual exposure measurements were available for cases or 

controls. The disagreements between the two industrial hygienists demonstrate the inherent inaccuracy 

of the exposure assessment (the exposure misclassification presumably caused a conservative bias). 

Because the study relied on interview data for assessing exposures, possible “recall bias” could have 

led to over reporting of exposures by cases (or their next-of-kin) compared to controls. Although 

industrial hygienists estimated the potential for formaldehyde exposure based on reported jobs, the cases 

compared to controls may have been more likely to remember and report jobs that involved chemical 
FORMALDEHYDE 108 

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exposure. In addition, next-of-kin interviews were necessary for a substantial number of cases. Response 

rates were fairly low (64%) for next-of-kin interviews for cases as well as controls, and those who chose 

to participate (especially among families of deceased cases) compared to nonparticipants may have been 

those who tended to be aware of jobs held by the decedent that involved chemical exposures. 

Hansen and Olsen (1995) investigated the risk of cancer due to occupational exposure to formaldehyde in 

Danish male workers. A total of 126,347 men born between 1897 and 1964 and diagnosed with cancer 

during the period of 1970–1984 were identified from the Danish Cancer Registry. The risk of cancer at a 

specific site was estimated from the standardized proportionate incidence ratio (SPIR), which was the 

proportion of cases of a specific cancer among workers from formaldehyde-associated industries versus 

the number of cases of the same cancer among all Danish workers. Of the 91,182 subjects with a full 

employment history, 2,041 had their longest length of employment at least 10 years prior to their cancer 

diagnosis. Among these 2,041 subjects, there were significant increases in the relative risk of cancers of 

the sinonasal cavity (SPIR=2.3), kidney (SPIR=1.3), and colon (SPIR=1.2). When analyzed by intensity 

of formaldehyde exposure and co-exposure to wood dust, there was a significant elevation in sinonasal 

cancers among workers exposed to formaldehyde and wood dust (SPIR=5.0) and workers moderately 

exposed to formaldehyde and probably not exposed to wood dust (SPIR=3.0). Workers with a low 

exposure to formaldehyde had a SPIR close to unity. The authors concluded that the increased incidences 

of kidney and colon cancers were biologically irrelevant due to the rapid metabolism of formaldehyde. 

Strengths of this study included the observation that this population-based proportionate morbidity ratio 

study used the entire adult white male population of Denmark as the population at risk. The 

determination of exposure status required at least a 10-year interval between first potential exposure to 

formaldehyde and the diagnosis of cancer (although a longer interval may have been more appropriate) 

and, because the study used cancer incidence (rather than mortality) based on cancer registry records, 

disease misclassification was probably low. Several weaknesses were also noted in this study. First, the 

exposure classification was crude and was based on having worked in a company that used or 

manufactured at least one kilogram of formaldehyde per worker (no exposure measurements were 

available), and it was based solely on the longest job held. Exposure misclassification is therefore likely. 

In the extreme case, some workers classified as “exposed” could have had shorter exposure durations than 

some who were classified as unexposed. The study authors point out that the study excludes exposures 

that occurred before April 1964, so nondifferential exposure misclassification probably occurred. They 

correctly state that any nondifferential misclassification should cause a conservative bias (i.e., the SPIR 

would underestimate the true magnitude of the association). In addition, use of the 
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“longest job held” approach for classifying exposure status could lead to confounding if, for example, the 

longest job was associated with formaldehyde exposures and other shorter jobs were associated with 

wood dust exposure. However, there is no reason to believe that such confounding actually occurred. 

Exposure intensity was based on white collar/blue collar status, which presumably is also a surrogate for 

socioeconomic status. Confounding by socioeconomic status (e.g., from nutrition differences) could have 

occurred between the lower and higher exposure categories. 

Gerin et al. (1989) investigated the cancer risk involved with occupational exposure to <1 ppm 

formaldehyde in a study which included 3,726 subjects. From the data collected, the OR between 

formaldehyde exposure and each type of cancer was estimated. The only cancer with a slightly elevated 

OR was adenocarcinoma of the lung in the long-duration/high-exposure group (OR=2.3). The 95% CI 

was 0.9–6 and the authors concluded that this result was compatible with the null hypothesis of no 

carcinogenic effects of formaldehyde. Cancer diagnoses were pathologically confirmed and extensive 

information was collected about possible nonoccupational confounders. Because, by definition, this casecontrol study sampled on disease rather then exposure status, the study population included persons from 

many different jobs and industries where formaldehyde exposure occurred, and the assessment of such 

exposures was necessarily limited. Controls were samples from electoral lists; registered voters might 

differ from the overall population (and the cases) in some respects (e.g., socioeconomic status), although 

the investigators presumably collected data that would allow control of such differences. The very low 

prevalence of substantial formaldehyde exposures among study participants leads to low statistical power 

for detecting exposure-disease associations. The authors also mention that the probable formaldehyde 

exposure levels in the "high" group was a TWA of >1 ppm. They further state that the small number in 

this group likely led to imprecise results. The study also analyzed the data after correcting for 

confounding factors; these factors (listed above) may play a role in the cancer risk. 

Animal Cancer Studies. As discussed previously in Section 2.2.1.2 subsection entitled Chronic 

Inhalation Animal Studies, chronic exposure to airborne formaldehyde concentrations ranging from about 

6 ppm to 15 ppm induced increased incidences of nasal tumors (squamous cell carcinomas, squamous cell 

papillomas, or polyploid adenomas) in three bioassays with Fisher 344 rats (Kamata et al. 1997; Kerns et 

al. 1983b; Monticello et al. 1996; Swenberg et al. 1980). Increased incidences of lower respiratory tract 

tumors or distant site tumors were not found in these studies, and exposure to concentrations of 2 ppm 

and lower induced no malignant nasal tumors. 
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In the earliest chronic inhalation rat bioassay (Kerns et al. 1983b; Swenberg et al. 1980), polyploid 

adenomas in the nasal cavity were found in 1/232, 8/236, 6/235, and 5/232 Fisher 344 rats (males and 

females were included) exposed 6 hours/day, 5 days/week for 24 months to 0, 2, 5.6, and 14.3 ppm, 

respectively. Malignant nasal tumors (predominately squamous cell carcinomas) were found in 

0/232 control, 0/236 2-ppm, 2/235 5.6-ppm, and 106/232 14.3-ppm rats (Kerns et al. 1983b). 

Monticello et al. (1996) exposed male Fisher 344 rats to 0, 0.7, 2, 6, 10, or 14 ppm, 6 hours/day, 

5 days/week for 24 months. Nasal polypoid adenomas, located in or adjacent to the lateral meatus, were 

found in 10-ppm (5/90) and 15-ppm (14/147) rats. No polypoid adenomas were found in the control 

group or in the 0.7-, 2-, or 6-ppm groups. Squamous cell carcinomas were found in the nasal cavities of 

1/90 6-ppm rats, 20/90 10-ppm rats, and 69/147 15-ppm rats. These tumors also were located 

predominately in the anterior lateral meatus. Squamous cell carcinomas were not found in the control, 

0.7-, or 2-ppm groups. Buccal squamous cell carcinomas were observed in three 15-ppm rats and one 

2-ppm rat. 

Kamata et al. (1997) exposed groups of 32 male Fisher 344 rats to 0, 0.3, 2, or 15 ppm, 6 hours/day, 

5 days/week for up to 28 months, and found nasal squamous cell carcinomas only in the 15-ppm group 

(13/32 rats). In contrast to the studies by Kerns et al. (1983b) and Monticello et al. (1996), no polyploid 

adenomas were found, but squamous cell papillomas were found in 3/32 rats in the 15-ppm group. 

In experiments with male Sprague-Dawley rats, nasal tumors (predominately squamous cell carcinomas) 

were observed in 10/100 rats exposed to 14.2 ppm, 6 hours/day, 5 days/week for 588 days, compared 

with 0/100 in controls (Albert et al. 1982) and in 60/100 rats exposed to 14.8 ppm for up to 128 weeks, 

compared with 0/99 in controls (Sellakumar et al. 1985). No tumors were found in the trachea or lungs in 

these studies, and tumors found at extra-respiratory sites were not considered by the investigators to be 

exposure-related. 

Wistar rats appear to be less carcinogenically responsive than Fisher 344 or Sprague-Dawley rats. 

Woutersen et al. (1989) observed nasal squamous cell carcinomas in only 1/26, 1/28, and 1/26 Wistar rats 

exposed to 0.1, 1, or 10 ppm, respectively 6 hours/day, 5 days/week for 28 months compared with 0/26 in 

controls; early physical damage to the nasal mucosa (electrocoagulation) increased the carcinogenic 

response only with subsequent exposure to 10 ppm (15/58 with 28-month exposure to 10 ppm versus 

1/54 in nonexposed Wistar rats with electrocoagulation treatment). In 28 Wistar rats exposed to 10 ppm 
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2. HEALTH EFFECTS 

for 3 months followed by a 25-month observation period, only one had a nasal squamous cell carcinoma 

and one had a nasal polypoid adenoma (Woutersen et al. 1989). 

In an earlier experiment by the same laboratory, groups of 44–45 male Wistar rats were exposed to 0, 10, 

or 20 ppm, 6 hours/day, 5 days/week for 4, 8, or 13 weeks followed by observation periods as long as 

126 weeks (Feron et al. 1988). Nasal tumors were found in 1/45 (polyploid adenoma), 1/43 (polyploid 

adenoma), and 4/44 (3 squamous cell carcinomas and 1 polyploid adenoma) 20-ppm rats exposed for 4, 8, 

or 13 weeks, respectively, compared with 0/45 in a control group. Two other nasal tumors found in the 

10-ppm groups were not considered by Feron et al. (1988) to be induced by formaldehyde exposure. 

These results suggest that if nasal epithelial damage from intermediate exposure is sufficiently severe, 

then the risk for nasal tumors in later life may be increased. 

Nasal tumors, similar to those observed in rats, were observed in two male B6C3F1 mice exposed to 

14.3 ppm, 6 hours/day, 5 days/week for 24 months; no nasal tumors were found in control mice or mice 

exposed similarly to 2 or 5.6 ppm (Kerns et al. 1983b). No other neoplastic responses were found at other 

sites. In each group in this bioassay, less than 25 of the approximately 120 male mice in each group lived 

beyond 18 months. Reduced survival among males was attributed to fighting and infections of the 

genitourinary tract associated with group housing. The exact incidence of occurrence of nasal tumors in 

the Kerns et al. (1983b) mouse study could not be determined from the published report, but the available 

data suggest that mice are less carcinogenically responsive to inhaled formaldehyde than rats. 

No nasal tumors or tumors at other respiratory tract sites were found in groups of 50 Golden Syrian 

hamsters exposed to either 10 ppm, 6 hours/day, 5 days/week for life or 30 ppm, 6 hours/day, once a 

week for life (Dalbey 1982). Hyperplastic and metaplastic areas were seen in the nasal epithelium of 5% 

of the hamsters exposed to 10 ppm, but were not seen in controls. 

NTP (1998) noted that formaldehyde is reasonably anticipated to be a human carcinogen, and IARC 

(1995) determined that formaldehyde is probably carcinogenic to humans (Group 2A) based on specific 

evaluations that there is limited evidence in humans for the carcinogenicity of formaldehyde and 

sufficient evidence in experimental animals. 
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EPA (1991a; IRIS 1999) classified formaldehyde in Group B1 - probable human carcinogen, based 

on an evaluation of limited human evidence and sufficient laboratory animal evidence. 

EPA (1991a) used dose-response data for nasal tumors in rats exposed to high concentrations of 

formaldehyde (from Kerns et al. 1983b) to extrapolate to human cancer risk at low exposure 

concentrations, using rates of DNA-protein cross links in target tissue as a measure of delivered dose. 

Relationships between formaldehyde air concentrations and rates of formation of DNA-protein cross links 

in nasal epithelial tissue of rats (Casanova et al. 1989) or of Rhesus monkeys (Casanova et al. 1991; Heck 

et al. 1989) and adjustments to continuous exposure were used to calculate lifetime human cancer unit 

risk estimates of 3.3x10-4 per ppm formaldehyde based on the monkey data, and 2.8x10-3 per ppm 

formaldehyde based on the rat data (see Section 2.4.3). 

Using the monkey-based human cancer unit risk estimate, air concentrations associated with cancer risk 

levels of 10-4 to 10-7 from lifetime exposure are 0.3 to 3x10-4 ppm, respectively, and are plotted in 

Figure 2-1. The CEL values from each reliable study for cancer in each animal species and duration 

category are recorded in Table 2-1 and plotted in Figure 2-1. 

2.2.2 Oral Exposure 

Most of the available reports of controlled studies of health effects from oral exposure to formaldehyde 

have not provided information regarding how frequently dosing solutions were analyzed for 

formaldehyde content. Some studies reported how frequently formaldehyde solutions were prepared 

(e.g., in drinking water studies, Til et al. [1988b, 1989] and Tobe et al. [1989] prepared solutions weekly 

and twice weekly, respectively), or how frequently formaldehyde was added to the diet (e.g., Hurni and 

Ohder [1973] daily sprayed formaldehyde solutions [that were prepared weekly] on food just prior to 

feeding dogs). Other study reports, however, provide no information regarding solution-preparation 

frequency, conditions of storage, or analysis of test material for formaldehyde content (e.g., Johannsen et 

al. 1986; Soffritti et al. 1989; Takahashi et al. 1986a). Because of this reporting deficiency, and because 

formaldehyde solutions are very unstable (due to formaldehyde’s high reactivity and volatility), the reader 

should be aware that there is uncertainty associated with oral dose levels reported in this profile. 

Another issue of uncertainty regards the impurity of commercially available aqueous solutions of 

formaldehyde (often called formalin) which normally contain approximately 10–15% methanol to 

prevent polymerization. Reports of human poisonings from formalin and animal studies that used 

formalin (e.g., Marks et al. 1980; Takahashi et al. 1986a) are included in this profile. Attempts have 
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2. HEALTH EFFECTS 

been made, however, to note when formalin was the source of the ingested formaldehyde, so that the 

reader will be aware of possible confounding effects from methanol. 

Exposure to formaldehyde by the oral route can occur, but exposure is not as common as by the inhalation 

route because of the instability of formaldehyde in aqueous solution. Much of the information available 

about the effects of formaldehyde after oral exposure in humans comes from case reports of acute 

poisoning. Small amounts of formaldehyde can occur in foodstuffs, usually added as a preservative. 

2.2.2.1 Death 

In humans, death has been associated with acute oral exposure to formaldehyde. Four cases are described 

in detail here. Burkhart et al. (1990) describe the case of a 58-year-old man who swallowed 4 ounces of 

formalin (517 mg formaldehyde/kg) in a suicide attempt. The man was found unconscious by a coworker about 1 hour after his shift began. In the emergency room, the subject regained consciousness but 

was lethargic. Laboratory results indicated significant acidosis. Approximately 3 hours after ingesting 

the formalin, the patient complained of abdominal pain and began retching without emesis; he was 

admitted for observation and treated with ethanol. The patient's abdominal pains became more severe and 

he had difficulty breathing. At 5.5 hours after ingestion, the patient became obtund, and both his 

respiratory rate and blood pressure fell significantly; he was intubated and placed on 100% oxygen. 

Shortly thereafter, the patient began to experience seizures; treatment with diazepam and phenytoin was 

unproductive, but pancuronium was effective in treating the seizures. Intravenous bicarbonate and 

ethanol therapies were begun after the seizures started. The patient was transported for dialysis, but on 

arrival, had clinical signs of intravascular coagulopathy. He subsequently sustained a cardiac arrest from 

which he could not be revived. At autopsy, the patient’s stomach was hard, white, and leathery; the 

esophagus and intestines appeared to be normal. 

A 55-year-old woman and a 34-year-old man ingested, with suicidal intent, an unknown amount of what 

was reported to have been formalin (Koppel et al. 1990). The female patient was found in a coma and 

admitted to the hospital with shock (systolic blood pressure 50 mm Hg), respiratory insufficiency, and 

metabolic acidosis. The male patient, who had a history of alcohol abuse, was also hospitalized with 

shock (systolic blood pressure 60 mm Hg), respiratory insufficiency, and metabolic acidosis. Both 

patients underwent hemodialysis and hemofiltration treatment. Analysis of the formaldehyde samples 
FORMALDEHYDE 114 

2. HEALTH EFFECTS 

ingested by both patients showed no evidence that these products contained methanol, although it was 

expected to have been detected. A chemical-toxicological screening indicated that no drugs other than 

formaldehyde had been ingested; neither methanol or ethanol were detected in blood samples. Three 

weeks after ingestion of formaldehyde, the female patient died of cardiac failure refractory to 

catecholamine therapy. The male patient developed adult respiratory distress syndrome and died 8 weeks 

after formaldehyde ingestion with signs of cardiac failure. 

Eells et al. (1981) describe the case of a 41-year-old woman who swallowed 120 mL formalin (37% 

formaldehyde solution; 624 mg formaldehyde/kg). The woman was brought to the emergency room 

within 30 minutes. The patient complained of abdominal pain and subsequently lost consciousness. 

Upon admission, the patient was cyanotic, apneic, and hypotensive. Laboratory results indicated 

significant acidosis. The patient was intubated, ventilation was initiated, and gastric lavage was 

performed. Intravenous fluid therapy consisting of Ringers solution followed by 5% dextrose, 

epinephrine, and sodium bicarbonate was initiated and the patient was transferred to intensive care. The 

patient was maintained via endotracheal respiration and dopamine therapy. The patient became anuric 

approximately 7.5 hours after admission, and her health continued to deteriorate over the next day; she 

died 28 hours after admission. 

Mortality data for acute duration experimental animal studies do not present a consistent picture. Reports 

of death in animal studies after acute oral exposure were found (Tobe et al. 1989), although other studies 

showed no mortality. For instance, groups of male and female Wistar rats were given formaldehyde at 0, 

10, 50, and 300 mg/kg/day in their drinking water (Tobe et al. 1989). Animals given 300 mg/kg/day were 

observed to have died as early as 9 days after the start of the treatment. The number and sex of rats that 

died were not reported. In a group of 34 pregant mice given gavage doses of 185 mg/kg/day on gestation 

days 6–15, 22 died by gestation day 18 (Marks et al. 1980). Marks et al. (1980) noted that the drinking 

water contained 0.6–0.75% methanol (60–75 mg/kg/day) which possibly could have contributed to the 

lethality. However, Johannsen et al. (1986) reported no mortality after acute-duration exposure of 

Sprague-Dawley rats of both sexes to doses #150 mg/kg/day. Similarly, Takahashi et al. (1986a) 

observed no mortality after exposure of male Wistar rats to 258 mg/kg/day of formaldehyde (as formalin) 

for acute duration. 

Intermediate-duration exposure of animals to orally administered formaldehyde resulted in a more 

consistent picture of mortality. Vargova et al. (1993) observed no treatment-related mortality in male 
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2. HEALTH EFFECTS 

Wistar rats exposed to doses of formaldehyde by gavage of #80 mg/kg/day for 4 weeks. No deaths were 

reported in weanling SPF-bred rats (Cpb WU, Wistar random) that received up to 125 mg/kg/day 

formaldehyde in their drinking water for 4 weeks (Til et al. 1988b), in male and female Sprague-Dawley 

rats given up to 150 mg/kg/day formaldehyde in drinking water for 90 consecutive days (Johannsen et al. 

1986), or in male Wistar rats after administration of 258 mg/kg/day formaldehyde (as formalin) in 

drinking water for periods up to 32 weeks (Takahashi et al. 1986a). Mortality rates were calculated for 

male and female Wistar rats given 0, 10, 50, or 300 mg/kg/day formaldehyde in drinking water for 

#12 months (Tobe et al. 1989). For the high-dose group, mortality at 3, 6, and 9 months was 10, 15, and 

20% for male rats, respectively, and 25, 30, and 30% for female rats, respectively. No mortality was 

reported in the low- and mid-dose groups after exposure for periods #9 months (Tobe et al. 1989). 

Four male and 4 female pure-bred Beagle dogs were administered 0, 50, 75, or 100 mg/kg/day 

formaldehyde in the diet for 90 consecutive days (Johannsen et al. 1986). No deaths or abnormal 

reactions were observed in the treated dogs. 

In chronic-duration animal studies, no dose-related excess mortality was seen in male and female 

Sprague-Dawley rats after 104 weeks of exposure to doses #300 mg/kg/day (males) or in SPF-bred rats 

exposed to 0, 1.2, 15, or 82 mg/kg/day (males) and 0, 1.8, 21, or 109 mg/kg/day (females) in their 

drinking water for 2 years (Til et al. 1989). Deaths were significantly higher than control in males at 

15 mg/kg/day in the Til study, but not at 82 mg/kg/day. 

Mortality rates were calculated for male and female Wistar rats given 0, 10, 50, or 300 mg/kg/day 

formaldehyde in drinking water for up to 24 months (Tobe et al. 1989). For the high-dose group, 

mortality at 12, 15, and 18 months was 45, 67, and 67% for male rats, respectively, and 55, 55, and 70% 

for female rats respectively (Tobe et al. 1989). All animals in the high-dose group died by 21 (females) 

or 24 (males) months. 

The LOAEL values from each reliable study for death in each species and duration category are recorded 

in Table 2-4 and plotted in Figure 2-2. 


















 

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2.2.2.2 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 2-4 and plotted in Figure 2-2. 

Respiratory Effects. Respiratory effects have been observed in humans after ingestion of 

formaldehyde. A 55-year-old woman and a 34-year-old man ingested an unknown amount of formalin 

with suicidal intent and were admitted to the hospital (Koppel et al. 1990). Respiratory insufficiency was 

noted upon admission to the hospital. Both patients died; however, the man developed adult respiratory 

distress syndrome prior to death. 

Burkhart et al. (1990) describe the case of a 58-year-old man who swallowed 4 ounces (517 mg/kg) of a 

formaldehyde solution in a suicide attempt. The man was found unconscious by a co-worker about 1hour 

after his shift began. In the emergency room, the subject regained consciousness, but was lethargic. At 

5.5 hours after ingestion, the patient became obtund, and his respiratory rate fell significantly; he was 

intubated and placed on 100% oxygen. He subsequently sustained a cardiac arrest from which he could 

not be revived. 

Eells et al. (1981) described the case of a 41-year-old woman who was brought to the emergency room 

30 minutes after ingesting 120 mL of formalin (37% formaldehyde solution; 624 mg/kg). Upon 

admission, the patient was cyanotic, apneic, and hypotensive. The patient was intubated and ventilation 

was initiated. The patient was maintained via endotracheal respiration and dopamine therapy; she died 

28 hours after admission. Other adverse respiratory effects have been noted in other reports of human 

ingestion including difficulty breathing and speaking (Freestone and Bentley 1989), increased cough, and 

tachypnea after 234 mg/kg formaldehyde (Kochhar et al. 1986). 

Intermediate-duration oral exposure data on respiratory effects in experimental animals are limited to 

organ weight and/or histopathological results, and are negative. After 90-day exposure to doses of 

#150 mg/kg/day formaldehyde in drinking water, male and female Sprague-Dawley rats showed no 

adverse effects on lung weight or histopathology (Johannsen et al. 1986). Til et al. (1988b) saw no effect 

on the histopathology of the nose and pharynx of male and female Wistar rats after 4 weeks of exposure 

to 125 mg/kg/day formaldehyde in drinking water. Vargova et al. (1993) saw no adverse effect on the 

histopathology of lung tissue of male Wistar rats after 4 weeks of gavage exposure to doses of 
 

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formaldehyde of #80 mg/kg/day. No adverse effects on lung weight or histopathology were seen in 

Beagle dogs exposed to 100 mg/kg/day of formaldehyde in the diet for 90 days (Johannsen et al. 1986). 

Chronic-duration exposure data are similarly limited in scope. Til et al. (1989) saw no adverse effect on 

nose and lung tissue or lung weight in male and female Wistar rats exposed to doses #82 mg/kg/day 

(male) or 109 mg/kg/day (females) in drinking water for up to 2 years. Tobe et al. (1989) also saw no 

effect on lung weight or histopathology from doses of formaldehyde of #300 mg/kg/day in drinking water 

administered to male and female Wistar rats for up to 24 months. 

Cardiovascular Effects. Shock and cardiac failure have been noted in patients after intentional 

ingestion of formaldehyde solution (Koppel et al. 1990). Burkhart et al. (1990) describe the case of a 

58-year-old man who swallowed 4 ounces of formalin (517 mg/kg formaldehyde) in a suicide attempt. 

The man was found unconscious by a co-worker about 1hour after his shift began. In the emergency 

room, the subject regained consciousness, but was lethargic. At 5.5 hours after ingestion, his blood 

pressure fell significantly. He subsequently sustained a cardiac arrest from which he could not be 

revived. Other reports of cardiovascular effects in humans after ingestion of formaldehyde include 

hypotension after 624 mg/kg formaldehyde (as formalin) (Eells et al. 1981), circulatory collapse 

(Freestone and Bentley 1989), and sinus tachycardia after 234 mg/kg formaldehyde (Kochhar et al. 1986). 

Intermediate-duration exposure data on cardiovascular effects in experimental animals are limited to 

organ weight and/or histopathological results, and are negative. After 90-day exposure to doses of 

#150 mg/kg/day formaldehyde in drinking water, male and female Sprague-Dawley rats showed no 

adverse effects on heart weight or histopathology (Johannsen et al. 1986). No significant effects on the 

histopathology of the heart were observed in Wistar rats after 12 months of exposure to up to 

300 mg/kg/day in drinking water (Tobe et al. 1989). In addition, 90-day treatment of male and female 

Beagle dogs with doses of #100 mg/kg/day formaldehyde in the diet found no effect on heart weight or 

histopathology (Johannsen et al. 1986). 

Til et al. (1989) saw no adverse effect on heart tissue or organ weight in male and female Wistar rats 

exposed to doses #82 mg/kg/day (male) or #109 mg/kg/day (females) in drinking water for up to 2 years. 

Tobe et al. (1989) also saw no effect on heart weight or histopathology of doses of formaldehyde of 

#300 mg/kg/day in drinking water administered to male and female Wistar rats for up to 24 months. 
 

FORMALDEHYDE 136 

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Gastrointestinal Effects. Formaldehyde is corrosive to mucosal tissues. Intentional ingestion of 

formaldehyde has been associated with extensive congestion, hemorrhaging, and necrosis of the 

gastrointestinal mucosa (Koppel et al. 1990). Burkhart et al. (1990) described the case of a 58-year-old 

man who swallowed 4 ounces (517 mg/kg formaldehyde) of formalin in a suicide attempt. 

Approximately 3 hours after ingesting the formalin, the patient complained of abdominal pain and began 

retching without emesis; he was admitted for observation and treated with ethanol. The patient’s 

abdominal pains became more severe, and he subsequently died from cardiac arrest. At autopsy, the 

patient’s stomach was hard, white, and leathery; the esophagus and intestines appeared to be normal. 

Eells et al. (1981) described the case of a 41-year-old woman who was brought to the emergency room 

30 minutes after ingesting 120 mL formalin (624 mg/kg formaldehyde). The patient complained of 

abdominal pain and subsequently lost consciousness; she died 28 hours after admission. Freestone and 

Bentley (1989) describe gastrointestinal effects after presumed gargling with formaldehyde, including 

dysphagia due to esophageal mucosal damage. The patient was placed on parenteral feeding to allow 

resting of the gut and to improve nutritional status. After several weeks in intensive care, the patient was 

taken off of ventilation; after two additional months, the patient was released. 

A 26-year-old woman who ingested 234 mg/kg formaldehyde exhibited extensive gastrointestinal damage 

(Kochhar et al. 1986). Immediately after ingesting formaldehyde, the patient experienced repeated 

vomiting with occasional streaks of blood. Anti-emetics and antacids were prescribed but did not relieve 

symptoms. Examination of the oropharynx revealed ulceration and sloughing of the soft palate and 

posterior pharyngeal wall. Indirect laryngoscopy revealed ulceration of the epiglottis, pyriform fossae, 

and arytenoids. At 96 hours, an upper gastrointestinal endoscopy revealed that the esophageal mucosa 

was edematous and ulcerated with patches of black slough along the entire length. Areas of the stomach 

were hyperemic, and there was superficial ulceration in the distal body and antrum; the duodenal mucosa 

appeared normal. The patient underwent a feeding jejunostomy and made an uneventful recovery. At 

4 weeks, a repeat endoscopy revealed a normal esophagus. The stomach appeared normal with the 

exception of slight hyperemia and limited distensibility of the antrum. Barium examination revealed 

scarring of the antrum and distal portion of the gastric body. At 6 weeks, the patient was asymptomatic. 

Intermediate-duration exposure data on gastrointestinal effects in experimental animals are limited to 

organ weight and/or histopathological results, but are sufficient to describe a no-effect level for 

gastrointestinal effects in rats. After 90-day exposure to doses up to 150 mg/kg/day formaldehyde in 
FORMALDEHYDE 137 

2. HEALTH EFFECTS 

drinking water, male and female Sprague-Dawley rats showed no adverse effects on the histopathology of 

the gastrointestinal mucosa (Johannsen et al. 1986). In contrast, erosions and/or ulcers, associated with 

regenerating mucosa, were noted in the limiting ridge of the fundic mucosa in glandular stomach of male 

Wistar rats exposed to 0.5% formalin (258 mg/kg/day formaldehyde) in drinking water for 32 weeks 

(Takahashi et al. 1986a). Erosions were described as “diffuse deep gastric pits with clearly increased 

numbers of mucous neck cells in the fundic mucosa”. Benign papillomas in the forestomach also were 

noted in 8 of the 10 exposed rats in this study, compared with none in 40 controls. Increased incidences 

of forestomach squamous cell hyperplasia and glandular stomach glandular hyperplasia were observed in 

Wistar rats exposed for 12 months to 300 mg/kg/day in drinking water, but not in rats exposed to 

50 mg/kg/day (Tobe et al. 1989). Til et al. (1988b) saw thickening of the limiting ridges of the stomach 

and hyperkeratosis in the forestomach of male and female Wistar rats after 4 weeks of exposure to 

125 mg/kg/day formaldehyde in drinking water. One of the 10 females receiving this dose also exhibited 

moderate papillomatous hyperplasia, presumably of the glandular stomach. Focal atrophic inflammation 

was also observed in the glandular stomach. No adverse effects of treatment were observed at 

25 mg/kg/day formaldehyde in either sex. An intermediate-duration MRL of 0.3 mg/kg/day was derived 

from the data of Til et al. (1988b). The MRL of 0.3 mg/kg/day was based on a NOAEL of 25 mg/kg/day 

for lack of gastrointestinal effects in rats and calculated as described in the footnote to Table 2-4 and in 

Appendix A of this profile. 

Vargova et al. (1993) saw no adverse effect on the histopathology of stomach tissue of male Wistar rats 

after 4 weeks of gavage exposure to doses of #80 mg/kg/day formaldehyde. In addition, no effect of 

90-day treatment of male and female Beagle dogs with doses of #100 mg/kg/day formaldehyde in the diet 

was found on stomach weight or histopathology (Johannsen et al. 1986). 

Til et al. (1989) observed adverse gastrointestinal effects at 82 mg/kg/day formaldehyde in male and 

109 mg/kg/day formaldehyde in female Wistar rats exposed in drinking water for up to 2 years. Lesions 

were first seen after 53 weeks. These adverse effects included papillomatous hyperplasia with 

hyperkeratosis, chronic atrophic gastritis, focal ulceration in the forestomach, and hyperplasia in the 

glandular stomach. No adverse gastrointestinal effects were noted in the male rats receiving a dose of 

15 mg/kg/day. A chronic-duration oral MRL of 0.2 mg/kg/day was derived from the data of Til et al. 

(1989). The MRL of 0.2 mg/kg/day was based on a NOAEL of 15 mg/kg/day for lack of gastrointestinal 

effects in male rats and was calculated as described in the footnote to Table 2-4 and in Appendix A of this 

profile. 
 

FORMALDEHYDE 138 

2. HEALTH EFFECTS 

Tobe et al. (1989) also saw forestomach hyperkeratosis at a drinking-water dose of 50 mg/kg/day and 

severe degenerative lesions in the epithelium of the forestomach and glandular stomach at 300 mg/kg/day 

in male and female Wistar exposed for up to 24 months. 

Hematological Effects. Some hematological effects have been noted in humans after acute 

ingestion, but do not appear to be primary effects in formaldehyde poisoning. Burkhart et al. (1990) 

described intravascular coagulopathy in the case of a 58-year-old man who swallowed 4 ounces of 

formalin (517 mg/kg formaldehyde) in a suicide attempt. However, Kochhar et al. (1986) indicated that 

normal hematology was observed in a 26-year-old female who ingested a formaldehyde dose of 

234 mg/kg (Kochhar et al. 1986). Other reports of human ingestion do not indicate adverse effects on the 

hematological system (Eells et al. 1981; Freestone and Bentley 1989; Koppel et al. 1990). 

Intermediate-duration exposure data on hematological effects in experimental animals are limited to 

routine hematological parameters and are negative. After 90-day exposure to doses of #150 mg/kg/day 

formaldehyde in drinking water, male and female Sprague-Dawley rats showed no adverse effects on 

hematocrit or hemoglobin (Johannsen et al. 1986). Similarly, Til et al. (1988b) saw no effect on 

hemoglobin concentration, packed cell volume, or erythrocyte counts in male and female Wistar rats after 

4 weeks of exposure to 125 mg/kg/day formaldehyde in drinking water. In a companion study, no effect 

was seen on hematological variables in male and female rats exposed to doses #82 mg/kg/day (males) or 

109 mg/kg/day (females) for #52 weeks (Til et al. 1989). Vargova et al. (1993) saw a statistically 

significant increase in the hematocrit of male Wistar rats after 4 weeks of gavage exposure to doses of 

40–80 mg/kg/day formaldehyde. At 80 mg/kg/day, erythrocyte count and hemoglobin were statistically 

significantly increased, whereas mean corpuscular hemoglobin was significantly depressed compared to 

control animals (Vargova et al. 1993). Vargova et al. (1993) reported that the hemotological effects 

noted, although statistically significant, were within the background range for Wistar rats, and were 

therefore of questionable clinical significance. No effect of 90-day treatment of male and female Beagle 

dogs with doses of #100 mg/kg/day formaldehyde in the diet was found on hematological parameters 

including hematocrit and hemoglobin (Johannsen et al. 1986). 

Til et al. (1989) observed no adverse hematological effects in male and female rats exposed to 82 and 

109 mg/kg/day formaldehyde, respectively, in drinking water for up to 2 years. Similarly, Tobe et al. 

(1989) observed no exposure-related effects on red blood cell count, hematocrit, or hemoglobin in rats 

exposed to drinking water doses up to 300 mg/kg/day for up to 24 months. 
 

 

FORMALDEHYDE 139 

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Musculoskeletal Effects. No reports of musculoskeletal effects in humans after acute-, 

intermediate-, or chronic-duration oral exposure to formaldehyde were found in the literature. 

Til et al. (1989) observed no adverse histopathological effects on the skeletal muscle of male and female 

rats exposed to 82 and 109 mg/kg/day formaldehyde, respectively, in drinking water for up to 2 years. 

Hepatic Effects. Intentional ingestion of formaldehyde in a suicide attempt has been associated with 

hepatomegaly, icterus, and congestion of the hepatic parenchyma (Koppel et al. 1990). Some reports of 

human ingestion of formaldehyde include hepatotoxicity and increased liver enzymes (Freestone and 

Bentley 1989), although other reports do not indicate hepatic effects (Eells et al. 1981). 

Intermediate-duration exposure data on hepatic effects in experimental animals are limited to 

measurement of liver weight and histopathology and are mostly negative. After 90-day exposure to doses 

of #150 mg/kg/day formaldehyde in drinking water, male and female Sprague-Dawley rats showed no 

adverse effects on liver weight or histopathology (Johannsen et al. 1986). Similarly, Til et al. (1988b) 

saw no effect on liver weight or histopathology in male and female Wistar rats after 4 weeks of exposure 

to 125 mg/kg/day formaldehyde in drinking water; however, a decrease in plasma protein and albumin 

concentration was observed. Vargova et al. (1993) saw an increase in the incidence of hepatocellular 

vacuolization in male Wistar rats after 4 weeks of gavage exposure to doses of 80 mg/kg/day 

formaldehyde. No effect of 90-day treatment of male and female Beagle dogs with doses of 

#100 mg/kg/day formaldehyde in the diet was found on liver weight, histopathology, or activities of 

serum enzymes indicative of liver damage (Johannsen et al. 1986). 

Til et al. (1989) observed no adverse effects on organ weight or histopathology of the liver of male and 

female rats exposed to 82 and 109 mg/kg/day formaldehyde, respectively, in drinking water for up to 

2 years. Likewise, hepatic weight determinations and histopathology were negative in the study 

conducted by Tobe et al. (1989), wherein male and female Wistar rats were exposed to 0, 10, 50, or 

300 mg/kg/day formaldehyde in drinking water for up to 24 months. However, serum protein, albumin, 

and total cholesterol were all statistically significantly decreased in both sexes at 300 mg/kg/day at 

12 months in this study. In exposed rats, serum hepatic enzyme levels (alkaline phosphatase, 

glutamate-oxaloacetic transaminase, and glutamic-pyruvic transaminase) were either not different from or 

were significantly lower than control values (Tobe et al. 1989). 
 

FORMALDEHYDE 140 

2. HEALTH EFFECTS 

Renal Effects. Renal failure has been associated with acute intentional ingestion of formaldehyde 

(Eells et al. 1981; Freestone and Bentley 1989; Koppel et al. 1990). In the case reported by Eells et al. 

(1981), the patient, who ingested 624 mg/kg formaldehyde (as formalin), became anuric approximately 

7.5 hours after ingestion, and her health continued to deteriorate over the next day; she died 28 hours after 

admission. Koppel et al. (1990) also describe renal failure prior to death, occurring soon after ingestion 

of an unknown quantity of formaldehyde. However, in the report by Freestone and Bentley (1989), 

hypoalbuminemia and renal failure were noted upon admission to the hospital after the patient gargled 

with formaldehyde. Dopamine was given until renal function improved. After several weeks in intensive 

care, the patient was taken off of ventilation; after two additional months, the patient was released. 

Intermediate-duration exposure data on renal effects in experimental animals are limited to kidney weight 

measurement and histopathology and are mostly negative. After 90-day exposure to doses of 

#150 mg/kg/day formaldehyde in drinking water, male and female Sprague-Dawley rats showed no 

adverse effects on kidney weight or histopathology (Johannsen et al. 1986). Similarly, Til et al. (1988b) 

saw no effect on kidney histopathology in male Wistar rats after 4 weeks of exposure to 125 mg/kg/day 

formaldehyde in drinking water. Vargova et al. (1993) saw no effect on the weight or histopathology of 

the kidneys in male Wistar rats after 4 weeks of gavage exposure to doses of 80 mg/kg/day formaldehyde. 

No effect of 90-day treatment of male and female Beagle dogs with doses of #100 mg/kg/day 

formaldehyde in the diet was found on kidney weight or histopathology (Johannsen et al. 1986). Til et al. 

(1989) reported, however, that male and female Wistar rats had increased urine density, decreased urine 

volume, and occult blood (males only) after exposure for 27 to 82 weeks to 109 mg/kg/day formaldehyde 

in drinking water, respectively. 

In a 2-year drinking water study, Til et al. (1989) observed an increase in the incidence of renal papillary 

necrosis in male rats exposed to 82 mg/kg/day and an increase in renal papillary necrosis accompanied by 

increased relative kidney weight in female rats exposed to 109 mg/kg/day. Kidney weight determinations 

and histopathology were negative in the study conducted by Tobe et al. (1989), wherein male and female 

Wistar rats were exposed to 0, 10, 50, or 300 mg/kg/day formaldehyde in drinking water for up to 

24 months, but blood urea nitrogen was increased in the 300-mg/kg/day group at 12 months. 
 

 

 

FORMALDEHYDE 141 

2. HEALTH EFFECTS 

Endocrine Effects. No reports describing endocrine effects of acute-, intermediate-, or chronicduration oral exposure to formaldehyde in humans or acute-duration oral exposure in animals were found. 

After 90-day exposure to doses of #150 mg/kg/day formaldehyde in drinking water, male and female 

Sprague-Dawley rats showed no adverse effects on adrenal or thyroid weight or histopathology 

(Johannsen et al. 1986). Similarly, Til et al. (1988b) saw no effect on adrenal and thyroid weight in male 

Wistar rats after 4 weeks of exposure to 125 mg/kg/day formaldehyde in drinking water. Vargova et al. 

(1993) saw no effect on the weight of the adrenals or pituitary in male Wistar rats after 4 weeks of gavage 

exposure to doses of 80 mg/kg/day formaldehyde. No effect of 90-day treatment of male and female 

Beagle dogs with doses of #100 mg/kg/day formaldehyde in the diet was found on adrenal and thyroid 

weight or histopathology (Johannsen et al. 1986). 

Til et al. (1989) observed no effect on the weight of the adrenal, pituitary, and thyroid, or histopathology 

of the adrenal, pituitary, thyroid, or pancreas in male and female rats exposed to 82 and 109 mg/kg/day 

formaldehyde, respectively, in drinking water for up to 2 years. Adrenal, pituitary, and thyroid weight 

determinations and histopathology, in addition to histopathology of the pancreas, were not influenced by 

exposure in the study conducted by Tobe et al. (1989), wherein male and female Wistar rats were exposed 

to 0, 10, 50, or 300 mg/kg/day formaldehyde in drinking water for up to 24 months. 

Dermal Effects. No reports of dermal effects of acute-, intermediate-, or chronic-duration oral 

exposure of humans to formaldehyde were found in the literature. 

No adverse histopathology was noted in skin samples from male and female Wistar rats receiving 

#109 mg/kg/day formaldehyde in drinking water after 2 years of exposure (Til et al. 1989) 

Ocular Effects. No reports of ocular effects after acute-, intermediate-, or chronic-duration oral 

exposure of humans, or acute- or intermediate-duration oral exposure of animals to formaldehyde were 

found in the literature. 

Til et al. (1989) observed no effect on the histopathology of the Harderian and exorbital lachrymal glands 

and eye of male and female rats exposed to 82 and 109 mg/kg/day formaldehyde, respectively, in 

drinking water for up to 2 years. 
 

FORMALDEHYDE 142 

2. HEALTH EFFECTS 

Body Weight Effects. No reports of body weight effects in humans after oral exposure to 

formaldehyde were located. 

Groups of Sprague-Dawley rats (sex not specified) were administered formaldehyde at 0, 37.5, 75, 150, 

or 225 mg/kg/day by gavage for 2 weeks (Johannsen et al. 1986). Mean body weight decreased at 

concentrations above 75 mg/kg/day. However, another pilot study conducted by Johannsen et al. (1986), 

Sprague-Dawley rats given formaldehyde at 0, 75, 150, or 225 mg/kg/day in drinking water for 2 weeks 

showed no significant changes in final body weights. Til et al. (1989) noted a decrease in body weight 

gain (unspecified) after 1 week of exposure of male Wistar rats to 82 mg/kg/day formaldehyde in 

drinking water, with statistically significant decreases in food consumption reported at 82 mg/kg/day for 

males and 109 mg/kg/day for females. No effect on body weight was noted until week 24 in female rats 

in the same study exposed to a high dose of 109 mg/kg/day. Body weight was not affected in male and 

female Wistar rats exposed to formaldehyde in drinking water at doses #125 mg/kg/day for 4 weeks (Til 

et al. 1988b). Likewise, Vargova et al. (1993) saw no effect on body weight in male Wistar rats exposed 

by gavage 5 days/week for 4 weeks, to doses of #80 mg/kg/day formaldehyde. 

Johannsen et al. (1986) noted that significant decreases in body weights occurred in both sexes of 

Sprague-Dawley rats exposed to 150 mg/kg/day in drinking water for 90 days and in males exposed to 

100 mg/kg/day, and that these decreases were associated with decreased water, but not food, 

consumption. Terminal mean body weights at these dose levels were about 10–15% lower than control 

values, whereas at 50 mg/kg/day for both sexes, and at 100 mg/kg/day for female rats, they were within 

10% of control body weight values. In contrast, no significant effects on body weights were noted in 

male Wistar rats exposed to 0.5% formalin (258 mg/kg/day formaldehyde) in drinking water for 32 weeks 

(Takahashi et al. 1986a). Male and female Beagle dogs exposed to 100 mg/kg/day formaldehyde in the 

diet for 90 days had significantly reduced body weights, compared with controls, but not at lower 

exposure levels of 50 or 75 mg/kg/day (Johannsen et al. 1986). The magnitude of the decreased body 

weight was not specified. Significantly reduced food consumption was noted in males, but not in females, 

in the 100-mg/kg/day group and in females, but not males, in the 75-mg/kg/day group. 

Wistar rats exposed for up to 2 years to estimated daily drinking water doses of 300 mg/kg/day lost 

weight during the first 2 weeks of exposure, whereas control rats and rats exposed to up to 50 mg/kg/day 

increased their body weights by about 20–30% during the same period (Tobe et al. 1989). Mean body 

weights and food and water intakes were markedly decreased in the 300-mg/kg/day rats, compared with 
 

 

FORMALDEHYDE 143 

2. HEALTH EFFECTS 

controls, throughout the study. After 5–10 weeks of exposure, body weights were about 20–30% lower 

than controls. Mean terminal body weights were about 40–45% lower than controls. At doses up to 

50 mg/kg/day, terminal body weights were within 10% of control body weights throughout the study. 

In another chronic drinking water study, mean body weights were significantly decreased, compared with 

controls, in male Wistar rats after 1 week and in female rats after 24 weeks of exposure to doses of 82 and 

109 mg/kg/day, respectively (Til et al. 1989). These decreases were associated with decreases in food 

and water intake. Terminal body weights were approximately 10–15% lower than controls. Body weights 

were within 10% of control values in male and female rats exposed to up to 15 and 21 mg/kg/day, 

respectively. 

Metabolic Effects. Metabolic effects have been noted in patients after ingestion of formaldehyde. 

Metabolic acidosis, high plasma formic acid, and hyperlactatemia were noted in two patients who 

intentionally ingested formaldehyde in suicide attempts (Koppel et al. 1990). Burkhart et al. (1990) 

describe the case of a 58-year-old man who swallowed 4 ounces of formalin (517 mg/kg formaldehyde) in 

a suicide attempt. The man was found unconscious by a co-worker about 1 hour after his shift began. 

Laboratory results at the emergency room indicated significant acidosis. Intravenous bicarbonate and 

ethanol therapies were begun after the seizures started. Eells et al. (1981) described the case of a 

41-year-old woman who was brought to the emergency room 30 minutes after ingesting 120 mL of 

formalin (624 mg/kg formaldehyde). Laboratory results indicated significant acidosis. Intravenous fluid 

therapy consisting of Ringers solution followed by 5% dextrose, epinephrine, and sodium bicarbonate 

was initiated and the patient was transferred to intensive care; she died 28 hours after admission. 

No reports were found of metabolic effects in animals orally exposed to formaldehyde. 

Other Systemic Effects. Some effects of acute-duration oral exposure to formaldehyde have been 

seen on food and water consumption in animal studies, and may be related to taste aversion at higher 

doses in some cases. For example, Johannsen et al. (1986) reported that Sprague-Dawley rats given 

formaldehyde at 0, 75, 150, or 225 mg/kg/day in drinking water for 2 weeks showed no significant 

changes in food consumption, but mean water consumption decreased proportionately to dose in all three 

treated groups. In contrast, food and water consumption were reduced at levels above 75 mg/kg/day in 

other groups of Sprague-Dawley rats given formaldehyde at 0, 37.5, 75, 150, or 225 mg/kg/day by 

intubation for 2 weeks (Johannsen et al. 1986). 
FORMALDEHYDE 144 

2. HEALTH EFFECTS 

Intermediate-duration exposure data on food and water consumption are also available from animal 

studies. In Sprague-Dawley rats exposed to formaldehyde in drinking water for 90 days, decreases in 

water intakes (>10% of control values) were found in females exposed to 100 or 150 mg/kg/day and in 

males exposed to 50, 100 or 150 mg/kg/day, but in both sexes, food consumption was not significantly 

affected (Johannsen et al. 1986). Four-week exposures to 125 mg/kg/day in drinking water were 

associated with 25–42% decreased water intake and decreased food intake in male and female Wistar rats 

(Til et al. 1988b). Food consumption was significantly decreased in male Beagle dogs during 90 day 

dietary exposure to 100 mg/kg/day; food consumption was significantly decreased in females at 

75 mg/kg/day(Johannsen et al. 1986). 

With chronic drinking water exposure to formaldehyde, statistically significant decreases in food intake 

(ranging from about 7–14% of control values) and water intake (ranging from about 20–50% of control 

values) occurred at various intervals throughout a 2-year period of exposure to 82 mg/kg/day in male 

Wistar rats and to 109 mg/kg/day in female Wistar rats, but not at respective exposure levels #15 and 

21 mg/kg/day (Til et al. 1989). In the other 2-year drinking water study by Tobe et al. (1989), 

significantly decreased food intake (about 10–25% of control values) and water intake (about 40–50% of 

control values) occurred throughout the exposure period in male and female Wistar rats exposed to 

300 mg/kg/day, but not at dose levels of 50 mg/kg/day and lower. In general, the repeated oral exposure 

animal studies indicate that dosage levels associated with decreased food and/or water consumption were 

associated with decreased body weights and with the development of gastrointestinal tract lesions. 

2.2.2.3 Immunological and Lymphoreticular Effects 

Little information is available about immunological and lymphoreticular effects of formaldehyde 

ingestion in humans. Splenomegaly was observed in one woman who ingested formaldehyde in a suicide 

attempt (Koppel et al. 1990). However, this effect was most likely secondary to extensive hemorrhaging 

and necrosis of the gastrointestinal system. 

Til et al. (1988b) saw no effect on spleen or thymus weight in male or female Wistar rats after 4 weeks of 

exposure to 125 mg/kg/day formaldehyde in drinking water. 

No effect of 90-day treatment of male and female Beagle dogs with doses of #100 mg/kg/day 

formaldehyde in the diet was found on spleen weight or histopathology (Johannsen et al. 1986). 
FORMALDEHYDE 145 

2. HEALTH EFFECTS 

Vargova et al. (1993) administered 20, 40, or 90 mg/kg/day formaldehyde 5 days/week for 4 weeks to 

male Wistar rats by gavage. Increased absolute and relative lymph node weights were observed 

beginning at 40 mg/kg/day. Antibody production was assayed by measurement of total blood IgG and 

IgM, a hemagglutination assay, a plaque-forming cell assay, and by measurement of IgM production in 

spleen cells. Only the hemagglutination assay showed a significant effect; the combined IgG and IgM 

titers were significantly lower than controls at 20 mg/kg/day and above, although individual IgM and IgG 

titers were only significantly different from controls at 40 and 80 mg/kg/day. 

Weanling, SPF-bred rats were exposed to 0, 1.2, 15, or 82 mg/kg/day (males) and 0, 1.8, 21, or 

109 mg/kg/day (females) formaldehyde in their drinking water for up to 2 years (Til et al. 1989). There 

was no effect of treatment on spleen weight or histopathology, or the histopathology of the mesenteric 

and axillary lymph nodes. Spleen weight determinations and histopathology, in addition to 

histopathology of the lymph nodes, were negative in the study conducted by Tobe et al. (1989), wherein 

male and female Wistar rats were exposed to 0, 10, 50, or 300 mg/kg/day formaldehyde in drinking water 

for up to 24 months. 

The LOAEL value decreased IgG and IgM titers and increased lymph node weights in rats (Vargova et al. 

1993) and the highest NOAEL values from each reliable study for immunological/lymphoreticular effects 

in each species and duration category are recorded in Table 2-4 and plotted in Figure 2-2. 

2.2.2.4 Neurological Effects 

Little information is available about the neurological effects of formaldehyde ingestion in humans. 

However, neurological effects appear to be prevalent in reported cases of formaldehyde ingestion. A 

woman who ingested formaldehyde in a suicide attempt was found in a coma (Koppel et al. 1990). Other 

neurological effects observed include lethargy, seizure, and loss of consciousness at 517 mg/kg 

formaldehyde (Burkhart et al. 1990). Loss of consciousness was also observed in another woman (Eells 

et al. 1981) after ingesting 624 mg/kg formaldehyde. 

No effect of 90-day treatment of male and female Sprague-Dawley rats with doses of #150 mg/kg/day 

formaldehyde in drinking water was found on brain weight or histopathology (Johannsen et al. 1986). Til 

et al. (1988b) saw no effect on brain weight in male or female Wistar rats after 4 weeks of exposure to 

125 mg/kg/day formaldehyde in drinking water. Tobe et al. (1989) saw no effect on the weight or 
FORMALDEHYDE 146 

2. HEALTH EFFECTS 

histopathology of the brain of male and female Wistar rats exposed to doses of #300 mg/kg/day 

formaldehyde in drinking water for 12 months. No effect of 90-day treatment of male and female Beagle 

dogs with doses of #100 mg/kg/day formaldehyde in the diet was found on brain weight or 

histopathology (Johannsen et al. 1986). 

Weanling Wistar rats were exposed to 0, 1.2, 15, or 82 mg/kg/day (males) and 0, 1.8, 21, or 

109 mg/kg/day (females) in their drinking water for up to 2 years (Til et al. 1989). Relative brain weights 

were statistically significantly increased (by 7–17%) in the high-dose groups of both sexes. However, no 

effect of treatment on brain histopathology or the histopathology of the spinal cord or sciatic nerve was 

observed. Brain weight determinations and histopathology were negative in the study conducted by Tobe 

et al. (1989), wherein male and female Wistar rats were exposed to 0, 10, 50, or 300 mg/kg/day 

formaldehyde in drinking water for up to 24 months. 

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 2-4 and plotted in Figure 2-2. 

2.2.2.5 Reproductive Effects 

No reports were found describing reproductive effects in humans after acute-, intermediate-, or chronicduration oral exposure to formaldehyde. 

Male Wistar rats (5 per group) were weighed and fasted for 18 hours overnight (Cassidy et al. 1983). 

Rats were then administered single dosages of 100 and 200 mg/kg formaldehyde orally. Eleven days 

after dosing, rats were weighed, sacrificed, and necropsied. There were no significant changes in testes 

weights observed in animals treated with 100 or 200 mg/kg formaldehyde. At 200 mg/kg formaldehyde, 

testicular sperm head counts were significantly increased (19%) compared to control values. The 

percentage of abnormal sperm heads also significantly increased (5%) in the 200 mg/kg dose groups 

compared to control groups. The toxicological significance of these changes in sperm head number and 

percentage of abnormal sperm heads is not known since no functional tests of reproductive competence 

were conducted. 

Pregnant CD-1 mice were given formaldehyde at 0, 74, 148, and 185 mg/kg by gavage on gestation days 

6–15 (Marks et al. 1980). The formaldehyde solution given to the animals in this study contained 
FORMALDEHYDE 147 

2. HEALTH EFFECTS 

12–15% methanol as a preservative. These animals received formaldehyde solution at 185 mg/kg, which 

contained 0.6–0.75% methanol, resulting in a concurrent dose of 60–75 mg/kg/day of methanol. On 

gestation day 18, the mice were sacrificed, implantation sites were counted, and general condition of each 

conceptus were recorded. Formaldehyde at 74 or 148 mg/kg/day had no consistent and statistically 

significant effects on indices of reproduction (e.g., the number of resorptions and the number of 

implantation sites per dam), but only 12 of the 34 dams who were exposed to 185 mg/kg/day survived to 

gestation days 18. Marks et al. (1980) noted that the methanol could have contributed to the lethality. 

Among the 12 surviving 185-mg/kg/day dams, only 8 (67%) remained pregnant at gestation day 18; the 

average percent of resorptions per litter was increased in these dams, compared with controls, but not to a 

statistically significant extent. 

Formaldehyde was evaluated in the Chernoff/Kavlock developmental toxicity screen (Seidenberg and 

Becker 1987). Based on range-finding studies, timed-pregnant ICR/SIM mice were administered a single 

minimally toxic dose (not reported) by gavage on gestation days 8–12. Three or four compounds and a 

vehicle (corn oil or distilled water) were tested concurrently. Dams were allowed to deliver. The litters 

were counted and weighed on days 1 and 3. Dead pups were examined for external abnormalities. Dams 

that had not given birth by gestation days 21 or 22 were necropsied, and their uteri were examined for 

possible implantation sites. Formaldehyde was designated as a nonteratogen or non-embryotoxin based 

on results of the developmental toxicity screen. 

No adverse effects of 90-day treatment of male and female Sprague-Dawley rats with doses of 

#150 mg/kg/day formaldehyde in drinking water were found on gonad weight or histopathology 

(Johannsen et al. 1986). Til et al. (1988b) saw no effect on testis weight in male or ovary weight in 

female Wistar rats after 4 weeks of exposure to 125 mg/kg/day formaldehyde in drinking water. Tobe et 

al. (1989) saw no effect on the weight or histopathology of the testis of male and ovary of female Wistar 

rats exposed to doses of #300 mg/kg/day formaldehyde in drinking water for 12 months. Vargova et al. 

(1993) saw no effect on testis or prostate weight of exposure to 80 mg/kg/day formaldehyde by gavage 

5 days/week for 4 weeks in male Wistar rats. No effect of 90-day treatment of male and female Beagle 

dogs with doses of #100 mg/kg/day formaldehyde in the diet was found on gonad weight or 

histopathology (Johannsen et al. 1986). 

Weanling Wistar rats were exposed to 0, 1.2, 15, or 82 mg/kg/day (males) and 0, 1.8, 21, or 

109 mg/kg/day (females) in their drinking water for up to 2 years (Til et al. 1989). There was no effect of 
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treatment on ovary or testis weight or histopathology, or the histopathology of the mammary gland, 

epididymides, prostate, or uterus. Testis and ovary weight determinations and histopathology were 

negative, as was histopathological evaluation of the uterus in the study conducted by Tobe et al. (1989), 

wherein male and female Wistar rats were exposed to 0, 10, 50, or 300 mg/kg/day formaldehyde in 

drinking water for up to 24 months. 

Hurni and Ohder (1973) investigated the effects of oral administration of formaldehyde on reproductive 

function in female beagle dogs during gestation. Formaldehyde was sprayed on the pelleted food at 

dietary levels of 125 and 375 ppm (calculated by authors to be equivalent to 3.1 and 9.4 mg/kg, 

respectively). Although the feed was not assayed for formaldehyde content, the authors reported that 

formaldehyde solutions, prepared weekly from a commercial 40% aqueous solution, were sprayed daily 

on the food just prior to feeding. Ten to 11 mated females were fed the treated feed on gestation 

days 4–56. Exposure to formaldehyde did not affect pregnancy rates, maternal body weights, or litter 

size. 

The serious LOAEL value for rats (Cassidy et al. 1983) and the highest NOAEL value from each reliable 

study for reproductive effects in each species and duration category are recorded in Table 2-4 and plotted 

in Figure 2-2. 

2.2.2.6 Developmental Effects 

No studies were located regarding developmental effects in humans after oral exposure to formaldehyde. 

Pregnant CD-1 mice were given formaldehyde at 0, 74, 148, and 185 mg/kg by gavage on gestation days 

6–15 (Marks et al. 1980). On gestation day 18, mice were sacrificed, implantation sites were counted, 

and general condition of each conceptus was recorded. Live fetuses were weighed individually, sexed 

internally, and examined for external malformations. The viscera of at least one-third of the fetuses of 

each litter, as well as stunted fetuses and those having external malformations, were examined for 

abnormalities. The heads of the fetuses which were subjected to visceral examination were cut off at the 

base and prepared for free-hand sectioning. The formaldehyde solution given to the animals in this study 

contained 12–15% methanol as a preservative. Formaldehyde solution at 185 mg/kg contained 

0.6–0.75% methanol or 60–75 mg/kg/day. No attempt was made to remove the methanol. There were no 

statistically significant effects on fetal weight, ratio of males to females, or incidences of visceral or 
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skeletal fetal malformations in any exposed group, compared with the control group, even though at the 

highest dose group, only 12 of 34 dams survived to gestation day 18. 

Formaldehyde was evaluated in the Chernoff/Kavlock developmental toxicity screen (Seidenberg and 

Becker 1987). Based on range-finding studies, timed-pregnant ICR/SIM mice were administered a single 

minimally toxic dose (not reported) by gavage on gestation days 8–12. Dams were allowed to deliver. 

The litters were counted and weighed on days 1 and 3. Dead pups were examined for external 

abnormalities. Dams that had not given birth by gestation days 21 or 22 were necropsied, and their uteri 

were examined for possible implantation sites. Formaldehyde was designated as a nonteratogen or 

nonembryotoxin based on results of the developmental toxicity screen. Neonatal development was not 

affected by formaldehyde treatment. Formaldehyde had no effect in the number of live neonates per litter 

or on the average neonatal body weight at birth in this investigation. 

No exposure-related effects on pregnancy success, maternal weight gain, gestation length, litter size, pup 

body weight, number of stillborn pups, or numbers of live pups that survived to weaning were found in a 

study in which groups of 9–10 pregnant Beagle dogs were fed diets delivering reported doses of 0, 3.1, or 

9.4 mg/kg/day on gestation days 4–56 (Hurni and Ohder 1973). In the few stillborn pups that were found, 

no internal or skeletal malformations were observed. Formaldehyde solutions were prepared weekly from 

a commercial 40% aqueous solution and sprayed daily on the food just prior to feeding. The study 

identifies 9.4 mg/kg/day as a NOAEL for maternal and fetal developmental effects. 

The highest NOAELs for developmental effects in the Hurni and Ohder (1973) and Marks et al. (1980) 

studies are recorded in Table 2-4 and plotted in Figure 2-2. 

2.2.2.7 Genotoxic Effects 

No reports of genotoxic effects in humans or animals were found after oral exposure to formaldehyde. 

Genotoxicity studies are discussed in Section 2.5. 
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2. HEALTH EFFECTS 

2.2.2.8 Cancer 

No studies were located regarding cancer in humans orally exposed to formaldehyde. 

Takahashi et al. (1986a) administered 0 or 0.5% formalin (about 0.185% formaldehyde=1,850 ppm 

formaldehyde) in drinking water to groups of 10 male Wistar rats for 32 weeks, and evaluated surviving 

animals for neoplasms at 40 weeks. An estimated dose of 258 mg/kg/day was calculated using an average 

reported body weight of 0.280 kg and a water consumption rate of 0.039 L/day calculated with an 

allometric equation based on body weight (EPA 1988e). No carcinoma-bearing animals were reported; 

however, 8 of 10 (80%) rats showed benign papillomas of the forestomach in the exposed group 

compared with none in 40 control rats. No tumors (benign or malignant) were found in the fundus, 

pylorus, or duodenum of the glandular stomach in exposed rats, but erosions and/or ulcers associated with 

regenerating mucosa were found along the limiting ridge of the fundic mucosa in exposed rats. 

Soffritti et al. (1989) administered formaldehyde in drinking water to Sprague-Dawley rats for life 

beginning at various ages. Groups of 50 male and 50 female rats were exposed to 0 (methanol:water 

control), 10, 50, 100, 500, 1000, or 1,500 ppm from 7 weeks of age for life. Another control group 

consisted of 100 male and 100 female rats exposed to plain drinking water. Two groups of 18–20 male 

and 18–20 female breeders were exposed to 0 or 2,500 ppm formaldehyde starting at 25 weeks of age for 

life. Offspring of the breeders, 36–59 males and 37–49 females, received, for life, the same levels of 

formaldehyde as their parents. Estimated average doses were calculated, using reference values for 

Sprague-Dawley rats of 0.431 kg body weight and 0.054 L water consumed/day (EPA 1988e), as follows: 

0, 1, 6, 13, 63, 125, 188, and 313 mg/kg/day. In rats treated from 7 weeks of age, leukemia was reported 

in controls and exposed groups at the following incidences: 8/100 (methanol control), 7/200 (plain 

control), and 3/100, 9/100, 9/100, 12/100, 13/100, and 18/100 for the 10- through 1,500-ppm groups, 

respectively. Leukemia was described as lymphoblastic leukemias and lymphosarcomas, immunoblastic 

lymphosarcomas, or hemolymphoreticular neoplasias. Lymphoblastic leukemia-lymphosarcomas were 

predominant among the leukemias noted. Pair-wise comparisons using the Fisher exact test (performed 

by Syracuse Research Corporation) indicate that only the high-dose incidence was significantly (p<0.05) 

increased compared with the methanol controls, but comparisons to the combined control incidence 

indicated significantly increased incidence at the 500-, 1,000- and 1,500-ppm levels. In the breeders 

exposed from 25 weeks of age, incidences for leukemia were 1/40 for controls and 4/36 for the 
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2. HEALTH EFFECTS 

2,500-ppm group, and 6/108 for control offspring and 4/73 for 2,500-ppm offspring. Pair-wise 

comparisons of these incidences indicate no statistical difference between control and exposed groups. 

