**************************************************************

http://groups.yahoo.com/group/aspartameNM/message/1110
Toxicological Profile for Formaldehyde 2/4 plain text, 112 to 228 of 468
pages USA DHHS PHS ATSDR 1999 July: Murray 2004.08.31 rmforall

[ Rich Murray, MA Room For All rmforall@...
1943 Otowi Road, Santa Fe, New Mexico 87505 USA 505-501-2298

Comments by Rich Murray are in square brackets. I have taken some time to
provide this passable, complete plain text copy, which can be posted easily
on the Net and readily searched and copied. However, I was not able to
copy all the lengthly Figures and Tables. I have added spacing to somewhat
increase clarity, and to emphasize some points. Each section has the same
introduction and table of contents. The four sections have URLs
/1109, /1110, /1111 , /1112 in
http://groups.yahoo.com/group/aspartameNM/message/1109 ,
but are truncated in the archive to 64 KB. They are available in full at
http://health.groups.yahoo.com/group/aspartameNM/files/ and
http://health.groups.yahoo.com/group/aspartame/files/ and
bionet.neuroscience ]

http://www.atsdr.cdc.gov/toxprofiles/tp111.pdf 4 MB

TOXICOLOGICAL PROFILE FOR FORMALDEHYDE
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service Agency for Toxic Substances and Disease Registry
July 1999

[ http://groups.yahoo.com/group/aspartameNM/message/1108
faults in 1999 July EPA 468-page formaldehyde profile:
Elzbieta Skrzydlewska PhD, Assc. Prof., Medical U. of Bialystok, Poland,
abstracts -- ethanol, methanol, formaldehyde, formic acid, acetaldehyde,
lipid peroxidation, green tea, aging, Lyme disease:
Murray 2004.08.08 rmforall

http://groups.yahoo.com/group/aspartameNM/message/1106
hangover research relevant to toxicity of 11% methanol in aspartame
(formaldehyde, formic acid): Calder I (full text): Jones AW:
Murray 2004.08.09 rmforall ]

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. [ I could not locate any more recent updates
than July 1999 via Google. ]

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

[ http://www.atsdr.cdc.gov atsdric@... 888-42-ATSDR
404-498-0110 fax 404-498-0093

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

To order toxicological profiles, contact
National Technical Information Service 5285 Port Royal Road Springfield,
VA 22161 Phone: (800) 553-6847 or (703) 487-4650

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.
http://www.cdc.gov/nceh/ 888-232-6789
http://www2.cdc.gov/nceh/contactnceh/frmSubmit.asp email contact
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.
http://www.cdc.gov/niosh/homepage.html eidtechinfo@...
Contact: NIOSH, 200 Independence Avenue, SW, Washington, DC 20201 . Phone:
513-533-8328 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 fax 513-533-8573

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.
http://www.niehs.nih.gov/
Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive,
Research Triangle Park, NC 27709 . Phone: 919-541-3212.
Office of Communications 919-541-3345 TTY 919-541-0731

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
Web Page: http://www.aoec.org/ e-mail: AOEC@...

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.
http://www.acoem.org/ http://www.acoem.org/feedback/ email contact
Contact: ACOEM, 55 West Seegers Road, Arlington Heights, IL 60005
Phone: 847-818-1800 FAX: 847-818-9266. ]

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

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.

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 ix

CONTRIBUTORS

CHEMICAL MANAGER(S)/AUTHORS(S):

Sharon Wilbur, M.A. [ Not a PhD level degree ]
[ Environmental Health Scientist ]
ATSDR, Division of Toxicology, Atlanta, GA

M. Olivia Harris, M.A. [ Not a PhD level degree ]
ATSDR, Division of Toxicology, Atlanta, GA
[ Environmental Health Scientist
1600 Clifton Road NE, E29 Atlanta, GA 30333
P: 404-639-5091 F: 404-639-6315 oxh0@... ]

Peter R. McClure, Ph.D., DABT [ Veterinarian ]
Syracuse Research Corporation, North Syracuse, NY
[ Syracuse Research Corporation Environmental Science Center
301 Plainfield Road Suite 350 Syracuse, New York 13212 (315) 452 8420
mcclure@... ]

Wayne Spoo, DVM, DABT, DABVT [ Veterinarian ]
Research Triangle Institute, Research Triangle Park, NC
[ Jerry Wayne Spoo Operations Director, Life Sciences and Toxicology
919-541-6000 jwspoo@... http://www.rti.org
http://www.abvt.org/ ]

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;
[ http://www.ahf.org/contact/ 914-789-7210 914-789-7243
1 Dana Road Valhalla, NY 10595
300 E. 42nd. Street New York, NY 10017

http://www.ifcp.us/Scientists-Scientists-Carson_Conaway.cfm
Carson Clifford Conaway, Ph. D., DABT [ Veterinarian ]
Research Scientist phone: (914) 789-7210 email: cconaway@...
Institute for Cancer Prevention
In addition to his research work, Dr. Conaway is an Adjunct Associate
Professor in the Department of Pharmacology, New York Medical College. In
that capacity, he is called upon to present lectures in toxicology to
graduate students in the College of Basic Medical Sciences and in the School
of Public Health.

