Document ID: EPA-HQ-OPP-2008-0121-0020
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2018-05-01T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC 20460

OFFICE OF           

PREVENTION, PESTICIDES,

AND TOXIC SUBSTANCES

June 30, 2008

MEMORANDUM:

Subject:	Formaldehyde:  Preliminary Risk Assessment for the Registration
Eligibility Decision (RED). DP Barcode: 348474

To:	Sharon Carlisle, Chemical Review Manager 

Antimicrobials Division

From: 	Timothy F. McMahon, Ph.D., Senior Toxicologist/Risk Assessor	

	Antimicrobials Division

	Jonathan Chen, Ph.D., Toxicologist

		Srivivas Gowda, Ph.D., Microbiologist/Chemist

		A. Najm Shamim, Ph.D., Chemist

		Richard C. Petrie, Agronomist

	Timothy C. Dole, CIH, Industrial Hygienist 

	

		Risk Assessment and Science Support Branch

	Antimicrobials Division

		

Attached is the Preliminary Risk Assessment for Formaldehyde for the
Reregistration Eligibility

Decision (RED).  The supporting disciplinary science chapters are
included as attachments

and are listed on the following page.

Supporting chapters discussed in this Risk assessment are as follows:

Formaldehyde: Revised Occupational and Residential Exposure Assessment
for the Reregistration Eligibility Decision (RED).  Timothy C.Dole, CIH.
 April 4, 2008.

Product Chemistry Chapter for the Formaldehyde Reregistration
Eligibility Decision Document (RED).  Srinivas Gowda, Microbiologist. 
January 25, 2008.D348487. 

Product Chemistry Chapter for the Paraformaldehyde Reregistration
Eligibility Decision Document (RED).  Srinivas Gowda, Microbiologist. 
January 25, 2008.D348487. 

Ecological Hazard and Environmental Risk Assessment of Formaldehyde and
Paraformaldehyde for the Reregistration Eligibility Decision (RED)
Document.  Richard C Petrie, Agronomist. January 29, 2008. D348768.

Dietary Risk Assessment for Formaldehyde for the RED Process.  A. Najm
Shamim, Ph.D., Chemist.  January 29, 2008.

Drinking Water Assessment Formaldehyde Reregistration Eligibility
Decision (RED) Process. A. Najm Shamim, Chemist. January 30, 2008.
D346239. 

Toxicology Disciplinary Chapter for the Reregistration Eligibility
Decision (RED) Document, Timothy F. McMahon, Ph.D.  January 29, 2008.

Environmental Fate Assessment of Formaldehyde for the Reregistration
Eligibility Decision (RED) Document. A. Najm Shamim, Ph.D., Chemist. 
January 23, 2008. D348766.

 

Incident Reports Associated With Formaldehyde.  Jonathan Chen, Ph.D.  
January 30, 2008. 

	 

The Antimicrobials Division, Office of Pesticide Programs, acknowledges
the assistance of the National Center for Environmental Assessment
(NCEA) in the development of this risk assessment. 

TABLE OF CONTENTS

  TOC \o "1-2" \h \z \u    HYPERLINK \l "_Toc195349007"  1.0	EXECUTIVE
SUMMARY	  PAGEREF _Toc195349007 \h  4  

  HYPERLINK \l "_Toc195349008"  2.0	PHYSICAL AND CHEMICAL PROPERTIES	 
PAGEREF _Toc195349008 \h  14  

  HYPERLINK \l "_Toc195349009"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc195349009 \h  14  

  HYPERLINK \l "_Toc195349010"  3.1	Hazard Profile	  PAGEREF
_Toc195349010 \h  14  

  HYPERLINK \l "_Toc195349011"  3.2	FQPA Considerations	  PAGEREF
_Toc195349011 \h  15  

  HYPERLINK \l "_Toc195349012"  3.3	Dose-Response Assessment	  PAGEREF
_Toc195349012 \h  16  

  HYPERLINK \l "_Toc195349013"  3.4	Endocrine Disruption	  PAGEREF
_Toc195349013 \h  19  

  HYPERLINK \l "_Toc195349014"  4.0	EXPOSURE ASSESSMENT AND
CHARACTERIZATION	  PAGEREF _Toc195349014 \h  19  

  HYPERLINK \l "_Toc195349015"  4.1	Summary of Registered Uses	  PAGEREF
_Toc195349015 \h  19  

  HYPERLINK \l "_Toc195349016"  4.2	Dietary Exposure and Risk	  PAGEREF
_Toc195349016 \h  20  

  HYPERLINK \l "_Toc195349017"  4.3	Drinking Water Exposures and Risks	 
PAGEREF _Toc195349017 \h  20  

  HYPERLINK \l "_Toc195349018"  4.4	Residential Exposure/Risk Pathway	 
PAGEREF _Toc195349018 \h  20  

  HYPERLINK \l "_Toc195349019"  5.0       AGGREGATE RISK ASSESSMENT AND
CHARACTERIZATION	  PAGEREF _Toc195349019 \h  28  

  HYPERLINK \l "_Toc195349020"  6.0	CUMULATIVE EXPOSURE AND RISK	 
PAGEREF _Toc195349020 \h  28  

  HYPERLINK \l "_Toc195349021"  7.0	OCCUPATIONAL EXPOSURE ASSESSMENT	 
PAGEREF _Toc195349021 \h  29  

  HYPERLINK \l "_Toc195349022"  7.1	Occupational Handler Exposures	 
PAGEREF _Toc195349022 \h  29  

  HYPERLINK \l "_Toc195349023"  7.2	Occupational Handler Risk Summary
and Characterization	  PAGEREF _Toc195349023 \h  33  

  HYPERLINK \l "_Toc195349024"  7.3	Occupational Post-application
Exposures	  PAGEREF _Toc195349024 \h  34  

  HYPERLINK \l "_Toc195349025"  8.0	HUMAN HEALTH RISK MITIGATION
RECOMMENDATIONS	  PAGEREF _Toc195349025 \h  35  

  HYPERLINK \l "_Toc195349026"  9.0	ENVIRONMENTAL RISKS	  PAGEREF
_Toc195349026 \h  37  

  HYPERLINK \l "_Toc195349027"  9.1	Ecological Hazard	  PAGEREF
_Toc195349027 \h  37  

  HYPERLINK \l "_Toc195349028"  9.2	Environmental Fate Assessment	 
PAGEREF _Toc195349028 \h  44  

  HYPERLINK \l "_Toc195349029"  9.3	Environmental Exposure and
Ecological Risk Assessment	  PAGEREF _Toc195349029 \h  45  

  HYPERLINK \l "_Toc195349030"  9.4	Endangered Species Considerations	 
PAGEREF _Toc195349030 \h  45  

  HYPERLINK \l "_Toc195349031"  10.0	INCIDENT REPORTS	  PAGEREF
_Toc195349031 \h  46  

  HYPERLINK \l "_Toc195349032"  11.0	REFERENCES	  PAGEREF _Toc195349032
\h  48  

 

Appendix A - Physical and Chemical Properties of Formaldehyde and
Paraformaldehyde

Appendix B - Toxicity Profile for Formaldehyde and Paraformaldehyde 

Appendix C - Mutagenicity Profile for Formaldehyde and Paraformaldehyde

1.0	EXECUTIVE SUMMARY

Introduction

Formaldehyde as an antimicrobial pesticide is used as a fumigant in
agricultural premises such as poultry and swine farms and processing
plants as well as in citrus and mushroom houses.  It is also used as a
hard surface disinfectant in commercial premises, industrial premises
and veterinary clinics.  Formaldehyde containing products are also used
in oil drilling wells for preservation of processing waters.
Formaldehyde is also registered as an in-can preservative for consumer
products such as laundry detergents, general purpose cleaners and wall
paper adhesives.  Paraformaldehyde is used for in-drawer fumigation of
hair cutting equipment and as a mildewcide in closets and unoccupied
vacation homes.  Currently, there are 6 products containing formaldehyde
as the active ingredient (a.i.) and two products containing
para-formaldehyde as the a.i..  The formaldehyde products are formulated
as liquid concentrates or liquid ready to use solutions with
formaldehyde concentrations that range from 2.28% to 54%.   The
paraformaldehyde products are formulated as solids with paraformaldehyde
concentrations of 62.3% and 91%.

Hazard Characterization

Technical grade formaldehyde (37% a.i.) has a moderate order of acute
toxicity in experimental animals via the oral and dermal routes
(Toxicity Categories II and III). Inhalation toxicity studies on
formaldehyde are extensive and include both acute exposures and longer
term exposures. Toxicity from acute exposures is characterized by
pathology of the respiratory epithelium and has been observed in rats
exposed for 4 hours to a concentration of 10 ppm (Bhalla, 1991), while
longer term exposures of rats (3 ppm for 6 hours/day for 5 days) also
results in respiratory tract lesions (Buckley et al., 1984).  Repeated
exposure to 40 ppm formaldehyde for 6 hours/day, 5 days/week for 13
weeks results in mortality in 80% of B6C3F1 mice whereas exposure to 20
ppm formaldehyde for the same time period produced no mortality
(Maronpot et al., 1986). Formaldehyde is a severe eye and skin irritant
(Toxicity Category I) and is positive for dermal sensitization.  

In one repeated dose (90 day) oral toxicity study in the rat
irritability, weight loss, hair loss, yellowing of teeth, and decreased
food consumption were observed at 0.6% formaldehyde in male Hotzman
rats.  In another 90-day oral toxicity study in the rat (Johannsen et
al.,1986), decreased body weight gain was observed at 100 mg/kg/day in
male Sprague-Dawley rats.. In a 28-day drinking water toxicity study in
rats (Til et al., 1988), decreased protein and albumin levels in blood
plasma and histologic changes were observed at 125 mg/kg/day in rats..
In a 90-day oral toxicity study in non rodents (Johannsen et al., 1986),
reduced body weight gain was observed in beagle dogs at 100 mg/kg/day. 

In a 90-day inhalation toxicity study in the rat (Woutersen et al.,
1987) a marked increase in the number of labeled nasal epithelial
showing clear squamous metaplasia and hyperplasia was observed at 12
mg/m3 formaldehyde administered 6 hours/day for 5 days/week. In another
90-day inhalation toxicity study conducted by the Chemical Industry
Institute of Toxicology, formaldehyde was administered to 20 mice and
rats at concentrations of 4, 12.7, or 38.6 ppm (4.96, 15.74 and 47.84
mg/m3, respectively), for 6hrs/day, 5 days/week for 13 weeks. The
systemic LOAEL was 12.7 ppm (15.74 mg/m3), based on body weight decrease
and nasal erosion. 

In a repeat dose toxicity study conducted by Battelle, Pacific Northwest
laboratories, B6C3F1 mice (5/sex/group) were exposed to concentrations
of 15, 25, 50, 100, and 200 ppm (18.59, 30.98, 61.96, 123.93, and 247.85
mg/m3)  vaporized formaldehyde for a period of 6 hours per day for a
total of 10 exposures.  Mortality was observed at the two highest
concentrations after only two days of exposure.  Listlessness, dyspnea,
and ocular irritation were also observed in mice at these concentrations
after two exposures. By the third exposure mice at the lowest
concentration also exhibited these clinical signs. Mild suppurative
rhinitis was observed in the 18.59 mg/m3 dose level dose level while
necrosis and sloughing of the mucosa in the turbinates, trachea, and
proximal bronchi were seen the 61.96 mg/m3 animals. 

Developmental toxicity of formaldehyde by inhalation has been examined
in the open literature.  Saillenfait et al. (1989) exposed
Sprague-Dawley rats to 5, 10, 20, and 40 ppm formaldehyde 6 hours/day on
gestation days (GDs) 6–10.Ddams exposed to 40 ppm exhibited reduced
body weight, indicative of general toxicity. This exposure concentration
also led to a significant decrease in fetal body weight (FBW). There was
also a slight, albeit statistically significant, decrease (from 5.61 to
5.35 g/litter) in male FBW in dams exposed to 20 ppm formaldehyde.   No
other significant signs of fetal malformations were reported., In a
similar study, Martin (1990) reported the effects of exposure of
Sprague-Dawley rats to 2, 5, and 10 ppm 6 hours/day on GDs 6–15. Food
consumption and dam weight gain were reduced significantly in dams
exposed to 10 ppm formaldehyde. These studies indicate that inhalation
of formaldehyde is unlikely to be teratogenic at maternally toxic doses,
although high doses may generally be fetotoxic. 

In a dermal developmental toxicity study by Overman (1984), pregnant
Syrian hamsters were administered 0.5 mL formaldehyde (37% a.i.) 2
hrs/day from gestation day 8 through 11. Treatment had no effect on
maternal weight gain. The treatment did not influence fetal C- R length.
Mean fetal weight was slightly increased in experimental animals, but
the difference was not statistically-significant. No skeletal
malformations were found and no other malformations were observed.

Reproductive toxicity of formaldehyde was examined. In one study   (MRID
00143291), formaldehyde (40% a.i.) was provided to Beagle dogs in the
diet at concentrations of 0, 3.1 or 9.4 mg/kg/day on gestation days 4
through 56. There were no formaldehyde-related effects in any of the
parameters other than   pup weights, which were lower by group in
litters of dams exposed to formaldehyde Cassidy et al. (1983)
administered single oral doses of 100 or 200 mg/kg to five male Wistar
rats/group. Testes from these animals and 20 controls were excised and
examined for spermatogenic abnormalities 11 days after dosing. Although
no significant toxicological effects of formaldehyde on total sperm
counts were observed at either tested dose, an increased incidence (19%)
of testicular sperm head counts was observed in rats exposed to 200
mg/kg-day formaldehyde. The percentage of abnormal sperm heads also
significantly increased (5%) in the 200 mg/kg-day dose group compared to
controls. These data suggest that formaldehyde can induce morphological
abnormalities in the germ cells of male experimental animals at dose
levels that did not significantly affect testis weights or sperm counts.

	Chronic toxicity and carcinogenicity of formaldehyde has been examined
in several studies.  In one study, groups of F344 rats and C57BL/6 x C3H
F1 (B6C3F1) mice (approximately 120/sex/concentration) were exposed to
0, 2.0, 5.6, and 14.3 ppm formaldehyde gas, 6 hours/day, 5 days/week for
24 months (Kearns et al, 1983). Lesions in the nasal cavity were the
primary formaldehyde related effect in both mice and rats throughout the
study.  However, examination of the histopathology tables also suggested
an increase in mouse lymphomas and rat leukemia in female animals. 

The Chemical Industry Institute of Toxicology (CIIT) performed a second
bioassay on inhaled formaldehyde in 9-week-old male F344
(CDF[F344]/CrlBr) rats (Monticello et al., 1996). The rats were exposed
6 hours/day, 5 days/week for 24 months to 0, 0.7, 2.0, 6.0, 10.0, and
15.0 ppm. Nasal neoplasms included SCC and polypoid (transitional)
adenomas and were similar in morphological characteristics to those
described in the Kerns et al. (1983) chronic bioassay. The incidence of
SCC was increased at 6 ppm and above, with a NOAEL of 2 ppm for this
effect. 

	In a chronic toxicity study in the rat (Kamata et al., 1997), male
Fischer 344 rats were exposed via the inhalation route to formaldehyde
(37% a.i.) at concentrations of 0, 0.3, 2, or 15 ppm (0, 0.4, 2.5, or 19
mg/m3), 6hr/day, 5 days/week. A highly nonlinear response for SCC and
proliferative lesions in the nasal cavity was observed in animals
exposed to 15 ppm formaldehyde, while animals in the 2 ppm group showed
a statistically significant increase in some epithelial lesions.

In studies by Hauptmann et al. (2003, 2004), retrospective cohort
mortality studies of U.S. workers involved in the production or use of
formaldehyde was examined.  These studies were   large epidemiology
studies, and provide individual quantitative exposure estimates for the
workers. The NCI cohort consisted of 25,619 workers (88% male) employed
in any of the 10 plants prior to 1966; the current follow-up analyzes
8,486 deaths (178 attributed to lymphohematopoietic malignancy and 9 to
nasopharyngeal cancer). A detailed exposure assessment was conducted for
each worker based on exposure estimates for different jobs held and
tasks performed (Stewart et al., 1986).  Exposure estimates were made
using several different metrics - peak exposures, average intensity,
cumulative exposure, and duration of exposure. Respirator use and
exposures to formaldehyde particles and other chemicals were also
considered.

Quantitative carcinogenicity assessments for formaldehyde have been
published by the U.S. EPA’s IRIS program as well as by Schlosser et
al. (2003).  The IRIS assessment in 1991 published a weight-of-evidence
characterization for carcinogenicity of formaldehyde, classifying
formaldehyde as a B1 probable human carcinogen with a potency factor of
1.3 E-5 per (μg/m3),  based on the results of Kerns et al., (1983), who
reported increased incidence of squamous cell carcinoma in the nasal
cavity of mice exposed to formaldehyde vapor at 5.6 and 14.3 ppm for 6
hours/day, 5 days/week, for 24 months.

Conolly et al. developed an innovative biologically motivated
mathematical model for formaldehyde, which coupled nasal dosimetry
simulations of formaldehyde flux and formation of DNA-protein
cross-links with formaldehyde with labeling index data statistically
fitted to tumor incidence data for Fischer 344 rats from Kerns at al.
(1983). Schlosser et al. (2003) published an analysis using benchmark
dose modeling as well as pharmacokinetic modeling to estimate human
cancer risks from exposure to formaldehyde, using the data from Kerns et
al (1983).  

Based of the on going development of the science to predict carcinogenic
potential of formaldehyde within EPA, OPP has decided to present the
formaldehyde cancer risks for the pesticidal uses using both the
existing 1991 IRIS cancer unit risk of 1.3 E-5 per (µg/m3) and the CIIT
biologically-based dose-response (BBDR) model until any new cancer
estimates are fully peer reviewed.  OPP also acknowledges the wide range
in cancer risks using these approaches and will coordinate with other
offices in EPA on the outcome of the upcoming peer review process on the
carcinogenicity of formaldehyde.  The formaldehyde IRIS assessment is
scheduled to begin internal review in May 2008 and is scheduled to start
external peer review in January 2009. Because formaldehyde air
concentrations approach those associated with ocular and respiratory
tract irritation, the risk mitigation measures to be implemented in the
meantime for the pesticidal uses will be based on mitigating the
non-cancer effects at a limit of 0.01 ppm.  It is believed that this
level will reduce exposures sufficiently such that the cancer risks
would not be of concern.  The EPA process of regulating pesticides
allows for reevaluation at any time if new information from the peer
review process of the carcinogenic potential of formaldehyde warrants.

Formaldehyde’s mutagenicity has been examined in a variety of in vitro
and in vivo test systems. In a bacterial reverse mutation test (MRID
00132156), formaldehyde (2%) was tested at concentrations of 0.001,
0.01, 0.10, 1.0, or 5.0 µL and found to be negative. In a second
submitted study (MRID 00132157), formaldehyde (2%) was tested at
concentrations of 3.0, 15.0, 75.0, 150, or 300 µg/plate and found to be
positive in the bacterial reverse mutation assay. Formaldehyde caused a
positive response (3.2-fold increase) on tester strain TA98 without
metabolic activation. A 1.9-fold increase was observed on TA98 with
metabolic activation. Also, increases of 2.2-fold and 1.7-fold were
observed on tester strain TA100 with and without activation,
respectively. In an in vitro mammalian chromosome aberration test (MRID
00132168), formaldehyde (37% formalin), was tested on Chinese hamster
ovary cells at concentrations of 28.43, 37.91, or 50.55 nL/mL. The test
article caused a significant dose-dependant increase in the frequencies
of chromosome aberrations in the Chinese Hamster Ovary cells, both with
and without S-9 activation. One submitted study (MRID 00132169), tested
formaldehyde (37%) for Unscheduled DNA synthesis (UDS) in Primary rat
liver hepatocytes. The test material was tested at concentrations of
0.0005, 0.001, 0.005, 0.01, 0.02, or 0.04 µL/mL and found to cause no
significant increase in UDS in rat hepatocytes. 

In published studies, formaldehyde has shown both positive and negative
results in the Ames Salmonella assay (Donovan et al., 1983; Connor et
al., 1983, 1985;  Frei et al., 1984; Fiddler et al., 1984; Oerstavik and
Hongslo, 1985; Takahashi et al., 1985; Schmid et al., 1986; Zielenska
and Guttenplan, 1988;  Le Curieux et al., 1993; O’Donovan and Mee
(1993) Watanabe et al., 1996; Dillon et al., 1998; Ryden et al., 2000;
Wilcox et al., 1990; Jung et al., 1992; Marnett et al., 1985; Mueller et
al., 1993).

Temcharoen and Thilly (1983) examined the capacity of formaldehyde to
induce forward mutations to 8-azaguanine resistance in S. typhimurium TM
677, a his+ revertant of TA 1535. Both toxicity and mutagenicity were
obtained at formaldehyde concentrations of 0.17 mM in the absence of S9
and 0.33 mM in the presence of S9 Dillon et al. (1998) employed
Salmonella strains TA102 and TA104 because they are more sensitive to
oxidative mutagens. Formaldehyde was mutagenic in both strains, as well
as in TA100. However, the authors reported that the mutagenic activity
was not reduced in TA104 in the presence of S9 from either
Aroclor-induced male Fischer F 344 rats or male B6C3F1 mice. 

In another study, formaldehyde induced forward mutations to
trifluorothymidine resistance in mouse lymphoma L5178Y tk+/- cells both
in the absence and presence of rat liver S9 (higher concentrations
required for effect with S9). Both toxicity and mutagenicity were
abolished when formaldehyde dehydrogenase was incorporated in the
exposure medium (Blackburn et al., 1991).

Ross and Shipley (1980) used a [14C]-thymidine-incorporated mouse L1210
cell line to monitor formaldehyde-induced DNA strand breaks and DPX.
Single strand breaks (SSB) and DNA-protein cross links   were induced by
formaldehyde, with SSB at concentrations greater than 200 M and a
reduction of radiation-induced breaks (indirect measure of DPX) at 50
M. Formaldehyde-induced DPX were repaired 24 hours after the compound
was removed from the culture.

	

In vivo, no treatment-related increases in either micronuclei or
chromosome aberrations were observed following intraperitoneal exposure
to formaldehyde at 0, 6.25, 12.5, or 25 mg/kg. (Natarajan et al.1983). 
Similarly, chromosomal analysis of spermatocytes at metaphase I did not
reveal any chromosomal lesions in Q strain mice injected
intraperitoneally with 50 mg/kg of the compound (Fontignie-Houbrechts,
1981).   Exposure of male and female Fischer F-344 rats to 0.5, 6, or 15
ppm (0.6, 7.4, 18.5 mg/m3) formaldehyde by inhalation for 6 hours/day
for 5 days showed no increases in either SCE or chromosome aberrations
at any dose level (Kligerman et al. (1984) )  . 

In a neurotoxicity screening battery (Malek et al., 2003a), rats were
exposed to 0, 1.0, 2.5, or 5.0 ppm (0, 1.23, 3.08, or 6.15 mg/m3)
formaldehyde for 2 hours and locomotor activity was assessed for 1 hour
in an open field 2 and 24 hours after termination of formaldehyde
exposure. Reductions in horizontal movements (crossed quadrants) were
observed after two hours at 1.0 ppm. In another neurotoxicity study
(Malek et al., 2003b), rats (10 per group) were exposed at 0, 0.1, 0.5,
or 5.0 ppm (0, 0.123, 0.615, or 6.15 mg/m3) formaldehyde for 2 hours and
open field behavior tests were conducted on each animal 2 hours after
formaldehyde exposure. Significant reductions in motor activity in males
were observed at 1.0 ppm after 2 hours. In a third neurotoxicity study
(Pitten et al., 2000), adult male Wistar rats were exposed to 0 ppm, 2.6
ppm (0.25% formaldehyde solution to yield 3.06 ± 0.77 mg/m3 ), or 4.6
ppm (0.70% formaldehyde solution to yield 5.55 ± 1.27 mg/m3)
formaldehyde, 10 minutes/day, 7 days/week for 90 days. The animals were
assessed for performance in the maze every seventh day, at least 22
hours after the exposure on the previous day.  Neurotoxicity was
observed at 2.6 ppm,   based on statistically significant performance
errors as compared to the control group and increased run times through
the maze. In a behavioral and neurotoxicity study conducted by Boja et
al., 1985, Sprague-Dawley rats were exposed to either air or
formaldehyde at concentrations of 5, 10, or 20 ppm (6.20, 12.39, or
24.79 mg/m3) via inhalation for 3 hours on two days. Exposure to 5 ppm
(6.20 mg/m3) formaldehyde resulted in statistically significant
decreased motor activity within 15 minutes 

From the ATSDR Toxicological review on formaldehyde (ATSDR, 1999),
formaldehyde is rapidly metabolized primarily by formaldehyde
dehydrogenase, a widely distributed enzyme present in all tissues,
particularly nasal mucosa. Unmetabolized formaldehyde can form
cross-links between proteins and between protein and DNA. Jeffcoat et
al. (1983) examined disposition of dermally applied formaldehyde in
rats, guinea pigs, and monkeys and observed between 5-8% excretion in
urine of rats and guinea pigs and 0.7-1.5% excretion in feces. Excretion
in monkeys was less than 1% of the applied dose by all routes. Trapped
expired air constituted the largest percentage of excretion in rats and
guinea pigs (21-24% of the administered dose).

FQPA Safety Factor

There are no tolerances for formaldehyde or paraformaldehyde and the use
patterns considered for the reregistration eligibility decision do not
involve dietary exposure.  As a result, a FQPA safety finding is not
applicable.

Dose-Response Assessment

	

Acute and chronic dietary endpoints were not selected for formaldehyde
as the registered uses do not involve dietary exposure.  

Incidental oral endpoints were also not selected for formaldehyde.
Formaldehyde is highly volatile with a low percentage of active
ingredient in those products with residential exposures (laundry
detergents, general household cleaners) and residues available for
incidental oral exposure are not expected to occur.  An accidental
ingestion is considered a misuse and is not a regulatory endpoint.
Therefore, no incidental oral endpoint was selected.  

Dermal endpoints were not selected for formaldehyde for the registered
antimicrobial uses. Residential uses do not involve purposeful contact
with the skin.  Use in laundry detergents and household cleaners is not
expected to result in any significant dermal exposure based on the high
water solubility of formaldehyde and the volatility of the active
ingredient. 

Inhalation exposure is considered a major route of exposure to
formaldehyde for which toxicity endpoints were selected.  For assessment
of non-cancer risk, a value of 0.1 ppm was selected for all durations of
exposure based on both the 2001 ACGIH TLV documentation as well as
published scientific studies on effect levels in humans from
occupational exposures. A Margin of Exposure of 1 was determined to be
adequate for occupational risk assessments.  For residential risk
assessments, a Margin of Exposure of 10 was applied to the 0.1 ppm
endpoint.  The common effects of formaldehyde exposure are various
symptoms as a result of irritation of the mucosa in the eyes and upper
airways. In the non-industrial indoor environment, sensory reactions are
typical effects, but there are large individual differences in the
normal population and between hyper-reactive and sensitized people. 
Thus, the Margin of Exposure of 10 is for intra-species variation. 

In response to comments made by the Formaldehyde Council, additional
characterization was made regarding the selection of the 0.1 ppm
non-cancer inhalation endpoint. This additional characterization is
found in the une 24, 2008 report of the Antimicrobials Division Toxicity
Endpoint Committee. 

	 

Residential Exposure and Risk 

There is one product containing formaldehyde that is labeled for use as
in can preservative of consumer products such as laundry detergents,
general purpose cleaners and wall paper adhesives.   There is also one
paraformaldehyde mildewcide product that is labeled for treatment of
closets and vacation homes.  Residential handler inhalation exposures
were assessed for handlers of formaldehyde treated laundry detergent,
general purpose cleaners and wall paper adhesives.  Post application
inhalation exposures were assessed for formaldehyde treated wall paper
adhesive and for the use of paraformaldehyde mildewcide. 

Residential Handler Risk Estimates

The EPA’s Consumer Exposure Module (CEM) was used to estimate air
concentrations resulting from the use of laundry detergent and general
purpose cleaner preserved with formaldehyde. The margin of exposure
(MOE) for peak exposure is 0.4 for the laundry detergent scenario and
0.8 for the general purpose cleaner scenario. Both of these MOEs are
less than the target MOE of 10 and are of concern.   The estimated
cancer risk for the laundry detergent scenario ranges from <3 x 10-9
when using the CIIT model to 8 x 10-6 when using the IRIS unit risk. 
The estimated cancer risk for the general purpose cleaner scenario
ranges from <3 x 10-9 when using the CIIT model to 2 x 10-6 when using
the IRIS unit risk.

The EPA’s Wall Paint Exposure Model (WPEM) was used to estimate
handler inhalation exposures resulting from the use of wall paper
adhesive preserved with formaldehyde.  The MOE for peak exposure is 6.7
and is of concern.  The estimated cancer risk ranges from 

<3 x 10-9 when using the CIIT model to 7 x 10-7 when using the IRIS unit
risk.

Residential Post Application Inhalation Risk Estimates

The EPA’s Wall Paint Exposure Model (WPEM) was used to estimate post
application exposures resulting from the use of wall paper adhesive
preserved with formaldehyde.  The MOE for peak exposure is 20 and is not
of concern. The estimated cancer risk ranges from 

<3 x 10-9 when using the CIIT model to 6 x 10-7 when using the IRIS unit
risk. 

The EPA’s Consumer Exposure Module (CEM) was used to estimate post
application inhalation exposures resulting from the use of
paraformaldehyde mildewcide in closets of occupied homes.   The MOE for
the mildewcide use is less than 0.1, which is below the target MOE and
is of concern.  The estimated cancer risk ranges from <8 x 10-7 when
using the CIIT model to 3 x 10-3 when using the IRIS unit risk.

Residential Risk Characterization

The non-cancer risk estimates are based upon EPA exposure models which
are generally believed to be conservative.   The fact that the vapor
pressure of 1.0 mm hg, which is based on formaldehyde in formalin, was
used in these models rather than the vapor pressure of pure
formaldehyde, which exists only as gas, is a source of uncertainty. 
There are also uncertainties regarding the use of the WPEM model because
it is based on test data for paint solvents that have different
physical/chemical properties than formaldehyde.

The IRIS cancer risk estimates provide an upper-bound on risk. In
addition, the cancer risks are conservative because they are based on
100 percent market penetration.  Information regarding market
penetration could be used to further characterize the cancer risks.   