Stomach and intestinal tumors were also reported in the Soffritti et al. (1989) study. In rats treated from 

7 weeks of age, a few stomach tumors were found (2/100 at 10 ppm, 1/100 at 1,000 ppm, and 2/100 at 

1,500 ppm, but none in the other groups), but no statistically significant association with exposure was 

found. A few intestinal tumors were also reported (1/100 at 10 ppm, 2/100 at 50 ppm, 1/100 at 

1,000 ppm, and 6/100 at 1,500 ppm), but only the incidence at 1,500 ppm was significantly (p<0.05) 

increased compared with the methanol control using the Fisher Exact test (performed by Syracuse 

Research Corporation). No significant difference was found in incidence of either type of gastrointestinal 

tract tumor in the control and 2,500-ppm exposed breeders, but offspring displayed significantly (p<0.05) 

increased incidence of stomach tumors (5/73 versus 0/108) and intestinal tumors (8/73 versus 0/108). 

The neoplasms included benign tumors (papillomas and acanthomas of the forestomach and adenomas) 

and malignant tumors (including adenocarcinomas and leiomyosarcomas). Leiomyosarcoma was the 

most frequent malignant tumor. The majority of the malignant tumors of the intestine was found in the 

duodenum, jejunum, and ileum. 

Two other chronic-duration rat drinking water studies showed no evidence for formaldehyde-induced 

carcinogenicity. Groups of 70 male and 70 female Wistar rats were exposed for 2 years to formaldehyde 

in drinking water at concentrations that delivered average measured doses of 0, 1.2, 15, or 82 mg/kg/day 

(males) and 0, 1.8, 21, or 109 mg/kg/day (females) (Til et al. 1989). Average drinking water 

concentrations were reported to be 0, 20, 260, and 1,900 ppm (mg/L). In high-dose animals, 

histopathological examination revealed gastric changes (including papillary epithelial hyperplasia 

accompanied by hyperkeratosis and focal ulceration in the forestomach and focal chronic atrophic 

gastritis), but no increased incidences of nonneoplastic lesions were found in groups exposed to lower 

concentrations compared with controls. No statistically significant increased incidences of tumors, 

benign or malignant, were found in exposed groups compared with controls. Til et al. (1989) concluded 

that exposure to 82–109 mg/kg/day formaldehyde in drinking water produced severe damage to the 

gastric mucosa, but no tumors. In the other experiment, groups of Wistar rats (20 males, 20 females) 

were exposed to formaldehyde in their drinking water at concentrations of 0, 200, 1,000 or 5,000 ppm for 

24 months (Tobe et al. 1989). Estimated average doses of 0, 10, 50, and 300 mg/kg/day were reported by 

the authors. All animals in the 5,000-ppm group died before 24 months and showed degenerative lesions 

in the forestomach (erosions and/or ulcers and hyperplasia of the squamous epithelium with or without 
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hyperkeratosis) and glandular stomach (erosions and/or ulcers accompanied by submucosal inflammatory 

cell infiltrates). In animals exposed to 50 mg/kg/day formaldehyde, forestomach hyperkeratosis was 

observed in 1 of 6 males and in 1 of 8 females. There were no lesions of the forestomach or glandular 

stomach in the 10-mg/kg/day groups. There were no significant differences in the incidences of any 

tumors in any exposed group compared with controls. 

The evidence for the carcinogenicity of formaldehyde in rats exposed to formaldehyde-containing 

drinking water is not strong due to inconsistency of findings across studies and inconsistent evidence of a 

dose-response relationship for either leukemia or gastrointestinal tumors in the Soffritti et al. (1989) 

study. 

Among the four studies that assessed the potential carcinogenicity of formaldehyde in drinking water 

(Soffritti et al. 1989; Takahashi et al. 1986a; Til et al. 1989; Tobe et al. 1989), only Soffritti et al. (1989) 

reported increased incidence of leukemia in exposed rats. Feron et al. (1990) have questioned whether the 

increased leukemias may have been “chance effects unrelated to formaldehyde ingestion”, due to reported 

wide variation in leukemia incidences in groups of untreated Sprague-Dawley rats of the same colony, 

citing reports of leukemia incidences in controls as high as 19% (the highest incidence in Soffriti et al. 

exposed groups was 18/100). Another limitation to the strength of the evidence for formaldehydeinduced leukemia is the lack of a consistent dose-response relationship in the Soffritti et al. study. 

Although IARC (1995) has noted that a statistically significant trend for increasing leukemia incidence 

with increasing exposure concentration can be demonstrated in the Soffritti et al. data for rats exposed 

from 7 weeks of age to dose levels ranging from 1 to 188 mg/kg/day; the second part of the Soffriti et al. 

(1989) study found no statistically increased incidence of leukemia in groups of breeding pairs of rats or 

their offspring exposed for life to the higher dose level of 313 mg/kg/day. A further limitation is the 

absence of corroborating evidence for effects at sites distant from portals-of-entry in the other drinkingwater rat studies, and in inhalation-exposure animal studies. 

Findings for formaldehyde-induced gastrointestinal tract tumors are not consistent across the available 

drinking-water rat studies. Significantly increased incidences of intestinal tumors were found only in rats 

exposed to 188 mg/kg/day from 7 weeks of age and in offspring of breeding pairs of rats exposed to 

313 mg/kg/day, but were not found in groups exposed to lower concentrations or to the breeding pairs 

exposed to 313 mg/kg/day (Soffritti et al. 1989). Stomach tumors were found at increased incidence only 

in the 313-mg/kg/day offspring of the breeding pairs in the Soffriti et al. (1989) study and in 8/10 rats 
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2. HEALTH EFFECTS 

exposed to 258 mg/kg/day in the Takahashi et al. (1986a) study. Takahashi et al. (1986a) reported only 

benign forestomach papillomas, whereas Soffritti et al. (1989) reported papillomas, adenocarcinomas, and 

leiomyosarcomas. In contrast, Til et al. (1989) found no increased incidence of gastrointestinal tract 

tumors in rats exposed to average dose levels up to 82 or 109 mg/kg/day for life, and Tobe et al. (1989) 

likewise found no increase in gastrointestinal tumors in rats exposed to up to 300 mg/kg/day for life. Til 

et al. (1989) noted that the difference between their finding of forestomach papillary epithelial 

hyperplasia and the finding Takehashi et al. (1986a) of forestomach papillomas might be ascribed to the 

use of different lesion-classification criteria. Although there are inconsistencies among the available 

studies with respect to formaldehyde-induced gastrointestinal tract tumors from oral exposure, the studies 

consistently show that exposure to drinking water dose levels >50 mg/kg/day can damage epithelial tissue 

of the gastrointestinal tract, especially at dose levels >100-200 mg/kg/day. The possibility of tumor 

occurrence as a portal-of-entry effect from high-level exposure appears biologically plausible given the 

reactive nature of formaldehyde, its cytotoxicity at high levels that exceed protective mechanisms, and the 

findings for upper respiratory tract tumors in rats exposed to high, but not low, levels of airborne 

formaldehyde. 

Given the equivocal nature of the evidence for carcinogenicity from existing studies of rats exposed to 

formaldehyde in drinking water, no CEL values are recorded in Table 2-4 or plotted in Figure 2-2. 

2.2.3 Dermal Exposure 

2.2.3.1 Death 

Studies regarding death in humans after dermal exposure to formaldehyde were not located. Repeated 

dermal exposure of mice to solutions containing up to 10% formaldehyde produced no increased 

mortality. Iversen (1988) applied 4% formaldehyde to the shaved skin of Sencar mice twice weekly for 

58 weeks. No increase in mortality was observed. Similarly, applications of 1 or 10% formaldehyde to 

the backs of hr/hr Oslo mice for 2 days/week for 60 weeks did not affect mortality (Iversen 1986). 
 

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2. HEALTH EFFECTS 

2.2.3.2 Systemic Effects 

No studies were located regarding cardiovascular, gastrointestinal, hematological, musculoskeletal, 

hepatic, or renal health effects in humans or animals after dermal exposure to formaldehyde. 

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 2-5. 

Respiratory Effects. No reports were located regarding respiratory effects in humans after 

predominantly dermal exposure to formaldehyde or in animals after acute or intermediate-duration dermal 

exposure to formaldehyde. 

Iversen (1988) tested the carcinogenic potential of formaldehyde via classical skin-painting experiments. 

Formalin (37% formaldehyde volume for volume) was dissolved in distilled water and used at final 

concentrations of 1 and 10% formaldehyde. Hairless mice (hr/hr Oslo strain, in which spontaneous 

tumors have not been noted) were used. One group consisting of 16 males and 16 females was dosed 

with 200 μL of 1% formaldehyde in water on the skin of the back twice per week (Tuesdays and Fridays) 

for a total of 60 weeks. A second group of identical composition received a 10% formaldehyde solution 

in an identical manner for 60 weeks. Small, nonspecific granulomas were found in the lungs of 

two animals from the 10% group. No exposure-related lesions were found in the nasal mucosa. 




 

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2. HEALTH EFFECTS 

Dermal Effects. As discussed earlier in Section 2.2.1, occupational exposures to formaldehyde have 

been associated with dermal irritation and the diagnosis of allergic contact dermatitis by patch tests. 

Reported historical percentages of subjects with skin problems showing positive allergic responses to 

formaldehyde in patch tests performed by dermatologists using aqueous solutions with 1 or 2% 

formaldehyde include 7.8% in North America between 1992 and 1994 (Marks et al. 1995), 1.6% in a 

1983–1984 Swedish study (Meding and Swanbeck 1990), 2.6% in a 1988–1989 European study (Menné 

et al. 1991), and 3.7% in a 1990–1994 Polish study (Kiec-Swierczynska 1996). Fischer et al. (1995) 

generally concluded that, in more than 30 years of experience with patch test reporting, about 1–4% of 

tested subjects are sensitive to formaldehyde. With standard patch testing protocols, formaldehyde 

concentrations of 2% and higher may produce skin irritation in nonsensitized individuals demonstrating 

that concentrations that evoke a skin irritation response can be similar to those evoking allergic skin 

responses (Fischer et al. 1995; Maibach 1983). Because of the reactive and irritating properties of 

formaldehyde, early use of formaldehyde concentrations as high as 5% in patch tests, and inexperience on 

the part of test administrators, Maibach (1983) speculated that many cases of irritant responses have been 

incorrectly interpreted as allergic responses. Lack of specific exposure information for many cases 

precludes determining the degree to which reported cases of dermal sensitization may have been caused 

by direct dermal contact to formaldehyde in liquids or by contact with formaldehyde gas in air, but the 

widespread use of formaldehyde or formaldehyde-releasing chemicals in cosmetics and cleaning agents 

(Flyvholm 1991; Rastogi 1992) suggest that the dermal route of exposure may be the more important 

sensitizing route. Studies showing that allergic skin responses in sensitized subjects exposed to 

formaldehyde in aqueous solutions are rare at concentrations below 0.025–0.05% are discussed in 

Section 2.2.3.3. 

A study by Nethercott and Holness (1988) examined the prevalence of cutaneous disease in selected 

funeral service workers in Toronto, Canada. Eighty-four workers from funeral homes in the Toronto area 

were evaluated via a questionnaire which focused on past and family medical histories, present 

symptoms, and work practices. Physical examination of the participants’ skin was performed, and all 

participants underwent skin-patch testing for formaldehyde and glutaraldehyde sensitivity. Embalmers 

were divided into high- and low-exposure groups for comparative analysis. Cutaneous examinations 

revealed a greater incidence of contact dermatitis among exposed workers (11%) compared to controls 

(0%), and the prevalence of positive skin-patch tests for formaldehyde was greater among exposed 

workers (3%) than among controls (0%). Among exposed workers, there were no differences between 
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2. HEALTH EFFECTS 

the high- and low-exposure groups with regard to prevalence of contact dermatitis or positive skin-patch 

results. 

Cases of contact dermatitis caused by formaldehyde released from “no-iron” textiles were described 

frequently in the literature from the late 1950s until the mid-1970s; after this period, the finishing 

processes for these types of textiles were changed so that only small amounts of formaldehyde are 

released after finishing (see Peters and Heese 1997 for review). In most cases of clothing-induced contact 

dermatitis, the dermatitis developed specifically in areas of very close contact between the skin and the 

clothing (e.g., the underarms, the elbows, the insides of the thighs). 

Formaldehyde has also been shown to cause dermal allergic reactions in nurses and doctors (Rudzki et al. 

1989). One hundred-sixty-seven doctors, 92 dentists, and 333 nurses were patch-tested with a standard 

panel of allergens plus allergens common to their work environment. Among nurses, formaldehyde was 

the disinfectant that most frequently caused allergic reactions (9.6%). Three doctors also had positive 

skin tests for formaldehyde. 

Albino guinea pigs (Hartley strain) were treated with 0.1 mL of various dilutions of formalin (1, 3, and 

10% formalin; –0.4, 1.2, and 4% formaldehyde) to demarcated test sites, and the formalin solution was 

gently rubbed into the skin with a cotton-tipped applicator (Wahlberg 1993). An unexposed control site 

and a vehicle control were used in each series. The sites were left unoccluded and the treatments were 

repeated once daily immediately after skin-fold measurements. Each site was examined prior to skin-fold 

measurements for the presence of erythema, edema, fissuring, and scaling. From a mean of 10 sites, 

erythema appeared on day 2 (4%), day 5 (1.2%), and day 6 (0.4%). Increased skin-fold thickness was 

statistically significant on day 3 (4%), day 7 (1.2%), and day 9 (.04%) after daily treatment with various 

concentrations of formaldehyde. 

Iversen (1988) tested the carcinogenic potential of formaldehyde via classical skin-painting experiments. 

Formalin (37% formaldehyde volume for volume) was dissolved in distilled water and used at final 

concentrations of 1 and 10% formaldehyde. Hairless mice (hr/hr Oslo strain, in which spontaneous 

tumors have not been noted) were used. Two groups consisting of 16 males and 16 females were dosed 

with 0.2 mL of 1 or 10% formaldehyde in water on the skin of the back twice per week (Tuesdays and 

Fridays) for a total of 60 weeks. Animals dosed with 10% formaldehyde, but not with 1% solutions, 
 

 

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2. HEALTH EFFECTS 

generally had slight epidermal hyperplasia, and a few mice had cutaneous ulcers. These studies indicate 

that formaldehyde applied dermally is irritating to the skin (hyperplasia and ulcers) and can also induce 

an inflammatory response. 

Ocular Effects. As discussed in Section 2.2.1.2 (in the Respiratory Effects and Ocular Effects 

sections), health surveys of occupationally-exposed workers and acute controlled exposure studies with 

volunteers have demonstrated that exposure to formaldehyde air concentrations in the range of 

0.4–3.0 ppm and above can cause eye irritation. 

To examine the dependence of ocular response to formaldehyde irritation on the trigeminal sensory nerve, 

Krootila et al. (1986) topically applied a 1% solution of formaldehyde in an aqueous phosphate buffer 

(pH 7.4) to the right eye of a group of unoperated male Sprague-Dawley rats and two groups of 

denervated rats. Rats were anesthetized with pentobarbital for the experiments and operations. Sensory 

denervation of the right eye was accomplished in one group by coagulation of the intracranial, opthalmic 

branch of the right trigeminal nerve, and, in the other group, unilateral sympathetic denervation was 

accomplished by removing the right superior cervical ganglion. Application of 1% formaldehyde to the 

eye of unoperated rats caused a breakdown of the blood-aqueous barrier of the eye indicated by increased 

protein concentration in the aqueous humor or increased leakage of Evans blue dye from the iris vessels. 

This response was also observed in rats without the right superior cervical ganglion, but was absent in rats 

with a coagulated right trigeminal nerve. The authors concluded that the irritative response of the eye to 

formaldehyde is dependent on the trigeminal sensory nerve, but not the superior cervical ganglion. 

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

dermal exposure to formaldehyde. 

Exposure-related effects on body weight were not found in pregnant hamsters dermally exposed during 

gestation to 0.5 mL solutions of 37% formaldehyde (Overman 1985) or in guinea pigs dermally exposed 

for 9 days to 4% formaldehyde solutions (Wahlberg 1993). In the Overman (1985) experiment, the 

control and exposed pregnant hamsters were anesthetized during treatment to prevent grooming; exposure 

was for 2 hours on gestation day 8, 9, 10, or 11. 
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2.2.3.3 Immunological and Lymphoreticular Effects 

As discussed earlier in Section 2.2.1.2, 2.2.1.3, and 2.2.3.2, formaldehyde is a commonly diagnosed 

contact allergen, accounting for about 1–4% of cases presented at dermatology clinics (Fischer et al. 

1995; Kiec-Swierczynska 1996; Maibach 1983; Marks et al. 1995; Meding and Swanbeck 1990; Menné 

et al. 1991). Studies of concentration-response relationships for skin allergic reactions induced by 

occluded dermal exposures to formaldehyde in formaldehyde-sensitive subjects suggest that a dermal 

allergic response to formaldehyde concentrations below about 0.025–0.05% is rare. In a serial dilution 

test, the lowest concentration tested, 0.1%, produced allergic reactions in 8/35 formaldehyde-sensitive 

subjects (DeGroot et al. 1988). Another serial dilution test, examining concentrations of 1, 0.5, 0.25, 

0.13, 0.063, 0.032, and 0.015% in 25 formaldehyde-sensitive subjects, found decreasing frequency of 

response with decreasing exposure concentration; positive reactions were found in 3/25 at 0.063%, 

1/25 at 0.032%, and 1/25 at 0.015% (Fischer et al. 1995). Flyvholm et al. (1997) reported that, in an 

occluded patch test study of 20 sensitized subjects and 20 healthy volunteers, no skin irritation occurred 

in the controls exposed to 1% formaldehyde. In sensitized subjects, the frequency of response decreased 

with decreasing formaldehyde concentrations as follows: 9/20 at 0.5%, 3/20 at 0.1%, 2/20 at 0.05%, and 

1/20 at 0.025%. 

A report by Maurice et al. (1986) describes the case study of 20-year-old woman who experienced 

anaphylactic shock after exposure to a dialyzer sterilized with formaldehyde. The woman, who required 

long-term hemodialysis due to renal failure, had previously experienced mild episodes of localized, 

delayed-type hypersensitivity contact dermatitis from adhesives sterilized with formaldehyde. After 

experiencing the episode of anaphylaxis, the patient was tested for formaldehyde sensitivity by a skinprick test using 0.1 and 1% formaldehyde solutions, and a skin-patch test using a 1% solution. The 

patient developed a strong positive response to skin pricks using both 0.1 and 1% formaldehyde solutions. 

Twenty-six hours after skin application of formaldehyde, the patient developed anaphylactic symptoms 

characterized by laryngeal edema and bronchospasm. The patient was treated with subcutaneous 

epinephrine and all symptoms other than angioedema resolved rapidly. 

Potter and Wederbrand (1995) examined the IgE response to dermal exposure to formaldehyde in female 

BALB/c mice. Ten mice per dose received 0.42–6.8 mg formaldehyde in 50 μL water:acetone (50:50), 

administered topically to the shaved flank. Seven days later, the animals received 25 μL of a halfstrength solution, applied to the dorsal surface of each ear. Serum samples were collected 14 days after 
FORMALDEHYDE 163 

2. HEALTH EFFECTS 

the initial treatment. Dermal exposure to 0.42–6.8 mg formaldehyde in acetone:water did not induce IgE 

production. 

Hilton et al. (1996) assessed the sensitizing properties of topical applications of formaldehyde in guinea 

pigs using standard tests (guinea pig maximization test and Buehler test) and in mice using a test for IgE 

production after dermal exposure, a local lymph node assay, and an assay for cytokine secretion by 

draining lymph node cells. In the guinea pig maximization test, pretreatment with a series of intradermal 

injections of 0.25% formaldehyde solutions and occluded patch exposure to 10% formaldehyde produced 

sensitization to 48-hour occluded patch dermal exposures to 2% formaldehyde solutions in 100% of 

treated animals. In the Buehler test, a series of 6-hour occluded patch dermal exposures to 

5% formaldehyde solutions produced sensitization to subsequent exposures to 1% formaldehyde in 70% 

of treated animals. In mice treated with topical applications of solutions containing up to 50% formalin 

(approximately 18.5% formaldehyde), no increase in serum IgE concentrations occurred, whereas in mice 

similarly treated with solutions containing 25% trimellitic anhydride, a well-documented respiratory 

sensitizing agent, serum concentrations of IgE were markedly increased. Application of 10, 25, or 50% 

formalin solutions (3.7, 9.25, and 18.5% formaldehyde) to the dorsum of ears of mice stimulated cellular 

proliferation in lymph node cells cultured from draining auricular lymph nodes excised from the mice. 

Profiles of cytokines produced by draining lymph node cells from mice topically treated with 10, 25, or 

50% formalin solutions were different from those produced by a solution of 10% trimellitic anhydride; 

formalin solutions stimulated production of IFN-γ, whereas trimellitic anhydride stimulated production of 

IL-10. The investigators concluded that these data are consistent with studies of occupationally-exposed 

workers suggesting that formaldehyde is a contact dermal allergen, but an equivocal agent for respiratory 

sensitization. 

The highest NOAEL values and all LOAEL values from each reliable study for immunological/ 

lymphoreticular effects in each species and duration category are recorded in Table 2-5. 

2.2.3.4 Neurological Effects 

No studies were located regarding neurological effects in humans or animals following dermal exposure 

to formaldehyde. 
FORMALDEHYDE 164 

2. HEALTH EFFECTS 

2.2.3.5 Reproductive Effects 

No reports of reproductive effects in humans after dermal exposure were found. 

Overman (1985) conducted a study designed to evaluate the embryotoxic effects of topical exposure to 

formaldehyde in pregnant hamsters. Virgin female hamsters (Lak LVG[SYR] Golden Syrian) were bred 

and then treated directly on the skin with 0.5 mL formaldehyde solution (37%) on gestation days 8, 9, 10, 

or 11 for 2 hours. The animals (including controls) were anesthetized during treatment to prevent 

grooming. After the 2-hour treatment period, the skin of the animals was washed thoroughly with water 

to remove any remaining formaldehyde. Fetuses were recovered by laparotomy at gestation day 15, fixed 

in Bouin's fixative or in 95% ethyl alcohol. Fixed fetuses were blotted dry, weighed, measured (crownrump length), and examined for malformations by free-hand sectioning technique. Fetuses fixed in ethyl 

alcohol were cleared and stained for skeletal tissue observation. Exposure did not significantly affect 

maternal weight gain, but a statistically significant increased incidence of resorptions in treated litters was 

observed (3–8% of sites resorbed versus none in controls). Overman (1985) suggested that this effect 

may have been caused by the stress of treatment during pregnancy rather than to a direct effect of 

formaldehyde, noting that exposed animals scratched at treated areas and were “irritable and hard to 

handle” for 1 to 2 days after treatment. 

The LOAEL value of 0.5 mL of a 37% solution for increased resorptions is recorded in Table 2-5. 

2.2.3.6 Developmental Effects 

No reports of developmental effects in humans after dermal exposure to formaldehyde were found. 

In the hamster study by Overman (1985) described in the previous section, formaldehyde treatment did 

not significantly change fetal crown rump length or fetal body weights. After treatment on day 8, 

two fetuses from the same litter were significantly smaller than their littermates (>3 sd below mean). 

After treatment on day 10, one fetus of normal size had a subcutaneous hemorrhage in the dorsal cervical 

region. There were no skeletal malformations found, and no other malformations were observed during 

the course of the study. 

The NOAEL value of 0.5 mL of 37% solution for no developmental effects is recorded in Table 2-5. 
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2.2.3.7 Genotoxic Effects 

No studies were located regarding genotoxic effects in humans or animals after dermal exposure to 

formaldehyde. Other genotoxicity studies are discussed in Section 2.5. 

2.2.3.8 Cancer 

Studies on cancer incidence in humans exposed occupationally to formaldehyde are discussed in 

Section 2.2.1.8. 

In one laboratory animal study reported by Iversen (1986), the carcinogenic potential of formaldehyde 

using classical skin painting experiments was determined. Formalin (37% formaldehyde volume/volume) 

was dissolved in distilled water at final concentrations of 1 and 10% formaldehyde. Groups of hairless 

mice (hr/hr Oslo strain) consisting of 16 males and 16 females were dosed with 0.2 mL of 1% 

formaldehyde in water on the skin of the back twice per week for a total of 60 weeks. A second group of 

identical composition was dosed with a 10% formaldehyde solution in like manner for 60 weeks. A third 

group of mice was initially painted with 51.2 μg dimethylbenz(a)anthracene (DMBA) in 0.1 mL acetone 

and 9 days later, received a twice weekly treatment regimen of paintings with 10% formaldehyde in 

water. Animals dosed with 10% formaldehyde generally had slight epidermal hyperplasia, and a few 

animals had cutaneous ulcers and scratches. In animals dosed with DMBA followed by formaldehyde, 

3 animals developed lung adenomas, while 11 animals developed a total of 25 skin tumors (3 squamous 

cell carcinomas and 22 papillomas). There was no evidence of any other tumor type. Skin painting with 

either 1 or 10% formaldehyde alone had no significant carcinogenic potential; however, dermal exposure 

to 10% formaldehyde after DMBA dosing significantly reduced the latency period of DMBA-induced 

tumors. 

No statistically significant increased incidence of formaldehyde-induced skin tumors was found in a 

second study with SENCAR mice, a strain of mouse bred for maximal sensitivity to chemically induced 

tumors (Iverson 1988). Groups of 16 male and 16 female mice were dosed with 0.1 mL acetone or 

0.2 mL 4% formaldehyde (in water) twice weekly for 58 weeks. Two animals with small benign skin 

papillomas were found in the exposed group and also in the acetone-control group. In this study, twice 

weekly dermal application of 0.2 mL 4% formaldehyde following application of a single 51.2 μg dose of 

DMBA did not significantly affect the skin tumor yield compared with DMBA alone, but, like in the 
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study with hr/hr Oslo mice, decreased the latency period for the appearance of DMBA-induced skin 

tumors. The report of this study did not mention if non-neoplastic skin lesions were produced by 

exposure with 4% formaldehyde solutions. 

2.3 TOXICOKINETICS 

The toxicokinetics of formaldehyde after inhalation, oral, or dermal exposure has been reported in several 

species by many investigators. The toxicokinetics in all of the animals studied is similar across species 

lines. Formaldehyde is an essential metabolic intermediate in all cells. It is produced during the normal 

metabolism of serine, glycine, methionine, and choline and also by the demethylation of N-, S-, and 

O-methyl compounds. After oxidation of formaldehyde to formate, the carbon atom is further oxidized to 

carbon dioxide (CO2) or incorporated into purines, thymidine, and amino acids via tetrahydrofolatedependent one-carbon biosynthetic pathways. Exogenous formaldehyde appears to be readily absorbed 

from the respiratory and gastrointestinal tracts, but poorly absorbed following dermal application. 

Formaldehyde is metabolized to formate by the enzyme formaldehyde dehydrogenase; this appears to 

take place at the initial site of contact. Being normal components of intermediary metabolism, neither 

formaldehyde nor formate are stored to any significant extent in any tissue of the body. Formate is either 

excreted in the urine (primarily as formic acid), incorporated into other cellular molecules, or oxidized to 

carbon dioxide and exhaled. 

In the metabolic labeling studies using 14C-formaldehyde discussed below, it should be noted that the 

detection of the 14C radiolabel does not imply that it is still in the form of unmetabolized formaldehyde. 

2.3.1 Absorption 

Formaldehyde vapors are readily absorbed from the respiratory tract. Due to rapid metabolism to 

formate, little, if any, intact formaldehyde can be found in the blood of humans or animals exposed to 

formaldehyde. Formaldehyde is also readily absorbed from the gastrointestinal tract and meets with the 

same metabolic fate as formaldehyde after inhalation exposure. The studies available in the open 

literature suggest that very little formaldehyde is absorbed via the dermal route. In all cases, absorption 

appears to be limited to cell layers immediately adjacent to the point of contact. Entry of formaldehyde 

into the blood (i.e., systemic absorption) occurs to a very limited extent, if at all. 
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2.3.1.1 Inhalation Exposure 

Formaldehyde is absorbed by the tissues of the respiratory tract during inhalation exposure in several 

species. Heck et al. (1985) determined the fate of inhaled formaldehyde in humans. Four men and 

two women were exposed to a 1.9 ppm air concentration of formaldehyde in a large walkin chamber for 

40 minutes. Shortly before and shortly after the exposure, venous blood samples were taken from each 

person (each person served as his/her own control) and the blood was analyzed for formaldehyde content. 

Mean venous blood formaldehyde concentrations in humans prior to exposure showed a blood 

concentration of 2.61±0.41 μg/g of blood. Individual variability was markedly present. Immediately 

after a 40-minute exposure, mean blood concentration of formaldehyde was 2.77±0.28 μg/g of blood. 

There was no significant difference between pre- and postexposure blood concentrations of formaldehyde 

at the formaldehyde air concentrations tested in this study. This result suggests that formaldehyde was 

absorbed only into the tissues of the respiratory tract. The absence of increased formaldehyde 

concentrations in the blood is likely due to its rapid metabolism in these tissues and/or fast reaction with 

cellular macromolecules. 

Heck et al. (1985) also determined the fate of inhaled formaldehyde in the rat. Male Fischer 344 rats 

were placed in a nose-only inhalation chamber and exposed to a 14.4±2.4 ppm air concentration of 

formaldehyde for 2 hours, were sacrificed, and a venous blood sample was collected and analyzed for 

formaldehyde content. Unexposed control rats had a mean formaldehyde blood level of 2.24±0.07 μg/g 

of blood. Rats exposed to the 14.4 ppm air concentration of formaldehyde had blood concentrations of 

2.25±0.07 μg/g. These results indicate that during a nose-only inhalation exposure of rats to this 

concentration of formaldehyde, no significant quantities of formaldehyde could be detected in the blood. 

Lack of increase in blood formaldehyde levels indicates that only local absorption took place and 

absorbed formaldehyde was metabolized before reaching the bloodstream. In a similar study by Heck et 

al. (1983), Fischer 344 rats were exposed by inhalation to 14C-formaldehyde at 8 ppm for 6 hours. 

Concentrations of total 14C radioactivity (most likely as 14C-formate) in the whole blood and plasma were 

monitored for an additional 8 days. Plasma concentrations of 14C increased over the exposure period, 

reaching a maximum at the termination of exposure. Plasma 14C concentrations then declined slowly over 

the next few days. 

Using dogs as a model, Egle(1972) determined the respiratory fate of formaldehyde and other aldehydes. 

This study measured the retention of formaldehyde along the entire respiratory tract, both upper and 
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lower portions, and measured the effects of ventilation rate, tidal volume, and concentration of inhaled 

formaldehyde. Mongrel dogs of both sexes (at least 4 dogs per experiment) were anesthetized and 

exposed to 0.15–0.35 μg (122–235 ppm) of formaldehyde vapor produced from formalin. The retention 

of formaldehyde was measured over the entire respiratory tract, including the upper region only (nose and 

trachea, down to the bifurcation of the trachea), lower region only (from the bifurcation of the trachea, 

bronchioles, and below), and over the entire respiratory tract. Retention of formaldehyde (amount of 

formaldehyde not returning after an exhalation) when the entire upper and lower respiratory tract was 

exposed to formaldehyde vapors was near 100% and seemed to be independent of the airborne 

concentration of formaldehyde or variations in the tidal volume. When the upper respiratory tract was 

isolated from the lungs, the 2-way exposures showed a 100% uptake of formaldehyde. The 1-way 

exposures of formaldehyde showed that the retention of formaldehyde was slightly lower than in the 

2-way exposure, but the uptake of formaldehyde still exceeded 95% at all respiratory rates. When the 

lower respiratory tract was isolated and examined, the uptake of formaldehyde still exceeded 95%; 

however, it appeared to decrease slightly as the ventilation rates increased. This study concluded that 

when formaldehyde is inhaled at the concentrations studied, very little formaldehyde vapor would 

actually reach the lower respiratory tract. 

In another study by Casanova et al. (1988), blood levels of formaldehyde were determined in Rhesus 

monkeys after exposure to 6 ppm formaldehyde for 6 hours/day, 5 days/week for 4 weeks. Immediately 

after the last exposure, the monkeys were sedated and blood samples were collected within 7 minutes and 

at 45 hours after exposure. Blood samples were analyzed for formaldehyde content by gas 

chromatography/mass spectrometry (GC/MS). Mean blood concentrations at 7 minutes and 45 hours 

postexposure were 1.84 and 2.04 μg/g, respectively. Blood concentrations of formaldehyde in the 

three nonexposed monkeys (2.42 μg/g) were not significantly different from those of the exposed group. 

The authors concluded that exposure to moderately high levels of formaldehyde had no effect on blood 

concentrations due to rapid local metabolism. 

2.3.1.2 Oral Exposure 

Formaldehyde is absorbed from the gastrointestinal system after ingestion. Eells et al. (1981) described 

the case of a 41-year-old woman who swallowed 120 mL (624 mg/kg) of a formaldehyde solution (as 

formalin). Formic acid accumulated in the blood rapidly after formaldehyde ingestion. Burkhart et al. 

(1990) describe the case of a 58-year-old man who swallowed 4 ounces of a formaldehyde solution 
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containing methanol in a suicide attempt. Blood methanol levels continued to climb throughout 12 hours 

of observation. The apparent half-life for formaldehyde was 3.3 hours. 

In a study by Galli et al. (1983), the absorption, fate, and excretion of the complexes between 

14C-formaldehyde and milk proteins in mice and rats, and their toxicological significance were examined. 

Male Sprague-Dawley rats were given a single oral dose of 2.2 g (18 μCi) 14C-labeled grana cheese. 

Groups of rats were sacrificed 4, 8, 16, 32, and 64 hours after the end of food consumption. Blood, liver, 

gastrointestinal tract, kidneys, spleen, testes, brain, muscle, and adipose tissues were removed, and urine 

and feces were collected from metabolic chambers. In all cases, the biological samples were immediately 

frozen after removal until used for radioactivity measurement. Within 32 hours of administration, 67% of 

the radioactivity had been excreted in the feces and urine and 28% of the radioactivity had been exhaled 

as 14CO2 in rats, indicating absorption from the ingested cheese. In the companion study, male Swiss 

albino mice (CD-1) were given a single oral dose of 0.5 g (4 μCi) 14C-labeled grana cheese. The cheese 

was made by following the usual process but using milk with added 14C-formaldehyde. Rats fed with 

unlabeled cheese were used as controls. Groups of mice were sacrificed after 2, 4, 8, 16, 32, 64, and 

96 hours and 8 and 12 days. Within 32 hours of administration, 64% of the radioactivity had been 

excreted in the feces and urine and 24% of the radioactivity had been exhaled as 14CO2, indicating 

absorption from the ingested cheese. 

A study by Barry and Tome (1991) sought to quantitate the concentration of formaldehyde in the milk of 

goats given feed containing varying amounts of formaldehyde-treated soybean oil-meal. The goat ration 

consisted of 750 g medium quality grass hay, 600 g maize-based concentrate, and 600 g soybean oilmeal; the soybean oil-meal was either treated with formaldehyde, untreated, or a 50:50 mixture. Five 

lactating adult Alpine goats each received 1 of 3 diets (no formaldehyde; 28 mg/kg formaldehyde; a 

50:50 mixture of the 2 rations, equal to 14 mg/kg formaldehyde) for 1 week. Milk samples from the last 

5 days of each dosing period were collected and analyzed for formaldehyde content by high performance 

liquid chromatography. Mean milk formaldehyde concentrations were 0.033, 0.083, and 0.153 mg/kg in 

the 0, 14, and 28 mg/kg/day groups, respectively. These values were significantly different from each 

other (p<0.05), and were highly correlated with formaldehyde intake (r=0.938, p<0.01), and indicate 

absorption from the gastrointestinal tract. 

Buckley et al. (1988) measured formaldehyde levels in the milk and blood of dairy cows given formalintreated whey. Twelve Holstein cows in their first trimester of lactation were used in a series of three 
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feeding trials lasting 35 days and separated from each other by 14 days. Six of the cows received a diet 

consisting of low-energy pelleted concentrate, liquid acid whey, and grass hay. The whey was fed once a 

day beginning at 10:00 am, and all whey was consumed by 4:30 pm. In the three trials, the calculated 

amounts of ingested formalin were 19.9, 39.7, and 59.4 mg/kg/day, respectively. The remaining six cows 

received untreated whey throughout the three trials. Morning milk was sampled on days 3, 2, 3, 4, 5, 6, 

13, 20, 27, and 34 of each 35-day trial. Blood samples were collected on the day before initiation of the 

third trial, and on days 9 and 33. Formaldehyde levels were below detectable limits prior to and at 

46 hours after the completion of each trial. The levels of formaldehyde in milk were positively correlated 

to dose (p<0.01, no other details given). In a companion study (Buckley et al. 1988), formaldehyde levels 

were measured in the muscle tissues of dairy calves fed formalin-treated whey. Eighteen Holstein bull 

calves were fed diets containing whey treated with formalin at doses of 0, 0.05, or 0.1% (n=6 per 

treatment group). Calves were individually fed the formalin-treated whey in two equal feedings daily. 

Two calves from each treatment group were sacrificed at days 81, 88, and 95. Blood samples were 

collected on the day before sacrifice. At sacrifice, sections of muscle, kidney, liver, and heart were 

obtained for formaldehyde determinations. Concentrations of formaldehyde in fresh muscle samples of 

the high-dose group (0.256 μg/g) were significantly greater than those of controls (0.178 μg/g) (p<0.05). 

Concentrations of formaldehyde in fresh blood and frozen heart, kidney, liver, and muscle samples of 

treated animals were similar across treatment groups. 

2.3.1.3 Dermal Exposure 

Jeffcoat et al. (1983) studied the absorption and disposition of 14C-formaldehyde administered topically to 

Fischer 344 rats, Dunkin-Hartley guinea pigs, and Cynomolgus monkeys. One day prior to formaldehyde 

exposure, each monkey had a portion of its posterior shaved and had a carotid artery catheter implanted. 

Monkeys were placed in restraining chairs for drug delivery, and plexiglass hoods were placed around the 

animals’ heads for the collection of expired air. Animals were dosed with 2 mg 14C-formaldehyde in 

200 μL of aqueous carrier solution, applied to an 18 cm2

 area. The 14C content in each dose was 

approximately 590–730 μCi. Blood samples were collected at 1, 2, 3, 4, 7, and 24 hours after dosing. 

Urine and feces were collected at daily intervals for 3 days. Expired air was passed through two sodium 

hydroxide (NaOH) traps which were changed each time a blood sample was collected. Rats and guinea 

pigs were housed individually in glass metabolism cages, which allowed the collection of urine, feces, 

and the combination of expired air and evaporation products from excreta. One day prior to 

formaldehyde exposure, each animal had a portion of its back shaved and had a carotid artery catheter 
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implanted. Animals were dosed with an aqueous solution which was applied to a 2 cm2 area. The dose 

applied was either 0.1 mg in 10 μL of solution or 11.2 mg in 40 μL of solution; the 14C content in each 

dose was approximately 30 μCi. Blood samples were collected at 1, 2, 3, 4, 7, and 24 hours after dosing. 

Animals were sacrificed 72 hours after exposure began. Data from the monkeys were more variable than 

the rats and guinea pigs. The sum of 14C recovered in the excreta of monkeys (urine, feces, and expired 

air) was <1%. The concentration of 14C in the blood was extremely low, averaging approximately 

0.015% of the dose over the estimated blood volume. After 72 hours, no large accumulation of 

formaldehyde occurred in any tissue measured. The application site contained approximately 9.5% of the 

14C dose. In rats dosed with 0.05 or 5.6 mg/cm2 14C-formaldehyde, the total recoveries of 14C for the low 

and high doses were 73.4 and 60.4%, respectively. Approximately 28% of the low dose and 22% of the 

high dose was collected in the air traps, most within the first 2 hours. Less than 3% of 14C in the air was 

in the form of CO2. The concentration of 14C in the blood remained fairly constant throughout the 

experiment, averaging approximately 0.12% of the low dose and 0.13% of the high dose over the total 

estimated blood volume. At 72 hours, no large accumulation of formaldehyde occurred in any tissue 

measured. The application site contained approximately 16% of the low-14C dose and 3% of the high 

dose. In guinea pigs receiving 0.05 or 5.6 mg/cm2 14C-formaldehyde, total recoveries of 14C for the low 

and high doses were 70 and 63.6%, respectively. Approximately 21% of the low dose and 24% of the 

high dose was collected in the air traps, most within the first 2 hours. Less than 3% of 14C in the air was 

in the form of CO2. About 6% of the low dose and 8% of the high dose was excreted in the urine and 

feces combined. The concentration of 14C in the blood remained fairly constant throughout the 

experiment, averaging approximately 0.1% of the low dose and 0.09% of the high dose of the estimated 

blood volume. After 72 hours, no large accumulation of formaldehyde occurred in any tissue measured. 

The application site contained approximately 16% of the low-14C dose and 4% of the high dose. It 

appears that the skin of the monkey is much less permeable to formaldehyde than the skin of the rodent. 

Significant evaporation of formaldehyde from the skin application site also probably occurred in this 

study. 

Bartnik et al. (1985) sought to characterize the absorption and excretion of percutaneously applied 

formaldehyde in male and female WISW rats. Twenty-four hours prior to dosing, the dorsal skin hair of 

all rats was carefully clipped to avoid abrasions. Ten male and 4 female rats were dosed with 200 mg of 

cream containing 0.1% 14C-formaldehyde. The dosing area of each rat was covered with a glass capsule; 

in all cases except two males, the glass capsules were perforated, resulting in a nonocclusive application. 

The dose areas of the remaining two males were covered with solid glass capsules, resulting in an 
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occluded application. The cream remained on the skin for 48 hours, during which time urine, feces, and 

air samples were collected. Air samples were passed through a series of filters to separate 

14C-formaldehyde and 14CO2. At the end of the study, rats were sacrificed, the treated area of skin was 

removed and dissolved, fecal samples and the remaining carcass were homogenized, and air-trap samples 

were processed for 14C determinations. The amount of 14C remaining in the treated skin was similar in 

occluded and nonoccluded animals (69.9 versus 70.2%). Total percutaneous absorption in 48 hours was 

6.1% of the applied radioactivity. Of this amount, 38% was recovered in urine, 11% in the feces, 21% as 

respired CO2, and 30% in the carcass. Absorption was lower in occluded (3.4%) than in nonoccluded 

animals (6.1%). The authors speculate that the greater formaldehyde absorption seen in the animals with 

nonoccluded dose sites was due to some of the volatilized formaldehyde being inhaled by the animals 

prior to being trapped. The authors did not specify the fate of dose in the treated skin (i.e., loose or bound 

on surface, or actually integrated into skin). 

2.3.2 Distribution 

2.3.2.1 Inhalation Exposure 

No studies were located that described the distribution of formaldehyde or its metabolites in humans after 

inhalation exposure. Several studies are available that describe the distribution of formaldehyde in 

laboratory animals. Heck et al. (1983) examined the fate of 14C-formaldehyde in Fischer 344 rats. Rats 

were exposed by inhalation to 14C-formaldehyde at 8 ppm for 6 hours. Concentrations of total 

radioactivity in the whole blood and plasma were monitored for 8 days. The terminal half-life of the 14C 

was approximately 55 hours, which was considerably longer than the known half-life of formaldehyde 

(about 1.5 minutes in monkeys), indicating both the metabolism of 14C-CH2O to other molecules (i.e., 

formate) and incorporation into other molecules. Radioactivity in the packed blood cell fraction was 

multiphasic; it initially increased during exposure, declined during the first hour postexposure, then began 

to increase again, reaching a maximum at approximately 35 hours postexposure. The terminal phase of 

the packed red blood cell fraction had a very slow decline in radioactivity, which would likely continue 

for several weeks after exposure ended (half-life >55 hours). 

Heck et al. (1983) also examined distribution of 14C-formaldehyde in formaldehyde-naive and 

formaldehyde-pretreated male Fischer 344 rats. Pretreated rats were exposed whole-body to 15 ppm 

formaldehyde 6 hours/day for 9 days. On the tenth day, these rats and the formaldehyde-naive rats (never 
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exposed to formaldehyde vapors) were then exposed head-only to 14C-formaldehyde at concentrations of 

14.9 ppm for 6 hours. All rats were sacrificed immediately after completion of the 14C-formaldehyde 

exposure. Immediately after completion of the inhalation exposure, 14C concentrations were greatest in 

the mucosal tissues. At 15 ppm, 14C concentrations were as follows: nasal mucosa, 2 μmole equivalents/g 

tissue; trachea, 0.3 μmole equivalents/g tissue; and plasma, 0.1 μmole equivalents/g tissue. Radioactive 

concentrations were relatively equivalent in all of the mucosal linings monitored. Tissue concentrations 

of 14C in naive and pretreated rats did not differ from each other. Tissue concentrations of 14C were low, 

resembling plasma concentrations; the ratio of 14C in internal organs to that in plasma were: esophagus, 

4.94±1.23; kidney, 3.12±0.47; liver, 2.77±0.25; intestine, 2.64±0.48; lung, 2.05±0.36; spleen, 1.59±0.50; 

heart, 1.09±0.09; brain, 0.37±0.06; testes, 0.31±0.05; and erythrocytes, 0.30±0.08. 

Distribution studies by Chang et al. (1983) investigated the effects of previous formaldehyde exposure on 

its distribution after inhalation exposure in male Fischer 344 rats and male B6C3F1 mice. Some rats and 

mice were exposed to only one dose of 14C-formaldehyde (15 ppm for 6 hours) (naive mice), while 

another group was exposed to formaldehyde (nose-only) at a concentration of 15 ppm for 6 hours/day for 

4 days and then additionally exposed to 14C-formaldehyde (nose-only) at a concentration of 15 ppm for 

6 hours (pretreated group). After exposure, the mice were immediately sacrificed and prepared for wholebody radiography. The amounts of radioactivity deposited in the nasal cavities of naive and pretreated 

rats were similar. Pretreated rats had less visceral radioactivity compared to naive animals. However, 

more radioactivity was found in the nasal cavity of naive mice than in pretreated mice. The decreased 

visceral radioactivity seen in the pretreated mice was thought to be due to decreased grooming and 

mucociliary clearance. 

Early studies by Casanova-Schmitz et al. (1984a) examined the mechanisms of labeling of 

macromolecules (DNA, RNA, and proteins) in the respiratory and olfactory mucosa and bone marrow of 

male Fischer 344 rats. Rats were exposed nose-only for 6 hours to 0.3, 2, 6, 10, or 15 ppm mixtures of 

14C and 3

H-formaldehyde 1 day after a 6-hour exposure to the same concentration of unlabeled 

formaldehyde. The predominant route of macromolecule labeling was metabolic incorporation. There 

was some evidence of DNA-protein cross linking present in the nasal tissues. It was found that 

concentrations of 14C DNA in respiratory and olfactory mucosa tissues increased linearly with dose; at 

any given dose, the concentrations of 14C DNA in respiratory mucosa tissues were approximately two to 

three times that in olfactory mucosa tissues. Incorporation of 14C into DNA increased with exposure 

concentrations #6 ppm, but decreased at 10 and 15 ppm, suggesting an inhibition of DNA synthesis. 
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Studies by Casanova et al. (1991a, 1991b) described the formation of DNA-protein cross links in the 

respiratory tract measured in male Fischer 344 rats and Rhesus monkeys. Rats were exposed nose-only to 

a mixture of 14C-labeled and nonradiolabeled formaldehyde at concentrations of 0.3, 0.7, 2, 6, or 10 ppm 

for 6 hours. Formaldehyde-DNA-protein cross links were detected at all concentrations tested. Male 

Rhesus monkeys were exposed to 0.7, 2, or 6 ppm formaldehyde 14C-labeled and nonradiolabeled mixture 

for 6 hours, and it was determined that approximately 90% of all 14C was associated with the thymine, 

while 10% was associated with the guanine and adenine. Concentrations of formaldehyde-protein cross 

links were greatest in the middle turbinate tissues and lowest in the nasopharyngeal tissues. Some 

evidence of cross link formation was seen in the larynx/trachea/carina and major intrapulmonary airway 

tissues of two monkeys in the high-dose group. No evidence of cross link formation was seen in the sinus 

or lung tissues at any exposure concentration. 

2.3.2.2 Oral Exposure 

In a study by Galli et al. (1983), the fate of the complexes between 14C-formaldehyde and milk proteins in 

mice and rats, and their toxicological significance were examined. Male Sprague-Dawley rats were given 

a single oral dose of 2.2 g (18 μCi) 14C-labeled grana cheese. The cheese was made by following the 

usual process but using milk with added 14C-formaldehyde. Animals fed with unlabeled cheese were used 

as controls. Groups of rats were sacrificed 4, 8, 16, 32, and 64 hours after the end of food consumption. 

Blood, liver, gastrointestinal tract, kidneys, spleen, testes, brain, muscle, and adipose tissues were 

removed, and urine and feces were collected from metabolic chambers. In all cases, the biological 

samples were immediately frozen after removal until used for radioactivity measurement. Peak 

radioactivity concentrations in the tissues occurred 16 hours after food consumption. The maximum 

concentrations of 14C-activity equivalent to a value of 0.08% of the dose were present after 8 hours in the 

rat blood. In the companion study, male Swiss albino mice (CD-1) were given a single oral dose of 0.5 g 

(4 μCi) 14C-labeled grana cheese. The highest concentrations of radioactivity in the liver, kidney, adipose 

tissue, spleen, testes, brain, and muscle occurred 4 hours after administration. The maximum 

concentrations of 14C-activity equivalent to a value of 0.03% of the dose were present after 2 hours in the 

blood of mice. 

Buckley et al. (1988) measured formaldehyde levels in the milk and blood of dairy cows given formalintreated whey. There was a high degree of variability in milk and blood concentrations, presumably due to 

the variable amount of time (several minutes to 7 hours) taken to consume the treated feed. In a 
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companion study, Buckley et al. (1988) measured formaldehyde levels in the muscle tissues of dairy 

calves fed formalin-treated whey. Eighteen Holstein bull calves were fed diets containing whey treated 

with formalin at doses of 0, 0.05, or 0.1%. Calves were individually fed the formalin-treated whey in two 

equal feedings daily. Two calves from each treatment group were sacrificed at days 81, 88, and 95. 

Blood samples were collected on the day before sacrifice. At sacrifice, sections of muscle, kidney, liver, 

and heart were obtained for formaldehyde determinations. Concentrations of formaldehyde in fresh 

muscle samples of the high-dose group (0.256 μg/g) were significantly greater than those of controls 

(0.178 μg/g). Concentrations of formaldehyde in fresh blood and frozen heart, kidney, liver, and muscle 

samples were similar across treatment groups. 

2.3.2.3 Dermal Exposure 

Jeffcoat et al. (1983) studied the disposition of 14C-formaldehyde administered topically to Fischer 

344 rats, Dunkin-Hartley guinea pigs, and Cynomolgus monkeys. One day prior to formaldehyde 

exposure, each monkey had a portion of its posterior shaved and had a carotid artery catheter implanted. 

Monkeys were placed in restraining chairs for drug delivery, and a plexiglass hood was placed around 

their heads for the collection of expired air. Animals were dosed with an aqueous solution which was 

applied to an 18 cm2

 area. A dose of 2 mg in 200 μL of solution was applied to the skin surface; the 14C 

content in each dose was approximately 590–730 μCi. Blood samples were collected at 1, 2, 3, 4, 7, and 

24 hours after dosing. Urine and feces were collected at daily intervals for 3 days. Expired air was 

passed through two NaOH traps which were changed each time a blood sample was collected. At 

72 hours after dosing, the animals were sacrificed and the following tissues were collected and analyzed 

for 14C content: heart, liver, lung, spleen, kidney, leg, brain, gonads, application site skin, and distant skin; 

the remaining carcass was also analyzed for 14C content. Rats and guinea pigs were housed individually 

in glass metabolism cages, which allowed the collection of urine, feces, and the combination of expired 

air and evaporation products from excreta. One day prior to formaldehyde exposure, each animal had a 

portion of its back shaved and had a carotid artery catheter implanted. Animals were dosed with an 

aqueous solution which was applied to a 2 cm2

 area. The dose applied was either 0.1 mg in 10 μL of 

solution or 11.2 mg in 40 μL of solution; the 14C content in each dose was approximately 30 μCi. Blood 

samples were collected at 1, 2, 3, 4, 7, and 24 hours after dosing. Urine and feces were collected at daily 

intervals for 3 days. Air exiting the metabolism cages was passed through two NaOH traps which were 

changed each time a blood sample was collected and at 48 and 72 hours after dosing. At 72 hours after 

dosing, the animals were sacrificed and the following tissues were collected and analyzed for 14C content: 

heart, liver, lung, spleen, kidney, leg, brain, gonads, application site skin, and distant skin; the remaining 
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carcass was also analyzed for 14C content. Data from the monkeys were more variable than the rats and 

guinea pigs. The sum of 14C recovered in the excreta (urine, feces, and expired air) was <1%. The 

concentration of 14C in the blood was also low, averaging approximately 0.015% of the dose over the 

estimated blood volume. At 72 hours, no large accumulation of formaldehyde occurred in any tissue 

measured. The total amount of radioactivity recovered in all internal organs combined was <0.05% of the 

applied dose; the 14C was distributed fairly evenly across all tissues. 

In rats, the application site contained approximately 9.5% of the 14C activity, with a total recoveries of 14C 

for the low and high doses of 73.4 and 60.4%, respectively. Less than 3% of 14C in the air was in the 

form of CO2. About 7% of the low dose and 9% of the high dose was excreted in the urine and feces 

combined. The concentration of 14C in the blood remained fairly constant throughout the experiment, 

averaging approximately 0.12% of the low dose and 0.13% of the high dose over the total estimated blood 

volume. After 72 hours, no large accumulation of 14C radioactivity occurred in any tissue measured in 

rats. The application site contained approximately 16% of the low-14C dose and 3% of the high dose. 

In guinea pigs, total recoveries of 14C for the low and high doses were 70 and 63.6%, respectively. 

Approximately 21% of the low dose and 24% of the high dose were collected in the air traps, most within 

the first 2 hours. Less than 3% of 14C in the air was in the form of CO2. About 6% of the low dose and 

8% of the high dose was excreted in the urine and feces combined. The concentration of 14C in the blood 

remained fairly constant throughout the experiment, averaging approximately 0.1% of the low dose and 

0.09% of the high dose over the total estimated blood volume. After 72 hours, no large accumulation of 

14C occurred in any tissue measured. The application site contained approximately 16% of the 

low-14C dose and 4% of the high dose. The authors concluded that topically applied formaldehyde, once 

absorbed, was primarily excreted by the urinary and fecal routes. 

2.3.3 Metabolism 

Formaldehyde is rapidly metabolized and storage is not a factor in its toxicity. The metabolism of 

formaldehyde to formate (via formaldehyde dehydrogenase/class III alcohol dehydrogenase) takes place 

in all of the tissues of the body as a consequence of endogenous formation of formaldehyde, and the 

formate is quickly removed by the supporting blood supply (Heck et al. 1982). Formaldehyde 
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dehydrogenase (FDH) is the major metabolic enzyme involved in the metabolism of formaldehyde in all 

of the tissues studied; it is widely distributed in animal tissues, particularly in the rat nasal mucosa, and is 

specific for the glutathione adduct of formaldehyde. If formaldehyde is not metabolized by FDH, then it 

can form cross linkages between proteins, between protein and single-stranded DNA (see Figure 2-3) or 

enter the 1 carbon intermediary metabolic pool by initially binding to tetrahydrofolate (Bolt 1987). 

Several enzymes can catalyze the reaction that oxidizes formaldehyde to formic acid (i.e., nonspecific 

aldehyde dehydrogenase and catalase); however, FDH is the primary enzyme that performs this function 

and is specific for formaldehyde; other aldehydes are left intact in the presence of FDH. Endogenous or 

exogenous formaldehyde enters the FDH metabolic pathway and is eliminated from the body as 

metabolites, primarily as formate or CO2. Formaldehyde dehydrogenase activity does not increase (i.e., 

not inducible) in response to formaldehyde exposure (Casanova-Schmitz et al. 1984b); thus no increase in 

metabolism occurs. 

A summary of the metabolic pathways for formaldehyde metabolism is represented in Figure 2-3. 

2.3.3.1 Inhalation Exposure. 

Heck et al. (1985) determined the fate of inhaled formaldehyde in the human. Four men and two women 

were exposed to a 1.9±0.06 ppm air concentration of formaldehyde in a large walk-in chamber for 

40 minutes. Shortly before and shortly after the exposure, venous blood samples were taken from each 

person (each person served as his/her own control) and the blood was analyzed for formaldehyde content. 

Mean venous blood formaldehyde concentrations in humans prior to exposure showed a blood 

concentration of 2.61±0.41 μg/g of blood. Individual variability was markedly present. Immediately 

after a 40-minute exposure, mean blood concentration of formaldehyde was 2.77±0.28 μg/g of blood. 

There was no significant difference between pre- and postexposure blood concentrations of formaldehyde 

at the formaldehyde air concentrations tested in this study, most likely indicating rapid metabolism and/or 

local absorption in the respiratory tract mucosa rather than systemic absorption into the blood. In the 

same report by Heck et al. (1985), the fate of inhaled formaldehyde was determined in the rat. Male 

Fischer 344 rats were placed in a nose-only inhalation chamber and exposed to a 14.4±2.4 ppm air 

concentration of formaldehyde for 2 hours, were sacrificed, and a venous blood sample was collected and 

analyzed for formaldehyde content. Unexposed control rats had a mean formaldehyde blood level of 

2.24±0.07 μg/g of blood while rats exposed to the 14.4 ppm air concentration of formaldehyde had blood 

concentrations of 2.25±0.07 μg/g. These results indicate that during a nose-only 

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inhalation exposure of rats to this concentration of formaldehyde, no significant quantities of 

formaldehyde can be detected in the blood, most likely indicating fast metabolism and/or local absorption 

in the respiratory tract mucosa. 

Heck et al. (1982) studied the effects of formaldehyde exposure on nasal mucosal tissue in male 

Fischer 344 rats. Rats were exposed to clean air or air containing 6 ppm formaldehyde for 10 days, 

6 hours/day. Immediately after the last exposure, animals were sacrificed and nasal mucosal tissues were 

isolated. The tissues were homogenized and formaldehyde was extracted and analyzed by GC/MS. The 

mean concentration of formaldehyde in the nasal mucosal tissues of rats exposed to 6 ppm formaldehyde 

(0.39 μmol/g tissue) was not significantly different from the mean concentrations found in the tissues of 

control animals (0.42 μmol/g tissue). The authors attributed this to the rapid metabolism of formaldehyde 

to formate or the rapid irreversible binding of formaldehyde to macromolecules. 

The ability of respiratory and olfactory tissues to oxidize formaldehyde was examined in male 

Fischer 344 rats. To determine the effects of repeated formaldehyde exposure on enzyme activities, rats 

were exposed to 15 ppm formaldehyde 6 hours/day for 10 days. At the completion of formaldehyde 

exposure, rats were sacrificed and respiratory and olfactory mucosal tissues were harvested. The 

enzymatic capacity of the tissues was determined in the presence and absence of glutathione. Tissue 

homogenates from both the respiratory and olfactory mucosae demonstrated the ability to oxidize 

formaldehyde; the oxidation of formaldehyde occurred at similar rates in the respiratory and olfactory 

mucosal homogenates (Casanova-Schmitz et al. 1984b). 

The effects of glutathione depletion on the cross linking of formaldehyde with macromolecules (DNA, 

RNA, and proteins) in the respiratory and olfactory mucosa and bone marrow of male Fischer 344 rats 

were examined by Casanova and Heck (1987). Rats were exposed nose-only for 3 hours to 0.9, 2, 4, 6, or 

10 ppm mixtures of 14C- and 3

H-formaldehyde 1 day after a 3-hour exposure to the same concentration of 

unlabeled formaldehyde. Two hours prior to the second exposure, five of the rats were injected with 

phorone in corn oil, and the other three were injected with corn oil alone. Phorone successfully depleted 

nonprotein sulfhydryls levels to minimal values. The metabolic incorporation of label into 

macromolecules was significantly decreased by this treatment, whereas the amount of DNA-protein cross 

linking significantly increased. Since formaldehyde oxidation depends on glutathione, this experiment 

suggests that when this process is inhibited, formaldehyde levels rise high enough to form DNA-protein 

cross links. 
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2.3.3.2 Oral Exposure. 

Eells et al. (1981) describe the case of a 41-year-old woman who was brought to the emergency room 

30 minutes after ingesting approximately 120 mL of formalin (624 mg/kg formaldehyde). Formic acid 

accumulated in the blood rapidly after formaldehyde ingestion. 

2.3.3.3 Dermal Exposure 

No information on metabolism of formaldehyde after dermal exposure was found in the literature. 

2.3.4 Elimination and Excretion 

2.3.4.1 Inhalation Exposure 

Heck et al. (1983) examined the fate of 14C-formaldehyde in male Fischer 344 rats. Rats were exposed to 

0.63 or 13.1 ppm formaldehyde for 6 hours. Upon completion of the exposure, the rats were placed in 

metabolic cages which allowed the continuous collection of urine, feces, and expired air; they remained in 

the cages for 70 hours and were then sacrificed. The average 14CO2 excretion was biphasic, with a rapid 

decline over the first 12 hours followed by a more gradual decline in excretion over the remainder of 

time. Changing the concentration of formaldehyde did not affect the proportion of dose recovered in each 

type of excreta. Radioactivity in urine accounted for 17.6 and 17.3% of the total radioactivity detected 

for low- and high-dose rats, respectively; radioactivity in feces accounted for 4.2 and 5.3% of the total 

respective amounts of recovered radioactivity. Exhalation was the major route of excretion, accounting 

for 39.4% of the low dose and 41.9% of the high dose. The amount of 14C remaining in the carcass after 

70 hours was roughly equivalent (38.9% of low dose; 35.2% of high dose) to that expired over the same 

period. At 15 ppm, 14C concentrations exposure were as follows: nasal mucosa, 2 μmole equivalents/g 

tissue; trachea, 0.3 μmole equivalents/g tissue; and plasma, 0.1 μmole equivalents/g tissue. 

2.3.4.2 Oral Exposure 

In a study by Galli et al. (1983), the excretion of the complexes between 14C-formaldehyde and milk 

proteins in mice and rats, and their toxicological significance were examined. Male Sprague-Dawley rats 

were given a single oral dose of 14C-labeled grana cheese. Rats fed with unlabeled cheese were used as 
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controls. Groups of rats were sacrificed at 4, 8, 16, 32, and 64 hours after the end of food consumption. 

Blood, liver, gastrointestinal tract, kidneys, spleen, testes, brain, muscle, and adipose tissues were 

removed, and urine and feces were collected from metabolic chambers. In all cases, the biological 

samples were immediately frozen after removal until used for radioactivity measurement. Within 

32 hours of administration in rats, 67% of the radioactivity had been excreted in the feces and urine and 

28% of the radioactivity had been exhaled as 14CO2. The half-life calculated from the regression line of 

the β phase (where C(t)=C0 [e-αt

 + e-βt]) in blood was found to be 26.4 hours for the rats. The liver was the 

only tissue where the radioactivity concentration/g tissue was equivalent to more than 0.1% of the 

administered dose 64 hours after the ingestion of 14C-labeled cheese. Excretion of radioactivity by all 

routes from rats was completed within 32 hours. In the companion study, male Swiss albino mice (CD-1) 

were given a single oral dose of 0.5 g (4 μCi) 14C-labeled grana cheese. Mice were sacrificed 2, 4, 8, 16, 

32, 64, and 96 hours and 8 and 12 days. Within 32 hours of administration, 64% of the radioactivity had 

been excreted in the feces and urine and 24% of the radioactivity had been exhaled as 14CO2. The halflife calculated from the regression line of the β phase in blood was found to be 27.8 hours for the mice. 

After 96 hours in all of the mouse tissues, the radioactivity concentration/g tissue was lower than 0.5% of 

the administered dose, and no radioactivity was detectable after 8 days. Excretion of radioactivity by all 

routes from mice was completed within 32 hours. 

A study by Barry and Tome (1991) sought to quantitate the concentration of formaldehyde in the milk of 

goats given feed containing varying amounts of formaldehyde-treated soybean oil-meal. Mean milk 

formaldehyde concentrations were 0.033, 0.083, and 0.153 mg/kg in the 0, 14, and 28 mg/kg/day groups, 

respectively. These values were significantly different from each other (p<0.05) and were highly 

correlated with formaldehyde intake (r=0.938, p<0.01). The authors concluded that dietary formaldehyde 

is excreted in the milk of goats. 