2. John Egle, Jr., Professor, Department of Pharmacology and Toxicology,
Medical College of Virginia, Smith Bldg., Room 656, Richmond, VA 23219; and
[ http://www.medschool.vcu.edu/ John L. Egle, Jr no longer listed. Last
PubMed study in 1995 . Studies on formaldehyde, 2 in 1974, 1 in 1972, no
PubMed abstracts for these. ]

3. Vincent Garry, Director, Environmental Medicine, University of Minnesota,
421 29th Ave., SE Minneapolis, MN 55414.

[
http://www.iatp.org/foodandhealth/library/admin/uploadedfiles/Vincent_Garry_Bio.\
pdf
Vincent F Garry Title: Professor
Department: Lab Medicine/Pathology (office: Lab Med/Pathology Department)
Dept Campus: UMN Twin Cities
E-mail Address: garry001@...
Office Address: Lab Med/Pathology Department
225 Mayo 8609 420 Delaware St SE Minneapolis, MN 55455
Campus Mail: Lab Medicine and Pathology
MMC 609 Mayo 8609 420 Delaware St SE Minneapolis, MN 55455
Office Phone: +1 612-626-3354 Fax:+1 612-626-3380
Address: 4829 Girard Ave So Minneapolis, MN 55409
Phone: +1 612-827-7316

Toxicol Appl Pharmacol. 2004 Jul 15; 198(2): 152-63.
Pesticides and children.
Garry VF.
Department of Laboratory Medicine and Pathology and Program in Toxicology,
University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.

Prevention and control of damage to health, crops, and property by insects,
fungi, and noxious weeds are the major goals of pesticide applications.
As with use of any biologically active agent, pesticides have unwanted
side-effects. In this review, we will examine the thesis that adverse
pesticide effects are more likely to occur in children who are at special
developmental and behavioral risk. Children's exposures to pesticides in the
rural and urban settings and differences in their exposure patterns are
discussed.
The relative frequency of pesticide poisoning in children is examined.
In this connection, most reported acute pesticide poisonings occur in
children younger than age 5.
The possible epidemiological relationships between parental pesticide use or
exposure and the risk of adverse reproductive outcomes and childhood cancer
are discussed.
The level of consensus among these studies is examined.
Current concerns regarding neurobehavioral toxicity and endocrine disruption
in juxtaposition to the relative paucity of toxicant mechanism-based studies
of children are explored. PMID: 15236951 ]

FORMALDEHYDE xiii

CONTENTS

FOREWORD . . . v [ text omitted ]

LEGISLATIVE BACKGROUND ...vi [ text omitted ]

QUICK REFERENCE FOR HEALTH CARE PROVIDERS . . . vii

CONTRIBUTORS . . . ix

PEER REVIEW . . . xi

CONTENTS . . . xiii

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 112 2. HEALTH EFFECTS

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

FORMALDEHYDE 113 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

FORMALDEHYDE 115 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.

FORMALDEHYDE 134 2. HEALTH EFFECTS

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

FORMALDEHYDE 135 2. HEALTH EFFECTS

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 2. HEALTH EFFECTS

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 2. HEALTH EFFECTS

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

FORMALDEHYDE 148 2. HEALTH EFFECTS

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

FORMALDEHYDE 149 2. HEALTH EFFECTS

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.

FORMALDEHYDE 150 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

FORMALDEHYDE 151 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

FORMALDEHYDE 152 2. HEALTH EFFECTS

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

FORMALDEHYDE 153 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).

FORMALDEHYDE 154 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.

FORMALDEHYDE 159 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

FORMALDEHYDE 160 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 dilu
tions 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,

FORMALDEHYDE 161 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.

FORMALDEHYDE 162 2. HEALTH EFFECTS

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-ã, 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.

FORMALDEHYDE 165 2. HEALTH EFFECTS

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

FORMALDEHYDE 166 2. HEALTH EFFECTS

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.

FORMALDEHYDE 167 2. HEALTH EFFECTS

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

FORMALDEHYDE 168 2. HEALTH EFFECTS

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

FORMALDEHYDE 169 2. HEALTH EFFECTS

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

FORMALDEHYDE 170 2. HEALTH EFFECTS

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

FORMALDEHYDE 171 2. HEALTH EFFECTS

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

FORMALDEHYDE 172 2. HEALTH EFFECTS

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

FORMALDEHYDE 173 2. HEALTH EFFECTS

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 3H-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.


FORMALDEHYDE 174 2. HEALTH EFFECTS


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 le

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