Aggregate Exposure and Risk

In order for a pesticide registration to continue, it must be shown
“that there is reasonable certainty that no harm will result from
aggregate exposure to pesticide chemical residue, including all
anticipated dietary exposures and other exposures for which there are
reliable information.”  Aggregate exposure is the total exposure to a
single chemical (or its residues) that may occur from dietary (i.e.,
food and drinking water), residential, and other non-occupational
sources, and from all known or plausible exposure routes (oral, dermal,
and inhalation).  

	Acute and chronic dietary aggregate assessments were not conducted for
formaldehyde because there are no uses for formaldehyde attributable to
the dietary route of exposure. 

Occupational Exposure and Risk

Occupational Handler Exposures

Because formaldehyde has a high vapor pressure (1.0 mm Hg in formalin),
the inhalation unit exposure data from PHED and CMA are generally not
applicable.   Although there are many studies of formaldehyde
occupational exposures reported in the literature, these studies
involved the non-biocidal uses and there is very little information
concerning exposures from the biocidal uses. Since it was not possible
to quantitatively assess the formaldehyde exposures that result from
biocide uses, a qualitative assessment was done based upon work
practices listed on the labels. In general, it was determined for these
scenarios that if the label requirements such as closed system loading,
remote application and adequate ventilation are followed, exposures
would be reduced to levels that are not of concern.  Wall paper adhesive
application was assessed using the WPEM model.  The MOE for non-cancer
risk is 1.6 which is above the target MOE of 1 and is thus not of
concern. The estimated cancer risk ranges from <1 x 10-8 when using the
CIIT model to 6 x 10-5 when using the IRIS unit risk.  

Occupational Post Application Exposures

Formaldehyde is used for fumigating poultry and swine containment
buildings and post application exposure can occur when the workers
re-enter the fumigated areas. These exposures were assessed using the
single chamber decay formula from the Multi-Chamber Concentration and
Exposure Model (MCCEM) and a ventilation rate of 4 air changes per hour.
The ventilation rate is based upon poultry and animal housing design
criteria.  Given these conditions, the formaldehyde air concentration
declines from the application rate of 25,000 ppm to 0.1 ppm after 183
minutes. 

Human Health Risk Mitigation

Formaldehyde Residential Risk Mitigation 

	The only available option to mitigate the residential risks arising
from the use of formaldehyde as a preservative is the reduction of the
treatment rates.  The non-cancer risks require product rate reductions
to 40, 72 and 67 ppm for the laundry detergent, general purpose cleaner
and wall paper adhesive handler scenarios, respectively to achieve the
target MOE of 10.  The non-cancer risk for the wall paper post
application scenario does not require a product rate reduction.   The
cancer risks may or may not require mitigation depending on which
approach is used and which cancer risk target is selected.   Even if the
most conservative approach is taken, however, and the mitigation is
based in the IRIS cancer risk with a risk target of 1 x 10-6, the
required mitigation would be less than that required for non-cancer
risks.   

Formaldehyde Occupational Risks Mitigation

	Formaldehyde should be only be used with appropriate work practices and
engineering controls such that exposures do not exceed the EPA level of
concern of 0.1 ppm. This can be accomplished by one or more of the
following:

The open pouring of formaldehyde solutions should be minimized to low
volume applications. Automatic addition systems that minimize operator
exposure to the concentrated product should be used when handling larger
amounts of formaldehyde. If this is not feasible then local exhaust
ventilation should be used to reduce formaldehyde exposure.

Fogging of poultry houses should only be done in such a way that the
operator is outside the poultry house when applying the fog. 

The labels should be updated to eliminate cloth, mop or spray
applications of formaldehyde.

Paraformaldehyde Risks

To mitigate the occupational risks from paraformaldehyde use in beauty
salons and barber shops, it is recommended that these areas have general
ventilation that meets ASHRAE recommendations and/or local exhaust
ventilation that meets ACGIH recommendations.

To mitigate the residential risks from paraformadehyde use in closets
and vacation homes it is recommended that these uses be limited to
unoccupied areas that can be thoroughly ventilated prior to
re-occupancy. 

Environmental Hazard and Risk

Formaldehyde and paraformaldehyde labeled uses including oilfield uses
such as treatments of drilling muds and waterfloods are considered by AD
to pose little adverse risk to non-target organisms or listed species.
Antimicrobials are typically minor use chemicals, diluted and greatly
reduced before discharge into water, and are often regulated by other
Federal or EPA offices (OW, Office of Solid Waste, OPPTS, state NPDES
permits). In the case of oil fields, the US Department of the Interior,
Minerals Management Service (MMS) had jurisdiction over the
environmental impacts of synthetic drilling fluids in terrestrial and
aquatic areas.  

Terrestrial oil fields typically use berms and catch basins to prevent
surface runoff of oil drilling muds and wastes from oil drilling areas.
Estuarine and marine aquatic organisms may be temporarily exposed during
marine drilling, however, impacts are limited to a defined area around
the oil well (Neff, 2000).  

The AD hazard labeling review for low environmental exposure sites and
terrestrial oilfield pesticides requires the submission of three
ecotoxicity tests: one acute oral bird, one acute freshwater fish, and
one acute freshwater aquatic invertebrate. If the pesticide is to be
used in estuarine or marine environments, three additional acute
estuarine/marine toxicity studies are required. The ecological hazard
assessment has determined that formaldehyde product labels must state:
“This product is toxic to oysters.” 

Endangered Species

For certain use categories, including all current formaldehyde and
paraformaldehyde uses, the Agency assumes there will be minimal
environmental exposure, and only a minimal toxicity data set is required
(Overview of the Ecological Risk Assessment Process in the Office of
Pesticide Programs U.S. Environmental Protection Agency - Endangered and
Threatened Species Effects Determinations, 1/23/04, Appendix A, Section
IIB, p 81). Uses in these categories do not undergo a full
screening-level risk assessment and are considered to generally fall
under a “no effect” determination, however, an endangered species
effect determination will not be made at this time

Incident Reports

There are many reported incidents associated with formaldehyde exposure,
but only a limited few are associated with its use as an antimicrobial
agent (biocide). Formaldehyde is a dermal irritant and a dermal
sensitizer. The primary dermal effects that have been reported are rash,
burning sensation, itching, dry scaling irritation, cracking and
thickened skin, itching, and blisters and rash on hands. Symptoms
associated with eyes are the primary reported illness in all associated
incidences. Nausea, dizziness, headache, and sore throat are the primary
systemic effects that have been reported. Allergic reactions and
asthma-like conditions also have been reported following occupational
exposures. Only limited acute cases with oral exposure to formaldehyde
have been published in scientific literature. Formaldehyde has been
demonstrated to be genotoxic in many reported epidemiological studies.
Formaldehyde exposure has been associated with respiratory cancer
(especially nasopharyngeal cancer), leukemia, and other nonrespiratory
cancers in humans. 2.0	PHYSICAL AND CHEMICAL PROPERTIES

The chemical identities of formaldehyde and paraformaldehyde are listed
in Table 2.1. 

Table 2.1   Chemical Identity of Formaldehyde and Paraformaldehyde

Parameter	Formaldehyde	Paraformaldehyde

PC Chemical Code	043001	043002

CAS Number	50-00-0	30525-89-4

Molecular Formula	CH2O (Gas or anhydrous form)

H2C(OH)2 or C1H4O2 (Formaldehyde monohydrate)	HO(CH2O)nH (n = 6 - 100 )

Chemical Name	Formaldehyde (Gas)

Formaldehyde monohydrate (Aqueous solution)	Paraformaldehyde

Synonyms	Formaldehyde, Formalin	Paraformaldehyde

Structure	

       HYPERLINK "http://www.chemvip.com"  www.chemvip.com 	

      HYPERLINK "http://www.answers.com"  www.answers.com 

The physical and chemical properties for formaldehyde and
paraformaldehyde are listed in Appendix A.

3.0	HAZARD CHARACTERIZATION

3.1	Hazard Profile

Acute Toxicity

Adequacy of database for Acute Toxicity: The acute toxicity database for
formaldehyde is considered complete. Technical grade formaldehyde (37%
a.i.) has a moderate order of acute toxicity in experimental animals via
the oral and dermal routes (Toxicity Categories II and III). Inhalation
toxicity studies on formaldehyde are extensive and include both acute
exposures and longer term exposures. Toxicity from acute exposures is
characterized by pathology of the respiratory epithelium and has been
observed in rats exposed for 4 hours to a concentration of 10 ppm
(Bhalla, 1991), while longer term exposures of rats (3 ppm for 6
hours/day for 5 days) also results in respiratory tract lesions (Buckley
et al., 1984). Repeated exposure to 40 ppm formaldehyde for 6 hours/day,
5 days/week for 13 weeks results in mortality in 80% of B6C3F1 mice
whereas exposure to 20 ppm formaldehyde for the same time period
produced no mortality (Maronpot et al., 1986). Formaldehyde is a severe
eye and skin irritant (Toxicity Category I) and is positive for dermal
sensitization.  

The acute toxicity data for Formaldehyde is summarized below in Table
3.1

.

Table 3.1.  Acute Toxicity Data for Formaldehyde Technical a.i.

Guideline Number	Study Type/ Test substance 

(% a.i.)	MRID

Number/ Citation	Results	Toxicity Category

870.1100

(§81-1)	Acute Oral – Guinea Pig 

Purity 37.3% - Formaldehyde	00058054	LD50 = 260 mg/kg	II

870.1200

(§81-2)	Acute Dermal – Rat

Purity  37.3% - Formaldehyde	00058054	  SEQ CHAPTER \h \r 1 LD50 = 300
mg/kg

	II

870.1200

(§81-2)	Acute Dermal – Rabbit

Purity  37.3% - Formaldehyde	00058054	  SEQ CHAPTER \h \r 1 LD50 = 240
mg/kg

	II

870.1200

(§81-2)	Acute Dermal – Dog

Purity  37.3% - Formaldehyde	00058054	  SEQ CHAPTER \h \r 1 LD50 = 550
mg/kg

	II

870.1300

(§81-3)	Acute Inhalation – Mouse and Rat	See Open Literature studies
in Toxicity Profile for Formaldehyde

870.2400

(§81-4)	Primary Eye Irritation -

Purity  37.3% - Formaldehyde	00058054	Severe eye irritant	I

870.2500

(§81-5)	Primary Dermal Irritation – 

Purity  37.3% - Formaldehyde	00058054

	Formation of vesicles with superficial necrosis or nodules.	I

870.2600

(§81-6)	Dermal Sensitization – Guinea pigs

Purity 40.0% - Formaldehyde	40161103	Extreme Sensitizer	NA

NA – Not Applicable

3.2	FQPA Considerations

Under the Food Quality Protection Act (FQPA), P.L. 104-170, which was
promulgated in 1996 as an amendment to the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug and
Cosmetic Act (FFDCA), the Agency was directed to "ensure that there is a
reasonable certainty that no harm will result to infants and children"
from aggregate exposure to a pesticide chemical residue.  The law
further states that in the case of threshold effects, for purposes of
providing this reasonable certainty of no harm, "an additional tenfold
margin of safety for the pesticide chemical residue and other sources of
exposure shall be applied for infants and children to take into account
potential pre- and post-natal toxicity and completeness of the data with
respect to exposure and toxicity to infants and children. 
Notwithstanding such requirement for an additional margin of safety, the
Administrator may use a different margin of safety for the pesticide
residue only if, on the basis of reliable data, such margin will be safe
for infants and children."

Although formaldehyde has no food tolerances and the registered
antimicrobial uses do not involve dietary exposure, the database with
respect to determining susceptibility to infants and children shows no
increased susceptibility, based on results of developmental and
reproductive toxicity testing. Assessments of the reproductive and
developmental toxicity of formaldehyde conducted by the Australian
government (  HYPERLINK "http://www.nicnas.gov.au"  www.nicnas.gov.au )
as well as the Agency for Toxic Substances and Disease Registry (ATSDR,
1999)support this conclusion. 

3.3	Dose-Response Assessment 

3.3.1	Summary of Toxicological Endpoints for Formaldehyde

Table 3.2. Summary of Toxicological Doses and Endpoints for Formaldehyde

  SEQ CHAPTER \h \r 1 Exposure

Scenario	Dose Used in Risk Assessment

(mg/kg/day) 	Target MOE, UF, 

Special FQPA SF* for Risk Assessment	Study and Toxicological Effects

Dietary Risk Assessments

Acute Dietary

(general population including infants and children) 	An acute dietary
assessment is not needed for the registered antimicrobial uses of
formaldehyde. 

Chronic Dietary

(all populations)	 A chronic dietary assessment is not needed for the
registered antimicrobial uses of formaldehyde. 

Non-Dietary Risk Assessments

Incidental Oral  

	 An incidental oral risk assessment is not required for the registered
antimicrobial uses of formaldehyde. 

Dermal (all durations)	A dermal risk assessment is not required for the
registered antimicrobial uses of formaldehyde. 

Inhalation

(all durations) 

	NOAEL (human) = 0.1 ppm 

 

	UF = 1 (occupational)

UF = 10 (residential)

 	ACGIH 2001 publication on formaldehyde

Horvath, E.P. et al. (1986): JAMA 259(5): 701-707.  Based on complaints
of eye, nose, and throat irritation in particle board workers at
concentrations of formaldehyde from 0.4 – 1.0 ppm.  

Redden, J. (2005): Section 18 Emergency Exemption for the use of
Paraformaldehyde: U.S. Army Medical Research Institute of Infectious
Diseases.

Cancer	Formaldehyde is currently classified as a  B1 (probable human
carcinogen) in EPA’s IRIS assessment. IARC has classified formaldehyde
as “carcinogenic to humans.” The Agency has decided to present the
formaldehyde cancer risks for the pesticidal uses using both the
existing 1991 IRIS cancer unit risk of 1.3 E-5 per (µg/m3) and the CIIT
BBDR model until any new cancer estimates are fully peer reviewed

3.3.2	Dermal Absorption

Only two studies from the open literature were located that examined
dermal absorption of formaldehyde (Jeffcoat et al., 1983; Bartnik et
al., 1985). In the Bartnik et al. study, a cosmetic cream containing
0.1% formaldehyde was applied an 8 cm2 area of the shaved dorsal skin of
male and female rats under non-occlusive and occlusive conditions. Urine
and feces were collected up to 48 hours post-dose. Under non
–occlusive conditions, absorption of radiolabeled formaldehyde in the
cosmetic cream preparation was published as 6.1% in males and 9.2% in
females. Occlusive conditions reported absorption as 3.4% in males. In
the study be Jeffcoat et al., rats, guinea pigs, and monkeys were used
in experiments to determine dermal absorption of 0.1 and 2.0 mg doses of
radiolabeled formaldehyde from application to a 2 cm2 area for 24 hours.
In rats, between 6-9% of a dose of 0.1 or 2.0 mg formaldehyde was
absorbed, while in guinea pigs results were similar. In monkeys, less
than 1% was absorbed. 

3.3.3	Classification of Carcinogenic Potential 

The Agency is currently reevaluating the carcinogenic potential of
formaldehyde. The historical and ongoing development of an inhalation
unit risk value to assess the carcinogenic potential of formaldehyde is
briefly summarized below. Contributors to this summary included
scientists from several EPA program offices (Office of Pesticide
Programs [OPP], Office of Pollution, Prevention, and Toxics [OPPT],
Office of Research and Development,/National Center for Environmental 
Assessment [ORD/NCEA], Office of Research and Development/National
Health Effects Exposure Research Laboratory [ORD/NHEERL], and Office of
Air and Radiation [OAR] ). 

 

In 1991 the EPA’s Integrated Risk Information System (IRIS) published
a weight-of-evidence characterization for carcinogenicity of
formaldehyde, classifying formaldehyde as a B1 probable human carcinogen
with a potency factor of 1.3 E-5 per (μg/m3) on the basis of squamous
cell nasal tumors observed in a two-year study in rats (Kerns et al.,
1983).  

In 1999 the Chemical Industry Institute of Toxicology (CIIT) developed a
health risk assessment for formaldehyde based upon the animal toxicology
data (CIIT, 1999).  This document presented the dose-response modeling
of these data in two distinct parts: 1). based upon a biologically-based
dose response (BBDR) model , 2) benchmark dose models that were based
upon point of departures at various response levels of the tumor and
precursor data.  Both these approaches made extensive use of the
available time-to-tumor and mechanistic information. The 1999 assessment
was subsequently published in various articles in peer-reviewed journals
(Kimbell et al., 2001; Schlosser et al., 2003; Conolly et al., 2002,
2003, 2004).

In 1999, the U.S. EPA’s Office of Air and Radiation and Office of
Research and Development, in conjunction with Health Canada, conducted
an external peer review workshop for the CIIT BDDR model as well as an
external written peer review and public comment period for their
assessments. While the review was largely positive on the overall
approach in the assessment, reviewers also pointed to the potential for
significant uncertainty due to model mis-specification and uncertainties
in key parameters involved in the BBDR model

Based on the peer review of the CIIT model, OAR determined in 2004 that
the CIIT model was the most appropriate tool for risk assessment for
formaldehyde.   OAR has subsequently used the formaldehyde cancer
potency derived using the CIIT model for a number of risk assessments
involving formaldehyde emissions to the atmosphere such as the Plywood
and Composite Wood Products National Emission Standard for Hazardous Air
Pollutants (final rule 2004, reconsidered final rule 2006, remanded to
EPA by court 2007); Control of Hazardous Air Pollutants from Mobile
Sources (Final Rule 2007); and Proposed Rule for National Emission
Standard for Combustion Turbines (2004). Health Canada, Australia, the
World Health Organization, and the German MAK Commission have also used
the CIIT model. Model strengths include consideration of the mode of
action data for formaldehyde and an approach to account for potential
direct DNA interaction and mutation induction.  Model uncertainties
include variability for some of the parameters of the model (e.g., cell
proliferation) which can affect predictions of risk (Subramanian et al
2007;   2008 [in press]).

In 2004, NCEA convened a panel of experts, including scientists from
CIIT, to provide advice on these and other critical biological and
statistical uncertainties.  The strength of the CIIT model is its
consideration of mode of action and extensive mechanistic information.

Although current OAR assessments still use the CIIT model, these
assessments now acknowledge previously unknown uncertainties with the
CIIT model when characterizing the risk results.   

In 2004, the International Agency for Research on Cancer (IARC)
characterized formaldehyde as a human carcinogen based on their review
of the current literature (IARC, 2004), including data in humans on 
nasopharyngeal cancer,  cancer of the nasal cavity and paranasal
sinuses,and  leukemia.  It should be noted that some epidemiology
studies did not find a reported association between formaldehyde
exposure and carcinogenicity. For example, Coggon et al, 2003 studied
over 14,000 workers exposed to formaldehyde in industrial workplaces and
reported no excesses of either leukemia or nasal and nasopharyngeal
cancer.

In 2005, the Scientific Review Panel (SRP) of the California Office of
Environmental Health Hazard Assessment (OEHHA) responded to the CA Air
Resources Board request to reevaluate the carcinogenic potential of
formaldehyde.  The SRP noted in this 2005 review that OEHHA’s November
2002 evaluation of a petition had included the 1999 report on the CIIT
model and other information, and that California’s OEHHA had concluded
that “the evidence…(1) did not change the determination that
formaldehyde is a carcinogen; (2) presented information that considered
the possibility of non-linear dose response relationships, but presented
no clear grounds to review the original “no threshold”
determination; and (3) did not provide any new epidemiology or bioassays
supporting a change in potency.   In addition, there was insufficient
information to fully evaluate the CIIT model, issues such as model
uncertainty were not adequately addressed….”   The Scientific Review
Panel’s overall conclusion in 2005 was, “there was not sufficient
new data to support the petition to review the [OEHHA’s earlier 1992]
formaldehyde risk assessment.  In addition, the newly published studies
represented relevant new information, but they did not allow
determination of a causal relationship between formaldehyde exposure and
leukemia.  These studies deserve further evaluation over time given
their potential importance.”  Froines (2005).

 

EPA is currently completing a new IRIS assessment that will include a
cancer  unit risk value for formaldehyde; the reassessment is scheduled
to start internal peer review in May 2008 and begin independent external
peer review in January 2009 (  HYPERLINK
"http://cfpub.epa.gov/ncea/iristrac/index.cfm?fuseaction" 
http://cfpub.epa.gov/ncea/iristrac/index.cfm?fuseaction  =view
Chemical.showChemical&sw_id=1031).  EPA anticipates that the peer review
of the formaldehyde assessment will not be finished before   EPA
completes the reregistration process for formaldehyde pesticidal uses,
scheduled to conclude in September 2008.	

Based on the on going re-evaluation of the science  to predict
carcinogenic potential of formaldehyde, OPP has decided to present the
formaldehyde cancer risks for the pesticidal uses using both the
existing 1991 IRIS cancer unit risk of 1.3 E-5 per (µg/m3) and the CIIT
BBDR model until any new cancer estimates are fully peer reviewed.  OPP
also acknowledges the wide range in cancer risks using these approaches
and will coordinate with other offices in EPA on the outcome of the
upcoming peer review process on the carcinogenicity of formaldehyde. 
Because formaldehyde air concentrations approach those associated with
ocular and respiratory tract irritation, the risk mitigation measures to
be implemented in the meantime for the pesticidal uses will be based on
mitigating the non-cancer effects at a limit of 0.01 ppm.  It is
believed that this level will reduce exposures sufficiently such that
the cancer risks would not be of concern.  The EPA process of regulating
pesticides allows for reevaluation at any time if new information from
the peer review process of the carcinogenic potential of formaldehyde
warrants.

3.4	Endocrine Disruption

EPA is required under the Federal Food, Drug and Cosmetic Act (FFDCA),
as amended by the Food Quality Protection Act (FQPA), to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was a
scientific basis for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system. 
EPA also adopted EDSTAC’s recommendation that EPA include evaluations
of potential effects in wildlife.  For pesticides, EPA will use FIFRA
and, to the extent that effects in wildlife may help determine whether a
substance may have an effect in humans, FFDCA authority to require the
wildlife evaluations.  As the science develops and resources allow,
screening of additional hormone systems may be added to the Endocrine
Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, formaldehyde may be
subject to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	EXPOSURE ASSESSMENT AND CHARACTERIZATION

4.1	Summary of Registered Uses

	

Formaldehyde application sites include agricultural premises and
equipment, railroad car fumigation and oil production.   Formaldehyde is
also registered as an in can preservative for use in consumer products. 
Formaldehyde is not registered for use in paints.  The in-can
preservative use that is listed on the formaldehyde 37 label (8133-32)
is applicable to only a few consumer products, including floor and
furniture and detergent products, dish detergent, laundry detergent,
disposable wipes, batting, carpet backing, wallpaper adhesive, and
reflective tape for runners. Paraformaldehyde uses include closets,
vacation homes, and beauty salons/barber shops.

4.2	Dietary Exposure and Risk

Formaldehyde is a gas at room temperature and at use level it is
dissolved in water and/or alcohol. However, it has a tendency to escape
from the solution. Half lives in air and water are short, so the
likelihood of formaldehyde persisting on pots, pans, and dishes is
little to none. AD has no dietary concerns for formaldehyde for the AD
use patterns at this time.

4.3	Drinking Water Exposures and Risks

Formaldehyde is a gas at room temperature and at use level it is
dissolved in water and/or alcohol. However, it has a tendency to escape
from the solution. Half lives in air and water are short, so
formaldehyde is not expected to contaminate ground water. Thus there is
not expected to be any risk to drinking water.

4.4	Residential Exposure/Risk Pathway

There is one product (8133-32) containing formaldehyde that is labeled
for use as in can preservative of consumer products such as laundry
detergents, general purpose cleaners and wall paper adhesives. There is
one product (4972-43) containing paraformaldehyde that is labeled for
treatment of closets and vacation homes. The residential exposure
scenarios that correspond to these products are included in Table 4.1.

Table 4.1 Formaldehyde Residential Exposure Scenarios

Use	

Exposure Scenario	

Application Rate (ppm)

Inhalation Exposures from Formaldehyde Uses

Material Preservation of Laundry Detergent	

Handler Exposure While Using Treated Laundry Detergent	

1000 ppm product

Material Preservation of Floor and Furniture Polish and Detergent
Products	

Handler Exposure While Using Treated General Purpose Cleaners	150 ppm
product

Material Preservation of Wall Paper Adhesive	Handler Exposure While
Using Treated Wallpaper Adhesive 	100 ppm product

	Post Application Exposure from Wallpaper Adhesive

	Inhalation Exposures from Paraformaldehyde Uses

Mildewcide for clothing and linen in closets	Post Application Exposure	4
ounce of product per 750 ft3

Mildewcide for Vacation Homes	Post Application Exposure	4 ounce of
product per 750 ft3

4.4.1	Residential Handler Inhalation Exposures from Formaldehyde Uses 

Because formaldehyde has a high vapor pressure (pure formaldehyde is a
gas at room temperature and 37% formaldehyde has a vapor pressure of 1
mm hg at 25 C), the unit exposure data from PHED are not applicable
because these data are generally based upon chemicals that have a much
lower vapor pressure (less than 1.0 x 10-4 mm Hg).  When the vapor
pressure is less than 1.0 x 10-4 mm Hg, chemicals are airborne primarily
as aerosols, while at a vapor pressure of 1 mm or above, chemicals are
airborne primarily as vapors or gases. In addition, the toxicology
endpoints were derived from observational human studies where
formaldehyde was in the gas or vapor form.  

4.4.1.1   Residential Laundry Detergent Inhalation Exposure Assessment  
                                   

The EPA’s Consumer Exposure Module (CEM) was used to estimate air
concentrations resulting from the use of laundry detergent preserved
with formaldehyde.    Detailed information and the executable model can
be downloaded from http://www.epa.gov/opptintr/exposure. The CEM laundry
detergent scenario, which assumes that the homeowner is exposed to the
chemical in laundry detergent when using the laundry detergent in the
utility room of a house, was used for this assessment. The following
general inputs were used in CEM:

The molecular weight of formaldehyde is 30 amu.

The vapor pressure is 1.0 mm for formaldehyde as a liquid in formalin.

The weight fraction of 0.00037 is based upon the maximum product
application rate of 1000 ppm and the formaldehyde weight fraction of
0.37 in the product.

The air exchange rate is 0.45 air exchanges per hour.

To assess non-cancer risks, the following inputs were used to calculate
a peak concentration:

The amount of laundry detergent used per day is 400 grams which is the
default high end value in CEM.   

The duration of exposure is 0.667 hours which is the default high end
value in CEM.

	To assess cancer risks, the following inputs were used to calculate a
lifetime average daily concentration.

The frequency of use was set to 104 events per year based on
professional judgment. 

The exposure duration was set to 57 years which is the default value in
CEM. 

The amount of product used per event was set to 200 grams which is a
central tendency value in CEM. 

The event duration was set to 0.333 hours which is a central tendency
value in CEM.

Laundry Detergent Risk Summary

The results of the CEM model run for the laundry detergent scenario are
included in Table 4.2 and the model run details are included in Appendix
B of the ORE assessment.  The margin of exposure (MOE) for non-cancer
risks is 0.4, which is below the target MOE of 10, and is of concern. 
The estimated cancer risk for both the IRIS and CIIT approaches are
presented and range from <3 x 10-9 when using the CIIT model to 8 x 10-6
when using the IRIS unit risk.   

Table 4.2 - Inhalation Risks for Laundry Detergent Handlers

Non-Cancer Risks from Daily Exposures

Weight Fraction	Amount Used Per Day/ 

Duration of Use	Exposure Duration	Peak Concentration	MOEC

(target MOE = 10)

0.00037	

400 grams/0.667 hoursA

	One day per event	240 ppb 	0.4

Cancer Risks from Lifetime Exposures

Weight Fraction	Amount Used Per Day/ 

Duration of Use	Frequency of Use 	LADCD	Cancer Risk

IRISE	CIITF

0.00037	200 grams/0.333 hoursB	104 times per year 	 0.5 ppb

(0.61 ug/m3)	8 x 10-6	<3 x 10-9

A.  High end default assumptions as listed in the CEM Model
documentation.

B.  Central tendency default assumptions as listed in the CEM Model
documentation.

C.   MOE = NOAEL/Peak Concentration where the NOAEL = 0.1 ppm (100 ppb).

D.   LADC = Lifetime Average Daily Concentration assuming exposure 104
days per year and 57 years per 75 year lifetime.

E.   Cancer Risk = LADC * Unit Risk, where the Unit Risk = 1.3 x 10-5
per ug/m3 as listed in IRIS

F.   CIIT Cancer Risk is taken from Table 8 of Conolly et. al. 2004. 
This table lists a cancer risk of 2.9 X 10-9 based on the               
Hockey stick shaped CRCP for non-smokers exposed continuously to 0.001
ppm (i.e. 1 ppb)

4.1.1.2	  Residential Handler General Purpose Cleaner  Exposure
Assessment

The EPA CEM model was used to estimate air concentrations resulting from
the use of general purpose cleaners. The default scenario for the
general purpose cleaner was used for this exposure assessment because it
most closely represents the use pattern of the treated products.   This
scenario assumes that the homeowner uses the general purpose cleaner in
the kitchen of a house.   The following general inputs were used in the
model:

The molecular weight of formaldehyde is 30 amu.

The vapor pressure is 1.0 mm for formaldehyde as a liquid in formalin.

The weight fraction of 0.000056 is based upon the maximum product
application rate of 150 ppm and the formaldehyde weight fraction of 0.37
in the product.

The air exchange rate is 0.45 air exchanges per hour.

	To assess non-cancer risks, the following inputs were used to calculate
a peak concentration.

The amount of general purpose cleaner used is 123 grams which is the
default high end value.   

The duration of exposure is 1.42 hours which is the default high end
value from CEM.

	To assess cancer risks, the following inputs were used to calculate a
lifetime average daily concentration.

The frequency of use was set to 52 events per year based on professional
judgment.

The exposure duration was set to 57 years which is the default value in
CEM. 

The amount of product used per event was set to 61.5 grams which is a
central tendency value. 

The event duration was set to 0.667 hours which is a central tendency
value. 

General Purpose Cleaner Risk Summary

The results of the CEM model runs for the general purpose cleaner
scenario are included in Table 4.3 and the model run details are
included in Appendix B of the ORE Assessment.  The MOE for non-cancer
risks is 4.8, which is below the target MOE of 10, and is of concern.  
The estimated cancer risk ranges from <3 x 10-9 when using the CIIT
model to 2 x 10-6 when using the IRIS unit risk.  