Buckley et al. (1988) measured formaldehyde levels in the milk and blood of dairy cows given formalintreated whey. Twelve Holstein cows in their first trimester of lactation were used in a series of three 

feeding trials lasting 35 days and separated from each other by 14 days. Six of the cows received a diet 

consisting of low-energy pelleted concentrate, liquid acid whey, and grass hay. The whey was fed once a 

day beginning at 10:00 am, and all whey was consumed by 4:30 pm. In the three trials, the calculated 

amounts of ingested formalin were 19.9, 39.7, and 59.4 mg/kg/day, respectively. The remaining six cows 

received untreated whey throughout the three trials. The average total excretion of formaldehyde in milk 

in each of the three dose groups during each trial was 0.53, 1.41, and 2.80 mg, respectively. 
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2.3.4.3 Dermal Exposure 

Jeffcoat et al. (1983) studied the elimination of 14C-formaldehyde administered topically to 

Fischer 344 rats, Dunkin-Hartley guinea pigs, and Cynomolgus monkeys. Data from the monkeys were 

more variable than the rats and guinea pigs. The sum of 14C recovered in the excreta (urine, feces, and 

expired air) was >1%. In rats, total recoveries of 14C for the low and high doses were 73.4 and 60.4%, 

respectively. Approximately 28% of the low dose and 22% of the high dose was collected in the air traps, 

most within the first 2 hours. Less than 3% of 14C in the air was in the form of CO2. About 7% of the low 

dose and 9% of the high dose was excreted in the urine and feces combined. In guinea pigs, total 

recoveries of 14C for the low and high doses were 70 and 63.6%, respectively. Approximately 21% of the 

low dose and 24% of the high dose was collected in the air traps, most within the first 2 hours. Less than 

3% of 14C in the air was in the form of CO2. About 6% of the low dose and 8% of the high dose was 

excreted in the urine and feces combined. The authors concluded that the fate of topically applied 

formaldehyde differed significantly from that of formaldehyde administered internally. 

Bartnik et al. (1985) sought to characterize the absorption and excretion of percutaneously applied 

formaldehyde in male and female WISW rats using occluded and nonoccluded application. Ten male and 

four female rats were dosed with 200 mg of cream containing 0.1% 14C-formaldehyde. Excretion of 14C 

(presumably formate) via feces, urine, and expired air was consistently lower in animals with occluded 

dose sites (0.2 versus 0.7%; 1.2 versus 2.3%; and 0.9 versus 1.3%, respectively). The authors speculate 

that the greater formaldehyde absorption seen in the animals with nonoccluded dose sites was due to some 

of the volatilized formaldehyde being inhaled by the animals prior to being trapped. The authors did not 

specify the fate of dose in the treated skin (i.e., loose or bound on surface, or actually integrated into 

skin). 

2.3.5 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 
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pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

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 et al. 

1987; Andersen and Krishnan 1994). 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 parametrization, (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) is 

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 
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2. HEALTH EFFECTS 

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 2-4 shows a conceptualized representation of a PBPK model. 

PBPK models for formaldehyde are discussed in this section in terms of their use in risk assessment, 

tissue dosimetry, and dose, route, and species extrapolations. 

Pharmacokinetic models to describe, as a function of formaldehyde air concentration, the rate of 

formation of formaldehyde-induced DNA-protein cross links in different regions of the nasal cavity have 

been developed for rats and monkeys (Casanova et al. 1991; Heck and Casanova 1994). Rates of 

formation of DNA-protein cross links have been used as a dose surrogate for formaldehyde tissue 

concentrations in extrapolating exposure-response relationships for nasal tumors in rats to estimate cancer 

risks for humans (EPA 1991a; see Section 2.4.3). The models assume that rates of cross link formation 

are proportional to tissue concentration of formaldehyde and include saturable and nonsaturable 

elimination pathways, and that regional and species differences in cross link formation are primarily 

dependent on anatomical parameters (e.g., minute volume and quantity of nasal mucosa) rather than 

biochemical parameters. The models were developed with data from studies in which concentrations of 

DNA-protein cross links were measured in different regions of the nasal cavities of rats (Casanova et al. 

1989) and Rhesus monkeys (Casanova et al. 1991; Heck et al. 1989) exposed by inhalation to 

radiolabeled formaldehyde. In agreement with the observed data, the models predict that overall rates of 

DNA-protein cross link formation in rat respiratory mucosa are higher than rates in Rhesus monkeys, and 

that there is a nonlinear, convex relationship between this dose surrogate in nasal tissues and increasing 

air concentrations of formaldehyde (Casanova et al. 1991). Similar nonlinear, convex exposure-response 

relationships have also been observed in formaldehyde-exposed rats for nasal tumor incidence (Kerns et 

al. 1983b; Monticello et al. 1996) and cell proliferation indices in regions of the rat nasal epithelium 

where tumors develop (Monticello et al. 1996). 

Computational fluid dynamics (CFD) models of airflow in the nasal passages of rats, monkeys, and 

humans have been developed to determine the degree to which interspecies and interregional differences 

in uptake patterns along airway passages may account for differing distributions of formaldehyde-induced 

upper respiratory tract lesions in rats and primates. These models enable extrapolation of exposures 

associated with upper respiratory tract tissue damage in rats or monkeys to human exposures 
FORMALDEHYDE 185 

2. HEALTH EFFECTS 

Figure 2-4. Conceptual Representation of a Physiologically Based
 

Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance
 

Skin 

Kidney 

Richly 

perfused 

tissues 

Slowly 

perfused 

tissues 

Fat 

Liver 

Lungs 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

GI 

Tract 

Vmax Km 

Urine 

Chemicals in air 

contacting skin 

Inhaled chemical Exhaled chemical 

Ingestion 

Source: adapted from Krishnan et al. 1994 

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. 
FORMALDEHYDE 186 

2. HEALTH EFFECTS 

(Cohen Hubal et al. 1997; Kepler et al. 1998; Kimbell et al. 1993, 1997a,1997b; Morgan 1997; Morgan et 

al. 1991; Subramaniam et al. 1998). Airflow pattern is expected to be one of three important determinants 

of upper respiratory tract tissue uptake, along with interactions at the airway/tissue interface such as offgassing and tissue properties influencing absorption rates (e.g., mucociliary clearance or rate of 

metabolism). 

Driving forces behind the development of these airflow models include: (1) differences in nasal anatomy 

and breathing patterns between rats and primates; (2) observations that nonneoplastic respiratory tract 

lesions in rats exposed to 6 ppm formaldehyde are confined to epithelial tissue in specific anterior regions 

of the nose posterior to the vestibule (Chang et al. 1983; Morgan et al. 1986b), whereas monkeys exposed 

to 6 ppm formaldehyde show a wider distribution of similar epithelial lesions in the nose posterior to the 

vestibule and some extension of the lesions into the tracheal and bronchial regions (Monticello et al. 

1989); (3) histochemical localization observations suggesting that regional differences in formaldehyde 

dehydrogenase, a key enzyme in formaldehyde detoxification, were insufficient to account for localized 

toxicity in the rat nose (Keller et al. 1990); and (4) observations of correlations between sites of 

formaldehyde-induced lesions in the nasal epithelium of rats and Rhesus monkeys and site-specific rates 

of DNA-protein cross link formation (a putative internal dosimeter for formaldehyde as discussed earlier; 

Casanova et al. 1989, 1991, 1994) or site-specific rates of cellular proliferation (Monticello et al. 1989, 

1996). 

Using three-dimensional reconstructions of the nasal passages of a F344 rat (Kimbell et al. 1993), a 

Rhesus monkey (Kepler et al. 1995), and a human (Subramaniam et al. 1998), CFD models were 

developed to predict patterns of airflow and regional uptake of formaldehyde in the nose of these species. 

The rat and monkey models were constructed from tracings of embedded tissue specimens, whereas the 

human model was constructed from tracings of magnetic resonance image scans. The CFD models 

assume that: (1) rat, monkey, and human nasal epithelial tissues are similar in all characteristics except 

thickness and location in nasal airways (values for these parameters were estimated from the literature or 

measured); (2) formaldehyde is absorbed only during inspiration, and that major patterns of inhaled 

airflow during resting breathing are similar to those at steady-state; (3) air is an incompressible 

Newtonian fluid; (4) the air-phase diffusivity of formaldehyde is constant throughout the nasal passages; 

(5) the nasal airway walls are inflexible and have no mucus movement or nasal hairs; and (6) 

formaldehyde absorption is maximal (i.e., fast and complete) in mucus-covered, nonsquamous epithelium 

regions of the nose so that concentrations at the surface of these airway walls are taken to be zero. 
FORMALDEHYDE 187 

2. HEALTH EFFECTS 

Simulations of airflow patterns were comparable with descriptions and measurements of flow in nasal 

molds of each species (Kepler et al. 1998; Kimbell et al. 1997a; Subramaniam et al. 1998). 

Regions of high flux predicted by the rat and monkey CFD models correlated with the distribution of 

formaldehyde-induced squamous metaplasia in nasal passages of rats exposed to 10 or 15 ppm 

formaldehyde for 6 months (Kimbell et al. 1993, 1997a) and of Rhesus monkeys exposed to 6 ppm 

formaldehyde for 6 weeks (Kepler et al. 1998). Results from these studies support the hypothesis that 

airflow patterns are key determinants of the amount of formaldehyde reaching the site of formaldehydeinduced nasal lesions. 

The rat CFD model and a modified version of the Casanova et al. (1991) pharmacokinetics model of 

formaldehyde disposition in the rat nasal lining have been linked to make predictions of DNA-protein 

cross link formation rates in nasal epithelial regions as a function of formaldehyde concentration in air 

(Cohen Hubal et al. 1997). The rat nasal lining model assumed a single compartment with three 

competing disposition processes for formaldehyde: saturable metabolism, nonsaturable metabolism, and 

DNA-protein cross link formation. The model parameters were kinetic rate constants for formation and 

loss of DNA-protein cross links, the nasal-lining thickness, rate constants for formaldehyde metabolism 

by saturable pathways (Vmax and Km), and a pseudo-first-order rate constant for nonsaturable 

formaldehyde metabolism. Saturable and nonsaturable metabolic rate constants were estimated by 

iterative fitting of the model to whole-nose data for DNA-protein cross links in rats exposed for 6 hours to 

radiolabeled formaldehyde, collected by Casanova et al. (1989). The combined airflow and 

pharmacokinetics models were then used to predict DNA-protein concentrations in the rat nasal epithelial 

region with high tumor incidence; predicted values compared well with measured DNA-protein cross link 

values in this region of the rat nasal epithelium (Cohen Hubal et al. 1997). 

The Chemical Industry Institute of Toxicology and the U.S. EPA (CIIT 1998) are currently exploring 

options in using the CFD and pharmacokinetic models to extrapolate exposure-response relationships for 

formaldehyde-induced rat nasal tumors and related end points, such as rates of cellular proliferation in 

specific regions of the nasal epithelium, to derive estimates of cancer risk in humans exposed to inhaled 

formaldehyde. One approach being explored makes predictions for nasal and lung tumor risk in humans 

exposed to inhaled formaldehyde using two-stage clonal-growth cancer models incorporating data on cell 

division rates, numbers of cell at risk, tumor incidence, and site-specific flux of formaldehyde (see also 

CIIT 1998; Conolly et al. 1992; Conolly and Andersen 1993; Morgan 1997). A second approach (a 
 

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2. HEALTH EFFECTS 

benchmark dose approach) makes predictions of nasal cancer risk in humans using curve fitting of 

relevant rat exposure-response data (e.g., nasal tumors or precursor lesions such as preneoplastic foci or 

squamous papillomas, rates of cellular proliferation, or rates of DNA-protein cross link formation) and 

CFD modeling and/or pharmacokinetic modeling for extrapolation purposes (CIIT 1998). 

2.4 MECHANISMS OF ACTION 

2.4.1 Pharmacokinetic Mechanisms 

Absorption. Formaldehyde is a small, reactive, water soluble molecule (molecular weight 30.03) 

which is readily absorbed in the tissues of the respiratory tract (inhalation exposure) and gastrointestinal 

tract (oral exposure). Absorption from the nasal portion of the respiratory tract is estimated to be at or 

near 100%. Studies in obligate nose-breathing animals (rats, mice) have demonstrated near 100% 

absorption in the nasal cavity/mucosa (Casanova-Schmitz et al. 1984a; Casanova et al. 1991; Heck et al. 

1982, 1983) primarily in the anterior nasal mucosa in rats (Chang et al. 1983). Absorption from the nasal 

mucosa, trachea, and bronchi is expected for the oronasal-breathing animals (primates, humans, dogs 

etc.). Tracheal and bronchial absorption ultimately results from deeper penetration because of the 

formaldehyde vapors not passing over and coming into contact with the nasal mucosa; however, near 

100% absorption of the formaldehyde vapor is still likely, at least in the dog (Egle 1972) and very likely 

in humans as well. Studies in humans exposed to 1.9 ppm for 40 minutes failed to detect increases in 

blood formaldehyde levels, which is probably related to formaldehyde's very fast metabolism by one or a 

combination of metabolic pathways (see Figure 2-3) and not due to lack of local absorption. Similar 

results were obtained in rats exposed to 14.4 ppm for 2 hours (Heck et al. 1985). Little information is 

available on the oral absorption characteristics of formaldehyde in humans; however, based on two 

studies, either the formaldehyde is quickly metabolized to formate in the gastrointestinal tract and the 

formate is absorbed fairly quickly, the formaldehyde is absorbed quickly and is metabolized to formate in 

the blood, or a combination of the two mechanisms is responsible for the sharp increases in blood formate 

levels (Burkhart et al. 1990; Eells et al. 1981). Formaldehyde appears to be rapidly absorbed after oral 

exposure in rats (Galli et al. 1983) and food-producing animals (Barry and Tome 1991; Buckley et al. 

1988). Dermal absorption in monkeys has been shown to be quite low (0.5% of the applied dose); most 

was either lost to evaporation or bound within the skin (Jeffcoat 1983). 
 

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Distribution. Formaldehyde does not appear to be absorbed into the blood stream as an intact 

molecule, except possibly at very high doses that overwhelm the metabolic capabilities of the tissue with 

which it comes into contact. Given this rapid metabolic capability of animal tissues, the distribution of 

the intact formaldehyde molecule to other more distant organs (kidney, fat, spleen, etc.) in the body is not 

likely and is not considered a major factor in formaldehyde toxicity. Toxicity is generally demonstrated 

at the point of formaldehyde contact (see Mechanisms of Toxicity, below). Heck et al. (1983) found that 

in rats, inhaled 14C-formaldehyde (8 ppm for 6 hours) had elevated concentrations of radioactivity in their 

blood for several days after exposure (terminal half-life 55 hours). Since it is known that blood 

formaldehyde levels do not increase after inhalation exposure (Heck et al. 1985), the data suggested that 

there was an incorporation of 14C into the macromolecules of the body. The long plasma half-life may 

also have been due to formaldehyde's rapid metabolism to formate or CO2 awaiting excretion into the 

urine and lung, respectively. 

In one study (Casanova et al. 1991), much of the 14C was localized in the nasal mucosa; however, 

detectable levels of 14C activity were noted in the esophagus, kidney, liver, intestine, lung, spleen, heart, 

brain, testes, and erythrocytes in some reports (Heck et al. 1983; Swenberg et al. 1983). The geometry of 

the nasal passages of different species, which results in different airflow patterns through the nose, has a 

large effect on the local distribution of formaldehyde vapor as well (Schreider 1986). In a study by 

Casanova-Schmitz et al. (1984a) using male rats exposed to concentrations of 0.3–15 ppm of 14C and 3

H 

labeled formaldehyde for 6 hours, concentrations of 14C-formaldehyde in respiratory and olfactory 

mucosa tissues increased linearly with dose and at any given dose, the concentrations of 

14C-formaldehyde in respiratory mucosa tissues were approximately 2–3 times that in olfactory mucosa 

tissues. The 3

H and 14C radioisotopes were chosen to distinguish between metabolic incorporation of 

oxidized formaldehyde metabolites (14C) and covalent binding (3

H) into macromolecules. At all exposure 

concentrations, RNA was the most heavily 14C-labeled macromolecule in the respiratory and olfactory 

mucosa. DNA from the respiratory and olfactory mucosa was 14C-labeled at equivalent or greater levels 

than proteins. In the bone marrow, DNA was the most heavily 14C-labeled macromolecule. DNA-protein 

cross links have also been identified in male rats and male Rhesus monkeys exposed to formaldehyde 

concentrations of #9.87 ppm for 6 hours. Concentrations of formaldehyde-protein cross links were 

greatest in the middle turbinate tissues and lowest in the nasopharyngeal tissues, with some evidence of 

cross link formation seen in the larynx, trachea, carina, and major intrapulmonary airway tissues of two of 

the monkeys tested (Casanova et al. 1989a). 
 

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Metabolism. Formaldehyde is a normal metabolic product of animal metabolism, with varying 

endogenous levels present at all times (Bolt 1987). The major sources of endogenously produced 

formaldehyde are glycine and serine. 

Formaldehyde is rapidly metabolized and storage is not a factor in its toxicity. The metabolism of 

formaldehyde to formate (via FDH/class III alcohol dehydrogenase) takes place in all of the tissues of the 

body as a consequence of endogenous formation of formaldehyde and is quickly removed by the 

supporting blood supply (Heck et al. 1982). FDH is the major metabolic enzyme involved in the 

metabolism of formaldehyde in all of the tissues studied; is widely distributed in animal tissues, 

particularly in the rat nasal mucosa; and is specific for the glutathione adduct of formaldehyde. If 

formaldehyde is not metabolized by FDH, then it can form cross linkages between protein and singlestranded DNA (see Figure 2-3) or enter the 1 carbon intermediary metabolic pool by initially binding to 

tetrahydrofolate (Bolt 1987). Several enzymes can catalyze the reaction that oxidizes formaldehyde to 

formic acid (i.e., nonspecific aldehyde dehydrogenase and catalase); however, FDH is the primary 

enzyme tasked to perform this function and is specific for formaldehyde; other aldehydes are left intact in 

the presence of FDH. Endogenous or exogenous formaldehyde enters FDH metabolic pathway and is 

eliminated from the body as metabolites, primarily as formate or CO2. FDH activity does not increase 

(i.e., not inducible) in response to formaldehyde exposure (Casanova-Schmitz et al. 1984b). Heck et al. 

(1985) provided some indirect evidence in both the human and the rat that inhaled formaldehyde (1.9 ppm 

for 40 minutes for the human, 14.4 ppm for 2 hours in the rat) is quickly metabolized (probably by FDH) 

and did not raise blood formaldehyde concentrations beyond the measured endogenous levels, although 

this finding may have also been due to low systemic absorption. Little information about the metabolism 

of formaldehyde after oral or dermal exposures was available. 

Increasing the amounts of formaldehyde in the diet of some lactating ruminants (cows, sheep, goats, etc.) 

will increase the amount of intact formaldehyde present in their milk (Barry and Tome 1991; Buckley et 

al. 1988). Neither of these reports offered an explanation for these findings. However, given the marked 

differences in blood and plasma characteristics and the differences in gastrointestinal anatomy, it is 

plausible to assume that there are some fundamental differences between formaldehyde metabolism in 

ruminant animals and in humans (or other monogastrics), which leads to increased milk levels of 

formaldehyde. There is a close relationship between the amount of formaldehyde ingested and the 

amount of formaldehyde present in the milk (Barry and Tome 1991). Milk formaldehyde concentrations 
 

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are not influenced by the level of milk production, which suggests that the passage of formaldehyde from 

the blood to the milk is a passive event (Barry and Tome 1991). 

Excretion. Given the rapid conversion of formaldehyde to formate and subsequent incorporation into 

naturally occurring cellular constituents, excretion does not appear to be a factor in the toxicity of 

formaldehyde. The metabolism of formaldehyde to formate takes place in all of the tissues of the body as 

a consequence of endogenous formation of formaldehyde. Exogenous formaldehyde enters this pathway 

and is eliminated from the body as metabolites, primarily CO2. For example, in rats exposed to 

14C-formaldehyde via inhalation, 40% of the radioactivity was recovered as 14CO2 (Heck et al. 1983). 

After oral exposure to formaldehyde in male rats administered 2.2 g (18 μCi) of 14C-formaldehyde, 67% 

of the radioactivity dose was excreted in the feces and 32% exhaled as CO2 within 32 hours after dosing. 

The 14C plasma elimination half-life was calculated to be 26.4 hours (Galli et al. 1983); however, it is 

unclear what percentage of this activity involves intact formaldehyde and what involves metabolites (i.e., 

formate). In a similar study in male mice administered 0.5 g (4 μCi) of 14C-formaldehyde, 64% of the 

total dose of radioactivity was eliminated via the feces and 24% eliminated as exhaled CO2. The plasma 

half-life was calculated to be 27.8 hours in this study (Galli et al. 1983). Intact formaldehyde is excreted 

in the milk in goats (Barry and Tome 1991) and dairy cows (Buckley et al. 1988). 

2.4.2 Mechanisms of Toxicity 

The exact mechanism by which formaldehyde exerts its irritant, corrosive, and cytotoxic effects is not 

known. Aldehydes as a group are reactive chemicals with a highly electronegative oxygen atom and less 

electronegative atoms of carbon(s), and hence have a substantial dipole moment. The carbonyl atom is 

the electrophilic site of these type of molecules, making it react easily with nucleophilic sites on cell 

membranes and in body tissues and fluids such as the amino groups in protein and DNA (Feron et al. 

1991). 

It is also known that formaldehyde can form cross links between protein and DNA in vivo. 

Casanova-Schmitz et al. (1984a) reported that the predominant route of formaldehyde metabolism was 

metabolic incorporation into macromolecules (DNA, RNA, and proteins) in the respiratory and olfactory 

mucosa and bone marrow of male Fischer 344 rats. Rats were exposed nose-only for 6 hours to 0.3, 2, 6, 

10, or 15 ppm mixtures of 14C and 3

H-formaldehyde 1 day after a 6-hour exposure to the same 

concentration of unlabeled formaldehyde. There was some evidence of DNA-protein cross linking 
FORMALDEHYDE 192 

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present in the nasal tissues. Concentrations of 14C DNA in respiratory and olfactory mucosa tissues 

increased linearly with dose; at all doses, the concentrations of 14C DNA in respiratory mucosa tissues 

were approximately two to three times that in olfactory mucosa tissues. Later studies by Casanova et al. 

(1991a, 1991b) described the formation of DNA-protein cross links in the respiratory tract measured in 

male Fischer 344 rats as well as in Rhesus monkeys. Rats were again exposed nose-only to a mixture of 

14C-labeled and nonradiolabeled formaldehyde, using concentrations of 0.3, 0.7, 2, 6, or 10 ppm for 

6 hours. Formaldehyde was again observed in the form of formaldehyde-DNA-protein cross links, and 

was detected at all concentrations tested. Male Rhesus monkeys were exposed to 0.7, 2, or 6 ppm 

formaldehyde 14C-labeled and nonradiolabeled mixture for 6 hours and it was determined that 

approximately 90% of all 14C was associated with the thymine, while 10% was associated with the 

guanine and adenine. Concentrations of DNA-protein cross links were greatest in the middle turbinate 

tissues and lowest in the nasopharyngeal tissues, with some evidence of cross link formation observed in 

the larynx/trachea/carina and major intrapulmonary airway tissues of two monkeys in the 6-ppm dose 

group. No evidence of cross link formation was seen in the sinus or lung tissues at any exposure 

concentration. 

The mechanism by which formaldehyde exerts its toxicological effects is not known; however, it is 

known that formaldehyde readily combines with free, unprotonated amino groups of amino acids to yield 

hydroxymethyl amino acid derivatives and a proton (H+

), which is believed to be related to its germicidal 

properties. Higher concentrations will precipitate protein (Loomis 1979). Either one of these mechanistic 

properties or perhaps other unknown properties may be responsible for the irritation effects seen with 

formaldehyde exposure. It is probable that formaldehyde toxicity occurs when intracellular levels 

saturate formaldehyde dehydrogenase activity, overwhelming the natural protection against 

formaldehyde, and allowing the unmetabolized intact molecule to exert its effects locally. The primary 

metabolite of formaldehyde, formate, is not expected to be as reactive as formaldehyde itself and is 

subject to excretion as a salt in the urine, entrance into the one-carbon metabolic pool for incorporation 

into other cellular components, or further metabolism to carbon dioxide. 

The toxicity of formaldehyde is route-dependent. Irritation at the point of contact is seen by inhalation, 

oral, and dermal routes. High doses are cytotoxic and result in degeneration and necrosis of mucosal and 

epithelial cell layers. These observations are consistent with the hypothesis that toxic effects are 

mediated by formaldehyde itself and not by metabolites. No specific target molecule has been identified, 

although DNA-protein cross links have been identified (Casanova and Heck 1987). As discussed in 
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2. HEALTH EFFECTS 

Section 2.2, oral and inhalation toxicity studies with animals generally have found that toxic effects from 

formaldehyde are restricted to portal-of-entry tissue, but there are scattered reports of toxic effects at sites 

distant from portals-of-entry. The mechanism whereby distant site toxicity may be expressed is unclear, 

but given the highly reactive nature of formaldehyde and the ubiquitous metabolic capability of cells to 

metabolize formaldehyde, it is plausible that distant site effects may occur only when the capacity for 

local disposition of formaldehyde is exceeded. 

An example of a local effect of formaldehyde vapor was demonstrated in the rat nasal epithelium. In rat 

studies where cell turnover was measured (a measure of formaldehyde cytotoxicity), the no-effect level is 

approximately 2 ppm (Monticello et al. 1991; Swenberg et al. 1983) for 6 hours/day exposures for 

#9 days. At higher concentrations (6, 10, or 15 ppm), higher rates of cell turnover were seen (Monticello 

et al. 1991), and a dose-response was observed. The increase in cell proliferation (as measured by 

thymidine incorporation) was more sensitive to formaldehyde exposure than histopathological changes. 

Similar results were seen in a 6-week experiment at these same doses in which the rats were exposed 

5 days/week. The relationship between concentration and total dose has been studied in experiments 

where rats were exposed to a range of concentrations for various lengths of time so that the total inhaled 

dose was constant (Wilmer et al. 1987, 1989). Studies have shown that formaldehyde concentration in 

the inspired air may be more important than exposure duration in determining the extent of nasal damage 

(Wilmer et al. 1987, 1989) (see Section 2.5). Monticello et al. (1996) also determined that the nasal cell 

target population size, increased cell proliferation of specific target cells (due to differences in regional 

airflow with the rat nasal cavity), and the nonlinear kinetics of formaldehyde binding to DNA explain 

why specific regions of the rat nose are more prone to develop formaldehyde-induced nasal squamous cell 

carcinomas than other sites in the nasal cavity. 

Correlation of regional and nonlinear formaldehyde-induced nasal cancer with proliferating populations 

of cells has been studied. Monticello et al. (1996) assessed the role of regional increases in nasal 

epithelial cell proliferation in the formation of formaldehyde-induced nasal cancer in male Fisher 344 rats 

whole-body exposed to formaldehyde up to 15 ppm for 24 months. The majority of formaldehydeinduced neoplasms consisted of squamous cell carcinomas and polyploid adenomas; however, cell 

proliferation was not affected by formaldehyde exposures of 6.01 ppm or less. Increases in the cell 

labeling index were significant at the 10 and 15 ppm exposure levels, and there was a highly significant 

correlation between formation of tumor cells and proliferating cells within the rat nasal cavity. 
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Although there is evidence to suggest that exposure concentration is more important than exposure 

duration in determining the extent of formaldehyde-induced nasal epithelial damage, the development of 

formaldehyde-induced nasal squamous cell carcinomas is likely to require repeated and prolonged 

damage to the nasal epithelium. Several key points or events determine the mechanism by which 

formaldehyde induces cancer in rats. First, a single high dose (#40 ppm) for acute durations is not likely 

sufficient to induce squamous cell carcinoma cancer (Bhalla et al. 1990; Monteiro-Riviere and Popp 

1986; Wilmer et al. 1987); repeated exposures for protracted durations are required to induce nasal cancer 

in rats. Second, the data indicate that a sequence of cellular events must occur in order to induce nasal 

carcinomas. The induction of nasal cancer in rats by formaldehyde requires repeated exposure for 

prolonged periods of time to high concentrations that are both irritating and that cause cell damage to a 

population of the nasal mucosa cells lining the nose. Exposure to high concentrations for prolonged 

periods during inhalation exposure overwhelms or otherwise exhausts the inherent defense mechanisms to 

formaldehyde (mucociliary clearance, FDH, DNA repair). This cellular and tissue damage inflicted by 

unmetabolized formaldehyde is then followed by a regenerative hyperplasia and metaplasia phase (Chang 

et al. 1983; Feron et al. 1988; Rusch et al. 1983; Wilmer et al. 1987; Woutersen et al. 1987, 1989), which 

results in increased cell-turnover rates within the mucosa. Formaldehyde has been demonstrated to be 

genotoxic in some (but not all) cell lines and test systems (Basler et al. 1985; Donovan et al. 1983; 

Grafstrom et al. 1985, 1993; Rithidech et al. 1987; Snyder and Van Houten 1986; Valencia et al. 1989; 

Woodruff et al. 1985; Yager et al. 1986). DNA-protein cross links have been demonstrated in 

experimental animals after inhalation exposure to formaldehyde and can cause mutation or chromosomal 

aberrations if not repaired prior to cell replication. The DNA damage that occurs in these altered cells is 

carried into subsequent cell populations and thereby greatly enhances the progression of preneoplastic 

cells to cancer. In this manner, formaldehyde likely can act as a complete carcinogen (providing 

initiation, promotion, and progression) with repeated and prolonged duration of exposure at cytotoxic 

concentrations. Point mutations in the p53 tumor suppressor gene were found in 5 of 11 nasal tumors 

examined from rats exposed to 15 ppm formaldehyde for 2 years (Recio et al. 1992). The tissues in the 

Recio et al. (1992) study were reanalyzed using antibodies against p53. One was a monoclonal antibody 

to mutant p53, and the other a polyclonal antibody directed against epitopes in mutant and wild type p53 

(Wolf et al. 1995). Morphologically normal nasal mucosa and metaplastic and hyperplastic tissues were 

negative for p53 immunoreactivity. In squamous cell carcinomas (the five with previously identified p53 

mutations and three of six tumors with no mutations identified), p53 immunoreactivity was focal to 

diffuse, and the authors stated that their results using these antibodies were solely from reactions with 

mutant p53. 
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2.4.3 Animal-to-Human Extrapolations 

The target organs for formaldehyde appear to be similar in humans and laboratory animals exposed to 

airborne, ingested, or dermally-applied formaldehyde. As discussed in Section 2.2.1, airborne 

formaldehyde is an acute contact irritant in humans and laboratory animals, causing irritation of the eyes 

and upper respiratory tract during an inhalation exposure. Repeated exposure to airborne formaldehyde 

has been associated with region-specific damage to the upper respiratory tract epithelium in rats, 

monkeys, and mice (e.g., Kamata et al. 1997; Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al. 

1989, 1996), and evidence for similar lesions has been found in nasal tissue specimens sampled from 

occupationally-exposed workers (Ballarin et al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom 

et al. 1989c). Lifetime exposure to formaldehyde concentrations between 10 and 15 ppm produced nasal 

tumors in rats, but no evidence of malignant neoplastic lesions has been found in numerous rat studies at 

concentrations #2 ppm (e.g., Kamata et al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Woutersen et 

al. 1989). Some studies of formaldehyde-exposed workers, typically exposed to average concentrations 

below 2 ppm, have found evidence for an increase in nasopharyngeal cancer death rate, whereas other 

studies of other groups of exposed workers have found no cases of nasopharyngeal cancer (see 

Section 2.2.1.8). Gastric lesions have been induced in rats (e.g., Til et al. 1988b) and in humans 

(Burkhart et al. 1990; Eells et al. 1981; Kochhar et al. 1986; Koppel et al. 1990) after oral exposure. 

Formaldehyde is produced endogenously in all animal species studied. Absorption, distribution, 

metabolism, and excretion of formaldehyde are similar across species; however, species differences in 

upper respiratory tract anatomy and physiology likely play a role in determining the location of 

nonneoplastic (and neoplastic) lesions from inhaled formaldehyde. Formaldehyde-induced epithelial 

lesions, such as squamous metaplasia, showed a wider distribution of occurrence in the upper respiratory 

tract of Rhesus (Monticello et al. 1989) and Cynomolgus (Rusch et al. 1983) monkeys than similar 

lesions which were mostly confined to the anterior portion of the nasal cavity in formaldehyde-exposed 

rats (Bhalla et al. 1991; Monteiro-Riviere and Popp 1986; Morgan et al. 1986a; Wilmer et al. 1987; 

Woutersen et al. 1987). The differences in location of these lesions are likely due to differences in 

airflow pattern through the nasal cavity, resulting in different deposition patterns. The fact that rats are 

obligate nose-breathers and monkeys have an oronasal breathing pattern likely also has an impact on the 

location of these lesions. Other species differences have been noted between rats and mice. Mice tend to 

be more efficient at reducing their minute volumes during formaldehyde exposures than rats, which may 
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2. HEALTH EFFECTS 

partially account for the differences in the decreased incidences of nonneoplastic lesions (Maronpot et al. 

1986) and neoplastic lesions in mice compared rats (Chang et al. 1981, 1983). 

Available studies of animals exposed by the oral or inhalation routes clearly show that formaldehydeinduced health effects are restricted to portals-of-entry and that inhaled formaldehyde, at 

concentrations $6 ppm, produces nasal tumors in rats (as discussed earlier in Section 2.2.1.8). In contrast, 

epidemiology studies of occupationally-exposed humans have provided only equivocal evidence for 

respiratory tract cancer. Even so, this does not negate the need to determine human cancer risk estimates, 

perhaps by employing means other than epidemiological information. The U.S. EPA (1991a) used doseresponse data for nasal tumors in rats exposed to high concentrations of formaldehyde to extrapolate to 

human cancer risk at low exposure concentrations, using the rate of DNA-protein cross links in target 

tissue as a measure of delivered dose. Estimates of delivered dose and observed rat nasal tumor incidence 

were modeled with a linearized multistage procedure (i.e., were fit to an exponential polynomial model) 

to obtain a 95% upper confidence limit on the slope in the low-dose region of the dose-response curve (a 

rat unit cancer risk estimate of 1.6x10-4 per [pmol DNA-protein cross links/mg DNA/day]). Relationships 

between formaldehyde air concentrations and rates of formation of DNA-protein cross links in nasal 

epithelial tissue of rats (Casanova et al. 1989) or of Rhesus monkeys (Casanova et al. 1991; Heck et al. 

1989) and adjustments to continuous exposure were then used to calculate lifetime human cancer unit risk 

estimates of 3.3x10-4 per ppm formaldehyde based on the monkey data, and 2.8x10-3 per ppm 

formaldehyde based on the rat data. 

The use of DNA-protein cross link formation as a formaldehyde dosimeter in cancer target tissues is 

supported by correlative observations of nonlinear (convex) relationships between DNA-protein cross 

link formation in nasal epithelium of rats and monkeys and formaldehyde air concentrations and similar 

convex exposure-response relationships for formaldehyde-induced tumors in rats (Casanova et al. 1991; 

EPA 1991a). The convex nature of these relationships may be explained by a number of mechanisms, 

including saturation of enzymes involved in metabolism of formaldehyde, a decrease in the functioning of 

the mucociliary apparatus that may trap and remove formaldehyde before it reaches target tissues, 

saturation of protein-binding kinetic mechanisms, and saturation of inherent DNA-protein cross link 

repair mechanisms. 

As discussed in Section 2.3.5, The Chemical Industry Institute of Toxicology and the U.S. EPA (CIIT 

1998) are currently exploring options in using CFD models of nasal airflow and uptake of formaldehyde, 
 

 

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pharmacokinetic models of nasal disposition of formaldehyde, and two-stage clonal growth cancer 

models to derive estimates of cancer risk in humans exposed to inhaled formaldehyde based on nasal 

epithelial responses observed in rats chronically exposed to formaldehyde. 

2.5 RELEVANCE TO PUBLIC HEALTH 

Overview. 

Although formaldehyde is a normal intermediary cellular metabolite involved in the biosynthesis of 

purines, thymidine, and several amino acids, it is a highly reactive molecule that can be directly irritating 

to tissues with which it comes into contact. Human and animal studies indicate that formaldehyde, at 

appropriate exposure levels, can be irritating to the upper respiratory tract and eyes with inhalation 

exposure, to the skin with dermal exposure, and to the gastrointestinal tract with oral exposure. Reports 

of allergic dermal sensitization to formaldehyde are widespread and supported by results from animal 

studies, but the evidence that formaldehyde sensitizes the respiratory tract is less convincing. 

Studies of volunteers exposed to airborne formaldehyde for short periods of time (8 hours or less) indicate 

that eye, nose, and throat irritation occurs at concentrations in the range of 0.4–3 ppm (Andersen and 

Molhave 1983; Bender et al. 1983; Day et al. 1984; Gorski et al. 1992; Krakowiak et al. 1998; Kulle et al. 

1987; Pazdrak et al. 1993; Weber-Tschopp et al. 1977; Witek et al. 1986). At the lower end of this range, 

the irritation is typically described as mild and noted by a lower percentage of exposed subjects than at 

the upper end of the range. Studies of monkeys, rats, and mice exposed to higher concentrations in the 

range of 3–9 ppm for acute to intermediate periods of time demonstrate that formaldehyde nonneoplastic 

toxic effects are restricted to lesions (squamous metaplasia and hyperplasia) in the epithelium of the upper 

respiratory tract (Chang et al. 1983; Monticello et al. 1989; Morgan et al. 1986a, 1986c; Rusch et al. 

1983; Woutersen et al. 1987; Zwart et al. 1988). 

Studies of animals exposed for life to formaldehyde in air or drinking water also show that formaldehyde 

primarily damages tissue at portals-of-entry (i.e., the upper respiratory tract and the gastrointestinal 

tract); evidence for toxic effects at distant sites is less consistent. Replicated inhalation studies have 

shown that formaldehyde induced malignant nasal tumors in rats at high exposure concentrations (10– 

15 ppm) that also induced nasal epithelial necrosis and cellular proliferation, but not at lower 

concentrations (0.3–2 ppm) that did not markedly damage nasal epithelial tissue (Albert et al. 1982; 
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2. HEALTH EFFECTS 

Kamata et al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Woutersen et al. 1989). Exposure-related 

cancer or noncancer lesions at other sites were not found in these studies. Statistically significant 

increased incidences of nasal tumors, however, were not found in mice exposed by inhalation for 2 years 

(Kerns et al. 1983b) or in hamsters exposed for 18 months (Dalbey 1982) at concentrations similar to 

those producing nasal tumors in rats. Nonneoplastic nasal epithelial damage was found in mice exposed 

to 14 ppm, but not in mice exposed to 2 ppm (Kerns et al. 1983b). Three lifetime drinking-water 

exposure studies in rats that found no consistent, exposure-related cancer or noncancer effects at sites 

distant from the gastrointestinal tract (Soffriti et al. 1989; Til et al. 1989; Tobe et al. 1989) provide 

support for the expectation that formaldehyde-induced health effects are restricted to portals-of-entry. 

More than 40 epidemiology studies (cohort studies of industrial workers, cohort studies of medical 

specialists and embalmers, and case-control studies) examining the potential for occupational 

formaldehyde exposure to induce cancer have provided only equivocal evidence of a relationship between 

formaldehyde and nasopharyngeal cancer in humans, and even less convincing evidence for extrarespiratory cancer. 

Occupational and residential exposure to formaldehyde has been associated with reports of symptoms of 

eye, nose, and throat irritation from exposure to airborne formaldehyde (Garry et al. 1980; Holness and 

Nethercott 1989; Horvath et al. 1988; Ritchie and Lehnen 1987), and there are numerous reports of skin 

irritation and contact dermatitis most likely resulting from dermal exposure to formaldehyde in liquids 

(Fischer et al. 1995; Kiec-Swierczynska 1996; Maibach 1983; Meding and Swanbeck 1990; Menné et al. 

1991). Several cross-sectional studies of nasal epithelial tissue specimens from workers exposed to 

airborne formaldehyde in the approximate average concentration range of 0.2–1 ppm found evidence in 

some of the workers for mild lesions (stratified squamous epithelium and mild dysplasia) that are 

indicative of the irritant and reactive properties of formaldehyde (Ballarin et al. 1992; Boysen et al. 1990; 

Edling et al. 1988; Holmstrom et al. 1989c). 

The apparent restriction of formaldehyde-induced noncancer and cancer effects to portals-of-entry is 

consistent with the highly reactive nature of formaldehyde and the existence of physiological mechanisms 

of protection, such as the nasal mucosal barrier and the detoxifying metabolism of formaldehyde in most, 

if not all, cells. The available weight of evidence indicates that distant site effects from formaldehyde 

may occur only when the capacity for local disposition of formaldehyde is exceeded. 
 

 

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Issues relevant to children are explicitly discussed in Sections 2.6 Children’s Susceptibility and 

5.6 Exposures of Children. 

Minimal Risk Levels for Formaldehyde. 

The details regarding calculations of the MRLs for formaldehyde are described in Appendix A. 

Inhalation MRLs 

An MRL of 0.04 ppm has been derived for acute-duration inhalation exposure (14 days or less) 

to formaldehyde. 

The MRL was calculated from a minimal LOAEL of 0.4 ppm for symptoms of increased itching, 

sneezing, mucosal congestion, and transient burning sensation of the eyes and of the nasal passages, and 

elevated eosinophil counts and a transient increase in albumin content of nasal lavage fluid in volunteers 

exposed to formaldehyde for 2 hours (Pazdrak et al. 1993). The LOAEL was divided by an uncertainty 

factor of nine (three for the use of a minimal LOAEL and three for human variability) as described in 

Appendix A. 

The selection of 0.4 ppm as an acute exposure concentration that produces mild eye, nose, and throat 

irritation in some human subjects is supported by reports of: nasal irritation, sneezing, and eye irritation in 

3/13 subjects with formaldehyde contact dermatitis and eye irritation in 1/5 normal subjects exposed to 

0.4 ppm for 2 hours (Gorski et al. 1992); increased eosinophil counts and protein in nasal lavage fluid in 

other groups of 10 healthy subjects and 10 workers with purported formaldehyde-induced bronchial 

asthma exposed to 0.4 ppm for 2 hours (Krakowiak et al. 1998); eye and nasal irritation in 3/16 healthy 

subjects exposed to 0.2 ppm for 4 hours (Andersen and Molhave 1983); and decreased eye irritation 

response time in 5/12 subjects exposed to 0.35 ppm for 6 minutes (Bender et al. 1983). Several other 

acute controlled exposure studies with volunteers have noted higher percentages of subjects reporting 

mild eye, nose, and throat irritation at concentrations between 1 and 2 ppm (Day et al. 1984; Kulle et al. 

1987; Weber-Tschopp et al. 1977; Witek et al. 1986). The Anderson and Molhave (1983) study 

identified an apparent effect level (0.2 ppm) based on subjective reports of irritation that is lower than the 

effect levels (0.35–0.4 ppm) in the studies by Pazdrak et al. (1993), Krakowiak et al. (1998), and Bender 

et al. (1983) which used more objective measures of acute irritation. Because of the use of objective 

measures of toxicity and the general weight of the available data indicating that some people will not 
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experience eye or upper respiratory tract irritation from formaldehyde even at 1 ppm, the Pazdrak et al. 

(1993) LOAEL of 0.4 ppm was considered a minimal LOAEL in a group of potentially sensitive 

individuals (some subjects had dermal hypersensitivity to formaldehyde) and was selected as the basis of 

the acute MRL. 

An MRL of 0.03 ppm has been derived for intermediate-duration inhalation exposure 

(15–364 days) to formaldehyde. 

The MRL is based on a NOAEL of 0.98 ppm for clinical signs of nasopharyngeal irritation (hoarseness 

and nasal congestion and discharge) and lesions in the nasal epithelium (squamous metaplasia and 

hyperplasia) observed in Cynomolgus monkeys exposed to formaldehyde for 22 hours/day, 5 days/week 

for 26 weeks (Rusch et al. 1983). The LOAEL was 2.95 ppm. As described in Appendix A, the NOAEL 

was divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human 

variability). 

Intermediate-duration inhalation studies with several species of animals clearly identify the upper 

respiratory tract as the critical target tissue for airborne formaldehyde and suggest that degenerative 

changes to the upper respiratory tract epithelium may not occur with exposure to concentrations #1 ppm. 

Formaldehyde-induced epithelial damage in the upper respiratory tract similar to that observed in the 

Cynomolgus monkeys has been observed in: Rhesus monkeys exposed to 6 ppm for 6 hours/day, 

5 days/week for 6 weeks (Monticello et al. 1989); several strains of rats subchronically exposed to 

concentrations greater than 2 ppm (Appelman et al. 1988; Feron et al. 1988; Monticello et al. 1991; Rusch 

et al. 1983; Woutersen et al. 1987); and mice exposed to concentrations $4 ppm (Chang et al. 1983; 

Maronpot et al. 1986). Although there are numerous human studies of acute inhalation toxicity from 

formaldehyde (controlled-exposure and occupational exposure studies) and numerous investigations of 

toxic effects from chronic occupational exposures, studies of humans strictly exposed for intermediate 

durations were not located. In contrast, the database for studies of animals (including primates) exposed 

by inhalation to formaldehyde is rich, providing data describing exposure-response relationships for 

formaldehyde-induced effects on the upper respiratory tract system in several species (rats, mice, 

hamsters, and monkeys). The study by Rusch et al. (1983) examined a number of species and identified 

the lowest effect level among the available sets of data. Given this observation, the absence of suitable 

human intermediate-duration data, and the putatively greater relevance of monkeys, compared with 
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rodents, to humans, the monkey NOAEL of 0.98 ppm and LOAEL of 2.95 ppm for clinical signs of 

nasopharyngeal irritation were selected as the basis of the intermediate-duration MRL. 

An MRL of 0.008 ppm has been derived for chronic-duration inhalation exposure (365 days or 

more) to formaldehyde. 

The MRL is based on a minimal LOAEL of 0.24 ppm for histological changes (loss of cilia, goblet cell 

hyperplasia, and cuboidal and squamous cell metaplasia replacing the columnar epithelium) in nasal 

tissue specimens from a group of 70 workers employed for an average 10.4 years (range 1–36 years) in a 

chemical plant that produced formaldehyde and formaldehyde resins for impregnating paper (Holmstrom 

et al. 1989c). The MRL was derived by dividing the LOAEL by an uncertainty factor of 30 (3 for the use 

of a minimal LOAEL and 10 for human variability) as described in Appendix A. 

Several cross-sectional studies of groups of formaldehyde-exposed workers chronically exposed to 

estimated concentrations ranging from about 0.1 to 0.6 ppm (Ballarin et al. 1992; Boysen et al. 1990; 

Edling et al. 1988; Holmstrom et al. 1989c) have found histological evidence for mild damage to nasal 

epithelial tissue such as the damage described for exposed workers in the Holmstrom et al. (1989c) study. 

The observed effects were consistently mild, but each study reported a statistically significant, albeit 

small, increase in average histological score (increasing scores indicating increasing severity of change) 

for exposed groups compared with nonexposed control groups: 2.8 exposed versus 1.8 on an 8-point scale 

(Edling et al. 1988); 2.16 versus 1.46 on an 8-point scale (Holmstrom et al. 1989c); 1.9 versus 1.4 on a 

5-point scale (Boysen et al. 1990); and 2.3 versus 1.6 on a 6-point scale (Ballarin et al. 1992). The 

Holmstrom et al. (1989c) study was selected as the basis of the MRL from among these four crosssectional studies (they each examined equivalent end points and are of similar quality of design) primarily 

because the statistically significant effects were found in a group exposed to formaldehyde in the absence 

of potentially confounding exposures to wood dust. A full uncertainty factor of 10 was used to account 

for human variability because the observed mild effects were seen in groups of chronically exposed 

workers that were otherwise in apparent good health; a healthy worker effect may have operated causing 

sensitive individuals to avoid employment in the studied workplaces. 

Additional supporting evidence for mild histological changes to the nasal epithelium with chronic 

exposure to concentrations below 1 ppm comes from rat studies. Although several studies of rats 

exposed for life (generally with an exposure protocol of 6 hours/day, 5 day/week) found no statistically 

significant increases in incidences of nonneoplastic lesions in the nasal epithelium of rats exposed to 
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0.1 to 2 ppm (Kerns et al. 1983b [F344 rats]; Monticello et al. 1996 [F344 rats]; Woutersen et al. 

1989 [Wistar rats]), Kamata et al. (1997) reported that some F344 rats, after 28 months of exposure, 

displayed a mild response at 2 ppm and even at 0.3 ppm. A statistically significantly increased incidence 

for nasal epithelial squamous metaplasia without hyperplasia was observed in rats exposed to 2 ppm 

compared with control rats (5/32 versus 0/32); the incidence for nasal epithelial cell hyperplasia with 

squamous metaplasia was also significantly elevated compared with controls (7/32 versus 0/32). In rats 

exposed to 0.3 ppm, incidences of the same respective nasal epithelial lesions were also greater than 

control incidences (1/32 versus 0/32 and 4/32 versus 0/32), but not to a statistically significant degree. 

Oral MRLs 

Case reports of acute poisoning in humans ingesting doses of formaldehyde greater than 200 mg/kg have 

reported gastrointestinal effects and symptoms that reflect the chemical reactivity of formaldehyde and 

have reported other effects (e.g., cardiovascular dysfunction, coma, and renal and hepatic dysfunctions) 

that are consistent with the exceedance of the capacity of local detoxification mechanisms at these high 

dose levels (Burkhart et al. 1990; Eells et al. 1981; Kochhar et al. 1986). The acute human poisoning 

data, coupled with the results from studies of animals orally exposed to formaldehyde for intermediate 

and chronic durations, suggest that gastrointestinal irritation and damage are the most likely critical 

effects from acute oral exposure. A no-effect level is not identified by the human data, however, and 

available studies of animals exposed for acute durations provide no dose-response information for this 

end point. Available acute-exposure animal data are restricted to 2-week, oral administration studies that 

only examined body weight in rats (Johannsen et al. 1986) and a 10-day gavage administration study of 

testicular weight and sperm variables in rats (Cassidy et al. 1983). In the absence of dose-response data 

for gastrointestinal irritation and damage from acute oral exposure, no acute-duration MRL was derived. 

An MRL of 0.3 mg/kg/day has been derived for intermediate-duration oral exposure 

(15–364 days) to formaldehyde. 

The MRL was based on a NOAEL of 25 mg/kg/day for gastrointestinal effects in rats exposed to 

formaldehyde in drinking water (Til et al. 1988b). The LOAEL was 125 mg/kg/day. An uncertainty 

factor of 100 (10 for extrapolation from animals to humans and 10 for human variability) was applied to 

the NOAEL to derive the MRL. The Til et al. (1988b) study used groups (10 males and 10 females) of 

weanling Wistar rats that received 0, 5, 25, or 125 mg/kg/day formaldehyde in their drinking water for 

4 weeks. Control groups (20 males and 20 females) were given unsupplemented tap water. A water­
 

FORMALDEHYDE 203 

2. HEALTH EFFECTS 

restricted group (10 males and 10 females) received the same amount of unsupplemented drinking water 

as the amount of liquid consumed by the group given the highest dose of formaldehyde. Dosing solutions 

were prepared fresh every week and fresh drinking water containing a calculated concentration of 

formaldehyde was provided to the rats every day. The authors did not report if or how often the drinking 

water was assayed for actual formaldehyde content, so it is not known, due to possible oxidation, 

polymerization, or evaporation, if the full dose of formaldehyde was received. Histopathology revealed 

thickening of the limiting ridges, hyperkeratosis in the forestomach, and focal atrophic inflammation in 

the glandular stomach in animals given a high concentration of formaldehyde. Moderate papillomatous 

hyperplasia was seen in one female given a high concentration of formaldehyde. Types of lesions in 

males given 125 mg/kg formaldehyde are as follows: slight-to-moderate focal hyperkeratosis of 

forestomach, slight-to-moderate focal gastritis, and slight-to-moderate submucosal mononuclear-cell 

infiltrate. Types of lesions in females given 125 mg/kg formaldehyde are as follows: very slight, slightto-moderate focal hyperkeratosis of forestomach; very slight, slight-to-moderate focal gastritis; focal 

papillomatous hyperplasia; and polymorphonuclear leucocytic infiltration. No gastrointestinal effects 

were noted at the 25 mg/kg/day dose of formaldehyde. 

Gastrointestinal irritation and damage have been observed in both humans and animals after ingestion of 

formaldehyde. In human poisoning studies, effects observed include: ulceration and sloughing of the soft 

palate and posterior pharyngeal wall; ulceration of the epiglottis, pyriform fossae, and arytenoids; 

edematous and ulcerated esophageal mucosa with patches of black sloughed tissue along the entire length; 

hyperemic areas of the stomach; and superficial ulceration in the distal body and antrum after a single 

dose of 234 mg/kg formaldehyde (Kochhar et al. 1986); abdominal pain and retching; and hard, white, 

and leathery stomach after a dose of 517 mg/kg (Burkhart et al. 1990); or abdominal pain after a dose of 

624 mg/kg (as formalin) (Eells et al. 1981). In human poisoning studies in which the dose of 

formaldehyde is not known, gastrointestinal symptoms included mucosal damage, ulceration and bleeding 

of the buccal cavity and tonsils, and dysphagia due to esophageal mucosal damage (Freestone and 

Bentley 1989); necrosis of the esophagus and stomach, extensive congestion, peptic plaques in esophagus 

and stomach, colitis, congestion, diffuse necrosis and hemorrhage of gastric and duodenal mucosa, burns 

in gastrointestinal mucosa, and ileitis (Koppel et al. 1990). In rat studies in which formaldehyde was 

administered orally for longer periods of time, consistent evidence has been found for gastrointestinal 

irritation and damage, but the evidence for orally-induced neoplastic lesions is equivocal due to 

inconsistent findings among the studies (Soffritti et al. 1989; Takahashi et al. 1986a; Til et al. 1989; Tobe 

et al. 1989). 
 

204 

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FORMALDEHYDE 

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An MRL of 0.2 mg/kg/day has been derived for chronic-duration oral exposure (365 days or 

more) to formaldehyde. 

The MRL was based on a NOAEL of 15 mg/kg/day for gastrointestinal effects in male rats exposed to 

formaldehyde in drinking water (Til et al. 1989). The LOAEL was 82 mg/kg/day. An uncertainty factor 

of 100 (10 for extrapolation from animals to humans and 10 for human variability) was applied to the 

NOAEL to derive the MRL. The Til et al. (1989) study used groups of Wistar rats that received 

formaldehyde in their drinking water for 2 years. Estimated formaldehyde doses in this study were 0, 1.2, 

15, or 82 mg/kg/day for males and 0, 1.8, 21, or 109 mg/kg/day for females. Dosing solutions were 

prepared fresh every week and fresh drinking water containing a calculated concentration of 

formaldehyde was provided to the rats every day. The authors did not report if or how often the drinking 

water was assayed for actual formaldehyde content, so it is not known, due to possible oxidation, 

polymerization, or evaporation, if the full dose of formaldehyde was received. Necropsy findings of 

high-dose rats killed in weeks 53, 79, and 105 revealed a raised and thickened limiting ridge of the 

forestomach in most male and female rats of the high-dose group and in some males and females of the 

other groups, including the control group. Also, several rats in the high-dose groups showed irregular 

mucosal thickenings in the forestomach and/or glandular stomach. These changes were also found in rats 

of the other groups as well as the control groups. In high-dose animals, histopathological examination 

revealed gastric changes including papillary epithelial hyperplasia accompanied by hyperkeratosis and 

focal ulceration in the forestomach and focal chronic atrophic gastritis, occasionally accompanied by 

ulceration and/or glandular hyperplasia, in the glandular stomach. There were no gastric tumors observed 

apart from two benign papillomas, one in the male of the low-dose group and one in a female control rat. 

Death. Cases of death in humans acutely exposed to airborne formaldehyde were not located. Death 

after the ingestion of formaldehyde (or a formalin solution) in humans has been reported in connection 

with attempted suicides. Metabolic acidosis has been noted prior to death, along with respiratory, cardiac, 

and renal failure; autopsy revealed corrosive damage to gastrointestinal mucosa (Burkhart et al. 1990; 

Eells et al. 1981; Koppel et al. 1990). Increased rates of cancer-related mortality associated with 

occupational exposure to formaldehyde (predominately by inhalation) have been found in some 

epidemiological studies, but not in others (see Section 2.2.1.8 and Section 2.5). Animal studies indicate 

that subchronic inhalation exposure to concentrations below 20 ppm are not lethal (Feron et al. 1988; 

Maronpot et al. 1986; Martin 1990; Rusch et al. 1983; Saillenfait et al. 1989; Woutersen et al. 1987), but 

lifetime inhalation exposure to formaldehyde has been associated with early mortalities associated with 
 

FORMALDEHYDE 205 

2. HEALTH EFFECTS 

nasal tumors in rats exposed to concentrations $10 ppm (Albert et al. 1982; Kamata et al. 1997; Kerns et 

al. 1983b; Monticello et al. 1996; Woutersen et al. 1989). Lifetime administration of 5,000 ppm 

formaldehyde in drinking water (approximate dose of 300 mg/kg/day) to rats resulted in early mortalities 

associated with degenerative lesions in the epithelium of the forestomach and the glandular stomach 

(Tobe et al. 1989). 

Systemic Effects. 

Respiratory Effects. Results from human and animal studies consistently indicate that the upper 

respiratory tract is a critical target of airborne formaldehyde at concentrations ranging from 0.4 to 

20 ppm. 

Controlled exposure human studies indicate that short-term exposure to air concentrations ranging from 

0.4 to 3 ppm induces eye, nose, and throat irritation that is generally described as mild by most subjects, 

especially at the lower end of this range, and that is experienced by a greater percentage of subjects at the 

upper end, compared with the lower end, of the range (Andersen and Molhave 1983; Bender et al. 1983; 

Day et al. 1984; Gorski et al. 1992; Krakowiak et al. 1998; Kulle et al. 1987; Pazdrak et al. 1993; 

Schachter et al. 1986; Weber-Tschopp et al. 1977; Witek et al. 1986). Changes in nasal lavage fluid 

contents (elevated eosinophil counts and protein content), consistent with mild irritation of the nasal 

epithelium, have been found in several studies of groups of subjects exposed to 0.4 ppm for 4 hours 

(Gorski et al. 1992; Krakowiak et al. 1998; Pazdrak et al. 1993). The studied groups included healthy 

subjects, as well as groups of subjects with dermal sensitivity to formaldehyde (Pazdrak et al. 1993) and 

groups with purported formaldehyde-induced bronchial asthma (Krakowiak et al. 1998). 

Formaldehyde effects on pulmonary function variables, such as FVC, FEV1, and forced expiratory flow 

rates, have not been found in most studies between 0.4 and 3 ppm, even in studies of subjects with 

bronchial asthma or with dermal sensitivity to formaldehyde (Andersen and Molhave 1983; Day et al. 

1984; Gorski et al. 1992; Harving et al. 1986, 1990; Kulle et al. 1987; Schachter et al. 1986; Witek et al. 

1986). A few controlled exposure studies have found only subtle or infrequent effects of formaldehyde 

on lower respiratory tract function in this concentration range, supporting the hypotheses that the upper 

respiratory tract is a more likely target of formaldehyde toxicity than the lower respiratory tract and that 

pulmonary hypersensitivity to formaldehyde is rare (Green et al. 1987; Nordman et al. 1985; Sauder et al. 

1986). 
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2. HEALTH EFFECTS 

In groups of humans who experienced repeated exposure to airborne formaldehyde under occupational or 

residential conditions, symptoms of eye, nose, and throat irritation were frequently reported (Boysen et al. 

1990; Edling et al. 1988; Garry et al. 1980; Holmstrom et al. 1989c; Holness and Nethercott 1989; 

Horvath et al. 1988; Ritchie and Lehnen 1987). Mild lesions in biopsied nasal epithelium tissue (e.g., 

stratified squamous epithelium and mild dysplasia) that are indicative of the irritant and reactive 

properties of formaldehyde were consistently found in four cross-sectional studies of groups of workers 

exposed to estimated average workplace air concentrations ranging from about 0.1 to 1 ppm (Ballarin et 

al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c). Some studies assessing 

pulmonary function variables (e.g., FVC, FEV1, FEFR) in groups of formaldehyde-exposed workers, 

generally experiencing average workplace air concentrations below 2 ppm, have found no changes that 

can be attributed to exposure (Bracken et al. 1985; Holness and Nethercott 1989; Horvath et al. 1988). 

Other studies have presented evidence for formaldehyde-induced changes in pulmonary function 

variables in groups of subjects exposed in their homes or workplaces, but the changes in these studies 

were generally small or subtle (Alexandersson and Hedenstierna 1988, 1989; Khamgaonkar and Fulare 

1991; Kriebel et al. 1993; Krzyzanowski et al. 1990; Malaka and Kodama 1990). 

Studies in animals confirm that the upper respiratory tract is a critical target for airborne formaldehyde. 

Studies of monkeys, rats, and mice exposed to concentrations in the range of 0.3–40 ppm for acute to 

chronic periods of time demonstrate that formaldehyde nonneoplastic effects are restricted to lesions 

(squamous metaplasia and hyperplasia) in the epithelium of the upper respiratory tract (Chang et al. 1983; 

Kamata et al. 1997; Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al. 1989, 1991, 1996; Morgan 

et al. 1986a, 1986c; Rusch et al. 1983; Woutersen et al. 1987, 1989; Zwart et al. 1988). In several 

lifetime rat studies, exposure to 0.1–2 ppm formaldehyde (6 hours/day, 5 days/week) produced no 

statistically significant increased incidence of rats with nonneoplastic nasal epithelial lesions (Kerns et al. 

1983b; Monticello et al. 1996; Woutersen et al. 1989). Another 28-month study, however, found 

significantly increased incidence of nasal epithelial lesions (squamous metaplasia without hyperplasia and 

epithelial cell hyperplasia with squamous metaplasia) in a group of rats exposed to 2 ppm by the same 

exposure protocol (Kamata et al. 1997). Incidences of the same lesions in rats exposed to 0.3 ppm also 

were greater than control incidences, but the difference was not statistically significant. 

In rats exposed to the lower concentrations in the 2–20 ppm range, formaldehyde-induced lesions 

(evidence of which could be found after a few days of exposure) occurred in the anterior regions of the 

nasal epithelium just posterior to the vestibule and progressed to more posterior regions of the upper 
FORMALDEHYDE 207 

2. HEALTH EFFECTS 

respiratory tract epithelium with higher exposure concentrations (Chang et al. 1983; Monticello et al. 

1991; Morgan et al. 1986a, 1986c; Zwart et al. 1988). Results from studies in rats comparing nasal lesion 

severity following intermittent or continuous exposure protocols at varying concentrations suggest that 

effects are more concentration-dependent than duration-dependent (Wilmer et al. 1987, 1989). Monkeys 

exposed to 6 ppm formaldehyde for 6 weeks (Monticello et al. 1989) displayed epithelial lesions similar 

to those displayed by rats exposed to the same concentration for 6 weeks (Monticello et al. 1991), but the 

lesions in the monkeys showed a different regional distribution that extended into the trachea. Recent 

analyses using computational fluid dynamics models to predict airflow and regional uptake of 

formaldehyde in the upper respiratory tract of monkeys and rats found that predicted regions of high 

airflow were well correlated with epithelial regions with lesions (Kepler et al. 1998; Kimbell et al. 1993, 

1997a). These results support the hypothesis that the rat and monkey may be equally susceptible to 

formaldehyde-induced tissue damage and that airflow patterns, determined by anatomical features, are 

key determinants of the amount of formaldehyde reaching sites where lesions develop. 

Data on effects on the respiratory tract changes after oral exposure to formaldehyde in rats show no 

changes attributable to formaldehyde with respect to histopathology and/or lung weights in studies of 

intermediate (Johannsen et al. 1986; Til et al. 1988b; Vargova et al. 1993) and chronic (Til et al. 1989; 

Tobe et al. 1989) duration. 

Cardiovascular Effects. It is unlikely that formaldehyde is responsible for any significant toxicological 

effects in organs other than the respiratory tract, particularly after inhalation or dermal exposures that 

might be encountered in the workplace or home. However, effects on the cardiovascular system, such as 

decreased blood pressure and hypotension (Burkhart et al. 1990; Eells et al. 1981), circulatory collapse 

(Freestone and Bentley 1989), and sinus tachycardia (Kochhar et al. 1986) due to the ingestion of high 

doses of formaldehyde in humans have been reported. It is not clear how formaldehyde induced these 

symptoms or if other existing conditions contributed in whole or in part to these cardiac responses, but is 

likely related to the large dose of formaldehyde ingested in a very short period of time. 

Rats displayed 5–25% increases in blood pressure, compared with resting values, in response to 

intravenous administration of formaldehyde doses ranging from 0.5 to 5 mg/kg (Egle and Hudgins 1974). 

In contrast, an intravenous dose of 20 mg/kg significantly decreased blood pressure by about 30% and 

induced a transient cardiac arrest. The depressor effect at the high dose level was abolished by vagotomy 

in the neck region, and only the pressor effect was observed in vagotomized rats exposed to 20 mg/kg. 
FORMALDEHYDE 208 

2. HEALTH EFFECTS 

Egle and Hudgins (1974) suggested that the low-dose pressor effects are caused by formaldehyde-induced 

release of epinephrine from sympathetic nerve endings and catecholamines from the adrenal medulla, and 

that the vagal nerve is stimulated at high doses leading to bradycardia and decreased blood pressure. Egle 

and Hudgins (1974) reported that 1-minute exposures to formaldehyde in inspired air at a concentration of 

2 mg/L (1,628 ppm) did not significantly affect blood pressure or heart rate in anesthetized rats. This 

concentration was reported to be 20-times higher than formaldehyde concentrations in inhaled cigarette 

smoke. These results indicate that acute cardiovascular effects are not expected at environmentally 

relevant exposure levels. 