Table 4.3 - Inhalation Risks for General Purpose Cleaner Handlers

Non-Cancer Risks from Daily Exposures

Weight Fraction	Amount Used Per Day/

Duration of Use	Exposure Duration	Peak Concentration	MOEC

(target MOE = 10)

0.000055	

123 grams/1.42 hoursA

	One day per event	21 ppb	4.8

Cancer Risks from Lifetime Exposures

Weight Fraction	Amount Used Per Day/ 

Duration of Use	Frequency of Use	LADCD	Cancer RiskE

IRISE	CIITF

0.000055	61.5 grams/0.667 hoursB	52 days per year	0.12 ppb

(0.17 ug/m3)	2 x 10-6	<3 x 10-9

A.  High end default assumptions as listed in the CEM Model
documentation.

B.  Central tendency default assumptions as listed in the CEM Model
documentation.

C.   MOE = NOAEL/Peak Concentration where the NOAEL = 0.1 ppm (100 ppb).

D.   LADC = Lifetime Average Daily Concentration assuming exposure 52
days per year and 57 years per 75 year lifetime.

E.   Cancer Risk = LADC * Unit Risk, where the Unit Risk = 1.3 x 10-5
per ug/m3

F.    CIIT Cancer Risk is taken from Table 8 of Conolly et. al. 2004. 
This table lists a cancer risk of 2.9 X 10-9 based on the            
Hockey stick shaped CRCP for non-smokers exposed continuously to 0.001
ppm (i.e. 1 ppb)

4.1.1.3  Residential Wallpaper Handler Inhalation Exposure Assessment

	The exposures from formaldehyde contained in wallpaper adhesive were
assessed using the EPA’s Wall Paint Exposure Model (WPEM).  Although
this model was developed for paint it was used for wallpaper because the
wall paper adhesive is applied in a similar manner as paint.  

For this exposure assessment, the WPEM default scenario for the
homeowner painter (RESDIY) was used and was modified to account for the
use of wallpaper instead of paint.  This WPEM default scenario assumes
that the homeowner is exposed to the chemical in paint when painting the
bedroom of a house (Zone 1) and subsequently in adjacent rooms (Zone 2)
after painting.  This default scenario includes 3 hours of painting in
Zone 1, 15 hours in Zone 2 and 6 hours outside of the house.   The
following inputs and assumptions were used in the model:

The molecular weight of formaldehyde is 30 amu.

The vapor pressure is 0.1 mm hg.

The weight fraction of formaldehyde in wallpaper adhesive is 0.000037
based upon the Formaldehyde 37 product application rate of 100 ppm and
the formaldehyde weight fraction of 0.37 in the product.

The air exchange rate is 0.45 air changes per hour which is the median
value from the Exposure Factors Handbook (US EPA, 1997).  This is a
standard assumption in the WPEM model.

The wall paper application is done in a house that has an internal
volume of 441 m3 (15,583 ft3) which is the mean value from the Exposure
Factors Handbook (US EPA, 1997).  This is a standard assumption in the
WPEM model.

The walls of one bedroom are papered and the papered surface area is 452
ft2.  This is a standard assumption in the WPEM model.

The wallpaper adhesive has a coverage of 200ft2/gallon based on an
internet survey of several brands of wall paper adhesive.  For products
produced by the Roman Company, which claims to be the largest supplier
of wall covering adhesive, the coverage ranges from 160 ft2 for Vinyl
over Vinyl Pro-555 to 300 ft2/gallon for Ultra-Pro-880 Clear Adhesive.  
The products produced by the Zinnser Company also have a similar
coverage range which is 230 ft2/gallon for Suregrip to 280 ft2/gallon
for Suregrip 122.   These values are similar to default coverage values
used in the WPEM model which is 200 ft2/gallon for primer and 400
ft2/gallon for paint.

The wallpaper adhesive has a density of 4500 grams/gallon based upon a
specific gravity of 1.2.  This is an upper percentile estimate based on
the products listed above.  The actual specific gravities range from 1.0
to 1.31.

The duration of wall paper application is 3.42 hours and 2.26 gallons of
adhesive are applied.   This is based on the labor rate information for
painting encoded within the WPEM model.

The exposure frequency for cancer risk calculations is 1 day per year
based upon the 7 to 10 year service life of wallpaper (Wallcoverings
Association, 2008) and the fact that only a few rooms of a house, such
as bathrooms and kitchens, are typically wallpapered.

The exposure duration for cancer risk calculations is 57 years of a 75
year lifespan.  This is a standard assumption used in the WPEM model.

It was assumed that the background concentration is zero.

The length of the model run was set to 365 days.

WPEM Model Results

The WPEM model results are summarized in Table 4.4 and the detailed
model runs are included in Appendix B of the ORE Assessment.  The MOE
for non-cancer risks is 6.7, which is below the target MOE of 10, and is
of concern. The estimated cancer risk ranges from <3 x 10-9 when using
the CIIT model to 7 x 10-7 when using the IRIS unit risk.

Table 4.4 – Residential Handler Inhalation Risks for Wallpaper
Adhesive

Non-Cancer Risks from Daily Exposures

Weight Fraction	Amount Used Per Day/

Duration of Use	Exposure Duration	Peak Concentration	MOEB

(target MOE = 10)

0.000037	2.26 gallons/3.42 hoursA	One day per event	 15 ppb	6.7

Cancer Risks from Lifetime Exposures

Weight Fraction	Amount Used Per Day/ 

Duration of Use	Exposure Frequency	LADCC	Cancer Risk

IRISD	CIITE

0.000037	2.26 gallons/3.42 hoursA	1 day per year	0.044 ppb

(0.053 ug/m3)	7 x 10-7	<3 x 10-9

A.  High end default assumptions as listed in the WPEM Model
documentation.

B.  MOE = NOAEL/Peak Concentration where the NOAEL = 0.1 ppm (100 ppb).

C.  LADC = Lifetime Average Daily Concentration assuming exposure 1 day
per year and 57 years per 75 year lifetime.

D.  IRIS Cancer Risk = LADC * Unit Risk , where the Unit Risk is 1.3 x
10-5 per ug/m3 as listed in IRIS 

E.  CIIT Cancer Risk is taken from Table 8 of Conolly et. al. 2004. 
This table lists a cancer risk of 2.9 X 10-9 based on the             
Hockey stick shaped CRCP for non-smokers exposed continuously to 0.001
ppm.

4.4.2.	Residential Post-Application Exposures 

	Representative postapplication scenarios assessed include inhalation
exposures from wallpaper adhesive treated with formaldehyde as a
materials preservative and inhalation exposures from paraformaldehyde
used as a mildewcide in closets and vacation homes.  

		

4.4.2.1	   Post Application Exposure Assessment of Wall Paper Adhesive

                                       

The Wall Paint Exposure Model (WPEM) was used to estimate air
concentrations resulting from the use of wall paper adhesive preserved
with formaldehyde.  The default assumptions from the WPEM RESADULT
scenario were used and were modified as appropriate to account for the
use of wallpaper instead of paint.  This scenario assumes that the home
occupants are exposed to the chemical in paint in adjacent rooms (Zone
2) during painting and in the painted room (Zone 1) after painting. 
This scenario includes 7 hours in Zone 2, 8 hours in Zone 1 and 6 hours
outside of the house.   The following inputs and assumptions were used
in the model:

The molecular weight of formaldehyde is 30 amu and the vapor pressure is
1.0 mm Hg.

The weight fraction of formaldehyde in wall paper adhesive is 0.000037
based upon the application rate of 100 ppm.

The air exchange rate is 0.45 air changes per hour which is the median
value from the Exposure Factors Handbook (US EPA, 1997).

The papering is done in a house that has an internal volume of 15,583
ft3 which is the mean value from the Exposure Factors Handbook (US EPA,
1997).

The walls of one bedroom are papered and the papered surface area is 452
ft2.

One coat of adhesive which has a coverage of 200 ft2/gallon is applied.

The wallpaper adhesive has a density of 4500 grams/gallon.

The adult occupant is in the house being papered, but not in the papered
area.

The duration of wall paper application is 3.42 hours and 2.26 gallons of
adhesive are applied.   This is based on the labor rate information for
painting encoded within the WPEM model.

The exposure frequency for cancer risk calculations is 1 day per year
based upon the 7 to 10 year service life of wallpaper (Wallcoverings
Association, 2008) and the fact that only a few rooms of a house, such
as bathrooms and kitchens, are typically wallpapered.

The exposure duration for cancer risk calculations is 57 years of a 75
year lifespan.  This is a standard assumption used in the WPEM model.

It was assumed that the background concentration is zero.

The length of the model run was set to 365 days.

The result of the WPEM model run for the wallpaper adhesive
postapplication scenario is included in Table 4.5 and the model run
details are included in Appendix B of the ORE Assessment.   The MOE for
non-cancer risk is 20 which is greater than the target MOE of 10 and is
not of concern.   The estimated cancer risk ranges from <3 x 10-9 when
using the CIIT model to 6 x 10-7 when using the IRIS unit risk.  

 

Table 4.5 – Residential Post Application Inhalation Risks for
Wallpaper Adhesive

Non-Cancer Risks from Daily Exposures

Weight Fraction	Amount Used Per Day/

Duration of Use	Exposure Duration	Peak Concentration	MOEB

(target MOE = 10)

0.000037	2.26 gallons/3.42 hoursA	One day per event	4.9 ppb	20

Cancer Risks from Lifetime Exposures

Weight Fraction	Amount Used Per Day/ 

Duration of Use	Exposure Frequency	LADCD	Cancer Risk

IRISE	CIITF

0.000037	2.26 gallons/3.42 hoursA	1 day per year	0.038 ppb 

(0.047 ug/m3)	6 x 10-7	<3 x 10-9

A.  High end default assumptions as listed in the WPEM Model
documentation.

B.  MOE = NOAEL/Peak Concentration where the NOAEL = 0.1 ppm (100 ppb).

C.  Lifetime Exposure Events = Exposure Events per Year (1.0) * Exposure
Years per Lifetime (57)

D.  LADC = Lifetime Average Daily Concentration assuming exposure 1 days
per year and 57 years per 75 year lifetime.

E.  IRIS Cancer Risk = LADC * Unit Risk , where the Unit Risk is 1.3 x
10-5 per ug/m3 as listed in IRIS 

F.  CIIT Cancer Risk is taken from Table 8 of Conolly et. al. 2004. 
This table lists a cancer risk of 2.9 X 10-9 based on the             
Hockey stick shaped CRCP for non-smokers exposed continuously to 0.001
ppm (i.e. 1 ppb).

		

4.4.2.2.   Post Application Exposure Assessment of Closet Treatment Uses

	The EPA’s CEM model was used to estimate air concentrations resulting
from the use of the Sun Pac Mildewcide in a closet of an occupied home.
The default scenario for the air freshener was used for this exposure
assessment. This scenario assumes that the homeowner places air
freshener in the bathroom of a house. The following general inputs were
used in the model: 

The molecular weight of formaldehyde is 30 amu.

The vapor pressure is 1.0 mm for formaldehyde as a liquid in formalin.

The weight fraction of 0.91 (i.e. 91 percent) is from the Sun Pac label
(4972-43).

The air exchange rate is 0.45 air exchanges per hour.

	To assess non-cancer risks, the following inputs were used to calculate
a peak concentration:

The weight of the air freshener is 113.4 grams (i.e. 4 ounces) based on
the 

      Sun Pac label.

The event duration is 720 hours which is the default central tendency
value from CEM (i.e. the air freshener lasts for 720 hours or 30 days). 
The high end value of 2160 hours was not used because it dilutes the
exposure over a longer time period.

	To assess cancer risks, the following inputs were used to calculate a
lifetime average daily concentration.  

The frequency of use was set to 6.12 events per year which the default
value in CEM. 

The duration was set to 57 years which is the default value in CEM. 

The amount of product used per event was set to 52.7 grams which is a
central tendency value from CEM. 

The event duration is 720 hours which is the central tendency value from
CEM. 

Sun Pac Mildewcide Risk Summary

The results of the CEM model runs for the Sun Pac Mildewcide scenario
are included in Table 4.6 and the model run details are included in
Appendix B of the ORE Assessment.   The MOE for non-cancer risks is less
than 0.1, which is below the target MOE of 10 and is of concern.   The
estimated cancer risk ranges from <8 x 10-7 when using the CIIT model to
3 x 10-3 when using the IRIS unit risk.  



Table 4.6 - Inhalation Risks for Sun Pac Closet Treatment

Non-Cancer Risks from Daily Exposures

Weight Fraction	Amount of Product Used 	Duration of Use	Duration of
Exposure	Peak Concentration	MOEB

(target MOE = 10)

0.91

	113.4 grams	720 hoursA	1 day	 78,000 ppb	<0.1

Cancer Risks from Lifetime Exposures

Weight Fraction	Amount of Product Used	Duration of Use	Frequency of Use
per Year 	LADCC	Cancer Risk

	IRISD	CIITE

0.91	113.4 grams	720 hoursA	6.12 times 	170 ppb

(210 ug/m3)	3 x 10-3	<8 x 10-7

A.  Central tendency default assumptions as listed in the CEM Model
documentation.

B.   MOE = NOAEL/Peak Concentration where the NOAEL = 0.1 ppm (100 ppb).

C.   LADC = Lifetime Average Daily Concentration

D.  IRIS Cancer Risk = LADC * Unit Risk , where the Unit Risk is 1.3 x
10-5 per ug/m3 as listed in IRIS 

E.  CIIT Cancer Risk is taken from Table 8 of Conolly et. al. 2004. 
This table lists a cancer risk of 7.5 X 10-7 based on the             
Hockey stick shaped CRCP for non-smokers exposed continuously to 0.20
ppm (i.e. 200 ppb). 

4.4.2.3.   Post Application Exposure Assessment of Vacation Home Uses

	The Sun Pac product label indicates that the product should only be
used in unoccupied rooms and that the rooms should be ventilated
thoroughly before reentry.  Depending on how long the house is
unoccupied, the emission rate of the Sun Pac product and the amount and
duration of ventilation that is performed, formaldehyde exposures may or
may not exceed the level of concern of 0.01 ppm for a few hours after
occupancy.   It is recommended that emission rate data be submitted so
that the potential exposures and ventilation requirements can be
quantified. 

4.4.3.	Residential Risk Summary and Characterization

	A summary of the residential risks for formaldehyde is included in
Table 4.7.     The non-cancer risks are of concern for three of the
scenarios because the MOEs are less than the target MOE of 10.  The
non-cancer risk estimates are based upon EPA exposure models which are
generally believed to be conservative.   The fact that the vapor
pressure of 1.0 mm hg, which is based on formaldehyde in formalin, was
used in these models rather than the vapor pressure of pure
formaldehyde, which exists only as gas, is a source of uncertainty. 
There are also uncertainties regarding the use of the WPEM model because
it is based on test data for paint solvents that have different
physical/chemical properties than formaldehyde.

  The estimated cancer risks range from <3 x 10-9 when using the CIIT
model to 8 x 10-6 when using the IRIS unit risk.  The IRIS cancer risk
estimates provide an upper-bound on risk.  

Table 4.7 – Residential Risk Summary for Biocidal Uses of
Formaldehyde

Scenario	Peak Air Concentration	MOE

(Target MOE =10)	LADC	Cancer Risk

IRIS	CIIT

Laundry Detergent Handler	240 ppb	0.4	0.5 ppb	8 x 10-6	<3 x 10-9

General Purpose Cleaner Handler	21 ppb	4.8	0.12 ppb	2 x 10-6	<3 x 10-9

Wall Paper Adhesive Handler	15 ppb	6.7	0.044 ppb	7 x 10-7	<3 x 10-9

Wall Paper Adhesive 

Post Application	4.9 ppb	20	0.038 ppb	6 x 10-7	<3 x 10-9

Paraformaldehyde

The non-cancer risk is of concern for the Sun Pac closet use because the
MOE of less than 0.1 is below the target MOE of 10.  The estimated
cancer risk ranges from <8 x 10-7 when using the CIIT model to 3 x 10-3
when using the IRIS unit risk. 

Conversations with the Sun Pac registrant have indicated that Sun Pac is
primarily intended to be used in un-occupied homes.  If this is the
case, then the risks for the closet scenario are not relevant.

5.0       AGGREGATE RISK ASSESSMENT AND CHARACTERIZATION

Aggregate exposure to formaldehyde via the inhalation route could
potentially occur from residential use of formaldehyde-containing
detergent, general purpose cleaner, and wall paper adhesive.  There are
also potential non-cancer and cancer risks of concern from the use of
the Sun Pac product in closets although the product is intended for use
in unoccupied homes. As noted from the residential risk assessment in
this document, these exposure scenarios individually present with
non-cancer and/or cancer risks of concern from inhalation.  Measures to
reduce exposure from each of these sources to meet acceptable MOEs
and/or acceptable cancer risk are required in order that an aggregate
risk be considered acceptable. 

6.0	CUMULATIVE EXPOSURE AND RISK

	Another standard of section 408 of the FFDCA which must be considered
in making an unreasonable adverse effect determination is that the
Agency considers "available information” concerning the cumulative
effects of a particular pesticide's residues and "other substances that
have a common mechanism of toxicity.” 

		

Risks summarized in this document are those that result only from the
use of sodium fluoride. The Food Quality Protection Act (FQPA) requires
that the Agency consider “available information” concerning the
cumulative effects of a particular pesticide’s residues and “other
substances that have a common mechanism of toxicity.” The reason for
consideration of other substances is due to the possibility that
low-level exposures to multiple chemical substances that cause a common
toxic effect by a common toxic mechanism could lead to the same adverse
health effect as would a higher level of exposure to any of the
substances individually. Unlike other pesticides for which EPA has
followed a cumulative risk approach based on a common mechanism of
toxicity, EPA has not made a common mechanism of toxicity finding for
formaldehyde. For information regarding EPA’s efforts to determine
which chemicals have a common mechanism of toxicity and to evaluate the
cumulative effects of such chemicals, see the policy statements released
by EPA’s Office of Pesticide Programs concerning common mechanism
determinations and procedures for cumulating effects from substances
found to have a common mechanism on EPA’s website at   HYPERLINK
"http://www.epa.gov/pesticides/cumulative/_" 
http://www.epa.gov/pesticides/cumulative/ .

7.0	OCCUPATIONAL EXPOSURE ASSESSMENT

	 	

7.1	Occupational Handler Exposures

Occupational Handler Scenarios

	The term “handler” applies to individuals who mix, load, and apply
pesticide products. There are several occupational handler exposure
scenarios that involve formaldehyde products. These scenarios are listed
below:

Mechanical Fumigation

Evaporative Fumigation

Catalyzed Evaporative Fumigation 

Hard Surface Disinfection of Animal Housing Areas and Equipment

Material Preservation

Oil Production 

Wall Paper Adhesive Application

Occupational Handler Exposure Assessment Rationale 

Because formaldehyde has a high vapor pressure (1.0 mm Hg in formalin),
the inhalation unit exposure data from PHED and CMA are generally not
applicable because these data are generally based upon chemicals that
have a much lower vapor pressure (less than 1.0 x 10-4 mm Hg). When the
vapor pressure is less than 1.0 x 10-4mm Hg, chemicals are airborne
primarily as aerosols, while at a higher vapor pressure, chemicals are
airborne primarily as vapors.   

Although there are many studies of formaldehyde occupational exposures
reported in the literature, these studies involved the non-biocidal uses
and there is very little information concerning exposures from the
biocidal uses.  Since it not possible to quantitatively assess the
formaldehyde exposures that result from biocide uses covered by
scenarios 1 through 6 listed above, these scenarios were assessed
qualitatively based upon work practices listed on the labels.   The
remaining scenario (wall paper adhesive application) was assessed using
the WPEM model   

7.1.1	Occupational Handler Exposure and Risk Assessment

Mechanical Fumigation  

Formaldehyde Solution 37 has instructions for mechanical fumigation of
large areas including Poultry and Swine Confinement Buildings, Mushroom
Houses, and Citrus Packing Houses. This fumigation is done by mechanical
methods such as sprinkler application, spray sled application, steam
injection or spray manifold application.  Mixer/Loader exposures are
expected to be of low risk because the label requires that formaldehyde
solutions be transferred to the mixing tank through a closed system. The
actual exposure and risk for a particular worksite will depend on the
characteristics of the particular closed system in use and the
configuration of the mixing tank and associated local exhaust
ventilation systems. If the loading system is used as designed, well
maintained and if the mixing tank is either closed or has local exhaust
ventilation at the openings, then the formaldehyde exposures should be
below any level of concern. 

Applicator exposures are also expected to be of low risk because the
product labels require that all applications should be carried out and
controlled from outside the area being fumigated. 

Evaporative Fumigation of Hatching Eggs

The Formaldehyde Solution 37 label has instructions for evaporative
fumigation of incubator hatchers. This fumigation is done by pouring the
formaldehyde solution into a pan at rate of 2 fluid ounces per 1000 eggs
and allowing it to evaporate. Mixer/Loader exposures only occur during
the brief period that the solution is poured into the pan. 

Applicator exposures are expected to be of low risk because the product
labels require that incubators be ventilated to the outside and that the
incubator room also have adequate ventilation. If this ventilation is
designed correctly, the incubator will be under slight negative pressure
such that the formaldehyde vapors will not migrate into occupied areas.
The label also states that the last application should be done at least
12 hours prior to chick pulling so that the pan contents will be
completely evaporated before the incubator is opened to remove the
chicks. 

Catalyzed Fumigation of Fumigating Rooms and Railcars

Catalyzed fumigation is similar to evaporative fumigation with the
exception that potassium permanganate (KMnO4) is added to catalyze the
release of formaldehyde gas.  The application rate is 16.6 ounces of
KMnO4 and 20 ounces of formaldehyde per 1000 cubic feet. The application
is made by pouring the formaldehyde solution into a small pan containing
KMnO4 and leaving the room immediately.

The handler exposures for this application might be significant
depending upon how long it takes the handler to exit the treatment area
and how quickly the formaldehyde gas is released.

Hard Surface Disinfection of Poultry and Livestock Buildings and
Equipment

The DC&R Product label has instructions for hard surface disinfection of
farm buildings and equipment which are used for poultry and livestock
production. The application rate is one ounce of product per gallon of
water and the solution is applied as a spray to saturate surfaces for
ten minutes. Given that DC&R contains 2.28 percent formaldehyde, this
application rate yields a formaldehyde solution strength of 0.018
percent or 180 ppm.

Given that the spray is manually applied by the handlers, some
formaldehyde exposure may occur. If it is assumed that the spray volume
is one gallon per 135 square feet, based on the Virkon S label
(62432-1), which has a similar use pattern, then 220 gallons would be
applied to a typical 30,000 sf poultry house. If it is assumed that the
formaldehyde is released as the spray dries, then 152 grams would be
released. Given an interior volume of 300,000 ft3 (based on an 8 foot
sidewall and a four foot roof peak) then the maximum theoretical
formaldehyde concentration would be 18 mg/m3 (14 ppm). The actual
formaldehyde concentration would probably be much lower, particularly if
the ventilation system is operated during the spray application. 

Hard Surface Disinfection of Veterinary Buildings and Equipment

The DC&R Product label has instructions for hard surface disinfection of
veterinary clinics and kennels to control canine parvovirus and feline
panleukopenia.  The application rate is 3 ounces of product per gallon.
The solution is applied with a mop, sponge or cloth, as a spray or by
soaking. Given that DC&R contains 2.28 percent formaldehyde, this
application rate yields a formaldehyde solution strength of 0.053
percent or 540 ppm. 

Material Preservation

The Formaldehyde Solution 37 label includes in-container preservation of
a variety industrial and household consumer products. The label
indicates that the use range is 0.1 to 1000 ppm in the final product.
The label does not specify if closed system transfer is required.

Mixer/Loader exposures could be of significant risk if the solution 37
is transferred manually to the container preservation process.  

Oil Production

There are two product labels that are used for oil production. The
application rates range from 25 to 5000 ppm for oil recovery injection
water systems and 100 to 500 for drilling muds, work over fluids and
packer fluids. Both product labels specify that closed systems must be
used and therefore handler exposures are expected to be minimal. It is
not known what if any exposures might occur from the treated water, muds
and fluids.

7.1.2	Professional Painter Inhalation Exposure Assessment

The professional painter inhalation exposure to formaldehyde vapors
during wallpaper adhesive application was assessed using the WPEM Model.
 The WPEM default scenario (RESPROF) for the professional painter was
used and this scenario assumes that two professional painters are
exposed to a chemical in paint while painting an entire apartment in a
work day.  The following inputs were used:

The molecular weight of formaldehyde is 30 amu and the vapor pressure is
1 mm Hg.

The weight fraction of formaldehyde in wallpaper adhesive is 0.000037
based upon the application rate of 100.

The air exchange rate is 0.45 air changes per hour which is the median
value from the Exposure Factors Handbook (US EPA, 1997).

The papering is done in an apartment that has an internal volume of
7,350 ft3 which is the mean value from the Exposure Factors Handbook (US
EPA, 1997).  

The surface area papered is 2131 ft2.

One coat of adhesive which has a coverage of 200 ft2/gallon is applied.

The adhesive has a density of 4500 grams/gallon.

The amount of adhesive used is 10.66 gallons. 

The duration of wall paper application is 8 hours based on the
assumption that the adhesive would be applied onsite with a wallpaper
pasting machine.  

The exposure frequency for cancer risk calculations is 240 day per years
based upon 48 weeks of work per year and 5 days of work per week.  

The exposure duration for cancer risk calculations is 57 years of a 75
year lifespan.  This is a standard assumption used in the WPEM model.

The model was set to run for one day.

It was assumed that the background concentration is zero.

WPEM Model Results

	The WPEM model results are summarized in Table 7.1 and the detailed
model runs are included in Appendix B of the ORE Assessment.  The MOE
for non-cancer risks is 1.6 which is above the target MOE of 1, and is
not of concern.  The estimated cancer risks range from 

<1 x 10-8 when using the CIIT model to 6 x 10-5 when using the IRIS unit
risk.  The CIIT model prediction is based on an 80 year lifetime which
includes 40 years of work and an environmental exposure of 4 ppb during
off work hours.   The light work cancer risk was selected from Table 8
of Conolly 2004 because it represents a slightly higher exposure due the
increased nasal flux at the lower breathing rate of 25 liters per
minute.  The heavy work cancer risk is slightly lower (i.e. 1.1 x 10-8)
because it is based on breathing rate of 50 liters per minute which
reduces exposure to the nasal mucosa.

Table 7.1 – Occupational Handler Inhalation Risks for Wallpaper
Adhesive 

Non-Cancer Risks from Daily Exposures

Weight Fraction	Amount Used Per Day/

Duration of Use	Exposure Duration	Peak Concentration	MOEB

0.000037	10.66 gallons/6.3 hoursA	One day per event	 63 ppb	1.6

Cancer Risks from Lifetime Exposures

Weight Fraction	Amount Used Per Day/ 

Duration of Use	Lifetime Exposure EventsC	LADCD	Cancer Risk

IRISE	CIITF

0.000037	10.66 gallons/6.3 hoursA	8400	3.5 ppb 

(4.2 ug/m3) 	6 x 10-5	<1 x 10-8

A.  High end default assumptions as listed in the WPEM Model
documentation.

B.  MOE = NOAEL/Peak Concentration where the NOAEL = 0.1 ppm (100 ppb).

C.  Lifetime Exposure Events = Exposure Events per Year (240) * Exposure
Years per Lifetime (35)

D.  LADC = Lifetime Average Daily Concentration

E.  IRIS Cancer Risk = LADC * Unit Risk , where the Unit Risk is 1.3 x
10-5 per ug/m3 as listed in IRIS 

F.  CIIT Cancer Risk is taken from Table 8 of Conolly et. al. 2004. 
This table lists a cancer risk of 1.45 X 10-8 for occupational     
exposures at 0.01 ppm (Light work, Hockey stick CRCP, nonsmoking).

7.2	Occupational Handler Risk Summary and Characterization

Non-Cancer Risks

If the label requirements such as closed system loading, remote
application and adequate ventilation are followed, it is reasonable to
assume that exposures would not exceed the EPA level of concern of 0.1
ppm. Since the actual exposure at a particular worksite would depend on
worksite specific factors such as the type and condition of the closed
system transfer system and the design and maintenance status of the
ventilation systems, workplace specific monitoring is recommended to
verify that exposures are acceptable. 

Cancer Risks

If workplace conditions are maintained such that peak exposures do not
exceed 0.1 ppm, daily average exposures will at least 3 times less than
0.1 ppm because workplaces exposures from even the most well controlled
processes have a within day variability of at least 3. If it is assumed
that there is no additional exposure away from work then the 24 hour TWA
is 0.01 ppm.  If it assumed that workers are exposed for 240 days per
year for 35 years out of a 70 year lifetime, the lifetime average daily
concentration (LADC) is 4.5 ug/m3(3.7 ppb).  A shown in Table 7.2,  the
estimated cancer risk ranges from <1 x 10-8 when using the CIIT model to
6 x 10-5 when using the IRIS unit risk.  As discussed previously for
residential risks, the IRIS cancer risk estimates provide an upper-bound
on risk and the actual carcinogenic risks are likely below the upper
bound estimates and may be closer to the biologically based CIIT model
estimates.

Table 7.2 – Occupational Handler Cancer Risks

Average Daily Concentration at Work

(8 hour TWA)	Average Daily Concentration at Work and at HomeA

(24 hour TWA)	Lifetime Average Daily ConcentrationB	Cancer Risk

	IRISC	CIITD

0.03 ppm 

(41 ug/m3)	0.01 ppm 

(13.7 ug/m3)	4.5 ug/m3

(3.7 ppb)	6 x 10-5	<1 x 10-8

A.  ADC AW/AH = 8 hour TWA * (8 hours per work/24 hours per day)

B.  LADC = ADC * (240 days per year/365)*(35 years per lifetime /70 year
lifetime)  

C.  IRIS Cancer Risk = LADC * Unit Risk , where the Unit Risk is 1.3 x
10-5 per ug/m3 as listed in IRIS 

D.  CIIT Cancer Risk is taken from Table 8 of Conolly et. al. 2004. 
This table lists a cancer risk of 1.45 X 10-8 for occupational exposures
at 0.01 ppm (Light work, Hockey stick CRCP, nonsmoking).

Wallpaper Adhesive Scenario

	The WPEM model results indicate that peak exposures is 0.063 ppm.  
Since the WPEM model is based on paint application there are some
uncertainties with its use for assessing exposure to wallpaper adhesive.
 Although the adhesive is applied to the same area and at the same
coverage rate as primer paint, the fact that the adhesive is covered by
the paper suggests that the formaldehyde emissions might be slower than
they would be if the formaldehyde in the paint.   This is particularly
true if a vinyl based wall covering were applied which would slow the
rate of evaporation.   The net result of this effect is that the peak
exposures would be less than that predicted by the WPEM model.

	The estimated cancer risks based on the exposures predicted by WPEM
model range from <1 x 10-8 when using the CIIT model to 6 x 10-5 when
using the IRIS unit risk.   In addition to the uncertainties resulting
from the WPEM model, there are uncertainties with the exposure duration
assumptions used to calculate cancer risk.  It highly likely that
estimated exposure duration of 240 days for 35 years is much greater
than the actual exposure duration, therefore the cancer risk estimate is
highly conservative and could easily be an order of magnitude lower. 
Information regarding the market penetration of formaldehyde treated
adhesives could be used to refine the cancer risk.

7.3	Occupational Post-application Exposures

Formaldehyde

 tc \l3 "6.2.3	Fogging 

Formaldehyde is used for fumigating poultry and swine containment
buildings.   Exposures to formaldehyde can occur after fumigating when
the workers re-enter the fogged area to finish cleanup. Only inhalation
exposures were assessed, because dermal post application exposures are
presumed to be negligible. The inhalation exposure assessment was
conducted using the single chamber decay formula from the Multi-Chamber
Concentration and Exposure Model (MCCEM v1.2). This assessment was based
upon the application parameters listed in the Champion Technologies
Formaldehyde Solution 37 Label (EPA Reg #8133-32). The following
assumptions were made:

The application rate is 60 ounces per 1000 cubic feet (ft3) based upon
the maximum rate listed for Mixing/Loading Instructions for remote house
application methods on label #8133-32.

The application rate in terms of a.i. is 1.56 lb a.i. per 1000 ft3 based
upon the following: 

	(60 fluid oz applied per 1000 ft3 / 128 fluid oz per gallon) x (9.0 lb
per gallon * 37% a.i.)

The initial concentration is 25,000 mg/m3 based upon the following:

	(1.56 lb a.i. * 454,000 mg per lb) / (1000 ft3 * 0.0283 m3 per ft3)

The area being fogged is a one-chamber barn with dimensions of 300 ft
x50 ft x10 ft (AD standard assumption).

All openings such as windows and doors are closed and the ventilation
system is turned off during the application of the fog.

After the fog has been applied and given time to penetrate, the
ventilation system is activated. 

The ventilation system provides an air exchange rate of 4 air changes
per hour. (Jacobson, 2005).  

	The calculations are included in Spreadsheet A and a summary of the
results is included in Table 7.4. The air concentrations decline to less
than the OSHA-Ceiling in 140 minutes and to less than the TLV Ceiling in
170 minutes. The air concentration declines to less than the EPA level
of concern of 0.1 ppm after 183 minutes. 

Table 7.4. Formaldehyde Air Concentrations Following Poultry House
Fumigation

Elapsed Time After Ventilation Activation (minutes)	Air Concentration

(ppm)	Relevant Standard

(ppm)

0	25,000	2 ppm  - OSHA Ceiling

140	1.8	2 ppm  - OSHA Ceiling

170	0.24	0.3 ppm – ACGIH TLV Ceiling

183	0.10	0.1 ppm - EPA Level of Concern

Paraformaldehyde

	There is one paraformaldehyde product (Steri-Dri Fumigant) that is used
in hair/beauty salons and barber shops. It is packaged in ½ ounce
containers, which are placed in sanitizer cabinets, implement drawers,
roller trays, student implement kits, covers or doors which are to be
kept tightly closed. There are two exposure studies that reported air
concentrations from this use, details of which are found in the
occupational and residential exposure chapter for this RED. Results of a
study conducted by NIOSH in 1988/1989 showed air concentrations of
formaldehyde ranging from less than the limit of quantitation to 2.1 ppm
depending on location of sampling. A study by Olcerst in 1999 measured
formaldehyde air concentrations associated with the use of Steri-Dri
fumigant in a vocational high school.  The measurements were made with
an Interscan Model 4160/D direct reading instrument which has a range of
0.02 to 1.5 ppm.  Formaldehyde levels as high as 1.3 ppm were observed
for a brief instant upon opening a cosmetic box and inserting the
instrument probe.  These levels dropped sharply within minutes and
reached background levels within twenty minutes. 

 tc \l2 "6.3	Occupational Post-application Exposures 

8.0	HUMAN HEALTH RISK MITIGATION RECOMMENDATIONS 

Formaldehyde Residential Risks 

The only available option to mitigate the residential risks arising from
the use of formaldehyde as a preservative is the reduction of the
treatment rates. A listing of the scenarios considered and the rate
reduction that would be necessary to mitigate the risks is given in
Table 8.1.  The non-cancer risks require product rate reductions to 40,
72 and 67 ppm for the laundry detergent, general purpose cleaner and
wall paper adhesive handler scenarios, respectively to achieve the
target MOE of 10.  The non-cancer risk for the wall paper post
application scenario does not require a product rate reduction.   The
cancer risks may or may not require mitigation depending on which
approach is used and which cancer risk target is selected.   Even if the
most conservative approach is taken; however, and the mitigation is
based in the IRIS cancer risk with a risk target of 1 x 10-6, the
required mitigation would be less than that required for non-cancer
risks.   

Table 8.1-Formaldehyde Residential Risk Mitigation

Use	MOE	Mitigation Required to Achieve MOE of 10	Cancer Risk	Mitigation
Required to Achieve IRIS Cancer Risk of 1.0 x 10-6

	CIIT	IRIS

	Laundry Detergent	0.4	Reduce product application rate to 40 ppm.	<3 x
10-9 	8 x 10-6	Reduce product rate to 125 ppm.

General Purpose Cleaner	4.8	Reduce product rate to 72 ppm.	<3 x 10-9	2 x
10-6	Reduce product rate to 75 ppm.

Wall Paper Adhesive Handler	6.7	Reduce product rate to 67 ppm	<3 x 10-9
6 x 10-7	No mitigation required

Wall Paper Adhesive Post Application	20	No mitigation required	<3 x 10-9
6 x 10-7	No mitigation required

Formaldehyde Occupational Risks 

Formaldehyde should be only be used with appropriate work practices and
engineering controls such that exposures do not exceed the EPA level of
concern of 0.1 ppm.  This can be accomplished by one or more of the
following:

The open pouring of formaldehyde solutions should be minimized to low
volume applications where the amount of concentrate handled is less than
a couple of gallons per day.  

Automatic addition systems that minimize operator exposure to the
concentrated product should be used when handling larger amounts of
formaldehyde.  If this is not feasible then local exhaust ventilation
should be used to reduce formaldehyde exposure.

Fogging of poultry houses should only be done in such a way that the
operator is outside the poultry house when applying the fog.

Manual spray applications of formaldehyde solutions should only be
conducted in well ventilated areas. 

Re-entry by unprotected persons should be allowed only after the
formaldehyde concentration has been reduced to 0.1 ppm. 

Paraformaldehyde Occupational and Residential Risks

To mitigate the occupational risks from paraformaldehyde use in beauty
salons and barber shops, it is recommended that these areas have general
ventilation that meets ASHRAE recommendations and/or local exhaust
ventilation that meets ACGIH recommendations.

To mitigate the residential risks from paraformadehyde use in closets
and vacation homes it is recommended that these uses be limited to
unoccupied areas that can be thoroughly ventilated prior to
re-occupancy. 

9.0	ENVIRONMENTAL RISKS

9.1	Ecological Hazard

9.1.1	Toxicity to Terrestrial Animals

9.1.1.1   Birds, Acute

	In order to establish the toxicity of formaldehyde to avian species for
indoor, aquatic, and industrial uses, the Agency requires an acute oral
toxicity study using the technical grade active ingredient (TGAI). The
preferred test species is either the mallard duck (a waterfowl) or
bobwhite quail (an upland game bird). The results of one acute oral
toxicity study, submitted for formaldehyde, are provided in the
following table (Table 9.1).

Table 9.1.  Acute Oral Toxicity of Formaldehyde to Birds

Species	

Chemical,

% (a.i.) 

Tested	

Endpoint

(ppm)	

Toxicity Category	

Satisfies Guidelines/

Comments	

Reference

(MRID)

Bobwhite quail

(Colinus virginianus)	Formaldehyde

37%

(as Surflo-B315)	LD50 = 790

NOAEL = 464	Slightly toxic	 Yes/core study

- 21-day test duration

	00148774

Formaldehyde:

	The results from one core study using bobwhite quail (00148774)
indicate that 37% a.i. formaldehyde is slightly toxic to avian species
on an acute oral basis. This study fulfills guideline requirement
71-1/OPPTS 850.2100 for formaldehyde.

Paraformaldehyde:

	No studies are available.

CONCLUSIONS:

	Formaldehyde formulations up to 37% a.i. are not expected to pose a
significant hazard to avian species. Paraformaldehyde formulations
contain up to 91% a.i., however, the two active paraformaldehyde labels
indicate that they are packaged in sealed bags, boxes, or other
containers that would prevent spills from occurring.  Therefore, the
avian hazard label statement is not required on formaldehyde or
paraformaldehyde product labels.

9.1.1.2	   Birds, Subacute

A subacute dietary study using the TGAI may be required on a
case-by-case basis depending on the results of lower-tier ecological
studies and pertinent environmental fate characteristics in order to
establish the toxicity of a chemical to avian species. The preferred
test species is either the mallard duck or bobwhite quail. The results
of two subacute dietary toxicity studies submitted for formaldehyde are
provided in Table 9.2.

Table 9.2.  Subacute Oral Toxicity of Formaldehyde to Birds

Species	Chemical,

% a.i. Tested	Endpoint

(ppm)	Toxicity Category	Satisfies Guidelines/

Comments	Reference

(MRID)

Bobwhite quail

(Colinus virginianus)	Formaldehyde 37%

(as Surflo-B315)	LC50 (diet) = >5000	Practically nontoxic	   Yes/core
study

-	8-day test duration	00148773

Mallard duck

(Anas platyrhynchos)	Formaldehyde 

37%

(as Surflo-B315)	

LC50 (diet) > 5000	Practically nontoxic	  Yes/core study

- 8-day test duration	00148775

Formaldehyde:

The results from two core studies (00148773 and 00148775) indicate that
37% a.i. formaldehyde is practically nontoxic to avian species through
subacute dietary exposure. These studies fulfill guideline requirements
71-2a (quail) and 71-2b (duck) /OPPTS 850.2200 for formaldehyde. 

Paraformaldehyde:

No studies are available.

CONCLUSIONS:

Formaldehyde formulations up to 37% a.i. are not expected to pose a
significant hazard to avian species. Paraformaldehyde formulations
contain up to 91% a.i., however, the two active paraformaldehyde labels
indicate that they are packaged in sealed bags, boxes, or other
containers that would prevent spills from occurring.  Therefore, the
avian hazard label statement is not required on formaldehyde or
paraformaldehyde product labels.

9.1.1.3   Mammals, Acute and Chronic Toxicity

Wild mammal testing is not required by the Agency. In most cases, rat
toxicity values obtained from studies conducted to support data
requirements for human health risk assessments substitute for wild
mammal testing.  Refer to the human toxicology chapter of this RED for
additional mammalian toxicity data.

9.1.2	Toxicity to Aquatic Animals

9.1.2.1   Freshwater Fish, Acute

	

	In order to establish the acute toxicity of formaldehyde and
paraformaldehyde to freshwater fish, the Agency requires one freshwater
fish toxicity study using the TGAI. The preferred test species is the
rainbow trout (a coldwater fish) or the bluegill sunfish (a warmwater
fish). The results of 25 freshwater fish acute studies for various
formulations and concentrations of formaldehyde a.i. are presented in
Table 9.3. The results of two freshwater fish acute studies submitted
for paraformaldehyde are presented in Table 9.4.

Table 9.3. Acute Toxicity of Formaldehyde to Freshwater Fish

Species	Chemical,

% a.i. Tested	Endpoint

(ppm)	Toxicity Category	Satisfies Guidelines/

Comments	Reference

(MRID)

Rainbow trout (Oncorhynchus mykiss)	Formaldehyde

37%	LC50 = 118

NOAEC = 70

	Practically nontoxic	Yes/core study

   - 96-hr test duration

   - static test system	00132485

Rainbow trout (Oncorhynchus mykiss)	Formaldehyde 25.9%

(as Surflo-B16)	LC50 = 73.3

(a.i.)	Slightly toxic	  No/supplemental study

-  96-hr test duration

-  static test system	00101857

Rainbow trout (Oncorhynchus mykiss)	Formaldehyde 32.37%

(as Surflo-B17)	LC50 = 2.24

(a.i.)	Moderately toxic	  No/supplemental study

-  96-hr test duration

-  -  static test system	00101857

Rainbow trout (Oncorhynchus mykiss)	Formaldehyde

27.75%

(as Surflo-B19)	LC50 = 1.41

(a.i.)	Moderately toxic	  No/supplemental study 

-  96-hr test duration

-  -  static test system	00101857

Rainbow trout (Oncorhynchus mykiss)	Formaldehyde

18.8%

(as Russell’s Incubator Fumigant)	LC50 > 100 

	Practically nontoxic	  No/ supplemental study

-  -  96-hr test duration

-  -  static test system	00134124

Bluegill sunfish

(Lepomis macrochirus)	Formaldehyde

37%	LC50 = 100

NOAEC = 50	Slightly toxic	  Yes/core study 

-  -  96-hr test duration

-  -  static test system	00132485

Bluegill sunfish

(Lepomis macrochirus)	Formaldehyde 25.9%

(as Surflo-B16)	LC50 = 41.4	Slightly toxic	  No/supplemental study 

-  - 96-hr test duration

-  - static test system	00101857

Bluegill sunfish

(Lepomis macrochirus)	Formaldehyde 32.37%

(as Surflo-B17)	LC50 = 1.79	Moderately toxic	  No/supplemental study 

-  - 96-hr test duration

-  - static test system	00101857

Bluegill sunfish

(Lepomis macrochirus)	Formaldehyde

27.75%

(as Surflo-B19)	

LC50 = 1.51	Moderately toxic	  No/supplemental study

-  - 96-hr test duration

-  - static test system	00101857

Bluegill sunfish (Lepomis macrochirus)	Formaldehyde 

37%

(as Parson’s Formaldehyde)	LC50 = 68	Slightly toxic	  No/supplemental
study

-  - 96-hr test duration 

   - static test system	00134126

Bluegill sunfish (Lepomis macrochirus)	Formaldehyde  8.8%

(as Russell’s Incubator Fumigant)	LC50 > 118 	Practically nontoxic
No/supplemental study

	- 96-hr test duration

-	- static test system	00134123

Atlantic salmon

(Salmo salar)	Formaldehyde

37%	LC50 = 173	Practically nontoxic	No/supplemental study

-	- 96-hr test duration

-	- static test system	00132485

Lake trout 

(Salvelinus namaycush)	Formaldehyde

37%	LC50 = 100	Slightly toxic	No/supplemental study

-	- 96-hr test duration

-	- static test system	00132485

Black bullhead

(Ameiurus melas)	Formaldehyde

37%	LC50 = 62.1	Slightly toxic	No/supplemental study

-	- 96-hr test duration

- static test system	00132485

Channel catfish

(Ictalurus punctatus)	Formaldehyde

37%	LC50 = 65.8	Slightly toxic	No/supplemental study

-	- 96-hr test duration

- static test system	00132485

Green sunfish

(Lepomis cyanellus)	Formaldehyde

37%	LC50 = 173	Practically nontoxic	 No/supplemental study

-	- 96-hr test duration

- static test system	00132485

Smallmouth bass

(Micropterus dolomieu)	Formaldehyde

37%	LC50 = 136	Practically nontoxic	 No/supplemental study

-  - 96-hr test duration

- static test system	00132485

Largemouth bass

(Micropterus salmoides)	Formaldehyde

37%	LC50 = 143	Practically nontoxic	 No/supplemental study

-	- 96-hr test duration

- static test system	00132485

Table 9.4.  Acute Toxicity of Paraformaldehyde to Freshwater Fish

Species	Chemical,

% (a.i.)

Tested	Endpoint

(ppm)	Toxicity Category	Satisfies Guidelines/

Comments	Reference

(MRID)

Rainbow trout (Oncorhynchus mykiss)	Paraformaldehyde

91%

(as Aldacide)	LC50 = 51.2 (a.i.)

NOAEC = 32 (a.i.)	Slightly toxic	No /supplemental study 

-	- 96-hr test duration

-  - static test system	00101865

Bluegill sunfish

(Lepomis macrochirus)	Paraformaldehyde

91%

(as Aldacide)	LC50 = 39.1

NOAEC = 32 (a.i.)	Slightly toxic	   No /supplemental study 

-  - 96-hr test duration

-  - static test system	00101865

Formaldehyde:

Freshwater fish endpoints from various formaldehyde formulations (8.8%
to 37%) ranged from 1.41 mg a.i./L to185.0 mg a.i./L.  Of 9 fish species
tested, the Rainbow trout and Bluegill sunfish were the most sensitive. 
No TGAI studies are available.

Paraformaldehyde:

The results of two supplemental studies for paraformaldehyde indicate
that paraformaldehyde is slightly toxic to freshwater fish.

CONCLUSIONS:  

	

	The results of one core formulation study for the rainbow trout
(00132485) and one core formulation study for the bluegill sunfish
(00132485) indicate that up to 37% a.i. formaldehyde is slightly to
practically nontoxic to freshwater fish on an acute basis. These studies
fulfill guideline requirement 72-1c (rainbow trout)/OPPTS 850.1075 and
guideline requirement 72-1a (bluegill)/OPPTS 850.1075 for formaldehyde
and paraformaldehyde. The core studies are supported by numerous
supplemental studies that indicate formaldehyde (up to 37% a.i.) ranges
in toxicity from moderately to practically nontoxic freshwater fish
species on an acute basis. Two TGAI studies for paraformaldehyde (91%
a.i.) indicate that it is slightly toxic to freshwater fish.  

	Formaldehyde formulations up to 37% a.i. are not expected to pose a
significant hazard to freshwater fish species. Paraformaldehyde
formulations contain up to 91% a.i., however, the two active
paraformaldehyde labels indicate that they are packaged in sealed bags,
boxes, or other containers that would prevent spills from occurring.
Toxicity data further indicate that a warning statement is not necessary
for paraformaldehyde labels.  

	The freshwater fish hazard label statement is not required on
formaldehyde or paraformaldehyde product labels. 

9.1.2.2   Freshwater Invertebrates, Acute

The Agency requires a freshwater aquatic invertebrate study using the
TGAI to establish the acute toxicity to freshwater invertebrates. The
preferred test species is Daphnia magna. The results of one study
submitted for formaldehyde are provided in Table 9.5.

Table 9.5.  Acute Toxicity of Formaldehyde to Freshwater Invertebrates 

Species	Chemical,

% a.i. Tested	Endpoint

(ppm)	Toxicity Category	Satisfies Guidelines/

Comments	Reference

(MRID)

Waterflea 

(Daphnia magna)	Formaldehyde 37%

(as Surflo-B315)	LC50 = 14.31	

Slightly toxic	No/supplemental study

-  48-hr test duration

-  static test system	00148772

Formaldehyde:

The results of a supplemental LC50 study in Daphnia (00148772) indicate
that formaldehyde is slightly toxic to freshwater invertebrates. This
study does not fulfill guideline requirement 72-2a/OPPTS 850.1010 for
formaldehyde and must be repeated.  Study MRID 00148772 was not useful
for determining an EC50.

Paraformaldehyde:

No data are available.

CONCLUSIONS:

Formaldehyde formulations up to 37% a.i. are not expected to pose a
significant hazard to freshwater invertebrate species. Paraformaldehyde
formulations contain up to 91% a.i., however, they are packaged in
sealed bags, boxes, or other containers that would prevent spills from
occurring.  Therefore, the freshwater invertebrate hazard label
statement is not required on formaldehyde or paraformaldehyde product
labels.

9.1.2.3   Estuarine and Marine Organisms, Acute

Acute toxicity testing with estuarine and marine organisms using the
TGAI is required when the end-use product is intended for direct
application to the marine and/or estuarine environment or effluent
containing the active ingredient is expected to reach this environment.
Three acute estuarine/marine aquatic species tests are required due to
potential for spills to occur during oil drilling water or mud
injections and packer fluid use.  The acute estuarine/marine toxicity
tests are used for hazard labeling purposes. The preferred fish test
species is the Atlantic silverside. The preferred invertebrate test
species are shrimp and the Eastern oyster. The results of 13 toxicity
studies on estuarine or marine organisms submitted for formaldehyde are
presented in Table 9.6. The results of three toxicity studies on
estuarine or marine organisms submitted for paraformaldehyde are
presented in Table 9.7.

Table 9.6.  Acute Toxicity of Formaldehyde to Estuarine and Marine
Organisms

Species	Chemical,

% a.i. Tested	Endpoint

(ppm)	Toxicity Category	Satisfies Guidelines/

Comments	Reference

(MRID)

Silverside

 (Menidia enidia)	Formaldehyde 37%	LC50 = 69	Slightly toxic	  Yes/core
study

- 96-hr test duration

- static test system	00148770

Pink shrimp (Penaeus duoratum)	Formaldehyde 37%	LC50 = 143	Practically
nontoxic	 Yes/core study

- 96-hr test duration

- static test system	00148770

Pink shrimp (Penaeus duorarum)	Formaldehyde

27.75%

(as Surflo-B19)	LC50 = 7.6	Moderately

toxic	 No/supplemental study

- 96-hr test duration

- static test system	00126396

Pink shrimp (Penaeus duorarum)	Formaldehyde

25.9%

(as Surflo-B16)	LC50  = 358	Practically

nontoxic

	 No/supplemental study

- 96-hr test duration

- static test system	00128086

Pink shrimp (Penaeus duoratum)	Formaldehyde

32.37%

(as Surflo-B17)	LC50 = 12	Slightly

toxic	 No/supplemental study

- 96-hr test duration

- static  test system	00126394

Eastern oyster (Crassostrea virginica)	Formaldehyde

37%	EC50 = 1.8	Moderately toxic	 Yes/core study

- 48-hr test duration

- static test system	00148770

Eastern oyster (Crassostrea virginica)	Formaldehyde 27.75%

(as Surflo-B19)	EC50   = 0.30	

Highly toxic	 No/supplemental study

- 48-hr test duration

- static test system	

00126396

Eastern oyster (Crassostrea virginica)	Formaldehyde25.9%

(as Surflo-B16)	EC50 = 2.9	Moderately

toxic

	No/supplemental study

- 48-hr test duration

- static test system	00128086

Eastern oyster (Crassostrea virginica)	Formaldehyde32.37%

(as Surflo-B17)	EC50   = 0.47	Highly toxic	No/supplemental study

- 48-hr test duration

- static  test system	00126394

Fiddler crab

(Uca pugilator)	Formaldehyde 25.9%

(as Surflo-B16)	LC50 > 1000	Practically nontoxic	No/supplemental study

- 96-hr test duration

- static test system	00128086

Fiddler crab

(Uca pugilator)

	Formaldehyde

27.75%

(as Surflo-B19)	EC50 = 380	Practically nontoxic	No/supplemental study

- 96-hr test duration

- static test system	00126396

Fiddler crab

(Uca pugilator)	Formaldehyde

32.37%

(as Surflo-B-17)	EC50= 290	Practically nontoxic	No/Supplemental study

- 96-hr test duration

- static test system	00126394

Florida pompano

(Trachinotus carolinus)	Formaldehyde

37%	LC50 = 69	Slightly toxic	No/supplemental study

- 96-hr test duration

- static test system	00065640



Table 9.7.  Acute Toxicity of Paraformaldehyde to Estuarine and Marine
Organisms

Species	Chemical,

% a.i. Tested	Endpoint

(ppm)	Toxicity Category	Satisfies Guidelines/

Comments	Reference

(MRID)

Pink shrimp (Penaeus duoratum)	Paraformaldehyde

91%

(as Aldacide)	LC50 = 31

	Slightly toxic	  Yes/core study 

- 96-hr test duration 

- static test system 	00126395 

Eastern oyster (Crassostrea virginica)	Paraformaldehyde

91%

(as Aldacide)	EC50   >3.2, <5.6

	Moderately toxic	  Yes/core study

- 48-hr test duration 

- static test system	00126395

Fiddler crab

(Uca pugilator)	Paraformalde-hyde

91%

(as Aldacide)	LC50 = 213	Practically nontoxic	 No/supplemental study

-  96-hr test duration

-  static test system	00126395

Formaldehyde:

The results of a core study in the silverside (00148770), a core study
in the pink shrimp (00148770) and a core study in the eastern oyster
(00148770) indicate that formaldehyde is slightly toxic to
estuarine/marine fish and practically nontoxic to moderately toxic to
estuarine/marine invertebrates on an acute basis. The core study in the
silverside fulfills the guideline requirement for an acute toxicity test
for estuarine/marine fish (72-3a/OPPTS 850.1075) for formaldehyde. The
core study in the pink shrimp fulfills the guideline requirement for an
acute toxicity test for estuarine/marine shrimp (72-3c/OPPTS 850.1035)
for formaldehyde. The core study in the eastern oyster fulfills the
guideline requirement for an acute toxicity test for an estuarine/marine
mollusk (72-3b/OPPTS 850.1025) for formaldehyde. Supplemental studies in
invertebrates indicate that formaldehyde is moderately toxic to shrimp,
highly toxic to eastern oysters, and practically nontoxic to fiddler
crabs.  

Paraformaldehyde:

	The results of a core study in the pink shrimp (00126395) and a core
study in the eastern oyster (00126395) indicate that paraformaldehyde is
slightly to moderately toxic to estuarine/marine invertebrates on an
acute basis. A supplementary study in the fiddler crab indicates that
paraformaldehyde is practically nontoxic to this species.

CONCLUSIONS:

The most sensitive estuarine/marine organisms to formaldehyde and
paraformaldehyde are oysters followed by shrimp, followed by fish,
followed by crabs.  Two E. oyster toxicity tests indicate high toxicity,
therefore, formaldehyde product labels must state:  “This product is
toxic to oysters.”  

Paraformaldehyde formulations contain up to 91% a.i., however, the two
active paraformaldehyde labels indicate that they are packaged in sealed
bags, boxes, or other containers that would prevent spills from
occurring.  The oyster hazard warning statement is not required on
paraformaldehyde labels.

9.1.2.4   Aquatic Organisms, Chronic

Chronic toxicity testing (fish early life stage and aquatic invertebrate
life cycle) is required for pesticides when certain conditions of use
and environmental fate apply. The preferred freshwater fish test species
is the fathead minnow, but other species may be used. The preferred
freshwater invertebrate is Daphnia magna. This testing is not required
for formaldehyde or paraformaldehyde because of the current use
patterns. 

9.1.3	Toxicity to Plants

Nontarget plant phytotoxicity testing is required for pesticides when
certain conditions of use and environmental fate apply.  Testing is
conducted with 5 aquatic plants:  aquatic macrophyte Lemna gibba
(850.4400), green algae Selenastrum capricornutum (850.5400), blue-green
cyanobacteria Anabaena flos-aquae (850.5400), freshwater diatom Navicula
pelliculosa (850.5400), and a marine diatom Skeletonema costatum
(850.5400). Depending on the use pattern, seedling emergence and
vegetative vigor studies using the rooted aquatic vascular plant rice
(Oryza sativa) may be required as well.  

Nontarget plant phytotoxicity tests are not required for current
formaldehyde or paraformaldehyde use patterns.

9.2	Environmental Fate Assessment

There are currently 6 active products containing formaldehyde and 2
active products containing paraformaldehyde. The chemicals are used as
disinfectants, bacteriocides, algaecides, fungicides and also used in
oil drilling to preserve oil field water systems. There are no inert
uses for Formaldehyde or Paraformaldehyde.

The Agency’s in-house database does not have environmental fate and
transport data on formaldehyde or paraformaldehyde. The Antimicrobials
Division has thus relied on open literature for fate and transport
studies. There are no published studies on the fate and transport of
paraformaldehyde. When left alone, paraformaldehyde off-gases as
formaldehyde from a solution containing formaldehyde/paraformaldehyde.
It is therefore, assumed that paraformaldehdye in different
environmental media will have fate and transport behavior similar to
formaldehyde. 

 Half-live of formaldehyde has been reported between 24-168 hours (1-7
days) in surface water and 48-336 hours (2- 14 days) in groundwater
based on scientific judgment and estimated aqueous aerobic
biodegradation half lives. Formaldehyde, therefore, is not likely to
persist in natural waters. The ATSDR notes that when formaldehyde is
released into water it biodegrades to low levels in a few days. 

  

A Koc value of 1.567 was estimated for formaldehyde; therefore, it is
not expected to adsorb to soils and is likely to be mobile in soils.
Compounds with a Koc value of less than <100 are considered to be
moderately mobile in soils and may contaminate groundwater.
Octanol/Water partition is low (log Kow = 0.65). Therefore formaldehyde
is not likely bioaccumulate in aquatic organisms.

Half life of formaldehyde in air has been found to depend on the time of
the day, intensity of natural light, temperature, and location. Based on
its reaction with hydroxy radical using hydroxyl radical rate constant),
half life of formaldehyde in air varies between 7 to 70 hours. One study
even estimated the air half life to vary between 0.3 to 250 hours. This
study, however, assumed there was hydroxyl or hydroperoxyl radicals were
present. It is not likely to persistent in air. Degradation products
from this interaction likely are: water, formic acid, carbon monoxide
and intermediate adduct likely hydroperoxyl/formaldehyde. Air photolytic
half life of formaldehyde has been estimated between 1.6 to 6 hours.

One study has shown that formaldehyde in lake water metabolizes
aerobically as well as anaerobically. Half-life under aerobic conditions
was about 30 hours and under anaerobic conditions about 48 hours. 

9.3	Environmental Exposure and Ecological Risk Assessment

Formaldehyde and paraformaldehyde labeled uses including oilfield uses
such as treatments of drilling muds and waterfloods are considered by AD
to pose little adverse risk to non-target organisms or listed species.
Antimicrobials are typically minor use chemicals, diluted and greatly
reduced before discharge into water, and are often regulated by other
Federal or EPA offices (OW, Office of Solid Waste, OPPTS, state NPDES
permits). In the case of oil fields, the US Department of the Interior,
Minerals Management Service (MMS) had jurisdiction over the
environmental impacts of synthetic drilling fluids in terrestrial and
aquatic areas.  