Results from repeated exposure animal studies suggest that cardiovascular effects due to formaldehyde 

toxicity after inhalation are negligible, regardless of the duration of exposure at the concentrations tested 

(#40 ppm). After inhalation exposure, organ weights and/or histopathology remained unchanged from 

control animals in studies using rats (Appelman et al. 1988; Kerns et al. 1983b; Woutersen et al. 1987, 

1989), monkeys (Monticello et al. 1989; Rusch et al. 1983), and mice (Kerns et al. 1983b; Maronpot et al. 

1986). Fewer reports were available on cardiovascular toxicity of formaldehyde after oral exposure at 

doses up to 300 mg/kg/day; however, the findings of no significant effects (weight or histopathology) on 

this system were consistent in both rats (Johannsen et al. 1986; Til et al. 1988b, 1989; Tobe et al. 1989; 

Vargova et al. 1993) and dogs (Johannsen et al. 1986). 

Gastrointestinal Effects. Formaldehyde did not have a detectable effect on the gastrointestinal tract after 

inhalation exposure of animals (Appelman et al. 1988; Kamata et al. 1997; Kerns et al. 1983b; Maronpot 

et al. 1986; Monticello et al. 1989; Woutersen et al. 1987) and only nonspecific effects, such as intestinal 

cramps, and flatus, were reported in four patients that had been exposed occupationally to formalin or 

phenol-formaldehyde resins (Kilburn 1994). Formaldehyde acts as a contact irritant and corrosive agent 

after oral exposures of acute, intermediate, and chronic durations. After large doses taken by mouth 

(acute exposure), lesions can be found in the oropharynx, consisting of ulceration and/or necrosis of the 

soft palate and phalangeal structures, ulceration of the epiglottis, and esophageal lesions (which may 

result in dysphagia) (Freestone and Bentley 1989; Kochhar et al. 1986). More vague clinical signs of 

emesis (with or without hematoemesis) and abdominal pain or cramping were also present in some cases 

(Burkhart et al. 1990; Eells et al. 1981); these are due, at least in part, to a contact irritant effect, but may 

also be attributable to corrosive lesions found in the stomach after the ingestion of formaldehyde. In 

cases which afforded an examination of the duodenum and other portions of the intestinal tract after the 

stomach, no lesions attributable to formaldehyde intoxication were noted, indicating that the oral cavity 
FORMALDEHYDE 209 

2. HEALTH EFFECTS 

and the stomach share the brunt of the toxicity of formaldehyde after ingestion. Similar findings in the 

stomachs of Wistar rats noted in one intermediate-duration study (Til et al. 1988b) consisted of 

hyperkeratosis of the forestomach (indicative of chronic irritation) and focal atrophic inflammation of the 

glandular stomach at doses of 125 mg/kg/day. Another study by Til and coworkers (1989) found gastric 

anomalies, consisting of hyperplasia/hyperkeratosis, atrophic gastritis, and ulcerations in Wistar rats at 

doses ranging from 82 to 109 mg/kg/day in drinking water. Similar effects were also observed in Wistar 

rats at doses of 50–300 mg/kg/day for up to 2 years (Tobe et al. 1989) and in Wistar rats, exposed to 

250 mg/kg/day in drinking water for up to 32 weeks (Takahashi et al. 1986a). Other studies found no 

significant effect on the gastrointestinal system in both Sprague-Dawley rats (Johannsen et al. 1986; 

Vargova et al. 1993) and dogs (Johannsen et al. 1986) at doses ranging from 80 to 300 mg/kg/day. The 

data suggest that formaldehyde has a strong potential to cause damage to the upper gastrointestinal tract 

(oral cavity, esophagus, and stomach) after oral exposure, and although laboratory animal data are similar 

to human data, species differences may account for slight differences in the dose required to initiate the 

damage to the gastrointestinal tract. Evidence for oral exposure to formaldehyde causing tumors of the 

gastrointestinal tract is discussed below under Cancer Effects. 

Hematological Effects. Intravascular coagulopathy was reported in one man who ingested a large dose of 

formaldehyde (Burkhart et al. 1990); however, the other reports of human ingestion of lower doses 

suggest no effects on the blood and blood-forming organs (Eells et al. 1981; Freestone and Bentley 1989; 

Kochhar et al. 1986; Koppel et al. 1990). No consistently significant hematological effects were noted in 

several studies using the inhalation (Appelman et al. 1988; Kamata et al. 1997; Kerns et al. 1983b; 

Woustersen et al. 1987) and oral (Johannsen et al. 1986; Til et al. 1988b, 1989; Tobe et al. 1989) routes of 

exposure in laboratory animals. The oral studies with rats used drinking water as the vehicle, with doses 

ranging from 82 to 150 mg/kg/day, with no hematological effects noted. The lack of toxicity is likely 

related to rapid metabolism prior to the formaldehyde reaching the blood and blood-forming components 

(bone marrow). Some evidence suggests, however, that the rapid metabolic capabilities can be 

overwhelmed to some degree (Vargova et al. 1993), resulting in some minor alterations in blood 

parameters. In that study, affected male rats received a gavage dose level of 80 mg/kg/day formaldehyde 

for 4 weeks. This dosing method may have resulted in large doses of formaldehyde being absorbed over 

a shorter period of time than in the drinking water studies. In this situation, some unmetabolized 

formaldehyde may have been responsible for the alterations in erythrocyte count and hemoglobin and 

mean cellular hemoglobin values. 
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2. HEALTH EFFECTS 

Musculoskeletal Effects. The only reports available that described some manifestations of adverse 

musculoskeletal effects in humans included vague signs of muscle and joint stiffness after chronicinhalation exposures to formaldehyde (Holness and Nethercott 1989). It is unlikely that inhalation 

exposure to formaldehyde is responsible for these complaints, and they may represent an effect from a 

confounding factor in that study. The lack of human data and the lack of musculoskeletal effects in 

animal studies (Kamata et al. 1997; Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al. 1989; Til 

et al. 1989), coupled with the available toxicokinetic data, suggest that formaldehyde has no adverse 

effects on the musculoskeletal system. 

Hepatic Effects. Hepatic effects (e.g., congestion of hepatic parenchyma and increased serum enzymes 

associated with liver damage) have been reported for some human cases of acute poisoning from 

ingestion (e.g., Freestone and Bentley 1989; Koppel et al. 1990), but not reported for other cases (e.g., 

Burkhart et al. 1990; Eells et al. 1981). Increased incidence of hepatocellular vacuolization was found in 

rats exposed to gavage dose level of 80 mg/kg/day for 4 weeks (Vargova et al. 1993), but other studies 

found no exposure-related changes in liver weight or histopathology in rats exposed to drinking-water 

doses as high as 150 mg/kg/day for 90 days (Johannsen et al. 1986), 125 mg/kg/day for 4 weeks (Til et al. 

1988b), 82–109 mg/kg/day for 2 years (Til et al. 1989), and 300 mg/kg/day for 2 years (Tobe et al. 1989). 

Liver weight and histopathology were likewise unaffected in Beagle dogs exposed to up to 

100 mg/kg/day in the diet for 90 days (Johannsen et al. 1986), as were serum enzyme activities indicative 

of liver damage in rats exposed to up to 300 mg/kg/day for up to 2 years (Tobe et al. 1989). Increased 

activities of enzymes indicative of liver damage have been reported in rats exposed to air concentrations 

of 35 ppm for 18 hours (Murphy et al. 1964) or 20 ppm 6 hours/day, 5 days/week for 13 weeks 

(Woutersen et al. 1987), but accompanying structural changes in the liver were not detected with light 

microscopy. Other studies with rats have not found evidence for increased serum liver enzymes in rats 

exposed to air concentrations up to 15 ppm, 5 days/week for up to 28 months (Appelman et al. 1988; 

Kamata et al. 1997). Several other inhalation studies of intermediate or chronic duration have found no 

evidence for formaldehyde-induced histological changes in the livers of monkeys exposed to 6 ppm 

(Monticello et al. 1989), rats exposed to up to 14.3 ppm (Kerns et al. 1983b), or mice exposed to up to 

40 ppm (Kerns et al. 1983b; Maronpot et al. 1986). 

In general, the information from reports of acute poisoning in humans ingesting formaldehyde and reports 

of studies of animals exposed to formaldehyde in air, in drinking water, or in the diet indicate that the 

liver is not a prime target of formaldehyde toxicity, and that hepatic effects from exposure to 
FORMALDEHYDE 211 

2. HEALTH EFFECTS 

formaldehyde are expected to occur only when the capacity of dispositional processes for formaldehyde 

are exceeded at portals-of-entry. 

Renal Effects. The available data suggest that the renal system is not a major target organ of toxicity for 

formaldehyde. Renal failure/anuria was noted in three case reports involving people ingesting various 

large or unknown amounts formaldehyde (Eells et al. 1981; Freestone and Bentley 1989; Koppel et al. 

1990); however, the mechanism of action for the induction of renal failure is not known. Data for 

laboratory animals exposed by inhalation for intermediate- and chronic-duration to formaldehyde 

concentrations ranging from 0.19 to 40 ppm are fairly consistent in the failure of formaldehyde to elicit 

gross or histological lesions, alterations in renal weight, or to produce significant changes in urine 

composition (Appelman et al. 1988; Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al. 1989; 

Woutersen et al. 1987). Appelman et al. (1988) did report oliguria in rats exposed to 10 ppm for 

52 weeks, but Kerns et al. (1983b) did not report a similar finding in rats and mice exposed to up to 

14.3 ppm for 2 years. Similarly, lack of renal effects was also reported after intermediate- and 

chronic-duration oral exposure in most studies (Johannsen et al. 1986; Til et al. 1988b; Tobe et al. 1989; 

Vargova et al. 1993), but renal papillary necrosis was reported for rats that received 82–109 mg/kg/day in 

drinking water for 2 years (Til et al. 1989), and increased blood urea nitrogen was reported in rats that 

received 300 mg/kg/day in drinking water for up to 12 months (Tobe et al. 1989). 

Endocrine Effects. No information was available that reported the effects of formaldehyde on the 

endocrine system of humans after inhalation, oral, or dermal exposure. Formaldehyde has been reported 

not to exert adverse effects on organs of the endocrine system in laboratory animals and, hence, is not a 

major target organ for formaldehyde toxicity after inhalation (Appelman et al. 1988; Kamata et al. 1997; 

Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al. 1989; Woutersen et al. 1987) or oral 

(Johannsen et al. 1986; Til et al. 1988b, 1989; Tobe et al. 1989; Vargova et al. 1993) exposure. No data 

regarding endocrine effects in animals after dermal exposure were located. 

Dermal Effects. Formaldehyde is a widely recognized skin irritant and dermal sensitization agent in 

humans (see also Immunological and Lymphoreticular Effects section). Patch testing for dermal 

sensitization to formaldehyde has been carried out with either 1 or 2% solutions because, for most 

individuals, acute exposure to such concentrations does not produce signs of nonimmune irritation (e.g., 

erythema [redness], induration, flaking, and/or blistering). Some earlier patch testing procedures utilized 

concentrations as high as 5%, a practice that has been largely discontinued, presumably because of the 
FORMALDEHYDE 212 

2. HEALTH EFFECTS 

difficulty in discerning between irritant and immune responses at this exposure level (Maibach 1983). 

Increased incidences of contact dermatitis or allergic contact dermatitis associated with dermal exposure 

to formaldehyde solutions have been observed in funeral service workers (Nethercott and Holness 1988) 

and among medical workers (Rudzki et al. 1989). Allergic contact dermatitis from formaldehyde released 

from “no-iron” textiles was frequently reported until textile finishing processes were changed (in the mid 

1970s) so that only small amounts of formaldehyde were released from clothing made from such textiles 

(Peters and Hesse 1997). Experiments with guinea pigs (Wahlberg 1993) and mice (Iversen 1986) 

indicated that repeated exposure of skin to concentrations for acute periods as low as 0.4% can be 

damaging (i.e., produce erythema, epidermal hyperplasia, or increased skin-fold thickness). 

Animal studies with repeated exposure to airborne formaldehyde concentrations between 1 and 40 ppm 

(Appelman et al. 1988; Kamata et al. 1997; Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al. 

1989; Woutersen et al. 1987) and oral doses as high as 109 mg/kg/day (Til et al. 1989) indicate that 

clinically significant dermal effects are not a concern by these routes of exposure, although mice exposed 

to the highest air concentration (40 ppm) in these studies showed a “loss of skin elasticity” (Maronpot et 

al. 1986). Eberlein-Konig et al. (1998) reported that a 4-hour exposure of dermally sensitized human 

subjects to airborne formaldehyde concentrations as low as 0.08 ppm increased transepidermal water loss 

compared with nonsensitized subjects, but the clinical significance of this effect is uncertain. 

Ocular Effects. Eye irritation is one of the most common complaints among people exposed to airborne 

formaldehyde. In acute, controlled exposure studies with volunteers, mild to moderate eye irritation has 

been reported at low-level concentrations in the range of 0.4–4 ppm; at the upper end of this range, 

greater percentages of subjects experienced eye irritation (Akbar-Khanzadeh and Mlynek 1997; AkbarKhanzadeh et al. 1994; Bender et al. 1983; Day et al. 1984; Gorski et al. 1992; Kulle 1993; Kulle et al. 

1987; Schachter et al. 1986; Weber-Tschopp et al. 1977; Witek et al. 1986, 1987). Other results 

indicating formaldehyde’s eye-irritation potential include reports that average rates of eye-blinking were 

significantly increased during exposure to 2.1 ppm, but not to 1.2 ppm (Weber-Tschopp et al. 1977), and 

that percentages of subjects with shortened response times (i.e., the time taken for the subjects to note eye 

irritation) were significantly increased with exposure to 1 ppm, but not to lower concentrations (Bender et 

al. 1983). In addition, survey studies have reported increased rates of eye irritation in groups of persons 

who have been repeatedly exposed to formaldehyde in residences or workplaces, compared with groups 

of nonexposed persons (Garry et al. 1980; Holness and Nethercott 1989; Horvath et al. 1988; Ritchie and 

Lehnen 1987). 
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2. HEALTH EFFECTS 

Histological examinations of eyes from animals repeatedly exposed to airborne formaldehyde 

concentrations as high as 6–40 ppm have not found formaldehyde-induced changes (Appelman et al. 

1988; Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al. 1989; Swenberg et al. 1980; Woutersen 

et al. 1987). Ophthalmoscopic examinations likewise revealed no exposure-related changes in rats or 

mice examined at several intervals during 2-year exposures to concentrations as high as 14.3 ppm (Kerns 

et al. 1983b), but clinical signs of eye irritation during exposure to 2–15 ppm have been noted in several 

animal studies (Dinsdale et al. 1993; Monticello et al. 1989; Morgan et al. 1986c). Chronic exposure of 

rats to drinking water doses as high as 89–102 mg/kg/day produced no histological changes in eyes or 

Harderian and exorbital lachrymal glands (Til et al. 1989). Direct application of formaldehyde solutions 

into eyes is expected to be irritating. Krootila et al. (1986) provided evidence that application of a 

1% solution of formaldehyde to the eyes of rats caused a breakdown of the blood-aqueous barrier and that 

the irritative response of the eye is dependent on the trigeminal sensory nerve. 

Body Weight Effects. Whereas no reports of body weight effects in formaldehyde-exposed humans were 

located, numerous reports are available of biologically significant body weight decreases in animals 

repeatedly exposed to formaldehyde by the inhalation route (Appelman et al. 1988; Kamata et al. 1997; 

Kerns et al. 1983b; Maronpot et al. 1986; Rusch et al. 1983; Woutersen et al. 1987, 1989) and by the oral 

route via drinking water or diet (Johannsen et al. 1986; Til et al. 1989; Tobe et al. 1989). Exposurerelated effects on body weight were not found in pregnant hamsters dermally exposed during gestation to 

37% formaldehyde solutions (Overman 1985) or in guinea pigs dermally exposed for 9 days to 

4% formaldehyde solutions (Wahlberg 1993). Air concentrations associated with decreased body weights 

in repeatedly exposed animals were mostly at or above exposure levels ($10 ppm) that produced severe 

upper respiratory tract lesions. Oral dosage levels associated with decreased body weights in repeatedly 

exposed animals were generally $80–100 mg/kg/day and also associated with the development of 

gastrointestinal tract lesions and decreases in food and water intake. 

Metabolic Effects. Metabolic acidosis has been observed in patients who ingested large (>500 mg/kg) 

single doses of formaldehyde (Burkhart et al. 1990; Eells et al. 1981; Koppel et al. 1990). The rapid 

metabolic production of formate at these high dose levels was likely involved in the observed acidosis. 

Other Systemic Effects. Decreased food and water consumption have been observed in animals exposed 

to oral doses generally greater than 100 mg/kg/day (Johannsen et al. 1986; Til et al. 1989; Tobe et al. 
 

FORMALDEHYDE 214 

2. HEALTH EFFECTS 

1989). The decreased consumption was generally associated with decreases in body weight and with 

development of gastrointestinal lesions with intermediate or chronic exposure. 

Immunological and Lymphoreticular Effects. Allergic contact dermatitis from formaldehyde is 

commonly reported at dermatological clinics throughout the world. Patch test reporting from clinics 

indicates that about 1–4% of tested patients with skin problems are dermally sensitive to formaldehyde 

(Fischer et al. 1995; see also: Kiec-Swierczynska 1996; Maibach 1983; Marks et al. 1995; Meding and 

Swanbeck 1990; Menné et al. 1991). Given the widespread use of formaldehyde in cleaning solutions 

and cosmetics (Flyvhom 1991; Rastogi 1992), it is likely that most patients presenting with formaldehyde 

contact dermatitis experienced sensitization through dermal contact, but dermal sensitization through 

contact with airborne formaldehyde cannot be ruled out. Severe allergic responses to formaldehyde 

appear to be rare, but one case report was located of a severe response to a patch test with a 1% 

formaldehyde solution in a woman who was sensitized after exposure to a dialyzer sterilized with 

formaldehyde (Maurice et al. 1986). Twenty-six hours after the application of the patch, the patient 

developed anaphylactic symptoms of laryngeal edema and bronchospasm that resolved on administration 

of subcutaneous epinephrine. 

Although formaldehyde is widely recognized as a dermal irritant that can sensitize the skin in humans, the 

evidence for immunologically-mediated sensitization of the respiratory tract is weak. Despite the 

widespread use of formaldehyde in several occupational exposure scenarios (and the widespread 

occurrence of formaldehyde in tobacco smoke), there are only a few available case reports of 

formaldehyde-exposed workers who display marked changes in pulmonary function variables (e.g., 

FEV1 and FEFR) in response to acute challenges with inhaled formaldehyde that are consistent with an 

immunologically-mediated mechanism of response (Burge et al. 1985; Hendrick et al. 1982; Lemiere et 

al. 1995; Nordman et al. 1985). Other studies found no marked response to challenges of inhaled 

formaldehyde in previously-exposed subjects who complained of asthma-like symptoms (Day et al. 1984; 

Krakowiak et al. 1998; Reed and Frigas 1984). Several studies have found no consistent evidence for 

increased serum levels of formaldehyde-specific IgE antibodies in groups of formaldehyde-exposed 

subjects including groups with complaints of respiratory symptoms (Dykewicz et al. 1991; Gorski et al. 

1992; Grammar et al. 1990; Krakowiak et al. 1998; Kramps et al. 1989; Thrasher et al. 1987, 1990). 

The only other suggestive evidence of IgE-mediated sensitization to formaldehyde comes from a study of 

schoolchildren who were exposed to particleboard-paneled classrooms with estimated formaldehyde air 
FORMALDEHYDE 215 

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concentrations of 0.075, 0.069, and 0.043 ppm and reported respiratory tract symptoms consistent with 

the irritant properties of formaldehyde (Wantke et al. 1996a). Elevated serum levels of formaldehydespecific IgE antibodies were detected in these children. The investigators noted that the elevated levels 

were not correlated with the number and severity of symptoms, but decreased serum levels were 

measured in a subgroup of the children 3 months after they were moved to another school with lower air 

concentration of formaldehyde (0.023–0.029 ppm). The significance of these findings is uncertain, as the 

reported symptoms were more typical of an irritant response than of asthma-like symptoms that are 

expected to be mediated through IgE antibodies. 

Animal studies examining the sensitizing properties of formaldehyde present evidence consistent with the 

hypothesis that, although formaldehyde can sensitize skin, it apparently lacks a potential to sensitize the 

respiratory tract (Hilton et al. 1996). Strong positive responses to formaldehyde were found in three 

animal assays indicative of skin-sensitization potential (guinea pig maximization test, Buehler occluded 

patch test and the murine local lymph node assay). However, in a mouse IgE test and an assessment of 

cytokine secretion patterns by lymph node cells, formaldehyde was negative, producing responses that 

were not like those produced by trimellitic anhydride, a well-established respiratory tract allergen in 

animals and humans (Hilton et al. 1996). Although these results suggest a lack of ability to sensitize the 

respiratory tract, another animal experiment suggests that exposure to formaldehyde may enhance allergic 

responses of the respiratory tract to other respiratory allergens (Tarkowski and Gorski 1995). This study 

found that that the production of ovalbumin-specific IgE antibodies in response to intranasal 

administration of ovalbumin was four-fold greater in mice preexposed to 1.6 ppm formaldehyde for 

10 consecutive days, compared to the response in mice without formaldehyde preexposure. In similar 

experiments, groups of guinea pigs preexposed to a formaldehyde concentration of 0.25 ppm, 8 hours/day 

for 5 days followed by inhalation exposure to 0.5% ovalbumin were found to have a higher percentage of 

ovalbumin-sensitized animals than control groups with no preexposure (10/12 versus 3/12) (Riedel et al. 

1996). Further research is necessary to confirm the hypothesis of formaldehyde facilitation of other 

respiratory allergens and to determine if this is relevant to humans exposed to formaldehyde. 

Other animal studies indicate that repeated inhalation exposure to formaldehyde at high concentrations, 

between 10 and 15 ppm, did not produce significant effects in several assays of immune function 

including resistance to intravenous or subcutaneous injection of neoplastic cells in mice (Dean et al. 

1984), resistance to intravenous injection of bacterial cells in mice (Dean et al. 1984), and IgM response 

to tetanus immunization and IgG response to tetanus toxoid in rats (Holmstrom et al. 1989b). 
 

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Neurological Effects. Few studies have reported neurological effects after exposure to formaldehyde 

in humans; however, these studies tend to report vague symptoms. For example, men exposed to 

formaldehyde vapors at concentrations #0.98 ppm for 5.5 hours reported such symptoms as fatigue, 

headaches, and "heavy head" (Bach et al. 1990). Reaction times also decreased as formaldehyde 

concentrations increased. After the ingestion of formaldehyde in humans, coma (Koppel et al. 1990), 

lethargy, seizures (Burkhart et al. 1990), and loss of consciousness (Burkhart et al. 1990; Eells et al. 

1981) have been reported. Kilburn and colleagues have reported evidence for neurological symptoms and 

impaired performance in neurobehavioral tests in groups of formaldehyde-exposed histology technicians, 

but confounding exposure to other neurotoxic solvents prevents drawing definitive conclusions regarding 

the neurotoxicity of formaldehyde from this source (Kilburn 1985b; Kilburn et al. 1987; Kilburn and 

Warshaw 1992; Kilburn 1994). 

Male rats exposed to 15 ppm formaldehyde showed restless behavior within the first 10 minutes of 

exposure (Morgan et al. 1986a). Exposure to 5 ppm formaldehyde for 3 hours in male rats resulted in 

decreased motor activity within 15 minutes from the beginning of exposure; increased concentrations of 

5-hydroxyindoleacetic acid (a 5-hydroxytryptamine metabolite), 3,4-dihydroxyphenylacetic acid (a 

dopamine metabolite), and dopamine were present in the hypothalamus at the end of the 3-hour exposure 

(Boja et al. 1985). With repeated exposure, mice developed an increased sensitivity to the acute sensory 

irritant properties of formaldehyde; the increased sensitivity attributed, at least in part, to a conditioning 

(i.e., learning) process (Wood and Coleman 1995). No abnormal clinical signs were noted in mice treated 

with doses #10 ppm formaldehyde for 6 hours/day, 5 days/week for 13 weeks; however, listlessness and 

hunched posture were observed in the mice exposed to 20 ppm formaldehyde, and these symptoms plus 

ataxia were observed in the 40-ppm dose group (Maronpot et al. 1986). No obvious signs of neurological 

effects were noted in rats (Appelman et al. 1988; Kerns et al. 1983b; Woutersen et al. 1987) or mice 

(Kerns et al. 1983b) in chronic-duration inhalation studies. No obvious neurological effects were 

observed in rats receiving 150 mg/kg/day for 90 days in drinking water (Johannsen et al. 1986), in rats 

receiving 125 mg/kg/day for 4 weeks in drinking water (Til et al. 1988b), or in rats exposed to 

300 mg/kg/day for 12 months in drinking water (Tobe et al. 1989). Beagle dogs exposed to formaldehyde 

in drinking water at concentrations #100 mg/kg/day experienced no effect on brain weight or 

histopathology. Similar negative findings were noted in studies of chronic duration at doses 

#300 mg/kg/day in drinking water in rats (Til et al. 1989; Tobe et al. 1989). It appears that formaldehyde 

has major effects on the nervous system only after large doses are ingested; such as low-level and vague 

symptoms after chronic, low-level exposure. 
 

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Reproductive Effects. Studies regarding possible reproductive effects in humans exposed to 

formaldehyde are restricted to a study that found no evidence for effects on sperm numbers or 

morphology in a small number of pathologists (Ward et al. 1984) and a study that found no evidence for 

increased rates of miscarriage among a group of 275 persons with presumed residential exposure to 

formaldehyde (Garry et al. 1980). 

Studies of animals exposed to formaldehyde in air, in drinking water or diet, or applied to the skin 

indicate that the reproductive organs are not a critical target for formaldehyde toxicity, but comprehensive 

assessments of reproductive performance (e.g., 2-generation studies) in formaldehyde-exposed animals 

were not located. 

No effects on histology or weight of reproductive organs were found in rats or mice exposed repeatedly to 

air concentrations as high as 20 ppm (Appelman et al. 1988; Maronpot et al. 1986, Woutersen et al. 

1987), in dogs repeatedly exposed to formaldehyde in the diet at doses up to 100 mg/kg/day (Johannsen et 

al. 1986), or in rats exposed to oral doses up to 300 mg/kg/day (Johannsen et al. 1986; Til et al. 1989; 

Tobe et al. 1989; Vargova et al. 1993). Ovarian and uterine hypoplasia were observed in female mice 

exposed to air concentrations of 40 ppm for 13 weeks, but was attributed to the general weight loss and 

poor health of these animals rather than to a direct effect of formaldehyde (Maronpot et al. 1986). 

Maternal toxicity, expressed as a marked decrease in weight gain, occurred in pregnant rats exposed 

during gestation by inhalation to 40 ppm, but reproductive variables (e.g., numbers of implantations or 

resorptions) were not affected (Saillenfait et al. 1989). At lower air concentrations, no signs of maternal 

toxicity were observed in this and another rat study of gestational exposure (Martin 1990). Exposure 

during pregnancy to gavage dose levels of 185 mg/kg/day, but not 145 mg/kg/day, produced severe 

maternal toxicity in pregnant mice (22/34 dams died), but did not affect reproductive variables such as 

numbers of implantation sites or resorptions (Marks et al. 1980). No effects on reproductive variables 

were found in pregnant dogs exposed to 9.4 mg/kg/day in the diet on gestation days 4–56 (Hurni and 

Ohder 1973). Dermal exposure of pregnant hamsters to 37% solutions of formaldehyde produced a small 

increase in resorption rate without affecting maternal weight gain, but the authors of this study proposed 

that the effect may have been caused by stress associated with the applied treatment protocol (Overman 

1985). Single gavage dose levels of 200 mg/kg, but not 100 mg/kg/day, produced changes in sperm 

morphology in rats (Cassidy et al. 1983), but with no tests of reproductive performance, the toxicological 

significance of this finding is uncertain. In a review of available reproductive and developmental toxicity 

data, WHO (1989) concluded, “There is no convincing evidence that formaldehyde is a teratogen in either 
 

 

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2. HEALTH EFFECTS 

animals or human beings. Formaldehyde has not produced any adverse effects on reproduction in test 

animals or human beings.” IARC (1995) reached a similar conclusion in a more recent review. 

Developmental Effects. Studies of possible developmental effects in humans exposed to 

formaldehyde are restricted to a study that found no statistically significant difference in incidence of low 

birth weights among groups of mothers who lived in residential districts with differing ambient air levels 

(up to 38 ppb) of formaldehyde (Grañulevi...iene et al. 1998). Exposure of pregnant rats to air 

concentrations up to 10 ppm during gestation days 6–15 produced no distinct effects on fetal development 

(Martin 1990). In another study with several exposure levels, pregnant rats exposed during gestation days 

6–20 to the highest concentration, 40 ppm, showed a 51% reduction in weight gain (Saillenfait et al. 

1989). Fetal weights were decreased in male offspring from dams exposed to 20 ppm and in female 

offspring from dams exposed to 40 ppm, but no effects attributable to formaldehyde were noted in the 

incidences of pregnancies, number of implantations or resorptions, number of dead or live fetuses, fetal 

sex ratios, or incidences of skeletal or visceral anomalies (Saillenfait et al. 1989). Similarly, no effects on 

fetal development were found in studies of pregnant rats exposed during gestation days 6–15 to gavage 

dose levels as high as 185 mg/kg/day (Marks et al. 1980), pregnant dogs exposed to up to 9.4 mg/kg/day 

in the diet during gestation days 4–56 (Hurni and Ohder 1973), and pregnant hamsters dermally exposed 

to a 37% aqueous solution of formaldehyde on gestation day 8, 9, 10, or 11 (Overman 1985). 

Genotoxic Effects. Formaldehyde has been demonstrated to have genotoxic properties in human and 

laboratory animal studies. Peripheral lymphocytes in anatomy students exposed to 0.73–1.95 ppm 

formaldehyde for 8 weeks showed a small increase in SCE (Yager et al. 1986). Lymphocytes from wood 

workers chronically exposed to formaldehyde also showed increased levels of chromosomal aberrations; 

however, there were no significant changes in the rates of SCE (Chebotarev et al. 1986). Increases in 

micronuclei formation, primarily in nasal passage ciliated cells, were found in wood workers chronically 

exposed to 0.07–0.08 ppm formaldehyde (Ballarin et al. 1992). An increased incidence in chromosomal 

abnormalities in pulmonary macrophages was noted in male rats exposed to 15 ppm formaldehyde for 

5 days (Dallas et al. 1992). No reports of genotoxicity strictly related to the oral or dermal exposure 

routes were found in the available literature. 

Conversely, a number of studies have failed to demonstrate the genotoxic potential of formaldehyde. 

Fleig et al. (1982) performed chromosome analyses on 15 exposed and 15 non-exposed employees from 
FORMALDEHYDE 219 

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formaldehyde-manufacturing facilities with average exposure concentrations not exceeding 5 ppm prior 

to 1971 and 1 ppm after 1971. There were no differences between exposed and control groups in the 

incidence of chromosomal aberrations. Connor et al. (1985b) tested urine obtained from hospital autopsy 

service workers exposed to formaldehyde who had actual exposures to formaldehyde of 0.1–5.8 ppm, 

with the TWA exposures to formaldehyde in work areas were estimated to be 0.61–1.32 ppm. 

Mutagenicity tests using S. typhimurium TA 100 and TA 98 were conducted, with or without rat 

S9 suspension. Increases in mutation rates were not produced by the urine of workers exposed to 

formaldehyde, compared to control urine, in the presence or absence of S9. 

Formaldehyde has been found to be genotoxic in a number of in vivo and in vitro test systems. Tables 2-6 

and 2-7 present a cross-section of some of the genotoxicity data that are available for formaldehyde 

examined in in vivo and in vitro test systems. With in vivo test systems, the data are mixed. 

Formaldehyde has been found to induce chromosomal aberrations (Chebotarev et al. 1986; Dallas et al. 

1992; Rithidech et al. 1987) and to cause increases in micronucleus formation (Ballarin et al. 1992), SCE 

(Yager et al. 1986), DNA-protein cross links (Casavova et al. 1989, 1991b, 1992; Lam et al. 1985; 

Shaham et al. 1996a), sperm head abnormalities (Topham 1980), and p53 suppressor gene mutations 

(Recio et al. 1992). Other reports present negative genotoxic findings (Kligerman et al. 1984; Natarajan 

et al. 1983; Thomson et al. 1984). 

Formaldehyde has also been found to be genotoxic in S. typhimurium in most cases (Connor et al. 1983, 

1985a; Donovan et al. 1983; Glass et al. 1986; Haworth et al. 1983; Schmid et al. 1986; Takahashi et al. 

1985) and not mutagenic in others (DeFlora 1981; DeFlora et al. 1984). A number of human cell lines 

have been tested with formaldehyde giving positive results without activation, resulting in mutations, 

DNA damage, chromosomal aberrations, and SCEs (Dresp and Bauchinger 1988; Garry et al. 1981; 

Goldmacher and Thilly 1983; Grafstrom et al. 1983, 1984, 1985; Krieger and Garry 1983; Liber et al. 

1989; Schmid et al. 1986; Snyder and Van Houten 1986). Laboratory animal models, such as the Chinese 

hamster cell lines (Basler et al. 1985; Galloway et al. 1985; Grafstrom et al. 1993; Miller and Costa 1989; 

Natarajan et al. 1983), Golden Syrian hamsters (Hatch et al. 1983), and rodent cell lines (Basler et al. 

1985; Blackburn et al. 1991; Cosma and Marchok 1988; Cosma et al. 1988a; Frazelle et al. 1983; Heck 

and Casanova 1987; Ragan and Boreiko 1981, 1983; Ross and Shipley 1980) have demonstrated similar 

results. 
Table 2-6. Genotoxicity of Formaldehyde In Vivo 

Species (test system) End point Result Reference Mammals: 

Mouse (spleen lymphocytes) Chromosomal aberrations + Rithidech e

Human (occupational exposure) Chromosomal aberrations – Vasudeva a

Human (occupational exposure/nasal mucosa) Micronucleus increase + Ballarin et Human (occupational exposure/urine) Mutagenicity – Connor et aHuman (occupational exposure/lymphocytes) DNA-protein cross links, not + Shaham et 

formaldehyde specific 

Human (occupational exposure/white blood Chromosome aberrations and – Thomson e

cells) sister chromatid exchange Human (occupational exposure/lymphocytes) Sister chromatid exchange + Yager et al

Human (occupational exposure/lymphocytes) Chromosomal aberrations + Cherbatere

Rat (pulmonary lavage) Chromosomal aberrations + Dallas et alRat (nasal mucosal cells) DNA-protein cross links + Casanova eRat (nasal mucosal cells) DNA-protein cross links + Lam et al. Rat (bone marrow) Chromosomal aberrations – Dallas et al

Rat (lymphocytes) Mitotic activity, sister chromatid – Kligerman 

exchange, chromosomal aberration 

Monkey (respiratory tract) DNA-protein cross links + Casanova e

Non-mammals: 

D. Melanogaster Mortality and sterility + Valencia et 

D. Melanogaster Lethal mutation + Woodruff e

+ = Positive result; – = negative result; (+) = weakly positive result; DNA = deoxyribonucleic acid 
Table 2-7. Genotoxicity of Formaldehyde In Vitro 

Result 

With Without 

Species (test system) End point activation activation Referen

Prokaryotic organisms: 

Salmonella typhimurium TA 98, TA 100, TA Gene mutation (+) (+) Glass et 1535, TA 1537, UTH8414, UTH 8413 (Ames test) S. typhimurium TA 98, TA 100 (Ames test) Gene mutation No data + TakahasS. typhimurium TA 100 (Ames test) Gene mutation + + Schmid 

Escherichia coli Gene mutation No data + TakahasS. typhimurium TA97, TA98, TA100 (Ames Gene mutation No data + Donovatest) S. typhimurium TM677, TA100 (Ames test) Gene mutation + + DonovaS. typhimurium TA97, TA98, TA100, Gene mutation – – DeFlora 

TA1535, TA1537, TA1538 (Ames test) S. typhimurium TA98, TA100, TA1535, Gene mutation –a –a DeFlora TA1537, TA1538 (Ames test) S. typhimurium TA98, TA100, UTH8413, Gene mutation (+) (+) Connor 

UTH8414 (Ames test) S. typhimurium TA98, TA100, UTH8413, Gene mutation (+)a (+)a Connor 

UTH8414 (Ames test) S. typhimurium TA1535, TA1537, TA98, Gene mutation No data + Haworth 

and TA100 

Eukaryotic organisms: 

Mammalian cells: Mutations No data + Grafstro

Human (bronchial fibroblast culture) Human (foreskin fibroblast culture) DNA damage No data + Snyder Human (lymphocyte cell culture) Chromosomal aberrations No data + Dresp anHuman (lymphocyte cell culture) DNA damage No data + Liber et 

Table 2-7. Genotoxicity of Formaldehyde In Vitro (continued) 
Result 

With Without 

Species (test system) End point activation activation Referen

Human (lymphocyte cell culture) Sister chromatid exchange + + Schmid 

and chromatid-type aberrations 

Rat (tracheal epithelium culture) DNA damage No data + Cosma eRat (tracheal epithelium culture) DNA damage No data + Cosma a

Rat (nasal mucosa) DNA binding No data + Heck an

Mouse (lymphoma L5178Y TK ±) Mutagenicitiy + + BlackbuChinese hamster (V79 cell culture) Sister chromatid exchange – + Basler e

Chinese hamster (V79 cell culture) Mutations No data + Grafstro

Chinese hamster (ovary cell culture) DNA damage No data + Miller aChinese hamster (ovary cell culture) Chromosomal aberrations; + + Nataraja

sister chromatid exchange 

Chinese hamster (ovary cell culture) Chromosomal aberrations; (+) (+) Gallowa

sister chromatid exchange 

Golden Syrian hamster (embryo cell Viral transformation No data + Hatch et 

culture) C3H/10T1⁄2 mouse embryo fibroblasts Focus transformations (+) – Frazelle 

Rodent (Yoshida sarcoma cells) DNA cross links No data (+) Bedford Calf (thymus chromatin) Histone redistribution No data + Polacow 

C3H/10T1⁄2 mouse embryo fibroblasts Focus transformations + – Ragan aC3H/10T1⁄2 mouse embryo fibroblasts Focus transformations + – Boreiko C3H/10T1⁄2 mouse embryo fibroblasts Focus transformations + No data Frazelle Mouse leukemia L1210 cells DNA single strand breaks No data (+) Ross anMouse leukemia L1210 cells DNA protein cross links No data + Ross anHuman (lymphocyte cultures) Sister chromatid exchange No data + Kreiger 
Table 2-7. Genotoxicity of Formaldehyde In Vitro (continued) 

Result 

With Without 

Species (test system) End point activation activation Referen

Human (bronchoial fibroblast cells) DNA cross links and singlestrand breaks No data + Grafstro

Human (bronchoial epithelial cells) DNA cross links and singlestrand breaks No data + Grafstro

Human (skin fibroblast cells) DNA cross links and singlestrand breaks No data + Grafstro

Human (bronchoial epihtelial cells) DNA cross links and singlestrand breaks No data + Grafstro

Human (bronchoial fibroblast cells) DNA cross links and singlestrand breaks No data + Grafstro

Human (lymphoblastoid TK6 cells) DNA mutation No data + Goldma

Human (cultured lymphocytes) Sister chromatid exchange No data + Garry et 

atest compound was formalin 

– = negative results; + = positive results; (+) = weakly positive result; DNA = deoxyribonucleic acid 
 

FORMALDEHYDE 224 

2. HEALTH EFFECTS 

In summary, no reports of genetic effects in humans were located, but formaldehyde has displayed 

genotoxic activity in the majority of studies in a variety of in vivo tests with organisms ranging from 

bacteria to rodents and a variety of in vitro tests including tests with cultured human cells. The weight of 

evidence indicates that formaldehyde itself is capable of directly reacting with DNA, and producing 

genotoxic effects, especially when metabolic capacities are exceeded. 

Cancer. As discussed in Section 2.2.1.8, there are more than 40 epidemiology studies (cohort 

mortality studies of industrial workers, cohort mortality studies of medical specialists and embalmers, and 

case-control studies) examining the potential for occupational formaldehyde exposure to induce cancer. 

Two meta analyses of these studies calculated aggregate relative risks (with 95% CIs noted in 

parentheses) for nasopharyngeal cancer deaths in occupationally exposed workers of 1.2 (0.8–1.7) and 

2.0 (1.4–2.90), and noted that an exposure-response relationship for nasopharyngeal cancer could be 

demonstrated by grouping the studies in exposure categories of “low/medium” and “substantial” (Blair et 

al. 1990a; Partanen 1993). A third meta analysis (Collins et al. 1997), using the same studies plus 

additional cohort mortality data not available for the earlier analyses, reported meta relative risks of 

1.0 (0.5–1.8) for nasopharyngeal cancer across 14 available cohort studies, 1.2 (0.4–2.5) for six available 

cohort studies of industrial workers, and 1.3 (0.9–2.1) for seven case-control studies. Collins et al. (1997) 

concluded that their analysis of the data did not support an exposure-response relationship for 

formaldehyde exposure and nasopharyngeal cancer. 

Other reviewers also have arrived at differing conclusions regarding the evidence from the 

epidemiological studies. On one side, IARC (1995) and EPA (1991a) judged that there was limited 

evidence in humans and NTP (1998) judged that formaldehyde was reasonably anticipated to be a human 

carcinogen; whereas McLaughlin (1994) and ECETOC (1995), on the other side, concluded that a causal 

relationship was not established by the available data. A more recent collaborative review of the data by 

EPA and CIIT (1998) appears to take a middle stand concluding that “it appears that a weak association 

between nasopharyngeal cancer and formaldehyde exposure cannot be completely ruled out”. 

In contrast to the equivocal, limited, or weak nature of the evidence in humans, replicated inhalation 

studies have consistently shown that formaldehyde induces nasal tumors in rats exposed to high 

concentrations (10–15 ppm) that also induce nasal epithelial necrosis and cellular proliferation, but not 

when exposed to lower concentrations (0.3–2 ppm) that do not markedly damage nasal epithelial tissue 

(Albert et al. 1982; Kamata et al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Sellakumar et al. 
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2. HEALTH EFFECTS 

1985; Woutersen et al. 1989). Exposure-related cancer or noncancer lesions at sites distant from the 

portal-of-entry were not found in these studies, consistent with the water solubility and reactivity of 

formaldehyde and the ubiquity of rapid cellular metabolism of formaldehyde. 

No information is available as to whether oral exposure to formaldehyde increases the risk of cancer in 

humans. The evidence for formaldehyde-induced carcinogenicity from four available rat drinking water 

studies is equivocal due to inconsistent findings (Soffritti et al. 1989; Takahashi et al. 1986a; Til et al. 

1989; Tobe et al. 1989). Two studies reported no increased incidence of gastrointestinal tract tumors in 

rats exposed for life to formaldehyde in drinking water at doses up to 109 mg/kg/day (Til et al. 1989) or 

300 mg/kg/day (Tobe et al. 1989). Another study reported increased incidences of gastrointestinal tumors 

(papillomas, adenocarcinomas, and leiomyosarcomas) in some groups of rats exposed for life to drinking 

water doses of 188 mg/kg/day, but not in groups exposed to 313 mg/kg/day (Soffritti et al. 1989). The 

fourth study reported that benign papillomas were found in the forestomach of 8/10 rats exposed for 

32 weeks to drinking water doses of 258 mg/kg/day (Takahashi et al. 1986a), but others (Til et al. 1989) 

have questioned whether a different histologist would have classified the observed lesions as papillary 

hyperplasia. The weight of the animal evidence suggests that gastrointestinal tract tumors may occur as 

portal-of-entry effects in rats chronically exposed to formaldehyde in drinking water only at high doses, 

and that tumors are not likely to occur at dose levels that do not damage the gastric mucosa. The animal 

studies suggest that there is little likelihood that chronic exposure to non-irritating levels of formaldehyde 

in drinking water will increase cancer risks in humans. 

No studies were located regarding cancer rates in humans predominantly exposed to formaldehyde via the 

dermal route. Animal cancer studies of dermal exposure are restricted to two studies that found no 

statistically significant increased incidences of skin tumors in mice exposed twice weekly for 58–60 

weeks to solutions containing up to 4% (Iverson 1988) or 10% formaldehyde (Iverson 1986). 

NTP (1998) has determined that formaldehyde may reasonably be anticipated to be a human carcinogen, 

and IARC (1995) made the overall evaluation that formaldehyde is probably carcinogenic to humans 

(Group 2A) based on specific evaluations that there is limited evidence in humans for the carcinogenicity 

of formaldehyde and sufficient evidence in experimental animals. 

EPA (1991a; IRIS 1999) classified formaldehyde in Group B1 - probable human carcinogen based on an 

evaluation of limited human evidence and sufficient laboratory animal evidence. EPA (1991a) used dose­
 

FORMALDEHYDE 226 

2. HEALTH EFFECTS 

response data for nasal tumors in rats exposed to high concentrations of formaldehyde to extrapolate to 

human cancer risk at low exposure concentrations, using rates of DNA-protein cross links in target tissue 

as a measure of delivered dose. Relationships between formaldehyde air concentrations and rates of 

formation of DNA-protein cross links in nasal epithelial tissue of rats (Casanova et al. 1989) or of Rhesus 

monkeys (Casanova et al. 1991; Heck et al. 1989) and adjustments to continuous exposure were used to 

calculate lifetime human cancer unit risk estimates of 3.3x10-4 per ppm formaldehyde based on the 

monkey data, and 2.8x10-3 per ppm formaldehyde based on the rat data. EPA (1987d, 1991a; IRIS 1999) 

did not derive a cancer risk estimate for oral exposure to formaldehyde. EPA and CIIT (CIIT 1998) are 

currently working on options to derive new estimates of cancer risk in humans exposed by inhalation 

using CFD models of nasal airflow and uptake of formaldehyde in rats, monkeys, and humans; 

pharmacokinetic models of nasal tissue disposition of formaldehyde; and two-stage clonal growth cancer 

models incorporating data on cellular proliferation rates. 

2.6 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 

effects on the fetus and neonate due to 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 5.6 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 
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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 and 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 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 the newborn who has a low glomerular filtration rate and has 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 lifetime 

in which to express damage from chemicals; this potential is particularly relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility while others may 

decrease susceptibility to the same chemical. For example, the fact that infants breathe more air per 

kilogram of body weight than adults may be somewhat counterbalanced by their alveoli being less 

developed, so there is a disproportionately smaller surface area for absorption (NRC 1993). 

Whereas there are numerous studies of adults occupationally exposed to formaldehyde and exposed under 

acute controlled conditions, data regarding the toxicological properties of formaldehyde in children are 

limited. Nevertheless, the same type of effects that occur in adults are expected to occur in children (e.g., 

damage in portal-of-entry tissues at exposure levels that exceed tissue detoxification mechanisms). 

Symptoms expected to occur in children include eye, nose, and throat irritation from exposure to airborne 

concentrations between 0.4 and 3 ppm, and dermal irritation from exposure to dermal contact with liquids 

containing more than 2% formaldehyde. Given the water-soluble and reactive nature of formaldehyde 

and the apparent ubiquity of rapid cellular metabolism of formaldehyde, it is expected that the irritant 

effects of formaldehyde would be restricted in children, as in adults, to portals-of-entry, although no 
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information was located comparing rates of formaldehyde metabolism in children’s tissues with rates in 

adult tissues, either in humans or animals. However, studies of adult humans or rats exposed for short 

periods to air concentrations of 1.9 ppm or 14.4 ppm, respectively (Heck et al. 1985), and monkeys 

exposed to 6 ppm for up to 4 weeks (Casanova et al. 1988) found no appreciable changes in circulating 

blood levels of formaldehyde; these results are consistent with the protective action of rapid metabolism 

of formaldehyde in portal-of-entry tissues. The developing fetus or nursing infant would be expected to 

be protected from exposure to formaldehyde (via inhalation, oral, and dermal contact) by the pregnant or 

breast-feeding mother. Studies of animals exposed during pregnancy to formaldehyde in air (Martin 

1990; Saillenfait et al. 1989), in the diet or by gavage (Hurni and Ohder 1973; Marks et al. 1980), or on 

the skin (Overman 1985) have found no distinct or consistent effects on fetal development, even at 

exposure levels that produced severe maternal toxicity (e.g., Marks et al. 1980). 

Two studies were available providing suggestive evidence that children may be more sensitive than adults 

to the irritant properties of airborne formaldehyde (Krzyzanowski et al. 1990; Wantke et al. 1996a). 

Krzyzanowski et al. (1990) questioned a group of 298 children (aged 6–15 years) and 613 adults 

concerning respiratory symptoms, measured PEFR during evenings and mornings for up to 14 days, and 

made measurements of household air concentrations of formaldehyde in several rooms of 202 houses. 

Preliminary reports of this study were published in an earlier report (Quackenboss et al. 1989). Bedroom 

air concentrations were #0.040 ppm for more than 80% of the subjects, between 0.04 and 0.06 ppm for 

about 8–10% of the subjects, and greater than 0.06 ppm in about 3% of children and 6% of adults in the 

study. A few cases were measured with air concentrations exceeding 0.09 ppm, with a maximum value of 

0.14 ppm. Regression analysis found no significant relationship between exposure category of children 

and prevalence rates of subjectively reported respiratory symptoms, but physician-diagnosed chronic 

bronchitis or asthma prevalence rates were elevated in children with household air concentrations greater 

than 0.06 ppm, especially in households with environmental tobacco smoke. In adults, neither respiratory 

symptoms or physician-diagnosed chronic bronchitis or asthma were significantly related to 

formaldehyde air concentrations. In children, a statistically significant trend for decreasing PEFR values 

with increasing formaldehyde exposure concentrations was found; the estimated decrease in PEFR 

associated with 0.06 ppm was 22% compared with mean values for low-level children. In adults, PEFR 

values (mornings only) were also related to formaldehyde concentrations, but the effect was relatively 

small; the estimated decrement in adults associated with 0.10 ppm was about 1%. 
 

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School children who attended particleboard-paneled classrooms with estimated formaldehyde air 

concentrations of 0.075, 0.069, and 0.043 ppm reported respiratory tract symptoms consistent with the 

irritant properties of formaldehyde including rhinitis, cough, nosebleed, and headache (Wantke et al. 

1996a). These concentrations are low compared to workplace air concentrations or exposure chamber 

concentrations associated with irritant symptoms in adults (0.4–3 ppm). Formaldehyde-specific IgE 

antibodies were detected in serum of 40% of the children. The investigators noted that the elevated levels 

were not correlated with the number and severity of symptoms, but serum levels and incidence of 

symptoms decreased in a subgroup of the children 3 months after they were moved to another school with 

lower air concentration of formaldehyde (0.023–0.029 ppm). As stated earlier when discussing this 

study, the significance of these findings is uncertain as the reported symptoms were more typical of an 

irritant response than of asthma-like symptoms that are expected to be mediated through IgE antibodies. 

Additional research is necessary to confirm or discard the hypothesis that children may be more 

susceptible than adults to the irritant effects of formaldehyde and to understand the mechanistic basis of 

this possible difference. 

2.7 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). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. 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 or 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 
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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 formaldehyde are discussed in Section 2.7.1. 

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 formaldehyde are discussed in Section 2.7.2. 

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 2.9. 

2.7.1 Biomarkers Used to Identify or Quantify Exposure to Formaldehyde 

Formaldehyde is a simple one-carbon molecule and is rapidly absorbed and metabolized by animals, 

including humans. A thorough review of the available literature failed to produce any reliable biomarkers 

of exposure to formaldehyde. 

As discussed in Section 2.3, formaldehyde is rapidly absorbed by the inhalation and oral routes of 

exposure. Once absorbed, there are four major metabolic pathways associated with formaldehyde 

metabolism, with the metabolism to formate and CO2 the most heavily used (see Figure 2-3 in Section 

2.3.3). 

Attempts have been made to determine if either blood or urinary levels of formaldehyde or formate could 

be used as potential biomarkers of exposure, but with disappointing results. Heck et al. (1985) exposed 
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four men and two women to a 1.9±0.06 ppm air concentration of formaldehyde in a large walk-in 

chamber for 40 minutes. Shortly before and shortly after the exposure, venous blood samples were taken 

from each person (each person served as his/her own control) and the blood was analyzed for 

formaldehyde content. No significant differences were found between pre- and postexposure blood 

concentrations of formaldehyde at the concentration tested. In the same study, male Fischer 344 rats were 

placed in a nose-only inhalation chamber and exposed to a 14.4±2.4 ppm air concentration of 

formaldehyde for 2 hours; rats were sacrificed, and venous blood samples were collected and analyzed for 

formaldehyde content. Even by using the higher exposure concentration of formaldehyde, no significant 

differences in blood formaldehyde concentrations were found between the pre- and postexposure blood 

samples. In addition, the rapid intravenous injection of formaldehyde in monkeys showed a plasma halflife of only 1.5 minutes, with a corresponding increase in blood formate levels. 

Einbrodt et al. (1976) exposed students to 0.26–0.92 ppm formaldehyde vapors for 3 hours, with urine 

samples collected immediately after exposure and 21 hours after exposure. Urine formaldehyde and urine 

formic acid (formate) concentrations were found to be higher immediately after exposure compared to 

21 hours later; however, no baseline sample was obtained prior to exposure. If historic formaldehyde and 

formic acid baseline levels were assumed, then a closer examination of these data indicates that more 

formaldehyde (and metabolite) was excreted in the urine than could have possibly been absorbed by 

inhalation, indicating another route of exposure (perhaps dermal), or co-exposure to another chemical that 

also has formate as a metabolite (e.g., methanol), or higher personal exposures than were actually 

measured. There was also no indication that the urine formate levels were adjusted to compensate for 

urine specific gravity using urine creatinine levels, which may have markedly influenced the test results. 

Gottschling et al. (1984) monitored 35 anatomy laboratory students exposed for 2 hours, once a week for 

3 weeks, with exposures ranging from 0.036 to 0.111 ppm. Urine was obtained prior to exposure and 

during the exposure. Wide variations were noted in the urine formate levels prior to exposure, with large 

intrapersonal and interpersonal variations; mean postexposure urine formate concentrations were elevated 

after exposure to formaldehyde vapors, but not significantly. In the study by Einbrodt et al. (1976), urine 

formate levels were significantly elevated in both anatomy laboratory students and in four factory 

workers exposed to 1 ppm formaldehyde; however, the mass-balance equations for both groups 

indicated other factors may have influenced the amount of formate found in the urine. Formate 

production is not specific to formaldehyde because other chemicals such as methanol, halomethanes 

(e.g., dichloromethane), and acetone have formate in their metabolic pathways (Ferry et al. 1980; 
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Kornbrust and Bus 1983; Liesivuori and Savolainen 1987). This indicates that even if blood or urine 

formate levels were elevated, it may be due to individual variation, formaldehyde exposure, or other 

chemical exposures that result in formate formation. Thus formate blood and urine levels appear to be 

equally unreliable as definitive biomarkers for formaldehyde exposure. 

Formaldehyde that is not rapidly metabolized to formate can react with a variety of cellular components 

including nucleotides, proteins, and glutathione, forming adducts, such as N6-hydroxymethyldeoxyadenosine and N2- hydroxymethyldeoxyguanosine, and DNA-protein cross links. Several of these 

formaldehyde-induced products have been examined as potential biomarkers of exposure for repeated 

exposure to formaldehyde. A method for detecting biomarkers such as N6

-hydroxymethyldeoxyadenosine and N2

-hydroxymethyldeoxyguanosine (the major adducts formed by formaldehyde in vitro) 

had experimental complications and does not appear to provide useful biomarkers of formaldehyde 

exposures (Fennel 1994). Many studies (Casanova-Schmitz et al. 1984a; Casanova and Heck 1987; 

Casanova et al. 1989a, 1989b, 1991, 1994) utilized radiolabeled compounds tagged with 14C and/or 3

H to 

facilitate detection of DNA-protein cross links; however, this approach would not work to detect past 

exposures in humans. The formation of DNA-protein cross links in isolated rat nasal epithelial cells 

(respiratory and olfactory epithelial cells) incubated with formaldehyde has also been reported 

(Kuykendall et al. 1995). Utilizing a sensitive technique to detect total DNA-protein cross links, Shaham 

et al. (1996a) reported that cultured human white blood cells showed increasing quantities of DNAprotein cross links when cultured in media with increasing formaldehyde concentrations and that a small 

group of formaldehyde-exposed persons had a significantly greater mean amount of DNA-protein cross 

links in their white blood cells than did a group of nonexposed persons. Although DNA-protein cross 

links are known to be formed by other agents such as ionizing radiation and alkylating agents, Shaham et 

al. (1996a) concluded that their results suggested that levels of DNA-protein cross links in white blood 

cells may provide an indicator of formaldehyde-induced tissue damage and a biomarker of occupational 

exposure to formaldehyde. Shaham et al. (1996b) noted that a larger study of the potential of DNAprotein cross links in white blood cells as a biomarker of effect and exposure was in progress. 

Immunological biomarkers of effect (IgG and IgE antibodies against formaldehyde conjugated to human 

serum albumin) have been examined as potential biomarkers of exposure to airborne formaldehyde. 

Some studies have reported that increased serum levels of antibodies against formaldehyde-human serum 

albumin in groups of human subjects correlated with exposure to airborne formaldehyde and symptoms of 

respiratory distress (Thrasher et al. 1987, 1988b, 1989, 1990), whereas other studies of human subjects 
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have not found similar correlations (Dykewicz et al. 1991; Grammer et al. 1990; Patterson et al. 1989; 

Wantke et al. 1996a, 1996b). The hypothesis, put forth by Nordman et al. (1985), concluded that 

immunological hypersensitivity of the respiratory tract to airborne formaldehyde is rare, and casts doubt 

that immunological biomarkers for formaldehyde would have been useful biomarkers to indicate 

exposure. However, Carraro et al. (1997) recently reported that the presence of IgG antibodies against 

formaldehyde-human serum albumin was significantly associated with smoking habits, but not with selfreported occupational exposure to formaldehyde, in a group of 219 healthy subjects. When only nonsmokers were included in the analysis, a statistically significant association was found between the 

presence of formaldehyde-specific antibodies and occupational exposure to formaldehyde. An indirect 

competitive immunoenzyme assay for anti-formaldehyde-human serum albumin antibodies was 

developed for this study. These results suggest that smoking produces a detectable immunological 

response to formaldehyde and that the technique employed may be useful to indicate occupational or 

residential exposure to formaldehyde especially in the absence of exposure to tobacco smoke. 

Development of biomarkers for exposure is complicated by the fact that the metabolism of many 

xenobiotics can result in formaldehyde production in vivo. Carbon tetrachloride, endrin, paraquat, 

2,3,7,8-tetrachlorodibenzo-p-dioxin (Shara et al. 1992), and dichloromethane (Dekant and Vamvakas 

1993) are all known to generate formaldehyde during their metabolism. 

2.7.2 Biomarkers Used to Characterize Effects Caused by Formaldehyde 

Increased eosinophil concentration and increased levels of albumin and total protein have been found in 

nasal lavage fluid taken from subjects exposed to 0.4 ppm formaldehyde for 2 hours (Krakowiak et al. 

1998; Pazdrak et al. 1993). Although these variables are not expected to be only influenced by 

formaldehyde, they appear to be promising biomarkers of acute respiratory irritation from airborne 

formaldehyde. 

As discussed in the previous section, DNA-protein cross links in white blood cells (Shaham et al. 1996a) 

and anti-formaldehyde-human serum albumin IgG antibodies in serum (Carraro et al. 1997) are potential 

biomarkers of both exposure and effect associated with intermediate- or chronic-exposure to 

formaldehyde. 

Li et al. (1995) evaluated the validity of the modified lymphocyte transformation assay for detecting 

contact hypersensitivity of formaldehyde. Female Hartley guinea pigs were sensitized to formaldehyde 
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by receiving subcutaneous injections of 1.85% formaldehyde (6 sites, 0.1 mL per site) followed 7 days 

later by epicutaneous exposure to 0.5 mL of a 1.85% formaldehyde solution. Cells were collected from 

lymph nodes tissue. Exposure to increasing concentrations of formaldehyde resulted in significant 

increases in T-lymphocyte blastogenesis (p<0.05). Although further refinement of this assay would be 

required (i.e., use of peripheral blood lymphocytes in lieu of lymph node samples), it does have potential 

for providing nonspecific biomarker of effect for formaldehyde sensitization. 

Another potentially useful biomarker of effect for repeated inhalation exposure to formaldehyde involves 

the histological examination of nasal biopsy samples. Histological changes in nasal biopsy tissue samples 

(e.g., loss of ciliated cells, squamous dysplasia and hyperplasia) have been associated with formaldehyde 

exposure in several cross-sectional studies of formaldehyde-exposed and nonexposed workers (Ballarin et 

al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c). Each of these studies used a 

morphological grading method that assigned an increasing point value for histological changes ranging in 

severity from loss of ciliated cells to the presence of malignant cells. Prevalence of different types of 

changes and mean histological scores were compared between exposed and nonexposed groups. The 

findings from rat studies indicating that the development of formaldehyde-induced nasal cancer is 

preceded by repeated damage to the upper respiratory tract epithelium suggests that monitoring of 

formaldehyde-exposed workers for cytological abnormalities in nasal biopsy samples may be useful to 

prevent the development of upper respiratory tract tissue damage or cancer. Similar findings of epithelial 

squamous dysplasia and hyperplastic nasal mucosa have been found in chronic occupational exposures to 

formaldehyde (Boysen et al. 1990; Edling et al. 1988); however, as discussed in Section 2.5, these human 

studies do not conclusively prove that formaldehyde was the primary toxicant responsible for the 

observed nasal lesions. The squamous metaplasia and mucosal hyperplastic lesions may be useful 

indicators of more severe formaldehyde-induced effects; however, its usefulness in human exposures is 

likely to be limited. 
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2.8 INTERACTIONS WITH OTHER CHEMICALS 

The study by Albert et al. (1982) reported the carcinogenic responses to the combined and separate 

exposures to formaldehyde and hydrochloric acid in male inbred Sprague-Dawley rats. Rats were 

exposed for 588 days to formaldehyde alone (14.2 ppm); formaldehyde (14.1 ppm) and hydrogen chloride 

(HCl) (9.5 ppm) combined but not premixed; formaldehyde (14.3 ppm) and HCl (10.0 ppm) combined 

and premixed; HCl alone (10.2 ppm); or room air. The data did not indicate a synergistic effect on 

mortality from combined formaldehyde and HCl exposure; no synergism was noted between combined 

HCl and formaldehyde exposure and the induction of nasal cancers. Rats exposed to formaldehyde alone 

experienced about a 9% depression in body weights compared to controls; those exposed to HCl alone 

experienced no noticeable weight loss; exposure to formaldehyde and HCl combined resulted in a 14% 

depression in body weight, indicating a synergistic adverse effect on body weight from combined HCl 

and formaldehyde exposure. Lam et al. (1985) studied the effects of inhalation co-exposure to acrolein 

and formaldehyde in male Fischer 344 rats. Rats were exposed for 6 hours to room air (controls), 2 ppm 

acrolein, 6 ppm formaldehyde, or a combination of 2 ppm acrolein and 6 ppm formaldehyde. The 

animals were sacrificed immediately after completion of exposure and their nasal tissues were harvested. 

Exposure to formaldehyde significantly increased the percentage of interfacial DNA (a measure of 

DNA-protein cross linking) compared to rats exposed to room air only (12.5 versus 8.1%, p<0.05). 

Co-exposure to acrolein resulted in further increases in the percentage of interfacial DNA (18.6%) which 

were significantly greater than the effect of formaldehyde alone (p<0.05). The authors concluded that 

simultaneous exposure to acrolein enhanced formaldehyde-induced DNA-protein cross linking and that 

depletion of glutathione by acrolein inhibited the metabolism of formaldehyde, thereby increasing 

formaldehyde-induced DNA-protein cross link formation. 

To investigate the possibility of additive or potentiating interactions between inhaled aldehydes, Cassee et 

al. (1996b) compared responses in nasal epithelial histopathology and cell proliferation in groups of male 

Wistar rats exposed for 3 days (6 hours/day) to 1.0, 3.2, or 6.4 ppm formaldehyde alone; to 0.25, 0.67, or 

1.40 ppm acrolein alone; to 750 or 1,500 ppm acetaldehyde alone; or to several mixtures of these 

aldehydes. At the concentrations tested, the histological and cell proliferation responses measured in the 

nasal epithelium of rats exposed to the mixture which produced effects (3.2 ppm formaldehyde; 

1,500 ppm acetaldehyde; 0.67 ppm acrolein) were attributed by the investigators to the acrolein alone 

with no additional effects from the formaldehyde or acetaldehyde. The investigators concluded that 
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combined exposures to these aldehydes at exposure levels in the vicinity of individual no-effect-levels 

was not associated with a greater hazard than that associated with exposure to the individual chemicals. 