Terrestrial oil fields typically use berms and catch basins to prevent
surface runoff of oil drilling muds and wastes from oil drilling areas.
Estuarine and marine aquatic organisms may be temporarily exposed during
marine drilling, however, impacts are limited to a defined area around
the oil well (Neff, 2000).  

The AD hazard labeling review for low environmental exposure sites and
terrestrial oilfield pesticides requires the submission of three
ecotoxicity tests:  one acute oral bird, one acute freshwater fish, and
one acute freshwater aquatic invertebrate. If the pesticide is to be
used in estuarine or marine environments, three additional acute
estuarine/marine toxicity studies are required. The ecological hazard
assessment has determined that formaldehyde product labels must state:
“This product is toxic to oysters.” 

9.4	Endangered Species Considerations

Section 7 of the Endangered Species Act (ESA), 16 U.S.C. Section
1536(a)(2), requires that federal agencies consult with the National
Marine Fisheries Service (NMFS) for marine and andronomus listed
species, or with the United States Fish and Wildlife Services (FWS) for
listed wildlife and freshwater organisms, if proposing an "action" that
may affect listed species or their designated habitat. Each federal
agency is required under the Act to insure that any action they
authorize, fund, or carry out is not likely to jeopardize the continued
existence of a listed species or result in the destruction or adverse
modification of designated critical habitat. To jeopardize the continued
existence of a listed species is to "to engage in an action that
reasonably would be expected, directly or indirectly, to reduce
appreciably the likelihood of both the survival and recovery of a listed
species in the wild by reducing the reproduction, numbers, or
distribution of the species." 50 C.F.R. §402.02.

To comply with subsection (a)(2) of the ESA, EPA’s Office of Pesticide
Programs has established procedures to evaluate whether a proposed
registration action may directly or indirectly appreciably reduce the
likelihood of both the survival and recovery of a listed species in the
wild by reducing the reproduction, numbers, or distribution of any
listed species (U.S. EPA 2004). If any of the Listed Species LOC
Criteria are exceeded for either direct or indirect effects in the
Agency’s screening-level risk assessment, the Agency identifies any
listed or candidate species that may occur spatially and temporally in
the footprint of the proposed use. Further biological assessment is
undertaken to refine the risk. The extent to which any species may be at
risk determines the need to develop a more comprehensive consultation
package as required by the ESA.

For certain use categories, including all current formaldehyde and
paraformaldehyde uses, the Agency assumes there will be minimal
environmental exposure, and only a minimal toxicity data set is required
(Overview of the Ecological Risk Assessment Process in the Office of
Pesticide Programs U.S. Environmental Protection Agency - Endangered and
Threatened Species Effects Determinations, 1/23/04, Appendix A, Section
IIB, p 81). Uses in these categories do not undergo a full
screening-level risk assessment and are considered to generally fall
under a “no effect” determination, however, an endangered species
effect determination will not be made at this time.  

10.0	INCIDENT REPORTS

	The Agency reviewed the following information for human poisoning
incidents related to formaldehyde use: (1) OPP Incident Data System
(IDS) – The Office of Pesticides Programs (OPP) Incident Data System
contains reports of incidents from various sources, including
registrants, other federal and state health and environmental agencies
and individual consumers, submitted to OPP since 1992; (2) California
Department of Pesticide Regulation (1982-2004) - The California
Department of Pesticide Regulation pesticide poisoning surveillance
program consists of reports from physicians of illness suspected of
being related to pesticide exposure since 1982. (3) National Poison
Control Centers (PCC) (1993-1996). (4) Incident Reports /
Epidemiological Studies Published in Scientific Literature

(1) OPP Incident Data System (IDS	

Seven incidents reported for human exposure to formaldehyde occurred in
hospital workers (sterilization of instruments and spill clean-up) and
in persons handling or being in close proximity to pesticide
formulations containing this active ingredient (in combination with
other chemicals). Five of the 7 incidents reported were solely due to
inhalation of these chemical vapors. In one incident, where deliberate
and intentional disposal of 9 gallons of formaldehyde (together with
other variable quantities of chemicals) into the school drains exposed
students to several mixtures of chemical vapors. One of the students
affected was hospitalized due to severe respiratory problems. In a
second incident, the person was exposed to a mixture of chemicals
(formaldehyde, glacial acetic acid and sodium meta-bisulfite) in a
holding tank, next to his work station; and suffered from insomnia,
disorientation, bronchitis, sore throat and severe pain in hands and
feet. Following a six month period, this person became totally
non-functional. In the third incident, respiratory and gastro-intestinal
tract problems were observed in 17 hospital workers who cleaned up
spills of chemicals containing 4% glutaraldehyde and 3% formaldehyde. In
the fourth incident, a technician working in proximity to glutaraldehyde
and formaldehyde experienced asthma, arrhythmia, rhinitis, and was
diagnosed as being sensitized to formaldehyde. Similar effects were
observed in the fifth incident of human exposures to formaldehyde in
combination with other chemicals.  

The remaining 2 of 7 incidents occurred via combined routes (inhalation,
dermal and ocular). A hospital worker exposed to formaldehyde and
glutaraldehyde developed asthma, arrhythmia, airway disease, mucous in
the throat, shortness of breath, rhinitis, dermatitis, eye irritation,
focusing difficulties and symptoms of corneal burn. In another incident,
a female worker selling industrial/laundry chemicals and pesticides
(chlorinated organophosphorous pesticides, diazinon, malathion,
formaldehyde, methyl ethyl ketone, perchloroethylene, sodium cyanide,
benzene, toluene, vinyl chloride, DDT, chlordane, hepatochlor,
trichloroethene, sodium sulfate, sodium chloride, sodium hypochlorite,
chloroethene, herbicides, volatile organics, acid components, base
neutral compounds and dissolved metals) experienced headaches, mental
confusion, cutaneous T-cell lymphoma, syncopal spells, seizures,
dizziness, loss of equilibrium, nausea, dermatitis, skin irritation and
a rash, that continued for seven years.

(2) California Department of Pesticide Regulation (1982-2004)

There are 116 incidences that have been reported in the California
Pesticide Surveillance Program Database (1982-2004) as definitely or
probably related to formaldehyde alone or in combination. Symptoms
associated with eyes are the primary reported illness in all the
associated incidences. Nausea, dizziness, headache, and sore throat are
the primary systemic effects that have been reported. The primary dermal
effects that have been reported are rash, burning sensation, itching,
dry scaling irritation, cracking and thickened skin, itching, and
blisters and rash on hands. Although there were some people who were
unable to work after exposure for a certain period of time, no one was
hospitalized.

(3) National Poison Control Centers (PCC) (1993-1996).

No incidences were reported in the Poison Control Center Data.

(4) Incident Reports / Epidemiological Studies Published in Scientific
Literature

Numerous reported incidents and epidemiological studies have been
published in the open scientific literature regarding effects from
formaldehyde exposure.  Non-cancer effects reported have included
allergic contact dermatitis from dermal exposures, irritation of the
mucosa of the eyes and upper airways, headache, fatigue, asthma, and
decreases in pulmonary function from inhalation exposure, and
gastrointestinal damage and abdominal pain from oral exposure.
Carcinogenic effects reported in numerous epidemiological studies have
included both nasopharyngeal cancer and lymphohematopoietic cancer
associated with formaldehyde exposures. 

11.0	REFERENCES

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meta analysis of the epidemiologic evidence. Scand. J. Work Environ.
Health 19(1):8-15.  

Paustenbach, D., Y. Alarie, T. Kulle, N. Schachter, R. Smith, J.
Swenberg, H. Witschi, and S.B. Horowitz. (1997). A recommended
occupational exposure limit for formaldehyde based on irritation. J.
Toxicol. Environ. Health 50(3): 217-263. 

Porter JAH. (1975). Acute respiratory distress following formalin
inhalation. Lancet 1:603-604. 

Rudzki E, Rebandel P, Grzywa Z. (1989). Patch tests with occupational
contactants in nurses, doctors and dentists. Contact Dermatitis
20:247-259. 

Sneddon, I.B.  (1968). Dermatitis in an intermittent haemodialysis unit.
 Br. med. J., 1: 183-184. 

Solomons K, Cochrane JWC. (1984). Formaldehyde toxicity: Part 1.
Occupational exposure and a report of 5 cases. S Afr Med J 66:101-102. 

Solomons K, Cochrane JWC. (1984). Formaldehyde toxicity: Part 1.
Occupational exposure and a report of 5 cases. S Afr Med J, 66:101-102. 

Uba, G., et al. (1989). Prospective Study of Respiratory Effects of
Formaldehyde among Healthy and Asthmatic Medical Students. Am. J. Ind.
Med. 15: 91-101.   

Weber-Tschopp A, Fisher T, Granjean E. (1977). Irritating effects of
formaldehyde on men. Int Occup Environ Health. 39:207-218. 

WHO (World Health Organization). (1989). Formaldehyde WHO Environmental
Health Criteria , 89 (1989) 219 p 

WHO (World Health Organization). (2002). Formaldehyde, Concise
International Chemical Assessment Document 40. Geneva: World Health
Organization 

Wilson, JT Jr., M.D. (1987). Formaldehyde Exposure Following Urea
Formaldehyde Insulation.  Environmental Health and Safety News,
University of Washington, v.26.



APPENDIX A – Physical and Chemical Properties of 

Formaldehyde and Paraformaldehyde



Table A1.  Physical/Chemical Properties for Formaldehyde and
Paraformaldehyde

Parameter	Formaldehyde	Paraformaldehyde

Molecular Weight	30.03 (Gas)

48.03 (Aqueous solution)	(30.03)n g/mole

Color	Clear Colorless (54% soln.)

Clear Colorless (37% soln.)

Colorless (Gas)	White prill

White crystalline solid

White solid flakes

Physical State	Liquid (54% solution)

Liquid (37% solution)

Gas	Solid, flakes, Powder

Odor	Pungent (54% solution)

Pungent (37% solution)

Pungent, suffocating  irritating odor (Gas)	Pungent formaldehyde odor

Melting Point	N/A (54% & 37%  solution)

N/A (Gas at room temperature)

-92ºC (Gas)	120 to 170ºC closed tube

Boiling Point	~100ºC (54% solution)

101ºC (214ºF) (37% soln.)

-19.5ºC (-3ºF) – (Gas)

-21ºC (Gas)	Solid at ambient temperature

Slowly sublimes to formaldehyde gas.

760 mm Hg

Sublimes at 150ºC

Density/Bulk Density/Specific Gravity	8.83 lbs/gal – 54% soln

Sp gr. 1.067 – 54% soln

8.75 to 9 lbs/gal – 37% soln

Sp gr. 1.05 at 75ºF – 37% soln

Sp gr. 1.08 at 20ºC – 37% soln

0.8153 gm/cm3 @ 20ºC (Gas)

0.815 g/mL at 20ºC (Gas)

1•kg·m-3 (Gas)	750 to 850 kg/m3 

Density: 1.46 g/ml @ 15ºC

Density varies with particle size and degree of compaction.

Free flowing: approx. 37 lbs/cu ft

Packed: approx.  42 lbs/cu ft

ents at 25˚C (g/100 ml)	At low temperatures, liquid formaldehyde is
miscible in all proportions with a wide variety of non-polar organic
solvents such as toluene, ether, chloroform and ethyl acetate. 

Polar solvents such as alcohols, amines or acids either act as
polymerization catalysts or react to form methylol or methylene
derivatives.

Soluble in ether, alcohol, acetone, and benzene.	Acetone: Soluble to
insoluble

Dilute Alkali: Very Soluble

Dilute Acid: Very Soluble

Insoluble in alcohol, ether.  Insoluble in most organic solvents.
(TOXNET).

Solubility (Room Temperature):

• Ethanol 2.37%

• Methanol 4.71%

• Hexane 5.10 ppm

• Ether 108 ppm

• 1.0 N NaOH 22.9%

• 0.1N NaOH 22.8%

Solubility	Miscibility 100% in water (54% & 37% solutions).	>90% in
water at pH 9.0

Slightly soluble in cold water.

Difficulty Soluble.

Partial – dependent on pH, temperature and molecular weight.

The higher polymers are insoluble in water. The rate at which
paraformaldehyde dissolves (hydrolyzes) in water is at a minimum at pH
3-5; it increases rapidly at lower or higher pHs. (TOXNET)

Dissolves slowly in cold water, more rapidly in hot water, hydrolyzing
and depolymerizing as it dissolves.

Vapor Pressure

Vapor Density	40 mmHg 30ºC – 54% soln

40 mmHg 30ºC – 37% soln

1 mm Hg /Formalin (TOXNET)

A 37% formaldehyde solution has a vapor pressure of about 1.3 mm Hg at
68ºF, and 67 - 88 mm Hg at 98ºF

3,890 mm Hg @ 25ºC (Gas) (TOXNET)

1.04 (Air=1 at 20 deg. C) (Gas)	1.45 pCH2 (mm) depolymerization pressure
at 25ºC

1 mm Hg @ 30ºC

1.4 mm Hg @25ºC

1.55 mm Hg

@30ºC mm Hg Dry Air 1; Dew point 3

@60ºC mm Hg Dry Air 5; Dew point 15

10.5 mm Hg @ 25ºC (TOXNET)

1.03 (Air=1)

Dissociation constants in water	(54%)The dissociation constant in a
water solution at 25ºC is 1.62 x 10-13

37% soln.:

1.6 X 1OE-13 aqueous formaldehyde, no formic acid.

1.8 X 1OE-4 for formic acid.

Formaldehyde will have no dissociation constant In the gaseous state.
1.6 x 10E-13 aqueous formaldehyde no formic acid

1.8 x l0E-4 for formic acid

pKa = 15.50 @ 25ºC (TOXNET)

Partition coefficient

(n-octanol / water)	1.06 at a concentration of 25.42% (Gas)

-0.65 (calculated)

log Kow= 0.35 (Gas) (TOXNET/ EPI Suite)	-0.65 (calculated)

pH	5.5 – 6.2  (54% soln)

5.83 (54% soln)

3.5 – 4.5 (37% soln)

4 to 5 (37% soln)

Formaldehyde gas has no pH	3.5 – 4.5 (In aqueous  solution)

A 5% suspension in water is neutral to litmus (TOXNET).

Stability to normal and elevated temperatures. 

Stability to metals.

Stability to metal ions.	>30 days at 50ºC (54% soln)

A thirty-seven percent (37%) formaldehyde/water solution is stable at
35ºC for periods of six months to one year.

In excess of 2 years (37% soln)

Stable under ordinary conditions of use and storage (37%).

Formaldehyde gas is unstable and can polymerize quite easily (Gas).
Stable.

Paraformaldehyde is stable on exposure to sunlight, elevated
temperatures (54°C) and elemental metals, copper, iron and aluminum.

Stable under ordinary conditions of use and storage.  Releases
formaldehyde gas slowly as it sublimes at room temperatures.  (Slowly
sublimes to formaldehyde).

High temperature causes liberation of formaldehyde gas.

Stable for up to 12 months when stored at ambient temperatures.

Flammability	Closed cup (PM) +54ºF (54% soln)

~100ºF (54%)

Flash Pt. 134ºF

Flash point: 122ºF (37% soln)

>140ºF – 37% soln

Flashpoint 60ºC (Gas)

Flammability limits at 25ºC 7–73%

Autoignition temperature 300ºC

Flammable (Gas)	~71ºC tag closed cup; 93ºC

Flash point: 70°C

158F Tag Closed Cup (TCC)

200F Tag Open Cup (TOC)

Flash Points: Closed Cup: 70°C (158°F).

158F Tag Closed Cup (TCC)

200F Tag Open Cup (TOC)

Storage stability	>30 days at 50ºC (54% & 37% solutions)

A thirty-seven percent  formaldehyde/water solution is stable at 35ºC
for periods of six months to one year.

Formaldehyde gas is unstable and can polymerize quite easily.	Stable for
up to 12 months when stored at ambient temperatures.

Product must be store at temperatures not higher than 25ºC.

Explodability	Upper ~70%; Lower ~7%  (54% & 37% soln)

37% Soln:

Lower Explosion Limit: 7 %

Upper Explosion Limit: 73%	Upper~70%; Lower~7%

Explosion limits: 7.0 – 73%

Autoignition temp: 300ºC (572ºF)

Viscosity	3 – 5 CPS @ 25ºC (54% soln.)

5–10 CPS @ 75ºC (37% soln)	N/A  Product is solid at 25ºC

Miscibility	Miscibility 100% in water (54% & 37% solutions)	~90% in
water at pH 9.0

Corrosion Characteristic	Moderate (54% & 37% solns.)

Aqueous formaldehyde is corrosive to carbon steel (TOXNET)

Corrosive to metal (Gas)	Moderate

Dielectric Breakdown Voltage	45e @20ºC

N/A	~450e @20ºC

Oxidation/Reduction: Chemical Incompatibility	Oxidation:

2HCHO + H2O2 + 2NaOH > 2HCOONa + 2H2O + H2 

HCHO + ½ O2 > HCOOH

HCHO + O2 > CO2 + H2O [Requires very high temperatures > 300 ºC]

2HCHO + O2 > 2CO + 2H2O

Reduction:

HCHO + H2 < > CH3OH

37% soln: Reacts with alkalies, acids, and oxidizers.

.

Incompatibility (Materials to Avoid): Strong oxidizing agents, caustics,
strong alkalies, isocyanates, anhydrides, oxides, and inorganic acids.

Gas:  Incompatibilities: Reacts explosively with peroxides, nitrogen
oxide and performic acid; can react with hydrogen chloride or other
inorganic chlorides to form bis(chloromethyl)ether (Source: Literature)
Oxidation:

2HCHO + H202 + 2NaOH > 2HCOONa + 2H20 + H2

HCH0+1/2 O2 > HCOOH

HCHO + 02 > C02 + H20 [Requires very high temp - >300°C]

2HCHO +02 > 2C0 + 2H20

Reduction:

HCHO + H2 < > CH3OH

Incompatibility:

Incompatible with strong acids, organic acids, strong oxidizing

agents, oxides, alkalies, strong bases, amines.  Combustible. Dust may
form an explosive mixture with air.  Liberates poisonous gases on
combustion.

Incompatibilities:

Caustics, strong alkalis, isocyanates, anhydrides, oxides and inorganic
acids.

Paraformaldehyde or concentrated formalin solutions may react violently
with strong oxidizing agents, ammonia, strong alkalis, isocyanates,
peracids, anhydrides and inorganic acids.

Hazardous Polymerization:

Will not occur.

APPENDIX B - Toxicity Profile for Formaldehyde and Paraformaldehyde



Table B1. Subchronic, Chronic, Other Toxicity Profiles for Formaldehyde
and Paraformaldehyde

Guideline Number/

Study Type/

Test Substance (% a.i.)	MRID Number (Year)/

Citation/ Classification/ Doses	Results

Subchronic Toxicity

870.3100

90-Day oral toxicity in rodents

Purity: 37% a.i.

	MRID 00124677

Driedger, A.; Walker, J.; Galloway, F. (1973) Letter sent to C. Smart
dated Oct 1, 1973: “Rat tolerance to Dietary Formaldehyde: Reference
No. AD-114-73, JRW-341-73.” (Unpublished study; submitted by Celanese
Chemical Co., Dallas, TX; CDL:094622-H)  

Not Reviewed 

10 male Holtzman rats/dose  

0, 0.3, 0.6, 1.2, or 2.4 % formaldehyde

	NOAEL:  0.3% formaldehyde

LOAEL: 0.6% formaldehyde, based on irritability, weight loss, hair loss,
yellowing of teeth, and decreased food consumption 

icantly different from controls are expected at formaldehyde
concentrations ≥ 0.50 %, believed due to decreased food consumption.

870.3100

28-Day oral toxicity in rodents

Purity: 60% a.i.

	MRID 00134114

Viguera, C.; Kundzins, M. (1960) “28-Day Oral Administration--Rats:
U.F. Concentrate-85|.” (Unpublished study; prepared by Hazleton
Laboratories, Inc.; CDL: 105284-C)  

Not Reviewed

10 Male Sprague-Dawley rats/dose

0, 79, 158, or 316 uL/kg/day, once daily, 5 days/ week, 20 doses

	Statistical evaluation of overall body weight gains and total food
consumption revealed no significant differences between the control
group and test groups. The appearance and behavior of the test rats were
comparable to those of the control rats. No pathological findings
associated with the oral administration of the test substance were
observed.

One rat exposed to 158 uL/kg/day died during the 4th week. Autopsy
revealed a pale, mottled liver. Three rats receiving the high dose of
formaldehyde showed slight salivation during the 4th week of the study.

870.3100

90-Day oral toxicity in rodents

Purity: 95% a.i., aqueous paraformaldehyde

	Johannsen, F.R., G.J. Levinskas A.S. Tegris (1986) Effects of
Formaldehyde in the Rat and Dog following Oral Exposure.  Toxicology
Letters 30:  1-6.  

Open Literature

Sprague-Dawley Albino Rat  

(15/sex/dose)

Formaldehyde was administered in the drinking-water at target doses of
0, 50, 100, or 150 mg/kg bw/d for 13 weeks (91 consecutive days)

	NOAEL: 50 mg/kg/day (M), 100 mg/kg/day (F)

LOAEL: 100 mg/kg/day (M), 150 mg/kg/day (F), based on decreased body
weight gain

No deaths or abnormal reactions were observed in rats administered
formaldehyde for 90 days.  Significant reductions in weight gain were
observed in both sexes at 150 mg/kg and in male rats given 100 mg/kg.
There was a dose-related decrease in liquid consumption in both male
rats (9%, 18%, and 31%) and females (13%, 22%, and 30%) administered
formaldehyde in their drinking water. There were no overall differences
in mean food intake or feed efficiency in rats at any test level, thus
reductions in body weight gain are considered to be a reflection of
systemic effects of formaldehyde. No statistically-significant
differences were observed in hematologic parameters in any treated rats.
No specific treatment-related effects were observed on any organ or
tissue, including possible target organs like the kidney, liver, and
lung. Clinical chemistry and urinalysis studies failed to indicate any
necrotic effects on muscle, kidney, liver, or heart. No differences were
apparent between absolute or relative organ weights of treated rats. No
treatment-related pathological changes were observed microscopically.

870.3100

28-Day oral toxicity in rodents

Paraformaldehyde (95% a.i., aqueous)

	Til, H.P., et al. (1988) Evaluation of the Oral Toxicity of
Acetaldehyde and Formaldehyde in a 4-week Drinking Water Study in Rats. 
Fd. Chem. Toxic. 26(5):  447-452. 

Open Literature

Rat (10/sex/dose)

0, 5, 25, or 125 mg/kg/day; a water-restricted group (10/sex) received
the same amount of water as liquid consumed by the high-dose groups

	NOAEL= 25 mg/kg/day

LOAEL = 125 mg/kg/day, based on yellowish fur from week 3 onward,
decreased food intake, decreased protein and albumin levels in blood
plasma, and histologic changes.

There were no deaths and the rats appeared healthy throughout the study.
 

The fur of the rats receiving 125 mg/kg/day showed a yellowish
discoloration from week 3 

onwards. Food intake of animals receiving the high dose was
significantly lower, whereas females receiving the low- and mid- dose
groups had increased food intake.  There were no significant changes in
hematology among the test groups.  Total protein and albumin levels in
the blood plasma were decreased in males in the high dose. Relative
kidney weights were increased at 125 mg/kg/day (p>0.05). Histologic
examination of test groups revealed: focal hyperkeratosis of the
forestomach (20/20); Focal gastritis (3/10 males, 3/10 females);
submucosal mononuclear-cell infiltrate (1/10 males); focal papillomatous
hyperplasia (1/10 females); and polymorphonuclear leukocytic
infiltration (1/10 females).  

The water- restricted group had slightly higher blood cell values in
males. Clinical chemistry and blood plasma changes observed include:
increased urea in males and females; decreased bilirubin levels and
increased chloride and sodium levels in males and decreased sodium,
calcium, and phosphorus in females.  Increased relative organ weights
were observed in male gonads (p<0.01), brains (males: p<0.05, females: 
p<0.01), male hearts (p<0.01), kidneys (p<0.01), and in the liver
(males:  p<0.01, females:  p<0.05). Histopath examination revealed
dilated fundic glands (2/10) in males.

870.3150

90-Day oral toxicity in nonrodents

Purity: Paraformaldehyde (95% a.i., aqueous)	Johannsen, F.R., G.J.
Levinskas, A.S. Tegris. (1986). Effects of Formaldehyde in the Rat and
Dog following Oral Exposure.  Toxicology Letters 30:  1-6. 

Open Literature

Beagle Dog (4/sex/dose)

0, 50, 75, or 100 mg/kg/day in drinking water for 90 days

	NOAEL: 75 mg/kg/day (M/F)

LOAEL: 100 mg/kg/day (M/F), based on reduced weight gain

No deaths or abnormal reactions were observed. Significant reductions in
weight gain were observed in both sexes at 100 mg/kg/day. Treated
animals had reduced food consumption and feed efficiency even at the
lower dosages (50 and 75 mg/kg/day) which did not depress weight gain.
Hematological values from treated dogs fell within normal limits.No
specific treatment-related effects were observed on any organ or tissue,
including possible target organs like the kidney, liver, and lung. 

870.3465

90-Day inhalation toxicity

	MRID 00082134

Coon, R.A. et al. (1970) Animal Inhalation Studies on Ammonia, Ethylene
Glycol, Formaldehyde, Dimethylamine, and Ethanol. Toxicology and Applied
Pharmacology 16:  646-655. 

Not Reviewed

15 Sprague-Dawley  and Long-Evans rats (M/F), 15 Princeton-derived
guinea pigs (M/F), 3 New Zealand rabbits (M), 3 squirrel monkeys (M), 2
Beagle dogs (M)

Formaldehyde Continuous exposure to 4.6 mg/m3, 8 hours/day, 5 days/week,
6 weeks	One of the 15 rats died; none of the other animals showed signs
of illness or toxicity. Hematologic values were normal. On
histopathologic examination, the lungs of all species consistently
showed varying degrees of interstitial inflammation. The hearts and
kidneys from guinea pigs and rats showed focal chronic inflammatory
changes.

870.3465

6-Week inhalation toxicity

Purity = 4.96%

	MRID 00149755

Rusch, G.; Rinehart, W. (1980) A 26 Week Inhalation Toxicity Study of
Formaldehyde in Monkey, Rat, and Hamster: Project No. 79- 7259.
Unpublished study prepared by Bio/dynamics Inc. 184 p.

Core-Supplementary 

Fisher 344 rats – 10/sex/dose; Syrian golden hamsters –
10/sex/doseand Cynomolgous monkeys – 6 males/dose

Test material (Formaldehyde, Lot #0611N-79) was administered at 0, 0,
0.20, 1.00, or 3.00 ppm equivalent to 0, 0, 0.19, 0.98 and 2.95 ppm,
respectively, for 26 weeks. 

	Treatment-related effects during the study were not seen. Compared to
controls, monkeys receiving 1.00 ppm showed increased incidence of dried
material around the nose, increased incidences of hoarseness and
congestion. 

Body weight

Compared to controls, no significant body weight changes were seen for
monkeys and hamsters throughout the study. The 3 ppm male and female
rats showed significant differences (p ≤ 0.01) from week 2-26 compared
to controls. 

Organ weight

Organ weights for monkeys and hamsters were not significantly different
compared to controls. Male and female rats in the 0.2 ppm group had
significant mean heart weight depression (p ≤ 0.01) compared to the
control. Males in the 3.0 ppm test group had significantly (p ≤ 0.01)
depressed mea absolute heart and kidney weights compared to the
controls, but the relative weights of these same tissues were
significantly increased for these same rats. Females in the 3.0 ppm test
group had significantly (p ≤ 0.01) depressed absolute heart weights
with the mean relative heart weight significantly increased (p ≤
0.01). For the 3 ppm group, the mean absolute and relative liver weights
were significantly depressed (p ≤ 0.01) compared to the controls. 

Gross and Microscopic Pathology

In monkeys, hamsters and rats, no abnormalities were seen in or
attributable to formaldehyde vapors. 

870.3465

90-Day inhalation toxicity

Purity: 97-99% a.i.	Woutersen, R.A. et al. (1987) Subchronic (13-week)
Inhalation Toxicity Study of Formaldehyde in Rats.  Journal of Applied
Toxicology, 7(1): 43-49. 

Open Literature

Rats (10/sex/dose)

0, 1.0, 10, or 20 ppm (0, 1.2, 12, or 24 mg/m3), 6 hr/day, 5 days/week

	NOAEL: 1.2 mg/m3

LOAEL: 12 mg/m3

In the high-dose group, uncoordinated locomotion, and climbing of the
cage walls were observed only during the 1st 30 minutes of each exposure
period.  Statistically-significant growth retardation occurred in males
and females of the high-dose group. Treatment-related changes were not
observed in the autopsy, except for a yellowish fur of mid- and
high-dose animals. No relevant differences were found in the
hematological and urinary parameters measured. Dose-related
histopathologic changes in the nose were observed in the mid- and
high-dose groups. Half of the 24 mg/m3 male rats showed squamous
metaplasia, occasionally accompanied by keratinization, of the
epithelium lining the vocal cord region of the larynx. The nasal
turbinates of rats exposed to12 or 24 mg/m3 formaldehyde exhibited a
marked increase in the number of labeled cells, practically all of which
were present in areas of the epithelium showing clear squamous
metaplasia and hyperplasia.

870.3465

90-Day inhalation toxicity

	Appelman, L.M. et al. (1988)  One-year Inhalation Toxicity Study of
Formaldehyde in Male Rats with a Damaged or Undamaged Nasal Mucosa. 
Journal of Applied Toxicology, 8(2):  85-90. 

Open Literature

Male albino Wistar rats  (Cpb:WU) -40/dose

Formaldehyde exposure via inhalation route for 6 hr/day, 5 days/week, 13
or 52 weeks at concentrations of  0.1, 1, or 10 ppm (0, 0.12, 1.24, or
12.4 mg/m3), 1/2 with bilaterally damaged nasal mucosa

	NOAEL = 1.24 mg/m3

LOAEL = 12.4 mg/m3, based on body weight retardation, incidence of
oliguria, and incidence of lesions of the respiratory and olfactory
epitheliums for damaged and undamaged animals

The nose damaged by electrocoagulation is more susceptible to cytotoxic
action of formaldehyde than the undamaged nose.  

8 animals (7 with damaged and 1 with undamaged nose) randomly
distributed among control and test groups, had to be killed in extremis
or were found dead. Growth retardation was observed in animals with or
without a damaged nose after 2 weeks exposure to 12.4 mg/m3
formaldehyde.

No relative differences were found between the hematological and urinary
parameters, with the exception of frequent oliguria (p<0.05) in the
high-dose group without nasal coagulation killed in week 53.

13 weeks: Histopathologic examination revealed focal squamous metaplasia
and focal basal cell hyperplasia (p<0.01) and focal rhinitis (p<0.05) in
the respiratory epithelium of the undamaged 12.4 mg/m3 dose group. In
the damaged 12.4 mg/m3 dose group, focal thinning/ disarrangement of the
olfactory epithelium was identified (p<0.05).

52 weeks: The undamaged 0.12 mg/m3 and 1.24 mg/m3 dose groups displayed
squamous metaplasia of the respiratory epithelium (p<0.05).  At 12.4
mg/m3, the undamaged group had squamous metaplasia, basal cell
hyperplasia, and focal rhinitis (p<0.05) of the respiratory epithelium.
The 12.4 mg/m3 damaged dose group displayed thinning/disarrangement and
loosely arranged submucosal connective tissue (p<0.01) in the olfactory
epithelium and squamous metaplasia (p<0.05) of the respiratory
epithelium.

870.3465

90-Day inhalation toxicity

Purity = ???

	Chemical Industry Institute of Technology – info in memo but study
untraceable

20 Mice and Rats

Test material administered at concentrations of 4, 12.7, or 38.6 ppm for
6 hours each day, five days a week for 13 weeks. 

	NOAEL = 4 ppm (LDT)

Systemic LOAEL = 12.7 ppm, based on body weight decrease and nasal
erosion. 

No adverse effects observed in the 4 ppm group. At 12.7 ppm, a decrease
in body weight and evidence of nasal erosion in two exposed rats was
observed. Ulceration and necrosis of the nasal mucosa seen at 38.6 ppm
resulted in termination of exposure after 2 weeks.  

870.3465

90-Day inhalation toxicity

Purity = ???

	– citation not provided in memo

Test material administered at concentrations of 0.0098, 0.028, 0.82, or
2.4 ppm for 3 months. 

25 Rats

	Systemic NOAEL = 0.028 ppm

Systemic LOAEL = 0.82 ppm, base don proliferation of lymphocytes,
histiocytes in the lungs, perivascular hyperemia. 

ChE NOAEL = 0.82 ppm

ChE LOAEL = 2.4 ppm

At 2.4 ppm there was a significant decrease in cholinesterase activity;
at 2.4 and 0.82 ppm, there was proliferation of lymphocytes and
histiocytes in the lungs and some peribronchial and perivascular
hyperemia. There were no significant findings at the two lower
concentrations. 

870.3465

90-Day inhalation toxicity

Purity: Not Reported

	Dubreuil, A., G. Bouley, J. Godin, and C. Boudène. (1976). Continuous
inhalation of low-level doses of formaldehyde: Experimental study on the
rat. Eur. J. Toxicol. 9:245-250. 

Open Literature

25 rats

Test material administered at concentrations of 1.6, 4.55, or 8.07 ppm
for 45-90 days. 	NOAEL = 1.6 ppm 

The only adverse effect seen at 1.6 ppm was discoloration of hair. The
4.55 ppm group was exposed for 45 days and had a decrease in rate of
weight gain. The 8.07 ppm was exposed for 60 days and has respiratory
and eye irritation, a decrease in food consumption, and a decease in
liver weight. 

Developmental Toxicity

870.3700a 

Prenatal Developmental Toxicity 

Purity: 35% a.i.

	MRID 00082136, 00123770

Schnurer, Lars- Bentil (1963) Maternal and Fetal Responses to Chronic
Stress in Pregnancy:  A Study in Albino Rats. Acta Endocrinologica,
Supplement 80:  1-96. 

Not Reviewed	

Rats (56, 67, 50, 44/group, respectively)

Subcutaneous injection, Pregnant rats exposed to 0.25 mL of 2% solution,
pregnant control rats, non-pregnant rats exposed to 0.25 mL of 2%,
control non- pregnant rats; 2x/day, GD 2-19 to 22

	Formalin exposure resulted in small, subcutaneous necroses. No
differences in smear cytology were noted between the pregnant treated
and pregnant control rats.

No stress-induced changes of the gastric mucosa were seen. The following
treatment- related organ weight changes were observed:  thyroid weight
was significantly lower in formaldehyde-exposed non-pregnant rats;
adrenal weights increased significantly in exposed non-pregnant rats.  

Formaldehyde- exposed pregnant rats yielded 56 litters, totaling 551
fetuses. Pregnant controls yielded 67 litters, 662 fetuses.
Formaldehyde-exposed rats had heavier fetuses than controls. No
instances of malformed limbs or cleft palate were observed.  Fetal
thyroid and adrenal weight reductions may be due to passage of
corticosteroids from exposed mothers to fetuses.  

870.3700a

Prenatal 

Developmental Toxicity (rodent);  Purity: 6%	MRID 00123769

Ranstrom, S. and Schrurer, L. (1956) Stress and Pregnancy.  Acta Pathol.
Microbiol. Scandinavia.  Supplement III, 113-114.

Not Reviewed

Pregnant rats were treated with subcutaneous injections of formalin
solution 0.25 ml during gestation.  Just before expected delivery, the
rats were killed.

Pregnant White Rat – No Information on Number and Type provided

	The fetuses showed higher mean weight (5.1 gm) in comparison with the
controls (4.7 gm). The fetuses of the treated group showed further-lower
adrenal weight, the difference was greater in the fetuses with low body
weight than in those with a high one. They also seemed to show more
rapid disappearance of extramedullary hematopoiesis than the controls. 
In the pregnant rats the formalin treatment induced an adaptation with
enlargement of the adrenals, atrophy of the thymus and a slight ? of the
reticulo-endothelium with formation of pyroninophil cells.  The local
reactions after the formalin injections seemed to be less pronounced in
the pregnant than in non-pregnant controls. (poor quality copy) –
Study report illegible

870.3700a

Prenatal

Developmental

Toxicity (rodent)

Purity: Fischer certified ACS solution, contains 12-15% methanol

	MRID 00164652

Marks, Thomas A. et al. (1980) Influence of Formaldehyde and Sonacide
(Potentiated Acid Glutaraldehyde) on Embryo and Fetal Development in
Mice.  Teratology 22:  51-58. 

Oral gavage (76/29/35/34 animals/dose) 0, 74, 148, or 185 mg/kg/day, GD
6-15

Female CD-1 Mice

	Maternal Toxicity:

NOAEL = 0 mg/kg/day

LOAEL = 74 mg/kg/day, based on decreased body weight gain.

The 185 mg/kg/day dose of formaldehyde was clearly toxic; 22 of the 34
pregnant mice died before day 18. Methanol, 12-15% of the original
solution, may have contributed to this toxicity. There was also a
significant decrease in average weight gain during pregnancy at 74
mg/kg/day. The test solution did not have a significant effect in the
incidence of malformed mouse fetuses. Doses of 148 and 74 mg/kg/day had
no significant effect on the unborn offspring or on the pregnant dam.

870.3700a

Prenatal

Developmental

Toxicity 

Purity: 37% a.i.	Saillenfait, A.M., et al (1989) The effects of
maternally inhaled formaldehyde on embryonal and foetal development in
rats.  Fd. Chem. Toxic. 27(8):  545-548. 

Open Literature

Female Sprague-Dawley rats (25/dose)

0, 5, 10, 20, or 40 ppm (0, 6.2, 12.4, 24.8, or 49.6 mg/m3) for 6
hr/day, GD 6-20	

	Maternal Toxicity:  

NOAEL = 24.8 mg/m3

LOAEL = 49.6 mg/m3, based on decreased body weight gain         

Offspring Toxicity:

NOAEL = 12.4 mg/m3

LOAEL = 24.8 mg/m3, based on reduced fetal 

weight gain  

Not teratogenic, slightly fetotoxic without overt signs of maternal
toxicity.  

There were no significant differences between groups in the numbers of
implantations, number of resorptions and the stage of gestation at which
they occurred, or the numbers of dead or live fetuses. Exposure to
formaldehyde had no detectable adverse influence on the incidence of
pregnancy or the fetal sex ratio.  

External, visceral and skeletal examination of the fetuses did not
reveal any major abnormalities. The only outward sign of a fetal
response was a significant concentration-related reduced in fetal body
weight gain (fetal body weight was 5% less at 24.8 mg/m3 and 21% less at
49.6 mg/m3).                   

870.3700a

Prenatal

Developmental

Toxicity (rodent)

Purity: 37% a.i.	Overman, D.O. (1984) Absence of Embryotoxic Effects of
Formaldehyde after Percutaneous Exposure in Hamsters.  Toxicology
Letters 24: 107-110. 

Open Literature

Pregnant Charles river Lak:LVG (SYR) Golden strain hamsters – Number
of animals not reported

0.5 mL, 2 hours/day, GD 8-11

	Treatment had no effect on maternal weight gain. The treatment did not
influence fetal C- R length. Mean fetal weight was slightly increased in
experimental animals, but the difference was not
statistically-significant. Two fetuses from the same litter after
treatment on day 8 were significantly smaller than their litter mates
(>3 SD below mean).  The same was true for 2 fetuses from different
litters after treatment on day 10. One fetus of normal size treated on
day 10 had a subcutaneous hemorrhage in the dorsal cervical region. No
skeletal malformations were found and no other malformations were
observed.

Reproductive Toxicity

870.3800

Reproduction and fertility effects

Purity: 40% a.i.

	MRID 00143291

Hurni, H. and H. Odher (1972) Reproduction Study with Formaldehyde and
Hexamethylenetetr-amine in Beagle Dogs.  Fd. Cosmet. Toxicol. 11: 
459-462.  

51 female Beagle dogs

0, 3.1, or 9.4 mg/kg/day

Not Reviewed

	The study revealed no teratogenic action.

The treatments did not affect the pregnancy rate. The body weight
increased regularly during pregnancy in all groups and the duration of
gestation was unaffected by the treatments. The mean litter size was
within the normal range for all groups, demonstrating that fecundity was
not affected by treatment. Neither the adult dogs nor their litters
showed any signs of physiological or skeletal abnormalities or disorders
of reproduction.

870.3800

Reproduction and fertility effects

Purity: 40% a.i.

	

Cassidy, S.L., K.M. Dix, and T. Jenkins (1983) Evaluation of a
testicular sperm head counting technique using rats exposed to
dimethoxyethyl phthalate (DMEP), glycerol a-monochlorohydrin (GMCH),
epichlorohydrin (ECH), formaldehyde (FA), or methyl methanesulphonate
(MMS). Arch. Toxicol. 53:71-78  

Open Literature

Male Wistar rats (5/group for treatment, 20 controls)

Treatment groups  were dosed once orally with 100 or 200 mg/kg
formaldehyde and killed 11 days after dosing

	

200 mg/kg: A statistically significant increase in total sperm heads per
gram testis, as well as an increase in percentage of abnormal sperm
heads. Data indicated that "the induction of increased levels of
abnormal sperm may be a measurable index of the mutagenic potential of a
chemical for mammalian germ cells”.

Chronic Toxicity

870.4100a

Chronic Toxicity

Purity: 9.20%	Battelle, Pacific Northwest Laboratories.  (1980) 

"Tracor Jitco Inhalation Carcinogenesis Bioassay: Repeated Dose Study
Report on Formaldehyde."

Open Literature

B6C3F1 Mouse (5/sex/group)

Mice were exposed to one of five concentrations of vaporized
formaldehyde for a period of 6 hours per day for a total of ten
exposures.  The target concentrations were 15, 25, 50, 100, and 200 ppm
(18.59, 30.98, 61.96, 123.93, and 247.85 mg/m3).  

	Concentrations of 123.93 mg/m3 or greater produced 100% mortality.  The
highly irritating nature of this chemical was evident microscopically in
all dose levels examined, ranging from minimal to mild supportive
rhinitis in the 18.59 mg/m3 dose level dose level, to necrosis and
sloughing of the mucosa in the turbinates, trachea, and proximal bronchi
in the 61.96 mg/m3 animals.  

Differential weight gains of both male and female mice at 18.59, 30.98,
and 61.96 mg/m3 was significant as compared to the controls. At 123.93
and 247.85 mg/m3, only female mice showed significant weight loss, as
the early mortality of the males precluded obtaining any meaningful
data.

870.4100a

Chronic Toxicity

Purity: 37% a.i.	Kamata, Eiichi et al. (1997) Results of a 28-month
Chronic Inhalation Toxicity Study of Formaldehyde in Male Fischer-344
Rats.  The Journal of Toxicological Sciences 22(3): 239-254.  

Open Literature

Male Fischer 344 rats (32/dose) 

0, 0.3, 2, or 15 ppm (0, 0.4, 2.5, or 19 mg/m3), 6hr/day, 5 days/week
via inhalation

	NOAEL: 0.4 mg/m3

LOAEL: 2.5 mg/m3

Nasal tumors were macroscopically evident in the 19 mg/m3 group from the
14th month. Histopathological examination revealed squamous cell
papillomas and carcinomas. No nasal tumors were observed in the lower
exposure groups (0.4 and 2.5 mg/m3 groups). In the high-dose group,
frequent face washing, coughing and/or crouching position, lacrimation,
nasal discharge, and yellow discoloration of the haircoat were observed.
Significant decreased food consumption was observed and 20 rats died by
the 24th month.  Reduced triglyceride levels and liver weights,
presumably related to reduced food intake, were also seen in the 19
mg/m3 group. Epithelial cell hyperplasia, hyperkeratosis, and squamous
metaplasia were apparent in all exposure groups. Inflammatory cell
infiltration, erosion, or edema was apparent in all exposure groups,
including the controls. The benchmark dose for squamous metaplasia and
epithelial hyperplasia were 0.30 and 0.31 mg/m3, respectively.

Carcinogenicity

870.4200a

Oncogenicity (Rat)

 

	MRID 00143288

Watanabe, F., et al. (1954) Study on the Carcinogenicity of Aldehyde.
1st Report.  Experimentally Produced Rat Sarcomas by Repeated Injections
of Aqueous Solution of Formaldehyde.  Two unpublished translations of
Japanese article published in Gann 45(2-3):451-452.

Rat

Repeated subcutaneous injections of 1 cc of an aqueous formaldehyde
solution at 0.6% to0.8%.  With 0.4% to 0.5% aqueous formaldehyde
solutions it was possible to inject subcutaneously once or twice a week.
Subcutaneous injections of 1 cc of a 0.4% aqueous formaldehyde solution
were continued on 10 rats once a week for about 1 year and three months.
0.6% to 0.8%: necrosis, the formation of an ulcer, while the area around
the injection spot formed a tuber which was very difficult to heal

0.4% - 0.5%: rare occurrence of an ulcer.  After two to five months
after having stopped the injections observations revealed the occurrence
of sarcomas either at the injection spot or in the internal organs of 4
out of 10 of the rats.  

870.4200a

Oncogenicity (Rat)

 

	Tobe, M., T. Kaneko, Y. Uchida, et al. 1985. Studies of the inhalation
toxicity of formaldehyde. National Sanitary and Medical Laboratory
Service (Japan). p. 1-94.

Open Literature

32 Male Fischer 344 rats/dose

Test material was administered at concentrations of 0, 0.3, 2.0 or 15
ppm in aqueous solution methanol, 6 hours/day, 5 days/week for 28
months. The exposure at 15 ppm was tested for 24 months. A positive
control – 3.3 ppm methanol and a nonexposure (NE) control were also
used. 

	During the exposure running noses, running tears and crouching were
seen in the 15 ppm dose group. These symptoms decreased as the number of
exposures increased. Hair around the abdominal region was observed to be
yellow in color and bleeding from the forelimbs was seen. Yellow
discoloration of abdominal hair was also seen in the 2.0 ppm dose group
although it was light. Significant suppression of weight gain and a
decrease in the amount of food gain were seen in the 15 ppm dose group.
20 of 24 animals in the 15 ppm dose group died in the 24 month dosing
period giving a high death rate of 88.3%. 

Recognizable tumors were observed in the 15 ppm group from the 420th day
onwards and tumors were recognized macroscopically in eight animals by
the 24th month. Squamous cell carcinoma was recognized in 14 rats and
pappiloma in 5 rats. Unclassified carcinoma was seen in 1 rat in the
nonexposure group which died on the 825th day. 

No neoplastic changes were seen in the 0.3 and 2.0 ppm and exposure
control dose groups. Excessive secretion was seen in the nasal cavity,
rhinitis accompanied by desquamation, squamous epithelial metaplasia and
epithelial cell hyperplasia were recognized in the 0.3 and 2.0 ppm dose
groups and these were significant in the 15 ppm dose group. 

A decrease in the T-GLY and a decrease in liver weight, assumed to be
changes accompanying decrease in food intake due to formaldehyde
exposure were seen in the 15 ppm dose group. However, these changes were
not accompanied by histological changes.   

870.4200a

Oncogenicity (Rat)

 

	Takahashi et al. (1986) Effects of Ethanol, Potassium Metabisulfate,
Formaldehyde, and Hydrogen Peroxide on Gastric Carcinogenesis in Rats
after Initiation with N- methyl-N'nitro-N'nitrosoguanidine. Jap. J.
Cancer Res. 77: 118-124. 

Open Literature

Male Wistar rats

A two-stage carcinogenesis bioassay was conducted in which
N-methyl-N'nitro- N'nitrosoguanidine was administered at 100 mg/l in the
drinking water for the first 8 weeks of the study, followed by
administration of formalin (dose not specified).  	Formalin did not
produce malignant tumors when given alone.  Forestomach papillomas
occurred in 8/10 animals administered formalin alone.

In the group administered both MNG and formalin, forestomach papillomas
occurred in 15/17 animals, adenocarcinoma of the pylorus in 4/17,
preneoplastic hyperplasia of the pylorus in 7/17, and adenocarcinoma of
the duodenum in 1/17.

870.4200b

Oncogenicity

(Mouse)

Purity: 1% and 10%

	Iversen, Olav Hilmar. (1986)  Formaldehyde and Skin Carcinogenesis.  
Environ Int 12:541-544. 

Open Literature

Hairless mice of the hr/hr Oslo Strain (16/sex)

Topical application of 200 ug formaldehyde in water on the back skin
twice a week for 60 weeks	Nonspecific granulomas in the lung; slight
hyerplasia of the epidermis, small skin ulcers

870.4200b

Oncogenicity

(Mouse)

Purity: 10%

	Krivanek, N.D., N.C. Chromey and J.W. McAlack, "Skin initiation-
promotion study with formaldehyde in CD-1 mice", E.I. du Pont de Nemours
& Company, Inc. In: Formaldehyde: Toxicology, Epidemiology, and
Mechanisms, Clary, J.J., J.E. Gibson, and R.S. Waritz, Eds., N.Y.,
Marcel Dekker, Inc., 1983.

Open Literature

Female CD-1 Mouse

Mice were treated on shaved dorsal skin with up to 10 mg formaldehyde,
followed by repeated doses.  Formaldehyde was also applied once at 5
mg/mouse to assess initiation potential.  Promoter potential was tested
at 0.1, 0.5, and1.0 mg/mouse, applied 3 times/wk for 26 wk. Positive
controls [150 mg benzo(a)pyrene (BaP) as initiator, 2.5 mg 12-O-
tetradecanoylphorbol-13-acetate(TPA) as promoter], or negative control
(acetone) were used.	Repeated doses of 2-5 mg caused mild to moderate
skin irritation, whereas 1 mg caused only mild irritation.

As expected, BaP/TPA gave a high tumor yield (28/29 mice, 9 of which had
malignant tumors. Benign test site tumors were keratoacanthomas or
squamous papillomas. No other combinations gave yields significantly
different from controls. Thus the test is negative under study
conditions, with the caveat that one cannot be certain whether
formaldehyde underwent significant degradation to formic acid or other
products.

870.4200b

Oncogenicity

(Mouse)

 

	Spangler, F. and J.M. Ward, "Skin initiation/promotion study with
formaldehyde in Sencar mice". Study location: Microbiological Associates
(Bethesda, MD) in conjunction with NCI.  In: Formaldehyde: Toxicology,
Epidemiology, and Mechanisms, Clary, J.J., J.E. Gibson, and R.S. Waritz,
Eds., N.Y., Marcel Dekker, Inc., 1983.

Open Literature 

Female Sencar Mice (30/group)

Mice were treated in various combinations with or without an initiator
(DMBA) or promoter [12-O-tetradecanoylphorbol-13- acetate (TPA)]. All
test compounds were applied to back skin of mice with acetone, which was
used as a negative control in some treatment combinations Formaldehyde
was tested for initiating and promoting capability. In all cases,
formaldehyde was applied in acetone; however the amount of this solution
applied was not specified. All tests of initiators (including
formaldehyde, when tested for such potential) were as a single dose.
Promoters (including formaldehyde, when tested for such potential) were
applied once or twice a week. This is an interim report, relating counts
of skin papillomas as of the first 48 weeks of the study.	Study found no
evidence of formaldehyde as an initiating agent, nor as a complete
carcinogen, however investigators considered there to be "a slight
possibility that formaldehyde may be a very, very weak promoting agent",
based on a very small tumor yield when formaldehyde was tested as a
promoter in mice treated with DMBA.

870.4200

Oncogenicity

 

	Dalbey, W.E. (1982). Formaldehyde and tumors in hamster respiratory
tract. Toxicology. 24: 9-14.

Open Literature

88 male Syrian golden hamsters

Test material was administered at a 10 ppm concentration 5 times/week
for lifetime. 

	Lifetime exposure to formaldehyde reduced survival time (P < 0.05)
relative to unexposed controls. No tumors were observed in the
respiratory tract of non-exposed hamsters or of those exposed to
formaldehyde. There was, therefore, no evidence of carcinogenic activity
of formaldehyde under the given exposure conditions. 

Little evidence of toxicity from formaldehyde exposure was observed in
the nasal epithelium, expected to be a prime target issue. There was no
increase in the incidence of rhinitis related to exposure (observed in
31% of untreated animals and 24% of the formaldehyde-exposed hamsters).
Hyperplastic and metaplstic areas were each observed in the nasal
epithelium of 5% of hamsters exposed to formaldehyde while none were
observed in control animals. 

870.4300

Chronic/ Oncogenicity

 	MRID 00143289

Kerns, W.D. et al. (1983) Carcinogenicity of Formaldehyde in Rats and
Mice after Long-Term Inhalation Exposure. Cancer Research 43: 4382-4392.

Rat (Fischer 344)  and Mice (B6C3F1) - approx 120/sex/dose

0, 2.0, 5.6, or 14.3 ppm (0, 2.5, 6.9, or 18 mg/m3), 6 hrs/day, 5
days/week, up to 24 months

	From exposure weeks 3 to 103, mildly (15 to35 g) decreased body weights
(p<0.05) in male and female rats (6.9 and 18 mg/m3) were observed.
Animals in the 2.5 mg/m3 exposure group had sporadically reduced body
weights (p>0.05) throughout the exposure period.  Male and female rats
in the 18 mg/m3 exposure group exhibited significantly increased
mortality (p<0.001) from the 12th month onward. Male rats in the
intermediate exposure groups showed a statistically-significant
concentration-dependent decrease in cumulative survival from 17 months
onward.  

In male mice, there were no differences in survival. The number of male
mice surviving a minimum of 18 months were 41, 33, 32, and 25 for the 0,
2.5, 6.9, and 18 mg/m3 exposure groups, respectively. There were no
differences in cumulative survival among the female mice.  

There were no alterations in the clinical pathology or ophthalmologic or
neurofunctional data that were considered related to formaldehyde
exposure.  

Exposure to formaldehyde produced a concentration-dependent increase in
yellow discoloration of the hair.  Other significant macroscopic
observations (at the 18 mg/m3 group) included dypsnea, emaciation, and
large facial swellings that were proliferative lesions (carcinomas)
protruding from the nasal cavity.  Neoplastic lesions were first
observed clinically at Day 358 in females and Day 432 in males. 
Formaldehyde-induced microscopic lesions were confined to the nasal
cavity and the proximal trachea.  

Exposure to 18 mg/m3 formaldehyde for 24 months produced a high
incidence of nasal cancer in male and female rats. The tumors had a
sharp concentration-response relationship, with the 2 carcinomas in the
intermediate group identical to the 103 squamous cell carcinomas
observed in rats exposed to 18 mg/m3. Although the incidence of
polyploid adenomas in the nasal cavity was not statistically
significant, there was a positive concentration response for the
occurrence of benign neoplasms in male rats. There was no evidence of
progression of polyploid adenoma to squamous cell carcinoma.  

Two male mice exposed to 18 mg/m3 of formaldehyde developed squamous
cell carcinomas in the nasal cavity similar to the neoplasms in the
rats. Formaldehyde-induced lesions (squamous metaplasia and
inflammation) in mice were much less severe than similar lesions in
rats. The incidence of squamous cell carcinomas in mice exposed to 18
mg/m3 was similar to rats exposed to 6.9 mg/m3. 

Neurotoxicity

870.6200

Neurotoxicity screening battery

Purity:

(2003a) - 37% stock solution was used to prepare solutions of 0.5%, 1%,
and 2.5%

(2003b) – 0.1%, 0.2%, and 1%

	

Malek, FA; Moritz, KU; Fanghanel, J.  (2003a) Formaldehyde inhalation
and open field behaviour in rats.  Ind J Med Res 118:90-96. 

Malek, FA; Moritz, K-U; Fanghaenel, J.  (2003b) A study on specific
behavioral effects of formaldehyde in the rat. J Exp Anim Sci
42:160-170. 

Open Literature

Male and Female LEW.1K Rat 

Malek et al. (2003a): Rats were exposed to 0, 1.0, 2.5, or 5.0 ppm (0,
1.23, 3.08, or 6.15 mg/m3) formaldehyde for 2 hours. Mean formaldehyde
levels of 1.01 ± 0.29 ppm, 2.51 ppm (standard deviation is missing) and
5.04 ± 0.27 ppm were achieved.  Locomotor activity was assessed for 1
hour in an open field 2 and 24 hours after termination of formaldehyde
exposure.  

Malek et al. (2003b):  Rats (10 per group) were exposed at 0, 0.1, 0.5,
or 5.0 ppm (0, 0.123, 0.615, or 6.15 mg/m3) formaldehyde for 2 hours.
Open field behavior tests were conducted on each animal 2 hours after
formaldehyde exposure.  

	

Malek et al. (2003a):

LOAEL = 1.0 ppm, 2 hours  

In general, sniffing was increased after formaldehyde exposure and
movement was decreased (crossed quadrants and climbing) in both male and
female rats (p<0.05). Significant reductions in horizontal movements
(crossed quadrants) were observed at all dose levels and were
characterized by a U-shaped dose response. The lowest dose tested (1
ppm) demonstrated higher level of activity suppression than the two
higher doses, but all groups were still suppressed relative to controls.
 Although female rats displayed a greater level of activity overall, a
similar U-shaped dose-response pattern was also observed.

After 24 hours, as expected, controls demonstrated habituation to the
test apparatus exhibiting only 20% of the motor activity observed on day
1. In contrast, formaldehyde-treated animals failed to demonstrate the
same degree of habituation. Activity levels for males observed on day 2
were 60-80% of the activity levels seen on day 1. Formaldehyde-treated
females also failed to habituate and actually demonstrated increases in
activity on day 2 relative to day 1 at all formaldehyde exposure levels.

Malek et al. (2003b):  

LOAEL (M) = 0.1 ppm, 2 hours 

The number of crossed quadrants for both controls and a 5 ppm group are
comparable to those observed in the first study. Horizontal movement was
decreased by formaldehyde exposure in a dose dependent manner with
significant reductions in motor activity as low as 0.1 ppm in males and
0.5 ppm in females. The consistency of the data across studies and
between genders provides greater confidence in the effects of low level
formaldehyde exposure on this standard test of neurotoxicity.

870.6500

Schedule-controlled operant behavior

 

	Pitten, FA; Kramer, A; Herrmann, K; et al.  (2000) Formaldehyde
neurotoxicity in animal experiments.  Pathol Res Pract 196:193-198. 

Open Literature

Adult Male and Female Wistar Rat (5 to 8/sex/group)

Pitten et al. (2000) evaluated the effects of very brief formaldehyde
exposures (10 minutes) but prolonged duration (90 days) on previously
learned performance in a land version of the labyrinth maze. Rats were
acclimated to the task for 14 days, 2 trials/day. Animals were required
to make a series of five consecutive turns from the entrance of the maze
to retrieve a piece of cheese placed in the goal box at the opposite
end. Animals were exposed to 0 ppm, 2.6 ppm (0.25% formaldehyde solution
to yield 3.06 ± 0.77 mg/m3 ), or 4.6 ppm (0.70% formaldehyde solution
to yield 5.55 ± 1.27 mg/m3) formaldehyde, 10 minutes/day, 7 days/week
for 90 days. Animals were assessed for performance in the maze every
seventh day, at least 22 hours after the exposure on the previous day. 
At the end of the 90-day exposure period, monitoring of maze performance
continued once every 10 days for an additional 40 days.	LOAEL: 2.6 ppm,
10 min/90 days

The authors reported that no gender differences existed as a function of
formaldehyde treatment; therefore, data were presented by combining
sexes. Control rats showed no change in error rate but a slight decrease
in running time through the maze during the course of the experiment. 
The formaldehyde-exposed groups began with a similar performance level
and error rate as controls, but their performance degraded over the
course of formaldehyde exposure.  By the fourth week of exposure,
increased numbers of errors were evident in both exposed groups relative
to controls. This trend reached statistical significance by the
thirteenth week for a greater than twofold increase in error rate
(p<0.05). Formaldehyde-treated rats also tended to have increased run
times through the maze (p=0.04), but no difference was seen by
formaldehyde concentration. By 4 weeks after termination of exposure, no
statistical differences among the three groups were evident, but the
tendency for the two exposed groups to make more errors and have longer
latencies remained. Since Pitten et al. (2000) tested animals after the
task was acquired, these results indicate deficits in the retention of a
previously learned task.

Other

Purity: 96%	Boja JW, Nielsen JA, Foldvary E, et al. (1985) Acute
Low-Level Formaldehyde Behavioural and Neurochemical Toxicity in the
Rat. Prog Neuro-Psychopharmacol Biol Psychiat 9:671-674.