As discussed previously in Sections 2.2 and 2.5, experiments with mice (Tarkowski and Gorski 1995) and 

guinea pigs (Riedel et al. 1996) indicate that exposure to low levels of formaldehyde enhances allergic 

responses to intranasal administration of ovalbumin and suggest the possibility of formaldehyde 

facilitation of allergic responses to other respiratory allergens. Mice pre-exposed to 1.6 ppm, 6 hours/day 

for 10 consecutive days produced four-fold greater ovalbumin-specific IgE antibodies in response to 

intranasal administration of ovalbumin mice that were not pre-exposed (Tarkowsi and Gorski 1995). A 

group of guinea pigs exposed to 0.25 ppm formaldehyde, 8 hours/day for 5 days showed a greater 

percentage of bronchial, presumably allergic, responses to inhaled ovalbumin than a control group 

without preexposure to formaldehyde (10/12 versus 3/12) (Riedel et al. 1996). 

2.9 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to formaldehyde than will most 

persons exposed to the same level of formaldehyde 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 may result in reduced detoxification or excretion of formaldehyde, or compromised 

function of target organs affected by formaldehyde. Populations who are at greater risk due to their 

unusually high exposure to formaldehyde are discussed in Section 5.6. 

Two populations of humans have received considerable attention in the literature as being particularly 

sensitive to formaldehyde exposure following inhalation and/or dermal exposure. The first population is 

asthmatics, and concern focuses on the changes in lung function parameters that formaldehyde may 

produce (Harving et al. 1990; Kulle et al. 1987; Pazdrak et al. 1993; Reed and Frigas 1984; Sauder et al. 

1986; Schachter et al. 1986; Witek et al. 1986). Most of these studies concluded that there is no evidence 

of increased airway reactivity as a result of formaldehyde exposure in either normal or asthmatic 

individuals. Formaldehyde exposures at the concentrations tested (usually >3 ppm) did not exacerbate 

existing asthmatic conditions, either at rest or after exercise. However, Nordman et al. (1985), in a human 

population of 230 persons suffering asthmatic symptoms and exposed to formaldehyde, found that 

when exposed to 2.04 ppm formaldehyde for 30 minutes, eight subjects demonstrated an immediate 

bronchial reaction, four subjects demonstrated a delayed reaction, and two subjects demonstrated both an 
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immediate and a delayed reaction. Peak expiratory flow rates dropped 19–49% in the immediate-reaction 

group and 21–47% in the delayed-reaction group. In a study of seven subjects with a history of 

occupational exposure to glutaraldehyde and asthma, peak expiratory flow rates were decreased in 3/7 

subjects by 27–33% in response to a bronchial challenge with 1% formaldehyde (Gannon et al. 1995). 

Gannon et al. (1995) suggested that respiratory sensitivity produced by exposure to glutaraldehyde may 

have cross-reactivity to formaldehyde in some subjects. 

The second population of potential concern is people with dermal sensitization. Several cases have been 

reported. Formaldehyde liquid, but neither the gaseous phase nor formalin, is considered to be a dermal 

sensitizer (Hilton et al. 1996). Anaphylactic reactions have been reported in the literature (Maurice et al. 

1986), in a description of a case in which anaphylaxis occurred in a patient due to skin contact with 

adhesives sterilized with formaldehyde prior to her hemodialysis therapy. Dermal allergic reactions have 

also been reported in doctors and nurses exposed to formaldehyde (Rudzki et al. 1989) as well as in 

fiberglass workers (Kilburn et al. 1985a). 

Data from acute controlled-exposure studies, supported by data from animal studies, generally indicate 

that formaldehyde does not induce airway hyper-reactivity at concentrations #3 ppm, but further studies 

with asthmatics may be required because of somewhat conflicting data in this potentially sensitive 

population. Other persons with dermal sensitization to formaldehyde are not likely to develop signs of 

respiratory insufficiency. Persons with multiple chemical sensitivities may represent a third potentially 

sensitive population, but studies linking this syndrome with exposure to formaldehyde were not located. 

2.10 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to formaldehyde. 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 formaldehyde. 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 formaldehyde: 

Aaron, CK and Howland, MA (eds.) (1994). Goldfrank's Toxicologic Emergencies. Appleton and 

Lange, Norwalk, CT. 
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Dreisbach, RH and Robertson, WO, (eds.) (1987). Handbook of Poisoning. Appleton and Lange, 

Norwalk, CT. 

Ellenhorn, MJ and Barceloux, DG, (eds.) (1988). Medical Toxicology: Diagnosis and Treatment of 

Human Poisoning. Elsevier Publishing, New York, NY. 

Gossel, TA and Bricker JD (1994). Principles of Clinical Toxicology. 3rd edition, Raven Press, 

New York, NY. 

Haddad, LM and Winchester, JF, (eds.) (1990). Clinical Management of Poisoning and Drug 

Overdose (2nd edition). WB Saunders, Philadelphia, PA. 

The primary concern after oral intoxication with formaldehyde is correcting the severe acidosis and 

decreased blood pressure that this chemical induces. Treatment should aimed at increasing the blood 

pressure to a somewhat normal state (sympathomimetic drugs may be used) as well as treating the 

acidosis with bicarbonate (Aaron and Howland 1994; Gossel and Bricker 1994). Dialysis may also be 

used to remove excess formate (as formic acid) in the blood in order to correct the acidosis (Burkhart et 

al. 1990; Eells et al. 1981). 

2.10.1 Reducing Peak Absorption Following Exposure 

Human exposure to formaldehyde may occur by inhalation, ingestion, or dermal contact. There are no 

known antidotes to formaldehyde poisoning in humans, particularly after oral exposure. General 

recommendations for reducing absorption of formaldehyde include removing the exposed individual from 

the contaminated area and removing contaminated clothing, if applicable. If the eyes and skin were 

exposed, they should be flushed with copious amounts of water. Since formaldehyde is highly corrosive, 

vomiting after oral ingestion should not be induced. The stomach contents can be diluted with milk or 

water by mouth if the patient is alert and responsive, otherwise gastric lavage may be indicated. A bolus 

of charcoal and isotonic saline cathartic may also be useful (Aaron and Howland 1994). 

2.10.2 Reducing Body Burden 

Formaldehyde is not stored to any appreciable extent in the human body and is mostly metabolized to 

formate and carbon dioxide (see Section 2.3). The half-life of formaldehyde in monkeys has been 

observed to be about 1.5 minutes following an intravenous injection. Furthermore, an inhalation 

exposure study found that no formaldehyde was present in the blood after a 1.9 ppm exposure for 
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40 minutes, indicating formaldehyde is metabolized very quickly either in the respiratory tract tissues or 

in the blood. 

Despite a relatively fast clearance of formaldehyde from the body, toxic effects may develop in exposed 

individuals, particularly in cases of acute oral poisonings which quickly overwhelm the body’s natural 

mechanisms to metabolize formaldehyde (particularly via formaldehyde dehydrogenase; see Figure 2-3). 

There is no standard method or practice to enhance the elimination of the absorbed dose of formaldehyde 

(Aaron and Howland 1994; Ellenhorn and Barceloux 1988). 

2.10.3 Interfering with the Mechanism of Action for Toxic Effects 

Target organs of formaldehyde toxicity while in the gaseous phase are the respiratory tract and eyes. 

After oral exposure, the tissues that formaldehyde comes into contact with on its way to the stomach and 

intestines (i.e., lips, oral pharynx, esophagus) are the target tissues; after dermal exposure, the adverse 

effects of formaldehyde are usually localized to the contact area, although other systemic reactions have 

been reported (Maurice et al. 1986) (see Section 2.2). Formaldehyde readily combines with free, 

unprotonated amino groups to yield hydroxymethyl adduct derivatives resulting in proton liberation 

(Loomis 1979). In higher concentrations (5–10%), formaldehyde will precipitate protein, which is the 

reason for its use in current histological techniques. The mechanism that causes the primary irritant 

effects is not presently known, but may involve one of the two mechanisms mentioned above. Currently, 

there are no procedures or therapies that specifically focus on interfering with the mechanism of action of 

formaldehyde. Supportive care by trained medical personnel is highly recommended. 

2.11 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 formaldehyde 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 formaldehyde. 
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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. 

2.11.1 Existing Information on Health Effects of Formaldehyde 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

formaldehyde are summarized in Figure 2-5. The purpose of this figure is to illustrate the existing 

information concerning the health effects of formaldehyde. 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 (ATSDR 1989), is substance-specific 

information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a 

data gap more broadly as any substance-specific information missing from the scientific literature. 

As seen in Figure 2-5, information is available regarding death, acute and chronic systemic effects, 

immunological, neurologic, reproductive, developmental, genotoxic, and cancer effects in humans after 

inhalation exposure to formaldehyde. Lesser amounts of information are available for humans exposed to 

formaldehyde after oral and dermal exposure. The oral and dermal health effects data are primarily 

limited to death and acute systemic toxicity data, immunological data (skin sensitization) after dermal 

exposure, and neurological data after acute oral poisonings. 

As also seen in Figure 2-5, significantly more information is available on the inhalation, oral, and dermal 

effects of formaldehyde in laboratory animals. The information on health effects in animals exposed 

orally or by inhalation is particularly rich but data regarding dose-response relationships for 

gastrointestinal effects from acute oral exposure and reproductive effects in multiple generations represent 

the most notable information gaps (see Section 2.11.2 for further discussion). Information was not 

located regarding death, systemic effects from intermediate-duration exposure, neurologic effects, and 

genotoxic effects in animals dermally exposed to formaldehyde. 
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FORMALDEHYDE 242 

2. HEALTH EFFECTS 

2.11.2 Identification of Data Needs 

Acute-Duration Exposure. Results from human and animal studies indicate that portal-of-entry 

tissues are the critical targets of acute-duration exposures to formaldehyde: the nose and eyes with 

inhalation exposure; the gastrointestinal tract with oral exposure; and the skin with dermal exposure. 

Studies of humans under controlled conditions clearly indicate that acute exposures to air concentrations 

ranging from 0.4 to 3 ppm: 

C	 induce reversible eye, nose, and throat irritation (Andersen and Molhave 1983; Bender et al. 1983; 

Day et al. 1984; Gorski et al. 1992; Krakowiak et al. 1998; Kulle 1993; Kulle et al. 1987; Pazdrak et 

al. 1993; Schachter et al. 1986; Weber-Tschopp et al. 1977; Witek et al. 1986); 

C	 produce changes in nasal lavage fluid contents, indicative of irritation of the nasal epithelium
 

(Gorski et al. 1992; Krakowiak et al. 1998; Pazdrak et al. 1993); and 

C	 do not consistently or markedly affect pulmonary function variables in most individuals (Andersen 

and Molhave 1983; Day et al. 1984; Gorski et al. 1992; Green et al. 1987; Harving et al. 1986, 

1990; Kulle et al. 1987; Nordman et al. 1985; Sauder et al. 1986; Schachter et al. 1986; Witek et al. 

1986). 

Acute inhalation animal studies confirm that air concentrations below 10–20 ppm produce damage only in 

specific regions of the epithelium of the upper respiratory tract in rats, mice, and monkeys and not at 

distant sites (Bhalla et al. 1991; Cassee and Feron 1994; Chang et al. 1983; Dinsdale et al. 1993; Kamata 

et al. 1996b; Monticello et al. 1989, 1991; Monteiro-Riviere and Popp 1986; Morgan et al. 1986a, 1986c; 

Wilmer et al. 1987). An acute inhalation MRL of 0.04 ppm was derived based on the LOAEL of 0.4 ppm 

for transient symptoms of eye and nose irritation and increased albumin content of nasal lavage fluid in 

volunteers exposed to formaldehyde for 2 hours (Pazdrak et al. 1993). Confidence is high that this MRL 

will protect the general public health due to the wealth of data, but confidence may increase with 

additional information about exposure-response relationships for formaldehyde-induced respiratory 

effects in potentially susceptible populations of individuals, such as asthmatics. 

An acute oral MRL for formaldehyde was not derived because data describing dose-response 

relationships for gastrointestinal tract irritation in humans or animals after acute oral exposure are lacking. 

The reports of gastrointestinal effects and symptoms in humans who ingested single large doses 

(>200 mg/kg) of formaldehyde (Burkhart et al. 1990; Eells et al. 1981; Kochhar et al. 1986), coupled with 
 

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data from studies of animals exposed orally for intermediate- and chronic-durations (Til et al. 1988b, 

1989; Tobe et al. 1989), indicate that gastrointestinal irritation and damage are the most likely critical 

effects from acute oral exposure. However, as discussed in Section 2.5, the human data do not identify a 

no-effect level, and the available animal studies of acute oral exposure (Cassidy et al. 1983; Johannsen et 

al. 1986) did not examine this end point. At least one comprehensive acute oral toxicity study of at least 

one animal species exposed to several dosage levels may be needed to generate appropriate data for 

deriving an acute oral MRL for formaldehyde. 

Formaldehyde is a well-known skin irritant and dermal sensitization agent, but systemic distant-site 

effects from acute dermal exposure are not expected given the reactive nature of formaldehyde, the ability 

of most cells to rapidly metabolize formaldehyde, and the low rates of formaldehyde absorption through 

the skin (Jeffcoat et al. 1983). This expectation is additionally supported by the observation that no 

effects on fetal development were found in pregnant hamsters dermally exposed during pregnancy to a 

37% formaldehyde solution (Overman 1985). Exposure-response relationships for dermal effects from 

acute dermal exposure are well characterized in humans and animals. Experience with various types of 

formaldehyde solutions in the workplace and results from widespread patch testing in skin clinics indicate 

that acute dermal exposure to formaldehyde concentrations of 2–5% can evoke a mild to moderate nonallergic skin irritation response in some individuals; concentrations greater than 5% are expected to be 

irritating to most individuals (Fischer et al. 1995; Maibach 1983). In studies of dermally sensitized 

individuals, allergic skin reactions to concentrations as low as 0.025–0.05% have been reported (DeGroot 

et al. 1988; Fischer et al. 1995; Flyvholm et al. 1997). The cases of clothing-induced contact dermatitis 

that were frequently cited in the literature from the late 1950s until the mid-1970's when newly developed 

“no-iron’ textiles that released formaldehyde were used (Peters and Heese 1997) further demonstrate the 

skin irritation potential of formaldehyde. Experiments with guinea pigs given daily non-occluded dermal 

doses of solutions of formaldehyde indicate that concentrations as low as 0.4% can produce erythema and 

increased skin thickness within a 10-day period (Wahlberg 1993). 

Intermediate-Duration Intermediate-duration exposure to formaldehyde is expected to affect the 

same critical targets as acute exposure: the upper respiratory tract with inhalation exposure; the 

gastrointestinal tract with oral exposure; and the skin with dermal exposure. 

Studies of health effects in humans after intermediate-duration inhalation exposure were not located. 

Studies of humans with predominately chronic inhalation exposure to formaldehyde under occupational 
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or residential conditions, however, consistently have reported increased incidences of symptoms of upper 

respiratory tract and/or eye irritation among exposed groups of people (Edling et al. 1988; Garry et al. 

1980; Holness and Nethercott 1989; Horvath et al. 1988; Ritchie and Lehnen 1987). Several studies have 

found nasal epithelial lesions, consistent with the irritant and reactive properties of formaldehyde, in 

biopsy specimens from workers repeatedly exposed to average concentrations ranging from about 0.2 to 

0.5 ppm (Ballarin et al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c). Other 

studies of similarly exposed groups of workers have either found no, or only small and subtle, exposurerelated changes in pulmonary function variables, thus supporting the identification of the upper 

respiratory tract as the critical target of repeatedly inhaled formaldehyde (Alexandersson and 

Hedenstierna 1988, 1989; Bracken et al. 1985; Holness and Nethercott 1989; Horvath et al. 1988; 

Khamgaonkar and Fulare 1991; Kriebel et al. 1993; Malaka and Kodama 1990). Although the persons in 

these studies are considered to have been exposed for chronic durations, the results, together with the 

results from the acute controlled inhalation human studies, provide strong evidence that the critical target 

from intermediate-duration inhalation exposure to formaldehyde will be the upper respiratory tract. 

Results from studies of animals exposed by inhalation for intermediate durations provide supporting 

evidence for the upper respiratory tract as the critical target and describe concentration-response 

relationships sufficiently well for describing an intermediate-duration inhalation MRL. Data describing 

intermediate-duration exposure-response relationships for upper respiratory tract lesions and 

concentrations ranging from 0.2 ppm to as high as 40 ppm are available for rats (Appelman et al. 1988; 

Casanova et al. 1994; Monticello et al. 1991; Rusch et al. 1983; Woutersen et al. 1987; Zwart et al. 1988), 

Cynomolgus monkeys (Rusch et al. 1983), hamsters (Rusch et al. 1983), and mice (Maronpot et al. 1986). 

Comprehensive histological examination of tissues and organs (including the lungs and eyes) in three of 

these studies (Appelman et al. 1988; Maronpot et al. 1986; Woutersen et al. 1987) and in another study of 

Rhesus monkeys that included only one exposure concentration (Monticello et al. 1989) found no 

consistent evidence for lesions outside of the upper respiratory tract. These results confirm the 

identification of the upper respiratory tract as the target of concern. Other intermediate-duration 

inhalation exposure studies in rats (Wilmer et al. 1987, 1989) provide evidence that the extent and 

severity of formaldehyde-induced epithelial lesions in the upper respiratory tract may be more strongly 

influenced by exposure concentration than duration of exposure. 

The intermediate-duration inhalation MRL of 0.03 ppm is based on a NOAEL of 0.98 ppm and a LOAEL 

of 2.95 ppm for clinical signs of nasopharyngeal irritation and nasal epithelium lesions observed in 
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Cynomolgus monkeys (Rusch et al. 1983) and an uncertainty factor of 30. Computational fluid dynamic 

models of airflow and formaldehyde uptake in nasal passages and pharmacokinetic models of tissue 

disposition of formaldehyde in rats and humans are currently under development (Kimbell et al. 1993, 

1997a, 1997b; Subramaniam et al. 1998). The application of these models to the rat intermediate-duration 

exposure-response data is likely to decrease uncertainty in deriving an intermediate-duration inhalation 

MRL from animal data. Such models are being developed for Rhesus monkeys (Kepler et al. 1998; 

Kimbell et al. 1997b), not Cynomolgus monkeys, but the available intermediate-duration data for Rhesus 

monkeys do not adequately describe concentration-response relationships; therefore a no-effect level 

cannot presently be estimated. Application of the monkey and human dosimetric models, when they are 

developed, to data from another Rhesus monkey study that would include multiple exposure levels 

represents another approach to decreasing uncertainty in the intermediate-duration inhalation MRL. 

There is some uncertainty regarding whether or not inhaled formaldehyde can affect the lower respiratory 

tract by inducing bronchoconstriction or exacerbating asthma in humans, and whether or not repeated 

exposure may influence these possible, but incompletely understood, effects. As discussed earlier, 

several acute controlled exposure studies with humans (Andersen and Molhave 1983; Day et al. 1984; 

Gorski et al. 1992; Green et al. 1987; Harving et al. 1986, 1990; Kulle et al. 1987; Nordman et al. 1985; 

Sauder et al. 1986; Schachter et al. 1986; Witek et al. 1986) and studies of chronically exposed persons in 

workplaces or residences (Alexandersson and Hedenstierna 1988, 1989; Bracken et al. 1985; Holness and 

Nethercott 1989; Horvath et al. 1988; Khamgaonkar and Fulare 1991; Kriebel et al. 1993; Malaka and 

Kodama 1990) have found only mild or no changes in pulmonary function variables, except in a few rare 

cases (see Nordman et al. 1985). However, Amdur (1960) and Swiecichowski et al. (1993) reported that 

acute inhalation exposure to fairly low levels of formaldehyde (0.3 to 9 ppm) induced 

bronchoconstriction (i.e., increased pulmonary airway resistance) in guinea pigs. Swiecichowski et al. 

(1993) further reported that airway reactivity to infused acetylcholine increased after acute exposure to 

formaldehyde and that when the duration of exposure to formaldehyde was increased from 2 to 8 hours, 

lower concentrations of formaldehyde were effective in increasing airway reactivity to infused 

acetylcholine. The mechanism underlying these pulmonary effects is not understood, but Swiecichowski 

et al. (1993) have hypothesized that formaldehyde may change airway epithelial biochemistry leading to 

release of mediators of bronchoconstriction. Studies to test this hypothesis were not located. The 

relevance of the guinea pig findings to the report that a group of children living in homes with 0.06–0.12 

ppm formaldehyde showed a greater prevalence of bronchitis and asthma than children living in homes 
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2. HEALTH EFFECTS 

with less than 0.06 ppm (Krzyzanowski et al. 1990) has been questioned (Swiecichowski et al. 1993), but 

remains unknown. 

Studies of health effects in humans after intermediate-duration oral exposure to formaldehyde were not 

located. Intermediate-duration oral-exposure toxicity studies in animals that examined a range of tissues 

and organs are extensive and include a 90-day drinking water rat study that found only weight gain 

decreases at dosage levels of 100–150 mg/kg/day (Johannsen et al. 1986), a 4-week drinking water rat 

study that identified a NOAEL of 25 mg/kg/day and a LOAEL of 125 mg/kg/day for forestomach and 

glandular stomach lesions indicative of irritation (Til et al. 1988b), a 4-week gavage rat study that 

identified a NOAEL of 40 mg/kg/day and a LOAEL of 80 mg/mg/day for hepatocellular vacuolation and 

a LOAEL of 20 mg/kg/day for a decrease in IgM and IgG titers and increased relative lymph node weight 

(Vargova et al. 1993), a 90-day dietary exposure dog study that reported a NOAEL and LOAEL of 75 and 

100 mg/kg/day for body weight decreases and no other effects (Johannsen et al. 1986), and a 52-day 

dietary exposure pregnant dog study that found no evidence of maternal toxicity and no effects on fetal 

development at doses up to 9.4 mg/kg/day (Hurni and Ohder 1973). In addition, a 32-week drinking 

water study that focused on the gastrointestinal tract found papillomas in the forestomach and erosions 

and/or ulcers in the limiting ridge of the fundic mucosa of the glandular stomach in rats exposed to 

258 mg/kg/day (Takahashi et al. 1986a). 

The findings from the intermediate-duration oral exposure studies by themselves do not consistently 

identify gastrointestinal tract irritation as the critical effect. However, the weight of evidence from 

chronic oral administration animal studies (Til et al. 1989; Tobe et al. 1989) and the numerous 

intermediate inhalation toxicity studies (as previously cited), together with mechanistic understanding of 

formaldehyde’s mode of toxic action, supports the selection of it as the critical effect from intermediate 

duration. Thus the selection of forestomach and glandular stomach lesions in rats (Til et al. 1988b) as the 

basis of the intermediate-duration oral MRL of 0.3 mg/kg/day is well-supported. As mentioned in the 

introduction to Section 2.2.2, there is uncertainty regarding the actual doses that were experienced by 

animals in the published oral exposure studies because of the lack of reporting regarding how frequently 

dosing solutions were analyzed for formaldehyde and the well-known instability of aqueous solutions of 

formaldehyde. Given this uncertainty and the lack of consistency in the findings from the available 

intermediate-duration oral studies, confidence in the MRL may be improved with additional intermediateduration dose-response data from another comprehensive dietary or drinking water study of rats that 

includes frequent monitoring of dosing solutions. Dose-response data for gastrointestinal tract 
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effects in a primate species may provide an additional means of decreasing uncertainty in the intermediate 

oral MRL. 

Formaldehyde is a well-known skin irritant and skin sensitizer in humans that accounts for about 1–8% of 

all cases of allergic dermatitis presented at skin clinics (Fischer et al. 1995; Kiec-Swierczynska 1996; 

Marks et al. 1995; Meding and Swanbeck 1990; Menné et al. 1991). Studies of embalmers (Nethercott 

and Holness 1988) and medical workers (Rudzki et al. 1989) with expected repeated dermal exposure to 

formaldehyde presented evidence for increased prevalence of formaldehyde-induced skin irritation and 

dermal allergic reactions. Exposure-response relationships for skin irritation and dermal allergic 

responses from acute exposure are well characterized (under patch testing conditions) in both normal and 

sensitized individuals, indicating that 1% solutions are not expected to be irritating to most people, and 

that allergic dermal reactions in sensitized individuals can occur with concentrations as low as 

0.015% (DeGroot et al. 1988; Fischer et al. 1995; Flyvholm et al. 1997; Maibach 1983). No published 

dose-response data were located for dermal irritation or the development of dermal sensitization in 

humans for intermediate- or chronic-duration exposure. Given the high reactivity, volatility, and aqueous 

solubility of formaldehyde and its rapid metabolism by cells, it is likely that dose-response relationships 

for dermal irritation from acute exposure may not be widely different from relationships for intermediateand chronic-duration exposures. This hypothesis is supported by the results from inhalation exposure 

studies in rats indicating that exposure concentration is more important than exposure duration in 

determining the extent and severity of formaldehyde-induced epithelial lesions in the upper respiratory 

tract (Wilmer et al. 1987, 1989). Nevertheless, additional animal studies comparing dose-response 

relationships for skin irritation for acute, intermediate, and chronic exposure durations may be useful in 

estimating concentrations that will not damage the skin with repeated exposures. 

The potency of formaldehyde as a contact allergen is demonstrated by the observation that occluded 

dermal exposure of guinea pigs to 5% formaldehyde for 3 weeks sensitized 70% of the animals to later 

dermal challenges with 1% formaldehyde (Hilton et al. 1996). However, published studies that describe 

dose-response relationship or no-effect levels for the development of dermal sensitization in animals with 

intermediate- or chronic-duration exposure were not located. Such studies are likely to be useful in 

estimating concentrations of formaldehyde that would minimize the development of dermal sensitization 

to formaldehyde in humans. 
 

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Chronic-Duration Exposure and Cancer. As with the shorter durations of exposure, the critical 

targets of chronic inhalation, oral, or dermal exposure to formaldehyde are expected to be portal-of-entry 

tissues. For the inhalation route, the data are abundant, of good quality, and include both human and 

animal data. Less health effects data are available for chronic oral and chronic dermal exposure, but the 

weight of the available data is consistent with this expectation. 

Studies of humans chronically exposed to airborne formaldehyde concentrations in the approximate range 

of 0.1–1 ppm have consistently reported increased incidences of upper respiratory tract and eye irritation 

(Edling et al. 1988; Garry et al. 1980; Holness and Nethercott 1989; Horvath et al. 1988; Ritchie and 

Lehnen 1987), evidence for mild histological changes in the nasal epithelium (Ballarin et al. 1992; 

Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c), and either no or only mild changes in 

pulmonary function variables (Alexandersson and Hedenstierna 1988, 1989; Bracken et al. 1985; Holness 

and Nethercott 1989; Horvath et al. 1988; Khamgaonkar and Fulare 1991; Kriebel et al. 1993; Malaka 

and Kodama 1990). Several chronic inhalation studies in rats (Kamata et al. 1997; Kerns et al. 1983b; 

Monticello et al. 1996; Swenberg et al. 1980; Woutersen et al. 1989) and one study in mice (Kerns et al. 

1983b) adequately describe concentration-response relationships for formaldehyde effects on the nasal 

epithelium and have identified no-effect levels ranging from 0.1 to 2 ppm. No consistent evidence for 

formaldehyde-induced effects at extra-respiratory sites was found in rats (Kamata et al. 1997; Kerns et al. 

1983b) or mice (Kerns et al. 1983b) exposed to concentrations as high as 15 ppm. A chronic inhalation 

MRL of 0.008 ppm has been derived based on a minimal LOAEL of 0.24 ppm for histological changes in 

nasal epithelial specimens from a group of workers involved in the production of formaldehyde and 

formaldehyde resins (Holmstrom et al. 1989c) and an uncertainty factor of 30. Although confidence in 

this MRL is high due to the wealth of available data, increased confidence may result from additional 

prospective longitudinal studies of nasal tissue specimens from groups of workers experiencing varying 

formaldehyde exposure levels to investigate if nasal epithelial damage progresses in incidence or severity 

with longer duration or higher levels of exposure. Computational fluid dynamics models of airflow and 

formaldehyde uptake in nasal passages and pharmacokinetic models of tissue disposition of formaldehyde 

in rats and humans are currently under development (Kimbell et al. 1993, 1997a, 1997b; Subramaniam et 

al. 1998). Application of these models to chronic rat concentration-response data for nasal lesions 

represents another research approach to decreasing uncertainty in the chronic inhalation MRL. 
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No studies were located regarding health effects in humans with chronic oral exposure to formaldehyde. 

Two chronic drinking water studies with rats (Til et al. 1989; Tobe et al. 1989) provide enough reliable 

data to identify gastrointestinal tract mucosal damage as the critical target for chronic oral exposure and to 

describe dose-response relationships and estimates of no-effect levels. Results from the chronic oral 

studies are supported by results from the intermediate-duration rat studies showing gastrointestinal tract 

effects and associated no-effect levels (Johannsen et al. 1986; Takahashi et al. 1986a; Til et al. 1988b). 

The chronic MRL of 0.2 mg/kg/day was based on a NOAEL of 15 mg/kg/day and a LOAEL of 

82 mg/kg/day for tissue damage in the forestomach (papillomatous hyperplasia, atrophic gastritis, and 

ulceration) and glandular stomach (hyperplasia) in male rats (Til et al. 1989) and an uncertainty factor 

of 100. As with the intermediate-duration data, some uncertainty is associated with the described chronic 

dose-response relationships due to a lack of reporting of the frequency of analysis of the drinking water 

for formaldehyde content in the available studies. Results from another intermediate-duration drinking 

water rat study, rather than a chronic-duration study, that includes frequent monitoring of the drinking 

water for formaldehyde, may decrease this source of uncertainty in the both the intermediate and chronic 

oral MRLs, given that the weight of evidence that concentration of formaldehyde at the site of toxic 

action is likely to be more important in determining cytotoxicity than duration of exposure. 

As discussed in the Identification of Data Needs section for intermediate-duration exposure, additional 

animal studies comparing exposure-response relationships for skin irritation for acute- intermediate- and 

chronic-exposure durations would be useful in estimating concentrations of formaldehyde solutions that 

will not damage the skin with repeated exposures. Although no comprehensive toxicity studies in 

animals were located regarding chronic dermal exposure, understanding of formaldehyde toxicokinetics 

and mechanism of action suggests that distant-site toxicity is not a concern at environmentally or 

occupationally relevant dermal exposure levels. 

The potential for occupational exposure to formaldehyde to cause cancer in humans has been examined in 

more than 40 epidemiology studies (cohort mortality and case-control studies). In general, these studies 

have provided inconsistent evidence for carcinogenicity in humans chronically exposed to low levels of 

formaldehyde in workplace air. In most studies finding statistically significant associations between 

occupational formaldehyde and human cancer, the associations have not been strong. The 

epidemiological studies each have shortcomings, such as limited follow-up, limited exposure 

information, possible misclassification of disease, presence of confounding risk factors, or small numbers 

of subjects, that make the establishment of a causal relationship between occupational exposure to 
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formaldehyde and human cancer difficult. Some of the epidemiological studies have found some 

scattered evidence for extra-respiratory site cancers in groups of formaldehyde-exposed workers, but the 

data are not consistent across studies and adjustment for potential confounding factors often has not been 

possible. 

Three meta-analyses of the epidemiologic data are available (Blair et al. 1990a; Collins et al. 1997; 

Partanen 1993). Each meta-analysis has focused on findings for respiratory cancer deaths based on the 

premise that the respiratory tract is the most biologically plausible site for cancer from exposure to 

airborne formaldehyde. Strong support for this premise comes from animal studies showing that chronic 

inhalation exposure to formaldehyde concentrations between approximately 6 and 15 ppm, but not lower 

concentrations, induces carcinogenic responses in rats that are restricted to the nasal cavity (Albert et al. 

1982; Kamata et al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Sellakumar et al. 1985; Swenberg et 

al. 1980; Woutersen et al. 1989). Similar tumors were found in chronically exposed mice (Kerns et al. 

1983b), but were not found in chronically exposed hamsters (Dalbey 1982). The two earlier metaanalyses showed weak overall associations between formaldehyde exposure and nasopharyngeal cancer. 

Relative risks and associated 95% CIs of 1.2 (0.8–1.7) and 2.0 (1.4–2.9) were reported by Blair et al. 

(1990a) and Partanen (1993), respectively. The associations were somewhat stronger in studies classified 

with “substantial” (as opposed to “low/medium”) exposure. Relative risks for substantial exposures in the 

two analyses were 2.1 (1.1–3.5) and 2.7 (1.4–5.6). The meta-analysis by Collins et al. (1997) also 

showed a weak association across all available studies for relative risks of nasopharyngeal cancer 

(RR=1.3 [1.2–1.5]), but after adjusting the cohort studies for underreporting of nasopharyngeal cancer 

(RR=1.0 [0.5–1.8]) and analyzing the case-control studies separately (RR=1.3 [0.9–2.1]), no statistically 

significant associations were found. 

Given that exposure information in case-control studies is generally poor, it seems that additional casecontrol studies are unlikely to clarify the potential relationship between occupational formaldehyde 

exposure and human cancer. Future research approaches that may be helpful include establishing 

prospective cohort mortality studies or updating existing cohort studies focusing on nasal cancer in 

groups of workers who have experienced high levels of exposure to formaldehyde or who will experience 

varying levels of formaldehyde exposure and in groups of appropriately matched nonexposed workers. It 

may be useful to conduct such a prospective study in a country in which occupational exposure levels to 

formaldehyde are expected to be higher than those in the United States. 
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Mechanistic studies indicate that the carcinogenic response to inhaled formaldehyde in rats originates in 

regions of the nasal cavity epithelium that initially show non-neoplastic damage and provide support for 

the hypothesis that formaldehyde-induced cancer will occur only at exposure levels that extensively 

damage epithelium tissue (e.g., Monticello et al. 1996). Comparison of the non-neoplastic upper 

respiratory tract response in rats and monkeys to intermediate-duration formaldehyde exposure has 

indicated that both monkeys and rats are similarly susceptible to formaldehyde cytotoxicity but display 

some regional differences in sites of tissue damage within the upper respiratory tract (Casanova et al. 

1989, 1991; Heck et al. 1989; Monticello et al. 1989). These observations support the use of data from 

rodent studies to extrapolatively estimate risks for nasal tissue damage and nasal cancer with human 

exposure scenarios. 

The application of dosimetric models (e.g., CFD models of airflow and uptake in nasal passages and 

PBPK models of nasal disposition of formaldehyde) currently under development (Cohen Hubal et al. 

1997; Kepler et al. 1998; Kimbell et al. 1993, 1997a, 1997b; Morgan et al. 1991; Subramaniam et al. 

1998) holds promise of reducing uncertainties in estimating human cancer risks from the available rodent 

data (Morgan 1997). Ongoing efforts (see CIIT 1998; Conolly et al. 1992; Conolly and Andersen 1993) 

to develop two-stage clonal-growth cancer models (i.e., pharmacodynamic models) incorporating data on 

formaldehyde-induced cell proliferation rates, numbers of cells at risk, tumor incidence, and site-specific 

flux of inhaled formaldehyde are also likely to reduce uncertainties in estimating the risks for neoplastic 

damage to the upper respiratory tract in humans exposed to low levels of airborne formaldehyde. 

Results from four drinking water rat studies provide some inconsistent evidence for formaldehydeinduced gastrointestinal tract tumors (Soffritti et al. 1989; Takahashi et al. 1986a; Til et al. 1989; Tobe et 

al. 1989). As discussed in Section 2.5, the weight of evidence from the rat studies suggests that 

gastrointestinal tract tumors may occur as late-developing portal-of-entry effects only from repeated 

exposure to high oral doses that damage the gastric mucosa, and that tumors are not likely to develop at 

dose levels that do not damage the gastric mucosa. It is unlikely that a human population with high oral 

exposures to formaldehyde can be identified to study possible relationships to cancer, but better 

characterization of no-effect levels for gastric mucosal damage in animal species exposed repeatedly to 

formaldehyde in drinking water may provide additional information to support the hypothesis that low 

levels of formaldehyde in water samples associated with hazardous waste sites do not present 

considerable risks for cancer. 
 

 

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No studies were located examining potential relationships between skin cancer in humans and dermal 

exposure to formaldehyde, but two mouse-skin cancer bioassays found no evidence for increased 

incidence of skin tumors after 58–60 weeks of twice-weekly exposure to formaldehyde solutions at 

concentrations of 4% (Iverson 1988) and 10% (Iverson 1986). Additional animal bioassays employing 

lifetime dermal exposure scenarios would provide more complete assessments of the possible dermal 

carcinogenicity of formaldehyde. 

Genotoxicity. Formaldehyde has been demonstrated to have genotoxic properties in human and 

laboratory animal studies. Peripheral lymphocytes in anatomy students exposed to 0.73–1.95 ppm 

formaldehyde for 10 weeks showed a small average increase in SCEs (Yager et al. 1986). Lymphocytes 

from wood workers chronically exposed to formaldehyde also showed increased levels of chromosomal 

aberrations; however, there were no significant changes in the rates of SCE (Chebotarev et al. 1986). 

Other positive findings for genotoxicity include increases in micronuclei formation in wood workers 

(Ballarin et al. 1992) and an increased incidence in chromosomal abnormalities in pulmonary 

macrophages in rats (Dallas et al. 1992). 

Formaldehyde has been found to be genotoxic in a number of cells and genetic end points. Formaldehyde 

has been found to induce chromosomal aberrations (Dresp and Bauchinger 1988; Natarajan et al. 1983), 

increases in micronucleus formation (Ballarin et al. 1992), and SCEs (Yager et al. 1986), as well as 

numerous other genotoxic end points (Recio et al. 1992; Topham 1980). Formaldehyde has also been 

found to have genotoxic properties in S. typhimurium (Donovan et al. 1983) and in human cell lines 

(Grafstrom et al. 1985; Snyder and Van Houten 1986). The weight of evidence indicates that 

formaldehyde is capable of directly reacting with DNA. No reports of genotoxicity strictly related to the 

oral or dermal exposure routes were found in the available literature. Further cytogenetic analysis of cells 

from formaldehyde-exposed individuals would possibly provide useful information about the ability and 

mechanisms by which formaldehyde induces its genotoxic end points. 

Reproductive Toxicity. Results from human and animal studies indicate that formaldehyde is not a 

likely reproductive toxicant at low levels of exposure. No effects on sperm numbers or sperm 

morphology were found in a group of formaldehyde-exposed pathologists (Ward et al. 1984), and 

increased rates of miscarriage were not found among persons with presumed residential exposure to 

formaldehyde (Garry et al. 1980). Studies of reproductive outcomes in groups of formaldehyde-exposed 

workers may be useful to confirm that the potential for reproductive effects from formaldehyde is low. 
 

FORMALDEHYDE 253 

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Results from such a study will have a better chance of being conclusive if a population is identified that is 

exposed only to formaldehyde. 

Animal studies of inhalation exposure found no direct effects of formaldehyde on reproductive organ 

histopathology or weight (Appelman et al. 1988; Maronpot et al. 1986; Woutersen et al. 1987) and, with 

exposure during gestation, no effects on maternal reproductive variables other than decreased body 

weight gains at high exposure levels (Martin 1990; Saillenfait et al. 1989). Similarly, oral exposure of 

animals has not been associated with histopathologic or weight changes in reproductive organs 

(Johannsen et al. 1986; Til et al. 1989; Tobe et al. 1989; Vargova et al. 1993) or with maternal 

reproductive variables such as numbers of resorptions at non-lethal exposure levels in pregnant animals 

(Hurni and Ohder 1973; Marks et al. 1980). Changes in sperm morphology were noted in rats given 

single gavage doses of 200 mg/kg/day, but not 100 mg/kg/day (Cassidy et al. 1983). Overman (1985) 

reported a small increase in resorption rate in pregnant hamsters dermally exposed to 37% formaldehyde 

solutions, but attributed this effect to treatment stress rather than to a direct effect of formaldehyde. 

Assays of reproductive performance in formaldehyde-exposed animals were not located, but may be 

useful to confirm that formaldehyde is not a reproductive toxicant. 

Developmental Toxicity. Results from a human study and several animal studies indicate that 

formaldehyde is not a likely developmental toxicant at low levels of exposure. No associations were 

found between incidence of low birth weights and ambient air levels of formaldehyde among groups of 

mothers living in different residential districts (Grañulevi...iene et al. 1998). No embryolethal or 

teratogenic effects of formaldehyde were found in gestational-exposure studies of rats exposed to air 

concentrations up to 40 ppm (Martin 1990; Saillenfait et al. 1989), rats exposed to gavage dose levels up 

to 185 mg/kg/day (Marks et al. 1980), dogs exposed to dietary doses up to 9.4 mg/kg/day (Hurni and 

Ohder 1973), and hamsters dermally exposed to 37% formaldehyde solutions (Overman 1985). 

Formaldehyde was designated as a nonteratogen and nonembryotoxin in the Chernoff/Kavlock 

developmental toxicity screening test in mice (Seidenberg and Becker 1987). The need for additional 

developmental toxicity studies may not have a high priority, given the evidence from other repeatedexposure animal toxicity and pharmacokinetic studies indicating that health effects from formaldehyde 

are likely to be restricted to portals-of-entry. 
 

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Immunotoxicity. Dermal sensitization to formaldehyde in humans is well recognized from results of 

patch testing at dermatological clinics throughout the world (Fischer et al. 1995; Kiec-Swierczynska 

1996; Maibach 1983; Marks et al. 1995; Meding and Swanbeck 1990; Menné et al. 1991) and a few 

studies of formaldehyde-exposed workers (Nethercott and Holness 1988; Rudzki et al. 1989). Severe 

allergic responses to dermally applied formaldehyde, however, appear to be rare; only one case of a 

severe anaphylactic response to formaldehyde was located (Maurice et al. 1986). The potency of 

formaldehyde as a contact allergen is demonstrated by the observation that occluded dermal exposure of 

guinea pigs to 5% formaldehyde for 3 weeks sensitized 70% of the animals to later dermal challenges 

with 1% formaldehyde (Hilton et al. 1996). However, published studies that describe dose-response 

relationships or no-effect levels for the development of dermal sensitization in animals with intermediateor chronic-duration dermal exposure were not located. Such studies are likely to be useful in estimating 

concentrations of formaldehyde that would minimize the development of dermal sensitization to 

formaldehyde in humans. 

Although formaldehyde is widely recognized as a dermal irritant that can sensitize the skin in humans, the 

evidence for immunologically-mediated sensitization of the respiratory tract from exposure to airborne 

formaldehyde is weak. There are only a few available case reports of formaldehyde-exposed workers 

who display marked changes in pulmonary function variables in response to acute challenges with inhaled 

formaldehyde that are consistent with an immunologically-mediated mechanism of response (Burge et al. 

1985; Hendrick et al. 1982; Lemiere et al. 1995). Nordman et al. (1985) reported that, among 

230 patients with formaldehyde exposure who reported asthma-like symptoms, only 12 showed marked 

pulmonary responses to acute formaldehyde challenges. Other studies found no marked response to 

challenges of inhaled formaldehyde in other groups of previously-exposed subjects who complained of 

asthma-like symptoms (Day et al. 1984; Krakowiak et al. 1998; Reed and Frigas 1984). Several studies 

have found no consistent evidence for increased serum levels of formaldehyde-specific IgE antibodies in 

groups of formaldehyde-exposed subjects including groups with complaints of respiratory symptoms 

(Dykewicz et al. 1991; Gorski et al. 1992; Grammar et al. 1990; Krakowiak et al. 1998; Kramps et al. 

1989; Thrasher et al. 1987, 1990). Elevated serum levels of IgE antibodies and respiratory tract 

symptoms were found in groups of children exposed to classroom air concentrations of 0.075, 0.069, and 

0.043 ppm formaldehyde (Wantke et al. 1996a). However, the relevance of these findings to the 

possibility of respiratory tract sensitization to formaldehyde is uncertain because the elevated levels of 

IgE were not correlated with the number and severity of symptoms, and the symptoms were more 
 

FORMALDEHYDE 255 

2. HEALTH EFFECTS 

indicative of irritant responses than asthma-type responses expected to be mediated through IgE 

antibodies. 

Results from studies with guinea pigs confirm that formaldehyde is a potent skin sensitizer, but does not 

elicit IgE responses and lymph node cytokine secretion patterns that are typically induced by other potent 

respiratory tract allergens such as trimellitic anhydride (Hilton et al. 1996). Other animal studies indicate 

that repeated exposure to formaldehyde at air concentrations between 10 and 15 ppm did not produce 

significant effects in several assays of immune function including resistance to intravenous or 

subcutaneous injection of neoplastic cells in mice (Dean et al. 1984), resistance to intravenous injection of 

bacterial cells in mice (Dean et al. 1984), and IgM response to tetanus immunization and IgG response to 

tetanus toxoid in rats (Holmstrom et al. 1989b). However, two other studies indicate that exposure to 

airborne formaldehyde may enhance allergic responses of the respiratory tract to other respiratory 

allergens (Riedel et al. 1996; Tarkowski and Gorski 1995). Further research is necessary to confirm the 

hypothesis that exposure to airborne formaldehyde may facilitate immunological responses to other 

respiratory allergens and to determine if this is relevant to humans exposed to formaldehyde. 

Information about immunological and lymphoreticular effects in humans orally exposed to formaldehyde 

is restricted to a report of splenomegaly in a case of acute poisoning (Koppel et al. 1990). In animal 

studies, decreased IgM and IgG titers in a hemagluttination assay and increased lymph node weights were 

found in rats exposed to gavage doses of 20 mg/kg/day and higher, but other measures of IgG and IgM 

production were not affected by exposure (Vargova et al. 1993). No effects on weights or histopathology 

of spleen and lymph nodes were found in other studies of orally exposed animals (Til et al. 1988b, 1989; 

Tobe et al. 1989). The data do not clearly identify immunological effects from oral exposure to 

formaldehyde as effects of concern. Further research on the possible immunotoxicity of ingested 

formaldehyde may not be warranted given the likelihood that oral exposures to formaldehyde may be low 

in most groups of people, due to the instability of formaldehyde in aqueous solutions. 

Neurotoxicity. The nervous system does not appear to be a major target organ for formaldehyde 

toxicity; however, some vague neurological symptoms may occur after inhalation exposure in humans. 

These may include headaches, "heavy head," fatigue, and increased reaction time (Bach et al. 1990). 

Kilburn and colleagues have reported evidence for neurological symptoms and impaired performance 

in neurobehavioral tests in groups of formaldehyde-exposed histology technicians, but confounding 

exposure to other neurotoxic solvents prevents drawing definitive conclusions regarding the 
 

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neurotoxicity of formaldehyde from this source (Kilburn 1985b; Kilburn et al. 1987; Kilburn and 

Warshaw 1992; Kilburn 1994). Restless behavior (Morgan et al. 1986a), increased levels of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and dopamine in the hypothalamus (Boja et al. 1985), 

and evidence for the development of a conditioned avoidance behavior (Wood and Coleman 1995) have 

been reported in rats. The restless behavior may be attributable to the respiratory irritant effects of the 

formaldehyde vapor; however, the significance of the increased chemical content in the hypothalamus of 

rats is unclear. Other studies have found no perceptible effects of formaldehyde on the nervous system of 

rats and mice at #15 ppm (Appelman et al. 1988; Kerns et al. 1983b), although obvious clinical signs of 

neurological impairment were observed in mice (Maronpot et al. 1986) and rats (Woutersen et al. 1987) 

exposed to high concentrations ($20 ppm) of airborne formaldehyde. 

Reports of neurotoxicity in humans after an oral exposure to formaldehyde are limited to case reports. 

Coma, lethargy, seizures, and loss of consciousness have been reported in humans after drinking 

formaldehyde (Burkhart et al. 1990; Eells et al. 1981; Koppel et al. 1990). No consistent effects on the 

nervous system after oral exposure to formaldehyde were found in several toxicity reports using 

laboratory animal models (Johannsen et al. 1986; Til et al. 1988b, 1989; Tobe et al. 1989). Increased 

relative brain weights were observed in one group of rats chronically exposed to drinking water doses of 

82–109 mg/kg/day (Til et al. 1989), but not in another group exposed to 300 mg/kg/day (Tobe et al. 

1989). The data suggest that the nervous system may be affected by formaldehyde exposure, especially if 

it is ingested in large quantities or if chronically inhaled in low doses in an occupational setting. 

Additional prospective evaluations of performance on neurobehavioral tests in groups of formaldehydeexposed workers may be useful in ascertaining if there are subtle neurological effects from chronic 

inhalation exposure to formaldehyde. Results from such studies would be most useful if the studied 

workers were not exposed to other neurotoxic airborne agents; this is a condition which may be difficult 

to find in occupational settings. 

Epidemiological and Human Dosimetry Studies. Results from many acute controlled-exposure 

human studies and cross-sectional studies of groups of persons repeatedly exposed to airborne 

formaldehyde provide strong evidence that the upper respiratory tract is the critical target of airborne 

formaldehyde for any duration of exposure, allow reasonable estimates to be made of minimal risk levels 

for acute and chronic durations of exposure, and provide strong support for deriving intermediateduration minimal risk levels from animal exposure-response data. There is considerable confidence that 

adherence to these values will protect persons living near formaldehyde-contaminated hazardous waste 
FORMALDEHYDE 257 

2. HEALTH EFFECTS 

sites from developing upper respiratory tract health problems. Longitudinal studies that examine nasal 

specimens from groups of workers with varying air exposure levels will provide information that may 

further increase confidence in the estimated minimal risk levels. 

There does not appear to be a pressing need for epidemiology studies of people exposed orally to 

formaldehyde given the instability of formaldehyde in environmental sources of water and the 

implausibility of identifying groups of people exposed to oral doses of formaldehyde that are sufficiently 

high to damage gastrointestinal tract tissue. 

The relatively frequent reporting of dermal sensitization to formaldehyde at dermatological clinics 

(Fischer et al. 1995; see also: Kiec-Swierczynska 1996; Maibach 1983; Marks et al. 1995; Meding and 

Swanbeck 1990; Menné et al. 1991) suggests that cross-sectional and longitudinal studies of dermal 

exposure levels and prevalence of skin problems in groups of workers with expected dermal exposure to 

cleaning and disinfectant solutions (e.g., janitorial and/or medical personnel) may be useful to better 

describe exposure-response relationships for the development of formaldehyde-induced skin irritation and 

contact dermatitis from intermediate- or chronic-duration exposure to formaldehyde. 

Epidemiological studies of occupationally exposed groups of persons have not found consistent or strong 

evidence for an association between occupational exposure to airborne formaldehyde and cancer, 

although animal studies have found consistent evidence for formaldehyde-induced nasal tumors with 

chronic exposure to air concentrations in the range of 6–15 ppm. The available epidemiological studies 

have shortcomings such as limited exposure information or follow-up, presence of confounding risk 

factors, or small numbers of subjects, but one plausible explanation for the lack of a consistent response 

across the studies is that workplace air levels often may be below values necessary for formaldehyde to 

induce upper respiratory tract cancer. Studies in animals have shown that no increased incidences of 

nasal tumors were found in rats with lifetime exposure to low (0.3–2 ppm) air concentrations (Kamata et 

al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Woutersen et al. 1989), that damaged regions of the 

nasal epithelium after short-term exposure are correlated with regions that eventually develop tumors 

with chronic exposure (Monticello et al. 1996), and that regions of the nasal epithelium with epithelial 

damage correlate with regions of predicted high airflow and uptake of formaldehyde (Cohen Hubal et al. 

1997; Kepler et al. 1998; Kimbell et al. 1993, 1997a). Further development is needed of human nasal 

airflow and formaldehyde uptake models, human pharmacokinetic models for formaldehyde disposition, 

and human pharmacodynamic models for preneoplastic events in upper respiratory tract tissue. 
 

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2. HEALTH EFFECTS 

Application of such models, with associated rat dosimetric models, to the available rat exposure-response 

data for tumors and preneoplastic events will allow better estimations of air levels presenting minimal 

risks for cancer in humans. 

Biomarkers of Exposure and Effect. 

Exposure. Attempts have been made to determine if formaldehyde could be used as a potential 

biomarker of short-term exposure (Heck et al. 1985); however, no significant difference between pre- and 

postexposure blood concentrations of formaldehyde could be demonstrated at the concentration tested. In 

the same study, similar findings were noted in male Fischer 344 rats placed in a nose-only inhalation 

chamber and exposed to 14.4 ppm formaldehyde for 2 hours. Monitoring blood or urine formate levels 

has also been considered. Rapid intravenous injection of formaldehyde in monkeys showed a plasma 

half-life of only 1.5 minutes, with a corresponding increase in blood formate levels; however, formate 

production is not specific to formaldehyde metabolism (Ferry et al. 1980; Kornbrust and Bus 1983; 

Liesivuori and Savolainen 1987). Urine formate levels were examined by Einbrodt et al. (1976) and urine 

formaldehyde and urine formic acid (formate) concentrations were found to be higher immediately after 

exposure; however, study design posed interpretation concerns. Gottschling et al. (1984) monitored 

anatomy students exposed to low levels of formaldehyde vapor; wide variations were noted in the urine 

formate levels prior to exposure, with large intrapersonal and interpersonal variations. Mean 

postexposure urine formate concentrations were not significantly elevated after exposure. Based on the 

available data, it appears that the detection of the intact formaldehyde molecule in the blood and tissues, 

as well as blood and urine formate, are unreliable and poor indicators of formaldehyde exposure in 

humans and laboratory animals. 

Studies of animals have used radiolabeling techniques to measure DNA-protein cross links in nasal 

epithelium tissue (Casanova-Schmitz et al. 1984a; Casanova and Heck 1987; Casanova et al. 1989a, 

1989b, 1991, 1994) and described relationships between exposure levels and the amounts of DNA-protein 

cross links in regions of the nasal epithelium. Such a technique is impractical for monitoring humans 

exposed to formaldehyde, but Shaham et al. (1996a) proposed that measurement of total DNA-protein 

cross links by a different technique in white blood cells may be useful as a biomarker of repeated 

exposure to formaldehyde. In support of this proposal, it was reported that white blood cells from 

12 formaldehyde-exposed anatomists and pathologists had significantly higher average levels of DNAprotein cross links than those from eight subjects without known occupational exposure to formaldehyde 
FORMALDEHYDE 259 

2. HEALTH EFFECTS 

(Shaham et al. 1996a). Additional research to apply these methods to larger groups of occupationally 

exposed and nonexposed persons may help to determine the reliability of this variable as a biomarker of 

exposure and to determine the extent to which individuals vary in this response to formaldehyde. 

Additional research to apply the DNA-protein cross link methods to nasal biopsy specimens may lead to 

an increased sensitivity of this potential biomarker of exposure and effect. Shaham et al. (1996b) 

reported that a larger scale study was in progress, but results are not available. 

Antibodies (IgG and IgE) against formaldehyde conjugated to human serum albumin have been found to 

be elevated in some people, but not in others, exposed to formaldehyde (Dykewicz et al. 1991; Grammer 

et al. 1990; Patterson et al. 1986; Thrasher et al. 1988b, 1989, 1990; Wantke et al. 1996a). The 

apparently rare frequency of IgE-mediated allergy responses to airborne formaldehyde (Grammer et al. 

1990; Kramps et al. 1989; Nordman et al. 1985) suggests that elevation of antibodies against 

formaldehyde may be too rare to be useful as a generic biomarker of exposure. However, the findings of 

significant associations between (1) the presence of IgG antibodies against formaldehyde-human serum 

albumin and smoking habit in a group of healthy subjects, and (2) the presence of such antibodies in nonsmokers and occupational exposure to formaldehyde suggest that this biomarker of immunological 

response may serve as a qualititative biomarker of exposure (Carraro et al. 1997). Additional studies of 

formaldehyde-specific IgG antibodies in non-smoking groups of formaldehyde-exposed and nonexposed 

persons may be useful to determine the reliability of this qualitative biomarker of intermediate or chronic 

exposure to formaldehyde. Additional research may help to further develop the Carraro et al. (1997) 

assay so that it might be useful for quantifying exposure levels or exposure durations. 

Effect. Increased eosinophil concentration and increased albumin and total protein levels have been 

found in nasal lavage fluid taken from subjects exposed to 0.4 ppm formaldehyde for 2 hours (Krakowiak 

et al. 1998; Pazdrak et al. 1993). Although these variables are not expected to be specifically influenced 

by formaldehyde, they appear to provide biomarkers of acute respiratory irritation from airborne 

formaldehyde or other upper respiratory irritants. Further research on relationships between 

concentrations of these variables in nasal lavage fluid and prevalence or severity of respiratory symptoms 

in humans exposed acutely to varying concentrations of formaldehyde may help to confirm their use as 

biomarkers of effect. 

As discussed in the previous section, DNA-protein cross links and anti-formaldehyde-human serum 

albumin IgG antibodies are potential biomarkers of effect and exposure from intermediate- or chronic­
 

FORMALDEHYDE 260 

2. HEALTH EFFECTS 

duration of exposure. Another potentially useful biomarker of effect for repeated inhalation exposure to 

formaldehyde involves the histological examination of nasal biopsy samples (Ballarin et al. 1992; Boysen 

et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c). Whereas detection of these biomarkers can 

represent biological responses to repeated exposure to formaldehyde, it is uncertain to what degree their 

detection indicates that adverse health effects will occur. Prospective studies of these end points in 

formaldehyde-exposed and nonexposed workers may decrease this uncertainty and describe temporal 

relationships between formaldehyde-induced upper respiratory tract tissue damage and/or dysfunction and 

exposure-related intensity changes in these variables. 

Absorption, Distribution, Metabolism, and Excretion. Results from studies of rats exposed for 

short periods (6 hours) to airborne radiolabeled formaldehyde concentrations between 0.63 and 13.1 ppm 

indicate that inhaled formaldehyde is rapidly absorbed and metabolized, primarily in the upper respiratory 

tract, and that, at these exposure concentrations, very little formaldehyde reaches the blood or is 

transported to distant-site tissues and organs (Heck et al. 1983). In these studies, radioactivity recovered 

within 70 hours after exposure was found in the expired air (39-42%), the urine (17%), feces (4-5%), and 

in tissues and the carcass (35-39%). These results are consistent with rapid oxidative metabolism to 

formate and CO2 and rapid incorporation of the carbon from formaldehyde into cellular constituents. 

Consistent with these studies, another experiment showed that 2-hour exposures to formaldehyde of rats 

(to 14.4 ppm) and humans (to 1.9 ppm) did not significantly increase formaldehyde concentrations in 

blood when measured immediately after exposure (Heck et al. 1985). Casanova et al. (1988) also showed 

that blood concentrations of formaldehyde were not elevated, immediately after exposure, in rhesus 

monkeys exposed to 6 ppm (6 hours/day, 5 days/week) for 4 weeks. These toxicokinetic results, together 

with the weight of evidence from inhalation toxicological studies of animals showing effects only in the 

upper respiratory tract, provide high confidence that the disposition of inhaled formaldehyde by the upper 

respiratory tract in this concentration range and below is nearly complete. Additional animal studies 

designed to compare formaldehyde-specific metabolic capacities in nasal mucosal tissues from adult and 

immature animals may be useful in determining a possible mechanistic basis for possible age-related 

differences in susceptibility to irritation from airborne formaldehyde (see Children’s Susceptibility data 

needs section below). 

Ingested formaldehyde is also expected to be rapidly absorbed, rapidly metabolized to formate and CO2, 

and rapidly incorporated into cellular consituents, but descriptive toxicokinetic studies of orally 

administered formaldehyde in animals were not located. Observations of elevated formate levels and 
 

FORMALDEHYDE 261 

2. HEALTH EFFECTS 

metabolic acidosis in cases of acute formaldehyde poisoning (Eells et al. 1981; Burkhart et al. 1990) are 

consistent with rapid absorption and metabolism of ingested formaldehyde. A study is available of the 

dispositional kinetics of radioactivity in rats and mice after ingestion of a cheese made from milk with 

added radiolabeled formaldehyde (Galli et al. 1983), but the radioactivity in the material fed to the 

animals was largely (80%) linked to proteins. Given that the levels of formaldehyde in sources of food 

and water for humans are expected to be very low due to formaldehyde’s high reactivity, additional 

animal studies to more completely describe the absorption, distribution, metabolism, and elimination of 

orally administered formaldehyde do not seem to warrant a high priority. 

Results from a study of rats, guinea pigs, and monkeys under nonoccluded dermal exposure conditions 

indicated that evaporation from the skin was a major disposition route (Jeffcoat et al. 1983). Additional 

animal studies of absorption, distribution, and metabolism under occluded conditions of dermal exposure 

would provide information regarding maximal rates of dermal absorption and local tissue metabolism, 

and may help to confirm that distant-site effects from dermal exposure are unlikely. 

Comparative Toxicokinetics. Experiments with humans, rats, and monkeys indicate that inhaled 

formaldehyde is absorbed and metabolized so rapidly that blood concentrations do not vary during shortterm exposures (Casanova et al. 1988; Heck et al. 1985). These results are consistent with the upper 

respiratory tract being the critical target of inhaled formaldehyde in each of these species as indicated by 

the available health effects data. The marked differences between rodents and primates in breathing 

habits (i.e., rodents are obligate nose breathers) and nasal anatomy led to some early questions about the 

human relevance of the well-characterized nonneoplastic and neoplastic responses of nasal epithelium in 

rats to chronic exposure to airborne formaldehyde. However, observations of similar non-neoplastic 

changes in upper respiratory tract epithelium in Rhesus and Cynomolgus monkeys exposed for 

intermediate durations (Monticello et al. 1989; Rusch et al. 1983) and observations of histological 

changes in nasal tissue from occupationally exposed subjects (Ballarin et al. 1992; Boysen et al. 1990; 

Edling et al. 1988; Holmstrom et al. 1989c) have provided support for the relevance of the rat data. These 

results have led to the ongoing development of, for each of these species, anatomical models of nasal 

airflow and uptake, pharmacokinetic models for nasal tissue metabolism, and pharmacodynamic models 

of development of tumors and preneoplastic tissue changes to be applied to the rodent data to better 

estimate air levels that will present minimal risks for upper respiratory tract damage in humans (CIIT 

1998; Cohen Hubal et al. 1997; Conolly et al. 1992; Conolly and Andersen 1993; Kepler et al. 1998; 

Kimbell et al. 1993, 1997a, 1997b; Morgan 1997; Morgan et al. 1991; Subramaniam et al. 1998). 
 

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2. HEALTH EFFECTS 

In contrast, mice and hamsters appear to be less susceptible to upper respiratory tract damage from 

inhaled formaldehyde. The basis for this apparent species difference in susceptibility is unknown, but 

may involve, at least partially for the case of the mouse, the greater efficiency of mice, compared with 

rats, to reduce minute volumes during exposure to formaldehyde (Chang et al. 1981, 1983). 

As with exposure to airborne formaldehyde, portal-of-entry tissues are expected to be the critical targets 

of orally or dermally administered formaldehyde in humans and animals. Gastrointestinal effects from 

high oral doses are expected based on reports of gastrointestinal tract irritation and symptoms in humans 

who ingested large doses of formaldehyde, together with results from studies of rats exposed orally to 

formaldehyde for intermediate- and chronic-durations (e.g., Til et al. 1988b, Til et al. 1989; Tobe et al. 

1989). Skin irritation in humans with dermal occupational exposure to formaldehyde concentrations in 

the range of 2-5% and greater is expected based on occupational experience and clinical experience in 

patch-testing (Fischer et al. 1995; Maibach 1983); additionally, the development of dermal sensitization 

to formaldehyde is frequently found among patients presenting skin problems at dermatology clinics. The 

expectation of skin irritation and dermal sensitization, without systemic distant-site effects, from exposure 

to formaldehyde is supported by results from dermal-exposure toxicity studies in animals (e.g., Overman 

1985; Wahlberg 1993) and toxicokinetic studies with rats, guinea pigs and Cynomolgus monkeys 

(Jeffcoat et al. 1983); although results from the latter studies indicated that monkey skin may be more 

permeable to formaldehyde than rat skin. In contrast to inhalation exposure, however, there is no 

information indicating that species differ in susceptibility to formaldehyde toxicity by these routes of 

exposure. Thus, additional studies comparing species differences in toxicokinetic variables with oral or 

dermal exposure to formaldehyde do not appear to have a high priority at this time. 

Methods of Reducing Toxic Effects. Due to formaldehyde’s high water solubility and reactivity 

and the rapidity of cellular metabolism of formaldehyde to formate and CO2, toxic effects from 

formaldehyde are expected to be principally caused by formaldehyde itself (not metabolites) and to be 

restricted to portal-of-entry tissues, except at high exposure levels that exceed metabolic capacities of 

these tissues. Thus, following acute exposures to formaldehyde, treatments that dilute or remove nonabsorbed or non-reacted formaldehyde from the site of exposure or that present alternative substrates for 

reaction (e.g., washing of the skin or eyes or dilution of ingested formaldehyde with milk or water) may 

prevent the occurrence of toxic effects if applied in a timely manner. Methods that may enhance the 

capacity of portal-of-entry tissues to metabolize formaldehyde may be expected to act against the toxic 

action of formaldehyde, but no such methods have been established. There are no established treatment 
 

FORMALDEHYDE 263 

2. HEALTH EFFECTS 

protocols to repair tissue damage that may have been caused by formaldehyde at portals-of-entry or to 

enhance natural repair mechanisms. 