Open Literature

88 M Sprague-Dawley Rat

Rats were exposed to either air or formaldehyde at concentrations of 5,
10, or 20 ppm (6.20, 12.39, or 24.79 mg/m3) via inhalation for 3 hours
on two days

	Exposure to 6.20 mg/m3 formaldehyde resulted in statistically
significant decreased motor activity within 15 minutes.  At the
beginning of day 2, all of the rats exposed to formaldehyde on day 1
displayed lower activity levels. Similar effects on motor activity were
seen at the 12.39 mg/m3 formaldehyde exposure level, whereas effects
seen after 24.79 mg/m3 exposure were reported to be “not readily
interpretable” and were not shown. Exposure to 6.20 mg/m3 formaldehyde
statistically significantly increased concentrations of 
5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and dopamine
in the hypothalamus.

Metabolism

870.7485

General Metabolism

 	Casanova, Mercedes, Donald F. Deyom and Henry D'A. Heck (1989)
Covalent Binding of Inhaled Formaldehyde to DNA in the Nasal Mucosa of
Fischer 344 Rats:  Analysis of Formaldehyde and DNA by High-Performance
Liquid Chromatography and Provisional Pharmacokinetic Interpretation. 
Fundamental and Applied Toxicology 12: 397-417. 

Open Literature

	

Rat (4/group), nose-only exposure

0, 0.3, 0.7, 2, 6, or 10 ppm (0.37, 0.87, 2.5, 7.4, or 12 mg/m3) for 6
hours 	DNA-protein crosslinking occurred at all concentrations. The
formation of crosslinks was interpreted in terms of a nonlinear
pharmacokinetic model incorporating oxidation of inhaled formaldehyde as
a defense mechanism. The slope of the fitted concentration-response
curve at 12 mg/m3 is7.3-fold greater than at 0.37 mg/m3, and the
detoxification pathway is half-saturated at an airborne concentration of
3.2 mg/m3.

870.7485

General Metabolism

 	Casanova-Schmitz, Mercedes, Thomas B. Starr, and Henry D'A. Heck
(1984) Differentiation between Metabolic Incorporation and Covalent
Binding in the Labeling of Macromolecules in the Rat Nasal Mucosa and
Bone Marrow by Inhaled (14C)- and (3H) Formaldehyde.  Toxicology and
Applied Pharmacology 76: 26-44. 

Open Literature

Rats (4/group)

14C and 3H- formaldehyde was administered at doses of 0, 0.3, 2, 6, 10,
or 15 ppm (0, 0.37, 2.5, 7.4, 12, or 19 mg/m3) for 6 hours

	The major route of nucleic acid labeling at all concentrations and in
all tissues was metabolic incorporation; protein labeling in the
respiratory mucosa was mainly due to covalent binding at the higher
formaldehyde concentration.  Incorporation of 14C- formaldehyde into DNA
in the respiratory mucosa was maximal at 7.4 mg/m3 but decreased at
higher concentrations, whereas labeling of DNA in the olfactory mucosa
and bone marrow increased monotonically with concentration. Evidence for
covalent binding of formaldehyde to respiratory mucosal DNA was obtained
at formaldehyde concentrations equal to or greater than 2.5 mg/m3. The
concentration of formaldehyde covalently bound to DNA at 7.4 mg/m3 was
10.5-fold higher than at 2.5 mg/m3, indicating significant nonlinearity
of DNA binding with respect to the inhaled formaldehyde concentration
under these conditions.  Covalent binding to proteins increased in an
essentially linear manner with increases in the airborne concentration.
No evidence was obtained for the formation of covalent adducts with
macromolecules in the olfactory mucosa or bone marrow. The nonlinear
increase in covalent binding to respiratory mucosal DNA with increasing
formaldehyde concentrations may be explained either by a decrease in the
efficiency of defense mechanisms or by an increase in the availability
of reaction sites on the DNA resulting from increased cell turnover.

Special Studies

Modeling

 

	Conolly R.B., et al. 2003. Biologically Motivated Computational
Modeling of Formaldehyde

Carcinogenicity in the F344 Rat. Toxicol. Sci. 75: 432–447.

Open Literature

3-D F344 Rat Model 

Biologically based quantitative modeling of the relationship between
formaldehyde inhalation and the development of nasal squamous cell
carcinoma on the basis of the Kerns et al. (1983) and Monticello et al.
(1996) data.  	The analysis suggested evidence of: 1) a
cytolethality-regenerative cellular proliferation (CRCP) mechanism with
little or no involvement of direct mutagenesis; and 2) a J-shaped
dose-response relationship between formaldehyde and squamous cell
carcinoma.  

Sensitization

 	Ohtsuka, R; Shuto, Y; Fujie, H; et al.  (1997) Response of respiratory
epithelium of BN and F344 rats to formaldehyde inhalation.  Exp Anim
46:279-286. 

Ohtsuka, R; Shutoh, Y; Fujie, H; et al.  (2003) Rat strain difference in
histology and expression of Th1- and Th2-related cytokines in nasal
mucosa after short-term formaldehyde inhalation.  Exp Toxicol Pathol
54:287-291.

Open Literature

18 F344 and 18 Brown Norway (BN) Rats

Rats were exposed to formaldehyde aerosol for 3 hours/day, 5 days/week
for 2 weeks.  The aerosol was generated from a 1% formaldehyde solution
by a two-fluid atomizer and formaldehyde level maintained at 2 mg (1%
sol.)/L (approximately 16 ppm or 20 mg/m3), by adjusting the flow rate
for formaldehyde solution to the atomizer.

	Although no pulmonary measurements were made, the authors observed
fewer clinical signs of respiratory irritation in the BN rats compared
to F344 rats, such as abnormal respiration (three versus five) and nasal
discharge (three versus five). Formaldehyde-treated F344 rats showed
less body weight gain over the 2-week treatment, resulting in lower body
weight at week 1 and week 2 than F344 controls (p<0.05 and 0.01). BN
rats were more resistant to epithelial cell damage than F344 rats,
exhibiting milder lesions that impacted a smaller portion of the URT. 
Squamous metaplasias were present in the respiratory epithelium (Levels
1 and 2) in both strains in formaldehyde-treated rats. However, a
distinct keratinized layer was noted in Level 1 epithelium of F344 rats,
and the extent of lesions in Level 2 respiratory epithelium was much
greater than that seen in BN rats.  Additionally, the olfactory
epithelium (Level 2) in formaldehyde-exposed F344 rats exhibited
degeneration, necrosis, and desquamation not seen in BN rats.  Mild
squamous metaplasia was noted in Level 3 of the respiratory epithelium
in the treated F344 rats but not the BN rats. The authors note that
their earlier research indicated the BN rats have well-developed
submucosal glands and that greater mucus flow may be partly responsible
for the greater resistance of BN rats to the histological signs of
formaldehyde toxicity. 

In a subsequent study in the same laboratory, Ohtsuka et al. (2003)
compared cytokine profiles in the nasal mucosa of formaldehyde-treated
F344 and BN rats.  Formaldehyde aerosol was generated as above and rats
(nine per group) were exposed 3 hours/day for 5 days to approximately 16
ppm of formaldehyde (20 mg/m3). 

The incidence and severity of clinical signs in F344 rats was greater
than BN rats as previously observed (Ohtsuka et al., 1997).  Also,
lesions and neutrophil infiltrations were more severe in F344
formaldehyde-exposed rats compared to treated BN rats. F344 rats had
various lesions in all three levels of epithelium examined, which
impacted both respiratory and olfactory epithelium.  Mucosal lesions in
formaldehyde-treated BN rats only impacted the respiratory epithelium of
Levels 1 and 2. Although changes in cytokine mRNA expression were
modest, there was a depression of T-lymphocyte helper 1 (TH-1)-related
cytokines in formaldehyde-treated BN rats (INF-g, Il-2) and a similar,
although not statistically significant, decrease in TH-2 cytokines
(IL-4, IL-5) compared to unexposed BN rats.  There were no treatment
differences in cytokine expression in F344 rats.  Type 1
hypersensitivity reactions generally result in increased TH-2 cytokines.
Therefore, although modest changes in cytokine profile were seen in
formaldehyde-treated BN rats, they were not consistent with Type 1
hypersensitivity.

Sensitization

Purity: 37% formalin	Biagini, RE; Moorman, WJ; Knecht, EA; et al. 
(1989) Acute airway narrowing in monkeys from challenge with 2.5 ppm
formaldehyde generated from formalin.  Arch Environ Health 44:12-17. 

Open Literature

9 Cynomolgus Monkeys known to be hyperreactive to methacholine
(acetyl-β-methacholine chloride) 

nkeys were exposed to increasing levels of methacholine for 10 minutes
(0, 0.125, 0.5, 2.0, and 8.0 mg/mL) as an aerosol (0.065 mL/min with a
mean aerodynamic diameter of 1.0-1.5 μm).  After a 2-week recovery
period, pulmonary mechanics were measured before and after a 10-minute
exposure to 2.5 ppm formaldehyde (2, 5, and 10 minutes post-exposure).
Methacholine challenge increased pulmonary flow resistance at increasing
levels of methacholine (0.125, 0.5, 2.0, and 8.0 mg/mL) to 196 ± 16,
285 ± 57, 317 ± 64, and 461 ± 120 % of baseline levels respectively. 
Similarly, formaldehyde exposure increased pulmonary flow resistance
from 11.3 ± 1.4 cm H2O prior to formaldehyde exposure, to 16.1 ± 2.1,
16.9 ± 2.8, and 20.0 ± 3.4 cm H2O, at 2, 5, and 10 minutes after
formaldehyde exposure (with 142, 150, and 177% change, respectively).
Although bronchial constriction, seen as increased pulmonary flow
resistance, was increased by both methacholine and formaldehyde, there
was not a correlation between methacholine responsiveness and the
magnitude of effect after formaldehyde exposure (p>0.1). Therefore
although formaldehyde exposure stimulated BC similarly to a known direct
stimulating agent, formaldehyde may not work through the same site of
action as methacholine.

Sensitization

	Fujimaki, H; Kurokawa, Y; Kunugita, N; et al.  (2004) Differential
immunogenic and neurogenic inflammatory responses in an allergic mouse
model exposed to low levels of formaldehyde.  Toxicology 197:1-13. 

Open Literature

Mice were exposed to 0, 0.082, 0.393, or 1.87 ppm formaldehyde (0, 0.1,
0.48, or 2.3 mg/m3), 16 hours/day, 5 days/week for 12 weeks.  Six mice
at each exposure level were given intraperitoneal injections of OVA plus
adjuvant before the initial exposure and on weeks 3, 6, 9, and 11 of the
experiment.  Five mice at each formaldehyde-exposure level did not
receive OVA injections.  One day after the last exposure, spleens were
collected and disaggregated and spleen cells harvested for cell culture.
Lymphocyte proliferation in response to lipopolysaccharide (LPS),
phytohemagglutinin A (PHA), or OVA was determined after 72 hours in
culture. Splenocytes were cultured for 48 hours in the presence of LPS,
PHA, and OVA (immunized mice only), and supernatants were collected for
cytokine analysis (IL-4, IL-5, and INF-γ). Splenocytes were cultured
for 24 hours in the presence or absence of OVA to assess chemokine
production (MCP-1 and MIP1-α). Anti-OVA IgE, IgG1, IgG2, and IgG3 were
quantified in blood plasma.

	In nonimmunized mice, spleen weights were reduced by formaldehyde
exposure from 152 mg in control to 128, 118, and 121 mg in mice exposed
to 0.08, 0.40, and 1.8 ppm formaldehyde, respectively.  However, spleen
weights were unchanged by formaldehyde exposure in OVA-immunized mice. 
In immunized mice exposed to 1.8 ppm formaldehyde, the total number of
BAL cells, MPs, and eosinophils were increased (9.65 versus 2.84, 7.22
versus 2.74, and 2.0 versus 0.02 ×104 cells, respectively).

Levels of IL-1β in BAL of immunized mice were decreased by formaldehyde
exposure (p<0.05 at 1.8 ppm formaldehyde).  Immunization with OVA
significantly increased the neuropeptide nerve growth factor (NGF) in
BAL. However, this increase with OVA immunization was attenuated by 0.08
and 0.40 ppm formaldehyde exposure. A similar response was seen in blood
plasma NGF levels, where the increase with OVA immunization was
attenuated in mice exposed to 0.08 and 0.40 but not to 1.8 ppm
formaldehyde.  Plasma level of Substance P (a mediator of neurogenic
inflammation) was increased by formaldehyde exposures in non-immunized
mice. Although Substance P was increased by OVA immunization, this again
seemed to be attenuated by formaldehyde exposure, reducing Substance P
levels to undetectable levels.

Formaldehyde exposure (1.8 ppm) increased INF-γ fourfold in LPS
stimulated cultured spleen cells from non-immunized mice. OVA in vitro
stimulation significantly increased the chemokines MIP-1 and MCP-1 for
control and formaldehyde-treated OVA-immunized mice. The OVA stimulated
release of MCP-1 in vitro was enhanced by formaldehyde exposure in a
concentration dependent manner, increasing threefold and fourfold at
0.40 and 1.8 ppm, respectively. 

Anti-OVA IgG1 was slightly depressed in immunized mice exposed to 0.40
ppm formaldehyde, and anti-OVA IgG3 was depressed in immunized mice
exposed to 0.08 and 0.40 ppm formaldehyde.  

Pulmonary Hypersensitivity

	MRID 43167201

Burleigh- Flayer, H. D. and W.J. Kintigh (1992) Glutaraldehyde and
Formaldehyde:  Vapor Pulmonary Hypersensitivity Study in Guinea Pigs. 
Bushy Run Research Center (Export, PA), Union Carbide. Study ID 92U1123,
dated February 28, 1992, Unpublished. 

Minimum

Guinea Pig (8/group)

Induction:  14 ppm (17 mg/m3), 60 minutes, 5 consecutive days Challenge:
5 ppm (6.2 mg/m3) for 60 minutes, at days 14, 21, and 35 following
induction	Formaldehyde did not cause increased respiratory rate or
altered respiratory waveform indicative of pulmonary hypersensitivity
during the challenge exposures. No mortality, clinical signs, body
weight effects, or gross lesions were observed

870.1300

Acute Inhalation Toxicity

Purity: 95%

	Dean et al. (1984) Studies of Immune Function and Host Resistance in
B6C3F1 Mice Exposed to Formaldehyde.  Toxicology and Applied
Pharmacology, v.72, p. 519-529.  

Open Literature

255 Female (SPF) B6C3F1 Mice

21-Day (6 hr/day, 5 days/week) inhalation exposure to 18.59 mg/m3
formaldehyde to test a series of immune function and host resistance
parameters.	Decrease in the absolute number of monocytes. In the absence
of a difference in recovery of peritoneal cells, the change in monocyte
number may signal only a peripheral response to the local nasal
inflammation and healing which occurs following HCHO exposure.  

Inhalation

	Casanova, Mercedes, et al. (1991) Covalent Binding of Inhaled
Formaldehyde to DNA in the Respiratory Tract of Rhesus Monkeys: 
Pharmacokinetics, Rat- to-Monkey Interspecies Scaling, and Extrapolation
to Man.  Fundamental and Applied Toxicology 17: 409-428.  

Open Literature

9 Male Rhesus Monkey (Macaca mulatta)

14C-Formaldehyde was administered at 0, 0.7, 2, or 6 ppm (0, 0.87, 2.5,
or 7.4 mg/m3) for 6 hours

	DNA protein cross-links were formed in the respiratory tract of rhesus
monkeys exposed to formaldehyde. Concentrations of cross-links (pmol/mg
DNA) were highest in the mucosa of the middle turbinates; lower
concentrations were produced in the anterior lateral wall/septum and
nasopharynx. Very low concentrations were found in the
larynx/trachea/carina and in the proximal portions of the major bronchi
of some monkeys exposed to 7.4 mg/m3 but not to 9.87 mg/m3.  No
cross-links were detected in the maxillary sinuses or lung parenchyma.
The pharmacokinetics of cross-link formation in the nose were
interpreted using a model in which the rate of formation is proportional
to the tissue concentration of formaldehyde.  Using this model, the
concentration of cross-links formed in corresponding tissues of
different species can be predicted by scaling the pharmacokinetic
parameter depending on minute volume and quantity of nasal mucosal DNA.
The concentration-response curve for the average rate of cross-link
formation in the turbinates, lateral wall, and septum of rhesus monkeys
as predicted from that of F344 rats exposed to similar conditions. 
Concentrations of cross-links that may be produced in the nasal mucosa
of adult men were predicted based on experimental data in rats and
monkeys. The results suggest that formaldehyde would generate lower
concentrations of cross-links in the nasal mucosa of humans than of
monkeys, and much lower concentrations in humans than in rats. The rate
of formation of DNA-protein cross-links can be regarded as a surrogate
for the delivered concentration of formaldehyde.

Inhalation

	D'A. Heck, Henry, and Merccedes Casanova (1987) Isotope Effects and
Their Implications for the Covalent Binding of Inhaled (3H) and (14C)
Formaldehyde in the Rat Nasal Mucosa.  Toxicology and Applied
Pharmacology 89: 122-134. 

Open Literature

Male F-344 (CDF/ CrIBR) rats

Isotopic effect on DNA-protein crosslinking by 3HCHO and H-14-CHO: Rat
hepatic nuclei incubated with 3H and 14C formaldehyde

Isotopic effect on the oxidation of 3HCHO and H14-CHO: homogenates of
the rat nasal mucosa incubated with 3H and14C formaldehyde at total
formaldehyde concentrations ranging from 0.1 to 11 uM, NAD+ (1 mM), GSH
(15 mM), and pyrazole (1mM)	Isotopic effect on DNA-protein crosslinking
by 3HCHO and H-14-CHO:

A small (3.4 +- 0.9%) isotope effect was detected on this reaction,
which slightly favored 3HCHO over H14CHO in binding to DNA.  The
magnitude of this isotope effect cannot account for the high isotope
ratio observed in the crosslinked DNA in vivo.

Isotopic effect on the oxidation of 3HCHO and H14-CHO:

3HCHO is oxidized significantly more slowly than H14CHO under these
conditions. A similar isotope effect was observed in the absence of GSH,
presumably due to the oxidation of 3HCHO and H14CHO, which can bind to
DNA resulting in an isotope ratio higher than that of inhaled gas. The
isotope effect on the oxidation of 3HCHO and H14CHO suggests that
previous estimates of the amount of formaldehyde covalently bound to
nasal mucosal DNA may have been too large; especially at low airborne
concentrations and that the shape of the concentration-response curve
for DNA-protein cross linking is more nonlinear than reported
previously.

Inhalation

	Morgan, K. et al. (1986) Responses of the Nasal Mucociliary Apparatus
of F-344 Rats to Formaldehyde Gas.  Toxicology and Applied Pharmacology
82: 1-13. 

Open Literature

Rat

0, 0.7, 2, 6, or 15 ppm (0, 0.62, 2.5, 7.4, or 19 mg/m3) 6 hour
exposures for up to 3 week duration

	NOAEL: 2.5 mg/m3

LOAEL: 7.4 mg/m3

Rats exposed to 2.5, 7.4, or 19 mg/m3 exhibited concentration-related
evidence of eye and nose irritation, including ocular and nasal
discharge, and reddish exudate in the nasal passages.  

Defects in mucociliary function in specific regions of the nose, such as
cessation or severe slowing of mucus flow (mucostasis), loss of ciliary
activity (ciliastasis), or altered mucus flow patterns, were readily
detected.  These changes were clearly related to formaldehyde
concentration and duration exposure, and only minimal variation was
observed between animals within each exposure group.  Mucostasis was
usually more extensive than ciliastatsis, but in some areas mucus was
flowing over areas of inactivated cilia. Inhibition of
mucociliaryfuction by 19 mg/m3 formaldehyde was most frequently observed
on the dorsal and medial aspects of the maxilloturbinate, especially the
hook-like scroll of this turbinate (lateral scroll), the ridge dorsal to
this scroll (lateral ridge), and the lateral wall. These changes were
progressively more extensive with increasing number of days of exposure
and showed little or no evidence of recovery 18 hours after the last
exposure. At 7.4 mg/m3, the effects were much less extensive and they
were minimal or absent at 2.5 mg/m3.  Localized inhibition of ciliary
activity on the ventral margin of the nasoturbinate was observed in a
few animals exposed to 2.5 mg/m3 for 9 days.

Slowing or cessation of mucus flow was detected in the more anterior
regions of the maxilloturbinate following exposure for 1 day to 19
mg/m3, and more posterior regions were affected after 9 days. In rats
exposed to 7.4 mg/m3 formaldehyde, no consistent effects on the mucus
flow rate were observed except in areas exhibiting mucostasis. At 2.5
mg/m3, there was no evidence of reduced mucus flow rate.

In rats exposed to 19 mg/m3 formaldehyde, there were lesions in the
respiratory epithelium which became more extensive with increasing
number of days of exposure. Lesions were most severe in the anterior
nasal passages on the lateral, dorsal, and medial aspects of the
maxilloturbinate, the lateral and ventral surfaces of the nasoturbinate,
and the lateral wall. Exposure to 19 mg/m3 for 6 hours produced minimal
effects, characterized by separation of epithelial cells and
intravascular margination and local tissue infiltration by neutrophils
and monocytes in the regions which later exhibited severe, degenerative
changes. Over affected areas, a layer of floccular material was covered
by a continuous membrane. These layers were presumed to be coagulated
mucus and were not present elsewhere in the nose. The surface coagulum
was absent in animals killed 18 hours after a single 6-hour exposure,
and cilliated cells in affected areas were variably disintegrated while
infiltrating phagocytes were more numerous.  Following 2 days exposure
to 19 mg/m3, epithelial damage and inflammation were more severe and
extensive with a serofibrinous exudate present over damaged areas. 
These changes were even more advanced after 4 days. Epithelial lesions
had extended posteriorly along the lateral wall where exfoliating
ciliated and non-ciliated cells were located frequently over areas of
cellular proliferation and early squamous metaplasia. The distribution
of epithelial lesions correlated with the areas of inhibition of the
mucociliary function. No epithelial lesions were detected in areas
exhibiting mucostasis without ciliastasis. Similar, but less severe
changes were found in rats exposed to 7.4 mg/m3. There was a good
correlation between the distribution of epithelial lesions and
inhibition of ciliary activity. No epithelial lesions were detected in
rats exposed to 0.62 or 2.5 mg/m3.

Inhalation Short and Intermediate term

	Monticello, et al. (1991) Regional Increases in Rat Nasal Epithelial
Cell Proliferation following Acute and Subchronic Inhalation of
Formaldehyde.  Toxicology and Applied Pharmacology 111:  409-421.

Open Literature

Rats (36/group)

0, 0.7, 2, 6, 10, or 15 ppm (0, 0.87, 2.5, 7.4, 12, or 19 mg/m3), 6
hr/day for 1, 4, or 9 days, or 6 weeks (5 days/week)

	NOAEL: 2.5 mg/m3 

LOAEL: 7.4 mg/m3

Animals exposed to 2.5 mg/m3 or less had no microscopic evidence of
formaldehyde-induced lesions.  Formaldehyde-induced lesions at higher
doses were confined to nasal passages primarily involving the
cuboidal-transitional and respiratory epithelium. Light microscopic
lesions were not observed in the trachea, carina, or more distal
conducting airways. Lesions exhibiting an anterior-posterior severity
gradient varied over exposure time and were concentration-dependent.  

For acute exposure (1 to 9 days), rats exposed to 12 or 19 mg/m3
formaldehyde had nasal lesions which became more severe and extensive
with increasing exposure time. Formaldehyde-induced lesions were more
severe in the anterior nasal passages on the lateral aspect of the
nasoturbinate, the lateral wall, and the lateral, dorsal, and
dorsomedial aspects of the maxilloturbinates. Less severe
formaldehyde-induced lesions were present on the midseptum at Levels II
and III and the midlateral wall at Level III. More severe effects were
observed at the higher dose.  

Following one 6-hour exposure to 10 or 15 ppm (12 or 19 mg/m3)
formaldehyde, lesions were characterized by epithelial cell vacuolar
degeneration, individual cell necrosis, epithelial exfoliation, and
multifocal erosions. There was also a mild mixed inflammatory cell
infiltrate consisting primarily of neutrophils with fewer numbers of
lymphocytes and plasma cells.  Formaldehyde-induced lesions progressed
by day 4 to erosions, locally extensive ulceration, and an increased
neutrophilic infiltrate.  There was evidence of early epithelial
hyperplasia with karyomegaly. Following 9 days of exposure, epithelial
hyperplasia and squamous metaplasia were also evident. These lesions
extended posteriorly to include the midlateral walls and the midventral
septum at Level III, and occasionally they included the ventral floor of
the nasopharynx.  

Lesions induced by exposure to 7.4 mg/m3 formaldehyde were much less
severe than at higher concentrations, primarily confined to Site 1 of
Level II. They were characterized by mild, multifocal, individual cell
necrosis, a very mild neutrophilic infiltrate, mild, patchy, epithelial
cell hyperplasia, and squamous metaplasia observed only after 9 days of
exposure.

For subchronic exposure (6 weeks), lesions in the 12 and 19 mg/m3 groups
consisted of epithelial hyperplasia, squamous metaplasia, and a mild
neutrophilic cellular infiltrate. These lesions were located on the
lateral wall, the midventral septum of Level II, and the lateral walls
of Level III. Lesions were also present in the nasopharynx,
characterized by mild epithelial hyperplasia and squamous metaplasia.
For animals exposed to 7.4 mg/m3, lesions were present at Level II,
characterized by mild hyperplasia and squamous metaplasia of the lateral
wall epithelium.

There were no detected treatment-induced responses in cell proliferation
indices in the two lowest formaldehyde concentration groups. Elevations
in cell proliferation were first detected following 1 day of
formaldehyde exposure in the 7.4, 12, and 19 mg/m3 groups. Increases in
the ULLI were present in every site except the nasal septum.
Statistically significant elevations in cell proliferation following 6
weeks of exposure to 7.4 mg/m3 were confined to the lateral wall and the
maxilloturbinate of Level II only. The levels of cell proliferation at
the lateral wall site decreased significantly (p<0.05) from Level II to
Level III, demonstrating a clear anterior-posterior response gradient.
Statistically significant increases in the ULLI at Level III were
present at Days 1, 4, and 9 for the lateral wall and at Days 4 and 9 for
the septum, even though epithelial lesions were not observed by light
microscopy in these locations.  

For the 12 and 19 mg/m3 dose groups, statistically significant increases
in the ULLI were observed at each site at days 1, 4, 6, 9, and 6 weeks,
with the exception of the maxilloturbinate at day 1. At Level III
following 6 weeks of exposure, the lateral wall site in both the 12 and
19 mg/m3 groups had a greater magnitude increase in cell proliferation
over controls, as compared to the Level II nasal spetal site. The
anterior-posterior gradient of the cell proliferation response observed
at 7.4 g/m3, was not apparent at these higher concentrations.

Other – Sensory Irritation

Purity: 37%

	Kane, Laurel E.; and Alarie, Yves.  (1977)  Sensory Irritation to
Formaldehyde and Acrolein During Single and Repeated Exposures in Mice. 
American Industrial Hygiene Association Journal, v.38, p. 509-522. 

Open Literature

M SPF Swiss Webster Mouse (4/group)

Mice were exposed via inhalation for 3 hours/day for 4 days to a
concentration of formaldehyde that would be expected to produce a 30%
decrease in respiratory rate within the first 10 minutes of

exposure (as predicted by the 

concentration-response relationship) or to an atmosphere containing a
concentration equal to 1/10 the RD50 for formaldehyde for 3 hr/day for 3
days.  	RD50: 3.84 mg/m3

Other - Sensory Irritation

	Steinhagen, WH; Barrow, CS.  (1984) Sensory irritation
structure-activity study of inhaled aldehydes in B6C3F1 and
Swiss-Webster mice.  Toxicol Appl Pharmacol 72:495-503. 

Open Literature

M Swiss Webster and B6C3F1 mice (3-4/dose)

10 minute head-only exposure to formaldehyde and other aldehydes

	RD50: 3.2 ppm  (2.1–4.7 ppm) (Swiss Webster)

RD50: 4.90 ppm (3.9–6.4 ppm) (B6C3F1)

The difference in results between strains was not statistically
significant. On the average, α, β unsaturated aliphatic aldehydes and
formaldehyde were approximately 2 orders of magnitude more potent than
cyclic aldehydes and about 3 orders of magnitude more potent than
acetaldehdye and other saturated aliphatic aldehydes. The authors
hypothesized that the difference might be due to differences in the
degree to which a particular aldehyde undergoes hydration and its
subsequent hydrate dissociation constant (Khyd). This proposed mechanism
could account for the difference in RD50 between acetaldehyde with a
hydration of 49.7% and a Khyd value of 0.99 compared to formaldehyde
with a hydration of >99.8% and a Khyd value of >100 (Schauenstein et
al., 1977).

870.1300

Other - Sensory Irritation

Purity: 5% 

	Gardner, RJ; Burgess, BA; Kennedy, GL, Jr.  (1985) Sensory irritation
potential of selected nasal tumorigens in the rat.  Food Chem Toxicol
23:87-92. 

Open Literature

8-week-old Crl-CD male rats (4/group)

The RD50 of eight chemicals was determined to determine whether there
was a correlation between the ability of a chemical to produce sensory
irritation and tumorigenic potency.  Groups of rats were exposed for 15
minutes to various concentrations of formaldehyde ranging from 0.77 to
24.9 ppm after a 5-minute pretest exposure to control air.  

	RD50: 13.8 ppm

Estimate was about threefold less than the 31.7 ppm reported for male
F344 rats (Barrow et al., 1983).  This may indicate differences in
responsiveness to formaldehyde among different strains of rat. 
Concentrations of 5.5 ppm or more produced considerable depression in
respiratory rate. The decrease was observed during the first minute of
exposure and achieved a maximum at about 3 minutes. Some recovery was
observed during exposure from 3 to 10 minutes after the start but was
incomplete during the first 5 minutes after exposure. Taking the results
of the eight chemicals together, sensory irritation potency did not
correlate with the carcinogenic potency indicated by long-term
inhalation experiments.

870.1300

Other - Sensory Irritation

Purity: 95% paraformaldehyde	Chang, JC; Barrow, CS.  (1984) Sensory
irritation tolerance and cross-tolerance in F-344 rats exposed to
chlorine or formaldehyde gas.  Toxicol Appl Pharmacol 76:319-327. 

Open Literature

M Fischer 344 (CDF[F 344]Crl/Br) rats (4/group)

Chang and Barrow (1984) determined whether tolerance would develop in
rats exposed to formaldehyde.  Tolerance was defined as return of
respiratory rate to baseline levels following an initial decrease
induced by test gas exposure.  Groups of rats were exposed in
double-chamber plethysmographs for 10 minutes after a 20-minute
acclimation and a 5-minute baseline period.  This measurement was
performed 18 to 24 hours after any pretreatment.  Pretreatment exposures
were carried out in a glass chamber for 6 hours/day, 5 days/week, for
various durations.	Exposure to formaldehyde at 15 ppm for 6 hours/day, 5
days/week failed to induce tolerance. However, tolerance was observed
following exposure to 28 ppm formaldehyde for 4 days. The
concentration-response curve in these animals was significantly
different than that of naïve animals, with an increase in RD50 estimate
for this exposure duration from 31.7 to 70.2 ppm.

870.1300

Other - Sensory Irritation

Purity: 90%-92% Paraformaldehyde

	Cassee, FR; Arts, JH; Groten, JP; et al.  (1996) Sensory irritation to
mixtures of formaldehyde, acrolein, and acetaldehyde in rats.  Arch
Toxicol 70:329-337. 

Open Literature

M Wistar rats (4/dose)

Cassee et al. (1996) determined the RD50 values for formaldehyde,
acetaldehyde, and acrolein as a result of a 30-minute nose-only
exposure.	RD50: 10.0 (95% CI 4.7–13.7)

870.1300

Other - Sensory Irritation

Purity: 95% Paraformaldehyde

	Kulle, TJ; Cooper, GP.  (1975) Effects of formaldehyde and ozone on the
trigeminal nasal sensory system.  Arch Environ Health 30:237-243. 

Open Literature

Adult M Sprague-Dawley rats (5/experiment)

The effects of formaldehyde on trigeminal nerve afferent activity in
rats was investigated.  Electrodes were implanted through a dissection
in the right eye orbit. The authors state that because the ethmoid nerve
and trigeminal nerve responded similarly the experiments were performed
with the nasopalatine nerve to eliminate potential contribution from the
mechanoreceptor fibers in the ethmoid nerve.  The sensory threshold was
determined by extrapolation from the measured nerve response to a range
of formaldehyde concentrations (0.5–2.5 ppm) or ozone (5.0–29 ppm)
for an exposure duration of 2 minutes. Amyl alcohol exposure (0.3–10.0
ppm) was for 25 seconds.  

Kulle and Cooper (1975) also investigated the effects of prolonged
exposure on trigeminal nerve activity using the in situ preparation
described above.  Formaldehyde (0, 0.5, 1.0, 1.5, or 2.0 ppm) was
presented continuously for 1 hour. Pre-exposure responsiveness was
determined to a test series of amyl alcohol (0.3, 0.7, 1.0, 3.3, 6.7, or
10.0 ppm).  After exposure to formaldehyde and a 10-minute recovery
period of exposure to control air, the amyl alcohol series was repeated
to evaluate reversibility.  If formaldehyde produced any depression or
enhancement of nerve activity as evidenced by the amyl alcohol test
series, another recovery period of control air ensued and the test was
repeated. Control tests with amyl alcohol were run for 8 hours to
establish that there were no significant changes in response to
prolonged exposures to the referent gas.  It was also determined if
there was a difference when the formaldehyde concentration was
progressively increased to 2.0 ppm in a series of exposures at the
concentrations above or presented separately at 2.0 ppm.	The mean
thresholds were 0.25 ppm for formaldehyde, 5.0 ppm for ozone, and 0.30
ppm for amyl alcohol.

There was a progressive depression in response to amyl alcohol with
increasing stimulus of formaldehyde concentration [p < 0.01, analysis of
variance (ANOVA)]. The effects of exposure to 2.0 ppm were similar
regardless of whether it was presented immediately as a separate
exposure or as the final concentration of a progressively increasing
series.  The response to amyl alcohol did not fully recover within the
1-hour extended recovery period. Thus it appeared that the afferent
function depression was not due to receptor adaptation or insufficient
time for formaldehyde diffusion away from receptor sites.

870.1300

Other - Sensory Irritation

	Tsubone, H; Kawata, M.  (1991) Stimulation to the trigeminal afferent
nerve of the nose by formaldehyde, acrolein, and acetaldehyde gases. 
Inhal Toxicol 3:211-222. 

Open Literature

M Wistar Rat (6/group)

The afferent activity of the surgically isolated ethmoidal nerve (a
branch of the trigeminal nerve) during delivery of formaldehyde
(0.32–4.7 ppm) into the cannulated URT of rats at a flow rate of 200
mL/minutes for 22 seconds was recorded. Each exposure was repeated two
to four times at different concentrations.	The vapor concentration
associated with a 50% increase in nerve activity over the level of
control gas was calculated as approximately 1.8 ppm for formaldehyde.

Sensory Irritation

Formaldehyde, Lot No. 420807, 10 %a.i. (methanol free)

	MRID No. 43170601

Werley et al. (1994). Glutardehyde and Formaldehyde: Sensory Irritation
Study in Swiss-Webster Mice.  Union Carbide Lab Project No. 91U0123.

acceptable/non-guideline

Male Swiss-Webster ND4 mice (40-55 days old at start of study), 4
animals/dose

0, 0.34, 1.4, 6.9, 18.8, or 80.0 ppm (0, 0.42, 1.73, 8.55, 23.3, or 99.1
mg/m3), 30 min, head-only chambers	No treatment related mortality was
observed. Mice exposed to formaldehyde showed no treatment-related
clinical findings. All mice exposed to formaldehyde at 99.1mg/m3 showed
increased lacrimation and periocular wetness.  Slight reductions in body
weight were observed in some of the mice at the highest exposure doses
for formaldehyde.

Immunologic Sensitization

	Tarkowski, M. and Gorski, P. 1995. Increased IgE antiovalbumin level in
mice exposed to formaldehyde. Int. Arch. Allergy Immunol. 106:
422–424.

Open Literature

F Balb/c Mouse

Groups were exposed to 2 mg/m3 formaldehyde either 6 hours/day for 10
days, or to 6 hours/day once a week for 7 weeks.  Then all mice were
sensitized intranasally with ovalbumin.  	Following sensitization, titer
of serum anti-ovalbumin IgE antibodies were significantly higher in mice
exposed to formaldehyde 6 hours/day for 10 days, compared to mice
exposed 6 hours/week for 7 weeks or untreated. The authors concluded
that formaldehyde facilitates animal sensitization to ovalbumin through
histological changes occurring in the upper respiratory tract.  

Immunologic Sensitization

	Riedel, F., et al. C.H.L. 1996. Formaldehyde Exposure Enhances
Sensitization in the Guinea Pig. Allergy 51: 94–99.

Open Literature

Guinea Pig (12/group)

Animals were exposed to formaldehyde concentrations of 0 (controls), 160
or 310 ug/m3 (0.13 and 0.25 ppm) for 5 days, followed by sensitization
to inhaled ovalbumin at days 5 and 19.  On day 26, a bronchial
provocation test with ovalbumin was performed, followed by repeated lung
function measurements to monitor bronchial obstruction.  Also, blood
samples were taken on day 0 (before formaldehyde exposure) and day 25
(before bronchial provocation test) and tested for anti-ovalbumin IgG1
antibodies.

	Following ovalbumin challenge, 10/12 animals exposed to 310 ug/m3
showed bronchial obstruction, compared with 3/12 control animals
(p<0.01); animals exposed to 160 ug/m3 were not significantly different
from controls. Anti-ovalbumin IgG antibodies were not detectable (<10
ELISA units or EU) in any animal at day 0, but were detectable in 0/12
controls, 3/12 animals exposed to 160 ug/m3, and 6/12 animals exposed to
310 ug/m3 at day 25.   

Immunological

	Jakab, GJ.  (1992) Relationship between carbon black particulate-bound
formaldehyde, pulmonary antibacterial defenses, and alveolar macrophage
phagocytosis.  Inhal Toxicol 4:325-342. 

Open Literature

White Female Swiss Mouse

Mice were exposed to formaldehyde after bacterial infection (Regimens A
and C), before bacterial infection (Regimen B), or before and after
infection (Regimen D).  In the first trial mice were exposed to 0, 1.0,
5.0, 10.0, or 15.0 ppm formaldehyde (0, 1.2, 6.2, 12.3, or 18.5 mg/m3). 
The remaining mice were exposed to 0, 0.5, or 1.0 ppm formaldehyde (0,
6.2, or 1.2 mg/m3).  A 30-minute exposure to an infectious aerosol of S.
aureus deposited 2x105 staphylococci in the lungs. Bacterial loading was
determined in homogenized lung tissue by culturing diluted aliquots for
an estimate of bacteria present immediately after loading and 4 hours
later.  

	Mice exposed to 15 ppm formaldehyde for the 4 hours following bacterial
infection (Regimen A) had approximately an 8% increase in bacteria,
indicating decreased host resistance (p=0.006).  Pre-infection exposure
to 0.5 or 1.0 ppm did not change bacterial loading 4 hours after
infection (Regimen B).  However, combining an 18-hour pre-infection
formaldehyde exposure with a 4-hour post-infection 1 ppm formaldehyde
exposure increased pulmonary bacterial loading by approximately 6.5%
(p<0.05).  Increased bacterial loading indicates that formaldehyde
exposure (Regimens A and D) reduced pulmonary bacterial resistance. 
This is in apparent contradiction to the findings of increased host
resistance by Dean et al. (1984).  However, there are important
differences between the studies. The studies by Jakab (1992) are acute
studies examining effects at the respiratory tract where direct effects
are possible. Additionally, in some cases, the exposures were concurrent
with bacterial infection, and it is difficult to distinguish the
potential for formaldehyde effects directly on the mucociliary apparatus
as a barrier to infection.

Other

	Adams, D.O. et al. (1987) The Effect of Formaldehyde Exposure upon the
Mononuclear Phagocyte System of Mice. Toxicology and Applied
Pharmacology 88: 165-174.  

Open Literature

Female Mouse

15 ppm (19 mg/m3), 6 hr/day, 5 days/week. 3 weeks	Exposure of mice to 19
mg/m3, 6 hr/day, 5 days/week for 3 weeks did not appreciably alter the
number of resident macrophages in the peritoneal cavit+y or that
elicited in response to MVE-2.

Dermal absorption

	Bartnik, F.G., Gloxhuber Chr., and Zimmermann V.  (1985)  Percutaneous
Absorption of Formaldehyde in Rats.  Toxicology Letters. v. 25. p. 167 -
172.  

Open Literature

10 Male/4 Female Rat

[14C] Formaldehyde as a tracer and non-labeled formaldehyde were
incorporated into a cream and dermally applied at 200 mg to occluded and
nonocclusive dosing areas for 48 hours	Under non –occlusive
conditions, absorption of radiolabeled formaldehyde in the cosmetic
cream preparation was published as 6.1% in males and 9.2% in females.
Occlusive conditions reported absorption as 3.4% in males.

Other

Purity: Not Reported	Hester, et al. (2003) Formaldehyde-Induced Gene
Expression in F344 Rat Nasal Respiratory Epithelium.  Toxicology 187:
13-24. 

Open Literature

8 F344 Male Rats 

40 ul aliquots of water or formaldehyde (400 mM) were instillled into
nostrils using a pipette.  Twenty-four hours after treatment, nasal
epithelium was recovered from which total RNA was used to generate cDNA
probes.	Siginificance analysis of microarrays (SAM) hybridization data
revealed that 24 of the 1185 genes queried were significantly
up-regulated and 22 genes were significantly downregulated. The
identified genes with FA-induced change in expression belong to the
functional gene categories xenobiotic metabolism, cell cycle, apoptosis,
and DNA repair. These data suggest that multiple pathways are
dysregulated by formaldehyde exposure, including those involved in DNA
synthesis/repair and regulation of cell proliferation.

870.3100

Other

 Purity: 28.44%

	Vargova M, Wagnerova J, Liskova A, et al. (1993) Subacute
immunotoxicity study of formaldehyde in male rats. Drug Chem Toxicol
16:255-275.

Open Literature

Male Wistar Rat

Formaldehyde was administered by gavage at doses of 0, 20, 40, and 80
mg/kg/day for 4 weeks, 5 days/week, 1x/day	NOAEL: 40 mg/kg/day

LOAEL: 80 mg/kg/day for an increase in the incidence of hepatocelluar
vacuolization

870.3465

Other

Purity: 14-C Paraformaldehyde (97.3-99%),

 Unlabeled paraformaldehyde (95%)	Casanova, Mercedes, et al. (1994)
DNA-Protein Cross-links and Cell Replication at Specific Sites in the
Nose of F344 Rats Exposed Subchronically to Formaldehyde.  Fundamental
and Applied Toxicology 23:  525-536. 

Open Literature

Rats inhalation (20 rats/group, 10 of which are preexposed (PE), 10 not
(N))

0.7, 2, 6, 10, or 15 ppm (0, 0.87, 2.5, 7.4, 12.4, or 18.6 mg/m3)
Preexposed animals whole-body exposed 6 hr/day, 11 weeks +4 days) On the
5th day of the 12th week, animals exposed once nose-only for 3 hours
H14-CHO using nominal concentrations DPX estimation: 6 ppm or 10 ppm
(7.4 or 12.4 mg/m3) On 5th day of 12th week, exposed to unlabeled
formaldehyde once nose-only for 3 hours using nominal concentration 

	NOAEL: 2.5 mg/m3

LOAEL: 7.4 mg/m3

Visible lesions were only observed in animals exposed to 18.6 mg/m3 for
12 weeks. No formaldehyde-induced lesions were observed in the squamous
and olfactory regions of the nose. Rats exposed to 0.87 or 2.5 mg/m3
were indistinguishable from controls. At 7.4 mg/m3, lesions were
confined to multifocal epithelial hypertrophy, hyperplasia, and squamous
metaplasia of the lM, while the rest of the nose was unaffected. At
12.39 mg/m3, the most characteristic response was squamous metaplasia of
the transitional epithelial lining of the LM and medial
maxilloturbinate, and mild epithelial hyperplasia of the midseptum with
generally mild inflammatory cell infiltration.

At 18.6 mg/m3, formaldehyde-induced lesions were more severe than all
other exposure groups. Rats exposed for 12 weeks exhibited extensive
damage to the lining of the LM (high tumor site) with epithelial
erosions, transitional epithelial hyperplasia, squamous metaplasia,
intraluminal and mucosal infiltration by inflammatory cells, and
keratinizing epithelial plaques associated with subepithelial
inflammation. Animals exposed to 18.6 mg/m3 also exhibited thickening of
the periosteum of bones adjacent to severe epithelial damage, and
moderate degrees of edema and hyperemia of the lamina propria in these
regions. At 7.4 and 18.6 mg/m3, significantly (p<0.01) greater
incorporation of 14C into DNA occurred in the lateral meatus of
preexposed rats. Significantly (p<0.01) greater incorporation also
occurred in the medial and posterior meatuses of preexposed rats at 18.6
mg/m3.

APPENDIX C - Mutagenicity Profile for Formaldehyde and Paraformaldehyde



Table C1. Mutagenicity data for Formaldehyde

Guideline No./

Study Type	MRID No./

Reference Information/

Study Classification	Dosing and Animal Information	Results

Mutagenicity

870.5100

Bacterial reverse mutation test

	MRID 00132156

Jagannath, D. (1978) Mutagenicity Evaluation of Dantoin DMDMH-55 40-697
737543 in the Ames Salmonella/Microsome Plate Test: LBI Project No.
20838. Final rept. (Unpublished study received May 9, 1983 under
38906-5; prepared by Litton Bionetics, Inc., sub- mitted by Glyco, Inc.,
Greenwich, CT; CDL:250313-A)

Supplementary	0.001, 0.01, 0.10, 1.0, or 5.0 µL. 

Salmonella tester strains TA-98,

TA-100, TA-1535

TA-I 537 and TA-1538. Saccharamyces indicator organisms, strain 04.

 

	Negative

870.5100

Bacterial reverse mutation test	MRID 00132157

Haworth, S.; Lawlor, T.; Burke, P.; et al. (1982). Salmonella/

Mammalian-microsome Preincubation Mutagenicity Assay (Ames Test): Test
Article 447:34-3: Study No. T1804.502. (Unpublished study received May
9, 1983 under 38906-5; prepared by Microbiological Assoc., submitted by
Glyco, Inc., Greenwich, CT; CDL:250313-B).

Acceptable	Test material (447:34-3, MA #T1804) tested at concentrations
of 3.0, 15.0, 75.0, 150, or 300 µg/plate. 

Tester strains TA98, TA100, TA1535, TA1357, TA1358 ± metabolic
activation with araclor induced rat liver microsomes. 

	Positive

Test article caused did cause a positive response (3.2-fold increase) on
tester strain TA98 without metabolic activation. A 1.9-fold increase was
observed on TA98 with metabolic activation. Also, increases of 2.2-fold
and 1.7-fold were observed on tester strain TA100 with and without
activation, respectively.

870.5100

Bacterial reverse mutation test

	O'DONOVAN, MR AND MEE,CD; FORMALDEHYDE IS A BACTERIAL MUTAGEN IN A
RANGE OF SALMONELLA AND ESCHERICHIA INDICATOR STRAINS; MUTAGENESIS
8(6):577-581, 1993

Open Literature

	0-200 ug/plate, pre-incubation exposure and standard plate-
incorporation assays

S. typhimurium Strains TA1535, TA1537, TA1538, TA98, TA100, and TA102 
and E.coli Strains WP2(pKM101) and WP2uvrA (pKM101)  

Purity: 37%	Pre-incubation exposure: positive for mutagenicity in TA98,
TA100, and TA102 and both E.coli strains.

Standard plate-incorporation assays:  

Consistent mutagenicity was seen only for TA100 and WP2uvrA (pKM101).

No evidence of mutagenicity was seen for TA1535, TA1537, or TA1538 using
either method of exposure.

870.5100

Bacterial reverse mutation test

	Schmid, E., W. Goggelmann; and M. Bauchinger.  (1986)
Formaldehyde-induced Cytotoxic, Genotoxic, and Mutagenic Response in
Human Lymphocytes and Salmonella typhimurium.  Mutagenesis vol. 1 no. 6
p. 427-431. 

Open Literature	The tests were carried out using the plate incorporation
assay and the pre-incubation method +/- S9 activation at doses of
0-1.5mM and 0-0.3mM formaldehyde, respectively.  

The incubation mixture consisted of 0.5 ml phosphate buffer or S9 mix
and10 ul of an appropriate concentration of formaldehyde in water. 

S. typhimurium Strain TA100 (0.1 ml bacterial suspension of about 10*8
cells were used in the pre-incubation method)

Purity: 37%	Plate Assay: weak positive response

Pre-Incubation Method: Without S9 mix, a1.6-fold increase of revertant
numbers over controls was induced.  With S9 mix, a 2.7-fold increase of
revertant numbers over controls was induced.

870.5100

Bacterial reverse mutation test	Temcharoen, P; Thilly, WG.  (1983) Toxic
and mutagenic effects of formaldehyde in Salmonella typhimurium. Mutat
Res 119:89-93. 

Open Literature	The capacity of formaldehyde to induce forward mutations
to 8-azaguanine resistance in was examined. Formaldehyde concentrations
of 0.17 mM in the absence of S9 and 0.33 mM in the presence of S9.  

S. typhimurium TM 677, a his+ revertant of TA 1535

Purity: 37%	Both toxicity and mutagenicity were obtained at formaldehyde
concentrations of 0.17 mM in the absence of S9 and 0.33 mM in the
presence of S9. The authors noted that, while the S9 might be enzyme
inactivating formaldehyde, the binding of formaldehyde to amino groups
of proteins in the S9 would effectively reduce the concentration of
formaldehyde entering the cells.  

870.5200

Mouse visible specific locus test	Mouse Lymphoma L5178Y Cell TK Locus
Assay for Mutagenicity; A Study with Formaldehyde.  (DuPont, 7/28/80,
Haskell Laboratory Report No. 581-80).

Open Literature 

	Doses of 0, 0.1, 0.5, 1, 5, 10 or20 ug/ml without activation only, four
trials

Mouse Lymphoma L5178Y Cell 

Purity: 37%	An increase in mutation frequency was reported, especially
at 10 and 20 ug/ml.

870.5275

Sex-linked recessive lethal test in Drosophila melanogaster	Valencia,
R., J.M. Mason, and S. Zimmering. (1989) Chemical Mutagenesis Testing in
Drosophila. VI. Interlaboratory Comparison of Mutagenicity Tests After
Treatment of Larvae. Environmental and Molecular Mutagenesis, v. 14, p.
238-244.

Open Literature	Doses of 2,600 and 1,100 ppm  

D. melanogaster (Canton-S M and Basc F)  

Purity: 37%

	Positive

870.5375

In vitro mammalian chromosome aberration test

	MRID 00132168

Thilagar, A.; Kumaroo, P.; Pant, K. (1982) Cytogenicity Study: Chi- nese
Hamster Ovary (CHO) Cells in vitro: Test Article 447:34-1: Study No.
T1802.338. (Unpublished study received May 9, 1983 under 38906-5;
prepared by Microbiological Assoc., submitted by Glyco, Inc., Greenwich,
CT; CDL:250313-M)

Acceptable	Test material (447:34-1) was tested at concentrations of
28.43, 37.91, or 50.55 nL/mL. 

Chinese hamster ovary cells (cell repository number CCL, 61)

Purity: 37% Formalin	Positive

Test article caused a significant dose-dependant increase in the
frequencies of chromosome aberrations in the Chinese Hamster Ovary
cells, both with and without S-9 activation.

870.5375

In Vitro mammalian chromosome aberration test	Natarajan, A.T. et al.
(1983) Evaluation of the mutagenicity of formaldehyde in mammalian
cytogenics assays in vivo and vitro.  Mutation Research 122: 355-360. 

Open Literature	In Vitro

CHO cells exposed to 0, 0.003, 0.006, 0.012, or 0.024 uL/mL
paraformaldehyde

In Vivo Mouse

0.4 mL paraformaldehyde injected intraperitoneally to achieve doses of
0, 6.25, 12.50, or 25.00 mg/kg

 	In Vitro: Positive

Frequencies of chromosomal aberrations and SCEs increased with
increasing dose. All classes of aberration, i.e. gaps, breaks, and
exchanges, were induced by formaldehyde. All the aberrations were
chromatid-type, indicating that formaldehyde acts as an S-dependent
agent. The addition of mammalian metabolic activation system reduced the
frequencies of formaldehyde-induced aberrations at all doses. 
Similarly, there was also a reduction in the frequencies of SCEs induced
by formaldehyde, if the treatment was done in the presence of S9.  

In Vivo: Negative 

None of the concentrations used increased the frequencies of micronuclei
over the control level.  Formaldehyde was not effective in inducing
chromosomal aberrations.

870.5380

Mammalian spermatogonial chromosomal aberration test
Fontignie-Houbrechts, N. (1981) Genetic Effects of Formaldehyde in the
Mouse.  Mutation Research, v. 88, p. 109-114. 

Open Literature

	Mice received an i.p. injection of 50 mg/kg formaldehyde 

M Q Strain Mouse (200 spermatocytes/ animal)

Purity: 35%	Negative

No chromosomal lesions were revealed

870.5450

Rodent dominant lethal assay	Fontignie-Houbrechts, N. (1981) Genetic
Effects of Formaldehyde in the Mouse.  Mutation Research, v. 88, p.
109-114. (as cited in Ma and Harris) 

Open Literature	Mice received an i.p. injection of 50 mg/kg formaldehyde
and 10 males were caged with 2 virgin females each for one week.  The
females were renewed each week during 7 weeks.   

M Q Strain Mouse

Purity: 35%	Embryonic death or pre-post implantation death at 1 and 3
week periods

870.5450

Rodent dominant lethal assay	Odeigah, P.G.C.  (1997) “Sperm Head
Abnormalities and Dominant Lethal Effects of Formaldehyde in Albino
Rats.” Mutation Research 389: 141-148.

Open Literature   	Five daily interperitonial injections of 0.125,
0.250, and 0.6 mg/kg formaldehyde.  Males   were caged with 2 untreated
virgin females which were replaced weekly for 3 consecutive weeks giving
a total of 24 females for the periods 1-7, 8-14, and 15-21 days
post-injection, respectively.  All females were sacrificed 13 days after
the mid-week of their caging.  At autopsy, each female was scored for
total implants.     

Albino Rats (12 M/group)

Purity: 37% solution (stabilized with 10% methanol)	Positive

The frequency of dominant lethal mutations in female rats sired by males
exposed to formaldehyde was significantly higher than the control group.
 

870. 5550

Unscheduled DNA synthesis in mammalian cells in culture

	MRID 00132169

Thilagar, A.; Pant, K. (1982) Unscheduled DNA Synthesis in Rat
Hepatocytes: Test Article 447:34-1: Study No. T1802.380002. (Un-
published study received May 9, 1983 under 38906-5; prepared by
Microbiological Assoc., submitted by Glyco, Inc., Greenwich, CT;
CDL:250313-N)

Acceptable	Test material (447:34-1) was tested at concentrations of
0.0005, 0.001, 0.005, 0.01, 0.02, or 0.04 µL/mL. 

Primary rat liver hepatocytes – Sprague-Dawley rats, 2.5 x 105
HPC/plate 

Purity: 37% a.i.	Negative

The test article did not cause a significant increase in UDS in rat
hepatocytes. 

870.5900

In Vitro Sister Chromatid Exchange Assay	A. Basler, W. v. d. Hude, and
M. Scheutwinkel-Reich (1985) “Formaldehyde-Induced Sister Chromatid
Exchanges in vitro and the Influence of the Exogenous Metabolizing
Systems S9 Mix and Primary Rat Hepatocytes.” Arch Toxicol 58: 10-13.  

Open Literature

	The test compound was added to cell cultures 18 hours after seeding 5 x
105 cells per 25 cm2 flask.  The exposure time was 1, 2, 3, or 28 hours.
In the experiments with short-term exposure (1-3 hours), the medium was
removed after this treatment. The cells were restored in medium
supplemented with 5-bromo-2-deoxyuridine (BrdU).  The cells were
cultured in the presence of BrdU (10-5 M) for 28 h, with colcemide (0.1
µg/ml) for the last 4 h.  In the experiments with long-term exposure,
the cells were cultured in the presence of BrdU and the test compounds
for 28 hr. In tests with S9 mix, the cells were incubated with 0.5 ml S9
mix per 25 cm2 flask and 0.033, 0.067, 0.13, 0.2, 0.27, 0.4, and 0.54 mM
formaldehyde for 3 h, followed by incubation for 28 hr in the presence
of BrdU as described above. In tests with primary rat hepatocytes, 106
viable hepatocytes were added to the monolayer. After 2 hr, the
nonattached hepatocytes were sucked off and the different concentrations
of formaldehyde were added. The medium was complemented with BrdU and
incubated for 28 h as above. S9 fraction was prepared from Aroclor
1254-induced male Wistar rats.

Chinese Hamster V79 Cells

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d the SCE frequency to nearly that of the control range. It could be
demonstrated that the reduction was not due to an unspecific binding of
formaldehyde to macromolecules of the added S9 mix. The decrease in
genotoxic effects, due to rapid metabolisation of formaldehyde in vitro
and un vivo, explains the differences between results obtained in the in
vitro experiments – performed without metabolizing systems – and in
vivo results.   

870.5915

In Vivo Sister Chromatid Exchange Assay	Kligerman,AD; Phelps, MC;
Erexson, GL.  (1984) Cytogenetic analysis of lymphocytes from rats
following formaldehyde inhalation.  Toxicol Lett 21:241-246.

Open Literature	Rats were exposed to 0.5, 6, or 15 ppm (0.6, 7.4, 18.5
mg/m3) formaldehyde by inhalation for 6 hours/day for 5 days.   Blood
was obtained by cardiac puncture within 1 h of the last exposure and
cultured with BrdU for sister chromatid exchange (SCE) analysis.   

M and F Fischer F-344 Rat 

Purity: 95% a.i.? (Not reported in study) 	There were no increases in
either SCE or chromosome aberrations at any dose level.  

In vitro human lymphoblasts	Craft, T.R., E. Bermudez, and T.R. Skopek
(1987) Formaldehyde mutagenesis and formation of DNA-protein crosslinks
in human lymphoblasts in vitro.  Mutation Research 176:  147-155. 

Open Literature	0, 15, 30, 50, 125, or 150uM

Human Lymphoblasts (4x 10^5 cells/mL)

Formaldehyde (37% w/w 10-15% methanol)	Positive

Concentrations ≥ 30 uM yielded statistically significant responses
(p<0.05).  

Multiple treatments of 15, 30, and 50 uM also resulted in increases in
mutant fractions. Lymphoblasts exposed repeatedly to these lower
concentrations accumulate formaldehyde-induced mutations, but at a lower
rate than if a single 150uM treatment was given at one time.  

In vitro human lymphoblasts	Liber, HL; Benforado, K; Crosby, RM; et al. 
(1989) Formaldehyde-induced and spontaneous alterations in human hprt
DNA sequence and mRNA expression.  Mutat Res 226:31-37. 

Open Literature

	Liber et al. (1989) followed up the findings of Crosby et al. (1988) by
performing Northern blot and sequence analysis on the 16 induced and 10
spontaneous mutants not showing deletions. 

Human Lymphoblasts 

Purity: 37%	Northern blot analysis showed that the point mutations fall
into four categories; normal size and amount of RNA, normal size but
reduced amounts of RNA, reduced size and amounts of RNA, and no RNA. 
Sequence analysis of recombinant DNAs from HRPT mRNA in compound-induced
mutants showed a preferential AT to CG transversion at a single site,
with other changes represented to a lesser degree.  

Other	Graves, RJ; Trueman, P; Jones, S; Green, T.  (1996) DNA sequence
analysis of methylene chloride-induced HPRT mutations in Chinese hamster
ovary cells: Comparison with the mutation spectrum obtained for
1,2-dibromoethane and formaldehyde.  Mutagenesis 11:229-233. 

Open Literature	DNA sequence analysis of formaldehyde-induced HRPT
mutations

Chinese Hamster Ovary Cell

Purity: 40%	Single-base pair transversions, including three AT to TA at
position 548 of exon 8, one GC to TA, and two AT to CG transversions at
other sites.  

Other	Blackburn, GR; Dooley, J, III; Schreiner, CA; et al.  (1991)
Specific identification of formaldehyde-mediated mutagenicity using the
mouse lymphoma L5178Y TK positive negative assay supplemented with
formaldehyde dehydrogenase.  In Vitro Toxicology 4:121-132. 

Open Literature	Forward mutation assay

Mouse lymphoma L5178Y tk+/- cells

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ty and mutagenicity were abolished when formaldehyde dehydrogenase was
incorporated in the exposure medium.

	

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