Children’s Susceptibility. Suggestive evidence from two studies is available indicating that children 

may be more susceptible to the locally-acting irritant properties of formaldehyde (Krzyzanowski et al. 

1990; Wantke et al. 1996a). Additional health survey studies of groups of children known to experience 

indoor air concentrations exceeding 0.05–0.1 ppm may be helpful in confirming or discarding this 

hypothesis. 

Studies of laboratory animals, as well as studies of adult humans under acute controlled exposure or 

occupational exposure conditions, indicate that the irritant effects of formaldehyde are restricted to tissues 

at portals-of-entry due to the water-solubility and reactivity of formaldehyde and the ability of cells to 

rapidly metabolize (and detoxify) formaldehyde. Studies designed to compare formaldehyde-specific 

metabolic capacities and efficiencies in portal-of-entry tissues (e.g., nasal mucosa, gastrointestinal 

mucosa) from adult and immature animals of varying ages may be useful in determining a possible 

mechanistic basis for possible age-related differences in susceptibility to formaldehyde. 

2.11.3 Ongoing Studies 

Ongoing studies pertaining to formaldehyde have been identified and are shown in Table 2-8. 
FORMALDEHYDE 264 

2. HEALTH EFFECTS 

Table 2-8. Ongoing Studies on Formaldehyde 

Investigator Affiliation Research description Sponsor 

B.K. Andrews, Southern Regional Res Center, Durable Press Fabrics from US Dept. of Agriculture 

B. Morrell and New Orleans, LA No- and De-minimus LevelN.M. Morris Formaldehyde Finishes 

A.E. Blair NCI, NIH Studies of Occupational Division of Cancer 

Cancer Etiology 

T.P. Brown and University of Georgia College of Poultry Toxicosis: Evaluation US Dept. of Agriculture 

G.E. Vet Medicine, and Amelioration 

Rottinghaus Athens, GA 

A. Cederbaum VA Medical Center, Interaction of Pyrazole and National Institute of 

New York, NY Glycerol with Human Alcohol Abuse and 

Microsomes and P-450IIEI Alcoholism 

B.J. Collier Louisiana State University School Measurement of US Dept. of Agriculture 

of Human Ecology, Formaldehyde Release from 

Baton Rouge, LA Durable Press Cotton Fabrics 

& Other Products 

J.T. Coyle Massachusetts General Hospital, Psychosis and Brain National Institute of 

Boston, MA Glutamate Mental Health 

J. Cwi Survey Research Associates, Support Services for Division of Cancer 

Baltimore, MD Occupational Studies Etiology 

L.M. Ferrari and State Pollution Control Indoor Air Quality and NERDDP 

F. Catell Commission, Energy Conservation 

Sydney, NSW 

J.B. Guttenplan NYU Dental Center, Smokeless Tobacco National Institute of 

New York, NY Carcinogenesis and Oral Dental Research 

Tissue 

G. Hager NCI, NIH Chromatin Structure and Gene Division of Cancer 

Expression Etiology 

A.T. Hastie Thomas Jefferson University, Pollutant Interactive Effects NIEHS 

Philadelphia, PA on Ciliary Defense 

G.A. Jamieson American Red Cross, Characterization and Isolation National Heart, Lung, and 

Rockville, MD of Platelet ADP Receptors Blood Institute 

K. Knapp, Atmospheric Research and Hazardous Air Pollutant Office of Research and 

D. Pahl and Assessment Laboratory, Regulatory Activities Development 

F. Black Research Triangle Park, NC 

J. Merchant University of Iowa, Core--Occupational Health NIEHS 

Iowa City, IA Research 

S.S. Mirvish University of Nebraska Medical Nitrosamine Metabolism and National Cancer Institute 

Center, Esophageal Cancer 

Omaha, NE 

R. Monson Harvard University, Occupational Health NIEHS 

Boston, MA 
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2. HEALTH EFFECTS 

Table 2-8. Ongoing Studies on Formaldehyde (continued) 

Investigator Affiliation Research description Sponsor 

T.N. Pappas Dept. of Veterans Affairs Medical 

Center, 

Durham, NC 

Animals Models of 

Inflammatory Bowel Disease: 

Relationship to Substance P 

Receptor Up Regulation 

Dept. of Veterans Affairs 

T. Shibamoto University of California 

Environmental Toxicology, 

Davis, CA 

Isolation and Identification of 

Mutagens and Carcinogens in 

Foods 

US Dept. of Agriculture 

G.M. Thiele Omaha VA Medical Center, 

Omaha, NE 

Alcohol and Liver Endothelial 

Cells in Immune Responses 

National Institute on 

Alcohol Abuse and 

Alcoholism 

J-P. Von Sattel Massachusetts General Hospital, 

Boston, MA 

Core--Neuropathology National Institute of 

Neurological Disorders 

and Stroke 

NCI = National Cancer Institute; NIEHS = National Institute of Environmental Health; NIH = National Institutes of 

Health; NERDDP = National Energy Research, Development and Demonstration Program 

FORMALDEHYDE 267 

3. CHEMICAL AND PHYSICAL INFORMATION 

3.1 CHEMICAL IDENTITY 

Information regarding the chemical identity of formaldehyde is located in Table 3-1. 

3.2 PHYSICAL AND CHEMICAL PROPERTIES 

Information regarding the physical and chemical properties of formaldehyde is located in Table 3-2. 
FORMALDEHYDE 268 

3. CHEMICAL AND PHYSICAL INFORMATION 

Table 3-1. Chemical Identity of Formaldehyde 

Characteristic Information Reference 

Chemical name 

Synonym(s) 

Registered trade name(s)

 For 37% aqueous solutiona

 For polymeric formb 

Chemical formula 

Chemical structure 

Identification numbers: 

CAS Registry 

NIOSH RTECS 

EPA Hazardous Waste 

OHM/TADS 

DOT/UN/NA/IMCO 

HSDB 

NCI 

Formaldehyde 

Formic aldehyde, methanal, methyl 

aldehyde, methylene oxide 

Formalin, Formol, Morbicid, Veracur 

Paraformaldehyde, Polyoxymethylene, 

Paraform, Formagene 

CH2O 

O 

H C H 

50-00-0 

LP8925000 

U122 

7216732 

CLASS 3/UN1198/IMCO 3.2 

164 

No data 

Lide and Frederikse 

1996 

Budavari et al. 1989 

Budavari et al. 1989 

Budavari et al. 1989 

Aster 1995 

Lide and Frederikse 

1996 

Aster 1995 

HSDB 1995 

HSDB 1995 

HSDB 1995 

NFPA 1994 

HSDB 1999 

HSDB 1999 

a Aqueous solutions of formaldehyde available commercially often contain 10-15% methanol to inhibit 

polymerization. b Paraformaldehyde is a polymer of formaldehyde and has the formula (CH2O)n. 

CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substance 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 
FORMALDEHYDE 269 

3. CHEMICAL AND PHYSICAL INFORMATION 

Table 3-2. Physical and Chemical Properties of Formaldehyde 

Property Information	 Reference 

Molecular weight	 30.03 Lide and Frederikse 1996 

Color	 Colorless Budavari et al. 1989 

Physical state	 Gas Budavari et al. 1989 

Melting point	 -92 EC Budavari et al. 1989 

Boiling point	 -21 EC ASTER 1996 

Density at -20 EC	 0.815 g/mL Lide and Frederikse 1996 

Odor	 Pungent, suffocating odor; highly irritating Budavari et al. 1989; 

odor NFPA 1994 

Odor threshold: 

Water 50 ppm HSDB 1999 

Air 0.5–1.0 ppm Klaassen 1996 

Taste	 50 ppm HSDB 1999 

Solubility: 

Freshwater at 20 EC Very soluble; up to 55% Budavari et al. 1989 

Saltwater at 25 EC No data 

Organic solvent(s) Ether, alcohol, acetone, benzene Lide and Frederikse 

1996; Budavari et al. 

1989 

Partition coefficients: 

Log Kow 0.350 SRC 1995b 

Log Koc 1.567 Calculated from Lyman 

1982 

No data, negligible HSDB 1999 

Vapor pressure at 25 EC Gas: vapor pressure>bp; 3,883 mm Hg HSDB 1999; 

Howard 1989 

Polymerization Polymerizes; polymerizes readily in water Budavari et al. 1989 

Photolysis Half-life (in sunlight) 1.6–19 hours producing Lewis 1993 

H2 and CO or H+

 and HCOHenry's law constant at 25 EC 3.27x10-7 atm-m3

/mol Howard 1989 

Autoignition temperature 300 EC NFPA 1994 

Flashpoint 60 EC Budavari et al. 1989 

Flammability limits at 25 EC 7–73% NFPA 1994 

Incompatibilities Reacts with alkalies, acids, and oxidizers NFPA 1994 

Conversion factors (25 EC) 1 ppb (v/v) = 1.23 μg/m3 Calculated 

1 μg/m3

 = 0.813 ppb (v/v) 

Explosive limits 7–73% Lewis 1993 

FORMALDEHYDE 271 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

4.1 PRODUCTION 

Because of its low cost and high purity, formaldehyde has become one of the most important industrial 

and research chemicals in the world. Between 1958 and 1968, the annual growth rate for formaldehyde 

production averaged 11.7% (Gerberich et al. 1980). During the late 1960s, production averaged 71% of 

capacity. The recession of the mid-1970s, however, caused production to drop as low as 54% of capacity 

(Gerberich et al. 1980). From 1988 to 1997, formaldehyde production averaged an annual growth rate of 

2.7% per year (Anonymous 1998). In 1992, formaldehyde ranked 22nd (8.28 billion pounds produced) 

among the top 50 chemicals produced in the United States (Anonymous 1994). Total annual capacities 

for the 15–17 U.S. companies listed as the top formaldehyde manufacturers or processors for 1988, 1990, 

and 1992 were 8.94, 9.70, and 10.08 billion pounds, respectively (SRI 1988, 1990, 1992). The estimated 

total annual formaldehyde capacity in 1998 was 11.3 billion pounds (Anonymous 1998). With 

production volumes varying between 6.43 billion pounds and 8.11 billion pounds for 1990, 1991, and the 

period 1993–1995, formaldehyde ranked either 24th or 25th among the top 50 chemicals produced 

(Anonymous 1992, 1994, 1995a; Kirschner 1996). 

As of 1998, three manufacturers of formaldehyde were responsible for 50% of the annual capacity for the 

United States: Georgia-Pacific Resins, Inc. (Albany, Oregon; Columbus, Ohio; Conway, North Carolina; 

Crossett, Arkansas; Grayling, Michigan; Hampton, South Carolina; Healing Springs, North Carolina; 

Houston, Texas; Lufkin, Texas; Russellville, South Carolina; Taylorsville, Mississippi; Vienna, Georgia; 

White City, Oregon), Hoechst Celanese Corporation (Bishop, Texas; Rock Hill, South Carolina), and 

Borden, Inc. (Baytown, Texas; Demopolis, Alabama; Diboll, Texas; Fayetteville, North Carolina; 

Fremont, California; Hope, Arkansas; Kent, Washington; La Grande, Oregon; Missoula, Montana; 

Sheboygan, Wisconsin; Springfield, Oregon; Vicksburg, Mississippi) (Anonymous 1998; SRI 1997). In 

addition to the above facilities, the following companies also contributed to the overall U.S. capacity: 

Capital Resin (Columbus, Ohio); D.B. Western (Las Vegas, New Mexico; Virginia, Minnesota); Degussa 

(Theodore, Alabama); DuPont (LaPorte, Texas; Parkersburg, West Virginia); Hercules-Aqualon 

(Louisiana, Montana); ISP (Calvert City, Kentucky; Texas City, Texas); Monsanto (Alvin, Texas); Neste 

Resins (five sites); Perstorp (Toledo, Ohio); Praxair (Geismar, Louisiana); Solutia (Alvin, Texas); 

Spurlock (Malvern, Arkansas; Waverly, Virginia); Trimet Technical Products (Mallinckrodt); 
FORMALDEHYDE 272 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

(Allentown, Pennsylvania); and Wright Chemical (Acme, North Carolina) (Anonymous 1998; SRI 1997). 

Formaldehyde production is predicted to increase 2–3% per year through 2002 (Anonymous 1998). 

Table 4-1 lists the facilities in each state that manufacture or process formaldehyde, the intended use, and 

the range of maximum amounts of formaldehyde that are stored on site. The data listed in Table 4-1 are 

derived from the Toxics Release Inventory (TRI96 1998). Only certain types of facilities were required 

to report. Therefore, this is not an exhaustive list. Table 4-2 shows capacity and production volumes for 

selected years between 1960 and 1978. 

Formaldehyde has been manufactured primarily from methanol since the beginning of the century 

(Gerberich et al. 1980). Because methanol is manufactured from synthesis gas, usually produced from 

methane, there have been extensive efforts to develop a one-step process that partially oxidizes methane 

to formaldehyde. Although a successful commercial process has not been developed, a wide range of 

catalysts and oxidation conditions have been studied (Gerberich et al. 1980). During the decades 

following World War II, approximately 20% of the production volume in the United States was 

manufactured by vapor phase, non-catalytic oxidation of propane and butane (Gerberich et al. 1980). 

Two primary methods of manufacturing formaldehyde from methanol are used today. The first uses 

silver as a metal catalyst in its reactions. In earlier years, facilities used a copper catalyst in this process. 

The simultaneous reactions involved in the metal catalyst process occur at essentially atmospheric 

pressure and 600–650 EC (Gerberich et al. 1980). Approximately 50–60% of the formaldehyde produced 

using the metal catalyst process is formed during an exothermic reaction; the remainder is formed from an 

endothermic reaction. The overall yield for this process is 86–90% formaldehyde. The domestic 

licensors for this process include Borden Chemical Company and Davy Powergas, Inc. (Gerberich et al. 

1980). 

The second method uses a metal oxide catalyst. All of the formaldehyde is produced from an exothermic 

reaction occurring at atmospheric pressure and 300–400 EC. The patent for formaldehyde production 

using a vanadium pentoxide catalyst was issued in 1921. Although the patent for an iron oxidemolybdenum oxide catalyst was issued in 1933, the first commercial facility did not begin operating until 

1952 (Gerberich et al. 1980). 

Gaseous formaldehyde can be regenerated from paraformaldehyde by heating (Gerberich et al. 1980). 
FORMALDEHYDE 273 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 4-1. Facilities That Manufacture or Process Formaldehyde 

Number of Range of maximum amounts 

Statea facilities on site in poundsb Activities and usesc 

AK 1 100,000 - 999,999 8 

AL 30 0 - 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 

AR 15 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 12 

AZ 3 100 - 9,999 1, 5, 7, 9, 12, 13 

CA 26 100 - 9,999,999 1, 3, 4, 5, 7, 8, 9, 11, 12 

CO 2 0 - 9,999 12 

CT 8 100 - 9,999,999 2, 3, 7, 8, 12 

DE 1 10,000 - 99,999 8 

FL 6 0 - 99,999 1, 6, 7, 9, 11, 13 

GA 35 0 - 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13 

IA 5 1,000 - 999,999 7 ,8 ,9 ,10 

IL 27 0 - 999,999 1, 2, 3, 5, 7, 8, 9, 10, 11, 12, 13 

IN 15 100 - 999,999 1, 5, 7, 8, 9, 11, 12,13 

KS 8 100 - 999,999 1, 2, 5, 7, 8, 11, 13 

KY 8 1,000 - 9,999,999 1, 3, 4, 7, 8, 10, 11, 12, 13 

LA 31 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 13 

MA 10 1,000 - 9,999,999 1, 3, 4, 7, 8, 9, 11, 13 

MD 2 1,000 - 9,999 7, 8, 9 

ME 3 1,000 - 999,999 1, 5, 6, 7, 12 

MI 33 0 - 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13 

MN 15 0 - 999,999 1, 5, 6, 7, 8, 9, 10, 11, 12 

MO 12 0 - 9,999,999 1, 3, 4, 6, 7, 8, 11, 12, 13 

MS 16 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9 

MT 4 0 - 9,999,999 1, 3, 4, 6, 7, 8, 9 

NC 39 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13 

NH 4 100 - 999,999 7, 11, 12 

NJ 18 100 - 999,999 1, 3, 5, 7, 8, 9, 10, 12, 13 

NM 1 100 - 999 9 

NV 1 1,000 - 9,999 7 

NY 25 100 - 999,999 1, 2, 3, 5, 7, 8, 9, 10, 11, 12, 13 

OH 50 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13 

OK 4 100 - 999,999 1, 6, 7, 8 

OR 25 100 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 11, 13 

PA 21 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13 

PR 4 1,000 - 99,999 2, 3, 7, 11, 12, 13 

RI 4 100 - 99,999 1, 3, 5, 7, 8, 9, 10, 11 

SC 40 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13 

SD 1 100 - 999 8 

TN 8 0 - 9,999,999 1, 5, 7, 8, 11, 12, 13 

TX 55 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13 

UT 4 1,000 - 9,999 1, 5, 7, 11 

Table 4-1. Facilities That Manufacture or Process Formaldehyde (continued) 
FORMALDEHYDE 274 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Number of Range of maximum amounts 

Statea facilities on site in poundsb Activities and usesc 

VA 26 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13 

VT 1 100 - 999 2, 3, 9, 11 

WA 8 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 11 

WI 24 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 11, 13 

WV 10 100 - 9,999,999 1, 3, 5, 7, 8, 10, 11 

Source: TRI96 1998 

a

 Post office state abbreviations used 

b

 Range represents maximum amounts on site reported by facilities in each state 

c Activities/uses:

 1. Produce	 8. Formulation component

 2. Import	 9. Article component

 3. Onsite 10. Repackaging

use/processing
 

 4. Sale/distribution 11. Chemical processing aid

 5. Byproduct	 12. Manufacturing aid

 6. Impurity	 13. Ancillary/other uses

 7. Reactant 
FORMALDEHYDE 275 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 4-2. U.S. Formaldehyde Capacity and Production 

Capacity Production volume 

Year (103

 tons/year) (103 tons/year) 

1960 1,111 848 

1965 1,613 1,409 

1970 Not available 2,008 

1975 3,803 2,067 

1977 4,005 2,742 

1978 4,086 2,948 

1982 Not available 2,185 

1986 Not available 2,517 

1990 Not available 3,048

 Source: Gerberich et al. 1980; data for 1982, 1986, and 1990 are from IARC 1995. 
FORMALDEHYDE 276 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

4.2 IMPORT/EXPORT 

The Chemical Marketing Reporter (CMR) reported that 140 million pounds of formaldehyde were 

imported into the United States in 1997. In 1994, import and export volumes were 87 and 25 million 

pounds, respectively (Anonymous 1995b). The export volume for the same year was reported as 

25 million pounds (Anonymous 1998). 

4.3 USE 

Formaldehyde has been used for many years in consumer goods to deter spoilage caused by microbial 

contamination (WHO 1989). It has been used as a preservative in household cleaning agents, dishwashing liquids, fabric softeners, shoe-care agents, car shampoos and waxes, and carpet-cleaning agents 

(WHO 1989). Generally, the formaldehyde content in these products is less than 1% (WHO 1989). 

Formaldehyde is used as a chemical intermediate in the manufacture of a large variety of organic 

compounds, ranging from amino and phenolic resins to slow release fertilizers (Gerberich et al. 1980). 

Table 4-3 shows the distribution of formaldehyde use for select periods between 1963 and 1977. The 

demand for formaldehyde in North America was 11.6 billion pounds in 1995, a slight increase from the 

11.3 billion pounds reported for 1994 (Anonymous 1995b). These figures include the import and export 

volumes discussed in Section 4.2. The demand for formaldehyde will continue to track the demand in the 

housing industry and the various board products used in residential construction and furniture 

(Anonymous 1998). The most prominent use of formaldehyde in the United States is manufacturing 

urea-formaldehyde resins; 23% of the annual capacity is used in this market (Anonymous 1998). In 1993, 

the urea-formaldehyde resins market was described as being mature. Approximately 95% of the particle 

board products manufactured are based on urea-formaldehyde resins; the remainder are based on 

phenolic-resins (Gerberich et al. 1980). The market’s average annual growth rate of 1–1.5% is projected 

to continue through 1997 (Anonymous 1993). Urea formaldehyde resins are also used as urea 

formaldehyde foam insulation or as reinforcing foams in the insulation of buildings and in mining, where 

hollow areas are filled with the foam (WHO 1989). Anonymous (1993) also reports that the fastest 

growing formaldehyde market in the United States is in the production of acetylenic chemicals and 

methylene diisocyanate (MDI). The most recent breakdown found for formaldehyde use is the following: 

urea-formaldehyde, 23%; phenolic resins, 19%; acetylenic chemicals, 12%; polyacetal resins, 11%; 

MDI, 6%; pentaerythritol, 5%; urea-formaldehyde concentrates, 4%; hexamethylenetetramine 
FORMALDEHYDE 277 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 4-3. Distribution of Formaldehyde Production 

According to Uses in the United States 

Percentage of consumption 

1963 1969 1972 1975 1977 

Phenol-formaldehyde resins 22 22 26 22 25 

Urea-formaldehyde resins 21 25 26 25 25 

Acetal resins 4 6 7 7 9 

Acetylenics Not available 2 4 7 6 

Melamine resins 6 7 6 3 5 

Pentaerythritol 9 7 7 7 5 

Hexamethylenetetramine 6 9 6 5 5 

Fertilizer 3 3 4 4 Not available 

Trimethylolpropane Not available 1.1 1.5 1.5 Not available 

Ethylene glycol 12 4 0 0 0 

Miscellaneous 17 14 12 18 20 

Source: Gerberich et al. 1980 
FORMALDEHYDE 278 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

(HMTA), 4%; melamine resins, 4%; and miscellaneous (including chelating agents, trimethylolpropane, 

pyridine chemicals, nitroparaffin derivatives, textiles treating, and trimethylolethane), 12% (Anonymous 

1998).

 The use of formaldehyde in the manufacture of chelating agents represents a modest but important 

market for formaldehyde. Approximately 75% of the formaldehyde used in the synthesis of chelating 

agents is consumed in the manufacture of ethylenediaminetetraacetic acid (EDTA). The remaining 25% 

is used to produce nitrilotriacetic acid (NTA), primarily for export (Gerberich et al. 1980). 

Products manufactured using organic compounds, where formaldehyde is used as a chemical intermediate 

in their production, include: plywood adhesives, abrasive materials, insulation, foundry binders, and 

brake linings made from phenolic resins; surface coatings, molding compounds, laminates, and wood 

adhesives made from melamine resins; phenolic thermosetting, resins curing agents, and explosives made 

from hexamethylenetetramine; urethanes, lubricants, alkyd resins, and multifunctional acrylates made 

from trimethylolpropane; plumbing components from polyacetal resins; and controlled- release fertilizers 

made from urea formaldehyde concentrates (WHO 1989). Polyacetal plastics produced by 

polymerization of formaldehyde are incorporated into automobiles to reduce weight and fuel 

consumption. They are also used in the manufacture of functional components of audio and video 

electronics equipment (IARC 1995). 

Formaldehyde solutions have also been used for disinfecting dwellings, ships, storage houses, utensils, 

and clothing (Windholz et al. 1983). Solutions containing 2–8% formaldehyde have been used as 

germicides to disinfect inanimate objects (HSDB 1999). Formaldehyde is used as a tissue preservative 

and disinfectant in embalming fluids. 

In the agricultural industry, formaldehyde has been used as a fumigant, as a preventative for mildew and 

spelt in wheat, and for rot in oats (HSDB 1999). It has been used as a preplanting soil sterilant in 

mushroom houses (HSDB 1999). Formaldehyde has been used as a germicide and fungicide for plants 

and vegetables; as an insecticide for destroying flies and other insects; and in the manufacture of slowrelease fertilizers. Approximately 80% of the slow-release fertilizer market is based on 

urea-formaldehyde-containing products (HSDB 1999). During the early 1980s, seed treatments, starch 

formulations, and paper production were included among the minor uses for formaldehyde (IARC 1982). 

Formaldehyde continues to be used in the manufacture of glass mirrors, explosives, artificial silk, and 
FORMALDEHYDE 279 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

dyes; for waterproofing fabrics; for preserving and coagulating rubber latex; and for tanning and 

preserving animal hides (Windholz et al. 1983). In the photography industry, formaldehyde has been 

used for hardening gelatin plates and papers, toning gelatin-chloride papers, and for chrome printing and 

developing (Windholz et al. 1983). 

Formaldehyde is used as an antimicrobial agent in many cosmetics products, including soaps, shampoos, 

hair preparations, deodorants, lotions, make-up, mouthwashes, and nail products (IARC 1995). 

Formaldehyde is incompatible with ammonia; alkalies; tannin; iron preparations; and salts of copper, iron, 

silver, potassium permanganate, iodine, and peroxide (Windholz et al. 1983). When it is used as a 

preservative in shampoos, formaldehyde may interact unfavorably with both fragrance components and 

color additives (HSDB 1999). Some cosmetics have reportedly contained 0.6% formaldehyde, while 

concentrations as high as 4.5% have been detected in nail hardeners. Formaldehyde concentrations in 

dry-skin lotions, creme rinses, and bubble bath oils have reportedly ranged from 0.4 to 0.5% (WHO 

1989). Formaldehyde has also been found in sun-tan lotion and hand cream (Bartnik et al. 1985), bath 

products, mascara and eye make-up, cuticle softeners, nail creams, vaginal deodorants, and shaving 

creams. Trace amounts of formaldehyde found in cosmetic products could also result from its use as a 

disinfectant of the manufacturing equipment (WHO 1989). 

Compared to its use in product manufacturing, the use of formaldehyde in the medical fields is relatively 

small. Consumption in this area averages approximately 1.5% of the total production volume (WHO 

1989). Some of the earlier, minor, medicinal applications for formaldehyde included its use during 

vasectomies, as a foot antiperspirant or as a preservative in such products, as a treatment for athlete’s foot, 

and as a sterilant for echinococcus cysts prior to their surgical removal (IARC 1982). In veterinary 

medicine, formaldehyde has been used therapeutically as an antiseptic and as a fumigant. It has also been 

used to treat tympany, diarrhea, mastitis, pneumonia, and internal bleeding in animals (Windholz et al. 

1983). In animal nutrition, formaldehyde is used to protect dietary protein in ruminants. It is used as a 

food additive to improve the handling characteristics of animal fat and oilseed cattle food mixtures (WHO 

1989). 

Other industries using formaldehyde in their processes include the sugar industry where formaldehyde is 

used as an infection inhibitor in producing juices; the rubber industry where it is used as a biocide for 

latex, an adhesive additive, and an anti-oxidizer additive for synthetic rubber; and the food industry 

where it is used for preserving dried foods, disinfecting containers, preserving fish and certain oils and 
FORMALDEHYDE 280 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

fats, and modifying starch for cold swelling (WHO 1989). It has been use as a bacteriostatic agent in 

some foods, such as cheese (IARC 1995). In the petroleum industry, formaldehyde is used as a biocide in 

oil well-drilling fluids and as an auxiliary agent in refining. Formaldehyde has been used as an anticorrosive agent for metals. In the plastics industry, for the preparations of phenol, urea, and melamine 

resins, where the presence of water could interfere with the production process, paraformaldehyde may be 

used in place of aqueous formaldehyde solutions (IARC 1995). In addition to its use in selected pesticide 

applications, paraformaldehyde has also been used in making varnish resins, thermosets, and foundry 

resins, the synthesis of chemical and pharmaceutical products, the preparation of disinfectants and 

deodorants, and the production of textile products (IARC 1995). Formaldehyde was used in the textile 

industry as early as the 1950s when formaldehyde-based resins were initially used to produce creaseresistant fabrics. Postproduction analysis indicated that these early resins contained a substantial amount 

of extractable formaldehyde (more than 0.4% by weight of the fabric) (IARC 1995). With the 

introduction of new resins and other process modifications in the 1970s, the level of extractable 

formaldehyde in crease-resistant fabrics gradually decreased to 0.01–0.02% (IARC 1995). 

4.4 DISPOSAL 

The regulations governing the treatment and disposal of formaldehyde-containing wastes are detailed in 

Chapter 7. Formaldehyde manufacturing is listed among the regulations for commodity organic 

chemicals for which process waste water discharges are regulated by the Clean Water Effluent Guidelines 

given in Title 40, Section 414, of the Code of Federal Regulations (CFR) (EPA 1987a). 

The Resource Conservation and Recovery Act (RCRA) identifies formaldehyde as a toxic waste if it is 

discarded as a commercial product, manufacturing intermediate, or off-specification commercial chemical 

product (EPA 1980). Formaldehyde is identified as the hazardous constituent in waste assigned the 

hazardous waste number U122 under RCRA (EPA 1988b). Formaldehyde is also among the chemicals 

that are on the listed hazardous waste identified by the #K010 (EPA 1981). The technology-based 

standards given in 40 CFR 268.42 identify wet air oxidation, chemical, or electrolytic oxidation followed 

by carbon adsorption, or incineration as the treatment process for waste waters containing formaldehyde 

(EPA 1986b). For nonwaste waters, the regulations suggest that the materials be used as fuel substitutes 

in hazardous waste disposal units (EPA 1986b). When formaldehyde is disposed of in a rotary kiln 

incinerator, the unit should be operated at a temperature range of 820–1,600 EC (HSDB 1999). 

Disposal of formaldehyde in a fluidized bed incinerator requires an operating temperature range 
FORMALDEHYDE 281 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

of 450–980 EC (HSDB 1999). The residence time identified for incineration is a matter of seconds. 

Evaporation and alkaline hydrolysis are not recommended for the disposal of formaldehyde or 

formaldehyde-containing wastes (IRPTC 1985). 

FORMALDEHYDE 283 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.1 OVERVIEW 

Formaldehyde is produced by both anthropogenic and natural sources. Combustion processes account 

directly or indirectly for most of the formaldehyde entering the environment. Direct combustion sources 

include power plants, incinerators, refineries, wood stoves, kerosene heaters, and cigarettes. 

Formaldehyde is produced indirectly by photochemical oxidation of hydrocarbons or other formaldehyde 

precursors that are released from combustion processes (NRC 1981). During smog episodes, indirect 

production of formaldehyde may be greater than direct emissions (Fishbein 1992). Oxidation of methane 

is the dominant source of formaldehyde in regions remote from hydrocarbon emissions (Staffelbach et al. 

1991). Other anthropogenic sources of formaldehyde in the environment include vent gas from 

formaldehyde production; exhaust from diesel and gasoline-powered motor vehicles; emissions from the 

use of formaldehyde as a fumigant, soil disinfectant, embalming fluid, and leather tanning agent; 

emissions from resins in particle board, and plywood; emissions from resin-treated fabrics and paper; 

waste water from the production and use of formaldehyde in the manufacture of various resins and as a 

chemical intermediate; and waste water from the use of formaldehyde-containing resins (EPA 1976a; 

Kleindienst et al. 1986; NRC 1981; Verschueren 1983). Natural sources of formaldehyde include forest 

fires, animal wastes, microbial products of biological systems, and plant volatiles. 

Formaldehyde has been identified in at least 26 of the 1,428 current or former EPA National Priorities 

List (NPL) hazardous wastes sites (HazDat 1996). However, the number of sites evaluated for 

formaldehyde is not known. The frequency of these sites within the United States can be seen in 

Figure 5-1. 

Although formaldehyde is found in remote areas, it probably is not transported there but is generated from 

longer-lived precursors that have been transported there (NRC 1981). Formaldehyde is soluble and will 

transfer into rain and surface water. Based upon the Henry's law constant for formaldehyde, volatilization 

from water is not expected to be significant. No experimental data were found concerning the adsorption 

of formaldehyde to soil, but because of the low octanol/water partition coefficient (log Kow=0.35) (SRC 

1995b), little adsorption to soil or sediment is expected to occur. No evidence of bioaccumulation has 

been found. 
Figure 5-1. Frequency of NPL Sites with Formaldehyde Contamination 

Derived from HazDat 1996 
 

FORMALDEHYDE 285 

5. POTENTIAL FOR HUMAN EXPOSURE 

The input of formaldehyde into the environment is counterbalanced by its removal by several pathways. 

Formaldehyde is removed from the air by direct photolysis and oxidation by photochemically produced 

hydroxyl and nitrate radicals. Measured or estimated half-lives for formaldehyde in the atmosphere range 

from 1.6 to 19 hours, depending upon estimates of radiant energy, the presence and concentrations of 

other pollutants, and other factors (Atkinson and Pitts 1978; DOT 1980; EPA 1982; Lowe et al. 1980; Su 

et al. 1979). When released to water, formaldehyde will biodegrade to low levels in a few days (Kamata 

1966). In water, formaldehyde is hydrated; it does not have a chromophore that is capable of absorbing 

sunlight and photochemically decomposing (Chameides and Davis 1983). 

Levels of formaldehyde in the atmosphere and in indoor air are well documented. In a survey of ambient 

measurements of hazardous air pollutants, a median formaldehyde concentration of 2.5 ppb was found for 

a total of 1,358 samples collected at 58 different locations (Kelly et al. 1994). In several separate studies 

involving rural and urban areas in the United States, atmospheric concentrations ranged from 1 to 68 ppb 

(Grosjean 1982; Salas and Singh 1986; Schulam et al. 1985; Singh et al. 1982). Generally, indoor 

residential formaldehyde concentrations are significantly higher than outdoor concentrations. 

Formaldehyde concentrations measured in complaint homes (homes where people have complained of 

adverse symptoms), mobile homes, and homes containing large quantities of particle board or ureaformaldehyde foam insulation (UFFI) have been measured at 0.02 ppm to 0.8 ppm, with levels as high as 

4 ppm, sufficient to cause irritating symptoms, observed in some instances (Gold et al. 1993). Since the 

time many of the above monitoring studies were performed, plywood and particle board manufacturing 

methods have been changed to reduce the formaldehyde emission levels in the finished product (EPA 

1996). Similarly, home construction methods have changed and the use of UFFI has been greatly reduced 

since the mid-eighties (CPSC 1997). A recent pilot study on a newly constructed home reported localized 

formaldehyde concentrations of 0.076 ppm (Hare et al. 1996). Approximately 30 days after the 

installation of pressed wood products, the average indoor concentration attained a level of 

0.035–0.45 ppm. Older conventional homes tend to have the lowest indoor concentrations of 

formaldehyde, with values typically less than 0.05 ppm (Gold et al. 1993), and mobile homes the highest 

due to their low rate of air exchange (Wolff 1991). 

Although pressed wood products may be a source of formaldehyde in indoor air, there are numerous 

others. These include permanent press fabrics, fiberglass products, decorative laminates, paper goods, 

paints, wallpaper, and cosmetics (Kelly et al. 1996). Its presence in indoor air also results from 

combustion sources, such as stoves, heaters, or burning cigarettes (Matthews et al. 1985; NRC 1981). 
FORMALDEHYDE 286 

5. POTENTIAL FOR HUMAN EXPOSURE 

Formaldehyde may also arise from the degradation of volatile organic chemicals commonly found in 

indoor air (Weschler and Shields 1996; Zhang et al. 1994b). 

Formaldehyde is unstable in water; however, it has been detected in municipal and industrial aqueous 

effluents, rainwater, lake water, and some waterways (EPA 1976b; Hushon et al. 1980). Formaldehyde 

levels in rainwater collected in California are low, ranging from not detectable to 0.06 μg/mL (Grosjean 

and Wright 1983). Measured concentrations of formaldehyde range from 0.12 to 6.8 mg/L in fogwater 

(Igawa et al. 1989; Muir 1991); from 1.4 to 1.8 mg/L in cloudwater (Igawa et al. 1989); and from 0.25 to 

0.56 mg/L in mist samples (Grosjean and Wright 1983). No data on formaldehyde levels in soil could be 

found in the literature. 

Formaldehyde was found in three types of chewing tobacco (Chou and Que Hee 1994) and in cigarette 

smoke (Mansfield et al. 1977). Formaldehyde has also been found at levels ranging from 1 to 3,517 ppm 

in fabric samples (Schorr et al. 1974). 

A major route of formaldehyde exposure for the general population is inhalation of indoor air; releases of 

formaldehyde from new or recently installed building materials and furnishings may account for most of 

the exposure. Environmental tobacco smoke may contribute 10–25% of the exposure. Since 

formaldehyde in food is not available in free form, it is not included in estimated exposures (Fishbein 

1992). Consumers can be exposed to formaldehyde gas through its use in construction materials, wood 

products, textiles, home furnishings, paper, cosmetics, and pharmaceuticals. Dermal contact with 

formaldehyde containing materials, including some paper products, fabrics, and cosmetics, may also lead 

to consumer exposure. Commuters may be exposed to formaldehyde while riding in automobiles or 

subways, walking, and biking (Chan et al. 1991). 

Occupational exposure to formaldehyde can occur during its production and during its use in the 

production of end products, in the garment industry, in the building materials industry, and in 

laboratories. Health care professionals may be exposed to formaldehyde vapors during preparation, 

administration, and/or cleanup of various medicines. Pathologists, histology technicians, morticians, and 

teachers and students who handle preserved specimens may also be exposed. The National Occupational 

Exposure Survey (NOES), conducted from 1981 to 1983 indicated that 1,329,332 workers in various 

professions were exposed to formaldehyde in the United States (NIOSH 1995b). 
FORMALDEHYDE 287 

5. POTENTIAL FOR HUMAN EXPOSURE 

A subpopulation with potentially high exposures to formaldehyde are residents of mobile homes due to 

the frequent use of pressed wood products and their low rate of air exchange (Wolff 1991). Members of 

the general population who come in contact with a large amount of unwashed permanent press fabrics 

treated with formaldehyde-releasing resins may also be exposed to high levels. 

5.2 RELEASES TO THE ENVIRONMENT 

According to the Toxics Release Inventory (TRI), in 1996, 21 million pounds (9.6 million kg) of 

formaldehyde were released to the environment from 674 domestic manufacturing and processing 

facilities (TRI96 1998). This number represents the sum of all releases of formaldehyde to air, water, 

soil, and underground injection wells. An additional 1.8 million pounds (0.8 million kg) were transferred 

to publicly owned treatment works (POTWs), and 1.3 million pounds (0.6 million kg) were transferred 

off-site (TRI96 1998). Table 5-1 lists amounts released from these facilities. The TRI data should be 

used with caution because only certain types of facilities are required to report (EPA 1995). This is not 

an exhaustive list. 

5.2.1 Air 

Formaldehyde is released to outdoor air from both natural and industrial sources. Combustion processes 

account directly or indirectly for most of the formaldehyde entering the atmosphere. One important 

source of formaldehyde is automotive exhaust from engines not equipped with catalytic converters (WHO 

1989). Automobiles were found to emit about 610 million pounds (277 million kg) of formaldehyde each 

year (EPA 1976a). Emissions were reduced with the introduction of the catalytic converter in 1975 

(Zweidinger et al. 1988); although they have been found to rise again with the introduction of 

oxygenated fuels (Kirchstetter et al. 1996). Gaffney and coworkers found that in urban areas the 

introduction of oxygenated fuels led to increased anthropogenic emissions of formaldehyde during the 

winter, the season these fuels are used (Gaffney et al. 1997). Formaldehyde in vehicle emissions in 1994 

were found to increase by 13% within 2 months after the average oxygen content of fuels sold in the San 

Francisco Bay area increased from 0.3 to 2.0% by weight (Kirchstetter et al. 1996). 
Table 5-1. Releases to the Environment from Facilities that Manufacture or Process Formaldeh

Total of reported amounts released in pounds per year a 

Stateb 

Number of 

Facilities Airc Water Land 

Underground 

Injection 

Total 

Environmentd 

POTWe 

Transfer 

AK 1 375 0 0 0 375 0 

AL 31 477,346 1,312 361 0 479,019 2,854 

AR 15 204,464 735 5 0 205,204 1,015 

AZ 3 12,873 0 0 0 12,873 13,000 

CA 25 417,661 250 769 0 418,680 68,609 

CO 2 2,062 0 0 0 2,062 170 

CT 6 27,833 4,581 0 0 32,414 29,641 

DE 1 1,965 0 0 0 1,965 0 FL 6 95,126 1,522 37 0 96,685 0 

GA 36 702,021 714 500 0 703,235 4,600 

IA 4 30,736 400 0 0 31,136 580 

IL 24 37,944 2,084 204 0 40,232 22,900 

IN 15 76,532 0 0 0 76,532 47,761 

KS 8 278,316 0 0 27,000 305,316 10,320 

KY 8 65,275 21,902 0 0 87,177 1,510 

LA 31 330,423 15,674 382 8,601,956 8,948,435 0 

MA 10 60,059 10 1,500 0 61,569 809,791 

MD 2 5,517 0 0 0 5,517 0 

ME 3 121,198 0 0 0 121,198 5,229 

MI 30 205,766 2,396 12,553 250 220,965 493,193 MN 15 536,241 0 0 0 536,241 17,250 

MO 12 441,774 1,127 5 0 442,906 19,343 

MS 16 477,785 1,102 2 0 478,889 0 

MT 4 100,214 0 0 0 100,214 0 

NC 39 1,048,939 6,689 1,201 0 1,056,829 15,905 

NH 4 5,582 9,419 4,100 0 19,101 6,372 

NJ 18 52,595 3,977 250 0 56,822 42,613 

NM 1 4,570 0 0 0 4,570 0 
Table 5-1. Releases to the Environment from Facilities that Manufacture or Process Formaldehyde (c

Total of reported amounts released in pounds per year a 

Number of Underground Total POTWe 

Stateb Facilities Airc Water Land Injection Environmentd Transfer 

NV 1 4,001 0 0 0 4,001 0 NY 23 280,861 8,409 40 0 289,310 8,103 

OH 49 1,031,374 87,225 87,335 13,000 1,218,934 126,617 

OK 4 64,911 4 0 0 64,915 0 

OR 25 1,070,119 3,600 20 0 1,073,739 24,928 PA 21 274,854 1,331 0 0 276,185 0 

PR 4 2,766 0 0 0 2,766 20,827 

RI 4 4,753 0 0 0 4,753 2,042 

SC 39 752,317 57,542 3,800 0 813,659 16,718 

SD 1 55,731 0 0 0 55,731 0 TN 8 295,461 1,170 397 0 297,028 8,329 TX 55 996,970 31,770 500 761,069 1,790,309 4,557 

UT 4 18,313 0 0 0 18,313 23,568 VA 25 369,447 956 232 0 370,635 15,059 VT 1 333 0 0 0 333 0 

WA 8 109,080 45,720 0 0 154,800 3,028 

WI 22 138,117 7,422 213 0 145,752 17,204 WV 10 128,600 960 0 0 129,560 5,136 

Totals 11,419,200 320,003 114,406 9,403,275 21,256,884 

Source: TRI96 1998 

a Data in TRI are maximum amounts released by each facility b Post office state abbreviations used 

 The sum of fugitive and stack releases are included in releases to air by a given facility d The sum of all releases of the chemical to air, land, water, and underground injection wells; and transfers off-site by a given facility e POTW = publicly-owned treatment works 

c
FORMALDEHYDE 290 

5. POTENTIAL FOR HUMAN EXPOSURE 

Formaldehyde concentrations in jet engine exhaust have been found to range from 0.761 to 1.14 ppm 

(Miyamoto 1986). Formaldehyde is formed in large quantities in the troposphere by the oxidation of 

hydrocarbons (Calvert et al. 1972; WHO 1989) leading to elevated formaldehyde levels shortly after 

periods of high vehicular traffic (Grosjean et al. 1996). 

Statistical analyses of formaldehyde data from four sites in New Jersey have been used to evaluate the 

effects of automobile traffic and photochemical formation on formaldehyde concentrations (Cleveland et 

al. 1977). Integrated formaldehyde concentrations during the hours 5:00 a.m. to 8:00 p.m. decreased from 

workdays to Saturdays to Sundays, corresponding to a decrease in motor vehicle traffic. On workdays, 

formaldehyde concentrations were higher on days with more photochemical activity. 

Altshuller (1993) investigated the sources of aldehydes in the atmosphere during the night and early 

morning hours (between 9:00 p.m. and 9:00 a.m.). At night, the predominant sources of aldehydes should 

be the reaction of alkenes with O3 and NO3; during the early daylight hours, OH radical reactions with 

alkenes and alkanes will also contribute to aldehyde production. Altshuller (1993) found that, although 

the emissions of formaldehyde from vehicular exhaust are substantial relative to emissions of alkenes 

from vehicular exhaust, the secondary atmospheric production of aldehydes from the alkenes emitted 

from all vehicular sources during the period 9:00 p.m. to 9:00 a.m. can exceed the primary emissions of 

formaldehyde. However, if there is a large shift in the future to vehicles fueled with methanol and/or 

natural gas, formaldehyde emissions from the exhaust could predominate over the secondary emissions of 

formaldehyde during the 9:00 p.m. to 9:00 a.m. period. It should be noted that the rate of secondary 

production of aldehydes during the period 9:00 p.m. to 9:00 a.m. is much less than during the late 

morning and afternoon hours (Altshuller 1993). 

Grosjean et al. (1983) estimated the relative contributions of direct emissions and atmospheric 

photochemistry to levels of formaldehyde and other carbonyls in Los Angeles using measurements made 

simultaneously at a near-source site and at a site where the air quality was dominated by transport of 

polluted air masses from the downtown area (downwind smog receptor site). They found that the 

formaldehyde/carbon monoxide ratios were substantially higher at the downwind locations (average 

values, 3.2–11.7) than at the near-source site (average value, 1.8), indicating that photochemical 

production predominates over direct emissions in controlling formaldehyde levels in Los Angeles air. 

Using two models, their data were translated into formaldehyde photochemical production rates of 

12–161 tons per day. 
FORMALDEHYDE 291 

5. POTENTIAL FOR HUMAN EXPOSURE 

The amount of formaldehyde released to the atmosphere in 1996 by U.S. industrial facilities sorted by 

state is given in Table 5-1 (TRI96 1998). According to TRI96 (1998), an estimated total of 11.4 million 

pounds (5.2 million kg) of formaldehyde, amounting to approximately 54% of the total environmental 

release, was discharged to the air from 674 manufacturing and processing facilities in the United States in 

1996. The TRI data should be used with caution since only certain types of facilities are required to 

report. This is not an exhaustive list. 

Dempsey (1993) estimated the masses of selected organic emissions from hazardous waste incinerators 

(HWIs) on a nationwide scale using "reasonable worst-case" assumptions. Formaldehyde emissions 

formed during combustion of hazardous wastes were estimated to be 892 ng/L, which would result in a 

release of 7.8 tons of formaldehyde to the air per year. When compared to the 1990 TRI air release data 

from U.S. manufacturing operations, formaldehyde emissions from HWIs were found to be very 

small (0.12%). 

There is a potential for release of formaldehyde to air from hazardous waste sites. Formaldehyde has 

been detected in air samples collected at 5 of the 26 hazardous waste sites where formaldehyde has been 

detected in some environmental medium (HazDat 1996). 

Pressed wood products contribute to indoor formaldehyde levels. Combustion sources and phenolformaldehyde resin bonded products generally are weak emitters to indoor air. Common indoor 

combustion sources include gas burners and ovens, kerosene heaters, and cigarettes (Matthews et al. 

1985). 

Formaldehyde also arises in the atmosphere from natural sources. In monitoring studies performed in 

New Mexico, 1993–94, Gaffney and coworkers looked at total (average) formaldehyde concentrations 

and formaldehyde:acetaldehyde ratios (Gaffney et al. 1997). These researchers reported that if 

formaldehyde and acetaldehyde were being formed solely from the atmospheric oxidation of naturally 

occurring alkenes, the ratio of the two chemicals would be expected to be about 10. In this study, the 

formaldehyde:acetaldehyde ratio was lowest during the winter months and highest in the summer months. 

Gaffney et al. (1997) concluded that atmospheric formaldehyde in urban areas resulted from both 

anthropogenic emissions and natural sources in the summer and primarily from anthropogenic sources 

during the winter. 
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5. POTENTIAL FOR HUMAN EXPOSURE 

In a study conducted at the Inhalation Toxicology Research Institute, formaldehyde release rate 

coefficients were measured for six types of consumer products (Pickrell et al. 1983). Release rates 

calculated per unit surface area (μg/m2

/day) were used to rank the products in the following order: pressed 

wood products > >clothes . insulation products . paper products > fabric > carpet. Release rates from 

pressed wood products ranged from below the limit of detection for an exterior plywood to 

36,000 μg/m2

/day for some paneling. Other release rates were: for articles of new clothing not previously 

washed, 15–550 μg/m2

/day; for insulation products, 52–620 μg/m2/day; for paper plates and cups, 

75–1,000 μg/m2

/day; for fabrics, from below the limit of detection to 350 μg/m2/day; and for carpets, 

from below the limit of detection to 65 μg/m2

/day. In a follow-up to Pickrell’s study (Pickrell et al. 

1984), performed as a result of changes to product manufacturing processes, many of these release rates 

were reinvestigated. Formaldehyde release rates for a variety of bare urea-formaldehyde wood products 

(1/4 to 3/4") were reported to range from 8.6 to 1,578 μg/m2

/hr, coated urea-formaldehyde wood products 

from 1 to 461 μg/m2

/hr, permanent press fabrics from 42 to 214 μg/m2/hr, decorative laminates from 4 to 

50 μg/m2

/hr, fiberglass products from 16 to 32 μg/m2/hr, and bare phenol-formaldehyde wood products 

from 4 to 9 μg/m2

/hr (Kelly et al. 1996). Paper grocery bags and towels had emission rates of 0.4 and 

<0.3 μg/m2

/hr, respectively. For wet products, the emission rates were: latex paint 591 μg/m2/hr; more 

expensive latex paint 326 μg/m2

/hr; fingernail hardener 215,500 μg/m2/hr; nail polish 20,700 μg/m2/hr; 

and commercially applied urea-formaldehyde floor finish 421 and 1,050,000 μg/m2

/hr for base and 

topcoats, respectively (Kelly et al. 1996). 

Formaldehyde may also arise in indoor air through the degradation of other organic compounds. 

Naturally occurring unsaturated hydrocarbons, such as limonene and pinene (which may also be released 

from consumer products), and anthropogenic compounds, such as 4-vinylcyclohexene (an emission from 

carpet padding), and other alkenes commonly found in indoor air have been found to produce 

formaldehyde via their initial reaction with ozone (Weschler and Shields 1996; Zhang et al. 1994b). 

Reiss and coworkers estimated that the amount of formaldehyde released by this process is 0.87 μg/sec in 

winter months and 2.43 μg/sec in the summer (Reiss et al. 1995). 

In another study on indoor formaldehyde emissions, quasi steady-state emission rates of formaldehyde 

from new carpets were measured in a large-scale environmental chamber (Hodgson et al. 1993). The 

emission rates were 57.2 and 18.2 μg/m2

/hour at 24 and 168 hours, respectively, after the start of each 

experiment. Similar results were observed in a Swedish study where indoor formaldehyde levels were 

found to be higher in homes having wall to wall carpeting (Norback et al. 1995). Another recent 
FORMALDEHYDE 293 

5. POTENTIAL FOR HUMAN EXPOSURE 

Swedish study on indoor emissions reported that oil-based skin care products known to contain 

formaldehyde precursors (donors) released formaldehyde to the air even if the material had been in 

storage for one year (Karlberg et al. 1998). 

Formaldehyde release from pressed wood products is due to latent formaldehyde. During the pressing 

process, hot steam from moist wood particles transfers heat, formaldehyde, and other volatiles from the 

surface of the mat to the core of the board where unreacted urea-formaldehyde resin components 

accumulate. The resulting formaldehyde concentration in the core is approximately twice that of the 

surface. Release of formaldehyde is diffusion-controlled and gradually decreases over time (Meyer and 

Hermanns 1985). Formaldehyde can also be produced by hydrolytic cleavage of unreacted hydroxymethyl groups in the formaldehyde resins. Melamine formaldehyde resins generally are more stable, and 

the amounts of formaldehyde emitted from them are much lower (WHO 1989). 

A formaldehyde emission rate of 0.48 μg/kilojoule has been determined for normal operation of unvented 

gas ranges; however, this emission rate leads to relatively low indoor formaldehyde concentrations 

(Moschandreas et al. 1986). Formaldehyde emission rates ranging from 0.43 to 4.2 μg/kilojoule were 

measured from eight well tuned, unvented gas-fired space heaters operated at full fuel input in an 

environmental chamber with low ventilation (Traynor et al. 1985). In another study, formaldehyde 

emissions factors from unvented kerosene heaters ranged from 0.18 to 0.47 μg/kilojoule (Woodring et al. 

1985). 

Using an average cigarette consumption rate of approximately 10 cigarettes per indoor compartment per 

day with a measured formaldehyde emission rate of 0.97±0.06 mg/hour, Matthews et al. (1985) calculated 

an average formaldehyde emission rate of 0.4±0.03 mg/hour over 24 hours. Triebig and Zober (1984) 

report that the level of formaldehyde in side stream cigarette smoke is fifty times higher than main stream 

smoke, while the National Research Council (NRC 1986) put the value at five to eight times more 

formaldehyde in side stream smoke. Levels of formaldehyde in nonsmoking office buildings ranged from 

not detected to 0.22 ppm, while they ranged from not detected to 0.6 ppm where smoking was permitted 

(Sterling et al. 1987). 

Formaldehyde can also be emitted into indoor air from fish during cooking. Amounts of formaldehyde 

that formed in a headspace when various kinds of fish flesh were heated at 200 EC ranged from 0.48 μg/g 

of mackerel to 5.31 μg/g of sardine (Yasuhara and Shibamoto 1995). 
FORMALDEHYDE 294 

5. POTENTIAL FOR HUMAN EXPOSURE 

The general population may also participate in activities that release formaldehyde to outdoor air. The 

concentration of formaldehyde in mosquito-coil smoke was found to be 10.9–21.3 ppm/g (Chang and Lin 

1998). Composting household waste was also found to emit formaldehyde to air (Eitzer et al. 1997). 

5.2.2 Water 

Formaldehyde is released to water from the discharges of both treated and untreated industrial waste 

water from its production and from its use in the manufacture of formaldehyde-containing resins. 

Formaldehyde can also be formed in seawater by photochemical processes (Mopper and Stahovec 1986). 

Calculations of sea-air exchange have indicated that this process is probably a minor source of 

formaldehyde in the sea (Mopper and Stahovec 1986). 

The amount of formaldehyde released to surface water and POTWs in 1996 by U.S. industrial facilities 

sorted by state is shown in Table 5-1 (TRI96 1998). According to TRI96 (1998), an estimated total of 

320,003 pounds (145,153 kg) of formaldehyde, amounting to 2% of the total environmental release, was 

discharged to surface water in 1996. An additional 1.9 million pounds (0.8 million kg) of formaldehyde 

were discharged to POTWs (TRI96 1998). The TRI data should be used with caution since only certain 

facilities are required to report (EPA 1995). This is not an exhaustive list. As a result of secondary 

treatment processes in POTWs, only a fraction of the formaldehyde that enters POTWs is expected to be 

released subsequently to surface water; however, this percentage is not known for formaldehyde. 

Experiments conducted at three full-scale drinking water treatment plants and a pilot plant provided 

evidence that ozone treatment resulted in the production of measurable levels of formaldehyde in all of 

the plants studied (Glaze et al. 1989). 

There is a potential for release of formaldehyde to water from hazardous waste sites. Formaldehyde has 

been detected in surface water samples collected at 5 of the 26 hazardous waste sites and in groundwater 

samples collected at 4 of the 26 hazardous waste sites where formaldehyde has been detected in some 

environmental medium (HazDat 1996). 
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5. POTENTIAL FOR HUMAN EXPOSURE 

5.2.3 Soil 

Formaldehyde is released to soils through industrial discharges and through land disposal of 

formaldehyde-containing wastes. The amount of formaldehyde released to land in 1996 by U.S. 

industrial facilities sorted by state is shown in Table 5-1 (TRI96 1998). According to TRI96 (1998), an 

estimated total of 114,406 pounds (51,894 kg) of formaldehyde, amounting to 0.54% of the total 

environmental release, was discharged to land from U.S. manufacturing or processing facilities in 1996. 

An additional 9.4 million pounds (4.3 million kg), constituting about 44% of total environmental 

emissions, were released via underground injection (TRI96 1998). Also, some of the estimated 

1.3 million pounds of formaldehyde wastes transferred off-site (see Table 5-1) may be ultimately 

disposed of in land. The TRI data should be used with caution since only certain facilities are required to 

report (EPA 1995). This is not an exhaustive list. 

There is a potential for the release of formaldehyde to soil from hazardous waste sites. Formaldehyde has 

been detected in soil samples collected at 1 of the 26 hazardous waste sites and in sediment samples 

collected at 1 of the 26 hazardous waste sites where formaldehyde has been detected in some 

environmental medium (HazDat 1996). 

5.3 ENVIRONMENTAL FATE 

In reviewing the fate of formaldehyde in the environment, it should be noted that the environmental 

factors that influence the bioavailability to humans of formaldehyde from contaminated air, water, or 

plant material have not been studied. 

5.3.1 Transport and Partitioning 

Formaldehyde is released to the atmosphere in large amounts and is formed in the atmosphere by the 

oxidation of hydrocarbons. However, the input is counterbalanced by several removal paths (Howard 

1989). Because of its high solubility, there will be efficient transfer into rain and surface water, which 

may be important sinks (NRC 1981). One model has predicted dry deposition and wet removal half-lives 

of 19 and 50 hours, respectively (Lowe et al. 1980). Although formaldehyde is found in remote areas, it 

probably is not transported there, but is generated from longer-lived precursors that have been transported 

(NRC 1981). 
FORMALDEHYDE 296 

5. POTENTIAL FOR HUMAN EXPOSURE 

No information concerning the fate of formaldehyde in groundwater could be found in the literature. 

Based upon the Henry's law constant for formaldehyde (3.27x10-7 atm-m3

/mol) (Dong and Dasgupta 

1986), volatilization from water should not be significant (Lyman 1982). Also, little adsorption to 

sediment would be expected to occur. 

No information could be found concerning the adsorption of formaldehyde to soil. However, its low 

octanol/water partition coefficient (log Kow = 0.35) (SRC 1995b) suggests that adsorption to soil is low. 

Using the log Kow of 0.35, a log Koc of 1.57 can be calculated (Lyman 1982). This value of log Koc 

suggests a very high mobility and leaching potential of formaldehyde in soil (Swann et al. 1983). At high 

concentrations, formaldehyde gas adsorbs somewhat to clay mineral, which is important to its use as a 

soil fumigant (De and Chandra 1979). 

Plants, such as kidney beans and barley, can absorb gaseous formaldehyde through their leaves (EPA 

1976a). Experiments performed on a variety of fish and shrimp showed no evidence of the 

bioaccumulation of formaldehyde (Hose and Lightner 1980; Sills and Allen 1979). Because 

formaldehyde is rapidly metabolized (Casanova et al. 1988), bioaccumulation is not expected to be 

important. 

5.3.2 Transformation and Degradation 

Formaldehyde undergoes a number of different transformation and degradation reactions in the 

environment as discussed in the following sections. The resulting environmental transformation products 

within different media are shown in Table 5-2. 

5.3.2.1 Air 

Formaldehyde is removed from the atmosphere by direct photolysis and oxidation by photochemically 

produced hydroxyl radicals. Formaldehyde absorbs ultraviolet (UV) radiation at wavelengths of 360 nm 

and longer (DOT 1980); therefore, it is capable of photolyzing in sunlight. A half-life of 6 hours has been 

measured for photolysis in simulated sunlight (Su et al. 1979). There are two photolytic pathways, one 

producing H2 and CO, and the other producing H and HCO radicals (Calvert et al. 1972; Lowe et al. 

1980). When the rates of these reactions are combined with estimates of actinic irradiance, the predicted 

half-life of formaldehyde due to photolysis in the lower atmosphere is 1.6 hours at a solar zenith angle of 
 

 

FORMALDEHYDE 297 

5. POTENTIAL FOR HUMAN EXPOSURE 

Table 5-2. Environmental Transformation Products of Formaldehyde by Medium
 

Reaction Comments Reference
 

Air

 CH2O + hν 6 HCO + H Photolysis, pathway 1 Calvert et al. 1972 

CH2O + hν 6 H2 + CO Photolysis, pathway 2 Calvert et al. 1972

 CH2O + NO3 6 HCO + HNO3 H-atom abstraction by NO3 Kao 1994

radical 

CH2O + HO 6 H2O + HCO H-atom abstraction by HO NRC 1981 

radical 

Dilute Aqueous Solution

 CH2O + H2O 6 CH2(OH)2 Formation of gem-diol Kumar 1986 

methylene glycol; k298E = 

7.0x103

 M atm -1 

Concentrated Solution

 CH2O 6 H(CH2O)nOH + C3H6O3 Formation of EPA 1991c 

paraformaldehyde and trioxane 

Cloudwater

 CH2(OH)2 + OH 6 CH(OH)2 + H2O (1)

 CH(OH)2 + O2 6 HO2 + (HCOOH)aq (2) 

Formation of formic acid; 

k1 = 2x109

 M-1 s-1 

k2 = 4.5x109 M-1 s-1 

Chameides and Davis 

1983 
FORMALDEHYDE 298 

5. POTENTIAL FOR HUMAN EXPOSURE 

40 degrees (Calvert et al. 1972). Based on its rate of reaction with photochemically produced hydroxyl 

radicals, formaldehyde has a predicted half-life of approximately 19 hours in clean air and about half that 

time in polluted air (Atkinson and Pitts 1978; DOT 1980; EPA 1982). Lowe et al. (1980) report the 

lifetime of formaldehyde in the sunlit atmosphere, due to photolysis and reaction with hydroxyl radicals, 

is 4 hours. Singh et al. (1982) report an estimated daily loss rate of formaldehyde of 88.2% on the basis 

of hydroxyl radical activity and photolysis. The hydroxyl-radical-initiated oxidation of formaldehyde 

also occurs in cloud droplets to form formic acid, a component of acid rain (Chameides 1986; Chameides 

and Davis 1983). Calculations by Benner and Bizjak (1988) suggest that removal of formaldehyde by 

H2O2 is probably negligible in atmospheric droplets. When formaldehyde is irradiated in a reactor, the 

half-life is 50 minutes in the absence of NO2 and 35 minutes in the presence of NO2 (Bufalini et al. 1979; 

EPA 1976a). The primary products formed are formic acid and CO (Su et al. 1979). The reaction of 

formaldehyde with nitrate radicals, insignificant in the daytime, may be an important removal mechanism 

at night (NRC 1981). Formaldehyde reacts with the NO3 radical by H-atom extraction with a half-life of 

12 days, assuming an average nighttime NO3 radical concentration of 2x109

 molecules per cm3 (Atkinson 

et al. 1984). 

5.3.2.2 Water 

When released to water, formaldehyde will biodegrade to low levels in a few days (Howard 1989). In 

nutrient-enriched seawater, there is a long lag period (.40 hours) prior to measurable loss of 

formaldehyde by presumably biological processes (Mopper and Stahovec 1986). Formaldehyde in 

aqueous effluent is degraded by activated sludge and sewage in 48–72 hours (EPA 1976a; Hatfield 1957; 

Heukelekian and Rand 1955; Verschueren 1983). In a die-away test, using water from a stagnant lake, 

degradation was complete in 30 hours under aerobic conditions and 48 hours under anaerobic conditions 

(EPA 1976a). Bhattacharya and Parkin (1988) used anaerobic chemostats to study fate and kinetic effects 

of sludge and continuous additions of formaldehyde to acetate and propionate enrichment systems. The 

high reduction of formaldehyde with continuous addition is indicative of biodegradation, since the 

combination of volatilization, adsorption, and chemical transformation should account for less than 25% 

of the removal. Up to 80% of the formaldehyde was removed, with biodegradation accounting for 

55–60%. 

Chameides and Davis (1983) postulated that formaldehyde dissolved in cloudwater should not 

photolytically decompose because CH2(OH)2 is not a chromophore, and that the more probable fate of 
FORMALDEHYDE 299 

5. POTENTIAL FOR HUMAN EXPOSURE 

dissolved formaldehyde is oxidation by OH with the ultimate formation of formic acid. Experiments 

performed by Mopper and Stahovec (1986) suggest that formaldehyde is formed and consumed in 

seawater as a result of a number of interacting photochemical, biological, and physical processes. Diurnal 

fluctuations of formaldehyde ranging from 15 to 50 nM were measured in humic-rich waters off the west 

coast of Florida over a 3-day sampling period. 

Concentrated solutions containing formaldehyde are unstable, both oxidizing slowly to form formic acid 

and polymerizing (Gerberich et al. 1980). In the presence of air and moisture, polymerization takes place 

readily in concentrated solutions at room temperature to form paraformaldehyde, a solid mixture of linear 

polyoxymethylene glycols containing 90–99% formaldehyde (EPA 1984). 

5.3.2.3 Sediment and Soil 

The fate of formaldehyde in soil has not been determined (Howard 1989). 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation for human exposure to formaldehyde depends in part on the reliability of supporting 

analytical data from environmental samples and biological specimens. In reviewing data on 

formaldehyde levels monitored 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. 

5.4.1 Air 

A recent survey of emission data from stationary and mobile sources was used as input for an atmospheric 

dispersion model to estimate outdoor toxic air contaminant concentrations for 1990 for each of the 

60,803 census tracts in the contiguous United States (Woodruff et al. 1998). The average long term 

background concentration estimated for formaldehyde was 0.2 ppb (Woodruff et al. 1998). 

In a survey of ambient measurements of hazardous air pollutants, a median formaldehyde concentration 

of 2.5 ppb was found for a total of 1,358 samples collected at 58 different locations (Kelly et al. 1994). 

Air samples collected daily in Schenectady, New York, during the months of June through August 1983 

had formaldehyde concentrations ranging from 1 to 31 ppb. There was a significant daily variation that 
FORMALDEHYDE 300 

5. POTENTIAL FOR HUMAN EXPOSURE 

appeared to correlate with traffic conditions (Schulam et al. 1985). In the same study, formaldehyde 

levels measured on the summit of Whiteface Mountain in Wilmington, New York, ranged from 0.8 to 

2.6 ppb. Ambient formaldehyde concentrations at the California State University Los Angeles campus 

ranged from 2 to 40 ppb during the period from May to June 1980; concentrations in Claremont, 

California, ranged from 3 to 48 ppb from September 19 to October 8, 1980 (Grosjean 1982). 

Formaldehyde was measured in urban ambient air in 8 cities for 2- to 3-day periods from June 1980 to 

April 1984. The average concentrations were 11.3 ppb in St. Louis, Missouri (June 5–7, 1980); 12.3 ppb 

in Denver, Colorado (June 23–24, 1980); 2.3 ppb in Denver, Colorado (April 1–2, 1984); 19 ppb in 

Riverside, California (July 8–10, 1980); 14.3 ppb in Staten Island, New York (April 3–4, 1981); 18.5 ppb 

in Pittsburgh, Pennsylvania (April 15–16, 1981); 11.3 ppb in Chicago, Illinois (April 27–28, 1981); 

15.5 ppb in Downey, California (February 28–March 1, 1984); and 3.8 ppb in Houston, Texas (March 

18–19, 1984). The maximum concentration in each city ranged from 5.5 ppb in Denver in April to 

67.7 ppb in Downey (Salas and Singh 1986; Singh et al. 1982). 

Formaldehyde was detected in 99% of 48 ambient air samples obtained in Ohio urban centers, June-July 

1989, at a mean and maximum concentration of 3.0 and 15.5 ppb, respectively (Spicer et al. 1996). The 

diurnal changes in concentration were found to be consistent with initial direct emissions from vehicles 

followed by secondary photochemical production and, ultimately, atmospheric removal. These data 

indicate that formaldehyde concentrations in urban atmospheres are expected to be the highest during, or 

shortly after rush hour, or other periods of high vehicular traffic. Similar results were obtained when 

temporal formaldehyde concentrations were measured during a smog event in California, September 1993 

(Grosjean et al. 1996). In central Los Angeles, higher formaldehyde concentrations were found to 

correlate with vehicular traffic while at a downwind location, the concentration was found to spike later in 

the day. The average atmospheric formaldehyde concentration for all sites was 5.3 ppbv (parts per billion 

by volume) in this study, while the background concentration from San Nicolas island (off the Southern 

California coast) was 0.8 ppmv (parts per million by volume). Average annual formaldehyde 

concentrations in California have been reported to vary from a minimum of 3.2 ppbv in the San Francisco 

Bay area to 4.9 ppbv in the South Coast Air Basin (Seiber 1996). 

Several monitoring studies have been conducted in the United States to measure the concentration of 

formaldehyde in indoor environments (EPA 1987d; Gammage and Hawthorne 1985; Hawthorne et al. 

1985, 1986b; Stock 1987). The results for a variety of housing types and ages have been compiled by 

Gold et al. (1993) and are presented in Table 5-3. Much of the data was collected in older homes, in 
Table 5-3. Indoor Concentrations of Formaldehyde in U.S. Homes 

Concentration (ppm) 

Building type Number Range Mean References With UFFI >1,200 0.01–3.4 0.05–0.12 EPA 1987d; GammagWithout UFFI 131 0.01–0.17 0.025–0.07 Gammage and HawthComplaint Mobile homes >500 0.00–4.2 0.1–0.9 Gammage and Hawth

Non-complaint 

Conventional, randomly selected 560 <0.005–0.48 0.027–0.091 EPA 1987d; Stock 19Mobile homes, randomly selected .1,200 <0.01–2.9 0.091–0.62 EPA 1987d 

By age 

Mobile homes 

new 260 0.86 Gammage and Hawtholder, occupied — 0.25 Gammage and Hawth

Conventional homes 

0–5 years 18 0.08 Hawthorne et al. 1985–15 years 11 0.04 Hawthorne et al. 198>15 11 0.03 Hawthorne et al. 198Overall 40 <0.02–0.4 0.06 Hawthorne et al. 198

UFFI = Urea formaldehyde foam insulation 
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5. POTENTIAL FOR HUMAN EXPOSURE 

homes that had UFFI, or in homes in which occupants had filed complaints of formaldehyde irritant 

symptoms. Since the time many of these monitoring studies were performed, plywood and particle board 

manufacturing methods have been changed to reduce the formaldehyde emission levels in the finished 

product (EPA 1996). Similarly, home construction methods have changed, and the use of UFFI has been 

greatly reduced since the mid-eighties (CPSC 1997). A recent pilot study on a newly constructed and 

unoccupied house set up to measure formaldehyde emissions from construction materials had a maximum 

localized formaldehyde concentration of 0.076 ppm, which occurred shortly after a high loading of 

pressed wood materials, such as kitchen cabinets (Hare et al. 1996). The average indoor concentrations 

measured in this study were 0.035–0.45 ppm, which was attained approximately 30 days after either high 

or low loadings of formaldehyde releasing materials were installed. 

Earlier studies evaluating randomly selected, non-complaint homes have appeared in the literature. 

Despite the wide variety of conditions under which these residential formaldehyde studies were 

conducted, results for given types of housing were consistent within certain broad ranges. In general, 

indoor residential formaldehyde concentrations were significantly higher than outdoor concentrations 

which ranged from 0.002 to 0.006 ppm in remote, unpopulated regions from 0.01 to 0.02 ppm (and 

sometimes 0.05 ppm) in highly populated areas and industrial urban air (Gold et al. 1993). The range of 

formaldehyde concentrations measured in complaint homes, mobile homes, and homes containing large 

quantities of particle board or UFFI were 0.02–0.8 ppm, with levels as high as 4 ppm, sufficient to cause 

irritating symptoms, observed in some instances. Formaldehyde levels in more recently built (<1 year 

old) conventional homes generally were within the range of 0.05–0.2 ppm, with few measurements 

exceeding 0.3 ppm. Older conventional homes had the lowest indoor concentrations of formaldehyde 

with values typically less than 0.05 ppm (Gold et al. 1993), consistent with the expected decrease in latent 

formaldehyde release from wood-based building materials as they age (EPA 1996; Zinn et al. 1990). 

The Texas Department of Health measured formaldehyde in 443 mobile homes between April 1979 and 

May 1982 at the request of the occupants. Concentrations ranged from below detectable limits 

(<0.5 ppm) to 8 ppm (Norsted et al. 1985). Of the homes #1 year old, 27% had mean concentrations 

$2 ppm, while 11.5% of older homes has concentrations $2 ppm. The concentration of formaldehyde in 

mobile homes would be expected to be higher than that found in conventional homes due to their lower 

rate of air exchange (Wolff 1991). 
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5. POTENTIAL FOR HUMAN EXPOSURE 

Sexton et al. (1989) selected an age-stratified random sample of 470 mobile homes, from the more than 

500,000 in California, for measurement of 1-week, average indoor formaldehyde concentrations during 

the periods July–August 1984 and February–March 1985. They observed relatively little variation in 

formaldehyde concentrations between summer and winter, with average 1-week formaldehyde values of 

0.07–0.09 ppm. Of the homes, 31% exceeded the maximum concentration of 0.1 ppm formaldehyde 

recommended at the time of the study by AIHA, EPA, and the American Society of Heating, 

Refrigerating and Air Conditioning Engineers. The investigators noted that formaldehyde levels appeared 

to have been decreasing in mobile homes manufactured since about 1980, probably as a result of 

increased use of low-formaldehyde-emitting building materials. 

The Indiana State Board of Health measured formaldehyde in four specific office and commercial 

establishments that had poor ventilation. The concentrations ranged from 0.01 to 1.01 ppm. In one case, 

the source of formaldehyde was urea-formaldehyde foam. In the others, it was particle board, plywood 

subflooring, and furniture (Konopinski 1983).

 Shah and Singh (1988) collected indoor and outdoor data for volatile organic chemicals from both 

residential and commercial environments. The average daily outdoor concentration of formaldehyde for 

all outdoor site types (remote, rural, suburban, urban, and source-dominated) was 8.3 ppbv; the average 

daily indoor concentration of formaldehyde was 49.4 ppbv. 

Zhang et al. (1994b) made simultaneous indoor and outdoor measurements of aldehydes at six residential 

houses in suburban New Jersey during the summer of 1992. Formaldehyde was the most abundant 

aldehyde, with a mean outdoor concentration of 12.53 ppb (.60% of the total outdoor aldehyde 

concentration) and a mean indoor concentration of 54.56 ppb (.87% of the total indoor aldehyde 

concentration). 

Krzyzanowski et al. (1990) measured formaldehyde concentrations in 202 households in Pima County, 

Arizona, and found an average value of 26 ppb. Concentrations varied slightly with locations in the 

house, with the highest levels generally found in the kitchens. Only a few concentrations exceeded 

90 ppb, with a maximum value of 140 ppb. The average indoor formaldehyde concentrations measured in 

homes in Pullman, Washington, ranged from approximately 5–72 ppb (Lamb et al. 1985). 
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5. POTENTIAL FOR HUMAN EXPOSURE 

Formaldehyde concentrations measured on two different days inside a tavern during normal smoking 

conditions were 85–72 ppb (Lofroth et al. 1989). In the same study, the average airborne formaldehyde 

yield of a cigarette was found to be 2 mg. Levels of formaldehyde in nonsmoking office buildings ranged 

from not detected to 0.22 ppm, while it ranged from not detected to 0.6 ppm where smoking was 

permitted (Sterling et al. 1987). 

5.4.2 Water 

Formaldehyde is unstable in water; however, it has been detected in municipal and industrial aqueous 

effluents, including those resulting from chemical, oil, and coal processing (EPA 1976b; Hushon et al. 

1980). Formaldehyde was not detected in the National Organics Reconnaissance Survey of Suspected 

Carcinogens in Drinking Water (EPA 1975). 

Formaldehyde levels in rainwater collected in California were low, ranging from not detectable to 

0.06 μg/mL (Grosjean and Wright 1983). Concentrations of free formaldehyde measured in fogwater in 

Corvallis, Oregon, ranged from 0.4 to 3 mg/L with a volume-weighted mean of 1.8 mg/L (Muir 1991). 

Free formaldehyde concentrations in fogwater in Riverside, California, ranged from 4.1 to 228 μM 

(0.12–6.8 mg/L), with approximately half of the samples measuring less than 90 μM (3 mg/L) (Igawa et 

al. 1989). Stratus cloudwater at Henninger Flats, California, which typically is highly acidic and 

concentrated in inorganic pollutants, had concentrations of free formaldehyde ranging from 45.9 to 

61.5 μM (1.4–1.8 mg/L), comparable to the mid-range of Corvallis fogwater concentrations (Igawa et al. 

1989). Formaldehyde concentrations ranging from 11 to 142 μM were found in cloudwater samples 

collected in the Los Angeles Basin (Richards et al. 1983). Formaldehyde concentrations in mist samples 

in Long Beach and Marina del Ray, California, were 0.25–0.56 μg/mL, respectively (Grosjean and 

Wright 1983). 

5.4.3 Sediment and Soil 

No data on formaldehyde levels in sediment and soil could be found in the literature. 
FORMALDEHYDE 305 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.4.4 Other Environmental Media 

Fresh shrimp from four local commercial markets in Atlanta, Georgia were found to have formaldehyde 

levels ranging from 0.39 to 1.44 mg/kg (Radford and Dalsis 1982). In the same study, shrimp kept live in 

the laboratory were found to contain 0.99 mg/kg immediately after sacrifice, and the level rose to 

2.15 mg/kg after refrigeration for 6 days. 

Chou and Que Hee (1994) measured the concentrations of carbonyl compounds in artificial saliva 

leachates of three chewing tobaccos. They found formaldehyde concentrations of 110, 670, and 

530 ng/mL (0.11, 0.67, and 0.53 μg/mL, respectively) in three different commercial brands. Mansfield et 

al. (1977) used liquid chromatography to measure formaldehyde as a combustion product in tobacco 

smoke from six different brands of American filter tip cigarettes. The average amount of formaldehyde 

by brand ranged from 45.2 to 73.1 μg/cigarette and from 5.1 to 8.9 μg/puff. Triebig and Zober report that 

the level of formaldehyde in side stream cigarette smoke is fifty times higher than main stream smoke 

(Triebig and Zober 1984) while the National Research Council put the value at five to eight times more 

formaldehyde in side stream smoke (NRC 1986). 

Formaldehyde has also been found at levels ranging from 1 to 3,517 ppm in 112 fabric samples, with 

18 of the samples having a free formaldehyde concentration greater than 750 ppm (mg/kg) (Schorr et al. 

1974). 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

The contribution of various atmospheric environments to the average exposure to formaldehyde is given 

below (Fishbein 1992): 
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5. POTENTIAL FOR HUMAN EXPOSURE 

Source mg/day 

Air 

Outdoor air (10% of time) 0.02 

Indoor air 

Home (65% of time) 

Conventional 0.5–2.0 

Prefabricated (chipboard) 1.0–10.0 

Workplace (25% of time) 

Without occupational exposure 0.2–0.8 

With 1 mg/m3

 occupational exposure 5 

Environmental tobacco smoke 0.1–1 

Smoking (20 cigarettes/day) 1 

The major route of exposure is inhalation of indoor air, with releases of formaldehyde from chipboard and 

other building and furnishing materials composing the bulk of the exposure. Environmental tobacco 

smoke contributes 10–25% of the total indoor exposure. Since formaldehyde in food is not available in 

free form, the intake of formaldehyde from the ingestion of food (1–10 mg/day) has not been included 

(Fishbein 1992). 

Consumers can be exposed to formaldehyde gas through its emission from construction materials, wood 

products, textiles, home furnishings, paper, cosmetics, and pharmaceuticals (Bartnik et al. 1985; Pickrell 

et al. 1983; WHO 1989). Members of the general population may also be exposed to formaldehyde by 

dermal contact with many of these products. Based on a study of dermal absorption of formaldehyde in 

rats from cosmetic products, Bartnik et al. (1985) made rough estimates of the formaldehyde that could be 

absorbed through the use of products such as hand cream or sun-tan lotion. In the case of hand cream, 

approximately 2 g is used per application, containing 2 mg formaldehyde. Assuming 5% absorption, 

0.1 mg of formaldehyde would be absorbed. For a whole-body product such as sun-tan lotion, 

approximately 17 g of the product (containing 17 mg of formaldehyde) would be used, resulting in an 

absorption of 0.85 mg of formaldehyde. 

A study was conducted in Boston to examine the commuter’s exposure to six gasoline-related volatile 

emissions, including formaldehyde, in four different commuting modes (Chan et al. 1991). The mean 

formaldehyde concentrations (in μg/m3

) measured while driving private cars, riding in subways, walking, 

and biking were 5.1 (n=40), 4.5 (n=38), 5.5 (n=31), and 6.3 (n=11), respectively. The maximum 

concentrations in all commuting modes were usually three to five times higher than the mean 
FORMALDEHYDE 307 

5. POTENTIAL FOR HUMAN EXPOSURE 

concentrations. A similar study in the New York/New Jersey area found that the mean in-vehicle 

concentration of formaldehyde during commutes was 0.3 μg/m3

 (Lawryk et al. 1995; Lawryk and Weisel 

1996). 

Occupational exposure can occur during the production of end products in which formaldehyde is used, in 

the garment industry, during various preservation processes, and in laboratories. Health care 

professionals (pharmacists, physicians, veterinarians, dentists, nurses, etc.) may be exposed to vapors 

during the preparation, administration, and/or cleanup of various medicines. Pathologists and histology 

technicians, morticians, and teachers and students who handle preserved specimens may also be exposed 

(Fleisher 1987; Holness and Nethercott 1989; Korky et al. 1987; Perkins and Kimbrough 1985; Skisak 

1983). The laser cutting of felt, woven fabrics, formica, plexiglass, and acrylic materials has been found 

to release formaldehyde (Kiefer and Moss 1997). Formaldehyde exposure for workers at a fiberglass 

insulation manufacturing plant were found to range from 49 to 516 μg/m3

 (Milton et al. 1996a). Midrange photocopiers (30–135 copies per minute) have also been found to emit formaldehyde (Leovic et al. 

1996). 

The National Occupational Exposure Survey (NOES), conducted from 1981 to 1983, indicated that 

1,329,332 workers employed in various professions were potentially exposed to formaldehyde in the 

United States (NIOSH 1995b). The NOES database does not contain information on the frequency, 

concentration, or duration of exposure; the survey provides only estimates of workers potentially exposed 

to the chemical in the workplace. OSHA has estimated that in the late 1980s over 2 million workers in 

over 112,000 firms were exposed to formaldehyde; about 45% of these workers are estimated to be in the 

garment industry. About 1.9 million were exposed to levels of formaldehyde between 0.1 ppm and 

0.5 ppm (mainly in apparel, furniture, paper mills, and plastic molding); approximately 123,000 were 

exposed to levels of formaldehyde between 0.5 and 0.75 ppm (mainly in apparel, textile finishing, 

furniture, laboratories, and foundries); and about 84,000 were exposed to between 0.75 and 1 ppm 

(mainly in apparel, furniture, and foundries) (OSHA 1996). 

OSHA has estimated that in the United States approximately 107,000 employees are exposed to 

formaldehyde concentrations greater than 1 ppm, and approximately 430,000 employees are exposed to 

concentrations ranging from 0.5 to 1 ppm (Fishbein 1992). An initial evaluation of formaldehyde 

exposures in a sewing plant using fabrics with a postcure resin found time-weighted average (TWA) 
 

FORMALDEHYDE 308 

5. POTENTIAL FOR HUMAN EXPOSURE 

exposure levels #1.2 ppm, with a mean of 0.9 ppm (Luker and Van Houten 1990). A modification that 

decreased the amount of residual formaldehyde in the fabric reduced worker exposure by 80–85%. Area 

concentrations of formaldehyde in a plywood company ranged from 0.28 to 3.48 ppm; the average 

personal exposure was 1.13 ppm formaldehyde (Malaka and Kodama 1990). Airborne formaldehyde 

concentrations ranging from 0.187 to 0.783 ppm have been measured during particle-board-sanding 

operations (Stumpf et al. 1986). Formaldehyde concentrations of 0.5–7 ppm have been measured in 

leather tanning facilities (Stern et al. 1987). An average airborne formaldehyde level of 0.36±0.19 ppm 

was measured during 22 embalming procedures (Holness and Nethercott 1989). Fire fighters are exposed 

to formaldehyde concentrations as high as 8 ppm during knockdown (bringing the main body of fire 

under control) and #0.4 ppm during overhaul (searching for and extinguishing hidden fire) (Jankovic et 

al. 1991). Formaldehyde levels #0.3 ppm have been measured inside a fire fighter's self-contained 

breathing apparatus (Jankovic et al. 1991). 

The current OSHA permissible exposure limit (PEL) for all workplaces covered by OSHA is 0.75 ppm 

for an 8-hour TWA, and the short-term exposure limit (STEL) is 2 ppm over a 15-minute period. The 

"action level" is 0.5 ppm measured over 8 hours (OSHA 1996). NIOSH has recommended a 0.1 ppm 

ceiling exposure concentration over a 15-minute period in the workplace (NIOSH 1992). 

5.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans and briefly 

considers potential pre-conception exposure to germ cells. Differences from adults in susceptibility to 

hazardous substances are discussed in Section 2.6 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, and 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; they put things in their 

mouths; they may ingest inappropriate things such as dirt or paint chips; they spend more time outdoors. 

Children also are closer to the ground, and they do not have the judgement of adults in avoiding hazards 

(NRC 1993). 
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5. POTENTIAL FOR HUMAN EXPOSURE 

Children are exposed to formaldehyde mainly from its presence in air. Formaldehyde levels are typically 

higher indoors (Gold et al. 1993) where younger children may spend a significant amount of time. 

Exposure for children outdoors will be similar to adults. It is likely to be greatest during rush hour 

commutes (Spicer et al. 1996) or near known sources of formaldehyde release, such as factories using 

formaldehyde or during the use of products (Shah and Singh 1988) that emit formaldehyde. Children 

may also be dermally exposed to formaldehyde as a result of its release from permanent press fabrics or 

its presence in cosmetic products. Only a limited number of studies that address formaldehyde exposure 

to children or body burden measurements have been identified (Krzyzanowski et al. 1990; Wantke et al. 

1996a). 

In the home, formaldehyde sources include household chemicals, pressed wood products (especially when 

new) (EPA 1996), combustion sources (NRC 1986), and some new fabrics (Schorr et al. 1974) and 

garments. A number of common household products may release formaldehyde to indoor air, including 

antiseptics, medicines, dish-washing liquids, fabric softeners, shoe-care agents, carpet cleaners, glues, 

adhesives, and lacquers (Kelly et al. 1996). If children use or play with some of these products, or are 

present when they are used, additional exposure to formaldehyde may occur. Many cosmetic products 

contain formaldehyde and some, such as nail polish and nail hardeners, contain high levels (Kelly et al. 

1996). If children place these products in their mouth or on their skin, or sniff them, they will be exposed 

to elevated levels of formaldehyde. 

New carpets have been found to release formaldehyde (Hodgson et al. 1993). Older carpets, especially 

wall-to-wall carpets, have been found to be a sink for formaldehyde if there are other indoor sources 

(Norback et al. 1995). In addition, some carpet cleaners may contain formaldehyde. Infants may be 

exposed to formaldehyde while crawling on carpets or on newly cleaned carpets (IARC 1982; WHO 

1989). Similarly, young children may be exposed while sitting or playing on indoor carpeting. 

Formaldehyde is typically not found in water or soil, and children are not expected to be exposed by these 

routes. Because it is a gas, formaldehyde is not brought home on a parent’s work clothes or tools. 

Occupants of newly constructed homes, including children, may be exposed to formaldehyde due to its 

release from pressed wood construction materials (see Section 5.7), a process that slowly decreases with 

time. As discussed above, formaldehyde is released to indoor air from many sources. Children that live 

in mobile homes may be exposed to higher levels of formaldehyde compared to those that live in 

conventional homes because mobile homes have lower air exchange rates. Children that live in 
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5. POTENTIAL FOR HUMAN EXPOSURE 

households that have a cigarette, cigar, or pipe smoker will also be exposed to higher levels of 

formaldehyde due to its presence in side stream smoke (Triebig and Zober 1984). 

Formaldehyde is released from many pressed wood products used in the construction of furniture 

(Konopinski 1983). When placed in a new crib manufactured from these materials, infants may be 

exposed because of their proximity to the furniture’s structural components. Also, small rooms that have 

new furniture manufactured from pressed wood products installed may have localized, elevated 

concentrations of formaldehyde because of their low total volume. 

Formaldehyde is highly water soluble, very reactive, and is rapidly metabolized by tissues at portals of 

entry. Thus, parental exposure at typical indoor, outdoor, or occupational levels is not expected to result 

in exposure to parental germ cells or the developing fetus (See Section 2.6 for additional information). 

Since formaldehyde is typically found in the air, and since its concentration in indoor air is typically 

higher than that found outdoors, formaldehyde exposure to children can be reduced by bringing fresh air 

into the home. This can be accomplished by opening windows or using ventilation fans. It has been 

established that coated or laminated pressed wood products release less formaldehyde than those that are 

uncoated (Kelly et al. 1996; Pickrell et al. 1983), so sealing these surfaces would be expected to reduce 

formaldehyde levels in the home. Since formaldehyde is also formed in indoor air by the degradation of 

other volatile organic chemicals, such as solvents (Weschler and Shields 1996), commonly found in the 

home, removing the source of these materials or using them with adequate ventilation will reduce indoor 

levels of formaldehyde. 

Material that acts as a sink for formaldehyde, such as carpets (Norback et al. 1995), can also be removed 

from the home to lower levels. Securing cosmetic products and other materials that have higher 

formaldehyde concentrations away from children’s reach and not allowing individuals to smoke in the 

house will also lower levels of exposure. 
FORMALDEHYDE 311 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Workers in industries where formaldehyde is used or released may receive potentially high exposures. 

Members of the general population who live in newly constructed homes or homes where pressed wood 

products have recently been installed may be exposed to high levels of formaldehyde by inhalation for 

short periods of time until the latent formaldehyde has been released. Exposures in mobile homes are 

expected to be higher than conventional homes due to their lower rate of air exchange (Wolff 1991). 

Members of the general population that handle large amounts of permanent press fabrics treated with 

formaldehyde-releasing resins may also receive potentially high exposures. The use of some cosmetics, 

such as nail hardeners, may result in high short-term exposure. 

Smokers and persons who live in a home with a cigarette smoker also may be exposed to higher levels of 

formaldehyde. Environmental tobacco smoke, which is a combination of diluted sidestream smoke 

released from a cigarette’s burning end and mainstream smoke exhaled by an active smoker, can 

contribute 10–25% (0.1–1 mg/day) of the total average indoor exposure to formaldehyde (Fishbein 1992). 

5.8 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 formaldehyde is available. Where adequate information is 

not available, ATSDR, in conjunction with the 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 formaldehyde. 

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. 
 

 

 

FORMALDEHYDE 312 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of formaldehyde are 

well characterized and allow prediction of the transport and transformation of the compound in the 

environment. 

Production, Import/Export, Use, Release, and Disposal. Knowledge of a chemical’s 

production volume is important because it may indicate the magnitude of environmental contamination 

and human exposure. Data regarding the production, trend, use pattern, and disposal of formaldehyde are 

available. 

According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. 

Section 11023, industries are required to submit chemical release and off-site transfer information to the 

EPA. The Toxics Release Inventory (TRI), which contains this information for 1996, became available in 

May of 1998. According to the Toxics Release Inventory (TRI), in 1996, 21 million pounds (9.6 million 

kg) of formaldehyde were released to the environment. This database will be updated yearly and should 

provide a list of industrial production facilities and emissions. 

Environmental Fate. The environmental fate of formaldehyde in air has been well studied (Bufalini 

et al. 1979; Calvert et al. 1972; Chameides and Davis 1983; DOT 1980; EPA 1976a; Kao 1994; Kelly et 

al. 1994; Lowe et al. 1980; Su et al. 1979). Formaldehyde is removed from the atmosphere by direct 

photolysis and oxidation by photochemically produced hydroxyl and nitrate radicals. Solutions of 

formaldehyde are unstable, both oxidizing slowly to form formic acid and polymerizing. When released 

to water, formaldehyde will biodegrade to low levels in a few days, with little adsorption to sediment 

(Howard 1989; Lyman 1982). No significant volatilization from water is expected to occur (Lyman 

1982). No experimental or estimated values for the half-life of formaldehyde in ambient water were 

found in the literature. Aqueous solutions of formaldehyde that are released to soil may leach through the 

soil (Lyman 1982; SRC 1995b; Swann et al. 1983). Although formaldehyde is known to biodegrade 

under both aerobic and anaerobic conditions, the fate of formaldehyde in soil is still unknown (Howard 

1989). There is a need for data on the fate and transport of formaldehyde in soil, including half-life 

values. The environmental fate of formaldehyde’s predominant degradation product, formic acid, is well 

documented. In air, formic acid is expected to rapidly degrade (half-life approximately 1 month) through 
 

 

 

FORMALDEHYDE 313 

5. POTENTIAL FOR HUMAN EXPOSURE 

its reaction with hydroxyl radicals or it is expected to undergo wet deposition to the earth’s surface 

(HSDB 1999). In water or soil, formic acid is expected to rapidly biodegrade. 

Bioavailability from Environmental Media. Inhalation is the major pathway for exposure to 

formaldehyde (Fishbein 1992). The environmental factors that may influence the bioavailability of 

formaldehyde from contaminated air, water, or plant material have not been studied. The role of sorption 

may not be significant in determining the bioavailability of formaldehyde from soil since formaldehyde is 

not expected to adsorb to soils and sediments (Lyman 1982). The factors affecting the bioavailability of 

formaldehyde from soil and other environmental media need further investigation. The bioavailability of 

formaldehyde from the ingestion of food is not known although it is not expected to be significant. 

Food Chain Bioaccumulation. Experiments performed on a variety of fish and shrimp showed no 

evidence of the bioaccumulation of formaldehyde (Hose and Lightner 1980; Sills and Allen 1979). 

Because formaldehyde is rapidly metabolized (Casanova et al. 1988), bioaccumulation is not expected to 

be important. No further information is needed. 

Exposure Levels in Environmental Media. The levels of formaldehyde in air are well 

documented (EPA 1987d; Gammage and Hawthorne 1985; Gold et al. 1993; Grosjean 1982; Hawthorne 

et al. 1985, 1986a; Kelly et al. 1994; Krzyzanowski et al. 1990; Lamb et al. 1985; Lofroth et al. 1989; 

Norsted et al. 1985; Salas and Singh 1986; Schulam et al. 1985; Sexton et al. 1989; Shah and Singh 1988; 

Singh et al. 1982; Stock 1987; Zhang et al. 1994a). Some data on the concentrations of formaldehyde in 

rainwater, fogwater, and mist have been reported (Grosjean and Wright 1983; Igawa et al. 1989; Muir 

1991), but more recent data on the levels of formaldehyde in water would be useful in assessing 

exposures. No data on levels of formaldehyde in soil were found in the literature. Soil concentrations 

also are needed to assess exposures. 

Reliable monitoring data for the levels of formaldehyde in contaminated media at hazardous waste sites 

are needed so that the information obtained on levels of formaldehyde in the environment can be used to 

assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste 

sites. 
 

 

 

FORMALDEHYDE 314 

5. POTENTIAL FOR HUMAN EXPOSURE 

Exposure Levels in Humans. Data are available concerning exposure levels in occupational 

settings (Anonymous 1984a; Fishbein 1992; OSHA 1996). Results of the National Occupational 

Exposure Survey (NIOSH 1995b) are indicative of the number of workers potentially exposed to 

formaldehyde in various occupations; however, the database does not contain information on the 

frequency, concentration, or duration of exposure. Available data indicate that the general population 

may be exposed to formaldehyde through inhalation and dermal contact; however, because of the wide 

variety of exposure sources (conventional homes versus mobile homes, smoking versus nonsmoking 

environment, usage patterns for consumer products, etc.), it is difficult to estimate average daily intakes 

by these routes. Up-to-date comprehensive monitoring data would be useful in determining the typical 

amount of formaldehyde to which the general population is exposed. This information is necessary for 

assessing the need to conduct health studies on these populations and persons residing near hazardous 

waste sites. 

Exposures of Children. Because formaldehyde is found predominately in the air, the main exposure 

pathway for children is the same as adults. Formaldehyde concentrations in indoor air have been 

reported, although many of the studies were obtained before manufacturing methods for formaldehydereleasing building materials were changed to reduce emissions. Current, comprehensive studies that 

account for all formaldehyde release sources to indoor air would aid in determining the body burden to 

children. Studies that take into account the different lifestyles of children would be also helpful. For 

example, formaldehyde emissions to indoor air may be source dominated (e.g., emission from pressed 

wood furniture). For a given emission level, the resulting formaldehyde concentration would be expected 

to be greater in children’s rooms compared to those of adults because the volume is smaller. Information 

to address child specific formaldehyde exposure issues is not available. 

Exposure Registries. No exposure registries for formaldehyde were located. This substance is not 

currently one of the compounds for which a subregistry 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. Workers in industries where formaldehyde is used or produced should be 

considered for inclusion in an exposure registry. Given that formaldehyde is routinely found in indoor air 

samples, members of the general population should also be considered for inclusion in the exposure 

registry. 
FORMALDEHYDE 315 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.8.2 Ongoing Studies 

As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environmental 

Health Laboratory Sciences Division of the National Center for Environmental Health, Centers for 

Disease Control and Prevention, will be analyzing human blood samples for formaldehyde and other 

volatile organic compounds. These data will give an indication of the frequency of occurrence and 

background levels of these compounds in the general population. 

The Federal Research in Progress (FEDRIP 1996) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 5.8.1. These 

studies are summarized in Table 5-4. 
FORMALDEHYDE 316 

5. POTENTIAL FOR HUMAN EXPOSURE 

Table 5-4. Ongoing Studies on the Potential for Human Exposure to Formaldehyde 

Investigator Affiliation Research description Sponsor 

K. Knapp, EPA-AREAL Characterization of emissions, including EPA 

D. Pahl, and Research Triangle Park, NC formaldehyde, from motor vehicles using both 

F. Black traditional and alternative fuels. 

B.J. Collier Louisiana State University Development of textile materials for USDA 

Baton Rouge, LA environmental compatibility and human 

health and safety. 

D.V. Sandberg Pacific Northwest Assessment of firefighter exposures to USDA 

and R.D. Forest and Range Experiment potential health hazards, including 

Ottmar Station formaldehyde. 

Portland, OR 

T. Shibamoto University of California Isolation and identification of mutagens and USDA 

Davis, CA carcinogens in foods. 

J.S. Gaffney Argonne National Laboratory Atmospheric chemistry of organic oxidants USDOE 

Argonne, IL and aldehydes. 

P. Davidovits Boston College Laboratory studies of heterogeneous gas- NSF 

Chestnut Hill, MA liquid interaction of atmospheric trace gases, 

including formaldehyde. 

R.C. Bales and University of Arizona Determination of the atmosphere-to-snow NSF 

M. Conklin Tucson, AZ transfer function for peroxide and 

formaldehyde, whose deposition is reversible. 

R.C. Bales and University of Arizona Distribution of reactive chemical species, NSF 

M. Conklin Tucson, AZ including formaldehyde, in ice and snow. 

V.A. Mohnen State University of Examination of the involvement of natural NSF 

New York hydrocarbons for the formation of peroxide 

Albany, NY and formaldehyde in air. 

B.G. Heikes University of Background atmospheric measurements of NSF 

Rhode Island hydrogen peroxide, organic hydro-peroxides, 

Kingston, RI and formaldehyde. 

S.S. Que Hee UCLA School of Carbonyl compounds air sampling method. NIOSH 

Public Health 

Los Angeles , CA 

R.R. Fall University of Colorado Biogenic sources of oxygenated hydrocarbons NSF 

at Boulder in the troposphere. 

Boulder, CO 

EPA = Environmental Protection Agency; NSF = National Science Foundation; USDA = United States Department 

of Agriculture; USDOE = United States Department of Energy; NIOSH = National Institute for Occupational Safety 

and Health 
FORMALDEHYDE 317 

6. ANALYTICAL METHODS
 

The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or 

measuring, and/or monitoring formaldehyde, its metabolites, and other biomarkers of exposure and effect 

to formaldehyde. 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. 

6.1 BIOLOGICAL SAMPLES 

Methods for the determination of formaldehyde in biological samples are given in Table 6-1. 

Formaldehyde has been measured in blood by gas chromatography (GC) in conjunction with mass 

spectrometry (MS) after derivatization of the formaldehyde to the pentafluorophenylhydrazone (Heck et 

al. 1985) and in rat urine by high-performance liquid chromatography (HPLC) with ultraviolet (UV) 

absorbance detection following formation of the 2,4-dinitrophenylhydrazone derivative (Shara et al. 

1992). Although the method was used for rat urine, it would be expected that human urine could also be 

utilized. The determination of formaldehyde in breath has been demonstrated by Lin et al. (1995) 

following the formation of 2,4-dinitrophenylhydrazone using 2,4-dinitrophenylhydrazine-impregnated 

silica cartridges. Formaldehyde has been determined in “biologicals” (vaccines) at concentrations as low 

as 100 ppb following the formation of the formaldehyde phenylhydrazone (Shrivastaw and Singh 1995). 

It was noted by the authors that this method was free from interferences from proteins and bacterial cells 

so it might have applicability to biological fluids such as blood or urine. Formic acid or formate is 

produced from formaldehyde arising from both exogenous and endogenous sources and can be measured 

as reported by Baumann and Angerer (1979). Although no literature citations were found, it would seem 

that formate in urine and blood could be determined by a method based on ion chromatography (IC). The 

measurement of formaldehyde conjugates of IgE and IgG in people exposed to formaldehyde has been 

shown (Thrasher et al. 1989), but has not resulted in a routine method. 
Table 6-1. Analytical Methods for Determining Formaldehyde and Metabolites in Biological Sam

Analytical Sample Percent 

Sample matrix Preparation method method detection limit recovery R

Venous blood Addition of water and pentafluorophenylhydrazine in dilute phosphoric acid; addition 

of a known amount of labeled formaldehyde as internal standard; equilibration for 2 hours at 50 EC; extraction with hexane/methylene chloride. 

GC/MS (SIM) No data No data H

Breath Collection of expired air into Douglas bag, 

then Tedlar bag; drawing of breath through DNPH-coated silica; elution with acetonitrile 

HPLC/UV No data 95.6 

(SD= 3.6) 

L

and addition of internal standard; evaporation of solvent and redissolution. 

Urine (rat) Dilution of urine with water, addition of 

DNPH in 2 N HCl and pentane followed by intermittent shaking for 30 minutes; extraction with additional aliquot of pentane followed by solvent evaporation; redissolution in acetonitrile. 

HPLC/UV 10 pmole/mL 

(0.3 μg/L, 0.3 ppb) 

No data 

Biologicals (vaccines) Addition of 1 mL of sample to 3 mL of 

water, addition of phenyl hydrazine, concentrated HCl, methanol, and chloroform 

Absorbance at 529 nm 

100 ng/mL (100 ppb) 

No data S

1

followed by shaking for 10–30 seconds; isolation of chloroform layer for spectrophotometric analysis. 

Blood, urine (formic acid) 

Formic acid transformed by concentrated sulfuric acid into water and carbon monoxide; carbon monoxide converted to 

GC/FID No data No data B

1

methane in chromatographic system. 
Table 6-1. Analytical Methods for Determining Formaldehyde and Metabolites in Biological Samples (

Sample matrix Preparation method 

Analytical method 

Sample detection limit 

Percent recovery R

Blood (human serum albumin-formaldehyde conjugate; IgE, IgG) 

Addition of diluted sample to coated microtiter test plates; ELISA using orthophenyldiamine as substrate. 

Absorbance at 490 nm 

No data No data T

DNPH = 2,4-dinitrophenylhydrazine; ELISA = enzyme-linked immunosorbent assay; FID = flame ionization detector; GC = gas chromHPLC = high-performance liquid chromatography; IgE = immunoglobulin E; IgG = immunoglobulin G; MS = mass spectrometry; SD SIM = selected ion monitoring; UV = ultraviolet absorbance detection
FORMALDEHYDE 320 

6. ANALYTICAL METHODS 

6.2 ENVIRONMENTAL SAMPLES 

Methods for the determination of formaldehyde in environmental samples are given in Table 6-2. 

Formaldehyde in air can be trapped using impingers filled with water (Fan and Dasgupta 1994; 

Hoogenboom et al. 1987; Petreas et al. 1986); an aqueous solution of sodium bisulfite (NIOSH 1989a; 

Petreas et al. 1986); an acidic, aqueous solution of 2,4-dinitrophenylhydrazine (DNPH) (EPA 1988d); or 

buffered Girard T reagent (NIOSH 1989b). Formaldehyde released into air from textiles has been 

collected onto moist filter paper (Naruse et al. 1995). Cofer and Edahl (1986) have reported a sampling 

device that uses a nebulization/reflux approach that is essentially a modification of the impinger device 

capable of collecting samples at high flow rates (7–8 L/minute). Formaldehyde trapped into water or 

aqueous bisulfite is subjected to chemical derivatization prior to analysis (see below). Formaldehyde 

collected into water has been shown to degrade rapidly (a 50% loss in 50 hours) upon ambient and 

refrigerated storage (Daggett and Stock 1985) while those samples in bisulfite are stable for periods 

ranging from 1 week (Daggett and Stock 1985) to 4 weeks (Balmat and Meadows 1985). The method of 

EPA (1988d) traps the formaldehyde as it reacts with DNPH to form the 2,4-dinitrophenylhydrazone 

derivative. The formation of the formaldehyde dinitrophenylhydrazone has been extended to solid-phase 

samplers including DNPH-coated silica (Grosjean et al. 1993; Millipore Corporation 1992), DNPHcoated glass fiber filters (Dalene et al. 1992), and annular denuders coated with DNPH (Possanzini et al. 

1987). These solid-phase samplers are much more convenient, especially for personal samples where 

impinger-based devices can easily be spilled. Commercially prepared DNPH-silica cartridges are 

available from Millipore Corporation (Milford, Massachusetts) and Supleco (Bellefonte, Pennsylvania). 

Nondek et al. (1991, 1992) have collected formaldehyde as dansylhydrazone through reaction of 

formaldehyde as it passed through dansylhydrazine-coated porous glass particles. Yet another approach 

is based on the collection of formaldehyde as its oxazolidine derivative using the polymeric sorbent 

XAD-2 coated with hydroxymethyl piperidine (NIOSH 1994a). A passive collection device is also 

available commercially and is based on the stabilization of formaldehyde as its adduct with sulfite after 

passage of formaldehyde through a membrane (3M Company 1985). Formaldehyde adsorbed to 

particulate matter has also been recovered using a water extraction of the particles prior to the formation 

of the DNPH derivative (NIOSH 1994b). 
Table 6-2. Analytical Methods for Determining Formaldehyde in Environmental Samp

Sample Percent 

Sample matrix Preparation method Analytical method detection limit recovery 

Air Drawing of air through two impingers in series each of 

which contains 1% sodium bisulfite. Addition of chromotropic acid and concentrated sulfuric acid, heating to 95 EC for 15 minutes, cooling to room temperature (Method 3500). 

Absorbance at 580 nm 

0.05 μg/m3 

(0.04 ppb in 100 L sample) 

No data 

Air Drawing of air through an XAD-2 sorbent coated with 

10% 2-hydroxymethyl piperidine, elution of the oxazolidine derivative with toluene (Method 2541). 

GC/FID (can use GC/NPD for improved sensitivity) 

0.028 mg/m3 

(23 ppb in 36 L sample) 

No data 

Air particulates (textile or wood) 

Drawing of air through 25 mm PVC filter (5 μm pore size), extraction of formaldehyde from particulates into water, derivatization with 2,4-dinitrophenylhydrazine (Method 5700). 

HPLC/UV 0.076 μg/m3 

(0.062 ppb) 

96 (1.1% 7 μg/sam

Air Drawing of air through a midget bubbler containing 15 

mL buffered (pH = 4.5) Girard T reagent (NIOSH 3501). 

DC polarography 0.3 mg/m3 

(0.24 ppm) 

100 

Air Preparation of passive monitor (3M 3721), 

formaldehyde in air diffuses through a membrane and adsorbs onto bisulfite-impregnated paper, desorption with water, addition of chromotropic acid and concentrated sulfuric acid. 

Absorbance at 580 nm 

<34 μg/m3 

(<0.028 ppm) 

100 (±5%

Air Drawing of sample through impinger containing 2N 

HCL/0.05% 2,4-dinitrophenylhydrazine and isooctane; removal of isooctane layer, extraction of aqueous layer with 70/30 hexane/ methylene chloride, combining of organic layers and evaporation of solvent; redissolution in methanol (TO5-1). 

HPLC/UV 1.2–2.4 μg/m3 

(1–2 ppb) 

>75 (15–20% 

Air Drawing of air through DNPH-coated silica SPE, 

elution with acetonitrile. 

HPLC/UV 0.49 μg/m3 

(0.40 ppb) 

96 (7.1% 
Table 6-2. Analytical Methods for Determining Formaldehyde in Environmental Samples (co

Sample detection Percent r

Sample matrix Preparation method Analytical method limit 

Air Drawing of air through DNPH-coated silica; elution 

with acetonitrile. 

HPLC/UV <1.2 μg/m3 

(< 1 ppb) 

>95 for sampling up to 2 L

Air (tropospheric) 

Drawing of filtered air through a nebulization/reflux concentrator (scrubber) at rate of 7–8 L/min where formaldehyde is reacted to form DNPH derivative. 

HPLC/UV 0.12 μg/m3 

(0.1 ppb) 

90–96 

Air Drawing of air through impinger filled with 1% 

sodium bisulfite; addition of CTA, concentrated 

Absorbance at 580 nm 

No data 98.7±4.7 

sulfuric acid; equilibration for 1 hour. 

Air Drawing of air through impinger containing water; 

addition of pararosaniline (PRA) hydrochloride, sodium sulfite, and equilibration for 60 minutes at 

Absorbance at 570 nm 

No data 91.9±6.9 

room temperature. 

Air Drawing of air through glass fiber filter impregnated 

with DNPH. After collection, elution of derivative with acetonitrile and elution through a cation exchange column to remove excess reagent; evaporation of solvent and redissolution in toluene containing internal standard. 

GC/TSD 10 μg/m3 

(8.1 ppb) 

92 at 600 (5% RSD

Air Drawing of air through tube that contains a smaller, 

concentric tube made of Nafion (semipermeable) through which water flows in the opposite direction and serves to trap formaldehyde; addition of 1,3-cyclohexanedione, in acidified ammonium acetate to form 

Fluorescence (FIA) 0.011 μg/m3 

(9 ppt) 

.50 (%R0.07 ppb 1.5%) 

dihydropyridine derivative in flow injection analysis system. 

Air Drawing of air through impingers containing pH 7 

phosphate buffer and EDTA; addition of bisulfite, reaction of excess bisulfite with 5,5'-dithiobis(2­nitrobenzoic acid) (indirect measure of formaldehyde). 

Absorbance at 412 nm 

12 μg/m3 

(0.01 ppm in 88 L) 

99.9 (1.7% RS
Table 6-2. Analytical Methods for Determining Formaldehyde in Environmental Samples (co

Sample detection Percent r

Sample matrix Preparation method Analytical method limit 

Air Drawing of air through microcartridges packed with 

porous glass particles impregnated with dansylhydrazine; cartridge placed in-line with HPLC mobile phase. 

online HPLC/Fluorescence 

0.01 μg/L (0.01 ppb in 1 L) 

No data 

Air (off-gassing from textiles) 

Placement of filter paper moistened with distilled water into a vial and incubation of the open vial with textiles at 40EC for 24 hours in 12.7 L chamber; 

Absorbance at 414 nm 

< 15 ppm No data 

addition to vial of solution containing ammonium acetate, water, acetic acid, and acetylacetone and incubation at 40EC for 30 min. 

Atmospheric water 

Reaction of formaldehyde in water with ammonium acetate and 2,4-pentanedione in FIA system to form 3,5-diacetyl-1,4-dihydrolutidine. 

FIA/fluorescence 3 μg/L 

(3 ppb) 

No data 

Drinking water Reaction of 1 L water with DNPH in 2M acid, 

extraction with chloroform, solvent exchange to methanol. 

HPLC/UV 20 μg/L 

(20 ppb) 

>90 at 20μg/L 

Drinking water Buffering a volume of water to pH 3 followed by 

derivatization at 40 EC for 1 hour with DNPH. Derivative recovered using C18 SPE and elution with 

methanol (Method 554). 

HPLC/UV 8.1 μg/L 96 (7.9% 

at 250 μg

Fog water Free formaldehyde: addition of 200 μL of DNPH 

solution in 2N HCl was added to 200 μL of sample followed by addition of 400 μL of iso-octane and reaction for 45 minutes; direct analysis of an aliquot of organic layer. Total formaldehyde: addition of NaOH to increase pH to 13 to decompose formaldehydebilsulfite adduct followed by addition of DNPH in 2.7 N HCl and isooctane; direct analysis of an aliquot of the organic layer. 

HPLC/UV 3 μM 

(90 ppb) 

No data (analyticvariabilitas ±1 μM
Table 6-2. Analytical Methods for Determining Formaldehyde in Environmental Samples (co

Sample detection Percent r

Sample matrix Preparation method Analytical method limit 

Maple syrup Distillation of 3 mL of water from 20 g of sample, 

addition of Nash reagent (ammonium acetate, acetic acid, acetyl acetone) followed by heating for 30 minutes at 37 EC (Method 964.21). 

Absorbance at 415 nm. 

<1 ppm (<1 mg/L) 

No data 

Milk Addition of acidified DNPH and hexane to 2 mL of 

sample, reaction with stirring for 30 minutes at room temperature; filtration through Celite, washing with hexane; evaporation of solvent; redissolution in acetonitrile. 

HPLC/UV Estimated at 

0.009 mg/kg (9 ppb) 

89.9±3.9 (0.1 μg/m

Fish flesh Heating of 100 g of fish to 200 EC and purging of 

volatiles through two impingers in series, each containing cysteamine solution; equilibration for 30 minutes to form thiazolidine derivative; extraction with methylene chloride, cleanup using silica-gel; addition of internal standard. 

GC/NPD 5.8 pg (for GC 

detection only; not a method LOD) 

No data 

Coffee Addition of 0.75 g cysteamine to 250 mL of brewed or 

reconstituted instant coffee to liquid-liquid continuous extractor; adjustment of pH to 8 and extraction with 70 mL chloroform for 3 hours; removal of water using sodium sulfate, addition of internal standard, volume 

GC/NPD No data >100 at 1 

adjustment. 

CTA = chromotropic acid; DNPH = 2,4-dinitrophenylhydrazine; EDTA = ethylene diaminetetraacetic acid; FIA = flow injection analysis; GC = gas cHPLC = high-performance liquid chromatography; LOD = level of detection; NPD =nitrogen-phosphorus detector; PRA = pararosaniline; RSD = relaSPE = solid phase extraction; TSD = thermionic specific detection; UV = ultraviolet absorbance detection 
FORMALDEHYDE 325 

6. ANALYTICAL METHODS 

Most of the measurement methods reported rely on spectrophotometry or chromatography, either GC or 

HPLC, although one of the NIOSH methods (Method 3501, NIOSH 1989b) is based on polarography. 

There are many spectrophotometric methods available. Method 3500 (NIOSH 1989a) is often used as a 

reference method during the development of new methods. This method relies on the reaction of the 

formaldehyde-bisulfite adduct with chromotropic acid (4,5-dihyroxynaphthalene-2,7-disulfonic acid) in 

the presence of concentrated sulfuric acid to form a highly colored product that is measured by its 

absorbance at 580 nm. Phenols in 8-fold excess over formaldehyde produce a -10 to -20% bias; small 

negative interferences can also result from ethanol and higher molecular-weight alcohols, olefins, 

aromatic hydrocarbons, and cyclohexanone (NIOSH 1989a). Little interference is seen from other 

aldehydes. 

The method of Fan and Dasgupta (1994) relies on the reaction of formaldehyde with 1,3-cyclohexanedione in acidified ammonium acetate to form the fluorescent dihydropyridine derivative in a flow 

injection analysis system. Formaldehyde trapped in water can be reacted with pararosaniline and sodium 

sulfite under mild conditions (neutral pH, room temperature equilibration) to produce a colored product 

that is measured at 570 nm (Petreas et al. 1986). The presence of bisulfite is an interference in this 

reaction so the method cannot be used to sample atmospheres that contain sulfur dioxide. In addition, the 

method is reported to suffer from interferences resulting from the presence of other aldehydes and phenol 

(Hoogenboom et al. 1987). The indirect method of Hoogenboom et al. (1987) relies on the reaction of 

excess bisulfite in an aqueous solution of formaldehyde with 5,5'-dithiobis(2-nitrobenzoic acid) to form a 

colored product, the absorbance of which is measured at 412 nm. The method reported by Naruse et al. 

(1995) relies on the formation of a colored product obtained by reacting the aqueous formaldehyde with 

acetylacetone and ammonium acetate in acetic acid. Absorbance is measured at 414 nm. 

The separation of dinitrophenylhydrazones using HPLC and absorbance detection is widely used for the 

measurement of formaldehyde and other carbonyl compounds (EPA 1988d; Grosjean et al. 1993; 

Millipore Corporation 1992; NIOSH 1994b). The reactivity of carbonyl compounds other than 

formaldehyde with DNPH requires the use of a chromatographic method to resolve the derivatives of the 

other compounds from that of formaldehyde. Ozone present in the atmosphere being sampled reacts with 

DNPH and the DNPH derivative of formaldehyde (Arnts and Tejada 1989), especially when using 

DNPH-coated silica gel cartridges. Ozone can be scrubbed from the sample stream by passing the air 

through a copper tube coated with potassium iodide before passing the air through the DNPH-coated 

silica (Millipore Corporation 1992). In some cases, the DNPH derivatives are separated using GC, but 
FORMALDEHYDE 326 

6. ANALYTICAL METHODS 

this mode of analysis requires an additional cleanup step to remove the excess DNPH reagent (Dalene et 

al. 1992). Caution must be used to avoid exposure of DNPH-silica cartridges or eluted samples to 

aldehyde and ketone sources. Laboratory air often holds high concentrations of acetone. Labeling inks, 

adhesives, and packaging containers (including vials with plastic caps) are all possible sources of 

contamination (Millipore Corporation 1992). Field blanks should always be used. 

Methods for the collection and determination of formaldehyde in water show great similarity to those 

methods for air described above. The methods of Tomkins et al. (1989) and EPA (1992b) for 

formaldehyde in drinking water and the method of Facchini et al. (1990) for formaldehyde in fog water 

all rely on the formation of the DNPH derivative followed by HPLC. The method of Dong and Dasgupta 

(1987) relies on the reaction of formaldehyde in atmospheric water with a diketone (2,4-pentanedione) 

and ammonium acetate to form a fluorescent derivative that is measured spectrophotometrically in a flow 

injection analysis system. 

A few methods for the determination of formaldehyde in foods were found in the literature. The method 

of Kaminski et al. (1993b) for formaldehyde in milk relies on the formation of the DNPH derivative with 

analysis by HPLC and absorbance detection. Formaldehyde in maple syrup (Helrich 1990) is determined 

spectrophotometrically after the reaction of formaldehyde with acetyl acetone (Nash reagent or 

2,4-pentanedione) in the presence of ammonium acetate in an acidic solution. Formaldehyde in fish flesh 

(Yasuhara and Shibamoto 1995) and in coffee (Hayashi et al. 1986) has been determined through the 

formation of the thiazolidine derivative (a reaction product of formaldehyde with cysteamine) followed 

by GC in conjunction with nitrogen-phosphorus detection. Yasuhara and Shibamoto (1995) noted that 

the accuracy of formaldehyde determination can be affected by the adsorption of formaldehyde onto glass 

surfaces and the generation of artificial formaldehyde during heating of nitrogen-containing compounds 

such as trimethylamine oxide. 

Two other methods for the determination of formaldehyde in gases and liquids have been described but 

are too complex, given the simplicity of the other methods available. One method is based on enzymatic 

processes (Barzana et al. 1989; Ho and Richards 1990) followed by spectrophotometry; the other is based 

on pH changes associated with formaldehyde metabolism by genetically altered cells (Korpan et al. 

1993). 
 

FORMALDEHYDE 327 

6. ANALYTICAL METHODS 

6.3 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 formaldehyde is available. Where adequate information is 

not available, ATSDR, in conjunction with the 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 formaldehyde. 

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. 

6.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. Methods for the determination of formaldehyde in blood (Heck et al. 1985), breath (Lin et al. 

1995), and urine (Shara et al. 1992) have been published. However, formaldehyde concentration in body 

fluids or expired air is not expected to be a reliable biomarker of exposure, even for acute exposure, 

because of its high reactivity and rapid metabolism. Methods for the detection of formate, the principal 

metabolite of formaldehyde, in urine are also available, but urinary levels of formate did not appear to be 

consistently associated with exposure levels in studies of students exposed to formaldehyde in anatomy 

laboratories (Einbrodt et al. 1976; Gottschling et al. 1984). One plausible contributing factor to the lack 

of consistency in the use of formate concentrations as a measure of exposure is that the metabolism of 

other chemicals can lead to the formation of formate. Further research to increase the sensitivity or 

reliability of methods to quantify formaldehyde or formate does not seem warranted. 

In contrast, DNA-protein cross links in white blood cells (Shaham et al. 1996a) and the presence of serum 

IgG antibodies to formaldehyde conjugated to human serum albumin (Carraro et al. 1997) are 
FORMALDEHYDE 328 

6. ANALYTICAL METHODS 

potentially useful biomarkers of intermediate- or chronic-duration exposure to formaldehyde that may be 

developed further with additional research. 

Methods to detect DNA-protein cross links have been published (Cohen et al. 1990; Shaham et al. 1996a; 

Zhitkovich and Costa 1992) that reportedly have greater sensitivity than earlier methods that relied on 

alkaline elution techniques (Brutlag et al. 1969). Although the formation of DNA-protein cross links is 

not specific to formaldehyde (i.e., other agents can form them), Shaham et al. (1996a) demonstrated that 

cultured human white blood cells showed increasing quantities of DNA-protein cross links when cultured 

in media with increasing formaldehyde concentrations and that a small group of formaldehyde-exposed 

persons had a significantly greater mean amount of DNA-protein cross links in their white blood cells 

than did a group of non-exposed persons. Additional research to apply these methods to larger groups of 

occupationally exposed and non-exposed persons may help to determine the reliability of this variable as 

a biomarker of exposure and to determine the extent to which individuals vary in this response to 

formaldehyde. Additional research to apply the DNA-protein cross link methods to nasal biopsy 

specimens may lead to an increased sensitivity of this potential biomarker of exposure and effect. 

Carraro et al. (1997) developed an indirect competitive immunoenzyme assay to detect serum IgG 

antibodies against formaldehyde conjugated to human serum albumin. This technique was used to 

compare the presence or absence of the antibodies in 219 healthy subjects who differed in smoking habits 

(tobacco smoke is a significant source of formaldehyde exposure) and occupational exposure to 

formaldehyde. The indirect competitive immunoenzyme assay was developed and applied as a qualitative 

method. Additional research is needed to determine if the method can be modified to provide a reliable 

and precise measure to quantify exposure level or exposure duration. 

Effect. As discussed in the previous section, DNA-protein cross links and anti-formaldehyde-human 

serum albumin IgG antibodies are potential biomarkers of effect and exposure. Whereas detection of 

these biomarkers can represent biological responses to repeated exposure to formaldehyde (the first is not 

specific to formaldehyde, but the second is), it is uncertain to what degree their detection indicates that 

adverse health effects will occur. Further research on relationships between formaldehyde-induced upper 

respiratory tract tissue damage and/or dysfunction and: (1) DNA-protein cross links in either white blood 

cells or nasal biopsy tissue; or (2) levels of formaldehyde-specific IgG antibodies may help in 

determining if improved detection methods are needed. 
 

FORMALDEHYDE 329 

6. ANALYTICAL METHODS 

Various methods have been published to examine nasal lavage fluid for cellular and chemical contents 

that may be indices of acute allergic or inflammatory responses to formaldehyde or other respiratory 

irritants (Pin et al. 1992; Prat et al. 1993; Wang et al. 1995). Increased eosinophil concentration and 

increased albumin and total protein levels have been found in nasal lavage fluid taken from subjects 

exposed to 0.4 ppm formaldehyde for 2 hours (Krakowiak et al. 1998; Pazdrak et al. 1993). Although 

these variables are not expected to be specifically influenced by formaldehyde, they appear to provide 

biomarkers of acute respiratory irritation from airborne formaldehyde or other upper respiratory irritants. 

Further research on relationships between concentrations of these variables in nasal lavage fluid and 

prevalence or severity of respiratory symptoms in humans exposed acutely to varying concentrations of 

formaldehyde may help to confirm their use as biomarkers of effect. 

Histological changes in nasal biopsy tissue samples have been observed in several cross-sectional studies 

of formaldehyde-exposed and non-exposed workers (Ballarin et al. 1992; Boysen et al. 1990; Edling et al. 

1988; Holmstrom et al. 1989c). Each of these studies used a morphological grading method that assigned 

an increasing point value for histological changes ranging in severity from loss of ciliated cells to the 

presence of malignant cells. Prevalence of different types of changes and mean histological scores were 

compared between exposed and non-exposed groups. As with the use of cellular and biochemical 

changes in nasal lavage fluid, the changes are not expected to be only due to formaldehyde, but appear to 

provide biomarkers of upper respiratory tract tissue damage. Further research on the possible progression 

of nasal tissue damage in workers with increasing duration of exposure may help in determining if 

methods for detecting and quantifying nasal epithelial tissue damage need further improvement. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Methods are available for the determination of formaldehyde in air, water, and a limited 

number of foods. Regarding methods for air, very low limits of detection (LODs) are possible. The 

chromotropic acid method (NIOSH 3500) (NIOSH 1989a) has an LOD of 0.04 ppb. Typical LODs 

possible using dinitro phenyl hydrazine (DNPH) derivatization, either from an impinger-based sample 

collection procedure or through derivatization on DNPH-coated silica, are 1–2 ppb (EPA 1988d), 0.4 

ppb (Grosjean et al. 1993), and less than 1 ppb (Millipore Corporation 1992). Other methods that 

form fluorescent derivatives, such as the method of Nondek et al. (1992), can provide greater sensitivity 

(LOD reported to be 0.01 ppb) and are applicable; however, they require specialized equipment 

not available in most laboratories. Assuming an intermediate inhalation exposure minimal 
FORMALDEHYDE 330 

6. ANALYTICAL METHODS 

risk level (MRL) of 0.01 ppm, all of the above methods are adequate. If a chronic-duration inhalation 

MRL of 0.0008 ppm (0.8 ppb) is assumed, the methods of NIOSH (1989a), Grosjean et al. (1993), and 

Nondek et al. (1992) are adequate. For monitoring of air, formaldehyde concentrations at the 

intermediate (0.01 ppm) and acute (0.05 ppm) MRLs, the above methods, in addition to those of 

Millipore Corporation (1992) and EPA (1988d), are adequate. No additional methods for formaldehyde 

in air are needed. 

Methods for the determination of formaldehyde in drinking water are available and they utilize the same 

detection methods as those utilized for the analysis of formaldehyde in air, with LODs reported to be 

20 ppb (Tomkins et al. 1989) and 8.1 ppb (EPA 1992b). The MRL for chronic oral exposure to 

formaldehyde is 0.2 mg/kg/day. If a 70-kg person is assumed, the maximum intake is 14 mg/day. If a 

daily intake of 2 L of water or 2 kg/day of food per day is assumed, then any analytical method must have 

an LOD of less than 7 mg/L for water or 7 mg/kg (ppm) for food. The cited methods for detecting 

formaldehyde in water have LODs far below the needed value and are sensitive enough to measure 

background levels in the environment; no additional methods for formaldehyde detection in water are 

required. Other than for milk (Kaminski et al. 1993b, LOD=9 ppb), no methods for formaldehyde 

detection in food were found. Additional methods for detection of formaldehyde in foods are needed. 

Methods for the detection of formaldehyde in soil are not adequately described in the available literature. 

6.3.2 Ongoing Studies 

The Environmental Health Laboratory Sciences Division of the National Center for Environmental 

Health, Centers for Disease Control and Prevention, is developing methods for the analysis of 

formaldehyde and other volatile organic compounds in blood. These methods use purge and trap 

methodology, high resolution gas chromatography, and magnetic sector mass spectrometry which gives 

detection limits in the low-parts-per-trillion (ppt) range. 

The information in Table 6-3 was found as a result of a search of Federal Research in Progress (FEDRIP 

1996). 
FORMALDEHYDE 

6. ANALYTICAL METHODS 

331 

Investigator 

Creighton University 

Albion Instruments 

Spectral Sciences, Inc. 

Southwest Sciences 

Table 6-3. Ongoing Studies on Formaldehyde 

Affiliation Research description Sponsor 

Studying products of altered 

lipid metabolism, including 

formaldehyde, associated with 

exposures to TCDD, endrin, 

and lindane in pregnant mice. 

Specifically, they are 

concerned with the exposures 

of the fetus to these products 

and will be determining 

formaldehyde concentrations 

in maternal serum and 

amniotic fluid. 

NIEHS 

Salt Lake City, 

UT 

Investigating the utility of 

solid-state lasers for 

monitoring escaped clinical 

gases. 

DHHS 

Burlington, MA Development of diode laserbased remote monitoring of 

trace gas concentrations over 

long open-air paths. 

The target analytes include 

those covered by the Clean 

Air Act (CAA), formaldehyde 

among them. 

DOE 

Santa Fe, NM Diode laser-based sensors for 

gases, including 

formaldehyde, in harsh hightemperature, high-pressure 

environments. 

DOE 

DHHS = Department of Health and Human Services; DOE = Department of Energy; NIEHS = National 

Institute of Environmental Health 

FORMALDEHYDE 333 

7. REGULATIONS AND ADVISORIES
 

The international, national, and state regulations and guidelines regarding formaldehyde in air, water, and 

other media are summarized in Table 7-1. 

ATSDR has derived an acute inhalation MRL of 0.04 ppm on the basis of clinical symptoms (increased 

itching, sneezing, mucosal congestion, transient burning sensation of the eyes and of the nasal passages) 

and nasal alterations (elevated eosinophil counts and a transient increase in albumin content of nasal 

lavage fluid) in humans (Pazdrak et al. 1993). This MRL is based on a minimal LOAEL of 0.4 ppm and 

an uncertainty factor of nine (three for use of a minimal LOAEL and three for human variability). 

An intermediate-duration inhalation MRL of 0.03 ppm was derived based on a NOAEL of 0.98 ppm and 

a LOAEL of 2.95 ppm (22 hours/day, 5 days/week for 26 weeks) for clinical signs of nasopharyngeal 

irritation (hoarseness and nasal congestion and discharge) and lesions in the nasal epithelium (squamous 

metaplasia and hyperplasia) observed in monkeys (Rusch et al 1983). An uncertainty factor of 30 (3 for 

extrapolation from animals to humans and 10 for human variability) was used to derive the MRL. 

A chronic inhalation MRL of 0.008 ppm was derived based on a minimal LOAEL of 0.24 ppm for 

histological evidence of mild damage to the nasal epithelial tissue (squamous metaplasia, loss of ciliated 

cells, goblet cell hyperplasia, and mild dysplasia in biopsied tissue) in formaldehyde exposed chemical 

workers (Holmstrom et al. 1989c). To derive the MRL, the minimal LOAEL was divided by an 

uncertainty factor of 30 (3 for the use of a minimal LOAEL and 10 for human variability). 

An intermediate oral MRL of 0.3 mg/kg/day was based on a NOAEL and LOAEL of 25 and 

125 mg/kg/day for gastrointestinal tract effects in rats exposed for 4 weeks to formaldehyde in drinking 

water (Til et al. 1988b). An uncertainty factor of 100 (10 for extrapolation from animals to humans and 

10 for human variability) was applied to the NOAEL to derive the MRL. 

ATSDR derived a chronic oral MRL of 0.2 mg/kg/day based on a NOAEL and LOAEL of 15 and 

82 mg/kg/day for gastrointestinal tract effect in rats exposed for up to 2 years to formaldehyde in drinking 

water (Til et al. 1989). An uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 

for human variability) was applied to the NOAEL to derive the MRL. 
FORMALDEHYDE 334 

7. REGULATIONS AND ADVISORIES 

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde 

Agency Description	 Information References 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenic classification 

WHO	 Drinking-water guideline values for 

health-related organics 

NATIONAL 

Regulations: 

a. Air: 

OSHA Permissible Exposure Limit (PEL) 

8-hr. Time weighted average (TWA) 

15-min. Short-term exposure limit 

(STEL) 

EPA-OAR	 Hazardous Air Pollutants 

Standards of Performance for New 

Stationary Sources 

Equipment Leaks of VOCs in the 

Synthetic Organic Chemicals 

Manufacturing Industry (SOCMI) 

VOC Emissions from SOCMI Air 

oxidation unit processes-chemicals 

affected 

VOC Emissions from SOCMI 

Distillation operation-chemical 

affected 

VOC Emissions from SOCMI Reactor 

processes-chemicals affected 

National Emission Standards for 

Organic Hazardous Air Pollution from 

the Synthetic Organic Chemical 

Manufacturing Industry-Delegation of 

Authority 

Chemical Accident Prevention 

Provisions-Regulated Toxic Substances 

and Threshold Quantities for 

Accidental Release PreventionFormaldehyde Solution 

Group 2Aa	 IARC 1995 

None	 WHO 1984 

0.75 ppm	 29 CFR 1910.1048 

OSHA 1992 

2 ppm 

Yes	 Clean Air Act 

Amendment Title 

III, Section 112 (b) 

U.S. Congress 1990 

Yes	 40 CFR 60.489 

EPA 1983a 

Yes	 40 CFR 60.617 

EPA 1990a 

Yes	 40 CFR 60.667 

EPA 1990b 

Yes	 40 CFR 60.707 

EPA 1993a 

Yes	 40 CFR 63.106 

EPA 1994a 

15,000 pounds	 40 CFR 68.130 

EPA 1994b 

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued) 

Agency Description	 Information References 

NATIONAL (cont.) 
 

 

FORMALDEHYDE 335 

7. REGULATIONS AND ADVISORIES 

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued) 

Agency Description	 Information References 

EPA-OAR	 Regulation of Fuels and Fuel AdditivesReformulated Gasoline-Simple 

Emission Model 

Complex emissions models; baseline 

exhaust emission 

Vehicle test procedures 

Measurement methods for 

formaldehyde and actelaldehyde 

Conventional gasoline baseline 

emissions determinations 

Control of Air Pollution from New and 

In-use Motor Vehicles and New and Inuse Motor Vehicle EnginesCertification and Test Procedures 

NESHAP for Source Category; Pulp 

and Paper Production (proposed rule) 

List of Regulated Substances and 

Thresholds for Accidental Release 

Prevention (proposed rule) 

Control of Air Pollution from New and 

In-use Motor Vehicles and engines; 

Technical Amendments to the Test 

Procedures for Methanol-fueled Motor 

Vehicles and Motor Vehicle Engines 

and Petroleum-fueled Motor Vehicles 

(proposed rule) 

HAP: Proposed Regulations Governing 

Constructed, Reconstructed or Modified 

Major Sources (proposed rule) 

b. Water 

EPA-OW	 Designation of Hazardous SubstancesList of Hazardous Substances, Table 

116.4 

Yes	 40 CFR 80.42 

EPA 1994c 

Phase I 40 CFR 80.45 

Summer Winter EPA 1994d 

 (mg/mile) 

4.85 7.27 

Phase II 

Summer Winter

 (mg/mile) 

9.38 15.84 

Yes	 40 CFR 80.51 

EPA 1994e 

Yes	 40 CFR 80.56 

EPA 1994f 

Yes	 40 CFR 80.90 

EPA 1994g 

Yes	 40 CFR 86 

EPA 1977a 

Yes	 58 FR 66078 

EPA 1993b 

500 pounds 58 FR 5102 

(threshold) EPA 1993c 

Yes	 58 FR 11816 

EPA 1993d 

Yes	 59 FR 15504 

EPA 1994h 

Yes	 40 CFR 116.4 

EPA 1978 

NATIONAL (cont.) 
FORMALDEHYDE 336 

7. REGULATIONS AND ADVISORIES 

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued) 

Agency Description	 Information References 

Determination of Reportable Quantities 

for Hazardous Substances- RQ Pursuant 

to Section 311 CWA, Table 117.3 

EPA Permit Programs: NPDES-Toxic 

Pollutants and Hazardous Substances 

Required to be Identified by Existing 

Dischargers if Expected to be Present, 

Table V 

Criteria and Standards for the NPDESInstructions for Form 2C, Application 

for Permit to Discharge Wastewater 

Organic Chemicals, Plastics, and 

Synthetic Fibers 

Commodity organic chemicals 

(applicability) 

c. Food: 

FDA	 Indirect Food Additives: Adhesives and 

Components of Coatings 

Indirect Food Additives: Paper and 

Paperboard 

Components of paper and paperboard 

in contact with aqueous and fatty 

foods 

Components of paper and paperboard 

in contact with dry food 

d. Other: 

EPA-OERR	 List of Hazardous Substances and 

Reportable Quantities 

EPA-OSW	 Identification and Listing of Hazardous 

Waste 

Definition of a Hazardous Waste 

Discarded commercial chemical 

products, off-specification, container 

residues, and spills 

100 pounds	 40 CFR 117.3 

EPA 1985b 

Yes	 40 CFR 122, App. 

D 

EPA 1983b 

Yes	 40 CFR 125 

EPA 1984 

Yes	 40 CFR 414.60 

EPA 1987a 

Yes	 21CFR 175.105 

FDA 1977a 

Yes	 21 CFR 176.170 

FDA 1977 b 

Yes	 21 CFR 176.180 

FDA 1977c 

1000 pounds	 40 CFR 302.4 

(453.6 kg) EPA 1985a 

(statutory) 

100 pounds 

(45.4 kg) 

(final RQ) 

Yes	 40 CFR 261.3 

EPA 1992a 

Yes	 40 CFR 261.33 

EPA 1980 
FORMALDEHYDE 337 

7. REGULATIONS AND ADVISORIES 

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued) 

Agency Description Information References 

NATIONAL (cont.) 

Basis for listing hazardous wastes- Yes 40 CFR 261, App. 

constituent for listing (K010) VII 

EPA 1981 

Basis for listing - hazardous Yes 40 CFR 261, App. 

constituent (U122) VIII 

EPA 1988b 

Standards for Management of Specific 

Hazardous Wastes Facilities 

Regulation of residues Yes 40 CFR 266.112 

EPA 1985c 

Methods Manual for Compliance Yes 40 CFR 266, App. 

with BIF Regulations (Method IX 

0011A, Analysis of Aldehydes and EPA 1991b 

Ketones by High Performance Liquid 

Chromatography) 

Land Disposal Prohibition and Yes 40 CFR 268.10 

Establishment of Treatment Standards- EPA 1986a 

Waste to be evaluated by 8/8/88 

Treatment Standards-Applicability Yes 40 CFR 268.4 

EPA 1987b 

Emergency Planning and Notification­ 100 pounds 40 CFR 355, App. 

Extremely Hazardous Substances and (RQ) A 

Their Threshold Planning Quantities EPA 1987c 

500 pounds 

(threshold) 

Toxic Chemical Release Reporting: Yes 40 CFR 372.65 

Community Right-to-Know--Specific EPA 1988c 

Chemical Listing-Chemicals and 

Chemical Categories 

Hazardous Waste Management System; 1 pound 59 FR 9808 

Carbamate Production Identification (statutory RQ) EPA 1994i 

and Listing of Hazardous Waste and 

CERCLA Hazardous Substance 

Designation and Reportable Quantities 

(notice of proposed rulemaking-K157 

waste) 

Land Disposal Restrictions for Newly Yes 62 FR 7502 

Identified and Listed Hazardous Wastes EPA 1997 

and Hazardous Soil 
 

 

FORMALDEHYDE 338 

7. REGULATIONS AND ADVISORIES 

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued) 

Agency Description	 Information References 

NATIONAL (cont.) 

Treatment standards, U122 waste Wastewater 

WETXO or CHOXD; 

CARBN; or INCIN

 Nonwastewater 

CMBST 

Guidelines: 

a. Air: 

ACGIH	 Ceiling Limit for Occupation Exposure 0.3 ppm ACGIH 1998 

(TLV-STEL) (0.37 mg/m3

) 

NIOSH	 Recommended Exposure Limit for 0.016 ppm NIOSH 1992 

Occupation Exposure (8-hr TWA) 

Recommended Exposure Limit for 0.1 ppm 

Occupation Exposure (15-min Ceiling) 

Immediately Dangerous to Life and 20 ppm 

Health 

b. Water: 

EPA 1-d Health Advisory (child)-draft 10 mg/L EPA 1995; IRIS 

1999 

10-d Health Advisory (child)-draft 5 mg/L 

Lifetime Health Advisory (adult)-draft 1 mg/L 

Longer-term Health Advisory-draft 5 mg/L (child) 

20 mg/L (adult) 

d. Other: 

ACGIH 

Group (Cancer Ranking) A2b ACGIH 1998 

EPA	 Cancer Classification B1c IRIS 1999 

RfD	 0.2 mg/kg/day 

NIOSH Cancer Classification Cad NIOSH 1992, 

1994c 

STATE 

Regulations and Guidelines: 

a.	 Air: Average Acceptable Ambient Air EPA 1992c 

Concentrations 

AZ	 1 hour 2x101

 μg/m3
 

24 hours 1.2x101 μg/m3
 
FORMALDEHYDE 339 

7. REGULATIONS AND ADVISORIES 

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued) 

Agency Description Information References 

STATE (cont.) 

Annual 8x10-2 μg/m3 

CT 8 hours 1.2x101 μg/m3 

FL-FtLdle 8 hours 1.5x10-2 μg/m3 

FL-Pinella 8 hours 4.5 μg/m3 

24 hours 1.8 μg/m3 

Annual 7.7x10-2 μg/m3 

IN 8 hours 6 μg/m3 

Annual 7.7x10-2 μg/m3 

IN-Innap 8 hours 1.8x101 μg/m3 

KS Annual 7.69x10-2 μg/m3 

KS-KC Annual 7.69x10-2 μg/m3 

LA Annual 7.69 μg/m3 

MA 24 hours 3.3x10-1 μg/m3 

Annual 8x10-2 μg/m3 

ME 15 minutes 6.7x101 μg/m3 

1 year 4x10-2 μg/m3 

MI Annual 8x10-2 μg/m3 

NC 15 minutes 1.5x10-1 μg/m3 

NC-Forco 15 minutes 1.5x101 μg/m3 

ND NA BACT 

NV 8 hours 7.1x10-2 μg/m3 

NY 1 year 5x10 μg/m3 

OK 24 hours 1.2x101 μg/m3 

PA-Phil 1 year 7.2 μg/m3 

Annual 4.82 ppb 

SC 24 hours 7.5 μg/m3 

SD 8 hours 1.2x101 μg/m3 

TX 30 minutes 1.5x101 μg/m3 

Annual 1.5 μg/m3 

VA 24 hours 1.2x101 μg/m3 

VT Annual 8x10-2 μg/m3 

WA-Olympia 5x10-2 ppm 

STATE (cont.) 
FORMALDEHYDE 340 

7. REGULATIONS AND ADVISORIES 

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued) 

Agency Description Information References 

WA-SWEST Annual 7.7x10-2 μg/m3 

b. Water 

Water Quality Criteria: Human Health 

CA Drinking water (guideline) 30 μg/L FSTRAC 1995 

MD Drinking water (guideline) 10 μg/L 

ME Drinking water (guideline) 30 μg/L 

NJ Drinking water (guideline) 100 μg/L 

a

 2A = probable human carcinogen c B1 = probable human carcinogen b

 A2 = suspected human carcinogen d Ca = potential occupational carcinogen 

BACT = Best Available Control Technology; BIF = Boilers and Industrial Furnaces; CARBN = Carbon adsorption; CERCLA = 

Comprehensive Environmental Response, Compensation, and Liability Act; CHOXD = Chemical or electrolytic oxidation; 

CMBST = Combustion; CWA = Clean Water Act; EPA = Environmental Protection Agency; FDA = Food and Drug 

Administration; FSTRAC = Federal State Toxicology and Regulatory Alliance committee; FSUBS = Fuel Substitution; HAP = 

Hazardous Air Pollutants; IARC = International Agency for Research on Cancer; INCIN = Incineration; MCLG = Maximum 

Contaminant Level Goal; NA = not applicable; NAS = National Academy of Sciences; NESHAP= National Emission Standards 

for Hazardous Air Pollutants; NIOSH = National Institute of Occupational Safety and Health; NPDES = National Pollution 

Discharge Elimination System; OAR - Office of Air and Radiation; ODW = Office of Drinking Water; OERR = Office of 

Emergency and Remedial Response; OSHA = Occupational Safety and Health Administration; OSW = Office of Solid Wastes; 

OTS = Office of Toxic Substances; PEL = Permissible Exposure Limit; RCRA = Resource Conservation and Recovery Act; RfD 

= Reference Dose; RQ = Reportable Quantities; SOCMI = Synthetic Organic Chemicals Manufacturing Industry; STEL = Shortterm exposure Limit; TLV= Threshold Limit Value; TWA = Time-weighted Average; VOC = Volatile Organic Compound; 

WHO = World Health Organization; WETOX = Wet Air Oxidation 

No acute-duration oral MRL value was derived for formaldehyde. A more detailed discussion of MRLs 

for formaldehyde is presented in Section 2.5 and in Appendix A of this profile. 

The EPA oral reference dose (RfD) for formaldehyde is 0.2 mg/kg/day for causing gastrointestinal 

damage. No reference concentration (RfC) was reported for the compound (IRIS 1999). 

The National Toxicology Program (1998) noted that formaldehyde is reasonably anticipated to be a 

human carcinogen. The International Agency for Research on Cancer (IARC) has classified 

formaldehyde as 2A, probably carcinogenic to humans, based on limited evidence of carcinogenicity in 

humans and sufficient evidence of carcinogenicity in animals (IARC 1995). The EPA has classified 

formaldehyde as a B1 compound, probable human carcinogen based on limited evidence in humans and 

sufficient evidence in animals (EPA 1991a; IRIS 1999). 
FORMALDEHYDE 341 

7. REGULATIONS AND ADVISORIES 

Formaldehyde is on the list of chemicals subject to the requirements of “The Emergency Planning and 

Community Right-to-Know act of 1986" (EPCRA) (EPA 1988a). Section 313 of Title III of EPCRA, 

requires owners and operators of certain facilities that manufacture, import, process, or otherwise use the 

chemicals on this list to report annually their release of those chemicals to any environmental media (U.S. 

Congress 1986). 

OSHA requires employers of workers who are occupationally exposed to formaldehyde to institute 

engineering controls and work practices to reduce and maintain employee exposure at or below 

permissible exposure limits (PELs). The employer must use controls and practices, if feasible, to reduce 

exposure to or below an 8-hour time-weighted average (TWA) of 0.75 ppm. The 15-minute, short-term 

exposure limit (STEL) for formaldehyde is 2 ppm (OSHA 1992). 

The EPA regulates formaldehyde under the Clean Air Act (CAA) and has designated formaldehyde as a 

hazardous air pollutant (HAP). The major source category for which formaldehyde emissions are 

controlled is the synthetic organic chemicals manufacturing industry (SOCMI)—equipment leaks, air 

oxidation unit processes, and distillation operations (EPA 1983a, 1990a, 1990b). 

Formaldehyde is regulated by the Clean Water Effluent Guidelines as stated in Title 40, Section 414, of 

the Code of Federal Regulations (EPA 1987a). The point source category for which specific Regulatory 

Limitations are listed is the waste water discharge from the manufacture of formaldehyde as a commodity 

organic chemical (EPA 1987a). The Resource Conservation and Recovery Act (RCRA) identifies 

formaldehyde as a toxic waste if it is discarded as a commercial product, manufacturing intermediate, or 

off-specification commercial chemical product. Formaldehyde is assigned the hazardous waste 

number, U122 (EPA 1980). 

Under the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), 

owners of vessels or facilities are required to immediately report release of formaldehyde equal to or 

greater than the reportable quantity of 100 pounds (45.4 kg) (EPA 1985a). When formaldehyde is used as 

a post-harvest fungicide for various raw agricultural commodities that are used only as animal feed (e.g., 

barley, corn, rye grass soybean hay, and oats), the Federal Insecticide, Fungicide, and Rodenticide Act 

(FIFRA) exempts formaldehyde from the tolerance requirement for residues in or on the commodity 

(EPA 1975). 
FORMALDEHYDE 342 

7. REGULATIONS AND ADVISORIES 

The Food and Drug Administration (FDA) identifies formaldehyde as an indirect food additive for use 

only as a component of adhesives (FDA 1977a). When used in accordance with specified conditions, the 

food additive formaldehyde may be safely used in the manufacture of animal feeds (FDA 1976). 
FORMALDEHYDE 343 

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FORMALDEHYDE 415 

9. 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 a 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 which 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. 

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. 
FORMALDEHYDE 416 

9. GLOSSARY 

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 which 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 uncertainities 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 occurrs. 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. 

FEFR25–75—Forced expiratory flowrate between 25 and 75%. 

FEV1.0—Forced expiratory volume in 1.0 seconds. 

FVC—Forced vital capacity. 

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. 
FORMALDEHYDE 417 

9. GLOSSARY 

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. 

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. 

Immunological Effects—Functional changes in the immune response. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

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 which 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 which 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. 
FORMALDEHYDE 418 

9. GLOSSARY 

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 uncertainity 

factors. The default value for a MF is 1. 

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) which 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 odds ratio of greater than 1 is considered to indicate greater risk 

of disease in the exposed group compared to the unexposed. 

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 science of quantitatively predicting 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 
FORMALDEHYDE 419 

9. GLOSSARY 

which, in general, do not represent real, identifiable anatomic regions of the body whereby the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically-based doseresponse model which quantitatively describes the relationship between target tissue dose and toxic end 

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. 

ppbv—Parts per billion by volume. 

ppmv—Parts per million by volume. 

Proportionate Mortality Ratio (PMR)—The ratio of a cause-specific mortality proportion in an 

exposed group to the mortality proportion in an unexposed group; mortality proportions may be adjusted 

for confounding variables such as age. Cause-specific mortality proportions can be calculated when the 

cohort (the population at risk) cannot be defined due to inadequate records, but the number of deaths and 

the causes of deaths are known. 

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) concentrations 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 
FORMALDEHYDE 420 

9. GLOSSARY 

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. 

Relative Risk (RR)—The risk expressed as a ratio of the incidence of diseased subjects exposed to a 

particular risk factor to the incidence of diseased subjects in a non-exposed referent group. 

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. 

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 casual 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. 

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 min 

continually. No more than four excursions are allowed per day, and there must be at least 60 min 

between exposure periods. The daily Threshold Limit Value - Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—The ratio of a cause-specific mortality rate in an exposed cohort 

during a given period to the mortality rate of an unexposed cohort; mortality rates are often adjusted for 

age or other confounding variables. 

Standardized Proportionate Incidence Ratio (SPIR)—Similar to a Proportionate Mortality Ratio 

(PMR) in that it is a ratio of a proportion of a specific disease in an exposed group compared with the 

proportion in an unexposed group. 
FORMALDEHYDE 421 

9. GLOSSARY 

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 study of the absorption, distribution and elimination of toxic compounds in the 

living organism. 

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 one can be 

used; however a reduced UF of three may be used on a case-by-case basis, three being the approximate 

logarithmic average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 
FORMALDEHYDE 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. 
FORMALDEHYDE A-2 

APPENDIX A 

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 

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 a hundredfold 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, 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, Agency for Toxic Substances and Disease 

Registry, 1600 Clifton Road, Mailstop E-29, Atlanta, Georgia 30333. 
 

[FORMALDEHYDE] A-3 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical name: Formaldehyde 

CAS number(s): 50-00-0 

Date: April 20, 1999 

Profile status: Final 

Route: [X] Inhalation [ ] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Key to figure: 15 

Species: Human 

MRL: 0.04 [ ] mg/kg/day [X] ppm [ ] mg/m3 

Reference: Pazdrak, K, Gorski, P, Krakowiak, A and Urszula, R (1993). Changes in Nasal Lavage Fluid 

Due to Formaldehyde Inhalation. Int Arch Occup Environ Health 64: 515-519. 

Experimental design: This study investigated the effects of formaldehyde exposure on the severity of 

symptoms of nasal and eye irritation and the cellular makeup of nasal discharge in occupationally 

exposed patients with skin hypersensitivity to formaldehyde and unexposed (control) patients. The study 

was comprised of 2 study groups, all of whom were non-smokers. Group 1 consisted of 7 male and 

3 female volunteers, all of whom suffered from skin hypersensitivity to formaldehyde; group 2 consisted 

of 11 healthy males with no history of allergic diseases, normal serum IgE levels, and negative skin tests 

to common allergens. Nasal washings were performed in both groups immediately before and after a 

2-hour exposure to 0 (placebo) and 0.5 mg/m3

 (0.4 ppm) formaldehyde, and at 4 and 18 hours after 

completion of the 2-hour exposure periods. Washings were analyzed for eosinophil, neutrophil, basophil, 

and mononuclear cells, and albumin content. Symptoms of irritation (number of sneezes, degree of 

mucosal edema, rhinorrhea, and itchy eyes) were evaluated through the exposure period and through 4­

and 18-hour periods after the exposure period. A symptom score was compiled for each subject by 

summation of points assigned to the following symptoms (maximum score = 7): sneezing (0 points/0 

sneezes; 1 point/1-4 sneezes; 2 points/ > 4 sneezes); rhinorrhea (0 points /none; 1 point/mild; 2 

points/abundant); mucosal edema (0 points/none; 1 point/mild; 2 points/nasal block); and itching (0 

points/none; 1 point/itchy eyes). 

Effects noted in study and corresponding doses: In both groups, placebo inhalation periods were without 

effects on nasal wash cellular contents or symptom score. During exposure to 0.4 ppm formaldehyde, 

both groups showed statistically significantly increased average symptom scores compared with average 

placebo scores (about 4 versus <0.5). Symptom scores were no longer elevated 18 hours after exposure. 

In both groups, eosinophil counts were elevated at all time points after 0.4 ppm formaldehyde exposure, 

while the proportion of epithelial cells declined after formaldehyde exposure. Albumin levels also 

increased in both groups after formaldehyde exposure, but remained elevated only briefly (10 minutes). 

There were no significant differences between allergic and healthy patients in nasal washing 

characteristics after formaldehyde exposure. No changes in basophil numbers were noted in either patient 

group and there was no evidence of mast cell degranulation. The authors concluded that the symptoms 

observed were the result of a non-specific, non-allergic process in response to low-level formaldehyde 

vapor exposure. The authors also noted that further study is required to understand the significance of the 

increased release of eosinophils noting that eosinophils may have both protective (e.g., they can neutralize 

histamine) and damaging (e.g., they may liberate mediators that damage epithelial surfaces) properties. 
[FORMALDEHYDE] A-4 

APPENDIX A 

Dose and end point used for MRL derivation: 

The only concentration tested, 0.4 ppm, is a minimal LOAEL for nasal and eye irritation 

[ ] NOAEL [X] LOAEL 

Uncertainty factors used in MRL derivation: 

[X] 3 for use of a minimal LOAEL- the observed symptoms of irritation were mild and reversible, 

and the clinical significance of the changes in nasal lavage fluid content is uncertain at present . 

[ ] 10 for extrapolation from animals to humans 

[X]	 3 for human variability - the observed symptoms of irritation were observed in a potentially 

sensitive group of subjects (they displayed dermal sensitivity to formaldehyde). 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? 

NA 

Was a conversion used from intermittent to continuous exposure? 

NA 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: 

NA 

Other additional studies or pertinent information that lend support to this MRL: 

The Anderson and Molhave (1983) study identified an apparent effect level (0.2 ppm), based on 

subjective reports of irritation that is lower than the effect levels (0.35-0.4 ppm) in the studies by Pazdrak 

et al. (1993), Krakowiak et al. (1998), and Bender et al. (1993), which used more objective measures of 

acute irritation (eosinophil counts and protein concentrations in nasal lavage fluid or time to first 

reporting of irritation: see section 2.2.1.2 Systemic Effects - Respiratory Effects Acute Controlled 

Exposure Human Studies.) Because of the use of objective measures of toxicity and the general weight of 

the available data indicating that some people will not experience eye or upper respiratory tract irritation 

from formaldehyde even at 1 ppm (see Day et al. 1984; Kulle et al. 1987, Weber Tschopp et al. 1977, and 

Witek et al. 1986), the Pazdrak et al. (1993) LOAEL of 0.4 ppm was considered a minimal LOAEL in a 

group of potentially sensitive individuals (some subjects had dermal hypersensitivity to formaldehyde) 

and selected as the basis of the acute MRL. 

Agency Contact (Chemical Manager): Sharon Wilbur 
[FORMALDEHYDE] A-5 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical name: Formaldehyde 

CAS number: 50-00-0 

Date: April 20, 1999 

Profile status: Final 

Route: [X] Inhalation [ ] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Key to figure: 49 

Species: Cynomolgus Monkey 

MRL: 0.03 [ ] mg/kg/day [X] ppm [ ] mg/m3 

Reference: Rusch, G, Clary, JJ, Rinehart WE and Bolte, HF (1983). A 26 Week Inhalation Toxicity 

Study with Formaldehyde in the Monkey, Rat and Hamster. Toxicol Appl Pharmacol 68: 329-343. 

Experimental design: Groups of 6 male Cynomolgus monkeys were exposed to 0, 0.19±0.02, 0.98±0.08, 

or 2.95±0.18 ppm for 22 hours per day, 7 days per week for 26 weeks. All monkeys were weighed and 

clinically assessed weekly. At sacrifice, adrenals, kidneys, liver, and heart were weighed. Sections of 

lung, nasal turbinate, trachea, and any other tissue with gross abnormalities were prepared for histologic 

examination. 

Effects noted in study and corresponding doses: Body weights in the monkeys were normal in all groups 

throughout the study. Monkeys in the 2.95-ppm group exhibited increasing hoarseness, nasal congestion, 

and nasal discharge, especially during the last 13 weeks of the study. While some nasal symptoms were 

noted in the 0.19- and 0.98-ppm groups, they were observed to be inconsistent and were not substantiated 

histologically. All organ weight data were unremarkable. No treatment-related effects were noted in 

internal organs upon gross inspection. A statistically significant increased incidence of squamous 

metaplasia and hyperplasia of the nasal epithelium was clearly observed in the 2.95-ppm group, but no 

significant increase in the incidence of epithelial squamous metaplasia/hyperplasia was found in the 0.19 

and 0.98-ppm groups. The response was seen most clearly in the mid-region of the nasoturbinates. No 

ultrastructural changes were noted in other sections of the turbinates, trachea, or lungs at any of the doses 

of formaldehyde tested. 

Dose and end point used for MRL derivation: 

Clinical signs of nasopharyngeal irritation (hoarseness and nasal congestion and discharge) and lesions in 

the nasal epithelium (squamous metaplasia and hyperplasia) were observed at 2.95 ppm; no effects were 

observed at 0.98 ppm. Thus, the NOAEL and LOAEL for nasopharyngeal irritation are 0.98 and 2.95 

ppm, respectively. 

[X] NOAEL [ ] LOAEL 

Uncertainty factors used in MRL derivation: 

[ ]	 10 for use of a LOAEL 

[X]	 3 for extrapolation from animals to humans - an uncertainty factor of 3 was used, instead of 10, 

because similar nasal effects have been reported at similar concentrations in different species and 

different studies indicating few pharmacodynamic differences in species susceptibility 
[FORMALDEHYDE] A-6 

APPENDIX A 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? 

NA 

Was a conversion used from intermittent to continuous exposure? 

The exposure concentration was not adjusted to a continuous exposure basis based on evidence that 

concentration is more important than the product of concentration and duration of exposure in 

determining the severity of formaldehyde-induced epithelial damage in the upper respiratory tract 

(Wilmer et al. 1987). 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: 

In the absence of reference nasal cavity surface areas and minute ventilations for Cynomolgus monkeys, a 

default regional gas dose ratio of 1 was assumed (EPA 1994). 

Other additional studies or pertinent information that lend support to this MRL: 

Although there are numerous human studies of acute inhalation toxicity from formaldehyde (controlledexposure and occupational exposure studies) and numerous investigations of toxic effects from chronic 

occupational exposures, studies of humans exposed for intermediate durations were not located. In 

contrast, the database for studies of animals (including primates) exposed by inhalation to formaldehyde 

is rich, providing data describing exposure-response relationships for formaldehyde-induced effects on 

the upper respiratory tract system in several species (rats, mice, hamsters, and monkeys) . The study by 

Rusch et al. (1983) examined a number of species and identified the lowest effect level among the 

available sets of data. Given this observation, the absence of human intermediate-duration data, and the 

putatively greater relevance of monkeys, compared with rodents, to humans, the monkey NOAEL of 0.98 

ppm and LOAEL of 2.95 ppm for clinical signs of nasopharyngeal irritation were selected as the basis of 

the intermediate-duration MRL. 

Agency Contact (Chemical Manager) : Sharon Wilbur 
 

[FORMALDEHYDE] A-7 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical name: Formaldehyde 

CAS number: 50-00-0 

Date: April 20, 1999 

Profile status: Final 

Route: [X] Inhalation [ ] Oral 

Duration: [] Acute [ ] Intermediate [X] Chronic 

Key to figure: 86 

Species: Human 

MRL: 0.008 [ ] mg/kg/day [X ] ppm [ ] mg/m3 

Reference: Holmstrom M, Wilhelmsson B, Hellquist H, et al. 1989c. Histological changes in the nasal 

mucosa in persons occupationally exposed to formaldehyde alone and in combination with wood dust. 

Acta Otolaryngol (Stockh) 107:120-129. 

Experimental design: Holmstrom et al. (1989c) examined histological changes in nasal tissue specimens 

from a group of 70 workers in a chemical plant that produced formaldehyde and formaldehyde resins for 

impregnation of paper, a group of 100 furniture factory workers working with particle board and glue 

components, and a nonexposed, control group of 36 office workers in the same village as the furniture 

factories. Mean durations of employment in the groups were 10.4 years (SD 7.3, range 1–36 years) for 

the chemical workers and 9.0 years (SD 6.3, range 1–30 years) for the furniture workers. Estimates of 

personal breathing zone air concentrations ranged from 0.04 to 0.4 ppm (median 0.24±0.13 ppm) for the 

chemical workers, from 0.16 to 0.4 ppm (median 0.20±0.04 ppm) for the furniture workers, and from 

0.07 to 0.13 ppm in the late summer for the office workers with a year-round office worker median 

reported as 0.07 ppm with no standard deviation. The mean wood dust concentration in the furniture 

factory was reported to have been between 1 and 2 mg/m3

. Nasal mucosa specimens were taken from the 

medial or inferior aspect of the middle turbinate. Histology scores were assigned to each specimen based 

on a 0–8 scale, identical to the scale used by Edling et al. (1988; described previously). Nasal mucosal 

biopsy sections for each subject were examined and assigned scores as follows: 0 - normal respiratory 

epithelium; 1- loss of ciliated epithelium cells; 2 - mixed cuboid/squamous epithelium, metaplasia; 3 ­

stratified squamous epithelium; 4 - keratosis; 5 - budding of epithelium; 6 - mild or moderate dysplasia; 7 

- severe dysplasia; and 8 - carcinoma. 

Effects noted in study and corresponding doses: Nasal histology scores ranged from 0 to 4 (mean 2.16; 

n=62) for the chemical workers, from 0 to 6 (mean 2.07; n=89) for the furniture workers, and from 0 to 4 

(mean 1.46; n=32) for the office workers. The mean histological score for the chemical workers, but not 

the furniture workers, was significantly different from the control score, thus supporting the hypothesis 

that the development of the nasal lesions is formaldehyde-related and not obligatorily related to possible 

interaction between formaldehyde and wood dust. The most severe epithelial change found (light or 

moderate epithelial dysplasia) was found in two furniture workers. Among the chemical workers (not 

exposed to wood dust), loss of cilia, goblet cell hyperplasia and cuboidal and squamous cell metaplasia 

replacing the columnar epithelium occurred more frequently than in the control group of office workers. 

Within both groups of formaldehyde-exposed workers, no evidence was found for associations between 

histological score and duration of exposure, index of accumulated dose, or smoking habit. 
[FORMALDEHYDE] A-8 

APPENDIX A 

Dose and end point used for MRL derivation: 

Clinical symptoms of mild irritation of the eyes and upper respiratory tract and mild damage to the nasal 

epithelium were observed in workers exposed for 10.4 years (range 1-36 years) to an average TWA 

concentration of 0.24 ppm (range: 0.04 to 0.4 ppm). The LOAEL of 0.24 ppm is considered to be a 

minimal LOAEL. 

[ ] NOAEL [X] LOAEL 

Uncertainty factors used in MRL derivation: 

[X] 3 for use of a LOAEL - the exposed histological effects are considered to be mild and subclinical 

in nature, suitable for 0.24 ppm to be designated as a minimal LOAEL 

[ ] 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? 

NA 

Was a conversion used from intermittent-to-continuous exposure? 

The exposure concentration was not adjusted to a continuous exposure basis based on evidence that 

concentration is more important than the product of concentration and duration of exposure in 

determining the severity of formaldehyde-induced epithelial damage in the upper respiratory tract 

(Wilmer et al. 1987). 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: 

NA 

Other additional studies or pertinent information that lend support to this MRL: 

Several cross-sectional studies of groups of formaldehyde-exposed workers chronically exposed to 

estimated concentrations ranging from about 0.1 to 0.6 ppm (Holmstrom et al. 1989c; Edling et al. 1988; 

Boysen et al. 1990; Ballarin et al. 1992) have found histological evidence for mild damage to nasal 

epithelial tissue such as the damage described for exposed workers in the Holmstrom et al. (1989c) study. 

The observed effects were consistently mild, but each study reported a statistically significant, albeit 

small, increase in average histological score (increasing scores indicating increasing severity of change) 

for exposed groups compared with nonexposed control groups: 2.8 exposed versus 1.8 on an 8-point scale 

(Edling et al., 1988); 2.16 versus 1.46 on an 8-point scale (Holmstrom et al., 1989c); 1.9 versus 1.4 on a 

5-point scale (Boysen et al., 1990); and 2.3 versus 1.6 on a 6-point scale (Ballarin et al., 1992). The 

Holmstrom et al. (1989c) study was selected as the basis of the MRL from among these four crosssectional studies (they each examined equivalent endpoints and are of similar quality of design) primarily 

because the statistically significant effects were found in a group exposed to formaldehyde in the absence 

of potentially confounding exposures to wood dust. A full uncertainty factor of 10 was used to account 

for human variability because the observed mild effects were seen in groups of chronically exposed 

workers that were otherwise in apparent good health; a healthy worker effect may have operated causing 

sensitive individuals to avoid employment in the studied workplaces. 
[FORMALDEHYDE] A-9 

APPENDIX A 

Additional supporting evidence for mild histological changes to the nasal epithelium with chronic 

exposure to concentrations below 1 ppm comes from rat studies. Although several studies of rats exposed 

for life (generally with an exposure protocol of 6 hours/day, 5 day/week) found no statistically significant 

increases in incidences of nonneoplastic lesions in the nasal epithelium of rats exposed to 0.1 to 2 ppm 

[Kerns et al. 1983b (F344 rats); Monticello et al. 1996 (F344 rats); Woutersen et al. 1989 (Wistar rats)], 

Kamata et al. (1997) reported that some F344 rats, after 28 months of exposure, displayed a mild response 

at 2 ppm and even at 0.3 ppm. A statistically significantly increased incidence for nasal epithelial 

squamous metaplasia without hyperplasia was observed in rats exposed to 2 ppm compared with control 

rats (5/32 versus 0/32); the incidence for nasal epithelial cell hyperplasia with squamous metaplasia was 

also significantly elevated compared with controls (7/32 versus 0/32). In rats exposed to 0.3 ppm, 

incidences of the same respective nasal epithelial lesions were also greater than control incidences 

(1/32 versus 0/32 and 4/32 versus 0/32), but not to a statistically significant degree. 

Agency Contact (Chemical Manager) : Sharon Wilbur 
 

[FORMALDEHYDE] A-10 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical name(s): Formaldehyde 

CAS number(s): 50-00-0 

Date: Aprile 20, 1999 

Profile status: Final 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Key to figure: 17 

Species: Rat 

MRL: 0.3 [X] mg/kg/day [ ] ppm [ ] mg/m3 

Reference: Til HP, Woutersen RA, Feron VJ, Clary JJ (1988b). Evaluation of the oral toxicity of 

acetaldehyde and formaldehyde in a 4-week drinking-water study in rats. Fd. Chem. Toxic 26: 447–452. 

Experimental design: Groups (10 males and 10 females) of weanling, SPF-bred rats (Cpb:WU; Wistar 

random) received 0, 5, 25, or 125 mg/kg/day formaldehyde in their drinking water for 4 weeks. Fresh 

formaldehyde dosing solutions were made once per week; however, the authors did not provide 

information on if or how often the dosing solutions were analyzed for actual formaldehyde content. Due 

to this procedural discrepancy, it is unclear how much formaldehyde each animal actually received in the 

drinking water, since polymerization, oxidation, or evaporation may have occurred during the study. 

Control groups (20 males and 20 females) were given unsupplemented tap water. A water-restricted 

group (10 males and 10 females) received the same amount of unsupplemented drinking water as the 

amount of liquid consumed by the group given the highest dose of formaldehyde. Rats were weighed 

weekly and observed daily for condition and behavior. Food and water intake were measured over 

weekly periods throughout the study. Hematological parameters (hemoglobin concentration, packed-cell 

volume, erythrocyte and leucocyte counts) were determined. Whole blood from fasted animals was 

examined for glucose. Blood samples were analyzed for alkaline phosphatase, aspartate 

aminotransferase, alanine aminotransferase, total protein, albumin, total bilirubin, urea, creatinine and 

calcium, inorganic phosphate, chloride, and sodium and potassium. In week 4 of treatment, rats were 

deprived of water for 24 hours and of food for 16 hours. Urine was collected during the last 16 hours of 

the deprivation period. Density and volume of urine were determined. The rats were killed in week 5, 

organs (adrenals, brain, liver, heart, kidneys, spleen, testes, thymus, thyroid, and ovaries) were weighed 

and organ-to-body weight ratios determined. Histopathological examination was performed on the liver, 

kidneys, tongue, pharynx, esophagus, stomach, and nose. The fur of rats receiving 125 mg/kg/day 

formaldehyde showed yellowish discoloration from week 3 onward. Food intake was significantly 

reduced at all dose levels for female rats. At 125 mg/kg/day formaldehyde, water intake was significantly 

reduced in both sexes; body weight was not affected. There was no effect on the density (except that in 

5 mg/kg treated males and water-restricted males, density significantly decreased) or volume of the urine 

collected. Hematological parameters showed no significant changes in animals treated with formaldehyde 

at any dose level. Male rats given 125 mg/kg/day formaldehyde showed statistically significant decrease 

in plasma protein and albumin concentrations. Female rats given 25 mg/kg/day formaldehyde showed 

statistically significant decrease in plasma alkaline phosphatase; alanine aminotransferase activities also 

decreased but was not significant. At 125 mg/kg, kidney weights in females were significantly increased. 

There were no other organ weight changes observed at any dose level, treatment-related, or 

histopathological changes in any of the tissues examined except the stomach. Necropsy findings revealed 

thickening of the limiting ridges and hyperkeratosis in the forestomach and focal atrophic inflammation in 

the glandular stomach in animals given the high concentration of formaldehyde. Moderate papillomatous 

hyperplasia was seen in one female given a high concentration of formaldehyde. Types of lesions in 
 

[FORMALDEHYDE] A-11 

APPENDIX A 

males given 125 mg/kg formaldehyde are as follows: slight-to-moderate focal hyperkeratosis of 

forestomach, slight-to-moderate focal gastritis (location in stomach not reported), and slight-to-moderate 

submucosal mononuclear-cell infiltrate (location in stomach not reported). Types of lesions in females 

given 125 mg/kg formaldehyde are as follows: very slight, slight-to-moderate focal hyperkeratosis of 

forestomach; very slight, slight-to-moderate focal gastritis (location in stomach not reported); focal 

papillomatous hyperplasia (location in stomach not reported); and polymorphonuclear leucocytic 

infiltration. 

Effects noted in study and corresponding doses: 

25 mg/kg/day: NOAEL for gastrointestinal effects. 

125 mg/kg/day: Thickening of the limiting ridges and hyperkeratosis in the forestomach and focal 

atrophic inflammation in the glandular stomach; slight-to-moderate focal hyperkeratosis of forestomach. Slight-to-moderate focal gastritis, and slight-to-moderate 

submucosal mononuclear-cell infiltrate in males (location in stomach not reported); 

very slight, slight-to-moderate focal hyperkeratosis of forestomach. Very slight, 

slight-to-moderate focal gastritis and focal papillomatous hyperplasia (location in 

stomach not reported). Polymorphonuclear leucocytic infiltration in females, 

moderate papillomatous hyperplasia in one female (less serious LOAEL). 

Dose end point used for MRL derivation: NA 

[X ] NOAEL [ ] LOAEL 25 mg/kg/day 

Uncertainty factors used in MRL derivation: 

[X] 1 [ ] 3 [ ] 10 (for use of a LOAEL)
 

[ ] 1 [ ] 3 [X] 10 (for extrapolation from animals to humans)
 

[ ] 1 [ ] 3 [X] 10 (for human variability)
 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? 

If so, explain: None 

Was a conversion used from intermittent to continuous exposure? 

If so, explain: None 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: NA 

Other additional studies or pertinent information that lend support to this MRL : Gastrointestinal irritation 

and damage have been observed in both humans and animals after ingestion of formaldehyde. In human 

poisoning studies, effects observed include: ulceration and sloughing of the soft palate and posterior 

pharyngeal wall; ulceration of the epiglottis, pyriform fossae and arytenoids; edematous and ulcerated 

esophageal mucosa with patches of black, sloughed tissue along the entire length; hyperemic areas of the 

stomach; and superficial ulceration in the distal body and antrum after a single dose of 234 mg/kg 

formaldehyde (Kochhar et al. 1986); abdominal pain and retching; hard, white and leathery stomach after 

a dose of 517 mg/kg (Burkhart et al. 1990), or abdominal pain at 624 mg/kg (Eells et al. 1981). In human 

poisoning studies in which the dose of formaldehyde is not known, gastrointestinal symptoms including 

mucosal damage, ulceration and bleeding of the buccal cavity and tonsils, and dysphagia due to 

esophageal mucosal damage (Freestone and Bentley 1989), necrosis of the esophagus and stomach, 

extensive congestion, peptic plaques in esophagus and stomach, colitis, congestion, diffuse necrosis and 
[FORMALDEHYDE] A-12 

APPENDIX A 

hemorrhage of gastric and duodenal mucosa, burns in gastrointestinal mucosa, and ileitis (Koppel et al. 

1990). In animals, gastrointestinal irritation and damage (Til et al. 1989; Tobe et al. 1989), and neoplastic 

lesions (Soffritti et al. 1989; Takahashi et al. 1986a) have been observed in other studies in which 

formaldehyde was administered orally for longer periods of time. Vargova et al. (1993) reported 

immunological effects related to formaldehyde exposure (increased relative lymph node weight and a 

decrease in combined IgM and IgG titers), while Dean et al. (1984) failed to produce observable changes 

in immunological parameters. The Vargova et al. (1993) study was not used for MRL calculation because 

actual individual IgG and IgM titers were not significantly reduced until the dose reached 40 mg/kg/day, 

and because it used a gavage method of dosing, which is less relevant to human exposure than the 

drinking water study of Til et al. (1988b). It appears from the available data that immunological changes 

resulting from formaldehyde exposure are unclear and perhaps not a viable toxicological endpoint for 

determining formaldehyde toxicity. Thus, gastrointestinal effects appear to be an appropriate indicator of 

an adverse reaction to oral exposure to formaldehyde. 

Agency Contact (Chemical Manager) : Sharon Wilbur 
 

[FORMALDEHYDE] A-13 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical name(s): Formaldehyde 

CAS number(s): 50-00-0 

Date: April 20, 1999 

Profile status: Final 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Key to figure: 38 

Species: Rat 

MRL: 0.2 [X] mg/kg/day [ ] ppm [ ] mg/m3 

Reference: Til HP, Woutersen RA, Feron VJ, Hollanders VHM, Falke HE, Clary JJ (1989). Two-year 

drinking-water study of formaldehyde in rats. Fd. Chem. Toxic 27: 77-86. 

Experimental design: Target concentrations of 5, 25, and 125 mg/kg/day formaldehyde (95% 

paraformaldehyde) were administered to groups of weanling SPF-bred rats (Cpb:WU; Wistar random) in 

their drinking water for 2 years. Actual formaldehyde concentrations reported in this study were 0, 1.2, 

15, or 82 mg/kg/day for males and 0, 1.8, 21, or 109 mg/kg/day for females when adjusted for body 

weight. Fresh formaldehyde dosing solutions were made once per week; however, the authors did not 

provide information on if or how often the dosing solutions were analyzed for actual formaldehyde 

content. Due to this procedural discrepancy, it is unclear how much formaldehyde each animal actually 

received in the drinking water, since polymerization, oxidation, or evaporation may have occurred during 

the study. Daily observations were made of the condition and behavior of the rats. Body weights were 

recorded at the start of the study, at weekly intervals in the first 12 weeks, and once every 4 weeks 

thereafter. Water intake was measured over weekly periods throughout the study and food intake was 

determined over weekly periods during the first 12 weeks, then over 2-week periods every 3 months. 

Hematological parameters (hemoglobin concentration; packed-cell volume; erythrocyte, leucocyte, and 

thrombocyte counts) were determined in weeks 26 and 103 from 10 rats/sex/group. Whole blood taken 

from 10 rats/sex/group after overnight fasting in weeks 27, 52, 78, and 104 was examined for glucose. 

Blood samples taken from 10 rats/sex/group on weeks 26, 53, 79, and 105 were analyzed for alkaline 

phosphatase, aspartate aminotransferase, alanine aminotransferase, total protein, albumin, total bilirubin, 

urea, creatinine, cholesterol, g-glutamyl transferase and calcium, inorganic phosphate, chloride, sodium, 

and potassium. Urinalysis was performed from pooled urine samples collected in weeks 27 and 104 and 

observed for protein, glucose, occult blood, ketones, urobilinogen, and bilirubin. pH determinations were 

carried out in weeks 27, 52, 78 and 104. Surviving rats of the first (10 rats/sex/group), second (10 

rats/sex/group) and third (50 rats/sex/group) subsets were killed in weeks 53, 79, and 105, respectively. 

Organs (adrenals, brain, heart, kidneys, liver, ovaries, pituitary, spleen, testes, and thyroid) were weighed 

and organ-to-body weight ratios determined. Microscopic examination was performed on the these 

organs and samples of the skin, skeletal muscle, mammary glands (females), Harderian and exorbital 

lachrymal glands, nose, lungs, aorta, parotid, submandibular and sublingual salivary glands, esophagus, 

forestomach, glandular stomach, small and large intestine, pancreas, urinary bladder, epididymides, 

prostate, uterus, sternum, mesenteric and axillary lymph nodes, spinal cord, sciatic nerve, and eye in 

control and high-dose groups. The liver, lungs, stomach, and nose of the low- and mid-dose groups were 

examined as well as the adrenals, kidneys, spleen, testes, thyroid, ovaries, and pituitary and mammary 

glands (females) of the third subset killed in week 105. Necropsies were performed on rats found dead or 

killed when moribund in the course of the study. A slight yellowing of the fur in the rats given mid- and 

high-dose levels were observed from week 3 onward; this effect was more pronounced in the high-dose 

group. Liquid consumption decreased 40% in high-dose animals of both sexes; in mid-dose groups, 
[FORMALDEHYDE] A-14 

APPENDIX A 

liquid consumption decreased as compared to controls, but the differences were not statistically 

significant. Food consumption at the high dose was significantly decreased in males but showed a less 

pronounced effect in females. The mean body weights of the high-dose group were decreased from week 

1 onward in males and from week 24 onward in females. At the end of the study, there had been a 15% 

decrease in body weight in males at the 82 mg/kg/day dose and a 10% decrease in females at the 109 

mg/kg/day dose. There were no significant differences in the hematological parameters monitored. In the 

high-dose groups, increased urine density and decreased volume of urine in males (in weeks 27 and 52) 

and females (in week 27) were observed. Occult blood was found in males of all dose groups in week 27 

and in females of the mid- and high-dose groups in week 104. Clinical chemistry variables evaluated 

between groups during weeks 53 and 105 showed no statistically significant differences and, therefore, no 

toxicological significance was attached to the slight changes in plasma alkaline phosphatase activity, total 

plasma protein content, plasma urea level, cholesterol levels, and plasma potassium concentration in 

weeks 27 and 79 of the study. Absolute heart and liver weights in high-dose males were significantly 

decreased in weeks 79 and 105, testes weight in week 79, and kidney weight in week 105. These 

decreases in weight were attributed to lower body weights of animals in this group. Relative kidney 

weight in females increased in the high-dose group in weeks 53, 79, and 105. Relative brain weight 

significantly increased in high-dose males in weeks 53, 79, and 105 and in females in week 105. Relative 

testes weight increased in the high-dose groups in week 105. Necropsy findings of high-dose rats killed 

in weeks 53, 79, and 105 revealed a raised and thickened limiting ridge of the forestomach. The limiting 

ridge of the forestomach was raised and thickened in most male and female rats of the high-dose group, 

and in some males and females of the other groups, including the control group. Also, several rats in the 

high-dose groups showed irregular mucosal thickenings in the forestomach and/or glandular stomach. 

These changes were also found in rats of the other groups as well as the control groups. The incidence of 

discoloration and an irregular surface of the kidneys, which was frequently accompanied by enlarged 

parathyroids, was lower in males of the high-dose group (12%) than in the controls (33%) in week 105. 

The incidence of testicular atrophy in the high-dose group (6%) was also remarkably low as compared to 

controls (24%). In high-dose animals, histopathological examination revealed gastric changes including 

papillary epithelial hyperplasia accompanied by hyperkeratosis and focal ulceration in the forestomach, 

and focal chronic atrophic gastritis, occasionally accompanied by ulceration and/or glandular hyperplasia, 

in the glandular stomach. Histopathological examinations of the kidneys showed that the incidence and 

degree of renal papillary necrosis increased in week 105 in high-dose animals. Non-neoplastic lesions 

found in organs other than the stomach or kidneys were not treatment-related. There were no gastric 

tumors observed apart from two benign papillomas, one in the male of the low-dose group and one in a 

female control rat. 

Effects noted in study and corresponding doses: 

15 mg/kg/day: NOAEL for gastrointestinal effects in males. 

82 mg/kg/day: gastric changes including papillary epithelial hyperplasia accompanied by 

hyperkeratosis and focal ulceration in the forestomach and focal chronic atrophic 

gastritis, occasionally accompanied by ulceration and/or glandular hyperplasia, in 

the glandular stomach (less serious LOAEL in males), and renal papillary necrosis. 

Dose end point used for MRL derivation: NA 

[X ] NOAEL [ ] LOAEL 15 mg/kg/day 

Uncertainty factors used in MRL derivation: 

[X] 1 [ ] 3 [ ] 10 (for use of a LOAEL) 
 

[FORMALDEHYDE] A-15 

APPENDIX A 

[ ] 1 [ ] 3 [X] 10 (for extrapolation from animals to humans) 

[ ] 1 [ ] 3 [X] 10 (for human variability) 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? 

If so, explain: None 

Was a conversion used from intermittent to continuous exposure? 

If so, explain: None 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: NA 

Other additional studies or pertinent information that lend support to this MRL : Gastrointestinal irritation 

and damage have been observed in both humans and animals after ingestion of formaldehyde. In human 

poisoning studies, effects observed include: ulceration and sloughing of the soft palate and posterior 

pharyngeal wall; ulceration of the epiglottis, pyriform fossae and arytenoids; edematous and ulcerated 

esophageal mucosa with patches of black, sloughed tissue along the entire length; hyperemic areas of the 

stomach; and superficial ulceration in the distal body and antrum after a single dose of 234 mg/kg 

formaldehyde (Kochhar et al. 1986); abdominal pain and retching; hard, white and leathery stomach after 

a dose of 517 mg/kg (Burkhart et al. 1990), or abdominal pain (Eells et al. 1981). In human poisoning 

studies, in which the dose of formaldehyde is usually not known with any accuracy, the gastrointestinal 

symptoms include mucosal damage, ulceration and bleeding of the buccal cavity and tonsils, and 

dysphagia due to esophageal mucosal damage (Freestone and Bentley 1989). In addition, necrosis of the 

esophagus and stomach, extensive congestion, peptic plaques in esophagus and stomach, colitis, 

congestion, diffuse necrosis and hemorrhage of gastric and duodenal mucosa, burns in gastrointestinal 

mucosa, and ileitis (Koppel et al. 1990) have also been reported. In animals, gastrointestinal irritation and 

damage also occurs, which includes thickening of the limiting ridges and hyperkeratosis in the 

forestomach and focal atrophic inflammation in the glandular stomach. In addition, slight-to-moderate 

focal hyperkeratosis of forestomach, slight-to-moderate focal gastritis, slight-to-moderate submucosal 

mononuclear-cell infiltrate (males), focal papillomatous hyperplasia, polymorphonuclear leucocytic 

infiltration (females), and moderate papillomatous hyperplasia in one female were noted in rats after 

administration of 125 mg/kg/day formaldehyde in the drinking water for 4 weeks (Til et al. 1988b). Tobe 

et al. (1989) noted forestomach hyperkeratosis in rats given 50 mg/kg/day formaldehyde in the drinking 

water for 15–24 months; neoplastic lesions (Soffritti et al. 1989; Takahashi et al. 1986a) have been 

observed in other studies in which formaldehyde was administered orally for longer periods of time. 

Thus, gastrointestinal effects appear to be an appropriate indicator of an adverse reaction to oral exposure 

to formaldehyde. 

It was also noted that the data showed that at 104 weeks of administering 15 mg/kg/day formaldehyde, 27 

male rats in the 15 mg/kg group died, which differed significantly from corresponding control values. 

However, the deaths were not dose-related, since deaths at 82 mg/kg/day were not significantly different 

from control animals. Otherwise, no toxicologically significant difference in mortality was found 

between controls and treated animals. This study was also used to derive the EPA Reference Dose (RfD) 

of 0.2 mg/kg/day, which is the same number as this chronic oral MRL. 

Agency Contact (Chemical Manager) : Sharon Wilbur 
FORMALDEHYDE 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 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables (2-1, 2-4, and 2-5) and figures (2-1 and 2-2) 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, minimal risk levels 

(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 conjunction with the text. All entries in these tables and figures 

represent studies that provide reliable, quantitative estimates of No-Observed-Adverse- Effect Levels 

(NOAELs), Lowest-Observed-Adverse-Effect Levels (LOAELs), or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 

LEGEND 

See LSE Table 2-1 

(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. When sufficient 

data exists, 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 

Table 2-1, 2-4, and 2-5, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1) 

and oral (LSE Figure 2-2) routes. Not all substances will have data on each route of exposure and 

will not therefore have all five of the tables and figures. 
FORMALDEHYDE B-2 

APPENDIX B 

(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 2 

"18r" data points in Figure 2-1). 

(5)	 Species The test species, whether animal or human, are identified in this column. Section 2.5, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and Section 

2.3, "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 regimen 

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 1,1,2,2-tetrachloroethane via inhalation 

for 6 hours per day, 5 days per week, for 3 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. 

(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, 1 systemic effect (respiratory) was investigated. 

(8)	 NOAEL A No-Observed-Adverse-Effect Level (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 Lowest-Observed-Adverse-Effect Level (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 endpoint 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 8 of the profile. 
FORMALDEHYDE B-3 

APPENDIX B 

(11)	 CEL A Cancer Effect Level (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 the NOAEL of 3 ppm in key number 18 was used to derive an 

MRL of 0.005 ppm. 

LEGEND 

See Figure 2-1 

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 intermediate and chronic 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. 

(16)	 NOAEL In this example, 18r NOAEL is the critical endpoint for which an intermediate inhalation 

exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates 

to a NOAEL for the test species-rat. 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 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The diamond 

symbol refers to a Cancer Effect Level 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 

upper-bound 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. 
SAMPLE

1 6 TABLE 2-1. Levels of Significant Exposure to [Chemical x] – Inhalat

Key to figurea Species 

Exposure frequency/ duration System 

NOAEL (ppm) Less serious (ppm) 

LOAEL (effect) 

Serious (ppm) 

2 6 INTERMEDIATE EXPOSURE 

5 6 7 8 9 

6 Systemic 9 9 9 9 9 

6 18 Rat 13 wk Resp 3b 10 (hyperplasia) 

5d/wk 6hr/d 

3 4 

CHRONIC EXPOSURE 

11 

Cancer 938 Rat 18 mo 20 (CEL, multiple 

5d/wk organs) 7hr/d 

39 Rat 89–104 wk 10 (CEL, lung tumor

5d/wk nasal tumors) 6hr/d 

40 Mouse 79–103 wk 10 (CEL, lung tumor

5d/wk hemangiosarcom6hr/d 

a The number corresponds to entries in Figure 2-1. 

6 b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 10-3 ppm; dose adjusted for intermittent e

12 an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 
13

Death Respiratory Hematological Death Respiratory Hematological HepaticReproductive Cancer

13 

SAMPLE 

Figure 2-1. Levels of Significant Exposure to [Chemical X] – Inhalation 

Acute Intermediate 

(≤14 days) (15-364 days) 

14
 15
 (ppm)
 

10000
 

1000
 

100
 

10
 16
 

1
 

0.1 

0.01 

0.001 

0.0001 

0.00001 

0.000001 

0.0000001 

Systemic Systemic 

37m 

30r 34r

17r 20m 20m 31r 35m 16r 24g 18r 22g 21r 28m 29r 27r 18r 22m 34r 33r 

18r 

* 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 end point. 

Key 

r Rat m Mouse h Rabbit g Guinea Pig k Monkey 

The number next to each point corresponds to entries in the accompanying table. 

Minimal risk level for effects other than cancer 

LOAEL for serious effects (animals) LOAEL for less serious effects (animals) NOAEL (animals) CEL - Cancer Effect Level 

38r 

40m 39r
 

10-4
 10-5
 10-6
 10-7
 
FORMALDEHYDE B-6 

APPENDIX B 

Chapter 2 (Section 2.5) 

Relevance to Public Health 

The Relevance to Public Health section provides a health effects summary based on evaluations of 

existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to present 

interpretive, weight-of-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 section covers end points in the same order they appear within the Discussion of Health Effects by 

Route of Exposure section, by route (inhalation, oral, 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 section. If data are located in the scientific literature, a table of genotoxicity information is 

included. 

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 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, we have derived minimal risk levels (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. They 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 2.5, "Relevance to 

Public Health," contains basic information known about the substance. Other sections such as 2.8, 

"Interactions with Other Substances,” and 2.9, "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 the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses for lifetime exposure (RfDs). 
FORMALDEHYDE B-7 

APPENDIX B 

To derive an MRL, ATSDR generally selects the most sensitive endpoint 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 endpoint are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest 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 LSE Tables. 

FORMALDEHYDE C-1 

APPENDIX C 

ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ADI Acceptable Daily Intake 

ADME Absorption, Distribution, Metabolism, and Excretion 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

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 

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 

CFD computational fluid dynamics 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CNS central nervous system 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

d day 

Derm dermal 

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 

DOL Department of Labor 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

DWEL Drinking Water Exposure Level 

ECD electron capture detection 
 

FORMALDEHYDE C-2 

APPENDIX C 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FDH Formaldehyde dehydrogenase 

FEFR25–75 forced expiratory flow rate between 25% and 75% FVC 

FEMA Federal Emergency Management Agency 

FEV1 forced expiratory volume in 1 second 

f-HSA formaldehyde-human serum albumin 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

ft foot 

FR Federal Register 

FVC forced vital capacity 

g gram 

GC gas chromatography 

Gd gestational day 

gen generation 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

hr hour 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IDLH Immediately Dangerous to Life and Health 

IARC International Agency for Research on Cancer 

ILO International Labor Organization 

in inch 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LCLo lethal concentration, low 

LC50 lethal concentration, 50% kill 

LDLo lethal dose, low 

LD50 lethal dose, 50% kill 

LT50 lethal time, 50% kill 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

m meter 

MA trans,trans-muconic acid 

MAL Maximum Allowable Level 
FORMALDEHYDE C-3 

APPENDIX C 

mCi millicurie 

MCL Maximum Contaminant Level 

MCLG Maximum Contaminant Level Goal 

mg milligram 

min minute 

mL milliliter 

mm millimeter 

mm Hg millimeters of mercury 

mmol millimole 

mo month 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NA/IMCO North America/International Maritime Dangerous Goods Code 

NAAQS National Ambient Air Quality Standard 

NaOH sodium hydroxide 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCI National Cancer Institute 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NFPA National Fire Protection Association 

ng nanogram 

NLM National Library of Medicine 

nm nanometer 

NHANES National Health and Nutrition Examination Survey 

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 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 
FORMALDEHYDE C-4 

APPENDIX C 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH Polycyclic Aromatic Hydrocarbon 

PBPD Physiologically Based Pharmacodynamic 

PBPK Physiologically Based Pharmacokinetic 

PCE polychromatic erythrocytes 

PEFR peak expiratory flow rate 

PEL permissible exposure limit 

PID photo ionization detector 

pg picogram 

pmol picomole 

PHS Public Health Service 

PMR proportionate mortality ratio 

ppb parts per billion 

ppbv parts per billion volume 

ppm parts per million 

ppm parts per million volume 

ppt parts per trillion 

PSNS Pretreatment Standards for New Sources 

REL recommended exposure level/limit 

RfC Reference Concentration 

RfD Reference Dose 

RNA ribonucleic acid 

RTECS Registry of Toxic Effects of Chemical Substances 

RQ Reportable Quantity 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

sd standard deviation 

sec second 

SIC Standard Industrial Classification 

SIM selected ion monitoring 

SMCL Secondary Maximum Contaminant Level 

SMR standardized mortality ratio 

SNARL Suggested No Adverse Response Level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC Total Organic Compound 

TPQ Threshold Planning Quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TRI Toxics Release Inventory 

TWA time-weighted average 

U.S. United States 

UF uncertainty factor 

UFFI urea-formaldehyde foam insulation 

VOC Volatile Organic Compound 

yr year 
FORMALDEHYDE C-5 

APPENDIX C 

WHO World Health Organization 

wk week 

> greater than 

> 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